Occasional Essay

A Century of Tuberculosis
John F. Murray
Division of Pulmonary and Critical Care, University of California San Francisco, San Francisco, California

Here are the facts: during the last 100 years in the thousands of years-long history of tuberculosis, we have beneted from unquestioned scientic and clinical progress; but at the same time we have witnessed a global increase in the number of victims and a worsening of the efcacy of control manifested by a rising prevalence of drug resistance in many countries. Today, tuberculosis is relatively easy to diagnose; when the right combination of medications is made available and taken by the patient, the disease can be cured more than 95% of the time; and in certain targeted populations, the manifestations of the disease can be attenuated by vaccination and even prevented by chemotherapy. Despite these remarkable achievements, the estimated number of new cases of tuberculosis in the world during each of the last several years has steadily increased: from 8.0 million in 1997 to 8.3 million in 2000, and is expected to reach 10.2 million in 2005 (1, 2). There are more people infected with Mycobacterium tuberculosis in the world this year than ever before, and from 1997 through 2000 the number of new cases of tuberculosis and the per capita incidence worldwide rose 1.8% per year and 0.4% per year, respectively (2). Although the overall global tuberculosis situation is deteriorating, it is actually improving in some countries. In the United States, for example, the incidence of newly reported cases of tuberculosis has fallen steadily since 1992 to its lowest level ever, and in 2002 (last report) was 5.2/100,000 population (3)a stunning public health accomplishment. Such impressive progress, however, is found only in rich (industrialized) nations, although problems remain in many of their marginalized innercity communities; moreover, the reverse is occurring in many poor (developing) countries, which is where the great majority, 86%, of the worlds total population live. And not only are these destitute regions home to 95% of all the worlds cases of active tuberculosis and 98% of the nearly 2 million deaths from the disease each year, exactly the same countries are now being ravaged by the pandemic of human immunodeciency virus (HIV) infectionthe most powerful factor ever known to favor the development of tuberculosis (4). This historical review examines the century-long paradox of tuberculosis and illustrates an important point made by others (5): the conquest of tuberculosis by medical advances alone will never occur until the prevailing global inequities of wealth and health care are corrected.

general agreement that consumption, the common name for tuberculosis in its early days, increased dramatically in Europe and North America during the seventeenth and eighteenth centuries and then began to decline (6). One of the models that illustrates this sequence (Figure 1, derived from material in References 7 and 8) shows death rates from tuberculosis peaking in the year 1800, a phenomenon undoubtedly linked to the appalling socioeconomic conditions (overcrowding, poor nutrition, lack of hygiene and sanitation, dearth of medical care) that prevailed during the early years of the unfolding industrial revolution (8). Mortality from tuberculosis was colossal: one of every four deaths recorded in parish registries from England at the end of the eighteenth century was attributed to the disease (9); moreover, consumption was probably the most common killer of American colonial adults, and accounted for more than 25% of deaths in New York City between 1810 and 1815 (10). But then a major reversal occurred and death rates began to fall. No one knows exactly why, but three explanations have been advanced (11): improved socioeconomic conditions that led, in turn, to better nutrition and living and working standards; application of primitive public health measures; and the dawning realization that tuberculosis was probably an infectious disease and the beginning sequestration of (contagious) consumptives in hospitals and sanatoriums. Toward the end of the nineteenth century, long after death rates from tuberculosis had begun their remarkable downward trend, two historic events occurred that had tremendous subsequent impact on the diagnosis and management of the disease. In 1882, Robert Koch discovered M. tuberculosis and in 1895, Wilhelm Konrad Rontgen discovered X-rays. These scientic triumphs were quickly applied to clinical medicine, so that around 1905, the time our historical narrative begins, doctors could make a precise diagnosis of consumption by demonstrating abnormalities in a patients chest radiograph and nding tubercle bacilli in his or her sputum.

