The Plot Against Asthma and Allergy Patients

THE PLOT AGAINST ASTHMA AND ALLERGY PATIENTS
Asthma, Allergies, Migraine, and Chronic Fatigue Syndrome are Curable,
but the Cure Is Hidden from the Patients
Felix Ravikovich, M.D.
As featured on CBCs fifth estate
KOS
Publishing
BOOKS ON MEDICINE THAT WORKS
ACKNOWLEDGMENTS
This book is my first and only literary child. It took nine long years to carry it, and I would not have been able to deliver it without the support of several people. I want to pay tribute to the late Drs. Bayard Horton and Kenneth Melmon for their fascination with histamine, their devotion to it, their research and their belief that one day histamine will serve patients. This book would not be possible without my wife Galina who is, actually, my co-author. She conceived the idea and for two years, while I was fighting in the courts, she worked on it alone, researched the medical sources collected by me and began to put my ideas on paper. When I joined her, she became my sounding board, the only knowledgeable person with whom I could share my astonishing, at times dramatic discoveries made during my detective search of medical literature. The situation forced her to immerse herself so deeply into some of the most serious fields of medicine and science that by the end, she became, albeit unofficially, the equivalent of a professional in clinical immunology. Her background as a university professor enabled her to work out how to present the most complicated material in the way digestible not only for those who have a medical or biological education, but also for intellectuals with little or no such experience. I express my love to my son Alex who was a comforting friend, whose advice I sought in many critical situations during the process, and who patiently corrected my imperfect English. I would like to express my special thanks to Klemmens Fass, my unofficial lawyer, who remained faithful to me when my other lawyers betrayed me. He
Acknowledgments
iii
refused outright to be paid for the long hours of discussions during the years of my prosecution by the College. He also became my behind-the-stages law teacher, and his advice helped me to go through all the stages of the legal proceedings as well as the writing of this book. I am grateful to Denise Crawford for her willingness to help with the numerous technical and linguistic problems that I encountered through the years of writing. I appreciate the enormous work done by Isidor Zelinkovsky at the early stages of my prosecution by the College of Physicians and Surgeons of Ontario. He managed to get the Canadian Broadcasting Corporation interested in the histamine affair and persuaded them to give the opportunity to my patients to tell their stories of their almost miraculous improvement and outright recoveries with histamine therapy and the despair over losing it. The program aired in Canada and in parts of U.S. created the necessary publicity, which, in my opinion, contributed to my having not lost my license outright; I was given a reprimand and forbidden to use histamine. I am thankful to Ed Sprague, a patient who has become a close friend and as such accompanied me to all of my meetings with the lawyers and through the many stages of my trial as a silent witness. The numerous improprieties he saw have changed his views on our justice system forever. Later on, he was the most active organizer of press releases sent to the medical institutions, media and government bodies of Ontario. I cannot overestimate the tremendous support of Elizabeth and Daniel Gamper that enabled me to go on with my work and book writing. My gratitude goes to Tom Hirsch, my first literary agent, who became a passionate advocate of histamine therapy and was willing to give up his fees just to see this book published. Last, but not the least, I thank Helke Ferrie who has dared to publish this book. The people of Ontario should be grateful to her for the courage to fight the medical regulatory authorities and for regularly publishing the facts about the crimes committed by them against patients and doctors. I am thankful to those of my patients who organized PRET (Patients Rights for Effective Treatment), a group that arranged the meeting at CBCs fifth estate television studio, demonstrated in front of the building which houses the College of Physicians and Surgeons of Ontario, published and distributed information on histamine therapy, attended the legal proceedings and kept writing letters of support.
Copyright 2003 by Felix Ravikovich All Rights reserved. No part of this book may be reproduced in any manner whatsoever without prior written permission from the publisher except in the case of brief quotations embodied in review. National Library of Canada Cataloguing in Publication Ravikovich, Felix, 1938 The plot against asthma and allergy patients: asthma, allergies, migraine, chronic fatigue syndrome are curable, but the cure is hidden from patients / Felix Ravikovich.
Includes bibliographical references and index. ISBN 0-9731945-1-0
1. AllergyTreatment. 2. AsthmaTreatment. 3. MedicineResearch. I. Title. RC584.R39 2003 616.97'06 C2003-906757-2
Cover and text design/layout: Heidy Lawrance Associates Printed in Canada on recycled paper
Published and distributed by KOS Publishing Inc. 1997 Beechgrove Road, Alton, ON Canada L0N 1A0 Tel: (519) 927-1049 Fax: (519) 927-9542
Quantity discounts available
TABLE OF CONTENTS
Acknowledgements ii Introduction by Helke Ferrie vii PART 1 Immune Mechanisms 1 PART 2 Causes and Triggers in Allergy 69 PART 3 Allergic Inflammation 98 PART 4 Histaminegate 106 PART 5 Medications 173 PART 6 Allergy Skin Testing and Immunotherapy 203 PART 7 Bronchial Asthma 238 PART 8 Diseases of Hypersensitivity 318 A. Chronic Rhinitis B. Skin Allergies C. Hay Fever PART 9 Functional Encephalopathies 344 A. Vascular Headache B. Chronic Fatigue and Immune Dysfunction Syndrome C. Depression D. Attention Deficit and Hyperactivity Disorder E. Irritable Bowel Syndrome F. Other Histamine-Related Encephalopathies Epilogue Eppur Si Mouve! 387 Bibliography 390 Appendix 396 Abstracts presented by Dr. F. Ravikovich at international conferences and his article Letter by Dr. K. Melmon to Dr. F. Ravikovich Press release by the patients committee, PRET Notice to the reader Index 408
Introduction: Renovating Medicine
Practicing medicine without knowledge of biochemistry and physiology is merely pop-gun pharmacy. Sir William Osler, 18901 Far too large a section of the treatment of disease is today controlled by the big manufacturing pharmacists, who have enslaved us in a plausible pseudo-science. Sir William Osler, 1909
As the publisher and editor of this book it is an exceptional pleasure to be asked to write an introduction to this most unusual work. Many readers who know me from my regular articles on the politics of medicine published in Vitality Magazine, Alive and others, share my conviction that the greatest problem modern medicine faces in our time is the perverting influence of political and corporate power on good medical practice and medical research. To make medicine once again patient-centered, not patent-centered, and to free medical research from corporate priorities, is the task of our time as surely as it was the task in the 18th century to remove political power from kings and put it into the hands of the people. Indeed, the most profound insight I have experienced first as a medical science writer, and now as a publisher of Books on Medicine that Works, is the discovery that in virtually all areas of medicine the basic scientific breakthroughs achieved in the leading research institutions are rarely communicated to people, are very often not even taught to medical students, and are not readily available to practicing doctors.
viii THE PLOT AGAINST ALLERGY PATIENTS
What IS readily available to everybody is information on yet another supposedly miraculous drug which promises to alleviate the symptoms of any known disease. Pick up any recent edition of Macleans Magazine, for example, and attached to its outside you will find, courtesy of GlaxoSmithKline, in dramatically colored red, white, and black a folder stating: IMPORTANT INFORMATION FOR PEOPLE WITH ASTHMA ENCLOSED. A handy little quiz inside allows the reader to be sure in seconds that he or she may suffer from asthma more seriously than previously thought and that their asthma is not under control. This message comes to you courtesy of GlaxoSmithKline, the worlds largest producer of steroid puffers. You are holding in your hands a book that, unlike the above advertisement, really does contain important information for people suffering from asthma. Dr. Ravikovich is fully familiar with the world-wide basic science research on allergic diseases, successfully used a cure and reported on his results at international conferences. He also tells you why that cure is not generally known or available. Here is the story of a doctor who fought for his patients. This book provides the reader with a political revelation, a medical tour de force, and a scientific detective story. It will take you into the world of the immune system and its biochemistry and you will become thoroughly familiar with the worlds leading medical journals and the medical research into the bio-chemistry of the causes of asthma and allergic disease. But this is also a shocking detective story: you will learn how those very same medical researchers, who to this day are celebrated leaders in the community of immunologists, mysteriously disavowed their own findings and effectively betrayed patients worldwide as they bowed to corporate agendasfor reasons best known to themselves. Although this seems unbelievable at first, it is not without precedent. The same developments have been published with regard to cancer and psychiatric illnesses. There, too, some of the leading researchers who had discovered the underlying mechanisms of both areas of illness with the potential cures for both, and had published their findings in the worlds most prestigious science journals, What is significant here is to understand clearly, that none of that research in allergy, cancer and psychiatry was superceded by new findings, or in any way proven incorrect, or found to be a dead end for scientific research. The astonishing revelations contained in this book are supported by what happened in cancer and psychiatric research because in those areas, the revival of all that useful medical research is beginning to
Introduction
ix
happen now. It is my fervent hope that this outstanding book will start the same process of revival for asthma and allergy. Today, the sell-out of medical practice to agendas that have nothing to do with curing the sick, is nearly total. Patients are now referred to as consumers who are encouraged to believe that they have choices of treatment offered in that enormous market of modern medicine run as a business. It is as if illness has become an accepted life-style choiceright after the car industry. After all, Pfizer is not only the worlds largest pharmaceutical corporation, but also the worlds second largest corporation. The representatives of the drug companies are accepted as stake-holders in medicine to the point where they are part of determining standards of practice, sit on the councils of the medical licensing authorities, virtually control all medical research in the absence of publicly funded research (but not in most of continental Europe), and act as policy and fundraising staff for our political leaders.2 As for the business mantra of consumer choice, for the asthma and allergy patient its basically steroids or steroids or steroids: mint flavored syrups for kids, or laced with antibiotics (to cover all bases), or as shots, as creams, and usually as the ever present puffer shaped as a toy for kids, handy and pretty like a lipstick for the ladies. As for the cure, profits can only be harvested from chronic disease a CEO of a pharmaceutical giant observed in a recent shareholders meeting.3 But whose responsibility is it to fix this situation? Consider this then: The worlds most prestigious science journal, Nature (March 28, 2002), ran an article entitled Can you believe what you read? showing how the editors of the most respected medical journals have begun to do some radical housecleaning when it became overwhelmingly apparent that published research too often reflects corporate interests to the point of distorting the observed facts. On June 27th 2002 Nature reported that even medical bio-ethicists are now being offered stock board positions, consulting contracts, research grants, and even stock options by pharmaceutical companiesand they accept these goodies! Two international conferences were held in 2002 on conflicts of interest in medicine (Atlanta and Warsaw). The former editor of the New England Journal of Medicine, Marcia Angell, justly famous for her fearless scrutiny of corruption in medicine, now works closely with the Center for Science in the Public Interest (www.csip.org), a watchdog exposing unethical behavior of doctors selling out to industry and industrys false or self-servingly incomplete product claims.
THE PLOT AGAINST ALLERGY PATIENTS
Just how bad things have become can be measured by the fact that on February 5 2002 the prestigious journal, Annals of Internal Medicine (vol. 136, no. 3) and the UKs famous Lancet simultaneously published the Physicians Charter as a new manifesto to guide medicine (www.professionalism.org). The charter asserts that it is time doctors get back to the basics. The Charter reads like the Hippocratic Oath of 2,500 years ago translated in modern English. The message is simple and blunt: dont abuse your patients financially or sexually, dont hurt them, let them chose among available treatments, and treat them properly even if they are black, Jews, poor, retarded, dying, just plain old, or dont have any money, and dont blab about them to others without their consent. Central among all these ancient basics of medical ethics was the admonishment that a doctor must not lie when you do research because somebody offers to pay you for it. (The immunologists whose work is discussed in this book would do well to read this Charter.) Wow! This document was prepared by an international team of medical ethicists for the international effort called the Medical Professionalism Project. It states at the outset: We share the view that medicines commitment to the patient is being challenged by external forces of change which tempt physicians to forsake their traditional commitment to the primacy of patients interests. So, that is what the international medical community admits, Dr. Ravikovich provides in this book evidence in support of this urgent need for a major renovation of the House of Medicine and why that renovation must start with doctors, after which the pharmaceutical industry is easily tamed. This book is not simple. But neither is living with asthma, hives, irritable bowel syndrome, chronic fatigue, constantly itchy skin, the annual round of hay fever, or potentially fatal food allergies. The information in it is not alternativethe research is entirely mainstream. Here you will learn why you are sick, why your standard treatments dont work very well and make you sicker through so-called side effects, how you could become healthy, or at the very least greatly improved and get off drugs, and what you can do to help make this healing treatment available. This is no ordinary self-help bookindeed I wish it was. This book is a crash course in asthma and allergy medicine designed to empower you with knowledge and hopefully inspire you with a holy rage and the determination to help bring out these facts so they become generally known to doctors and patients alike.
Introduction
xi
A good book like this does not need my recommendation, but a quick guided tour might help the reader who is new to this material. Thus, Part 1 provides the technical detail of how the immune system works, as is generally agreed upon by scientists in this field. For the beginner Part 2 may serve as a useful beginning; Part 5 will help patients understand why they are not improving and what is known in mainstream pharmacology about these drugs and their serious limitations and dangers. Part 4 has the provocative title Histaminegate which refers intentionally to the Watergate scandal of the 1970s. This chapter deserves the readers closest attention and is worth reading with the greatest attention to detail. The remaining chapters provide information on the various allergic diseases which will be of special interest to different readers. The Epilogue is something of a bombshell because it describes the most recent publication on allergy research that came out only two weeks before this book was submitted in its manuscript form to me. This research paper fully validates everything you read in this book and returns to the research that was more and more successfully hidden over the past two decades. The politically significant fact of this development is that this was published by the Swiss governments research institution funded by tax money, not drug companies. The equally important medical historical facts are that now the truth which was denied entrance through the door has forced its way in by the windowas the Russian proverb puts it and as Dr. Ravikovich is fond of reminding us. The Appendix contains documentation on the terrible struggle Dr. Ravikovich became involved in when his life-saving treatment was attacked by the medical licensing authorities, and suggestions are included on what you, as the reader or friend of an asthma and allergy patient, can do to change the current situation. Treating asthma, allergy and related diseases successfully, at a fraction of the current cost of mere limited symptom control, is an art and a science easily learned by any interested doctor. There is currently a great deal of interest in therapies that cure and are not merely symptom control methods generally employed by the majority of physicians. What suffering patients often dont realize is how terrible the frustration of doctors is who wish to help but often are prevented by the regulatory systems from employing new methods.
xii
If doctors want this scientifically validated treatment approach to use, it could be learned within a week or two. It is founded on basic science and as a treatment validated through experience. However, here in Ontario the use of histamine to treat asthma is literally forbidden since 1996 even though blocking medical innovation and overruling patient choice is contrary to the Medicine Act of Ontario and the Helsinki Accord on Human Rights which Canada signed in 1988. This ban was ordered without a single item of supporting scientific evidence and bypassed all mandatory debate required for the formulation of medical standards of practice. You can change that. Read this book and consider the information given in the Appendix and exercise your rights as a citizen and as a patient. Helke Ferrie
1. Michael Bliss, William Osler: A Life in Medicine, University of Toronto Press 1999 2. See The Olivieri Report, published by the Canadian Association of University teachers, Lorimer, 2002. For cancer see S. Epstein, The Politics of Cancer Revisited, 1998, East Ridge Press. Epstein is one of the worlds leading oncologists known especially for his success in getting DDT banned and refocusing cancer research onto the science of carcinogens. He is responsible for laws protecting workers from asbestos, pesticides, radiation etc. throughout North America and the European Union. For psychiatry see the new book by the world-renowned pharmacology scientists and corporate whistleblower David Healey, Let Them Eat Prozac, Lorimer 2003, published by the Canadian Association of University Teachers. 3. J. Robinson, Prescription Games: Money, Ego and Power Inside the Global Pharmaceutical Industry, McClelland & Stewart, 2001.
PART ONE
IMMUNE MECHANISMS
CELLS Almost a century and a half ago, a German scientist, Rudolf Virchow, made a revolutionary discovery: the body is actually a state consisting of citizenslive cells, each of which is a perfectly balanced unit. A deviation from the cellular balance is a disease, that is, lack of ease. Cells are our invisible natural workforce and best health guardians. Therefore it is important to understand what can go wrong with their complicated functioning, how to help them restore their rhythmical work, and how to achieve this with minimal introduction of suppressive medications. What is a cell? It is a tiny basic operative unit of a live body. If we accept Virchows view of our body as a state, then it is populated with over 100 trillion citizens working in coordination with each other. Our health and quality of life depend totally on how our cells function. Cells have different colours, sizes, and shapes and can be stationary or in motion. Under the membrane of each cell, there is a chemical lab, and the chemicals it generates determine the cellular function. Similar cells unite in teams to form tissues and organs. Cellular teams work in unison, no matter where in the body they reside, and produce the same chemicals at any given moment. A cell contains over a billion molecules, and each carries specific chemical messages. Cells communicate with each other in a cell-to-cell talk through these chemicals, just as we communicate with words, spoken or written. The more chemicals a cell is able to manufacture, the more verbal it is. Some cells perform limited local functions only, and their inner labs are fairly simple. Others are complex pharma-
ur body consists of cells, which are tiny chemical labs of various complexities. The chemicals released by cells are the language of their communication. They listen attentively to each others talk, and therefore, the work of different groups of cells is interrelated. This makes the functioning of the organs comprised of these cells also interrelated.
ceuticals able to produce as many as 300,000 different proteins: these cells perform numerous complex functions. The possibility of cloning an animal from just one cell makes it clear how intricate its lab can be. Cells are very friendly with one another. They lie in close proximity, and if something is wrong with one group, and it changes its chemistry, the neighbors express their sympathy by changing their chemistry as well. You definitely experienced it many times: your boss yells at you, and your legs give way, your pulse accelerates, your stomach turns into a knot, and you are ready to rush to the washroom. All this happens because the cells in your nerves, muscles, intestines, vascular wall and endocrine glands identify with your hurt feelings regulated by the brain cells. The opposite happens when your satisfied or elated brain cells start to release endorphins, natural narcotics, and the cells all over the body respond by participating in the joy. You feel as if you can fly, able to lift heavy objects and solve most difficult problems. This is what the unity of the different departments of the body means.
GENES All cells comprise the same set of over 30,000 minuscule particles within its nucleus. They are called genes. A gene is a biological unit of heredity that passes certain physical characteristics from parents to their children. Genes determine everything from such evident things as the eye colour, the voice timbre or the height, to such imperceptible minutiae as actual operations of a cellular lab. Every cellular chemical has its gene that governs its function. Genes are behind each cellular operation and secretion. In their chemical language, they instruct the cells what proteins and in what amount to produce in particular situations. A cells performance depends on the performance of the genes. The same genes work synchronically in all cells and send the messages from within, and the genetic instructions influence the labs activity qualitatively and quantitatively. If there is no genetic error or mutation affecting the functioning of our cells, our health is good. Nature is not faultless. Our dissatisfaction with something in our appearance is actually a reflection of how we perceive our visible genetic imperfec-
Immune Mechanisms
tions. Health problems often reveal genetic imperfections hidden from the eye. We may be born with genetic errors or may acquire them inexplicably in the course of life or through exposure to a harmful factorsuch as radiation, toxic environment, etc. The term for genetic changesmutationcomes from the Latin mutareto change. Defective genes send flawed messages to the cellular lab, leading to the inappropriate production of the corresponding chemicals. The resulting imbalanced chemistry means a disease in the organ or system comprised of cells that produce this substance. Several genes or even a group of them may be responsible for each disease. Changes in DNA, the nucleic acid which is the iny particles inside carrier or genetic code, can be structural and funccells called genes are tional. The latter means that the genes are, in princarriers of our heredity. ciple, structurally normal, but have some variations The genes govern in their activity. This is of key importance for clinical cellular functioning, and medicine, since if only the genes functioning is hence, chronic diseases impaired, attempts to correct it can be successful. Not are mainly the result of by deleting and replacing them, as is planned in the incorrect messages sent current trend towards potentially dangerous genetic to the cellular lab by engineering, but by tuning them up instead. faulty genes. Genetic Once initiated, a genetic change is potentially changes occur spontatransmissible, and may be passed by parents to their neously or through the children, grandchildren, etc. Genetic errors leading to impact of external health problems may be so subtle that their existence factors and may be remains unnoticed for years until time and/or strong passed to future effect deepen the hidden flaw. Doctors often see generations. If the parents that are taken aback when their child is diaggenetic faults are of a nosed with asthma or other allergic disease that functional, rather than neither of them seems to have; it is the combination of structural nature, mediparents genes that has amplified their own noncine has a chance to apparent genetic errors in their offspring. attempt a correction.
THE INTERRELATED FUNCTIONING OF GENES AND CELLS Each gene performs the same operation again and again. It is like a tiny perpetual motor operating in a sophisticated machinery that includes the interdependent work between the genes and the cells. The relationship of the chemical lab and the genes that lie at the heart of each cell is not unilateral, as
it may seem. It is not simply a matter of the genes governing and the lab obeying. Genes need fuel or feedback for their functioning, and certain chemicals generated by the cellular lab itself play this role as do some chemicals coming from outside. Some activate the genes functioning, others inhibit it. Genes can give proper instructions to the cells only when they get an adequate fuel supply. Indeed, as Dr. Craig Venter, one of the two leaders of the Genome Project, said on April 23, 2002 at the Gairdner Foundation International Awards event, proteins are the building structure of life, not genes. The understanding of the reciprocity in the functioning of the genes and cells may turn the dream of medicinesafe and efficient genetic engineering into reality. Use of proper substances may gently correct the functioning of the genes and hence, rectify their messages to the cells. These substances would be genomodulators, and their effect upon the genes he activity of the would be genomodulation. To modulate means to adjust. cellular lab and the The Latin root modulare means to bring out characterisfunctioning of the genes tics peculiar to a definite region; thus, genomodulation are interdependent. would mean a repair of genetic functioning to the Moreover, cellular normal level. Such type of genetic engineering would production at large can be non-invasive and safe. Since medicine does not use affect the genes this sort of genomodulation, one would think that such activity. Medicine can proteins-modulators are not known or are commeruse this fact as the key cially unavailable. Wrong. This book will discuss later to access the genes if two powerful genomodulators that work in harmony their defects are only with each other like a unit. functional, not struc1. One is a chemical generated by the cells and tural, and thus realize released into extracellular space, also existing safe genetic engiin a form of a drug. neering. The use of a 2. The other is an intracellular enzyme. well known synthetic Both have been known for decades as messengers version of a bodys informing the cellular lab. If their harmonious work is chemical triggers the impaired, we may use a synthetic version of the first in response of an intracelinjections, and it will naturally engage the other. lular enzyme and Numerous chronic conditions can improve or be cured enables the latter to by this. The improvement means that the genetic funcrestore the functioning tioning in the patients treated this way was corrected of impaired genes. temporarily or for good.
Immune Mechanisms
IMMUNITY ur immunity consists Everybody knows that immunity is the bodys defence of highly complex against disease, but, among laymen, few are aware that groups of cells called it is, actually, a defence realized by cells called immuno- immunocompetent cells. competent. These cells are competent in recognizing the They work in coordinaenemy and producing the chemistry that protects the tion with each other and host. We are born only with the seeds of immunity. The specialise to fight fighting ability of immunocompetent cells is dormant different diseases. These for the first several months of life. Exposure to an cells start to malfuncenemy wakes them up. Each exposure provides a chal- tion if the genes lenge for them to specializeto become competent in governing the immune fighting a particular enemy. Some cells neutralize viruses response are mutated. and bacteria, some fight cancer, others react to allergens in those who are prone to allergic reactions. Each category of the specialized cells performs its specific function. Thus, many groups of cells are united under the concept of immunocompetence. Their coordinated work can be compared to a well-rehearsed orchestra, and the released chemistry is the music. Immunocompetent cells are located throughout the body. Certain genes govern all aspects of their functioning. As was recognized a century ago, immune diseases are the result of changes of the genes that govern all the activity of the immune cells. The instructions of defective genes are, naturally, defective, so are the kinds and the amounts of the chemicals liberated by these cells. An error may turn the cellular music into a cacophony the way a poorly tuned piano key can turn a concerto into a disaster. The uncoordinated music of the immunocompetent orchestra means a poor defence against diseases, no defence at all, or a distorted defence/reaction.
ENEMIES OF THE IMMUNE SYSTEM We live in a world full of microorganisms that try to invade the body mainly through our respiratory and gastrointestinal tracts and skin. These organisms may cause a disease, but may also play a positive role in challenging our immune system, causing the cells to produce defensive proteins and thus, couching them how to defend us. We also have our inner enemies such as excessive stress, hormonal changes due to puberty, pregnancy, menstrual period, extreme temperature swings, etc., which require extra effort for the body to adjust. When not in excess, an adjustment strengthens our immune system, since the cells learn in the process what substances to produce and in
what amounts to deliver them. For example, the longer life span among women compared to men is considered to be due to the frequent hormonal challenges that strengthen their immune system. However, our society has created numerous challenges that exceed the ability of our immune system to resist them with success. Our food is full of colorants and preservatives, some indicated on labels, others hidden. We breathe toxic fumes and drink contaminated water. We feed the cattle and chicken with antibiotics and hormones that speed their growth. We enes malfunction even legalize the hazardous effects of these drugs by due to inborn errors allowing their permissible amount in meat and or those acquired in the poultry. Cattle are fed grass and grain treated with fertilprocesses of life. Their izers, and we allow a certain amount of these poisons in functioning may also canned goods that use dairy and meat products. To change under the influcompound our problems, we often take medications ence of extreme envibecause we do not want to tolerate a slight discomfort, ronmental factors. even for a short period of time, and easily find a doctor Genetic changes are willing to write out a prescription. The respect of the called mutations. society to drugs is so high that we write them with capital Mutations create a letters. We are forced into vaccinating our children predisposition to cellular although the generally accepted hygiene theory by S. malfunctioning, since Romagnani recognizes that the increased exposure to flawed genes send vaccinations is among the factors contributing to the wrong signals to the spread of allergies and asthma.1 cells they govern. Social pressures in our competitive society are also important health hazards. Our biological evolution has not caught up with the fast pace of civilization and its stressful and sustained emotional factors that contribute to the destruction of our great defenderthe immune system. This destruction starts with the genes that govern the pharmaceutical lab of immunocompetent cells. Apart from accumulating unfavourable external conditions that affect our genes, their malfunctioning and/or mutation may occur spontaneously in the course of life, without any obvious reason.
ALLERGY AS A CELLULAR OVERREACTION The very term allergy indicates that a patients body functions differently from a normal body: Greek allos means other, while ergon means work. Like an abused child who snaps at suspects an enemy even in a friendly stranger,
Immune Mechanisms
an immune system governed by impaired genes sees enemies not only in viruses, bacteria or cancer cells but in the things and events which would leave a healthy immune system undisturbed. It may snap mmunocompetent at a pollen particle, fur/dander of a pet, a favorite cells genetically food, the texture of fancy underwear, a pleasant scent of a perfume, a weather change, a mood fluctu- predisposed to malfuncation or a natural rise or fall in ones own hormonal tioning are hypersensilevels. The cells may also overreact without any tive and may overreact challenge, that is, spontaneously, which means that spontaneously without they start releasing certain chemicals in disproportional a trigger, or react to a amounts. Such chemical overreaction of immuno- friendly environment by competent cells is called hypersensitivity or hyper- releasing wrong chemistry. This brings on releasability. Allergies are genetically predetermined. They start allergy symptoms. Only with the malfunctioning of the regulatory genes those people whose responsible for the balanced work of the allergy depart- genes are mutated have ment of the immune system. Genetic predisposition is chronic allergic the primary dominant factor in the production of diseases. Exposure to a allergic diseases, while the environment may become a harmful environment complimentary factor. In the absence of genetic muta- may only augment the tion, the effect of the environment is mostly temporary genetic defect and and leads to acute reactions and temporary symptoms, through this lead to not to chronic allergic diseases. This explains why hyperreleasability of the some people develop lasting allergy symptoms upon immunocompetent cells. a certain exposure, while others get away with an acute episode. A slight genetic defect, mostly inherited, occasionally acquired, may remain unnoticed for years. However, time itself and/or cumulative effects of the hazards may break the back of the camel. In other words, the initial small defect in the genes may become magnified, and as a result, the operation guided by these genes may cause the cells to respond with a pathological reaction to what they would have perceived as harmless before. Since the language of the cells is their dynamic chemistry, the malfunctioning immunocompetent cells speak in chemically improper syntax and thus produce the signs of disease. Conventional allergy dwells on the environment as allergy cause and rarely spells out the fact that a trigger may provoke a recurrent allergic disease only in people with the underlying genetic defects or predisposition. Allergic
reactions without any trigger are also left unexplained. This deflects attention from primary errors to secondary events.
IS TREATMENT OF ALLERGIES ON THE GENETIC LEVEL FEASIBLE? Knowledge of the alphabet is not sufficient to enable one to combine the letters into words, and words into sentences. In a similar way, we cannot say that the current listing of about 30,000 genes gives us the knowledge of their functions and, most importantly, their interrelations, not to mention, the patterns of their manipulations. The understanding that genetic malfunctioning lies at the core of allergies means that its correction would be the best possible treatment for diseases of hypersensitivities. The interrelationship of genes responsible for one single disease, as well as their interrelationship with the rest of the genome, are extremely complex processes and may never be fully understood. Besides, the procedure of correcting or replacing flawed genes is technically very complicated, and is, therefore, as the leading geneticists say, many years away. Francis Collins, head of the Human Genome Project of the National Institutes of Health, predicts, that by 2010, we may have about 25 tests for genetic predisposition to about 25 major causes of diseases and death. Diagnostic tests, not therapies! One ought to think also about the many possible physiological, moral, and ethical issues involved in such therapies. There is another obstacle. Rationing of knowledge is common in modern medicine, and drug companies have already started battling over patenting the genome discoveries. Drugs or new methods of genetic therapy can rightly be considered discoveries, but the industry wants to patent that knowledge! Imagine what would have happened if the inventors of alphabets had decided to patent the letters. If the industry finds support for this plan from our corrupt governments, the possibility of genetic cures will be moved to still further into the future. Another problem is related to the enormous amount of money needed to fund the development of procedures for the intricate process of penetrating genes. Thus, as an every day treatment, genetic engineering is not feasible, even theoretically, in the near future. Fortunately, allergies and asthma, although multigenic and multifactorial diseases, arise mostly not from structurally defective genes but from deviations in the genes functioning. This means that in order to reverse an allergic disease, we need only to tune up these genes. The fact that in allergies, the performance of the
Immune Mechanisms
governing genes is correctable should make medicine happy. More so because the prevalence of allergy and asthma grows rapidly.
HOMEOSTASIS To understand how medicine can tune up the body and help it to reverse allergies on its own, we must understand a basic law of naturehomeostasis. The word consists of two roots: home(o)sameness and stasisstanding, and thus, the term denotes the tendency to preserve a balance. Nature strives for harmony and endowed us with delicate self-regulatory systems. Whenever unfavourable forces affect our body, these systems are challenged and, without our awareness, adjust to the changes, thus protecting us. For example, exposure to cold causes shivering, which is he body functions the bodys way of warming up, while exposure to hot normally when all the weather automatically causes profuse sweating that cellular substances are prevents overheating. Both the warming and the produced in balanced cooling are achieved through spontaneous changes in amounts. A healthy body the cellular chemistry. possesses regulatory Look how clever the body deals with dieting: after tools through which it an initial weight loss, the metabolism slows down to corrects imbalances. make better use of the smaller amount of food the The main condition dieter consumes. In fact, weight loss may practically under which the immune stop despite the reduced food intake. While this may system functions upset dieters, our metabolism is computerized to normally is a homeohelp the body to survive during food-deficient times. static production of all Another example: if you eat a lot of sweets, the chemicals by the high level of blood sugar mimics the condition of immunocompetent cells. diabetes and may lead to metabolic changes. To prevent complications, the body has a mechanism to cope with the dangerous excess: the insulin-producing gland gets the instruction to increase its output to metabolize the sugar. Any deviation from the norm, be it a deficit or a surplus, may be equally harmful, and these examples show that a healthy body self-rectifies such changes through its protective autoregulatory switches governing all functions. The tendency towards maintaining equilibrium, no matter whether it is body temperature, blood pressure or hormone production or, in fact, production of any chemical, is an inborn feature that keeps the body alive and is a part of the universal law of homeostasis.
10
Homeostasis is the core of immune system functioning. Health is balanced cellular production of all chemicals, or harmonious cellular functioning. Each time our immune system fights an invader, its only task is to restore the balanced production of chemicals by immunocompetent cells. Unlike other immune-related chronic diseases, allergies and asthma are much more easily reversible because permanent changes in the tissues interior occur only in the very advanced stages. The spontaneity of relapses and remissions in allergies and asthma indicates that it is possible to restore the functioning of the immunocompetent cells involved in them because the mutation of the underlying genes is only functional.
ells have various receptors, and each kind senses specific stimuli and/or chemical messages. The receptors then change chemically in response to the stimulus or bind to the substances that carry these messages and pass the digested information to the inner lab for production of certain chemicals and hence, physiological effects.
CELLULAR RECEPTORS What are the tools through which a healthy body regulates the production of all of its substances? Knowing them in general, we could probably find the ailing regulatory tools in allergy patients, repair them and help these people. The instruments through which the body establishes homeostatic amounts of cellular secretions are cellular receptors, which all cells have either on the surface of the cell membrane, or inside the cell itself. Receptors are molecules of protein that work like antenna, each very selective in their response to the surrounding environment. Each type of receptor is tuned to a certain signal. Some discern a signal of pain, others of temperature, sound, color, a specific chemical substance, etc. Signals come in the form of chemicals, the language of the cells. Each receptor selectively binds to a specific substance, or picks up the information contained in a physical stimulus, and then dispatches the obtained information to the cellular lab. The received signals affect the manufacturing process in the inner cellular lab. The information travels with a lightning-like speed. The more complex the cellular lab, the more varied its receptors are. Different groups of cells may have the same type of receptors and hence, respond to the same signal by changing their chemistry in tandem. Intracellular signaling followed by chemical effects is called signal transduction, while cell-to-cell talk is signal transmission. The development and activity of all cellular receptors are determined by genes.
Immune Mechanisms
11
A cell with its receptors can be compared to an insect whose antenna detect signals from its peers or the environment. In response to a stimulus, a signal, the insects body produces certain chemicals, and that changed chemistry conveys a message for action. The signal may prompt the insects body to exude venom to repel/kill an enemy or to secrete pheromones specific to the situation: to alert its peers of a danger, to attract an insect of the opposite sex, to call for help. Similarly, receptors are conductors of such cellular messages. Imagine an insect with its antennas severed: all its communication with the peer community and the environment are is cut off, and the insect is doomed to die. Similarly, the cells ability to synthesize and release chemicals depends on its receptor functioning and our health depends on proper receptor functioning.
RECEPTORS AS SWITCHES A cell is a generator of chemicals, and like any generator, it is supposed to have switches to turn the he body corrects any processes on or off. An immunocompetent cell unbalanced cellular synthesizes numerous chemicals and has switches for production through each of the chemicals it generates. Cellular receptors receptors that work like play the roles of switches that intensify or temper the turn-on and turn-off cellular production process. To make sure that the switches. Every cellular cell produces just the right amount of a particular chemical is regulated by substance, there are receptors that switch on its its specific receptors, release and other receptors that switch it off. Each and like switches, they cellular switch works within a range. The regulation adjust production to is implemented the same way the temperature of an cellular norm. Only propiron is increased or reduced by turning the lever, erly working on/off depending on the type of the fabric being pressed. switches provide the Proper control over the synthesis and release of correct release of each chemicals is vital because both excess and deficit can cellular chemical. lead to disease, as is, for instance, the case of a coma resulting from blood sugar excess or its shortage. Each receptor type is tuned to a certain chemical. Cells measure the amount of this chemical in the surrounding space with their receptors in the same way that an insects antenna senses the environment for specific signals and then passes its message to the inner lab. The lab responds accordingly either with intensification or inhibition of the release. This receptor-mediated process goes on incessantly.
12
nly well developed receptors are able to sense and correct the release of cellular chemicals by increasing or decreasing their production. If one kind of receptor is inefficient, the cells release the chemicals according to the signals of its opposite. Thus, the inefficiency of a turn-off receptor type leads to the predominance of the chemistry generated by its rival turn-on receptor. None of the current allergy medications repairs the prime defectinefficient receptorsthey do not restore the protective ability of the immune system. Instead, all of them block the activity of the efficient receptors.
If a certain receptor type, say an off switch, is inefficient, its counterpart, the on switch, works unopposed. This can make the cell generate so much of a chemical that it inundates the tissues and leads to disease. Only efficient on/off receptors can provide balanced output.
RECEPTOR EFFICIENCY DETERMINS PROPER CELLULAR WORK In the same way a high grade TV antenna determines the number of stations and the quality of the image, cellular receptors provide a proper message transmission. For adequate cellular functioning, both the quantity and the quality of receptors are important: the cells should have enough cellular receptors, and these should be well developed. Scarce, underdeveloped or inefficient receptors cannot adequately discern signals, nor can they transmit coherent information to the interior of the cellular lab. As was said, the operation of any on-switch must be counterbalanced by the off-switch. An example is a warm shower: only functional taps can provide one. Otherwise, we would have either cold or hot water only. In every-day life, nobody tries to resolve the problem of a broken cold water tap by reducing the flow from the hot tap. It is the broken tap that needs to be repaired. Every-day logic that prompts us to fix the broken tap, fails when it comes to fixing our health. Here is proof. The immune system is designed as a self-regulatory machinery, and allergies are among self-regulatory diseases. This knowledge allows us to develop medications that will stimulate or block receptors depending on the purpose. Medications can relieve the symptoms either by blocking the active healthy receptors or by stimulating the inactive ones. Activation of the inefficient tool is preferable since it not only rectifies the primary defect but also preserves the integrity of the rest of functioning system. Strangely, drugs designed to stimulate deficient responses are a rarity in medicine in general and are
Immune Mechanisms
13
absent in allergy, but allergy therapy concentrates primarily on blocking the active, normal (!) responses. Logically, help should come in the form of facilitating the repair of the primary defect. But conventional allergy practice completely disregards this simple logic and uses only suppressors.
CONVENTIONAL TREATMENT OF ALLERGIES Each organ with unhealthy immunocompetent cells expresses its malfunctioning through the symptoms typical of its specific nature. Thus, the lower respiratory tract expresses its disease through cough and bronchial obstruction; a runny/stuffy nose is a sign of the affliction of the nasal lining, while itch and rash indicate the involvement of the skin. Two kinds of medications are used to treat allergies. The purpose of both is symptomatic relief, not cure. These are symptomatic drugs that target the end organbronchi, nasal passages, skin, etc. They are supposed to block the release of the bad chemistry that causes the symptoms and thus to relieve bronchial obstruction, an itch or a nasal congestion. Actually, the bad chemistry is secondary to the primary cause which is the deficient turn-off receptors, but unfortunately the restoration of their activity with proper stimulants never becomes the treatment target. Given the fact of the mutated genes causing the harmful functioning of the flawed receptors, allergy patients are doomed to perpetual medicalization and regular visits to medical offices. Moreover, the suppression of the excessive release fails too often, and then other drugs are prescribed. These not only attempt to reduce the effect of the bad chemistry, but suppress all the processes in the cellular lab, bad and good, and that is why they are called immunosuppressants. Worse yet, even at the cost of cellular suppression, these medications provide only temporary relief, because they do not eliminate the cause of the malfunction in the cells, but merely suppress all the work of the cellular lab. This suppression covers all immunocompetent cells, and their protective functions are also shut down. These medications suppress the functioning of the cells far beyond the immune system, and thus, these side effects greatly overshadow even their apparent shortterm benefits once taken for a long period. Of course, allergy is a chronic disease, and so these medications are often taken daily, which undermines the bodys entire immunity in addition to all those side effects. The immunocompetent cells, already compromised by the pre-existing genetic malfunctioning, lose their innate ability to produce their protective chemistry. This deprives the patient consuming the drug of most immune defences and, hence, severely affects the course of the allergic illness for which the drugs are prescribed.
14
odern allergy therapy focuses on the end organ by blocking the natural on-receptors responsible for the overproduction of those substances which, in excess, cause the symptoms. Most commonly, and especially in asthma, it uses immunosuppressive medications that allegedly target the bad chemistry, but in reality suppress the work of all immunocompetent cells. Blocking is too often inefficient. Suppression destroys the cellular ability to produce protective chemistry, which results in the generally undermined immunity, and, in the long run, worsening of the primary disease and/or other side effects of various kinds and severity. Neither approach aims to restore the functioning of the immune system and by that, resolve the allergy problem.
In general, we often learn about drugs side effects only when the fatalities from their consumption rise too high to be ignored. Such drugs are taken off pharmacy shelves, replaced by others, allegedly safer products, and only time exposes the adverse effects of those newer products. In allergies and especially in asthma, immunosuppressive medications are, however, the only effective ones, and allergists try to reduce the side effects of these widely prescribed drugs. Adverse effects are rarely discussed in medical sources and are usually missing from medical textbooks as well. No wonder, that in the long run, the course of the disease, for which these medications are prescribed, becomes worse. Napoleon Bonaparte is said to have remarked: Doctors will have more lives to answer for in the next world than even we generals.
T-CELLS Any discussion of a self-regulatory disease should start with the commanders of the immune cells. They are the T-cells or T-lymphocytes. These cells are a natures masterpiece. The verbs used to define the T-cells role in immune response and function affirm that they initiate, propagate and orchestrate all immune reactions. T-cells mainly direct the battles by telling other immunocompetent cells what chemicals to generate and in what amounts. They also most actively participate in all processes where their subordinates are involved, and immediately respond to the messages coming from other cells. Various chemicals signal these commands and responses. T-cells possess a unique ability to learn how to participate in immune reactions and govern them. At first, these cells are nave. In a medical context this word is used to describe the fact that an immune cell has not yet been exposed to invaders and, therefore, has not yet had a chance to express its fighting potential. Exposure to a virus, microbe, or any other
Immune Mechanisms
15
intruder provides the cell with information that causes it to become educated. This activation signifies the beginning of their specialization in the corresponding field. The process continues with repeated exposure to the trigger in a way similar to muscle training when exercise results in a corresponding muscle development. Allergy is a deviation from the norm. T-cells are supposed to be our protectors, but in the allergic patient they lack their regulatory ability. This creates the background for an exaggerated activity of -cells are central to the subordinate immune cells, now promoting disease. immunity. They In allergy-prone people, any foreign substance or any specialize in fighting unspecified event may become a trigger of a diseasepromoting immune response. T-cells called different diseases. After T-helpers (TH1 and TH2) now unfortunately help to an encounter with an invader, which they produce chemicals promoting the allergic response. The only other subdivision of T-cells that never perceive as an enemy, fails us and stays in the disease fighting mode are the they retain memory of T-suppressors. T-suppressors get activated simulta- what chemicals to neously and in response to the activity of all other produce for any future helper cells. In the 70s, the term was introduced that fight. In allergy, there labeled suppressors as T-suppressor regulatory cells are two natural opposing denoting that they regulate all responses, especially in subdivisions of T-cells allergies.2 Suppressors moderate not only the host- helpers that are mainly hostile activity of helpers, but also the disease- on the diseasepromoting activity of other immunocompetent cells. promoting side, and In the process of maturation, all T-cells, T-suppressors suppressors that funcand both kinds of T helpers, become memory T-cells. tion to promote health This means, that like the brain, they remember how to and also control the participate in the fight by releasing certain chemicals work of T-helpers. Both characteristic for their and activities in promoting or kinds of cells, once specialised, become suppressing disease. memory cells and remember how to fight T-SUPPRESSORS T-suppressors are our protectors in the immune for or against the systems war we call allergy. Their overall activity disease.
determines whether allergy will or will not take place. The conclusion is that if one has allergy symptoms, T-suppressors are for some reason insufficient. Interestingly, since 1991, discussion of these cells, central for
16
-suppressors are controllers of all allergy-related immune responses, and their activity and memory are the keys to the normal functioning of all participating cells. Inability of T-suppressors to control T-helpers and organize the defence against them explains allergy symptoms. Inexplicably, during the 90s, these cells have practically disappeared from all allergy-related scientific publications, which creates the false view of our immunity as a system ruled and operated totally by negative forces.
allergic processes, has disappeared from medical sources on allergy, even though, of course, these cells are still present and doing their work as they always have done. At the same time, the same publications describe in detail helpers, TH1 and TH2, which are subordinate to T-suppressors. A legitimate question is: why? There can be only one logical explanation for this: by removing the protectors, T-suppressors, from the stage, the discussion now centers only on the diseasepromoting T-helpers. By not discussing the role of T-suppressors, which restore the bodys disease-fighting ability, the unlimited use of various medications is justified. By acting as if T-suppressors are not significant, the human body is portrayed by medical science as if it was unable to regain its disease-fighting ability. This, view justifies the unlimited use of various medications, including very potent ones. The most frightening fact is that, along with controlling the disease-promoting activity of the immune cells, these drugs collaterally also crush the activity of our saviours, T-suppressors. While the symptoms may temporarily be controlled, the price for this temporary relief may be the obliteration of our T-suppressors and thus also their ability to fight for us against disease. The fact that T-suppressors are ignored in medical discussion is, from a scientific point of view, incomprehensible; it was science that discovered them and elucidated their activity. Ignoring T-suppressors also contradicts the laws of homeostasis upon which a functioning immune system depends, namely that disease-promoting action always also stimulates the disease-fighting forces, in order to defend the host.
MAST CELLS Among the closest subordinates of T-cells, two kinds play a special part in allergic reactions. They are sister cellsstationary mast cells and mobile basophils. Mast cells reside in tissues, while basophils flow with blood. Due to the similarity of their functions, when speaking about mast cells, we imply basophils as well, even though they enter an allergic reaction at different stages.
Immune Mechanisms
17
If T-cells are the conductors of the orchestra of allergy-participating cells, mast cells are the lead instrument. Their leading role indicates that all the properties of mast cells and basophils are realized in allergy as in no other disease. They start and maintain allergic reactions. Mast cells are major generators of chemicals in allergic reactions. The word mast comes from the German verb to feed, thereby indicating that these cells feed the immune processes with their abundant chemistry, which then provides for the various immune reactions. The most important and prolific chemical among them is histamine. Although histamine has been known for almost a century as a cellular chemical, in 1952, it was discovered to be a product of the mast cells. Since then, it has always been emphasized in all textbooks and medical dictionaries as the most distinctive feature of these cells and allergic diseases. Each mast cell contains 50200 histamine granules densely packed under the cellular membrane. Mast cells are very touchy in general, but especially in allergy patients: upon certain chemical changes in the surrounding space, the granules crack like fragile egg shells and leak out histamine. This act is called degranulation. Histamine leaks abundantly in many diseases where there is an infectious or immune-related inflammation, or an injury. However, in allergies, mast cell release of histamine is especially profuse, and, therefore, histamine release is accepted as the start and the hallmark of allergic reactions. In humans, histamine is the only pre-stored mediator that participates in allergic reactions; it causes initial activation of all immune cells participating in allergy, and it changes their chemistry. Because mast cells concentrate in the skin, air passages, brain, gastrointestinal tract, histamine spill occurs predominantly in these areas. Mast cells initiate allergic reactions by overspilling histamine, while their sister cells, basophils, take over at a delayed stage and maintain the process. Their histamine production constitutes about 90% of all histamine released. While mast cells can produce numerous mediators of allergy, apart from histamine, basophils produce mainly histamine. The hyperresponsiveness of mast cells and basophils, and their exaggerated release of histamine, as the major driving force, allows us to call allergies diseases of hypersensitivity. The mast cells hyperactivity in releasing histamine is a sign of the persons inborn predisposition to allergy, which means that certain genes governing the function of these cells are faulty. In his work on mast cells and basophils, Dr. L. Lichtenstein, the pioneer of histamine research, and the 1994 president of the American Academy of
18
ast cells and basophils are the cells that unleash and maintain allergic reactions. Their central feature is the presence of histamine granules under the membrane. In allergy patients, these cells are abnormally sensitive and may release excessive amounts of histamine in response to virtually any trigger and do so spontaneously. The histamine spill ignites allergic reactions. Uncontrollable release of histamine from these cells is a genetically predetermined feature and is a major indicator that the host has allergies. The exaggerated histamine release from mast cells and basophils is the key event in allergy, which clinical and even theoretical allergy medicine now basically ignores.
Allergy and Immunology (AAAI), reaffirmed this idea in his presidential address published in the most prestigious immunological periodical.3 To the present day, this concept has not been rejected or even questioned. However, in the latest medical sources histamine leakage at early and late stages of allergic reaction is described solely under the unrevealing mast cell releasability or mast cell degranulation, activation, or recruitment, with the word histamine always omitted. At the same time, the names of other, qualitatively and quantitatively inferior mediators of allergy are emphasized. In this way, the impression is created that mast cells are disconnected from their central product, histamine, and, thereby, their role in allergic reactions appears as seemingly insignificant. Instead, what is put forward as significant are other cells that neither initiate allergic reactions nor keep the allergic response going, or/and enter the game only in response to a histamine spill at much later stages. This conceals the inseparability of mast cells and basophils from histamine granules as their most characteristic feature, and deflects attention from the fact that a massive histamine spill signals the onset of allergic symptoms and maintains these at later stages.
DENDRITIC CELLS The third type of cells important in allergies is the dendritic cell. The name dendritic comes from the Greek tree. Indeed, threadlike extensions of dendritic cells resemble a branched treethe image that inspired their name. These cells secretory products are more diverse than those known for any other cells of the immune system, states the leading medical textbook on internal medicine.4 There are several types of dendritic cells, and they densely populate the skin, the lungs, the lymph nodes, and the nasal mucosa. One kind is of particular interest for us because of its regulatory activity in immune processes, its ability to affect the performance of T-cells, and its cardinal role in skin allergies and related skin conditions. These are Langer-
Immune Mechanisms
19
hans cells, or simply LCs. These cells are a repository of numerous chemicals, histamine among them. They bind to the intruder and present it to T-cells for identification and action. LCs also possess the unique migratory ability of traveling from the skin to the regional lymph nodes and inform T-cells of the presence of intruders encountered on the skin or in the air passages. In addition, the changing chemistry of LCs following their encounter mong immunocomwith an intruder, can directly involve other immunopetent cells, there is competent cells. LCs have another unique feature the family of dendritic affinity with nerve cells, which also belong to the family of dendrites. The extensions from LCs stretch to the cells. One type, dendrites of nerve cells, thus forming their continua- Langerhans cell or LCs, tion. These connections, as well as the cells reciprocal are especially important chemistry, become the bridges for their communica- in allergy. They densely tion. The involvement of LCs on the skin inevitably populate the skin, while leads to the involvement of the nerve cells and vice versa. other members of the Skin diseases of neurological origin, such as psoriasis or dendrite family reside neurodermatitis, are the best examples of the ties and all over the body. Upon interdependent functioning of the immune and an encounter with an enemy, LCs bind to it nervous systems in the body. and present it to T-cells, thus activating them. HISTAMINE Since all allergic reactions start and continue with a Dendritic cells have a histamine spill, histamine will become central to this special affinity to nerve book. Practically speaking, allergies and asthma are cells, which are also diseases of one substancehistamine. When a person dendrites, hence the does not have allergies, histamine release in that easy involvement of persons immunocompetent cells is balanced. That is both in each others activities. why it is so important to clarify what histamine is.
The word histamine is made up of two Greek roots: histios meaning pertaining to tissue and amino denoting a chemical group, an integral constituent of all proteins. Histamine is a compound found in different concentrations in all body tissues. It is an active participant in all health-promoting as well as all disease-promoting processes. Its precursor is histidine, one of the nine essential amino acids. The term essential in regard to amino acids denotes that it is one of the nine compounds without which there is no life. Being similar to all essential amino acids, histidine cannot be synthesized by humans and is obtained only from food. In the
20 THE PLOT AGAINST ALLERGY PATIENTS
body, it naturally transforms into histamine. Numerous food proteins contain a different inherent amount of this histamines predecessor. Especially rich are seafood, certain fish and meats (mackerel, sole, pork), cheeses, red wines, chocolate, citrus fruits, nuts, beer. Consumption of such foods leads to increased formation of histamine, and therefore, hypersensitive people often have an allergic reaction after eating them. Like everything in the body, the innate histamine concentration in tissues is genetically predetermined. This is highly individual and also fluctuates depending on the physiologic state of the body at any given moment. The increasing histamine concentration in tissues may occur due to the overreaction of its main repositorythe mast cellsto their internal environment. That is why allergy symptoms may instantaneously flare up upon the slightest change in the bodys chemistry. Such changes may occur when a person sleeps less or more than usual, gets warm or cold, or even when a sudden mood change takes place. Sometimes, histamine overspill may occur without any trigger at all, simply spontaneously.
WHAT HISTAMINE DOES IN THE BODY In normal body functioning, although pre-stored mainly in mast cells and basophils, all immunocompetent cells contain histamine. Moreover, they start to synthesize it de novo upon activation, and this makes histamine the most important messenger in immune processes or, as science calls it, a mediator, in all aspects of immune function. Nerve cells and endocrine cells also synthesize histamine. In the nervous system, where it passes on its most important messages, histamine is called a neurotransmitter. Each cell in the body is connected to nerve cells; therefore histamine messages reach each cell and affect its functioning. Every substance in the body carries its own specific information. For instance, adrenalin mobilizes defensive mechanisms of the body, while insulin is responsible for the carbohydrate metabolism. Histamines scope of activity is inconceivably wide. Indeed, histamine regulates (!) various activities of the brain, such as the arousal state, brain energy metabolism, locomotor activity, neuro-endocrine, autonomic and vestibular functions, feeding, drinking, sexual behaviour and analgesia (pain). 5 This means that when we sleep or wake up, move, think, feel pain, eat, make love, etc. histamine is active passing its messages, which will vary depending on the organs or tissues function.
Immune Mechanisms
21
Another theoretical work that covers the multiple areas of histamine activity emphasizes that histamine proved to be important for the immune homeostasis.6 Since balanced immunity signifies health, this knowledge from the basic sciences confirms that not only the allergy-related functions of the immune system depend on histamine, but also its general functioning. It logically follows, that an imbalanced production of histamine must inevitably affect the above-named functions, and such symptoms as insomnia, or excessive fatigue, joint and muscle pains, poor vascular tone, low libido, and even general weakening of the immunity are a possibility. Basic science teaches that histamine not only participates in numerous functions, but regulates many of them. If we develop this idea further, it logically follows that by blocking its activity with medications such as the antihistamines or the highly popular antacids (which are antihistamines for gastrointestinal disorders), we inevitably disrupt all the above-listed functions. Did you know that? I bet you didnt even though you may have consumed some of these drugs and possibly also experienced their side effects. Your doctor may not know about the regulatory properties of histamine because he or she was not taught about the scope of histamine activity, but was taught simply to prescribe antihistamines and antacids. Doctors generally know histamine only as an evil mediator of allergy, which, being spilled from mast cells, initiates and conducts pro-disease messages among the cells participating in allergic reactions. They also know that histamine excess leads to excessive secretion of gastric acid. Therefore, for doctors who are taught this limited view, histamine suppression seems the right thing to do.
HISTAMINE IS AN AUTACOID The word autacoid comes from the Greek autosself and akosremedy or medicine. There are several autacoids, such as adrenalin, a powerful hormone that increases blood pressure, accelerates the heart rate, etc. Then there is serotonin, familiar to migraine and depression sufferers, since its imbalance leads to these conditions. Too much adrenalin can be fatal; at the same time, synthetic adrenalin saves lives in critical situations. Autacoids are substances of bifocal activity: too much can be harmful, as can be too little. Not all medical dictionaries list the word autacoid, but if you are lucky to find it, you will read that histamine is an autacoid as well. Strangely, in the same dictionaries, the entry for the word histamine will not mention its remedial properties.
In a few old textbooks this positive aspect of histamine is mentioned. Today, most textbooks emphasize only its disease-promoting activity in allergies, migraine headaches or production of gastric acidity istamine is a and the need to suppress this activity. This is so despite substance produced the fact that histamine is a substance of dual effect, by all of the bodys cells. as is, for instance, adrenalin also. It participates in Something is wrong: Why does standard medicine numerous functions and fight histamines excessive activity with drugs? Why regulates many. does it pretend that the only role for histamine is a Histamine transmits negative one when, in fact, it belongs to the family of numerous vital messages, autacoids? How can the substance contained in all cells without which our body of healthy (!) people be considered so hazardous to the would not be able to body? What is wrong with Mother Natures design? function. It is crucial for the proper work of the HISTAMINE HOMEOSTASIS immune and nervous Allergy and related diseases are conditions caused by systems that regulate the the initiation of inappropriate histamine release and functioning of the rest of activity. This does not make histamine a harmful the body. Despite this chemical, since it is an inherent part of life and organ fact, medical textbooks functioning. It is the imbalanced release and unconmostly avoid mentioning trolled activity of this substance that become harmful. histamine, and when they The overspill means that the switches that control do present it, they dwell histamine release are inefficient. solely on its allergyThe existence of such switches is evident from the contributing properties. way a healthy body extinguishes an acute allergic reacThis justifies the use of tion. Here is an example of how it happens. Exposure to numerous medications an allergenic food or a strong smell may occasionally that block its activity provokes mast cells degranulation in a healthy host. which results in the The tissues full of these cells are the first to respond disruption of numerous with symptomshives, itchy eyes, a congested nose, vital functions. etc. This signals that the impact was too strong even for
the healthy self-regulatory switches, and they were unable to turn off the histamine leakage. However, the disruption of their otherwise normal functioning is brief, the bodys chemistry shifts to a diseasecontributing mode only for a short period. If the patient does not want to put up with these temporary symptoms, he may take an antihistamine. At some point, the receptors regain their ability to turn off the flood, and the
Immune Mechanisms
23
symptoms stop. The body was able to reverse the disease on its own. Things are different in a hypersensitive patient. There is no effective turn-off, therefore the reaction lingers and may progress due to a shift towards pro-disease chemistry. Something is permanently wrong with the protective regulatory mechanisms in the immune system, and this defect maintains the symptoms. Now the patient may be forced to turn to a never-ending, pill-swallowing regime. It is clear that in allergy patients, histamine turnoff receptors need help to be able to establish homeostatic production. Only the restoration of receptor functioning may end allergy symptoms and save the patient from daily medications. Despite the fact that receptor repair would be of much more benefit, allergy medicine recognizes only the blocking approach: it either inhibits the functioning of the healthy receptors, or suppresses the activity of the cells totally. In either case, the effect is temporary, since it does not correct the prime defect.
HISTAMINE RECEPTORS Histamine-synthesizing cells have not one but several kinds of histamine receptors that regulate its synthesis and release. They are marked by the letter H that stands for histamine and numbers that denote their type. We will speak mostly about three kinds of histamine receptors and just mention the forth, although science has identified more. All four receptorsH1, H2, H3, H4 are important in passing numerous histamine messages. Since H receptors operate with the substance that participates and regulates numerous immune and neurological functions, these functions depend on the efficiency of these receptors. In allergy, H1 receptors are turn-on switches for histamine synthesis and release. H2 and H3 receptors are off switches. Only when H2/3 receptors are deficient, the normal H1 receptors become disease-promoting tools because they contribute to the histamine
istamine is a substance of dual activity. It does cause allergy as well as some other disorders, but only when it is released excessively. More important is the fact that histamine is responsible for messages of health among the cells. By originally including histamine into the group of autacoids, science recognized its healing properties. By excluding it now, the medical profession has distorted scientific fact. Silence about the vital role of histamine for the functioning of the whole body and its curative ability is of special concern in clinical immunology and allergy where histamine is of overwhelming importance.
ike any substance, histamine overproduction is controlled in a healthy body by certain turn-off receptors. If these receptors are inefficient, the exaggerated histamine release leads to the prevalence of histamine-induced disease-promoting chemistry, and hence, allergy symptoms characteristic for the tissues and organs in which the flood occurs. The two options an allergy patient has are: a) medications that either inactivate the work of the healthy turn-on receptors or suppress all the activity of the cellular lab; b) repair of the inefficient turn-off receptors in order to enable them to control the leakage. Conventional allergy medicine prefers the blocking approach with its temporary effect.
release. In the areas other than allergies, the application of these receptors is different and is not discussed in this book. H4 receptor generates and activates immunocompetent cells in allergy and other diseases. The H1 receptor type was discovered over half a century ago. The role of these receptors in the excessive production of histamine has been studied thoroughly and described in all textbooks. H2 receptors were discovered by James Black, a Nobel Prize winner. These receptors are fairly well described by basic science, but practicing physicians are only taught their role in excessive gastric acid production, while their central immunoregulatory role in allergies, asthma and other immune-related diseases is almost always excluded from the program. H3 receptors were discovered on nerve cells in 1983 by the French neurophysiologist J. Arrang and a team of European scientists. Later on, these receptors were identified on other cells, including immunocompentent cells. I doubt that the neuro- and immunoregulatory role of these receptors is known to most practicing physicians. The H4 receptor was first described by D. G. Raible and his colleagues in 1994. This receptor plays a major role in bone marrow activity. The H4 receptor is vital for the production of immunocompetent cells and hence, the functioning of the immune system. Standard medical textbooks generally do not contain any information on this receptor. A Canadian research team working in the Winnipeg cancer institute discovered another class, namely the intracellular receptor H1C that delivers histamine messages to the heart of each cells genetic material.7 From a paper sent to me by a renowned American immunologist, I learned about the existence of yet another type, Hx receptor. With time, still more histamine receptors may be identified. The existence of multiple histamine receptors, each of which mediates different cellular functions, indicates the
Immune Mechanisms
25
importance of the substance whose messages they conduct. All immunocompetent and nerve cells, those of the vascular walls and the endocrine glands, indeed, the cells of all regulatory systems, synthesize histamine, and thus they have histamine receptors. The distribution and functional activity of all H receptors are the central factor that determines the release of histamine by different cells. This release affects the work of numerous organs and systems, and when impaired, manifests in various physiological and clinical effects.
H1-SWITCH VS. H2/3 SWITCH All H receptors are meant to respond primarily to histamine. In allergy, H1-receptors are responsible for the symptoms. They are activated by the histamine present in the extracellular space and signal the cellular lab to generate histamine. The body moder- receptors; they do not ates histamine release through H2/3 receptors. Their contain information on messages are opposite to the H1-receptor messages. the healthy regulatory When the messages of H1 receptors are counterbal- effects on the nervous anced by the messages of H2/3 receptors, histamine is and immune systems produced in the amount needed for the normal func- through the role of the tioning of the tissues, such as cellular growth, wound H2/3 receptors. healing, muscular and vascular tone, pain reduction, proper hormone production, etc. If H2 and H3 receptors are inefficient, as it is in allergy, histamine liberation becomes excessive. This results in the prevalence of disease-promoting chemistry, and the areas especially rich in mast cellsthe lungs, skin, gut and brainrespond with symptoms specific to them. Histamine overactivity involves all cells possessing histamine receptors. The more histamine receptors the cell has, the greater its involvement. Histamine surplus has a negative effect on neighboring cells, and they start to generate disease-oriented chemistry. This amplifies the pathological process, and creates a situation where the strong H1-receptor messages prevail, and thereby maintain allergy symptoms. The inactivity of H2/3 receptors turns normal H1 receptors into the target for the main allergy medications, antihistamines. Substances that inactivate
istamine production and activity are regulated by stimulatory and inhibitory receptors marked with the letter H. By now, several kinds of H receptors have been discovered and their mode of action established as different in different organs. The fact is that clinical textbooks tend only to contain information that leads to the production of medications that block stimulatory H1
receptor response are called antagonists, and antihistamines are H1-receptor antagonists. Antihistamines immobilize H1 receptors for the period they circulate in the body; that is, until excreted, and then, another dose of the drug is needed to keep H1 receptors under control. A negative side of antihistamines is that, while they circulate in the bloodstream, all the health-promoting histamine messages are inhibited: wound healing slows down, vascular tone weakens, the brain loses its clarity, etc. Two questions arise: 1. Why are H2/3 receptors weak and unable to provide the balanced release of histamine? 2. Is it possible to boost the efficiency of these receptors? I will try to answer both. istamine release is induced through H1 TWO WAYS TO CONTROL ALLERGY receptors, while H2 and Nature programmed the body, and especially the H3 receptors inhibit its immune system, to function in such a way that any negarelease. Thus, in allergy, tive effect could be easily counteracted. In relation to H1 are on-switches, and histamine balance, this is so unless there is an inherited H2/3 are off-switches. or acquired error in the genes responsible for the formaAllergy symptoms occur tion and/or activity of H2/3 receptors. Due to an error, when the off-switches these receptors may be underdeveloped, inefficient are unable to turn off and/or scarce. If the error is minor, histamine release will the histamine release, be slightly in excess, and the bearers of the deficient and the leakage receptors may experience negligible symptoms. At some continues unabated. point, a seemingly irrelevant event or simply a time factor may reinforce the genetic defect and make it obvious through a full-blown allergic condition. Medicine knows that the blocking effect of H1-antihistamines is, at best short-lived and that they are required on a regular basis. Medicine also knows that suppression of any cellular functioning for extended periods of time is highly undesirable because of the potential health hazards. Logic tells us that the only effective and safe way to control histamine release is to activate the H2/3 receptors, and enable them to perform their natural function. Moreover, basic science provides us with the additional knowledge that the H1 receptor, proclaimed as bad in allergy, is not solely allergy-oriented, but is also protective: it assists the H2 receptor in its protective activity. This confirms the opinion of a number of research teams who found that H1-antihistamines, designed to block the receptors activity, might not be ideal therapeutic strategy since they also inhibit normal histamine metabolism.8
Immune Mechanisms
27
Can we correct the receptor functioning with the presence of the faulty genes that govern it? Can we do this without invasive genetic interference? Yes, we can. Let us see how it can be done.
hen the off receptors, H2 and H3, are
CELLULAR AND SYNTHETIC HISTAMINE Exercise develops muscles, and similarly, activation strengthens receptors. The scientific term for substance that activates receptors is agonist. In nature, strengthening of the inefficient H2/3 receptors occurs through histamine. Its synthetic version has been available for almost a century. Can it be used for activation? Yes, it can. In this connection, questions arise: If extracellular histamine keeps H1 receptors active all the time, why cant it activate H2/3 receptors? If synthetic histamine can activate the inefficient H2/3 receptors, what is the difference between synthetic histamine and our bodys histamine? Let us start by looking at the difference between histamine found in our cells and the one in the commercially available form. To establish the potency of a drug, one measures its level in the blood and tissues. All substances in the body start to break down and are metabolized after a certain amount of time. The time it takes for half of the drug to be metabolized is known as its half-life. So, the half-life of an antihistamine determines how many hours apart a tablet should be taken. The difference between the half-life of natural histamine in our cells and its drug version is cells, and this makes the most important distinguishing fact between them. Unfortunately, medical textbooks almost never activation of the weak explain the difference between the two. In fact, although receptor more logical. both are called histamine, they are far from being identical in terms of their action in the body. Intracellular histamine is stored in the granules of mast cells and basophils for about three weeks. Being released into extracellular space, it disintegrates within few minutes. In a healthy body, histamine release is smooth, and its much-needed messages spread all over the
genetically defective and/or scarce, there is little or no opposition to the normal H1 receptors, and histamine release turns into a flood. Histamine excess causes the production of prodisease chemistry by the participating cells. The tissues full of histamine-induced chemistry respond with corresponding allergy symptoms. The two ways to treat patients are: 1) temporarily control histamine release by blocking H1 receptors and provide symptomatic relief; 2) activate H2 and H3 receptors and fix the problem. Continual blocking disrupts normal functioning of the tissues with H1-receptor-bearing
body. In a sick person, it leaks excessively, which leads to an allergic reaction. Although the spilled histamine is metabolized within minutes, the constantly cracking granules of mast cells and basophils maintain its high levels in the tissues. Moreover, this exaggerated leakage provokes the manufacture, or synthesis, of additional histamine, particularly by other immunocompetent cells, T-cells which begin to make ynthetic histamine more and more of it as well. This increases the amount differs fundamentally of histamine in the extracellular space and thereby from the cellular chemcauses a whole cascade of illness-contributing chemical. It has a short halfistry. This is like gasoline being poured over a smollife, its concentration is dering fireit inflames the affected tissues. Indeed, very low, and it is indethe term that describes the process is inflammation. pendent of the diseaseSuch inflammation has nothing to do with an infection; promoting chemistry. it is a tissue reaction to the cascade of pro-disease Injected histamine chemicals. cannot produce and Synthetic histamine differs from its natural cellular maintain the state of chemical counterpart in several aspects. First, mandisease the way cellular made histamine is usually employed in a diluted form histamine can. and can, therefore, be much less concentrated than the natural substance. Second, injected histamine is an uncombined isolated substance, which means it is a foreigner in the chemical soup simmering in the tissues. It is like a new log thrown into a fire, and time is required for it to start burning. But, actually, there is no time for that: although the half-life of both cellular and synthetic histamine is only a few minutes the injected drug breaks down completely, whereas the immensely exaggerated liberation of cellular histamine goes on due to the continuous degranulation. Just compare the impact of a few minutes of man-made lowdose histamine with the incessant oozing of histamine from mast cells/basophils. These qualitative and quantitative aspects explain why the synthetic chemical cannot lead to a disease the way the bodys histamine can.
H1- AND H2/3 -RECEPTOR RESPONSE TO CELLULAR AND SYNTHETIC HISTAMINE Synthetic histamine cannot lead to disease, but can it lead to recovery? Yes. Receptors respond differently to cellular and injected histamine. Theoretically, both kinds should activate all histamine receptorsH1, H2 and H3, but this is not the case. When H2/3 receptors are deficient, the pro-inflammatory chemistry
Immune Mechanisms
29
is too overwhelming for them. However, they discern the isolated mild signal of the injected histamine amid the frenzy of the pro-disease signals and respond to it by getting more active. A signal enables them to turn off the H1-tap. We may compare the weak H2/3 receptors with a child who passes by a huge rock that looks like a mountain for him, but picks up a small stone. The healthy H1 receptors feel comfortable within the milieu full of histamine and histaminetriggered pro-inflammatory mediators; a small dose of the injected histamine will not be strong enough to incite them to adverse activity. This is why we achieve the H2/3 effect by injecting small doses of histamine. To see how both kinds of histamine work, let us take asthma as an example. The lung tissue, if spread out, would occupy an area the size of a tennis court. The lungs have the largest number of mast cells and basophils, the main producers of histamine. Add to this the disease-promoting chemistry induced by the initial spill. Now, compare this ocean with a small amount of histamine in a syringe. Not only the small dose of diluted synthetic histamine is too mild to activate H1 receptors, but its half-life is only a few minutestime not sufficient to unleash, not to say sustain, a disease process. However, the time and the dose are enough to activate H2/3 receptors and hence, lead to the production of pro-health chemistry by all participating cells. The protective H2/3 effect opposes the H1 effect exactly in the way a healthy body does. Even though medicine operates mostly by measuring and crunching numbers to establish what is less than normal, and what is beyond the range of the normal, qualitative effects may be more important in regulatory diseases than mere measured quantities. In allergy, it is not so much the amount of the opposing chemistry that reverses the disease process, but the regulatory potency of the newly introduced mediators. For an asthma patient, it means relief of the symptoms. The degree of the improvement varies and depends on the functional resilience of these receptors and the degree of their original deficiency. The exact concentrations of histamine which activate only H2 receptors and control H1-receptor activation (from 109 M to l04M) have been scientifically established.9 The H2/3 receptors react synergistically, which means they are more effective when working together, and the H3 receptors are sensitive to even lower doses of synthetic histamine. Within a few minutes, the injected histamine starts breaking down and leaves behind only its stimulatory effect. Like a pendulum that swings for some time after it is released, the weak receptors temporarily continue their natural function of turning off histamine leakage. The length and degree of their activation
ontinuous and excessive histamine spillage from the cells that have inefficient H2/3 receptors (off
switches) produces mostly unopposed H1 effect, and this maintains histamine leakage and the disease state. Synthetic histamine, with its short half-life, much lower concentrations and independence of the pro-disease chemistry, produces only a mild signal, which leaves H1 receptors
cannot be determined by any test; they become clearly evident through observation of the patient during the course of treatment. The judgment is clinical, which means it is based on observed and reported improvement. Through careful observation, a doctor quickly gains experience on how to gauge the dose that would provide further stimuli to keep the H2/3 receptors active. Since histamine injections involve all the H2/3receptor-bearing cells, the tissues containing these cells improve their functioning. The change of the symptoms after each injection is the indicator what organs are involved in the disease. Similar to an exercise program, repeated histamine injections strengthen the receptors and enable them to oppose the negative H1receptor effect.
THE BIAS AGAINST HISTAMINE RECEPTORS IN ALLERGY MEDICINE unresponsive, but stimuBias in the description of the H1 and H2/3 receptors in lates the weak receptors allergy and related diseases is obvious: while H1 receptor is described in detail, the role of H2 and H3 which are sensitive to receptors in allergy is virtually absent from medical H2 and H3 receptors. Activation of H2/3 recepsources of the 90s. Most of the commercially available tors counterbalances or allergy medications are designed to block the activity of reduces the diseasethe H1 receptors. All antihistamines are such medicapromoting H1-receptor tions. Description of the H2 receptors is also drugeffect. Repeated stimuoriented and limited to their role in blocking excessive lation strengthens H2/3 gastric secretions, which promote the use of the H2receptors and enables receptor blockers. Yet, the knowledge exists that H2them to balance the receptor activation may enable the immune system to cellular production. control allergy without medications. Similarly, the selfinhibiting features of histamine could also help in certain gastrointestinal disorders, and this will be discussed later in the book. But making this scientific data widely known would go against the interests of the drug industry. It is no secret that the medical elite is closely connected with drug developers and depends on them for most of their research funding.10 This explains why the curative H2-receptor effect in allergy is not common
Immune Mechanisms
31
knowledge. The H3-receptor effect is also kept in the theoretical domain even though both animal testing and trials on humans are very promising.
HISTAMINE: THEORY AND PRACTICE Histamine was first synthesized by two German chemists, A. Windhause and W. Vogt in 1907, and its physiological activity was discovered by Sir Henry Dale and P. Laidlaw in 1910. Shortly afterhe histaminewards it was empirically used as a drug for asthma inhibiting ability of and allergies. Over all these years, histamine has fascinated physicians as a naturally occurring chem- the H2/3 receptors is ical and as a medication. During Sir Henry Dales obscured in the allergy time, a Histamine Club was formed to unite those literature and virtually scientists and doctors who studied and/or used never applied in prachistamine. In the 60s, with the establishment of tice, primarily because allergy as a medical branch, interest was channeled in of the financial interests involved in the widethree directions: spread sales of numerous a) allergists were busy with presenting histamine in its medications designed negative light only, developing antihistamines to only to block histamine suppress it and advertising their drugs; activity. b) researchers, using animal and human tissues, were accumulating information on the multiple functions of histamine in the body. c) practitioners, dissatisfied with conventional methods, used it in treating various allergic manifestations, for desensitization in cases of hypersensitivity, and in the treatment of peripheral vascular diseases, Menieres disease, and headache.11 Below are a few of the examples of how histamine was researched and employed. There is no precedent in the history of medicine for the establishment of an international research society that studies the activity of one (!) substance only. There are societies that focus on a disease or group of substances, but none that researches one substance. In this connection, the existence the European Histamine Research Society (EHRS) with members also from North America becomes even more surprising in light histamine has been downplayed in the contemporary medical community. The EHRS was founded in 1972 on the basis of the Histamine Club, and as its Home Page on the internet states, it unites the medical professionals who have a common love: histamine. The societys annual meetings take place in different countries, and the
speakers at the meetings include internationally renowned allergists and immunologists. EHRS even has an anthem, every line of which ends with the word histamine. Leaving out the literary significance of this song, we can state that an anthem devoted to a bodys substance is yet another unprecedented phenomenon. In 1995, EHRS was incorporated into the Inflammation Society, and its publication, Agents & Actions, changed its title to Inflammation Research. This can only make one wonder if the importance of histamine for the bodys functioning has plummeted, and if so, why this has not been reflected in basic science. The other explanation would be that somebody wanted to eliminate the very name of histamine. Thus, although the society still exists, conducts its forums, continues to study histamine (mostly theoretically), it has formally disappeared. This is a real mysteryone of many surrounding this substance. Further evidence of histamines uniqueness is the unprecedented number of antagonists, antihistamines and antacids, developed to suppress its activity. No other chemical in the body has so many versions of antidotes. The power of histamine is such that it continues to inspire the drug industry to manufacture its antagonists, which constitute the worlds largest group of medications. One of the most prolific researchers of the physiological and pathological roles of histamine was J. Parrot, the world-famous French physiologist, editor of the journal de Physiologie, and the founder of the Histamine Club. His chapter, Etiologie generale des affections allergiques, in the medical textbook, J. Charpin: Traite des maladies allergiques 1980, predicts the great success of histamine in clinical medicine. J. Parrot made a presentation before European physicians in 1980, which is only available in English as a short Summary and in a rather poor translation. Parrot said: it is possible to decrease in vivo (in a live body F.R.) the activity of (cellular histamine F.R.) or to protect the patient by injecting in him a mixture in adequate ratio of serum gammaglobulin and histamine. The mixture of histamine and gammaglobulin (a class of body protein) is called histaglobulin or histaglobin. The dose of gammaglobulin in the compound is so small that it acts rather like a solvent instead of being a biologically active, while the fixed dose of histamine is within of high therapeutic activity. Since 1959, histaglobulin has been used in Europe in hay fever, rhinitis, allergic dermatitis, and asthma, and has shown in practice and studies much better results than other medications. The proof of biological neutrality of gammaglobin in the mixture is the fact that, in the control groups, it was usually used against histaglobulin as a placebo, an inert substance.
Immune Mechanisms
33
Through the thirties and fifties, Bayard Horton, a world-renowned American neurologist, employed histamine in diseases such as vascular headaches, multiple sclerosis, Alzheimers, Menieres disease. Hortons name is assigned to two medical conditions. One of them, Hortons syndrome, has another namehistamine cephalgia (headache). So great were the achievements of this scientist that in 1988, seminars were held by American neurologists in honour of his work. Although the doses of histamine used by Horton were not homeopathic, he abided by the principal of homeopathylike treats like. He fought the excessive histamine release by injections of synthetic histamine: big fire is best extinguished by another big fire. As often happens with geniuses, Horton received posthumous acknowledgement, while during his life, he had often been ridiculed for his obsession with histamine and his belief that nature heals but histamine cures. Patients were coming to him from Texas, from Oregon and Washington, and from the mid-west to mobile home sites near the hospital, and were rolling in with their campers to receive histamine treatment.12 Yet, his 1,402 medical charts have not yet been evaluated. Hortons treatment was later revived by S. Diamond who is now world leader in vascular headaches and director of the Diamond Headache Clinic in Chicago. In the past, his team used histamine for cluster headaches in addition to other therapeutic measures and had a 40% success rate.13 Around 1989 or 1990, I saw a documentary on TV that showed the use of histamine in that clinic and wrote a letter to Dr. Diamond. Responding on August 10, 1990 Dr. Diamond and his colleague Dr. F. Freitag stated that, like myself, they had achieved excellent results in selected patients with intractable cluster headache and regretted that in the past this excellent technique was inappropriately used, which led to its falling into disfavor in the medical community. The professors wrote that they were interested in my research and would want more information on my own method of selecting patients for histamine therapy. I wrote to them that the method was described in my published article that had accompanied my first letter, and that clinical implementation of my method would require meeting personally. I received no further reply. From the flyers now advertising annual seminars conducted by the Diamond Headache Clinic for practitioners, I know that these no longer include histamine therapy. As a more recent example of the never-dying interest in histamine is the Web site of the American Council for Headache Education that in Headache
News refers to successful trials of histamine injections for migraines, which had proven resistant to other therapies (http://www.achenet.org/news/ older/101999.php). In the 60s and 70s, histamine was extensively studied all over the world on animals and people, described in articles and entered in textbooks. For instance, U. Serafini wrote in the Handbook of Experimental Pharmacology 1971 of successful histamine therapy in various allergies, including bronchial asthma.14 Extensive research laid the foundation for theoretical allergy in the late 60s and 70s in USA. This research described the roles of the cells in allergic reactions; the dual action, negative and positive, of the processes; classification of the two already discovered histamine receptors; the key role of the H2 receptor in strengthening of the protective part of immunity; the positive effect of histamine on gene expression; the indicators for the prime genetic defects that distinguish allergy patients from normal subjects. The researchers synthesized histamine congeners (analogues) and used them in patients. All this research we will discuss in detail in a later chapter entitled Histaminegate. Spectacular results of histamine testing led to assumptions that its therapeutic efficiency could surpass the efficiency of the treatment with hormones of exogenous origin (corticosteroid drugsF.R.).15 As knowledge of histamineinhibitory receptors was only in its infancy then, different hypotheses were formulated to explain its curative effect. One of them suggested that the body increases its tolerance to injected or inhaled histamine, as it does to any drug, and repeated doses can enable the patient to tolerate an exaggerated histamine release by the cells. Another hypothesis speculated that histamine stimulates the body production of internal corticosteroids, and this removes the need of their synthetic form prescribed in allergies and asthma, which are especially resistant to treatment. As it turns out, each of these ideas contains some truth. In the 70s and 80s, injectable histaglobulin was successfully employed in Europe and Japan for allergies and asthma in numerous open clinical trials and also in several double-blind studies in Japan. These significant trials are ignored because they were published in Japanese and have not been easily available. I accidentally found them among references to an article.16 Thanks to a patient of mine who was of the Japanese origin I was able to read these articles. On my request, she located them in the local library during her visit to Tokyo and translated them into English for my benefit. J-P. Girard, Chief of the Allergy Clinic in Geneva, conducted similarly successful open clinical studies as well as a double-blind trial on allergy and
Immune Mechanisms
35
asthma patients using histaglobulin.17 As in the majority of the studies involving histaglobulin, the control group received gammaglobulin as a placebo, which proves it is histamine that is the active ingredient in the combination. Since the work did not exist in English, I had it officially translated and then, submitted to Dr. R. B. Haynes, a recognized expert in epidemiology and biostatistics, professor at the McMaster University in Hamilton, Ontario, for assessment of the reliability of the data. Professor Haynes, provided a written confirmation that Girards trial had been conducted properly, which means it provided a reliable basis for therapy. Up to now, Girards clinical employment of histamine is unknown to physicians in North America, and the numerous open clinical studies carried out in a number of European countries are equally unknown. By the mid-90s, the information on histamine trials was already so well hidden that the authors of the monograph entitled Allergens and Allergen Immunotherapy18 actually asserted that histamine desensitization introduced in 1932 had been initially encouraging and designed to modulate immune functions, but its benefits could not be determined without controlled clinical trials. If the leaders in the field (Dr. R. Lockey, the author of this monograph, is an ex-president of the American Academy of Allergy, Asthma and Immunology, AAAAI) are unaware of successful trials, it is only natural that practising physicians not known about histamine desensitization and its value for patients. Ergot is known as the fungus growing on cereals and containing high amounts of histamine. It is of interest that conventional medicine uses drugs which have ergot in their name. Among them, there are cafergot and ergotamine often prescribed for migraine headaches. Studies show that if cafergot is taken long enough, the results are better than with other medications prescribed for migraine headaches. A relatively new nasal spray (dihydroergotamine mesylate) is credited with safety and efficiency for migraine. The drug is actually decades old, although not in the form of a nasal spray. Medical sources indicate histamines connection with ergot, and this makes it easy to trace the role of histamine in these medications. My reference library contains several works that indicate the importance of histamine in autoimmune disease such as rheumatoid arthritis. One of them is a chapter in Therapeutic Immunology 1996, in which a Stanford team confirms the curative role of histamine in various immune-related diseases, including arthritis. The professor of Immunopharmacology and Internal Medicine at Stanford,
K. Melmon, the developer of histamine congeners, headed the research. Although arthritis is a debilitating chronic disease of high incidence, and the situation is crying for help, nobody suggests the use of histamine therapy, and probably nobody ever will. It is astounding but true, that the second edition of Therapeutic Immunology published in 2001 no longer contains the chapter written by the Stanford scientists. Has immunology become disinterested in curing rheumatoid arthritis? Recently, interest in the combination of histamine and caffeine has been revived, and a patented drug was approved by the FDA and advertised for use in multiple sclerosis. Considering the overwhelming potency of histamine and its diverse activity in the body, one can assume it is not caffeine but histamine that produces most of the effect. Equally remarkable are the articles that document tumor shrinkage following histamine use. They describe how the physical condition improves within 57 weeks even in terminally ill cancer patients.19 Unfortunately, the authors did not make any theoretical observations to support their encouraging findings, although older information exists describing the immune mechanisms that cause the tumor-reducing effect. The lack of connection between theory and practice shows in another publication written a year later. This time, it is a purely theoretical article on the destructive effect of histamine on cancer cells.20 This work does not contain any references to earlier trials, nor does it make suggestions for future clinical trials. The positive effect of histamine on tumour regression is not that unexpected. Some conformation is already found n the findings of the Manitoba Institute of Cell Biology, Canada. Several articles of that institutes researchers state that a lasting use of antihistamines might lead to cancer. This concern is shared by the FDA.21 Strangely, physicians often learn about the concerns expressed on the highest levels of regulatory agencies only due to accidental revelations by journalists. The facts on the connection between commercial antihistamines and cancer made it into the mainstream media in the mid-nineties. However, information regarding the potentially beneficial effect of histamine on cancer is virtually inaccessible for journalists. The implication of histamines cancer-promoting role comes from yet another recent example. A drug manufacturer in San Diego developed a medication that combines histamine with a cellular chemical (interleukine Il-2). Resistance to cancer is proportional to the killer cells efficiency, and this drug, when taken in a certain kind of cancer, produced a 62-fold (!) increase
Immune Mechanisms
37
in the number of killer cells. Interestingly, it produced only a 5-fold increase with the interleukine alone. Make your own judgment as to which is, in fact, the active ingredient. Since I do not have personal experience of treating cancer, I can only speculate on the success of this combination and its potentially far-reaching implications. Some of the most compelling information can be found in the works of the worlds leading geneticists from the Harvard Medical School. They acknowledge the curative role of histamine and the protective role of mast cells by saying that histamine release from mast cells may paradoxically limit the extent of inflammatory and immune reactions via the H2 receptor.22 Moreover, on page 284 of this same article, whose research was supported by the National Institutes of Health, the writers state that histamine modulates gene expression and thus corrects the imperfect functioning of the genes! The authors specifically name allergies and rheumatoid arthritis among the diseases that may be positively affected by such a correction of gene expression. Up until now, researchers refer to this work for support. One of the most recent being a paper titled Histamine alters gene expression .23 This should not come as a surprise, since for 3 decades, it has been known that for the immune cells, histamine is the most potent stimulant of a vitally important enzyme called cAMP. This enzyme stops inflammation in the immune system. One can only wonder why no author has so far suggested the use of this simple biochemical pathway to be investigated through clinical trials. But allergists do know about the pivotal role of cAMP in allergy. We know this because the worlds leading allergists, L. Lichtenstein and S. Holgate, use this knowledge in the development of asthma medications that achieve a similar effect in a roundabout way. The drugs first trials showed low efficacy, but I am sure they will appear in the pharmacies. At the same time, the straightforward method of elevating the enzyme cAMP levels with histamine injections appears to be unacceptable to the industrymost likely because it works too effectively. Perhaps the best example of the central importance of histamine for the functioning of our body comes from the proceedings of the international conference Histamine and Disease conducted in California in 1989. Here we had yet another unprecedented eventan international event devoted to one substance only. This event resulted in a special issue of the worlds most cited medical periodical in the fieldJournal of Allergy and Clinical and ImmunologyJACI.24 High profile scientists made declarations about hista-
mines cardinal role in various chronic conditions, especially in allergies. No practical applications were suggested. (We will tell you more about this conference later in the chapter Histaminegate.) The interest in histamine did not die in the nineties, but the tendency was becoming more and more obvious to stress its negative effects and at the same time to silence its immunomodulatory and neuroregulatory ability and ignore the tools that realize it. This obvious bias did not go unnoticed by some scientists who were evidently unaware of this organized plot. Here is an example from the international journal that presents pharmacological agents, medications, and their applicationPharmacology & Therapeutics.25 The authors speak on the one hand, about histamine antagonists, which we know as the H1-antihistamines and certain antacids or H2-antihistamines, and on the other, about agonists, which, in fact, are various versions of synthetic histamine: In this article, we review the recent developments in the field of histamine research, they say. The article states that H2-receptor antagonists get the approval for their efficiency, whereas potential uses of H2 agonists so far have not led to clinical application. At this point, the authors refer to the 1982 work written, among others, by a former president of AAAI, L. Lichtenstein, who thirty years before (!) had thoroughly described the immunomodulatory H2receptor activity. On page 450, the text continues: An attractive application of H3 agonists seems to be in asthma (!). H3 agonists would reduce .the release of histamine from mast cells. This time, the reference is given to another worlds leading scientist, P. Barnes. In addition, the authors indicate that histamine H3 receptors play an important role in the homeostasis of several neurotransmitters, such as histamine itself, adrenaline and serotonin. Even one such statement makes it clear that science does know that by activating H3 receptors, histamine is able to establish not only its own balance but also the vital for health balance of other neurotransmitters. But so far, no useful applications of H3 agonists have been found, the article concludes with regret. As all these numerous theoretical works on histamine make clear that histamine, due to its bifocal property and its centrally important regulatory role in the functioning of various systems of the body, obeys the Law of Nature. According to the Oxford English Dictionary, a law of nature is correct statement of invariable sequence between specified conditions and specified phenomenon. The immense amount of available knowledge on histamines dual function and its regulatory activities is uncontested because it is based on molecular biology, physiology and pathophysiology (physiology of disordered functioning)sciences that may
Immune Mechanisms
39
change sometimes in the interpretation of the events, but rarely on the events repeatedly seen under the microscope or even with just the naked eye. Furthermore, documented clinical trials have repeatedly confirmed theory. Still, since the early 90s, allergy medicine has continuously ignored this immense body of knowledge by disregarding, silencing and actively distorting the facts that could lead to the restoration of health in millions of people. This fact is observed so frequently (as we discussed above), appears to be so well orchestrated, and is so clearly visible in the works of different authors that it is hard not to suspect what I would call a plot against histamine. The finishing touch, as it were, of this obvious conspiracy is the silent and inexplicable removal of all the material on histamines immunomodulatory properties from the recent editions of several textbooks on allergy and clinical immunology. This removal did not occur because of new findings which discredit everything known so far about histamine, but was undertaken without scientific debatequietly. Here are several examples: In 1985, the chapter written by R. Rocklin in the textbook Allergy spelled out all histamine-centered and related mechanisms of allergy. The 1997 edition of this same textbook, still used in universities, is now updated: this specific chapter has been eliminated; no revision of the discarded scientific data is reported. The 1982 textbook Immunopharmacology contained a chapter with a detailed analysis of histamine and its role in immunity; the textbook has not been reprinted. The second edition of Therapeutic Immunology excluded the only chapter contained in its first edition on the immunomodulatory effects of histamine in chronic immune diseases, including rheumatoid arthritis. In 1990, S. Hill, a renowned immunopharmacologist who specialized in histamine research, wrote the chapter Classification of Histamine Receptors in the 1990 edition of Pharmacological Reviews. In the 1997 edition, this chapter became 12 pages shorter and much less informative. The vital fact that histamine works as a modulator of the immune response, as Hill had called it in 1990, was taken out seven years later. Also gone is the idea of the possibility to use H2 agonists as immune suppressant agents, as is the fact that a number of histamine congeners (agonists) have now been produced. Stephen Holgate is one of the worlds most respected contemporary immunopharmacologists and one of the most prolific authors in this field.
Recently, he acknowledged the significance of histamine in medicine by saying that The discovery of histamine by Dale and Laidlaw in 1911 created a new scienceimmunopharmacology. This science studies the nature, chemistry, effects and uses of drugs and their effect on immunity. Histamine, according to Holgate, has stimulated the development of antagonists26 This means histamine gave a huge boost to the drug industry and doctors in drug research, and both continue to thrive on it. This also means that histamine launched Holgates career as an immunologist. For this, allergists and the drug industry thanked histamine in a perverted way: today, everything related to histamine is avoided, and its remedial features are thoroughly and purposefully obliterated. Allergology and immunopharmacology have been effectively hijacked by commercial interestsmuch to the detriment of the patients. Still, histamine is such an amazing substance that theoreticians continue to research it. In April 2002, the editors of JACI summarized the articles of interest.27 They say that histamine might have a chronic antiallergic effect, and that it it is known that histamine might exert modulatory effects on some immune and inflammatory responses. They point to the H2 receptor as the tool that causes a negative feedback effect on histamine release, which means it inhibits its own destructive over-release. The editors reference is also to the most recent publication.28 These quotes are yet another example of the fact that the knowledge on the curative properties of histamine is available, but it is prevented from entering clinical practice.
CYTOKINES Histamine is the primary mediator of allergic reactions. Among other participants, there are also cytokines. This term has recently become an inherent part of immunology. The word comes from the Greek, where cyto means cell, and kinesismovement. Cytokines are products of the immune system; they are proteins released by immunocompetent cells. They provide kinesis, the dynamics in the cells and among cellular mediators. In a broad sense, the words mediators and cytokines are interchangeable: both denote cellular chemicals taking part in immune reactions. The difference is that cytokines are regulatory chemicals, choreographers rather than the actual dancers in the ballet called allergy. In different immune diseases, there are different choreographers, but they always preserve their guiding role. Cytokines can be roughly divided into two groups: disease-promoting and disease-inhibiting, or, as science calls them, pro-inflammatory and anti-
Immune Mechanisms
41
inflammatory. When they are released into the extracellular space, their presence works as a command telling cells what to doto carry on with the state of illness or to undo that process. The amount, kind and activity of cytokines determine which way the course of the disease will turn.
ellular products HISTAMINE-INDUCED CYTOKINES carry certain Cellular production of chemicals is an interdependent process. Profuse histamine release announces the messages and are called beginning of an allergic reaction and induces various mediators. Those chemical events. Like all mediators, pro- and anti- mediators that direct inflammatory cytokines are brought to life by the reactions are called original excessive histamine spill. Allergy medicine cytokines. The origin even named the two central groups of cytokines hista- of chronic immune mine-induced suppressor (or inhibiting) factors (HSF) diseases lies in the defiand histamine releasing factors (HRF), with the word ciency of antiinflammafactor as the substitute for cytokine. These two groups tory cytokines. The provide opposite effects during allergic reactions. An course of the disease allergic reaction is maintained through the prevalence depends on how of histamine releasing factors. As the term indicates, prevalent the prothey increase histamine release and hence, the cascade inflammatory cytokines of disease-promoting chemistry. Histamine releasing are over the anticytokines are produced by various immunocompetent inflammatory ones. cells when their H1 receptors are activated by histamine. Histamine-induced suppression works in the opposite direction: it reverses the disease process by inhibiting the liberation of histamine and histamine-related pro-disease chemistry. By calling these cytokines histamine-induced factors, science acknowledges that their formation is secondary to the histamine effect. Regrettably, the word induced is mostly omitted, which changes the meaning and correspondingly, the understanding of the notion. The use of the word induced indicates that those factors activated by histamine cause the suppression of histamine in its harmful function. By not using this terminology, one hides the original induction and also subsequent remedial role of histamine. The production of suppressing factors is induced when histamine activates the H2 receptors. The prime generators of suppressor factors are, as the name tells us, T-suppressors. T-suppressors possess a major regulatory influence in allergy, wrote R. Rocklin who discovered the first suppressor factor in 1977.29,31 His chapter in Allergy 1985 indi-
cated on page 176 the overwhelming importance of these cells as well as their product, the suppressor factors, for controlling allergic processes. On page 182, the author emphasized the fact that histamine is the originator and regulator of both pro- and anti-inflammatory effects. I referred to this chapter as being central to understanding allergies, and speculated that its elimination from the 1997 edition of the textbook was probably intentional for reasons totally unrelated to good medicine. As the law of homeostasis dictates, the ratio of histamine-induced proinflammatory to anti-inflammatory cytokines determines health. The universally known medical textbook, Harrisons Principles of Internal Medicine, which is published in new and updated editions every two years, stated the following already back in the 1987 edition: complex cellular interactions involve a delicate balance among positive and negative influences and ultimately result in expression of an appropriate immune response. The slightest imbalance in these immunoregulatory circuits may result in aberrant immune function leading to clinically apparent immune-mediated disease (p. 334). If the consequences of the slightest imbalance are that serious, the damage caused by disregarding a major imbalance of the pro- and antiinflammatory cytokines can hardly be overestimated. Once the topic was considered so important that an award-winning work covering the cytokines as the missing link in understanding allergies was presented at the AAAIsponsored lectures for post-graduate courses.30 We do not hear about this anymore. The interrelationship of histamine and the cytokines is further proof of natures wholeness: not only does the histamine spill lead to their release, but, in turn, the release of cytokines affects the further leakage of histamine. Thus, pro-inflammatory cytokines contribute to further histamine release, while anti-inflammatory ones inhibit it. A simplistic comparison of the interdependence would be a can of sardines in oil: sardines acquire the taste of the oil, while the liquid tastes of the fish.
HISTAMINE-INDUCED SUPPRESSOR FACTORS In allergy, there can be no recovery without histamine-induced suppressor factors. The first such factors were described in the 1970s by R. Rocklin and K. Melmon, then the worlds leading immunologists specializing in histamine. The ability of these cytokines to control allergic reactions proves the self-remedial effect of histamine, and the fact that they are primarily the products of
Immune Mechanisms
43
T-suppressors, proves the protective role of these cells in allergy. The central role of the histamine-induced cytokines in reversing allergic disease and bronchial asthma was confirmed by a number of eminent authors, and Dr. A. Kaplan, the editor of the two editions of the textbook Allergy and the 2003 President of World Allergy Organization, is one of them. In 1991, Dr. Kaplan was a member of the team that istamine, being a made a presentation at the 47th annual meeting of the substance of dual American Academy of Allergy and Immunology on activity, produces both histamine-induced cytokines. In that presentation it pro-inflammatory and was observed that: an imbalance of these factors may anti-inflammatory chemplay a role in the pathogenesis (mechanisms) of istry. The proportion disease in which histamine is an important mediator, of histamine-induced and these factors are an important regulatory mecha- protective and histanism in the releasability of histamine.32 Four years mine-induced diseaselater, this same team of authors again covered hista- promoting chemistry mine-induced cytokines as important participants in determines control or the chemical war in allergy. The views expressed in progression of allergic that article are consistent with the views on any war: reactions. The producvictory is achieved only when the less powerful party tion of histamine and succumbs to the more powerful one. The article histamine-induced admits that the ratio of histamine releasing factors to cytokines is interdesuppressor factors may be critical to pathogenesis of pendent. a wide variety of allergic and rheumatic diseases, and that it may determine the level of inflammation observed in allergic disease.32,33 Since histamine induces the production of both the pro-and anti-inflammatory chemistry, it controls the border between health and disease. This puts histamine into the very centre of allergic reactions. Equally important is also the fact that histamine plays a critical role in another group of immune-related diseases, namely the rheumatoid kind. Logically speaking, allergy should look at the two viable ways of preventing or aborting an allergic reaction, namely curb the activity of the disease mediators or increase the production of the protective factors. But it seems that the logic of allergy has become the servant of the drug manufacturers. At present, the protective regulatory cytokines that inhibit the pro-inflammatory activity without medications are hardly ever mentioned even in theoretical textbooks. Clinical allergy focuses totally on restraining the pro-disease chemistry, choosing to develop suppressors to each mediator and cytokine. As there are
legions of pro-inflammatory mediators, there may well be the opportunity to develop legions of suppressive medications. Strange things started to happen since the early 90s. T-suppressors that synthesize histamine-induced suppressive factors have disappeared from textbooks on allergy as well as from reports presented at international symposia. With the only remaining view of histamine as a villain and the health promoting abilities simply ignored, one cannot expect that there will be any discussion on how to increase the release of the protective cytokines. In The Cytokine Handbook of 1998, which has over 1000 pages, histamine induced suppressor factors are mentioned only in the abbreviated formHSF. This makes no sense at all because the text contains no indication what this abbreviation means. Its role and connection with histamine are also not mentioned. In 2001 an international workshop claiming to be state of the art was conducted in collaboration with the World Health Organization and sponsored by the AAAAI. This event serves as additional proof of the biased attitude of the medical establishment towards the cytokines in allergy.34 It stated (page S182) that for didactic reasons, only pro-inflammatory cytokines are discussed. No explanation is given what the didactic reasons for the exclusion of the suppressive factors are. To conceal the protective abilities of the immune system merely serves to make the cure for allergy and asthma ever more elusive.
T-SUPPRESSORS AS THE PRIMARY DEFENCE AGAINST ALLERGY T-suppressors work solely through the stimulation of the H2-receptors; defending us, unlike other immunocompentent cells that work depending on the circumstance.35 The scarcity of the H2-receptors or their inactivity cause suppressors to be deficient in their function. Only when these receptors are prolific and active, T-suppressors can be considered useful and only then are they able to actively participate in immune reactions and regulate the homeostatic activities of the participants. Like the hard drive of a computer, they retain the memory of how to reverse allergic reactions and guide subordinate functions. The size of this memory is highly individual and may last for up to 20 years. Can you imagine having a chance to live for 20 years without allergic symptoms? Can you imagine the financial losses of such a development for the drug manufacturers? Lately, allergy medicine has become a most puzzling field: well established knowledge disappears from debateand strangely, it seems to be mainly the
Immune Mechanisms
45
one which is most critical for recovery. Thus, recent textbooks and periodicals avoid the word histamine, and only occasionally, one may find out that there is a mediator called histamine. The fact that it is an autacoid, or a healing substance, can only be discovered if one is curious enough to undertake a purposeful, detective-style investigation through ince clinical the older literature on allergy. The protective function immunology (or of histamine H2 receptors in allergy is found in sources allergology) conceals on molecular biology or genetics. On the contrary, the negative effect of H2 receptors on the production of the anti-inflammatory gastric secretions is emphasized in textbooks, periodi- properties of histamine, cals and pharmaceutical compendia, obviously to it is only natural that it support the need for the overwhelmingly popular would also conceal the receptor-suppressive medications (zantac and pepcid). existence of histamineThis development is taking place in spite of the induced anti-inflammafact that medical science has shown that the tory cytokines and their T-suppressor cell is a unique cell with a unique func- primary producers, Ttion; that these cells are the key clues to the regula- suppressors. Thus allertion of function in the immune system, and provide gists totally disregard a functional cadre of T cells that act to downregulate the bodys own ability the immune response.36 In the past, allergists also to produce regulatory admitted that The suppressor cells abnormalities disease-fighting observed in allergic subjects may reflect a primary cytokines and never defect inherent to the atopic diathesis (allergy) seem to even think of (Allergy ed. by A. Kaplan 1985: 190). As was said, the activating their producchapter that stated this is gone from the second edition tion. Instead, they work of this textbook. With the disappearance of all these on the development of histamine-connected phenomena, gone is the under- numerous medications standing of what allergies and asthma are, and what that could suppress the should become the target for therapy. This explains why multitude of pro-disease cytokines. the conventional therapies are not successful. Interestingly, all allergy-related articles that simply cannot avoid references to T-suppressors usually call them CD8+ cells, but never identify them as suppressors. Calling them CD8+ effectively hides their protective role, since this term comprises two kinds of T-cells, not just T-suppressors. The abolishment of suppressors urgently needs a scientific justificationespecially so because on the cellular level, the regulatory role of T-suppressors can be compared to that of the heart or brain.
H2 AND H3-RECEPTOR EFFECT The growth and efficiency of H2-receptors are due to histamine stimulation, and there is a quantitative and qualitative aspect to both. The increase in the number of those H2 receptors indicates that more underdevelwhile on the cellular, it oped cells turn into efficient suppressors and thus is inactive T-suppressor multiply the defending army that promotes health.37 Histamine injections intensify the activity of these cells. Active molecules of the H2 receptor receptors by providing repeated signals. Science teaches promote the developthat the presence of the H3 or H2 receptors might alter ment of suppressors and susceptibility to H1 effects.38 In other words, histamine enable them to reverse hyperreleasability (the H1 effect) can be inhibited by allergic reactions. causing the H2 and H3 receptors to work together T-suppressors mature synergistically, for together they are even more only with activation of powerful; this is the H2/3 effect. So far, no H3 receptors H2 receptors, and this have been found on T-suppressor cells. However, mast makes these cells insepcells and neurons have both H2 and H3 receptors. As arable from histamine. was said before, H1 receptors need strong signals, The secrecy surrounding whereas H2 and H3 receptors respond to low concenthe remedial properties trations of histamine. So, through gentle stimulation of histamine has resulted with injected histamine, the number of H3 receptors on in the disappearance of immunocompetent cells and neurons grows, and the T-suppressors and H2 combined H2/3-receptor efforts amplify the diseasereceptors from scientific fighting activity. These facts and the potential for gene sources on allergy. modulation through the activation of the H2-receptors offer great promise for those chronically ill allergy patients who do not benefit from conventional therapies whose numbers are growing at an alarming rate. Very few doctors are aware of these scientific facts. Even in the 70s and 80s, when the functions of the H2 and (later) H3 receptors were first described, their protective effect was never made known for therapeutic application. In 2001, at an international workshop covered by the Journal of Allergy and Immunology 39 the H2 and H3 receptors were casually mentioned, but again, their protective functions in the immune and nervous systems being omitted.
n the molecular level, the primary defect in allergy patients is their underdeveloped H2 receptors,
Immune Mechanisms
47
Of course, it is difficult to involve all scientist into and H3 receptors the this concealment of important knowledge. 2perform a histaOccasionally one stumbles upon revelations such as this one where the truth, once again, peeks out unex- mine-inhibiting and antipectedly: Interestingly, in the 1980s, R. Rocklin and inflammatory role. The co-workers published several studies showing (that) combined H2/3 effect histamine-induced suppressor-cells activity and could oppose H1suppressor factor We can speculate that this factor receptor activity, stop might have been IL-10 (interleukin10, the recog- histamine spill and the nized key anti-inflammatory cytokine in allergy subsequent chemical F.R.). In summary, our data, considered in the reaction, and by that, context of these and other studies, strongly suggest relieve allergy sympthat histamine, apart from exerting potent effector toms. Basic science functions in inflammation and allergy, mainly via H1 has provided all the receptors, may have important immunoregulatory supporting data, but functions via H2 receptors expressed on immune clinical medicine does cells.40 Contemporary allergy keeps the following not teach them. It appears to conceal this facts secret, namely that knowledge purposefully. there are histamine-induced suppressor factors; the mysterious Il-10, the central cellular cytokine in controlling allergic reactions, is such a factor; T-suppressors are the main producers of these factors. Allergists have buried the curative mechanisms of the allergic part of our immune system, turned it into an enemy, and made it a convenient target for countless drugs which are only inhibitors.
H1 SUPPRESSION VS. H2/3 ACTIVATION You may ask why we should care what we use to treat a patient, antihistamines for blocking one kind of receptors, or histamine to stimulate two others, since the result is the samesuppression of an allergic reaction. Let us compare these approaches:
H1-receptor blocking Disrupts histamine messages and, as a consequence, reduces its activity not only in the allergy-participating cells, but also in all parts of the body, thus preventing their normal functioning. Requires regular drug replenishment due to its brief effect.
H2/3-receptor stimulation Restores normal functioning of all cells that have these receptors without disrupting H1-receptor messages.
Allows the body to function normally for a long time and eliminates the need for regular drugs. Rectifies the source of the problems strengthens the inactive H2/3-receptors. Alleviates the symptoms due to the restored ability of the cells to function properly.
Does not eliminate the main cause of the symptomsH2/3-receptor inactivity. If blocking is successful, it creates the illusion of good health while allowing the defect to deepen.
Just looking at the table, one can clearly see the advantage of the stimulatory effect over suppression. Why is it that modern medicine does not introduce the simple, biologically preferable approach of H2/3-receptor activation into clinical practice? Why, instead, would medicine insist on suppressing the activity of the H1 receptors and disrupt their needed messages throughout the body? The reason is simple: the slightest possibility of permanent or lasting correction of the functional genetic error endangers the profits of the drug market.
THE INTRACELLULAR ENZYME CYCLIC AMP Receptors are conductors relaying the messages of the substances that activate them. To be transformed into an action, these messages need fuel, and intracellular enzymes are this fuel. Enzymes are protein molecules that catalyze or inhibit chemical reactions. They are responsible for the energy of the cellular lab, its production and operation. One enzyme is of special importance for the whole body functioning and especially on behalf of the immune system. It is called cyclic AMP (cyclic adenosine monophosphate), or simply, cAMP.
Immune Mechanisms
49
It plays the key role in the activity of many hormones. he primary defect in allergy is H2/3The general perception is that the notion of hormone is applied solely to the products of endocrine glands, receptor inefficiency. and originally, medicine did use this word in a limited Blocking the efficient H1 meaning. Over time, the scientific term hormone has receptors by antihistaexpanded to cover any chemical able to produce wide- mines and other convenspread, regulatory effects on particular cells, both tional medications is locally and anatomically remote. When the effect is much less effective than systemic we consider it to be a systemic effect. stimulating the ineffiHistamine, for instance, is a local hormone that invokes cient H2/3 receptors due local as well as systemic effects. Hormones are the most to the brevity of the potent substances, which determine the work of all symptom relief and the organs and systems. The fact that the effectiveness of disruptive effect of so many hormones depends on the levels of cAMP these drugs upon the makes this enzyme so vitally important. Over 90% (!) cellular network. Only of the immune systems work depends on cAMP, activation of H2/3 receptherefore lower than normal quantities of this tors allows us to achieve enzyme predispose a person to certain immune a lasting relief or cure. diseases. As might be expected, it is only natural for Allergists prefer the medicine to research what body chemicals can effec- strategy of blocking the tively increase cAMP, and for the drug industry to H1 effect rather than develop medications that would reproduce the effect stimulating the H2/3 effect. Coincidentally, of these chemicals. There is special relationship between histamine this strategy provides and cAMP. Histamine is not just another local great and reliable hormone whose activity depends on cAMP. There is a revenues for the pharreciprocal interdependence between the enzyme and maceuticals. histamine. Histamine is recognized to be the most potent stimulant among the substances able to raise the levels of cAMP. Its signal sent via H2 receptors activates cAMP, and the enzyme, in turn, starts a chain of chemical reactions that engage the genetic material. The messages from the genes facilitate generation of defensive chemistry. Most authoritative sources affirm the histamine/cAMP interdependency and call for using this feature in the development of therapies. The best reference in this regard would be the universally used textbook Harrisons Principals of Internal Medicine. Already in the 1980s, it emphasized the real importance of cyclic AMP for medicine as a tool in understanding normal and pathologic regulation
rotein molecules called enzymes form the intracellular fuel that transmits messages relayed by different substances via their receptors. One such enzyme, cyclic AMP, is vital for the normal functioning of the cells in numerous organs and systems, and especially for the immune system. Science recognizes histamine as the primary activator of cAMP in immunocompetent cells. Histamine uses H2
receptor for communication. In theory, medicine recognizes the histamine/cAMP relationship as the key mechanism for reversal of immunerelated inflammation. However, these scientific facts have not had any effect on drug production.
and in developing new drugs (p. 374) and pointed to the H2 receptors as the route for elevating this enzymes levels. Excerpts from an international periodical devoted to drug research may serve as another example: stimulation of the H2 receptor leads to a massive production of cAMP. The H2 receptor is primarily coupled to the production of cAMP. Numerous reports have shown that histamine increases the levels of cAMP. The same ideas are developed in the earlier quoted work by a world-renowned geneticists who also point to the H2 receptor as a conductor of histamine messages that stimulate the enzyme and through it, regulate gene functioning: the activation of histamine H2 receptors results in generation of cAMP41,42 And as a final example, I will refer to the most recent work with the self-explanatory titleHistamine regulates cytokine productionwhich indicates that nothing has changed in basic sciences within the past three decades since the discovery of cAMP/histamine interdependent friendship. The article compares histamine with other activators of cAMP and states: none of the mediators of allergy has any comparable antiinflammatory cAMP-mediated effect.51
ALLERGY AND THE cAMP/HISTAMINE TEAM First, allergies are immune diseases, and cAMP is the central enzyme responsible for the proper functioning of the immune system. Second, allergies are caused by the excessive production of histamine. Therefore, the histamine/cAMP team and H2 receptorwhich is the connecting wire between the twoacquire extraordinary importance when we want to control allergic inflammation. The first evidence implicating cyclic AMP in control of leukocyte function goes as far back as 1968 when it was presented by two authors, one of whom is a former president of AAAI, L. Lichtenstein, the scientist who studied the cAMP/histamine interrelationship most extensively. There it is stated that the basic biochemical defect in allergy
Immune Mechanisms
51
patients is lower than normal levels of cAMP: if leukocytes or mast cells of asthmatics accumulate lesser amount of cyclic AMP than do the same cells in normal subjects, physiologic control of the release of inflammatory mediators might be deranged.43 All of this shows the lower than normal level of cAMP in allergy patients; the need to elevate it in order to diminish the intensity of allergic inflammation; the agent that increases the level of cAMPhistamine; the route through which histamine conducts the messageH2 receptor; the result of the implementation of the histamine-sent messagereduction of the immune inflammation; the cause of allergic inflammation eliminated by H2-receptor messages exaggerated histamine release. esearch of leading We must admire the authors who did this intensive allergists concludes research and wonder why none of this has been transferred to clinical allergy practice over the past three that histamine messages decades. Practical use of this information could rid delivered by its H2 millions of allergy and asthma patients of needless receptor intensify the activity of cAMP, the suffering. enzyme needed for the normal functioning of CORRECTING GENETIC FUNCTIONING WITH the immune system. The CELLULAR HISTAMINE Let us see how the messages of intracellular histamine primary biochemical reach the nucleus of the cell. Genetic functioning defect in allergy occurs in DNA (deoxyribonucleic acid). Today, patients is low levels of everyone knows that DNA is the carrier of the hered- cAMP, therefore histaitary biological material in all organisms, the major mine messages become constituent of genes. RNA, another acid (riboxynu- vital in raising these cleic), is at the service of DNA, and both constitute levels. Accumulation of genes. RNA creates templates for protein synthesis. cAMP results in the The part of RNA called messenger RNA instructs the production of protective cell what proteins to produce and in what amounts, chemistry by the which places messenger RNA at the centre of the immunocompetent cells, genetic performance. Now, it so happens that cAMP is inhibition of excessive the principal enzyme that regulates the synthesis of histamine release and messenger RNA, and through it maintains the opera- hence, reversal of tion of a large number of families of genes. These allergic reaction.
include the genes responsible for the function of the immune system, the brain, the lungs, the skin, the skeletal muscles, the heart, the endocrine glands, etc. Mother Nature never fails to surprise us, and cAMP is one of her greatest surprises. Not only does this enzyme always protect the body, but it is also flexible in its performance; therefore, depending upon the bodys need, cAMP may suppress the disease-promoting activity or activate the production of the disease-suppressing chemistry. Activity of this enzyme determines the fighting ability of the immune system. Nature combined the two miraclescAMP and histamineinto one unit to work for us. It really is a marvellously simple scheme: histamine, via H2 receptor generates cAMP, which in turn regulates the performance of the genes, and that results in a wide range of anti-inflammatory chemistry and disease-fighting effects. Working together as a pump that provides genetic fuel, histamine and cAMP form the backbone for signal transduction, cellular production and the subsequent cell-to-cell talk. The fact that histamine can change the functioning of immunocompetent cells and neurons permitted science to call histamine an immuno- and neur-omodulator. However, there is more to histamines miraculous features. All operations in the body are genetically driven, and this gene activity together with its subsequent effects has a name: gene expression. Histamine is capable of reaching the heart of the cell, and influence genetic functioning. In order to do its healing work, histamine needs as a prerequisite functionally adequate H2 receptors which provide the natural pathway for histamine messages to reach the genetic material. As we know, allergy symptoms are the result of the weakness of this very receptor.
THE PRIME DEFECTS IN ALLERGY We named several important defects known to exist in allergies: H2-receptor inefficiency, mast cells/basophil hyperreleasability, T-suppressor scarcity/ inefficiency and low levels of cAMP. How can it be that so many defects are of central importance? The explanation is: they are found on three different levels, but they stem from the same root. All three are the links of the same chain, and all three can be restored simultaneously if the target is properly selected. Here is a summary of what makes allergy patients different from healthy individuals, and how the deviations can be corrected.
Immune Mechanisms
53
All the defects are of GENETIC originmalfunctioning of the genes affects the protective aspects of istamine messages immunity, such as the allergy-participating cells, their via the H2 receptors receptors and products. In the absence of genetic activate the enzyme flaws, most of the effects of the environment on the cAMP. This enzyme production of symptoms are brief. This fact makes the ignites a chain of intrainner causes that require correction primary in impor- cellular chemical events tance, and the outer triggers secondary. that reach the genetic The first level is BIOCHEMICALpre-existing low material and change the levels of the enzyme cAMP, which provides fuel functioning of the genes for the operation of the defensive forces of our known as gene expresimmune system. Without this enzymes induction, sion. Successful correcthe balance shifts, and the overreacting immune tion of gene expression forces prevail. results in those The second level is MOLECULARhere we may corrected messages to find deficient, synergistically working molecules be transmitted to the called H2 and H3 receptors. This may cause an cellular lab. This brings inactivation of the enzyme cAMP, because this about normalized enzyme becomes activated only by healthy histacellular production, and mine messages via the H2 receptor. the end of allergy symp The third level is CELLULARhere a defect manifests, toms. To be able to first of all, in the mast cells/basophile high histadeliver stimulatory mine releasability and T-suppressor inefficiency, messages, these recepboth resulting from the H2/3-receptor inefficiency. tors must be efficient To correct the defects at all the levels, one should acti- and functional. vate H2 and H3 receptors with injections of histamine. Their synergistic operation will raise the levels of cAMP, inhibit histamine release from mast cells and basophils, and generate and activate T-suppressors. The understanding of the prime defects in allergy and asthma can then lead to a proper management of these diseases. Treating allergy and asthma is relatively easy when these principles are applied. This is not useful to the pharmaceutical corporations.
SYNTHETIC HISTAMINE IS A NATURAL GENE MODULATOR The most effective way to treat chronic diseases would be to change the functioning of the faulty genes. Todays genetic engineering is a technical procedure, in which undesirable parts of the genetic material are substituted with
he lasting correction of the gene expression
through histamine injections can be called gene modulation or natural genetic engineering. Unlike the more controversial and incomparably more complicated technical procedures, this is safe and efficient. Modulation of allergy-governing genes restores the functioning of the relevant cells with the subsequent control over the release of histamine and histamine-induced chemistry in a sustained way. Although many diseases, in which cAMP plays a role can be treated this way, allergies and a number of related conditions could gain maximum benefit, as their cause is excessive histamine release, and control over that release ends the disease. Three things make histamine a gene modulator of choice in immunerelated diseases: 1) its unique ability to activate cAMP; 2) its availability in synthetic versions; 3) its safety and low cost for society and for the patient.
the ones that are supposed to function better. The process is complicated and contains numerous ethical and legal problems. If medicine could duplicate natures methods by non-intrusive correction of functional defects, it would achieve the desired results in harmony with nature. Correction of gene expression is ultimately an attempt to imitate Nature. One can also call this gene modulation, a kind of genetic engineering. Implemented via histamine injections, it would be much safer than the invasive, unpredictable and technologically complex manipulation. It has already been tested clinically. Simplified, the scheme of allergic and other histamine-based diseases looks like this: the H2 receptor, genetically underdeveloped, is unable to 1) turn off the histamine spill by mast cells and basophils; 2) generate active T-suppressors for efficient defence; 3) accumulate cAMP. Gene modulation should come as repeated activation of the inefficient H2 receptors by histamine injections. This would lead to an accumulation of cAMP in all Hreceptor-bearing cells as they form a histaminergic system that transmits the histamine effects all over the body, including the genes. The team work of histamine and cAMP is especially beneficial for the tissues that have the most dense distribution of cells with the highest histamine productionsuch as the lungs, the skin, the nasal passages, the brain and the gastrointestinal tract. Lasting remissions in allergies, asthma, vascular headaches, irritable bowel syndrome, etc., following histamine therapy suggest that the relevant genes are functioning properly again. In my practice, I saw every day how gene modulation through histamine injections worked. I can attest to the truth of the statement made by Bayard Horton, also convinced of the efficacy of histamine therapy. He observed that histamine can make the lame walk, the
Immune Mechanisms
55
deaf hear, and the blind see. I know. I have seen it happen. More miracles in my experience have been wrought with histamine than with all other therapeutic procedures combined.44 Gene modulation in allergies and related diseases could be standard practice if only clinical immunologists employed the findings of their own research. However, they withhold the theoretical knowledge of all curative properties of histamine to prevent the use of its synthetic analogues in a clinical setting. Allergy medicine bears full responsibility for sabotaging the main task its professional status requireshelp its patients.
THE STIMULATORY APPROACH Medicine in general and clinical allergy specifically are based on symptomsuppressive medications. However, it would be wrong to say that medicine is completely devoid of drugs that stimulate protective cellular activity. Imitrex, a drug used to alleviate migraine headaches, is one example of highly praised family of medications able to relieve headaches that do not respond to the strongest pain blockers. How do Imitrex and similar drugs work? According to the law of homeostasis, when the level of any substance in the body rises, its further production is inhibited by the control mechanisms. As the existing theory states, migraine headaches occur due to an excessive release of the brain chemical serotonin. All migraine medications are, actually, painkillers. They block receptors passing messages of pain. Imitrex is a type of a serotonin analogue. It stimulates serotonin-inhibiting receptors, and the inhibition temporarily relieves the headache. The synthetic analogue pushes the button which the cellular serotonin, though in excess, could not push. There is an analogy in the performance of histamine and serotonin. Compare:
Histamine Excess of histamine causes allergy and related symptoms (including migraine headache) Injections of synthetic histamine restore the balance of internal histamine. Serotonin Excess of serotonin causes migraine headaches
Injections of imitrex (a serotonin analogue) restore the balance of the internal serotonin
Imitrex been universally accepted and has also received the highest pharmaceutical award as the best medication of the year. By contrast, histamine, even though it has many similar properties, has been resisted by the highest. This attitude to medications has deep social roots.
MEDICINE AS PART OF THE ECONOMY Our socio-economic philosophy provides the answers to all the questions surrounding histamine. Medicine is a major sector of our economy. Treatment of patients makes medicine a consumer product. Our society has come to expect ever-increasing profits from all businesses regardless of the field of endeavour. The health sector must be profitable too. Like any other sector, medicine has its producers and consumers. Leading medical professionals are involved in drug research, development and testing, and are, thus, interested in expanding the drug market. The rising incidence of allergy, asthma and related diseases creates the most favourable conditions for that, since the existing remedies are, at best, only temporarily helpful and therefore become products of daily use. The trend towards an increase in drug consumption provides the basis for skyrocketing revenues. Your interests, as a customer, are in conflict with the interests of the producers because you want to get an inexpensive, and, even more important, long-lasting or possibly even a curative product. Yet, such products reduce the market demand. From the standpoint of market economy, histamine is not a profitable drug. There are several reasons why synthetic histamine, unlike Imitrex, is doomed. First, Imitrex regulates serotonin production but leaves histamine, which is superior to serotonin, unregulated. Therefore, Imitrex and the newer Imitrex-like drugs are able to relieve ONE migraine attack. The duration of relief is different in different migraineurs. Another attack may start hours after and necessitate another dose. Cost of an Imitrex injection is about $50 Canadian dollars. Histamine may provide lasting regulation of its own production and lead to the regulation of the synthesis and release of the dependent serotonin. Histamine therapy rectifies the core chemical imbalance and thus allows the patient a long, medication-free period, while Imitrex tackles the secondary events. If the regulatory switches for histamine, the H2/3 receptors, are resilient by nature, it is possible that the patient may never again have migraine attacks. The present cost of a full course of histamine therapy would be somewhere between $20 and $100 Canadian dollars, depending solely on its availability as controlled by the drug companies.
Immune Mechanisms
57
hile drug developers Second, Imitrex and similar medications for successfully use migraine have been patented by FDA as new drugs, and this provides a great future for the producer in stimulation of inefficient terms of revenues. Histamine, on the other hand, has receptors to temporarily been on the market for almost a century, and there- regulate other body fore, no patent is needed to start producing it. No chemicals, they never do it with histamine. The patent means no profit for the producer. Third, the use of Imitrex is limited to migraines, wide range of immunowhereas histamine is highly effective for all sorts of logical and neuroregulavascular headaches, plus allergies, asthma and a tory effects produced by number of immune-related diseases. This universality histamine injections is may eliminate the need of numerous medications not employed by clinical after a treatment course with histamine injections and allergy. basically ruin the drug industry. Histamine as a conventional drug? Never, say the drug producers that provide sprays, pills and ointments for allergies and asthma, and painkillers for headaches. The drug developers have formidable power because they can pay for the best minds.
DUALITY IN NATURE An observation that may be worth exploring at this point is the logic of natures laws and the logic of histamine therapy that goes along with it. Let us speculate on duality. Everything in life is dual: life and death, love and hatred, health and disease. This has been depicted through the centuries in the two-faced god Janus, or Yin /Yang symbols, and in the eternal fight of Good and Evil. Opposing chemical processes co-exist in the body at any given moment, and the state of health vs. disease is determined by the prevalence of one over the other. For example, as long as the formation of new cells exceeds their degeneration, the body grows and develops. When degeneration takes over, ageing starts. Take another example. If the bodys consumption of food is well regulated by metabolism, we keep our weight under control. As we age, we become prone to gaining weight even with the same food intake. This happens because age wears out the mechanisms that regulate our metabolism, and it slows down. To stay in good shape, we should either reduce our food consumption, or boost the bodys chemical processes by exercise, or, better, do both. Balance is the answer to all problems. In a healthy body, balance is achieved through its innate autoregulatory mechanisms and systems. However, whenever damage does occur, relief
should come from fixing the processes, rather than using artificial, unreliable, or collateral means. Therefore a change in exercise level and diet is a better response to weight gain than the consumption of appetite-suppressing pills or radical stomach stapling. However, anything bad that does not exceed the bodys ability to overcome it, presents a challenge to the protective forces and keeps them active. For instance, the fight against a virus teaches the immune system how to defend the host if the virus repeats its attack. The virus expands the protective memory of the immunocompetent cells. In the same manner, any good possesses seeds of the bad. The bodys processes are never unilateral, moreover, bad and good ones go on simultaneously. Here is an example of a natural duality: a small sliver gets under the skin. To destroy it, immunocompetent cells specialised in fighting foreign bodies rush to the site, gobble it up and turn it into pus in the process. On the one hand, pus is the product of this protective activity, on the other, its potential release into the blood and lymph flow harbours danger such as a secondary generalized infection or sepsis. With the genes, this pattern of duality is also found in the actions of effectors and repressors. While the first kind gives instructions to the cells what chemicals to produce, the second type moderates the effectors activity. In many chronic illnesses, genetic changes are functional and therefore potentially correctable. The effector gene messages depend on the messages of the repressor. The H1-receptor effect implemented by T-helpers becomes overwhelming only if the counterbalancing H2 effect is inefficient. The duality of allergic reactions can be easily proven: allergy patients suffer but rarely die because the power of the pro-disease forces in the body is not absolute, and the defensive forces, though weakened tends to carry the day. The inborn ability of cellular histamine to stimulate both positive and negative forces is yet another confirmation of duality in allergy. Some effects of histamine are pro-inflammatory whereas others are anti-inflammatory, said a pioneer of histamine research, R. Rocklin.45 Thus, although histamine spill from mast cells initiates an allergic reaction, histamine release from mast cells may paradoxically limit the extent of inflammatory and immune reactions, and reduce the levels of pro-inflammatory cytokines.46 Duality is a law of nature especially applicable to such self-regulatory systems as the immune system. To ignore this is to defy nature itself. By presenting immune mechanisms in allergy as a unilateral process, allergy justi-
Immune Mechanisms
59
fies the one-sided approachsuppression of the evil forces. Modern allergy disregards the ability of the same immune cells to fight for us.
DUALITY AS A TOOL OF ALLERGY TREATMENT Allergic diseases are different from other immune diseases, in which we deal with physical obstacles. For example, in cancer, we deal with a tumor that must be shrunk; in rheumatoid arthritis, degeneration of tissues must be reversed, etc. Allergy, in contrast, is a purely chemical imbalance that can be changed, often in seconds or minutes. Spontaneous relief from a bout of sneezing or an asthma attack is achieved. Unless allergy has advanced so far that secondary degenerative changes in the lung tissue take place, asthma is the most reversible immunologic disease. Lasting drug-free remissions in asthma or other allergic diseases are proof. It is hard to overestimate the harm of the latest tendency to present allergies, and especially asthma, as a disease of structural changes in the tissues, similar to wound-repair processes. It is tragic, that today, we have diseases that can in many cases be reversed or greatly improved presented to the public as being conditions with irreversible organic changes. Since the body is erroneously thought of as lacking its own remedial tools, we are offered only harsh suppressive methods and even surgical procedures. Allergic diseases are diseases of hypersensitivity, and histamine duality is their essence. They can be compared to balancing scales with one pan full of disease-promoting mediators and the other, with disease inhibitors. In order to balance the scales, we can reduce the over-weighted scale H1 or increase the load on the under-weighted scale H2/3. The overloaded scale H1 would require constant support because of the seething histamine-induced chemistry maintained by the continuous release from the immunocompetent cells. This is exactly what conventional medicine dictatesconstant interference. This approach disregards the broken regulatory tools of the immune system and allows the damage to spread. Besides, although the aim of these drugs is to suppress allergy symptoms, they block histamine activity everywhere, even though other tissues need it for their normal functioning. Blocking is especially harmful in view of the chronic nature of the disease and hence, the chronic requirement for drug consumption. Make not thy stomach an apothecarys shop, a proverb warns. Yet, we do. The second way to balance the scales is to load the pan with diseaseinhibiting mediators. Stimulation of pro-health forces is called immunomodulation or immunotherapy. Immunotherapy strengthens the inefficient
receptors, and they establish lasting, balanced production of the good mediators. This approach helps avoid creation of additional health problems, so common in patients on daily drugs. Allergology medicine does not generally acknowledge the duality of allergic processes; therefore it cannot recognize the legitimacy of two opposing approaches in the management of allergic diseases. Allergy employs only the one that suits itsuppression of natural chemistry. Its creed isthe more suppression, the better.
DUALITY AND THE MEDICAL PROFESSION In a living body, all reactions are interrelated. Our society is a live organism, and its processes are inevitably interdependent. As a part of our economy, medicine is doomed to be market-oriented, with vested interests politicizing it. Medicine provides numerous jobs to many sectors of the economy and hence, income to a large number of people. In doing so, it creates its financial and political dictators. Unfortunately, we tend to overlook how heavily medicine is interlaced with politics and the market economy until we ourselves are affected by it. Doctors are both the supporters and the victims of the existing system. The sheer number of allergy/asthma patients turns allergy into a field of extreme interest for a medical practitioner. Any doctor treating an allergy patient faces the dilemmato cure or not to cure? In the case of a successful treatment, the patient stops visiting his doctor. Of course, by word-of-mouth, other patients will come leaving their former doctors who were unable to help them. However, this may bring their original doctors wrath upon the healer, especially if he is on a lower level of the hierarchical structure. Besides, imagine what the consequences would be if the successful treatment spread widely in this lucrative field of medicine. Would there be enough allergy patients for this sector of the medical profession to survive? Patients improvement versus doctors loss of profitthis duality is created by our over-doctored society. Another problem for the doctors is that to access true knowledge, they will have to dig it out of mountains of irrelevant and confusing information that conceals and/or misinterprets the facts. Not too many doctors are ready to replace their shiny stethoscopes with spades. Digging is tiring and unpaid. Moreover, the mind once stretched, never regains its original dimensions, as Oliver Wendell Holmes, a 19th century physician and writer said. Such a stretching is dangerous for the fathers of the field, since nobody should dare to know more than they do. Hence, in the confrontation of knowledge vs. peace of mind, the latter wins.
Immune Mechanisms
61
Doctors face yet another dilemma. Let us assume a doctor chooses to repair the immune system. Because of the individual sensitivity of the immune responses, dosage is a factor to be seriously considered. The inborn concentrations of histamine in the tissues are highly individualized and depend on the number of the histamine-releasing cells involved in the given area. This, together with the highly specific responsiveness of all the H receptors in different individuals, influences the dose of the synthetic version. Both T-cells and mast cells are extremely sensitive to histamine, but no test can accurately measure this sensitivity. Dose selection rests entirely upon the clinical judgment of each individual doctor, aided by his theoretical knowledge, his personal experience and intuition as well as the time spent with each patient. The dose should be sufficient to incite H2/3-receptor activity and to provide improvement, but at the same time, to avoid an aggravation, it should not activate the H1 receptors. Although transitory, any worsening of the condition would be especially undesirable in asthmatics and small children. Who needs all these troubles? It is much easier to prescribe a conventional pill or spray to be taken once or twice each day, with no personal responsibility. If a patient on a conventional therapy has a severe adverse reaction or even dies, the doctor is not guilty as long as everything was strictly according to the guidelines. Standards of practice in medicine serve two major purposes: doctors are held in tight reign, but the restrictions create lack of individual accountability and liability. The situation relieves the doctor of the need to make decisions and at the same time, it removes any personal responsibility. If a doctor does not challenge the medical authorities with daring innovations, they will defend him. In this way, they defend the rules established by them. Those who have tried to sue a doctor probably have first-hand experience of how unwilling the medical profession is to go against one of its own. At the same time, a practitioner who may have cured hundreds or thousands is still liable if his method does not fit the mould. Another case of duality: what is good for a patient is fraught with dire consequences for his doctor. My personal story is just one of probably many. For helping about 2,500 patients to live normal, medication-free life, I was punished. In a properly functioning society, a physician should, at least, be encouraged to continue with his therapy, even it goes beyond the so-called standards. Such handcuffing of ideas and good intentions are the best illustration of the real values of our society.
PATIENTS AND DUALITY Patients face a dilemma too. Many of those who have mild and moderate allergies do not realize the danger of medications because they do not abuse them. The side effects may not be evident for years. Besides, not only in allergy, but also in disease in general, people are tempted to seek out quick relief. A pill to alleviate a headache saves them time and effort they would otherwise need to learn to relax, to give up coffee or chocolate, change the regimen of sleep, etc. It is much easier to take appetite-reducing pills or go for liposuction than to exercise till one sweats and to forgo things like fries and mayonnaise. Human nature gravitates towards easy approaches to problems. Most often, when patients are given the choice between a temporary but fast fix or a lengthy corrective procedure that requires effort on their part, they will favor the easy way. However, nature does not like short cuts. We should follow nature and therefore leave conventional allergy and asthma medications for acute situations or as the last resort when repair of our immune system fails. We should use the duality of the bodys functions to its own benefit. As everything in the body is expressed through its chemistry, we should look for ways to shift the chemical balance in favor of health. The shift should be based on the restoration of those mechanisms that the body relies upon, in contrast to symptomsuppressing drugs that provide quick but brief relief and leave the underlying problem unattended. Not to mention the side effects of such drugs, which may be worse than the original disease. Logical? Yes. Good for health? Yes. Difficult? Absolutely. Difficult for both parties: for patients to select, and for doctors to implement. There is an excuse for patients choosing symptomatic medications. Immunotherapy or, allergy shots, would be the only known alternative to daily medications. Patients came to me who had been treated for 1015 years with allergy shots and told me their stories about the adverse reactions. The textbook Allergy 1985 supported the conclusion: with little evidence of efficacy for the technique as commonly practised, immunotherapy fell into disrepute in the scientific community at large.47 According to the consensus of the pillars of allergy, nothing has changed over the time and 10 years later, we read Safety, cost and efficiency should be considered prior to initiation of immunotherapy.48 By saying all that, both the textbook and the journal reveal that conventional allergy shots are potentially unsafe, obviously costly and inefficient. Knowing this, can we blame patients who are unwilling to undergo such immunotherapy? In fact, the most recent article points to the marked drop in immunotherapy.49
Immune Mechanisms
63
BASIC SCIENCES AND PRACTICAL MEDICINETHE DIFFERENCE To understand how access to thoroughly researched data can be blocked, one should understand the course of discoveries in medicine. Here is a general example to illustrate the process of a discovery. Step One. An unfamiliar molecule is found on (or in) a cell. To prove that it is a receptor, it is challenged pharmacologically with different substances, synthetic versions or analogues of the bodys chemicals. The challenge reveals, which of them activate or inactivate the receptor and in what concentrations. The activating chemicals are agonists, the blocking ones are antagonists. The challenge also shows the physiological role of this receptor or, as science calls it, the receptors expression. The response of the receptor to the challenge with inhibition or increase of the cellular production of a particular substancedetermines its role of a turn-off or turn-on switch. Other cells are searched for the same receptor type because the efficiency of the given receptor will affect the functioning of all cells possessing it. Naturally, the work of the organs comprised of these cells also depends on the tiny receptor, as underproduction or overproduction of the given chemical may result in a state of disease. This receptor underdevelopment, inefficiency or scarcity, may become the cause of a chronic disease affecting the whole body. All this necessitates a thorough investigation of the geographical location of the receptor and its functions in different cells and organs. Step Two. The development of pharmacological agonists or antagonists for the given receptor is considered. They are viewed as the basis for potential medications. When developed, these chemicals are tube- and tissue-tested, and then tried on animals. Limited studies on humans may be conducted. Step Three. To manufacture the drug or not will depend not so much on its effectiveness in the studies, but mainly on the thoroughly calculated potential profits for the pharmaceutical industry in general. From the point of view of any business, it is senseless to invest in a project known from the start to be a financial failure. The drugs effect is usually inversely proportional to the profit. Moreover, any drug that could restore the functioning of a defunct receptor may financially ruin not only its producer but undermine the industry on the whole, since it eliminates the need of daily symptom suppressors. Therefore, the most successful clinical trials may have limited, if any, publicity and may never reach the human testing stage.
LIFE BEFORE PROFIT For those of you who may believe in the goodness of the pharmaceutical industry, I will relate a fable written by Felix Krivin, a writer well known in the former Soviet Union. The fable is about Paris, a character from Greek mythology. Paris acquired an apple, the proverbial Apple of Discord, which he was supposed to give to the most beautiful goddess. Three of the goddesses were vying for the apple and were promising Paris rewards in return. One promised to make him rich; the second offered him power; the third would give him the love of the most beautiful woman. Paris hesitated. He loved wealth, power and women, but most of all, Paris loved apples. Our drug industry is like Paris. It loves its patients. It loves its reputation of being their benefactor. It loves doctors whom it constantly educates about its products and uses as promoters of those. But most of all, it loves its profits. Just remember the three-year court fight of the 25 million African AIDS patients with 39 drug companies for the right to have cheaper generic drugs. In 2001, the industry gave in only due to the strongest public opposition. Basic sciences are relatively less politicized. Looking into their microscopes, researchers do not yet know about the future fiscal implications of their findings. This permits the publication of the initial theoretical information. It is different with clinical medicine directly tied to revenues and thus dependent on and strictly controlled by pharmaceuticals. Any access to the information that may reduce profits is solidly blocked. Drugs with a wide scope of action and curative properties contradict the essence of the drug market. The failure of contemporary medicine in chronic disease forces the medical profession to find who is to be blamed for this, and the industry becomes the target. Thus, three editors of JACI, D. Leung, H. Nelson and S. Szefler making their comments on state of the art in allergic rhinitis and asthma, say: the pharmaceutical industry has failed to appreciate the magnitude of the suffering experienced by these patients and has not risen to the challenge of finding an effective and safe treatment for their affliction.50 However, a major detail appears to slips the attention of these respectable scientists: industry alone cannot do all the decision-making. The blame falls, first of all, on the scientists and doctors working for it and supporting it in its anti-patient policy. HISTAMINE AND THE DRUG INDUSTRY The story of histamine is the best illustration of how scientific developments are stonewalled. Histamine research and its empirical use for almost a century
Immune Mechanisms
65
provided prolific data, including the discovery of the H1 receptor in the early thirties. Medicine universally embraced histamine as the central allergy mediator that initiates and maintains allergic reactions. The development of H1receptor blockers known as antihistamines was consistent with the theoretical data existing at that time, and more than satisfactory from the standpoint of profit. Antihistamines met all the requirements needed by the drug manufacturers: they did not cure, were considered (at that stage) safe, and were to be taken on a daily basis (up to several times a day). On todays drug market, there are no drugs that can compete with H1-antihistamines for profitability. From the moment of its discovery, fascination with histamine prompted worldwide research, and new findings of its role in the body accrued through the years. The discovery of the H2 receptor signified another phase, during which outstanding discoveries were made. The first extensive descriptions were made in the sixties, and in the early seventies. L. Lichtenstein and M. Melmon found that the H2 receptor possessed an opposite function to the H1 type, allowing it to play the protective role in allergies. Moreover, H2 receptor possessed the unique ability to transform histamine messages into accumulation of the intracellular enzyme cAMP. H2-receptor stimulation enabled the body to reverse immune inflammations and allergic reactions, by turning off the histamine flood. This permitted science to classify histamine as an autacoid, a self-remedy of unprecedented importance in immunology. The curative properties of histamine and its synthetic analogues were thoroughly studied. In the 50s, Parrot developed histaglobulin, and in the 70s, K. Melmon and his team synthesized histamine congeners. Both proved to be safe and effective in allergic diseases and could thus become successful rivals to antihistamines and other conventional therapies. Up until now, histaglobulin is quietly employed here and there, while the congeners have remained unknown to clinical medicine. Also remaining concealed is the theoretical substantiation of the potential benefits of histamine therapy in other chronic immune disorders. The efficiency of histamine in allergy would be in inverse proportion to their marketability. Along with the stimulatory effect of the H2 receptor, the possibility of blocking it was also researched, and here, the results were different: a new drug categorythe H2receptor antagonists or H2 antihistamineswere developed to be used for excessive stomach acidity. They were welcomed by the drug industry, and together with H1 antihistamines, have become one of the most profitable pharmaceutical products.
In the early eighties, H3 receptors were found in nerve cells, and their histamine-inhibiting effect, which is similar to H2 effect, was described. Some time later, this receptor was found on immunocompetent cells as well. Further research showed that H3-receptor stimulation could regulate not only histamine release but also the release of other neurotransmitters, mediators of nerve cells. H3-receptor agonists were created and proved effective for neurological symptoms as well as certain immune-related conditions. Actually, H3 receptor could become the key to the new therapyneuromodulation. It could correct the imbalance of neurotransmitters and rid patients of a wide number of neurological symptoms, including such common ones as vascular headaches. Moreover, the synergism of the H3-receptor and H2-receptor functioning steps up the remedial effect in allergies as well. But, the improvement would be lasting or permanent, and this appears to have doomed H3receptor agonists. Still, nothing exposes the close ties between allergists and the drug industry more than developing a certain drug group for asthma, which I mentioned earlier. They target the enzyme cAMP, the levels of which are lower than normal in allergy patients. The simplest solution would be imitation of Nature which would mean H2-receptor stimulation. However, this avenue is closed, since it would lead to the unwelcome revelations about the demoted histamine. The drug developers choose a circuitous approach: through another enzyme, they try to inhibit the natural degradation of cAMP. This method is doomed from the start because with the pre-existent low level of this enzyme, the effect of the new medications will be limited. The inhibition may, at best, maintain the existing levels. This is contrary to the potentially successful straightforward increase through histamine. These allegedly novel drugs are, in fact, very old as they mimic the effect of the half-a-century-old theophyllines. The best illustration of the efficiency of theophyllines is given in the work supported by a research grant from the Agency for Healthcare Research and Quality. It says that theophyllines, which once dominated asthma therapy (63% of visits in 1978), were used in only 2% of visits in 2002.49 By looking towards the increase of the enzyme cAMP in the development of an asthma medication, allergists acknowledge its prime role in allergic inflammation. Of most peculiar interest is that the development of these drugs is headed by L. Lichtenstein, who had described in the late 60s and in the 70s the pathway that leads to cAMP activationH2-receptor activation.
Immune Mechanisms
67
The logical conclusion is: the choice of less efficient ways of asthma management is intentional. Somebody thoroughly calculated the potential fiscal loss from the use of histamine and its synthetic versions. The theoretical data on histamines possessing immune-, neuro- and gene modulation properties had imprudently been entered in theoretical sources through the unsuspecting 60s, 70s and 80s. It provided the solid basis for the clinical employment of histamine in chronic immune and neurological diseases. Open and double-blind clinical trials confirmed histamines efficiency in patients with allergy, asthma, and certain neurological disorders. Perversely, these trials spelled out histamines potential negative effect on the drug market. By the nineties, this blunder and its possible financial repercussions were fully realized. This explains how the information on histamine has been kept virtually out of the reach of doctors and patients.
ENDNOTES
S. Romagnani. The role of lymphocytes in allergic disease. JACI 2000;105:399-408 A. Kaplan, ed. Allergy, 1985, pages 8 and 176 JACI 1995;95:787 Harrisons Principles of Internal Medicine, 1987, p. 331 H. Wada et al. Is the histaminergic neuron system a regulatory centre for the whole-brain activity? Trends in neuroscience 1991;14:415-8. 6. L.Stunciu. Immunomodulation by histamine. Ann.Biol.Clin. 1990;48:623-5 7. Brondes et al. Histamine as an intracellular messenger. Biochemical Pharmacology 1990;40:1677-81. 8. L. Yan et al. Histamine Pharmacogenetics 2000;10:261-6, 9. R. Rocklin et al. Characterization of the human blood lymphocytes that produce a histamineinduced suppressor factor (HSF) Cellular Immunology 1980;51:226-237 10. See for example The Olivieri Report published by the Canadian Association of University Teachers, Lorimer, 2001, in which it is urged that the government pass legislation protecting research integrity, and thereby patients. 11. Dorlands Illustrated Medical Dictionary, 27th edition, p. 768. 12. D. Goldblast True Believer Bayard Taylor Horton. Seminars in Neurology 1988;8:339-342 13. S. Diamond et al. Treatment of Intractable Cluster, Headache 1986;26:42. 14. M. Rocha e Silva. Handbook of Experimental Pharmacology 1966;18/1:899 15. M. Cirstea. On the mechanism of desensitization by histamine. Rev. Roum. Physiol. 1971; 8:253-258 16. JACI December 1997 p. 816 17. J-P Girard. A double-blind study of triplex-histaglobin in the treatment of grass pollenosis. Praxis 1989;78:62-5 18. R. Lockey et al. Allergies and Allergen Immunotheraphy, 1999, second edition 19. L. Stanciu. Immunomodulation by Histamine, Ann. Biol. 1990, 48, 623-25); and see also C. Burtin et al.. The New England Journal of Medicine, Letters to the Editor, March 1983, 591-2 20. F.L. Pearce. Editorial: Biological effects of histamine: An overview, Agents and Actions 1991;33,1/2:4-6. 21. FDA reviews antihistamine mouse study. FDA Talk Paper 1994; May 17:2 1. 2. 3. 4. 5.
22. E. Vannier et al. Histamine Suppresses Gene Expression and Synthesis. J.Exp.Med. 1991;174:281-284. 23. D. Takeuchi et al. Histamine alters gene expression JACI 2001;107:310-4 24. JACI, 1990;86:589-686 25. R. Leurs et al. Molecular pharmacological aspects of Pharmacology & Therapeutics 1995;66:413-463 26. S. Holgate. The epidemic of allergy and asthma. Nature 1999;402:Suppl:B2-B4 27. B. Zweiman, M. Rothenberg. Beyond Our Pages. JACI 2002;109:728 28. J Clin Invest 2001;108:1865-73 29. Allergy 1985, p. 184 30. J.A.Grant et al. Histamine-releasing factors and inhibitors: historical perspectives and possible implications in human illness. JACI 1991;88:683-93 31. R. E. Rocklin, D. K. Greineder, K. L. Melmon. Histamine-induced suppressor factor Cell Immunol 1979;44:404 32. P. Kuna et al. IL-8 inhibits histamine release induced by histamine releasing factorsJACI 1991;87:207 33. P.Kuna et al. Chemokines of the alfa, beta-subclass inhibit human basophils responsiveness to MCAF/ MCP. JACI 1995;95:574-8 34. JACI 2001:108:S147-336 35. Allergy 1985 p.183-5 36. E. Sercarz, & U. Krzych. The distinctive specificity of antigen-specific suppressor T cells. Immunology Today 1991;12:110-117 37. R. Rocklin et al. Generation of antigen-specific suppressor cells N.Engl.J. Med,1980;302:1213. 38. M. White The role of histamine in allergic diseases, JACI 1990;86:605. 39. JACI 2001;108:S178 40. I. Elenkov et al. Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors. The Journal of Immunology, 1998, 161:2586-2593 41. R. Leurs et al. Molecular pharmacological aspects of histamine receptors. Pharmacology and Therapeutics. 1995;66:41342. E. Vanier et al. Histamine suppresses gene expression and synthesis of tumor necrosis factor via histamine H2 receptors. J.Exp. Med. 1991;174:281-4 43. H. Bourne, L. Lichtenstein, K. Melmon et al. Modulation of inflammation and immunity by cyclic AMP. Science 1974;19-28 44. B. Horton. Chronic progressive retrobulbar neuritis Boswell Hosp Proc 1979;5:4-20 45. Allergy 1985:188 46. E. Vannier et al.. Histamine Suppresses Gene Expression and J.Exp.Med 1991;174:281-284 47. A. Kaplan, ed. Allergy 1985. p. 679. 48. Focus On The Literature 1996;15:9 49. R. Stafford et al. National trends in asthma visits and asthma pharmacotherapy, 1978-2002. JACI 2003;111:729-35 50. The Editors Choice. JACI 2002;109:580 51. A Mazzoni et al. Histamine regulates cytokine production J Clin Invest 2001;108:1865-73
PART TWO
CAUSES AND TRIGGERS IN ALLERGY
CAUSE VS. TRIGGERS Differentiation between causes and triggers in allergy is of prime importance. Triggers vary from patient to patient, while causes create the background for triggers to ignite chemical changes. Without the underlying failure of the immunocompentent cells, which is the cause, triggers are harmless. Proof is found in the fact that exposure to the same allergens produces symptoms only in some of us. Thus, even during the worst allergy season in North Americaragweed timethere are many people who do not experience a single sneeze or itch. The true causes of allergies were described, although vaguely, in the 70s and 80s in a few theoretical textbooks and periodicals, and they were the subject of occasional reports at symposia. Causes of allergy were even taught at educational courses for medical postgraduates. Although the material was never presented systematically, it was responsible for progress in the field of allergy research. Sadly, these discoveries about causes were not further developed or applied clinically. Today, medical students are not generally taught what cellular defects are the basis of allergy symptoms. Through the nineties, the descriptions of causative mechanisms were reduced to a mere trickle and finally stopped. This means, that even though the known causes of allergy
were not in any way scientifically disproved, there was no factual reason to ignore this information and no new findings that rendered the known causes obsoletethe most important information for a student of allergy was simply left out of the new textbooks, and excluded from all publications and gatherings of allergists. In the absence of true knowledge false claims become inevitable. Todays allergy medicine exclusively connects allergic diseases to allergens, that is, the triggers, whereas the cellular defects, without which no allergen could provoke a chronic allergic condition, are never named as the key factors. Textbooks present allergies as reactions to he true cause of harmless substances, or a hypersensitive state acquired allergy is the genetithrough exposure to a particular allergen, or a disorder cally preconditioned in which the body becomes hypersensitive to particular hypoactive functioning allergens. Such descriptions distort the fact known to of the protective part of the majority of allergy sufferers: allergy symptoms may the immune system. arise in the absence of allergens. As a result of the Environmental factors distortion, medicine fights triggers and tries to control are triggers that may the secondary hypersensitivity processes provoked by only provoke or accelthem. It never considers re-activation of the originally erate the pre-existing hypoactive immune mechanisms in order to correct cellular malfunctioning. the condition.
THE REACTION OF THE NORMAL IMMUNE SYSTEM TO AN ENEMY To understand a deviation from the norm, one should be familiar with the norm. Therefore, to understand how the immune system of an allergic person responds in an exaggerated way to a non-offensive surrounding, one should know the basis of how a healthy body responds to external triggers. Every day, numerous proteins, viruses, microbes and various foreign substances penetrate the body through the airways, the digestive tube and the skin. All of them are a part of the flora and fauna that surround us. The scientific term for a stranger is antigen. The Greek root gennan means to produce: antigens are able to produce an immune response against them. The immune system organizes its chemical defense against those antigens, which it regards as potentially dangerous. This is how it happens: Antigen-presenting dendritic cells bind to the intruder and physically deliver it to T-cells and at the same time, transmit their chemical messages.
Causes and Triggers in Allergy
71
The name of T-cells comes from thymus, the gland from which they are derived upon maturation, the T-cells start to release cytokinestheir chemical orders to other participants. T-helper cells immediately launch the defensive operation by dispatching their own chemical instructions to B-cells, the factory of defensive proteins, which arise out of bone marrow (hence the name B-cells). B-cells go through a transformation stage and generate protective proteins called antibodies or immunoglobulins. The medical sign for Immunoglobulin is Ig, and it is followed by one of the four letters denoting its kind IgA, IgD, IgG, IgM. Actually, antibodies are cellular receptors for antigens, and like all receptors, they interact with the antigensbind to them. Thus, the primary function of immunoglobulin molecules is to bind to the antigen and inactivate it. Each antibody interacts with one specific antigen. For instance, an antibody to the virus causing measles is different from the antibody to the chickenpox virus. An antibody fits its antigen in the way a leather glove fits the hand. In medical language, we use the metaphor of the lock and the key: an antigen and its antibody match each other like a key fits in its specific lock. In other words, antigens are specific material triggers in response to which the body forms specific antibodies. It takes 3 to 14 days after the first exposure for the antibody to fully develop and be able to neutralize the antigen. As a rule, if another encounter with the same antigen happens before the formation of the antibodies is complete, the host is still defenceless. This maturation process makes it clear why we fall ill with infections upon our first exposure to a microorganism, whereas during its second intrusion, the antigen is inactivated. The presence of those specific antibodies left from the first encounter and/or the memory of the immunocompetent cells, which know
ntigen is a substance able to trigger an immune response. A healthy body defends itself from dangerous antigens by forming two major categories of specific proteins cytokines and antibodies. Cytokines are chemical instructions of T-cells to other cells: what chemicals to produce and in what amount. An instruction to produce antibodies is one of the many messages of T-helpers to the antibodyproducing B-cells. Antibodies need 314 days to develop after the first encounter of the host with the antigen, after which they are ready to inactivate those antigens in subsequent encounters. Proteins acting as antibodies are called immunoglobulins, and the sign for them is Ig. The chemistry of each antibody is compatible with the chemistry of the challenging antigen. Antibody formation is a protective act of a healthy immune system, and like any immune process, it is supervised by T-cells. T-helpers help in cytokine and antibody production, while T-suppressors implement control over the whole process. Antibody formation is a process secondary to the original T-cell activation.
how to organize a defence, also explains why certain infections do not occur twice. In the normally functioning immune system, during the course of antibody formation, different T-cells perform different functions, but all of them are protective. Thus, the role of T-helpers is to render help in the production of antibodies and cytokines, while T-suppressors implement the qualitative and quantitative control of the whole process, mainly by secreting their own cytokines.
THE REACTION OF THE IMMUNE SYSTEM TO ANTIGENS IN ALLERGY PATIENTS All textbooks describe the details of how the immune system of an allergy patient responds to specific triggers. We will do this too, but will emphasize the roles of the participating cells. Our task is to see what happens when a substance, harmless for a healthy immune system, becomes an instigator of an unnecessary immune response and allergic symptoms. The important point is that genetically compromised immune cells in an allergy patient are unable to tell a harmless stranger from a dangerous one, and thus the number of specific triggers becomes limitless. Because of the primary T-suppressor hypoactivity, the poorly controlled T-helpers become disease-promoting. They generate pro-disease chemistry and become internal enemies by facilitating the formation of unnecessary IgE antibodies by B-cells. IgE antibodies are formed to benign strangers and therefore behave differently than the protective antibodies would have done. T-suppressors still preserve their commanding role, but because they are compromised to begin with, their innate weakness prevents them from adequately controlling the reactions.
The stages of antibody formation are similar in health and in allergy: antigen presentation to T-cells by their specialized subordinates named antigen-presenting cells; activation of T-cells and their production of cytokines to conduct the immune response; messages from T-cells to B-cells to produce matching antibodies and to other cells to induce certain cytokines. The differences from the norm are: the enemy could be anything; the unusual IgE antibodies are not protective.
73
Similar to protective antibodies, IgE antibodies need time to develop. Upon that, they settle down on mast cells and basophils and wait to ambush the trigger. When the antigen shows up again, the Y-shaped IgE antibodies stick to it and form an inseparable antigen/ antibody complex. To immobilize the offender, the adjacent complexes start to clump together. As we learned earlier, each mast cell contains up to 200 histamine granules. These cells are very sensitive even in health. In allergy patients, their sensitivity is exaggerated and is one of the most determining factors of these diseases. The chemical events that take place on the outer membrane of the mast cells lead to perforation of the granules, a process medicine calls degranulation. Histamine, which is the only pre-stored allergy mediator, leaks through the pores of the cell membrane and starts the allergic reaction. Any itch, sneeze or cough is a manifestation of a local spill. The synthesis of inappropriate chemistry and antibodies by T-helpers means that they have abandoned their role as immune protectors; thus we are left with T-suppressors as our only defenders in allergy. Even being weak, they try as much as they can, to control the processes of improper chemical release and antibody production. If an allergy patient does not die it is only due to the efforts of the weakened but faithful suppressors which do not stop in their work to restore the original balance. Therefore, the disappearance of T-suppressors from all medical sources on allergies is as odd as talking about the solar system without mentioning the sun.
WHY DOES AN ALLERGEN-TRIGGERED REACTION LAST EVEN IN THE ABSENCE OF THE TRIGGER? The half-life of IgE antibodies is 23 days, after which they start to degrade. Knowing this, it is logical to assume that once the originally triggering antigen is
enetically malfunctioning T-cells may mistake any harmless substance for an enemy and order the formation of inappropriate chemistry that includes antibodies of the IgE type. Antibody formation in allergy patients is similar to the process in healthy people. However, unlike protective antibodies, IgE antibodies do not neutralize the trigger but lock with the antigens on the surface of mast cells and basophils. These cells are hypersensitive in allergy patients, and the presence of the unusual antigen/antibody complexes leads to an exaggerated release of histamine and the subsequent disease-promoting chemistry. The sites of the highest spill cause allergy symptoms. However, IgE antibody formation is the event secondary to the activation of the malfunctioning immunocompetent cells and therefore cannot be considered the cause of allergic diseases.
gone, the allergic reaction unleashed by it would abate after 23 days. This is exactly what happens, for instance, with hay fever patients: the end of the pollen season means the end of their allergy symptoms. This, however, is not so in too many instances. A reaction ignited by a certain trigger continues and may even intensify in its absence. In other words, the llergens only trigger antigen plays the role of the car starter, and after that, symptoms in those the motor runs on its own. What keeps the motor who have cellular running becomes most important in view of the fact defects related to H2that allergy medicine focuses on allergens and IgE antireceptor deficiency and bodies. The explanation is found in the excessive T-suppressor weakness. leakage of the disease-promoting chemistry orchesThese inner immune trated by T-cells. In chronically ill allergy patients, defects allow the disease liberation of histamine is continual because the weak to continue even when H2/3 receptors are unable to control it. It is accurate to the triggering antigens say that histamine is the central event that opens are no longer present, Pandoras box containing numerous diseaseand the IgE antibodies promoting chemicals. This chemistry is the biological have degraded. This marker of immune dysfunction, while IgE antibodies supports the view that are merely a part of this chemistry and the consecellular malfunctioning quence of the dysfunction. The severity of the symptoms is primary, and that depends not on the IgE count but on the degree of the IgE antibodies are H2/3-receptor weakness and the resultant pro-disease secondary in allergies. chemistry. This explains why the disease may continue even when the IgE antibodies have degraded.
NONSPECIFIC TRIGGERS IN ALLERGY So, an allergic reaction, provoked by specific allergens, may continue in their absence, moreover, it may even start without any allergen! A paradox: how can a disease which starts and/or without an allergen be called allergic? The human mind tends to choose the easiest way in its comprehension of events and their causes, therefore we easily accept as symptom-causing those triggers that can be seen, touched or at least imaginedspecific triggers. Still, a lot of triggers are not proteins, and it is more difficult to comprehend that allergy symptoms may result from sunlight, weather changes, emotional upheaval, physical exertion, electromagnetic fields, or physiological body changes such as sleep or awakening, pregnancy, menstrual cycle, etc. The reactions to the same event vary in different people. For instance, some may feel better after exercising or
75
making love, while in others, these may provoke or n ailing immune system may overaggravate symptoms. Such triggers are called nonspecific. Some of them may be determined or suspected react to nonspecific due to the cause-and-effect connection and the triggers, which can be commonality of allergy symptoms in certain circum- equally responsible in stances. Sometimes, just understanding what provokes provoking allergic sympthe symptoms may help patients overcome the toms as IgE-producing temporary suffering because they may be able to avoid identifiable triggers. or reduce the occurrence of certain situations. Both make T-cells However, in many allergy patients, symptoms may be generate diseasethe result of nonspecific phenomena that cannot be promoting cytokines and pinpointed and, therefore, cannot be controlled in mediators. The very view of their inexplicable spontaneity and lasting fact that a nonspecific nature. Practically any patient may experience aggra- trigger may produce vation without any evident reason. This may occur at symptoms proves that any time of the day, season, or life period and differ the core of the problem from patient to patient. Nonspecific influences are lies not with the trigger unpredictable, erratic, highly individual and mostly but with the inherent unavoidable even if one understands that they defects in the immune provoke allergy symptoms. They do not lead to the system. production of specific IgE antibodies but only activate T-cells and induce the release of pro-disease cytokines and mediators that involve other immune cells. It is vital to recognize the existence of both specific and nonspecific triggers, as well as to understand that allergy symptoms may arise without any identifiable antigen or phenomenon. You may wonder why it is so important. The answer is: as long as specific material triggers are not the only ones causing allergic symptoms, focusing on them alone should not be the sole objective in the management of allergy patientsas is now the case.
THE ROUTES OF NONSPECIFIC REACTIONS Reactions in response to immaterial nonspecific triggerstemperature changes, vibration, stress or the bodys hormonal changesare not all related to an allergen. Although medical textbooks mention the existence of allergic reactions to nonspecific triggers, when it comes to the explanation of the processes that underlie allergic reactions, the descriptions are limited to IgE-related mechanisms. However, what is known about the physiology of
cells provides a clear explanation of reactions that are not related to specific allergens. This is what happens during nonspecific reactions. It so happens, that the immune and nervous systems are interrelated. Nothing in the body acts in total isolation. T-cells, mast cells, dendritic cells, and neurons all live and work in tissues close to one another. They are washed by each others secretions and often have similar receptors responding to the same stimuli. All four groups of cells possess histamine receptors and, therefore, respond to its overspill. Any of the four may unleash that reaction. For instance, something as simple and common as an environmental change from warm to cold may affect sensory nerve endings in the skin, causing their chemistry to change, and in doing so involves mast cells that start to leak with histamine. The reactions that follow are similar to the ones provoked by allergens like ragweed. A local skin exposure to a low temperature may increase a systemic reaction, especially in the areas of the highest histamine spill. So, the patient may have a skin itch or get the hives, have a stuffy nose, or an asthmatic attack, with no allergen in the picture. Cold may directly activate mast cells, which are in abundance in the skin and airways, and their profuse spill of histamine will start a reaction. Dendritic cells in the skin may also react to cold, and their changing chemistry will also activate Tcells, followed by the engagement of the main histamine producers, mast cells. Finally, T-cells may become directly activated, as they are also found in large numbers in the skin and respiratory tract. The compromised T-helpers respond by producing disease-promoting cytokines and mediators similar to those observed in classical, allergen-provoked reactions. Histamine produced de novo by the participating cells, amplifies the disease process started by the leaking mast cells and basophils. The participating cells become the source of numerous diseases-promoting cytokines and mediators, which, in turn, contribute to further liberation of histamine and histamine-induced chemistry. This all leads to allergic symptoms characteristic of that organ or tissue, in which the reaction takes place. Thus, an asthma attack or a stuffy nose, upon exposure to low temperatures, is rather common even though often misdiagnosed as a cold. Also analogous are the processes that underlie allergy symptoms provoked by the bodys physiological changes. Here is an example. Awakening in the morning is accompanied by the activation of certain departments of the central nervous system dormant at night. That involves those brain areas that regulate the production of hormones needed by the body for its adapta-
77
tion to the working day after a nights sleep. The variety of hormones involved, as well as their levels in the blood, change according to those demands. The T- and mast cells found in large numbers are able to respond because they accept communications coming from this changing chemistry. If, however, these cells are faulty by nature, they overreact to the chemical messages with a histamine overspill and make matters worse by transmitting their alarm reaction to the peripheral structures via the histaminergic system. This explains why some patients have early-morning sneezing attacks or difficulty breathing upon awakening. These changes are, by the way, unpredictable in each individual. The T-cells, mast cells, dendritic cells and nerve cells, all become engaged in the same reaction, regardless of which one of the group initiated it. They work together as a well-trained army. Their activation by any non-specific stimulus, be it external or internal, provokes a histamine overspill. Its continuous leakage maintains the process and chemically involves all of them. While a nonspecific reaction bypasses the stage of specific IgE antibody formation, the final outcome of events remains very similar to a reaction triggered by an allergen. Although reactions to nonspecific trigger show that the presence of IgE antibodies is not a reliable indicator of allergies in a person, contemporary allergy medicine insists on focusing on IgE antibodies and, therefore, fails to explain all those commonly observed deviations from the standard. Sometimes these are even fatal reactions to peanuts, for example, in babies who have never been exposed to peanuts and, therefore, cannot have IgE antibodies to these nuts. The immune system supposedly only responds to a repeated exposure, once specific IgE antibodies have formed. The fact that babies may die during such a very first exposure does not fit the accepted concept, and leads to the unfounded search for the mothers consumption of peanuts during her pregnancy or breastfeeding, even though we know that IgE antibodies do not pass through the umbilical cord and have not been found in breast milk. There is an even more impressive example: the very first bee sting received in life can be fatal. The IgE-based concept cannot explain this phenomenon. Also vague are the explanations of the processes that underlie reactions due to such nonspecific factors as cold, sun light, physical exertion, etc., although the ability of these phenomena to provoke symptoms has forced allergists to recognize their existence and they even have a name for them, namely physical allergy. In all such cases, the cause is genetically predetermined-readiness of mast cells/basophils to release histamine.
onspecific triggers stemming from body chemistry or an environmental physical factor may cause a response of hypersensitive immunity similar to the one caused by specific triggers. The response always starts with an excessive histamine release from mast cells. The similarity of receptors, the cellular ability to produce and respond to the same chemicals histamine in particular and the shared chemical-electric language of communication explain the simultaneous engagement of nerve cells and immunocompetent cells in allergic processes. No matter what triggers these reactions, and what cells get activated first, the reactions are immunologic, since major immune cells and their products take part in them.
The inability to explain what processes underlie the symptoms induced by nonspecific triggers created their artificial classification as nonimmunologic, in contrast to the immunologic processes induced by specific triggers. The gross inaccuracy of this division is obviousall reactions with the participation of major immune cells cannot be anything but immunologic.
THE GREY ZONE Poor comprehension of the mechanisms of diseases of hypersensitivity by the medical profession is especially evident in the area that remains a grey zone today. Not only does the subject create heated discussions, it even leads to litigation initiated (and often lost) by patients. Let us consider this important and confusing area. The grey zone is represented by substances that, on one hand, have a chemical formula and thus materially exist, on the other, no antibodies to them have been detected. The prejudices ruling orthodox allergy do not permit recognition of these triggers because no IgE antibodies are found in such instances. Among these triggers are impurities, unwanted substances in the environment that may provoke negative responses. They include not only unpleasant fumes but also the gentle aromas of perfumes and other products. All these triggers are classified by allergy as air pollutants or irritants. Having created the new termirritantallergists fail to explain the mode of action of irritants. What do they irritate? Dont they irritate the same receptors on the same cells that allergens do, since there is no other way to change the cellular chemistry than through receptors? You may accuse me of splitting hairs and ask: Does it matter what terminology allergists use, if the only thing that matters is that patients suffer and should get treatment? It does matter. Such misclassification harms allergy sufferers. I will show you why.
79
Modern allergy medicine recognizes only specific IgE antibodies as the unarguable proof of allergy. Its position is that when the diagnosis is needed for legal purposes, the presence of IgE antibodies must be documented. Therefore, those who initiate litigation claiming that their sickness resulted, for instance, from staying in a certain polluted building will not be considered sick if IgE antibodies to suspected pollutants are not found. The conclusion will be: there is no evidence that these patients have an allergic disease. Nothing in the sealed building where they work could produce their symptoms. Especially so, if the symptoms are not something as unquestionable as asthma, but are of a less demonstrative, nonspecific nature, such as headaches, dizziness or fatigue. There is now good news for those who are sensitive to cigarette smoke: finally, the IgE antibodies to tobacco have been isolated and may thus become irrefutable proof of allergic illness being triggered by tobacco smoke. However, the remaining sufferers may still find themselves labeled as hypochondriacs because the existing standard consensus is: those symptoms are just a state of mind only. The complaints are viewed as purely psychological. The fact that the constant contact with the irritant could have damaged the inherently susceptible immune and nervous systems is not accepted, and no certificate will be provided even to those who become outright incapacitated. The absence of laboratory evidence of specific IgE antibodies provides a loophole for the patients employer, supervisor, or building owner. It relieves them of liability for the conditions in which the sufferer works or lives. For instance, it is easier to prove an allergy to cockroaches than to the pesticide used against them in your apartment, since the cockroach antibodies are identified in the traditional manner. The search for specific IgE antibodies remains the guiding criterion when providing patients suffering from diseases of hypersensitivity with certificates confirming their illness. Allergists are adamant in naming diseases of hypersensitivity allergies. Had lawyers known medicine, they could have easily exposed this concept. The best argument of the groundlessness and hypocrisy of the position taken by standard allergists is their ready recognition of the existence of occupational asthma and allergies which they agree result from exposure to pollutants, with no specific IgE antibodies found on testing.
THE ARTIFICIALITY OF CONVENTIONAL CLASSIFICATION The division of allergic diseases into the so-called immunologic (allergenrelated) and nonimmunologic (provoked by physical phenomena and irritants) is unscientific. I will give two examples. The already mentioned
cigarette smoke used to belong to the group of nonspecific irritants. Then IgE antibodies were identified, and this permitted re-classification of smoke into an allergen. Another example is latex. Opinions about latex as an allergen have recently been challenged. Latex allergy used to be limited to latex gloves, and medical professionals who wore them were considered to be a risk group. Not long ago, it was found that hypersensitivity to latex was also common in other groups of the population that never wore latex gloves. Toys, pacifiers, tires and other products of rubber are among the many sources of latex. Latex particles are found everywhere, and lately, latex has been relabeled by allergists as a pollutant. Has there been an observed physical change of the routes through which latex causes an allergic reaction? No. Will it change anything in the treatment? Absolutely not, since it has always been limited to avoidance. So, why is the strict classification so badly needed? This game-playing with real, biological events merely served to conceal the allergists inability to explain and treat allergies in general, specially when it comes to irritants. The cellular processes that lead to symptoms are never clarified in textbooks and only occasionally touched upon in periodicals. The focus is on triggers. Moreover, true science is further distorted when the symptoms to nonspecific triggers or irritants are presented as nonimmunologic even though allergy symptoms are the result of the involvement of immunocompetent cells. Strangely, allergists fiercely fight to keep patients with such nonimmunologic diseases in their purely immunologic practice. The truth is that in allergy, irritants or pollutants work through the same mechanisms as specific and nonspecific triggers. Upon inhalation or touch, irritants may: produce a direct effect upon T-cells, and these start to generate diseasepromoting chemistry; directly affect dendritic or mast cells and make them leak with histamine and histamine-induced disease-maintaining mediators; affect sensory nerve endings, and the changing chemistry of nerve cells may involve immune cells. The subsequent reactions are more or less similar: activation of mast cells/ basophils with their exaggerated release of histamine and histamine-induced chemistry. This is exactly what a combined team of scientists from England and Turkey said in an article on asthma: air pollutants... may modulate airway disease, such as asthma, by increasing the release of pro-inflammatory mediators.1
81
ALLERGY AND BORDERLINE DISEASES here are triggers, reactions to which The common origin of allergies with neurological symptoms is proven by their frequent coexistence. A are not classified by certain food can provoke a headache and itchy skin, so conventional allergy as does stress, while hay fever sufferers often experience immune-related because fatigue and headaches. Even those allergists whose no IgE antibodies to minds are made up on allergens being the only trig- them are found. The gers, have no choice but to recognize that migraine, a term used for such trigneurological symptom, is common in allergy patients. gers is air pollutants or The prevalence of symptoms related to the nervous irritants. Poor undersystem and the absence of allergy symptoms not standing of the undernecessarily indicate the purely neurological or lying cellular processes immune origin of the disease. It may result from the prevents modern allergy chemical imbalance in either type of these cells. The from explaining the nature of these cells to depend on each others chem- immune processes icals rests on the logic of the unity of the body as a invoked by pollutants. whole mechanism, in which the malfunctioning even Allergists call the of a small part affects the work of the whole structure. reactions provoked Histamine is not only the key mediator of allergies but by pollutants as nonalso a major neurotransmitter. Therefore, in the immunologic in absence of organic diseases, a great number of symp- contrast to immunotoms such as headaches, dizziness, fatigue, anxiety logic IgE-mediated or depression, vague arthritic-like joint or muscular allergies. The accepted pains (e.g. fibromyalgia), abdominal cramps, bloating, IgE-based dogma is diarrhea, constipation (e.g. irritable bowel syndrome), simply incorrect because frequent urge to urinate, etc., may well be signs of a all reactions, in which condition related to histamine dysregulation. Even if immune cells and their only allergic symptoms exist at a given time, the products are engaged, involvement of the neighboring neurons is possible at are immunologic. any stage. These histamine-provoked symptoms are manifestations of allergy-like processes in the central nervous system. At present, each symptom that accompanies allergies is often diagnosed and treated as a separate disease. The name of a disease that has become so commonchronic fatigue and immune dysfunction syndrome (CFIDS or CFS)comprises the symptoms of both nervous and immune systems, and may serve as an example of their interrelation.
mmunocompetent cells and nerve cells share certain receptors and respond to and release the same chemicals. They become inevitably involved in the reactions started by either kind. This explains why allergy symptoms are often accompanied by neurological symptoms. Histamine, as the central mediator in allergy and a governing neurotransmitter, can become the cause of both allergy and neurological symptoms if produced in exaggerated amount.
HISTORIC EXPLANATION OF WHY ALLERGY PRACTICE IS BASED ON ALLERGENS Let us trace how it happened that allergens, just one group of numerous triggers, have inappropriately been proclaimed as the cause of allergic diseases. The word allergy was first introduced in 1906 by the Austrian pediatrician Clemens von Pirquet whose name is connected in medicine with the diagnostic skin test for tuberculosis. The term comes from two Greek roots: allosdifferent, that is, a condition differing from the norm, and ergonwork. Thus, allergy simply means an abnormal body reaction. Pirquet called foreign substances capable of producing a reaction different from norm allergen. Both in allergen and antigen, the Greek root gennan means to produce. These words are roughly synonyms in the context of allergic diseases. Lay persons use the word allergen, while the scientific term is antigen. More than half a century passed before allergy took roots as a branch of medicine. Its practitioners were unsuccessfully fighting for scientific recognition until the 60s. The reasons for their rejection had to do with the way medicine changed since the time of Pirqueta change that was not the best. Pirquet, who unknowingly started allergy as a discipline, had made his greatest discoveries mostly due to clinical observations, which he considered to be the most important part of medicine. Traditional medicine removed itself from Pirquets principles and started to rely on laboratory proof more and more exclusively. At present, phenomena that cannot be proved by testing are treated as if they were nonexistent. Therefore, even though abnormal or allergic reactions were undeniable, scientists who studied them, searched for material proof of their existence. Without laboratory proof, allergy did not have a chance to be established as a legitimate part of internal medicine. The unpredictability of allergy symptoms was not helpful in recognizing the existence of this disease. In 1966, the brilliant guess made by Pirquet and his colleague Bela Schick of collision of antigen and antibody got confirmation:
83
unusual specific antibodies, IgE, were found in the hosts body and declared to be the hallmark of allergic diseases. Following this discovery, medicine proclaimed that only the presence of IgE antibodies confirms allergies. At that time, the scarcity of knowledge in this field justified such a declaration. Since then, accumulating information made it clear that the notion of allergy was much wider than the original, solely allergen-dependent theory, and that non-specific factors could also provoke allergy symptoms. This simply meant recognizing that patients might have allergy symptoms without showing the antigen/IgE antibody complex on mast cells. Their symptoms could equally well be the result of activation of their hyper-responsive immune mechanisms. At this point, allergy should have embraced the new data and reconsidered the stance that only IgE antibodies can be the single indicator of allergies. It did not happen. As history teaches us, the moral and ethical standards of those who have already come to power often become entrenched, and the bearers of new knowledge always seem to endanger those in power. To preserve their positions of authority, the supporters of the allergen/IgE antibody-based concept turned it into a cult, they started to conceal the existing findings and created a new hypotheses, which are not in agreement with observed facts. Proof that this concealment and distortion are intentional can be found in the entries on the word allergy in medical dictionaries: the original meaning, now obsolete, includes all states of altered immunological reactivity, immunity as well as hypersensitivity, allergic reactions to cold, heat, light, etc. are named physical allergy.2 Occasionally, the most renowned scientists dare publicly to recognize that the term allergy has become corrupted and is now frequently used synonymously with IgE-mediated allergic disease, whereas some allergic diseases develop through Ig-E-independent mechanisms3 However, these very scientists still continue to disseminate the IgE-based doctrine. Today, this dogma has become the Procrustean bed that all mechanisms of allergy must fit into, and the true causes are simply cut off because they do not fitas the legs were cut off from people who did not fit the bed created by the ogre Procrustos in the Greek myth. The best proof of the power of the allergen-based concept is the universal acceptance that allergies are caused by cats, mites, pollens, etc., and that by eliminating, avoiding or destroying these, one gets rid of the disease.
ELIMINATION AS THE MAIN TREATMENT If you are an allergy patient, your doctor has definitely instructed you to thoroughly vacuum your bedroom, strip carpets off the floors, seal your mattress with a plastic cover and regularly wash your pet with special soaps. You probably also received a list of no-no food products. You may have stopped wearing perfumes and lotions, got rid of your dog/cat, started buying foods only from Health Food stores and studying the labels on food packages for preservatives. Has it worked? Most probably not. It may even be that, despite all these measures, the symptoms are growing worse. The reasons are simple: the overwhelming majority of allergy patients present with a mixture of antigen-specific and non-specific symptoms. Washing and vacuuming may reduce the effect of potential allergens and, at best, somewhat mitigate the course of the disease but never mend the damage in the immune cells that bring on the symptoms. Being unchecked, the defect tends to worsen. The elimination procedure itself is often difficult to implement. For example, one cannot achieve complete sterility in the bedroom and make it free of dust mites. Or if you do not wear lotions or perfumes, those who work with you may not conform to your request not to use them. Your neighbor in the movie theatre may be a pet owner, and your hypersensitive airways feel the pets dander on his jacket. Few tiny particles of pollen that percolate through doors or windows may be enough to produce itchy eyes or an asthmatic cough. Even in the absence of smoke, an allergy patient may develop a reaction to the clothes that carry a faint tobacco smell. We do not live in a vacuum, and potentially dangerous encounters with triggers are unavoidable. In addition to the difficulty of eliminating the triggers, the expediency of it is questionable. Many authors suggest it may even do more harm than good. For instance, a study conducted on nursing mothers on an elimination diet as compared to those on a regular diet indicated that the babies breastfed by the mothers of the first group had an increased prevalence of eczema and allergy, and that infant food allergen exposure via maternal intake produces tolerance rather than sensitization4 In this respect, it would be interesting to know the opinion of allergists on the Indian and Thai cuisines with their high use of nuts, especially peanuts, and absence of anaphylactic reactions to nuts among that population. More and more popular is the advice to expose babies to potential allergens, pets in particular, for the purpose of preventing allergies in the future. In a similar way, microorganisms that have become a
85
normal part of the environment do not affect us but can be fatal only to the people with no previous exposure to them. Although allergy medicine has not been able to solve its version of Hamlets dilemma: to eliminate or not to eliminate, allergen elimination remains central in the management of allergies.
HOUSE DUST MITEENEMY No 1 Mite is a four-letter word in allergy medicine. House dust mites are attacked with the utmost ferocity. Although it is an organism seen only through a microscope, it is usually portrayed as a huge, monstrous, spider-like creature. No wonder such pictures make patients shudder and then declare war against the enemy, which is, in fact, the innocent fauna inhabiting the flora of all our rooms, especially bedrooms. Scientific papers devote numerous pages to the use of sprays developed for killing mites and cockroaches. The complex names of the ingredients of these aerosol preparations resemble a page from a chemistry textbook for university students. The authors often admit that extended studies are necessary to determine the safety of these chemicals and their efficacy in reducing allergic symptoms. Reading such articles, one can never be sure what the recommendations are: to use or not to use the aerosol that can denature the mite allergen and reduce levels from carpets and mattresses but does not kill the dust mites,5 or although effective... is not yet proven to be safe for long-term usage. Some of these sprays can probably do more harm to health than the allergens they intend to destroy. In The Toronto Star, on March 11, 1995:L17, I came across a remarkable piece of advice given by a Southampton pediatrician, Dr. Jill Warner: teddy bears and other stuffed toys should be put into a freezer during the day, so that asthmatic children could take them at night to bed. Low temperatures supposedly kill the mite and prevent attacks. The doctor did not say a word about the bedding that is also full of house dust mites. Should it also be kept in a freezer? What size of a freezer should a family with two or three asthmatic children have? A large article in the most recent issue of the most important immunological publication states: Few studies have investigated live house dust mite and mite allergen removal by washing machines. This particular research (supported by The Clorox Company exporting their product to over 100 countries) was studying the methods and percentage of mite removal during washing, which detergents and bleaches might do a better job, and what fibers
responded best.6 Of course, the higher percentage of the removed mites upon repeated washing with the given detergents is likely to expand the market for Clorox, but will it help allergy patients? The article does not provide the answer. In March 1996, the participants of the 52nd annual meeting of the AAAAI heard a report later published by the flagship journal on allergy.7 The study was designed to assess the clinical efficacy of special bedding covers in house dust mite respiratory allergy and was staged in a highly scientific setting with the use of placebo mattresses as opposed to mattresses with Intervent covers. The conclusion sounds like a scientific joke: allergen avoidance by Intervent covers is effective. However, in this group of moderate asthmatic patients, it did not improve allergic asthma. The question is what WAS effective, if the patients did not improve? It is not uncommon to read articles written by allergists on what types of air filters and vacuum cleaners to buy, how many minutes are needed to achieve the best results, what water temperature to use for washing the bedding to destroy the mites, and what sort of mattress pads to purchase so that body moisture does not contribute to the spread of the mites. Are these measures more effective than the effective Intervent mattresses that supposedly control the mites but do not relieve asthma? Many pseudoscientific arguments regarding dust mites can be easily rebuffed. For instance, nocturnal asthmatic attacks may well be related not to the spooky mites but to the low levels of activity of our hormones during the night, especially, natural corticosteroids and adrenalin. During the day, they are produced in higher amounts, and this diminishes the number and severity of the attacks. This explains the lesser need of medications in the day time by the majority of asthmatics. Additional proof of the insignificance or absence of an external effect is that there are those who soundly sleep in the same bedrooms full of mites. Yet further proof is that an allergy patient whose asthmatic attacks occur only at night can sleep in a tent with no mites around and still cough and wheeze. Should he look for these tiny culprits hiding in or behind the tent?
ALLERGY TO ANIMAL DANDER As a rule, allergists assert that pets should be removed from the house even if there is no direct indication that a member of the household develops symptoms upon contact with them. Literature contains protracted explanations on where the allergens come from (hair, saliva and glands with complicated
87
names), how an animals fur is contaminated during its self-grooming, and how public places may be full of this evil, readily airborne allergen. But one cannot escape from pets even if one removes them from ones own home. Many scientific papers seriously discuss whether non-allergenic dogs exist. Some suggest that the amount of dander produced by dogs is of importance, therefore shorthaired dogs are preferable. At the international conference on chest diseases in Toronto in 2000, cat dander was deemed by an asthma specialist from Torontos Mount Sinai Hospital to be the biggest culprit in causing asthma. He even blamed the dramatic rise in pet ownership for the rising hospitalization and mortality and joked that the same gene that predisposes people to asthma also makes them love their cats. It is a pity, this allergist did not consider more serious issues in his report, such as the extremely important point that only some people are victims of allergies. In general, cats are of special interest to allergists, and research is conducted on mind-boggling aspects of this supposed hazards. I fail to understand how researchers manage to make highly accurate calculations such as this one: males are more health-threatening than females, for they, allegedly, shed more dander. Once, I came across this: an adult cat allegedly sheds 1.5g of dander. To conduct such precise measurements, cats must have been closed in tiny cages to prevent the loss of the danger into the atmosphere or must have been wearing specially designed body-tight suits for dander collection. The Long Island College Hospital in Brooklyn, New York studied the effects of a cats color on the owners symptoms, and the results were presented in 2000 in San Diego, at the international conference for North American allergists, at their annual meeting. This report said that owners of dark-haired cats had allergies 6.1 more frequently than owners of light-haired cats. What accuracy! This phenomenon seems to support the centuries-old superstitions about black cats bringing bad luck. No explanation was offered as to how pigment could contribute to allergies. Paradoxically, a report made at the same conference by researchers from Detroit emphasized the protective effect of exposure to cats and dogs in early childhood. They found that infants exposed to pet dander during their first year of life were less likely to develop allergies, not only to these animals, but had overall less reactions to pollens and house dust mite. The team speculated that the harmful effect ascribed to pets should be reconsidered and referred to earlier European studies that had drawn similar conclusions. The titles of
some articles also speak in favor of pets. For instance: Does early exposure to cat or dog protect against later allergy development?8 So, before parting with your favorite pet, wait until science makes a final decision on whether they are dangerous or curative. An amazing study was once conducted at the Henry Ford Hospital in Detroit. It revealed that despite weekly bathing of cats with distilled water or their spraying with a preparation, which could reduce shedding, there was little improvement in the allergic patients. Although cats are not exactly animals that love bathing, distilled water cannot harm them. As for the spray, as a person who loves cats, I only hope the cats survived the chemical exposure. Water temperatures for washing pets and the frequency of the washing procedure are among highly debatable topics professionals carry out on the pages of their periodicals, at symposia and share with the lay sources. Will dry cleaning be the next issue for scientific research? Pets are so notorious among allergists that the 2000 issue Canadian guidelines on asthma specifically point to them: Have a non-allergic person bathe the pet weekly.9 Here, I want to refer to the official statistics on allergies. Although, they vary in different sources, I am inclined to believe those provided by the worlds leading immunologist, the editor of the European journal Clinical and Experimental Allergy, professor S. Holgate who said that 50% of the population suffer from allergies and asthma.10 In this connection, I feel sorry for pet owners: try to find a non-allergic nanny to bathe a cat in the society where every second person has some hypersensitivity! A formidable task. Despite the conflicting results of numerous studies, the guidelines worked out by the American allergists, and published in the March 2001 supplementary issue of The Journal of Allergy and Clinical Immunology have, among cockroaches and dust mites, a picture of a kitten as the most common indoor threat to be avoided or eliminated. Unexplained remains the fact that pets, as a part of the human household for hundreds of thousands of years, have never been considered so notorious in the production of diseases, even though exposure to animals must have been even higher in the past. Also unexplained is the fact that many pet owners remain symptom-free. In life, tragedy and farce often go hand in hand. The tragedy is that allergy has made the intentional decision to go off the right road and thus, leaves patients in a lurch. The farce is that phony science has been substituted and silly arguments about dogs and cats have been elevated to the level of the cause of the most common diseases of the century. The readily available unre-
89
stricted grants for research into irrelevant or insignificant areas contribute to their proliferation.
FOOD ALLERGY Allergists agree that allergy skin testing is unreliable for diagnostics, and this will be discussed in detail in the section on this topic. Still, despite their general agreement, skin testing for foods is often performed, and to the surprise of many, they are diagnosed with allergies to the foods they were consuming all their life without any reaction. These patients often end up with giving up on a productnaturally, without any relief in their allergy symptoms. Dieticians or doctors specializing in alternative medicine often suggest elimination diets to pinpoint the allergenic products. As a rule, patients know what foods cause severe reactions, and therefore those do not need analysis and challenge. Elimination of less allergenic products starts with keeping a journal on reactions that may occur when eating regular foods. The analysis of the notes may help to eliminate one or several foods that trigger mild to moderate reactions. Few comply with this lengthy and tiresome procedure. Besides, it is too often unsuccessful because allergy is mostly not limited to one or two food products; besides, traces of the allergenic substance may turn up in unexpected products, sometimes, even in allergy medications. According to the existing regulations, manufacturers must indicate on labels only those ingredients that exceed a specified amount, whereas a patient with a hypersensitive disease may overreact to a substance in minute quantities. Moreover, by excluding one or two allergenic foods, the patient may still develop allergic reactions to something he cannot pinpoint. These people are doomed to eating only at home and cooking from absolutely known ingredientsquite a difficult task. Misdiagnosis of lactose intolerance is especially common. Many patients came to me with such a diagnosis, but almost none of them had had the test necessary to establish that the particular hypoactive enzyme was missing. The diagnosis had been made solely on the basis of the medical history, or simply because dairy products, milk in particular, are among no-no products in the opinion of their doctor. They had given up on all dairy products, often with minimal or no success at all. A no-milk diet is especially difficult for children who are tempted with ice cream, milk chocolate and pastry, which their peers consume in their presence. Unable to resist temptation, these kids often eat the forbidden product and pay the pricesuffer from an itchy rash, a
stomach ache or discomfort, nausea, diarrhea, even an asthma attack. In most cases, however, the symptoms result from irritable bowel syndrome or an allergy to dairy products and not lactose intolerance. Although food allergy is considered to be an untreatable condition, like other allergies, it is readily treatable, in the majority of cases, with histamine injections because the causes and mechanisms underlying food allergies are the same as with other diseases of hypersensitivity. This explains why the symptoms disappeared or greatly diminished in my patients upon a short course of histamine therapy. This is different, however, with patients who have severe allergic reactions to certain identified foods, when a clear cause-effect relationship is evident. Histamine, successfully used for their other allergies, may not cover these foods, and they must be thoroughly avoided. Especially dangerous are anaphylactic reactions to nuts, and the patients prone to them should carry a special emergency kit and wear a bracelet that indicates the killer food. These cases require attention not only of the patients doctor but also of those who come into contact with the patient. I want to finish this topic with an unusual food allergencockroaches. According to the researchers from the University of South Florida, cockroach pieces are commonly found in different brands of flour. Dr. R. Lockey, an expresident of AAAAI and a member of the Editorial Board of JACI, the immunological journal, reported at the annual meeting of the Academy in San Diego in 2000 that the average person consumes two pounds of insect debris per year. The author suggested that many cases of allergy, including anaphylaxis, in which no known trigger is revealed, might be the result of the contamination with cockroaches. Now consider the following important fact: Cockroaches have existed almost as long as life on Earth, and thus, people have been involuntarily consuming them throughout their 6 million-year evolution. Now, it is clear that the standards of living, especially in the Western world, are improving, and regulations regarding the permissible amounts of bug debris are getting stricter. In fact, no other insect is fought with the ferocity that is used against cockroaches. I speculate that the amount of pesticides in our bread should be of more concern than the amount of the insects. Due to these chemicals, there should be fewer cockroaches in general and, hence, in flower, and this should decrease the allergy and asthma statistics at least in the cleanest countries. However, the opposite is happening: asthma incidence and morbidity are on the rise, especially in the industrialized world, and strangely, in relatively
91
unspoiled New Zealand. Paradoxically, the official statistics say that the countries without proper regulations on hygienic standards and, therefore, I assume, with the highest cockroach counts, such as India, have the lowest rates of allergies and asthma. Something must be wrong with the suggested concept, as there is evident discrepancy between the scientific declarations on allergy causes and the statistical figures existing in allergy theory.
SCIENCE LAUGHS OR A LAUGHABLE SCIENCE Suggestions regarding elimination are at times so confusing that they might sound humorous, were they not related to a serious medical problem. I will give several illustrations. Allergists often advise that patients with hay fever should keep the windows and doors closed so that less pollen gets into the house. Conversely, those patients whose allergies are allegedly triggered by dust mites, cockroaches and pet dander should always keep their windows open to prevent allergens piling up. What should those allergy patients do who have symptoms all year round: keep the windows closed or open? How can one enter or exit ones own home and not let pollen in? Can hay fever sufferers survive the long period from early spring until first frost with the doors and windows sealed against pollen infiltration? The answer can be found in a short story by the world-famous Canadian writer Steven Leacock. The author speculated on how to keep air fresh at home and made a suggestion: one should let in as much fresh air as possible, then close the windows and doors and never let this air out. Perhaps, this is the best way to get rid of allergies. Remarkably, Leacock gave his scientific advice without having a degree in allergy medicine. A serious medical source gives advice to those asthma patients who suffer most during ragweed growth: they should spend August and September in a ragweed-free parts of Europe or the west coast of North America. Should the same approach be taken by those who are sensitive to various pollens and suffer from April till the first frost? What if several family members have a similar problem? Will their bank account meet the need to change climates? In 1992, a Toronto allergist demonstrated a sense of humor when he told a journalist that avoidance of asthmatic triggers, such as pets and smoking, is preferable to the use of medications. If there is a cat, you have to get rid of the cat. If there is a father who smokes, you have to get rid of the father who smokes. Its that simple. In the year 2000, eight years after the interview and now in the role of the Vice President of the Canadian Allergy Society, this
immunologist repeated the same advice about cats and fathers, this time, in a medical periodical. A sense of humor is a commendable quality in a doctor, but in a medical publication, one would also expect a serious recommendation. There was none. Bernard Shaw once compared good advice to castor oil, which is easier to give than to take. Allergy patients are too often given castor-oil-advice. Moreover, if all these recommendations were given solely to patients, this could be considered part of their education on elimination of the offenders. Whether the patients followed the advice or not would be a matter of their choosing, savings in the bank and love for their pets and fathers. However, these astonishing masterpieces of medical thought are delivered by the experts in the field to an audience of fellow immunologists and become a part of established science. Look at the covers of Journal of Allergy and Clinical Immunology, and you will mostly see pictures of cats, mites and cockroaches. Although the work of allergists often incorporates things that do not exactly belong to immunology, they do such investigations as their professional (well-paid) mission.
THE CONFUSION OF TRIGGERS WITH CAUSES The confusion of triggers with causes reigns in this field of medicine; a scientific article in Contemporary Allergies (June 1993), can be considered the apotheosis of the confusion. It contains suggestions by the Allergy/Asthma Information Association as directed by the Canadian allergists. The association lists four factors as causes of childhood asthma and asserts that asthma develops when 1. the tendency for asthma or allergy is genetically inherited; 2. the baby is exposed to allergens; 3. he baby is exposed to pollutants; 4. the baby catches a viral infection.
The conclusion follows that if these four factors can be controlled during the first year of life, it is unlikely a baby will develop asthma. The authors name and title were not given, but in a scientific periodical on allergy such as this one, all articles are written or, at least, edited by an allergist. In science, to say that heredity and pollutants or infections can be controlled during the first year of a babys life sounds not like a scientific statement, but like a joke. The causes of allergy and asthma symptoms are within, not outside the body. The proof is that the most cared for babies who live in the cleanest environment may show symptoms of allergy and asthma.
93
Even among those representing the highest authorities in allergy, we can find these kind of incompatible notions. This is what a former president of the Canadian Association of Allergy and Asthma, wrote on page 67 in his article Asthma in Kids published in the Parkhurst Exchange in June 1996: Early viral infections, exposure to cigarette smoke and atopy seem to be the main causes. Viruses and smoke are triggers, while atopy is defined in medical dictionaries as some form of inherited predisposition to allergies. An evident discord. Unless triggers are differentiated from the real inner cause, we will read in scientific sources statements like: To explain the increasing prevalence of asthma in developed countries since the 1970s, experts have pointed to increases in indoor allergens because of better insulation of buildings.11 Although the author recognizes in passing that there are hereditary factors in the origin of asthma, he points his finger at insulation. Upon reading the article, patients may consider moving to a country where insulation is not needed. A perfect remedy to get rid of asthma! But then, why are there so many asthmatics in Arizona with its famous hot climate, which makes any insulation absolutely redundant? Do you know that, according to statistics, the worlds least polluted areas, Cunha Island in the Atlantic, the Western Caroline in the Pacific and Shetland Islands near Scotland have the highest asthma incidence? So does the close to sterile-clean New Zealand. At the same time, highly polluted India, as official statistics in allergy assure us, has one of the lowest asthma rates in the world. Another paradox.
WHATS IN A NAME? If allergies can start without an allergen, or, being started by one, can continue in the absence of this allergen, what is the legitimacy of the term allergic diseases? The conventional term allergy narrows and distorts the meaning of the diseases and unjustifiably pins them to allergens and thus, to IgE antibodies. It permits the medical profession to continue costly allergy testing to allegedly identify the offensive allergens but, strangely, almost never adjusts the treatment. It makes the search for triggers the centre of diagnostics and turns trigger elimination into the main, though ineffective, treatment method. Current concept of allergic diseases is confusing not only for laymen but for doctors as well. Furthermore, the absence of detectable allergens may be harmful to patients when a necessary medical certificate is denied because of
the prevailing orthodoxy and humiliates them by denying the reality of their physical disease, dismissing it as the condition of an unstable mind. This situation leads to absurdities such as the one in April 1998 when chronic fatigue syndrome was recognized as a physical disease by a Canadian court. Since when does medicine need judges to establish a diagnosis in medicine? In the majority of cases, symptoms are provoked by both identifiable specific and less easily identifiable nonspecific triggers; therefore strict categorization in this field of medicine only confuses the understanding of the immune processes; a change is urgently required. The idea of revising the term allergy is not new in science. In 1999, I came across an article unusual in its criticism.12 There I read that: There is probably no term more misused in medicine, both by physicians and medicine, than the term allergy. According to the author, restricting the disease to the IgE/mast cell mechanism is anachronistic, and there is a need to redefine all those terms invented decades ago. Will it be done? The change in terminology requires a change in understanding what underlies diseases of hypersensitivity. Expunging the word allergy from the medical vernacular would be a good start to better understand the pathophysiology of diseases, states the same source. In my opinion, expunging of the term now is difficult because it has become deeply rooted. Of course, the term hypersensitivity would be more appropriate as it points to the true cause of the symptoms, but then, what do you call the specialists that treat diseases of hypersensitivity? The more practical decision would be to leave the term as it is, but agree upon the real nature and meaning of hypersensitivity and to tell the truth about what is currently concealed. Namely that there is this duality of histamine and its chemistry, which lie at the heart of allergies. It is not the change of the term that is needed, but the change of these admittedly anachronistic views. Allergists do not consider it urgent, despite their every-day failure in the treatment. Allergen/IgE-based religion has become even stronger in the new millennium. Thus, in 2001, Harvard Medical School reaffirmed, in a study supported by a National Institutes of Health the concept that IgE plays a critical role in asthma pathogenesis (underlying mechanisms)13 The cover of the journal that published this article depicted the usual, most notorious allergensdust mites, pets, cockroaches, while nonspecific triggers have completely been excluded from the contents of this supplementary issue. Interestingly, just a decade ago, the data presented at the XIV Congress of the European Academy of Allergy and Clinical Immunology stated that only 15%
95
of asthma had allergic origin, 41% are non-allergic, and 44% were mixed.14 Have the diseases of hypersensitivity changed their origin, or has allergy medicine inexplicably changed its views within the decade that separates these works?
TO SIMPLIFY THE MATTER The suggestion below does not claim to be original, since all notions exist in this area of research. Still, they have never been acknowledged. For laymen, the term allergy is simpler than hypersensitivity, and both may co-exist in lay sources. However, science should operate with the terminology that reflects the real knowledge. Changing the name in scientific sources to diseases of hypersensitivity would immediately remove the limits erected by the narrow notions of allergen and allergies. Further, diseases of hypersensitivity could be divided into LATENT and ACTIVE. The term latent means hidden. The genetic defect is there, but the disease is dormant because the immune system is still strong enough to maintain equilibrium and withstand various stimuli. A person hit out of the blue by allergy symptoms will understand that he might have had the disease in a latent form, but in the absence of symptoms, considered himself healthy. The healthy parents of a sick child will realize that they might be the carriers of a minor genetic defect, which in combination, has become visible in their son or daughter. Specific IgE antibodies may be found in the absence of symptoms, which means that sensitization to certain allergens has already taken place, but the immune system of the host is (was) strong enough to withstand the assault. This explains why patients may, for example, not have symptoms in the pollen season, but tests reveal IgE antibodies to these pollens. With time, however, the cellular defects become stronger, and the disease may become active. An active hypersensitivity could further be usefully subdivided into several groups. Allergenic hypersensitivity as a term, should be limited strictly to the symptoms triggered by allergens. Hay fever, the condition due to pollens, may serve as an example. This form is practically always characterized by the presence of specific IgE antibodies and, more important, symptoms arising in the presence of the trigger(s). Physical hypersensitivity includes symptoms started by environmental events such as low or high temperatures, sunlight, vibration, pressure, electromagnetic waves, etc. These can be identified by a thorough
medical history and are often unavoidable. Naturally, no specific IgE antibodies are formed to physical factors. Physiologic hypersensitivity is the one in which the symptoms are provoked by natural chemical changes in the hosts body. These changes occur seemingly without any trigger, due to daily (called circadian rhythm), monthly or seasonal cyclic fluctuations, psychological stress, physical activity, etc. Moreover, the symptoms may seem to arise without a challenge, spontaneously, and may disappear in the same spontaneous manner. Physiologic factors are difficult to trace and even more difficult to avoid. Naturally, we cannot expect specific IgE antibodies in this sort of hypersensitivity. Chemical hypersensitivity, such as in cases of exposure to various occupational agents, pollutants, impurities and fumes may occur both in the absence and presence of the corresponding IgE antibodies. Mixed type is a combination of any of the above kinds of hypersensitivity and is most common.
Unlike the outdated IgE-based concept that fails to clarify the scope of the disease and appearance or escalation of symptoms in the absence of any evident allergen, this simple classification would remedy the situation. It would also save the often useless and painstaking efforts to find the offender and eliminate it. Such classification unites all five categories in the similarity of the underlying cellular processes, all of which are obviously immunologic and differ in details only. The main point, however, is that the re-classification would focus on the cause of the diseaseimproperly functioning cells and initial histamine hyperreleasabilityand thus lead to the potential for their repair.
Causes and Triggers in Allergy ENDNOTES

