Professional Documents
Culture Documents
COURSE
2013
Authors:
ef Lucrri Dr. Brndua ilea
ef Lucrri Dr. Carmen Chiriac
ef Lucrri Dr. Iringo Kezdi
ef Lucrri Dr. Anca Georgescu
ef Lucrri Dr. Cristina Grbovan
Asistent Univ. Dr. Andrea Incze
Asistent Univ. Dr. Nina incu
Contents
Preface
Introduction
Chapter 1
Antibacterial Treatment
Chapter 2
Scarlet fever
Erysipelas
Measles
Rubella
Varicella-zoster virus infections. Varicella (Chickenpox)
Herpes zoster (Shingles)
Mumps
Whooping cough
Epstein-Barr virus (infectious mononucleosis)
Diphtheria
Influenza
Viral respiratory infections
Parainfluenza virus infections
Human respiratory syncitial virus infections
Human metapneumovirus infections
Coronavirus infections
44
49
53
56
60
64
67
71
75
79
82
89
93
94
95
96
Chapter 3
Central nervous system infections
Encephalitis
99
125
Chapter 4
Leptospirosis
Rabies
Lyme borreliosis
Anthrax
Tetanus
132
135
139
149
153
Chapter 5
Enterovirus infections
Poliomyelitis
Acute infectious diarrheal diseases
Salmonellosis and typhoid fever
Shigellosis
Cholera
Botulism
158
163
169
178
186
190
195
Chapter 6
Acute viral hepatitis
198
Chapter 7
Sepsis
215
Chapter 8
Infection with the human immunodeficiency virus HIV (HIV)
232
Preface
Despite decades of dramatic progress in their treatment and prevention, infectious diseases
remain a major cause of death and debility and are responsible for worsening the living
conditions of many millions of people around the word.Our goal in publishing this book is to
offer convenient source to the medical students about the basic knowledgein infectiousdisease.
The physicians caring patients for infectious disease must cope with new challenges in diagnosis,
treatment and prevention. Infections frequently challenge the physicians diagnostic skill and
must be considered in the differential diagnoses of syndromes affecting every organ system.
The incidence of different kind of infections is an ever-changing pattern, which is one reason
why the study of infectious diseases is so interesting.We want to convince our students that in 21
century without basic knowledge about infectious diseases nobody can practice medicine
We hope that this book will prove valuable to medical students and young doctors in medical
training, in the day to day management of patients with infectious disease.
The authors
INTRODUCTION
Basic considerations
A century of advance in medicine and public health (better sanitation, clean food and
water supplies, good housing, personal hygiene, vaccines and drugs) has markedly controlled
some diseases and attenuated the risk of most infectious diseases. Because of this, the
epidemiology of infectious disease has changed.In the resource-poor developing countries
infectious diseases continue to cause significant morbidity and mortality.
In this days,there are a numerous emerging and reemerging infectious diseases.
In the last few years a lot of factors were identified as forces to contribute to diseases
emergence and reemergence, such as:
Climate change, global warming, could extend the geographical range of infections
(malaria)
Increased number of older persons, immunocompromised hosts leading to severe,
opportunistic infections
Transplant and cancer patients treated with cytotoxic drugs, become a feertile field for
formerly unusual pathogenic bacteria, fungus, viruses etc.
Environmental degradation could result in inadequate suppliesof safe food and water
Economic development (industrialization, urbanization, irrigation) changes human
demographics, behaviors
In developing and developed countries poverty and malnutrition, migrating people, wars
may bring high rates of diseases (like tuberculosis) into cities.
Genetic modification could, in theory, result in new human pathogens,
We must be prepared for the unpredictable and unexpected: bioterrorism and other
deliberate releases of biological agents
The picture of infectious diseases, at the beginning of the 21st century can be summarized as
follows.
Some infectious diseases start to disappaer: smallpox has been completely eradicated
(WHO 08.05.1980) although there is a potential threat of its deliberate release. Mosquito
control has removed malaria from Romania. Poliomyelitis is close to global eradication.
There are a few infections which have virtually disappeared as endemic diseases: cholera,
typhus, diphtheria.
Some Infections have become much less common or less virulent: scarlet fever, measles,
mumps, rubella, whooping cough, tetanus, Haemophilus influenzae type b diseases,
There are infections whose incidence has remained unchanged: respiratory infections,
chickenpox (except in countries practising universal childhood varicella vaccination) and
herpes zoster, gastroenteritis, infections of the nervous system, urinary infections etc.
There are infections whose incidence has increased: sexually transmitted infections,
infections in immunocompromised, dibilitated and intensive care unit patients,
methicilin-resistant Staphylococcus aureus (MRSA) infection,Clostridium difficile
infection, infections in intravenous drug users.
There are new infection problems like
a, Infections associated with the increasing travel to tropical countries: malaria, enteric
fever, ameobiasis, helminthiasis, exotic viral infections, travellers diarrhoea
b, Infections associated to newly identified agents: Human immunodeficiency virus
(HIV) infection, variant Creutzfeldt-Jakob disease, multidrug resistance in pneumococci,
4
Airborne
Airborne transmittal occurs when infectious agents traveltrough the air on small water or dust
particlesoften for great distances.
Diseases spread by airborne routes include:
Exanthemata: measles, rubella, chickenpox, scarlet fever.
Mouth and throat infections: diphteria, tonsilitis, mumps, herpes stomatitis.
Respiratory tract infections: whooping cough, influenza and other respiratory virus
infections, pulmonary tuberculosis.
General: meningococcal and staphylococal infection.
II.
Intestinal
Diseases spread by the intestinal route include typhoid and paratyphoid, salmonellosis,
dysentery, cholera, gastroenteritis, poliomyelitis and other enterovirus infections, and viral
hepatitis A and E.In another group of ingestion diseases, transmission is direct from
contaminated food. This group includes brucellosis, Q fever, salmonellosis, trichinellosis and
other helminth infections.
III.
Direct contact
Infection may be transmitted directly by local skin contact. This mostly involves cutaneous
infections and includes impetigo and scabies.
IV.