BEGINNINGS
Even though mortality from tuberculosis in Western Europe and North America had declined substantially from its peak around 1800, 100 years later it was still huge: 194/100,000 in the United States, making it the third most common cause of death after cardiovascular diseases and inuenzapneumonia (12). At the turn of the twentieth century, there were only a handful of professional and governmental organizations specically engaged with tuberculosis. By 1903, a few ad hoc groups scattered throughout the country were beginning to undertake various antituberculosis pursuits, such as planning congresses and exhibitions; and the need for a central association to coordinate and extend these functions was becoming imperative (13). On June 6, 1904, the efforts of a group of concerned people, both lay and professional, culminated in the formation of the National Association for the Study and Prevention of Tuberculosis (later the National Tuberculosis Association, the forerunner of todays

BACKGROUND
To fully appreciate what happened during the last 100 years, we need to look back, briey, to the preceding centuries. There is

(Received in original form February 1, 2004; accepted in final form March 2, 2004) Correspondence and requests for reprints should be addressed to John F. Murray, M.D., F.R.C.P., Box 0841, Pulmonary and Critical Care, University of California San Francisco, San Francisco, CA 94143-0841. E-mail: johnfmurr@aol.com Am J Respir Crit Care Med Vol 169. pp 11811186, 2004 DOI: 10.1164/rccm.200402-140OE Internet address: www.atsjournals.org

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Figure 1. Schematic model of the trend of mortality from tuberculosis in Western Europe from 1740 to 1985 (modified from Reference 8 and reprinted from Reference 51).

American Lung Association); Edward L. Trudeau was elected president and William Osler and Hermann M. Biggs were elected vice presidents. The following year, members of the National Association who were also active in the burgeoning sanatorium movement founded the American Sanatorium Association (the predecessor of the American Trudeau Society, which was renamed the American Thoracic Society in 1960). Their rst meeting was held in New York City on December 1, 1905; all 17 persons who attended and 17 others who were not present were elected to membership; yearly dues were set at $1.00 (14). At the time the American Sanatorium Association was founded, there were only 106 sanatoriums in the United States, which provided 9,107 beds for patients with tuberculosis. By contrast, during its peak year, 1954, there were 108,457 beds allocated to the disease; the magical appearance of isoniazid 2 years earlier and the development of effective treatment for tuberculosis (described subsequently) ended the need for longterm institutionalization (of interest is the fact that one of the sanatoriums to close its doors in 1954 was probably the most famous of all: the Adirondack Cottage Sanatorium, renamed 2 years after its founders death in 1915 as the Trudeau Sanatorium). Originally, the American Association was an exclusive club, but it gradually broadened its membership and portfolio of interests. Looking back now and refreshed from rereading Julius Wilsons three-part history of our organization (1416), it is clear that the heritage of the American Thoracic Society, from its inception, derives from a single preoccupation tuberculosisand that this disease dominated the rst halfcentury of the societys existence.

their vaccine Bacille Bilie (from bile) Calmette et Guerin, which was quickly shortened to Bacille Calmette Guerin, and then to its household name, BCG. With extreme prudence and caution, beginning in 1921, BCG was administered to an increasing number of babies and young children; by 1924, more than six hundred infants had been vaccinated with apparent protection and few serious side effects. BCG started to attract attention and to be more widely used until late 1929 and early 1930when a dreadful catastrophe intervened (18). According to Daniel (19), 251 babies in Lubeck, Germany were mistakenly given living virulent M. tuberculosis instead of impotent BCG. Tragically, 72 infants died, all but ve from acute tuberculosis (the number of vaccinees and deaths in the incident vary slightly from one account to another, but the essential facts are indisputable). Not enough attention, though, has been paid to the other 179 victims, the majority of whom developed clinical tuberculosis and a few others who remained healthy but developed positive tuberculin tests. Twelve years later, every one of these children was alive and free of tuberculosis (20), an evident demonstration that even in immunoincompetent infants, heavy inoculation with tubercle bacilli is by no means invariably fatal. Despite this setback, BCG has been given to untold millions of people and, not long ago, was the worlds most commonly used vaccine. Efcacy rates have varied enormously, from 0 to 80%; Brewer (21) concluded from a metaanalysis of published studies that BCG offers 50% protection, which doesnt seem to jibe with the apparent weakness of contemporary vaccines. Immunization seems most helpful in infants, protecting them from severe forms of tuberculosis, particularly miliary and meningeal disease, a conclusion that ts with the old observation that BCG-induced immunity does not prevent the subsequent establishment of infection with tubercle bacilli, but only retards their spread (17).