1. H. Bayram et al. Effect of ozone and nitrogen dioxide on the release of proinflamamtory mediators JACI 2001;107:287-94 2. Dorlands Illustrated Medical Dictionary 1988:49 3. Kay. Allergy and Allergic Diseases. New England Journal of Medicine. 2001;344:30-37 4. C.Pollard, Influence of maternal diet during lactation JACI 1996;97:240 5. Breathing Space 1993;l:3-5 6. L. Arlean et al. Mite and mite allergen removal. JACI 2003;111:1269-73 7. J. Birnbaum et al. Clinical study of bedding covers in mite-allergic asthmatic patients. JACI 1996;97:223 8. Hesselmar et al. Clin Exp Allergy 1999;29:611-7 9. Bowie & L-P. Boulet Whats new in asthma? Parkhurst Exchange. April 2000:121 10. J. Gleick Gasping for Breath. Time. September 1, 1991:36-43 11. A. Desjardins. Allergy Focus 1993;3:6-7 12. V. Beltrani. Point-Counterpoint. Journal of Cutaneous Medicine and Surgery. 1999;3:198-200 13. H. Oettgen, R. Geha IgE regulation and roles in asthma pathogenesis. JACI 2001;107:429-40 14. P. Plashke et al. Summary Service Review, 1989, p. 36.
97
PART THREE
ALLERGIC INFLAMMATION
THE TERM INFLAMMATION Whereas the term allergic inflammation is not new in relation to allergies and asthma, it has lately become especially accentuated. The classification of these diseases as inflammatory creates the impression that inflammation forms the basis for the symptoms, and that anti-inflammatory remedies for its suppression are justified. This concept has become so commonplace that often, medical sources do not even bother to name the inflammation as allergic, nor do doctors who prescribe anti-inflammatory medications explain to their patients what kind of inflammation it is. It is just inflammation. How well documented is the notion of allergies and asthma as inflammatory diseases? Allergy medicine provides only half-truths, probably to make it difficult to dethrone the declarations of the high efficacy of anti-inflammatory drugs in allergies and asthma. To reach the truth, we need to deal with the notion of inflammation. Dorlands Illustrative Medical Dictionary defines the word inflammation as a localized protective response elicited by injury or destruction of tissues (1988:835). Inflammation can be of different kinds. Tissue destruction that occurs due to bacteria or viruses is an infectious inflammation. Soft tissue injury due to laceration, contusion or burn may lead to a post-traumatic noninfectious inflammation or have a superimposed infection. At the site of inflammation, there can also be loss of normal tissue functioning. Irrespective of the origin, the inflamed area is red, swollen and painful due to tissue response to a microorganism, or due to damage and an increased number of various cells at the site. These cells destroy or neutralize the microor-
Allergic Inflammation
99
ganism and also participate in the healing process of the tissues. Depending on the severity of inflammation, there may be systemic symptomshigh fever and distress. The common features of all inflammations are their external cause and gradual development and resolution: the symptoms accumulate, reach their peak and slowly subside.
ALLERGIC INFLAMMATIONA PROPER TERM? The standard textbook of internal medicine, Harrisons Principles of Internal Medicine describes another inflammation and characterizes it as immunologically mediated. Such inflammation arises from excessive release of mediators and cytokines from mast cells, basophils and T-cells. As a deviation from the norm, this excess can become the basis for a disease. This kind of inflammation may not have a known external cause, and this makes it less understandable than the infectious or post-traumatic forms. Immune-related inflammation is the response or reaction of tissues to pro-inflammatory mediators. This implies the existence of events that precede it. Unlike other inflammations, in which the cause is external, in immune-related inflammations, the cause is internalan excessive mediator release. As in other inflammations, a local allergic event may grow into a systemic one by involving different organs through the transmission of signals from the cells in the affected area to those that are far away. Allergic inflammation fits perfectly well into the definition of reactive (to mediators) inflammation: it is a reaction of tissues and organs to the mediator/cytokine overspill by immune cells occurring as a result of deficient immune regulation. THE DIFFERENCES BETWEEN ALLERGY AND INFECTION Differences between allergic inflammation and other kinds of inflammations arise from its different nature. Indeed, the term allergic comes from the Greek different from ordinary. The first difference is that the originally dysregulated immune cells respond to an imaginary enemy, or there is no enemy at all. Therefore their response does not produce truly defensive chemistry.
llergic inflammation is a chemical, inflammation-like local and/or systemic reaction, secondary to dysregulated functioning of the immune cells. Unlike the external cause in other inflammations, immune-related inflammations arise from the internal cause deficient immunoregulatory forces responsible for excessive release of pro-disease mediators, of which histamine is the most important.
The second difference is the speed of progression of allergic inflammation compared to other types. An instantaneous, often unpredictable start and end are almost the norm in allergic inflammation, while it is the opposite with infections. Compare an abscess and hives. Have you ever seen an abscess form or disappear in front of your eyesredness, swelling, pain, pus? Never. It will go through predetermined stages: it will suppurate, rupture when ripe, and only then will the tissues start healing. Time is required for the invasion of bacteria, their conquest of the territory, the attraction of the numerous cells to the battlefield, and the pus production, which means, actually, that certain cells sacrificed their lives in the fight. The bacteria are gradually killed, either naturally by the cells or with the help of antibiotics. Only after the destruction of the enemy do the affected tissues start to restore their normal functioninga lengthy process as well. We see similar features in the case of injury or burn: all the hot or cold packs in the world applied to the area will not make the swelling disappear instantaneously. On the contrary, you may watch hives develop within minutes and fade in the same manner. Comparison of pneumonia and asthma is also helpful. You will never find a description of a miraculous instantaneous recovery from pneumonia such as: one minute a patient has a high fever, general weakness, productive cough, and in a twinkling of an eye, all is gone. In contrast, an asthma patient may experience a sudden attack, which seems to come from nowhere and total spontaneous relief in an instant, often with just one inhalation of a bronchodilator. This is how dynamic, volatile and erratic allergic inflammation can be. How volatile and dynamic allergic inflammation can be becomes obvious when considering the following typical situation. Imagine that it is ragweed season, and your asthma bothers you a lot. You board a plane, and as soon as it takes off, your symptoms disappear for the period you stay in the ragweedfree zone. However, no sooner does your plane land, your disease is back in full swing. If a common inflammatory process caused your symptoms, how could it immediately disappear when the trigger was gone? How could it develop again within seconds amid complete remission? If it was a flu or a tissue injury, the symptoms would not change on or off the plane. The speed with which your inflammation developed and resolved contradicts all the natural laws of the gradual development and resolution of an inflammatory process in tissues. The explanation is simple. On the plane, with the offender eliminated, the release of histamine slowed down, the cellular chemistry quieted down, and the
101
tissues immediately restored their normal functioning. So the symptoms disappeared. Having returned to the ragweed-saturated airport, your mast cells and basophils, hypersensitive to the offensive allergen, again exploded with histamine, and the shift of the chemistry followed. Your lungs and bronchi, the depots of mast cells and basophils, responded with a cough and constriction. If at that moment, we could watch the events in the bronchial area, we would see the signs similar to a true inflammatory processredness and swelling. Still, there was no time for a true inflammation to develop. In reality, the signs and symptoms were the result of the fluctuating cellular chemistry. The third essential distinction between infectious and allergic inflammations is in the number and specificity of inflammatory cells, which accumulate at the site. The degree of inflammation should correlate with the rising number of the cells ready to fight. The more severe the infection, the more cells participate. Their amassing manifests through the amount of secretions at the sitephlegm and pus. Logically speaking, in developed asthma, we should expect a high number of inflammatory cells in the bronchial tree mostly mast cells and T-cells (In trivial inflammation, we deal with different cells). Paradoxically, scientists often do not see the increase in the number of inflammatory cells at the site of apparent allergic reaction.1 This fact puzzles some authors, but it should not. It is not so much the number of the cells that determines the development of this inflammation, but the intensity of the pro-disease mediators secreted by them. Swift chemical fluctuations may trigger the most severe symptoms, with no time or need for many immune cells to accumulate. This dynamic pattern, however, carries a positive aspect: the quickly developed allergic reaction may resolve fast and easily, and this ease and speed are the proof of the reversibility of allergic inflammation. Of course, this is true only as long as the disease has not advanced to the point where the tissues involved have not structurally changed.
ANTIBIOTICS FOR ALLERGIES AND ASTHMA? Regrettably, the term inflammation used now both for infectious and allergic forms not only fudges over the facts in the perception of laypersons, but also for many doctors. The confusion of the terminology seriously affects therapeutic management. As a result, antibiotics, which are meant to target bacteria, are often used for allergies. Even during the height of the ragweed season or the warm months of tree pollination, congested and wheezy patients consume antibiotics for bronchitis in the absence of an identified bacterium. Sadly, the
patients condition depends on whether his doctor is capable (or willing) to differentiate these two processes and their causes. Causes of allergic and infectious inflammations are worlds apart, and so should treatment targets. In infections, it is eradication of the causative agent, while, in allergies, it should be restoration of the regulatory forces responsible for the balanced production of immune cells. Judging by textbooks and publications in the leading journal of immunology even in the new millennium, professorial staff of medical schools is often unaware of what underlies allergic inflammation: There is an increasing number of studies suggest that chronic asthma is associated with chronic infection, and that certain bacteria play an important role in the pathophysiology of asthma, states the leading periodical.2 The article continues: this opens another dimension for asthma pathophysiology and eventually for new treatment options, and then, the authors suggest antibiotics as a new option. The trend to present allergies and asthma as direct consequence of infections grows in parallel to the growing resistance and inability of the medical profession to help their patients. If this continues, medicine will never be able to treat allergies and asthma effectively. Proof of the irrelevance of antibiotics in allergies comes from a simple comparison: the majority of infectious conditions are cured by antibiotics, while statistics in allergies and asthma are getting bleaker with each day despite the frequent prescriptions of this drug group. Of course, it is also well known that uncontrolled and inappropriate use of antibiotics contributes to resistant bacteria exactly what we are seeing now.
ANOTHER GROUP OF ALLERGY MEDICATIONS The word anti-inflammatory in relation to drugs sounds innocent due to the unfortunate fact that antibiotics as an anti-inflammatory medication against bacteria, have become almost the norm in the treatment of even minor colds (usually viral in nature for which antibiotics do not work) and are perceived by the general population as safe. In relation to allergies, this inconspicuous term proposes that we should deal with the cellular chemistry in the same way bacteria are dealt with: kill the cells releasing pro-inflammatory chemistry. Antibiotics are unable to kill the disease-promoting chemistry, and so another group of medications called anti-inflammatory takes the stage. They are corticosteroids. These drugs have been in use for over half a century, and were first cautiously prescribed because of their side effects, but their use has recently been revived. The identity of the term anti-inflammatory applied both to
103
antibiotics and steroids strengthens the false impression of the analogy between infectious and allergic inflammations, and creates a sense of safetyalso false. With less and less hesitation, under the pressure of increasingly treatmentresistant allergies and asthma, and under the even worse pressure brought to bear upon doctors by those who formulate therapeutic guidelines, doctors prescribe and patients take steroids. What doctors rarely, if ever, reveal, and their patients are not informed of is that steroids belong to immunosuppressive remedies. The consequences? Read the word again. Can the already dysfunctional immune system of an allergy/asthma patient improve with a drug given to suppress the functioning of the immune system in general? Besides, all too often, consumption of steroids becomes as chronic as is the disease itself. Continuous suppression of the already weakened immunitynot a very encouraging prospect. Suppressed is the ability of the cells to produce not only the targeted bad mediators and cytokines , but the good ones as well, and in time, steroids disable the cellular lab. Not that doctors do this intentionally. Their textbooks keep them blissfully unaware of the origin of allergic inflammation, and the leaders in the field, as well as the manufacturers, assure them of the safety of steroids. With the primary cellular defects remaining unattended, the chances to arrest the resulting events are slim. The aggravating fact is that these immunosuppressive medications do not have any effective alternativeat least not as generally taught in medical schooland this justifies their aggressive prescription. The height of misunderstanding of what an allergic inflammation is, can be gauged by the fact that the notion of asthma being a chronic injury and repair response, with classic wound-repair factors participating in the disease is gaining popularity.3 There is an obvious conflict here. First, the nature of a wound is inapplicable to allergic processes. Second, a wound is a lasting condition incompatible with the reversibility of processes in allergies and asthma. Third, steroids impede wound healing, and therefore their imperative prescription for wound repair in allergies and asthma is more than contradictory; it is false.
WHAT UNDERLIES ALLERGIC INFLAMMATION No disease can be understood, classified or treated without the physicians comprehension of two notionsetiology and pathogenesis, therefore both acquire special importance. Etiology is the origin of a disease, the specific factors that cause it, while pathogenesis is the specific chemical and cellular
processes that occur in its development. The etiology of allergies has never been spelled out, and as a result, their pathogenesis is inconsistent. Inflammation is a nonspecific term of wide scope. Allergists have proclaimed inflammation as the cause of asthma and allergic diseases, therefore speaking of their etiology, we speak about the etiology of allergic inflammation. The etiology of allergies is the primary deficiency of the genes responsible for the protective regulatory immune tools, with the resulting low performance of the protective arm of the immune system that comprises T-suppressors, the histamine H2 receptors and cyclic AMP system. These etiological factors logically determine the pathogenesis of allergic inflammation. The Pathogenesis of allergies stems from the inability of the immune system to perform its autoregulatory role as nature designed it, namely to temper any negative response of the immune cells through their own energetic positive counteraction. The pathogenetic mechanisms include the primary excessive release of histamine and histamine-induced pro-inflammation cytokines and mediators, that is, prevalence of H1 negative effect over H2/3 positive effect. The response of the surrounding tissues mediated by this predominantly inflammatory chemistry is what science calls allergic inflammation. These definitions of the etiology and pathogenesis correlate with the textbook description of those in chronic diseases in general. As we have already quoted from the main medical textbook, the cell/mediator interactions involve a delicate balance among positive and negative influences and ultimately result in expression of an appropriate immune response. The slightest imbalance in these immunoregulatory circuits may result in aberrant immune function leading to clinically apparent immune-mediated disease.4 This is exactly what we see in allergies.
WHAT DETERMINES DRUG PRESCRIPTIONS? Knowing what underlies allergic inflammation, it is easy to understand what underlies the decisions regarding research, interpretation of the data and management of patients in todays allergy therapy. It is peculiar that with histamine being the core of all allergy processes, bad and good, at present, only from the name of the highly consumed anti-histamines can one guess this. All histamine-related positive forces of the immunity are apparently generally unknown. The person whose immune system has become an assailant needs to be defended from it, and the generous drug industry offers
105
its most powerful weapons. The main reason why allergists present allergic inflammation as the cause of allergies is to support the intention to expand the use of anti-inflammatory steroids. The unfortunate fact that physiological dependence develops over the time is also handy, for consumption grows with it. Although allergists insistently propagate the concept of allergic inflammation, they are evasive as to what causes it. Ask a doctor the same question about other inflammations, and you will get a clear answer: viruses, bacteria or injury. In relation to allergic inflammation, you will, most probably, hear about dogs, cats, dust mites and pollens as causes. Only medically uneducated patient can accept this idea, and a doctor must be equally illiterate to believe it. If you are lucky to find a doctor who mentions an exaggerated histamine release as the cause of your symptoms, ask him what makes you different from your neighbor who does not have this defect. Then, with the knowledge you have by now about histamine, ask this doctor what prevents medicine from using its self-remedial qualities. I doubt you will find a physician who will know what you are talking about. Do not blame him. Illiteracy in the field of allergy is a carefully nurtured fact, true knowledge is rejected, and research is supported in any area but the one that could help resolve the problemhistamine and related events and mechanisms. Instead of rejoicing in the reversibility that distinguishes allergy from other immune areas dealing with more resistant or therapeutically irreversible diseases, the leading allergists stonewall the spread of the existing true and relevant knowledge. The drug market has become the main source of medical information. It determines the value of drugs not from the standpoint of patients wellbeing but from the economic perspective. The drug market has become the underlying mechanism in the promotion of the secondary eventallergic inflammationas the origin of allergies. The etiology of this process is the sickness of our society in general and the sickness of medicine as its inseparable and the most lucrative field. These forces maintain the marriage of poor medicine and the rich drug industry.
ENDNOTES
1. 2. 3. 4. Editorial, The Lancet, 1991; 337:82-3 R. Martin et al. A link between chronic asthma and chronic infection. JACI 2001;107:595-601 Wenzel S. et al. Subepithelial basement membrane JACI 2003; 111:1345 Harrisons Principles of Internal Medicine, 1987 p. 334
PART FOUR
HISTAMINEGATE
If liberty means anything at all, it means the right to tell people what they do not want to hear. George Orwell Read not to contradict, nor to believe, but to weigh and consider Francis Bacon, The Essays
This chapter is for those whose educational background is in biology or medicine, and who are professionally interested in more specific details and references. It is also for patients who, out of need and/or despair, were forced to self-educate themselves scientifically in the field. The text includes the data covered in the part Immune Mechanisms but presents them on a deeper level. It also investigates the Watergate-type activities due to which allergy is losing its scientific credibility . The information in this chapter is based on the work of the pioneers in histamine research, researchers who are known to be the greatest authorities in modern clinical immunology. In medicine, unlike many other areas, the discoveries of basic and population science have no practical value unless they have clinical significance.1 Unfortunately, the research of these pioneers has not been applied. Had their discoveries been developed further and introduced into clinical practice, they would have helped save the world from the most common diseases of our timeallergies, asthma and numerous related conditions.
Histaminegate
107
First of all, although the researchers knew the mechanisms that underlie allergies in detail, they failed as clinicians because they were unable to observe clinical findings in patients and interpret them on the basis of their own theoretical discoveries. Second, when allergists realized how damaging these discoveries could be for the drug market, they used this lack of clinical substantiation to silence the well-researched theoretical findings many of which came from the labs of these allergy gurus. At present, this fundamentally significant material is virtually unknown, and the researchers themselves never mention their discoveries that form the foundation of allergy as a science. Astonishingly, some pioneers of histamine research have never actually declared a change in their position, they have gradually disappeared from public view during the 90s. Others, strangely propagate their newly acquired views on the immune processes in allergy and avoid the very name of the substance that launched their careershistamine. You may be curious to know if I believe that the scientists, whose works I am going to discuss and quote, are among the participants of the plot against histamine. My answer is: I do not know whether they have changed their stand voluntarily or under duressbut it is highly improbable that they are unaware of the vacuum that started to form around histamine in the early 90s, and which is now virtually complete. Their high status in medicine and their profound knowledge make it improbable for them not to have noticed the concealment of all the data pertaining to histamine, including their own earlier research. Conspicuous is also the absence of explanations of what necessitated the dramatic shift in their scientific views. Only time will reveal who was an involuntary witness, and who became a complicit participant in the plot. This chapter is a critical review of certain textbooks and numerous papers published in peer-reviewed journals. The authors are often the editors or board members of these journals, chairs of international conferences, writers and editors of textbooks, and they are thus, trend-setters in clinical immunology. By definition, a critical review is scholarship performed with the purpose to correct or improve. The concept of a critical review suggests analysis of the material with exposure of errors, misstatements and contradictions within a given text as well as comparison with other existing views. As any critical review, mine is not directed at the scientists, but at their works. Its purpose is to improve the existing bleak situation with regard to allergies and asthma. The emphasis is on the inexplicable turn in contemporary
allergology, on the active effort to silence and misinterpret those wellresearched notions and ideas that could preserve allergy as a science. Unlike most critical statements, books, and articles in the area of allergic diseases, this book offers a fairly easy concrete solution. I realize I am inviting the rage of allergists and hope that at least some of them will have the courage to admit publicly what they already acknowledge behind closed doors: their failure to manage patients with allergic diseases and asthma and to recognize the urgent need for a change. Experts are never right or wrong; they win or lose. Right and wrong are decided by proof; winning and losing are decided by who is doing the talking or talks the loudest, has the last, latest or only word, and is quoted by reporters, says a quote from The Globe & Mail. I understand, that my voice is a whisper compared to the loud chorus emanating from the central periodicals, huge textbooks and monumental monographs. To make myself heard, I choose to speak with their words taken from the same journals, textbooks and volumes and only point to the obvious discrepancies. Not merely in the details, but in the most essential material. For those who may say that being a general practitioner, I am unable to access and scrutinize the scientific work of the allergy moguls, I can say that my medical background does permit me to do this. I have a residency in internal medicine and specialization in allergology. For 8 years, I worked as an allergist in a republic of the former Soviet Union. The fact that in Canada, I did not acquire a local certification was due to the fact that I simply could not financially afford 4 or 5 years of residency here. For the 4 years of my internship and preparation for exams in Canada, my wife carried the heavy burden of being the only breadwinner in the family, and I felt I had a responsibility to start working as soon as possible. I am permitted to work as an allergist in Canada and nothing deprives me of my previous knowledge, or diminishes my interest and ability in this field. For 30 years, I have studied everything I could on histamine. In Canada alone, I have successfully treated about 2,500 patients with histamine, and many more back in Russia. In 1989 and 1992, I made presentations at international conferences about my own clinical experience and presented the supportive scientific data. These presentations covered the role of H2/3-receptor effects and the stimulation of cyclic AMP by histamine as the central regulatory mechanisms and therapeutic means. In the late 80s, I wanted to share my experience with others and suggested to the Ontario allergists having a discussion on histamine
Histaminegate
109
therapy. The response in Toronto was outright hostile. As Benjamin Disraeli once said, something unpleasant is coming when men are anxious to tell the truth. Indeed, on the initiative of allergists, without a single complaint from patients, I was persecuted and prosecuted. The College of Physicians and Surgeons of Ontario, CPSO, requested the scientific and medical proof for the validity of histamine therapy. When I submitted the irrefutable evidence, CPSO, instructed by its Deputy Registrar, Dr. John Carlisle, used such methods as false allegations (the fact later explained by the prosecutor, Robert Armstrong, as an error of a lay person in CPSOs committee), forgery of the signature of a court reporter, elimination of the central evidence, etc. My patients were the living proof of the efficacy of the histamine therapy. The scientific evidence I provided at my disciplinary hearings was so powerful that local allergists were unable to argue it on professional grounds, and the expert witness requested support from internationally renowned immunologists. The support did not come in as scientific sources or arguments but in the form of very short notes that rejected the therapy outright, without giving a single reason for the rejection. The allergy elite formed a united front in their denial of the therapywhich, I had proven, had restored the health of hundreds of my patients. Neither the allergists, nor the College which licenses doctors were interested in scientific fact or patients recovery. During and after my legal battles with the Ontario allergy medicine establishment, I continued to gather the relevant data. There is a Russian saying, that if the truth is not let in through the door, it flies in through a window. Indeed, despite the concealment and distortion reigning in allergology, there was sporadic leakage of the true findings even in the mid-90s which is the period of the peak of the suppression of information surrounding histamine. Todays situation in allergy medicine provides abundant evidence of a plot. I decided to uncover the conspiracy through disclosure of the hidden information. Extreme circumstances have made me the messenger, and this role obliges me to be impartial in the delivery of my message. The majority of the references in this chapter are from major textbooks and The Journal of Allergy and Clinical Immunology, JACI, the most frequently cited allergy/immunology journal in the field, as each issue proudly declares at its masthead. In many situations, the quotations do not reproduce a full sentence and may therefore look as if adjusted to suit my review. Not so. This is done out of need to simplify the text by cutting out those details that are not the topic of this book. Moreover, scientific texts
often seem to be written in a sort of medical legalese, incomprehensible for those who do not specialize in the field. Partially, this can be explained by the narrowness of the topic, but lately, mostly out of the need to hide certain elements, hence the need to talk allegorically. Besides. even the best researchers are not always the best writers. I abbreviate long complicated sentences to help understand the authors ideas and emphasize in bold those elements I consider most important. If you follow these quotations, you will see that the drastic changes in the views of the leaders in allergy can be traced back to 1991. That is when the key findings suddenly began to disappear from all major sources and were substituted by insignificant, distracting data that gradually started to acquire prime importance. The coup in allergy medicine was as smooth and fast as the velvet revolution in Prague. The well-organized concealment and the smoothness with which the changes occurred need major financial backing, and this makes one strongly suspect the pharmaceutical industry behind the scheme. Still, we cannot blame the sponsors as much as the performers of this revolution, since, like any other, this one could not have taken place without a zealous support of the highest medical authorities, doctors by profession. Medicine is considered to be a blend of science and art. This chapter will try to prove that contemporary allergology cannot be considered as either: it has thoroughly buried its basic findings and prevented their use in clinical practice. As a result, the incomplete and distorted data it presents as science cannot form the basis for science or art. The frightening official statistics in asthma and allergies are the undeniable proof of the failure of contemporary clinical allergy practice to manage patients properly. There is hardly any field in todays medicine so full of discrepancies, concealed information and misrepresentation. At the same time, there is hardly another area of basic science so deeply studied, and so evident in its conclusions about the origin of allergies and asthma, and what should be the target for therapy. The fact that, by definition, allergies and asthma are reversible diseases makes the concealment all the more scandalous. ROSS ROCKLIN was Professor of Medicine and Chief of Allergy Division at the New England Medical Center in Boston during the height of his histamine research. He later became Senior Associate Director of Clinical Research for Boehringer Ingelsheim and then for Astra, known then as Astra Zeneca. Both are pharmaceutical giants that produce allergy and asthma medications. I have not come across any publication by him in more than a decade.
Histaminegate
111
R. Rocklin was privileged to be an author in fundamental textbooks. This fact establishes him as a generally recognized scientist whose knowledge in this field is indeed vast. Among his many publications is a chapter in Immunopharmacology, a theoretical textbook published in 1982 (ed. by P. Sirois et al.)102 and another chapter was in Allergy 1985 (ed. by A. Kaplan),11 a textbook aimed at experts in allergy and clinical immunology throughout the world. Rocklins chapters are similar in both textbooks. No other textbook before or after has provided such a complete picture of the histamine-based regulatory immune mechanisms that underlie allergy. The author summarizes all the available research on histamine, including his own. Both texts are unique sources of extensive information on histamine as the principal participant of all pro- and anti-inflammatory immune processes in allergy and on its unique role in the functioning of the immune system. In Immunopharmacology, the title of Rocklins chapter is straightforward and explains what it is about: Immunomodulation of Immunity and Inflammation by Histamine. Although the title was later changed to Role Of Cell-Mediated Immune Responses in the textbook Allergy 3 years later, its essence did not change at all. Both chapters explain the principles involved in allergy, i.e. the genetically predetermined primary defects, namely the original H2-receptor defect that accounts for T-suppressor insufficiency and histamine hyperreleasability by mast cells and basophils. The author shows that this defect can be corrected through re-activation of these deficient receptors. Activation leads to the regeneration of T-suppressors and the inhibition of the harmful mast cell/basophile histamine release. Rocklins texts are forthright about the dual role of histamine in the functioning of immunity. One reads under the diagram on page 182 in Allergy 1985: Some effects of histamine are proinflammatory and enhance immune reactivity, whereas others are antiinflammatory and decrease immune reactivity. On page 192, Rocklin develops the concept that when immunotherapy with allergen extracts turns out to be successful, one observes H2 receptor activation with resultant generation of T-suppressor cells. This idea can be logically developed further. First, if active H2 receptors can end allergy symptoms, they should become the target of any therapy. Second, if well-selected allergen extracts can activate H2 receptors, histamine can definitely do it even better, as nature itself selected histamine for this. We may only speculate why in neither of these textbooks he consider histamine therapy, which must suggests itself. It may well be that this brilliant
scientist understood, even at that early stage that, as a therapeutic means, histamine treatment might be highly undesirable to financial sponsors of medical research. The fact that the central findings for allergy researched and published by Rocklin have gone into oblivion and exist only in past literature is indicative of financial issues involved. In 1981, a year before the publication of Immunopharmacology, in coauthorship with another giant in immunology research, K. Melmon, Rocklin wrote an article entitled Autacoids as Modulators of The Inflammatory and Immune Response.2 The paper is primarily on histamine, and the word modulator in the title says it all: histamine modulates immune inflammation. The text reads as follows: new drugs developed from mediators of inflammation might be effective modifiers of the immune processes. And further: As feedback control by autacoids can serve to modify immunity in a precise and predictable way, we should probably begin devising a strategy for using these self-medications as alternatives to drugs that are less selective in their actions. In 1984, a year before the publication of the textbook Allergy, Rocklin again expressed the idea of the anti-inflammatory features of histamine in his lectures at the Continuing Medical Education courses sponsored by the American Academy of Allergy and Immunology. The AAAI (now called the AAAAI, due to the added the word asthma to its name) is the flagship organization for all allergy and immunology experts, and these annual lectures are, in essence, the evolving guidelines for practicing physicians. Rocklins presentation that year was later published in JACI and states that only histamine and no other drugs leads to the elaboration of suppressor factor through T-suppressor activation. Pay attention: histamine is called drug! The title of the article, Histamineinduced suppressor-cells activity does not leave any doubt about the role of histamine in the functioning of the cells that control allergic reactions. Ability to activate suppressor cells... places histamine into the category of a ... physiologic ... autacoid,3 that is: a self-healing bodily substance. As was said before, autacoid is translated as self-remedy, while dictionaries define the word physiologic as characteristic of normal functioning, devoid of pathologic features. What else can one want of a medication? It can hardly be doubted that a safe chemical normalizes the functioning of the main allergy fighters is like no other drugs! This ultimately means that control of allergic inflammation is possible, and the patient has a medication-free life! The table on page 449 summarizes the regulatory effect of histamine upon the immune system,
Histaminegate
113
and its title is again forthright about the role of histamine in the immune system; it reads: Modulation of cellular-immunity by histamine. The article says: Once released, histamine presumably activates the suppressor limb of the immune reaction and dampens the response by decreasing production or release of inflammation-promoting lymphokines (cytokines). The suppressor limb involves mainly H2-receptor activation of T-suppressors that inhibit allergic reaction. It is of special importance that for support, Rocklins article sent the reader to an earlier work by L. Lichtenstein who is another pioneer in the research into the modulatory properties of histamine. His works will be discussed below. Rocklin devoted another lecture of his to immunotherapy.4 On page 332, the author names the therapeutic targets for immunotherapyinduction of suppressor cells/factors and decreased reactivity of mediator-releasing cells. This simply means that activation by histamine enables T-suppressors to inhibit all inflammation-promoting factors in allergy and also dampens the hyperreleasability of the immunocompetent cells. Rocklin reinforced these ideas two years later in the 1985 textbook Allergy by adding that not only are T suppressors activated by histamine, but also their very existence depends on it. On page 185, he talks about the generation of histamine-induced suppressor T cells and histamine activation of human suppressor T cells. There was no conspiracy around histamine at that time, and Rocklin could easily call a spade a spade. So could others. Through the 70s and 80s, the content of many articles and their titles were crystal-clear about the immunoregulatory role of histamine. For instance, some of the titles were: Histamine-induced suppressor factors or autacoids as modulators of the inflammatory and immune response; or Modulation of cellular-immune responses in vitro and in vivo by histamine receptor-bearing lymphocytes; or H2 receptor and the immune system, etc. All of this was before the era that started in the 90s when histamine became mysteriously taboo. Textbook have stringent requirements to present either the established information or explain that the given findings are being questioned or reconsidered. The requirements should be especially strict, if the presented material is based on morphology, physiology and molecular biologybasic sciences that do not usually change in essence but expand through new research. There is no doubt that A. Kaplan, the editor of both editions of the textbook Allergy, would have abided by these rules, or his position among his colleagues would have been untenable.
Now imagine my surprise when in October 1997, at the university bookstore, I unsealed a fresh copy of the second edition of Allergy.103 My first intention was to see if there was new information on histamine, therefore I looked up Rocklins name in the table of contents. By then, I had already noticed the growing tendency to omit all histamine-related immune-modulating tools and events. I had an inkling that, for medically unrelated reasons, the direction of the new textbook might shift. What I saw exceeded my worst fears. The only image I can think of here is that of a beheading. Allergy as a clinical science was beheaded: Rocklins chapter, the only one on the primary underlying mechanisms in allergy, had disappeared from this new edition. The strangest thing, however, had happened to T-suppressors. The very term T-suppressor was mentioned only in an allergy-unrelated chapter which on page 783 questioned the very existence of these cells by asserting, without any reasons given, that these cells had supposedly become one of the major controversies in immunology. A material cell disappeared. This raises a number of very basic and disturbing questions. How can one explain the existence of their marker, T8 or CD8+, evidenced by the most reputable medical textbooks and dictionaries? Are we suddenly to believe that Gershon and his colleagues had in 1972 discovered some sort of phantom cells, which they had capriciously named suppressors? Was this discovery a hoax or a fantasy? Furthermore, how can one explain the discovery of the Is (immune suppressor) genes that govern the functioning of the non-existing T-suppressors? How can counter-suppressor cells exist if there are no suppressors? How could the Clinical Immunology Committee of the International Union of Immunological Societies at the World Health Organization point to expanded suppressor cells as their target in the improvement of immunotherapy if all of this was fantasy? By whom, how and when were these cells abolished? Mind you: T-suppressor is not just another cell. It is (was?) the key figure in the regulation of all allergic processes of the immunity. If it was lost, banned or re-classified, this unique fact had to be registered in all medical sources and, above all, be explained! It had not. With the disappearance of T-suppressors from all the chapters of Allergy 1997, H2 receptors, which are the distinctive feature of these cells, also went missing. It is as if they were not discovered in the sixties by the Nobel Laureate James Blackwith the Nobel Prize seemingly being the only record left of this discovery. If one was cynical, one might now expect, that the next
Histaminegate
115
step will be the exclusion from the genome all of those already detected genes responsible for the functioning of both T-suppressors and H2 receptors. With Rocklins chapter excised, the facts and details, which substantiate the mechanisms that underly allergy and prove the inseparability of these mechanisms from histamine, we have a situation now in which there is no real explanation in the current textbook, Allergy 1997, for what allergy actually is. This disappearance of histamine cannot be accidental: all mechanisms of allergy, disease-promoting as well as protective, have an innate dependence on histamine, and hiding its central role has led to a fundamental misrepresentation. The burying of this knowledge was done cautiously, so that it wouldnt be too obvious. On the surface, everything appeared proper: the chapters in the revised textbook written by other authors listed all the cells (except Tsuppressors!) and their mediators and cytokines participating in allergic reactions (except, of course, the histamine-induced suppressor factors). However, listing of the cells is not enough to explain their effects, significance and interrelationship or show what to correct in the case of cellular malfunctioning. Now, with everything related to histamine being omitted, the events in allergic reactions have become hopelessly distorted. Thus, while the chapter on mast cells and basophils provides a general description of their functions, it does not specify that their release of histamine is the cardinal event both in the early and late phases of allergy. Nor is there an indication that the cause of these cells hyperreleasability is their deficient H2-receptors which are unable to turn off the leakage. Allergy 1997 is not so much a textbook, but a collection of puzzles with all the needed clues gone. It does not answer the main questions: what cells and what receptors control the balanced production of all cellular chemicals in healthy people, and what goes wrong and leads to the disease. The new textbook has created the impression that the immune system of an allergy patient consists of cells whose chemicals work solely against the host. Naturally, only the helping hand of the drug industry can correct this situation. Not surprisingly, therefore, the second edition of Allergy 1997 has increased in the number of pages now devoted to medicationthe antihistamines. You might object that as science develops, even some of the most solid findings of the past may become obsolete, and this could be the reason for changing the material in the textbook. That is a reasonable objection. However, if this had been the case during the 12 years that separate the two
editions of the textbook Allergy, why was it not indicated, explained or updated? Why was there not a word about such changes that would justify such an abrupt departure from previous findings? Why were the old data simply cut out? The fact is, the old findings have not changed. Nature has not suddenly abolished T-suppressors and H2 receptors or changed their central regulatory role in allergy. Rocklins description of the pivotal role of histamine and Tsuppressors in the immune functioning is as accurate today as it was in 1982 and 1985, when he wrote the chapters in Immunopharmacology in Allergy 1985. What is totally confusing is the fact that this new textbook, which went through such pains to excise all reference to the existence of regulatory cells in allergy, had no difficulty to accommodate these same regulatory cells in allergies in a separate chapter devoted to cancer and participating T-cells! The proof that Rocklins description of the immune mechanisms has remained the basis of allergy medicine can be found in Pharmacological Reviews, a huge collection of the most essential scientific papers and a most reputable source of references.5 The title of the sub-chapter on page 69 is H2 Receptors And The Immune System and reveals the special role of these receptors in the functioning of immunity; the author specifically refers to Rocklin and Lichtenstein as the discoverers of the immunomodulatory role of H2-receptors. So here, the established and unchallenged facts have snuck in by the back door. Up until now, Rocklins ideas have never been questioned or rejected as invalid. After a decade of silence, the immune mechanisms described by him can still be found in prestigious periodicals. Mostly, these are silent references, and only in very rare situations, the text gives him the credit for the discoveries. Earlier, we referred to the essential work sponsored by the National Institute of Health in which it is said: Interestingly, in the 1980s Rocklin and co-workers published several studies showing that histamine induced suppressor-cells activity and suppressor factor.6 The article names this factor, which is Il-10 (interleukine-10), and which is accepted by todays allergy medicine as the central tamer of allergic reactions. The authors of the article strongly suggest that histamine, apart from exerting potent effector function in inflammation and allergy (mainly via H1 receptors), may have important immunoregulatory functions via H2 receptors expressed on immune cells. Actually, this is the only contemporary work I came across among the many covering Il-10 that clarified that this central anti-inflammatory chemical is a histamine-induced suppressor factor. None of the numerous
Histaminegate
117
publications on Il-10 I have read related it to Rocklins discovery of suppressor factors in 1977. The creations of nature, such as cells and their products, seem to selectively disappear if they are in any way related to histamine. In 1992, CPSO, which is the medical regulatory agency that licenses doctors in the province of Ontario, initiated a Discipline Hearing against me and prosecuted me for my nontraditional (and successful) use of histamine. In 1993, in preparation to the hearings, my lawyer, Howard Kerbel, called Rocklin and asked him to confirm his theory on immunomodulation via H2 receptor and the protective properties of histamine. I was present at their telephone conversation. At first, Rocklin denied any research of his in the field! Finally he realized that the lawyer he was speaking to was well informed on the subject, and he said, You got me, but it would be a conflict of interest for me to speak on the subject. At least he was honest about the situation: his employer was now the pharmaceutical giant Boehringer, and his previous research on H2-receptor stimulation was the opposite of the histaminesuppressing allergy medications produced by the company. Rocklin suggested to my lawyer that he call K. Melmon. KENNETH MELMON was professor of Pharmacology and Medicine at Stanford University. Starting in the 60s, his research was primarily in histamine, its immunopharmacological properties, especially the biochemical stimulation of cAMP via H2 receptor. He also developed and tested histamine derivatives. Since the 90s, his name, like that of Rocklin, can be found mostly in references, and even this use is waning. Melmon died in April 2002 at the age of 67, and the central periodical for allergy, the JACI, did not even mention the death of this giant of immunological research. If one day, clinical allergy decides to put to clinical use his theoretical findings, or starts using his histamine congeners, he will acquire the reputation of the savior of all allergy patients. I say ifbecause the essence of his work would be totally at odds with the trends of contemporary therapy, which is drug and anti-histamine based. Melmon was a frequent co-author with R. Rocklin and L. Lichtenstein. As early as 1973, K. Melmon and L. Lichtenstein and others described how histamine self-inhibits its release via the H2-receptor and thus acts as an immunomodulator. They clearly elucidated the chain of events: histamine activates the H2 receptor; the receptor sends a signal to the intracellular system responsible for cAMP enzyme production;
the levels of this enzyme accrue; the messenger RNA governing the synthesis of anti-inflammatory chemistry is activated; the increased production of anti-inflammatory chemistry reverses allergic reaction. In this chain, the histamine/cAMP team becomes the core of the mechanisms controlling allergic reaction, and the authors therefore also suggested that the protective effect of histamine observed in vitro (in the test tube) should be examined in trials in vivo (in living animals and people).7 Still earlier, in 1971, the same authors thought of using the H2-receptor effect in treatment and suggested particular concentrations (10-6M) of exogenous histamine to stop the release of endogenous histamine.8 In laymens language this means that synthesized histamine inhibits production and release of body histamine. Congeners developed by Melmons team are drugs specifically targeting H2 receptors, and indeed, they show impressive results in animal testing. All drugs are first tested on animals and if they are safe and effective, they are subsequently subjected to human trials. In the case of histamine, it is most helpful that almost a century after its appearance, it is probably the most researched drug on the market, and its properties are known inside out. Being a physiologic autacoid, it lacks toxicitythe major concern in all drug developmentand its derivatives are safe and promising for clinical use. This is what Melmons article said in 1985; it had a most poignant title: Are Autacoids More Than Theoretic Modulators of Immunity? He wrote at that time: The autacoids include substances such as histamine... The hypothesis that autacoids might modulate immunity slowly emerged... In the last 1520 (!) years a number of investigators have proven the validity of focusing on this hypothesis.9 I emphasized the word focusing to show how far allergy has departed from that insight. Now, another 20 (!) years after that suggestion was made, and almost 4 decades having passed altogether, simply to mention histamine is equivalent to blasphemy, even worse, to speak of its self-remedial qualities. That article advocated application of histamine and its derivatives. It stated that in vivo immune modulation now seems appropriate and asks rhetorically, who is applying the observations clinically? Now read the following carefully: Why focus on histamine and its congeners as a prime investigative autacoid for immune modulation? So far, it is THE ONLY autacoid shown to have potential modulating influences on both early and late phases of immune inflammation.9
Histaminegate
119
Melmons works reveal that he never changed his opinion about the curative properties of histamine. The 1996 textbook Therapeutic Immunology (ed. by K. Austen et al.), with Melmon as an author, stated on page 192: Histamine appears to play an important role in limiting the inflammation processes unlike any mechanism known for classic immune-suppressive therapeutic agents. The authors believe in histamines potential as a therapeutic immune-suppressive agent.10 But, no matter how safe and good histamine congeners may be, one should have strong reasons to doubt that they will be used in medical offices in the near future, and this is why. From the above-cited article, we know that agents now are available that stimulate one or the other receptor on selected lymphocytes, which means that for, at least 20 years, safe and effective drugs have existed that could selectively activate the needed H2 receptor without activating its counterpartthe H1 receptor. Allergy sufferers are definitely interested in knowing where these agents are. So are doctors who deal with resistant allergies every day. Still, the congeners have not been tried even for those patients with immune-related inflammation who are not helped by any other medications. My opinion is that Melmons research reached that stage in clinical medicine where even the best minds are not free to choose the direction of their work. For example, research grants are almost entirely controlled by the pharmaceutical industry, and every contract contains a gag clause which provides the sponsor with the power to disband the research effort when its results begin to contradict the sponsors financial interests. These gag clauses are illegal in Canada, but they continue to control research anyway.12 This is equivalent to a Do not trespass! sign blocking practical application of all medical research. It seems that Melmons findings were so compelling that they had to be buried. Not surprisingly, the second (2001) edition of Therapeutic Immunology no longer contains that chapter written by this great scientist and his team. The process of research censorship appears to be systematic, because the earlier 1997 edition of this same source, the Pharmacological Reviews, already then excluded those parts contained in its even earlier 1990 edition, namely the information that stressed the anti-inflammatory features of histamine and the possibility of using histamine congeners developed by Melmon. For example, the following passage was dropped: These data suggest that histamine-inducible suppressor cells may be important for normal immune regulation and raise the possibility for the use of H2-selective and lymphocyte-selective agonists as immunosuppressant agents. An exciting advance in this area of
research has been provided by the development of lymphocyte-specific histamine derivatives. A number of histamine congeners have now been produced. Two references to Melmon are given at this point.13 The curative properties of histamine did not change with time, and only the editors know why the key elements needed for therapeutic purposes suddenly needed to be hidden and were deemed so irrelevant as to be removed from the text. This elimination makes even less sense in view of the regret the editor Dr. Hill expresses over the neglect of histamine in the report made by his team at the International Union of Pharmacology. This report was later included into the 1997 edition of Pharmacological Reviews.14 I can only imagine the disappointment Melmon must have felt when in the last years of his life he realized that all his gigantic work was unclaimed for clinical application and would not be used to help patients. I have read all the works by Melmon on histamine I could find. Within our correspondence, I was also privileged to view his not yet published work on a newly discovered histamine receptor. His extensive knowledge of histamine activity, and especially his desire to find a practical solution to the problem of immune inflammations through histamine and its derivatives, impressed me most. In 1991, I wrote Melmon a letter about my use of histamine for asthma and allergies and enclosed the following abstract, already accepted for the presentation at an international congress.
H2/3 Effect in Allergy
In acute state of allergy, the proportion of histamine to other mediators is 300:10(PGD2):1(LTC4); in pollinosis, H is the prevalent mediator. Unlike the pathological H1-receptor action, H2/3-receptor protective effect described in patholophysiology and pharmacology works mainly via a) activation of intracellular cyclic AMP in mediator cells; b) cytokines with histamine-induced suppressor factors determining Ig levels, perpetuation of allergic disease, its chronicity, including non-specific bronchial hyperresponsiveness; c) autoregulatory H3 receptors that together with H2 receptors provide histamine and other mediators inhibition. Thus, H2/3 effect is the key autoregulatory of humeral and cell-mediated immunity, hence, of allergic inflammation. The existing consensus re SUCCESSFUL hypo sensitization criteria emphasizes histamine-induced/ dependent mechanisms: decreased mediator release (basophile histamine release test) and stimulation of suppressor T-lymphocytes with generation of H2-
Histaminegate
121
receptor-bearing cells, while IgE level changes are inconsistent. This adds to the classical theory based on antigen-antibody mechanism unable to explain certain events in pathogenesis and suggests that the basis for allergy might be an inherited or acquired receptor/enzyme deficiency to be corrected by stimulatory H2/3 effect of exogenous histamine and/or conventional hypo sensitization. The hypothesis uniting non-specific and specific factors is supported by works of few authors successfully using histamine and by my experience with about 2,000 patients with various allergies, over 75% of whom were treated with histamine. The original technique for the method is described elsewhere. The preliminary results, especially in cases of hay fever in season and bronchial asthma, are superior to those by any other treatment 15 I asked Melmon if he was interested in the effect his research could have in clinical practice and if he did, I would send him additional information. In response to my letter and abstract, to prove the seriousness of his interest, Melmon supplemented his letter of August 28, 1991 with his impressive 30page curriculum vitae and his articles on the (crucially significant) dual role of histamine. He even sent me his yet then unpublished paper in which a hand-written sign confidential crossed each page. In his letter (see Appendix) the scientist wrote: I am substantially interested in knowing how you came to the conclusion, which I share, that H2/3 activity is likely to be immunosuppressive (suppresses allergic inflammation through activation of protective immunocompetent cells). Encouraged by his interest and support, I sent Melmon my recently published article, which had references to his work. Melmons second letter of December 3, 1991 ended with I do look forward to further opportunities to reviewing and sharing your excellent work. I was happy that the great researcher was supportive of my work, but our communication was interrupted for reasons of a nonmedical nature. In 1993, the journalists of the Canadian Broadcasting Corporation, who were sympathetic to the plight of allergy/asthma sufferers, were preparing a national TV program of the CPSOs actions against my histamine therapy. In a telephone conversation, they asked Melmon to comment on my work. Melmon refused to do so. By that time, I had already become a medical dissident. Melmon had been contacted by the prosecutor, as the latter admitted later during my discipline hearings, and, most probably, he had been told that it would be wiser to sever our communication!16
I have the highest respect for the work done by Rocklin and Melmon. I believe that for their contribution to allergy research, they deserve much more credit than allergists have given them. But the very reasons for which they should be revered are the reasons for concealing the essence of their work the histamine connection. LAWRENCE LICHTENSTEIN is a former president of the AAAI and Director of Johns Hopkins Asthma and Allergy Center, one of the worlds most prestigious medical schools. He is a recipient of the Research Career Development Award of the National Institute of Allergy and Infectious disease of the US Public Health Service given for his research on the underlying immune mechanisms of allergy. Lichtenstein is a prolific author and editor of papers and textbooks, key-note lecturer at international forums and committees, and a board member of leading medical periodicals. Lichtenstein and Melmon teamed up at the time of their most outstanding discoveries related to histamine and produced a number of articles of such basic importance to allergology that they continued to be referred to, even at the peak of the censorship of works on histamine. Curiously, at the time his own presentations began to show a dramatic change in his views on histamine. None of his works or oral presentations has provided any scientific explanation for these changes. Lichtenstein started to study the H2-receptor functions soon after their discovery by James Black and he was actually the first to show that this receptor is an instrument through which histamine realizes its immune modulating function. Together with Melmon, Lichtenstein specified the concentrations at which histamine self-inhibition actually takes place, namely at 106M (i.e. ten to the power of minus 6).17 Two years later, in another article with the self-explanatory title Inhibition of histamine release by histamine controlled by H2 receptor, they say: exogenous histamine could stop the release of endogenous [histamine]. In another article, he again pointed to mast cells and basophils as the major histamine-releasing cells and specified the concentrations at which the leakage stops.18 The article develops the idea that the H2 receptor located on the histamine-releasing cells, possibly mediates an inhibitory effect on the inflammatory responses. It is of interest that the authors compare the histamine effect to that of antihistamines and
Histaminegate
123
favor the first: no clear effect of antihistamines on the inhibition of histamine release was observed. Moreover, they add that in high concentrations, antihistamines were cytotoxic, that is, their toxicity disrupts cellular functioning. (It should be of great interest to patients that today, allergists are suspiciously silent about the self-inhibitory effect of histamine as well as about the toxic side effects of antihistamines, but instead are very vocal about their supposed benefits). Four years later, Lichtenstein was still researching the H2-receptor effect and wrote: Our results suggest that differentiation of T-cells is accompanied by appearance of histamine (H2) receptors; and again the authors specify the protective role of these receptors in allergy.19 In another paper written with Melmon, Lichtenstein expresses the idea of the exclusive anti-inflammatory role of the H2 receptors in the functioning of T-cells, mast cells and basophils. At this time of the most intensive research into histamine, the authors theorize about the possibility of transferring the histamine H2-receptor effect into clinical practice and so they wrote: understanding of such a regulatory mechanisms may open the way to new therapeutic approaches to treatment of immunologic and inflammatory disorders in man.20 In other words, activate the H2-receptors, and the differentiated T-regulator-suppressor cells will mediate an inhibitory effect on the inflammatory responses. Only the scientists themselves can tell why they stopped short of employing histamine clinically. Was it their insufficient clinical expertise? In the early 90s, Lichtensteins stand inexplicably changed. In 1994, Toronto allergist Dr. Allan Knight, was appointed as an expert witness by the CPSO during my disciplinary trial in order to disprove the benefits of the therapeutic use of histamine. The official transcripts contain his admission during cross-examination that he was unfamiliar with the H2-receptor immune modulating function described in depth by Lichtenstein 20 years before. Knights lack of expertise and knowledge in histamine properties and treatment prevented him from providing scientific arguments and/or sources against the histamine immunotherapy or desensitization I was using, and so the expert decided to come to the hearings with a better weapona personal letter from Lichtenstein. Judge for yourself whether this letter of January 19, 1994 can be recognized as providing a scientific basis for disproving histamine therapy:
Dear Dr. Knight: Thank you for informing me about the physician who is quoting my published work to defend his therapy. I have never written anything about histamine desensitization. There is no scientific fashion in which anything I have ever published could be used to defend histamine desensitization. I personally believe, together with all of my colleagues, that histamine desensitization has no role in any medical therapy. The high professional status of Lawrence Lichtenstein and his profound knowledge of immunology did not require him to solicit support of all of his colleagues in order to write this short note and point to the supposed consensus in rejecting histamine desensitization. I was an unknown general practitioner, whereas Lichtenstein was at that time the president of AAAI. Strangely, he did not say that histamine therapy would be dangerous or ineffective. He seems simply to have wanted to dissociate himself formally from his earlier histamine research by saying he had never written about histamine desensitization. His carefully worded 5-sentence note contradicted his own previous research: in the past, he had described histamines H2-receptor activity as immune modulating, whereas now, he opposed its therapeutic use for immune modulation. Moreover, the word immunomodulator can only mean the wide-scope activity of the drug in a live body. Lichtensteins note suggested that I had misinterpreted his ideas on possible histamine desensitization. If so, I was not the only one. The misinterpretation of Lichtensteins ideas continuously occurred and still occurs even at the highest level. Practically all authors who describe underlying mechanisms of allergy refer to his earlier works and thus, misunderstand him. Below are several examples. Chapter 3 included in the textbook Allergy 1985 and titled Biochemical Events in Basophile/mast Cell Activation and Mediator Secretion covers the biochemical reactions in allergies. The text on page 44 says: The desensitization signal is generated in parallel to a cell activation signal. In other words, histamine leakage from mast cells and basophils is not a unilaterally apro-inflammatory process, since, in parallel, it awakens the desensitizing forces as well. These forces, as page 45 indicates in a table, are the H2 receptors activated by histamine. To support this idea, the chapter provides 7 (!) references (6571) to Lichtenstein.
Histaminegate
125
Two of the worlds leading immunopharmacologists stated in 1990: release of histamine from human basophils is inhibited by histamine itself. The possible mechanisms of the inhibitory effect is H2-receptor mediated. Three references to Lichtenstein (8, 9, 10) follow.21 Pharmacological Reviews is the publication of the American Society for Pharmacology and Experimental Therapeutics.22 This publication is the constellation of those theoretical works that form the foundation for drug development. The included works are, actually, theories planned for implementation in clinical medicine. The authors of a subchapter H2-receptors and the Immune System dedicated to immunomodulation by histamine, also seem to have misunderstood Lichtenstein. On page 69 the text says: These data suggest that histamine-inducible suppressor cells may be important for normal immune regulation and raise the possibility for the use of H2 selective and lymphocyte-selective agonists as immunosuppressant agents. There are 4 references to Lichtenstein. We should disregard the oxymoron, when immune modulating histamine is called as immunosuppressive for its ability to suppress allergic inflammation. Otherwise, the text is clear: it is time to introduce histamine or its derivatives into clinical practice, and Lichtensteins research endorses this. The authors of another international publication devoted to drug research regret that potential uses of H2 agonists, such as a reduced release of mediators of allergy, like histamine itself, from, for example mast cells, so far have not led to a clinical application. In the middle of this sentence, they refer to the 1982 work co-authored by Lichtenstein that classifies histamine receptors.23 The publication of the European Histamine Research Society, which is devoted solely to histamine research, contains an article by Swedish authors who write about nonspecific desensitization implemented by histamine. A current belief is that the two processes, release and desensitization, proceed simultaneously. It is believed that desensitization exists as a normal regulatory process during the release of histamine in vivo. In their description of the desensitizing ability of histamine, the authors refer three times to Lichtenstein (ref. 57).24 Another international team wrote on the anti-inflammatory features of histamine in a recent issue of Nature,25 and they seem to be one more causality of misinterpretation. Reference 5 points to the paper
Selective Display of Histamine Receptors on Lymphocytes co-authored by Lichtenstein.26 If we look into this reference (which was also presented at my disciplinary hearings), we will read in the very first paragraph: histamine mediates several anti-inflammatory effects via histamine type 2 receptors. The use of these receptors in therapy is nothing but nonspecific desensitization. The fact that so many high profile authors understood Lichtenstein in the same way I did, means that all of us, in fact, understood him correctly: his research proves that histamine possesses desensitizing functions. In this connection, it is not clear why the histamine desensitization I conducted caused an outright rejection by Lichtenstein. All I did was put it to use successfully: I performed what the earlier award-winning research by this allergy guru had been suggesting. Of special interest is the dynamics of the changes in Lichtensteins views. In his later works, he presented histamine as the most infamous mediator.27 Even in his Presidential Address, when he spoke about his career and scientific achievements, Lichtenstein never mentioned histamines immune modulating role which he had discovered and researched.28 In none of his subsequent work does Lichtenstein any findings that would have had to have been the cause for his radically changed position. By describing histamine as a substance of solely disease-promoting activity and ignoring its innate selfremedial properties, he misrepresented his own thoroughly studied scientific data. This is regrettable, for he could be proud of his earlier work; decades ago, he had said what the editors of JACI now present as a very important issue: histamine might have a chronic antiallergic effect .29 Lichtensteins change in attitude becomes especially evident when one looks at the difference between his views on drugs in general and towards histamine as a potential drug. Here is an example. Along with histamine receptors, Lichtenstein studied beta-adrenergic receptors, which are the target of bronchodilators (also known as puffers) used in asthma. He writes in an earlier quoted article that asthma may be such an experiment of nature in which certain receptors (beta-adrenergic) are deficient. The deficiency, the text says, leads to bronchial spasms, and this justifies the therapeutic use of betastimulators called bronchodilators, which, upon inhalation, open the airways. This article20 casts doubt on Lichtensteins latest position: if he thinks its logical to activate one kind of deficient receptors (beta-adrenergic) with stimulators (bronchodilators), why is he against a similar activation of another
Histaminegate
127
inefficient type (H2) with histamine or its congeners? Especially so, because Lichtenstein knows and reported repeatedly that a bronchial spasm is an event secondary to the histamine-induced pro-inflammatory chemistry in the airways. His own role in establishing this scientific fact becomes evident in Chapter 10, written by Rocklin in Allergy 1985. When Rocklin wrote that deficient histamine H2 receptors are the primary cause of any allergy, he referred to Lichtenstein (references 55, 56).11 With this knowledge, the stimulatory effect of histamine should look more attractive than the use of beta-adrenergic drugs for several reasons. First, the effect of bronchial inhalers on beta-receptors is short-lived since it is applied to the secondary event; Second, it is a recognized fact that bronchodilator use is dangerous in the long run. Histamine, on the contrary, produces an immune modulating effect via the H2 receptors, and the effect can be lasting because it goes to the core of the problem. Being a physiologic autacoid, histamine is safe, as Lichtenstein once declared. Why, when and for what real reasons did these advantages turn into disadvantages in the opinion of the learned scientist? Anti-inflammatory immunosuppressive medications may serve as another example of the scientists positionnow biased towards drugs in spite of his own research. Compounds more commonly prescribed to alleviate the chronic inflammation of asthma are often helpful, writes Lichtenstein on inhaled steroids in 1993.30 By saying that, he encourages the use of these drugs, immunosuppressive in the generally accepted pharmacological classification, but immune modulating in the vocabulary of allergists. What could possibly be wrong then with the use of histamine, whose activity Lichtenstein had also called immunomodulatory ? Lichtenstein evidently saw the therapeutic use of histamine back in 1974, when he said: histaminemight limit the extent or severity of an inflammatory reaction31 and also three years later when he repeated the idea: histamine has marked modulatory effects on immunity32 Isnt modulating an inflammatory reaction the goal of any therapy in allergies? If so, why was histamine excluded from the list of the core allergy mediators taught at the AAAI-sponsored training program for allergists and immunologists in 1994 when Lichtenstein was its president?33
Interestingly, the material included antihistamines, and, logically speaking, even if histamine was now supposedly the most infamous mediator, it should have become the center of the lectured material in order to clarify and successfully sell the use of these wonderful new anti-histamines. I am not suggesting that Lichtenstein personally excluded histamine from the program. However, for decades, he has remained an undisputed authority in allergy, and that year, he was the spokesperson for American allergists, so he should have known what was being put onto the program. Just where is that line that separates research from clinical medicine? Why do scientists abandon their own outstanding work when it comes to its potentially successful application on patients? Nobody can answer this better than Lawrence Lichtenstein who possesses the highest expertise in immunology in general and histamine effects in particular. The projects Lichtenstein pursues today include the development of a better version of Claritin, and the sponsor is Schering, a drug-manufacturing giant. He also works on modification of therapeutic allergen extracts to make them safer and more efficient. At this point, we should go to his earlier admission that the target of any immunotherapy is the H2-receptor activation: In the context of allergic or inflammatory responses the H2 receptor, located on the histamine-releasing cells, possibly mediates an inhibitory effect on the inflammatory responses.34 It is unclear what advantage the scientist has found in new allergen extracts over histamine, designed by nature, to activate H2 receptors. Lichtenstein is also involved in the development of drugs that are called phosphodiesterase inhibitors, or shortly, PDE inhibitors. They are supposed to delay the degradation of cyclic AMP. Lichtenstein was ahead of others in pointing to the unique significance of this enzyme, the fact he admitted in another article he co-authored, in which he observed that back in 1968, he and Margolis presented in Science the first evidence implicating cyclic AMP as being in control of leukocyte function.35 To emphasize the point, I will repeat the quote made earlier from this same article: If leukocytes or mast cells of asthmatics accumulate lesser amounts of cyclic AMP than do the same cells in normal subjects, physiologic control of the release of inflammatory mediators might be deranged (p. 25). In other words, the primary biochemical defect in allergy patients is low levels of cAMP, which, correspondingly, results in the hypoactivity of certain immune cells. It is significant that Lichtenstein is also credited with classifying histamine receptors H1 and H2, as well as the findings that the enzyme cAMP accumulates upon the impulse delivered by the H2 receptor.
Histaminegate
129
Two decades after Lichtensteins article in Science, doctors and researchers are assured by Pharmacological Reviews that the ideas initiated and developed by Lichtenstein in the 60s and 70s on histamines acceleration of the enzyme cAMPs accumulation have remained unchanged. This highly scientific text is surprisingly clear and easily understood. On page 146 in Agents & Actions, the publication of the European Histamine Research Society, we read: Histamine is one of the most potent stimulants of cyclic AMP accumulation in mammalian brain slices. This increase in cyclic AMP induced by histamine involves both H1 and H2-receptors. Stimulation of H2 receptors produces a direct activation of the cyclic AMP-synthesizing enzyme adenylate cyclase, while H1 receptors act indirectly to augment the cyclic AMP response to H2receptor activation. The author provides references to Lichtenstein.36 (It is of interest that collaterally, we come to realize that H1-antihistamines interfere with the activity of H2 receptors.) Research in this vital area has never ceased, and the accrued data reaffirms the importance of the earlier works of Lichtenstein. Thus, researchers from the National Institutes of Health, Bethesda, Maryland, describe the existence of the protective CRH/mast cell axis (CRH stands for corticotropin-releasing hormone produced by the hypothalamus).37 This paper says: Over the last 10 to 15 years, strong evidence has emerged that histamine may have important immunoregulatory functions through H2 receptors that are expressed on immune cells. We have recently found that histamine, through the stimulation of H2 receptorsand the subsequent elevation of cAMPstimulates the production of Il-10 (central anti-inflammatory cytokine). The existence of this axis is the recognition of the interplay of the central regulatory systems, namely of the brain (hypothalamus is a reservoir of histaminergic neurons) and the immune system (mast cells and basophils with their histamine granules). This scheme not only puts the histamine/cAMP unit into the center of regulation, but also gives the direction for future therapies that can cover both regulatory systems, namely by H2-receptor stimulation with histamine. It is hard to overestimate the importance of the axis, which, as the text says, participates in the adaptation and, hence, survival of an organism. The existence of the axis reveals the urgent need to implement psychoneuroimmunology in clinical setting and employ histamine as the vehicle of curative messages in these regulatory systems. No doubt Lichtenstein is on top of all this information; especially so, because it relates to his previous extensive research on cAMP, and also because now, he
develops drugs for asthma that are supposed to target this enzyme cAMP. The drugs are phosphodiesterase inhibitors, or PDE inhibitors. Strangely, Lichtenstein, who described how exactly to reach this enzyme, chose a different, twisted approach. The drugs he is working on will have an effect similar to the one of theophylline. The Canadian Compendium of Pharmaceuticals and Specialties writes in the entry on Theo-Dur: The actions of theophylline may be mediated through inhibition of phosphodiesterase and a resultant increase in intracellular cyclic AMP. The above quoted article co-authored by Lichtenstein described as far back as 1974 the target of this drug group, and on page 20 of that 1974 Science article, we learn that it is inhibition of histamine. Thus, it is a case of all roads leading to Rome: control over histamine release is the unspoken but ever-desirable aim of allergy/asthma medications, and the novel PDE inhibitors are not an exception. Now that asthma has reached epidemic proportions, the idea of reinventing theophylline-like medications must be very attractive for drug producers. It kills two birds with one stone. First, by concentrating on retarding the metabolism of the enzyme cAMP with PDE inhibitors, allergy diverts attention from the possibility of raising it with histamine. Second, the development of theophylline-like medications will provide numerous scientists with work, and their gratitude will come back to the sponsors in the form of high profits. Will the newly synthesized inhibitors be more effective than their antiquated, not-so-effective older cousins? I doubt it, and, indeed, the first trials of the novel drugs are admittedly not very promising. There is nothing wrong with improving antihistamines, perfecting allergen extracts or creating new inhibitors. Allergy is a troubled field in clinical medicine today, and anything should be researched to put the best into practice. However, Lichtenstein who studied in depth the biochemical mechanisms that underlie allergies and knows the most efficient ways to treat these diseases, is now doomed to settle for ineffective ways based on false targets. He works on antihistamines once recognized by himself as cytotoxic. He tries to make allergen extracts safer, although at the time of his ground-breaking research on cAMP, he thought that understanding of such a regulatory mechanisms may open the way to new therapeutic approaches to treatment of immunologic and inflammatory disorders in man. He knows how to activate H2 receptor in order to increase the much-needed enzyme, but instead, he develops impotent inhibitors that may, at best, maintain its levels as they are.
Histaminegate
131
It is not a secret that medicine is largely controlled by the pharmaceutical industry, and that the latter has a purely money-based approach to any research. Today, cAMP has become one of the main focuses of attention in allergy, for this area carries a great potential in drug creation. Lichtensteins timely and actively propagated views helped to re-orient allergy. The research he started on the enzyme cAMP and his great contributions to immunology are now cast into relative oblivion, as is the work by Rocklin and Melmon. The Primer on Allergic and Immunologic Disease published in JACI in 200338 does not even reference his work anymore. Also, there is no mentioning of his work in the two supplements of JACI that cover major symposia and yet they are full of reports on cAMP.39 This is only natural, since reference to Lichtensteins articles would reveal the essence of allergic processes which is the cAMP/histamine connection. I doubt that a scientist can be happy with situation of oblivion. However, Lichtenstein may not share my views. I do not have the right to condemn any researcher for the betrayal of his work, as I know very well that the monstrous machinery of the drug industry would crush those who dared to contradict it. The drug industry, in terms of profit and economic principles, is justified in its opposition to histamine, but in terms of ethical principles society ought to support those doctors whose moral compass differs from that of drug developers. Today, doctors in research mainly toil to serve the industry, not their patients. They have become drug promoters, hiding the truth undesirable to research sponsors.40 Our society must help those who are eager to introduce the most significant discoveries into practice in the interests of patients, not the industry. At present, the role of a messenger in allergology is fraught with great danger, and the a la Hamlet dilemmato tell the truth or not to tellis solved negatively. Before going to the next authority in the field of histamine, Allen Kaplan, we need a preamble that will clarify the topic of his research, which is the chemistry induced by the initial histamine spill. Unchallenged is the fact that when the immune system of an allergy patient is activated, the easily excited mast cells/basophils start to leak histamine and pro-inflammatory chemistry. However, the very same immunocompetent cells, although flawed, defend the host and respond to the challenge by secreting anti-inflammatory chemistry such as histamine-induced suppressor (or inhibitory) factors, HSF or HRIF, which belong to anti-inflammatory cytokines. These suppressor factors are the primary protective weapon in the cellular fight with the inflammation promoting chemistry.
The first histamine-induced suppressor factors brought to life by H2receptor activation were described by Rocklin in 1977.41 Discovery of other histamine-induced suppressor factors soon followed. Along with that, the pro-disease histamine releasing factors, HRF, or pro-inflammatory cytokines, were discovered. In 1989, J. Grant and R. Alam (the latter received an award for this research) gave lectures at the annual meeting of the AAAI. These lectures formed the basis for their article published two years later.42 The authors called histamine-induced factors a missing link in the understanding of the underlying mechanisms of allergy. On page 690, one reads: Histamine, a major mediator of allergic injury, may have an additional effect by increasing synthesis of HRIF, a specific inhibitor of HRF, which may restore local homeostasis. [HRIFhistamine release-inhibitory factors, synonym of histamine-induced suppressor factors] Moreover, the clinical relevance of cytokine-dependent mediator release from mast cells/basophils extends beyond the boundary of the atopic (allergic) disease, and that similar effect is observed in many chronic inflammatory disorders. These include rheumatoid arthritis, ulcerative colitis and the rejection process of some tumors. Not only does this all point to the common roots of these chronic diseases, but also puts histamine into the center of various immune-related inflammations. Allergic inflammation is just one of them, but it is most closely related to histamine activity. This also means that the state of disease or health is determined by what histamine-induced factors prevailpro- or anti-disease. Naturally and unavoidably, the article has references to the works by L. Lichtensteinand also by A. Kaplan. At the time of this report, AAAI obviously did not realize how explosive this missing link could be in understanding allergies. The very mention of histamine-induced suppressor factors leads inevitably to considering T-suppressors that generate them. In turn, T-suppressors lead to H2 receptors because there are no active suppressor cells, or their protective factors without efficient H2 receptors because: differentiation of T-cells is accompanied by appearance of histamine H2 receptors, as Lichtenstein wrote.43 The chain logically ends with the final linkhistamine, as the best natural activator of H2 receptors. Melmons team described, and we earlier quoted, the reciprocal relationship of histamine and histamine-induced chemistry: Histamine regulates the release of lymphokines. Release of histamine is influenced and regulated by lymphokines.44 All this knowledge involuntarily leads to the seditious idea of using histamine with the purpose of counter-
Histaminegate
133
balancing pro-inflammation chemistry. To prevent doctors and researchers from taking this lead, all histamine-related links of the chain have mysteriously disappeared from contemporary scientific sources: histamine-generated suppressor cells, histamine-activated protective H2 receptors and histamine-induced suppressor factors. What was once called the missing link has now gone physically missing. During the 90s, allergy started to describe the chemistry in allergic reactions solely as a one-sided pro-inflammatory promoting event, with the antiinflammatory chemistry totally ignored as if it doesnt exist. The impression is that the role of the immune system is not to defend but to harm, and that the tendency to balance is not part of its nature. In reality, every action is opposed by an appropriate counteraction, and only the net effect determines, which way the disease goes. For instance, even the main culprits in allergy, namely the mast cells that start a reaction by their exaggerated histamine spill, have recently been described as having other properties that could be interpreted anti-inflammatory.45 Interestingly, such revelations can mostly be found in areas of medicine other than allergy, although allergies are the most reversible of all immune diseases, and allergic inflammation is nothing but histamine-induced bidirectional chemistry. If the need of balanced immune functioning is occasionally recognized by allergy as a theoretical possibility, patient management is based solely on the suppression of one or several disease- promoting mediators, or on the suppression of the cellular production on the whole. The natural suppressor factors able to counterbalance the activity of the inflammation promoting chemistry are never in the picture. Now, the person who especially contributed to this new unilateral approach is Dr. A. Kaplan, a former president of AAAI and the editor of both editions of the textbook Allergy. He is the 2003 President of the World Allergy Organization and the editor of the journal Allergy and Clinical Immunology International. ALLEN KAPLANs research always focused on histamine-induced factors. It is interesting to follow the changes in his presentation of the mechanisms of allergies. As mentioned earlier already, in the article Immune Mechanisms co-authored with Kaplan and presented at the 47th annual meeting of AAAI, it is stated that the ratio of histamine-induced pro- and anti-inflammatory factors may be critical to pathogenesis of a wide variety of allergic and rheumatic diseases and may determine levels of inflammation observed in allergic
diseases as well as other chronic immune diseases. The authors also wrote that this ratio may play a role in the pathogenesis of disease in which histamine is an important mediator and recognize that histamine induces the production of bifocal chemistry, which, in turn, is an important regulatory mechanism in the releasability of histamine. This echoes the above-quoted idea expressed by Melmon the same year in Agents and Actions: Histamine regulates the release of lymphokines. Release of histamine is influenced and regulated by lymphokines. Thus, in the interpretation of Kaplan and his team, histamine release becomes the determining factor in the development of immune-related inflammatory diseases. In 1995, as a co-author of another article, Kaplan still preserves the same views on allergic reactions: a balance between molecules of HRF or HRIF activities exists which may determine the level of inflammation observed in allergic diseases.46,47 Only two years separate this article from the second edition of the textbook Allergy edited by Kaplan (discussed above in some detail), but the revised edition inexplicably omits these determining factors, as does the chapter by A. Kaplan himself on cytokines. Only one sentence on page 78 reveals that the author does know that immune processes are a two way street: Some initial studies of asthma have examined the possibility that HRF, as inflammatory agonist, and HRIF, as control mechanisms, are important contributors to symptoms, and that the relative ratio of the two might determine the clinical course. For a reader not privy to this secretive information, the off-hand use of HRIF looks not as the determining event that could reverse allergic reactions but as an insignificant detail undeserving of clarification. There is no explanation that HRIF stands for histamine-induced release-inhibitory factors, which is, actually, a synonym of HSFhistamineinduced suppressor factors. With the absence of the required explanation, only those who have studied these factors since this research began will understand the meaning of the abbreviation HRIF. However, the author does more than just hide the protective chemistry. The pro-inflammatory factors described by Dr. Kaplan in the textbook make allergic reaction appear as if it was a unilaterally disease-oriented phenomenon. One can only wonder about the reasons for his preference for such an incorrect description of allergic reactions in the textbook, which, as Dr. Kaplans website states, is utilized in training programs throughout the world (www.alergycenters.salu.net/stuff/html).
Histaminegate
135
The best evidence that immunocompetent cells are enabled by nature to organize an effective defense is the existence of people who do not have allergies despite the numerous surrounding triggers. It is only legitimate to ask what cells organize such a successful defense, and indeed, the answer is basic scientific knowledge: T-suppressors are our main protectors, and suppressor factors are derived mainly from T-suppressors. But, as we have seen, T-suppressor cells are a forbidden subject now because of the fact that only histamine and no other drugs leads to the elaboration of suppressor factor.48 It is the uniqueness of histamine as a remedy, both cellular and synthetic, that has become the obstacle preventing allergists from even mentioning this substance. The fact is, that histamine as a drug or its congeners could generate and/or activate Tsuppressors and by that, intensify the production of anti-inflammatory chemistry. Histamine as a drug could, become a successful competitor to the numerous medications blocking the inflammatory chemistry. Only Dr. Kaplan himself can prove or disprove that his changed stance is in any way related to the dominant market concernprofits. Since Kaplans works once described the bifocal histamine-induced chemistry, its presentation as being only proinflammatory in the 1997 version of Allergy cannot be accidental; nor can the disappearance of the Rocklins chapter from the revised edition of the textbook edited by A. Kaplan. As was said before, in 1994, the CPSO was using the service of Dr. A. Knight as the expert witness in histamine therapy. Being unable to provide any subject-matter expertise on the topic, this professor of the University of Toronto solicited help from heavyweights, L. Lichtenstein and A. Kaplan, to support him in his task to discredit my therapy. Like Lichtenstein, Kaplan gave his opinion on the subject. His letter was to be admitted in the hearings as evidence, therefore the author was supposed to tell the truth, only the truth, and nothing but the truth. In my understanding, he did not. In his very short note dated January 20, 1994, he said: Dear Dr. Knight: The use of histamine in vivo as an immunomodulator (i.e. histamine injections) has no validity whatsoever at any dose. Any interpretation that the textbook entitled Allergy that I edited, recommends this therapy is a misrepresentation of what was described and has nothing to do with clinical disease. Let us investigate if this is so. It is true that Dr. Kaplan never suggested doctors use histamine as a therapy. However, contrary to what his note says, Allergy 1985 does provide ample evidence of histamines immunomodulatory
effects. Thus, on page 704 in the Index we find under histamine that there is the rubric immune response modulation by (histamine). The reference at this point sends the readers to pages 179189 on which Rocklins chapter convincingly, and in detail, covers immunomodulation with histamine. Pages 58 and 60 of this textbook are not included in the Index under histamine, which they should have been for their relevance. Page 58 says: cells with histamine receptors can also generate immunoregulatory substance upon activation with histamine. This immunoregulatory substance cannot be anything but histamine-induced suppressor factors studied by Kaplan. The table on page 60 names the H2-receptor function as immunomodulatory, and the very term points to the presence of a living body with its regulatory immune system. With all this being in the textbook, one can only wonder why the editor insisted that I had misinterpreted the data, as I simply implemented into practice the statements, data and ideas that A. Kaplan had accepted for publication. I conducted successful immunomodulation with the best natural activator of H2-receptors. Dr. Kaplans letter was misleading in not providing the true facts. The big flaw in Dr. Kaplans note is that it defies to the very foundation of medicine when it says that the theories I relied on have nothing to do with clinical disease. Theory and practice are inseparable in any area. As a saying goes: theory without practice is dead, practice without theory is blind. Theories in medicine must lead to therapies and cures, serve the sick and not be entertained in scientific labs simply to get more funding. Regrettably, Dr. Kaplan did not connect his own work with practice. Thus, when he stated that a balance between molecules of HRF or HRIF activities exists, which may determine the level of inflammation observed in allergic diseases,49 it was only natural to conclude that histamine-induced inhibiting factors materialize immunomodulation. This points to the duality of histamine. It was also natural to speculate how this duality could be used to balance the chemistry in disease and help allergy patients. Even though Dr. Kaplans text implies this, he never expanded on the material. Dr. Kaplans note surprised me because of the lack of concern it displayed for the plight of my allergy patients. When he condemned histamine therapy, which, in his opinion, has no validity whatsoever, he did not pay attention to the fact that about 2,500 of my patients, the majority of whom had failed
Histaminegate
137
to benefit from all conventional methods, improved or recovered due to histamine therapy. This figure falls into the category of the mathematical Law of Big Numbers which states that if an experiment is repeated a large number of times under identical conditions, then the relative frequency with which a certain event occurs and its probability should be approximately the same. Even if the expert witness, A. Knight, had not informed Dr. A. Kaplan about this numerical fact, the latter should have inquired what had happened to the patients subjected by Dr. Ravikovich to his invalid histamine therapy. The professor did not do that. His letter was, of course, most useful here in Toronto, as it supported the position of the CPSO, who on several occasions, made assertions such as that patient outcome is irrelevant or not terribly useful.50 What then, one wonders, is relavant or useful? The material selected by Dr. A. Kaplan for the second edition of the textbook Allergy reflects the changes that took place in his stand and in the stand of allergy as a science. Allergy 1997 should actually be called Allergy Revisited. The difference in presenting the information in the two books is such that one may suspect revolutionary discoveries that dictated the change of the accepted postulates. For instance, the second edition of the textbook has a new section called Immunologic Diseases that includes AIDS, vasculitis, lupus, cancer and other diseases that, by any standard, cannot possibly be viewed as allergy. The title of the bookAllergyis preserved, and one can only wonder what is behind this: or secondary the lack of material directly related to allergic diseases, or the desire to distract the reader from what is essential by providing information that is irrelevant in importance. Since the common origin of allergies with the presented immune diseases is not indicated, and as there is no deficit in the availability of data on allergy, the last assumption seems to be most logical. Another obvious difference between the two editions is that the first is centered on histamine, especially Rocklins (dropped) chapter on the underlying immune processes. In contrast, the second edition, although almost 200 pages larger than its 1985 predecessor, mentions histamine only in passing, as just another mediator. Histamine-related phenomena, H2 receptors and T-suppressors and histamine-induced suppressor factors have disappeared. It is only from the new chapter entitled Antihistamines, that one may indirectly infer the key role of histamine. These inexplicable changes could have been done only with the approval of the editor, Dr. A. Kaplan.
A. B. KAY is director of the Department of Allergy and Clinical Immunology at the National Heart and Lung Institute in London and a co-editor of the European journal Clinical and Experimental Allergy, the second most important professional journal after JACI. For over a quarter of a century, the activity of this scientist in the international arena of allergy research has steadily grown. He has become the most prolific and authoritative author, a member of the editorial boards of international journals and chair and key lecturer at international symposia. Critical review of his work is rather difficult because of the fact that he takes so many inexplicable turns back and forth in his scientific interpretations. Before the analysis of Kays work, which is rather like a detective operation, we should summarize the generally accepted, though concealed, data on mechanisms that underlie allergiesthe main topic of his work. The central players of allergic reaction are 1. mast cells that launch it by their exaggerated histamine release; 2. basophils that take over this role in the late-response phase and secrete over 90% of all histamine51 3. T-cells and particularly T-suppressors that seem to play a critical role in immune regulation. Suppressor cells have been implicated in virtually all of the immunological regulatory mechanisms that are presently recognized52 All three players are inseparable from histamine although in different ways. For mast cells and basophils, histamine is their main product. For T-cells, its role is immeasurable: histamine determines their differentiation, and the very existence; generation and efficiency of T-suppressors totally depend on histamine. As was said before, all T-cells become producers of histamine de novo when activated. Numerous works recognize the pivotal role of histamine, but we will illustrate this by two examples. The just-quoted article with the self-explanatory title The regulatory effect of histamine on the immune response is the result of the research supported by a grant from the Medical Research Council of Canada. It covers the roles of cells and the role of histamine in immune responses. The text states on page 56 says: A thorough evaluation of the role of histamine in the immune response could lead to the understanding of numerous clinical situations in which this hormone could be involved. And: Histamine also has direct effects on a variety of lymphocyte functions and may influence the expression of cell-mediated immune reactivity. The second citation comes from M. Kaliner, a top expert in histamine who gives the key role in allergies to mast cells/basophils as histamine-releasing
Histaminegate
139
cells: The bottom line is that the mast cells initiate the process. If you inhibit mast cells reactions, you inhibit both the immediate and late reactions.53 Let us trace Kays position on this who is who in allergic reactions at different times.
Mast cells/basophils The 1984 volume Asthma: Physiology, Immunopharmacology and Treatment is edited by A. Kay and L. Lichtenstein. It covers the Third International Symposium on Asthma and includes the informal discussions that take place at this gathering. Dr. Kay is one of the participants of these discussions, and we read on page 426: many of the features of asthma such as bronchial hyperactivity, and bronchial inflammation might be secondary to the primary mast cells defect. Kay explains what this primary defect in mast cells is: in asthma, mast cells are intermittently leaky, and the leakiness can be intermittent (episodic asthma) or continuous (chronic asthma) reflecting the severity of the disease. For support, Dr. Kay refers to his own earlier work published in the Lancet.54 Then he goes even further when on page 427, he points how to control asthma: To define the triggers and drugs that inhibit release it may be necessary to work with asthmatic mediator/mast cells. Another participant of the discussion, Dr. A. Kaplan, sees abnormal histamine release as the main cause of stimuli that trigger asthma (p.425). Dr. Kay, present at the discussion, does not argue against this fact. The position of science did not change in 1995, if we believe Dr. Kays co-editor, Dr. L. Lichtenstein, who still considered mast cells and basophils as the central mediator-containing cells at all stages of allergic reaction.55 In 1997, Dr. Kays views changed mysteriously. That year, he authored the 5-page chapter titled Late Allergic Responses in the second edition of the textbook Allergy. Those five pages are, actually, the replacement of Rocklins 20-page chapter entitled Role of Cell-Mediated Immunity, which was part of the first edition of the textbook Allergy, and which was excluded from its 1997 edition. An allergic reaction consists of two stagesimmediate response that lasts 24 hours and the subsequent late-response phase that may be short, but may last much longer and even become chronic. Allergy accepts that this late-response phase is actually ongoing allergic inflammation that, no matter what ignites it, continues due to the malfunctioning of the participating cells. Therefore, the knowledge of what cells are primary, what makes them malfunction, and how to correct their production becomes so essential,
both for understanding the pathogenesis, and for selecting the treatment target. The very name of the Rocklins chapter says that any immune allergic reaction depends on what cells are involved in the reaction. Rocklin did what he was supposed to do: he named all the participating cells, indicated their ranks in the process and specified the particular defects responsible for their malfunctioning. His meticulous description helps one understand the common origin of various allergic diseases and could help one find methods of correcting the failing immune tools, irrespective of the end organ in which the disease develops. Dr. Kay was supposed to do the same. The drastic reduction in the number of pages compared to Rocklin from 20 to 5would be irrelevant, if the problem had been presented concisely. As the editor, A. Kaplan was to ensure that the author, A. Kay, included this basic material into the replacement chapter. Have the author and the editor fulfilled their obligations? Both editions of Allergy are, actually, clinical textbooks grounded in basic sciences, since they present the processes on the cellular and molecular levels. Textbooks usually include those data from basic sciences that have been accepted by medicine and specify the phenomena that require more research. Kaplan included both Kay and Rocklin into the textbook Allergy 1985. The inclusion meant that the material presented by both authors was verified and solid, and that their views were compatible with the views of the editor. Speaking about the roles of the cells in the late-phase allergic reaction, Rocklin says on page 179: It has been recognized that many, if not all, delayed hypersensitivity reactions contain sizeable infiltrates of basophils. In fact, any definition of mast cells and basophils, be it in a textbook or a medical dictionary, starts with this most distinguished characteristic of theirs. Moreover, if mast cells can release other mediators apart from histamine, basophils release primarily histamine. Therefore the presence of a large number of basophils at the site of allergic reaction is unequivocal in its meaning, namely exaggerated spill of histamine. In 1987, just two years later, Dr. Kay also recognizes the well-documented association between mast-cell-derived products and late-phase reactions56 This means that covering the late phase in Allergy 1997, Dr. Kay was supposed to emphasize the well-documented histamine leakage from basophils. He was also expected at least to name the first stage launched by histamine overspill from mast cells. He did neither of this. Kay simply reduced mast cells and basophils to ordinary participants, but he did it skil-
Histaminegate
141
fully. Nobody can rebuke him for excluding mast cells: he focused on the late stage of reaction, and this allowed him to cut off the initial stage based solely on histamine as an initiator. However, even basophils that take over mast cells functioning in the late stage of allergic reaction now lost their importance as did the amount of crucial mediators and cytokines they produce, and this in spite of the uncontested fact that they release more than 90% of all the secreted histamine. As none of the works by this scientist had indicated that he started to have doubts about the well-established scientific data, we may only speculate what prompted him to turn basic immunology upside down by attaching the central role in allergy to another group of cells, namely the eosinophils that were never considered central. The fact that he did it in a textbook, and not in an article, makes all this especially hard to comprehend.
Eosinophils In 1985, in the first edition of Allergy, Kay wrote the chapter entitled Eosinophils nothing in it indicated that these cells were central players, in allergy. On the contrary, at that time, Dr. Kay described eosinophils as dependent on mast cells and T-cells: eosinophils appear to be recruited and activated as a result of T-lymphocyte-derived mediators and at least in part, their activation is a result of factors derived from mast cells. When in 1997, Kay assigns to the eosinophils a greater importance than to other participating cells, he comes into conflict not only with science in general, but also with logic. Given this fact Dr. Kay up to now remains a fervent supporter of the IgE antibody hypothesis as the origin of all allergies, he should have given the priority to mast cells and basophils, since they are the prime residence of IgE antibodies and the place for antigen/antibody reaction. This fact alone makes eosinophils inferior, at the very least, to mast cells that ignite and maintain the reaction. Another change in the views of Dr. Kay concerns the protective role of eosinophils for the immunity. In 1985, he recognized this by saying that the eosinophils dampen mast cell activity, that is, slow down histamine release. Thus, he wrote on page 96: A role for the eosinophil in deactivating histamine has been proposed by a number of workers, and the author does not argue this position. How could argue this, since the fact that eosinophils possess protective functions is common knowledge? In allergy, their activity is implemented in the same way as with the other cellsvia activation of
histamine receptors, as described on pages 176177 by M. Kaliner in his chapter entitled Histamine which is included in the huge volume Inflammation: Basic Principles and Clinical Correlates.57 In 1997, in the revised edition of Allergy, eosinophils, without explanation, acquire the property of being an affliction, plus they remodel the bronchial wall, that is, produce structural changes (Summary, page 298). In fact, changes in the bronchi occur as a result of the constantly seething pro-inflammatory chemistry coming, first of all, from mast cells and basophils. Moreover, they occur only at a far-advanced stage of asthma. Dr. Kay obviously forgot what he knew in 1987 when he wrote: inflammatory cells, recruited and activated as a result of the elaboration by mast-cells-associated chemotactic factors, lead to the local changes in and around the bronchi. In other words, it is not eosinophils, but, first and foremost, the poorly opposed mast cells/basophiles chemistry that is responsible for the changes. In 2001, Dr. Kay temporarily returns to his position as expressed in Allergy 1985 when he correctly denied eosinophils their prime role in allergy.58 Thus, he says on page 112 that elimination of eosinophils in patients had no apparent effect on the allergen-induced late-phase asthmatic reaction or nonspecific airway hyperresponsiveness. In 2003, he reiterates this again; this is his most recent presentation published as abstract No. 774: eosinophils are unlikely to cause redness, swelling and induration which characterizes the late-phase allergic response.59 One would expect that by now Dr. Kay would have finally found the proper role for these cells. Not so. In his latest articles, he once again declares eosinophils as the main evil, and describes the remodeling of airways supposedly performed by them, as the central event in asthma. By doing that, Dr. Kay simply turns asthma into an irreversible disease essentially characterized by serious, organic, degenerative changes in the lung and bronchi. Strangely, he makes no mention of the prerequisite pathological processes in the immune and nervous systems, without which such gross tissue damage cannot occur. There are always specific pathogenetic factors behind any serious structural change, but they are left out completely. If one accepts Dr. Kays views, removal of scar tissue may become the next popular step in management of asthma, and it will be considered a condition similar to cancer and rheumatoid arthritis, diseases that do have profound structural formations or changes. In reality, asthma is a volatile immune disease, the most reversible, by definition, in the majority of cases.
Histaminegate
143
Regrettably, numerous authors have picked up the idea put forward by Dr. Kay, namely that remodeling takes place through eosinophils, and that this is the core event in asthma. This is now shaping up to become a new trend in the perception of this disease. This is happening even though the author of the concept has again changed his views. In 2001, Drs. Kay and Kaplan were among the group of authors writing on the late-phase reaction, and once again the self-contradiction is amazing.60 On page 400, the text says that eosinophils are actually only bystanders in allergic reaction, which may go on without their active involvement: Taken together, these observations support the view that airways eosinophilia is not a prerequisite to the airway narrowing associated with late asthmatic reactions. This statement coincides with Kays (and Kaplans) views of 1987 but contradicts his (their) 1997 views. As a specialist in eosinophils, Dr. Kay undoubtedly knows the unique function of the recently-discovered histamine H4 receptor. Especially so, because an article that answers the question why there are numerous eosinophils at the site of allergic inflammation is published in the journal edited by him. This receptor passes histamine messages to bone marrow and stimulates production of immune cells. Therefore H4 receptor may make it a therapeutic target for the regulation of immune function, particularly with respect to allergy and asthma.61 Another authoritative pharmacological source also states that H4 receptor gives rise to numerous immunocompetent cells, including eosinophils, and the authors see a potential new role for histamine in allergy and asthma.62 Intensified production of immune cells is a natural defensive reaction of the body, and the fact that histamine induces such a production emphasizes its protective role in the functioning of the immune system. The increased production of eosinophils indicates their protective role, not a disease-promoting role, as ascribed to them by Dr. Kay. The specifics of the reparative role of eosinophils are not part of this review. However, the arguments whether their role in the production of asthma is nil or most important should not distract from the main fact, namely that a continuous profuse mast cell/basophile histamine release is the principal underlying event in allergy and asthma. Histamine, any reference to which Dr. Kay avoided, hit him unexpectedly: eosinophils, seemingly independent of histamine, turned out to be generated and activated only by it!
T-cells T-cells are another element fluctuating in significance in the works of Dr. Kay. They are universally recognized to be the leaders among the immunocompetent cells participating in allergic reactions, although in a different sense than mast cells and basophils. It has become common to describe them as the conductors of the immune orchestra. Even if we limit the functions of T-helper cells to their facilitation of antibody formation (negative in allergy), an increased IgE antibody formation is an indication of excessive activity of these cells. The only force able to restrain their disease-promoting effect is that of the regulatory T-suppressors. They control the number and the activity of all T-cells, IgE antibody levels, and also the chemical activity of all immunocompetent cells engaged in the allergic reaction. When Rocklin wrote in his now censored chapter in Allergy 1985: The suppressor cell abnormalities observed in allergic subjects may reflect a primary defect inherent to the atopic diathesis (pp. 190191), Dr. Kay had a similar position that found its way into his article written two years later. In this paper, he is even clearer about his knowledge of the true leading cells in allergic reactions.63 Here is a sentence from the introduction: successful immunotherapy has been associated with both an increase in the relative number of suppressor (OKT8) T-cells as well as an abrogation of allergen-induced latephase responses. Again, for support of the idea that suppressors are central in abrogating the reaction, Dr. Kay gives in reference 11 the article by Rocklin64 which forms the basis of Rocklins chapter in Allergy 1985, Role of Cell-Mediated Immunity, that centers on T-suppressors. Dr. Kay also writes: the possibility exists that OKT8 cells control these inflammatory events by preventing the release of helper T-cell-derived mediators. For instance, OKT8 cells produce a histamine-induced suppressor factor that inhibits lymphocyte proliferation and lymphokine production. At this point, there is reference 27 that leads us to the 1979 paper by Rocklin and Melmon entitled Histamine-induced suppressor factor (HSF): further studies on the nature of the stimulus and the cells which produce it. Dr. Kays article even specifies the underlying defect in asthma, namely a defect in suppressor cell function, and he also recognizes histamineinduced suppressor factor produced by T-suppressors as the vehicle of controlling allergic reactions. In 1997, the textbook Allergy does not mention of T-suppressors in Dr. Kays chapter on late-phase allergic reactions. The prime defender in allergy has inexplicably vanished.
Histaminegate
145
In 2001, Kay and Kaplan are among the group of scientists writing on the late-phase reaction. This article60 recognizes T-suppressors as the target for therapy. On page 401, when speaking of downregulation of late response in asthma, the authors say: CD8+ cells have been shown to be increased after successful immunotherapy. As CD8 is the marker of suppressors, this phrase is a repetition of the Rocklins statement in Allergy 1985: suppressor T cells bearing histamine receptors were generated during antigen desensitization. Rocklin was very precise in the description of allergic processes, and saying this, pointed out that failure to detect these cells in untreated patients may be a reflection of the underlying defect leading to the atopic diathesis, that is, allergy. In other words, the prime defect of allergy, according to Rocklin, is that the number of suppressors is too small. Now, after a decade and a half of hesitations, Dr. Kay (and Kaplan) once again share Rocklins position. Can we expect that they will publicly recognize their erred stand in Allergy 1997 and correct it in the next edition of the textbook? Finally, in 2003, Dr. Kay makes another indirect admission of his 1997 delusion regarding the position of the cells in the late-phase allergic response when, in co-authorship with a team of scientists, he proudly described the development of peptides as compounds that could be used for immunotherapy in asthma.65 And what does he now indicate is the concrete underlying mechanisms in allergy and the target for immunotherapy? Regulatory/suppressor Tcell! These cells, absent in his chapter on the main stage of allergic reaction, now suddenly rise from the ashesjust when Dr. Kay is involved in the creation of new drugs and cannot avoid showing the target for their pharmacological effect!
Histamine As was demonstrated in the 80s, Dr. Kay agreed with the position that it is histamine leaking from mast cells that launches allergic reactions; that reactions are over as soon as the leakage is stopped; that the defensive power of T-suppressors determines the course of allergic reactions; that this power is histamine-determined. The textbook Allergy 1997 mentions histamine only in passing. This makes an article published just a year later in the journal Clinical and Experimental Allergy, where Dr. Kay is a co-editor, especially striking.66 The very titleHistaminea major role in allergy?is amazing, and now the approach is presented affirmatively, even though the title has a question mark. This is what it says: Since its discovery in 1911, histamine has been recognized as a major mediator in allergic reactions and diseases Thus, findings indicate that
histamine is a crucial mediator in both the early and late-phase reactions of an allergic response, playing important roles in cytokine release Recent data have added considerably to our knowledge of its role. However, the greatest paradox really is that this major, crucial and important mediator described in the journal edited by Dr. Kay can hardly be found in his own latest works. Which is it: an illiterate author who (with the approval of the editor) puts an insignificant mediator ahead of all others, or purposeful omission by the editor of histamine and histamine-related phenomena in his own works? The inaccuracy of Dr. Kays presentation of scientific facts can only be explained by his desire to avoid all discussion of histamine. He also wrote an extensive two-part overview under the heading Advances in Immunology,67 the in which he stated that acute allergic reactions result from the release of preformed granule-associated mediators when an allergen interacts with IgE that is bound to mast cells or basophils. Although the long-overdue acknowledgement that mast cells and basophils are central for allergic reactions is a formal great step forward since he wrote his chapter in Allergy 1997, the plural for mediators is most confusing because there is only one mediator of allergy pre-stored in the granules of these cellsand that is histamine. Dr. Kay names histamine in the text only to deny its principal role in asthma and uses the inefficiency of antihistamines in these diseases as the basis for the denial. This is strange because antihistamines are not necessarily effective in other allergies either, although the frequency with which they are prescribed is evidence of the prevalence of histamine activity in these diseases. This two-part paper contains statements totally contradicting the authors previous works, including his chapter in Allergy 1997. Moreover, it contains contradictions within the same text. Dr. Kay commits a commonplace substitution of causes with triggers by focusing on the outdated IgE-based hypothesis. This gives the priority to environmental influences, which he discusses at length. Unfortunately, the examples given by the author are not at all supportive of his views. He points to the prevalence of allergies in Australasia, the United States and Western Europecountries absolutely different in their density of population, climate, development, and industrialization; the IgEbased concept fails to deal with this fact. Furthermore, his speculation that allergies are more frequent in areas where the developing immune system is deprived of the microbial antigens raises yet more questions. Isnt vaccination the analogue of microbial anti-
Histaminegate
147
gens? If not, why do we need it? If it is equal to natural microbial antigens, why is allergy/asthma incidence significantly lower in East Europe, where vaccination was compulsory under the communist regime? Puzzling yet is another factor he considersbeing born when pollen counts are high allegedly contributes to asthma in certain areas. Do couples in some countries have a strange preference in conceiving at a certain time of the year? It is interesting that even though Kay recognizes the role of genetics in the production of allergies, he does not elaborate what those prime genetic defects are in allergy patients and labels genetic malfunctioning in allergy as a mystery due in part to the multiple markers. Strangely, in the past, he himself specified these defects as defect in suppressor cell function.68 Although Dr. Kays article intended to cover mechanisms of allergy, it left them out. The truth is always simple. In allergy, like in any disease of dysregulation, we are dealing with two forces. The disease is an evil force, and our immunity is our savior, but in the presentation of the leading allergists, including Dr. Kay, the disease forces are always dominant, while the protective ones are nowhere to be found. Allergy medicine today unsuccessfully fights the evil forces with the help of the drug industry, and never gives a chance to the weakened, but still existing natural health promoting forces. This has already caused tremendous harm to asthma and allergy patients because of the concealment of the true and vital information. The damage both for science and patients will be enormously greater yet, if the latest concept of asthma as being a disease of primary structural bronchial changes is accepted. This concept welcomes the search for new approaches in the repair of the allegedly irreversible changes in the affected organ, and conceals the truth, which is that asthma is caused by a flawed, but reversible immune mechanism. Allergy research is causing nothing less than chaos, and its leaders should make a thorough critical review of their position. Now you may draw your own conclusions on how allergy medicine has developed. As any medical field, it is based on morphology, biology and physiology. Morphology studies the structure of the body and its parts, while physiology studies their functions. The structure of cells and events that underlie biological processes are studied by molecular biology. These basic sciences are not subject to frequent fundamental changes, but mostly build upon findings that add to what is already known. Once discovered, the cells and their receptors do not disappear on the will of researchers or for the conven-
ience of the pharmaceutical industry. Neither do their functions change. Why has it become so common to write on allergies without mentioning the main participating cells and their by-products? Why is it necessary to rewrite the events of allergic reactions and substitute the central players with those secondary in importance? By now, you already know why. The facts are clear and known, so let us summarize them: What are the main allergy fighters? T-suppressors. What makes T-suppressors efficient? Active H2 receptors. What activates them? Histamine. What could stop a histamine spill from mast cells and basophils? Efficient H2 receptors. What makes them efficient? Activation with histamine that does it like no other drug, say the pillars of allergy. Can we correct these genetic defects? Yes, we can if the needed changes in the governing genes are functional, not structural. How can it be done? By activating H2 receptor, we enable histamine messages to increase the enzyme cAMP, the effect that increases the intracellular activity and reaches the genes. Their corrected functioning results in health promoting messages to the immunocompetent cells. The H2 receptor, T-suppressors, at lower than normal levels of cAMP are links of the same chain. By restoring one link, the H2 receptors, we restore the functioning of the whole chain. The problem in allergy medicine today is that histamine so lies at the center of the sequence. We may not even whisper the word histamine. It is almost a mortal sin, unfashionable, in poor taste. But really, it is the financial implications involved in histamine that is the reason for silencing all discussion about it. Censorship in allergy has become so entrenched in the new millennium that the Editorial in the most prestigious immunological journal states on page 498: The mechanism by which immunotherapy works is unknown.69 Editorials reflect the opinion of the worlds most renowned allergists, and this statement indicates that even the editors of the central immunological periodical are unfamiliar (are they really?) with the works of the fathers of allergy research and are unaware of the role of T-suppressor cells as well as their regulatory chemistry in allergy. Such opinions pronounced by high-ranking specialists serves ultimately to close the door to the wealth of existing data that could contribute to successful immunotherapy and, instead, open the gates to research in numerous ineffective therapies.
Histaminegate
149
This is the natural result of the substitution of the key phenomena with numerous inferior minutia. Added to that is intermittent professional amnesia regarding some of the events and players and their reappearance under different names, without any clarification of their identity. The earlier described disappearance of histamine-induced suppressor factors for a whole decade, and then the frequent use of the term interleukin-10, without stating that it is a histamine-induced suppressor factor, is an example.70 However, allergy research, such as it is, cannot prevent other medical areas from publishing the data prohibited in its field, and indeed the compelling material coming from the National Institutes of Health and the Cancer Institute in the USA serves to expose the plot. The authors name histamine as the best activator of the enzyme cAMP and state that none of the other mediatorshas any effect on the production of Il-10. They also indicate the H2 receptor as the pathway for the induction of this interleukin.71 Another example of the determination of allergists never to call a spade a spade is the complete removal of T-suppressors from all allergy sources and the use of CD8+ or OKT8 cells. Without identifying these in allergy, both terms have the same meaning, namely T-suppressors. The concealment is such that today, the T-suppressors regulatory role has been attributed to other kinds of T-cells that possess innate defensive qualities, but whose activity is nonspecific in allergy. They have become the substitution to the abolished specific T-suppressors, and now immunologists seriously discuss their allegedly immunomodulatory activity in allergy. Funny, some authors, who are most probably not informed of the plot, inadvertently, at times, reveal the truth and declare that the newly proposed defenders are not really controllers of allergic reactions.71 Even the most fervent proponents of the new trend have not completely hidden those T-suppressors under their new name, and so they write: It is difficult to dismiss, however, the fact that CD8+ T cells may have some function in the control of immune response to inhaled proteins, and that independent studies have identified a potential role for CD8+ cells.72 One gets lost in this field of medicine, even as a specialist practicing in it; it is now so full of disassociated, misinterpreted, silenced or twisted theoretical events and notions, all of which are not applicable to clinical practice. Sadly, it is ultimately the patients who become the victims. The tacit ban on exploring histamine and histamine-dependent immune tools forces allergy to resort to disguising or avoiding T-suppressors and their
histamine-induced suppressor factors. T-suppressors, as was said, are suddenly identified as CD8+ cells. The devious thing is that this is not simply wrongbut it is a useful half-truth, which is always more convincing than a lie. CD8+ cells comprise up to 35% of all T-cells, and they combine two groups of cellscytotoxic cells that have no relevance to allergy and Tsuppressors, the cells operating as the main regulatory mechanism in allergy. Without differentiation, only those who know theoretical immunology will understand which of these two are relevant to an allergy-related text. To solve the problem of T-suppressors, I refer immunologists to Bernard Shaw who prefigured their existence and their key role in immunity. In his drama The Doctors Dilemma, the playwrite created a character modeled after his friend, Sir Almroth Wright, who specialized in vaccination and inoculation. Shaw put the words stimulate the suppressors into the mouth of the main character. It is a historic fact that Dr. Wright edited the medical aspects of the play, and thus, the words of his prototype confirm that even before T-suppressors were discovered, experienced scientist had guessed their existence. The main danger to truth is not so much in the complete omission of the central events and phenomena, but in their replacement with numerous details, some secondary in importance, some ridiculously irrelevant. These data are then zealously disseminated within the profession and among the lay public and acquire the status of real science. They distract from the primary cellular defects and eliminate the possibility of correction. This explains why the researchers of these postulates get unrestricted funds from the drug industry. Connections of the medical profession with pharmaceuticals have become so notorious that many doctors now try to dissociate themselves from the industry. In response, lately, independent trusts for research have been organized by pharmaceuticals, and one can only wonder how independent they are. When the cup is full, it will eventually overflow. True knowledge piles up, and it is very difficult to completely obstruct its leakage. It happens because research goes on in different directions including in the do-not-trespass zones where intellectual censorship has taken hold, and high profile scientists on research teams cannot be forever denied publication. Occasionally published results reveal the true mechanisms of allergy and indirectly point in the direction of useful therapy. Here is an example. An international team made a presentation at the annual meeting of the AAAAI and leaked the unwanted data: injected histamine inhibits the release of
Histaminegate
151
cellular histamine! To trace the effect of histamine on T-cells, the researchers labeled it with a fluorescent chemical and confirmed that inhibition of histamine release was realized via H2-receptor effect at all the stages of allergic reactions.73,74 This confirms the dual nature of histamine activity and proves that histamine injections work because of the well recognized phenomenon of negative feedback! Dorlands Illustrated Medical Dictionary defines negative feedback as the condition of maintaining a constant output of a system by exertion of an inhibitory control on a key step in the system by a product of that system. In plain words, when you push the key step (H2 receptor) by a product of the system (histamine), you maintain the steady production of the same substance (histamine). Simple and effective! In this connection, we will go to another world-famous scientist who is also relevant to my personal legal case. In the past, he wrote on the negative feedback of histamine and its key role in allergy, but he is silent about this today. Yet, according to his own recent admission made at the international forum of asthma specialists, his area of interest is asthma, its origin and treatment. STEPHEN HOLGATE is professor of Immunopharmacology Group, Respiratory, Cell & Molecular Biology Research Division, Southampton School of Medicine, UK. Since 1984, he and Dr. Kay are co-editors of the journal Clinical and Experimental Allergy. Holgate is an author and editor of numerous textbooks and monographs, chair and lecture at international forums, including annual meetings of the European Histamine Research Society. His work was always tied to histamine whose unprecedented significance for medicine he has recently acknowledged: The discovery of histamine by Dale and Laidlaw in 1911 created a new scienceImmunopharmacology.75 This means that for Holgate, who is an immunopharmacologist, histamine is the source and meaning of his professional career. The fact that this scientist is one of the central designers of research projects for allergies and asthma, as well as drug development for these diseases, makes it important to follow the fluctuations of his scientific position. His article entitled The Epidemic of Allergy and Asthma75 starts with a paradoxical declaration: The past 30 years have witnessed a spectacular increase in our knowledge of the cellular and molecular mechanisms of allergic diseases, which has been paralleled by the rising trends in the incidence and health impacts of these diseases worldwide. One would think medical discoveries should help reduce the figures, otherwise, they can hardly
be called discoveries. Unfortunately, this declaration accurately reflects the state of the art in the field, in which Holgate is a leader. Holgate, whose career as an immunopharmacologist was launched by histamine, knows better than anyone that all allergic processes, progression and regression, are inseparable from histamine and related phenomena. The book Management of Allergy in the 1990s which covers the XIII International Congress of Allergy and Clinical Immunology 1988 includes Holgates article100 The Role of Histamine in Asthma (pp.1420). There is a table on page 15 entitled Biological Role of Histamine. In a succinct form, it presents the accumulated knowledge on histamines role not only in asthma, but also in the immune system in general as well as in the nervous system. The word biological indicates that he describes the processes in a live body. The table shows how histamine implements negative feedback on histamine release. This biochemical mechanism means that histamine inhibits its own cellular leakage, and the process is realized when active H2 receptors stimulate accumulation of the enzyme cAMP. Holgates table shows that H2-receptor activation by histamine activates suppressor cells and produces histamineinduced suppressor factor. As we see, at that not-so-distant time in 1988, Holgate knew the true mechanisms of allergies and related diseasesthe H2 receptors, and the T-suppressors and histamine-induced suppressor factors were obviously not yet censored. Apart from immunoregulatory properties of histamine, the table lists its neuroregulatory role implemented by the H1/2/3 histamine receptors. The story of this table is of special interest because it became of prime importance to me personally. I presented it as a key item in my defense material, which I submitted to the CPSO during my discipline hearings. It was an exhibit of central importance to my defense as it provided the scientific validity for histamine therapy in clinical practice. So important was this table in supporting my therapy theoretically (in practice I already had proof of thousand of patients improved or curedwhich did not interest the prosecution) that the prosecution removed it from the article in which it was published thus destroying the entirety of the exhibit. By that time, there had already been so many legal improprieties committed by CPSO at my hearings that I had expected such developments to take place, sooner or later. Indeed, being a refugee from a totalitarian state, such as the former Soviet Union was, prepares one very well for abuses of power wherever one is forced to encounter them, even in Canada. I carefully observed the actions of the
Histaminegate
153
CPSOs prosecution lawyer, Robert Armstrong (who now is a provincial judge in Ontario) and realized that the prosecution understood very well the importance of this table as a perfect defense. I had noticed that the documentation I had submitted had been tampered with. According to legal procedure all documentation in a trial is supposed to be identical in the hands of both parties, the prosecution and the defense). I pointed to the removal of the table and requested it be reinstated. It was, but then it again vanished from the documents submitted by CPSO to all subsequent courts, including the Supreme Court of Canada, and it was no longer possible to reinstate it at that point. Indeed, the CPSO knew exactly what they were doing, abusive as it was legally, for Holgate was such an authority in allergy that this table not only provided incontrovertible and irrefutable evidence for histamines protective activity, but also provided me with a total and unassailable defense defeating the CPSOs charge against me (i.e. practicing medicine without scientific basis). So, the prosecution got rid of the evidence.100 I had a personal conversation with Holgate in September 1989 at an international symposium in West Berlin. I told him I had written an article about my histamine therapy and found scientific sources, including his work, that supported my understanding of the underlying processes. I asked him if I could submit the article for publication to his journal, and Holgate agreed to read the material, which I sent to him soon after. In his letter of response of November 2, 1989, Holgate explained why my paper could not be published in his journal. He stated that there was no evidence of a placebo-controlled trial. He suggested I consider initiating such trials because if the results are positive as have been claimed by yourself and a number of workers that I have met from China, then this would be quite an outstanding contribution to the field of allergy. The editor ended with I look forward to hearing further from you on this point. At that time, I was not aware that clinical and double-blind studies had already been conducted in Switzerland and Japan, and it is hard for me now to speculate whether Holgate knew about them. In any case, although Holgate formally rejected the article for publication, his letter indicated that my hypothesis was valid enough to be tested in trials. In 1994, the expert-witness for the prosecuting CPSO, Dr. A. Knight, was seeking help from the allergy giants. As mentioned already, he approached Lichtenstein and Kaplan, so now he asked Holgate to comment on my histamine therapy. Dr. Knight testified at the hearings that he had actually taken the trouble to travel to England to meet with Holgate for just this purpose,
which shows how very important it was to the CPSO to stop this therapy from being permitted. Interestingly, I was not permitted to see Holgates letter (another legally abusive turn of events), and learned about its existence only at the hearings themselves from the prosecutor, Bob Armstrong. Holgate allegedly wrote that his 1989 letter to me had not been the response of an editor to an author but a personal one, and that he had never approved of histamine therapy. His response is very strange indeed. First, my relationship with him was one of a purely professional kind, and such a letter of an editor to a writer cannot be anything but his official response. Second, it is highly improbable that this renowned scientist would suggest such a senseless project as scientific trials based on an invalid idea. Third, if Holgate did not believe that histamine therapy could be efficacious, why did he volunteer the information about its successful application in China. Moreover, at our meeting, Holgate suggested to me personally that should I talk to Dr. Busse whose research was related to the histamine-related mechanisms of allergies and asthma. Why would he needlessly burden his high profile colleague with an insignificant topic offered by an unknown doctor? (By the way, I met with Dr. Busse during that conference only to hear that his work was in another area. In fact, Dr. Busse, who later became the president of AAAAI, researched and continues to research underlying mechanisms of asthma.) In the nineties, the protective properties of histamine and histaminerelated elements were becoming more and more obscure. However, Holgate went further than obscurity. He, who had described T-suppressors as the key defense tools, inexplicably turned them into hostile cells. Thus, among immunocompetent cells that produce pro-allergic cytokines, he named CD8+ T cells, the other name for suppressors. He has never given an explanation as to what caused the transformation of this savoir into an evil force within a mere decade that separates this work from the above-discussed article, The Role of Histamine in Asthma. Holgates later articles now became full of the word antihistamines and reference to histamine is almost completely omitted. The 962-page volume Inflammatory Mechanisms in Asthma 1998, co-edited by him goes so far as to completely exclude all protective activities of the allergy-related immune system, histamine included. Nature and science has been edited and is presented in a fashion so biased as to be beyond recognition. Only once did the editors overlook a detail that exposed their knowledge of the true mech-
Histaminegate
155
anisms of allergies. They forgot to censor a reference to the 1991 article by R. Alam and A. Grant, cited by us earlier. That article discusses the balance of pro- and anti-inflammatory histamine-induced factors as the central missing link in understanding and management of allergies and asthma. With the passing years, Holgate has gone far away from his former views and provided no scientific explanation for this change. In the year 2002, we find him as one of the seven authors of an article discussing the interrelation of mast cells and muscle cells.76 The text may serve as an example of how skilful allergists have become in writing about central events without naming them. Thus, this article presents mast cells as predominant players in allergic reactions, and only if we know of the inseparability of histamine from mast cells, do we understand that histamine is the central figure. Allergic reaction in the bronchi is described properly and in detail, but in conclusion, muscle cell abnormalities become disproportionally elevated to a key element in the development of asthma. Since histamine is only mentioned in passing, the pro-inflammatory chemistry induced by its leakage is not in the picture either. This obscures the cause of the abnormal functioning of muscle cells and results in putting the cart before the horse, i.e. declaring that the secondary event is the primary one. This diverts attention from the primary event, prevents further research into it and contributes departure from the key elements. And this is exactly what followed. As Holgate is one of the most powerful figures in todays allergy research, this publication became the subject for discussion by two editorials in the same journal. One concludes: both the mast cell and the muscle cell play a part in the origin of asthma, and which of these has the primary role remains to be determined.77 Thus, the causative histamine-induced proinflammatory chemistry becomes equal to the secondary damage, the muscle cell malfunction. Moreover, the text on page 1742 says that mast cells are of paramount importance in the pathophysiology of asthma, and among the array of mediators released from the activated mast cells, 12 are listed, but histamine, which is these cells most distinguished product, is not among them! Either the concealment in allergy has become so total that even scientists and editors have forgotten what they had studied at their medical schools, or they are in collusion with those forces that have a vested interest in hiding the truth. The other editorial, This Week in the Journal, also strongly accentuates the primary role of muscle cell functioning. It says on page 1683 that asthma is
a chronic inflammatory disease with unknown pathogenic mechanisms. The suggestion follows: scientists should shift the focus of asthma research to abnormalities of airway smooth muscle and away from the general study of airway inflammation. Consider the logic of this suggestion: medicine supposedly does not understand the essence of chronic immune-related inflammation in asthma, but nevertheless should ignore this phenomenon and, instead, redirect its attention to less demanding, secondary events abnormalities of smooth muscle cells. Holgates recent concepts are conflicting in essence. Thus, in a highly reputable journal, he presents asthma as an immune disease and IgE antibodies as the pivotal element in its production: Atopy is the single strongest risk factor for the development of asthma.81 Few years later, as a guest editor at an international symposium of experts, he declares that asthma is a consequence of abnormal injury and repair responses and agrees that allergy does not really cause the process of asthma.79 At that gathering, Holgate declared a new paradigm for asthma pathogenesis that, according to the specialists present at the discussion, is fascinating because of the fact that it takes allergy out of the equation. Sadly, such a paradigm will further obscure asthma pathogenesis rather than clarify it. The truth, in fact, is very simple, if properly presented. First, all structural histological changes, tissue destruction and remodeling, occur only in a faradvanced asthma, and that all of them result from the T-lymphocyte-mediated chemistry. Second, the pro-inflammatory T-lymphocyte-mediated chemistry can be offset not through its suppression but through stimulation of the production of the disease-inhibiting chemistry. All this will inevitably reveal the true pathogenesis of asthma that lies in the balance of histamineinduced pro- and anti-inflammatory factors. Holgate delivered the introductory report at this symposium and said that he has focused his research efforts on the cellular and molecular mechanisms of asthma, with a special emphasis on applications to diagnosis and treatment. This self-appointed task, together with his high position, should make Holgate especially responsible for what he says. Those below look up to him both for theoretical support and guidance to clinical application of his ideas, and therefore his own directions should be made absolutely clear. Regrettably, as a shepherd, Holgate leads his flock astray. In his latest articles, Holgate stresses the need for steroids and at the same time dreams of treatments that will modify the disease outcome rather than simply suppressing the inflam-
Histaminegate
157
matory processes.81 By presenting asthma as an interplay between Tlymphocyte-mediated airway inflammation, tissue destruction, and remodeling, he plants such confusion that means his dream is not likely to come true. Over three decades ago, cyclic AMP was recognized as an effective mechanism to control allergic reactions, and the drug industry knows this very well. To help patients radically, one should follow natures way: use histamine H2 receptor as the pathway to increase that enzyme with the effect of activating the entire anti-inflammatory chemistry. An important article in basic science written by a group from the National Institutes of Health in Bethesda recognizes that cAMP provides the central mechanism for activating the immune system. This article also emphasizes that none of the agents stimulating cAMP is able to induce IL-10 (the key allergy-protective histamine-induced factor) and regulate the expression and secretion of a wide variety of cytokines released by immunocompetent cells.82 This article provides the proof that allergies are diseases of one predominant mediator, and recovery depends on its proper release and activity. The way for rectification lies in the cAMP activation via the H2 receptor. A well-read clinician can easily draw the logical conclusion on how to transfer this knowledge into practice. Likely success, as I have demonstrated in my practice, would be a serious problem for the pharmaceutical industry. It pays the best minds to search for other less efficient ways to reach cAMP. Such new drugs must, of course, never cure but only improve the condition of the sufferers when taken regularly. Like Lichtenstein, Holgate works on the development of phosphodiesterase inhibitors, drugs with a theophylline-like mode of action, and an article he co-authored expresses a hope that these drugs may emerge as a new anti-inflammatory therapy in the treatment of allergic diseases such as asthma.83 While acknowledging the prime role of cAMP in cellular regulation, by stating that increases in cellular cAMP are associated with a generalized downregulation of inflammatory cell activity, the references (especially nos 10 and 11) lead the reader to two articles that name histamine as one of the best activators of cAMP and Lichtenstein is the author of both! The leaders in the field know how to treat asthma in the most effective way. Both choose not to do it. PETER BARNES is another leading immunopharmacologist. Like A. Kay and S. Holgate, he presides at international gatherings, writes in prestigious
journals and is cited by many researchers. He is also a consultant to the largest asthma drug producer GlaxoSmithKline, and is considered to be a great authority on asthma management and medications. His research is funded by this manufacturer as well as other multinationals. Barnes knows what underlies allergic reactions, and how they can be controlled. The following passage was quoted earlier in this chapter and was written by Barnes: release of histamine from human basophils is inhibited by histamine itself. The possible mechanism of the inhibitory effect is H2receptor mediated. That same article emphasizes the tools needed for such inhibition: exogenous histamine inhibits the release of histamine from human basophils, acting via an H2 receptor.84 This work also states that the immunomodulatory role of H2 and H3 receptors may play a potentially important role in controlling the airway caliber of patients with asthma, and also control histamine release from mast cells by means of a negative feedback mechanism. Actually, that last sentence amounts to approval of histamine injections that activate those H2 and H3 receptors. A year after this publication, Barnes receives solid theoretical support for potentially successful clinical use of histamine in asthma from the Histamine Research Society.85 The authors write that histamine seems to participate in the mediation of stress-induced release of ACTH (corticotropin) and endorphins. If so, this indicates a more efficient functioning of the adrenals (that would mean no corticosteroids for asthma!) and also modulation of the production of endorphins, which are neurotransmitters that affect both the course of asthma and the occurrence of vascular headache, fatigue, pain syndrome, mood swings, and irritable bowel syndrome. The article also shows that histamine stimulates the release of peripheral catecholamines, which means more release of adrenalin, and thus, eliminating or lessening the need of bronchodilators. Together with the normalized steroid production, this would be a huge improvement for patients suffering from asthma for whom the combination of bronchodilator and steroids has become the norm. Regrettably, as all theoretical works, this work does not suggest these data be tried in clinical medicine, even though all research in medicine should be done for this purpose. Still, these observations have provided unintentional confirmation for the work of another scientist, J.-M. Arrang, the discoverer of the H3 receptors, who published an article in the same 1991 volume of Agents and Actions on pages 5567.
Histaminegate
159
With explicit reference to Barnes, Arrang and his co-authors state that in the respiratory field, one observes the inhibition of inflammatory process upon H3-receptor stimulation in guinea pigs in vivo or in human airway preparations in vitro. They conclude: These observations suggest that H3receptor agonists may constitute a novel approach in the treatment of asthma. The article also brings us the happy news that finally not only guinea pigs but people have been found deserving of the attention of medicine: Initial clinical studies (with histamine agonists) have shown to be well tolerated in asthmatic patients receiving the drug either via aerosols or the oral route, even in very high dosage. One would think that more than a decade after this initial success in the management of such a potentially fatal disease as asthma, science would seize upon histamine therapy and start helping asthmatics. Not at all! Even Dr. Barnes, the chief worlds strategist of asthma therapies, disregards the research on the theoretical aspects of asthma, successful trials on animals and man, and his own above-quoted pro-histamine ideas. Similarly to learned colleagues, Barnes, made an inexplicable turn in his views. In 2000, he wrote an article in the new JACI publication called New millennium: The conquest of allergy. There, he wrote that steroids, which are now first-line treatment for persistent asthma in all patients, often do not control the disease, produce side effects and are not curative, and inflammation recurs when they are discontinued.86 This would be the best time to suggest exogenous histamine, previously studied by himself after all, at least on those patients whose asthma is resistant to steroids. But he chose another way. Weighing the pros and cons of various treatments, including immunomodulation, which, as you know, in the language of allergists is not immunotherapy but the euphemism for immunosuppression, he considered the possibility of using a potent immunosuppressant as an immunomodulator. He used this oxymoron although, as an immunopharmacologist, he knows the difference between the two better than anybody. His article on the directions of how to treat asthma ends with the pessimistic: The possibility of developing a cure for atopy is remote, and the only feasible way, in his mind, is to inhibit or suppress components of the allergic inflammatory response. This of course, amounts to giving the drug industry a free hand, for which he works, to produce countless suppressantsimmune modulators in the ambiguous vocabulary of allergy medicine. The very word histamine is not used in the text and only once, does Barnes reveal his true knowledge of what the precise target of asthma therapy should
be. On page 11, speaking about immunomodulation (by immunosuppressors) the author writes that steroids also inhibit suppressor T cells that may modulate the inflammatory response. Thus, we learn in passing that immunomodulatory T-suppressors still exist despite the fact that clinical allergy has done its best to ignore their existence, that steroids disable the activity of these central protectors in allergy, and that the real meaning of the word modulate is change to the desirable, that is, normal active level, not to suppress below the norm. The only hope is found in the fact that true science breaks through, no matter how thoroughly quashed. For example, speaking about certain cytokines (that) have anti-inflammatory or immunomodulatory effects, Barnes assumes that their secretion may be defective in patients with asthma, and understanding these processes may give a better understanding of disease. This, he suggests, may also lead to novel therapeutic approaches, such as drugs that increase the release of endogenous inhibitors or mimic their effects.88 Not only does he admit that such therapeutic approaches are attractive since they may restore anti-inflammatory mechanisms to normal, but tells us that such drugs carry a lower risk of adverse effects. Although histamine and histamine-induced factors are not named in the text, the defective secretion in asthma means that the balance is favoring inflammation, and the degree of the imbalance explains the severity of the disease. While he mentions endogenous inhibitors or products that mimic their effect, it is strange that he does not name histamine, which, as a physiologic autacoid, carries a lower risk of adverse effects compared to conventional therapies. Histamine, its agonists and congeners are doomed to remain in the domain of experiments. We understand this when we read in the Arrangs article cited above from Agents and Actions that Ongoing studies are exploring the activity of the drug on various models of experimentally-induced bronchoconstriction in asthmatic volunteers. Why do we need to induce bronchial spasm in volunteers with so many asthmatics suffering from spontaneous bronchial spasms? The answer is simple: the use of histamine on real asthma patients could undermine the huge research into lucrative medications for asthma. The Real Drug Pushers by Joel Lexchin published in 1984 states on page 86 that the drug industrys focus is to develop major drugs for major markets. The key influence on the direction or misdirection of pharmaceutical research is whether or not the product can be patented. New uses of already existing chemicals cannot be patented, and therefore industry research
Histaminegate
161
tends to ignore these substances. Histamine is one such century old substance, not just ignored but viciously fought by allergists because it cannot be patented. It carries the potential for cure but not the potential favoring industry growth. The intention to conceal the self-regulatory forces in allergy is reflected in an ARIA document which states that it is intended to be state-of-the-art for the specialist as well as for the general practitioner.101 ARIA (see JACI 2001, 108) is the abbreviation for Allergic Rhinitis and its Impact on Asthma. This workshop took place at an international conference that drew the leaders of allergy medicine and was conducted under the auspices of the World Health Organization. As the document states on page S182, For didactic reasons, only pro-inflammatory chemistry is covered. For example, although the document is on allergies, the H2 receptor is presented solely as one responsible for gastric acid secretion, while its curative stimulation of the enzyme cAMP and its therapeutic negative feedback effect are not even mentioned. What are these didactic reasons that force one to conceal the defensive tools of the immunity. Somebody must take responsibility for the plot against histamine. The virtual disappearance of the central chemical involved in all allergic reactions, a major mediator and biological marker of all immune processes and a central regulatory neurotransmitter requires an explanation. It takes great effort to hide this immense body of research from visibility. Burning libraries has ever been the work of those who want total control over minds, states, people. These volumes of research are very much needed and most precious. History teaches us what happens when pages are torn out of books, or books are thrown into a fire. Usually authors follow, and obscurantism sets in. My histamine story can be reduced to a sentence: a doctor, who used a well-researched, inexpensive medication, helped or cured hundreds of patients with undiagnosed and/or resistant diseases, and was able to explain the underlying routes of their recovery, was not only prohibited from using his therapy, but prosecuted and punished.99 The situation is not new in society: What judgment shall I dread, doing no wrong?, asks Shakespeare in The Merchant of Venice. Medicine is just a part of society and lives by the same rules. I should have expected the judgment. Thinking, especially thinking differently, has always been considered as an occupational hazard. I just happened to study basic science and theoretical allergy research that described the biochemical immune mechanisms
lying at the roots of my histamine therapy as central and regulatory. I investigated the chaos of fragmented details, arranged the key elements into a logical system, introduced it into clinical practice and offered this to the medical world without any personal gain in mind. The very scientists who had researched and developed these fragments rejected them in their clinically implemented form. They have never given an explanation for their rejection, even though they have been unable to offer any alternative. This is because the truth must have scared them and threatened other, incompatible priorities.
HISTAMINE AND DISEASE: A FORUM ON CURRENT AND FUTURE MANAGEMENT The year 1991 appears to have been the cut off for publications on histamine. Publications in 19911992 on histamine still appeared probably due to the fact that the abstracts are usually accepted months or even years earlier. Before this boundary date, professional meetings could readily involve discussion of histamine. The title of this chapter is, in fact, the name of the conference of American allergists and clinical immunologists that took place in the summer of 1989. Dr. M. Kaliner was the guest editor of the supplementary issue of JACI that covered the forum. As he said in his Introduction, the participants were highly respected, the purpose for the gathering was to foster better patient care, and the topics reviewed ranged from basic science to treatment of common allergies.88 This forum was the last open discussion involving histamine. Probably, among the participants, there were still some researchers who naively believed that theory in medicine should and would serve application to patients. It might also be that a conference with this topic was possible only because at the organizing stage, the manufacturers of allergy and asthma drugs did not yet fully realize the danger of histamine, and the main sponsor, Merrell Dow Pharmaceuticals, did not produce asthma medications and was, therefore, indifferent. So, what ideas were presented at the forum? The author of the first report entitled Mast Cell Biology stated that the role of mast cells is complex. Their location at the host-environment interface suggests that they help protect (!) the host. And further: Mast cell, far from being simply a package of histamine may be an important factor in both homeostasis and disease. These statements indicate that histamine, as the mast cell central mediator, possesses, apart from inflammation promoting features also anti-inflammatory ones. The report also stated that the core of any allergic reaction lies with an exag-
Histaminegate
163
gerated histamine release by the hypersensitive mast cells, and not with allergens, and that in allergy, it is histamine hyperreleasability that is a link between non-IgE immune responses and mast cell activation.89 Actually, this concept leaves beheaded conventional allergy, which remains wedded to the IgE antibody dogma. The fact that histamine overspill may ignite allergic reaction without any IgE participation renders senseless the chase after mites, cats and cockroaches as causes. Ironically, in the new millennium, IgE and allergen elimination are still the core management of allergies and asthma. The presently propagated ideas imply that histamine is just one of many mediators of allergy and therefore does not deserve preferential consideration. Moreover, if other mediators are still named, histamine is often not even mentioned as an ordinary player. Such views can easily be refuted, first of all, by the very name of this international conference that concentrated solely on histamine and the possibility of its use in the management of patients. Secondly, even though histamine is only one of many mediators of allergic disease, it should be strongly considered when analyzing the cause and treatment of any mast cell-related disease, observed Dr. White, M. Kaliners co-author of the chapter Histamine in the authoritative volume Inflammation.90 She continues in the same article: The presence of the H3 or H2 receptor might alter susceptibility to H1 effects and also: H3 receptor is primarily responsible for turning off histamine secretion. This receptor is found in the brain, but some data suggest that it may also be present in the lungs and other tissues. Furthermore, the ability of the H2 receptor to turn off histamine secretion in the basophile may be mediated by the H3 receptor. In other words, efficient H2/3 effect wins over H1 effect (Later research proved the existence of H3 receptors in the lungs and other tissues). Like the discoverer of H3 receptors, J. Arrang, Dr. White emphasized the synchronized functioning of H2 and H3 receptors. Paradoxically, the author makes a statement that contradicts all she said before: she suggests H1 and H2 blockers be used together. Her informative report fails in its conclusions because blocking H2 receptors would make them even less effective. One can only ponder the logic of this suggestion. Along with the widely used statements that histamine is important in provoking asthma symptoms, some ideas that would today be considered outright seditious were expressed at the symposium. For instance: Mediators, perhaps including histamine, are important in immunomodulation. Or: Therapy directed at cells that produce these (histamine-releasing) factors
and cytokines may prove beneficial in the treatment of asthma.91 Unlike Dr. White, this researcher does not spell out the anti-inflammatory function of H2/3 receptors. As a result, the two reports, although supportive of each other, remain disconnected. Another conference participant, J. Hanifin, correctly presents allergy symptoms as the result of abnormal histamine releasing factors or, conversely, a lack of histamine released inhibitory factors.92 He also wrote that increased level of histamine releasing factors may account for abnormalhistamine releasability in allergies. The author outlines the two ways of controlling histamine release and therefore its symptoms: by diminishing the amount of the disease-promoting chemistry or increasing the amount of disease inhibiting chemistry. However, this article, as all the rest, is limited to naming the theoretical facts and leaves unheeded the clinical implications these facts carry. There is only the ever-present rhetorical comment: possibilities have yet to be studied in depth. We quoted in the first part of the book Dr. L. Mansfield who presented a report on the relatedness of asthma and allergic rhinitis to migrainea fact noted as far back as the early 1920s. Speaking about different neurotransmitters that participate in the production of vascular headaches, this author suggested the use of H3 agonists, which offer promise as prophylactic agents for people who suffer from vascular headaches.93 Yet, again we are confronted with the same paradox: having discussed agonists, Dr. Mansfield speculates what antagonists (antihistamines) are more effective. One can only assume that such a discrepancy between the description and the conclusions from a knowledgeable scientist would be due to the limits set by some outside force, which does not permit the scientist to speak out correctly. It is important to note, that this conference took place at a time when the development of serotonin-related drugs for migraine headaches was in full swing, thereby setting a specified invisible agenda. Not only was the relationship of allergic and neurological conditions reported at the conference, but also another chronic condition that plagues us, arthritis, was presented as one of a similar origin. Mast cells and their products are participants in some types of synovitis (joint inflammation). Indeed, several types of arthritisare characterized by mast cell degranulation and the resulting release and generation of mast cell mediators.94 The conclusion of the authors is that mast cells must be considered with other inflammatory cells in the genesis and perpetuation of arthritis. In the discussion that followed, the audience suggested a change in terms and notions and the need
Histaminegate
165
to focus our attention on allergic arthritis or hypersensitivity arthritis. Is this not proof that the allergists recognized the common roots of diseases of hypersensitivity and arthritis? This opinion coincides with the views of Melmon expressed in Therapeutic Immunology 1996, when he described histamine as the key immunomodulator in any chronic inflammation. A. Kaplan also believed at some point in the relatedness of allergies: mast cells degranulation (is) observed in a wide variety of immunologic disorders including chronic urticaria, atopic dermatitis, asthma and rheumatoid arthritis.95 The common roots of these disorders indicate the possibility of similar treatments. At the forum Histamine and Disease, nobody made a suggestion for practical implications deriving from the data presented. The Introduction to the forum stated that it was to cover Major advances made in both the understanding and treatment of allergic reactions, which are the cause of mans commonest chronic diseases. Now, more than a decade later, these advances remain speculative and, moreover, are censored and concealed, removing all hope for patients to benefit from them.
MORAL AND LEGAL ASPECTS OF THE CONCEALMENT OF KNOWLEDGE The purposeful omission, distortion and misinterpretation of pivotal scientific data, purging of textbooks, the dissemination of inaccurate theories, and the gagging of those who do not agree with such wholesale censorship all send us back to the Dark Ages. Every time I come across unfounded declarations of success or revolutionary changes in the management of allergy/asthma, I wonder whether the authors are familiar with the works that form the basis of allergy. If not, they do not have the right to profess themselves leaders, innovators and educators in their leading periodicals.96 For people in such a position, knowledge is a must. Here we must look at allergists both from the legal and moral perspective. The elite of allergy medicine are all medical doctors. They are also official representatives of the profession since they head medical institutes and govern research bodies as well as preside over professional forums. This puts three kinds of legal obligations on them: 1. As doctors, they have fiduciary obligations to provide their patients with the best available knowledge and therapies. 2. As citizens, they must not knowingly make false statements in public about vital issues in science and therapies, and disseminate falsified information. 3. As public health officials, they do not have the right to consider the health of individuals as a commodity or a commercial product .
The Ten Commandments are more than just religious laws. Their essence is the code of civil and social morality on which culture is founded. Not only the Bible, but also the collective morality of civilization demands that Thou shalt not give false testimony against thy neighbor. Those who know the truth, but give false testimony at their symposia or in their publications, reveal their lack of morals, a quality unacceptable in a medical doctor. Again, not only the Bible, but also the collective consciousness insists that Thou shalt not kill. They kill, although not directly. Allergists admit that their ability of controlling morbidity from asthma has been rather limited, and we all know that mortality from asthma is on the rise. At the same time, profound research has found ways of natural immunomodulation, and medications for this exist, namely synthetic histamine and its congeners. They may open the way to the creation of other modulators that will be preferable to immunosuppressive drugs. However, Animal models became preferred because of ease of implementing experiments in animal models of human immune-based diseases, and an unfortunate separation soon developed between human clinical immunologists and mouse immunologists, say two allergists of the highest stature.97 Allergists regret that research is all organ-based diseases, whereas it should concentrate on immune cells and their functioning, study immune regulation, immunotherapy, immunogenetics, and immunodiagnostics, and look for a cross-disciplinary approach to understanding of what allergic diseases are. What the authors do not say is that the existing mouse immunology is purposeful, and that any introduction of knowledge that may lead to efficient management of patients is routinely sabotaged. Furthermore, not only animals have undergone trials with histamine and its agonists. Double-blind studies on humans have also been successfully conducted in Switzerland and Japan, but they have been successfully hidden. Open clinical studies that took place in France and Poland were published in small periodicals, and their success has remained unknown. Only a general lack of interest and critical opposition permits such grossly unethical concealment of vital knowledge, its substitution with invalid contradictory hypotheses, and the diversion of allergy medicine into the wrong direction, all to the detriment of patients. The recently updated Hippocratic Oath and Charter on Medical Professionalism introduced in 1999 define such activity as professional and scientific misconduct.98 Indeed, one begins to believe that the fewer doctors there are, the healthier the world might be. Far from being dedicated professionals,
Histaminegate
167
we have become the abusers of people and substances, untrustworthy and unreliable. These words were pronounced by Dr. Ron Whelan, President of the Canadian Medical Association at his valedictory address on August 24, 1993. Why do doctors make such declarations only upon their retirement? Most probably, out of fear of being ostracized and severely punished by their powerful peers.
CONCLUSIONS ON THE IMMUNE MECHANISMS IN ALLERGIES AND RELATED DISORDERS