Venereal route
Blood-borne
Some infections are commonly transmitted via infected blood or blood products, e.g. hepatitis B,
HIV, hepatitis C.
These do not cover all the complex routes by which disease spreads.
Other diseases may spread by two or more alternative routes. For example, tuberculosis
commonly spreads by airborne infection, but may spreadvia milk by ingestion or even by direct
skin contact.
Pathogenesis of infections
Infectious diseasaes occurs when a pathogenic organism causes signs and sympthoms of
inflammation or organic dysfunction. An infecting agent can be from endogenous ( those
residing on mucosal surfaces or resting latent in various tissues) or exogenous source
5
(transmitted to host from source by direct or indirect contact). The infectious agent first
colonizes at the site of entry (the portal of entry). The most frequent portal of entry of
pathogenic bacteria are: respiratory, gastrointestinal, genital, urinary tracts. The appearence of
disease is supported when the infecting dose is sufficiently large and adherence to epithelium or
other tissue is possible. There are a few adherence factors like: surface hydrophobicity and net
surface charge (the more hydrophobic the bacterial cell surface, the greater the adherence to the
cell surface); specific surface molecules: pili (eg. E coli), fimbriae ( group A Streptococci):
lipoteichoic acid and M protein found on the fimbriae. They multiply and spread directly
through tissues or via the lymphatic system to the blood stream. Alternarively, the proliferative
phase may not result in invasive disease, but instead continue and cause prolonged excretion of
infectious organism-carrier state.
The fitness of a pathogen can be defined as its ability to multiply within a host,
disseminate from that host, translocate to a new host, colonize the new host, and cause infection.
This can be distinguished from the virulence from a pathogen, which refers to the severity of
clinical illness resulting from infection.The specific virulence factors allow pathogens to invade
tissue in a predictable way, they give the ability to evade the hosts immune system by the
production of enzymes: coagulase, beta-lactamases, streptokinases, etc. Outside the factors that
promote colonization, proliferation, and tissue invasion, other important virulence factors include
the capacity to form toxins (toxigenicity). The toxins are secreted proteins (exotoxins) or
structural portionst of the microorganisms (endotoxins).
Host responses to the release of this substances, by fever, chills, local inflamation,
leukocytosis, protein catabolism, serum acute phase reaction, etc. The pathogenesis of infectious
diseases is a complex interplay of microbial action and host reaction. Disease is a complex
phenomenon resulting from tissue invasion and destruction, toxin elaboration and host response.
Diagnosis of infectious diseases
The basic goals of diagnosis in infectious diseases are
-to determin which organ system is affected
-to determin which agent is responsabile
The methods used for the diagnosis of infectious diseases are as follows:
-Careful history, extensive review of occupational, travel, sexual and social informations
-Complete physical examination
-Laboratory tests: for direct and indirect detection of causative agent
Drugs parameters
-spectrum of activity
-pharmacokinetics
-pharmacodynamics
-toxicities
-interactions
b, mechanism underlying infectious agents resistance
c, strategies used by clinicians to prevent, limit resistance
II.
Patient-associated parameters:
-infection site
-other drugs being taken,
-allergies,
-immune status
-excretory status
Writing a prescription for infectious disease practical advices
To treat a patient with infectious disease is much more than prescribing a drug. To approach a
rational treatment, you must cover the folloing aspects:
-Where you want to treat the patient: at home or in hospital?
-Do the patiet need isolation or not?
-Do the patient need a total rest?
-What about his diet?
The chosen drugs must be efficient on
-causative agent (the ethiological treatment: antibacterial, antiviral, antifungal. etc)
-pathophysiology
-symptoms
Before writing a prescription for infectious disease........
It is a truism that any drug that can produce therapeutic benefit can also cause
unexpected, adverse effects (related to dose, to time-course, to patient susceptibility, to other
drugs interactions). Ask yourself if the patient has an infectious diseaseor not? Will the
treatment prevent the disease or not?
State the dose-write out in full
State the route of administration
State the frecvency of administration dosage interval
Give special instructions if necessary
Think about Carmeli s score if you use antibacterial or antifungal treatment
CHAPTER 1
ANTIBACTERIAL TREATMENT
Iringo Kezdi
The number of antimicrobial agents increased year by year because of resistance of new
and old pathogens to the previously used antibiotics.
Antimicrobial treatment is started empirically in most of the cases, because at the time
therapy is initiated, usually, the knowlidge of the infecting microorganism is not available.The
selection of antimicrobial drugs is based on antibacterial activity,susceptibility of infecting
microorganism, efficacy, toxicity, host factors, genetic factors, site of infection, drug
interactions, cost, etc.
These chapter deals with important informations concerning the antimicrobial drugs.
ANTIMICROBIAL DRUG CLASSES
1. -LACTAM ANTIBIOTICS
2. ERYTHROMYCIN GROUP (MACROLIDES)
3. TETRACYCLINE GROUP
4. CHLORAMPHENICOL
5. AMINOGLYCOSIDES
6. POLYMYXINES
7. ANTITUBERCULOUS DRUGS
8. RIFAMYCINS
9. SULFONAMIDES
10. BACITRACIN, MUPIROCIN
11. LINCOSAMIDES
12. METRONIDAZOLE AND TINIDAZOLE
13. GLYCOPEPTIDES
14. STREPTOGRAMINS
15. OXAZOLIDINEDIONES
16. DAPTOMYCIN/LIPOPEPTIDE
17. LIPOGLYCOPEPTIDE/TELAVANCIN
18. QUINOLONES
19. PENTAMIDINE AND ATOVAQUONE
20. URINARY ANTISEPTICS
1.-LACTAM ANTIBIOTICS
Those antibacterial drugs which share a commonchemical nucleus that contains a -lactam
ringare named -lactam antibiotics. These antibiotics areas follows:
I.monobactams
Aztreonam
II.dibactams:
1penicillins (penams)
1.1narrow spectrum
1.1.1- lactamase sensitive
natural penicillin: Phenoxymethylpenicillin (V)-oral
natural penicillin: Benzylpenicillin (G)Benzathine
benzylpenicillin, Procaine benzylpenicillin-parenteral
1.1.2- lactamase resistant
Cloxacillin, (Dicloxacillin, Flucloxacillin),
Oxacillin,
Meticillin,
Nafcillin
1.2extended spectrum penicillins
1.2.1 aminopenicillins:
Amoxicillin,
Ampicillin,
1.2.2.carboxypenicillins:
Carbenicillin(Carindacillin),
Ticarcillin,
Temocillin
1.2.3 ureidopenicillins:
Azlocillin,
Piperacillin,
Mezlocillin
1.2.4other:
Mecillinam(Pivmecillinam),
Sulbenicillin
2cephalosporins
Cefazolin, Cefacetrile, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine,
1stgeneration Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine,
Cefroxadine, Ceftezole
9
3carbapenems
Biapenem,
Ertapenem,
antipseudomonal : Doripenem, Imipenem, Meropenem
Panipenem
III.tribactams
Antimicrobial Action
-binding of the drug to receptors, penicillin-binding proteins, blockage of transpeptidation,
inhibitionof peptidoglycan synthesis
Only organisms actively synthesizing peptidoglycan (in the process of multiplication) are
susceptible to beta-lactam antibiotics. Nonmultiplying organisms or those lacking cell walls are
not susceptible.