CHEMOTHERAPY
M. tuberculosis is a tough and resilient microorganism that is well adapted to prolonged residence in its human host. Shielded by a waxen cell wall that protects against lethal enzymes and other deadly products elaborated by the bodys antibacterial defenses, tubercle bacilli are also sheltered against foreign chemicals such as gold, arsenic, mercury, calcium, iodine, quinine, creosote, turpentine, cod liver oil, and chaulmoogra oil, to mention just some of the many therapeutic substances of historical interest that had been tried in a fruitless effort to arrest or reverse the progress of consumption. The rst hint of a chink in the waxy armor of M. tuberculosis was discovered by physician and zoologist H. Corwin Hinshaw and his veterinarian colleague William Feldman during tests of Promin in their experimental model of tuberculosis in guinea pigs. In 1941, they reported (22), The results of this investigation seem to indicate that experimental infection with tubercle bacilli, as in the case of infections with certain other pathogenic bacteria, may be retarded or actually be subdued by a chemotherapeutic agent. Subsequent clinical studies on Promin and a promising derivative, Promizole, in patients with tuberculosis came to a halt, however, because of the discovery by Selman Waksman, a distinguished soil microbiologist, of a new and even more promising antibiotic: streptomycin (23). In January 1944, Schatz, Bugie, and Waksman (24) reported their discovery of streptomycin and detailed its potency against 22 different species of bacteria, including M. tuberculosis. In their table of results, they presented indisputable evidence that streptomycin was active against tubercle bacilli, but nowhere else in the article is that seminal fact mentioned or discussed. In looking back on this oversight, Birath (25) observed, No

VACCINATION
In the 1880s, Louis Pasteur invented the principle and devised the original means of deliberately attenuating the virulence of a living microbe to produce a successful vaccine, rst against fowl cholera and later against rabies and anthrax. Beginning in 1908, Albert Calmette and Camille Guerin borrowed Pasteurs technique to create a vaccine against tuberculosis. After serendipitously learning that growth in ox bile diminished the virulence of Mycobacterium bovis, Calmette and Guerin meticulously performed 230 serial passages of a single isolate of the organism, sufcient for it to lose its ability to cause progressive fatal tuberculosis in a variety of animals: guinea pigs, rabbits, cows, horses, monkeys, and chimpanzees. The attenuated bacilli did, however, induce self-limited infection as well as its accompanying state of partial resistance to reinfection with virulent M. tuberculosis and M. bovis (17). Not surprisingly, the bacteriologists called