CONCEPT OF DISEASE
Fundamental genes abnormalities Dysbalanced production of the cellular chemistry (cytokines, mediators, neurotransmitters) Malfunctioning of immune and nervous systems with resultant inflammation Chronic diseases of dysregulation such as asthma, allergies, vascular headaches, etc. This concept of disease is not new; it exists in basic sciences but is not assembled and spelled out as a structural notion in clinical medicine. The acknowledgement and understanding of this concept would allow clinical medicine to resolve many of todays unsolved problems, mainly, chronic diseases.
Concept Of Histamine-Related Allergic Diseases Abnormalities of the genes responsible for the functioning of T-suppressors and H2 and H3 receptors, levels of cAMP Inefficiency of cAMP, T-suppressors and H2/3 receptors on various cells Exaggerated release of histamine and histamine-induced pro-disease chemistry with resultant inflammation Allergies, asthma and symptoms characteristic of the organ or tissue with histamine hyperreleasability and/or hypersensitivity
These concepts of allergies and related diseases exist in fragmented data in basic sciences. They also exist, although not formulated clearly and fully, in theoretical works of leading immunologists and neurologists. The following quote and the references used to support it are the best proof of the ongoing censorship cursing modern allergology medicine. The textbook Allergy 1985 contains a chapter by L. Schwartz entitled The Mast Cell, which states on page 58 that the H2 receptor upon its activation with histamine mediates augmentation of T cells suppressor activity and downregulation of basophile and mast cell release of histamine. The cells with H2 receptor can also generate immunoregulatory substances upon activation with histamine, and the levels of these are low in allergy patients. In the same paragraph, the text says that the very activity of immunocompetent cells, eosinophils in particular, occurs solely through histamine-related mechanisms. These findings suggest a multifaceted role for histamine in acute allergic inflammation, the authors conclude. They write on the same page: In 1953, mast cells were noted to be the major source of tissue histamine, whereas human basophils are the major source of humoral histamine. The last sentence of this chapter means that allergies are diseases of one cell mast celland have one mediatorhistamine. As the chapter says, the understanding of this can facilitate the design of new therapies for mast cells-related disease. Among the numerous references given after the chapter, there are ones to L. Lichtenstein, A. Kay, S. Holgate, K. Melmon, R. Rocklin, A. Kaplan, M. Kaliner, which means their research formed the basis for the chapter. In fact, all those same works were the basis for my conclusions.
WHAT NEXT? Allergology should honestly admit that at present, genetic engineering, for example, is a hypothetical possibility not feasible in the near future. Logically, the next step should be to deal with these diseases on the level of their major productscytokines and mediators. The aim of the therapies should be the restoration of balanced chemical production through the restoration of those immune tools that are deficient. This would lead to the development of therapeutic agents capable of activating these tools, namely immuno- and neuromodulators. The repaired tools will acquire the ability to fight effectively on their own, and their restored functioning may even correct the functioning of the relevant genes. Since in many chronic diseases, the inefficient tools are certain polysystemic cellular receptors and enzymes, their activation
Histaminegate
169
should become the prime goal. Such interdisciplinary approach would lead to the introduction of psychoneuroendocrineimmunology in clinical medicine, whereas now, it exists mostly as a theoretical discipline. Simply put, clinical allergy ought to recognize the vast basic knowledge available to its field, and then properly consider and incorporate it. There are many weighty reasons why asthma, allergy and other histamine-induced diseases should and can be tackled right away: They affect a large percentage of the population. They are the fastest growing afflictions, now reaching epidemic proportions. They are functional, at least at the beginning, and are therefore much more reversible than other chronic diseases with organic changes. Effective medications in the form of synthetic histamine and its congeners exist. Targeting one allergic condition may and, in most cases does, cover related neurological symptoms. Indeed, every aspect of the origin of allergic and related diseases and their interdependence and therapy has solid support from basic science. Only one thing is lackingthe desire of those in power to implement all of this. Doctor, cure thyself first. Clinical allergy is in urgent need of curing itself by reconsidering all missing links and focusing on how to help its patients. Revolutions have never succeeded unless the establishment does threequarters of the work (Peter Ustinov). Does the allergy establishment feel the need of a revolution? Does it want to revolutionize its field? Or is it satisfied with its own impotence and the suffering of its patients?99
ENDNOTES
1. I.R. McWhinney. Why are we doing so little clinical research? Editorial. Canadian Family Physician 2001;47:1944 2. K. Melmon, R. Rocklin, R. Rosenkranz. American Journal of Medicine1981; 71:100-6 3. D. Beer, R. Rocklin, JACI 1984;73:439-52. 4. R. Rocklin. Clinical and immunologic aspects JACI, 1983;72:323-334 5. S. Hill. Pharmacological Reviews 1990;42 6. I. Elenkov et al. Histamne potently suppresses human Il-12 and stimulates Il-10 production via H2 receptors. The Journal of Immunology, 1998;161:2586-2593 7. H.R.Bourne, L.M. Lichtenstein, K.L. Melmon, et al. Modulation Of Inflammation & Immunity by Cyclic AMP, Science 1974;184:19-28 8. M.Bourne, K. Melmon, L. Lichtenstein, Science 1971;173:743
9. M. Khan and K. Melmon, Are Autacoids More Than Theoretic Modulators of Immunity? Clinical Immunology Reviews 1985;4(1):1-30 10. K. Austen, ed. Therapeutic Immunology 1996:192,198 11. A. Kaplan ed. Allergy, Churchill Livingstone Inc. 1985 12. For a detailed analysis of this system see The Olivieri Report published by the Canadian Association of University Teachers in 2001 13. S. Hill. Pharmacol Rev. 1990;42:69 14. S. Hill et al. Classification of Histamine Receptors. Pharmac Rev 1997;49:253-278 15. F. Ravikovich. H2/3 Effect in allergy. Allergie & Immunologogie 1992;24:72 16. The transcripts of my trial are in the public domain and can be checked by interested persons. 17. M.Bourne, K. Melmon, L. Lichtenstein, Science 1971; 173:743 18. L. Lichtenstein, E. Gillespie Nature 1973;24:287-8 19. L. Lichtenstein et. al. Selective Display of Histamine Receptors on Lymphocytes, Science1977;195: 683-5 20. R. Bourne, L.M. Lichtenstein, K.L. Melmon, et al. Modulation Of Inflammation & Immunity by Cyclic AMP, Science 1974;184:19-28 21. M. Ichinose, P. Barnes. Histamine H3 receptors modulate antigen-induced bronchoconstriction in guinea pigs. JACI 1990;86:491-5 22. S. Hill. Pharmacological Reviews,1990;42:69 23. R. Leurs et al. Molecular pharmacological aspects of histamine receptors. Pharmac. Ther. 1995;66:413-463 24. R.G. Andersson et al. Studies of the mechanism of desensitization of anti-IgE-mediated histamine release from human basophils. Agents and Actions; 1989;27, :25-28 25. M. Jutel, et al. Nature 2001,413:420-25. 26. W. Roszkowski, M. Plaut, L. Lichtenstein. Science 1977, 195:683-5 27. Allergy And The Immune System, Scientific American, Sept.1993:117-124. 28. Presidential address. JACI 1995;95:783-796 29. B. Zweiman, M. Rothenberg. Articles of Note. JACI 2002;109:375 30. Allergy and the immune system. Scientific American September 1993:117-124 31. Science 1974;184:19-28 32. Science 1977;195:683-5 33. AAAI Training Program Directors Committee: W. T. Shearer et al. Committee report. Core content outline for clinical and laboratory immunology. JACI 1994;94:933-41 34. L. Lichtenstein et al. Inhibition of histamine release by histamine controlled by H2 receptor. Nature 1973;244:287-8 35. Science 1974;184:19-28 36. S. Hill. New Perspective in histamine research. AAS 1991;33:145-159 37. G. Chrousos. Stress, chronic inflammation, and emotional and physical wellbeing: concurrent effects and chronic sequelae. JACI 2000;106S275-91 38. JACI 2003; Volume 111 No 2 39. JACI 2000;106 No5 Suppl. and 2002;110 No 6 Suppl. 40. For worldwide efforts being made to change this situation see www.doctorsforresearchintegrity.com; address: 81 Wychwood Park, Toronto, Ontario, M6G 2V5. 41. J. Imunol 1977;118:1734 42. J.A.Grant et al. Histamine-releasing factors and inhibitors: historical perspectives and possible implications in human illness, JACI 1991;88:683-693 43. L. Lichtenstein et al. Selective Display of Histamine Receptors on Lymphocytes. Science 1977;195:683-5 44. Agents and Actions 1991;33Supl.:376 45. M. Clerici et al. An immunoendocrinological hypothesis of HIV.Lancet 1994:343:1552-3
Histaminegate
46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. JACI 1991;87:207 P. Kuna et al. Chemokines JACI 1995;95:574-86 D. Beer, R. Rocklin, Histamine-induced suppressor-cell activity. JACI. 1984;73:439-452 JACI 1995; 95:574-86 For an overview of all these abusive prosecutions see www.collegeofphysicianswatchdog.com MC Lilu et al. Immediate and late inflammatory responses Am Rev Respr Dis 1991;144:51-8 Hebert et al. The regulatory effect of histamine on the immune response: characterization of the cells involved. Cellular Immunology 1980;54:49-57 M. Kaliner. A Hierarchy of mediators of the allergic reactions. JACI 1992;90:727-8 Lancet 1983;1:520 L. Lichtenstein. Presidential Address JACI 1995;95:783 M. C. Gonzalez et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) T-cells in asthma. Am Rev Respir Dis 1987;136:600-604 Ed. by J.I. Gallin et al. 1988 B. Kay. Allergic diseases and their treatment. New England J Med 2001;344:109-113 JACI 2003;111:S261 I. Hasaelden et al. Late asthmatic reactions provoked by intradermal injections JACI 2001;108:394-401 M. Church. H1-antihistamines and inflammation. Clinical and Experimental Allergy. 2001;31:1341-43) I. Liu et al. Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Molecular Pharmacology 2001;59:420-6 M. C. Gonzalez et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) T-cells in asthma Am.Rev.Respr. Dis. 1987;136:600-604 New.England J Med. 1980;302:1212 K. Shirley et al. T-cells peptide epitopes in man may be associated with the induction/ expression of a population of regulatory/suppressor T cells. JACI 2001;1007(2):S67 I. Bachert. a major role in allergy? Clin Exper Allergy Histamine 1998;28,S6:15-19 A. B. Kay. Allergy and Allergic Diseases. The New Eng J of Med 2001; 344:30-7) (A. B. Kay Allergic diseases and their treatment. New Engl J Med 2001;344:109-113 M. C. Gonzalez et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) T-cells in asthma Am Rev Respri Dis 1987;136:600-604 ARIA: Global guidelines and new forms of allergen immunotherapy. JACI 2001:108:497-9 J. Elenkov et al. Histamine potently suppressesJ. of Immunol 1998;161:25-86-93 A. Mazzoni et al. Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T-cell polarization. J. Clin. Invest. 2001;108:1865-73 H. Tiemessen et al. CD4+ CD25+ regulatory T cells are not functionally impaired in adult patients with IgE-mediated cows milk allergy. JACI 2002;110:934-6 G.Hoyne et al. Immunological tolerance to inhaled allergen. Am J Resp. Crit Care Med 2000;162:S169-S174 M. Jutel et al Differential Histamine H1 and H2-Receptor Expression Determines Up-regulation of Th1 and Down-regulation of Th2 Responses Following Histamine Stimulation. JACI 2000;105(II):157 S. Holgate. The epidemic of allergy and asthma, Nature 1999;402:SB2-B4 C. Brightling et al. Mast-cell infiltration of airway smooth muscle in asthma. N. England J Med. 2002;346:1699-1705 J. Black. The role of mast cells in the pathophysiology of asthma. N Engl J Med. 2002;346:1742-3 S. Holgate. The cellular and mediator basis of asthma in relation to natural history. The Lancet 1997;350 SII:5-9 S. Holgate. Role of systemic leukotrienesJACI 2003;111:S18-36.
171
75. 76. 77. 78. 79.
80. S. Holgate, M. Peters-Golden. Introduction. JACI 2003;111:S1-4 81. Lancet 1997;350:SII:5-9 82. A. Mazzoni. Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization. Journal of Clinical Investigation 2001;108:1865-1873 83. P.L. Harbinson et al. The effect of a novel orally active selective PDE4 isoenzyme inhibitor on allergen-induced responses in asthmatic subjects. Eur Resir J 1997;10:1008-14 84. M. Ichinose, P. Barnes. Histamine H3 receptors modulate antigen-induced bronchoconstriction in guinea pigs. JACI 1990;86:491-5 85. K. Knigge and J. Warder. Neuroendocrine functions of histamine. Agents and Actions Supplement 1991;33:29 86. P. Barnes. New Directions in Allergic Diseases. JACI 2000;106:5-16 87. P. Barnes. Endogenous inhibitory mechansims in asthma. Am J Respir Crit Care Med 2000;161:S176-181 88. JACI 1990;86:589 89. S. Wasserman, Mast cell biology. JACI 1990;86:590-3 90. M. White The role of histamine in allergic diseases. JACI 1990;86: 599-605 91. S. Peters. Mast cells and histamine in asthma,. JACI 1990;86:645 92. J. Hanifin. The role of antihistamines in atopic dermatitis. JACI 1990;86:666-8 93. L. Mansfield. The role of antihistamine therapy in vascular headaches, JACI 1990;86:673-6 94. J. Mican and D. Metcalfe, Arthritis and mast cell activation, JACI 1990;86:677-83 95. P. Kuna et al. JACI 1995;97:574-86 96. R. Zeiger, M. Schats. Effect of allergists intervention on patient-centered and societal outcomes. JACI 2000;106:995-1018 97. W. Shearer, C. G. Fathman. Defining the spectrum of clinical immunology. JACI 2003;111:S766-73 98. The Lancet 2002;359:520-22 99. I did not lose my license, but was reprimanded for the use of histamine and forbidden its future therapeutic use as well as any substance containing histamine. This ban on histamine is indefinite and naturally sends a clear message to any other physician wishing to learn and employ this method of therapy. 100. S. Holgate. The role of histamine in asthma. In Management of Allergy in 1990s; ed. M. Kaliner 1989:14-20 Hans Huber Publishers 101. ARIA Editorial. JACI 2001; 108:497-9 102. P. Sirios et al., Eds. Immunopharmacology. Elseveir Biomedical Press 1982. 103. A. Kaplan ed. Allergy Harcourt Publishers Ltd. 1997
PART FIVE
MEDICATIONS
SIDE EFFECTS OF MEDICATIONS What you have read in this book on the immune mechanisms of allergy is, in fact, simplified cellular biology. Now, it is time to study immunopharmacology in the same simplified form. This the name of the science that studies what medications do to the immune cells. Those who take medications for such chronic conditions as allergy and/or asthma need more than just to perceive them as good or bad. They should understand how these drugs interfere with the work of the participating cells and affect the course of allergic and related reactions. Immunopharmacology explains what immune mechanism is targeted by each usually highly publicized breakthrough and informs whether it is a new drug or a variant of an existing one. It is also important to know what price we really pay for temporary relief: a mere spike in the level of discomfort, lasting severe complications, or perhaps another chronic disease? This is very relevant in todays medicine, as, according to the World Health Organization there are only 326 essential drugs, while, Health Canada, for instance, has licensed over 5,200. Does this mean that almost 95% of these are needless medications? Dr. J. Lexchin in his book The Real Drug Pushers quotes an unpublished letter to a Canadian newspaper, written by W. M. Garton, the 1980 President of Pharmaceutical Manufacturers Association of Canada. The letter says, The pharmaceutical industry has never claimed to be motivated by altruism but rather by profit for survival. It is evident that the attitude of the industry towards drug consumers is not motivated by even a basic notion of ethics,
and this attitude forms their policy and influence on doctors who do the prescribing. Drugs are usually more toxic than is indicated on the labels, and the reasons for that are clearly outlined in the 1990 medical publication Drug Protocol by J. Rovers: 1. Groups of patients who undergo testing are rather small. 2 Those who may potentially mar the drug efficacy coefficient are excluded from the trials, such as old patients and patients with concurrent medical conditions requiring medicationsin short, most prescription-needy clients. 3. The period of testing is too short to enable anybody to notice a delayed adverse reaction, which may manifest years later. 4. The reports given by the doctors involved in trials have poor validity (the author assesses it as mediocre). Always keep in mind that the scientists and doctors who provide the information on the clinical drug use are often sponsored by drug manufacturers and thus have a conflict of interest. Given the fact that the principal approach in allergy treatment, elimination of allergy triggers, does not solve the problem, an allergy sufferer is forced into accepting occasional or daily allergy symptoms. Lucky are those whose symptoms are mild, and they can manage without taking drugs. For those whose symptoms become an obstacle to normal life, daily medications are the only answer. I am going to discuss allergy medications. Medications for asthma will be covered separately in the part entitled Bronchial Asthma.
ANTIHISTAMINES The largest group of allergy medications is antihistamines, which act on H1 receptors. The fact that they are the worlds most commonly used medications is not surprising in view of the increasing number of allergy patients. The name, antihistamines, indicates that medicine knows that histamine is at the heart of the problem, and to control its activity is to control the symptoms. As we know, the H1-receptor messages become exaggerated if H2/3 receptors are inefficient. Antihistamines block H1 receptors to prevent the negative effects of histamine. The blocking effect lasts only while the level of the drug in the body is high enough. Following the drugs natural excretion, its concentration falls, so does the potency, and another pill is needed.
Medications
175
The first antihistamine was developed in France in the early thirties, which makes this drug group 70 years old. Since their first appearance, H1 antihistamines have changed in two ways. One change affects the prolongation of their action, and as the packaging of some newer antihistamines promises, they work for up to 24 hours. The other change is the elimination of the sedative effect although, according to patients and even scientists, this adverse effect is never completely removed. The absence of sedation has, however, its negative aspect. If before, drowsiness would serve as an alarm against the overdose, now, the deceptive harmlessness of the drug invites patients to take more than is recommended on the label. Regrettably, this happens often in view of the low efficacy of antihistamines. I have seen people who actually tripled the dose and then experienced ringing in their ears, were drowsy, but still, the drug did not control their allergy symptoms. If at the same time, for another condition, a patient takes tranquillizers or other downers, or has an alcoholic drink, even as mild as a beer, the sedative effect, absent at the recommended dose, may intensify. This logically leads us to the question of whether the concept of a proper dose exists. The answer is no, since everything depends on the individual sensitivity and concurrently taken medications. Even with the recommended safe dose of a non-sedative antihistamine, some patients complain of drowsiness or a slowing reactivity to their surroundings. Children and older people, as well as patients on other concurrent medications may experience more adverse effects. The recently banned Seldane is confirmation. In 1997, Seldane was taken off the market because, prescribed concurrently with certain antibiotics and some other medications, or taken with grapefruit juice (!) it could produce serious complications such as cardiac arrhythmia, or even death. Presently, Seldane exists in a perfected form under the musical name Allegra, and is free, according to the manufacturer, of the previous side effects, but according to patients, it is also less effective than its predecessor. Similar adverse effects led to the ban of Hismanal, the second oldest non-sedating antihistamine. Are other antihistamines safer? Only time will tell, as they came onto the market later than Seldane and Hismanal. Non-sedating antihistamines are much more expensive than their predecessors. The price for one non-sedating pills may be up to 20 times higher than the price for a pill of the old sedating group. Quite an impressive difference!
SIDE EFFECTS OF ANTIHISTAMINES There is no such thing in medicine as a totally effective drug; therefore the question, which antihistamine is most potent, is pointless. Medication can be chosen only by trial and error. Moreover, the body develops tolerance to any chemical, and as a result, potent at the beginning, an antihistamine may lose its effect days later. Besides, antihistamines only relieve symptoms and do not mend the cause. Thus, with the progression of the disease, appearance of new symptoms and intensification of the existing ones become the natural course, and the formerly effective antihistamine starts to fail. All this forces one to search for a replacement. Doctors recognize that the latest non-sedating antihistamines are often less effective than the first-generation drugs, which are still popular on the market, Benadryl, Atarax, etc. In their attempts to find relief, allergy sufferers may jump from one drug to another and eventually resort to the older group. This group creates an occupational hazard through drowsiness, impaired coordination and poor concentration. If you take these drugs, dont drive, or perform work requiring concentration or dexterous functions. Lucky are those having work where they can relax, but they are rare. From the generally available information on the adverse effects of antihistamines, we are led to believe that they are much safer than other medications. Most common adverse reactions of antihistamines made known to us are dry mouth, upset stomach, drowsiness, fatigue, nervousness, palpitations, dizziness, insomnia, rash (including hives). Pharmaceutical compendia also mention occasional weight gain as a possible side effect. All this is fairly innocent. The worst side effect of occasionally taken antihistamines, their relatively poor efficacy, leads to their overuse. The abuse is easy because they are mostly over-thecounter drugs and are thus easily accessible. Regular consumption changes the view on the complications. Nowhere will you be able to read about the most severe side effects of antihistamines. Below are some of them. GENETIC INTERFERENCE From basic science, it is known that a certain gene plays the dominant role in the metabolism of histamine. This gene activates the enzyme called HNMT, which facilitates histamine break-up and hence, prevents its accumulation in the bodyan anti-allergy effect, so to say. Thus, the functional activity of this gene and its individual variation may determine the occurrence of allergies, their course and response to therapies. Antihistamines potently inhibit the HNMT enzyme and, therefore it might not be an ideal therapeutic strategy
Medications
177
to block the histamine (H1) receptor while also inhibiting at the same time the major pathway for the metabolic inactivation of histamine in bronchial epithelium.1 Paradoxically, this means that antihistamines interfere with the work of the gene that protects us from allergies and asthma. As a result, there may be worsening of the allergies, occurrence of asthma in those allergy patients who did not yet have it, or aggravation in those who had it along with allergies. This makes the authors dream of developing new kinds of antihistamines which do not inhibit HNMT.
IMMUNOSUPPRESSION BY ANTIHISTAMINES The findings of the suppressive effect of antihistamines on the adrenals were registered in trials on rats, and the description goes back to 1982. In 1992, an article covering this drug effect said: The antihistaminic activity is well documented in vitro (in a tube) but has not been investigated as thoroughly in vivo (in a live body).2 Quite naturally, over time, the low level of the adrenals. Vital hormones diminishes the fighting ability of the immune system. If we logically extend the idea, the long-term use of antihistamines will, in turn, necessitate later on the consumption of corticosteroid drugs, which, being immunosuppressive by definition, weaken the immune system even further. Now, twenty years after the first alarm sounded, it still remains unknown to clinicians if there have been similar investigations in people. Those rat trials were done by several major medical schools and clinics in the U.S. and supported by National Institutes of Health grants, but something must have prevented studies on humans from being done. ANTIHISTAMINES AND CANCER? As all chronic diseases, allergies tend to intensify over time, and so a patient may become a regular antihistamine user. In a series of articles, oncologists from the Manitoba Institute of Cell Biology, expressed their concern over tumor promotion, melanoma in particular, in those who took Seldane and Hismanal. The researchers compared the tumor-contributing effect of Tamoxifen (breast cancer drug) for which a 300% increase in uterine cancer has been documented,3 with the effects of antihistamines: given the similarities in the pharmacological profiles of the antidepressants4 and antihistamines (with Tamoxifen), we have real concerns.5 Most of the evidence comes from studies on mice, but some, from investigations on humans. The first data on these serious possible connections
were published in the early eighties, but allergists, the most passionate advocates of antihistamines, remained silent. In 1994, the information started to leak into lay magazines. To comfort the public, televised interviews with the producers of Seldane and Hismanal followed. They reassured the public by stating that mice could not serve as a model for making decisions regarding humans, and only epidemiological studies could prove or disprove similar side effects in humans. Besides, the defenders said, antihistamines did not cause new tumor formation but just accelerated the development of already existing cancers, and even then, not in all kinds of cancer.5,6 One can only ponder such declarations in silent amazement. First, due to the great similarity of the immune systems of mice and man, mice are used as the model to study the basic immune mechanisms. In the past, the tobacco industry created exactly the same defence, and it took half a century to arrive at the evident conclusion that the effect of tobacco on mice was the same as on people. Second, in many cases, it takes years for a cancer tumor to develop out of a few existing cancer cells. Any of us may have cancer cells, but they are regularly destroyed by our immune systems with the assistance of our H1 receptors. What if H1 antihistamines really speed up tumor growth? Seldane and Hismanal are the oldest medications of the non-sedating group, and, by the way, were taken off the shelves for side effects unrelated to cancer. Can the manufacturers of antihistamines guarantee that their newer products will not show similar carcinogenic effects over time? Is this possibility being tested elsewhere? After all, there are definite similarities in the effect of all H1 antihistamines despite some of the differences in their ingredients. Since you know how cells and their receptors work, it is easy to understand why H1 antihistamines may contribute to cancer. T-cells cannot efficiently function as cancer fighters, when they are deprived of histamine, as cytotoxic or T-killer cells become efficient when activated with histamine. Therefore blocking H1 receptors leads to a histamine deficit and thus undermines the efficiency of cancer-fighting T-cells. If an occasional disruption of immune functions in this area cannot harm severely, a regular blocking can. The individual potency of each antihistamine may only influence the speed of the cancer-contributing effect, and we should not be surprised if with time, other drugs of this group join Seldane and Hismanal in their probable carcinogenic effect. Do we have the luxury of postponing a decision for two or three decades, pending epidemiological studies, if chances of tumor growth in antihistamine consumers exist today? Will a belated sorry be enough if this
Medications
179
turns out to be true? So far, the US Food and Drug Administration doubts the need of epidemiological studies, since it considers the drugs safe.7 Have there been additional studies to prove or disprove the findings of the Manitoba researchers? I personally failed to find any such data. The initial shock and interest in the cancer connection with antihistamines soon subsided. Considering the few choices for allergy sufferers, antihistamines will continue to enjoy a wide market. New kinds will be synthesized, and only future generations may realize the full extent of the problem. One more thought to consider: epidemiological studies last decades, not years, since they have to cover different health-related events and their causes in order to determine the significance in the development of the given disease. Since the creed of medicine is to weigh the pros against the cons, the dilemma of whether to take or not to take antihistamines does not exist. This is because concerns for the few of those who may get tumors are superseded by the multitude of consumers wishing to get at least some relief from their allergy symptoms. An indirect confirmation of the possible tumorpromoting effect of antihistamines comes from two articles on tumor regression due to the histamine therapy.8 Quite logical: if histamine deprivation contributes to tumor growth, histamine stimulation shrinks tumors.
H2-ANTIHISTAMINES? Although, from the scientific standpoint, activation of the inefficient regulatory tools is the only logical solution, allergy has predominantly pursued the path of suppressing those bodys immune tools, which become overactive as a result of the inefficiency of their counterparts. Such is the case with H1 antihistamines, such has become the case with H2 antihistamines that target the already inefficient H2 receptors. H2-receptor blockers already exist as medications for stomach problems, such as Zantac and Pepcid. The main idea behind the suggested use of H2 antihistamines in allergy is that they prolong the clearance time of the conventional H1-antihistamines by acting through liver enzymes. Basically, it means that H2 antihistamines should be taken together with the conventional H1 antihistamines, and with that, the latter will be more effective. The drug industry will definitely find the idea most attractive: two drugs instead of one! For patients, H2 antihistamines will be a disaster as they will further paralyze the already deficient receptors and thus inhibit the self-remedial action of histamine. This will deprive the body of the major means of defense against allergy.
The knowledge of the danger of H2 blockers in allergy has been around for over 2 decades. Look what the highest ranking allergist, R. Rocklin, says in a textbook: Their administration to patients in vivo might. potentiate histamine release and worsen allergic symptoms. In fact, this seems to be the case.9 An article by world-renowned immunopharmacologists informs us that H2-receptor antagonists might increase the bronchoconstrictor response by facilitating the release of histamine...10 Simply speaking, it means asthma gets worse. With the knowledge of the protective effect of H2-receptors in allergy, their blockers should be contraindicated, and allergists should know that. Do they? It seems unbelievable, but is true that an article was published by leading Canadian allergists at the same time as the two above-quoted sources, in which they actually recommended (!) H2 blockers for those who develop anaphylactic reactions.11 Anaphylactic reactions are the extreme stage of allergy, at times fatal due to an explosion of histamine and histamine-induced pro-disease chemistry. It may happen upon eating a highly allergenic food, taking a drug or being stung by an insect. By excluding H2 receptors from the game, the body is left helpless at the mercy of the disease.
DECONGESTANTS Decongestants form another very popular group of short-term relief allergy medications, although their primary indication is for a stuffy nose in colds. Among them are Sudafed, Dristan, Otrivin. They constrict nasal vessels, and the resultant shrinkage of the swollen mucous membrane allows air to pass. These drugs should be taken in moderation in view of their well-known rebound action, that is, paradoxical aggravation, that may set in shortly after one starts using them. It is all right to take a decongestant for a cold that usually lasts a few days only. Allergies, however, have a lasting course, and after some period of using a decongestant, an allergy sufferer can never be sure whether the symptoms persist due to allergy, or they are the ricochet action of the drug. At times, just by discontinuing the drug, the patient may have a symptomatic improvement. The best known decongestant is ephedrine, a synthetic version of a plant ephedra used since ancient times. It also stimulates cardiovascular tone and the central nervous system, and for that reason, is sometimes used by athletes as an upper. By the way, Maradona, a world famous soccer star, and Laumann, a Canadian gold medalist in rowing, were both disqualified for using ephedrine.
Medications
181
Medicine does not put decongestants into the category of harmful drugs although, as adverse reactions to the stimulatory effect of ephedrine, its users may experience hyperactivity, anxiety, palpitation, tightness in the chest, general weakness, vomiting and fainting. As with Seldane and Hismanal revelations that came years after the drugs had virtually flooded the market, certain side effects of decongestants, undisclosed for decades, drew attention. The 1997 annual meeting of the American Academy of Neurology heard a report by Dr. L. Vives-Castro from the University of Pennsylvania on the risk of medications that contribute to vascular constriction. Among the high risk group are migraine sufferers and postmenopausal women on replacement estrogens. Instability of the vascular tone in migraineurs and the medications they take, as well as the predisposition to various vascular problems in estrogens users, put these patients at risk even if they do not abuse decongestants. The researchers suggested retroactive studies of patients with brain hemorrhage to see if there was a contributing factor from decongestants. They also considered the possibility of tightening the regulations covering this drug group, since, like antihistamines, decongestants are among the most common over-the-counter medications and can, thus, be easily abused. Within the five years that followed, those who suffered from migraine headaches or took synthetic estrogens had a choice: nasal congestion or a possibility of brain damage by a stroke. In May 2001, the FDA and Health Canada banned 63 cold remedies that contained a certain decongestant. Among them, there were the familiar Dimetap Cold and Sinus, Contac Cold and Alka-Seltzer Plus. American authorities documented about 200 to 500 strokes a year in young people who took these medications, the population group normally not known for such accidents. Numerous bleeding strokes were registered in adults under 50, women in particular. My suspicion is that the number of cases is higher. Many deaths could have been attributed to a different medical condition, since hardly any doctor would blame innocent decongestants for fatalities. As is to be expected, manufacturers will reformulate their cough and sinus medications and will replace the decongestant. Only time will show how safe the new ones are. Do not forget that the banned drugs had a long history of use and had originally been recognized as safe. Naturopaths and herbalists often suggest taking ephedra instead of synthesized decongestants. In essence, the net results are similar. Ephedra has
recently been banned in this country. So has pure ephedrine. Strangely, the legions of ephedrine-containing drugs continue to be widely used.
COMBINATION DRUGS It has become fashionable to design drugs that combine several into one, thus creating an allegedly new breakthrough product for diverse purposes. For instance, ephedrine and ephedrine-like drugs are often added to painkillers and antihistamines. You may recognize these compound drugs through the letter D for decongestant or word Extra on the label, for example, Claritin Extra, Tylenol D(econgestant). The only benefit of such medications is in taking one compound drug instead of taking two pills separately. Do not forget that although the combination drug offers all the benefits of the ingredients, their side effects are also preserved. Antitussives are drugs that suppress a cough, and codeine, a narcotic, is the most common cough-suppressive ingredient. Decongestants and antitussives are a popular combination. Cough-suppressing syrups, so often offered to your kids, are nothing more than a sweetened dose of codeine added to something else. One of the combo-drugs for allergy is Actifed. I chose it not because it is more dangerous than others, but due to the heated discussions it produced a decade ago. The experimental mice who were fed it showed a higher incidence of liver tumors. It may be that liver tumors do not develop in humans, although, even a low probability of having such a side effect makes a stuffy nose preferable. My purpose here is different: Actifed is a combination of an antihistamine, decongestant, antitussive and sometimes a painkiller. It is a typical pharmacological amalgam with the benefits and side effects similar to other combinations. The entry in the Canadian Compendium of Pharmaceuticals on Actifed, spells out under Precautions who should not take the drug: children under six years of age, people with persistent or chronic cough such as occurs with smoking, asthma or emphysema, patients with high blood pressure, heart or thyroid disease, diabetes or difficulty in urination, pregnant women and nursing mothers, patients on antidepressants. Also cautioned are those who may drive a motor vehicle or operate machinery requiring mental alertness. From this list one very important point is missingthe instruction as to who can take the medication that has so many contraindications. A healthy, nonpregnant adult who uses public transportation and can afford to be mentally relaxed at work? Are there many such people among allergy patients?
Medications
183
The compendium also expresses concern over an overdose of Actifed, which may result in nervousness, insomnia and dizziness. Sensitivity to a medication, as we know, is a highly individual feature; thus, the dose recommended to an average person may become an overdose for a hypersensitive person. I repeat, I use Actifed as an example only. Similar effects are common for other drug combinations of this group. Antihistamines, decongestants and antitussives are limited in their action and provide relief for only a short time. Coupled, tripled or quadrupled, the ingredients do not prolong the effect, while their side effects are additive. Yet, these products are in common use by allergy patients.
CORTICOSTEROIDS Corticosteroids, or simply steroids, are the most potent drugs generally prescribed for asthma and becoming more and more common as the treatment of choice in other allergies. The name corticosteroids is used to denote, first, natural hormones produced by our body and, second, the drugs, which are synthetic versions of these hormones. The general public often knows about a different kind of steroids (anabolics) that also exist in the form of drugs and are illegally taken by some athletes to build up muscles and increase performance. However, our topic is corticosteroids, and the short form steroids will be substituted. Synthetic steroids have been on the market for half a century. They are the first-line medications in such life-threatening conditions as shock, coma, poisoning, severe asthmatic attacks or allergic reactions. They are an integral part of the medical regimen of organ transplant recipients: by suppressing the immune system that tries to rid itself of a foreign organ, doctors suppress the rejection and prolong the patients life. Modern medicine extensively prescribes them in a lot of chronic diseases such as rheumatoid arthritis, ulcerative colitis, Crohns disease, cancer, etc. Steroid drugs are produced in various forms depending on their intended use: in pills; in injections that can be administered intramuscularly, directly into an inflamed joint or lesion, or are infused intravenously; in creams, lotions and ointments for skin application; in eye and ear drops; in sprays for nasal and chest allergies; as a rectal suppository. Should todays dentists fall under the charms of the steroid manufacturers, we will find steroid tooth paste on the shelves tomorrow. What is there about steroids that allows their wide-spectrum use and calls for manufacturing them in so many forms? Steroids are one of the greatest discov-
eries of medicine. This group of drugs is a miracle, for it saves lives in emergency situations and in severe debilitating illnesses. The picture changes when steroids are taken regularly. Any drug taken on a long-term basis may be harmful, still, few drugs can compete with steroids in the seriousness of their complications. All textbooks, articles and lectures on steroids urge dose reductions as soon as the patients condition allows. However, in view of their growing market share, transparency regarding steroid-related side effects is very limited. Moreover, the legend of their safety has been recently created in allergy, and this has skyrocketed their use. But I want to tell you what you will rarely hear from your doctors, but what you, as an allergy patient, should know. I intend to unravel the facts about one of the main causes of the growing severity of all allergic diseases and rising mortality from the most serious of them, bronchial asthma. The truth is thoroughly concealed from the public although, I admit, an inquisitive steroid consumer can find it in the drug insert or a pharmaceutical compendium. But who reads a terminologically complicated scientific text, especially if written in tiny letters? It is similar to the former microscopic warning against cigarette smoking on an attractive package with the brand name in capital letters. Generally, patients rely on the information they get from their doctors. Doctors, in turn, are expected to obey the practice guidelines which dictate the wide use of steroids. These are formulated by their own associations, usually with strong input from the pharmaceutical companies whose representatives sit on the medical councils; the doctors on these councils and professional associations are often themselves in conflict of interest due to the fact that their research grants are funded by pharmaceutical companies.12 Besides, very few doctors will tell you that, in the long run, steroids aggravate the very condition they are prescribed for. Some conceal this, others simply do not know.
ADRENALS Since corticosteroid drugs are a synthesized equivalent of the bodys hormones, we should know about the organ that produces the natural version of the chemical. We should also know what role steroids play in the functioning of the body, and what happens to their natural producer when synthetic hormones flow in the blood. The steroid producer is the adrenals, pea-size, paired endocrine glands situated above the kidneys. In Latin, ad means near, and ren stands for kidney.
Medications
185
The adrenals are vital for the body. This tiny gland has a wide spectrum of action: through its hormones, it regulates and maintains the metabolism of proteins, carbohydrates, fats and minerals, controls water balance and is also a source of sex hormones. Knowing this, it is easy to understand that malfunctioning of the gland may impact all of these processes. Steroids produced by the outer layer of the adrenals, its cortex (bark, shell, rind in Latin), correspondingly got their full name, namely corticosteroids. They are our power sourcehormones give us strength and resistance and life itself. Along with steroids, our body draws these powers from another hormone produced by the inner layer of adrenalsepinephrine. Its synthetic version, adrenalin, is also given to patients in emergency situations. The well-known Epipen carried by those prone to anaphylactic reactions is, actually, a syringe filled with adrenalin. We know that in critical situations, a man can lift a weight he is normally not able to lift, run away from danger at a speed inconceivable under normal circumstances and withstand the most extreme conditions for a certain period of time. This is possible because of the adrenals that start to work instantaneously at a high capacity in demanding situations and supply us with their wonder hormones. The adrenals hormones also protect us from stress. If in lay language, stress is usually associated with a psychological strain, as a medical term, stress has a much wider notion. It is defined as a bodys reaction to any adverse stimulus that may disturb its homeostasis. This includes hard physical effort and severe emotional pressure, intense pain and an infectionall extreme situations which put an extra load on the body and require adaptation to the situation. The adrenals are directly involved in the required adaptation process by increasing the production of corticosteroids and epinephrine, which mobilize the bodys resources. Immune diseases put great demands on the adrenals, and without corticosteroids and epinephrine, the body may perish. Severe allergy, and especially asthma, create a situation of stress, and for these patients, activity of the adrenals is of prime importance. In short, the hormones of the adrenals are the fuel, which this endocrine gland supplies for the proper functioning of all organs. The body cannot work without this organ, just as an engine cannot work without fuel. Therefore this gland should always be in good shape, not only to meet the every day demands of its hormones but also to be ready for any unexpected emergency.
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS To understand the vital importance of the adrenals to the functioning of the whole body, we must know the glands connection with the two other superior organs situated in the brainthe pituitary and the hypothalamus. Their functioning is inseparable. Different endocrine glands join the pituitary and the hypothalamus to form an axis, and each axis regulates the production of the hormones specific for the given gland. The adrenals team up with the pituitary and hypothalamus to form the hypothalamic-pituitary-adrenal axis, for short, HPA. The axis controls the production of steroids generated by the adrenals. It is a three-story structure: the adrenals are subordinate to the pituitary gland which, in turn, is subordinate to the hypothalamus. THE PITUITARY From the lower story, the adrenals, we can move up to the pituitary. Medicine calls it the master gland because it regulates the work of almost all endocrine glands. Hormones affect everythinggrowth, maturation, reproduction, behavior. The pituitary plays the role of a meter that determines the appropriate levels of hormones released by other glands into the blood and adjusts them to the required level. It communicates with other glands such as to intensify or slow down the production of their hormones. The bodys need of different hormones at any given moment depends on the time of the day, period of life, emotions, etc. For example, the need of adrenalin and steroids during sleep is lower than during daily activity. This, by the way, explains why asthmatics often feel worse at night or early in the morning: less defensive hormones are produced, and so allergic processes run against less resistance. The pituitary is multilingual: it uses its own special stimulatory hormones as a language of communication, different for each subordinate gland. Thus, the language it uses to communicate with the adrenals is the hormone called corticotropin. The pituitary assesses the amount of steroids in the blood that reaches it, decides if their production should be reduced or increased and correspondingly adjusts the amount of corticotropin that stimulates the adrenals. The master gland is not interested in whether the hormones are generated by the body itself or taken as medications. Its decisions are made purely on the quantitative measurements of their levels in the blood. THE HYPOTHALAMUS The hypothalamus is on the upper level of the HPA axis. This miniature regulatory center is a complex, supremely important structure of the brain, which,
Medications
187
similar to the pituitary, is the bridge between the nervous and endocrine systems. Although a tiny organ, the hypothalamus activates, controls and integrates the work of the major endocrine glands, some parts of the nervous system and the cardiovascular system. It supervises our behavior, sleep, appetite, body temperature, emotions, libido, etc. Hardly anything is left beyond its supervision. The pituitary is attached to the hypothalamus and receives all important directions from its superior, also in the form of special hormones. These hormones help the pituitary to properly regulate the endocrine glands at the periphery. Both the pituitary and the hypothalamus are a part of the brain, therefore in addition to hormones, they use another language of communication used by nerve cellsneurotransmitters.
SUPPRESSION OF ADRENALS The human body is a clever structure. For survival, it is programmed by nature to sacrifice less important substances or parts to preserve its most vital organs. Thus, in severe frost, the circulation to the extremities is shut off to keep enough blood supply for the internal organs. From the biological point of view, extremities are a small loss compared to life itself. Reasoning by analogy, the ultimate level of blood hormones is more important for the functioning of various organs than the normal performance of just one glandadrenals. An excess or a deficit of hormones equally impair the steady, homeostatic level needed by the body to function normally. A doctors prescription of steroids in immune-related inflammation has a logical basis: the body needs these power hormones to cope with a stressful situation. When steroid medication reaches the pituitary with the blood flow, it is perceived by the meter in the same way as would the natural hormones. The addition of the synthetic hormone to the natural hormones produced by the adrenals creates a surplus. The pituitary, indifferent to the source of the hormones, tries to correct the impaired imbalance by ordering the adrenals to diminish their steroid output and does this by reducing the amount of its corticotropin. Less stimulation by corticotropin means less active adrenals. Deactivation of the adrenals lasts as long as the steroid medications are taken. During periods of prolonged drug use, the adrenals, similar to muscles weakened by inactivity, also weaken. Their ability to generate steroids steadily reduces. The longer the drug is taken, the longer it takes the gland to restore its functioning when the medication is stopped. Therefore, when the patients condition improves, and the drug is discontinued, the long-suppressed adrenals are often unable to meet the bodys demand. During their regeneration
period, the patient is forced to rely on the synthetic steroids that make up for the deficit of the natural hormones. This physiological dependence is the reason why, unlike other medications, steroids cannot be stopped abruptly but should be weaned slowly, even if the disease for which they were prescribed, is controlled. In such situations, steroids are taken because of dependency and not because of the original symptoms. What happens if steroid tapering is done too suddenly? This was a question from an interview given by Dr. Teik Chye Ooi, and Associate Professor of Medicine at the University of Ottawa.13 His answer was that a number of problems may arise, and in the most extreme situation, sudden death can occur. This happens due to the adrenals shut-down and hence, sudden systemic shortage of their vital hormones. With sustained steroid consumption, the adrenals may atrophy, and such patients are doomed to take synthetic steroids for the rest of their life. The body possesses an amazing ability to keep the balanced production of its chemicals. Therefore, when synthetic hormones become a daily interference, the adrenals become redundant, and the body sacrifices them. Their atrophy is the price for the relative balance of the level of steroids in the blood. The result is the bodys dependence on the steroid drugs.
STEROIDS AS REGULAR MEDICATIONS The immediate effect of steroid drugs is striking in many of the cases. Since every cell has receptors responding to steroids, the whole body reacts to the synthetic version. Steroid drugs act like the adrenals functioning at full power. The dramatic relief they provide, creates the illusion of their safety. However, it is important to distinguish between an emergency need of steroid drugs and their chronic use. Asthma and allergies are chronic diseases. As their resistance to other medications grows, more and more often, steroids become the treatment of choice, and their consumers become victims of the medication. Synthetic steroids mimic the internal hormones, therefore the HPA axis is deceived. The best drug protocol cannot compete with the flexibility, with which the body conducts self-regulation of its chemicals. Just compare how skillfully the body monitors its blood sugar level in non-diabetics, even if they are chocoholics and cake abusers, and how jumpy sugar levels can be in those on insulin, despite regular careful adjustments of the dose. Similarly, with daily steroids, the most expert titration of the dose is still basically artificial
Medications
189
and clumsy by comparison to natures way. In a healthy body, the pituitary knows exactly how much corticotropin it needs in order to stimulate sufficient steroid production by the adrenals, whereas a steroid user is constantly deceived by the drug. The drug interferes with the regulatory processes. As, the production of all chemicals in the body is interrelated, the fluctuating levels of steroids affect the balanced production of others, and this leads to additional malfunctioning of different tissues, organs and systems. Synthetic steroids primarily affect the adrenals. As was said, the pituitary, satisfied with the steroid medications, reduces its production of the stimulatory corticotropin until it does not involve the adrenals at all. Without stimulation from the pituitary, the adrenals slowly die away and with time, become atrophied. The situation looks even grimmer as the advanced suppression of the adrenals may extend to the production of its other hormones. In a stress situation, adrenals protect us by increasing the synthesis of their hormones, and their failure shatters the whole body. It is a well-known fact that in a patient with failing adrenals, pneumonia and other infectious diseases become abnormally frequent and life-threatening. Equally lifethreatening is the ensuing adrenal failure itself. Now, all this starts a vicious circle: the compensatory dose of daily steroid medications goes up, and with it, complications grow. As we know, immunosuppressive steroids suppress the activity and the very life of all immunocompetent cells, T-cells specifically. Therefore, the patients health is further undermined by the direct suppressive effect on the T-cells protective activity, and he now faces a more severe course of chronic immune-related diseases, allergy and asthma among them.
PROS AND CONS OF DAILY STEROIDS If daily steroids are so dangerous, why are they still prescribed so often? Apart from acute life-threatening situations, there are circumstances when regular steroids are irreplaceable. As was said, they are an inherent part of the management of organ recipients. Rejection of a transplanted organ is a normal reaction of our immune system that tries to eliminate everything alien, be it a sliver or a transplanted organ. However, this protective immune response turns out to be fatal for a recipient who cannot survive without the transplant, and immunosuppressive drugs are prescribed to reduce the bodys innate ability to reject. Steroids are among them. Their prescription in the event of organ transplantation is justifiable because between the two evilslife with a vulnerable immunity or death without an organthe first choice is preferable.
Treatment options are different for allergy patients. Their diseases, excluding resistant asthma and severe anaphylactic reactions, are not fatal and cause discomfort or distress. For these patients, steroids are not vital, and potential consumers should be given this information so that they could weigh the pros and the cons before they opt for the serious side effects of or the physiological dependency on steroids. The patients are rarely, if ever, get to know the necessary information, and a lot of them take daily steroids even for mild asthma, without a clue that they may end up with a more severe form.
COMPLICATIONS OF STEROIDS Given the critical need of adrenal steroids for the normal functioning of all organs, we should not be surprised that many organs and systems suffer in cases of inadequate supply with a synthetic version. Complications arising from steroid use can be divided into: a) temporary adverse reactions which usually go away when the drug is discontinued; b) lasting complications which may subside with drug discontinuation, but may turn into a chronic condition due to the sustained drug use; c) development of new chronic diseases.
Most drugs are known to have unwanted side effects, but few are as notorious as steroids. Among the temporary adverse reactions listed by pharmaceutical compendia are nausea and vomiting, indigestion, headaches, dizziness, fainting, irregular heartbeat, elevated blood pressure, nose bleeds, frequent urination, moon-like face, weight gain, unusual tiredness, weakness, mood swings, insomnia, muscular cramps, joint pains, unusual bruising, etc. Allergology is full of paradoxes, and steroids prescribed in allergy is one of them: they may result in allergic reactions of various degreesfrom skin rashes and hives to systemic reactions. As was reported at a semi-annual meeting of the American Contact Dermatitis Society by the chairman of the department of dermatology in a New Orleans hospital, Dr. R. Rietschel, corticosteroid allergy is real and more common than expected. This doctor referred to systemic reactions and reported the findings in five comprehensive studies conducted in Europe and North America.14 Steroids produce numerous serious side effects that may not go away when the drug is discontinued after protracted use. They include hypertension, water retention, growth retardation in children, fragile skeletons in older people and menopausal women due to calcium loss (i.e osteoporosis), obesity and suscepti-
Medications
191
bility to diabetes due to the impairment of fat and carbohydrate metabolism, peptic ulcer, poor wound healing (an obstacle for any surgery), glaucoma, cataracts, various infections, excessive facial hair growth, etc. (The latter alone could stop women from taking steroids, since most would put up with any side effect but not loss of their femininity.) Read the list attentively. These are not just temporary adverse reactions, but rather diseases. These complications may diminish when the patient discontinues steroid use, but considering the chronic nature of allergies and asthma and the resultant equally chronic drug dependency, chances are high that the adverse effects will become diseases. Thus tendency to hyperglycemia (high blood sugar) may become diabetes, loss of bone mass leads to osteoporosis and fractures as well as stunned growth in children, elevated blood pressure turns into permanent hypertension, etc. Indeed, irreversible damage of organs and systems of organs is not so uncommon among steroid users. Steroids also affect our nervous system. A neuron conducts electrical-like impulses from one part of the body to another. It is a wire connecting the centrethe brain, with the peripherythe rest of the body. Neurons are the basis of our nervous system, and without them, we would not be able to see, hear, move, or think and exist as a live being. Neurons suffer immensely from the toxicity of steroids even when the hormone is excessively produced by ones adrenals. Thus, a person who experiences a lasting stressful situation becomes depressed, his memory span diminishes, and his learning ability falls. The psychological effect from the stress is augmented by the higher than normal amounts of internal steroids released to help us in overcoming this stress. They produce additional biochemical brain changes. For decades, medicine has known that lasting exposure to steroid drugs reduces the ability of nerve cells to survive in demanding situations and leads to their premature ageing and even death.15 Their premature ageing is our ageing. Since adrenal hormones regulate the metabolism of carbohydrates and fat, steroid drugs affect these too. They also affect the synthesis of insulin, the hormone that reduces higher levels of blood sugar. It is textbook knowledge that corticosteroids are a contra-insulin factor, and naturally, their surplus compromises the levels of insulin, and this, in turn, may lead to diabetes. Another grave side effect is suppression of growth hormone. For young steroid consumers, it means that the normal development of their bones is impaired, and they may not reach the height charted for them by nature. In medicine, however, growth is also understood in a broader sense than just
linear development. It is a qualitative process that involves cellular life and regeneration. Therefore, for older people, suppression of growth hormone means acceleration of the ageing processes. Growth hormone is also important for the maturation of the immune system. Our immunity is regulated by T-cells. Differentiation and maturation of T-cells takes place in and is propagated by the thymus, a tiny gland situated near the thyroid, and the letter T in T-cells comes from thymus. Stimulation of the thymus by growth hormone is one of the components of the maturation process of all T-lymphocytes. Synthetic steroids have a doubly serious adverse effect: first, they directly suppress all lymphoid tissues and cells and thus, the thymus; second, they suppress the growth hormone that stimulates thymus functioning. The thymus ceases its functioning with the completion of the bodys development. Therefore, if the steroid consumer is a child, the retardation of his T-cell maturation by the drug, will leave the immune system underdeveloped. Every chemical in the body has a special affinity with certain cells. For instance, T-cells, T-suppressors in particular, are especially responsive to histamine. The effect is stimulatory in nature, beneficial for us. Thus, upon histamine stimulation, T-suppressors grow in number, and their activity grows along with the strengthening of H2 receptors. T-cells are also very responsive to steroids but in a different way. Like no other cell, T-cells respond to the suppressive action of steroid medications. The suppression is both quantitative and qualitative, covering all T-cells and preventing their specialization. Steroids produce the effect of a tank moving against an army of tiny soldiers: the tank squashes all central immunity fighters. Among them, there are natural killer cells that fight cancer, B-lymphocytes that produce protective antibodies, T-cells that fight infections, T-suppressors that oppose allergies, etc. The latter is especially important for an allergy/asthma patient, since it results in a more severe course of the disease, now caused by the drug itself. All this contributes to the development of all sorts of immune diseases. A steroid user may start with just one problem, namely allergies, but end up with many more. The most far-reaching complication of steroid drugs is that they are capable of mutating genes. Steroid medications bind to the intracellular steroid receptor, which translocates to the nucleus and binds to DNA. This changes gene functioning, or as science calls it, gene expression. Distorted genetic instructions to the cells inhibit the production of regulatory cytokines, the balance of which determines the state of health or disease. The most aggravating factor is that
Medications
193
there is only one receptor that mediates the action of the steroid drugs. This makes it impossible to achieve only the desired positive effects and avoid the undesired negative effects of steroids, and the easy access of the corticosteroid receptor to the genetic material makes synthetic steroids especially dangerous.16 Compare this with the flexibility of histamine: different receptors implement stimulatory and inhibitory effects, which enables physicians to achieve the desired effect by targeting the ones needed. There is a huge difference between playing a one-key musical instrument and an instrument with several keys. Genes are interdependent in their work. Mutation of one gene may affect numerous characteristics and lead to complex abnormalities in the immune functioning. Therefore, any organ and even system of organs may suffer as a result of gene mutation. Genetic mistakes have a tendency to repeat in future generations, and the offspring of steroid consumers may inherit undermined health. Bernard Shaw once remarked, Science is always wrong: it never solves a problem without creating ten more. His remark is fully applicable to the use of steroids in allergies.
THE QUESTION OF THE DOSE Ask the doctor who prescribes you steroids about their side effects, and almost as a reflex, the answer will come that these are dose-related, that only oral steroids may be harmful, and that the drug taken in sprays or ointments is practically harmless. However, numerous medical investigations indicate the opposite. The statements that a sustained use of steroid creams or sprays are safe and only of local effect mean that those who prescribe them either do not know how the drug works or are hiding the truth. There are drugs introduced through patches or given in sprays, and even their manufacturers emphasize their systemic effect. For example, Nicoderm (nicotine patch) is applied to the skin surface only, but the drug administration is effective enough to mimic the nicotine effect in cigarettes. So do patches that replace oral hormones. Another example is smoking, which is a process of inhaling but may still result in cancer anywhere in the body. The complications associated with drugs are not eliminated when the delivery routes change. Of course, the dose matters a lot, and that is why pills are more harmful than sprays or creams. Still, even small doses can be detrimental if they are used daily. The results may not be evident for a while, but
as a constant flow of water wears away a stone, chronic use of steroids wears away the immunity. Here is one of the most recent confirmations coming from an annual meeting of the AAAAI.17 The authors write about steroid-containing nasal spray: data using more sensitive parameters suggest that low doses of inhaled fluticasone propionate (flonase) are associated with a significant degree of detectable systemic bio-activity, including HPA axis suppression. The article gives many references and concludes that doctors should use caution in terms of assessing the effects of therapeutic low doses of flonase on HPA axis. To say that there is no side effect at a lower dose also suggests that patients respond equally to that same dose, while certain groups, such as children, pregnant women, older people, patients on concurrent drugs, or those who have an innate exaggerated sensitivity to medications, can hardly be categorised as an average group. It is peculiar that with steroids having been around for half a century,well-controlled studies relating the safety of inhaled corticosteroids in pregnant women are not available, there are limited clinical data on the use of inhalers in children, and it is not clearly established whether inhaled corticosteroids are excreted in breast milk, etc. The quotations are from the Canadian Compendium of Pharmaceuticals 2000. But one does not even need trials on these groups. A thorough retrospective analysis of those kids, pregnant and lactating women who were forced, due to their asthma, arthritis or ulcerative colitis, to take steroids would be enough to draw appropriate conclusions. Most probably, this has been done, and not just once. Most probably, the results turned out to be unpleasant for the producers, and, most probably, a gag clause in the contract prevents the researchers from disclosing the results. All this indicates that the dose shown to be safe during the drug testing on healthy young males cannot be automatically applied as such to other categories. The history of Seldane is a classic example of how an extensively tested and supposedly safe medication turned out to be fatal in certain patients years later. The same is true for decongestants that have been on the market for well over a century, and only today, we learn that a recommended dose, meant to unplug a stuffy nose, may lead to a stroke in a migraine sufferer. This means that these medications were known to have side effects before, but only when these reached numbers too high to conceal, the truth came out. There is no such thing as a safe dose, especially if this dose is repeated daily.
Medications
195
STEROIDS AND ALLERGIC DISEASES Nearly all men die of their remedies and not of their illnesses, Moliere once said. One may wonder if his genius was predicting corticosteroids propagated more and more indiscriminately by Western medicine. Pharmaceutical compendia in each country list all the drugs produced there. All of them describe the numerous side effects of steroids, but the compendia rarely reach a lay person, and this knowledge remains the property of pharmacists and physicians. The entries on all steroid drugsoral, injectable, inhaled or used on the skinare strikingly unanimous in their recommendations to reduce the dose immediately in case of adverse reactions and to discontinue the drug in case of severe side effects. Regrettably, the descriptions do not indicate what to take instead. Is it because in the majority of cases, there is no other option? Still, while different complications are thoroughly described by the manufacturers, who otherwise could face legal problems, one side effect cannot be found in any sourcetextbooks or pharmaceutical compendia, the fact that steroids have a direct negative effect on allergies and asthma. Taken daily as ANTI-inflammatory medications, they are, in the long run, inflammation pro-inflammatory. Not only do steroids suppress the activity and reduce the number of all kinds of T-lymphocytes, but they also inhibit other immune cells. As it follows from the lecture given a decade ago (!) at a postgraduate course by an allergist from the Harvard Medical School, steroids directly facilitate the release of the greatest evil in allergy: inflammation promoting cytokine (Il-4). Furthermore, steroids increase the production of the pathological antibodies IgE, both of which are recognized by conventional allergy as indicators of allergic condition.18 Now, we face a paradox. The nature of allergic diseases is the inability of the immunocompetent cells, T-cells in particular, to produce enough disease inhibiting chemistry. Steroids, the most potent and common drugs in allergies and asthma, actually support and advance this defect by:
a) suppressing the cellular lab on the whole; b) reducing the number of the main allergy-fighting cells, the T-suppressors; c) augmenting the output of the disease-promoting chemistry (Il4 and IgE). Prescribed to relieve allergies and asthma, steroids eventually make the body absolutely defenceless against these diseases. On top of that, the weakening of the immunity on the whole paves the way for other chronic and acute medical conditions to set in. Doctors actually paralyse the immune
system by recommending the daily use of the drugs which, as they claim, are supposed to bring allergies under control. The alleged safety of steroids is evident from the earlier-cited interview with Dr. Teik Chye Ooi published in The Parkhurst Exchange, April 1994: Patients should wear a Medic Alert bracelet to show that they are on steroid therapy, and they should carry a prepackaged syringe with 4 mg of dexamethasone phosphate (also a steroid) for emergency use. Look around: more and more people suffer from severe allergies and asthma. Ask them what medications they have been taking and for how long. The majority are on steroids. At times, this becomes evident from the names of their medications that contain cort, which stands for corticosteroidspulmicort, nasocort, rhinocort, etc. Still, many steroid preparations are unrecognizable because they have been given decorous names. Consumers seldom read the inserts in the drug packaging, they are often convinced that their medications have nothing to do with the dangerous hormonal preparations they may have heard about. Should we be surprised by the growing severity of allergies and the rising curve of asthma mortality if we, doctors, help create this situation day by day? An alert should sound in every medical office and at every doctors conference. Allergy patients should also be informed of this drugs danger, no matter in what form it is taken, and behind what name it is hidden. Do not expect that to happen soon, though. The reason is simple: there is no drug in conventional allergy can use to replace steroids. We started with Moliere and will finish with D. Jerrold, the English humorist who said: In this world, truth can wait, shes used to it.
THE TREE OF ALLERGY To treat patients properly, a doctor should understand what underlies the symptoms. For example, a doctor cannot treat a chronic pain in the back without knowing what caused it: a twisted muscle, a nerve pinched by degenerated discs, or a tumor growth. A painkiller will be helpful only as a temporary measure, and the treatments will range from physiotherapy to complex surgery. In a similar way, if a doctor sees a wheezing patient and treats only his wheeze, or prescribes a decongestant to a patient who complains of a stuffy nose, he treats the secondary events. Steroids contained in many allergy prescriptions permit the doctor to assure you that, unlike symptomatic drugs, these are directed at the primary causeallergic inflammation. If this is the
Medications
197
case, and inflammation is indeed at the core of the problem, why do steroids never cure? Why are they needed again and again? Moreover, why does the course of allergies/asthma often get worse, and the dose of steroids rises accordingly? Because inflammation itself is not the origin of the problem. To sort out what is primary, and what is secondary in allergy, let us imagine an allergic disease as a tree. Its branches are the symptoms, its trunk is an allergic inflammation that gives rise to the branches. The roots that feed the trunk are the malfunctioning cells that produce predominantly inflammation-promoting chemistry. If the roots are rotten, no matter how thoroughly the gardener trims the branches or props up the trunk, the tree sickens and dies. Therefore, to keep the tree growing, he must be sure that the roots are healthy. Basic sciences provided us with the knowledge how to access the faulty genes, the seed from which this tree started: through the receptors of the cells that deliver messages to the genetic material. The main carrier of the protective immune messages, H2 receptor, if active, delivers the histamine/cAMP messages to the genes and corrects (yes, corrects!) their functioning. This process of accessing is called immunotherapy or immunomodulation. It can also be called geneomodulation. A term I have not come across, but suitable in this situation. This approach would be the best therapeutic modality for allergy sufferers. But the gardeners neglect the roots and start with the branches. They try to rid allergy patients of their cough, itch and sneeze by identifying and eliminating the allergens which, in their opinion, provoke the symptoms. As a rule, elimination fails, and doctors turn to antihistamines, decongestants and bronchodilators that relieve those symptoms for a period of time dependent on the drug clearance time and with a different degree of efficacy. In too many cases, such tending does not work at all or works insufficiently, and the failure shifts the attention from the branches to the trunkallergic inflammation. The notorious side effects of steroid drugs prompt some authors to caution in prescribing them for allergic disease. But some suggest even more potent immunosuppressive medications, which, although they ruin the immune system, can, at least, be discontinued at once since they do not produce physiological dependence. Indirectly, allergists admit that the essence of the problem is malfunctioning immunocompetent cells: allergic rhinitis and asthma need to be understood as inflammatory diseases arising from mediator release cytokine secretion. This statement comes from L.
Lichtensteins university department.19 Despite this knowledge, the causative immunogenetic defects are disregarded, and the most powerful treatment weapons are aimed at the secondary event, inflammation, with such force that they reach the roots and burn them out. Steroids destroy the immune cells and by that, stop the synthesis of all natural protective chemistry. I respect the honesty of Dr. S. Wasserman, past president of AAAAI, as the only frank participant at the round-table discussion of January 28, 1995.20 He disagreed with his powerful colleagues and sadly admitted that immunology is considered clinically irrelevant, and we probably have far more allergists and immunologists than we need to take care of the severe end of the spectrum. It means that we hardly need so many specialists to treat the end organ damage, instead of heeling the immunological roots of allergies.
IMMUNOTHERAPY VERSUS IMMUNOSUPPRESSION The word therapy comes from the Greek therapeiaservice done to the sick. In allergy, the sick immune system needs service. The purpose of immunotherapy is to do this service. If properly conducted, immunotherapy can be highly successful. The interrelation of the immune, nervous and endocrine systems makes it inevitable that the whole body gains from this healing of the immunity. The other approach, blocking and suppressing, is doomed for two main reasons:
a) In the same way, a tear or rip grows in size if not mended, the disregarded immune defect has a tendency to advance and to affect more and more mechanisms. b) All suppressive methods result in the adjustment of the body to the consumed medications, their foreign chemistry, their doses and their adversities. This adjustment, coupled with the ongoing disease, necessitates still more drastic measures and causes more and more damage to the cells. The stronger the suppression, the deeper the damage to the participating cells and, unfortunately, to the non-targeted cells. How do allergists view immunotherapy? On paper, they may say that it lies at the heart of our specialty.21 In real life, the general opinion of specialists is that immunotherapy should be tried only when other medications fail. Many suggest it be used only as an adjunct to anti-inflammatory treatments. It is hard to believe that allergists suggest first to immobilize the immune cells by the antiinflammatory drugs, which in their vague vocabulary means
Medications
199
immunosuppressive steroids, and only then to start reactivating these very cells with immunotherapy. It is still harder to accept the idea of the simultaneous use of these two diametrically opposed treatment approaches. Here we have yet another immunologic oxymoron.
A PIECE OF THE ACTION Allergies, asthma and related diseases are the largest group of chronic diseases. Just this factor alone provides a permanent patient supply. I do not think that the past president of AAAI, Dr. M. Kaliner had reasons to worry when he said: We are a small subspecialty, overlapped by large and powerful groups of physicians who would gladly absorb our patients 22 Inefficient therapies will surely keep the patient within the field of allergy. An allergy patient is perceived by many as a real dainty pie shared by other doctors as well. Different specialists get a tiny piece of an allergy patient here and there. Asthma patients, unable to receive help from allergists, visit respirologists; those with itchy skin wander off to dermatologists; congested noses often end up in the offices of ear-nose-and throat surgeons. The failure of allergists to relate the accompanying nonspecific symptoms with their field, forces their patients to roam from office to office of every imaginable doctorneurologists, psychiatrists, gastroenterologists, etc. Allergists are twice blessed in that their patients are generated by the general practitioners who dispatch their patients with signs of asthma and allergies to them. After a tour for allergy skin testing, the patients come back to their family doctor if not for physical help, at least, to share their frustration. This frustration is justified, since the diagnosed conditions often fail to respond to the prescribed medications, and in addition, there are undiagnosed symptoms, which, are, in fact, allergy-related. The lack of diagnosis comes from the poor understanding of the underlying mechanisms of allergy and their inseparability from the neurological mechanisms. Allergists do not limit themselves: the awesome and expensive procedure of skin testing has become almost a must even though it does not influence the pre-determined steroid-oriented therapy. Immunotherapy should have become a logical continuation of skin testing. Instead, it is conducted primarily in cases of allergic rhinitis, and even textbooks recognize its inefficiency: immunotherapy fell in disrepute with the scientific community at large.23 The dismal statistics on allergies and asthma necessitate a continuous search for more potent drugs (mostly versions of the already existing ones), and
allergists are undoubtedly the first to get paid by the pharmaceutical industry for their research, development and testing. In support of the allegedly wide spectrum of allergology, Dr. M. Kaliner, Chief Allergist in the National Health Institute, said at a round-table discussion24 that allergists provide certain aspects of care that may not be given by other physicians, including an emphasis on the environmental control of allergens and other triggers. Indeed, during patients visits to their offices, allergists may conduct individual educational classes on the makes of appliances, breeds of non-allergenic pets, delivery devices of medications and techniques of inhalers use. Of course, their time has a high price tag, although these aspects are hardly in the department of immunology. But if leading specialists say so Medicine and the areas servicing it should be grateful to allergists for job creation. Due to the success of allergists in breaking up the medical problem into a myriad of irrelevant issues, they keep themselves in the business, and also let many other medical professionals do so as well.
A NARROW FIELD Somebody once said that if you have one instrument only, and this instrument is a hammer, everything around will look like a nail. Allergy has one instrument, steroids, and they are as powerful as a hammer hitting all body cells at once. It may look as though histamine, I suggest using for all allergies and related diseases, is also a hammer in my hands, but this is wrong. I suggest medicine should accept the stimulatory approach. This would facilitate creation of various agents able to activate its immunomodulatory receptors. The advantage of histamine is that it and its congeners are already available and have undergone clinical and double-blind studies. All of them could be used right away for the sake of those who cannot find relief with conventional medications. Immunomodulation with histamine would be the natural way of restoring the functioning of the immune system. But allergology ignores and prohibits this approach. A quoted high profile allergist declared at the above-referred roundtable discussion that allergists are a small specialty with a narrow focus25 Is this so? Is immunology a narrow field isolated from other medical areas? I personally disagree. The narrower the specialization of a doctor, the broader his general knowledge of the bodys processes should be. For example, before performing complex operations, top heart surgeons do not just wield their scalpels, but
Medications
201
consider the multiple influences of other co-existing medical problems, as well as the ones that may develop afterwards. Immunotherapy, as the only logical and promising management, requires an understanding of the immune processes in disease and health. Instead, the vital information on the causative immune mechanisms of allergies and asthma is silenced, distorted and substituted with insignificant and irrelevant minutia, and the knowledge provided by contemporary textbooks is narrowed to fit an artificially designed framework. It is strange that having created this situation the leading allergists complain at their discussions that immunology is so poorly understood, practitioners simply do not see how it impacts on practice patterns. At the same time, they defend this illiteracy by saying that people are not referred for mechanisms; they are referred because they have wheezing bronchial tubes, or stuffy noses. Therefore doctors do not see their problems as T-cell problemsthey see wheezing patients who need to be kept out of the hospital.26 Such views justify and support the use of medications that, at best, relieve symptoms temporarily. Healthy immunity does not seem to have a place in clinical allergy, therefore immunotherapy is not applicable. No wonder that allergy patient always remains on drugs and nothing but drugs.
ENDNOTES
1. Lan Yan et al. Histamine N-methyltransferase pharmacogenetic. Pharmacogenetics 2000;10:261-6 2. M. Reilly, E. Sigg Suppression of histamine-induced adrenocorticotropic hormone release by antihistamines and antidepressants, J Pharmacol Exp Ther 1992;222(3):583-588 3. This is not a typographical error: Tamoxifen increases the risk of cancer especially in the liver, while slightly reducing cancer risk in the breast. See oncologist S. Epstein, M D, The Breast Cancer Prevention Program, 1999 4. For the adverse effects, including the 7-fold increase in cancer risk associated with antidepressants see Harvard Universitys J. Glenmullen, Prozac Backlash, 2001, and D. Healey, Let The Eat Prozac, Lorimer, 2003 5. Brandes L.J. et al: Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist in combination with various single antineoplastic agents, J.Clin Oncol 1994; 12:1281-90 6. Note: according to the regulations governing safety standards in Canada and the USA (not always followed, of course), the reason studies are conducted on mice, is because they largely share the same enzyme system with humans; extrapolating from mice to people regarding toxicity and carcinogicity has proven to be totally reliable. 7. FDA reviews antihistamine mouse study. FDA Talk Paper 1994; May 17:2 8. C.Brutin et al To the editor, The New England Journal of Medicine, 1983;308:591-2, S. Borgstrom et al To the Editor, The New England Journal of Medicine, 1983; 308:592 9. Immunopharmacology 1982:52 10. M.Ichinase, P. Barnes. Histamine H3 receptors modulate antigen-induced bronchioconstriction in guinea pigs. JACI 1990; 86:491-5 11. G. Sussman., J. Dolovich. Seminars in Dermatology 1989;8:158 12. According to the Journal of the American Medical Association, 87% of doctors who get clinical practice financially tied to the pharmaceutical industry. JAMA 2002;287;612-7 13. Parkhurst Exchange, April, 1994:76-9 14. Dermatology Times of Canada, Sept. 1996, p. 1 15. R. Sapolksy, et al Pulsender Wa Science, 1985;229(4720):1397-1400 16. P. Halloran. Four decades of glucocorticosteroid immunusuppression. Can Med Assoc J 1992;147(5):613-4 17. B.Lipworth, C. Jacson Effects of oral and inhaled corticosteroids on the hypothalamic-pituitaryadrenal axis, JACI 1999;104:13 18. R. Geha. Regulation of IgE synthesis in humans. JACI 1992;90:143-5 19. P. Creticos. Immunology and Allergy Clinics of North America, 1992; 12:26 20. JACI 1995; 97:870 21. Frew et al. Sublingual immunotherapy. JACI 2001;107:441 22. M. Kaliner. Presidential address. JACI 1997:99:729-34 23. Kaplan ed. Allergy 1985, p.679 24. JACI, 1995;97 25. Visions in Allergy: Impact on Health Care Reform. JACI 1995;97:864 26. Justifying a mechanism-based specialty. N. F. Adkinson et al. JACI 1995;97:868-71
PART SIX
ALLERGY SKIN TESTING AND IMMUNOTHERAPY
THE GOAL OF THIS CHAPTER This chapter is written as continuation of Medications, since immunotherapy is logically and scientifically the best means of management of such reversible diseases as allergies and asthma are. Application of therapy to the ailing immune system and restoration of its ability to fight the disease rids the patients of the above-discussed medications or, at least, drastically diminishes the need for them. Analysis is required as to why conventional immunotherapy tends to fail and is mostly avoided. Since criticism is helpful only when it is accompanied by recommendations on how to improve the situation, we will do bothprovide an overview of todays immunotherapy and show what should be done to turn it into the most effective therapy for all kinds of allergic diseases. With steroids being mainstream therapy, doctors believe that they can only reduce the intensity of the inflammatory response and never cure the disease. Therefore in 2001 more than 5,000 people die of asthma (in the U.S.) every year, and death rates.have increased or remained stable over the past decade.1 Asthma now is one of the commonest, if not the commonest, chronic disabling diseases of children and young adults in the western world, stated the textbook Allergy already back in 1985 (p. 367).3
The situation with asthma, the most serious allergic disease, is a reflection of the situation in allergy medicine as a medical field. The only treatment that could repair the ailing immune system is immunotherapy, but, as the same textbook wrote back then, with little evidence of efficacy for the technique as commonly practised, immunotherapy fell into disrepute in the scientific community at large (p. 679).3 Allergists blame the quality of the allergen extracts for this failure and produce guidelines to improve their standardisation and storage conditions. They also modify the production of the extracts to prevent aggravations and even deaths from them. Still, within the past two decades, nothing has changed the low efficacy and potential danger of allergy shots, as laymen call immunotherapy. It is required to last from 2 to 5 years and the first results (if any) manifest not earlier than 6 months after the start. It is not uncommon that immunotherapy is discontinued because of the various adverse reactions, both local and generalized, while the disease is still not controlled. For safety reasons, this treatment, meant to repair the ailing immunity, may be prescribed along with immunosuppressive steroids. It is mostly limited to allergic rhinitis and hay fever and is never recommended for skin allergies. All guidelines caution against using it in asthma even though it is asthmatics that need it most in view of the gravity of their disease. Immunotherapy is not even considered as a possibility for the related neurological and non-specific symptoms because their common roots with allergies are unknown to clinicians. All this has assigned a Cinderella role to immunotherapy among allergy/asthma therapies. So hopeless for patients and compromising for doctors is immunotherapy that an ex-president of AAAI, M. Kaliner acknowledged at a prestigious gathering of American allergists: immunotherapy is easy and lucrative. If we didnt have it, we would have a better specialty. Having said that, I think we are going to go where immunotherapy is going to be restricted.2 Something must be terribly wrong with this most logical and scientifically founded procedure if a top allergist thinks of restricting this already unpopular therapy. Actually, for patients, this means being condemned to medicalization for life. Dr. Kaliner is right in one respect though: any therapy based on its profitability for doctors instead of its benefit for patients ought to be restricted or even banned. Before suggesting changes, we should thoroughly scrutinise immunotherapy in its present performance. The scrutiny should start with allergy skin
Allergy Skin Testing and Immunotherapy 205
testing, AST, the diagnostic procedure that always precedes immunotherapy and provides the basis for the doctors judgement regarding the subsequent management. If we can prove that the procedure that forms the foundation of todays immunotherapy is deficient, we will prove that the subsequent treatment failure is inevitable, just as would be the collapse of a structure erected on shaky grounds. The opposite is also true: the properly done procedure becomes the prelude to successful immunotherapy.
THE MISGUIDED PURPOSE OF SKIN TESTING What am I allergic to? is the question insistently asked by all allergy patients who seek skin testing as the answer to their symptoms. They believe that by identifying the trigger and eliminating or avoiding it, they will find relief. Doctors support them in this belief. They conduct skin testing to pinpoint the offenders and offer advice on their avoidance or removal from the environment in which the patients live, work, rest. Every allergy patient knows how successful (or rather, unsuccessful) implementation of these measures is in every day life, and this is the best proof that todays allergy skin testing has a misguided purpose. Ideally, any diagnostic procedure should be performed not only to diagnose the condition but to find the best possible treatment. Unlike other medical tests, AST seldom satisfies these mandated criteria in medicine. Doctors are taught that skin testing should be nothing other than a trigger indicator. Therefore, AST is considered to have fulfilled its task with the avoidance advice. The treatment for the majority of allergy sufferers continues to rely on the same pills, puffers and sprays they used before. Even in the smaller portion of patients who are prescribed immunotherapy, it never aims at ridding them of their hypersensitivity, but at lessening the response to one or several allergens allegedly revealed by the testing. Skin testing, as a diagnostic means, fails in finding a therapy that will make the ailing immune system unresponsive or less responsive in general. THE TECHNICAL PART OF SKIN TESTING Let us see what AST consists of. The most common skin testing is epidermal. The word comes from the Greek dermaskin and epiover. Thus, epidermis is the upper skin layer. The dry scales we see when our skin peels are, actually, epidermis. Epidermal skin testing in allergy starts with a mandatory histamine test called positive controla drop of histamine and a prick through
the epidermis at that spot. Usually, an itchy wheal forms at the prick site often surrounded by redness or a flare, as it is called. A few minutes later, drops of allergen extracts (pollen, mould, house dust mite, animal dander, etc.) are put on the skin followed by a series of pricks at each spot. The size of the wheal and flare formed by each allergen is compared to that formed by the histamine prick, which is thus used as sort of the yard stick in the evaluation of the local reaction. As a rule, allergists also use a negative control, which is a drop of saline, to see if the patients sensitivity is so exaggerated that his skin reacts even to a neutral substance. The use of saline is not mandatory according to the FDA recommendations. Each allergen extract, to which no skin reaction occurs, becomes a negative control due to its neutrality in the hosts body. A localized reaction developing upon a prick is a typical appearance of what allergy calls allergic inflammation. Doctors explain it this way: Do you see the hives where I put mould (mites, pollens, etc.) extracts? It means you are allergic to them. In the majority of cases, at this stage, the patient is given a prescription for a conventional drug and told to avoid the offenders. In rare cases, when immunotherapy becomes the treatment of choice, the mixture prescribed for injections almost invariably contains those allergens that showed the most marked skin reactions. The doctor says: I will prescribe you the mixture of these allergens. By getting them in gradually increasing doses, you will be desensitized to the triggers and hopefully will get rid of your allergies. The explanation sounds logical. The patients are impressed by the solemn procedure and by the knowledge of the specialist who can do it and become optimistic of a successful outcome. Through this lengthy course of immunotherapy, the patients usually continue to use their previous medications. On the surface, the explanation given by specialists is faultless, but then, why do top specialists state that they would have a better specialty without immunotherapy?
THE CONCEPT OF ALLERGEN-TRIGGERED ALLERGIES Skin testing is based on the IgE concept proclaimed as central in allergies. It teaches that patients exposure to triggers results in the formation of the corresponding IgE antibodies that reside on mast cells. At the testing, if an allergen is introduced through a prick, the already existing antibodies bind to it to form complexes, and the new chemistry leads to a local histamine spill from the mast cells. The wheal and flare on the site of the prick are said to be the signs of this spill, and the indicators of the culprit(s). But, how solid is the IgE-based hypothesis? Skin testing exposes the flaws in this concept.
First, the name of the outer skin layer where testing is performed is epidermis, and the epidermis does not contain mast cells! No mast cells no complexesno reaction! Second, there is almost always a skin reaction to the initial prick with histamine which is not an allergen. So, what is this reaction in the absence of antibodies? Third, textbooks teach that in response to various stimuli, IgE-mediated histamine release with human mast cells requires 1540 minutes. In other words, skin reaction upon a prick with an allergen can not be observed right away. Then, why do doctors often see it within minutes? Conventional allergy does not provide answers to these questions. The deficiencies of AST do not end here. According to statistics, only 20% of urticaria (hives) and less than 50% of asthma are allergen-related, and therefore skin testing is not applicable for the remaining majority. Such non-IgE-mediated factors as, for instance, temperature or weather changes, touch to skin, stress, sun light or exercise cannot be verified in skin testing. Neither can be the vast group of pollutants, for example perfumes, as they do not exist in the form of standard allergen extracts. An additional complicating factor is that allergy patients overwhelmingly have symptoms in response to mixed triggers, i.e. specific and non-specific. In such patients, even if the offensive allergen is detected and eliminated, nonspecific factors remain still unidentifiable by pricks, and pinpointing specific triggers will not significantly change these patients management. Only those few lucky patients whose symptoms are solely allergen-produced may hope that skin testing will reveal their triggers. Ironically, it is in these cases that skin testing may often prove to be redundant. For example, if your symptoms always come in the same season when the radio stations remind us every hour of the rising ragweed count, and ingratiating TV ads incessantly promote medications for the pollen-triggered allergies, do you still doubt you have hay fever due to exposure to ragweed? Nevertheless, patients with obvious triggers are skin-tested. All these flaws make the procedure of AST useless even in reaching its narrow goaldetect the offensive allergens. Paradoxically, allergy patients leave specialists offices with the assurance that they can depend on the conclusions regarding the causative allergens. They are promised either to be desensitized against those or to get instructions on how to control the offenders. Doctors are also satisfied with the impression they produce by this procedure.
Besides, the subsequent allergy shots are lucrative, as we are informed by an ex-president of AAAI, Dr. M. Kaliner. An all round win-win situation! Although only a smaller part of allergy cases is allergen-related, search for a trigger, and hence, AST, is proclaimed to be the main avenue in the management of allergy patients.
FALSE POSITIVE AND FALSE NEGATIVE SKIN REACTIONS A diagnostic procedure must be reliable. In AST, skin reactions, its main indicator, is deceptive. A textbook states, A positive skin test reaction can be produced in any person allergic or non-allergic, if the test materials are sufficiently concentrated.3 A more recent publication states: IgE and positive AST indicate allergen sensitization, but are not necessarily indicators of allergic diseases.4 Even medical sources for lay people admit the unreliability of skin testing. For instance, The Canadian Allergy & Asthma Handbook 1996 admits on page 29 that if given skin tests, up to half the population would have a localized reaction to at least one common allergen, but the number of people with allergy problems is much less. This means that an extract of, say cat dander, which is a strong chemical, may form a large wheal and a flare, while testing does not find the corresponding IgE antibodies in the patients blood and tissues. The patient may have had a cat for years, without developing any symptoms. However, solely on the basis of the skin signs, doctors invariably recommend that the owner should part with his pet. How many a heart has been broken due to this needless separation? One can only wonder what prevents physicians from informing their patients about the imprecision of local reactions. The wheal and flare to an allergen extract not supported by corresponding symptoms are called false positive. They may confuse, rather than identify the trigger, if the doctor relies on them more than on the medical history. Too often allergists do exactly this. False negative reactions, although less common, may also occur. This means that an antigen that triggers allergy symptoms produces no skin reaction. The existence of false positive and false negative reactions creates additional doubts for the need to do testing with the sole purpose of detecting offensive allergens. All this renders the judgment regarding the contents of the therapeutic mixture for the following allergy shots even more questionable.
SKIN REACTION IN THE ABSENCE OF MAST CELLS? One of the questions that allergy leaves unanswered is: if the epidermis does not contain mast cells, what are the skin signs produced as a result of AST? During the course of an allergic disease, all the participating cells of the hosts immune system become competent, that is, acquire the ability to release various cytokines and mediators. Although there are no mast cells in the epidermis, it contains T-cells able to respond to any trigger directly, independent of IgE.5 The skin also has Langerhans cells, LCs. So fascinating is their multifunctional and especially in immunomodulatory activity that they have become the subject of books, international conferences and workshops. LCs carry the explanation of the processes that underlie skin reactions at the testing. Similar to mast cells and basophils, LCs have been shown to possess the receptor that binds to IgE antibodies, which means that, similar to mast cells, they may become the platform for an antigen/IgE antibody reaction. LCs are also the central antigen-presenting cells in the skin. They inform T-cells about an antigen on the skin. For that, they produce a protein in response to the antigen, and this protein binds to the stranger before presenting the latter to T-cells. Unlike stationary mast cells, LCs possess a unique migratory ability and chemical attraction to T-cells, and they transport the captured antigens to the regional lymph nodes for presentation. The new chemistry activates the T-cells, and they, in turn, engage other cells. LCs are a the depository of numerous pro- and anti-inflammatory cytokines and mediators, histamine among them; the homeostasis of LCs seems to be tightly controlled by a delicate balance of mediators Minor perturbations of this homeostasis by chemical, physical, or biological factors may signal danger to shift this balance.6 This means several things. First, LCs respond with their mediator spill even if the trigger is not an allergen, and a local reaction to the prick with histamine at skin testing is proof of this fact. Second, LCs activity is more than local, and they directly affect other cells functioning. When they respond to a stimulus, they chemically engage other cells. LCs relationship with nerve cells is yet another impressive fact. As a part of the dendritic or branched cells, LCs stretch their extensions to the dendrites of the nerve cells and thus spread their messages. This explains the exchange of chemical information between nervous and immune systems and coexistence of allergic and neurological symptoms. To summarise the functions of Langerhans cells:
Like mast cells, LCs possess IgE antibodies. LCs may respond to an antigen directly or by binding it with their own chemistry and delivering to T-cells. LCs may respond to an antigen immediately by changing their own chemistry and affecting the chemistry of other immune cells. LCs may change their chemistry not only in response to antigens but to any stimulus and thus bypass IgE antibody mechanism. LCs have direct connections with nerve cells, and a change in their chemistry may produce systemic effects in the nervous systems as well.
HOW IMPORTANT IS THE KNOWLEDGE OF LCs? You may be puzzled by now: does it really matter on what cells the antigen/IgE complex dances? What is the reason to hide the data that some other cells do what mast cells do? Why dont allergists know this? The answers are complex. The well researched knowledge of the navigating and recruiting abilities of Langerhans cells is so overwhelmingly important that the pharmaceutical industry has long been using it to develop therapies for allergic dermatitis. The effect of topical (placed on the skin) medications is due to the response of the Langerhans cells and their messages of the medications presence on the skin. This allows the use of nicotine or hormonal patches, for instance. Regrettably, what is essential in drug development loses its attraction in other areas and may even become a stumbling block, and the most explosive findings may be blocked from access. This is exactly what has happened with the information that immunocompetent cells, Langerhans cells in particular, are able to respond to any trigger on the skin, not just to allergens, and spread the news by secreting mediators. The knowledge that skin manifestations at testing may not be the antigen/IgE antibody reactions raises the question of what they are. As it turns out, Many authors believe that the allergic skin reaction occurs chiefly because of the liberation of histamine.7 Thus, wheal and flare are just a local spill of allergy mediators, first of all histamine, in response to a foreign protein (not necessarily allergenic) or any stimulus. Skin reactions do not specifically identify the triggers but indicate one thing: readiness of the hypersensitive immune cells in the skin to react chemically, i.e. this is spontaneous hyperreleasability. The situation can be compared to a scream in a dark house: A robber! The shout wakes up the whole family and makes them rush around without knowing exactly who the
Allergy Skin Testing and Immunotherapy
211
robber is. The vagueness of the scream (the wheal and flare) in identifying the culprit (allergen), is confirmation of the diagnostic imprecision of the todays AST. The true knowledge that the local reactions are mostly non-indicative is at best presented in a piecemeal way in professional papers. It is doubtful that practical physicians ever read them because the demands of daily practice leave little time for keeping up with the literature, while the work of finding the needed material, and especially interpreting it, is time-consuming. It is also highly undesirable to reveal the fact that LCs activity is not limited to the skin but echoes all over the body. Langerhans cells relatives, other dendritic cells, exist not just in the skin but in the lungs, nasal mucosa and conjunctiva. The chemical signals sent by LCs from the skin surface involve the whole network of immune and nerve cells. The involvement requires, histamine spill from mast cells and basophils followed by other chemical events. Thus, a local process started and spread by LCs turns into a cause for the whole body reaction. In other words, by touching the skin we touch other organs. This leads to a most important revelation: by treating the skin, we treat the whole body! However, what the drug industry can do, clinical medicine is prohibited from doing. And the best minds are used to help skilfully hide the fact that histamine can engage the whole body into recovery, and that LCs can help do the main job. You may think that I am splitting hairs, that this is a purely theoretical exposition, which is irrelevant to practical allergy medicine and not needed by allergy patients whose central concern is improvement. Wrong. This seemingly theoretical issue has a very practical outcome for patients. At present, the judgment regarding what you are allergic to, what components of the surrounding environment you should avoid or eliminate, and what allergen extracts must be used in your shots depends totally on what allergens form skin hives. You may be forced to spend money on irrelevant and impractical elimination measures, make an emotionally difficult decision to part with your pet, or turn your otherwise happy life upside down by deciding to move to a place where the offender does not exist. My prediction is: in either case, you will remain a consumer of allergy medications because mostly, the measures will not work. An incorrect judgment also dooms any subsequent immunotherapy because the therapeutic cocktail contains invariably irrelevant or therapeutically useless allergen extract(s).
DO WE NEED SKIN TESTING? If AST is so confusing practically and unsubstantiated theoretically, do we need it? Yes, but for a different purpose, performance and interpretation of the events that take place in its course. Today, this test is an isolated event that ends up with advice on the elimination of a trigger, which, as we found, cannot even be detected reliably. AST must be a dependable diagnostic procedure, the bridge that leads to a successful immunotherapy. Accordingly, immunotherapy must also change its targets: instead of trying to desensitise a patient to one or two triggers allegedly revealed by local skin reactions, it should strive for reduction of general spontaneous hyperreactivity and hyperreleasability of the ailing cells. No therapy can be successful if based on the premises that it is easy and lucrative. There are no immunology patients in practice, so the rank and file make their living on allergy, and asthma, and sinusitis.8 Conventional immunotherapy has this dubious basis and is, therefore, a failure. It needs to become science- and patient-oriented. Changes must start with an understanding of the processes that underlie skin testing, because a diagnostic procedure as unreliable in all aspects as the conventional AST is cannot be the correct guide for action. We are going to show what elements of allergy skin testing should become the basis for the doctors judgment regarding the subsequent therapy, and why the suggested approach logically leads to effective immunotherapy. THE SKIN AND SYSTEMIC REACTIONS As we are speaking about skin testing, we should know the basics of what the skin is. Not only it is an external case or cover for other organs, but it is also a large, live, highly sensitive organ full of immunocompetent and nerve cells. Therefore, the skin often becomes the victim of allergies and other immune and neurological diseases. This negative aspect has positive side in that the skin may become a prime target for therapeutic interventions to suppress, stimulate, or deviate cutaneous and systemic immune responses, and it has wide clinical use in the specific treatment of allergy.6 It is well known that even superficial contact of the skin with an allergen, for instance, with a cats fur, may provoke a reaction going beyond the skin cause nasal congestion or an asthmatic attack. In other words, skin reaction may grow into a systemic response because the same cells that populate the skin populate various organs. Their coordinated response to a trigger makes it clear that at AST, allergens and histamine get into the epidermis or dermis with
213
pricks and engage the network of related cells into a reaction. The immune and nerve cells work in unison and respond to a histamine spill in different parts of the body because they possess histamine receptors, and it does not really matter what cells start the reaction. The histamine-induced shift of the cellular chemistry is bound to bring about symptomatic bifocal changesimprovement or worseningbasically depending on the prevalence of anti- or pro-inflammatory cytokines. The more mediator-releasing cells a diseased organ contains, the more potential it has to be involved in the reaction, and the more pronounced the changes are in the corresponding symptoms. All this explains why it is only natural to expect that allergy skin testing may lead to systemic reactions. If the doctor who conducts skin testing does not detect systemic changes, it is because he does not anticipate and therefore does not observe them. In medical school, he was taught only how to assess the wheal and flare occurring on the skin surface and to view them only as an IgE antibody-mediated event pointing to a trigger. Doctors are never told that they should expect a histamine spill regardless of IgE existence. They also remain unaware of the involvement of other organs and systems through chemical changes started by skin pricks. Strangely, they do know about systemic reactions, up to anaphylactic shock, that may result from skin testing. They also know about whole-body reactions to topical medications, steroids in particular. Still, at AST, they limit their observations to the local skin signs and never ask patients about their baseline symptoms right before the testing and the symptomatic change afterwards. And this is the biggest diagnostic flaw of the procedure. Like a mirror, our skin reflects the chemical processes occurring in the tissues and organs stricken by immune and related diseases.9 A localized skin reaction at a prick site is the manifestation, first of all, of a local histamine spill. However, it is followed by a systemic reactiongeneral effects elsewhere due to the histamine-initiated changes all over the body. Doctors cannot see the organs inside the body, but monitoring of the symptoms before and after the pricks would help determine how the allergyinvolved organs respond to the bodys chemical changes. Just a few questions asked directly before the pricks could elicit all the needed information: Is your nose stuffy (runny)? Are your eyes watery (itchy)? Do you feel the urge to cough? Are you short of breath? etc. As histamine is a major neurotransmitter, the doctor should also ask about neurological or related symptoms such as a headache, fatigue, bloating, muscular pains, etc. The same questions asked
1015 minutes after the procedure may reveal changes and thus the relevance of these symptoms to allergies. Among the relevant symptoms, there may be those of migraine, depression, chronic fatigue syndrome, irritable bowel syndrome, etc. Some of these diseases are poorly interpreted, therefore undiagnosed and mostly unattended. Conventional interpretation of skin tests sees the tip of the iceberg only, but presents it as the whole iceberg. Allergists measure the size of the wheal without measuring the more essential partthe hidden immune mechanisms which are inevitably engaged in the process when histamine or allergens encounter the immune cells through skin pricks. The changing body chemistry reflected in such systemic reactions is not in the picture. If you have had allergy skin testing, try to remember whether the doctor who did it asked you questions about possible symptomatic changes. I bet he did not, although this is a must for a physician performing any diagnostic procedure. Apart from lack of proper theoretical knowledge, there are two banal reasons why no attention is given at AST to the accompanying systemic reactions. First, clinical observation is not a subject taught well enough at medical schools, hence, the inability of doctors to observe. Second, the Time is money slogan has become the creed of our life, and doctors simply do not want to invest time and effort to observe, analyze or make decisions. They prefer to follow standard guidelines. Lack of understanding what underlies local skin manifestations during allergy skin testing prevents clinicians from noticing systemic immune reactions and making the right judgment regarding the response of the numerous body organs.
REACTIONS WITH AGGRIVATION As was said, allergists are aware of a possibility of severe systemic reactions. The very title of the paper written by an ex-president of AAAI in the central periodical on immunology reveals this knowledge; it was entitled Fatalities From Immunotherapy And Skin Testing.10 The official medical and government sources also caution doctors about such reactions.11 Further proof of awareness comes from clinical medicine: allergists avoid skin testing in symptomatic patients with moderate to severe asthma as well as in small children for fear of provoking an attack. This is recognition of the test as an invasive procedure with the risk of severe adverse reactions, including fatality. Severe systemic reactions may become the basis
215
for a liability suit. Still, if the reactions do occur, obeying the technical rules of the procedure removes all liability from the doctor even in event of a patients death. It is of interest that theoretical sources have noticed that anaphylactic reactions after skin pricks may occur with minimal to no skin reactivity.12 In other words, a severe systemic reaction may occur to a prick that reveals few or no IgE antibodies. This, more than anything else, should tell allergists that systemic reactions are more important than the notoriously imprecise wheals and flares, since the chemical changes produced in the whole body are more important than the superficial, often non-indicative skin signs. An important point not taken into account by doctors, but suggested by common sense, is that reactions with aggravations do not necessarily lead to the death of a patient. The scope of worsening can be wide, ranging from a minor worsening to anaphylaxis, depending on the individual sensitivity. While the most sensitive patients respond with a severe reaction, in the rest, it is easy to detect minor changes only by comparing the symptoms before and after the pricks. Only a doctor who understands that the whole body becomes involved in the reactions following skin pricks expects a change and asks about the symptoms. It is natural that if at the testing, the patients attention is not drawn to the symptoms, he will not inform the doctor about symptomatic changes unless there is a dramatic worsening. Since ups and downs are normal in any allergic disease, the patient will accept a mild or moderate aggravation as such. As was said, selection of the therapeutic mixture for allergy shots is made solely on the basis of wheals and flares, and the cocktail of allergens may contain the aggravating ones. Unlike homeopathy that employs the method of administering tiny doses of offensive substances, conventional allergy starts with much higher doses and drastically raises them. Thus, if a mild dizziness or a more congested nose escapes the doctors attention, the situation may worsen during the subsequent immunotherapy. The lack of attention to the symptoms at allergy skin testing continues during immunotherapy and accounts for the fact that the worsening may be noticed only when it reaches a serious level. This is not so uncommon: a lot of patients experience acute systemic reactions. Besides, there is a general (unfounded) belief that it gets worse before it gets better, and the patients may still go on with their injections assuming that side effects are an inevitable part of the treatment. The expectations set during allergy skin
testing were so high! The situation is complicated by the fact that often, weekly injections are given by nurses according to a standard schedule of dose increment, and the doctors are unaware of the transitory aggravations until they strike severely. Unrecognized systemic reactions with aggravation during skin testing are the reason why conventional immunotherapy may be dangerous.
REACTIONS WITH IMPROVEMENT It is strange that pricks are not viewed as initial shots, which they actually are. No matter what skin layer the extract penetrates, the histamine spill, which it provokes, engages all the immunocompetent and related cells in the reaction. Therefore skin testing should be considered as the initial session of potential immunotherapy. Paradoxical is the fact that while the therapeutic cocktail selected on the basis of the testing pricks is given in injections to improve the symptoms, doctors do not expect an improvement during the testing with the highly concentrated ingredients of this cocktail. This is just further confirmation that allergy medicine views localized skin reactions as an event unrelated to the rest of the body. The scope of improvement may vary from slight relief to complete disappearance of the symptoms, and the degree depends on the individuals chemical sensitivity. Medical sources do at least caution doctors about the possibility of an aggravation at skin testing, but there has never been a single (!) description of improvement within the 130 years since the introduction of the procedure by Dr. Blackley. Relief obviously has more chances to go unnoticed by doctors because, unlike a severe aggravation, it is not fraught with liability and therefore draws less attention. As a result, if at AST, an allergen produces a symptomatic improvement and by that creates the perfect ground for its subsequent use in allergy shots, the chance of eliciting this particular allergen is missed. Patients do not observe a minor improvement for the same reasons they do not observe a mild worsening: volaility of their symptoms. Moreover, they may not inform their doctor even about pronounced relief: we tend to pay attention to our body only when something is wrong. Thus, we never think or say: None of my ten fingers hurts but will definitely recognize when one of them does. There is another factor contributing to positive reactions being missed: after AST, the majority of patients continue taking their medications regardless. Regular use of a pill or a puffer prevents knowing whether the improvement results from the testing or from the drug.
217
As was cited before, even fatalities may occur in the absence of local skin reactions. Similarly, symptomatic relief does not always correlate with the degree of the localized reaction. This is an important fact, since the cocktail prescribed for immunotherapy is based on those allergens that produce the most impressive wheals at the testing. If among the allergen extracts, one is a good match for a particular patient, even the prick with this extract may result in improvement. Thus, the potentially effective allergen may be excluded from the cocktail only because it does not produce a wheal, whereas systemic reactions with improvement, which could help finding the specific allergen suitable for immunotherapy, go unnoticed. This makes the judgment regarding allergy shots even more flawed. There is another factor that is not helpful in detecting positive systemic reactions. For fear of causing an aggravation, allergy and especially asthma patients are tested mostly in remission or under the protection of strong medications. However, to reveal an improvement, testing should be conducted in symptomatic patients, with the exception of those with life-threatening asthma or who are in a severe allergic episode, and the patients should certainly not take allergy medications at that time. Unrecognized systemic reactions with improvement make immunotherapy ineffective because the potentially effective allergen(s) may not be selected for the treatment.
SYSTEMIC REACTION TO HISTAMINE Systemic reactions to allergens at skin testing, positive or negative (apart from severe ones), are not observed because doctors ignore the basic facts that the skin is an immune organ, and that, by touching it, we may incite a reaction elsewhere in the body. Moreover, the sources that warn doctors about adverse reactions do not provide an explanation for what causes these reactions, and whether the reactions are preventable. The articles just caution about skin testing in asthmatics as a particularly unsafe group and instruct doctors to keep an emergency kit in the office. Completely ignored is the fact that allergy skin testing starts with a histamine prick, and that histamine is one of natures most potent biological substances contained, by the way, in almost all allergen extracts. In manufacturing allergen extracts, the biological activity of allergens is routinely measured against the biological activity of histamine. This makes histamine the measuring unit for the potency of allergen extracts. Since histamine possesses
both pro- and anti-inflammatory effects, theoretically speaking, an aggravation is as possible as an improvement. The scope of either reaction can be wide, and again, the degree depends on the individuals sensitivity. Knowing all this, can we be sure that the fatalities described in scientific journals are due to an allergen and not to the prick with histamine? Of course we cannot. Today, the role of histamine at skin testing is reduced to comparison with localized reactions: the wheal and flare formed by each allergen extract are measured against the wheal and flare produced by the histamine prick. Since systemic reactions are disregarded, allergists do not measure the systemic response to allergen extracts against the systemic response to histamine in the same manner they measure localized manifestations. Grave consequences can arise from this method of testing in highly sensitive patients. A histamine prick may overstimulate the H 1 receptors and call to life allergy proinflammatory mediators and cytokines. This will drastically aggravate the patients condition. If it is asthma, an attack may occur. Those who are prone to anaphylaxis may now have that reaction. Histamine is not in the picture in any article warning of possible complication and even fatalities at AST. If doctors knew about the phenomenon of systemic reactions in general and to histamine in particular, diluted histamine would be used for the first prick. A mild adverse reaction to a histamine prick such as a headache or increasing tightness in the chest, would warn the doctor not to proceed with another prick at an increased dose and thus prevent a more serious aggravation. Doctors are not taught this, moreover, the use of histamine as a placebo in double-blind trials of allergen extracts illustrates how little allergists know about this substance. As a result, a standard testing kit contains only concentrated histamine for a control prick. Unaware of the potential danger of this full-strength histamine, allergists use it in their every day practice. Dont be surprised that a small prick can result in a tragedy: a sting by a bee may kill, and histamine is the main active ingredient in bees venoms, up to 36%. Treating patients with histamine in my practice I observed that, in highly sensitive patients, the slightest dose elevation could lead to transient side effectsflushing, dizziness, a headache or tightness in the chest. Therefore one cannot exclude the possibility that the fatal reactions described in medical sources were the result of a prick with undiluted histamine. If even the well documented pro-inflammatory properties of histamine are not taken into account at skin testing, it is only natural that systemic improvement upon a prick with histamine escapes doctors attention. Doctors
219
are totally uninformed about the anti-inflammatory properties of histamine, even though these are observable even at a rather low concentrations. If a patients medical history indicates high sensitivity, allergy testing should start with diluted histamine. Some of my patients responded positively to histamine diluted 1,000 times, which correlates with the findings provided by Rocklin on the highly individual responses to histamine in allergy patients. In those patients who respond to a prick with mild improvement, a higher dose may provide further relief. Thus, for a patient with high sensitivity, one diluted prick may be enough to improve his pre-testing condition, while less sensitive patients may need several pricks to feel better. It is of interest that, like in the cases of allergen extracts, the size of the local reaction to histamine does not necessarily correlate with the degree of the systemic reaction: a minor skin hive may be accompanied by a dramatic symptomatic relief or the other way around. To monitor patients reaction, it is imperative to separate the histamine prick from the pricks with other extracts. They should be given at two different visits, not at the same visit as is done today. This will allow accurate observation of the reactions, to make the correct judgment as to what produced positive or negative effect, and what concentration of histamine is sufficient to produce it. All this could be applied later in decisions regarding immunotherapy: in choosing between histamine and an allergen extract and in finding the suitable starting dose of histamine if it becomes the treatment choice. The very fact that the histamine prick is given together with other allergens is proof that its biological potency and its dual action are completely disregarded, and it is erroneously perceived as a substance that forms a skin hive only. Since by pricking the skin, we activate immune and chemicallyrelated cells, allergy skin testing is an immunologic test, described in Allergy 1985 as the most sensitive technique for demonstrating the presence of immediate hypersensitivity (p. 217).3 Immediate sensitivity means, first of all, histamine liberation and thus, a potential systemic effect. Strangely, allergists do not consider that theoretical immunology is relevant in the clinical setting. Allergy skin testing will always be potentially dangerous if the powerful biological activity of histamine is disregarded. Immunotherapy will never be successful if the substance with the best potential immunemodulatory effect is not considered for therapy. Allergy will never be a science if in practice, it disregards and/or conceals the basic scientific data.
DELAYED SYSTEMIC REACTIONS Let us speak about yet another very important flaw of conventional AST. Different people react to the environment and to the bodys internal events differently. For instance, some of us can tolerate cold or heat better than others. Another example: there are lucky ones who have a metabolism that burns the calories consumed in cakes and chocolate so fast that not a gram of fat is deposited under the skin, while for many, it seems that each consumed calorie results in weight gain. Our immune systems also function differently in different people. The inner chemical lab contained in each cell may work fast or slowly, gently or furiously, easy-to-be-ignited or hard-to-be-turned on. Thus, when allergy skin testing is performed, the speed with which a persons immune system will respond is unknown. The systemic response may take place immediately or be delayed in time. This is not taken into consideration in conventional skin testing. If immunotherapy becomes the treatment choice, the decision on the composition of the allergen cocktail is made on the basis of the localized wheals right upon the testing. However, judgment needs to be delayed and based on systemic responses, because those are actually reliable. In this connection, an immediate systemic reaction with aggravation does not mean that a certain allergen cannot be used in the allergy shots. The patient should be instructed to monitor his symptoms for the next day. If later on, he feels better, does not need his regular medications, or is able to reduce their dosage, the overall effect should be considered as favorable. The initial, exaggerated response can be attributed to the patients innate hypersensitivity, and small doses at the start of immunotherapy may do the work. Allergen extracts may lead to both aggravation and relief even at the testing stage. Aggravation is rooted in the fact that some extracts may be the triggers of the symptoms. The improvement is the result of the initiation of desensitization: the offender given in a small dose challenges the cells to do their protective job. The same is true of a histamine prick given prior to allergens. It may also produce a delayed systemic reaction with improvement or aggravation. Both, in the case with allergen extracts and in the case of histamine, only lasting symptomatic improvement becomes a reliable ground for successful immunotherapy. Any allergic reaction signals the spill of histamine and the activation of histamine-induced chemistry. Thus, by measuring what produces a stronger reaction on the skin and systemic worseninghistamine or allergen extractsphysicians can actually measure what provokes more histamine
221
release locally and all over the body. Documented are anaphylactic reactions occurring within seconds or minutes after pricks in the absence of any skin reactivity. They are the best examples that even the most severe allergic symptoms may not have anything to do with IgE antibodies. The most powerful example instantaneous death due to a bee sting in a person never exposed to bees before and thus not having IgE antibodies to the venom. Histamine gushing from the mast cells of the bee sting victim is the cause. This proves that it is senseless to conduct skin testing solely for the purpose of finding IgE antibodies that allegedly point to the trigger(s). It is similarly improper to start immunotherapy based on such an unreliable diagnostic procedure and hope it will be successful.
WHO GETS PUBLISHED IN MEDICINE? I can imagine your disbelief that the trivial observations I just described, such as systemic reactions with improvement, have not been described by others. This has an explanation. Certainly, there are doctors who notice such events. However, with the theoretical knowledge being unavailable, they may not know what is behind the relief or may consider it coincidental and, therefore, do not make their observations public. My knowledge of these theoretical data can, of course, be explained by my general interest to basic science, but to a great extent, it was expanded due to the extensive detective search of medical sources, which I undertook under the pressure of my being prosecuted. The medical licensing authorities were not satisfied with the demonstration that my patients recovered and the numerous scientific references I provided. They demanded I find confirmation from the leaders in allergy research. The investigation was an eye-opener for me regarding the undercurrent life of the medical society, and rules governing it, including privileges for publication. The primary reason why such information does not turn up in journals is the difficulty involved in having an article published. For an author who does not have a name in the scientific world and is not supported by the authorities, the chances for publication are almost nil, especially so, if the expressed view goes against the existing trends. The primary sponsors of almost all medical publications are the pharmaceutical giants, and periodicals sponsored by them are full of ads promoting their products. The profile of the journals is in direct correlation with the manufacturing profile of the sponsors and the advertised products. Before being published all articles are censored, or, as it is called in science, peer-reviewed. The reviewers are usually the elite of the given medical
field whose names are on the lists of the Editorial Boards and Boards of Directors of all central journals. The majority, openly or in a hidden way, are connected with the drug manufacturers. Information about a symptomatic improvement in response to a prick with histamine would prove its systemic response, hence its curative properties. This could become hard evidence in favor of its beneficial employment in therapy. Histamine would become a strong competitor of the medications advertised in these very journals, and therefore information related to its neuro- and immunomodulatory properties will never pass censorship. The best proof that histamine must be considered a dangerous competitor for over two decades is found in the following fact: its successful use in double-blind trials conducted on asthma and allergy patients in the medically advanced Japan have not been published in English, the main language of science. I started to thoroughly study bibliographic sources after I had found that occasionally such information slips through inadvertently. Here are several of such papers published in the December 1997 issue of JACI:17 1. K. Ito. Clinical evaluation of histaglobin for bronchial asthma a double-blind study using human gammaglobulin as control. (in Japanese). Rinshoutokenkyuu 1979;56:3085-69. 2. A. Ito et al. Clinical effect of histaglobin on nasal allergy double-blind study (in Japanese). Jibiinkokatenbo 1979:22:38-49. 3. J. Kukita. A double-blind study of histaglobin on allergic dermatitis. (in Japanese) Nishinipponhifuka 1980;42:470-7. It is peculiar that the references warn you not to try to find the material in English by writing in brackets In Japanese. By pure luck, I was able to read the English translation of these articles done by a patient of mine. My personal experience also shows how undesirable for clinical immunology effective methods are. In the early 1990s, in Toronto, an international conference on chest diseases took place, and asthma was one of the topics. I submitted an abstract on my successful use of histamine on about 2,000 patients. The conference organizers rejected the abstract due to logistics problems: a noncompetitive problem, the answer stated. A new practical, and successful approach was of no interest to those who were organizing a conference on that disease. All this at the time when the mouthpiece of allergists, their central journal admits: Despite advances in the understanding and management of asthma, it remains the only treatable (!?) condition in the western world with increasing morbidity.13
ALLERGY SKIN TESTING AND IMMUNOTHERAPYSUMMARY Here is what makes allergy skin testing and, hence, immunotherapy based on it, failed enterprises. The interpretation of skin testing is based on the scientifically unfounded hypothesis that allergies are strictly IgE-based diseases, and that all triggers can be revealed at the testing. In fact, it is mainly mast cells histamine hyperreleasability that underlies the pricks. Since the majority of patients have non-specific or mixed forms of allergies, skin testing aimed solely at searching for IgE antibodies is frequently pointless, they are just bystanders. Many have allergies to substances that do not exist in the standard form of allergen extracts and cannot thus be used in testing; numerous pollutants are an example. There may be false-positive skin reactions to those allergens, which do not produce symptoms in real life. There may be false-negative skin reactions to allergens that provoke symptoms. This event completely undermines the IgE dogma. The selection of allergens to be employed in immunotherapy is made solely on the basis of the skin manifestations without taking into account the accompanying systemic reactions. Mild and moderate systemic reactions with aggravations are missed at the testing, therefore the subsequent allergy shots may contain aggravating and life-threatening allergen(s). Systemic reactions with improvement are missed because they are not expected to be observed, therefore the allergens potentially effective for therapy may be excluded from the therapeutic allergen cocktail. The judgment on the therapy does not include the delayed systemic response, whereas it is the net result that matters, and not the transitory initial reaction. Histamines high dual systemic activity is disregarded, and it is reduced to a measuring unit of the local reactions produced by other allergens. Histamine pricks and allergen pricks are given together, which prevents differentiation between the two systemic effects. Conventional diagnostic kits contain only concentrated histamine, and its high potency may lead to a severe reaction and even fatality in patients with high sensitivity. Histamines immunemodulatory effect is not known to clinicians. Therefore a possible improvement after a prick is left unheeded, and the chance to use histamine in therapy is lost.
The fact that histamine is a neuromodulator is unknown. Therefore potential changes in neurological or nonspecific symptoms that accompany allergies are missed and remain untreated. A chain is as strong as its weakest link, and in todays allergy practice, histamine is the one. This is because basic science teaches us that allergic reactions occur due to the inability of the protective histamine-related immune tools to control the negative histamine-related forces. In the chain of events during allergic reactions and their reversal, histamine is the central link. Since the theoretical knowledge about histamine, especially about its protective properties, is ignored in clinical allergy, the strongest turns into the weakest. The elimination of this vital information from medical textbooks has necessitated a substitution with nonessential data. The resultant misinformation has led to invalid concepts, redundant procedures, mistaken judgments, failed therapies, grave accidents and escalating morbidity in all allergic and related diseases and, most tragically, an ever-increasing rate of mortality in asthma. Allergy skin testing could be the test conducive to successful immunotherapy. Today, it is a procedure, which doctors cannot support theoretically or implement properly in practice. Conventional AST is a helpful decoya sort of placebo involving both the patient and the doctor in illusion. It inspires patients with hope and brings them to the offices of allergists who eagerly perform numerous pricks. The more pricks, the higher the pay. I saw a patient tested for camel (in Canada!). Many are tested for various foods even though such tests are considered inconclusive by allergists themselves. Almost all are tested for hay fever, even if no symptoms occur during the pollen season. When the purpose that guides the doctor is of a monetary nature, the pricks to camel in northern countries and to polar bears in California can be considered the norm. Todays skin testing is a performance impressively staged, lucrative for the performer and protected from any liability and/or responsibility if performed according to the existing guidelines.
THE BRIDGE TO SUCCESSFUL IMMUNOTHERAPY Only successful and risk-free immunotherapy can rid allergy patients both of their symptoms and daily medications. For immunotherapy to be effective, skin testing must become its reliable first step, and the following rules must be observed at the testing: Systemic reaction should become the focus in the interpretation of the tests, while the skin signs should be secondary in importance.
Patients should be skin-tested when they have symptoms, otherwise doctors will be unable to elicit the changes after having made pricksexactly what we have now. Hay fever patients are the exception, as their seasonal symptoms are always indicative of the diagnosis. However, testing in season with the provoking allergen may severely aggravate their condition. A histamine prick and pricks with allergen extracts should be given separately, one-two days apart, to observe and compare the systemic reactions after both sessions. The initial prick should be made with diluted histamine, and histamine concentration in further pricks should gradually increase either reaching the standard concentration or until a systemic reaction is observed, not just a skin hive. This will take into consideration the individual hypersensitivity and will, thus, help avoid accidents that may occur with the currently employed concentrated histamine. The decision regarding what to use for immunotherapyhistamine or an allergen extractshould be made upon the assessment of the delayed systemic response, and not only the immediate one. Symptoms other than allergic ones should also be elicited by proper questioning before and after the procedure, and the patients told to monitor the changes within the 2448 hours after the testing. Systemic reaction with improvement and not the size of the wheals should be the criterion for what should be used in allergy shots. Today, skin testing does not preclude the use of steroids, even though the drugs suppression of the immune responses stifles systemic reactions. Patients who do not have physiological dependence on steroids should stop taking them. In the case of dependence, the weaning process requires special measures and even then, it may not be possible due to the aggravation of asthma or drug dependence. Today, AST does not take into account delayed reactions. Therefore the patients are only instructed not take antihistamines shortly before the procedure, but they should refrain from taking any of their regular medications a day afterwards. Asthmatics should observe if their need for bronchodilators changes and not to use any if there is no breathing difficulty. All this will make the judgment regarding the systemic response unmarred.
ANTI-CHALLENGE TEST There is a notion in medicine called a challenge test. To confirm the diagnosis, doctors create a situation in which the patient is exposed to a major trigger, and
the symptoms are bound to occur. In other words, the purpose of a challenge test is to provoke an aggravation. For instance, to confirm the diagnosis of asthma, a patient inhales a substance that causes an asthma attack. If there is a recorded aggravation, doctors conclude that this asthma challenge test is diagnostically valuable. However, if a diagnostic test leads to an improvement, it stops being a challenge test and requires a different name. The fact that doctors are warned regarding possible adverse reactions and even fatalities means that allergology sees (at least subconsciously) AST as a variant of a challenge test to the skin. After having monitored hundreds of cases, the idea came to me that skin testing should also be viewed as a potential anti-challenge test, a non-existing notion in medicine. An anti-challenge test should be done with the purpose opposite to the challenge testto provoke symptomatic relief and use it as a guide in choosing the therapy. One prerequisite is needed for that: the doctor must know that skin testing is a procedure not only with a potential systemic reaction with aggravation, but one with possible improvement as well. Any physician who conducts the test must know the duality of the immune systems functioning. Only then, will he expect symptomatic relief as a possibility both upon a histamine prick and at the next session with allergen extracts. Having done both, he should compare the degree of the relief that occurs with each test. Before skin testing, the examiner obviously does not have a clue as to the possible reaction: will there be an aggravation? an improvement? no symptomatic change? The doctor will be able to find what to use in the subsequent immunotherapy only if the purpose of testing is to find what will improve the symptoms, and not what produces the biggest wheal. Already at the testing stage, the patients should be taught to observe their symptoms. Before testing, a thorough questioning about the symptoms experienced at the given moment and their changes afterwards clarifies the common origin of allergic symptoms and the ones that initially do not seem to be allergy-related. Among them, there may be an abdominal discomfort, muscular pains, headaches, irritability, fatigue, etc. Because AST can improve a number of symptoms and conditions, often nonspecific, it should be considered an antichallenge test worthy of conducting. During the course of immunotherapy, the observation continues. In fact, every allergy shot should be looked at as an anti-challenge test, since its purpose should be improvement. Do patients continue to improve? What symptoms go away and for how long? If the symptoms reappear, are they as strong as they were before the last injection or milder? Does the patients requirement for
drugs continue at the same level, or does he needs less drugs? Patients learn to inform the doctor about all the changes as well as the mildest side effects, so that further adverse effects are prevented by dose adjustment. Their feedback will also allow the doctor to speed up the recovery by accelerated dose increases, if the recovery is slow. The treatment based on the patients observations makes the patient responsible for providing the needed details. He becomes an active participant in the treatment process, and my experience shows patients love it. Reactions to allergen extracts or histamine are a pendulum that may sway in both directionspro-disease or anti-disease. Following the abovesuggested separation of histamine and allergens, use of diluted histamine and monitoring systemic reactions will inevitably lead to a safe test and later, to an effective immunotherapy. The use of a test which will reverse the symptoms is a dream come true in any field of medicine, and this dream is easier to realize in allergy than in other less reversible chronic conditions. Allergy can use skin testing and subsequent allergy shots as a tool to substantially improve the patients condition, or often even cure them. Recently, I found the information that gives legitimacy to my idea of antichallenge testing. The biological mechanism that underlies this test is explained by hormesis, the phenomenon especially common for the immune system functioning. Hormesis is the stimulatory effect produced by small concentrations of any offensive substance or any harmful effect on the organism, the immune system in particular. Mild stimulus cannot cause a significant aggravation; on the contrary, it challenges the protective forces. Even radiation in small doses can be beneficial for the health, as Japanese sources inform us. In a similar way, psychological stress, when short-lived and/or not too overwhelming, is helpful in making us stronger in withstanding stress in general. Introduction of sub-toxic amounts of offensive substances or influences teaches the cells to defend us. Defensive performance of the immune system is its production of protective chemistry. The symptomatic relief at AST is the result of the chemistry implemented, first of all, by the local units made up of T-suppressors, LCs, mast cells and then further involvement of other related cells. This proves the logic of conducting this diagnostic procedure with the expectation of relief, that is, as an anti-challenge test. Actually, homeopathy is based on the premises of hormesis; ironically, so is immunotherapy employed by allergists themselves. Mechanisms underlying immunotherapy remain obscure. Thus, it is difficult to develop a logical strategy for improving the treatment, states
an editorial of JACI and concludes: The onus is now on immunologists to develop coherent strategies from which improvements in treatment can be developed.14 All allergy medicine should do, is to accept the unarguable proof that histamine-related mechanisms underlie immunotherapy as they underlie all allergic processes, good and bad. This will allow them to use skin testing and subsequent allergy shots not blindly, as it is done today, but with the knowledge of the fundamental laws of nature.
ALLERGENICITY AND IMMUNOGENICITY Conventional immunotherapy is based on the postulate that the elevating doses of the offensive allergen extracts should desensitize the patient, i.e., make them less sensitive to these allergens. Such an improvement should be due to the protective immunogenic effect of the extract its immunogenicity. However, the expectation of the positive results is often shattered by adverse reactions. This is not surprising because the very penetration of a trigger into the body challenges the pendulum of the immune system and harbors the danger of a negative reaction, namely allergenicity. It is only individual sensitivity that delays an adverse reaction, but each dose increment potentially increases this risk. Patients with a higher sensitivity may have side effects even at an early stage, and the doctors disregard for these may lead to most severe accidents. Medical journals provide descriptions of deaths of asthmatics caused by ragweed or dust mite extracts provided during immunotherapy. At the same time, surprised authors write that patients desensitized to one allergen stop reacting to other triggers. Those who read Rocklin explanation of this phenomenon in Allergy 1985 (p. 192),3 would not be surprised: any successful immunotherapy results in the development of H2 receptors and in generation and maturation of T-suppressors. The suppressors gain the control over all allergic reactions, irrespective of what activates their receptors, allergen-specific triggers (allergen extract) or nonspecific triggers (histamine). PEPTIDES Any allergen extract that includes a trigger is potentially dangerous. Medicine dreams of a substance devoid of allergenicity and possessing only immunogenicity, a substance that could rid patients of their allergies, no matter what their trigger is. Do they exist? They do. Non-stimulatory peptides. Remember that word. Peptides are coming into fashion in allergy. Regrettably, not in clinical settings despite (or due to?) their potential efficiency.
An allergen protein consists of peptides (a group of amino acids). Nonstimulatory peptides are only fragments of the protein. If the whole protein can provoke symptoms when used in shots, a peptide, with its allergenic part removed, cannot. This almost completely eradicates the side effects of allergen extracts. Conventional allergy recognizes only specific immunotherapy, the one that eliminates hypersensitivity to the injected allergen. Injections of peptides are this, a nonspecific immunotherapy, since their specific, allergenic part is not there. Nonspecific peptides may invoke an immunomodulatory effect depending on what receptors they activate. For example, it is possible to develop peptides that will be able to stimulate only our protective H2/3 receptors and thus contribute to allergy-protective cytokine production. A peptide vaccine was shown to inhibit histamine release(it) reduced IgE antibody formation and serum histamine concentration, and abolished systemic anaphylactic reactions in response to allergen challenge. This peptide may form the basis of a vaccine in a new approach to the immunotherapy of atopic (allergic) disease. This comes from the most prestigious British medical journal The Lancet.15 Note the year of the publication1990. A Canadian source written five years later agrees that a peptide based on house dust mite extract has the potential for controlling and eliminating the patients specific allergy while providing a glimpse of the future.16 In fact, house dust mite extract, even if not reduced to its safe part, may play the role of a non-stimulatory peptide when it is administered to a patient who is NOT specifically allergic to it. When skin-testing with dust mite, I always watched for improvement. If there was one, I employed the dust mite extract for therapy, no matter what size of wheal it formed. The use of a nonspecific, so to say, irrelevant, substance for treatment is not new in medicine. It is done to stimulate defensive forces. Thus, substance P is the number one pro-inflammatory neuropeptide among sensory nerve mediators (like histamine among allergy mediators). However, substance P also possesses modulatory features (also like histamine), and its positive effect manifests in the pharmacological agent Capsaicin. This plantderived product provides relief when used in an ointment for arthritis (zostrix) and intranasally in chronic rhinitis (another proof of common roots of immune and some neurological symptoms). Although neither pharmaceutical compendia, nor researchers clearly explain the mode of action, the stimulatory effect of this seemingly irrelevant chemical is, actually, rather
simple. It is based on the principles of dual function of the immune and nervous systems. Capsaicin evidently activates those receptors that conduct anti-disease chemistry. Another example of therapy is successful treatment of bladder cancer with bacillus of tuberculosis vaccine, even though there is no immediately understood relationship between cancer and tuberculosis. However, in applying the weakened bacteria from the diagnostic TB vaccine, the bacilli appear collaterally to activate a lot of protective immune-related chemistry that usually accompanies the bodys fight against TB. Because the body works as a system, immune-related chemistry is rather like an army of mercenaries: properly invoked, they will fight anything and everything. Among the invoked newly-formed chemicals, there may be protective cytokines that nonspecifically reverse allergic reaction reactions. Allergy medicine knows that to reverse an allergic reaction, one must, first of all, inhibit histamine release. An immune stimulant can achieve this only via H2/3-receptor activation. Therefore we can confidently state that these extraneous substances possess the ability to activate the H2/3 receptors, and through this, contribute to the activity of T-suppressors and the release of anti-allergy mediators and cytokines. Active T-suppressors do not care what activates them and reverse any allergic reaction. My personal view is that, if peptides are effective in trials and show they can reduce not only the hypersensitivity to specific allergens, but also affect the general, nonspecific factors, they will most probably be kept in laboratories for decades similar to histamine and histamine congeners. The proof may be found in the fact that they were developed at least a decade and a half ago, but have not been used even on those for whom all other means have failed. The reasons are familiar: the range of a drugs effect must not exceed the desirable (by the manufacturer) effect and must comply with the basic marketing principles of repeated sales. No single drug is allowed to become the replacement of the rest of the existing drugs/allergen extracts. Only an extremely nave person can hope that the drug industry will willingly give up its numerous medications for the sake of allergy patients.
HISTAMINE VS. ALLERGEN VACCINES AND PEPTIDES Which of the three histamine, allergen extracts or peptides makes the best choice for immunotherapy?
231
Comparison of histamine with conventional allergen extracts is in favor of histamine. Histamine is a synthesized body product with well-studied immunomodulatory properties. Its virtue is that it obeys the laws of nature. Allergen extracts are substances which may unpredictably provoke a strong, even severe allergenic responses. Their foreign nature and allergenicity preclude predictability during immunotherapy; it is impossible to know which of the ingredients, and at what dose, they will induce an adverse reaction. This introduces a great risk and explains why specific immunotherapy is often accompanied by complications and is, therefore, often conducted under the protection of steroids and/or with resuscitation facilities at hand. Comparison of non-stimulatory peptides with allergen extracts favors peptides. The reason is that potentially hazardous elements of the substance are eliminated. At worst, peptides are ineffective but not harmful, since they are devoid of allergenicity, which is so common in allergen extracts. Comparison of histamine with peptides favors histamine. Since any successful immunotherapy inevitably results in the growth of the H2 receptors, we can hardly create a chemical better than the one nature specifically designed for developing them, namely histamine. Should we go against nature because drug companies say so? Besides, peptide-use in every day practice is in the remote future; they will definitely have a much higher price than histamine, and this burden will be borne by the consumers. No matter which consideration one explores, from the simple standpoint of cost effectiveness, therapy with the inexpensive histamine is more logical. Peptides can be developed as one more immunomodulatory tool. For now, we should not forget that we already have an inexpensive remedy available and at our fingertips. The wide scope of histamines activity in the body, its ability to involve the nervous system in the process of recovery, and through it, the rest of the body, adds further weight in its favor. The picture may look different depending on what motivates one: if one is trying to help patients who suffer, ones priorities are radically different from the point of view of the pharmaceutical alliance whose sole interest is their revenues. What is good for a patient is not necessarily good for the industry.
DEVELOPING THE NEW METHOLD Discoveries often come in the following manner: we all know how things are, but then someone comes along and wonders why they cannot be different.
Something of this sort happened to me. My understanding of reactions characterized by systemic improvement go back to my work in the Soviet Union. When I was in residency in internal medicine, allergic diseases were not taught. Allergy as a branch of science was only emerging in the world. IgE antibodies were discovered in 1966, and they were soon proclaimed to be the foundation for this new field which gained its general recognition as allergy medicine because of this discovery. I was among the first doctors in the former Soviet Union to specialize in allergy at the Moscow Allergy Institute that had opened in the early seventies. The knowledge I gained during my specialization adhered to the traditional scheme: allergic diseases and asthma are always allergen-triggered and therefore IgE-mediated; skin testing should focus on the signs produced on the skin which reveal the specific offenders; these offenders should be eliminated and/or used in extracts for desensitization. After specialization, I continued my work in the central teaching hospital in Petrozavodsk, the capital of Russias Northwest republic of Karelia. This hospital was the basis for teaching medical students and also the consulting centre for local hospitals. Complicated cases were referred here from all over the republic for diagnosis and initiation of the treatment, which was then to be continued by the referring doctors where the patients lived. Allergies and asthma were common but often remained undiagnosed and were treated as recurrent pneumonia and/or infectious bronchitis with antibiotics (as they are still now, by the way). An important difference between medicine in the Soviet Union and the West was the fact that drug pushing did not exist where I worked because of the absence of a market economy, the lack of influence by drug companies, and the resulting unavailability of many drugs. This explains why medicine in the Soviet Union, although technologically inferior to the West, placed a much higher value on the needs of the patient and doctors were trained to be far more attentive in their clinical approach. Doctors there were reluctant to prescribe steroids as frequently as their Western colleagues did, even when they became available. Experience had taught us that the immune system, not suppressed by steroids, is more resilient, and properly selected immunotherapy is more efficient in this setting than in cases of a steroid-scorched immune systems. This simple fact accounted for my success with immunotherapy which, from the very start, I perceived as the most logical treatment.
Medical service was free for everybody in the Soviet Union. The hospital where I worked provided free accommodation to the referred patients for a week or two. Within that short period, I had to be ready with the diagnosis and was expected to start the treatment. I did not have the luxury of rejecting severe asthmatics as candidates for immunotherapy, since the very fact of their being referred to his hospital meant that they had exhausted all other means at their local hospitals. Nor could I wait until they were in remission to skin-test them, even though, according to the accepted standards, symptomatic asthma patients were not suitable for testing. I was the last hope for those asthmatics. Under those conditions, necessity became the mother of invention. A thorough medical history was the first step in the decision whether to do skin testing. I was taught that in severe asthmatics, pricks with allergens could aggravate the condition. To prevent any adverse reaction to histamine, uniformly described in allergy medical literature as Evil Number One, I separated histamine pricks from the pricks with allergens and started to use diluted histamine. This enabled me to determine, in the case of aggravation, which of the two was the real cause of the reaction. In order to monitor the patients condition, I asked them about their symptoms right before giving the first pricks. My actions were dictated by professional prudence. Knowing the dangerous side of histamine, I repeated my questions regarding the symptoms after the pricks. To my surprise, time after time, I heard about systemic improvement, a fact I had not been taught and hence, had not expected. Testing with allergens the next day showed that they too could render an improvement. I learned that both histamine and allergens could sway the pendulum for the better, and this was not accidental. I started to compare when relief was more pronounced: with histamine or with allergens. The logic guiding me was that if a prick improved the symptoms, injections with the same substance could improve the condition still further. Naturally, this would apply the other way aroundthe substance that produced side effects during the tests should not be used for therapy, as it might worsen the symptoms. I worked intuitively, and my intuition was base on my initial observations and eleven-year clinical experience. In Russia, like in many European countries, along with allergen extracts, histaglobin (histaglobulin) was available as a conventional means of treating allergies, while histamine was used in testing only. The combination drug histamine plus gammaglobulinowed its effectiveness to histamine, since the
very small amount of gammaglobulin in it was below any biological effect. I started to use histaglobin effectively in various allergies and in asthma. I saw my patients daily for about two weeks and made detailed recordings of their symptoms. These records helped me understand many things, and among them, the importance of the delayed systemic reaction. I saw patients whose symptoms could change for better or worse within minutes after the pricks, and those in whom response would become evident hours later. I learned to instruct the patients to monitor their symptomatic changes, not only immediately upon the testing, but also within the 24 hours after they left the office. If a person listens to his body, he notices even a mild difference in his condition, as did my patients who readily shared their observations. I took the delayed response to the pricks into consideration before making decision on what to start immunotherapy withhistaglobulin or allergen(s). The analysis of the recorded symptoms revealed that even if there was an adverse reaction, it did not necessarily mean that histamine or the chosen allergen could not be used for treatment. A prick with histamine could be an overdose for a sensitive immune system, and thus could cause an immediate aggravation. However, the reaction was usually mild and brief, and after that, the patient often had a partial or complete symptomatic relief. I figured out that in such cases, the treatment should start with a lower dose and be effective. On the other hand, if the immediate relief was short-lived, it meant that the patients sensitivity was low, and to prolong the relief, the treatment would have to start with a higher dose. This practice of observation proved the accuracy of my interpretation of the responses. Developing this method further, I came to the conclusion that even if there was no reaction at the testing, positive or negative, this did not mean that the patient was not a good candidate for immunotherapy. For some non-responding patients, the testing dose could have been too low to invoke an immune response at once, but a higher dose could still make a breakthrough. I usually started treatment cautiously by gradually increasing the doses of histaglobulin. If several injections did not change the patients condition, I did the same with the selected allergen, and noticed that house dust mites produced the best effect among the extracts. The majority of patients at AST reported greater symptomatic relief after a histamine prick than after pricks with allergens, and for them, histaglobin became the treatment choice. What I was doing was not an experiment with severe asthmatics, since histaglobulin had been used all over the world. The novelty lay only in my
specific approach. First, I precluded the occurrence of aggravation by separating the pricks with allegedly dangerous histamine from the allergen extracts and also by using diluted histamine. Secondly, trying to avoid aggravation, I introduced detailed questioning and observation before and after the pricks. I did not conduct uniform skin pricking, but tailored it to each individual. Similarly, my immunotherapy was customized and not a one-sizefits-all approach. To my mind, this is a more scientifically rigorous approach. My thorough questioning and observations had one more benefit. Although I was treating allergies and asthma, I noticed that certain symptoms disappeared along with the targeted ones. Sometimes, it happened right after the skin testing. A question, What other symptoms are you having now? asked before the testing and, Are you still having (headache, stomach discomfort, fatigue, etc.) now? asked after the testing would often reveal that many non-allergic symptoms were, in fact, allergy-associated. Twice a year, when the patients would come for a follow-up consultation, they told me about the disappearance or improvement of unrelated medical problems in the course of their immunotherapy. Well matched therapy, be it histamine or an allergen extract, worked broadly and systemically. I published my observations regarding systemic reactions and how to handle the transition to immunotherapy in the most prestigious Russian medical journals, Therapeutic Archive and Clinical Medicine. My observations and conclusions about systemic reactions with improvement at allergy skin testing were the first, and as far as I know, the last of this kind in the worlds medical literature. In 1978, I spoke about my asthma treatment based on the evaluation of systemic reactions at the fourth International Symposium on Circumpolar Medicine in Novosibirsk, the scientific centre in Siberia. There, I reported that certain neurological symptoms, hypothalamic (or, as it was called in Russia, diencephalic) syndrome disappeared in a patient who was successfully treated for asthma. For several years, apart from a pediatrician who specialized in allergy, I was the only allergist in the republic and thus did not have any one else to consult with. Great personal responsibility for each case dictated that I should be on the lookout for even the slightest symptomatic changes. By nature, I attend painstakingly to details, and I am always inclined to analyze, assimilate and co-ordinate the numerous details I observe. All the while, I tried to relate my observations to what textbooks taught and found there were gaps in theory, which affected clinical application.
With much better access in Canada to the numerous theoretical sources, using the data that had accumulated within the 15 years of allergy research as a specialty, I searched for the scientific basis to my approach. I felt allergy alone was unable to explain the chemical processes of the immune system as well as its synchronized work with other major systems. It took me years of reading hundreds of theoretical sources in various fields to understand the basic mechanisms of the immune system and its interrelated functioning with other body systems. I discovered for myself psychoneuroimmunology, PNI, a new science that emerged in 1981, and understood it was the only one to have the explanation of the regulatory processes underlying immune and related diseases. I saw that basic scientific data related to allergic diseases were not recognized by conventional medicine and hence, not taught to medical students. I suddenly realized an appalling fact: anything that might lead to the application of these data in clinical medicine tended to be immediately concealed, and this concealment appeared to be very well organized. This secrecy in clinical medicine continues.
Allergy Skin Testing and Immunotherapy ENDNOTES