Microbial resistance to penicillins is caused by four factors:
1 Production of beta-lactamases, eg, by staphylococci, gonococci, Haemophilus species, and
coliform organisms, including extended-spectrum beta-lactamaseproducing bacteria;
2 Lack of penicillin-binding proteins or decreased affinity of penicillin-binding protein for betalactam antibiotic receptors (eg, resistant pneumococci, methicillin-resistant staphylococci,
enterococci) or impermeability of cell envelope;
3 Failure of activation of autolytic enzymes in the cell wall"tolerance," eg, in staphylococci,
group B streptococci;
4 Cell wall-deficient (L) forms or mycoplasmas, which do not synthesize peptidoglycans.
I. Monobactams
Monobactams, so named due their monocyclic beta-lactam ring.The sole marketed monobactam
10
CLINICAL USES
1. streprococcus
group
including
anaerobic streptococci
2. susceptible
and
moderately
susceptible pneumococci
3. nonbeta-lactamase-producing
staphylococci
4. meningococci
5. Treponema
pallidumand
other
spirochetes
6. Propionibacterium acnesand other
gram-positive anaerobic bacilli
7. non-difficile clostridia
8. actinomyces
Most infections due to susceptible organisms respond to aqueous penicillin G in daily doses of
12 million units administered intravenously every 46 hours. For life-threatening infections
(meningitis, endocarditis), increased doses (34 million units intravenously every 4 hours) are
required.
11
Pharmacokinetics
-wide extracellular distribution after parenteral administration
-lower levels in the eye, prostate, and central nervous system (however, with inflammation of the
meninges and with appropriate dosing, adequate levels in cerebrospinal fluid)
-benzathine penicillin release extended amount of penicillin, continuous blood and tissue levels
are achieved, allowing the treatment of syphilis.
-penicillin V is the oral penicillin of choice because of its superior bioavailability.
Penicillin is primarily renally eliminated by glomerular filtration and active tubular secretion.
-lactamase resistant penicillins
Antistaphylococcal Penicillins
Oxacillin, cloxacillin, dicloxacillin, and nafcillin are resistant to degradation by beta-lactamases
produced by staphylococci. They are less active than natural penicillins against
nonstaphylococcal gram-positive bacteria. The primary route of clearance of the above agents is
nonrenalthus, no dosage adjustment is needed in chronic kidney disease.
Methicilline is no longer approved in practice due to its nephrotoxicity
Extended-Spectrum Penicillins
The extended-spectrum group of penicillins includes the
Aminopenicillins: ampicillin, amoxicillin
Table 2. Antimicrobial spectrum and therapeutical indications of aminopenicillins
ANTIMICROBIAL ACTIVITY
CLINICAL USES
Amoxicillinis
infections
-Listeria,
-nonbeta-lactamase-producing
Haemophilus influenza
strains
given
orally
for
minor
of - acute sinusitis
- acute otitis media
-penicillin-susceptible pneumococcus
12
CLINICAL USES
-Pseudomonas aeruginosa
-Klebsiella.
-E faecalis
-pneumococci.
-Bacteroides fragilis
-Proteus
-Enterobacter spp
-Serratia marcescens
-Enterobacter cloacae
-Citrobacter
Piperacillin(in combination with tazobactam) is given intravenously and increased doses (200
300 mg/kg/d) are required for treatment of infections due to P aeruginosa.
Penicillins Combined with Beta-Lactamase Inhibitors
The addition of beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) prevents
inactivation of the parent penicillin by some, but not all, bacterial beta-lactamases.
Table 4 Marketed products include
Name
penicillin
Augmentin
amoxicillin
Unasyn
ampicillin
Timentin
ticarcillin
Zosyn
piperacillin
beta-lactamase
inhibitor
route
of
administration
125 mg
orally
0.5 g
1g
100 mg
intravenously
3g
4g
0.375 g
0.5 g
intravenously
tazobactam
intravenously
13
Drug combination
ANTIMICROBIAL ACTIVITY
generally
inactivate
beta-lactamases infections with sensitive germs
produced by Staphylococcus
aureus, H influenzae, Moraxella
catarrhalis, B fragilis
Timentin,
Zosyn
Unasyn, -ampicillin-susceptible
enterococci
P aeruginosa,
Serratia,
Klebsiella
Augmentin
CLINICAL USES
Staphylococcus
aureus,
H acute bacterial rhinosinusitis
influenzae, Moraxella catarrhalis, infections
resulting
from
B fragilis
animal and human bites
refractory cases of otitis media
The beta-lactamase inhibitors are variably and unpredictably effective against beta-lactamases
produced by certain aerobic gram-negative bacilli, such as Enterobacter
Toxicity and adverse events
All penicillins
-allergic reactions, ranging from anaphylaxis and bronchospasm, to macular papular rash
-diarrhea (higher incidence after amoxicillin-clavulanate use)
-liver toxicity (higher incidence after oxacillin use)
-inhibition of platelet aggregation after use of high doses of penicillins, particularlypiperacillin
with tazobactam)
-in excessive doses, particularly with decreased renal function, all penicillins have been
associated with seizures.