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comment whatever on this sensational nd is to be found in the text. The attention was wholly directed on other ndings. The discovery had consequently been made, but was not discovered by the discoverers themselves! Several months later, Schatz and Waksman (26) did go back and retest streptomycin against M. tuberculosis, largely because, according to Ryan (27), the strain they used in their rst experiments was harmless and they wanted to be sure the antibiotic could kill virulent (H37) tubercle bacilli. Hinshaw and Feldman knew about Waksmans work practically from its beginning and had tried to obtain some streptomycin for testing in their guinea pigs as early as November 1943, exactly 4 weeks after Schatz isolated the two strains of Actinomyces that produced the antibiotic; 10 grams of the precious material nally arrived at the Mayo Clinic in April, 1944, enough to treat only four guinea pigs (27). No doubt, though, about the outcome after additional experiments (28): a marked and striking difference in the results of the tuberculous infection between the controls and the treated animals. Next, on November 20, 1944, only 15 months after the discovery of streptomycin, in collaboration with Karl Pfuetze, and while further guinea pig experiments were still underway, Hinshaw and Feldman began treatment of the rst human subject to receive long-term streptomycin: Patricia, a young woman who was clearly dying from progressive pulmonary tuberculosis. Patricia miraculously survived but had a prolonged recovery; she left the hospital, got married, had three children, and led an active life (29). Others lucky enough to be treated also did well (30). Streptomycin was good, but far from perfect. It had signicant eighth nerve toxicity and its benets were often short lived owing to the development of resistance by the bacteria. Fortuitously, the future of chemotherapy of tuberculosis was saved by the nearly simultaneous development of another active agent, paraaminosalicylic acid (PAS), by Jorgen Lehmann in Sweden. Lehmanns discovery resulted from pure deduction based on published information that M. tuberculosis avidly metabolized salicylic acid. Lehmann wanted to nd a look-alike substance that hungry bacilli would feast on but that would kill rather than nourish. That chemical turned out to be PAS (31). After a series of promising laboratory studies, in partnership with Gylfe Vallentin, a distinguished tuberculosis specialist, Lehman tried PAS in patientsinitially by direct instillation into tuberculous empyema pockets; then, on October 30, 1944, orally. The rst patient to receive systemic PAS was a moribund young woman named Sigrid who made a dramatic recovery; other patients also improved. But clinical acceptance of the drug in Sweden was slow, much slower than that of streptomycin in the United States. As a consequence, even though Sigrid was treated with PAS 1 month before Patricia received streptomycin, in the chronicle of medical history, PAS appeared 2 years after streptomycin (32). Like streptomycin, PAS often produced only transient clinical benet before mycobacterial resistance developed. Shortly thereafter, the British Medical Research Council showed how this could be diminished. On the basis of preliminary evidence from the United States, a landmark clinical trial denitively documented the superior value of combined treatment with streptomycin and PAS compared with either agent alone (33) (I say landmark because not only did the trial establish one of the axioms of the therapy of tuberculosisnever use a single agent to treat active diseaseit introduced the statistical technique of random allocation of subjects to one treatment arm or another, a vital means of maximizing the experimental value of the scant supply of streptomycin.) When administered together, streptomycin preserved the potency of PAS by preventing tubercle bacilli from becoming resistant to it, and vice versa. Plus,

two antituberculosis agents have more therapeutic clout than just one. In 1951, in what must be one of the most extraordinary pharmaceutical coincidences of all time, it turned out that scientists at Bayer Chemical in Germany and at both Squibb and HoffmannLa Roche in the United States had discovered exactly the same miracle agent at exactly the same timeisoniazid, the wonder drug that everyone had dreamed of: powerful, safe, and inexpensive (34). It didnt take long to learn that most patients with pulmonary tuberculosis could be cured with combined therapy with isoniazid, streptomycin, and PAS; streptomycin had to be stopped after a few months, but it was necessary to take the other two antibiotics for a total course of 18 to 24 months (35). Triple therapy remained the standard treatment for all forms of tuberculosis for nearly 15 years. Not only did sanatoriums close, but also therapeutic mainstays like pneumothorax and pneumoperitoneum became obsolete, and surgical procedures such as thoracoplasty and the surgeons who did them disappeared. Finally, the availability of rifampin in the mid-1960s and the rejuvenation of pyrazinamide, an older agent that had been shelved owing to its toxicity, allowed the development of modern short-course antituberculosis chemotherapy, a particular triumph of Wallace Fox and Dennis Mitchison, and testimony to the wisdom of the long-term support of tuberculosis research provided by the British Medical Research Council (36). It was nally accepted that treatment of tuberculosisfrom beginning to endcould be given entirely on an outpatient basis, without hospitalization, something Fox proclaimed in 1959, from studies in his (later) celebrated Tuberculosis Chemotherapy Centre in Madras, India (37).