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. S. Szefler. Challenges in assessing outcomes for pediatric asthma.JACI 2001;107:456-64 General discussion. JACI 1996;97:885 Kaplan, ed. Allergy 1985, pp. 367,679,219,217,192 S. Repka-Ramirez et al. IgE levels in chronic fatigue and control subjects. JACI 2000; 105:S359 A. Kay. NEJM 2001;334:30 T. Jakob et al. Multistep navigation of Langerhans/dendritic cells in and out of the skin. JACI 2001;108:688-96 D. Engle et al. Comparison of the sensitivity and precision of four skin test devices. JACI 1992;90:985-91 M. Kaliner. Vision in Allergy: Impact on Health Care Reform. General discussion. JACI 1996;97:885 A. Frew, A. Kay. JACI 1988;81:1117-21 F. Lockey et al. JACI 1987;79:660-77 US Federal Register 1985;50,15:3097 K. Kelly et al. Skin and sereologic testing in the diagnosis of latex allergy.JACI 1993:91:1140-5 I. Amirav et al. What do pediatricians in training know about the correct use of inhalers and spacer devices? JACI 1994;94:669 M. Chapman. Editorial. JACI 1991;88:300-2 D. Stanworth et al. Allergy treatment with a peptide vaccine. Lancet 1990; 336:1279-81 I. Ferguson. House dust mites and asthma, The Can. Journal of Diagnosis, 1995;12:1-2 H. Yoshii et al. A couple of histamines JACI 1997;100:816
237
PART SEVEN
BRONCHIAL ASTHMA
THE GROWING PROBLEM OF ASTHMA Among diseases of hypersensitivity, bronchial asthma deserves special attention because, as the leading immunology journal states Asthma is the most common chronic disease among children and the most frequent cause of hospitalization, and it is a major cause of disability.1 Like all allergic diseases, asthma is growing both in incidence and mortality, however, unlike the rest of them, the seriousness of asthma is due to its risk of death. Interestingly, the disease has been known for at least five thousand years but until recently, was not generally considered as fatal. The statistics on asthma fatality given in 1987 in the leading textbook on internal medicine, Harrisons Principles of Internal Medicine, cite 3 people per million dying as a result of asthma. According to The Medical Post,2 mortality in Western countries was at 15% when the asthma epidemic began in the 60s. Within the 3 decades, the rate went up to 15% and then 2530% in certain areas, with New Zealand and Australia generally recognized as having the highest mortality rate. Todays numbers differ from source to source and from country to country, but if we are to believe the most recent statistics, Canada now is the leader in death from asthma with a shocking annual 10 deaths per 10,000 patients aged 5 to 45.3 The increase in mortality is tremendous all over the world and among different groups of the population, but the speed with which the asthma statistics are rising among children is beyond belief. Indeed, in 2002 the World Health Organization was forced to declare asthma a global epidemic.
Bronchial Asthma 239
In Canada and other western countries, morbidity has increased most among pre-school children, with a 300% increase in hospital admissions.4 In 2000, the leading immunological journal wrote in the chapter Crisis in Asthma Care that there has been a 75% increase in prevalence since 1980, and a 160% (!) increase in children under 5 years of age.5 The increasing severity and mortality of asthma observed lately in all countries but especially in the developed world necessitate a thorough analysis. There is no doubt that our technological and chemically-focused civilization with its characteristic abuse of nature is a contributing factor. This phenomenon is described by so many authors that there is no need to repeat the already well known facts. However, an exclusive focus on the environmental issues would mean turning environmental factors into the only causes of the disease, which would be unscientific. The priority of relatively nonpolluted New Zealand and Australia in asthma rates is proof, so is existence of people who live exactly in the same or much more polluted conditions without asthma. This results in another conclusion: Avoidance of allergens that provoke asthma is a keystone of treatment but is often easier said than done.6 Furthermore, it is not just the difficulty of the elimination of triggers that makes the treatment a failure, but rather the subsequent approach that turns the allergens into the cause. There is a major problem here and it is recognized by a leading expert in his article entitled The Epidemic of Allergy and Asthma.7 He observed: The past 30 years have witnessed a spectacular increase in our knowledge of the cellular and molecular mechanisms of allergic disease, which has been paralleled by the rising trends in the incidence and health impacts of these diseases worldwide. (Emphasis added by me.) This can mean one thing only: something must be terribly wrong with this knowledge so spectacular only because of its failure to help people; the treatments based on it must be reconsidered and a new approach must be found. Medicine ceases to be a useful science if it cannot help people, as that is its only goal. The purpose of the following sections is to discuss purely medical factors which underlie the origin of asthma and contribute to its severity. They are related to the misinterpretation of the disease of asthma, the manner in which it is misdiagnosed, and the way in which is management, which by any standard, cannot be considered effective. We will disclose some the information known to only few leaders in the field. This information is not generally known to doctors or the public. Only by changing our conceptual under-
standing of asthma, can we help the patients. The price asthma patients pay is too high, and society must do its utmost to save them.
PROBLEMS WITH CURENT DEFINITIONS OF ASTHMA Judging by the results of conventional management, what asthma really is remains unknown not only to the general public but to doctors as well. Once, I came across an article, in which two European respirologists wrote: In light of this enormous research effort, little real progress has been made since 1980s to clearly define asthma. To some degree, defining asthma is like defining love: we all know what it is, but no one can actually define it. This inspires lyrical images of the disease but gives little clarity. Medical textbooks define bronchial asthma as a disease of the airways. Then, they list the symptoms and potential triggers. This is correct only in the sense that the lungs and bronchi are the organs that manifest the symptoms. Emphasizing the role of allergens in a definition does not elucidate the nature of the disease, nor does it explain why symptoms may arise without any trigger, or why only some people respond to the triggers with symptoms, while others remain asymptomatic. Such definitions do not specify the origin or nature of the disease. It is like saying that a headache is a disease of the head characterized by pain in the head. An international panel of experts working under the auspices of the World Health Organization defined asthma as a chronic inflammatory disorder of the airways in which many cells play a role. With all due respect to the experts of the WHO, I find this wording rather vague because, after all, in all diseases, many cells play a role. For example, rheumatoid arthritis also fits this definition, so does chronic bronchitis, which even has the same locality as asthma. Another inaccuracy is that by calling asthma an inflammatory disease, one accentuates the general, non-specific, secondary aspect, whereas the primary defects that lead to the inflammation are not mentioned. Thus, the flu is not an inflammatory disease of the nose and throat but a viral disease. Moreover, the term inflammatory, mostly known as an infectious event, blurs the difference between two different medical notions, which are worlds apart: a microorganism as a causative agent in infections as opposed to a genetically predetermined malfunctioning of immunocompetent cells in asthma. The only precise thing in the WHOs definition is the location of the symptoms, but even that is not specific to asthma.
Bronchial Asthma
241
Dr. M. Sears, a leading Canadian asthma specialist, states that an allencompassing definition remains difficult to construct. He assumes that genetic studies may help but looks for the causes outside the body, and again, we hear about house-dust mites, indoor pollutants, passive smoking, childhood infections and their treatments. It is not surprising that the superficial, triggering events replace the inner predisposing factors, and his speculations over the definition of asthma relate it to the time of the first wheeze, sensitisation with cigarette smoke, risk of mothers smoking, etc.9 The leaders in allergy have recently started to present asthma as a disease characterized by degenerative structural changes in the bronchial tree and the lungs. The term invented for this is remodelling. In this interpretation, asthma is no longer the most reversible disease driven by the abnormal regulatory processes in the immune system, but an affliction characterized by tissue degeneration and scarring. Organic changes in the bronchi and lungs cannot occur without underlying pathological processes, but allergists do not provide clarification as to what these processes are. This new concept of remodelling is dangerous in several aspects. First, it dissociates the structural changes from the cause, without which they cannot occur, and which by definition cannot be reversed/ corrected. Second, it changes the perception of asthma as an immune disease and turns it into a disease of tissue degeneration. Third, it changes the general perception of asthma as being a reversible condition, into an irreversible one whereas organic tissue changes are observed in very advanced stages of the illness. If this concept is accepted, we will see the statistics in asthma getting grimmer day by day, because the treatment, should be applied to the core of the disease, not just the organ in which it develops. Otherwise, doctors will just manage the illness and wait and see if structural damage will occur.
FUNCTIONAL DEFINITION OF ASTHMA The definition of any disease must specify, apart from location, the etiology the cause, the pathogenesisthe inner defectsleading to the disease. It is hard to expect such a definition for asthma, since the received wisdom is that although many factors are known to trigger asthma attacks, relatively little is known about the underlying causes.10 The most reputable textbook also admits that No detailed definition of asthma has won universal acceptance.
The reasons are the histopathology is poorly understood, and most importantly, the underlying etiology is unknown.11 In asthma, as in all allergies and related diseases, triggers are presented as the causes and inflammation as the primary event. Medicine does not explain what factors predispose a person to this inflammation, as well as what is behind spontaneous asthma attacks that do not have an identified trigger. A scientific definition of asthma should incorporate the locationairways; the causesthe defects in the genes regulating immune responses and the resultant defects on three levels: biochemical, molecular, cellular; the primary molecular defect consequent to the genetic flawsH2/3-receptor inefficiency; the primary cellular defect consequent to the same receptor insufficiency qualitative and/or quantitative T-suppressor deficiency and exaggerated histamine releasability by mast cells/basophils; the primary biochemical defect accompanying the same receptor insufficiency or resulting from itlow levels of the intracellular enzyme cAMP, central for the normal functioning of the immune system; the cumulative effect when mostly pro-disease chemistry results in immunerelated, inflammation-like process; Such a definition would meet all the criteria needed to understand not only where in the body the disease develops but also where it originates, and what the stages of its development are. It would suggest the key target for treatment, i.e. the need for activation of the inefficient receptors, and through it, to activate the whole protective allergy-responsible aspect of immunity. A definition of this kind would also be in harmony with existing theoretical data. Moreover, the combination inflammation-like would indicate that allergic inflammation is different from the infectious form, hence the treatments should be different too. An accurate asthma definition should be similar to the definition of all allergic diseases, with the main difference being the organ in which they develop. Here is one possible version: Bronchial asthma is a reversible immune disease affecting the bronchial tree and the lungs. It is caused by the genetically predetermined inefficiency of histamine-inhibiting H2/3 receptors resulting in T-suppressor cells deficiency, mast cells and basophils hyperreleasability of histamine and histamine-induced pro-disease chemistry, and also low levels of
cAMPall leading to an inflammation-like process characterized by recurrent and variable airways obstruction (e.g. cough, shortness of breath, wheezing). Unfortunately, this kind of definition is unacceptable in contemporary allergy medicine because it would require accepting the following facts: the allergy-mediating aspects of immunity have their own protectors and regulators, namely T-suppressors; T-suppressors are able to control the disease only when their H2-receptors are well developed; H2 receptors, like all receptors, develop when activated; H3 receptors are synergetic with H2 receptors both in the way they become activated and in their effects; natures best activator of H2/3 receptors is histamine, and, hence, it is the best generator of T-suppressors; both immunocompetent and nerve cells possess H2/3 receptors, and hence, with receptor activation, the chemistry of both kinds of cells may change to a disease-inhibiting mode of action; stimulation of H2-receptors and T-suppressors is immunotherapy or immunomodulation; histamine messages via the H2 receptor increase the levels of cAMP and rectify the faulty genetic messages to the cells, which is a natural gene modulation; successful H2/3-receptor stimulation with histamine would in many instances replace the existing drugs for asthma and related diseases. These revelations are apparently too revolutionary for conventional allergy and its sponsors and they seem to find it necessary, therefore, to bury them. This is the reason why we still do not have a clear scientific definition of asthma.
ASTHMA SYMPTOMS Asthma is not an age-related disease, although most cases develop in early childhood. It hits men and women alike. It is marked by recurrent bouts of shortness of breath, wheezing, and cough. In the majority of cases, the disease is characterized by spontaneous attacks, and the length of symptom-free periods differs from patient to patient. The severity of the disease may fluctuate over the course of time. Some patients remain symptom-free for years.
This makes them believe they are disease-free, which is not the case for most asthmatics. Very few children outgrow asthma, but even in the lucky ones who experience a lasting remission, asthma may reoccur when it is least expected. An asthmatic attack is characterized by a spastic narrowing of air passages and/or swelling of the mucous membranes that may start to secrete phlegm. The constriction of the bronchi and/or their obstruction with phlegm result in shortness of breath. The spasm and/or phlegm moving with respiration in the narrow canal produces an effect of a whistlea wheezing sound. Cough occurs due to the need to overcome the spasm and/or evacuate the excessive accumulation of phlegm. Classic cases present all of these symptoms, while others are limited to one or another only. This leads to diagnostic mistakes: too often a resistant dry cough is diagnosed as a cold, while a cough with expectoration (coughed up phlegm) is taken for infectious bronchitis. A wrong diagnosis leads to the wrong therapy. The lungs function is to enrich the incoming blood with oxygen. Oxygen enters the lungs during inspiration. There, it gets into the blood vessels, and the oxygenated blood delivers it to other organs. When the bronchi are constricted in attacks, the lungs become hyper-inflated because the obstruction prevents the air from being exhaled. The trapped air cannot get out, and at the same time, the patient gasps for more and more airall this worsens ventilation and blood oxygenation. The functioning of the organs becomes impaired if not enough oxygen reaches them. The lack of oxygen supply to the tissues is called hypoxia. Hypoxia alone may lead to death in the worst cases. This clearly indicates that although asthma is a disease developing in the airways, it is a systemic disease and may affect the whole body when it strikes. In severe cases, attacks may follow one another with practically no break. This condition is called status asthmaticus. It requires urgent measures, at times, resuscitation. Over the years, protracted asthmatic attacks, with constant lung over-inflation, may result in degeneration of the lung tissue leading to an incurable disease called emphysema. In emphysema, lung tissue loses its elasticity, and live tissues are replaced by non-functional ones, and eventually, the lungs functional ability gets irreversibly reduced.
WHAT UNDERLIES THE SYMPTOMS Allergists recognize their lack of understanding of asthma/allergy etiology and pathogenesis and even speculate about future avenues to reduce our ignorance about the relevant causal factors for the inception of allergic diseases.12 And
again: the precise biologic mechanism underlying cellular responses is unknown, and despite the insights, a clear understanding of the pathogenesis of atopic asthma is lacking.13 In the year 2000, a Harvard group wrote that Little is known about the cellular mechanisms promoting the development of the allergic phenotype.14 In other words, the leading immunological periodical admits that the immune defects from which asthma, as well as the pathological mechanisms leading to it, originates are unknown. This is not true. Science knows very well that in asthma, like in other allergic diseases, no matter what the trigger isan allergen, a physical phenomenon such as exercise or a weather change, or a physiological factor such as an invisible change in the bodys chemistrythe hosts hypersensitive mast cells respond with an initial excessive liberation of histamine followed by other pro-inflammatory mediators. The end organ where allergic disease develops is the hosts Achilles heel, and for asthma patients, it is the bronchial tree and the lung. Besides, mast cells and basophils are deposited in the lungs more than any other part of the body, and therefore histamine-induced pro-inflammatory chemistry concentrates there. It produces the bronchial muscle spasm and causes mucosa to swell and form phlegmall leading to physical obstruction. The seething cytokine/mediator soup and the responding surrounding tissues produce what medicine calls allergic inflammation. But, this inflammation is secondary to the histamine spill. The symptomsbronchial constriction, obstruction and phlegmare the end effects of the pro-disease chemistry. Structural changes occur only in very advanced and complicated forms of asthma. Thus, the latest classification of asthma as a remodeling disease is as scientifically lame as it distorts the chain of events. To identify asthma as an inflammatory disease is incorrect because the inflammation is the resultant and not the initiating event. With the true operating forces ignored and not discussed, but kept hidden, it becomes easy to (mis)present the secondary and third-rate events as primary. And this is what allergist do.
ANTIBIOTICS FOR ASTHMA? The difference between allergic and infectious inflammations was thoroughly discussed before. However, inflammation as the cause is emphasized in asthma more than in any other allergy, and anti-inflammatory medications are heavily prescribed. Therefore certain important points need to be clarified. We already know what the differences between allergic and other inflammations are:
1. In infection, there is always an external causative agent, while in allergy, the cause is an internal, inborn or acquired cellular malfunctioning. 2. Infection is an acute episode in the majority of cases, while allergy is a chronic immunologic condition, readily apparent or smoldering, with possible recurrent acute attacks or spontaneous remissions. 3. The clinical picture of asthma vs. infectious bronchitis or pneumonia is different in that, like any infection, bronchitis and pneumonia are usually accompanied by pus formation and, as a rule, by fever, whereas asthma is not. 4. A graph of an acute infectious bronchitis, pneumonia or a severe cold is a time-limited curve which first climbs and then descends, while a graph of asthma, a recurrent disease by definition, looks more like unpredictable rises, falls and plateaus stretched indefinitely over time. Asthma is an inflammatory disease only in the sense of an erratically occurring chemical imbalance in the airways. Regrettably, doctors often handle the situation as if there is little or no difference between asthma and bacterial or viral inflammation. Asthma patients are too often diagnosed as having bronchitis or pneumonia and prescribed antibiotics, especially if their cough is productive (with phlegm). Certain antibiotics may provide temporary relief (although relief can also be spontaneous), which is not surprising because medications may have a collateral effect in addition to the direct one. For instance, the well-known aspirin, apart from its direct pain-reducing and anti-inflammatory properties, also works as an anticoagulant. Similarly, antibiotics may have a collateral effect in addition to their direct ability to destroy microorganisms, but it does not make them suitable as asthma drugs. They do not eradicate the original problem, and in the long run may even harm. Although antibiotics are not exactly a topic which a book on allergies should cover, in view of their frequent use in asthma, it is worth stressing the relevant points. Those who take antibiotics several times a year, and especially mothers whose children are frequent consumers of this drug category, should know certain facts.
WHAT YOU SHOULD KNOW ABOUT ANTIBIOTICS In its fight against an infectious agent, the body acquires the ability to defeat this particular agent on its own by imprinting the knowledge about that agent on the T- and B-cell memory. When antibiotics are taken, the body relies on the medication and does not participate in the fight. If there is another
encounter with the same agent, the memory of the T- and B-cells, previously excluded from the fighting process, is blank, and we need another prescription for antibiotics. Therefore, their use must be limited to cases of confirmed bacterial infection. If the causative agent is a virus, antibiotics are irrelevant since they are unable to fight viruses. A virus, like any live organism, has a limited life span. Therefore a viral infection is a self-limited condition that, as a rule, resolves spontaneously with as little effort as bed rest and drinking a lot of fluids. Asthma patients are often convinced by the appearance of the phlegm that they have infectious bronchitis. This is an unreliable sign because the colour and thickness of the phlegm depend on the ease of its removal from the airways. An airway obstruction may delay mucus evacuation, and its colour may change to green or dark yellow and resemble pus; it may even acquire a stale smell. To confirm pneumonia, a chest x-ray should be taken. Helpful for diagnosing pneumonia are the accompanying fever and distress, which usually increase in severity very rapidly. Antibiotic users should abide by the rule of completing the therapy course as prescribed. However, these drugs are toxicity, and various symptoms such as weakness, dizziness, various abdominal distress, etc. may develop during a treatment course. This forces patients to discontinue the medication as soon as the symptoms disappear. If not all bacteria are killed, they become resistant to the drug, and the next time, a new, stronger antibiotic may be needed to combat the same infection. Frequent and unnecessary courses of antibiotics may lead to unpleasant and even dangerous toxic and immune reactions. Some of these drugs are allergenic and may, thus, intensify allergy and asthma symptoms. Most important is that when they are prescribed to an asthmatic, antibiotics do not deal with the cause, and the patients asthma may continue to progress while the patient consumes irrelevant medications.
WHY ARE ANTIBIOTICS PRESCRIBED FOR ASTHMA? There are several reasons for prescribing antibiotics to asthmatics. Poor differentiation between an infectious and an allergic inflammation leads to misdiagnosis. The explanation lies in the doctors lack of knowledge of the immune processes underlying allergic inflammation in asthma. The confusion is deepened by the fact that the two different types of medications, antibiotics and steroids, are both called anti-inflammatory despite the
absolutely different nature of their action and hence, different pharmacological meaning and classification. Still, with the overwhelming number of asthmatics who visit doctors offices, it is inexcusable for a physician to misdiagnose the disease even if it is not the classical form as described by textbooks. No less a reason for the ease with which antibiotics are prescribed is that the social status of doctors is such that he or she gets away with it. A doctor is a figure put on a pedestal by our society and maintained there due to the efforts of the medical profession itself. In this position of grandeur it is easy to forgo additional learning about ones field of expertise, and this leads to ignorance. Only in purely medical publications, can one read such admissions as: It is paradoxical that the past decades have provided the introduction of new and more potent anti-asthma medications, especially inhaled corticosteroids, but the success of controlling morbidity from asthma has been rather limited.15 The patients are never informed about the weaknesses of the profession, and are often prescribed antibiotics for an alleged infection, often along with a bronchodilator to breathe easier, and not infrequently, along with a steroid puffer as well. Asthmatics are assured that they are prone to bacterial bronchitis and remain unaware that a prescription for an inhaled bronchodilator is an unspoken confirmation of asthma. Dr. S. Wolfe, the author of Worst Pills Best Pills writes in the chapter on antibiotics: After congressional hearings and numerous academic studies..., it has become the general consensus that 40 to 60% of all antibiotics in this country are misprescribed. We know very well the tendency to downplay unresolved medical problems, therefore, the actual figures are assuredly higher. Canadians should be especially wary, for according to statistics in this country, we have one of the worlds highest figures of asthma incidence. This may explain the fact that physicians here prescribe antibiotics twice as often as in US and five times the rate of European countries. It is due to the indiscriminate prescription of antibiotics that we face problems with antibioticresistant tuberculosis, flesh-eating infection resistant to all antibiotics, as well as the more common condition of resistant strep throat which can lead to permanent heart damage. The problem of antibiotic abuse has become so overwhelming that it has become known through the mainstream media. Regrettably, journalists write about the over-prescription of antibiotics in case of plain colds and totally miss the fact that these drugs are grossly abused in asthma.
IF YOU ARE PRESCRIBED ANTIBIOTICS... you need to do the following: ask your doctor to take a swab, when possible, to confirm the infectious origin of the symptoms before you or your child start taking them; be very cautious in the case of a recurrent cough or cold in the absence of fever. It may be allergy or asthma; question the diagnosis of respiratory infections if you have a history of frequent colds in the absence of fever, and are otherwise healthy; know that even if several members of your family have afebrile (without fever) colds at the same time, these may still be allergies arising due to the same trigger(s) and a shared genetic defect; if an inhaler is prescribed along with antibiotics, make sure you understand that you (or your child) have asthma, and the antibiotic is for a superimposed (though very rare) infectious bronchitis or pneumonia as proven by x-ray; in the case of true infection, make sure you do not stop taking the drug for the indicated period, otherwise, you may become a carrier of a resistant microorganism(s), and the infection may flare up again any time. If you have asthma, exacerbations slowly undermine airway functioning and potentially pave the road for superimposed infections. This worsen your asthma and prevents a differential diagnosis, increases prescriptions for antibiotics, and eventually undermines immunity still further. This vicious circle can be broken only through repair of the inefficient self-regulatory immune mechanisms. Unfortunately, a patient is not able to do that alone, and the majority of doctors do not know how to proceed. THE PROBLEMS OF ASTHMA DIAGNOSIS In the past 40 years asthma has become the most prevalent chronic disease of childhood in developed countries. Recent studies suggest that most asthmatic patients are diagnosed by the age of 6 years, with symptoms first occurring during infancy and early childhood, observed writers in JACI.16 This means that for 6 years, young children go undiagnosed, and hence, improperly treated. Not the best recommendation for contemporary medicine! I have my personal opinion why asthma often remains undiagnosed until the age of 6 and not 5 or 10 years. Inhaled steroids, as the central asthma medications, have according to standard practice guidelines not been recommended
under the age of 6, and only recently, the trend has changed towards prescribing them to children of 34 years old and even younger. Thus, children may cough for months, take courses of antibiotics without any effect or with only temporary relief and still be diagnosed as having colds or bronchitis instead of asthma. Finally, they reach the steroid-permissive age, asthma is diagnosed, and a prescription for a steroid inhaler is made. Not being able to relieve asthma symptoms effectively without steroids, doctors, actually, delay the diagnosis until they can prescribe them. The percentages of undiagnosed asthmatics vary in different sources, and some report up to 2540% undiagnosed cases. This significantly raises the official asthma figures. How the situation is downplayed can also be seen through a strange but fashionable trend to split asthma into several different conditions. Here are examples. Co-existence of a postnasal drip (back drip) and asthmatic cough is common, since their origin lies with the same immunologic imbalance. Recently, several sources presented postnasal drip as one of most common causes of chronic cough. No textbook has diseases called postnasal drip or chronic cough because they do not exist. This misinterpretation elevates postnasal drip to the level of a new and separate medical condition that allegedly provokes a chronic cough. Moreover, the very term chronic cough is diagnostically incorrect, since it is a symptom and not a disease. Although of no help to the patient, this helps the asthma figures look better. Another semantic innovation may also serve as an example of the continuous trend of belittling the asthma drama. Thus, a Canadian doctor, recognized in 1999 as Number One allergist, proudly announced her invention of a new term and therefore new medical diseaserhinobronchitis. Her explanation, however, did not differ from the postnasal drip/chronic cough phenomenon. In both cases, the first part, chronic rhinitis, is presented as the cause of the second, chronic bronchitis. Time will show whether the new term and the underlying meaning will be accepted, but I doubt it will be easier to cope with allergic rhinobronchitis than with asthma. Among other euphemisms for asthma I found in the works of specialists are wheeze and rattle given not as symptoms but as medical conditions, and these, allegedly, go away with time. There is also a disease called hyperresponsive airways strangely treated as asthma. Not uncommon is the diagnosis of alveolitis, although it is a totally different immunological degenerative disease of the lungs, mostly found in an occupational setting and caused by repeated inspiration of organic particles (such as pigeon
Bronchial Asthma
251
breeders lung). One thing is definite though: the innovative terminology that creates new diseases improves the asthma statistics. Some allergists and respirologists try to explain the statistical rise in asthma as being over-diagnosed. There is now a trend towards over-diagnosis, say two authors, one of whom is director of the Toronto Asthma Centre and president of Canadian Network for Asthma Care, Dr. K. Chapman.17 In these authors opinion, another disease must always be considered when treatment fails. If it is not asthma, what could it be? asks the article rhetorically and answers: emphysema, left ventricular failure, angina, cystic fibrosis, localized obstruction, vocal cord dysfunction, etc. How plausible is it? First, the common frequency of asthma compared to the rarity of the other named diseases increases the probability of asthma being the correct diagnosis. Secondly, emphysema is a disease that results from lasting and severe asthma or long-time smoking. This excludes emphysema as the diagnosis in young children, the fastest growing group of asthmatics. Similarly, angina should also be very low on the list of possibilities in those who are under 40. Ironically, the authors do give an involuntary explanation as to what lies in the origin of these symptoms at the beginning of their article: Despite an improved understanding of asthma and the many new treatments available for its control, a surprising number of patients appear refractory or unresponsive to the best management. Evidently, impotence in the management of the most prevalent chronic disease of our time prompts the medical profession to conveniently break it down into several allegedly different conditions, and by that remove the responsibility of recognizing the ineffectiveness of treatments. The internationally known authors of the book Asthma Epidemiology write on page 9: Virtually all reviewers have concluded that the increases (in asthma mortality) are real and are not solely due to changes in the diagnosis or classification of asthma.18 The non-wheezing form of asthma, or the one without shortness of breath, may present some diagnostic difficulty. Still, with the officially recognized 10% among adults and 1520% among children, every general practitioner has a fair number of patients with similar symptoms and must therefore detect the disease even in its non-classical form. A patient of mine treated for asthma immediately understood that her six month old son was also asthmatic when doctors in ER diagnosed croup and gave him a ventolin mask. Croup is an acute obstruction of the larynx due to infection (the child did not run a high
fever), new growth or a foreign body. The boys mother understood that it was asthma simply because he was prescribed a bronchodilatoras usual, to breathe better. One may only ponder why a medically illiterate woman could use her previous personal experience and diagnose the illness better than those who had studied the subject for years, and whose practice included a high percentage of asthmatics. Most probably the explanation is simple: if you diagnose a disease, you have to treat it effectively. As physicians fail with asthma, they, consciously or subconsciously, avoid the diagnosis. In other words, when they hear trotting, they think of zebras instead of horses.
THE DIAGNOSTIC TESTS FOR ASTHMA In general, conventional medicine relies too heavily on measurements and mathematics in diagnostics, and it does so with asthma as well. This is contrary to what the main medical textbook, Harrisons Principles of Internal Medicine, teaches: It is difficult to establish the diagnosis of asthma in the laboratory, for no single test is conclusive.19 Let us discuss why all diagnostic tests in asthma are unreliable. Pulmonary function testing measures the lung capacity and pattern of ventilation. It consists of a deep inspiration followed by an expiration into a device called a spirometer. The findings can be inconsistent because lung function is not impaired in mild asthma and is often also preserved in moderate asthma. Therefore, poor air flow may show only in a period of exacerbation. Even severe asthmatics may have normal air flow measurements in remission. When used for diagnosing, normal testing parameters (not an uncommon thing in asthmatics) only confuse. The patient is told that he does not have asthma, which can make him feel psychologically happy, but be puzzled as to what causes his recurrent cough and chest discomfort. Allergists and respirologists recognize the diagnostic deficiency of these tests but still conduct them even in cases of definite asthma, which only adds to the cost of asthma management but does nothing for asthma patients. Logically, pulmonary function testing should be used with discrimination, only in cases of a difficult differential clinical diagnosis. The daily measurements of peak expiratory flow through a portable device are a version of pulmonary function testing and are recommended to every asthmatic. Regrettably, this test is too often used as diagnostic means, despite it being helpful mainly in adjusting the dose and type of medications. As the majority of asthma drugs are notorious for their side effects, the flow meter may allow the patient to self-reduce the dose if the air flow improves.
Inhalation bronchial challenge test is another diagnostic procedure, and quite an aggressive method of determining hyperreactivity of the airways with the help of a spirometer. The patient is asked to inhale histamine (or metacholine) or a suspected allergen/trigger to provoke an asthmatic attack, after which the airway obstruction is measured. This test is used by allergists and respirologists only in specialized asthma centers, since the patient may require resuscitation. You may wonder why the inhaled histamine provokes an attack, whereas being injected, it relieves the symptoms. Surprisingly, even certified allergists are unable to answer this question. For example, the only expert witness asked by the CPSO to assess my work during my trial, Dr. A. Knight, a professor at the University of Toronto, was unable to answer as well. This means that allergists cannot explain the similar phenomenon with allergenic: extracts the use in immunotherapy: inhaled dust mites trigger symptoms, whereas dust mites extract is used in allergy shots to improve the symptoms. The reasons for the two opposite effects, be it histamine or an allergen extract, are as follows. A small dose of injected histamine (or a well matched allergen extract) comes into direct contact with the immune cells and corrects their work by gently stimulating the H2/3 receptors. It is different with inhaled histamine or a potentially offensive allergen given in a large dose. They go directly into the disease-stricken organ, lungs which is already enveloped in allergic inflammation. There, they trigger predominantly the H1 receptor effect and thus intensify the symptoms. This explains why the bronchial challenge test with histamine may result in a serious attack, even death, whereas histamine injections are curative. The lack of understanding of the dual nature of histamine and knowledge that it can only provoke asthmatic attacks upon its inhalation resulted in declaring histamine as nothing but dangerous. Skin testing is not exactly a test for asthma diagnosis in todays clinical medicine, whereas it could become one of the most sensitive tools for this very purpose. Conventional allergy skin testing is used to establish specific IgE antibodies to the trigger(s) given in pricks in order to find what you are allergic to although, even in this, as was said in the chapter on skin testing and immunotherapy, AST is not reliable. In fact, monitoring systemic reactions can provide reliable evidence for asthma if patients are tested during a symptomatic stage. Change in the breathing patterns before and after the pricks would indicate asthma because symptoms of bronchitis or pneumonia do not respond to the skin challenge with histamine or allergens. With systemic reactions left unobserved, and histamine pricks given simultaneously with
numerous allergens, the diagnostic value of standard allergy skin testing in asthma is almost zero. Not only is skin testing more accurate than other tests, but in many cases, it also provides a gentle challenge followed by improvement, unlike the dangerous provocation of an asthmatic attack in bronchial challenge testing.
WHAT IS RELIABLE IN ASTHMA DIAGNOSTICS? In the absence of reliable laboratory findings, a thorough medical history becomes the basis for asthma diagnosis, while tests can only support it, when needed. Family history is an inherent part of the medical history. The hereditary factor in asthma origin is confirmed by its clustering in families. Therefore, the family history should cover not only the parents, children and siblings but also more distant relativesgrandparents, uncles, aunts and cousins. Allergies and asthma may skip a generation or a group of immediate relatives, though still be carried in the faulty genes. Often, adult relatives (who are symptom-free) of a young asthmatic do not know about their hidden defect and thus consider themselves to be allergy-free. This is why an inability to trace asthma in the family history does not rule out its genetic roots. As with any allergic disease, the family members may not necessarily have asthma but another allergic or related condition due to a similar immunologic error. To elicit the essential facts, it is imperative that doctors know the common roots of allergies and borderline diseases and ask relevant questions. Asthma is striking younger patients more often than ever before, and children are diagnosed with asthma at a much earlier age than their parents were. This can be explained primarily by the naturally growing number of people who inherit flawed genes from their parents. It is only natural to expect the defects to be increased in the kids who have both parents with such genes. Another factor that explains the rise of asthma among children is the well documented innate progressive mutation of the genes defined by basic science as spontaneous or natural. Accumulating adverse environmental effects contribute to earlier manifestation of the disease. The clinical picture is most indicative for the diagnosis. It may include one or all of the following: cough (especially nocturnal), shortness of breath and/or wheezing upon exercise or exposure to a pet, house dust, smoke, cold air, etc. Co-existing allergy symptoms such as eczema, chronic or recurrent nasal congestion, migraine headaches, constant or intermittent unexplained
tiredness or hyperactivityall point to asthma rather than a cold. The volatility, long duration, and recurrence of the symptoms prompt the diagnosis of asthma and exclude an infectionespecially so, if they are not accompanied by a high temperature. Low-grade fever may also be a manifestation of an accompanying neurological symptom, temperature dysregulation, and not a sign of an infection. The leading medical textbook, Harrisons Principles of Internal Medicine, in defining what is required for accurate diagnosis states in Chapter 1, The Practice of Medicine: Each item of data must be interpreted in the light of what is known about the structure and function of the involved organs(s). Knowledge of anatomy, physiology and biochemistry must be combined into a plausible pathophysiologic mechanism.20 The sad truth is that the concealment of the true mechanisms, which underlie asthma, has made physicians ignorant in this area, and this prevents them from asking patients questions relevant to the main disease and from properly interpreting the accompanying symptoms. This is the reason why asthma remains too frequently undiagnosed, and the accompanying, allergy-related, often nonspecific symptoms are diagnosed as a separate disease.
ELIMINATION AS TREATMENT OF ASTHMA Let us assume that asthma is diagnosed. What should the management of this immune disease start with? Correction of the faulty immune mechanisms, would say a knowledgeable doctor. Trigger elimination, says conventional medicine. What to eliminate? Everything. House dust mite has always been the main culprit. Then come pets, and parting with them tends to result in broken hearts. Yet, it is true that many people, especially children, are prepared to suffer but not to give away their beloved dog or cat. Next come foods that need to be eliminated, and usually it is the most delicious. Am I against trigger elimination? Not at all. If there is an evident sole trigger, avoid it. However, it is next to impossible to eliminate triggers such as house dust mite or pollen. Even if you are lucky enough to succeed, the next day, you may realize there is yet another trigger for your symptoms, which is even more difficult to avoid. An asthmatic attack may also occur spontaneously, and you may not be able to figure out what triggered it, or your symptoms may intensify without any change in the environment, food or habits. The reason may well lie in the fact that, while you are chasing the offenders, the disregarded primary crack in you immunity deepens.
The western societies questions about the role of atopy (allergens) in asthma sound almost absurd, states the editorial with the self-explanatory titleIs asthma really linked to atopy? The author of this observation, E. von Mutius, an expert in asthma epidemiology, discusses the contradictory figures of IgE-mediated asthma in various countries and concludes with: Such reflections are not of purely philosophical interest, but may well help us to understand why current paradigms of, for example, allergen avoidance strategies aiming at reducing atopic sensitization, have failed to prevent the development of asthma.21 Paradoxically, elimination as the core of allergy treatment (confirmed by numerous studies) peacefully coexists with the ideas (also confirmed by multiple studies) that asthma rates are higher in regions with good outdoor air as well as among families with high cleanliness standards. Some researchers even dare to suggest that, it is a lack of exposure to allergens that plays the decisive negative role in the development of asthma, and the presence of a cat in the house is actually associated with a decreased risk of asthma, especially in young children.
THE SEARCH FOR ASTHMA CAUSES To know the origin of asthma is to be able to treat it. Allergy medicine obviously failed to find the cause(s) of asthma in the environment, otherwise why would Dr. L. Lichtenstein write that the incidence of asthma and the number of deaths it causes surged by more than 60 percent in the 1980s. The reasons for the rise are mysterious. Hypotheses to explain the overall mortality figures range from overuse or ineffectual use of bronchodilators to an increase in environmental pollutants and allergens.22 Asthma figures are so frightening in children, and especially among teenagers, that the World Health Organization formed a program called ISAAC, The International Study of Asthma and Allergies in Childhood, which conducts epidemiological studies. While this effort is commendable, the problem remains: allergists look for causes outside the body, and the wider the scope of their search, the further they are from the true inner causes of asthma. The strangest thing is that the findings of a general science called connectionism is closer to understanding asthma origin than the specific medical field devoted to the disease. Connectionism studies various things and phenomena not in isolation but in their complexity, as systems with multiple tasks: the inner causal connections, self-regulation through excitatory or inhibitory
processes, and the learning patterns, that is, how the system adapts and changes in order to restore its ability to self-regulate. The orientation of connectionism is that causality forms the basis for scientific understanding. Although this general science does not provide the answer to what causes asthma, it correctly points that: asthma is a fault in the activation pattern of the bodys self-regulatory network, and this fault is causally prior to the known inflammatory mediators. Asthma is a breakdown in the efficiency of that part of the network controlling inflammatory self-regulation in the lung that gives rise to the inflammatory mediators, while triggers are exacerbating or risk factors only. Correct understanding of the causative mechanisms, enables connectionist theory of asthma to name the regulation of the internal environment as the treatment target, and it predicts that if asthma is, in essence, a form of faulty learning within a network, then asthma can, in principle, be cured.23 If a general science looks at asthma as the disease with internal causes, why do those who specialize in asthma look for external causes? The title of the article written by the worlds leading experts in asthma epidemiology cited earlierHow much asthma is really attributable to atopy?is proof that allergy concentrates on the wrong aspects of the disease.24 This article, as well as a number of others are written primarily by the same group of researchers from New Zealand, who also wrote Asthma Epidemiology.25 The book summarizes hypotheses of asthma origin. The search concentrates on triggers and risk factors that remain speculative. Both the book, and the article that refers to the statistical investigation among 1314 year old asthmatic children from 42 countries,26 reveal that the most striking figures are especially characteristic for English-speaking countries. Reading that, one inevitably starts to wonder what evil role the English language plays in the course of asthma. Does it mean that French-speaking Canada should have lower rates than the rest of the country? Are asthma statistics lower in New Mexico and California where a large part of the population speaks Spanish? Why does India, with English as an official language, have one of the lowest asthma mortality figures of all countries included in the study? What is the mysterious link between the English language and asthma in such geographically, climatically, culturally and otherwise different countries such as New Zealand and United States? Indeed, one of the worlds cleanest countries, New Zealand, with its mild climate differs greatly from the United States, with its wide range of climatic zones and various degrees of pollution in different areas. How to explain the fact that China, Algeria and India, countries where there is hardly any law enforcement with respect to envi-
ronmental pollution, show mortality figures from asthma 20 or even 60 times lower than Australia and New Zealand? Beasleys research does not provide the answers. Asthma Epidemiology states that even such a hazardous factor as smoking does not directly affect asthma occurrence and severity. Thus, China with its overwhelming number of smokers is at the lower end of the official scale. All this challenges the generally accepted views on the direct effect of environmental pollution upon asthma figures and forces the authors of the book to admit that air pollution is not a major risk factor for the development of asthma. These confusing data question the practice of trigger elimination as the main trend in asthma management. The book also dismisses race as a possible explanation for asthma rates. Indeed, tracing of the genetic roots in a major part of the population in such multi-racial countries as United States or Australia would inevitably lead investigations to Easter Europe, China or India in which asthma prevalence, severity and mortality are incomparably lower according to official figures. Asthma Epidemiology only presents various hypotheses as to what countries with high asthma rates might have in common. I will suggest my own opinion based on the facts about what English-speaking countries share with respect to these tragic figures.
WHAT AFFECTS ASTHMA STATISTICS ? First of all, we should distinguish two thingsincidence and morbidity/ mortality. Higher than average incidence of asthma in the countries such as New Zealand, Australia, Ireland and some smaller islands can be explained by their isolation in the past and hence, smaller groups participating in the genetic exchange. In such circumstances, the offspring had higher chances to get defective genes from their parents and have genetically related diseases, including asthma, just as inbreeding produces defects in pedigree animals. Severity and death rates in asthma, however, belong in a different category. Civilization has undoubtedly brought things that undermine the immune system. Paradoxically, many of them are means to improve the quality of our lives, save time and effort: air humidifying and dehumidifying, food preservation, acceleration of cattle and poultry growth, tooth whitening, breath freshening, pesticides, etc. In our haste, only the immediate effect matters. Therefore, the fact that the improvements might, in the long run, lead to severe consequences has always been of minor, if any, consideration for
consumers and even the medical profession. These improvements are desired by the governments and industries as revenue-generating factors, and they are highly advertised and supported by government policies. Among the powerful consumer goods proclaimed to improve our lives, medications are of immense importance. They inundate the market in all industrialized countries. The high living standard there allows every person to resort to these drugs even if the discomfort is mild. A painkiller? Here it is. An antibiotic? No problem. You are going through a family problem and having trouble sleeping? The best remedy is a sleeping pill and/or a tranquillizer. Vaccination is now available even for the non-life-threatening chickenpox. Our immunity no longer has to develop naturally. The drugs will do the work instead. Side effects may show up in the future, moreover, the cause and the effect may be stretched over time for years or decades and will be hard to trace and prove. The pharmaceutical industrys main role is to please the consumer and temporarily relieve the symptoms, not to heal, as it falsely claims. To capture a customer, it uses seductive advertisement. Just listen to the TV ad offering a medication that allows one to get rid of toe-nail fungus. The sweet voice encouraging you to buy the medication inspires such a strong desire to have beautiful nails that liver or kidney damage listed at the end as possible complications sound almost like a reward. In other words, drugs have become a commodity and, paradoxically, one of the most potent health-aggravating factors. The birth country of the drug industry is Germany. However, being defeated during the war, it lost its priority in this area, and England and the US took over. It is only natural that the companies opened their branches in developed English-speaking countries. The largest of them made the US neighbor, Canada, their stronghold, and also stretched their tentacles to other industrial colonies, dominions and territories of the Commonwealth. And here comes the feature common to all countries with the highest asthma figuresEngland, US, New Zealand, Australia, Canada, Ireland: they are connected to the pharmaceuticals industry like a child to its mother by the umbilical cord. All these countries are industrially advanced and their well-off citizens are able either to pay for the drugs out of their own pocket or through the generous insurance plans. The populations in those countries abuse drugs from an early age. Medications are prescribed at the slightest sign of any discomfort, and an asthmatic can resort to the best remedies the moment he produces his first cough. In contrast, in India, although English-speaking, the percentage of the poor population is too large, and the social system of the country is unable to distribute these remedies
for free. Ironically, Indias poverty saves its people from the overwhelming morbidity and mortality caused by asthma in developed countries. Drug production in European countries lagged behind that in the rich North America, and the opposition to the foreign intrusiondrug importsdelayed the consumption there. The highly unsafe medications for asthma were therefore introduced in Europe later and at a slower pace, and this positively affected the asthma morbidity and mortality rates. The asthma figures in the former East Germany and West Germany may serve as a comparative example: in the heavily industry-polluted East Germany, asthma rates were paradoxically much lower than in its cleaner neighbor but have inexplicably started to rise lately. In my opinion, the aggressive medicalization of the population is the central factor uniting the countries with the highest figures of asthma morbidity and mortality. My assumptions are supported by a leading professional, Dr. W. Busse, the 2001 president of AAAAI. He blames conventional medications for the morbidity: It is estimated that about 5% to 10% of patients with asthma have severe disease that is recalcitrant to typical treatment modalities, including administration of systemic corticosteroids. This may occur as a result of chronic exposure to beta-agonists or corticosteroids.27 A recent report from the Centers for Disease Control and Prevention stated that the prevalence of and mortality due to asthma continue the upward trajectory that was begun more than 15 years ago, says another article from the same issue of the leading immunological periodical.28 We are witnessing a dramatically growing morbidity of asthma accompanied by the development of chronic conditions. The process is in parallel with the use of bronchodilators in the past, and now continues in parallel with the growing abuse of immunosuppressive corticosteroids that started to be aggressively advertised in the mid eighties. This is confirmed by the first-class source, an article written by researches from the National Institutes of Health, Bethesda.29 The authors investigated what factors make immune-related inflammatory diseases resistant, and say that corticosteroids modify the clinical phenotype and worsen the course of these diseases. Under phenotype, science understands the entire physical, biochemical and physiological makeup of an individual as determined both genetically and environmentally. In other words, a person formerly responsive to medications becomes resistant due to the consumption of the most common asthma medications. Is this not a direct recognition of the danger of these medications?
Bronchial Asthma
261
Admissions of this kind are done rarely and mainly in purely theoretical articles, with no proper conclusions (such as: lets give up on such medications), with no solution (which the authors mostly do not know). The public, including the medical profession, must not be disturbed. No high profile specialist has ever raised (or will raise) the question why, despite the fact that these drugs have been available for the treatment of asthma for almost 50 years and are still the most effective medication for this condition, information about their effects in vivo is limited.30 The lack of data on the complications of these highly prescribed medications for the most prevalent chronic disease cannot be accidental. Moreover, since no other drug is as effective in asthma as steroids, even such occasional admissions of their harm disappear in the ocean of steroid-supporting literature. Thus, the editor-in-chief of the Canadian Respiratory Journal started his editorial by saying that the most common topic in papers so far submitted to the Journal concerns the high rate of mortality from asthma in young people. After having consulted with specialists, one of whom was the world-famous Dr. M. Sears, the editor concludes that poverty and inadequate use of steroids are the central reasons.31 Strangely, neither the editor nor his consultant notices the obvious contradiction with the statistical data: the polluted India and China where steroid medications are unknown to and/or inaccessible for the majority of asthma patients lag behind the steroidadvanced New Zealand and Australia in asthma mortality. The 1993 president of AAAI, L. Lichtenstein, was once confident that the pharmaceutical and biotechnology industries and academia will help resolve these issues (effective and safe drugs for asthma) to a significant extent within the next few years.32 We do not see it happening now, a decade later. Judging by the almost universal switch to steroids and the massive inappropriate use of antibiotics for asthma during the last two decades, the drug industry only serves itself, and academia faithfully serves the industry. The industrially advanced English-speaking countries lead the trend and the rising statistics.
PERSONAL IMPRESSION ON THE OFFICIAL STATISTICS IN ASTHMA My recent visit to India made me question some of the data in the book Asthma Epidemiology. Seeing asthma patients every day, I have a good idea of how asthma sounds, and in India, I heard almost everybody around coughing a phlegmy cough. With the temperature in the soaring 30C+, it was hard to
suspect an epidemic of a flu or pneumonia. My interest prompted me to talk to a dozen of people, mostly young non-smokers, and I learned that many had shortness of breath, wheeze and typical accompanying symptoms such as allergic rhinitis, itchy skin, headaches, etc. They also had family members with similar symptoms. None of those I talked to had seen a doctor and hence, the had not been diagnosed as an asthmatic and included into the official data. This confirmed my suspicion that the official statistical figures were unreliable. I am sure that that the asthma incidence in India is underrated. My experience tells me the same is true in other third-world countries. However, we should distinguish incidence, which may be higher in polluted countries, and mortality that may really be much lower there than in the first-world countriesexactly what we see today. There are reasons for the discrepancy between the reality and statistics. Densely populated India does not have a government-funded medical insurance system that could create a flourishing drug market, and the drug industry is not going to supply its products for free. The total cost of asthma in United States was estimated to be $4.5 billion in the mid-80s, whereas in the first half of the 1990s, the estimate increased to a range from $6.2 to $10.7 billion.33 If the US suffers from the economic impact of asthma, a country like India would simply be crushed under such a financial burden. I am not aware of the source of the distorted figures that appear in the books and articles, but it is apparent that the greatly belittled asthma prevalence in the third world countries conceals both the scope of asthma and the urgency to treat the sufferers. This satisfies the governments and allows international medical bodies and the pharmaceutical enterprises to save face instead of saving patients. The positive side of this perverted situation in allergy is that without conventional drugs, which eventually do more harm than good, asthmatics in poor countries live longer. In 2002, I found a confirmation of my ideas in an article written by a professor of pharmacology at London University in the UK. Prior studies in near-fatal asthma have suggested that a contributing factor may be inadequate access to health care; however, the study by Mitchel et al. would suggest this is not true. In fact, the index cases had more contact with health-care systems than the control subjects, especially asthma specialists.34 This is a straightforward admission that those who regularly see specialists have near-fatal asthma more frequently. And it is not a secret that specialists are more aggressive in prescribing effective asthma medications than general practitioners.
THE IMMUNE SYSTEM UNDER ATTACK No matter how hard we try, we cannot avoid accumulation of toxins in view of their wide-spread use and our inability to eliminate them in the food, air and water. One lifetime will not be enough to fight all the industrial giants that pollute the environment, while our deeply corrupted governments delay the introduction of laws that could make the environment cleaner. Is there a way out? In this grim situation created by our civilized world, there is only one immediate and inexpensive way out: a helping hand extended to our sick immune system so that it can regain its fighting ability. The human body tries to adjust to this growing pollution. Of course, environmental hazards may eventually destroy it, and for now they seem to promote various chronic diseases, including diseases of hypersensitivity. However, the combined impact of the pollution from outside and the abuse by medications accelerates the damage. The much lower asthma mortality in countries with the highest environmental pollution and the lowest drug consumption is irrefutable evidence. THE CONFUSION GROWS No other chronic disease can beat asthma in its growth rates. It has also become a champion among all existing chronic diseases in morbidity and mortality, while among children, the figures quadrupled since the late seventies. This is because modern medicine never targets the prime events. Strategies aimed at secondary prevention would reduce morbidity and mortality, states Foreword in the prestigious journal, the Lancet.35 The article admits that patients would like asthma to be prevented or cured, but neither is likely to occur unless we understand why people develop asthma. One would think the author would suggest studying the cellular mechanisms that underlie the disease. Not at all. She suggests focusing on epidemiological factors rather than genetic factors (as) they may be more amenable to manipulation. Thus, the search for the true asthma causes is bypassed again. This approach has led to the proliferation of numerous irrelevant theories seriously discussed by allergists and delivered to the public by the media. So mind-boggling and contradictory are they, that at least some of them should be presented to the readers, so they can arrive at their own judgment about them. A popular hypothesis on asthma/parasite relationship was suggested in 1979 by A. B. Kay, a co-editor of the journal Clinical Allergy and Immunology.
L. Lichtenstein, also referred to the absence of parasite infestation or parasite infections as the cause of asthma in his article in Scientific American36 in which he states that allegedly, in the response to both allergens and parasites, the body produces high quantities of molecules known as immunoglubulin E (IgE) antibodies. Conventional allergy research presents IgE antibodies as the main indicator of allergy, but also as a defence mechanism against parasites. This is what is going on in the body, according to allergy moguls Kay and Lichtenstein. We inherit the immune system geared to fighting parasites but, unfortunately, now, when the civilized world successfully cleans the body, we are clear of them. So, we must suppose that the immune cells, not used to idling, busy themselves with creating IgE to innocent substances. (Should we assume that this is the reason of the statistically low asthma incidence in parasiteinfested third-world countries?) To the credit of Dr. Lichtenstein, he admitted that animal studies in this respect were inconclusive and thus left the relevance of the hypothesis up for speculation. In the nineties, it has become a part of the highly elaborated hygiene theory by the Italian researcher S. Romagnani. Eppur si muove! is the title of his article which uses the famous phrase ascribed to Copernicus in relation to the Sun/Earth relationship; he supposed to have said to his prosecutors about the Earth, And yet it does move!37 In other words, in the chaos of ideas on the origin of allergies, Romagnanis concept, which included the worm aspect, has proclaimed that idea of cleanness (including wormlessness) is central in the origin of allergies. Numerous allergists picked up this idea that has conquered the minds of many. Thus, Dr. Weiss, a Harvard University professor, published an article under the title: Parasites and asthma/allergy: What is the relationship?38 He wrote that individuals who are genetically the most resistant to helminthic infection may be the ones who have the most severe allergy and asthma in its absence. This makes worms look more attractive, and asthmatics, or at least those with a severe form, may start seriously thinking about acquiring parasites instead of gasping for air. (Just imagine how damaging the concept of parasites could become for the fast developing industry that offers various remedies to cleanse our bodies, which are allegedly full of worms!) Still, the absurdity of the idea is such that after his extensive deliberations, the Harvard professor is forced to conclude that decrease in helminthic infection cannot be seen as causally related to the asthma epidemic, although it may help to explain how other environmental exposures are contributing to the increased asthma burden in Western industrialized countries.
Nostalgia for the good old times when parasites and real infections, as counterbalance to IgE antibodies, were accessible to everybody still enjoys overwhelming recognition among scientists. The Cambridge University pathology professor, Anne Cooke, suggests developing an extract that would play a trick on the body: it will chemically imitate a worm and thus cause positive immune responses. In the Canadian newspaper The Globe & Mail on May 17, 2001, I read about another believer in such ideas, professor Koichiro Fujita of Tokyo Medical and Dental University who had implemented this idea in real life. He had suffered from hay fever and, encouraged by the worm/no-allergy hypothesis, had consumed three kinds of worm eggs to find relief. The inference one can draw from all this is that, being unable to perform immunomodulation, allergists should hand their jobs over to parasites. Surprisingly, the conclusion that exposure to infections, dirt and worms is allergy-protective, co-exists with the generally accepted and heavily disseminated ideas of the need to eliminate/avoid all potential environmental triggers. The contradictions are overwhelming. Numerous articles discuss hypotheses forwarded by different researchers but leave them as speculations. One idea is that large head circumference at birth is a risk factor for subsequent development of asthma.39 The conclusion here is that this intriguing finding may be associated with mothers higher nutritional habits that affect programming of the developing immune or respiratory system, predisposing to the subsequent development of asthma. So, better and more abundant maternal nutrition is supposedly the cause of asthma. Another article assumes that a small family size (is) associated with an increased risk of development of asthma. According to the researchers, large families have a chance to avoid asthma because natural infections, some of which may protect against asthma, are transmitted among the siblings, whereas an only child is protected from contamination through low contact with other children. Asthma Epidemiology refers to researches that name several infections allegedly incompatible with asthma. For instance, positive tuberculin responses have been found to protect against atopy (allergy) in Japan, and hepatitis A infections were found to protect against atopy in Italy. It simply means that those who have tuberculosis and hepatitis A do not develop asthma. The author refers to another team of scientists who concluded that measles infections have been found to protect against atopy in Guinea-Bisseau, and therefore it is also possible that immunization may
contribute (!?) to the development of asthma and atopy.40 This assumption actually questions government-enforced plans of massive immunization of the global population, since it would be better to suffer once through measles or hepatitis A, than to suffer life-long from asthma. I cannot resist the amusing notion that the one good thing about all these hypotheses is that they are democratic. In Soviet Russia, where I came from, if a person had asthma, he had to live with it all his life. In a democratic society we have the choice of hepatitis A, tuberculosis or parasites instead. The role of respiratory infections in asthma is another highly debatable question. The views are so conflicting that in one and the same paragraph of an editorial in the most prestigious journal, we read that infections may cause asthma, but as a whole (they are) probably protective against the development of asthma.41 In an interview, Dr. Andrew Saxon, the chief allergist at the UCLA Medical School, dwelled on the idea that during infections, the immune system learns to identify the attacker and eliminate it when it reenters the body. Nowadays, with fewer infections, the body looks for another target and attacks the more benevolent environment. This again raises the idea of the need of vaccination: if it predisposes children to allergies, then, by vaccinating our children, we consciously expose them to the potential of developing various allergies, including the potentially fatal asthma. I have not read any practical suggestions in this respect made by allergists. Asthma Epidemiology refers to the work of scientists who consider higher family income and overly hygienic condition in early life among high risk factors. The authors of the article published at the same time go even deeper in their conclusions: contamination from maternal microflora along the birth canal could be an advantage.(?)42 That article makes a further speculation: increasing maternal age decreases the risk of asthma and particularly allergic rhinitis. This concept obviously contradicts the reality: nowadays, women in the first-world countries where asthma figures are especially high tend to get married later and therefore have children later. If this should lead to the reduction of asthma rates, why do we observe the opposite? In general, the tendency to diminish the key role of genetically-driven immune-related defects and factors in allergies and asthma and to turn the attention instead to questionable contributing events becomes more and more pronounced in the works of numerous authors. Even the scientist with encyclopaedic knowledge in allergies, such as Stephen Holgate, states that Release of histamine account(s) for most of the early- and late-phase
responses, and that mast cells histamine releasability supposedly lies in the origin of allergic reactions. Although the author knows very well what compromised immune mechanisms make these cells leaky, he does not say so. Instead, in the very same article he points to environmental allergens as the central factor and names supposedly new (?) allergens such as nuts, soya and latex.43 If latex can rightly be considered as a recent industrial product, nuts and soya seem to have existed from time immemorial. We can only speculate why they have suddenly turned into potent allergens, and what made the immune system react viciously to them. Here is another example of looking for the causes of asthma outside the body. With bewilderment, one reads in a leading periodical in the section The New Millennium: Conquest of Allergy, that lifestyle factors relating to the socio-economic status of a population or a family, its size, and the number of siblings of a given individual, early childhood infections with viruses and bacteria, and a subjects dietary habits account for the high incidence of allergies, while genetic factors are unlikely to explain the prevalence of allergies.44 Medicine has come to the point when genetic predisposition to chronic diseases, well established a century ago, is almost completely discarded. Strangely, it is genetics and not the environment that is highly recognized in the breeds of our pets. Allergy tries to create picture that will more easily fit into the frame it has created. This position is dangerous and has its precedents. In Stalins Russia, genetics was also officially disregarded, which led to the degradation of science and perishing of its supporters in the Gulag. Shouldnt we learn from the past? The article, to which we referred earlier, contains more surprises. One of them is that out-door pollution of sulphur dioxide, diesel exhaust are not causally related with allergies. In other words, there is no need to fight for clean air. The other surprise is that passive smoking has convincingly been shown to increase the risk for asthma and bronchial hyperresponsiveness among exposed children. This does not correlate with the findings presented in Epidemiology of Asthma, written by the same author, that the lowest prevalence of asthma was observed in the community living in mainland China, despite the highest level of cigarette consumption. Now that tobacco companies are forced by the courts to pay for the casualties they have caused with their products, they have the unexpected support from allergists and may suggest that eliminating second hand smoking is unnecessary, so everyone should be an active smoker. Will this reduce asthma incidence in the first-
world countries to the officially recognized low level in China? The paradoxes of allergy in the new millennium! Along with the growing number of articles on the advantage of early-life exposure to common inhaled allergens, the popular dogma still reigns that dust mites, pet dander and cockroaches remain the key factors in asthma. Thus, the already cited article states that early-life cockroach allergen exposure at 3 months of age predicts activation of pro-inflammatory T-cells (helpers) and hence, asthma. The word cockroach is even given as a key word to the article.45 In general, the allergen/IgE-based theory became a citation classic, as is still believed by a world renowned North American allergist and respirologist Dr. D. Cockroft. In a recent article, the author claims that asthma is caused (not triggered) by allergens: IgE-mediated airway inflammation is, perhaps, the most important cause of airway hyperresponsiveness in asthma.46 Dr. Cockroft calculated that a classic paper written 23 years before by himself and three other Canadian specialists had been cited almost 800 times proving by that that this hypothesis on the origin of allergies and asthma is immortal. All of this despite the epidemiological evidence that the population-based proportion of asthma cases that are attributable to atopy (allergy) is usually less than one half, that there is a component to the asthma syndrome which is not related to atopy.47 I would suggest, however, that if more than half of asthma cases are allergen/IgEunrelated, it is high time to reconsider the classical but unfounded concepts. An American critic Eric Bentley once said: Ours is the age of substitutes: instead of language we have jargon; instead of principles, slogans; and instead of genuine ideas, bright ideas. Allergy is full of bright ideas on the origin of asthma. Contradictory and confusing, they peacefully co-exist, and nobody has made a critical review that would select the ones, which are scientifically sound. This creates real chaos, and in such a situation, the conquest of allergies is unlikely. The truththe genetically mediated malfunctioning of immune cellsdrowns in the ocean of inconsistent hypotheses, controversial data and collateral events. Instead of studying the faulted immune mechanisms and attempting their correction, immunologists look for numerous triggers of symptoms. Millions of dollars are wasted on investigations, at times laughable in their essence, on the role of unsubstantiated factors upon the occurrence of allergies and asthma. Research that distracts from the core of the problem receives unrestricted grants from the drug industry, and the results are published in most prestigious journals. Drug developers nurture pseudoscientific hypotheses because without a concrete therapeutic target, the asthma
problem will never be solved, and meanwhile, they can continue with their socalled pharmacologic advances aimed always and invariably at the secondary events. The bleakness of the asthma reality is confirmed in the very first article that covers the 2000 annual meeting of American allergists: In many ways, the epidemiology of asthma is in a situation similar to that of cancer epidemiology or cardiovascular disease epidemiology before major advances in understanding of the causes of these diseases in the 1960s.48 This is recognition that the knowledge of asthma lags behind even cancer. Time has come to differentiate science from pseudoscience. It is normal that in the course of scientific development, 8090% of all hypotheses turn out to be erroneous, but errors are not pseudoscience. Pseudoscience in clinical immunology is born out of purposeful lack of access to the true information and the resultant overwhelming illiteracy in the field. If the reasons for this illiteracy are not exposed, we will chase cockroaches and pets in futile attempts to curb asthma and see its ever-rising trajectory.
ASTHMA MENAGEMENT AND MEDICATIONS