CEPHALOSPORINS
The cephalosporins, consist of a beta-lactam ring attached to a dihydrothiazoline ring.
Substitutions of chemical groups result in varying pharmacologic properties and antimicrobial
activities. Cross reactions between penicillins and cephalosporins are related to similarities in the
molecular structure of side chains.
The mechanism of action of cephalosporins is analogous to that of the penicillins:
1 binding to specific penicillin-binding proteins,
2 inhibition of cell wall synthesis,
3 activation of autolytic enzymes in the cell wall.
Resistance to cephalosporins may be due to
-poor permeability of the drug into bacteria,
14
ANTIMICROBIAL
ACTIVITY
CLINICAL USES
First-generation
-aerobic
gram-positive
organismsStreptococcus
including
viridans
streptococci,
group
A
hemolytic
streptococcistreptococcus
pneumoniae,
(except
Enterococcus),
meti-Sstaphylococcus
Respiratory infections
Urinary infections
Skin infections,
tissue infections
soft
Prophylaxis of infection
of most clean surgical
procedures
some community-acquired
gram-negative organisms P
mirabilis, Escherichia coli,
Klebsiellaspecies
Second-generation
gram-negative bacteria
Otitis, sinusitis,
Tonsillitis ( if failure
with penicillin G, or
reccurences)
mixed
anaerobic
infections,
eg,
peritonitis
and
diverticulitis
Severe Infections:
Meningitis
Sepsis
Broncho-Pneumoniae
inconsistant activity versus: Nosocomial Infections
Serratia,
Acinetobacter, Surgery
Enterobacter
antibioprophylaxis
15
Fifth-generation
S Severe Infections:
Skin,
soft
tissues
gram-negative
spectrum infections
activity as third-generation Sepsis
Broncho-Pneumoniae
agents.
Nosocomial Infections
methicillin-resistant
aureus
present time, the cerebrospinal fluid penetration of ceftaroline is unknown and the drug has not
been studied in the treatment of meningitis.
The half-lives of these drugs are variable, resulting in differing dosage needs Ceftriaxoneis
eliminated primarily by biliary excretion, and no dosage adjustment is required in kidney
disease. The other drugs are eliminated primarily by the kidney and thus require dosage
adjustment in kidney disease.
Adverse Effects of Cephalosporins
Allergy, including anaphylaxis, fever, skin rashes, nephritis, hemolytic anemia. The frequency of
cross-allergy between cephalosporins and penicillins approximates 510%.
Toxicity
Ceftriaxone has been associated with a dose-dependent biliary sludging syndrome and
cholelithiasis due to precipitation of drug when its solubility in bile is exceeded.
Cefepimemay be associated with neurotoxicity, particularly with large doses and concomitant
kidney disease.
CARBAPENEMS
This class of drugs is structurally related to beta-lactam antibiotics.
Tabel Antimicrobial spectrum and therapeutical indications of carbapenems
Drug
ANTIMICROBIAL ACTIVITY
CLINICAL USES
Imipenem
most
gram-negative
rods
including P aeruginosa grampositive
organisms
and
anaerobes, with the exception of
Burkholderia
cepacia,
Stenotrophomonas maltophilia, E
faecium, and methicillin-resistant
S aureus and Staphylococcus
epidermidis
like imipenem plus extendedspectrum
beta-lactamaseproducing
E
coli
and
Klebsiellaspp
Respiratory infections
Urinary infections
intra-abdominal
infections
peritonitis and pelvic infections and
pyelonephritis
Meropenem
Doripenem
Ertapenem
18
Skin
infections,
infections
soft
tissue
Clinical use
Legionella,
Bronchitis
Mycoplasma,
Ureaplasma,
Atypical pneumonia
Skin infections
Campylobacter
Rhodococcus species
Bartonella species
Genital infections
ChlamydiaandChlamydophila(including
ocular and respiratory infections) organisms.
Toxoplasmosis (pregnancy)
Bacillary angiomatosis, hepatic peliosis
GN cocci,
Toxoplasma
gondii
(SPYRAMICINE,
ROXITHRO, CLARITHROMYCINE)
Atypical Mycobacteria
Bartonella
SINERGISTINS:
-
Clinical uses
Haemophilus ducreyi.
Atypical
mycobacteria
(Mycobacterium chancroid,nongonococcal urethritis in men
avium-intracellulare,
Mycobacterium and incubating syphilis, treating trachoma,
chelonei,
Mycobacterium
fortuitum, severe cholera
Mycobacterium marinum),
Weekly 1200-mg doses of azithromycin are
Toxoplasma gondii,
effective in preventing Mycobacterium
Campylobacter jejuni,
aviumcomplex infections in HIV-positive
patients, and doses of 500 mg daily are useful
Helicobacter pylori,
in M aviumcomplex pulmonary infections in
Borrelia burgdorferi.
nonHIV-positive patients.
azithromycin (500 mg weekly) is as effective
as benzathine penicillin in preventing
streptococcal infections
Clarithromycinhas been used for the therapy
of
-M avium complex infections, usually in
combination with other drugs (eg,rifabutin
and ethambutol), and can be given daily (500
mg twice daily) or three times weekly (1000
mg) as intermittent therapy.
oral clarithromycin (500 mg twice daily for 6
months), in combination with other agents
inM aviumcomplex infections
Clarithromycin in combination regimens for
the therapy of H pylori infections.
21
KETOLIDES
Telithromycin, the one available ketolide, is similar in structure to macrolides but has a broader
spectrum of activity. The dose is 800 mg/d orally, and no adjustment is needed for kidney
disease or liver insufficiency. Upon telithromycin's approval, upper gastrointestinal toxicity,
hepatotoxicity and visual disturbances were the most commonly observed adverse events.