RESURGENCE: UNITED STATES

Beginning in 1953, the year the current system of accurate national data collection and notication was installed, there was a steady annual decline of around 57% in the per capita incidence rate of reported cases of tuberculosis in the United States. In 1985, the rate went down again, but only slightly. In 1986, the unthinkable happenedfor the rst time in 33 years, the incidence rate of tuberculosis increased compared with the rate the previous year. The actual numbers of reported cases tell the story even better: in 1953, 84,304 Americans developed tuberculosis and 19,707 died of it; in 1985, the nadir of the three-decadelong reduction, there were 22,201 new cases and only 1,752 deaths (3). Thereafter, both the numbers of newly reported cases and the incidence rates edged upward, nally peaking in 1992, before resuming another steady decrease (Figure 2).

Figure 2. Incidence rates of tuberculosis per 100,000 persons in the United States from 1982 to 2002 (plotted from data in Reference 3).

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The reasons for the resurgence are complex, but four factors have generally been implicated: the arrival and spread of HIV infection; immigration of people from high-prevalence countries; the development of hot spots (e.g., hospitals, shelters, prisons) where tuberculosis ourished; and the deterioration of tuberculosis control (38). New York City was particularly hard hit. In 1992, the apex of the resurgence, although a large city, New Yorks inhabitants accounted for only 3% of the total U.S. population; in contrast, the same year, the citys 3,811 registered cases of tuberculosis comprised 14% of all those in the country. To compound the problem the Big Apple hosted 61% of the nations entire burden of patients with multidrug-resistant tuberculosis (39). In an exercise of horrible judgment framed in the belief that the consistently declining rates of tuberculosis in the United States meant that the disease was no longer a threatand over the dire predictions of public health expertsthe U.S. Congress decided to save money by changing tactics. Between 1970 and 1972, categorical (i.e., earmarked) federal funds for tuberculosis control were phased out and lumped together with several other categorical programs in the form of block grants, which were awarded to states for communicable diseases as a whole. States would know how best to use the largess and they were no longer required to allocate any funds at all to tuberculosis. After that switch, there was no way of knowing exactly how much the states did spend and for what activities, but there is little doubt that, overall, funding for tuberculosis control was, as the Institute of Medicine lamented, sharply curtailed (40). New York Citys Bureau of Tuberculosis Control was rendered helpless: stafng and services shrank to their all-time low and outpatient clinics were cut from 24 to 8. The scally induced programmatic dismantling occurred while the number of homeless was climbing; more and more people were turning to alcohol, heroin, and cocaine; mental institutions were shedding patients into the streets; and large numbers of immigrants from highprevalence countries arrived laden with M. tuberculosis. Then, the catalyst of HIVAIDS kicked in and the case rates of tuberculosis throughout New York Cityparticularly in Harlemwhich had been dropping, changed directions and soared (Figure 3). A high percentage of patients with tuberculosis who had been started on appropriate treatment while hospitalized were lost to follow-up after discharge (41): the inevitable consequence multidrug-resistant tuberculosis, a self-made curse that New York City has had to live with ever since (there are many countries and regions within countries throughout the world where promiscuous treatment and management practices have created rates of multidrug-resistant tuberculosis that rival those from New York City [42]).

Beginning in 1992, the Bureau of Tuberculosis Control greatly augmented its staff, upgraded its facilities, and set to work. Within 4 years, nearly 80% of all New Yorkers with tuberculosis were receiving directly observed treatment (43), which led to a decrease both in the number of reported cases and in the prevalence of multidrug-resistant strains of tubercle bacilli (44). The cost of congressional mischief? Over $1.0 billion.