BRONCHODILATORS
Asthma medications provide the best proof that allergy is operating in the dark. Allergists make it look as if there are numerous asthma medications, while in fact, there are actually only two groups. One, categorized as relievers or rescue drugs, cannot be avoided by any asthmatic. The real name of these drugs are bronchodilatorsthey dilate the constricted windpipe. They are the oldest anti-asthma medications. One such agent, ephedrine, was employed as a herbal preparation for asthma as far back as 5000 years ago in China and is still recommended for use by herbalists, though restricted by conventional medicine. Strangely, it is incorporated into various unrestricted decongestants and combo medications such as Claritin Extra. In the past, different tinctures, plant extracts, and even inhalation of morphine and marijuana were used for that same bronchodilating purpose. At the end of the nineteenth century, another fast-acting agent, adrenalin, came into practice. It is a synthetic analogue of a hormone produced by adrenals. Adrenalin is similar in action to ephedrine but has a much stronger effect. Both substances are still in use, although with the advent of the drug industry, other remedies have appeared on the market. At present, different types of bronchodilatorsinhaled, injectable and oralexist. Some provide immediate relief,
some delayed, the effect of others starts only with sustained consumption. There are bronchodilators taken in the event of an attack, others are taken on a daily basis. All of are similar in their purposeto open up the air passages. Take notice: The mode of action of all bronchodilators is their activation of the enzyme cAMP and subsequent inhibition of the release of histamine and histamine induced inflammation promoting chemistry.49 This is proof that the best activator of cAMP, histamine, is intentionally substituted by less effective stimulants.
INHALED BRONCHODILATORS
Inhaled bronchodilators, although younger than their oral relatives, are the most commonly used relievers. They belong in the group of Beta-adrenergic agonists, that is, activators of Beta-adrenergic receptors that open the bronchi. Beta-agonists are the most widely prescribed bronchodilator drugs for the symptomatic treatment of reversible airways disease. They alone generated revenues estimated at US $194 million in 1988, and represent a class of drug where the number of prescriptions is growing annually.50 The effect of shortacting bronchodilators starts within few minutes and may last up to 6 hours. The spontaneity and unpredictability of asthma dictate that these rescue drugs be carried in a pocket or purse even by patients with a mild form of the disease. An attackan inhalation of the magic stuff, and the patient can go on in the majority of cases. In the past, the fast symptomatic relief created the impression of the drugs safety. For decades, inhalers were recommended for use not only during attacks but also as a preventive measureto keep the bronchi free at all times. Certain adversities of bronchodilators were accepted as inevitable: dryness in the mouth and throat, trouble sleeping, restlessness, hyperness (especially in children), rapid heart beats, shakiness, dizziness, headaches and elevated blood pressure. However, weighing the cons against the pros was in favor of the inhalers. They gave the ability to breathe and literally saved lives. Not a common but possible consequence of their use is a paradoxical bronchoconstrictionwhen instead of opening the bronchial tube, the bronchi constrict. This was described in occasional cases but did not get any publicity, although pharmaceutical compendia do warn about this possible side effect. Like many other drugs, bronchodilators have a rebound effect: with long-term use, they start to worsen the condition instead of improving it. This rebound effect as a consequence of their frequent use became known
Bronchial Asthma
271
soon after their introduction. The five-fold increase in mortality rates among their users compared to non-users was reported in the forties. Only during the first major epidemics of asthma deaths in 1960s, did the matter receive extensive coverage. Regrettably, only the inhalers containing high concentrations were blamed for the casualties and not the group as a whole. The full scope of the damage of all types of bronchodilators was not realized until the early eighties. Only then, studies turned to all medications of this class. The dramatic rise of asthma morbidity and mortality hit Englishspeaking industrialized countries the hardest and necessitated epidemiological studies. Epidemiology investigates the relationship of different factors that determine and influence the frequency and distribution of phenomena in a defined human population. In this case, the object of the investigations was the effect of the lasting consumption of the life-saving bronchodilators upon the course of asthma. England, Australia and New Zealand initiated local trials as they were the countries that had a sevenfold (!) increase in the death rate among children between 1 and 14 years of age since the drugs introduction. The U.S.A. and Canada followed. The findings shocked the medical community. Morbidity and mortality from asthma appear to be increasing, and it has been suggested that medications used to treat asthma are contributing to this trend, informed an article in The New England Journal of Medicine in 1992. These findings were based on the unusually long (10 years) investigation period conducted in the province of Saskatchewan, Canada. We found that the use of. ..bronchodilators... was associated with an increased risk of the combined outcome of fatal and near-fatal asthma, as well as of death from asthma alone.51 The facts revealed that those asthmatics who used a placebo were much safer than the ones treated with bronchodilators. Placebo is a dummy medical treatment that has no specific pharmacological activity against the patients illness. It is a sugar pill, in the language of lay persons, that is administered to the control group in a scientific trial. In other words, the clinical control study concluded that putting up with some difficulty in breathing was, in the long run, better than to always have open airways. Therefore the countries most able to afford bronchodilators became the victims of the drugs accessibility. Many of the side effects of overuse are still unknown. One of them is, the rebound effect of bronchodilators, which turned out to be stronger and more lasting than had been assumed. Worn out by frequent stimulation, Beta-
receptors may completely atrophy, that is, lose their natural ability to dilate the bronchi. One day, they may not respond to the inhaler, or respond paradoxically by constricting. This is fatal for the patient. It is worth mentioning that all this knowledge had occasionally appeared in periodical literature within the two decades before the catastrophe became official, but the specialists had been too busy with prescribing bronchodilators to read and seriously consider the material. Those who set guidelines usually have close ties with the drug industry and have personal reasons to keep silent.52 A further well known side effect of the sustained use of bronchodilators is that they affect the cardiovascular system, and this may account for cardiac arrest. Another potential grave complication is that the patients body may start to produce antibodies to the receptors, and the immune system rejects them. Finally, one complication is the finding that bronchodilators shift the underlying chemistry in favor of allergy promoting inflammation. This explains the paradoxical increase in asthma morbidity and mortality associated with the chronic use of Beta-adrenergic agonists.53 Thus, not only do inhalers make the body defenseless locally by paralyzing the work of the vital receptors, but they also promote the underlying immune inflammatory process and by that, accelerate the progress of asthma on the whole. This, however, increases their consumption, and thereby their profitability. Up until now, most professionals, not to mention the public, remained unaware of all of this information. However, the declared facts were a blow to the inhaler manufacturers. They needed to save face (and revenues) and started to defend their products. Thus, in 1992, Glaxo Canada (i.e.GlaxoSmithKline), the worlds largest producer of the most frequently prescribed bronchodilator, ventolin (salbutamol sulphate), distributed a flyer thanking doctors for prescribing it. The flyer claimed that the drug had over 18 years of safety and efficacy behind it. It stated that by prescribing ventolin, doctors helped the company to sponsor special programs, in particular, respiratory fellowships, a career counseling program for medical students, support for symposia and the distribution of reference materials. The flyer said, So the next time you write a Ventolin-no-substitution prescription, do it with confidence and pride! Both your patients and your profession will benefit. To tell the truth, I dont think that Glaxo needed to worry. Considering the current state of asthma management, no patient can escape. At the time of the numerous epidemiological studies in the eighties, asthma rates in the North America, though on the rise, did not reach the
Bronchial Asthma
273
same high level as in other English-speaking countries for two main reasons. First, Australia and New Zealand, for better efficiency, used stronger concentrations of the aerosols than North America. Second, North America was ahead in the aggressive introduction of steroids, the use of which temporarily reduced the need for bronchodilators. The shocking statistics on the link between bronchodilators and mortality necessitated changes, i.e. cut the drug use. The conclusion was that doctors over-treated patients with these symptomatic medications and disregarded the underlying inflammation. This gave the green light to anti-inflammatory steroids whose casualties we have already started to count. Ironically, despite the universal caution concerning frequent use of inhaled bronchodilators, they have remained the most commonly (ab)used medications. In fact, we witness the rising resistance of asthma to all conventional medications, including steroids, and the need for air necessitates that asthmatics use bronchodilators more and more regardless of their risk.
LONG-ACTING BRONCHODILATORS
Bronchodilators that possess a prolonged mode of action12 hoursare a fairly recent product on the drug market. Basically, they are a variation of the short-acting bronchodilators because they merely target the same receptors. The lasting action of the newer subgroup is due to their delayed clearance, which means that their effect is similar to a frequent or sustained use of shortacting type inhalers. Long-acting inhalers became front-line medications but at the same time remained an add-on type. Thus, the entry of serevent (salmeterol) in the Canadian Compendium of Pharmaceuticals 2002 states that the drug is not a substitute for inhaled or oral corticosteroids, and that corticosteroids should not be stopped or reduced. The effect of long-acting inhalers starts 10 to 20 minutes after inhalation, this is why the use of longacting relievers still necessitates the concurrent use of fast relievers for emergency purposes. This recommendation simply means patients end up with two bronchodilators instead of one, and as a result, get much higher doses. The pharmaceutical giant, Novartis is the producer of a long-acting bronchodilatorforadil. Novartis is frank in describing the limitations of the product. Its brochure states that there is no data indicating that foradil provides greater efficacy than or additional efficacy to short-acting inhalers. Among the side effects, the manufacturer lists serious acute respiratory events, including fatalities and claims to be unable to determine whether
there is a causal relationship between long-acting inhalers and such acute events. However, the dismal experience with all types of bronchodilators seems to have motivated Novartis into discouraging the use of foradil in patients with worsening asthma. Most probably, this drug is neither worse, nor better than similar products from other manufacturers. Some authors in North America have started to associate long-acting inhalers with grave statistics of adverse reactions, as was the case with their short-acting relatives because, in principle, these drugs have the same mode of action: used twice daily, long-lasting bronchodilators differ from their short-lasting relatives only by the longer duration of their effect. Their delayed clearance may be handy in sparing the patient from getting up at night and searching for short-acting inhalers, but both preserve the same or similar adverse potential. Moreover, the prolonged mode of action contradicts, even violates the spirit of the generally accepted guidelines worked out in the early nineties, that warn about the danger of regularly using bronchodilators of any kind. long-acting Beta-agonists, such as salmeterol, have little place in the treatment of asthma if one follows the guidelines for therapy, concludes the article written in the early 90s.54 In medicine today, however, everything serves the drug industry, not the patients, and epidemiological studies on the lasting use of long-acting inhalers may only be done if the mortality figures become outrageous. I doubt doctors know about a study conducted back in 1992 that found a threefold, though not statistically significant (?!) excess of asthma deaths among approximately 15,000 patients dispensed the long-acting agent salmeterol (serevent), compared with subjects taking the short-acting salbutamol (ventolin) four times a day. 55 I did not expect my predictions about the drugs danger would come at the peak of its aggressive imposition on each and every person with asthama. On August 15, 2003, when my book was already with the publisher, a letter from Glaxo, signed by the Vice President and the Chief Medical Officer Anne Phillips, was sent to each doctor in Canada stating that multi-centre research studies had been stopped in the United States due to a small but significant increase in asthma-related deaths in patients receiving Serevent. Now, it has become a restricted medication, and doctors are advised to protect the wellbeing of their patients and cautioned about prescribing the drug.
Bronchial Asthma 275 THEOPHYLLINE
Theophylline, oral and injectable, is another older kind of bronchodilator. It does not produce the immediate effect of inhalers and is therefore prescribed for regular use along with them. With theophylline, there is a fine marginal line between a safe dose and an overdose, and the manufacturer writes in the pharmaceutical compendium that the margin of safety above therapeutic doses is small. This means that a dose considered therapeutically normal may easily induce side effects, or any minor increase may pose a threat. Theophylline has a cumulative effect, and its clearance from the body depends on many medications that may be concurrently taken both for asthma and for other medical problems. It is always an adjunct in the management of asthma, and an overdose may occur because of the other consumed drugs and their interaction. Smokers are in a higher risk group: they require larger doses due to chemical incompatibility of the drug with certain tobacco ingredients. To avoid an overdose in the case of poor clearance, all patients who continually take theophylline should undergo periodic blood tests to determine its level. Regrettably, less serious symptoms do not always show up as a warning before grave ones occur convulsions, cardiac arrhythmia, circulatory collapse, coma and even death. The world-famous 10 year Canadian survey conducted by Dr. Spitzer reveals that not only does the use of short-acting inhalers increase mortality, but the use of theophyllines, was also associated with an excess risk of a major adverse event. A major adverse event is the euphemism for death. Naturally, when theophylline is used together with short-acting bronchodilators, which is not so infrequent, the risk drastically rises. Their combined use is not so infrequent due to the growing asthma resistance and doctors desire to prescribe anything that will help their patients breathe. However, the main thing about theophylline is that, in addition to all its adverse potential, its potency is negligible. It used to be the first-choice bronchodilator.56 It was highly prescribed in the past because its role in asthma management was overestimated, but at present, there was complete accord among the consensus members about the declining role of theophyllines.57 This was said when bronchodilators as a group fell into disfavor. Resistant asthma prompted the leading allergists to develop drugs with an effect similar to theophylline, despite all the criticism of it in the recent past. The development of these drugs is currently led by L. Lichtenstein and S. Holgate, the worlds two most knowledgeable immunologists.
CONCLUSION ON BRONCHODILATORS Textbooks do not disclose the scientifically recognized mechanism of bronchial obstruction in asthma, which is the enzyme cAMP-dependent histamine-induced pro-inflammatory chemistry. This fact, however, has been known since 1968, when it was first described by L. Lichtenstein.74 Neither do pharmaceutical compendia disclose the cAMP-related mode of action of bronchodilators. Silent about this is the entry for ventolin, the most common short-acting bronchodilator. Still, the year 2000 entry on its cousin serevent, a long-acting inhaler, spills the beans: the medication offers more effective protection against histamine-induced bronchoconstriction. The side effects of this are well known: While such pharmacological effects are welcomed by patients, the practice of continually inhibiting mast-cell degranulation may not be as beneficial as originally believed. The text of this already-quoted article explains what makes the use of bronchodilators undesirable: Betaagonists can upregulate IgE production and induce a reduction in suppressor/ cytotoxic T-cells.58 You will recall that IgE antibodies are a pro-disease element, and that a low number of T-suppressors allows allergies to progress. As for cytotoxic cells, they help destroy viruses, bacteria and cancer cells. Now make your own judgment as to what is good for you. The effect of these drugs is known as being wide spectrum. By suppressing mast cells, they not only suppress their production of pro-inflammatory mediators and cytokines, but also of the ones that may be broadly considered anti-allergic or anti-inflammatory. The suppression could result in chronic tissue damage and increased scar tissue formation. Such changes are certainly consistent with the observed deleterious effects of regular treatment of asthmatics with beta-agonists, the article informs us. And so the wisdom of allowing this to occur on a chronic basis is questionable; the author thinks it is time to begin to clearly identify the underlying mechanisms. These mechanisms are known, but now, 10 years later, they still out of reach. If beta-agonists are deleterious, what about other drugs of this group? Since information on histamine is usually hidden, only an educated reader will understand that theophylline also aims at its inhibition. The 2002 Canadian Compendium of Pharmaceuticals writes on page 1683 that The actions of theophylline may be mediated through a resultant increase in
Bronchial Asthma
277
intracellular cAMP. Although the compendium states that the exact mechanisms(s) has not been determined, this is not true. As we know, the mechanism of increasing cAMP by different agents (theophylline included) was studied by L. Lichtenstein who said that histamine, like no other agent is effective in increasing cAMP, which, in turn, results in the inhibition of the cellular histamine release. Oh, this omnipresent histamine! For now, bronchodilators are a compulsory medication for all asthmatics. Their high use under the circumstances of growing asthma morbidity remains a cause of concern. Two authors, a medical doctor from the Washington Institute for Asthma and Allergy and a mother of an asthmatic child, who made the fight for better asthma treatment her lifes mission, grieve that the published literature is lacking in data on the frequency and severity of medication side effects in the general asthma population.59 They say that up to 79% of the surveyed 1834 asthmatics had unwanted sideeffects from their bronchodilators. When those patients complained to their doctors, the advice was either to change the brand (which helped little if at all) or put up with the complications. The authors conclude that there is a need for new, rapid-acting bronchodilators with fewer side effects. Given the current situation of complete secrecy surrounding histamine, asthmatics do not stand a chance of getting such medications. The knowledge that could lead to the reduction in the use of bronchodilators will not get through the barriers established by the drug producers who are readily supported by the medical Establishment. Solid proof of this claim is that Dr. M. White, one of the two authors of the article, had previously written the chapter Histamine in the extensive book Inflammation in co-authorship with M. Kaliner, Head of Allergic Diseases Section in the National Institutes of Health in Bethesda. Dr. M. White is also the author of the article The Role of Histamine in Allergic Diseases.60 Her works as well as her (earlier quoted) presentation at the symposium Histamine and Disease in 1989 on the cardinal role of the H2/3-receptor reveal that she is knowledgeable in the underlying mechanisms of allergy. There must be reason that prevents Dr. White from informing her co-author, Mrs. N. Sander, of that substance that has self-inhibiting and self-remedial propertieshistamine. This substance, if used in therapy, would probably help Mrs. Sanders daughter to avoid the dangerous bronchodilators.
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