Table 21. Antimicrobial spectrum and indications ketolides
Antimicrobial activity
Clinical uses
Gram- positive cocci, including: macrolides- There is no clear indication for this agent.
resistant Streptococcus pyogenes, S. aureus,
S. pneumoniae
Gram- negative pathogens: H. influenzae,
Moraxella catarralis, Legionella pneumophila,
Mycoplasma
pneumoniae,
Chlamydia
pneumoniae
TETRACYCLINE GROUP
The tetracyclines are a group of drugs with common basic chemical structures, antimicrobial
activity, and pharmacologic properties.These agentsare inhibitors of protein synthesis, they are
bacteriostatic for many gram-positive and gram-negative bacteria
Table 18. Antimicrobial activity and indications of tetracyclines
DRUG
DOSE-ADULT
DOSE-CHILD
1st Generation
Bronchopulmonary
infections,acne,Brucellosis,
Tularemia (in combination
with streptomycin),
TETRACYCLINE
OXYTETRACYCLINE
ROLITETRACYCLINE
3rd Generation
DOXICYCLINE
H influenzae
nd
2 Generation
LYMECYCLINE
METACYCLINE
-relapsing
fever,
actinomycosis, -nocardiosis,
MINOCYCLINE
-infections
marinum
caused
by
-malaria, malariaprophylaxis
(including multidrug-resistant
P falciparum).
22
Clinical uses
skin
and
soft-tissue
CHLORAMPHENICOL
Chloramphenicolbinds to the 50S subunit of ribosomes and inhibits protein synthesis.
Table . Antimicrobial spectrum and indications of cloramphenicol
Antimicrobial activity
Clinical uses
24
AMINOGLYCOSIDES
Aminoglycosides are a group of bactericidal drugs sharing chemical, antimicrobial,
pharmacologic, and toxic characteristics.
All these agents inhibit protein synthesis in bacteria by inhibiting the function of the 30S subunit
of the bacterial ribosome.
Resistance is based on
1 a deficiency of the ribosomal receptor (chromosomal mutant);
2 the enzymatic destruction of the drug (plasmid-mediated transmissible resistance of clinical
importance) by acetylation, phosphorylation, or adenylylation;
3 a lack of permeability to the drug molecule or failure of active transport across cell
membranes.
Resistance can be chromosomal (eg, streptococci are relatively impermeable
aminoglycosides) or plasmid-mediated (eg, in gram-negative enteric bacteria).
to
Anaerobic bacteria are resistant to aminoglycosides because transport across the cell membrane
is an oxygen-dependent energy-requiring process.
Amynoglycosides are not effective against anaerobes, pneumococcus, treponemes!
Absorption, distribution, metabolism, and excretion
Aminoglycosides are not absorbed from the gastrointestinal tract. They diffuse poorly into the
eye, prostate, bile, central nervous system, and spinal fluid after parenteral injection.
The serum half-life is 23 hours in patients with normal kidney function. Excretion is almost
entirely by glomerular filtration.
Adverse effects
All aminoglycosides can cause
-ototoxicity can be irreversible and is cumulative, presenting as hearing loss, or vestibular
damage, manifested by vertigo and ataxia.
-nephrotoxicity is usually reversible
-neurotoxicity appearsin very high doses, usually associated with irrigation of an inflamed
peritoneum, producing a curare-like effect with neuromuscular blockade that results in
respiratory paralysis.
Because of their considerable toxicity and the availability of less toxic agents, aminoglycosides
have been used less often in recent years.
Table 18. Antimicrobial activity and indications of aminoglycosides
DRUG
Antimicrobial activity
1st Generation
Streptomycin
Clinical uses
plague and tularemia;
enterococci,
penicillin-resistant
viridans streptococci, S aureus
endocarditis, S aureus and S
epidermidis,
francisella
tuleransis,
brucella,
25
-endocarditis caused by E
faecalisor
viridans
streptococci
(use
in
conjunction with penicillin or
vancomycin)
mycobacterium tuberculosis
Neomycin, Kanamycin
.
Paromomycin,
These
aminoglycosides
are
closely related, with similar
activity and complete crossresistance. Systemic use has been
abandoned because of ototoxicity
and nephrotoxicity
(in
with
2nd Generation
Gentamicin
Tobramycin
3rd Generation
Amikacin
negative
mycobacterial infections
Serratia organisms
M avium complex
M fortuitum are inhibited.
26
Netilmicin
with
POLYMYXINS
Basic polypeptides,the polymyxins (colistin and polymyxin B) are bactericidal for certain gramnegative aerobic rods, including Pseudomonas.Systemic use of these agents has been limited
bypoor distribution into tissues, substantial toxicity (nephrotoxicity and neurotoxicity),
It is used in infections caused by multidrug-resistant gram-negative organisms that are sensitive
only to the polymyxins.
Colistin has been used with succes in the treatment of pan-resistant Acinetobacter baumanii and
P aeruginosa.
Dosage adjustments are required with decreased renal function.
ANTITUBERCULOUS DRUGS
Mycobacterium spp are intracellular, have long periods of metabolic inactivity, and tend to
develop resistance to any one drug. Therefore, combined drug therapy is used to delay the
emergence of this resistance. First-line drugs, increasingly used together in all tuberculosis, are
isoniazid,
ethambutol,
rifampin,
pyrazinamide.
Alternative drugs in tuberculosis treatment
In cases of drug resistance (clinical or laboratory) to first-line drugs we can use:
Capreomycin- injectable agent given intramuscularly
Clofazimine - active in vitro against M avium complex and Mycobacterium tuberculosis, given
orally
Cycloserine,a bacteriostatic agent, orally
Ethionamide, like cycloserine, is bacteriostatic and is given orally
The fluoroquinolonesofloxacin, levofloxacin, ciprofloxacin, and moxifloxacinare active in vitro
against M tuberculosis, they have been demonstrated to be efficacious in treating tuberculosis in
patients unable to take isoniazid, rifampin, and pyrazinamide.
Linezolid is effective in achieving culture conversion in patients with treatment-refractory,
highly resistant pulmonary tuberculosis.