RESURGENCE: WORLD
In the mid-1970s, a redoubtable Czech, Karel Styblo, harnessed the meager resources of the International Union against Tuberculosis and Lung Disease and showed that, contrary to expert opinion, tuberculosis could be controlled in extremely poor countries: beginning in Tanzania, one of the poorest of them all. Comparable successes attended the establishment of similar programs in many other impoverished countries (38). Styblos approachhigh-level political commitment, detection of cases by direct sputum-smear microscopy, provision of a regular and reliable supply of antibiotics and reagents, direct observation of medications being swallowed, and accurate recording and reporting of results (45)was later adopted, packaged, and promoted by the World Health Organization (WHO) under the rubric, Directly Observed Therapy Short-Course, better known as DOTS. The DOTS strategy has proved to be an efcient, although underused, methodology for national programs to deal with tuberculosis. But neither Styblo nor the WHO could possibly have foreseen the coming of HIVAIDS and, with it, the undoing of tuberculosis control efforts in virtually all countries throughout the world where the two infections coexist in large numbers (46). Figure 4 illustrates a fact I have already emphasized: that trends in tuberculosis case notication rates in selected regions of the world differ substantially (47). The two chief problem areas today are in sub-Saharan Africa, especially in countries where 10% or more of the adults are infected with HIV (Figure 4, lower right panel), and in Eastern Europe, which includes countries of the former Soviet Union that were affected, rst by the degradation of public health services after the implosion of the Soviet Union and then by worsening HIV infection. HIV infection is now recognized as the most powerful risk factor ever identied that enhances the progression of tuberculous infection, whether recently or remotely acquired, to clinically active tuberculosis (4). Accordingly, tuberculosis is one of the leading worldwide causes of morbidity and mortality among people with HIVAIDS. In the year 2000, of the estimated 8.3 million new cases of tuberculosis, 9% were attributable to coexisting HIV infection, but the proportion was much higher (31%) in Africa (2). And the situation is worsening: most of the increased number of cases of tuberculosis projected during the year 2005 are HIV-linked and will occur in sub-Saharan Africa (1). There is no longer any doubt: spreading HIV infection is the main force driving the global resurgence of tuberculosis, and current efforts, including DOTS, to deal with rising case rates in heavily HIV-aficted countries have failed (46). Judging from this historical perspective, as long as HIV continues to worsen in countries with a high background prevalence of tuberculous infection, as is forecast (48, 49), the future of worldwide tuberculosis looks bleakuntil at least one member of the cursed duet is brought to a halt with an effective vaccine.

CONCLUSIONS
Figure 3. Incidence rates of tuberculosis per 100,000 persons in Harlem, New York City from 1970 to 1989 (plotted from data in Reference 41).

This brief review of the history of tuberculosis during the last 100 years has highlighted two distinct and diverging movements: rst, the great progress in scientic knowledge and its clini-

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Figure 4. Trends in case notification rates for selected countries with established market economies, from Eastern European countries, and from African countries with low and high HIV seroprevalence rates (below and above 10%, respectively) among adults 1549 years of age. The rates for all countries have been expressed relative to an arbitrary standard of 100 in 1990. Vertical bars show 95% confidence limits (modified from Reference 1).

cal application that has made consumption a diagnosable and curable disease; second, the rising numbers of cases and alarming rates of drug resistance worldwide. Together, these phenomena provide another example of the paradox that advances in the treatment of individual patients do not easily translate into global public health gains (50). When American Thoracic Society members look back on tuberculosis 100 years from now, I hope that they will nd that the distorted political and economic forces that shape health care have been balanced and that this ancient scourge has nally been eradicated. Otherwise, history will surely repeat itself.
Conflict of Interest Statement : J.F.M. has no declared conflict of interest. Acknowledgment : The author gratefully acknowledges the helpful comments and suggestions of Professor Donald A. Enarson.

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