INTAL AND TILADE
Modern medicine dictates that relievers be taken only with the protective background created by another group of medications, taken daily and allegedly targeting the underlying allergic inflammation. These drugs are called controllers and represent the second largest group of common asthma medications. The group is subdivided into corticosteroids and non-steroidal remedies. Among the non-steroidal anti-inflammatory, there are Intal and Tilade used as inhalers. Intal has been in regular use for decades, and mostly in children. Tilade is much younger. Both are intended for regular daily usage and should not be used as an alternative to bronchodilators, state pharmaceutical compendia. This simply means that they are adjunct drugs, and bronchodilators are their imperative companions. Consequently, not only bronchodilators are needed but, too often, steroid therapy is used as well. The pharmacological action of Tilade is inhibition of the release of mediators from mast cells, both pre-formed and generated, during an allergic reaction, as pharmaceutical compendia inform us. Since there is only one pre-formed mediator in mast cells, histamine, and the rest are induced by its initial spill, we can arrive at the only one logical conclusion: the anti-inflammatory action ascribed to Intal and Tilade is accomplished essentially through their inhibition of histamine release.
ZADITEN
Zaditen is a product of the early nineties. Its primary consumers are children, therefore the medication is sold mainly as a syrup. Our success is childs play, assures a picture advertising Zaditen. Let us see if it is so. The prescribing information classifies the medication as a paediatric asthma prophylactic and anti-allergic agent, as an add-on-medication in the chronic treatment of mild asthmatic children. Furthermore, several weeks of Zaditen therapy may be necessary before the therapeutic effect becomes clinically evident. Zaditen is recommended for children over three years of age, twice daily for six to twelve weeks, the objective being to achieve the greatest effect and to reduce the use of other concurrent medications, steroids in particular. The adverse effects are mentioned as being of a relatively low incidence. Among them are sedation, weight gain, rash, respiratory infections, headache, sleep disturbance, abdominal pain, rashes, ear infections, nose bleeds, puffy eyes. The text warns about amplification of the sedative
effect in kids taking antihistamines concomitantly, which is not so uncommon. The ad advises that Zaditen can significantly decrease the frequency and severity of acute asthma attacks, and there is a possibility of lessening the dose of other medications: It is not fully established, but some patients may be able to reduce corticosteroids. Wait a minute, there is a contradiction here: Zaditen is indicated for mild asthma, which in itself excludes the chances of severe attacks. However, if a child is on steroids but still has severe attacks, then his asthma is not that mild, and Zaditen should hardly be prescribed. The ad described in detail the danger of steroids and the weaning process, and this gave me a feeling that steroids were not among the product line of the Zaditens developer. The Compendium of Pharmaceuticals confirmed that. There is no need to argue that danger from Zaditen is minimal, especially compared to other asthma drugs. However, do not forget that Zaditen, Intal, and Tilade are supplementary medications, and the chances of adverse reactions from any drug increase in proportion to the length of its use. From childhood, an asthma patient is turned into a slot machine for ineffective drugs which have to be taken for a long time in combination with other allegedly more effective medications. All this in the expectation of a temporary improvement. This makes sense when seen in economic terms: Profits can only be harvested from chronic disease, investigative reporter Jeffrey Robinson was told by the CEO of a giant pharmaceutical company.61 It is of interest that among the pharmacological properties of Zaditen, the compendium lists its ability to inhibit histamine release through blocking the H1 receptors, which turns the drug into just another antihistamine. Indeed, Zaditen is often called a mast cell stabilizer. So far, due to the oversight by allergists, human mast cells are still described by all dictionaries and textbooks primarily as carriers of histamine granules, and to stabilize these cells can only mean to control their histamine spill.
ANTILEUKOTRIENESNEW DRUGS FOR ASTHMA Antileukotrienes are the first novel class of therapy introduced for asthma in the last 30 years, writes P. Barnes, one of the worlds leading immunopharmacologists and the chief consultant to asthma drug producers.62 This admission is striking in that every year, we hear about new breakthrough medications, and it turns out there were none for 3 decades. What are these novel drugs? They are inhibitors of a group of pro-inflammatory allergy mediators called leukotrienes
and work in a manner similar to the antihistamines blocking histaminic effect. Antileukotrienes, actually, guarantee the future prosperity for the drug manufacturers, and be assured, we will see many on the market. This is what P. Barnes says: Many inflammatory mediators are involved in atopic diseases, and in asthma, over 50 different mediators have been identified. This implies that inhibitors of single mediators would be unlikely to be of major clinical benefit. The author adds that some mediators may play a more dominant role, which means they will have priority for suppression. It is of interest that antileukotrienes are described by Dr. Barnes under the subtitle Mediator Antagonists. He starts the list with antihistamines, however, as is common today, and manages to write about them without once mentioning histamine to which they are anti! Accolate and Singulair are the first antileukotrienes ever developed. Singulair, the product of the pharmaceutical giant Merck-Frosst, received the Prix Galien Canada 2000 as the best drug of the year. When it appeared on the market it was called in the media bronchial Viagra. One can only hope that the real Viagra works better. Judge for yourself how effective antileukotrienes are. Before coming on the market, they had been tested on several hundred children with mild to moderate asthma for a few-week perioda time too short to make reliable conclusions. The drugs safety for pregnant women is not known, neither is safety for a fetus or nursing mothers. They are add-on medications, and the producer of Singulair insists it be taken along with the management drugsanother nice euphemism for steroids. As was admitted by antileukotriene researchers, the drugs are relatively efficacious only in asthma triggered by exposure to cold and exertion and also in aspirinsensitive patients, but even these groups should not part with their rescue bronchodilator. In a recently conducted study, adding an antileukotriene to inhaled steroids in a mild asthma did not show the results better than with the inhaler alone.63 Although anything that can relieve the fate of asthma patients would be great, the above-listed limitations do not permit one to seriously consider antileukotrienes as solution of asthma problem.
ANTI-IgE AGENTSANOTHER NEW PROJECT
Another group of novelty drugs is the anti-IgE agents tested mostly on animals and expected to be FDA-approved several years from now. The positive aspect of these drugs is that, unlike the most commonly used medications, they do not compromise the immune system. However, the best way to
Bronchial Asthma
281
expose an untenable position is to do it through the persons own admissions. The true efficacy of anti-IgE medications becomes evident from the statement made by the group of scientists who conducted the study on them: after 20 weeks, serum free IgE concentrations decreased by a mean of more than 95 percent, but the patients still continued to suffer from asthma (!?).64 Not only does this show the limited effectiveness of these new agents, but also indicates the insignificance of specific IgE antibodies in the production of asthma: cleared from antibodies, patients continued to suffer from asthma. Of special interest are accidental revelations made by the developers of anti-IgE medications: these drugs possess a stimulatory effect on T-cells and anti-inflammatory cytokines. Although the producer does not specify how it occurs, the mentioning of T-cells in this context can have one meaning only. The only established biochemical pathway for a positive effect is T-suppressor activation, which then activates anti-inflammatory cytokines, while T-helper activation plays mainly a negative role in allergy since they help to produce pro-inflammatory chemistry, including IgE antibody formation. In any case, the solution lies not in suppression of T-helpers and pro-disease chemistry by daily medications, but in T-suppressor activation that may free the patients of all drugs.
THE OXYMORON OF IMMUNOSUPPRESSIVE IMMUNOMODULATORS Dr. Barnes extensive review of asthma medications65 includes cytokine modulators, and corticosteroids are among them. Remember, the scope of their suppressive action goes beyond the quelling of the targeted disease-promoting cytokines and mediator and covers total cellular production. By definition, modulator is a specific inductor that brings out characteristics peculiar to a definite region.66 As the peculiar characteristic of the immune system is to defend, a modulator should facilitate this protective function. Steroids do the opposite: they suppress the immune system. The dictionary also defines immunomodulation as adjustment of the immune response to a desired level. Immune system suppression can hardly be desirable in asthma. Add to the suppression of immune cells another well-known pharmacological effect of steroids, namely gene suppression at large, and you have the basis for undermined health of the children of steroid users. Thus, by twisting the meaning of the term, allergists present a dangerous drug group as healing agents. Another immunomodulator suggested by Dr. Barnes is cyclosporine. Although new in asthma, this drug is old and has been used in cancer
chemotherapy to suppress tumor growth and in organ transplants to prevent graft rejection. Cyclosporine belongs to the group of drugs called cytostatic, the term defined by medical dictionaries as an agent that suppresses cell growth and multiplication.67 In other words, aiming at the reduction of allergic responses, the drug scorches the immunity. A bright prospect for its consumers! Still, cyclosporine has certain advantages over steroids: it does not cause such an array of complications, nor does it develop physiological dependence and can, therefore, be discontinued at any moment. This is the reason why allergists have turned to it.
OTHER OPTIONS IN ASTHMA MANAGEMENT In his review, P. Barnes sincerely admits that gene therapy is not feasible because atopic diseases are polygenic. In saying so, he undermines the rosy future professed for DNA immunization by two authors in the same journal.68 Barnes also mentions the positive results in allergy prevention from BCG (tuberculin) vaccination in Japan. Since later tests in Sweden failed to confirm this, the scientist does not propose, at least for now, the idea of using tuberculosis vaccine for asthma prevention, Despite the obvious deficiencies of the existing asthma medications, allergy medicine will not admit its impotence, and Dr. Barnes declares that Inhaled corticosteroids have dramatically improved the treatment of asthma and are now first-line treatment for persistent asthma in all patients. He forgets that just two paragraphs earlier, he made the contradictory statement that in order to avoid their (steroids) side effects, there is a need for the development of new treatments that deal with more severe asthma (which) is currently not well controlled by high doses of inhaled corticosteroids. THE CHOICES ALLERGISTS GIVE TO ASTHMA PATIENTS Considering that the latest guidelines insist that steroids be prescribed even for mild recurrent asthma, patients have two drug choicessteroids and bronchodilatorsand both are considered compulsory. Bronchodilators are taken for an immediate relief, steroids are taken daily as a means to prevent attacks. Neither of them cures asthma, and even combined and accompanied by adjunct medications, they are still, too often, inefficient. Therefore, an asthmatic is forced to choose not between two evils but both evils. The latest invention, combo drugs consisting of long-acting bronchodilators and inhaled steroids, cannot be proclaimed as particularly effective either. What to do at
step 3 of the asthma guidelinesincrease the dose of inhaled steroids or change the dose of a long-acting Beta-agonist drug? asks the title of the most recent editorial, one of the authors of which is R. Beasley, a renowned asthma epidemiologist.69 Step 3 is the state when the combo drug fails to relive asthma, while a higher dose of steroids gives serious side effects. The (doomed, in my opinion) decision is to continue to perscribe both drugs, and merely adjusting the dose. An embarras du choix, an embarrassment of choices, as the French say. In the eighties, the more alarming statistics on asthma in the United Kingdom compared to those in North America allowed two prominent Canadian allergists, Dr. M. Newhouse and Dr. J. Dolovich, to blame their less lucky colleagues for the high fatality rate caused by their failure to treat promptly, that is, use daily steroids. The comments caused an angry response from the British allergists who said that such theory unfairly stigmatizes the entire medical profession of certain countries such as England and Australia.70 They felt that the cause of the skyrocketing mortality was attributable to the extraordinarily high-dose bronchodilators used in their countries and not to their professional deficiency or bronchodilators in general. Who was right? At present, 15 years later, one can come to the conclusions that neither side saw the roots of the problem. Of course, high-dose bronchodilators could be blamed for the soaring death rates in the 80s. Yet, now that patients in all first-world countries are in steroids up to their neckties, why are asthma morbidity and mortality still on the rise? Why havent the overwhelmingly prescribed steroids diminished the need of bronchodilators? A much higher consumption of bronchodilators today is warranted by the combo medications that are becoming more and more popular even though, as we quoted earlier, long-acting beta-agonistshave little place in the treatment of asthma if one follows the guidelines for therapy.71 The rising popularity of such combo drugs makes one wonder about their mode of action, and this makes one suspect a well-organized plot. The idea behind this must be the ability of steroids to facilitate the stimulatory biochemical effect of Beta-agonists on cAMP with the resultant temporary inhibition of release of histamine and histamine-induced inflammation producing chemistry. This is stated as being the work designated for postgraduate courses; one of the authors is an ex-president of AAAAI, Dr. W. Busse.72 Dr. Busse has always worked on the histamine-related immune mechanisms, and this was the reason why during our meeting at the international symposium in 1989, S. Holgate recommended I talk to him. He cannot be unaware of the fact that histamine acts
through the same mechanism via H2-receptor stimulation and that it acts in a sustained and profound manner. It is obvious that attempts to achieve the desired effect by using less efficient tools cannot be accidental. A popular ad in medical periodicals shows a pretty young asthmatic woman who is able to extinguish candles on her birthday cake with such force that the cake itself flies away. This colourful ad assures that Advair, the first of such combo drugs, is more beneficial than bronchodilators and inhaled steroids taken separately. Besides, as the text on the ad indicates, the patients taking this combo drug must use short-acting bronchodilators for acute symptoms. The asthma candle is being burnt from both ends by the hazardous agents. Would you trust a technician who came to your house to repair your TV with a hammer and saw? Do you think our body is any less complex than a TV set? An immunosuppressive drug has become the main instrument in repairing the sophisticated ailing machineryour immune system! The book has been with the publisher, in October 2003, when the news came that the Canadian provice of Quebec was removing the combo medications, Advair by Glaxo and Symbicort by Astra-Zeneca from the drug plan formulary to prevent physicans from using them as first-line therapy. Other provinces will follow. This is the beginning of the end: the best asthma medication turned out to be so hazardous that caution is advised when they are prescribed. Now, the internationally accepted guidelines that had supported their priority among other drugs have to be reconsidered. Had the situation with asthma not been so grim, the conclusions of the medical elite could have been considered laughable: as a replacement of the combination of steroids and bronchodilators, these drugs ae suggested separately, steroids as the first and bronchodilators as the second line of therapy! Another embarrassment of choices!
OLD GUIDELINES Two periods can easily be traced in the management of asthma. They become obvious through the history of steroids. When steroids were first introduced in pills and injections, their powerful effect and the feeling of being able to move mountains, was so great that doctors started to prescribe them not only for rheumatoid arthritis and more rarely, in asthma, but also as a life style drug. The fact that steroids were a synthetically produced body chemical created the illusion of their safety. The realization of danger came soon when withdrawal symptoms and numerous side effects were noted, and this forced the medical profession to became cautious prescribing in the drug.
The prescribing pattern started to change with the appearance of the inhaled form in the seventies. Inhaled steroids (allegedly) worked in the lungs and bronchi, and this (allegedly) greatly reduced, almost eliminated, their side effects. With inhaled steroids, the era of a non-aggressive use of steroids came to an end. The late 80s and mid-90s became the transition period from the cautious use of steroids to their becoming the remedy of practically unlimited use. The change was necessitated by the situation in the mid eighties: asthma was becoming more and more resistant to all therapies, and mortality from bronchodilator abuse became too obvious to conceal. The need to prescribe more steroids was explained in the May 1993 guidelines on asthma management published in The British Medical Journal. On page 776, we read, Mortality and morbidity from asthma are unacceptably high. Many deaths and much unnecessary morbidity have been associated with over-reliance on bronchodilators, underuse of inhaled and oral corticosteroids...73 These guidelines were based on controlled trials and endorsed by the British Thoracic Society, Pediatric Association, the Research Unit of the Royal College of Physicians of London, and other authoritative medical societies of Great Britain. Although the recommendations promoted the greater use of inhaled steroids even in patients with apparently mild asthma, they still allowed the more timid, five-step approach to the disease. Steroids were to be introduced only if nonsteroidal anti-inflammatory drugs failed. The guideline creators said that their recommendations should be seen as a general framework within which most patients with asthma can be managed. This meant that the guidelines were not of a compulsory but of an advisory kind, as they should be. At that time, immunology moguls occasionally expressed their reservations about adverse effects of steroids. Thus, the same year, when the said British guidelines were published, Dr. S. Holgate wrote in the Lancet that the risks of early use of inhaled steroids in treating mild to moderate asthma could outweigh the benefits when treatments with long records of safety and proven efficacy are available as a prior alternative. It is a pity Dr. Holgate did not name the drugs with proven efficacy as an alternative to steroids. Do they exist? It is not a secret that medicine has become a subsidiary of the pharmaceutical industry and for this reason often disregards scientific data and the ethical norms of the profession. The lack of independence of medical scientists in expressing views becomes especially obvious when one looks at the sponsors of conferences. Their names
forecast what medications will be praised by the speakers. The Second Canadian Asthma symposium held in Ottawa in 1994 chaired by S. Holgate with speakers from Canada, U.S. and U.K. serves as an example. Fisons Pharmaceuticals, producer of Tilade and Intal, was the sponsor of the event. As should be expected, the participants somewhat exaggerated the effect of these drugs by equating it to the effect of steroids. The general opinion was similar to the one expressed by Dr. P. Konig from Columbia School of Medicine who said that the efficacy of nonsteroidal and steroidal drugs is comparable, but safety is better with nonsteroidal treatment, and the risk/benefit ratio, therefore, favors nonsteroidal agents. After 1994, symposia are sponsored, as a rule, by steroid producers, and, as should be expected, their products are now considered the only efficient and also safe asthma remedies. All practising doctors have to obey the steroiddominated guidelines, irrespective of their professional and legal rights not to accept any guidelines. They know that the disobedient will be skinned, scalped or at least weeded out. As the great Polish writer Ezhi Lentz once said, the word likemindedness is put together by cut-off heads. Only the growing awareness by the public of the side effects of steroids slightly tempers the zeal of prescribing these drugs.
WILL YOU COME INTO MY PARLOR? The drug industry is at its best when presenting its products that lure both doctors and patients. The steroids packaging is attractive, the devices are easy to use. While steroids can be injected or taken in tablets, the most common way is to inhale them. Because a high percentage of the drug consumers are children, the most wily ways are used to attract them and make the delivering device appealing. The plastic is of bright colours, and the medications look more like toys. Indeed, I have seen a puffer made in the shape of an animal. There are regular metered-dose inhalers, a spacer device with or without a mask for younger children, devices with compressors for babies and toddlers. The impression one gets from looking at the pictures of smiling mothers who hold their baby with a mask covering the kids face is that the parents are happy to see nicely fitting masks on their children. Young users may imagine they are playing war games as they wear their masks. Complete satisfaction! In other words, steroids to satisfy any taste! Shouldnt asthma patients be grateful to drug developers for their far-reaching care?
We must remember, however, a simple axiom: the worse our health, the higher the industrys profits. The natural chain of events fits this axiom: a chronic medical conditionchronic use of a medicationthe bodys adjustment to the drug and the need for a higher dosemore and more pronounced side effectsdrugs to relieve the side effects, etc. In asthma, even if a patient starts with inhaled steroids, the finale is dependence on them due to the failing or atrophied adrenals and decreasing ability of the stifled T-suppressors to defend the host. Even if the side effects of steroids do not appear at once and are minor for some time, the patient inevitably ends up with a cascade of them hitting different organs and eventually undermining the whole body. You say you take steroids in innocent small doses? For how many months? Years? Decades? Doesnt it remind you of smoking safe cigarettes with filters?
DOUBLETHINKING The universal acceptance of steroids was unable to exclude a hesitation: to give or not to give these drugs? What to use as a substitute if they produced significant side effects? Are there treatments with proven efficacy, as Dr. S. Holgate called them? At their meetings in the early nineties, allergists argued with each other, and at times, even with their own views. The inconsistency in the opinions of professionals on asthma is well demonstrated in the 1996 report Canadian Asthma Consensus.75 Here are some examples: Theophylline remains an effective anti-asthma drug. (p. 95) Theophyllines should not be used as first-line therapy in asthma (p. 96) (Why not, if the drug is effective?)