RIFAMYCINS
Rifampinused as a primary antituberculous agent, is used as an adjunct in the treatment of S
aureus infections.Is associated with rapid emergence of resistance when is used as monotherapy.
When is used in combinationwith primary antistaphylococcal agents, rifampin improves
outcomes in the treatment of infected prosthetic hardware.
Rifaximin, is a derivative of rifamycin, is nonabsorbable, reaches very high levels in the stool. It
27
is approved for use in nonpregnant women and for persons aged 12 years and older to treat
Rifapentine, a long-acting rifamycin, in combination with isoniazid, can be administered onceweekly for 12 weeks in the treatment of latent tuberculosis.
Table . Antimicrobial spectrum and indications of rifaximin
Antimicrobial activity
Clinical uses
aerobic and anaerobic gram-positive and noninvasive traveler's diarrhea (200 mg three
gram-negative organisms.
times daily for 3 days)
- prophylaxis of traveler's diarrhea (200 mg/d)
-recurrent disease with C difficile
-irritable bowel syndrome in certain patients.
-therapy of hepatic encephalopathy (400 mg
twice daily).
SULFONAMIDES
Antimicrobial activity
Sulfonamides are structural analogs of p-aminobenzoic acid (PABA) and compete with PABA to
block its conversion to dihydrofolic acid. Organisms that utilize PABA in the synthesis of folates
and pyrimidines are inhibited. Sulfonamides alone are rarely used in the treatment of bacterial
infection. In combination with other drugs, are useful in the treatment of toxoplasmosis and
pneumocystosis.
Trimethoprim and pyrimethamineare compounds that inhibit the conversion of dihydrofolic acid
to tetrahydrofolic acid by blocking the enzymedihydrofolate reductase.
Table . Antimicrobial spectrum of sulfonamides
DRUG
ANTIMICROBIAL ACTIVITY
SULFADIAZINE
SULFISOXAZOLE
SULFAMETOXAZOLE
SULFADOXINE
These two agents are generally used in combination with other drugs (usually sulfonamides) to
prevent or treat a number of bacterial and parasitic infections.
Table . Antimicrobial spectrum oftrimethoprim(one part) plus sulfamethoxazole (five parts)
ANTIMICROBIAL ACTIVITY
Clinical uses
Providencia, S maltophilia, B
cepacia(formerly
Pseudomonas
cepacia),
and
Burkholderia
pseudomallei, Nocardi S aureus
(including methicillin-resistant S
aureus) and about 50% of S
epidermidis isolates, M catarrhalis, H
influenzae,
H
ducreyi,
L
monocytogenes.
Clinical uses
Clinical uses
Vaginitis
caused
anaerobic gram-negative bacilli Anaerobic infections, active against virtually allB fragilis
(Bacteroides,
Prevotella, isolates.
Fusobacterium),
C difficilecolitis, is less expensive and equally as
Clostridium
efficacious as oral vancomycin
Brain abscess, in combination with penicillin or a thirdgeneration cephalosporin.
H pyloriinfections in combination with clarithromycin plus
omeprazole
After oral administration is well absorbed and is widely distributed in tissues. It penetrates well
into the cerebrospinal fluid, yielding levels similar to those in serum. The drug is metabolized in
the liver, and dosage reduction is required in severe hepatic insufficiency or biliary dysfunction.
Tinidazoleis identical in spectrum of activity to metronidazole.
GLYCOPEPTIDES
VANCOMYCIN AND TEICOPLANIN
Bactericidal for most gram-positive organisms, particularly staphylococci and streptococci;
bacteriostatic for most enterococci (vancomycin-resistant strains of enterococci, particularly E
faecium have emerged)
VANCOMYCIN
30
Vancomycin is not absorbed from the gastrointestinal tract and thus useful orally only for the
treatment of antibiotic-associated enterocolitis. For systemic effect, the drug must be
administered intravenously (30 mg/kg/d in two or three divided doses).
The excretion is via the kidneys. In end-stage kidney disease, the half-life may extend to 8 days.
Indications for parenteral vancomycininclude the following:
1 Severe staphylococcal infections in penicillin-allergic patients; for methicillin-resistant S
aureus and S epidermidisinfections and for serious infections (pneumonia, meningitis) due to
resistant S pneumoniae.
2 Severe enterococcal infections in the penicillin-allergic patient or if the enterococcus is
penicillin-resistant.
3 Other gram-positive infections in penicillin-allergic patients, eg, viridans streptococcal
endocarditis.
4 Surgical prophylaxis in penicillin-allergic patients.
5 For gram-positive infections due to organisms that
Corynebacterium jeikeium.
primary toxicity. Other adverse effects include neuropathy and mitochondrial toxicity with longterm use.
Table . Antimicrobial spectrum and indications of linezolid
Antimicrobial activity
Clinical uses
Community
pneumonia
Skin infections
and
hospital-
acquired
DAPTOMYCIN
Daptomycinis a bactericidal lipopeptide with a spectrum of activity similar to that of linezolidor
quinupristin-dalfopristin.
Table . Antimicrobial spectrum and indications of daptomycin
Antimicrobial activity
Clinical uses
methicillin-resistant staphylococci
vancomycin-resistant enterococci;
treatment of bacteremia
right-sided endocarditis
OF MICROBIOLOGIC CLASSIFICATION
Enterobacteriaceae
Nalidixic acid
32
Flumequine
Oxolinique acid
Piromedique acid
Pipemidique acid
Cinoxacine
Group II. Large spectrum
Pefloxacin
Neisseria spp.
Enoxacin
Norfloxacin
intracellular pathogens
Ciprofloxacin
Mycoplasma spp
Fleroxacin
P. aeruginosa
Lomefloxacin
Acinetobacter spp.
Ofloxacin
Vibrio cholera
M. tuberculosis
M. leprae
Temafloxacin
Tosufloxacin
S. pneumonia
Moxifloxacin
Streptococcus spp
Grepafloxacin
+/-
Clinafloxacin
Anaerobes
Gemifloxacin
Trovafloxacin
Levofloxacin
Gatifloxacin
Sitafloxacin
The synthetic analogs of nalidixic acid are the quinolones, with a broad spectrum of activity by
inhibition of bacterial DNA synthesis as result of blocking the enzymeDNA gyrase.