(add-on medications are) warranted in asthma... when toxicity or fear of toxicity from corticosteroids is a major concern (p. 96) If symptoms persist (when taking add-on medications), inhaled corticosteroids should be prescribed instead. (p. 96) (Despite their toxicity?) Immunotherapy is generally not recommended in the management of asthma. (p. 96) At present, immunotherapy... may be considered if disease activity is inadequately controlled by allergen avoidance and pharmacological therapy. (p. 96) (To consider the least effective treatment after all effective have failed?)
Air pollution is the principal outdoor irritant... linked to exacerbations of asthma (p. 92) Indoor irritants... appear to represent an even greater hazard to the health of the asthmatic. (p. 92) (Where should an asthmatic live indoors or outdoors?)
Various types of indoor air cleaners are available... shown to reduce levels of irritants significantly (p. 92) health benefits (of air cleaners) have yet to be consistently demonstrated. (p. 92) (So, to buy air cleaners or not to buy?) Only deep dissatisfaction with ones own results can produce such contradictory remarks within a single document ironically called Consensus, the word which dictionaries define as unanimity in opinions.
CONSENSUS ON THE LACK OF CONSENSUS Due to the dramatically rising incidence of childhood asthma and its growing severity, meetings in the late eighties and early nineties, followed one another in the hope of working out acceptable guidelines. An impressive one including delegates from 22 countries was held in 1991.76 The participants agreed that there have been many new questions but no dramatic advances in either the understanding of the condition or its management. They spoke about the vast literature of confusing information about virtually every aspect of the condition, the lack of hard data in many areas of management, and increasing concerns about many of the pharmacotherapies (drugs) at our disposal. From the legal point of view, in any medical field, guidelines are understood to be of purely educational and advisory nature, not as a compulsory directive. Therefore, inexplicable became the fact, that despite complete confusion and absence of any definitive knowledge in all areas of asthma, the participants called for strict guidelines in the management of asthma. Obligatory guidelines in an area full of questions can pursue only one aim to be authoritative, mandatory. And these guidelines were just that. Thus, after having recognized their lack of knowledge of asthma and the ineffectiveness of the treatment methods, the participants concluded that their guidelines must be a challenge to experts who have suggested alternative protocols. Thats it: we dont really understand the disease or its treatment, but dont dare try new ways without our regal permission! These reputable specialists warned that management which deviated from the consensus
recommendations might be viewed unfavorably in legal proceedings. Indeed, the threat of litigation is the best deterrent against potential deviations and the best way to enforce the undisputed orthodoxy. Such guidelines serve to ensure obedience, not the search for of better management of asthma. Why do specialists drive everybody into narrow regulations instead of searching for something more effective? Because a choir sounds impressive only when all vocalists sing in unison. Because the vocalists feel more confident if they hide their professional impotence behind their togetherness. Because abiding by the guidelines, no matter how confusing, can save them from potential liability. Because an alternative can destroy the thoroughly built structure of the ranks and therefore has to be subdued by the threat of potential litigation. Because the painted facadethe consensusconceals the decrepit scientific and medical structure, i.e. ignorance in all areas of asthma. This can be admitted in a closed circle and in whispers only. It is necessary for a choir to sing in unison although the universal agreement on any single opinion is in science dangerous both for science and for patients. The proof: a decade after these enforced guidelines we have such admissions as the following ones in the leading immunological publication: No treatment can consistently induce a lasting remission of asthma in adults, and Inadequate asthma control is a serious, widespread problem among children.77 Winston Churchill is supposed to have said that in the Soviet Union where everything was prohibited, what is not prohibited is compulsory. Todays treatment of asthma reminds me of the Soviet regime. An asthma patient has two choices: bronchodilators and steroids. Both choices are compulsory. All the rest is prohibited.
INHALED STEROIDS: ARE THEY LOCALLY ACTING DRUGS? Even the most fervent fans of inhaled steroids agree that these should be taken in as small doses as possible. The question is why if, as allergists assure us, inhaled steroids are supposedly safe. Since these drugs have become an inherent part of asthma management, we must thoroughly study their effects and dangers. Inhaled steroids were first introduced in 1972 with the purpose of reducing the notorious side effects of oral steroids, tablets. Allegedly inhalers work primarily locally in the lungs, and this spares the patient the systemic side effects. This is not true: There is minimal evidence for active biotransformation in the lung, and therefore most of the drugs reaches the systemic circulation.
Eighty percent of the systemic effect of these agents is via this route.78 Potential liability for not disclosing a drugs adverse effects forces drug companies to reveal them. At the same time, their desire to downplay side effects results in the kind of paradoxical entries as the one on Vanceril (Beclomethasone), a product of Schering. One sentence states that the drug has a strong local effect and minimal systemic effect. The next sentence reveals that only 1025% of a dose reaches the respiratory tract; the remainder is swallowed and absorbed from the gastrointestinal tract, and orally absorbed drug is metabolized by the liver. The drug producer does not explain how the drug, 7590% of which goes from the lungs into the liver, has a minimal systemic effect. If most of the inhaled steroids are absorbed by the gut, (which is systemic), they are akin to oral steroids, and this should stop all talk about the negligible adverse effects of inhalers. Moreover, steroids are by no means a cure, as symptoms recur soon after discontinuation in most patients.79 A recurrence means a return to the drug, and repeated drug courses lead to permanent complications.
INTERVIEWING THE COMPENDIUM OF PHARMACEUTICALS Compendium of Pharmaceuticals and Specialities, CPS, lists all drugs on the market and their effects and side effects. However, it seldom reaches a lay person, therefore I suggest an imaginary conference with the manufacturers of most popular steroid inhalersFlovent (fluticasone) and Pulmicort (budesonide). The answers to the questions commonly asked by asthma sufferers are the quotations taken from the 1998 and 2001 editions of Canadian CPS. I put in brackets my own remarks on the discrepancies in the texts. The answers are not snatchedout phrases but the text selected to match the questions. Besides, having attentively read the texts on several inhaled steroids in several compendia, I could find only insignificant differences in them.
Q. What sort of drugs are inhaled steroids? A. They are potent anti-inflammatory medications with strong topical (local) and weak systemic activity. (As was said, only Schering, the manufacturer of beclomethasone, acknowledges that 7590% of the inhaler is absorbed systemically, whereas other producers of inhaled steroids avoid this vital subject or distort it.) Q. What are they prescribed for? A. For treatment of steroid-responsive asthma. (This is an admission that not all asthma is responsive to steroids)
Bronchial Asthma
291
Q. To whom are steroid inhalers prescribed? A. To asthmatic patients who do not respond adequately to conventional therapy; and corticosteroid-dependent asthmatics when a reduction of systemic (oral) steroids is desirable. (This contradicts recent guidelines recommending inhaled steroids as first line medications even in a mild recurrent form of the disease.) Q. Why is it desirable to use inhaled steroids instead of systemic ones? A. Since with therapeutic doses, the minute amounts absorbed do not exert any significant systemic effect, inhalers can replace oral steroids with the elimination of the untoward effects of systemic therapy. Q. Does it mean that the inhaled drug is contained in the lungs? A. After administration by inhalation, approximately 10 to 25% of a dose reach the respiratory tract, the remainder is swallowed and absorbed from the gastrointestinal tract. (This statement implies that 7590% are systemically absorbed and thus contradicts the previous assertion that only minute amounts are systemically absorbed.) Q. How often and how long should the drug be taken? A. Regularly, even when the patient is asymptomatic. (All his life? Then, why do all guidelines recommend the dosage reduction upon improvement and weaning whenever feasible?) Q. Is it safe to take inhalers daily for a long time? A. The long-term effects in human subjects are still unknown. (After 3 decades of the drugs use the adverse effects are unknown! Are retrospective studies undesirable, or are the results silenced?) Q. How effective are inhaled steroids? A. Pre-treatment for 1 to 4 weeks may inhibit the immediate bronchial reaction. (Does it mean it may not?) Q. What if it does not? A. Exacerbations of bronchial asthma should be treated with a short course of systemic steroid which is gradually tapered as these symptoms subside. Q. Why is it necessary to taper off the drug instead of simply discontinuing it? A. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to inhaled corticosteroids.
Q. Is adrenal insufficiency reversible? A. A number of months is required for recovery of HPA function. The inhaler and the systemic steroid must be given concomitantly while the dosage of the latter is gradually decreased. If withdrawal symptoms appear, the previous dosage of the systemic drug should be resumed for a week before further decrease is attempted. Q. Are all patients able to discontinue steroids? A. There are some patients who cannot completely discontinue the oral corticosteroids. In these cases, a minimum maintenance dosage should be given in addition to inhaled steroids. Q. Can patients stop taking inhaled steroids when they wish? A. Treatment should not be stopped abruptly but tapered off gradually. (Why, if there is no or only a negligible systemic dependence/effect? Withdrawal is a systemic response.) Q. Can children use the inhaler? A. The inhaler is not presently recommended for children younger than 4 (6). (What should the younger kids be prescribed?) Q. Can pregnant women take the inhalers? A. There is inadequate evidence of safety during human pregnancy. (Why, if they have a low or no systemic effect?) Q. Is there a possibility of harm to the baby? A. Well-controlled trials relating to foetal risk in humans are not available. Like other glucocorticoids, the drug is teratogenic (producing birth defects) in rodent species. (Teratogenic effect can only result from the systemic effect. Can a drug known to be hazardous to an animal foetus be safe for a human foetus?) Q. Is there any danger to the baby of getting steroids with the mothers milk? A. The drug excretion into human breast milk has not been investigated, but it is suspected to be likely. (Arent the producers interested in the effect after the 30 years of inhaled steroids on the market? How can a drug that works not mostly in the lungs get into mothers milk?) Pharmaceutical compendia also advise that inhaled steroids long-term effects in human subjects are still unknown, and there is also no information about the possible long-term systemic effects, and therefore HPA axis
function and hematological status (blood) should be assessed periodically. GlaxoSmithKline, the manufacturer of Advair, that combines an inhaled bronchodilator with a corticosteroid, suggests in its fine print warning, under the drugs advertisement, published in medical journals: height should also be regularly monitored in children and adolescents receiving prolonged treatment with inhaled corticosteroids, which means that the locally acting medication affects growth! A real paradox. The principal defenders of the pharmaceutical products are doctors. If the drug manufacturers are legally obliged to express caution about their product, doctors do not do their best trying to expose the myths of allergies and asthma, one of which is that inhaled steroids are dangerous. Considering that the current guidelines both in Canada and US point out that steroids are rather underused than overused and are the first-line therapy in asthma, there is little wonder that doctors assure us: Inhaled medications, including corticosteroids, are currently the safest (?!) and most effective means to treat asthma. The quotation is taken from the July 1999 issue of the Canadian medical periodical Family Practice and expresses the consensus opinion.
SYSTEMIC STEROIDS Oral and injectable steroids are called systemic for their ability to affect the whole body. The published entries on oral steroids are carbon copies of the ones on inhaled steroids only in darker colours. They say that systemic steroids are prescribed for incapacitating allergic conditions and to steroid-responsive patients. The latter is admission that not every asthmatic responds to steroids in any form. These entries cautiously warn that drugs are able to affect any organ or system of organs. When taken for long periods of time, they are difficult or impossible to wean, even when the asthma, for which they are prescribed, comes under control. The compendium lists both the immediate and the long-term effects of oral steroids: a. cardiovascular systemprogressive development of atherosclerosis, cardiac arrhythmia, increased mortality after a recent myocardial infarction; elevation of blood pressure, excessive bleeding, stroke; b. metabolic complicationssalt and water retention (that is, weight gain and/or oedema); increased protein and bone loss as well as calcium excretion (osteoporosis) leading to spontaneous fractures and suppression of growth in children; increased appetite (weight gain); development of
c. d. e. f. g.
h. i.
diabetes mellitus and poor metabolism of the injected insulin in the existing diabetes; increased fat deposition. eye complicationscataracts, glaucoma, possible damage of the optic nerves; immunologic complicationshigh susceptibility to infections, development of severe resistant infections; poor healing or recovery process; psychoneurologic complicationsfrom insomnia and mood swings to personality changes, severe depression, seizures, psychic derangement; skin manifestationsthinning of the skin to atrophy, allergic dermatitis, fungal infections; hormonal changesmenstrual irregularities, miscarriages, infertility; reduced libido, impotence, hirsutism (facial hair growth), adrenal suppression to fatality; growth hormone suppression and hence, poor wound healing and stunt linear growth in children; muscular system complicationsmuscle weakness, loss of muscle mass; gastrointestinal complicationspeptic ulcer with possible perforation and haemorrhage, perforation of the small and large bowel, particularly in patients with inflammatory bowel disease.
Some complications cannot be distinctly referred to a certain category but are rather related to several interdependent systems that are affected by oral steroids. It is impossible to predict at what dose and after what period of use the side effects occur. Dosage ranges are extremely wide, and patient responses are quite variable, states the compendium and suggests the use of the lowest possible dose that provides adequate relief. The relief, nevertheless, can be partial, no matter what the dosage is, and the disease may re-appear and in a more severe form if the drug is discontinued. This, actually, turns chronically ill patients into life-long users of steroids doomed to developing all sorts of additional health problems. We should not be surprised that the statistical data about all these complications are practically unavailable. Epidemiological studies need funding, and steroid producers will not be among the sponsors of the investigations that may undermine their profits. At times, the truth comes out indirectly, through articles promoting medications other than steroids. The purpose is clearto make their own products more appealing, the manufacturers reveal the danger of steroids.
UNANSWERED QUESTIONS A lot of legitimate questions are left unanswered by pharmaceutical compendia and the allergy elite:
If steroids are prescribed for steroid-responsive asthma, what should be prescribed to the fairly large group of non-respondersabout 30%, but probably more? What is the alternative therapy for the patients who show severe side effects to steroids, but the dose cannot be reduced in view of the asthma severity? Since steroids contribute to diabetes, hypertension, peptic ulcers, obesity, osteoporosis, etc., what should those asthmatics be prescribed who already have these medical conditions? Manufacturers advise to weigh pros and cons when prescribing steroids. If the cons outweigh the pros, what else is there for resistant asthma apart from steroids? What should pregnant women or nursing mothers be prescribed if their asthma does not respond to other medications? Since inhaled steroids are not recommended for children under 4 (often under 6), what should the younger asthma sufferers be prescribed in case other medications fail? Why is it that neither the medical profession, nor the drug producers is interested in the delayed effects of inhaled steroids? Why is that within the more than 3 decades of their use, no retrospective epidemiological studies exist on any of the effects of inhaled steroids on young children? Nor on adults who have used them non-stop for many years? Nor on babies whose mothers were using the drug during breast-feeding? Nor on the babies born to mothers who used inhaled steroids during pregnancy? Steroids are lymphocyte-toxic and genotoxic, which means they paralyze both the functioning of the central immune cells and genes. Why is there only a rare mention of this in medical sources, including pharmaceutical compendia, and when it is mentioned, it appears as if only pro-inflammatory forces are suppressed? The fact that only one receptor conducts steroid messages makes it impossible to discriminate its effects and means that the suppression covers all immune forces.
The inhalers have been on the market long enough to enable access to such data. Were asthma a short-term disease, we would not have to worry about the side effects. However, in Greek, Chronos means time, and thus, chronic denotes a disease persisting over a long period. Chronic use of steroids, even in the inhaled form, must be re-evaluated by the medical profession rather than imposed more and more aggressively. As the number of asthmatics grows, with it grows the chance of having a huge percentage of the population
with undermined immune systems and numerous serious conditions (worsening asthma among them). The most effective and safe medications create the setting for this immense potential epidemic.
WHAT DOSE IS SAFE? The early 90s was the period when the wide-scale campaign of imposition of steroids began upon every asthmatic. This put pressure on those doctors who had a cautious prescribing pattern of the drugs always perceived as dangerous. The knowledge of the potential adverse effects resulted in the galvanizing effect of the word steroids. Here is one example. The Canadian Journal of CME covered the first Annual Pediatric Refresher Course at the University of British Columbia, and in its June 1993 issue on page 44, we read: Most children can be managed on low-dose steroids... Higher doses of inhaled steroids are required for some children and should be used to reduce oral steroid requirements. Alternate-day oral steroids are preferred to daily steroids on a chronic basis. Almost the same wording is preserved six years later, in The Canadian Asthma Consensus Report of 1999. Such stuttering has become a scientific habit when the topic of steroids is touched upon. The September 2000 issue of the central journal of allergists covered a meeting specifically devoted to asthma. One article writes: We have very little information on the long-term effects of asthma medications, especially inhaled glucocorticoids when administered to young children for prolonged periods of time. It has not been shown definitely whether glucocorticoids as a treatment strategy are the drugs of choice.80 The author also refers to a 1998 FDA documentation: The recent FDA meeting (showed) that there are no minimally effective and maximally safe doses (?!) of inhaled glucocorticoids defined for children. The effect of specific variables such as age, gender, race and genetics on the risk for adverse events, or lack of effects of medication also remains to be determined. On page 168 of the same issue, one may read another reference to this meeting of the FDA: Information was presented that suggested all ICSs (inhaled corticosteroids) have the ability to suppress short- and intermediate-term growth velocity. Even Low doses of most popular inhaled corticosteroids Flonase and Pulmicort are associated with a significant degree of detectable systemic bioactivity, including HPA axis suppression, states the earlier quoted source.81 In this connection, the order by the FDA ,which was obeyed by the manufacturers, to label inhaled steroids as drugs that may temporarily slow childrens growth, should be questioned regarding its accuracy.
This all means that among the numerous unknowns that surround inhaled steroids, one thing is unquestionabletheir serious side effects at any dose. They are just a matter of time. The fact that in children, the side effects manifest earlier is not surprising, since they are the most sensitive group of the steroid consumers. Similarly, the deaths of canaries in coal mines warn of the dangers that are yet unknown. A safe dose does not exist. What is proclaimed safe by some authors may be found by others to be dangerous. A dose, safely inhaled for few weeks may necessitate a drastic increase over a longer period of time, since asthma has a relentless tendency to relapse with time and/or dose reduction. In fact, any suggestion of a dose cut-back, be it in a textbook, periodical or pharmaceutical compendium, is accompanied by a warning of a possible worsening of the symptoms that can often be only by a high dosage. Steroid defenders assure us that side effects are usually reversible upon dose reduction or discontinuation of the drug. Can they guarantee the reversibility after repeated relapses and hence, repeated courses of steroids? Is a few months period, in which trials are conducted, long enough to come to conclusions about a safe dose if asthma, a life-time disease, may necessitate indefinite doses? With the phrase the clinical significance of these changes in the long-term treatment is not known, authors and drug developers free themselves from liability as well as the responsibility of answering these questions with yes or no. As a rule, conclusions are made on the basis of small groups studied for a short time, several months at most, although within the 30 years of inhaled steroids being on the market, it is logical to expect that data on their long-term complications be made available. More than a decade after the wide use of inhaled steroids, the chapter in the textbook Allergy 1985 (page 658) says: The effects, if any, of IS (inhaled steroid) drugs have not been adequately studied to date. Another decade later, in 1996, a world-renowned scientist warns that the longterm risks of their use are still a concern to many, patients and physicians alike.82 A textbook published in the new millennium again states: As with oral GC (glucocorticoid) therapy, high-dose inhaled GC therapy has been associated with adverse systemic effects, and it is still unclear whether long-term administration of inhaled GC will result in growth suppression and osteoporosis.83 The laments of the medical profession about inadequate information have not initiated an investigation into the thirty year use of inhaled steroids. Will steroid consumers sue the manufacturer and/or doctors years later when they realize that sustained drug use did produce irreversible side effects? We have examples of physicians admitting their wrongful support of smoking. We know the tobacco
industry has apologized to its victims by paying millions of dollars in liability payments. Despite all the recommendations to limit steroid use to the inhaled form, it is often impossible to avoid the oral form, and this dramatically increases the consumption and hence, complications. It may happen when the course of asthma worsens, and the patient has to switch from inhaled to oral steroids or takes both. It may also happen when, as a result of a protracted disease or severe injury, oral steroids are added to enable the patient to go through an ordeal. The very fact of adding oral steroids to the inhaled ones confirms that doctors do know that the patients using the safe inhaled steroids may, in fact, have a certain degree of adrenal deficiency and therefore need replenishment. Lucky are those asthmatics who face elective surgery and can be given high doses of injected or oral steroids beforehand. Those in emergency face a danger of perishing in case of an accident, for their adrenals may not be able to supply enough of the vital hormones, and there may not be enough time to provide an additional dose.
OPINIONS ON STEROIDS AND BONE DENSITY Basically, asthmatics cannot avoid steroids today and must, therefore, know the most common side effects. One of them is loss of bone density. It is an overwhelmingly important health factor leading to osteoporosis and growth retardation in children. The link of steroids to low bone density and hence, fragility, initiated numerous discussions even though it is common knowledge. Thus, the pharmaceutical compendium in its entry for Fosamax, the drug described as a bone metabolism regulator, lists under the heading Indications two main reasons to prescribe itfor prevention of osteoporosis in postmenopausal women and for treatment and prevention of steroid-induced osteoporosis. Despite the evidence, the tendency to downplay bone amelioration due to steroids can be found in numerous high profile sources. As is stated in the 2001 textbook Allergic Diseases. Diagnosis and Treatment on page 401, unfortunately almost all of the studies that have attempted to determine the effect of inhaled GC (glucocorticoids) on growth have been limited, making definitive conclusions regarding growth suppression difficult. Page 402 informs us that some studies have shown that short-term suppression (of growth) can occur in some children, and significant reductions in bone density of the femoral neck of asthmatics treated with inhaled GC compared to age-matched controls.84
Once Dr. L. Fraher from the Lawson Research Institute said, in his speech at an annual meeting of the American Society of Bone and Mineral Research in Minneapolis, that steroid users may end up with translucent skeletons full of holes that you can see through. We can add to this that for older patients, disabled by fractures occurring due to steroid consumption, these drugs may, actually, be fatal.
WHEN DOES THE HPA AXIS START TO CRACK? Another common consequence of steroid use is suppression of hypothalamopituitary-adrenal (HPA) axis, the regulatory system for the production corticosteroids. Although less obvious than bone amelioration, suppression of the axis is even more damaging to health and can be fatal. Therefore every article on steroids and every insert into the steroid packaging mentions the possibility of the HPA axis suppression. In the fourth decade of the inhaled steroids existence, there is no (and can be no) consensus on the dose at which the axis starts to decline, and a tendency exists to tie this complication solely to the oral form. A work published in JACI states that data using more sensitive parameters suggest that low doses of most popular inhaled corticosteroids are associated with a significant degree of detectable systemic bioactivity, including HPA axis suppression.85 Further, the article writes that within four (!) days of using 220 micrograms (the lowest dose in guidelines) twice daily produced on average 40% suppression of the axis. These data were collected among adults, and one can only speculate about the drugs effect on children. Indeed, Adrenal suppression, decreased bone metabolism, and decreased growth are of particular concern in children, in whom asthma is increasing in frequency, states an article that describes a herbal remedy.86 We can only expect more of such side effects since inhaled steroids are now introduced earlier in the course of asthma treatment in both Canada and the United States, and they are also used at higher doses than ever before.87 STEROIDS AND THE GENES As was said earlier, steroids obliterate gene expression, the functioning of the genes. As usual, we are told not a lie, but half truth: A key molecular mechanism by which glucocorticoids reduce airway inflammation in asthma is their suppression of the proinflammatory genes activated in allergic inflammation.88 The reference is made at that point to the article with the title Efficacy
and safety of inhaled corticosteroids. New developments. Since the authors of that reference are P. Barnes, the main strategist on asthma therapies, and W. Busse, the year 2001 president of AAAI, one is expected to believe them. Can steroids, universally known as indiscriminate immunosuppressors, be discriminate in their suppression of the genes? Can they selectively hit inflammation-promoting genes and avoid anti-inflammatory ones? They cannot. Steroids do a sweeping pharmacological job: quench equally the good and the bad. Thus, not only their consumers, but also their children may pay a high price for taking these safe and efficient medications.
THE HISTORIC OPINIONS ON ASTHMA The understanding of the chemical processes characteristic for each given disease is central to finding drugs for its treatment. The 2000 issue of JACI, whose cover depicts Hercules cutting off the heads of the monster called allergy/asthma, explains the meaning of the picture on page 5A: The allergist/immunologist seeks to stem the increasing prevalence of allergic diseases through a better understanding of their mechanisms. Thus, what is asthma? Until the eighties, asthma was proclaimed to be a disease of spasm-prone airways. Although information existed on what caused spasms, and why the airways in some people were so hyperreactive, this information was fragmented and never resulted in a clear concept of how to reach these causal mechanisms. The theory of hypersensitive bronchi led to the belief that asthma was treatable. Accordingly, bronchodilators started to be heavily used to keep the bronchi open at all times. In the late 80s to early 90s, the tragic aftermath of this management system forced medicine to look for another way to look at asthma which would allow the patients to breathe freely and physicians to explain away their previous failure. The old notion of the immune inflammation lying in the origin of asthma was pulled out of oblivion, and inflammation became the central target for medications. The lack of interest in causes allergic inflammation was obvious. Medicine was again fighting secondary events instead of paying attention to the primary causes. The frightening statistics on the effects of bronchodilators permitted an end to all discretion in prescribing steroids. In the same manner, a dress style enters the market and gradually conquers it until one does not see anything but the advertised pattern. The occasional voices about the underlying inflammation as the cause of asthma have now merged into a well rehearsed choir. Finally, at the 1997 Annual
Bronchial Asthma
301
Meeting of the AAAI in San Francisco, the choir sang in unison that allergic inflammation was the only proper dress to wear. All other styles were proclaimed as illegitimate. Asthma has become solely an inflammatory disease. Steroids, formerly prescribed with caution, flooded the drug market. Paradoxically, despite their proclaimed effectiveness, asthma morbidity and mortality have increased dramatically in the United States during the last 20 years necessitating still wider use of bronchodilators.89 The adverse effects of steroids are so obvious that even Peter Barnes, a consultant to the producers of asthma medications, admits that there is a need for the development of new treatments that would avoid the side effects that may be associated with anti-inflammatory drugs such as corticosteroids.90 He is pessimistic though: the possibility of developing a cure for atopy is remote. One may only wonder as to what destroyed his optimism expressed a year before in another article of his that was assuring us of the opposite: in the future there are real possibilities for the development of preventative and even curative treatments.91 Asthma patients cannot be overly optimistic either: according to the February 14, 2002 issue of the New England Journal of Medicine, drug makers spent $2.5 billion U.S. dollars in 2000 for advertising (for educational purposes) mostly anti-inflammatories and antihistamines. The revenues received from this investment by the manufacturers are impressive: In 1998, the annual cost of asthma was estimated at $12.7 billion, with medications the single largest cost component.92 Drug markets have no interest in a cure. Despite the numerous side effects of steroids and despite the dramatically rising mortality among their users, many authors see the problem of asthma in doctors prescribing too little steroids and too late in the disease course. They accuse parents of asthmatic children of noncompliance with the management based on steroids. They even invented a new term for this parental prednisone phobia. As usual, the ends do not meet: as was reported by a group of scientists from Iceland at the 58th annual meeting of AAAAI, inhaled glucocorticoids are widely and successfully used in over 90% of patients with moderate to severe asthma.93 This is almost universal successful coverage of asthmatics, and it is doubtful that American doctors are lagging behind their Iceland colleagues in their prescription patterns. However, even a figure as high as 90% does not satisfy the Chicago team whose report in the same issue (page S183) declares: There are a large number of persistent asthmatics who are not prescribed these medicines by
their primary physicians. This time, not parents, but physicians are supposedly reluctant to prescribe. What are the reasons for not prescribing steroids to every single asthma patient? Who dares not follow the steroid-enforcing guidelines? The article reveals that A significant percentage of pediatricians surveyed have discontinued inhaled corticosteroids due to perceived (!?) side effects. It is of interest that urban pediatricians and pediatricians who graduated from medical school after 1989 were more likely to use inhaled corticosteroids for all classes of persistent asthma. It means that in small towns and villages, where doctors know each person, they seem to discontinue medications when their young patients experience adverse effects. However, when the older doctors retire and urbanization reaches these small communities, steroids will reign in that obedient and impersonal world. So, now, we have an asthma epidemic. Soon, with the rising number of prescriptions for steroids, we may have an epidemic of deaths among asthma patients, but wait: the scientists will find new explanation for this too.
IS ASTHMA AN INFLAMMATION? It is important to understand why steroids should never have become first-line asthma remedies. We have already spoken about the phenomenon of allergic inflammation, immunogenic in nature. Unlike in other inflammations, the tissues may long remain physically intact even with the changing chemistry. For years, the integrity of the bronchi and lungs in asthma may be preserved, and their dysfunction may remain reversible. Tissue scarring appears only in advanced stages of the disease. Calling asthma an inflammatory disease without specification as to what causes this inflammation is wrong, in the sense that the inflammation in the respiratory tract is the process resultant from the histamine-induced cascade of mediators and cytokines. There is a parallel with migraine that occurs due to histamine- and serotonin-induced chemical changes in the neurovascular tissues, but is only occasionally labeled as a neurogenic inflammation. It is also unscientific to omit the specific causative chemicals when speaking about inflammation in asthma, because anti-inflammatory medications should have specific targets, concrete inflammatory mediators or cytokines. The generally accepted term inflammatory regarding asthma is dangerous because it justifies an early introduction of steroids as potent anti-inflammatory drugs allegedly targeting the cause of the symptoms, while in reality, targeting the secondary events. Contemporary allergy supports this term and, correspondingly, the aggressive use of steroids.
The dangerous signs of the suppressive approach are seen everywhere but are silenced, downplayed or distorted. Maybe one day, a daring journalist or a scientist will share with us the figures of steroid-dependent asthmatics who are crippled by frequent fractures (osteoporosis), suffer from diabetes, die of strokes (hypertension), undergo cardiac surgery or surgery for peptic ulcers, suffer vision loss because of cataracts, become infertile or have miscarriages . Will there be a journal that will publish this medical information and these statistics? Will there be a daring lawyer who files a class action suit similar to those against tobacco and asbestos industries? Will there be a court that will grant a judgment in favor of the victims, as were the judgments in those cases? Peer pressure forces even apparently independent leading experts to change their position (probably, not really their views) in favor of steroids. We have already quoted Dr. OByrne, a leading Canadian respirologist, who said in 1996 that the long-term risks of (steroid) use are still a concern to many, patients and physicians alike.82 In April 2000, the same scientist told the 200 professionals at the annual Allergy Update symposium in Toronto that inhaled steroids were free of unwanted effects in proper doses, and that they provided optimal control in most cases. Unfortunately, Dr. OByrne did not share with the audience what those encouraging data might be, and when and from where he had received them within the 4 year period between his declarations. The 1997 president of the Canadian Society of Allergy and Clinical Immunology, Dr. Z. Chad, proudly said in his interview with Family Practice that Canada was a world leader in treating asthma with higher doses of inhaled steroids, and even the U.S. was lagging a little behind in their early introduction. The Canadian updated guidelines recommend steroids at a very early stage, and this dubious practice makes the country the frontrunner. The guidelines start and end with steroids. This, certainly, has not helped to improve the asthma situation, and Asthma remains the only preventable disease where the morbidity and mortality are still increasing in most parts of the world.94 Of certain interest is that usually, guidelines recommend what to use and do not indicate what NOT to use, especially in resistant asthma, when anything that relieves the plight of the patients should be encouraged. So, the Canadian allergists became the frontrunners in advising against the use of histamine in their guidelines! I guess I should be flattered that my case has created a precedent in the century-old history of histamine. Regrettably, this is a dirty history, and the document produced by the Guideline Advisory Committee in February 2002 is the best illustration of this miserable situation.95
It indicates the areas of high need and the identification of future topics, in other words, what medical areas require most of the attention. Asthma is not even among them; in comparison, nonfatal, rather infrequent bronchitis has found its place there. This can be explained either by the reluctance of specialists once again to reveal their impotence with asthma, or because the effect of the efforts to conceal helpful knowledge has been so effective that even the guideline creators mix up asthma with trivial bronchitis.
COMPARISON OF MEDICINE AND LAW During my discipline hearings at the CPSO and in the subsequent courts, I became acquainted with the underlying mechanisms of litigation that, probably, have not changed since Shakespeare when the proverbial desire to kill all lawyers was annunciated. Lawyers on both sides make long speeches, and, judging by the bills, their preparation takes even more hours. They bring in irrelevant facts, dwell on redundant aspects and dress their ideas into a flowery garment of verbiage. They are not responsible for the results, since there is always a judge above them. His decision may not depend on the logic, documentation or evidence, but on the hidden interests of some powerful entities. The higher the profile of the case, the more dependent is the judges decision on these powers, and the more it is predetermined. However, this book is not about the legal system, it is about medicine. Regrettably, medical research is similar to litigation. Any research must have a grant, since its conductors need to have food on their plates. The grants come mostly from pharmaceuticals. If the results of the research are published and/or presented at a symposium (also sponsored by the drug companies) in addition to food, the scientists receive high tipsfree flights to and accommodation at the exotic or grand places where most of the gatherings take place. Therefore, the subject of study becomes of lesser importance than the generation of the number of topics to be researched. This produces numerous, irrelevant and redundant studies, even such laughable ones as asthma prevalence among those who are born with a large head circumference or in families following an anthroposophic philosophy. In the medical courts, the judges are the drug companies. They are guided by one desire onlyto increase the revenues from drug sales. Cure of a chronic disease means a loss of profit and must be prevented. Research in the areas distracting from the curative paths serves the purpose. The costs of the grants given to scientists are nothing compared to the returns from the
drug sales, and this explains why subsidies for research that prevents revealing dangerous true facts are especially lavish. If lawyers impress the audience by their court attire, doctors use their titles to impress. The opposing and even contradictory data look like professional dialogues, while the judge called Big Pharma (Big Brother?) allows this verbiage to continue and knows the decision in advance. The audience in the medical courts is the patients. They are misguided about the validity of new hypotheses through the medically uneducated and, therefore, easily misinformed media who are also usually misguided by the spokespersons for the drug companies. The public trusts journalists more than drug companies and does not suspect the behind-the-scene brainwashing of those who write the stories on the new discoveries. These stories cause enthusiasm through their terminology and the titles of the researchers. Patients try to fit their symptoms into the framework of every newly theory to find the explanation for their symptoms. The choice is so wide that there is always a suitable theory. While the deception of lawyers has become proverbial, patients still cannot believe that doctors may be corrupt as a profession. Three different provincial governments of Ontario knew about my Histaminegate. None interfered despite the letters they received from the patients deprived of histamine that had allowed them to live drug-free, despite major media coverage most sympathetic to my patients, and despite emergency rooms full of asthmatics. Governments lament the lack of money in the public health system, and with the quadrupling of asthma figures within the last two decades in Canada that necessitate over 600 million dollars annually, there was no intervention. All the courts, including the Supreme Court of Canada, disregarded the exhibits proving the great public interest in the asthma solution. They overlooked the forged and misrepresented the key evidence submitted by the CPSO in their court documents. They even turned a blind eye to the Colleges violation of its own bylaw as well as its violation of the federal law. The courts protected Verbatim, the court reporters, in their production of two versions of transcripts, one with a forged signature of a court reporter, and disallowed the cross-examination of the manager and/or the court reporter. The interests of the medical and legislative bodies merged somewhere. This was probably easy to do, since, like all legislative bodies, the College, is headed by lawyers. No appeal was ever granted. No explanation was ever given. This despite the fact that the tape produced by the Canadian Broadcast Corporation showed
a gathering of about 200 of my patients requesting the treatment, which, according to Canadian Law means that the appeal is in the interest of not only the appellant, but a group of people and has therefore to be considered. Up until now, on the Internet, the College presents false data of allegedly 5 existing complaints from my patients, whereas there never were (and are) none. The details of the improprieties would require a book, not a paragraph. For now, all I want to say is that although there are good and bad judges, histamine therapy created a problem that was beyond the ability of any judge or panel to decide upon. All laws are trampled when the Medical Mafia is in charge. When billions of dollars are at stake, the only judge is His Majesty Corporate Money. The idea is not new. John Polanyi, a Nobel Laureate said in March 1999 at the conference Secrecy in Science, which took place in the US, that scientists freedom to speak is being restricted today by industry and governments attempts to protect commercial interests. Secrecy in medicine is much deeper than in any field, since the profits from its product sales, drugs, are incomparably higher than in any other field. Secrecy in allergy is probably higher than in other medical areas first, due to the high prevalence of allergies and asthma, and second, due to their reversibility and hence, the potential resultant loss of patients as customers. Asthma patients, you are in the medical court. The medical elite enjoy their litigation process: they discuss what kind of steroids to prescribe and in what dose. They write papers on which is betterasthma, hepatitis A or tuberculosis. They try to solve the puzzle why asthma figures are much lower in the polluted India than in the sterile-clean New Zealand. Only in the US a judge enjoys the $10 billion plus from the annual sales of asthma therapeutics and provides unlimited grants for research that covers these topics. Meanwhile, the asthma figures get more frightening from day to day, and medical professionals have started to blame patients for the increase. Patient ignorance about asthma and its management has been identified as a major cause of morbidity and mortality, writes The Canadian Journal of CME in the March of 1996. In this context, ignorance means lack of interest in the knowledge of how and what inhaled or oral medications to use. Centers that proudly call themselves educational have opened in North America, and physicians teach asthmatics how to use inhalation devices properly and when to escalate the steroid dosage depending on the measurements of the peak flow meter. Another novel strategy has been dreamed up in
Canada with the purpose to change patient behavior such that they would be able to control their asthma rather than be controlled by their asthma. Sponsored by Health Canada and GlaxoSmithKlein, a new milieu for asthma carethe community pharmacy has been created, with pharmacists taking responsibility for outcomes, assessment of a patients readiness to change and tailoring education to that readiness and physician consultation to achieve asthma prescribing guidelines. Some 27 pharmacies and 33 pharmacists took part in the study, which showed the approach was cost-effective, as it reduced the number of visits to doctors offices as well as ER admission. There is no mention of the medications used that allegedly improved the situation; instead, the article emphasizes educational value of the enterprise. However, with no other means than steroids, we can be sure that the education included the proper use of puffers and the intensified use of steroids, most probably, the combination drugs, as is the fashion now. If this approach96 becomes accepted, the specialty of allergy as a medical discipline will be wiped out: the proper use of immunosuppressive medications will replace the need to study the immune mechanisms and repair them. Even by a wide stretch of the imagination, one cannot call these measures educational, since what they teach is skill, while education would mean the knowledge on what underlies asthma. But then, the doctors involved are not knowledgeable themselves. Doctors have actually removed themselves from the grim asthma statistics, and it is now the patients that shoulder the burden of the problem. Asthmatics should take care of themselves in every day life and inhale, swallow and sip steroids, while specialists operate in their medical courts, and save their patients in emergency rooms.
IMMUNOTHERAPY IN ASTHMASTATE OF THE ART Immunotherapy is the only way to cure asthma because it repairs the failing immune tools. Asthmatics are rarely prescribed it because. immunotherapy is an effective treatment under optimal conditions, but of course its safety is currently being questioned.97 This article published in JACI says: It has been observed that patients with asthma are particularly prone to develop systemic reactions during immunotherapy. Complications of conventional immunotherapy are rooted in the improper way of conducting and interpreting allergy skin testing, as we spoke about that at length earlier. Although in its potential, immunotherapy has remained the heart of our specialty98 allergists turn to it only when all other means fail. Absurdly, there is
consensus among the leading immunologists that immunosuppression by steroids should precede attempts to repair the immune system. The absurdity of this sequence is disregarded. Thus, the medical director of the Johns Hopkins Asthma and Allergy Centre in Baltimore told the delegates of the Tenth Annual Allergy Update symposium in Toronto in 1993 that immunotherapy is warranted only in the cases where medications are unsatisfactory or produce intolerable side effects. Evidently, the prescribers do not expect much from immunotherapy in a clinical setting. Otherwise, why did they suggest the already failed steroids to be taken concurrently with immunotherapy? Just think: specialists recommend steroids not only after they are discontinued due to their adversities, but along with immunotherapy. There can be one explanation only: the protection afforded against possible severe systemic reactions to allergy shots. Immunotherapy conducted along with steroids is deprived not only of a scientific basis but simple logic: two diametrically opposite treatments target the same T-cells! Steroids suppress them, while allergy shots try to restore! In view of unpredictability and growing morbidity of asthma and in view of the serious side effects of the primary medications, asthmatics are the most vulnerable group of allergy sufferers. Therefore, more than others, they need the immune repair. Unfortunately, their chances to get proper immunotherapy are almost zero. The conventional way of allergy testing can never lead to successful immunotherapy.
IN FAVOUR OF HISTAMINE THERAPY My criticism of the conventional asthma treatments, steroids in particular, inevitably sounds like advocacy for histamine. A critical reader may be suspicious that, like any drug, histamine is not devoid of side effects. There is only onethe possibility of triggering an aggravation if the dose is higher than needed. But then, everything is good in moderation. Given in a dose higher than the body needs, even some of the worshiped vitamins and minerals are harmful. In other words, histamine therapy may have a dark side, but is it equal to steroids in producing side effects? Not in the least. We are talking about two opposite treatments. Steroids are immunosuppressants, even though allergists call them immunomodulators, and the side effects of different doses differ only by the degree of the suppression of the cellular functioning. Histamine is recognized by science as immuno- and neuromodulator, and it is the extent to which it is able to regulate or modulate the cellular production that varies with the dose
and the individual. We thus compare the degree of the weakening of the immune system by steroids vs. the degree of its restoration by histamine. This is a huge difference. With daily suppressive steroids, the defensive part of the whole immune system slowly dies, and due to the shriveling adrenals and the growing resistance of asthma, the body starts to rely on the drugs more and more. Never forget that side effects of daily steroids are a reality at any dose. Many of the adverse effects are diseases, and some are more debilitating than asthma itself. At the same time, side effects of histamine are limited to temporarily intensified allergic and related symptoms: dizziness, a headache, a more congested or runny nose, more pronounced skin itch or heavier breathing. Even these manifestations are transitory, lasting only minutes and rarely a few hours. An observant doctor can reduce the adverse effects to minimum and provide a smooth recovery from the very start by asking the relevant questions before and after the skin testing and during treatment, before and after each therapeutic injection. The key difference between steroids and histamine lies in the fact that the degree of the (temporary) improvement due to steroids is proportional to the general suppression of the immunocompetent cells on the whole, including their production of the protective chemistry, whereas the strengthening of the targeted H2/3 receptors leads to the restoration of the normal cellular functioning of all receptor-bearing cells and hence, normalized production of histamine and numerous anti-disease mediators. Another fact in favor of the histamine immunotherapy is that one can stop it at any time, whereas steroids often require tapering because of the physiological dependence on them. Unlike steroids that are not recommended for kids under 4 or 6, histamine is especially effective in children and babies. As I said in my presentation at the international symposium in 1989 in West Berlin, the younger the child, the better the results. It can be due to a more resilient immune system of a young body. A lot of people, especially children, whom I treated with histamine remained symptomless and drug-free for years. Is there interaction of histamine with other medications? Yes. Histamine is incompatible with steroids since it tries to restore the functioning of the same cells the steroids extinguish. If steroids were taken before therapy with histamine, such immunotherapy may be less successful and require a longer treatment period, because to revive the suppressed cells is more difficult than to activate the ones that are untouched. Cells suppressed by steroids, T-cells first
of all, may never be able to regain their functioning. This explains why the immunotherapy conducted concurrently with steroids cannot thus be effective. Histamine therapy is also less effective in those patients who take H2receptor suppressors such as Zantac and Pepcid, prescribed for gastrointestinal problems. This is because histamine injections activate H2 receptors, and their simultaneous activation and suppression are impossible. Histamine injections are the therapy that repairs the flawed receptors and increases the efficiency of T-suppressor cells. In the majority of cases, the effect may even last months or years. Only in those with the most inflexible immune system, the treatment may continue throughout the patients life. Chances are high that the patients become independent from daily medications. Histamine may also eliminate the accompanying symptoms, seemingly allergy-unrelated, often nonspecific and therefore undiagnosed. Suffice to say that the normalized function of T-cells in general not only rids patients of allergies, but also strengthens the whole immune system and by that, rids them of superimposed infections. T-cell strengthening may also be beneficial in another respect. Recent studies in San Diego and Goteborg, Sweden, showed that the combination of histamine and inflammation-promoting mediators in melanoma increased the number of killer cells by 62 times, whereas the mediators alone provided only 5-fold increase. Since any defense against cancer is based on killer cells ability to destroy tumor cells, it is logical to assume that histamine can be beneficial in cancer. This subject was thoroughly studied in the 80s and early 90s and discussed in the publications of the Histamine Research Society Agents and Actions. The revived cellular talk of the immunocompetent cells with the nerve cells and the cells of endocrine glands positively affects the functioning of the nervous and endocrine systems. Most remarkable is the bolstering effect of histamine on the adrenals (via corticotropin) that synthesize corticosteroids. Their activation diminishes the need of the outside help with the synthetic version. Almost always, the improvement starts at the very beginning of the histamine treatment, actually, at the skin testing. By restoring the efficiency of T-suppressors and allowing them to fight allergic inflammation, histamine injections reduce the bodys need for crutchesother medications, including histamine itself. It is different with all other drugs when, due to the bodys adjustment to their regular use, the need of increasing dosages continues. Last but not the least I need to emphasize the cost of histamine therapy. It is very low compared to daily drugs and thus, saves personal and public
Bronchial Asthma
311
money. It is this advantage, however, that is viewed as a huge threat by the drug industry, and this outweighs all the beneficial properties of histamine therapy. The purpose of any treatment should be to rid patients of the disease, whenever possible, or at least control the rate of decline and symptoms for the longest period possible and by the safest means possible. Histamine injections reach the goal other medications are meant to reach, but does it with an immeasurably higher effect and lesser degree of complications. I saw that in asthma, histamine worked better than in any other allergic disease. This can probably be explained by several factors. Compared to other tissues, the lungs possess the highest concentrations of mast cells and basophils. The number of these cells exceeds those in other organs also due to the large lung surface and to the permeation with blood vessels for oxygenation. Thus, when histamine injections inhibit the leakage of histamine from these cells, the magnitude of the effect is most apparent in the lungs. The positive aspect of this is that the very same facts make asthma a very dynamic and reversible disease, in the absence of organic tissue changes common for advanced or neglected cases.
AN UNFAILING DRUG You may wonder if histamine works in all cases. Nothing is absolute in nature. There are, after all, asthmatics who do not respond to steroids. Basic sciences explain this phenomenon as the result of an irreversible defect of steroid receptors. One learns whether one is a responder or not only after trying a treatment. If steroids do not work, they should be stopped because they may only harm. The high doses prescribed in the hope of improvement may lead to serious consequences, particularly unreasonable because their consumers get no relief from their asthma. Unfortunately, in view of the lack of any substitute, steroids are still prescribed in escalating doses with the accompaniment of add-on drugs. These patients, in addition to having resistant asthma, acquire dependence on steroids plus numerous side effects. Histamine may not produce any effect when there is a genetically predetermined irreversible defect and/or irresponsiveness of the H2/3 receptors. However, a trial with histamine can do no harm. A potential temporary aggravation can be reduced to a minimum through a slow dose increment, and the attempts can be stopped at any moment. Practice proves overwhelmingly that the majority of patients who are not steroid-dependent, respond to histamine injections.
Would you want to try histamine therapy? Even if you would, you cant. Even if steroids fail in your case. Even if your condition forces you to abuse the condemned bronchodilators. Histamine therapy is not in the guidelines. In Canada, it was even banned when the medical Establishment realized that patients with allergies and asthma, whom I treated, recovered in large numbers. Regrettably, doctors all over the world who conduct histamine therapy are forced to do this empirically, since the theoretical knowledge that could support their therapy is hidden. They grope in the dark trying to select the dose. Having been taught that histamine is allergy-conducive only, they are afraid of aggravations, unable to explain them and may give up on the therapy that could save their patients. They cannot speed up the improvement because a higher dose does not necessarily mean a faster recovery. They often combine histamine therapy with different irrelevant substances and do not understand that the effect is due to histamine. The flaws in conducting histamine therapy belittle its wonderful properties and accentuate its negative role in allergy. The vital information disappeared even from those few textbooks that had once contained it. Medicine dictates you swallow or inhale daily steroids and bronchodilators and be happy if you are a responder.
TO USE A DRUG The US Food and Drug Act is based on the general premise that once a drug is approved to be marketed for any one indication, physicians are legally free to use it for any other indication without any additional evidence.99 This quotation is from an article published in one of the most prestigious medical periodicals, the Journal of American Medical Association. It is written by Dr. D. Eddy, Professor of Medicine and Mathematics, consultant to the U.S. Government on drug use and author of the monthly column Clinical Decision Making. Histamine therapy, described in the remote past in detail even in textbooks100 and later substantiated theoretically101 should be available and free to be employed by a trained doctor. As Eddy describes, hundreds of diagnostic tests, devices, procedures and services are currently used and paid for without any evidence of effectiveness for any indication. By contrast, the efficacy and safety of histamine are confirmed by numerous open clinical and double-blind studies. The recognition of its safety comes from the fact that histamine is a non-prescription drug. The most astounding fact exposing the deplorable lack of knowledge by immu-
Bronchial Asthma
313
nologists of the dual action and potency of histamine is its common use as a placebo (?!) in controlled trials for allergen extracts. Basic sciences know more about histamine than about most medications. It belongs to the group of autacoids due to its natural remedial effect. The regulations of the central legislative body of the drug industry do not prohibit the use of histamine since it fits into the framework of hundreds of other drugs referred to by D. Eddy as those once approved to be marketed. The 1988 Helsinki Accord on Human Rights, signed by the governments of all the participating countries, including US and Canada, states that a practitioner can use any remedy at his discretion if it is not more dangerous than the conventional means. So far, there has never been a report on the danger of histamine in clinical practice. On the contrary, clinical trials proved its success. But the august medical authorities will not allow it. Any pretext is good. Some say it is dangerousthen, why is it used as a placebo in trials? Others say it gives a psychological effect onlythen, why is it the standard of the biological activity of allergen extracts? Logic and scientific facts become redundant when the decision makers violate the very laws they created. Ultimately, you are just an asthma sufferer without medical knowledge, power or the right to make a decision for yourself or your child. You are doomed to succumb to the management imposed on you by the medicopharmaceutical conglomerate conveniently supported by governments and legal bodies, but not by law.
FREEDOM OF CHOICE IN SCIENCE What is the future for asthma sufferers? In my opinion, it is grim. Asthma must be viewed as a chronic and possibly irreversible (!) disorder, and therefore, prevention of this disorder will be the most effective treatment, declared Dr. W. Busse, the 2001 president of AAAAI, in his article published in the special issue of JACI covering the conference sponsored the National Institute of Allergy and Infectious Diseases.102 As the title of this meeting indicates21st Century Management of Upper Respiratory Allergic Diseases: A Focus on Allergy and Asthmaits purpose was to establish the guidelines for the next millennium. Since prevention in the language of allergists means steroids that allegedly prevent allergic inflammation, the verdictirreversiblesentences asthma patients to life-long consumption of steroids. This is confirmed by the Canadian Compendium of Pharmaceuticals 2001 that
lists inhaled steroids under the heading Asthma Prophylactics (p. 1642). Manufacturers of inhaled steroids are multinational companies, therefore the entries in the compendia in other parts of the world are the same or similar. The hands of those who offer an effective resolution to chronic medical problems are tied, and the recent strict guidelines are the manacles. Legally is a robust adverbit justifies many ill-gotten gains, said Honore de Balzac. Guidelines that should never be legislative, have become legal restrictions in allergy practice. The reasons for the restrictions are simple. Grants and funds for research are the central elements that drive the developments in medicine. The high costs of funding can more readily be turned into continuous profit streams by drugs that only offer temporary relief instead of an actual cure. Therapies that may provide full or lasting independence from daily drugs are unacceptable as loan repayments. Asthma patients from all over the world are paying the pharmaceutical industry for research into the drugs that may cripple or even kill them. As an extreme mockery, our democratic society gives asthma sufferers freedom of choice: 1) a bronchodilator of any kind with any imaginable delivery system; 2) a steroid drug in any form: oral, injectable, inhaled; 3) the recently developed (and already restricted) combo drugs consisting of a bronchodilator and a steroid; 4) a number of ineffective adjunct medications to be taken along with the main two. All the choices are compulsory. Asthmatics can also choose to wait until medicine sorts out all the genes, studies their interrelationship, develops methods of genetic engineering in asthma and starts using them on a wide scale. How soon will it happen? Gene therapies currently show little promise for treating this prevalent and generally nonmorbid disease, states another speaker of the conference.103 Paradoxically, we can be grateful for the fact that it is not going to happen soon, since, as legends say, the ancient Atlantis perished because its medical professionals got the false idea of their grand abilities and created genetic monsters such as mermaids and centaurs. It is evident that the status quo satisfies all parties involved in asthma but the patients. Drug developers get back what they invest into the new research, plus a little more (a little?), researchers get their grants and bonuses, doctors have an unceasing stream of asthmatics in their offices, engineers develop devices for asthmatics, hospitals enlarge the areas to accommodate all those who gasp for air, nurses get special training in teaching asthma patients how
Bronchial Asthma
315
to avoid environmental triggers and how to use their inhalers properly and become experts in reduction of steroid doses. And finally, pharmacists have joined the party and now not just dispense the medications, but consult patients and their doctors (!) on how to intensify the use of steroids. You may ask where the governments are that spend millions on health services? Governments corruption is an open secret, and their protection of the most lucrative industry is not a secret either. In the case of asthma, the annual direct casualties provided by the official statistics (definitely below the real figures) are only (!) 60,000 deaths annually among the 130 million sufferers in western countries.104 Death from asthma is rare, informs us a flyer sponsored by The Lung Association of Ontario. Is it? Are the figures of 5,000 plus and growing for the US and over 500 for Canada still too low for the governments to be bothered about? What figure will be good enough to start an inquiry?
ENDNOTES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. J. Donahue et al. Asthma pharmacotherapy JACI 2000; 106:1108-14 The Medical Post, September 11, 2001, p.67 S. Suissa & P. Emst. Inhaled corticosteroids. JACI 2001; 107:937-44 B. Lyttle & A. Hollestelle. Asthma. Canadian Family Physician. 1993; 39:793-798 R. Zeiger & M. Schatz. Effect of allergist intervention JACI 2000; 106:995-1018 Kaplan, ed. Allergy 1985 p. 390 S. Holgate, Nature 1999; 402:B2-4 The Medical Post, October 14, 2003, p. 84 Combination of these drugs as option as front line therapy M. Sears. Descriptive epidemiology of asthma. Lancet 1997; 350:SII:104 N. Pearce et al. Asthma Epidemiology: Principles and Methods, New York, Oxford University Press, 1998, preface Kaplan, ed.Allergy 1985, p. 369 E. Mutius. The environmental predictors of allergic disease. JACI 2000;105:9-19 R. C. Levitt et al. IL-9 pathway in asthmaJACI 1999;103:485-91 W. Finn et al. Children at risk for asthma. JACI 2000;105:933-42 R. Zeiger, M. Schatz Effect of allergist intervention JACI 2000;106:995-1018 P. Finn et al. Children at risk for asthma. JACI 2000;105:933-42 I. Sandrini, K. Chapman. The Canadian Journal of Diagnosis, January 2002: 63-74 Beasley et al. Oxford University Press 1998 1987, p. 1063 1987, page 3 Clinical and Experimental Allergy 2001; 31:1651-2 L. Lichtenstein. Allergy and the immune system. Scientific American. 1993;269:117-24 M. Hyland. A connectionist theory of asthma. Clinical & Experimental Allergy 1999;29:1467-73 N. Pearce et al. Thorax 1999;54:268-72 N. Pearce, R. Beasley, et al. Oxford University Press 1998 R. Beasley et al. Prevalence and etiology of asthma JACI 2000;205:466-72 W. Busse, et al. Pathophysiology of severe asthma. JACI 2000;106:1033-42 J. Donahue et al. Asthma pharmacotherapy JACI 2000;106:1108-14
29. T. Kino, G. Chrousos. Tissue-specific glucocorticoid resistance-hypersensitivity syndromes. JACI 2002; 109:609-13 30. M. Liu et al. Effects of prednisone on cellular response JACI 2001; 108:29-38 31. N. L. Jones. Can Respir J 1995;2:88 32. L. Lichtenstein, Allergy and the Immune System, Scientific American 1993;269:117-24 33. P. Gergen. Understanding the economic burden of asthma. JACI 2001;107:S445-8 34. C.P.Page. Beta-agonists and the asthma paradox. Practical Allergy & Immunology. 1992;7:87-94 35. A. Tattersfield. Foreword. Lancet 1997;350:SII 36. 1993;269:117-24 37. S. Romagnani. The Th2 hypothesis in allergy Eppur si muove! Allergy Clin Immunol Intern 1998;10:158-65 38. JACI 2000;105:205-10 39. R. Beasley et al. Prevalence and etiology of asthma JACI 2000;105:S466-72 40. N. Pearce et al. Asthma Epidemiology. University Press 1998 41. P. Avila Interactions between allergic inflammation and respiratory viral infections. JACI 2000;106:829-31 42. P. Nafstad et al Risk of childhood asthma and allergic rhinitis in relation to pregnancy . JACI 2000;106:867-73 43. S. Holgate. The epidemic of allergy and asthma. Nature 1999;402,S25:82-4 44. E. Von Mutius, The environmental predictors of allergic disease. JACI 2000;105:9-19 45. P. Finn et al. Children at risk for asthma JACI 2000;105:933 46. D. Cockcroft Allergen-induced increase in nonallergic airway responsiveness: A citation classic revisited. Can Respir J 2000;7:182-187 47. E. von Mutius. Editorial. Clinical and Experimental Allergy 2001;31:1651-2 48. E. Grant et al Observations on emerging patterns of asthma in our society JACI 1999;104:S1-9 49. H. Bourne, L. Lichtenstein, K. Melmon et al. Modulation of inflammation and immunity by cyclic AMP. Science 1974;184:19-28 50. A. Page. Beta-Agonists and the asthma paradox. Practical Allergy & Immunology 1992;7:87-94 51. F.E. Spitzer et al. Beta agonists and the risk of asthma death and near fatal asthma. Br. Med. J. 1992;326:501-6 52. According to the Journal of the American Medical Association, Feb. 2002, 87% of the experts who formulate practice guidelines for the whole profession have financial ties to the drug industry. Their subsequent published guidelines favor, in more than 90% of the cases, those very drugs that those drug companies make. 53. S. Agarwal, G. Marchall Jr. Beta-adrenergic modulation of human type-1/type 2 cytokine balance, JACI 1999;104:91-8 54. A. Page. Beta-agonists and the asthma paradox. Practical Allergy & Immunology 1992;7:87-94 55. M. Fitzgerald , p. Macklem. Proceedings of a workshop on near fatal asthma. Can Respr J 1995:2(2):113-126 56. Kaplan ed. Allergy 1985:393 57. Archives of Disease in Children. 1992;67:245 58. A. Page. Beta-agonists and the asthma paradox. Practical Allergy and Immunology 1992; 7:87-94 59. M. White, N. Sander Asthma from the perspective of the patient, JACI 1999;103:S47-52 60. JACI 1990;86:599-605 61. J. Robinson. Perscription Games, McClelland & Stewart Ltd., Toronto, 2001 62. P. Barnes New directions in allergic diseases: Mechanism-based anti-inflammatory therapies. JACI 2000;106:5-16 63. OSullivan et al. Am J Respir Crit Care Med 2003;167:745-50 64. H. Milgrom et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 1999;341:1966-73 65. P. Barnes JACI 2000;106:5-16 66. Dorlands Illustrated Dictionary, 1988:1045 67. Dorlands Illustrated Dictionary, 1988:429 68. R. Zeiger, M. Schatz Effect of allergist intervention of patient-centred and societal outcomes. JACI 2000;106:995-1018
Bronchial Asthma
M. Masoli et al. JACI 2003;112:10-11 P. Stolley, R. Schinnar. The New Engl. J. of Med. April 23, 1987:1090 Practical Allergy & Immunology 1992;7:87-94 A. Cypcar, W. Busse. Steroid-resistant asthma. JACI 1993;92:363-72 Guidelines for the management of asthma: Summary. British Thoracic Society et al. BMJ 1993;306:776-82 74. L. Lichtenstien, S. Margoles. Histamine release in vitro. Science 1968;161:902-3 75. Canadian Asthma Consensus Conference. Summary of recommendations. Can Respir J 1996;3(2):89-100 76. Special report. Archives of Disease in Children 1992;67:240-48 77. S. Szefter. Challenges in assessing outcomes for pediatric asthma. JACI 2001;107:S456-464 78. T. Bai. Clucocorticosteroid treatment of asthma. Can Fam Physician 1995;41:1921-27 79. BJ Lipworth JACI, 1999:104:713 80. S. Szefler. The changing face of asthma. JACI 2000;106:S139-143 81. I.J. Lipworth. JACI 1999;104:713 82. P. OByrne, et al. Efficacy and cost benefit of inhaled corticosteroids in patients considered to have mild asthma in primary care practice. Can. Resprirol J 1996; 3:169-75 83. P. Lieberman, J. Anderson. Allergic Diseases. Diagnosis and Treatment. Humana Press. 2001 84. P. Lieberman, J. Anderson. Allergic Diseases. Diagnosis and Treatment. Humana Press. 2001 85. BJ Lipworth JACI, 1999:104:713 86. Siu-Min Li et al. The Chinese herbal medicine formula JACI 2000;106:660-8 87. S. Suissa, P. Ernst. Inhaled corticosteroids: Impact on asthma morbidity and mortality. JACI 2001;107:937-44 88. K. Yamada et al. Molecular mechanisms of decreased steroid responsiveness JACI 2002;109:35-42 89. P. Gergen. Understanding the economic burden of asthma. JACI 2001;107:S445-8 90. P. Barnes. New directions in allergic diseases. JACI 2000;106:5-16 91. P. Barnes. Therapeutic strategies for allergic diseases. Nature 1999;402 S25:B31-7 92. A. Apter. Clinical advances in adult asthma. JACI 2003;11:S780-4 93. JACI 2002;109:S173 94. C. Page. Lancet 1991;337:717-20 95. Ontario Medical Review 2002;69:38-40 96. W. McLean et al. The BC community pharmacy asthma study Can Resp. J 2003;10:195-202 97. A. Hejjaoui et al. Systemic reactions occurring during immunotherapy with standardized pollen extract. JACI 1993;89:925 98. I. Frew. Sublingual immunotherapy. JACI 2001;107:441 99. JAMA 1993;270:522 100. Erich Urbach and Philip Gottlieb. Allergy 1949. Grune & Stratton 101. A. Kaplan ed. Allergy 1985 102. W. Busse. Current research and future needs in allergic rhinitis and asthma JACI 1998;101:S424-6 103. M. Sears. JACI 1998;101:S399 104. M. Sears. Descriptive epidemiology of asthma. Lancet 1997;350 SII:104 69. 70. 71. 72. 73.
317
PART EIGHT
ALLERGIC DISEASES
CHRONIC RHINITIS, SKIN ALLERGIES, HAY FEVER
All allergic diseases have, in principle, the same immune roots, but as they affect different organs, the manifestations are different.
INTRODUCTION
A. CHRONIC RHINITIS
We know its root rhino from the familiar rhinoceros, and both words come from the Latinnose. This chapter covers chronic rhinitis, which is a protracted, often life-long non-infectious, allergic inflammation of the nasal mucous membrane. The nose is a protective filter against physical, chemical and infectious agents. Its sieve-like structure with its narrow passages prevents particles from getting inside. The secretions of its mucous membrane are designed to neutralize those chemicals and disease-causing bacteria that do get in. Both
Allergic Diseases
319
infectious and allergic inflammation contribute to the impairment of the mucous membrane. As the lining loses its protective ability, the door to secondary infections is opened. The statistics on chronic rhinitis vary from source to source, but it is agreed that more than 25 per cent of the population suffers from it. However, it is important to note that chronic rhinitis is much more common than asthma. Then, the data reflect the diagnosed cases, while a lot of people have a mild form and these people do not become part of the numbers; for them it is mostly an inconvenience, too mild to visit a doctor. Many have episodic attacks which are usually misdiagnosed as a recurrent cold. All this distorts the statistics, and the true figures for rhinitis may be closer to 40% in the population.
CLASSIFICATION Chronic rhinitis exists in several forms. One is allergic rhinitis, which can be divided further into two kinds. A seasonal form provoked by pollen is a part of hay fever. The other group includes patients with perennial symptoms triggered by other allergens, for instance, dust mites. There is yet another form of chronic rhinitis, in which the symptoms are triggered not by allergens but by nonspecific factors such as changes of environmental temperature, air impurities, emotions, change of posture, awakening, biological cycles, etc. Nonspecific triggers are innumerable, and therefore these people may suffer all year round or have spontaneous relapses. Their rhinitis is called vasomotor and its Latin roots indicate that the condition is related to the fluctuations of blood flow in the vessels: vasusvessel and motormovement. In fact, the term is not very precise, as similar vascular changes are present in all forms of rhinitis. Allergen-related seasonal and/or perennial forms of rhinitis often coexist with nonallergic or vasomotor rhinitis in one and the same patient. Although conventional medicine labels these forms as allergic and nonallergic, the underlying mechanisms of all forms of chronic rhinitis are basically the same: they are all caused by malfunctioning immunocompetent cells, which are responsible for the allergy-controlling part of the immune system. Change in the body chemistry provoked by a histamine spill leads to two events which then lead to the symptoms of rhinitis: 1. an engorgement of the vessels and thus, an increase of the blood flow in the nasal mucosa; 2. excessive secretions, i.e. nasal discharge and/or obstruction.
THE SYMPTOMS It is fairly easy to differentiate chronic rhinitis from an infection, as it is often accompanied by other allergic or related symptoms. These may vary from patient to patient and include a chronic cough as a sign of the accompanying asthma, or various ear discomfort, or allergic dermatitis. The fluctuating nature of the symptoms is another clear indication of the allergic origin of chronic rhinitis. Family history often elicits allergies, asthma or related diseases in close relatives, and thus provides another proof of the allergic nature of the illness. Chronic rhinitis is a trivial disease when compared to the numerous debilitating conditions also found in this area of medicine. However, its persistent course and the accompanying allergic inflammation spreading to the surrounding areas create a dismal picture. Inflammation of the nasal membranes may produce local swelling and irritation leading to a prolonged itchy, drippy, plugged or runny nose and sneezing attacks. The obstruction, due to the swelling, can make simple breathing a difficult or even painful act. Nasal drippings become a nuisance and force the sufferers to carry boxes of tissue with them. Non-stop sneezing attacks are exhausting also. The symptoms, benign at first sight, can make a persons life miserable. At times, they are similar to a severe cold or flu without a high temperature. Indeed, in hay fever season, it looks as if there is a flu epidemic going around. The inability to breathe through the nose wakes the patients up at night. They often snore and thus may affect the sleep of others as well. The broken sleep pattern may lead to irritability, depression and insomnia. Thus, a simple conditiona stuffy noseoften turns into a devastating medical problem. Allergic inflammation of the nasal mucous membrane is seldom a spacelimited disease. It often spreads beyond the nasal area into the sinusesair cavities on the sides and above the nose. This creates a feeling of heaviness in the area, and patients with rhinitis often have sinus headaches. The term for this combined condition is allergic rhinosinusitis. As with other diseases of hypersensitivity, the term allergic is not accurate in relation to chronic rhinitis, since allergens may have nothing to do with the symptoms. Just how common this condition is becomes evident from the repeated TV advertising of drugs for the relief not only nasal symptoms but also of sinus headaches as well. These combo drugs contain antihistamines, decongestants and painkillers in different proportions. Postnasal drip is another unpleasant accompanying symptom. The phlegm formed by the secretions from the nasal lining gets into the throat
Allergic Diseases
321
and causes discomfort, soreness and a throaty cough (not to be mixed up with the chesty cough in asthma). Unfortunately, doctors do not routinely differentiate between a viral and bacterial throat infection and an allergic pharyngitis. Even worse, some allergy patients are diagnosed as having chronic tonsillitis and enlarged adenoids. As a result, many, especially children, end up having unwarranted tonsillectomy and/or adenoidectomy, and adults go through nasal surgery. It always reminds me of the saying that the best remedy for dandruff is a guillotine. Just how unnecessary and harmful such surgery tends to be is well described by a well-known American pediatrician R. Mendelssohn in his book Confessions Of A Medical Heretic. Lately, there is a strong tendency to single out postnasal drip as a separate condition leading to asthmatic-like cough instead of recognizing it as a symptom that may accompany chronic rhinitis and/or asthma.
RECURRENT OTITIS? Ear, nose and throat form one apparatus, hence the name of physicians who treat the diseases in this areaENT specialists. The spread of allergic inflammation to the eustachian tube that connects nasal passages with the eardrum area is accompanied by poor drainage and thus, accumulation of non-infectious fluid in the middle ear. The condition is called otitis. This term implies any inflammation in the ear, infectious or non-infectious, which naturally leads to confusion. As a result, recurrent allergic otitis, which usually appears in parallel with allergic rhinitis, is almost always misdiagnosed. When allergic inflammation spreads to ear passages, it may produce signs similar to infectious otitis, such as fluid accumulation behind the eardrum, plugged ears and poor hearing, itch, discomfort or even pain. The absence of a fever and/or pus points to an allergic nature of the condition and, therefore, does not call for antibiotic treatment. Besides, like any disease of hypersensitivity, allergic otitis has a characteristic course of frequent recurrence and fluctuations and is accompanied by other allergy symptoms; pre-existing chronic rhinitis is most common among them. Regrettably, a proper differential diagnosis seems to be a challenge for a lot of doctors. Furthermore, even though allergic otitis is so common, its discussion is virtually absent from medical textbooks as a disease in its own right or as a companion to chronic rhinitis. Allergic otitis often becomes the reason for numerous troubles in schoolchildren. Due to plugged ears, these young patients may not hear well and are
ashamed to admit that to their teachers. They may not even be aware of the problem. Poor hearing affects their concentration and comprehension of the material. Add to that the constant symptomatic discomfort from the other accompanying allergy symptoms, and you will understand why such a child is in trouble. The symptoms may be mild, and therefore the child disregards them. However, they distract from studies, and such a child is often labeled by the teachers as a poor learner. The child may carry the label through his entire school years. It may become a lasting psychological wound especially for sensitive children who, in reality, may be quite bright. The situation may traumatize the whole family. The number of kids having allergic rhinitis grows in proportion to the rising incidence of all allergies that are hitting the younger generation more and more frequently. This basically harmless illness (it doesnt kill one) does, however, continue to create various chronic medical and social problems. Mothers, not familiar with the medical subtleties, sometimes overreact to their childs symptoms, and with the very first complaint, take their kid to a doctor. Unfortunately, very few doctors take a swab, to confirm or disprove an ear infection, if they see redness in the external canal, which they interpret as inflammation. Hence, antibiotics are routinely over-prescribed. It is almost as if a prescription seems to be ready and waiting for the patients. In fact, even if the ear passages do look red and inflamed, these signs are nonspecific and common for allergic condition as well. Antibiotics may temporarily improve the condition due to their collateral non-specific action, although it is possible that a remission is spontaneous and reflects the fluctuating course of any allergy. The frequency of these prescribed courses of antibiotic drugs contributes to the evolution of antibiotic-resistant strains of bacteria, now one of the worst problems in world medicine. However, the real reason for prescribing antibiotics so liberally and unnecessary is the growing incidence of respiratory allergies and the inefficiency of allergy drugs. Antibiotics are, in fact, prescribed to camouflage the impotence of allergy therapy. Their danger to society prompted a series of articles in professional sources and in the media. Special medical committees started to warn doctors against over-prescription of antibiotics, and pamphlets addressed to patients began to explain the harm of the drugs. But the harm has already been done and is continuing: fatal, antibiotic-resistant infections threaten our civilization. As it often happens in medicine, it counts its losses decades later. It is of more than passing interest that Alexander Fleming, the discoverer in 1928
Allergic Diseases 323
of the first antibiotic, penicillin, warned in his 1945 Nobel Prize acceptance speech against bacterial antibiotic resistance as a very real danger that could make this great drug discovery helpless against infectious disease. Another way of treating chronic otitis is insertion of tubes into ears for better drainage even though it is a fact that many of the otitis cases are an allergic condition. Indirect confirmation of this comes from the skyrocketing incidence of allergies, chronic rhinitis in particular, and the correspondingly rising frequency of infectious otitis.
TREATMENT OF ALLERGIC RHINITIS If you are diagnosed with allergic rhinitis, the first advice given will be the same as in asthma: eliminate from your life anything suspected of triggering your symptoms. This will hardly relieve your nasal congestion, and there will be no escape for you from various drugs. However, the question arises, are those drugs really various? What the patients may chose from is as usual: antihistaminesone, decongestantstwo, steroidsthree... It turns out that those numerous names are ultimately many versions of these same three categories. And just how effective are they for chronic rhinitis? Only a small portion of allergy sufferers receives real relief from the existing treatments. The poor effects of the nondrowsy type of antihistamines, forces doctors to suggest the sedating ones instead because they, at least, allow the patient to get a good nights sleep. In other words, if antihistamines fail to perform their direct role of histamine inhibition, they play the role of sleeping pills. Decongestants in pills, syrups and nasal drops are used alone or in most fanciful combinations with antihistamines and painkillers. Their presence is marked with letter D or the words extra and sinus. The drug industry has the best word-smiths, and their latest contribution is the word liberator! The effects and side effects of decongestants were described earlier in the chapter Medications, but as they also possess a rebound effect, it is important to remember this: consumers should be careful not to worsen their symptoms by using the medication daily. The vasoconstrictive effect of these medications is especially dangerous for those allergy patients who have concurrent hypertension or other vascular conditions of the brain (one of them is simple migraine). For them, decongestants even in the generally recommended doses may be outright fatal. The seriousness of the problem (up to 500 strokes a year in US in young people!) forced the FDA to ban such popular decongestants as
Dimetapp, Contac-C, etc. However, it is easier to give advice to avoid frequent use of decongestants than to follow it, as patients take them for the simple need to be able to breathe. Over the time, patients develop tolerance to them, the efficiency of the medication fails, and this leads to the drug abuse. First-line therapy in chronic rhinitis is steroids, as they are in asthma. The best known steroid sprays are Flonase, Rhinocort, Nasocort and Nasonex. Specialists assure us that nasal sprays are not absorbed to the extent that they become harmful. However, what really happens we learn eventually from an allergy-unrelated area. Thus, an endocrinologist who assesses the effects of intranasal steroids states that these drugs can be absorbed into systemic circulation through airway and gastrointestinal routes, and that the absorbed drug would retain its native high potency in the systemic circulation.1 In case you are wondering why an endocrinologist makes this assessment, remember that one of the dangers of steroids is their harmful effect on the adrenal functioning and metabolism in generalthe areas studied by endocrinologists. Since manufacturers could be found liable for hiding the facts, they need to be more frank than allergists. The entries in the pharmaceutical directories clearly state that pregnant and lactating women, children under 6 years of age, people with elevated blood pressure and patients with certain chronic diseases should avoid steroids even in the form of nasal sprays. The drugs formal descriptions provided to professionals tell us that these sprays can decrease resistance to infections, suppress the adrenals and inhibit wound healing in those who have surgery or trauma. Such complications are proof that steroidal nasal sprays have an obvious systemic effect. There is more to steroids: even if they are effective, the groups that should avoid their use are astonishingly large: they include women during periods of pregnancy and breastfeeding, which may take place several times during their life time; young children; trauma/surgery patients, and patients with concurrent diseases that can be aggravated by steroids such as hypertension, diabetes, osteoporosis, peptic ulcer, etc. Add to that the steroid-resistant population (approximately one/third of the drug consumers), as well as those who experience severe side effects. The compendia advise to institute proper treatment in case where a patient falls into one of these categories. Since steroids are usually prescribed if antihistamines are ineffective, and decongestants fail or are contraindicated, the question arises: what should these patients take? All medical sources are silent on what proper means in these situations.
Oral steroids in chronic rhinitis are suggested only as short emergency courses at the height of the pollen season or during severe exacerbation of perennial rhinitis. Even then, they are to be used only for patients who do not have certain concurrent illnesses. The textbook Allergy 1985 recommends (p. 348) a burst of steroids to help patients discontinue the abuse of decongestants. However, with all their proclaimed potency, oral steroids not infrequently fail in severe allergic rhinitis. Otherwise, why would the authors recommend using them together with decongestants, which are the very drugs they want to discontinue? Are two ineffective drugs better than one? And on what known biochemical basis? Among other remedies, the textbook lists cool saline irrigations and humidified hot air. My impression is that the authors do not really believe that these simple methods will do anything for chronic resistant rhinitis, as they only casually mention these therapies at the end of the chapter on chronic rhinitis.
NASAL SURGERY AS A MEANS OF TREATMENT When all else fails, surgery is the treatment for the poor noses. Polypectomy (removal of nasal polyps) is not rare in patients with chronic rhinitis. Due to the constantly present allergic inflammation, the mucous lining loses its integrity, and secondary growth of excessive tissue is common. This paves the way to the formation of polyps (a Greek word for abnormal growth). Polyps together with the generally swollen mucous membrane create a physical obstacle, and surgery becomes the only way of giving the sufferer a chance to breathe. A swollen nasal lining may look on examination as if there is a polyp and thus become, in the interpretation of doctors, an indication for surgery. There are enough unscrupulous surgeons around who skillfully wield their scalpels and are ready to remove any extra part. Some of them do not even need evidence for polyps, and may settle for a swollen nasal lining. The patients, frustrated by their constant nasal congestion, which has resisted all of the effective therapies, out of sheer desperation agree to have an operation. Of course, given the fact that chronic rhinitis is actually a disease of the immune system and not a local problem in the nasal cavity, the operation cannot stop its progression. In most cases, the surgical procedure helps temporarily at best. Then a new lining grows, swells, and the congestion comes back. An allegedly deviated nasal septum is also commonly blamed for the problem of narrow nasal passages, and this adds another kind of surgery to the treatment of resistant rhinitis.
An interesting article was published in The Medical Post of November 9, 1993. On page 46 we read: At least one otolaryngologist has questioned the efficacy of functional sinus surgery, even though the procedure has been used to treat thousands of young children with chronic sinusitis over the past few years. The article covers the views of an ENT specialist from Florida. Speaking at a meeting of the American Academy of Otolaryngology and Head and Neck Surgery, he rejected surgery in chronic rhinitis and instead, suggested long courses of antibiotics. But are infections the cause of the chronic sinusitis? No. There may be cases of superimposed infections in people with compromised immunity, however, in the overwhelming majority of cases, constantly inflamed nasal lining is an allergy-related syndrome, which is misrepresented as the primary event of an infectious nature. In this situation, antibiotics can do more harm than good because, while targeting not very probable events, they allow the core defect to advance. Besides, in some patients, antibiotics may, and often do, aggravate allergies. The specialists speech did not include repair of the immunity. Instead, he blamed mothers for frequent surgeries. I dont do it until Im pushed, he said and suggested education of the mothers to make them more compliant with the long-term medicalization of their kids. One should feel sorry for the mothers who are ready to subject their children to the knife. Tired of perpetual courses of ineffective antibiotics, they evidently cannot bear to see their offspring suffer all the time. Besides, their own sleepless nights must be taking their toll, and, out of despair, they may push doctors for surgery. From any point of viewscience or logicit is absurd to treat an immune disease surgically. I would say that surgery is quite an exaggerated method in this situation, almost comparable to using a guillotine for dandruff. The blame for such operations should be placed on the doctors, not on mothers. Why does a stuffy nose need a scalpel? The answer is: even if doctors do confirm the allergic origin of rhinitis, they do not have an effective remedy to treat it, and surgery delays admission of their impotence in this field. Sadly but not unexpectedly, the scalpel does not cure the patient from the underlying problem, which is hyperreleasability of the immunocompetent cells. I know patients with chronic rhinitis who underwent several sinus surgeries in the past and continued to carry around boxes of paper tissues as ever before.
Allergic Diseases
327
IMMUNOTHERAPY IN CHRONIC RHINITIS Despite the fervent devotion of allergists to steroids, ENT specialists to the knife, and general practitioners and pediatricians to antibiotics, one may hear their occasional confessions that the existing means are less than satisfactory. Through the chorus advising these extreme means of treating the afflicted noses, admissions by allergists break through at times, and they agree that immunotherapy is the only immunomodulator that is available to reduce symptoms.2 Its value, as assessed by a Toronto allergist, is noteworthy: Used properly in appropriately selected cases, about 70% of patients got some relief with immunotherapy.3 Why is it only occasionally, relief can be dramatic, but more often it is incomplete, and therapy with medications is still required? What prevents doctors from using immunotherapy properly and appropriately selecting it? There are a number of reasons. First, conventional allergy shots, as we learned before, can lead to severe reactions and even be fatal. Although complications of immunotherapy are less dangerous for a runny/stuffy nose than for constricted bronchi in asthma, it is too early for the rhinitis group to rejoice: immunotherapy can be potentially dangerous even with them. They may be hidden or undiagnosed asthmatics, and unproperly selected allergy shots may reveal this by provoking an attack. Since all allergies are diseases of hypersensitivity, patients with chronic allergic rhinitis may also be prone to developing anaphylactic reactions with life-threatening respiratory distress and vascular shock. It is essential to balance the risk of anaphylaxis with the need to relieve symptoms, says Dr. Greenberger cited above. It means that before subjecting a patient to immunotherapy, doctors have to weigh the impact of the nasal congestion vs. the danger of anaphylaxis. I personally would reject any immunotherapy for a stuffy nose that carries even the slightest risk of death. Conventional immunotherapy has another limitation: it is indicated for allergic rhinitis, mostly in hay fever, and when skin testing reveals wheals to dust mite. Even then, it is indicated only when there is unavoidable and inescapable exposure to allergens. The larger groups of the vasomotor rhinitis and the patients with mixed type are to be excluded. Dr. Greenberger says that immunotherapy promises great savings for the Public Health system because it provides for the reduction of symptoms, greater productive hours in school and at work, and the avoidance of costly medications and electric bills for air conditioning. Thus, even conventional
immunotherapy, with all its side effects and limitations, still looks like a worthy treatment, and this contradicts the humble role it plays in todays practical allergy therapies.
FINAL REMARKS ON STUFFY NOSES Thousands of people miss days of work because of sinus headaches or sleepless nights due to inability to breathe normally. Thousands of children give the allergic salute by rubbing their itchy noses while tilting their heads upwards. Millions of dollars are spent on the development of yet another antihistamine, decongestant, their fancy combinations, or a steroid spray. Daily medications, dangerous, inefficient or irrelevant are the norm in the management of chronic nasal congestion. Effective immunotherapy is just a dream expressed on the pages of periodicals. Therefore, patients with chronic rhinitis would like to know the answers to the questions that bother them: Why does a nasal problem require daily medications? Why should a patient with a congested nose be medicalized to the extent that he may end up with a stroke? Why can a stuffy nose ruin the future of a person who, because of his medical problem, was labeled a poor learner in his childhood and became one as a result of this condition? Why should a stuffy nose ruins the life of a family that has a member who is unable to enjoy spring, summer, or fall due to pollens? Why should loving mothers be reduced to such despair that they urge doctors to perform surgery on their children who are unable to sleep or eat because of a clogged nose? Why does trivial nasal congestion lead to huge expenses for special electric appliances, covers, even trips abroad to flee the hay fever season? Histamine therapy is very successful in treating chronic rhinitis regardless of its type: be it in its seasonal allergic, perennial allergic, or vasomotor form. As with all allergies, the improvement often starts right at the point of the skin testing.
B. SKIN ALLERGIES
GENERAL DESCRIPTION
The general idea of skin allergies covers several types of diseases. As with other allergies, the term allergic is fundamentally wrong in the usual sense, since in the majority of cases, the symptoms are allergen-unrelated or only partially related. Like asthma and chronic rhinitis, skin allergies are diseases of hypersensitivity. To simplify the overview, I will still abide by the accepted terminology and use the term allergic.
Although the skin is a cover for our internal organs, it is not just a passive enclosure of the organs, but a large, living and very sensitive organ. The skin is the first physical barrier that protects the body as walls protect the inside of a house. It is also a chemical barrier due to the presence of blood vessels, nerve endings, and various cells with their several million kinds of receptors. These receptors respond to chemicals, environmental and body temperature changes, pain, pressure, light, vibration, etc., and the cellular chemistry induced by their signals protects us by neutralizing the enemies that contact the skin or try to penetrate it. The presence of immunocompetent cells makes the skin an immune organ, while the extensive spread of nerve cells indicates its close relation with the nervous system. The skins involvement in allergic reaction does not differ from the involvement of the bronchi or the nose. It may occur upon contact with an allergen, an assault of a nonspecific factor such as exposure to an environmental or physical factor, as a result of the hosts own changing chemistry, or it may arise spontaneously, without any apparent trigger. Usually, immune cells adjust both to outer attacks and to inner changes, and only if the impact is too strong, there may be a temporary symptomatic reaction. If the cells are generally healthy and, most importantly, able to restore their normal functioning, a spontaneous relief sets in after a while. In a patient with malfunctioning immune cells, various triggers may lead to the initial histamine overspill from the sensitive mast cells followed by an exaggerated response to that by other cells in the surrounding tissues. The inability of the cells to adjust to the insult protracts the reaction. The nerve cells in the vicinity become engaged too. The receptors disseminate the signal all over the body, and the reaction may spread to other tissues and organs in the same way as a fire that starts in a small area may engulf the whole house.
ATOPIC DERMATITISTHE RIGHT TERM? Atopic dermatitis is one of most common allergies. As was said before, the Greek derma means skin. Atopy is interpreted in the medical dictionaries as allergic, that is, an IgE-mediated condition, which, in relation to dermatitis, is scientifically unfounded. All medical sources agree that no consistent link between allergens/IgE antibodies and atopic dermatitis has ever been demonstrated. The statistics on atopic dermatitis vary in the percentage of allergen-related cases, but even with the lowest figures (20% of the population), we are dealing with an IgE antibody-unrelated condition. From the point of view of science, a
finding of one fifth of all cases being unrelated to IgE mediation, is a high figure because that means that this is an allergic disease in which allergens may play no role! However, unfortunately allergists do not explain this phenomenon. Chapter 10 written by R. Rocklin in the 1985 textbook Allergy thoroughly spells out all the mechanisms of allergy. This description is applicable to any allergic condition, and atopic dermatitis is no exception. (Strange as it is, another author writes on page 417 that the etiology and pathogenesis of atopic dermatitis remain enigmatic, whereas, all the author had to do was to read Chapter 10 in the same book.) In fact, the most essential component in atopic dermatitis is a skin reaction to a local histamine overspill followed by a cascade of the allergy mediators joining in. Like in any allergy, the genetic defect manifests in weak T-suppressors unable to counterbalance the pro-allergy chemistry produced by mast cells, basophils, Langerhans cells and T-helpers.
THE SYMPTOMS An allergic skin inflammation in dermatitis manifests in an intensely itchy rash. The skin also becomes scaly, crusty and cracks. Patches of affected areas usually cover the arms and legs, especially behind the knees and the inside of the elbows, the neck and face but may easily spread all over the body. At times, the itch is merciless. The constantly scratched surface becomes damaged, and this may cause a superimposed infectious inflammation. Children are more common sufferers of allergic dermatitis than adults, and another name for the disease is infantile eczema. Their eczematous skin may become infected because children are often unable to observe hygienic measures as well as refrain from scratching. With age, their dermatitis may disappear, but the skin may remain damaged with numerous scars. Disappearance of the dermatitis does not mean that the pathological immune process is over. It is known that often, it transforms and manifests years later in another allergic condition. Many asthmatics had atopic dermatitis in childhood, and it is gone by the time the first asthma symptoms appeared. This should prompt doctors to view allergic skin problems in a child as an early sign of potential allergic rhinitis and/or asthma in the future. All three diseases are known to medicine as the atopic triad. Allergic dermatitis may be a traumatizing disease not only because of its itchy cracking skin but also psychologically. The sight of the skin lesions may put off and scare those who are unfamiliar with the non-contagious nature of the disease. Parents may forbid their youngsters to play with a child who
Allergic Diseases
331
suffers from allergic dermatitis. The situation may turn dramatic when peers mock or tease the child. Even adults suffer psychologically when lesions are on the face, but the emotional impact of this on a child is especially severe. One can only hope that the child outgrows the disease, and his emotions will stabilize as well. Both can be wishful thinking, though.
THE MANAGEMENT OF ATOPIC DERMATITIS The lack of understanding of what mechanisms underlies atopic dermatitis dooms its treatment. It addresses what is on the surfacethe symptoms. The same textbook Allergy sees the goal of treatment as the reduction of itching. As in other allergic diseases, once again the end organ becomes the target for treatment, not the malfunctioning immune cells. Calling the disease atopic (allergic) implies that the first step should be elimination of the trigger. Although in the majority of cases, the offender is unidentifiable, elimination of the standard culpritsfoods, house dust mites, pets, etc. has become the norm in the management of dermatitis. However, environmental control and dietary restrictions are rarely successful. Helpful or not, these measures are especially difficult to implement with children whose active nature hates restrictions of any kind. Besides, the disease is rarely a result of a single trigger, and elimination of one or a few factors or a food is usually not enough to stabilize the condition and may help partially at best. Topical means pertaining to the surface, and in relation to drugs, the term means creams, ointments, and lotionsall remedies that are put on the skin. Standard, non-medicated topical remedies include lubricating oils to reduce skin dryness, and special bath preparations or non-irritating soap-like lotions instead of regular soaps. Those who have allergic dermatitis know how these means work, or better, do not work. One can rarely achieve pronounced relief of the itch with antihistamines. Doctors admit this but still prescribe them, probably, out of helplessness. Often patients are given the first generation antihistamines, which are sedative: to let the patient at least get a good nights sleep. Delayed sedation is common, and the next day, a drowsy child can hardly be a good learner at school, nor can a sleepy adult perform work that requires concentration. Like other allergy sufferers, patients with atopic dermatitis cannot escape steroids. In fact, steroids are the main and, actually, the only relatively effective remedy, which often provides temporary relief of symptoms. Numerous steroid-containing creams, ointments and lotions differ primarily in the
dosage of steroids, which determines the degree of their effect, both positive and adverse. The 1999 CPS writes on page 590 in the entry on Elocom that comes in a cream, ointment and lotion: (it) has been shown to have topical and systemic pharmacologic and metabolic effects characteristic of this class of drugs. And further: Any of the side effects that have been reported following systemic use of corticosteroids, including adrenal suppression, may also occur with topical corticosteroids, especially in infants and children. All this is not surprising, since the skin is an excellent absorbent of the drug. Children, as the most frequent victims of allergic dermatitis, become the main consumers of the steroid-based topical remedies. The producers warn of the increased danger of applying topical steroids over a large surface and for a long time. The disease is, however, chronic, and in many, the lesions cover large areas. All this means no escape from the drugs side effects. Paradoxically, one of the listed complications is skin thinning or even atrophy. Just think: the skin may get irreparably damaged due to the medications meant for its treatment! Steroids are frequently combined with antibiotics. Such topical centaurs are supposed to act like the stone that kills two birds: steroids aim directly at allergic dermatitis, while antibiotics treat secondary infections, which may develop due to the damaged skin. Infections may also be the result of the adverse affect of the steroids that make the skin more susceptible to infections. In such a case, one medication in the combo drug relieves the adverse effect of anothera common phenomenon in medicine. The paradoxes of allergy treatments continue: there is a possibility of an allergic reaction to antibiotics, the penicillin group in particular. The reaction may be skin-limited, which means appearance of rashes or lesions in response to the drug; it may also be systemicemergence of new allergic symptoms and/or worsening of the existing ones. And we know all too well what the most effective drug for all allergic reactions issteroids! This time, patients take them in inhaled, oral or injectable form. Oral steroids are prescribed in allergic dermatitis when topical ones fail, and the itchy rash becomes intolerable. Even in those patients who improve, the itchy rash may and often does come back as soon as the drug is discontinued. It is the same vicious circle that we saw in asthma treated with steroids. To avoid serious side effects of and dependence on steroids, medicine occasionally offers another group of miracle drugsCyclosporin, Tacrolimus and the most recent Pimecralimus. The CPS classifies them as highly potent
Allergic Diseases
333
immunosuppressants. Allergists call them immunomodulators even though these drugs disable the immune system. Those authors, who suggest oral Cyclosporin and topical Tacrolimus recognize that these medications do not resolve the problem, have a lot of side effects, and a rapid exacerbation is common once the treatment is stopped. Only desperation would prompt the use of such drastic means for allergic dermatitisa disease, which according to all standards, is not life-threatening. It is of interest that Allergy 1985 mentions, in passing, a theoretical possibility of resorting to immunotherapy in atopic dermatitis if it is accompanied by other allergy symptoms. Of course, only if all other methods fail. The fact that, except for few timid failed attempts, clinical allergy never uses immunotherapy for allergic dermatitis is understandable. First, how can one treat an impaired immune system if the problem still remains enigmatic and elusive? Second, allergists refer to allergen/IgE antibody-unrelated dermatitis as nonimmunogenic, that is, immune-unrelated. Dissatisfied with conventional methods, despondent patients try various sorts of herbs. They put oatmeal, camphor oil or baking soda into their bath to soothe the itch. Some travel to Israel and spend months on the Dead Sea, others go to geographically remote sites to swim in pools filled with exotic skin-eating fish. Publications and TV programs for lay people are full of such stories. A classic example of a sufferer is Marat, a leader of the French Revolution at the end of the 18th century. He was a doctor by profession. He regularly took soothing baths for his constant agonizing itch, and was murdered while taking one. The management has not become more successful since, and baths have remained the safest and least expensive means in the treatment of allergic dermatitis.
DO MASSAGE AND ACUPUNCTURE HELP? A study on children with atopic dermatitis conducted by the Touch Research Institute sponsored by the U.S. National Institute of Mental Health was conducted some time ago. Half of the young patients received only standard treatment, while the other half also received a 20-minute all-body daily massage done by their parents. The second group felt better and became calmer. A participating doctor explained it as a psychological effect of touching. However, skin itch is a symptom that has a material basiscellular malfunctioning, and the explanation must go to the root and be consistent with the concepts existing in psychoneuroimmunology. Thus, during the massage, sensory nerve endings
in the skin are engaged directly and invite the neighboring immunocompetent cells into the process by sharing their chemistry. It may also be the other way around: Langerhans cells and T-cells get activated by touch and involve others by their chemicals. In any case, both groups become participants in the reaction. A gentle massage does not over-activate H1 receptors. At the same time, the signals from the tender touching activate the inefficient H2/3 receptors, the cells start to produce more anti-disease mediators and cytokines, and this arrests the allergic reaction. Massage, acupressure and acupuncture work similarly in this respect. Highly qualified specialists in massage therapy and acupressure empirically know that pressure to the skin should not be too light but should not exceed a certain level. Only through experience, they acquire the feel of how much is too much or too little. It is also possible that the involved nerve cells send the message of the physical pleasure of the touch to the brain. The involvement of the brain is important for any immune process. In this case, the brain cells start to produce the inner morphine (endorphins) and anti-inflammatory cytokines. The favorably changing chemistry reverses the aftermath of the local histamine overspill, which initiated the disease. Is acupuncture helpful in atopic dermatitis? My answer: it is justifiable on theoretical grounds, although these are unknown or vaguely known to the practitioners who conduct the procedure, and, of course, it is safer than steroids or Tacrolimus. The efficacy of acupuncture is probably limited. I have seen very few cases when it had, at best, produced a slight, temporary relief, and never a case of substantial relief or a cure. Besides, those parents whose children have allergic dermatitis should welcome a chance to avoid or reduce the amount of steroid creams by resorting to daily skin massaging. Concluding thoughts on atopic dermatitis: I have treated many patients with atopic dermatitis. The majority improved to different degreesfrom diminished itch to complete recovery. In young children, the success was especially notable.
URTICARIA
GENERAL DESCRIPTION
Another kind of skin allergy is itchy hives, the scientific name for which is urticaria. The Latin word urtica means stinging nettlean herb armed with pricking, stinging hairs. This gives you an idea of the symptoms.
Unlike atopic dermatitis that has a chronic course, urticaria is a disease of a more spontaneous kind. Red, itchy wheals may develop all of a sudden either as a short episode, or may last, mostly intermittently, for months or even years. This makes the notion chronic urticaria rather conditional. Some textbooks define as chronic a disease that lasts over three weeks, while others indicate six weeks. In my view, this arbitrary mathematical approach (i.e. two weeks are acute urticaria, and six are chronic) makes no sense especially when it comes to the management of such patients. This condition should be considered chronic if patients are prone to frequent, recurrent hive development, no matter how long each episode lasts. As in other diseases of hypersensitivity, occurrence of chronic urticaria is unpredictable in the majority of cases. Only a few patients know exactly what provokes their symptoms and try to avoid those triggers. I saw many patients with a history of almost non-stop hives who were unable to pinpoint the stimuli. Statistics differ in the percentage of allergen-triggered urticaria. Older medical textbooks state that the atopic (allergen/IgE-related) form is as common as non-atopic. Other, more recent publications reduce the atopic kind to 20%, which means that up to 80% of all urticaria cases are due to nonspecified triggers. This means that only 20% of cases of this allergic disease are allergies in the conventional sense. What about the rest? To get a feeling for this situation imagine viral diseases, 80% of which are not caused by viruses!
URTICARIA AS A PURELY HISTAMINE-INDUCED CONDITION As specialists say, Chronic urticaria is a common condition, frustrating for both patients who suffer from it and for the many physicians involved in its management.4 In fact, urticaria is the simplest of all allergies. Why the simplest? Dictionaries define urticaria as a formation of wheals or hives, which are mostly itchy. An encounter with an allergen, a prick or pressure to the skin of a person with the innate predisposition to allergy may cause a histamine leak from the local mast cells and lead to a hive at the site. Doesnt it remind you of allergy skin testing when a prick with an allergen or histamine is actually a purposeful formation of hives? Hives in skin testing and hives in disease possess similar characteristics: redness, swelling, itch, rapid development and spontaneous resolution. They are a model of an allergic reaction, in which histamine plays the predominant role as a mediator. To watch the hive formation and regression both in urticaria and at a skin testing is to watch the highs and lows of an allergic
process not only on the skin but also processes hidden inside the body. When examining patients with urticaria, one can literally see their hives fade and disappear. Some authors write on similarities in the pattern of response observed in the lungs as being also observable on the skin. Allergy knows that: As a superficial part of the immune system, the skin makes a perfect object for a visual observation of how allergic inflammation goes on elsewhere during a disease and correlates with the processes in other immune organs.5 Thus, the simplicity of urticaria, which is purely a phenomenon of histamine-induced proinflammatory chemistry, allows one to observe with the naked eye the course of this disease and at the same time understand that similar ups and downs take place in other diseases of hypersensitivity. Other allergies are more complex than urticaria. They cannot be seen and are mostly judged on the basis of the information given by the patient and are rarely amenable to conventional testing. This makes their understanding and treatment more difficult. Even atopic dermatitis, which is also a skin disease, cannot provide precise information in this regard due its multifactorial nature. It is a blend of two medical fieldsallergy and dermatology, and has lower reversibility than most allergic conditions and asthma because of the potential of severe lesions and possible scarring. All this allows one to conclude that understanding of the true immune mechanisms involved in the simplest allergic disease, urticaria, helps us understand allergies in general. There is general lack of understanding of the similarity of the underlying mechanisms in urticaria and the phenomena observed during skin testing. Because for allergists, superficial signs are more important than the essence of the immune reactions, doctors conducting allergy skin testing do not monitor systemic reactions. Thus, they miss the reactions with improvement, which could form the basis for immunotherapy, or allergy shots. This, in turn, makes it clear why immunotherapy is never conducted in skin allergies. If allergists fail with the management of urticaria, how can they be expected to properly manage the more complex asthma, chronic rhinitis or atopic dermatitis?
TRIGGERS, CAUSES AND THE IMMUNE PROCESSES IN URTICARIA Dr. A. Kaplan, the editor of the textbook Allergy (1985) is also the author of the chapter on urticaria in that same textbook. On page 464, he writes that in most cases, the cause and pathogenesis are unknown. It is difficult to explain why he says so, since, as an author of numerous articles, which we discussed in the
Allergic Diseases
337
chapter Histaminegate, he indicates that allergies are, actually, the prevalence of histamine-induced proinflammatory factors (cytokines) over histamineinduced anti-inflammatory factors. These factors are the products of participating immunocompetent cells. Indeed, Kaplans chapter points on page 460461 to a ten-fold increase in the number of mast cells and increased amount of histamine at the site of hives. By pointing to this, Dr. Kaplan actually reveals the pathogenesis of urticaria as it is directly related to the genetically predetermined mast cells histamine hyperreleasability. Their histamine overspill creates the foundation for an allergic reaction, with hives as its manifestation. Another contradictory declaration made by A. Kaplan in the textbook is that he is not sure if allergen-unrelated urticaria is a process which is immunologically mediated. This uncertainty is more than strange because, in addition to the accumulation of mast cells, he states that there is a fourfold increase in T-cells in the areas affected by urticaria. If, according to Dr. Kaplan, interactions of these cells and their products are NOT immunologic mechanisms of allergies, what other department do they belong to? Such paradoxical statements are the result of the incorrect perception of what underlies allergies in general and hence, urticaria. Dr. Kaplans reveals this in the above-quoted phrase: in most cases the cause and pathogenesis are unknown. In fact, basic science informs us that in all cases, the cause (genetic make up) and pathogenesis (histamine-induced imbalanced cellular production) are the same. The misconception of the etiology and pathogenesis, the misinterpretation of the notion of a trigger, and the inability to differentiate between triggers and causes are common for all diseases of hypersensitivity, and urticaria is not an exception. The best illustration of the confusion is the editorial written by a leading Canadian allergist, an ex-president of both the Ontario and Canadian Society of Allergy, Asthma and Clinical Immunology whose area of expertise is urticaria. The author combines under the name trigger such incompatible phenomena as true triggers (allergens), cellular by-products (proteins that accompany various immune reactions in the body) and cytokines (regulatory mediators of immune reactions). Not surprisingly, this confusion results in the statement similar to the one made by Dr. Kaplan: the exact cause of chronic urticaria remains unknown.6 If Dr. A. Kaplan, the 2003 President of the World Allergy Organization, and a leading Canadian allergist, both specializing in urticaria, do not understand this conditions immunologic nature and mix up a trigger with the cause, one cannot expect more from an ordinary doctor.
LOGICAL QUESTION IN RELATION TO URTICARIA Allergy medicine is a field of immunology. As 80% of urticaria are nonimmunologic in origin, shouldnt allergists pass these non-immune cases to other departments of medicine? What specialists should those patients see whose urticaria is nonimmunologic? Who should treat cases of mixed urticaria? Should patients visit an allergist solely when they have allergen-triggered symptoms such as, for instance, hives in response to pet exposure, but not when their hives develop spontaneously, without any evident reason? Why should we stress the significance of allergen elimination in the mostly allergen-unrelated urticaria? Why are immunosuppressive medications prescribed in nonimmunologic urticaria? Only a clear picture of the underlying mechanisms can lead to proper management. I have not come across a work that would specify those. ANGIOEDEMA In a way, angioedema is urticaria at a different level. The skin has two layers, and symptoms reflect the degree of their involvement. In urticaria, the surface layer is primarily involved in the disease. Angioedema is a condition in which the reaction goes to the deeper skin layer as well as the subcutaneous layer, both of which have blood vessels. The Greek roots of the term mean vascular swelling. Urticaria has a vascular component with the swelling of the tiny local capillaries, while angioedema involves the bigger vessels as well. As a rule, both diseases are presented together in textbooks as different degrees of the same process, both local and systemic. Angioedema affects mostly the face, extremities, genitalia and occasionally respiratory and gastrointestinal mucosa. The condition is dangerous and may be fatal in cases where systemic swelling spreads to the throat and closes the airway. Those people are predisposed to angioedema who inherited or acquired impaired immune mechanisms governing the work of the allergy department of the immune system. Therefore, angioedema is not different from all other diseases of hypersensitivity. Like urticaria, angioedema may develop when the patient is allergic to certain foods and substances, insect bites, drugs, exposure to cold temperatures or to other physical triggers. In a lot of cases, triggers in angioedema, as in urticaria, are not identifiable.
Angioedema is usually classified into four major types. First, the hereditary type which is mostly the familial form, resulting from the bodys failure to synthesize certain enzymes and/or proteins, does not belong in diseases of hypersensitivity. Among the three other forms, there is an allergen-specific kind. Another type is nonspecific or physical allergy. The third is angioedema of unknown origin or idiopathic, as it is called in medicine. Idiopathic angioedema is, actually, a susceptibility to react in a hypersensitive way, a chronic form of the disease. Only one kind, allergen-specific, is potentially fatal. These patients develop reactions through exposure to certain triggers, among which peanuts are considered to be especially dangerous. At times, even the smell or touch of a peanut-containing product may cause a severe response. Reactions to penicillin, especially in injections, are another example. Such hypersensitivity is incurable, and the triggers, once identified, should be absolutely avoided. This type should not be confused with food allergies, which may be curable.
TREATMENT OF URTICARIA AND ANGIOEDEMA In acute severe urticaria and angioedema, an injection of adrenalin is given, and the emergency kit, which people prone to angioedema carry, contains it. In chronic and recurrent cases, contemporary allergy recommends antihistamines and, of course, oral steroids. Neither resolves the problem. Since urticaria and angioedema are mostly allergen-unrelated, conventional allergy cannot even resort to its habitual mantra of avoidance and elimination. It views these conditions, as the rest of allergies, as incurable. Immunotherapy is never considered as a choice, whereas, being histamine-based more than any other disease of hypersensitivity, chronic urticaria and angioedema can be successfully treated through a tune up of the ailing immune tools. Synthetic histamine, as a nonspecific immunomodulator, is the best means of therapy that can restore the imbalance induced by cellular histamine. With the confidence of a person who treated urticaria patients with histamine injections, I say that the majority of cases are treatable; many are helped and some even curable.
C. HAY FEVER
This section on hay fever will be short despite the high incidence of this disorder. The reason is that hay fever is like a bouquet of the diseases already described earlier, only in this case, they are seasonal and are triggered by pollen. Allergic rhinitis is the central manifestation although occasionally, it may not
be present. In addition come itchy/watery eyes, plugged/itchy ears, sore/itchy throat, throaty or chesty cough with wheezing, increased headaches, extreme tiredness, poor concentrationrather like a severe flu lasting for months, might be the best comparison. Strangely, despite the variety of symptoms, the overwhelming presence of rhinitis in the majority of cases makes many authors wrongly identify hay fever solely with seasonal rhinitis. Thus, Diagnostic Codes in the Ontario Health Insurance Plan provide for these diseases just one code, and the codes are suggested by specialists. Indirectly, statistics of hay fever prove that the statistical figures for chronic rhinitis are definitely higher than 2025%. Thus, official sources state that about 20% of the population suffer from hay fever. At the same time, since hay fever is included into the group of chronic rhinitis, the large group of those who have a vasomotor or mixed type is left unaccounted for. These simple arithmetic calculations tell us that the prevalence of chronic rhinitis, also about 25%, is seriously downplayed. Dr. John Bostoch was the first to describe hay fever in 1819, and in 1873, Charles Blackley showed that it is triggered by exposure to pollen. Every year, the approaching pollen season is announced by the escalating number of TV commercials on antihistamines which are lately called allergy drugs (to hide the very existence of histamine?). Newspapers and magazines are full of articles written by the journalists who often know about hay fever first-hand. We recognize that the season is coming upon us by seeing people with swollen faces, red eyes and noses, each carrying a box of tissue under the arm or in a half-open purse. We know the season is in full swing because people around us sneeze, cough, wheeze at the time most unsuitable for colds and flu, when the temperatures are 2030 degrees Celsius above zero. In emergency rooms at this time of the year, one hears coughing and wheezing in surround sound, and a line-up of frightened kids expecting a mask or an IV with steroids is the norm. This is the time when allergists provide their advice in newspapers, magazines, on the radio and TV. The quintessence of their recommendations was once expressed by a Canadian lay source as three As: awareness, avoidance and action. In other words: be aware that your season is coming. (As if sneezing attacks, itchy eyes and incessant cough will let you forget your annual agony!) Avoid make sure that the windows in your home, car, office are hermetically sealed. Put on a mask when outside. (We have already discussed the chances of relief through these measures).
Allergic Diseases
341
Act by listening to the announcements of the pollen count, start taking antihistamines two weeks prior to the season, stock up in advance with decongestants, puffers, eye drops and nasal sprays; stop all outdoor activities. (Does it mean to change ones profession if one is a gardener, a farmer, a landscape engineer, a constructor, a taxi or a bus driver?) In short: limit the area of your activity in general (no field trips or summer classes if you are a teacher, and no home visits if you are a doctor). Limit your company to a computer, a telephone, and a fax machine.
Does it help? Judging by the number of people who dread the coming of warm days, not a lot. Of course, the best choice would be to leave the country (province, or state) for the season. Do not forget to take your children with you because, most probably, they have inherited your allergies. You think such trips are expensive? Never mind, to be in debt is better than to suffer physically. There are several additional tips patients with hay fever can use on top of the Three As Program. Drive your car carefully in hay fever season. The roads are full of drowsy people either due to the drugs they take or to the sleepless nights they have had because of cough, congested nose and itchy skin. Driving may also be dangerous in another sense: spontaneous sneezing attacks are fraught with accidents. In 1989, while being in London, England, I read an article about a car accident, in which the drivers mother was killed. He was acquitted because he suffered from hay fever, and a severe sneezing attack had been the cause of a car crash. On August 16, 1997, a lucky Canadian driver got away with just few minor injuries after his car had turned upside down during a similar sneezing fit. As you see, hay fever is not an innocent condition to sneeze at. No matter how severe your cough is, do not rush to take antibiotics prescribed by your doctor for alleged bronchitis. First, the weather is getting warmer and warmer, second, you do not have a high fever. Even if your family got infected from you or the other way around, it may not be due to a viral epidemic, but simply because your children, siblings, parents and grandparents probably suffer from the same medical problemhay fever. Be positive: suffering together may unite your family still more. If antihistamines, decongestants and inhalers do not work, try to put up with the temporary inconvenience, for even the longest season is over with the first frost. You live in a place where pollens are in the air all year round? I am sorry
for you, but either you change your location or keep hoping that you will outgrow hay fever. Of course, it may take quite a few years or decades, but you still have a chance. In case the agony is intolerable or becomes dangerous due to your worsening asthma, you have one choice onlysteroids in nasal sprays, eye drops, inhalers, and pills. Their consumption during the pollen season goes up drastically, and lucky are those consumers who have hay fever limited to only a specific pollen and can restore their health from the steroid aftermath during the rest of the year. Pre-seasonal or year-round allergy shots are not very effective for the majority, at least judging by the seasonal demand of daily medications. The medical articles, though, often say the opposite. As soon as you start experiencing minor side effects from your shots, inform your doctor about that, and consider discontinuing them if the side effects become more and more pronounced. Remember: UK doctors prefer to have resuscitation facilities around when they provide allergy shots, and medical papers warn doctors about possible liability in administrating immunotherapy in their offices. Is your doctors office close to a hospital? My mockery is directed at the specialists proclaiming the high efficacy of allergy medications and the efficiency of their Three As Program and similar programs. Besides, laughter is the best cure, and smiling at this nonsense may help an allergy sufferer feel better at least while reading. Real help may come from histamine injections. Hundreds of my patients started to live a normal life due to histamine injections. Many hay fever patients came to me in a symptomatic stage. Within minutes of allergy skin testing, the eyes would stop itching, congested noses would open, headaches lift, shortness of breath or cough would disappear. The main change, however, was disbelief that it was so simple to feel better. It was still harder for them to believe that they would not be able to have this therapy anywhere else. Some of them traveled a long distance to get the treatment. Thanks to histamine, the majority of my patients became able to enjoy summer camping, do the unthinkable such as mow grass, keep their windows open, and drive without a fear that a sneezing attack could turn fatal.
Allergic Diseases 343 ENDNOTES

1. D. Allen. Systemic effects of intranasal steroids: an endocrinologists perspective. JACI 2000;106:S179-90 2. P. Greenberger, Immunology and Allergy Clinics Of North America, Preface, vol. 12, No 1, Feb. 1992 3. K. Binkley. Seasonal Allergic Rhinoconjunctivitis. The Canadian Journal of Diagnosis, June 2001:93-8 4. J. Sharma et al. Chronic urticaria. Journal of Cutaneous Medicine and Surgery, 2000;4:89-93 5. S. Worfel, L. Lichtenstein et al. JACI 1995;96:57-65 6. G. Sussman. Editorial. Allergy, June 1985
PART NINE
FUNCTIONAL ENCEPHALOPATHIES
WHAT IS ENCEPHALOPATHY? This word consists of two Greek roots: Cephalic meaning pertaining to the head, and pathosrelated to disease. Medical textbooks refer to encephalopathy only as a degenerative, organic disease of the brain often resulting from a systemic disease elsewhere in the body. Such are, for instance, advanced hepatic diseases, kidney failure resulting in dialysis, or lead poisoning. This interpretation of encephalopathies is incomplete, since many people have neurological symptoms in the absence of organic disorders. Their symptoms are solely due to the imbalance of neurotransmitters in the brain, a condition that should be classified as functional encephalopathy. Although very common, these diseases have never been described before as one group, and the classification functional encephalopathy does not exist in medicine. In this sense, mental and neurological diseases such as headaches, attention deficit and hyperactivity syndrome, depression and anxiety, chronic fatigue syndrome, autism, many seizure disorders, schizophrenia, etc. are functional encephalopathies. The general notion of functional encephalopathy does not have any place in nosology, the science that classifies diseases according to their origin and body mechanisms involved in disease causation. The explanation lies in the lack of understanding what mechanisms underlie the disorders united under this name.
Functional Encephalopathies 345
Our nervous system consists of the centerthe brain and spinal cord, and peripheral neurons and neural elements. Their distribution all over the body explains why chemical changes in the center may involve any tissue or organ in the disease. The central mediator in allergies, histamine, is also a major neurotransmitter in the central nervous system. It does bothmediates neurological processes and regulates many. The pathways through which neurons in the brain and elsewhere conduct histamine messages form a histaminergic neuron system. This section deals with those common encephalopathies that result from the chemical disturbances in neurotransmission and assesses to what extent histamine imbalance contributes to functional encephalopathies.
HISTAMINE AS A NEUROTRANSMITTER Histamine is an omnipresent cellular substance of a high physiological potency and multifaceted effects. Its messages are distributed by the receptors marked by the letter H. Each type of H receptor has its own function, that may differ depending on the organ in which this receptor is situated. Launched by a local trigger in any part of the body, histamine reaction can invoke not only local but also systemic effects. Therefore, inefficient performance of any of the histamine receptors may alter the normal signals in the whole histaminergic system and create a chemical imbalance both of histamine itself and also of other numerous chemicals whose activity and release depend on its regulatory messages. Like histamine, many of these chemicals are both allergy mediators and neurotransmitters. The role of histamine is magnified due to the fact that the main histamine producers, mast cells and basophils, are highly disseminated in various tissues including the brain. The degree of the involvement of the nerve cells determines the severity of neurological symptoms. They may accompany allergies but, if pronounced, can be isolated as a functional neurological disease. Long ago, observant clinicians noticed the co-existence of neurological and allergic symptoms. Indeed, immune and neurological diseases seem to cluster in families, although the predominance of certain symptoms over others may differ among the members of the same family. The earlier-quoted article by L. Mansfield1 gives historic references that go as far back as 1921, when the relationship between the occurrence of asthma and rhinitis (the immune system) and migraine (the brain) was noticed. Mansfield also refers
to the works of the 70s and 80s that confirm an increased histamine output in allergic dermatitis, food allergies as well as during migraine attacks. In many aspects, pathological processes in these functional encephalopathies are similar to the ones in allergies. This allows us to view these neurological manifestations as allergic conditions of the nervous system or rather, hypersensitivity of the nervous system.
HYPOTHALAMUS, HISTAMINE AND ENCEPHALOPATHIES The presence of histamine in the brain was first discovered in 1943. Since that time, basic sciences have progressed to identifying it as a central neurotransmitter and neuroregulator. The theoretical work by H. Wada et al.2 reviews the wide distribution of histaminergic neurons, and their effect on brain activity. Wadas research identifies the hypothalamus as the regulatory center of the histaminergic messages. This portion of the brain is like the hard drive of the bodys computer. It controls many vital functions in the body, including the hormone production by the endocrine glands, the vascular tone and the tone of our muscles and joints. It also regulates such bodily functions as water balance, appetite, thirst, temperature, sleep, sexual drive, etc. Hypothalamus is the governing level of the HPA axis (hypothalamus-pituitary-adrenals), which also regulates the functioning of our immune system. Since the hypothalamus is a reservoir of histamine and contains more of it than any other brain tissue, nature evidently planned a major role for histamine in the work of this vital organ. Quite recently, the main histaminergic pathway was identified and described. This pathway is called CRH-mast cells-histamine axis.3 This axis conducts histamine messages between the endocrine, nervous and the immune systems, and the connecting elements are hypothalamic corticotropin-releasing hormone (CRH), that governs the production of corticosteroids (through the pituitarys corticotropin), and mast cells, whose histamine spill initiates allergic reactions. The axis is the best proof of histamines influence on the functioning, regulation and interplay of all three systems. U. Knigge and J. Warberg described in their fundamental work the importance of histamine for the functioning of the hypothalamus and through it, for the rest of the body: Electrophysiological experiments have shown that microinfusion of histamine induces both excitatory (generally H1-mediated) and inhibitory (generally H2-mediated responses) in different hypothalamic areas.4
The presence of histamine receptors everywhere and the diversity of their effects emphasize the need for the knowledge of its involvement in the functioning of the regulatory systems. Without it, there cannot be any understanding of the origin of numerous immune and neurological symptoms (generally H1-mediated) and no possibility of developing treatments that cause their reversal (generally H2/3-mediated). This invariably leads to the idea, that the H2/3 effect vs. the H1 effect of synthetic histamine can successfully be employed not only for allergies but also for functional encephalopathies, especially those that originate in the hypothalamic disturbances. With numerous tasks to regulate, the activity of the hypothalamus becomes of immense importance to the work of all organs and systems. Therefore its malfunctioning may affect each of them and cause numerous symptoms that can be united under the syndrome called diencephalic. European clinicians acknowledge the diencephalic syndrome, but do not support its origin by theoretical data. In North American textbooks, the core symptoms are not even acknowledged. Some other symptoms are listed as diencephalic and ascribed to children only. The reasons for the confusion and misinterpretation may lie in the fact that this syndrome, by nature, is highly inconsistent in its clinical manifestations and does not have confirmatory lab tests. Among the symptoms are shakiness, severe and unusual dizziness, perspiration, palpitations, chest discomfort, sudden imperative urge to urinate or defecate, etc. They are of neurological origin and may strike in different combinations, unexpectedly and often unrelated to any evident stimulus. All this makes the syndrome a poorly defined medical condition. Women have diencephalic symptoms more frequently than men, which is most probably attributable to their hormonal fluctuations. Pre-menopausal women are the group that suffers most from this syndrome, at the same time, their blood tests may show normal levels of all hormones. The explanation is: their symptoms, including so-called hot flushes, are not only due to the agerelated fading ovaries but also, to a great extent, due to the reduction in the ability of the hypothalamus to conduct its regulatory chemical messages to the nervous and endocrine systems. Although there are encephalopathies rooted in the chemical disturbances of other parts of the central nervous system, those that originate in the hypothalamic malfunctioning are the clearest and best researched indications of this systems imbalance. Considering that the hypothalamus is full of histaminergic neurons, we may assert that diencephalic symptoms may, at least in
part, depend on histamine messages and are relieved if the histamine pathways re-acquire their normal regulatory functioning.
PITUITARY, HISTAMINE AND ENCEPHALOPATHIES The pituitary gland is another part of the brain and constitutes the second level of both the HPA axis and the CRH/mast cell/histamine axis. As the subordinate of the hypothalamus, the pituitary implements the directions given by its superior. It is called a master gland for its direct and indirect control over all hormonal production by other endocrine glands. It monitors growth, sexual behaviour, lactation, labour, insulin production, functioning of the thyroid, water retention and excretion. It also governs the bodys response to any stress through the regulation of the synthesis of various adrenal hormones including corticosteroids. The role of histamine in the performance of the hypothalamus, the existence of the histaminergic pathways between the hypothalamus and pituitary in the brain and their dissemination in the rest of the body make it inevitable that those diverse body functions involving the pituitary depend directly on histamine activity. The above-quoted theoretical source also states: The neurotransmitter histamine participates in the neuroendocrine regulation of pituitary hormone secretion by an indirect action at a hypothalamic level where histaminergic neurons are abundant.5 The authors describe the stimulatory (!) effect of histamine on the functioning of adrenals. The importance of the inner steroids is evident from the fact that synthetic steroids are the number one medication in such chronic diseases as asthma, rheumatoid arthritis, and ulcerative colitis. In this connection, the idea that synthetic histamine can naturally stimulate the functioning of adrenals and thus eliminate the need for immunosuppressive synthetic steroids should sound appealing to the medical profession. Apparently, it does not, for how else could one explain the existence of such data in the theoretical sources and their complete absence in clinical medicine? Among other hormones whose production histamine regulates, the authors name prolactine (lactation), growth hormone (linear growth, cellular repair, wound healing), oxytocin (labour, lactation), antidiuretic hormone (water balance), thyroid hormones (general metabolism), etc. Some of the effects of histamine are well researched, others less so; some are studied on animals, many on humans as well. One thing is clearthe regulatory ability of this neuro- and immunomodulator is hard to overestimate, and its implications in clinical medicine are of prime importance. Nature heals, but hista-
mine cures, said a world-famous neurologist, Bayard Horton, several decades ago. The total silence around histamine in clinical medicine is not just surprising, but shocking. The effect of histamine imbalance is disabling for the body because it affects the production of other major neurotransmitters. Among them, there are serotonin and noradrenalin (central participators in vascular headaches, depression and anxiety and irritable bowel syndrome), dopamine (a participator in parkinsonism and schizophrenia), endorphins (mediators of mood and pain relief, including vascular headaches).6 The presence of histaminergic pathways between the centerhypothalamus and the pituitary, and the peripherythe vascular wall, makes it inevitable that the vascular tone also depends on the activity of histamine.
HISTAMINE IMBALANCE IN THE BRAIN AND DISEASES Histamine is a major participant of the interrelated functioning of our regulatory systemscentral nervous, immune and endocrineand through them, of other systems and organs. When histamine release and activity is out of balance, different organs and systems may become affected. Histamine provides the solid proof that our body is an entity. Its imbalance affects the whole body and can manifest in the most varied symptoms: dizziness, poor appetite, increased thirst, raised or lowered blood pressure, low libido (the brain is, in effect, the main sex organ), increased or decreased locomotor activity (hyperactivity or muscular/joint weakness), slow linear growth in children, poor wound healing after surgery or trauma, heightened sensitivity to pain, depression, anxiety, insomnia, temperature dysregulation (for example, a mild fever is not necessarily a sign of an infection, so eagerly diagnosed by doctors). Since histamine activity is well researched, it can be viewed as a biological marker of interrelated regulatory systems, and the symptomatic changes in different organs may serve as indicators of its effects in the given area. The stimulatory effect of histamine, through the CRH/mast-cells/histamine axis, on the functioning of the adrenals is of special importance. Adrenal failure alone may reveal itself in an array of symptoms, especially those related to different areas of immunity. Too often, medicine views each symptom as an event disconnected from other accompanying symptoms and interprets it as a separate disease. The chronic nature of the symptoms leads to aggressive consumption of artificial steroids especially in asthe, which eventually results
in a still deeper depletion of the bodys hormones. Despite the supporting theoretical grounds, stimulation of the adrenals by histamine and the resultant normalized production of natural steroids is not considered even as a possibility. The strongest support of the profound involvement of H in encephalopathies comes from the fact that cAMP enzyme activates the nervous system in the way it activates the IS. Alterations of the cAMP second-messenger path way are essentially involved in the etlopathogenesis of mood disorders. Direct targeting of this pathway may be a promising strategy for developing novel therapeutic agents for the treatment of depression.21 Treatment of depression would be similar to the treatment of all encephalopathies. With H being the best activator of cAMP, we naturally come to the conclusion of its involvement not only in the origin of encephalopathies but their reversal.
A. VASCULAR HEADACHES
HEADACHES ARE A HEADACHE FOR ALL MANKIND
We exclude here those headaches that occur due to malignancy, inflammation, injury, etc. and limit our description to the ones originating from functional disruptions in the brain. Generally, textbooks do not present headaches as encephalopathies, although any medical condition brought about by a chemical imbalance in the brain is an encephalopathy. The three most common types of headaches arising from purely chemical processesmigraine, cluster and tension headacheswill be the topic of discussion here. All three are called vascular headaches. As the vascular tone depends primarily on the release of neurotransmitters, these headaches obviously belong in the category of encephalopathies. The medical term for a headache, irrespective of its kind, is cephalgia. According to Harrisons Principles of Internal Medicine, 1987, up to 30% of the population suffers from migraine alone.19 During the eighties, a drastic increase in the cases of vascular headaches was registered. It was estimated in the 1989 survey conducted by the National Institutes of Health in the U.S. that the incidence was up by a shocking 60%. Some ascribe the figure to better diagnosis, others, to a real jump. However, in the light of the dramatically increasing rates of asthma and allergies and their common roots with functional neurological diseases, the rising occurrence of headaches does not look coincidental. It is difficult to give precise figures because of the discrep-
Functional Encephalopathies
351
ancies of the official statistics. Besides, those having mild headaches may not consult doctors, and neither do the patients who, after having unsuccessfully tried numerous medications, realized the impotence of medicine in this area and are resigned to putting up with the pain. About 85% of male and 70% of female sufferers do not consult doctors after initially unsuccessful visits. Even if we assume that these figures from a lay magazine are exaggerated, they are still demonstrative, and with the unrecorded cases, the cost of headaches to the health system and the economy in all countries is enormous. The same U.S. survey in 1989 found that lost productivity due to headaches was estimated to be $1.4 billion annually. In 1999, the costs of migraine headaches to the Canadian economy were estimated at $592 million a year. The population of Canada is about one tenth the size of the U.S. Make your own calculation as to what this costs our neighbor. Conventional medicine offers only symptomatic relief for headaches, hence, there is no hope that in the near future, the medical, social and fiscal aspects of the problem will improve.
THE ROLE OF HISTAMINE IN VASCULAR HEADACHES
A detailed description of the symptoms is not my purpose. A reader may find an abundance of medical and lay sources that do that. My intention is to show that apart from the headaches resulting from organic causes, all other headaches (and they are the majority) have the same or similar chemical origin, and their treatment should thus be similar. The focus is on the role of histamine in the production of purely chemical headaches. The fact that vascular headaches are related to histamine imbalance is undisputed and found in standard medical dictionaries and textbooks. For instance, The Dorlands Illustrated Medical Dictionary writes that the former name for migrainous neuralgia is histamine cephalgia. Harrisons Principles of Internal Medicine (1987) points at the imbalance of neurotransmitters found in nerve fibers that innervate cerebral blood vessels as the cause of cluster headaches and directly labels them as histamine cephalgia. Referring to patients with migraine and tension headaches, the textbook again states that histamine can also cause (these) headaches. Another official name for cluster headaches is Hortons syndrome19 given to them in honor of the neurologist who first thoroughly described the condition. The latest 2001 edition of the textbook has inexplicably ascribed cluster headaches to another
researcherRaeder.20 By taking away the priority from Horton whose career was tied to histamine, the textbook has reliably concealed the histaminebased origin of clusters. In every day life, stealing is punished. Probably in science, it is normalcy. Although the knowledge on the histamine role in clusters has existed in the basic sciences for decades, it has not been utilized in practical medicine, despite the fact that the scope of the problem is such that there is a special journal called Headache. Clinical medicine does not even mention histamine in the production of headaches. An obvious similarity with allergy medicine: there we have antihistamines without knowing their core target, and here we have histamine headaches attributed to the imbalance of other mediators, but not histamine.
MIGRAINES
Migraine headaches take a special place due to their high prevalence, severity and, as a result, their grave monetary impact on society and the health system. They do not spare even small children. Although different studies give different figures on the percentage of children under 12, the latest estimates say that the headache frequency among them does not really differ from that in adults. In the early years, girls and boys suffer in equal proportions, but this changes by the age of puberty. Women are hit by migraine two-three times more often than men. Thus, the more frequent migraine attacks during menses are related to the fluctuations in the estrogen levels, while the change in hormones during pregnancy usually reduces their occurrence. Once again, the relationship of hormones and neurotransmitters leads us to the hypothalamus with its regulatory histaminergic neurons. Migraine is a temporal, mostly unilateral, throbbing headache, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Complicated migraine may have wide-spectrum symptoms up to a transient hemiplegia or blindness. The sufferers usually sense an approaching attack through various bizarre signs, especially eye symptoms, but are powerless to prevent it. This makes them irritable and anxious in advance of the attack. To arrive at the diagnosis of migraine headache should not present great difficulty in the majority of cases. Despite that, the fuss about inaccurate diagnostics goes on in periodicals and at conferences. A proverb teaches that when you hear trotting, first think of horses, then of zebras. Medicine often looks for the zebras first. As a result, patients with obvious symptoms and a family
history of migraine headaches undergo CT scans or other complex expensive testing meant to rule out tumors or other organic changes irrelevant to the caseneedless waste of public money.
CLUSTERS
These headaches are non-throbbing, unlike in migraine. They are extremely intense, last from 15 minutes to an hour and occur one after anotherin clusters. Similar to migraine headaches, the pain is mostly unilateral and located over the eye area. It can be excruciating and accompanied by a number of symptoms such is flushing, watering of the eyes, runny nose, temperature elevation. Attacks can be severe to the point of loss of consciousness. Clusters often develop during the dreaming stage of sleep called REM rapid eye movements. In contrast to migraine, clusters affect mostly men. They may occur weeks or even months apart and be followed by long remissions lasting for years. A lot of research indicates the involvement of the hypothalamus in clusters. The fact that the hypothalamus is actually packed with histaminesynthesizing neurons serves is the best evidence of the major role histamine plays in clusters. Still, scientific articles on clusters or headaches in general do not provide any clue that histamine plays any role at all. In fact, one would not be able to find the very word histamine in these publications even though old textbooks and medical dictionaries call clusters histamine cephalgia or histamine headaches or Hortons cephalgia. Not only did Dr. Bayard Horton discover their histaminic origin, but he also achieved wonderful results by treating his patients with histamine injections. For that, he was criticized by his peers blaming him for obsession with histaminean obsession for which his patients were, nonetheless, very grateful.
TENSION HEADACHES
These headaches are usually bilateral, often throbbing, lasting from hours to months. They are usually explained by the tension of neck muscles. Electromyographic investigations deny the neck muscle tone as their origin, and the fact that muscle relaxants do not really work for tension headaches is also proof. Tension headaches are secondary to the disorganized cerebral vascular tone, and as in migraine and cluster headaches, the pain is due to swollen dilated vessels that press on the brain structures. Since the vascular wall is lined with nerve cells, which are closely connected with mast cells, and
both possess histamine receptors, it is only natural that histamine plays an important, in fact, the leading role in the production of this kind of headache. The histaminic nature of tension headaches is also supported by their frequent co-existence with allergies. Often, patients have both tension and migraine headaches.
TREATMENT TARGET IN HEADACHES All three types of vascular headaches are chronic conditions. As in most chronic diseases, conventional treatment is directed at the end organ and almost never at the underlying mechanisms, namely the dysregulation of the mediator/neurotransmitter production. In the same manner as allergists confuse triggers with causes and look for allergens and irritants to imply that these are causes, neurologists look for psychological and environmental factors. Insomnia, stress due to problematic relationships, emotional and physical abuse, some foods or pollutants in the environmentall are turned into causes. These should be avoided, eliminated, rectified, normalized... easier to say than to implement. Moreover, even with identified offenders, in the majority of cases, taking such measures does not solve the problem. Infections such as sinusitis and the rather rare meningitis are also given exaggerated attention in the origin of headaches. Of course, all such factors may play a part in the production of headaches. However, recurrent sinusitis is mostly a misdiagnosed allergic condition, while the relative rarity of meningitis can never explain the vast occurrence of headaches. Therefore, in the end, after CT scanning, electroencephalograms and sinus x-rays, the sufferers of vascular headaches remain in solitude with their diagnosed but mostly untreatable headaches. All articles on headaches strongly emphasize the need to distinguish them and at the same time, provide a surprisingly small difference in their treatment. I am not trying to diminish the importance of the diagnosis, but the similarity of the origin should unite vascular headaches rather than differentiate them for the purpose of treatment. The majority of existing medications are, at best, able to relieve one single headache. This fact contradicts the existing theoretical knowledge that, with the exception of the headaches caused by organic phenomena such as tumors, hemorrhages, infection or injury, all of them result from the changing brain chemistry, and this abnormality is reversible. In their reversibility, headaches are similar to allergies and early-stage asthma. Science knows that increased levels of histamine correlate with
migraine attacks as well as with other vascular headaches, and this makes them analogous to allergies. Mansfield, quoted earlier, made a statement that migraine is probably atopic (allergic) disease7 He also established a bridge between therapies of neurological and allergic symptoms by saying: A productive approach to migraine treatment and prophylactics will require the same type of integrated analysis that is leading to better therapy of such disorders as asthma. His article points out that the histaminergic neuron system regulates serotonergic and noradrenergic activity via activation of H3 receptors and suggests H3-agonists as prophylactic agents for people who suffer from vascular headaches. This attributes to histamine far greater importance than to serotonin, at least in the production of vascular headaches. Clinical medicine ignores this scientific fact. The pioneering ventures of some doctors to correct histamine imbalance with histamine injections are discouraged quickly. Horton, being so famous, could at least publish his articles, whereas attempts by practitioners of a lower rank are doomed.
DRUGS FOR HEADACHES Existing therapies leave untouched the heart of the problem, therefore their ineffectiveness is only to be expected. Painkillers are the most common prescription. Aspirin is one of them. The name is as familiar as that of a friend. Its side effects range from simple allergic reactions to anaphylaxis. Luckily, the latter is not so common. When used for a long period even in small doses, aspirin contributes to heavy bleeding from cuts and wounds and for this reason is contraindicated before elective surgery. It may upset the stomach or even lead to bleeding ulcers and is therefore recommended after meals, with food or in coated pills. Caution is advised against taking aspirin in late pregnancy in order to avoid prolonged labor, profuse hemorrhaging during labor and unwanted effects on the fetusfrom low birth weight to death. The most recent finding of American scientists inform us that aspirin contributes to pancreatitis and even pancreatic cancer in women. Another common medication is Tylenol. It would not be an exaggeration to say that it is the most abused drug. Tylenol exists as a plain pill as well as in combination with codeine. Plain Tylenol is one of the least harmful drugs on the market if taken occasionally. However, its regular use, interaction with other medications and consumption in more than the recommended doses may result in rather serious complications such as serious damage to the liver
and kidneys. Forbes Magazine, in the December 1997 issue, states there were hundreds of fatalities of Tylenol overdose that year. Patients with headaches must be the prime drug consumers. The amount of dollars paid for liabilities is easily absorbed by the profits from the general drug sales, and the number of casualties remains unknown to the general public under the terms of the agreements between the manufacturer and the beneficiaries. Tylenol #2 contains 15 mg of codeine, while Tylenol #3 has 30 mg of the narcotic. Naturally, the more narcotic content, the better the pain relief. With time, headaches become refractory to medications, the transitory relief shortens, and correspondingly, the need of medications escalates. Narcotics taken for a long time and/or in large doses form a habit. Simply put, headache sufferers may involuntarily become drug addicts. Sadly, even upon the realization of the drug dependency, they may not be able to stop the medication because of withdrawal symptoms. In fact, a lot of headache sufferers are hidden drug addicts, and addiction is the price paid for the relief of every attack. Considering the amount of the narcotic ingredient consumed by the patients with headaches, one should not be surprised to find referrals to rehabilitation facilities among the treatments offered by Pain Management Clinics. The word rehabilitation is a substitution for detoxification. Narcoticcontaining painkillers are especially dangerous for pregnant women, as their babies may suffer withdrawal symptoms upon birth. Luckily, nature took care of the potential disaster created by medicine, and the hormonal changes are often favorable in that they rid pregnant women of headaches. Whether another painkiller, Advil, is better or worse than aspirin or Tylenol in relieving a headache, depends on the individual. Most patients with headaches experiment with all of them at some stage. Since headaches are common in allergy patients, Tylenol, Aspirin and Advil are often combined with other medicationsdecongestants, antihistamines, antitussives (cough suppressants), and expectorants. These all claim to relieve headaches, the accompanying cough, nasal congestion, and cold. The latter is mostly misinterpreted allergic rhinitis. Each of the ingredients has its side effects. I do not dare speculate about their interactions and cumulative effect, which is highly probable because the chronic nature of headaches and allergies forces a lot of patients to abuse the combo drugs. For fear of liability, the producers list complications of their products, and the responsibility lies entirely with the prescribers. Depending on the ingredients, the combination drugs may be contraindicated for patients with a
357
liver, kidney disease, peptic or intestinal ulcers, asthma or allergies, a heart problem, problems with urination, mental illness, thyroid disease, etc. Pregnant women and small children would be better to stay away from them. The advice given to these groups is to consult their doctor. Probably, the drugs show good temporary results within the several months testing on people who do not take concurrent medications and, apart from headaches, are generally healthy. Unfortunately, the prescriptions are often given to people who do not fit into this ideal. In addition to the inherent potential for adverse reactions from the ingredients contained in the headache medications and a possible addiction resulting from their most effective componentnarcotics, the existing therapies give a boomerang effect: a medication-induced headache has become a problem. This means that without painkillers, the headache sufferers might have been better off. Again and again, we face the same predicament in the treatment of chronic diseases: regular symptomatic drugs may aggravate and complicate the very condition for which they are prescribed. Only out of desperation would one resort to such procedures as cocainization of nervous knots, or surgery. However, these chop-off-your-head procedures created by Western medicine are among the headache therapies. Luckily, they are not very effective, as is admitted by the editor of journal Headache Dr. J. Edmeads, and therefore are not popular: surgical ablation of the trigeminal root or nervus intermedius is a last resort that helps only some.8 Intramuscular, intravenous and oral steroids are among the treatments. Fortunately, they are not very effective either. I say fortunately because otherwise, headache sufferers, would not only face the plight of becoming drug addicts but, similar to asthmatics, could start counting the complications resulting from steroid therapy. The knowledge of the ineffectiveness of the available treatments and the danger of the medications is thankfully growing among lay people. They try elimination diets, exercise, physical activities, but in the majority of cases, these measures are, at best, only partially helpful. The genetically predetermined chemical imbalance in the brain may manifest without any evident trigger or be precipitated by one which may be hard to eliminate. Among the unavoidable triggers are stress, environmental phenomena and natural physiological body changes. When all means fail, patients often end up having lessons on how to cope with the pain psychologically and physically. Selfsupport groups multiply.
Although prevention of headaches by medications is considered to be a part of the treatment, it is hardly ever achieved by the available therapies. In fact, it is wishful thinking. For prevention, antidepressants, calcium-channel blockers or beta-blockers, are sometimes prescribed. Their rather infrequent prescription is tacit admission of their inefficiency. Moreover, while the effect is negligible, the side effects may add up. For instance, the co-existence of asthma and headaches is common, and beta-blockers are antagonists to bronchodilators. This means the blockers may stir up a hidden asthma or aggravate the existing one. Dr. J. Edmeads suggests lithium and corticosteroids for prophylaxis. There is no need to dwell again on steroids, whereas lithium deserves a few comments. This is the drug used to treat manic states like manic depression. The side effects are gastrointestinal distress, irreversible renal failure, and neuromuscular symptoms. Lithium affects the central nervous system including epileptic seizures, leads to significant cardiac arrhythmia, thyroid hypofunctioning and goitre formation. Patients on lithium require regular blood tests to avoid toxicity. Still, even if toxicity is determined, there is no antidote to the drug, and the condition may be fatal. Ergot is a fungus that grows on such grains as wheat, has a high histamine content, and was once used for the production of medicinal histamine. The names of ergotamine and cafergot, conventional medications for migraine, have ergot as a root. In trials, ergotamine, if taken for a long time, showed a better and more lasting effect than Imitrex, considered by conventional medicine to be the king of all drugs for migraine headaches. Dr. Edmeads also recognizes the prophylactic value of ergotamine. Its connection with histamine is not acknowledged. Children are in a worse position compared to adults. They cannot be prescribed narcotics, and controlled studies on children for prophylactic remedies have not been conducted. Many drugs can be prescribed for teens only. By nature, children are impatient and reluctantly accept measures such as placement in a dark room and relaxation techniques. Counseling as to how to cope with the pain and psychotherapy sessions are almost of no help to young patients. School attendance and the childs ability to learn naturally suffer. Teachers impatience and inability to understand (believe in) the childs disease is another complication. A medical problem turns into a social one that involves the family, the school, and even the community.
THE PARADOXES WITH IMITREX The drug industrys revenues due to headaches must be enormous. Spend half an hour in front of the TV set, and you will see several commercials for the best drugs for the purpose. Once again, I go to Imitrex, the recognized champion for the relief of migraine headaches, the 1994 Winner of the Prix Gallien, the highest prize given to the best medication of the year. The flyer by its manufacturer, Glaxo Canada, is persuasive in showing the advantage of Imitrex over other medications. The drug producer reveals that Canadians annually consume 29 million analgesic tablets. The flyer refers to prescriptions only. Plain and extra strength Tylenol can be bought over the counter and are thus not included in the statistics. The actual figures must be frightening. The flyer admits that Canada has become a champion in per capita consumption of codeine, and that most patients start out with just episodic migraines and thus, an episodic pill but often end up as drug abusers. These statistics on the addictive nature of painkillers serve well in promoting Imitrex, which is not addictive. As was said before, it is an analogue of serotonin, a neurotransmitter known to play an important role in migraine headaches. Unlike painkillers, which relieve pain by blocking certain mediators of pain, Imitrex is an agonist of particular serotonin receptors. Its administration results in the inhibition of serotonin release. Now, let us conduct an investigation. HISTAMINE VS. SEROTONIN Histamine H3 receptors have been found to inhibit the release of serotonin, wrote L. Mansfield in the paper cited earlier and theorized that use of this regulatory pathway may prove to benefit migraine sufferers.9 His statement is based on the well established theoretical knowledge, which allows one to make a logical conclusion: serotonin balance is achieved by regulation of its governing substance, namely histamine. Long before Mansfield, this theoretical postulation had been proven clinically by B. Horton who had successfully used histamine for various neurological conditions, headaches in particular. Hortons follower, Professor S. Diamond, the head of the Chicago Diamond Clinic, was once proud of his 40% excellent results to intravenous histamine in patients who were treatment failures to more conservative and conventional outpatient therapies.10 The article says that the results of histamine therapy did not appear to diminish over time,
and that prolonged remission of chronic cluster may be achieved by this type of treatment, thus confirming the results of Horton. In spite of this information, the editor of Headache, Dr. Edmeads, states on page 62 in Conclusions that no biochemical or imaging markers have been observed in headaches, and the nature of the central nervous system dysfunction is unknown.11 Ironically, this very article exposes the nature of the dysfunction. It has abstracts in English and in French. In the English version, the title is Cluster headache, in French, it is La cephalee vaculaire de Horton, that is Hortons headache. Before a cluster headache was renamed as Hortons vascular headache, it had been called histamine cephalgia. Although Hortons name has been omitted in the main medical textbook, it still exists unchanged in medical dictionaries and clearly points to the cause of headaches. An interesting situation is created: theoretically, the more significant role of histamine (compared to serotonin) is well established; one kind of vascular headacheclusteris directly called histamine headache, and the central role of histamine in the two others is recognized; a prominent scientist (Mansfield) speculates about histamine agonists in headaches in his work based on 32 references; histamine congeners exist in the Stanford laboratory; histamine agonists are reported to be effective (by J. Arrang); oral histamine derivative (Serc) and injectable histaglobin underwent double-blind and open clinical studies, which are reported to be successful; a world-famous neurologist (Horton) leaves 1402 medical charts of the patients with neurological conditions, mainly headaches, whom, in the majority of instances, he successfully treated with histamine. The 1985 neurological symposium, where he was given awards posthumously, recognized him as an outstanding scientist whose belief that nature heals, but histamine cures was based on his considerable knowledge of pathophysiology; a group of contemporary professors of medicine (Diamond et al.) used histamine with a rather high degree of success in clusters that had not responded to other medications. We have the solid grounds to employ histamine or its congeners at least on those headache sufferers who are failures to any other therapy. Inexplicably, in the same article, Mansfield turns 180o from being a proponent of histamine to becoming a promoter of its antagonists. The knowledge of histamine
361
congeners and agonists are no longer detailed anywhere. Hortons medical charts are forgotten. The Chicago Diamond Clinic has never published another paper on their treatment of cluster headaches with intravenous histamine, and the annual seminars organized by the Clinic do not have histamine therapy on their agenda. All this looks, at the very least, strange. Two mediatorshistamine and serotoninare recognized to be important in the origin of migraine, with the superior, regulatory role given (in theory) to histamine. Medicine elevates the inferior serotonin to the position of the central player and gives it the green light in the form of a drug, which relieves only one given headache at a time. The superior, histamine, which could regulate its own balance plus the serotonin production, becomes an unspoken taboo. It is not studied, used, or even mentioned. It has become a medical secret. Allergology that developed hundreds of antihistamines is silent about histamine as the primary allergy mediator. In this connection, should we be surprised that histamine is eliminated from neurology where it is not the primary but one of the primary neurotransmitters? Why is the knowledge on histamine so dangerous? Unexpectedly, the answer can be found in another area, mathematics, which unemotionally explains a lot of things. I came upon interesting figures in The Medical Post, on March 7, 1995: the annual cost of migraine treatments in the pre-Imitrex era in Britain was $30 million (US). The estimated costs of Imitrex injections would exceed $2 billion. Of course, the price of the drug limits access to it, no matter how successful it may be, and not everybody will be able to afford it. However, because there is no better medication in relieving migraines, an agonizing pain may force even many needy sufferers to resort to Imitrex. As each headache necessitates another injection or pill, the revenues from the drug sales will be high. The picture would be different with histamine that could completely rid the sufferers of any vascular headache, including classical migraines. Besides, taken for headaches, histamine could relieve some neurological symptoms that also developed because of histamine imbalance. Add allergy and asthma symptoms which could also be drastically reduced with histamine therapy. No drug developer of sound mind would go for such an all encompassing and effective drug. Especially so, if it manufactures both allergy and migraine medications.
B. CHRONIC FATIGUE AND IMMUNE DYSFUNCTION SYNDROME