The earlier quinolones nalidixic acid, oxolinic acid, cinoxacin,were used only as urinary antiseptics.
The fluoroquinolonederivatives (ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin) have
more potent antibacterial activity, achieve clinically useful levels in blood and tissues, and have low
toxicity.
Table . Antimicrobial spectrum and indications of fluoroquinolones
33
Antimicrobial activity
Clinical uses
Haemophilus,Neisseria,
Brucella,
Moraxella, -sexually
transmitted
diseases
C
trachomatiscervicitis, urethritis, and proctitisShigella, ofloxacin.
Legionella,
Salmonella,
Campylobacter, Yersinia, Vibrio,Aeromonas -nongonococcal
urealyticum.
E coli but resistant strains emerged
P aeruginosalevofloxacin
only
urethritis
caused
by
2. M tuberculosis moxifloxacin,
M fortuitum,Mycobacterium kansasii.
infections
in
from
the
the
"respiratory
fluoroquinolones"are
gemifloxacin, levofloxacin, and moxifloxacin
are reserved forr the treatment of refractory
infections or high-risk patients, including those
with comorbidities or with recent receipt of
beta-lactam antibacterials.
Antimicrobial activity
Clinical uses
Nitrofurantoin
gram-positive
urinary therapy or prophylaxis of
pathogens E faecalis and cystitis in patients with
Staphylococcus
normal kidney function
saprophyticus,
gram-negative
urinary
pathogens E coli,Citrobacter
Fosfomycin
Antifungal activity
Clincal uses
Lipid-based amphotericin B
Aspergillus,
Histoplasma,
Cryptococcus,
-cryptococcal
meningitiscombined treatment with
flucytosine
Coccidioides,
Candida,
-systemic candidiasis.
Blastomyces,
Sporothrix
Nystatin
wide spectrum
oral candidiasis
Infections of skin
Flucytosine
Candida,
candiduria
Cryptococcus
Natamycin
Terbinafine
Candida, Aspergillus
Clotrimazole,
cutaneous
candida
Fluconazole
surgical
-cryptococcal meningitis in
patients with HIV/AIDS
-coccidioidal meningitis
-cutaneous leishmaniasis due
to Leishmania major
is
effective
prophylaxis
against
superficial
and
invasive fungal infections in
36
liver
Itraconazole
Histoplasma
capsulatum,
Blastomyces
dermatitidis,
Cryptococcus
neoformans,
Sporotrichum schenkii, and
various
dermatophytes
Aspergillus species
Voriconazol
Candida
and
molds, documented and suspected
Aspergillus,
Fusarium, fungal infections in febrile
Pseudallescheria,and others
neutropenic patients,
sporotrichosis, dermatophytic
infections (including those of
the nails, onychomycosis),
and oral and esophageal
candidiasis.
nonmeningeal
coccidioidomycosis,
and
skeletal disease.
disseminated aspergillosis
drug of choice in Fusarium
and Scedosporiuminfections
Ketoconazol
Posaconazol
Candida
and
molds, prophylaxis of neutropenia
Aspergillus,
Fusarium,
Pseudallescheria
plus
zygomycete
Echinocandins
Candida,
including drugs of choice in the
nonalbicans
species, treatment of infections due to
Aspergillus species.
C glabrata and C krusei.
candidemia
candidiasis
and
invasive
Natamycin
Natamycinis a polyene antifungal drug effective against many different fungi in vitro. The
toxicity after topical application appears to be low.
Terbinafine
Terbinafine, an allylamine, inhibits fungal cell membrane function by blocking ergosterol
synthesis.Most adverse effects are minor (diarrhea, dyspepsia) or transient (taste disturbance).
Rare cases of severe hepatic injury have occurred.
Antifungal Imidazoles and Triazoles
These antifungal drugs (Clotrimazole,Fluconazole, inhibit synthesis of ergosterol, resulting in
inhibition of membrane-associated enzymeactivity, cell wall growth, and replication.
Fluconazole, a bis-triazole with activity similar to that of ketoconazole, is water-soluble and can
be given both orally and intravenously. It penetrates well into the cerebrospinal fluid and eye.
Fluconazole is well absorbed after oral administration (> 90% bioavailability), and serum levels
approach those seen after administering the same dose intravenously. While generally well
tolerated, fluconazole is associated with dose-dependent nausea and vomiting. Altered liver
function tests (alanine aminotransferase, aspartate aminotransferase ) and hepatitis have been
reported.
Itraconazoleis an oral triazole with variable bioavailability. The drug is metabolized by the
liver, and no dosage adjustment is needed in kidney disease.
Adverse effects are; anorexia, nausea, vomiting, and abdominal pain occurring most commonly.
Skin rash has been reported in up to 8% of patients. Hepatitis and hypokalemia occur
uncommonly.
Voriconazoleis a triazole antifungal, oral administration leads to predictable absorption.
The primary toxicity associated with voriconazole is infusion-related, transient visual
disturbances, particularly during the first week of therapy. In addition, voriconazole is associated
with photosensitivity reactions.
Posaconazoleis an antifungal derivative of itraconazole. Posaconazole is superior to
fluconazoleas prophylaxis of neutropenia. The drug is only available as an oral formulation,.
Posaconazole should always be administered with food to ensure adequate oral bioavailability;
the drug is primarily eliminated via nonrenal mechanisms. Posaconazole has primarily upper
gastrointestinal adverse events and occasional liver function test abnormalities. posaconazole is
an inhibitor of cytochrome P450.
Ketoconazole, the first orally bioavailable azole, previously was used in the treatment of a
variety of fungal infections. However, the improved spectrum of activity, reduced toxicity, and
superior pharmacokinetics of newer azoles have reduced ketoconazole to a secondary role.