THE HISTORY OF THE SYNDROME
The word syndrome is of Greek origin and means a set of symptoms which occur together. The abbreviated form for the disease is CFIDS orCFS. Look attentively at the name of the disease. It sends the message that immunerelated and neurological events coexist, which is compatible with the morphology (structure) and physiology (functioning) of our body. Another message is that dysregulation in one of these systems finds, as a rule, finds its way to the other. In fact, CFS is the best illustration of the coordinated functioning of various regulatory mechanisms, their unity and interdependence in health and disease. The affliction of the two regulatory systems, nervous and immune, may manifest in such an assortment of symptoms that there has hardly ever been another disease causing so much discussion on its very existence. For doctors to master the concept of disease in principle and to understand the pathogenesis of this complex syndrome in particular, the knowledge of psychoneuroimmunology, PNI, becomes a must. PNI is the only science that studies the total body. Failure of the medical profession with CFS both diagnostically and treatment-wise is a perfect illustration of what happens when medicine excludes this science from its agenda. Since the end of the seventies, an unexplained epidemic has been spreading all over the world, especially in the developed countries. The main complaint was an unusual tiredness unrelated to the load of work performed or stress endured. It often affected young, otherwise healthy people, especially so-called yuppies. The question of why CFS has been initially registered among the younger and more educated people is of great interest, and does not have one answer. Definitely, ambition and psychological stress among the yuppies are higher than in the average population, and this contributes to the development of diseases. Another thing is that educated people care more about their health and hence, notice their ailments earlier. There is also a high professional demand to be fit, which explains their interest in medical achievements and desire to turn those into their service. Thus, yuppies consult doctors and start taking medications earlier than other groups of people, and the disease in this case had more to do with the awareness than with environment or genetics. The reasons are mainly of social, not medical nature.
Among the symptoms accompanying fatigue, there are headaches, poor concentration, confused thinking, memory loss, depression, poor sleep, poor appetite and as a result, weight loss; migrating aches and pains in muscles and joints; gastrointestinal symptoms with bloating, gas, constipation or diarrhea, sore throat without fever or with a mild one and enlargement of lymph nodes. The combination of the symptoms was so individual and fluctuating that it produced the impression of several co-existing medical problems rather than one common condition. The symptoms were ascribed to separate illnesses according to the organs that showed symptoms. Up until now, the approach has not changed much. Thus, constant tiredness is mostly conceived as a purely psychological factor or depression. The cause for migrating pains in muscles and joints is sought in blood tests, which are mostly non-indicative. Sore throat is taken for recurrent pharyngitis. Nonspecific gastrointestinal symptoms, after a series of demanding and uncomfortable tests are mainly undiagnosed or related to eating habits. Allergy and asthma symptoms also remain unconnected with the concurrent neurological symptoms of CFS. The CFS patients have become the most unlucky group that simply appears to be suffering from numerous concurrent diseases or psychological instability. The medical profession has been extremely resistant to recognizing a disease with such an indefinite clinical picture and unpredictable course.12 Besides, nothing decisively shows in blood tests, x-rays or other parameters needed by conventional standards to consider a medical condition real and not imaginary. This attitude has been taken despite the fact that there are numerous precedents with diseases not confirmed by such tests, and vascular headaches are the most demonstrative example. The same is true for psychiatry, a whole field of medicine. For a long time, medical professionals were unable, and probably therefore reluctant to deal with the syndrome. With time, however, the epidemic became too widespread to be ignored. Doctors and their families have not been spared, and this might have contributed to the recognition of the disease, although only after heated professional battles.
THE TRIGGER, THE CAUSEAN ETERNAL PROBLEM All diseases are given a name. David Bell in his The Disease of a Thousand Names13 says about CFS, the number of symptoms is probably exceeded only by the number of theories proposed to explain them. The name of the
disease was changing: Yuppie fludue to an allegedly unknown causative virus spread predominantly among yuppies; the Epstein-Barr syndromethe virus at first suspected and later rejected as causative; myalgic encephalomyelitis or fibromyalgiaa poorly understood syndrome, which, in fact, is nonspecific muscular or joint pain due to an inflammatory-like process in the nervous and immune systems. These are just few of the many names. A patient of mine once gave an amazingly descriptive namewhole-body migraine! Trying to explain the origin of CFS, medicine followed the well-trodden path: the triggers were described as causes. The question of the cause has not yet been solved. Up until now, official medicine has not completely ruled out a virus as the cause (not as a trigger). Thus, the FDA does not recommend blood donation from the patients with CFS in active form, although the question remains of what active means in regard to this chronic condition. The viral theory contradicts the fact that the majority of patients with CFS have the symptoms in the absence of any infection. It is especially interesting that a previous exposure to Epstein-Barr virus can be found in healthy people without CFS. Other not detected viruses are also suspected in the origin of CFS, even in patients whose symptoms came spontaneously, without any preceding infection. The explanation given by doctors is: these people must have had an infection without noticing it. A convenient way of thinking! Through the years, more and more researchers were coming to the conclusion that the central nervous system played a major role in this syndrome. In 1988, the disease acquired its latest namechronic fatigue syndrome. The involvement of the immune system became evident later, through the omnipresent statistics. The figures showed that about 20% of the population suffered from CFS, and at least half of them had asthma, while the overwhelming majority, up to 80%, had other respiratory and/or skin allergies. All of these observations resulted in final acceptance of the name. It includes chronic fatigue as the main symptom developed due to brain dysfunction and allergies as the sign of the malfunctioning immune system, plus some vague symptoms, which can be the result of the malfunctioning of either of these systems. Strangely, most doctors still ascribe the disease to a virus or say the cause is unknown. The growing statistics in CFS are consistent with the rising incidence and morbidity of allergies and asthma. This should not come as a surprise to whose who know how cells function. Abnormal brain chemistry involves immunocompetent cells (or the other way around) due to their proximity, involvement of the same receptors, synthesis of the same cytokines, mediators and neuro-
transmitters. Like many chronic diseases, CFS may not have any identifiable trigger. Therefore, the understanding of the genetically predetermined regulatory defects in the functioning of the immune and nervous systems becomes of utmost importance, while what triggers the process is of lesser significance. Nevertheless, the attention of clinical medicine is focused solely on the secondary events, and the fight is going on to eliminate those potential triggers, which are the products of our abusive attitude towards nature. The fight for cleaner air and water is justified. However, this fight for an improved environment would in no way be less justified if doctors started to focus on tuning up the immune and nervous systems of those who are now paying the high price for the progress of our civilization. Trigger elimination and environmental purification can hardly help them at their most immediate level.
CFS AS A SOCIAL PROBLEM Slowly, this disease, which mostly remains undiagnosed by lab tests, is becoming a physical and not a fictitious condition in the eyes of the medical profession. As with many things in medicine, the purely medical problem the recognition of the diseasedepends on other parts of the social organism. In the case of CFS, it lies with the rising insurance claims from those temporarily or permanently incapacitated whose laboratory findings are normal. So, real patients are often labeled as false claimants. The bizarre combination of the symptoms, the inability to confirm them through testing, and the very poor understanding of the underlying mechanisms of the disease, in combination with the resistance of the financial institutions, have created a situation unprecedented in medicine: the existence of a disease not fully recognized by the medical world. For a long time, patients with CFS were unable to even find a doctor with a sympathetic ear. Although those fairly rare doctors could not change the plight of the sufferers, they were able, at least, to make their life easier in the sense that the patients were believed not to be feigning the symptoms. In addition to the physical suffering, the CFS patients often have to put up with a stigma of being shams. Within the last decade, the disease is being recognized only by a portion of the medical profession. Ontario, for instance, still does not have a diagnostic code for CFS among the codes used by physicians in their billing. The plight of the CFS sufferers is worse than, say, the predicament of patients with severe hay fever. At least, the latter have an illusory three As program advertised by allergistsawareness, avoidance and
action. CFS patients are not given even this illusion of hope. Their disease does not have a specific season to make them aware of its approach. They do not know what to avoid, as there are no certain identifiable stimuli. They cannot act because not only are they physically unable, but they do not know what to do. The doctors are helpless, and the most sincere of them admit the fact. A lot of self-help groups have appeared. Probably, psychologically it is easier to know that you are not alone, and that many others suffer from the same mysterious general malaise that is often difficult to describe. A lot of patients see their families falling apart because other members are unable to cope with a permanently sick (pretending?) person or to comprehend that a severe illness may exist and not show in tests. Financial difficulties add up due to the inability of the sufferer to work. The combination of the untreatable physical symptoms and the resulting social problems takes its toll, and the number of suicides among CFS patients is rising.
THEAPIES FOR CFS Can we expect successful treatment for a disease not understood or fully recognized by the medical profession? Can medicine treat a condition the origin of which is a mystery, and which has the assortment of the symptoms that cannot be explained by any existing theory? The answer is No. I have read both scientific sources and literature written mostly by sufferers themselves. There is only one big difference between the two in their approach to resolution. While lay persons are ready to use and share any approach in search for improvement, doctors are a lot more reserved in their recommendation of remedies, which are not scientifically proven, that is, have not undergone double-blind trials. However, several patients having doctors in the family who suffer from CFS told me that those people were trying everything and anything without making it public knowledge. I do not blame these doctors, as they are between a rock (their disease) and a hard place (the establishment represented by their critical peers). Among the therapeutic modalities recommended by the sufferers themselves, there are relaxation techniques, exercise programs, meditation, herbal remedies, acupuncture, and avoidance of certain allergenic foods. The latter indicates the growing awareness of the patients of the co-existence of allergic and neurological symptoms. Patients ingest tons of vitamins and minerals, drink herbal tinctures, elixirs, and brews. No magic happens. I am not critical
367
of these therapeutic means. I am merely stating the sad fact of their failure to produce any significant positive effect. The list of medications prescribed by doctors includes antidepressants such as Prozac and Elavil, symptomatic drugs for intestinal disturbances, painkillers for aches, muscle relaxants for tense muscles, anti-inflammatory drugs for aching joints, antihistamines for allergic symptoms, and antibiotics for recurrent sore throat (despite the absence of any bacterial proof of such infections). As is the case with all chronic diseases, the drugs target the organs affected at a given moment. What if a patient has numerous symptoms at once? Imagine starting the morning with a pile of pills in front of you! To know how ineffective the medications are, one only needs to open any book on CFS or read patients pleas on the Internet. The panacea for all chronic conditionssteroidshas already put its foot in the door. Steroids are not yet the main drug in CFS, as they are in asthma, but wait, it is only the beginning. The idea of using them was born when a lab testing revealed that patients with CFS often have a decreased level of adrenal corticosteroids. A prescription for their replenishment with oral or injectable steroids was ready at once, with all the possible consequences. And again we hear assurances about the harmlessness of the low doses in which steroids are prescribed. Such is, for instance, the conclusion of one of the initiators of steroids in CFSthe research team at the National Institute of Health in Bethesda, Maryland, that has studied the illness since 1979. This idea has supporters. We have steroids as the first-line therapy in asthma and know their effect on the immune system. In case of CFS, steroids will inhibit the hosts already weakened immune system and also adrenals and thus deprive the sufferers of their central natural defense. For these patients, steroids may prove even more harmful, as depression is a common symptom of CFS, and it is also a typical side effect of steroids. The drugs may deepen the existing depression and increase the need of antidepressants later. The logic of medicine never fails to amaze me.
CFS FROM THE STANDPOINT OF PSYCHONEUROIMMUNOLOGY (PNI) Basic science possesses all the data that can explain what causes CFS. According to PNI, the central systems of the body are interconnected in their functioning, and imbalanced release of just one regulatory chemical can
involve the whole body in disease. Similarly, correction of the defect can rectify numerous problems. The following is what should be widely known about the functioning of the central regulatory systems and histamines involvement in it: the total body is not a mechanical construction made up of different isolated parts but an artful indivisible design of nature; the functioning of the nervous, immune and endocrine systems is reciprocal; the crossroads of these systems is the hypothalamus and pituitary unitthe brain structures controlling neuro-endocrine and immune mechanisms; histaminergic neurons are abundant in the hypothalamus and only relatively less in the peripheral nervous system; histamine is an inherent chemical in all body tissues and a major product of immunocompetent cells; all cells possessing histamine receptors form the histaminergic system that conducts and realizes its messages; histamine messages are central in allergy, asthma and are very important in other chronic immune inflammatory diseases; they also carry regulatory instructions to neurotransmitters in neurological disorders; histamine messages work through the CRH/mast-cell/histamine axis and thus involve the HPA axis (CRH stands for corticotropin-releasing hormone) histamine regulates CRHthe pituitary hormone-messenger, which activates the work of the adrenals, our main organ in adapting to all situations stressful to the body. histamine imbalance can affect the functioning of the whole body due to the spread of histamine-generating cells and histamine receptors. Since any functional encephalopathy arises as a result of a chemical imbalance in the brain, histamines ability to modulate the release of other important mediators and neurotransmitters may become crucial. Histamine governs serotonin, which is central to the origin of vascular headaches, depression, chronic fatigue syndrome, irritable bowel syndrome; norepinephrine, whose imbalanced release leads to depression, anxiety, chronic fatigue syndrome; dopamine, whose release is central in schizophrenia and Parkinsonism, and endorphins that affect mood and control any pain, including headaches. The impaired regulatory activity of histamine becomes the cause for functional encephalopathies, including CFS. You might say that dysregulation of any other major mediator or neurotransmitter can be equally responsible for the symptoms, and thus, histamine is not unique. That is correct, but partially only.
Science recognizes that it is histamine that regulates these mediators and neurotransmitters and not the other way around. Histamine reaches our genes and positively changes their functioningthe task no other neurotransmitter can fulfill. Histamine is the best activator of the intracellular enzyme cyclic AMP system whose activity is crucial for the immune and nervous systems and also for the production of various hormones, including the vital corticotropin-releasing hormone responsible for the functioning of the adrenals. Science may never fully understand the intricacies of mediator and neurotransmitter activity or their relationships, however, the already existing knowledge allows us to trace the basic processes and to make the conclusions needed to help the forsaken group of patients with CFS now.
STATE OF THE ART WITH CFS The 1,600 page of the textbook Merck Manual, Home Edition 1999 allotted only a tiny part of a page to CFS where it lists the symptoms and names the formerly suspected and later rejected Epstein-Barr virus as the cause. This, better than anything else, reflects the situation with this disease. As is with allergies, modern medicine does not seek support in basic sciences when it deals with CFS and takes the easy, superficial approach. Such symptoms of CFS as dizziness or headaches are allegedly the result of abnormally constricted/dilated brain vessels. Why the vascular tone is often impaired in those who are young is not explained. Depression is often viewed as the patients lack of motivation in life. There again the question remains unanswered as to why so many young people, often well educated, successful in their careers and living seemingly balanced lives all of a sudden become depressed. Fibromyalgia, common for CFS, is perceived as vague muscular and joint pains. Medicine explains these pains as resulting from the lack of exercise, whereas for many, this is not the cause but the effect of their disease. Frequent urge to urinate or hyperactive bladder, as the diaper-advertising companies often call this condition, is often explained as urinary tract infection even though urine culture test comes negative. Of course, each of these symptoms may be a manifestation of the malfunctioning of the corresponding organ. However, all together, in one patient, in combination with other signs and symptoms, allergies among them, they create a picture of one diseasea major chemical dysregulation in the central nervous systems and its inability to properly govern the functioning of end organs. The treatment should target the cells releasing mediators and neurotransmitters
in disproportionate amounts and strengthen the inefficient receptors of these cells. Instead, medicine treats the symptoms as isolated conditions with daily painkillers, antidepressants, antihistamines, and supplementary hormones. Why? Daily is the answer. Doctors found a convenient escape: many of them assure patients that CFS is mostly a self-limiting disease, and they can expect to recover or improve within a few years. Those who suffer from CFS know better after many years. I saw patients who had been suffering from it without being diagnosed for decades, and in many cases, their condition was getting progressively worse, not better. Pay attention to the second part of the syndromes name: immune dysfunction. This is a better guide than prophesies of well-wishing doctors: immune defects hardly ever spontaneously self-repair. There is a pressing need to resolve the problem. Histamine injections could be a way out for many. Unlike other important mediators and neurotransmitters, that may not have even been synthesized, histamine has had its commercial version for almost a century, therefore employment is just a matter of the willingness of the medical elite to do so. I treated CFS directly and also as a condition concurrent with allergies and asthma. Often, the results were amazing. I suggest to those who want to accuse me of professing the same treatment for every disease under the sun: look at the approach taken by conventional medicine that uses steroids for almost every existing chronic condition. Look up the words histamine and steroids in the Compendium of Pharmaceuticals at least from the standpoint of their potential side effects. Compare the entries. You will read a lot on the complications from steroids but very little from histamine. Even the acute reactions listed for histamine are the result only of the huge dose given in a specific diagnostic procedure; such a dose is never given in allergy treatment. Unlike the Compendium that warns against histamine in asthma, Dorlands Illustrated Medical Dictionary 1988 on p. 769 informs us that histamine has been used in treating various allergic manifestations... and in the treatment of peripheral vascular diseases, Menieres disease, and headache. As you see, medicine spills the beans at times and recognizes that immune, vascular and neurological symptoms respond to the same therapy. All this is strong confirmation of the common histamine-grounded roots of the ailments that affect these systems functioning. Is it not worth looking for the answer in basic sciences? Clinical medicine does not try to do that. On the contrary, it suppresses any attempt in this direction.
371
C. DEPRESSION AND ANXIETY

Depression and anxiety are two very common encephalopathies. Depression means a low level of psycho-emotional activity. Anxiety is exaggerated fear, uncertainty and apprehension. Although superficially, these are two diametrically opposite ailments, their coexistence is not infrequent. One may observe polar mood swings in one and the same patient, and manic-depressive illness is the climax of the fluctuating chemical imbalance in the brain. We exclude from our description depression and anxiety, which are secondary events of other disorders such as thyroid disease, stroke, certain tumors, Alzheimers disease, etc., and will cover only those disorders of dysregulation that arise from the abnormal release and correlation of brain neurotransmitters. As basic science states and clinical medicine accepts, anxiety and depression are mostly norepinephrine and serotonin-related. As science states and clinical medicine does not acknowledge, the balanced production of both is governed by the histaminergic system. The brain is the location not only of histaminergic neurons but also of immunocompentent cells, including the main histamine depots, mast cells. In depression and anxiety, similar to other encephalopathies, the correlated functioning of the nervous and immune systems is obvious: psychological and neurological symptoms are often accompanied by allergy symptoms and vice versa. Even if a patient does not have allergy symptoms, his family history often elicits these. Like all diseases of chemical imbalance, anxiety and depression may appear irrespective of the surrounding events, without any apparent stimulus. In other words, the luckiest people who live and work in a congenial environment and enjoy good health, may develop either of these conditions if their nerve or immune systems are predisposed to malfunctioning. Episodes of depression are specifically related to the chemical imbalance of serotonin and norepinephrine in the brain. The symptoms range from sadness, reduction in vitality to the degree of suicide attempts. Anxiety arises mostly from norepinephrine imbalance and manifests in a feeling of tension, apprehension, uncertainty, and trepidation. Panic attacks may come spontaneously and last from minutes to hours. The feeling of pervasive fear may be accompanied by profuse sweating, palpitation, shakiness, etc. It is of interest that both conditions are common in patients with chronic fatigue syndrome, which adds to the idea that they have the same origin. The inability of patients with these disorders to function properly is a great psychological burden not only for them but also for the family. The patients
are either depressed or agitated, or their mood inexplicably swings. Often, this is perceived as bad manners or an evil disposition. These people present a huge economic burden to society due to the treatment expenses, the low performance level at work, the high absenteeism and the disruptive effects on co-workers, family and friends.
THE EXISTING THERAPIES Conventional treatment depends on what symptoms prevail: antidepressants for depression and tranquillizers for anxiety. Both kinds of drugs are prescribed for daily use. Among the most common complications of antidepressants are drowsiness, dizziness, headaches, and weight gain. The Winnipeg group that studied the effects of antihistamines and antidepressants in mice, timidly mentioned their cancer-contributing features.14 It is predictable that epidemiological studies on humans may never be conducted. Who would pay for them? Obviously not the manufacturers of antidepressants who have neglected to do so for decades since the development of this drug group.15 However, evidence has now accumulated to show that drugs like Prozac carry a 700% risk of cancer in women, while smoking carries only a 400% risk. Tranquilizers prescribed for anxiety are notorious for their side effects. The most known and prescribed drugs are Valium and Ativan. According to statistics, in 1986, in the U.S., more than 86% of prescriptions filled were for minor tranquillizers or anti-anxiety pills. The figures are definitely higher now, almost two decades later. These drugs are too often prescribed for older people, and one of the known drug-induced complications is dementia. A lot of elderly patients with intellectual impairment surprisingly restore their mental ability when they stop taking tranquilizers. The main risk of tranquilizers is daytime sedation, profound confusion, and poor coordination. This makes the older consumers prone to falls, and the incidence of fractures is high among them. Tranquilizers are of even more danger for those many older people who take steroids for asthma or arthritis, as steroids decrease their bone density and make them especially vulnerable to fractures. Depression is one of the side effects of tranquilizers, which is the last thing needed for those patients who have a co-existing depression. These drugs also impair mental ability and concentration, and their users should not drive. The chance of an accident rises when tranquilizers are combined with other drugs or alcohol, even something as mild as a beer. The worst of all unwanted effects is an addiction that may develop after only several weeks of continuous
373
consumption. An abrupt discontinuation may bring on withdrawal symptoms such as anxiety, sweating, and hallucinations. Therefore, tranquilizers should be tapered down rather than abruptly discontinued. It is not the intention of this book to suggest which of the existing tranquilizers and depressants are more effective, less hazardous, and what interactions may occur in those who concurrently take other medications, etc. A patient may receive this information from his doctor, read in the Compendium of Pharmaceuticals and Specialties or the inserts put into the drug packaging, or find it in books such as The Worst Pills, The Best Pills. Instead, I want to point to the inexpensive, safe and effective therapy, which is not accepted by the medical profession ironically, due to the fact that it is inexpensive, safe and highly effective. You guessed it, I am referring to histamine injections. I treated allergy patients who had accompanying anxiety and depression, and the majority greatly improved or recovered with histamine therapy. For them, histamine was both effective and devoid of the side effects of the drugs used in the treatment of depression and anxiety.
D. ATTENTION DEFICIT AND HYPERACTIVITY DISORDER OR ADHD

ADHD is yet another encephalopathy also called minimal brain dysfunction or damage. The figures of school-aged children suffering from the disorder vary in different sources from 5 to 10 %. As usual, we cannot fully rely on the official statistics. My personal experience tells me that almost half of the children with allergies and asthma have ADHD of a different degree. As the name indicates, the disease is characterized by two symptoms. Patients may have just one part of the syndromeattention deficit or hyperactivity, or the disease may manifest both in deficient attention and in hyperactivity. Because of the more ingenuous nature of children who do not hide their problems, until recently, the disease was thought to happen solely among the young who allegedly outgrow it. Lately, medicine has started to recognize that this is not so, and that it is almost as common in adults as it is in children. The reason for this delayed recognition lies in the familiar phenomenon: reliance of the medical profession solely on laboratory tests for diagnostics. Similar to chronic fatigue syndrome, ADHD does not show in tests either. The underlying chemical imbalance, not caused by organic changes in the brain, is a fluctuating phenomenon, which is difficult to measure accurately. The lack of concrete
measurements of the neuro-chemical composition of the brain at any given moment doomed adults with ADHD to suffer without any diagnosis. Years later, often because their children were diagnosed with the syndrome, some of the adults became aware that it had not been short temper or an evil nature that had dictated their strange and aggressive actions or prevented them from comprehending academic material. It had been their disease. Despite the recognition of ADHD in adults, most of the medical and lay sources still continue to present it as a disorder affecting solely children. One of the components of the syndrome, hyperactivity, is on the surface, especially in children. They are fidgety, restless, aggressive, may attack others, including their parents, kick and bite their peers or undertake unreasonably risky actions. Although ADHD affects boys and girls in more or less the same proportion, it is diagnosed better in boys due to more pronounced manifestations of hyperactivity. The other component, attention deficit, may not be so obvious. You may talk to these children without knowing that they are not listening to you. Deficient concentration and memory make them poor learners. ADHD may not be diagnosed in their early years because the tasks in the elementary grades are not demanding, and the teachers are, as a rule, more patient. The studentteacher adjustment is also easier because a young child has only one or two teachers. With the higher grades, the responsibilities grow, the number of teachers increases, and more and more attention is required to develop memory and perform academic tasks. At that stage, the teachers start to notice not only an impulsivity, unruly conduct and poor peer communication, which are more on the surface, but also the less evident easy distractibility, low attention span and difficulty in remembering. Often, the label of a poor learner sticks to the person for life. Children labeled as aggressive and dumb may, in fact, only appear as such due to ADHD. There may be numerous reasons, other than chemical imbalance in the brain, that result in behavioral problems. Thus, disease-related behavior must not be confused with the misconduct of a spoiled child. Poor attention may also be rooted in innate low mental ability. The opposite may be true as well: our mainstream education program does not provide enough stimuli for bright children to learn. Some children may also have a poor environment at home or have some psychological problems in the family, or with friends, and their erratic behavior may be the reflection of that.
375
The diagnosis of ADHD requires participation of parents and teachers. In cases where the disease goes unattended, the chances of ADHD children becoming normal members of society are slim. The reasons are: first, the aggressive behavior of these children alienates their peers and teachers; second, because of their poor learning ability, they are undereducated. Both factors may turn them into school dropouts and antisocial people in their later life. Lucky are those who have loving understanding parents, sympathetic teachers, and knowledgeable doctors. Growing into adults, many of them cope with the symptoms, although with difficulty. They may carry through life their anger against those who could not tolerate their disease-caused misconduct. Many of these adults, often intelligent people, remember their unhappy childhood when they felt miserable among their normal school peers and were forced into therapy with child psychiatrists who were unable to help them. The disease remained undiagnosed at that time. Now, they see similar symptoms in their own children whose ADHD is, at least, recognized. In reality, the diagnosis of ADHD is not as complex as medicine often suggests. Certain physical and environmental factors, which may interfere with school, should be excluded as the main cause of low learning ability. Among them are poor hearing or eyesight, stressful home environment, innate low intellectual ability. The family medical history is indicative because, as other encephalopathies, ADHD is genetically predetermined, and at last, medicine has started to accept the genetic basis of the syndrome. It is of utmost importance for the doctor to understand that family members may not necessarily suffer from the same symptoms but allergies, asthma, migraine, CFS or other encephalopathies. The relation of hyperactivity to food allergies was noticed a long time ago by more observant doctors but laughed off by a lot of highbrow specialists. It looks like some are now forced to recognize the coexistence of allergies and ADHD.
RITALIN Every doctor agrees that the diagnosis of ADHD is of prime importance both from the medical and social points of view. Let us assume the doctor arrived at the diagnosis of ADHD. Can the disease be controlled? Yes, says mainstream medicine and prescribes Ritalin on a daily basis. At present, Ritalin is the principal medication for ADHD and, therefore, necessitates a special review.
Ritalin belongs in the group of brain-stimulating medications. The drugs mode of action in man is not completely understood, writes the pharmaceutical compendium. This means that it may not produce the desired effect, or there may be unknown complications. Among the adverse reactions are nervousness, hyperactivity and insomnia as the most commonjust what a hyperactive child needs! Transient neurological symptoms may include dizziness, drowsiness, and psychotic episodes including hallucinations. There may be nausea and abdominal pain, skin rashes, hair loss, blood pressure change, and cardiac arrhythmia. Among the warnings, Compendium lists possible weight loss and growth suppression in prolonged use. There is no explanation of what prolonged meansweeks, months or years. Long-term effects... have not been well established, states the drug description, and ADHD may be a lifetime disease requiring the drug. The manufacturer assures that side effects usually disappear with dose reduction or drug discontinuation. The question of how to reduce or discontinue Ritalin and still have control of ADHD is left unanswered. Unanswered also is the question of whether discontinuation is feasible due to the psychophysical dependence that develops in its consumers. The manufacturer is aware of potential addiction and recommends drug holidaysno Ritalin during weekends and vacations. Children who may start the drug at the age of 6 and take it until puberty, 1315, run the risk of becoming addicts by the time when, according to the producer, they can discontinue Ritalin use. The bitter truth is that many children with ADHD cannot escape daily Ritalin for two reasons. First, parents and teachers often do not have enough patience to deal with behavioral problems such as short temper, which may grow to aggressiveness, easy distractibility and poor concentration and memory. Second, ADHD is a chronic disease, and chronic patients have little chance of a spontaneous recovery. All this turns Ritalin into a straight jacket for these children, and unfortunately, too often, for simply misbehaved ones as well. It is easier to manage a drugged, docile lamb than to challenge a bright mind. Thus, even children without ADHD may become victims of the poorly managed educational system and school-pressured parents who put them on Ritalin. A lot of children who lag behind at school due to their inability to concentrate are prescribed the drug. If we exclude the kids under 6 years of age who should not be prescribed Ritalin, the majority of those remaining receive it because the diagnosis almost inevitably leads to a prescription.
377
Teenagers, always the most troublesome group, quickly understood the attractive brain-stimulating effect of Ritalin. For them, it has become an inexpensive legalized upper used at parties and gatherings just for fun. This increases the number of victims of this drug. Fatalities have been reported when Ritalin was combined with alcohol.
OTHER MEANS FOR ADHD Although almost universally prescribed for ADHD in children and adults, Ritalin, like all medications, does not work for everybody, and about one third of patients with ADHD do not respond to it. A large percentage remains untreated because there is no alternative drug. Non-medicated approaches to ADHD are educational and psychosocial interventions. Can these radically help a child whose brain is flooded with disease-promoting chemistry? The flaws in the management of ADHD are obvious to the medical profession, and in search for more effective ways, medicine suggests at times intriguing methods. One was studied by the department of psychiatry in Durham, Northern Carolina, and was described in The Medical Post on March 5, 1996. In this article entitled Nicotine Patches Useful for Hyperactive Children, Adults? it showed how desperate doctors must be to seriously suggest that kids use nicotine and how hopeless parents must feel to agree to turn their kids onto nicotne. Of special interest is that the same Canadian periodical on page 74 carries an article titled Doctors Must Do Everything They Can To Fight Tobacco Lobby. The paradoxes of medicine! Similar to chronic fatigue syndrome, ADHD is a chemical imbalance of neurotransmitters, mostly norepinephrine and dopamine. As you know, both are regulated by histamine. Mothers of the young patients whom I treated for allergies and asthma told me about the dramatic changes in their childrens behaviour. In some young patients, I observed similar changes minutes after the scratch test. A thorough questioning of the parents showed that often, the kids behaviour normalized even before their allergy and asthma symptoms were controlled. The success was compatible with the scientific grounds I dug out from basic science: along with immunomodulation, histamine provided the needed neuromodulation. Besides, H3 receptors, found in abundance on nerve cells, are more sensitive to histamine, which accelerates the response of the nervous system to histamine injections.
I usually explained to the parents the concurrence of neurological symptoms with allergies and suggested they monitor the childs behaviour during the therapy. It worked. Not a single parent complained that his child suffered from Ritalin deprivation.
E. IRRITABLE BOWEL SYNDROMEAN ENCEPHALOPATHY?

Irritable bowel syndrome or, for short, IBS, is not exactly an encephalopathy, nor is it a purely gastrointestinal disorder. It is both. Its origin lies in the dysregulated neurotransmission in the brain as well as the gut. Among the descriptive definitions of the syndrome we come across, hypersensitive bowel is especially indicative. The most authoritative medical source, the textbook Harrisons Principals of Internal Medicine, calls it neuromuscular hypersensitivity of the gastrointestinal area secondary to mental distress. The dependence of the stomach and intestine in their functioning on the central nervous system is a fact known not only to doctors but to laymen as well. We know that our gut responds with symptoms to anxiety and panic attacks. You may remember a knot in your stomach while taking an exam, or an urgent bowel movement upon receiving bad news. Advice given in jest to never wear ones best pants when going to war seems to be devised by someone who knew what IBS was. History gives us an example of how accurate the diagnosis of some doctors was at the time when no theoretical data were available to explain the origin of the disease. Thus, Rasputins lover, a rich Russian aristocrat, was diagnosed with neurasthenia of the bowel by her doctor. Both Stalin and Hitler suffered for years from gastrointestinal symptoms with no organic pathology registered in either, therefore one can assume they had IBS, especially probable in view of their severe psychopathic make-up or personalities. The information exists now that explains the origin of the syndrome. A chemical change originates in the brain chemistry and then echoes in the nerve functioning of the intestines. An occasional change in the brain chemistry produces a sporadic effect in the bowel, while chronic or recurrent imbalance of neurotransmitters results in a chronic bowel condition known as motility dysfunction. Similar to allergies and many other encephalopathies, IBS affects women 23 times as often as men. And as with other encephalopathies, the explanation is in their fluctuating hormonal levels, and hence, neuro-endocrine instability, the regulation of which starts in the hypothalamus. It was thought that the disease occurred mostly in adults, however,
379
more and more frequently, it is diagnosed in children. One can easily see the similarity in the growing prevalence of IBS along with the increase of other functional disorders such as allergies, asthma, chronic fatigue syndrome and attention deficit disorder. As all syndromes, IBS consists of a number of typical symptoms, which occur in various combinations. Among them, there is abdominal pain of varying intensity, at times so severe that the patients are rushed to ER. Abdominal discomfort, loose bowel movements or diarrhoea with mucus in the stool, constipation, bloating, gas, nausea, etc. are common. As a rule, patients with IBS undergo numerous tests in the offices of gastroenterologists to exclude peptic ulcer disease, inflammatory bowel disorders, lactase intolerance, etc. They learn, finally, that the tests do not show any organic cause. Lucky are those whose doctor at least diagnoses IBS and assures them that it is not a malignancy. The majority remain without any definite diagnosis, or are misdiagnosed. The textbook Harrisons Principles of Internal Medicine (1987) starts the description of the disease on page 179 with the following paragraph: The irritable bowel syndrome is the most common gastrointestinal disease in clinical practice, and although not a life-threatening illness, it causes great distress to those afflicted and a feeling of helplessness and frustration for the physician attempting to treat it. The textbook also explains the reasons for the frustration: Unfortunately, no specific drug or dietary regimen affords good relief in19 all patients, and thus a number of therapeutic manoeuvres need to be tried. The 2000 statistical data given by Dr. G. Kandel from the University of Toronto state that the symptoms of IBS are present in about 30% of the general population.16 This leads us to the inevitable conclusion that this is the single most prevalent disease in medicine. Since the disease has no treatment, it is especially interesting to see what medicine does for the people with IBS. Quite naturally, a poorly understood and generally misdiagnosed disease cannot be treated properly. Doctors do not treat the condition as a neuroregulatory disorder but as a gastrointestinal disease. It is not different from the treatment of allergies and asthma that are also dealt with in the end organ. Antacids and painkillers are common medications for abdominal cramps; opiates are given for diarrhoea and soluble fibre for constipation. Only a patient with IBS can understand how embarrassing it is to have a severe bloating or to feel an urge to defecate in the middle of a serious meeting. The few doctors who understand that its roots are in the brain chemistry, may prescribe antidepressants. This, however, does not resolve the
problem either. The chronic nature of the disease can make antidepressants regular medications and thus lead to a number of complications. The need to deal with additional symptoms intensifies the patients dissatisfaction and depression and by that, aggravates the course of IBS. Antidepressants may also be prescribed to patients with IBS because many of them become deeply frustrated with their never-ending bowel symptoms and do develop depression and/or anxiety. Some doctors may suspect an infection and prescribe antibiotics, medications completely inappropriate for IBS. This often creates paradoxical situations. Thus, one of the adverse effects of antibiotics is constipationthe symptoms the patient may already have. Other adverse reactions include headaches and muscle aches or pains; and again, the patients may already have those, as these symptoms commonly accompany encephalopathies. Modern medicine recognizes the presence of numerous symptoms that point to the central role of the brain in IBS. Dr. Kandel, for instance, discusses a constellation of them: mood swings, panic attacks, anxiety and depression as well as non-specific brain-related symptoms such as headaches, backache, fibromyalgia and urinary tract symptoms. Saying that, one would think science should seek the roots of all these manifestations in the chemistry of the brain as uniting regulatory arm. However, as with allergies and other encephalopathies, medicine points to the more evident superficial connections. This author, for instance, says that 40% of the patients with IBS have a history of sexual or physical abuse and pronounces these factors as central in the origin of the disorder. No argument, a severe stress, no matter of what nature, may contribute to the development of any chronic disorder, but such factors are not specific to IBS per se. This Canadian gastroenterologist makes another assumption that may even insult many syndrome sufferers: IBS is a disease of physician-seeking behaviour. In other words, patients see a physician in order to attract his attention or out of fear that their symptoms are the result of cancer or another dreadful disease. No wonder the author suggests that reassurance should become the pivotal point of management. Other specialists also support psychological encouragement, which in some cases is better than medications, at least from the standpoint of side effects thereby avoided. The answer to IBS, its cause and treatment is similar to that in all encephalopathies. The underlying cause lies in imbalanced neurotransmission in the brain-gut pathways. This inevitably indicates the involvement of
381
histamine, as a major neurotransmitter. The significance of histamine in the functioning of the gastrointestinal tract, although never indicated in clinical textbooks, becomes obvious from the fact that the intestines contain over 50% (!) of the bodys immunocompetent cells with their innate histamine activity. The description of CRH/mast cell/histamine axis in 2000 allows one to understand the interactions of the immune and nervous system via histamine pathways.17 The axis unites the hypothalamus through its corticotropinreleasing hormone and the immune system through mast cells with their most distinctive mediator, histamine. Its impaired production affects the gut, while correction rectifies neurotransmission in the gut. As Dr. W.G. Thompson, a Montreal professor who serves on international committees studying IBS states in his interview, 80% of serotonin activity is in the gut; its likely that drugs acting on the serotonin receptors could also modulate gut hypersensitivity.18 There is, however, not a word on histamine in his work, even though scientists working in this area recognize H2-antihistamines (Zantac, Pepsid) as the central medications for gastrointestinal disorders, and by that recognize the presence of histamine there as the main chemical event. They should also know that serotonin release is regulated by the histaminergic system. As everything related to histamine, the histaminergic neuron system is taboo in clinical medicine, and science is adjusted to the needs of the pharmaceutical industry. Therefore, the priority is given to serotonin. Indeed, Dr. Thompson informs us about the development of drugs influencing serotonin. The above-quoted gastroenterologist, Dr. Kandel, also suggests a 5-HT3 antagonist, which is a sort of antiserotonin. How effective will antiserotonins be? Dr. Kandel admits that the drugs effectiveness is limited and is close to placebo response. An analogy comes to mind. In migraine headache, Imitrex and its analogues stimulate certain serotonin receptors and by that, relieve a headache, but only the current headache. At the same time, even in those headaches that are known as histamine cephalgia, the very word histamine is concealed by renaming them. We may assume that serotonin-targeting medications for IBS will be as helpful as serotonin analogues in migraines at best, they will curb one attack at a time. Migraine sufferers say that another headache may start hours later. We may expect similar events with the serotonin-suppressing drugs for IBS. Just think of this peculiar approach: medicine prefers symptomatic relief to cause eradication. Serotonin-targeting drugs will create yet another lucra-
tive product, as they will also deal with the effects secondary to histamine imbalance. Patients should be happy if these medications provide at least short-lived improvements. The drug industry, with support of the medical academia, successfully fights nature in all that involves histamine. Almost half of the patients with allergies present with various degree of IBS, and it is most typical of patients with chronic fatigue syndrome. This is a direct indication that in their origin, these three most common chronic diseases merge. The majority of my patients came for the treatment of their allergies or asthma. I invariably asked them about their gastrointestinal symptoms, which, as a rule, they neglected to mention, not knowing the connection. It usually took a long time to explain what IBS was, and how it related to their other symptoms. To the patients surprise, my prediction that relief of their bowel symptoms might be a bonus often came true. Similar to other encephalopathies, the improvement was often obvious at the allergy skin testing: those who were experiencing symptoms at the time of the testing felt relief. Histamine therapy worked in almost all cases. The sad conclusion is: IBS, a disease of the highest incidence, is poorly understood, mostly misdiagnosed and does not have any treatment. Any manoeuvre, as the main medical textbook says, is worth trying in order to relieve the plight of these patients. Histamine could render that help. Still, it may never be allowed despite the available theoretical substantiation from basic sciences of its modulatory capacity, and despite its availability in several forms. The problem with histamine is that in all relevant areas, it turns out to be too effective and would thus shrink the drug market.
F. OTHER HISTAMINE-RELATED ENCELOPATHIES

It would be arrogant on my part to present myself as a specialist in neurology or psychiatry. However, I have read volumes on brain chemistry and treated quite successfully hundreds of patients with various vascular headaches, depression and/or anxiety, CFS, fibromyalgia, ADHD, and IBS. As a rule, they came to me with allergies, while the accompanying encephalopathies were revealed through questioning at the first examination. Apart from the above-described encephalopathies, there were autism, seizure disorder, menopausal symptoms as well as diverse nonspecific neurological manifestations. Using histamine therapy for their main symptoms, I indirectly reached the related neurological symptoms. My observations led me to the conclusions that histamine therapy
was highly effective in a wide variety of diseases. Correcting imbalance of neurotransmitters is nothing but neuromodulation. This is analogous to immunotherapy in allergies. A different name does not change the essence: histamine shows its self-regulatory ability in both body systems. Conventional immunotherapy, although not very effective, exists as a treatment, and although its goal is to reduce response to a specific allergen, in essence, successful immunotherapy is due to the inhibition of the excessive histamine release. Medical sources do not describe the relief of the accompanying neurological symptoms during successful immunotherapy, although, I am sure, this did occur, as both the immune and the nervous systems are parts of one histaminergic system that conducts histamine messages. Neuromodulation is never mentioned even as a possibility despite the fact that it is theoretically supported by the description of the neuroimmunologic mechanisms in basic science research. Irrespective of what sort of encephalopathy is diagnosed, in the absence of an organic cause, histamine therapy should be tried. It can be highly effective in many cases. Encephalopathies are sort of allergies of the nervous system, therefore their treatment with H is only logical. Among the neurological conditions responding to histamine therapy, fibromyalgia takes a special place. Conventional medicine has only started to cautiously recognize it as a disorder related to chemical imbalances in the brain and singled it out as a separate disease. In fact, it is mostly part of chronic fatigue syndrome. Since CFS is poorly diagnosed, and the mechanisms of its occurrence are not understood, fibromyalgia that stems from the same brain events also remains obscure. This has become the reason for its isolation from the syndrome, whereas very rarely do joint and muscle pains and/or stiffness present as the only symptoms. As a rule, they go along with other symptoms characteristic for CFS and are therefore a part of it. No matter, diagnosed as a separate disease or left undiagnosed, fibromyalgia is treated only with painkillers and reassurance. Joint pains, even in young people, are often diagnosed as arthritis and are treated correspondingly. As one may expect, the results are nil. . My experience with encephalopathies also includes patients with seizure disorder without an organic cause. It surprised me when several patients whom I treated for allergic conditions noticed disappearance of their seizures. Later on, I purposefully monitored the seizure occurrence in patients with a history of seizure disorder while treating them for allergies and asthma. Success was inevitable.
I had four patients with autism. The degree of improvement ranged. The best results were achieved in a boy with advanced autism, a savant, who stayed on the treatment for over two years. He was brought initially for food allergies, without the slightest expectation of improvement in his main problem. In the end, his performance at school improved dramatically, he started to make eye contact and logically answer questions. In fact, only a very close observation could find some minor deviations from the norm in his behavior. Prior to the histamine treatment, the boy had received a vast variety of unconventional treatments from North American and European specialists that his well-off parents could pursue. Another four-year old autistic child, for the first time in his life started to pronounce words after just four or five injections. Regrettably, the family could not travel the long distance and stopped the treatment. The third patient was a small girl with an advanced form of autism. She was treated for her allergies but showed better behavior, became calmer and stopped gritting her teeth. Her treatment was stopped because of the ban of histamine therapy imposed upon me by the CPSO, and this probably deprived her of further improvement. The forth was a young adult who became calm and compliant after a few injections. His elderly parents were unable to bring him on a regular basis, and the treatment stopped. Considering that no treatment exists for autism, histamine could at least be used on a trial basis. I also treated several children with uncontrolled urgency to urinate or with bedwetting. As it is common in medicine, if an organic cause is not found, the symptoms are considered to be of psychological origin. Therefore, parents of these children planned a visit to a psychiatrist on the advice of their family physician. I suspected the allergy-associated chemical imbalance in the area of the brain that regulated the bladder functioning. On my advice, the parents postponed the visit to a psychiatrist for the few weeks that I was treating their children for allergies and asthma. In all these cases, the symptoms of incontinence disappeared, often faster than the allergy symptoms. Of interest is a case of a nonspecific condition. The patient, a 7 year-old boy, suffered from nightmares. He would get up at night and walk around the house. His mother called my office several days after the initial prick test with histamine. The boy stopped his night wandering, and she decided to postpone the next visit, to see whether this was coincidental. She brought her son back half a year later when the symptoms resumed. A short treatment was successful.
There was another peculiar casean elderly man with ALS, amyotrophic lateral sclerosis, a fatal disease due to progressive degeneration of the neurons. The patient could not swallow and suffered from severe pains in his jaw. The neurologist who had seen him before and after my histamine treatment stated in his report, Interestingly, his pain was relieved by histamine injections. The menopausal hot flushes related to hypothalamic/pituitary dysfunction are treated by gynecologists and family physicians generally by synthetic hormonal replacement therapyHRT. The studies on HRT are contradictory in their findings, but lately, in view of dangerous complications, this treatment is recommended only in cases of severe symptoms. Histamine therapy almost completely eliminated or greatly relieved these symptoms as well as some others that often accompany menopause, such as insomnia, perspiration, dizziness, depression and anxiety. In these cases, the patients needed maintenance shots for a lasting period in view of the continuing hormonal changes. None reported any side effect but only positive changes. Blood vessels do not exactly belong in the area of neurology. However, vascular tone is regulated by neuro-endocrine processes and is thus affected by the hypothalamus. The abundant presence of histamine in the hypothalamus and histamine receptors in the vascular wall is the reason why hypertension may respond to histamine. The normal activity of histamine receptors improves the tone of the vessels, and blood pressure normalizes. There is another important point in the treatment of hypertension. Betablockers often prescribed for high blood pressure may become a trigger for asthma patients who have inefficient beta-adrenergic receptors. These receptors need stimulation, not suppression. Thus, not only does histamine therapy normalizes the vascular tone by activating H2/3 receptors in the vascular wall, but it also eliminates the need of beta-blockers and the resulting worsening in current asthma or the possibility of inciting a latent form. You may say that no drug is a panacea, and histamine cannot be one either. Right. However, human beings are whole entities. Our central regulatory systems function in coordination, and successful immuno- or neuromodulation resonates through the whole body by restoring numerous functions. The word holistic is defined in dictionaries as relating to the conception of man as a functioning whole. This is in perfect harmony with the most comprehensive field of medicinepsychoneuroimmunology, which remains primarily in the domain of theoretical sciences. Our market-focused medicine has lost the
holistic approach of ancient medicine. This is when other sciences are parting with the old hard-nosed materialism of the XIX century and switching to integrative holism of the XX century. Medicine has reached that shocking state where it cannot exist without its sponsorthe drug industry. If in the remote past, the industry was supposed to serve medicine, it is the opposite today. This has made medicine an exception among sciences and, as a result, it has become hostile not only to everything new but also to everything old that can be useful and healing. This is especially obvious in the most reversible diseasesallergies, asthma and functional encephalopathies.
ENDNOTES
1. JACI 1990;86:673-76 2. Is the histaminergic neurone system a regulatory centre for whole-brain activity? Trends on Neuroscience 1991;14:415-8 3. G. Chrousos. Stress, chronic inflammationJACI 2000;106:S275-91 4. U. Knigge, J. Warberg, The Role of Histamine in the Neuroendocrine Regulation of Pituitary Hormone Secretion, Acta Endocrinologica, Copenhagen 1991;124:609-19 5. U. Knigge, J. Warberg, The Role of Histamine in the Neuroendocrine Regulation of Pituitary Hormone Secretion, Acta Endocrinologica, Copenhagen 1991;124:609-19 6. H. Wada et al. Trends on Neuroscience 1991;14:415-8 7. L. Mansfield. The role of antihistamine theraphy in vascular headaches. JACI 1990;86:673-76 8. J. Edmeads. Cluster headache and its cousins: A family of pain management problems. Pain Res Manage 2000;5:58-63 9. JACI 1990:673-76 10. S. Diamond et al., Treatment of Intractable Cluster. Headache, Jan.1986:44-45 11. Pain Res Manage 2000;5(1):58-63 12. For a full discussion of the medical politics of this condition see the investigative report by H. Johnson, Oslers Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic, Penguin, 1996 13. Pollard Publishing 1990 14. Brandes L.J.et al. Stimuilation of malignant growth in rodents by antidepressant drugs at clinically relevant doses. Cancer Res 1992;52:3796-3800 15. For full understanding of the known danger of antidepressants, I refer you to the study by David Healey, Let Them Eat Prozac, 2003 16. G. Kandel. Irritable Bowel Syndrome. The Canadian J of Diagnosis, December 2000: 82-91 17. G. Chrousos. Stress, chronic inflammation and emotional and physical wellbeing: concurrent effects and chronic sequalae. JACI 200;106:S275-91) 18. Parkhurst Exchange Nov. 1999, p. p. 76-9 19. Harrisons Principles of Internal Medicine, 1987 20. Harrisons Principles of Internal Medicine, 2001 21. Thome J. et al. Cyclic AMP response element-binding protein and depression. Expert Reviews in Neurotherapeutics 2002; 2:347-54
EPILOGUE OR: EPPUR SI MOUVE! 1
Exactly one week before the submission of this manuscript to the publisher, the saga on histamine took an unexpected turn when I opened the latest issue of The Journal of Allergy and Clinical Immunology. To say that I was stunned is an understatement: there was a review article with the content-revealing title of Histamine in the Immune Regulation of Allergic Inflammation.2 The rubric under which the article was published was no less remarkable: Rostrumthis in Roman times, was the platform a person stepped onto in order to gain the publics ear. I do not have an explanation of how such an exotic fish could slip through the thick net that had solidly protected the steroid-saturated journals for more than a decade. However, the very appearance of this publication gives me a slight hope that the truth and medical ethics will one day be victorious in allergy. The authors are clinical immunologists from the Swiss Institute of Allergy and Asthma Research, and their work was sponsored by grants form the Swiss National Foundation (not a pharmaceutical company, but a tax-payer-funded national body). The paper is the most comprehensive and accurate overview of histamine and its functions since the times of R. Rocklin. It is based on 73 references and covers the histaminergic system and the four known histamine receptors on which its functioning depends. The theoretical work revives almost all the buried information on the histamine-related mechanisms of allergy with the emphasis on those that participate in the reversal of allergic inflammation. The authors unearth the immune- and neuromodulatory role of histamine; suggest a novel therapeutic approach in man: using H3-receptor agonists and implementing through them the negative feedback loop enables one to control excessive inflammatory responses;
point to the same mode of action (negative feedback) of H2 receptor in allergies: H2-receptor effector function seems to be an essential, potent suppressor of inflammatory and effector functions especially useful in immune regulation during specific immunotherapy. resurrect T-suppressors and their central anti-inflammatory product histamine-induced suppressor factors (HSF): histamine stimulation induced Il-10 production in both dendritic cells and T-cells, and the activity of regulatory-suppressor T cells represents a key event in the control of specific immune response; specify the mechanism through which histamine realizes its anti-inflammatory effects: histamine dose-dependently enhances intracellular cAMP levels and stimulates Il-10 secretion through H2 receptor; state that most of the existing therapies for asthma, including the leading pharmaceutical developments (the combination of steroids with long-acting Beta-agonists) are based on the same signal transduction patterns where B2-adrenergic receptors might function similar to H2 receptor in human subjects. The concept that all living organisms possess autoregulatory systems is recognized in science, and its proponent, Belgian chemist Ilya Prigogine, was awarded the Nobel Prize in 1977. Our immune and nervous systems, as the central parts of a living complex organism, are self-regulated, and there is a controller for each operation and production of immune and nervous cells. I share the ideas expressed in that article: in allergy and asthma, the major controllers are, indeed, the H2/3 receptors, cAMP, T-suppressors and the anti-inflammatory chemistry, which is the product of their interdependent work. They are the links of the chain that provides the balanced release of histamine and, therefore, histamineinduced chemistry. The genetically-predetermined weakness of these mechanisms is the cause of allergies. When earlier in the book, I said that the truth will fly in through the window if not allowed to come in through the door, I did not expect this to happen so soon. Now, that the truth has been given rostrum, even if accidentally, clinical medicine should acknowledge its existence. It is a crime to hide not just the substance, histamine, but the knowledge of the whole histaminergic system that spreads all over the body and is vital for the functioning of the immune and nervous systems. It is high time to acknowledge the existence of the protective H2/3-receptor effect and then introduce it into every day clinical
Epilogue 389
practice in order to help those millions who suffer needlessly only because somebody, obviously for personal reasons, decided to conceal the truth.3 Clinical allergy can break away from the drug industry and significantly reduce its dependence on it if, instead of medicating its patients with immunosuppressive steroids, it will start to revive the bodys sick regulatory tools with well-researched, safe, effective and inexpensive histamine. This would allow the national health systems to save billions of dollars that could be channeled into different problems. The statements coming from the rostrum should not fall on deaf ear. In this sense, this book is a litmus paper for the Medical Establishment: the way they treat the material presented here will be indicative of whether the patients interests are truly above their own interests.
ENDNOTES
1. This statement is attributed to Copernicus who is said to have muttered it as he left a trial before the Inquisition where he was forced to recant his mathematical proof showing that the sun, not the earth, is at the centre of our solar system. 2. C. Akdis, K. Blaser. Histamine in the immune regulation of allergic inflammation. JACI 2003;112:15-22 3. K. Melmons letter of August 28, 1991, to Dr. Ravikovich, that recognizes therapeutic H2/3 activity: See Appendix. p. 404.
Bibliography
Adkinson N. et al. Justifying a mechanism-based specialty. JACI 1995;97:868-71 Agarwal S. et al. Beta-adrenergic modulation of human type-1/type 2 cytokine balance. JACI 1999;104:91-8 Akdis C. et al. Histamine in the immune regulation of allergic inflammation. JACI 2003;112:15-22 Allen D. Systemic effects of intranasal steroids: an endocrinologists perspective. JACI 2000;106:S179-90 Amirav I. et al. What do pediatricians in training know about the correct use of inhalers and spacer devices? JACI 1994;94:669 Andersson R. et al. Studies of the mechanisms of desensitization of anti-IgE-mediated histamine release from human basophils. Agents and Actions 1989;27,1/2:25-8 Apter A. Clinical advances in adult asthma. JACI 2003;111:S780-4 ARIA (Allergic Rhinitis and its Impact on Asthma),Workshop Report, WHO. JACI 2001;108:S147-336 ARIA (Allergic Rhinitis and its Impact on Asthma) Editorial. Global guidelines and new forms of allergen immunotherapy. JACI 2001:108:497-9 Arlean L. et al. Mite and mite allergen removal. JACI 2003;111:1269-73 Arrang J-M. et al. Highly potent and selective ligands for histamine H3 receptors. Nature 1987;327:117-24 Asthma: follow up statement from an international paediatric asthma consensus group. (Special report.) Archives of Disease in Children 1992;67:240-8 Avila P. Interactions between allergic inflammation and respiratory viral infections. JACI 2000;106:829-31 Bachert C. Histaminea major role in allergy? Clin Exper Allergy 1998;28,S6:15-19 Bai T. Glucocorticosteroid treatment of asthma. Can Fam Physician 1995;41:1921-7 Barnes P. Endogenous inhibitory mechanisms in asthma. Am J Respir Crit Care Med 2000;161:S176-181 Barnes P. New directions in allergic diseases: Mechanism-based anti-inflammatory therapies. JACI 2000;106:5-16 Barnes P. Therapeutic strategies for allergic diseases. Nature 1999;402 S25:B31-7 Barnes P. et al. Efficacy and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998;157:S1-53 Bayram H. et al. Effect of ozone and nitrogen dioxide on the release of proinflamamtory mediators JACI 2001;107:287-94 Beasley R. et al. Prevalence and etiology of asthma. JACI 2000;205:466-72 Beer D., Rocklin R. Histamine-induced suppressor-cell activity. JACI 1984;73:439-52 Beltrani V. Point-Counterpoint. Journal of Cutaneous Medicine and Surgery 1999;3:198-200 Binkley K. Seasonal allergic rhinoconjunctivitis. Can J Diagn, June 2001:93-8 Birnbaum J. et al. Clinical study of bedding covers in mite-allergic asthmatic patients. JACI 1996;97:223 Black J. The role of mast cells in the pathophysiology of asthma. N Engl J Med 2002;346:1742-3 Borgstrom S. et al. To the Editor. New Engl J Med 1983; 308:592
Bibliography
Bourne H., Lichtenstein L., Melmon K. et al. Modulation of inflammation & immunity by cyclic AMP. Science 1974;184:19-28 Bowie D. et al. Whats new in asthma? Parkhurst Exchange. April 2000:121 Brandes L. et al. Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist in combination with various single antineoplastic agents. J Clin Oncol 1994; 12:1281-90 Brandes L. et al. Stimuilation of malignant growth in rodents by antidepressant drugs at clinically relevant doses. Cancer Res 1992;52:3796-3800 Brandes L. et al. Histamine as an intracellular messenger. Biochemical Pharmacology 1990;40:1677-81 Brightling C. et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002;346:1699-1705 Brown T. et al. Use of inhaled corticosteroids by pediatricians. JACI 2002;109:S183 (Abstr.) Burtin C. et al. To the Editor. The New Engl J Med, March 1983, 591-2 Busse W. Current research and future needs in allergic rhinitis and asthma. JACI 1998;101:S424-6 Busse W. et al. Pahtophysiology of severe asthma. JACI 2000;106:1033-42 Canadian Asthma Consensus Conference. Summary of recommendations. Can Respir J 1996;3(2):89-100 Chapman M. Editorial. JACI 1991;88:300-2 Charter on Medical Professionalism. Lancet 2002;359:520-7 Chrousos G. Stress, chronic inflammation, and emotional and physical wellbeing: concurrent effects and chronic sequelae. JACI 2000;106:S275-91 Church M. H1-antihistamines and inflammation. Clin and Exper Allergy 2001;31:1341-3 Cirstea M. On the mechanism of the desensitization by histamine. Rev. Roum. Physiol 1971;8:253-258 Clerici M. et al. An immunoendocrinological hypothesis of HIV. Lancet 1994;343:1552-3 Cockcroft D. Allergen-induced increase in nonallergic airway responsiveness: A citation classic revisited. Can Respir J 2000;7:182-7 Creticos P. Immunologic changes associated with immunotherapy. Immunology and Allergy Clinics of North America 1992; 12:26-7 Current status of allergen immunotherapy. Shortened version of WHO international union of immunological societies working group report. Lancet 1989, February 4:261 Cypcar D., Busse W. Steroid-resistant asthma. JACI 1993;92:363-72 Diamond S. et al. Treatment of Intractable Cluster. Headache 1986;26:44-45 Donahue J. et. al. Asthma pharmacotherapy JACI 2000;106:1108-14 Dorlands Illustrative Medical Dictionary 1988. W.B. Saunders Company Eddy D. Clinical decision making. Journal of American Medical Association 1993;270:522 Edmeads J. Cluster headache and its cousins: A family of pain management problems. Pain Res Manage 2000;5:58-63 Elenkov I. et al. Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors. The Journal of Immunology 1998;161:2586-93 Engle D. et al. Comparison of the sensitivity and precision of four skin test devices. JACI 1992;90:985-91 Essayan D. Cyclic nucleotide phosphodiesterase. JACI, 2001; 108:671-80 FDA reviews antihistamine mouse study. FDA Talk Paper 1994; May 17:2 Ferguson A. House dust mites and asthma. Can. J Diagn 1995;12:1-2 Finn P. et al Children at risk for asthma. JACI 2000;105:933-42 Fitzgerald M. et al. Proceedings of a workshop on near fatal asthma. Can Respr J 1995:2(2):113-26 Forum: Histamine and Disease. JACI 1990;86:589-686 Frew A. et al. Sublingual immunotherapy. J Allergy Clin Immuno 2001;107:441 Frew A. Sublingual immunotherapy. J Allergy Clin Immuno 2001;107:441 Frew A., Kay A. The pattern of human late-phase skin reactions to extract aeroallergenes. JACI 1988; 81:1117-21
391
Geha R. Regulation of IgE synthesis in humans. JACI 1992;90:143-50 Gergen P. Understanding the economic burden of asthma. J Allergy Clin Immuno 2001;107:S445-8 Girard J-P. A double-blind study of triplex-histaglobin in the treatment of grass pollenosis. Praxis 1989;78:62-5 Goldblast D. True believer Bayard Taylor Horton. Seminars in Neurology 1988;8:339-42 Gonzalez M. et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) T-cells in asthma. Am Rev Resp Dis 1987;136:600-4 Grant E. et al. Observations on emerging patterns of asthma in our society. JACI 1999;104:S1-9 Grant J. et al. Histamine-releasing factors and inhibitors: historical perspectives and possible implications in human illness. JACI 1991;88:683-93 Greenberger P. Preface. Immunology and Allergy Clinics Of North America 1992;12:ix Halloran P. Four decades of glucocorticosteroid immunusuppression. Can Med Assoc J 1992;147(5):613-4 Hanifin J. The role of antihistamines in atopic dermatitis. JACI 1990;86:666-8 Harbinson P. et al. The effect of a novel orally active selective PDE4 isoenzyme inhibitor on allergen-induced responses in asthmatic subjects. Eur Respir J 1997;10:1008-14 Harrisons Principles of Internal Medicine, McGraw-Hill, 1987 Harrisons Principles of Internal Medicine, 15th ed., McGraw-Hill, 2001 Hasaelden B. et al. Late asthmatic reactions provoked by intradermal injections of T-cell peptideJACI 2001;108:394-401 Hebert J. et al. The regulatory effect of histamine on the immune response: characterization of the cells involved. Cellular Immunology 1980;54:49-57 Hejjaoui A. et al. Systemic reactions occurring during immunotherapy with standardized pollen extract. JACI 1993;89:925 Helgadottir H. et al. Asthmatic patients exihibit different gene expression profiles depneding on their sensitivity to glucocorticoids. JACI 2002;109:S173 (Abstr.) Hesselmar B. et al. Does early exposure to cat or dog protect against later allergy development? Clin Exp Allergy 1999;29:611-7 Hill S. New Perspective in histamine research. Agents and Actions 1991;33:145-159 Hill S. Distribution, properties, and functional characteristics of three classses of histamine receptor. Pharmacological Reviews 1990;42:69 Hill S. et al. Classification of histamine receptors. Pharmac Rev 1997;49:253-78 Holgate S. et al. Introduction. JACI 2003;111:S1-4 Holgate S. The cellular and mediator basis of asthma in relation to natural history. Lancet 1997;350 SII:5-9 Holgate S. The Epidemic of allergy and asthma. Nature 1999;402:Suppl:B2-B4 Holgate S. The role of histamine in asthma. In: Management of Allergy in the 1990s; ed. M. Kaliner 1989:14-20 Hans Huber Publishers Holgate S. Role of systemic leukotrienes JACI 2003;111:S18-36 Holgate S. et al. eds. Inflammatory Mechanisms in Asthma 1998 Horton B. Chronic progressive retrobulbar neuritis Boswell Hosp Proc 1979;5:4-20 Hoyne G. et al. Immunological tolerance to inhaled allergen. Am J Resp. Crit Care Med 2000;162:S169-74 Hyland M. A connectionist theory of asthma. Clin Exp Allergy 1999;29:1467-73 Ichinose M., Barnes P. Histamine H3 receptors modulate antigen-induced bronchoconstriction in guinea pigs. JACI 1990; 86:491-5 Ito A. et al. Clinical effect of histaglobin on nasal allergy, double-blind study (in Japanese). Jibiinkokatenbo 1979;79:1539-51 Ito K. Clinical evaluation of histaglobin for bronchial asthmaa double-blind study using human gammaglobulin as control (in Japanese). Rinshoutokenkyuu 1979;56:3085-99 Jakob T. et al. Multistep navigation of Langerhans/dendritic cells in and out of the skin. JACI 2001;108:688-96 Jones N. L. Editorial. Can Respir J 1995;2:88 Jutel M. et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 2001; 413:420-5
Bibliography 393
Jutel M. et al. Differential histamine H1 and H2-receptor expression determines up-regulation of Th1 and down-regulation of Th2 responses following histamine stimulation. JACI 2000;105(II):157 Kaliner M. A hierarchy of mediators of the allergic reactions. JACI 1992;90:727-8 Kaliner M. General discussion. JACI 1996;97:885 Kaliner M. Presidential address. JACI 1997:99:729-34 Kandel G. Irritable Bowel Syndrome. Can J Diagn, December 2000: 82-91 Kaplan A. ed. Allergy. Churchill Livingstone Inc. 1985 Kaplan A. ed. Allergy. Harcourt Publishers Ltd. 1997 Kay A. Allergy and allergic diseases. N Engl J Med 2001;344:30-7 Kay A. et al. Effect of intravenous administration of mepolizumab JACI 2003;111:S261 (Abstr.) Kay A. Allergic diseases and their treatment. N Engl J Med 2001;344:109-13 Kay A. et al., eds. Asthma: Physiology. Immunopharmacology, and Treatment 1984. Academic Press. Kelly K. et al. Skin and serologic testing in the diagnosis of latex allergy. JACI 1993;91:1140-5 Khan M., Melmon K. Are autacoids more than theoretic modulators of immunity? Clin Immunol Reviews 1985;4(1):1-30 Kino T. et al. Tissue-specific glucocorticoid resistance-hypersensitivity syndromes. JACI 2002; 109:609-13 Knigge K. et al. Neuroendocrine functions of histamine. Agents and Actions 1991;33:S29 Knigge U. The role of histamine in the neuroendocrine regulation of pituitary hormone secretion. Acta Endocrinologica, Copenhagen 1991;124:609-19 Kukita J. A double-blind study of histaglobin on allergic dermatitis (in Japanese) Nishinipponhifuka 1980;42:470-7. Kuna P. et al. Chemokines of the alfa, beta-subclass JACI 1995;95:574-81 Kuna P. et al. IL-8 inhibits histamine release induced by histamine releasing factorsJACI 1991;87:207 Lan Yan et al. Histamine N-methyltransferase pharmacogenetic. Pharmagenetics 2000;10:261-6 Leff A. Pharmacologic management of asthma. JACI 1998;101:S397-9 Leung D., Nelson H., Szefler S. The Editors Choice. JACI 2002;109:580 Leurs R. et al. Molecular pharmacological aspects of histamine receptors. Pharmacology and Therapeutics. 1995;66:413-63 Levitt R. et al. IL-9 pathway in asthmaJACI 1999;103:485-91 Lexchin J. The Real Drug Pushers 1984. New Star Books Li Siu-Min et al. The Chinese herbal medicine formula JACI 2000;106:660-8 Lichtenstein L. Allergy and the Immune System. Scientific American 1993;269:117-24 Lichtenstein L. Presidential Address. JACI 1995:95:783-96 Lichtenstein L. et al. Inhibition of histamine release controlled by histamine H2 receptor. Nature 1973;244:287-8 Lichtenstein L. et. al. Selective Display of Histamine Receptors on Lymphocytes. Science 1977;195: 683-5 Lichtenstein L. et al. Histamine release in vitro. Science 1968;161:902-3 Lieberman P. et al. Allergic Diseases. Diagnosis and Treatment. Humana Press 2001 Lilu M. et al. Immediate and late inflammatory responses Am Rev Respr Dis 1991;144:51-8 Lipworth B. et al. Effects of oral and inhaled corticosteroids on the hypothalamic-pituitaryadrenal axis. JACI 1999;104:13 Liu C. et al. Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Molecular Pharmacology 2001;59:420-6 Liu M. et al. Effects of prednisone on the cellular responses JACI 2001;108:29-38 Lockey F. et al. Fatalities from immunotherapy and skin testing. JACI 1987;79:660-77 Lockey R. et. al., editors. Allergens and Allergen Immunotherapy 1999 Lyttle B. et al. Asthma. Can Fam Physician 1993;39:793-8 Mansfield L. The role of antihistamine therapy in vascular headaches. JACI 1990;86:673-6 Martin R. et al. A link between chronic asthma and chronic infection. JACI 2001;107:595-601 Masoli M. et al. What to do at step 3 of the asthma guidelinesincrease the dose of inhaled steroids or change the dose of a long-acting Beta-agonist drug? JACI 2003;112:10-11
Mazzoni A. et al. Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T-cell polarization. J. Clin Invest 2001;108:1865-73 McLean W. et al. The BC community pharmacy asthma study Can Resp J 2003;10:195-202 McWhinney I. Why are we doing so little clinical research? Editorial. Canadian Family Physician 2001;47:1944 Melmon K. In: Therapeutic Immunology eds. Austen K. et al. 1996:192, 198 Melmon K., Rocklin R., Rosenkranz R. Autacoids as modulators of the inflammatory and immune response. Am J Med 1981; 71:100-6 Mican J. et al. Arthritis and mast cell activation. JACI 1990;86:677-83 Milgrom H. et al. Treatment of allergic asthma with nomoclonal anti-IgE antibody. N Engl J Med 1999;341:1966-73 Nafstad P. et al. Risk of childhood asthma and allergic rhinitis in relation to pregnancy complications. JACI 2000;106:867-73 OByrne P. et al. Efficacy and cost benefit of inhaled corticosteroids in patients considered to have mild asthma in primary care practice. Can Resp J 1996; 3:169-75 Oettgen H., Geha R. IgE regulation and roles in asthma pathogenesis. JACI 2001;107:429-40 Ooi T. How to withdraw from steroids. Parkhurst Exchage 1994;April:76-9 Page C. One explanation of the asthma paradox. Lancet 1991;337:717-20 Page C. Beta-agonists and the asthma paradox. Practical Allergy & Immunol 1992;7:87-94 Pearce F. The Editorial. Biological effects of histamine: An overview. Agents and Actions 1991;33,1/2:4-6 Pearce N., Beasley R. et al. Asthma Epidemiology: Principles and Methods. Oxford University Press, 1998 Pearce N. et al. How much asthma is really attributable to atopy? Thorax 1999;54:268-72 Peters S. Mast cells and histamine in asthma. JACI 1990;86:645 Plashke P. et al. Summary Service Review. XIV Congress of European Academy of Allergy and Clinical Immunology 1989:36 Pollard C. Influence of maternal diet during lactation upon allergic manifestation in infants tolerisation or sensitisation? JACI 1996;97:240 Primer on Allergic and Immunologic Disease. JACI 2003;101, No 2. Ravikovich F. H2/3 Effect in allergy. Allergie & Immunologie 1992;24:72 (Abstr.) Second International Symposium on Pollenosis. Ravikovich F. Histamine therapy in allergy. Allergologie 1989; September:108-9 (Abstr.) XIV Congress of the European Academy of Allergology and Clinical Immunology. Ravikovich F. Specific diagnostic and hyposensitization in allergy. New Americans Collected Scientific Reports 1991;11:158-62 Reilly M. et al. Suppression of histamine-induced adrenocorticotropic hormone release by antihistamines and antidepressants. J Pharmacol Exp Ther 1992;222:583-8 Repka-Ramirez S. et al. IgE levels in chronic fatigue and control subjects. JACI 2000; 105:S359 (Abstr.) Rocha M. e Silva Handbook of Experimental Pharmacology 1966;18/1:899 Rocklin R. Chapter 10: Role of cell-mediated immune response in allergy. In: ed. Allergy ed. Kaplan A. 1985:175-95 Rocklin R. Chapter 4: Modulation of inflammatory and immune responses by histamine. In: Immunopharmacology. Eds. Sirois P. et al. 1982:49-72 Rocklin R., Greineder D., Melmon K. Histamine-induced suppressor factor Cell Immunol 1979;44:404 Rocklin R. et al. Characterization of the human blood lymphocytes that produce a histamineinduced suppressor factor (HSF). Cellular Immunology 1980;51:226-37 Rocklin R. et al. Generation of antigen-specific suppressor cells during allergen desensitization. N Engl J Med 1980;302:1213 Rocklin R. Clinical and immunologic aspects JACI 1983;72:323-34 Romagnani S. The role of lymphocytes in allergic disease. JACI 2000;105:399-408 Romagnani S. The Th2 hypothesis in allergyEppur si muove! Allergy Clin Immunol Intern 1998;10:158-65 Roszkowski W., Plaut M., Lichtenstein L. Selective display of histamine receptors on lymphocytes. Science 1977;195: 683-5
Bibliography 395
Roy D. The Brandes-Friesen case reports: How should we interpret the news? Can Med Assoc J 1995 September 1;153:569-71 Schwartz L. The Mast Cell. In: Allergy, ed. Kaplan A. 1985:58 Sears M. Descriptive epidemiology of asthma. Lancet 1997;350 SII:104 Sercarz E. The distinctive specificity of antigen-specific suppressor T cells. Immunology Today 1991;12:110-7 Sharma J. et al. Chronic urticaria. Journal of Cutaneous Medicine and Surgery 2000;4:89-93 Shearer W. et al. AAAI Training Program Directors Committee: Committee report. Core content outline for clinical and laboratory immunology. JACI 1994;94:933-41 Shearer W. et al. Defining the spectrum of clinical immunology. JACI 2003;111:S766-73 Shirley K. et al. Attenuation of cutaneous and bronchial late allergic reactions JACI 2001;107(2):S67 (Abstr.) Sirois P. et al., eds. Immunopharmacology. Elseveir Biomedical Press 1982 Spitzer F. et al. Beta agonists and the risk of asthma death and near fatal asthma. Br Med J 1992;326:501-6 Stafford R. et al. National trends in asthma visits and asthma pharmacotherapy 1978-2002. JACI 2003;111:729-35 Stanworth D. et al. Allergy treatment with a peptide vaccine. Lancet 1990;336:1279-81 Stunciu L. Immunomodulation by histamine. Ann Biol Clin 1990;48:623-5 Suissa S. et al. Inhaled corticosteroids: impact on asthma morbidity and mortality. JACI 2001;107:937-44 Szefler S. Challenges in assessing outcomes for pediatric asthma. JACI 2001;107:S456-64 Szefler S. The changing face of asthma. JACI 2000;106:S139-43 Takeuchi D. et al. Histamine alters gene expression JACI 2001;107:310-4 Tattersfield A. Foreword. Lancet 1997;350:S11 Thome J. et al. Cyclic AMP response element-binding protein and depression. Expert Reviews in Neurotherapeutics 2002; 2:347-54 Tiemessen H. et al. CD4+ CD25+ regulatory T cells are not functionally impaired in adult patients with IgE-mediated cows milk allergy. JACI 2002;110:934-6 Urbach E. et al., eds. Allergy. Grune & Stratton. New York 1949 US Federal Register 1985:50, 15:3097 Vannier E. et al. Histamine suppresses gene expression and synthesis of tumor necrosis factor via histamine H2 receptors. J.Exp.Med.1991;174:281-4 Visions in Allergy: Impact on health care reform. JACI 1995;97:861-71 Von Mutius E. Editorial. Clinical and Experimental Allergy 2001;31:1651-2 Von Mutius E. The environmental predictors of allergic disease. JACI 2000;105:9-19 Wada H. et al. Is the histaminergic neuron system a regulatory center for the whole-brain activity? Trends in Neuroscience 1991;14:415-8 Wasserman S. Mast cell biology. JACI 1990;86:590-3 Weiss S. Parasites and asthma/allergy: What is the relationship? JACI 2000;105:205-10 Wenzel S. at al. Subepithelial basement membrane JACI 2003;111:1345 White M. The role of histamine in allergic diseases. JACI 1990;86: 599-605 White M., Sander N. Asthma from the perspective of the patient. JACI 1999;103:S47-52 White M., Kaliner M. Histamine (chapter 11) In: Inflammation, Basic Principles and Correlates 1988;eds. J.Gallin et al. Raven Press Ltd. Worfel S., Lichtenstein L. et al. Preferential recruitment of activated memory T lymphocytes JACI 1995;96:57-65 Yamada K. et al. Molecular mechanisms of decreased steroid responsivenessJACI 2002;109:35-42 Yoshii H. et al. A complex of histamine JACI 1997;100:816 Zeiger R. Effect of allergist intervention on patient-centered and societal outcomes. JACI 2000;106;995-1018 Zweiman B., Rothenberg M. Articles of Note. JACI 2002;109:375 Zweiman B., Rothenberg M. Beyond Our Pages. JACI 2002;109:728
APPENDIX
Appendix 397
Appendix 399
Appendix
401
Appendix 403
Appendix 405
NOTICE TO THE READER If you wish to join in political action on behalf of asthma and allergy patients and the
doctors who want to help them (but are not allowed to do so) consider the following: writing to KOS Publishing Inc, 1997 Beechgrove Road, Alton, On, L0N 1A0; write to your local MPP, the Premier of Ontario, the Minister of Health, and the opposition critics. For their addresses call 416-325-7200 (LIB) 416-325-7272 (PC) 416-325-7116 (NDP). Below is a sample of the facts upon which you can base your demand for lifting the ban on histamine therapies.
SAMPLE
To The Premier of Ontario Your area MPP The media (TV, newspapers, radio) (Adjust the text to include your own story as a patient or physician.) Dear . . . I have read The Plot Against Asthma and Allergy Patients by Dr. Felix Ravikovich (KOS Publishing Inc. 2003) and learned that effective treatment for asthma and allergy exists and that it has been actively suppressed by the College of Physicians and Surgeons of Ontario (CPSO). I urge you to read this book and examine the documented facts regarding the highly effective and scientifically supported histamine therapy. The CPSO has indefinitely and arbitrarily forbidden its use in the absence of patient complaint or harm, despite scientific support and public protest by hundreds of patients helped by this treatment and denied access to it since 1992. One request that you: 1. order the CPSO to lift its ban on Dr. Ravikovichs use of histamine therapy and 2. take steps to allow Dr. Ravikovich to teach doctors willing to learn his technique. I base my demand on the Helsinki Accord on Human Rights, an international treaty to which Canada signed in 1988. Among its clauses you will find one by the World Medical Association, which in 2000 became part of Ontarios Medicine Act in 2000, but has been effectively ignored by the CPSO. It states the following: In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic measure, if in his or her judgment, it offers hope of saving life, reestablishing health, or alleviating suffering. I am looking forward to your reply. Signed
Index
A
ADHD . . . . . . . . . . . . . . . . . . . 372, 376 adrenals . . . . . . . . . . . . . . . . . . . . . . 185 suppression of. . . . . . . . . . . . . 187 ff allergens . . . . . . . . . . . . . . . . . . . . . . 82 allergic inflammation . . . . . . . . . . . . 99 allergy . . . . . . . . . . . . . . . . . . . . . 71, 93 borderline diseases, and. . . . . . . . 81 causes vs. triggers in . . . . . . . . . 69 f angioedema . . . . . . . . . . . . . . . . . 338 ff animal dander . . . . . . . . . . . . . . . . . . 86 antibiotics . . . . . . . . . . . . . . . . . . . . 101 and asthma. . . . . . . . . . . . . . . . . 245 anti-challenge test . . . . . . . . . . . . . . 226 antigen. . . . . . . . . . . . . . . . . . . . . 70, 72 antihistamines and cancer . . . . . . . . . . . . . . 36, 177 and FDA. . . . . . . . . . . . . . . . . . . . 36 and genetic interference of . . . . 176 and immunosuppression . . . . . . 177 and side effects . . . . . . . . . . . . 176 ff anti-inflammatory drugs . . . . . . . . 102 anti-IgE agents . . . . . . . . . . . . . . . . 280 antileukotrines . . . . . . . . . . . . . . . . 279 asthma antibiotics. . . . . . . . . . . . . . . . . . 101 as chronic inflammatory disease . . . . . . . . . . . . . 156, 302 as a growing problem . . . . . . . . 238 causes of . . . . . . . . . . . . . . . . . . . 256 conventional treatment for . . . . . 12 current definition. . . . . . . . . . . . 240 diagnosis of . . . . . . . . . . . . . . . . 249 historic understanding of . . . . . 300
old guidelines for . . . . . . . . . . . . 284 reversibility. . . . . . . . . . . . . 110, 143 statistics . . . . . . . . . . . . . . . . . . . 258 symptoms. . . . . . . . . . . . . . . . . . 243 tests. . . . . . . . . . . . . . . . . . . . . . . 254 theories. . . . . . . . . . . . . . . . 256, 263 vaccines . . . . . . . . . . . . . . . . . . . . . 6 atopic dermatitis . . . . . . . . . . . . . 329 ff autacoid . . . . . . . . . . . . . . . . . . . . 2, 112
B
B-cells . . . . . . . . . . . . . . . . . . . . . . . . 71 Barnes . . . . . . . . . . . . . . . . . . . . . 156 ff basic science . . . . . . . . . . . . . . . . . . . 63 bronchiodilators long-acting . . . . . . . . . . . . . 269, 275
C
cAMP. . . . . . . . . . . . . . . . . . . . . . 37, 50 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 immunocompetent . . . . . . . . . . . . 5 Chronic Fatigue Syndrome. . . . . . . 361 social problem . . . . . . . . . . . . . . 364 therapies for . . . . . . . . . . . . . . . . 365 psychoneuroimmunology and . 367f cluster headaches . . . . . . . . . . . . . . 351 combination drugs . . . . . . . . . . . . . 182 conventional classification of allergy 80 corticosteroids. . . . . . . . . . . . . . . . 183 f cytokines . . . . . . . . . . . . . . . . . . . . . 40 f
D
decongestants . . . . . . . . . . . . . . . . 180 f dendritic cells . . . . . . . . . . . . . . . . . . 18 depression . . . . . . . . . . . . . . . . . . . . 370
Index 409
Diamond Headache Clinic . . . . . . . . 33 Dristan . . . . . . . . . . . . . . . . . . . . . . 180 drugs for headaches . . . . . . . . . . . . 354 duality in allergy . . . . . . . . . . . . . . . . 59 in medicine . . . . . . . . . . . . . . . . . . . . 60 in patients . . . . . . . . . . . . . . . . . . . . . 62 Japanese research into . . . . . . . 222 f receptors. . . . . . . . . . . . . . . . . . . . 23 serotonin and . . . . . . . . . . . . . . . 358 synthetic . . . . . . . . . . . . . . . . . . . . 54 systemic reactions and . . . . . . . . 217 therapy . . . . . . . . . . . . . . . . . . 308 ff vs. allergen vaccine. . . . . . . . . . . 231 histidine. . . . . . . . . . . . . . . . . . . . . . . 19 Hismanal . . . . . . . . . . . . . . . . . . . . . 181 Holgate. . . . . . . . . . . . . . . . . . . . . 151 ff homeostasis. . . . . . . . . . . . . . . . . . . . . 9 H receptors . . . . . . . . . . . . . 24, 46f, 117 house dust mites . . . . . . . . . . . . . . . . 85 Horton . . . . . . . . . . . . . . . . . . . . . . . 33 hypothalamic-pituitary-adrenal axis (HPAA). . . . . . . . . . . . . . . . . . 186 ff hypersensitivity . . . . . . . . . . . . . . . . . . 7
E
economics in medicine . . . . . . . . . . . 56 encephalopathy . . . . . . . . . . . . . . . . 343 and histamine . . . . . . . . . . . . . . 347 eosinophils . . . . . . . . . . . . . . . . . . . 141 European Histamine Research Society . . . . . . . . . . . . . . . . . . . . 125
F
FDA bans. . . . . . . . . . . . . . . . . . . . . 181 food allergy . . . . . . . . . . . . . . . . . . . . 89
I G
gene mutations . . . . . . . . . . . . . . . . . . 3 genetic functions (histamine). . . . . . 51 genomodulation . . . . . . . . . . . . . . . . . 4 Imitrex . . . . . . . . . . . . . . . . . . 57, 357 ff immunomodulation . . . . . . . . . . . . 136 immunotherapy . . . . . . . . . . 225, 232 f immunotherapy versus immunosuppression . . . . . . . . . 198 immunosuppression . . . . . . . . . 13, 103 inhalation bronchial challenge test . 253 Intal . . . . . . . . . . . . . . . . . . . . . . . . . 277 intracellular enzyme cAMP . . . . . . 48 f Irritable Bowel Syndrome. . . . . . . . 377
H
hay fever . . . . . . . . . . . . . . . . . . . . 339 f headaches . . . . . . . . . . . . . . . . . . . 349 f histaglobin . . . . . . . . . . . . . . . . . . . 32 f histaglobulin . . . . . . . . . . . . . . . . . . 32 f histamine. . . . . . . . . . . . . . . . . . . . . . 17 as a cure . . . . . . . . . . . . . . . . . . . . 33 as neurotransmitter . . . . . . . . . . 344 asthma, and . . . . . . . . . . . . . . . . . 29 bias against. . . . . . . . . . . . . . . . . . 30 cellular vs synthetic . . . . . . . . . . . 23 congeners of . . . . . . . . . . . . . . . . 120 corrects genetic defect . . . . . . . . . 51 degranulation and . . . . . . . . . . . . 17 derivatives of . . . . . . . . . . . . . . . 120 disease and . . . . . . . . . . . . . . . . . 162 drug industry and. . . . . . . . . . . . 65f dual activity of . . . . . . . . . . . . . . . 43 encephalopathies and . . . . . . . 345 f homeostasis and. . . . . . . . . . . . . . 22 induced cytokines . . . . . . . . . . . 41 f
K
Kaplan. . . . . . . . . . . . . . . . . . 131, 133 ff Kay . . . . . . . . . . . . . . . . . . . . . . . . 138 ff
L
Langerhans cells . . . . . . . . . . . 18, 210 f Lichtenstein . . . . . . . . . . . . . . . . . 122 ff
M
mast cells. . . . . . . . . . . . . . . . 16ff, 139 f as protective . . . . . . . . . . . . . . . . 163 medications. . . . . . . . . . . . . . . . . . . 173 side effects of . . . . . . . . . . . . . . 173 f skin reactions and . . . . . . . . . . . 209 Melmon . . . . . . . . . . . . . . . . . . . . 117 ff
migraines. . . . . . . . . . . . . . . . . . . . . 351
N
negative feedback . . . . . . . . . . . . . . 158 neurotransmitters . . . . . . . . . . . . . . . 20 non-steroidal anti-inflammatory drugs (NSAID) . . . . . . . . . . . . 277 ff
P
Peptides . . . . . . . . . . . . . . . . . . . . . . 229
steroids . . . . . . . . . . . . . . . . . . 188, 289 allergic disease and . . . . . . . . . . 195 bone loss and . . . . . . . . . . . . . 297 ff complications of . . . . . . . . . . . . 190 genes and . . . . . . . . . . . . . . . . 299 ff marketing of. . . . . . . . . . . . 286, 292 problems with . . . . . . . . . . . . . . 294 safety of . . . . . . . . . . . . . . . . . . . 295 suppressor factors, histamine-induced. . . . . . . . . . . . 42
R
rhinitis . . . . . . . . . . . . . . . . . . . 318, 323 and immunotherapy . . . . . . . . . 326 Ritalin . . . . . . . . . . . . . . . . . . . . . . . 375 Rocklin. . . . . . . . . . . . . . . . . 421, 110 ff
T
T-cells. . . . . . . . . . . . . . . . . . 14, 70, 144 T-suppressors . . . . . . . . . . . . . . . . . 15 f as defence against allergy . . . . . 44 ff tension headaches . . . . . . . . . . . . . . 352 Tilade. . . . . . . . . . . . . . . . . . . . . . . . 277 Theophylline . . . . . . . . . . . . . . . . . . 274 treatments elimination as. . . . . . . . . . . . 84, 255 antibiotic. . . . . . . . . . . . . . . . . . 99 ff triggers vs causes. . . . . . . . . . . . . . . . 92 nonspecific . . . . . . . . . . . . . . . . . . 74
S
science and freedom . . . . . . . . . . . . 313 Seladane . . . . . . . . . . . . . . . . . . . . . 181 serotonin . . . . . . . . . . . . . . . . . . . 358 ff skin allergies . . . . . . . . . . . . . . . . . . . . . signal transduction . . . . . . . . . . . . . . 10 signal transmission . . . . . . . . . . . . . . 10 skin testing . . . . . . . . . . . . . . . 203, 253 and immunotherapy . . . . . . . . . 223 delayed systemic reaction . . . . . 220 false positive/negative . . . . . . . . 208 potential dangers of . . . . . . . . . . 219 reactions to as improvement . . . 216 systemic reaction to . . . . . . 212, 214
U
urticaria . . . . . . . . . . . . . . . . . . . . 334 ff
V
vascular headaches . . . . . . . . . . . . . 350 histamine in . . . . . . . . . . . . . . 351 ff
Z
Zaditen . . . . . . . . . . . . . . . . . . . . . . 278

The Plot Against Asthma and Allergy Patients

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Plot Against Asthma and Allergy Patients

Uploaded by

Copyright:

Available Formats

THE PLOT AGAINST ASTHMA AND ALLERGY PATIENTS

Asthma, Allergies, Migraine, and Chronic Fatigue Syndrome are Curable,

but the Cure Is Hidden from the Patients

Felix Ravikovich, M.D.

As featured on CBCs fifth estate

BOOKS ON MEDICINE THAT WORKS

Includes bibliographical references and index. ISBN 0-9731945-1-0

1. AllergyTreatment. 2. AsthmaTreatment. 3. MedicineResearch. I. Title. RC584.R39 2003 616.97'06 C2003-906757-2

Introduction: Renovating Medicine

viii THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

THE PLOT AGAINST ALLERGY PATIENTS

20 THE PLOT AGAINST ALLERGY PATIENTS

22 THE PLOT AGAINST ALLERGY PATIENTS

24 THE PLOT AGAINST ALLERGY PATIENTS

26 THE PLOT AGAINST ALLERGY PATIENTS

hen the off receptors, H2 and H3, are

28 THE PLOT AGAINST ALLERGY PATIENTS

30 THE PLOT AGAINST ALLERGY PATIENTS

32 THE PLOT AGAINST ALLERGY PATIENTS

34 THE PLOT AGAINST ALLERGY PATIENTS

36 THE PLOT AGAINST ALLERGY PATIENTS

38 THE PLOT AGAINST ALLERGY PATIENTS

40 THE PLOT AGAINST ALLERGY PATIENTS

42 THE PLOT AGAINST ALLERGY PATIENTS

44 THE PLOT AGAINST ALLERGY PATIENTS

46 THE PLOT AGAINST ALLERGY PATIENTS

48 THE PLOT AGAINST ALLERGY PATIENTS

50 THE PLOT AGAINST ALLERGY PATIENTS

52 THE PLOT AGAINST ALLERGY PATIENTS

54 THE PLOT AGAINST ALLERGY PATIENTS

he lasting correction of the gene expression

56 THE PLOT AGAINST ALLERGY PATIENTS

58 THE PLOT AGAINST ALLERGY PATIENTS

60 THE PLOT AGAINST ALLERGY PATIENTS

62 THE PLOT AGAINST ALLERGY PATIENTS

64 THE PLOT AGAINST ALLERGY PATIENTS

66 THE PLOT AGAINST ALLERGY PATIENTS

68 THE PLOT AGAINST ALLERGY PATIENTS

CAUSES AND TRIGGERS IN ALLERGY

70 THE PLOT AGAINST ALLERGY PATIENTS

Causes and Triggers in Allergy

72 THE PLOT AGAINST ALLERGY PATIENTS

Causes and Triggers in Allergy

74 THE PLOT AGAINST ALLERGY PATIENTS

Causes and Triggers in Allergy

76 THE PLOT AGAINST ALLERGY PATIENTS

Causes and Triggers in Allergy

78 THE PLOT AGAINST ALLERGY PATIENTS

Causes and Triggers in Allergy

80 THE PLOT AGAINST ALLERGY PATIENTS

Causes and Triggers in Allergy

82 THE PLOT AGAINST ALLERGY PATIENTS

Causes and Triggers in Allergy

84 THE PLOT AGAINST ALLERGY PATIENTS