Echinocandins
The echinocandins (anidulafungin, caspofungin, micafungin) act by inhibiting fungal cell wall
synthesis.Their long pharmacologic half-life confers the advantage of once-daily dosing. No
change in dose is necessary in patients with kidney disease; however, moderate to severe hepatic
disease necessitates a reduction in dosage for caspofungin.
ANTIVIRAL CHEMOTHERAPY
The Antiviral Agents start to develop in the last few years, still we have not so much experience
with them like with antibacterial drugs.
38
Rout
of Active against
administration
Clinical uses
Amantadine
oral
influenza A virus
prophylaxis
and
therapy of influenza A
infection
Rimantadine
oral
influenza A virus
prophylaxis
and
therapy of influenza A
infection
aerosol
influenza A and B
prophilactic
treatment
susceptibile
infections
Adamantanes
Neuraminidase inhibitors
Zanamivir
influenza A H1N1
parenteral
Oseltamivir
oral
Peramivir
Parenteral
aerosol
Respiratory
virus (RSV)
availableinvestigationally
Ribavirin
and
of
virus
prophilactic
treatment
susceptibile
infections
and
of
virus
virus
Influenza
A,
B
infection
older
children, adults severe
39
acute
respiratory
syndrome
oral or I.V
Lassa virus
Lassa fever
I.V
Hantaan virus
Hemorhhagic fever
Neuraminidase inhibitors
Zanamivir inhalers are difficult to use for some patients, especially those with asthma and
chronic obstructive pulmonary disease, in whom bronchospasm has been reported. Both drugs
are administered twice daily (oseltamavir, 75 mg orally; zanamivir 10 mg inhalation)
Gastrointestinal adverse events are the most commonly observed side effects with oseltamivir. In
addition, while cause and effect are not well-established, neuropsychiatric disorders, including
suicidal ideation, have been associated with oseltamivir.
Antivirals against herpesviruses
Table spectrum of activity, route of administration, indications of antivirals against
herpesviruses
Drug
Route
of Activ against
administration
Clinical uses
Acyclovir
oral
herpes simplex
intravenous
mucocutaneous herpes
simplex, varicella,
Citomegalovirus
herpes zoster
herpes encephalitis
prophylaxis
against
recurrent
mucocutaneous
and
visceral herpes viruses
infections in transplant
recipients
herpes simplex
topical
Famciclovir
Valacyclovir
Foscarnet
oral
oral
intravenous
herpes simplex,
mucocutaneous
orallesions
varicella
herpes simplex,
herpes zoster
varicella
CMV
prevention of CMV
infection
in
transplanted patient
CMV, herpes
varicella-zoster,
40
HHV6,
ganciclovir- HHV6
resistant CMV
immunossupressed
acyclovir-resistant herpes patients
in
simplex varicella-zoster
Cidofovir
intravenous
Ganciclovir
intravenous
CMV
CMV
retinitis,
esophagogastrointestinal
infections,
hepatitis,
pneumonitis, wasting
illness
in
imunosupressed
patients
prophilaxis of CMV
disease in transplant
recipients
Acyclovir
The absolute oral bioavailability of acycloviris 1030%. Dosage reduction in kidney disease is
required. Since hemodialysis reduces serum levels significantly, the daily dose should be given
after hemodialysis.Acycloviris relatively nontoxic. Resistance has been described, usually in
immunosuppressed patients who have received multiple courses of therapy.
Valacyclovir
Valacyclovir is a prodrug of acyclovirthat has significantly increased oral bioavailability when
compared with acyclovir. After absorption, it is converted to acyclovir and serum levels are three
to five times higher than those achieved with acyclovir.
Foscarnet
Foscarnetis a pyrophosphate analog that inhibits viral DNA polymerase of human
herpesviruses, and the reverse transcriptase of HIV. The drug is much less well tolerated than
acyclovir and ganciclovirand more difficult to administer. Dose adjustments are required for
even minimal impairment in kidney function.Foscarnetcan cause severe phlebitis, hypocalcemia
peripheral neuropathy, seizures and arrhythmias, hypomagnesemia, and hypophosphatemia,
nausea and vomiting
41
Cidofovir
The drug has a prolonged pharmacokinetic intracellular half-life, allowing for administration
every 12 weeks. Cidofovir is associated with a high incidence of nephrotoxicity, sometimes
severe Ocular toxicity, including uveitis and iritis.
Ganciclovir
This is an analog of acyclovirwith similar antiviral activity, including activity against CMV. The
major adverse effect is neutropenia, which is reversible but may require the concomitant use of
colony stimulating factors. Thrombocytopenia, nausea, rash, and phlebitis occur less commonly.
Antiviral drugs active against hepatitis viruses
Tabel Nr Antiviral drugs active against hepatitis viruses, spectrum route of
action,indications
Drug
Route
administration
Lamivudine(3TC)
oral
of Active against
Clinical uses
hepatitis B virus
HIV infection
HIV
Chronic
infection
HBV
prevention
HBV
associated with liver
transplantation
Adefovir
oral
hepatitis B virus
lamivudine-resistant
HBV
Chronic
infection
HBV
HIV
Herpes simplex
CMV
Tenofovir
oral
HBV, HIV
Entecavir
oral
Telbivudine
oral
Boceprevir
oral
HCV genotype 1
42
HIV-HBV
coinfection
only in combination
with peginterferon or
oral
ribavirin,
Chronic C genotype 1
hepatitis
Telaprevir
oral
HCV genotype 1
Human interferons
only in combination
with peginterferon or
oral
ribavirin,
Chronic C genotype 1
hepatitis
therapy of chronic
hepatitis
due
to
hepatitis B, C, and D
Lamivudine.
While lamivudine is useful, development of resistance is common with long-term therapy.
Adefovir
high doses have been associated with substantial nephrotoxicity, this complication is rare with
the lower doses (10 mg/d) used to treat hepatitis B.
Tenofovir
The antiretroviral is at least as effective as adefovir and is particularly useful in the treatment of
HIV- and hepatitis Bcoinfected patients.
Similar to adefovir, the primary toxicity associated with tenofovir is nephrotoxicity.
Entecavir
Adverse events are similar to those of other hepatitis B agents and include severe, acute
exacerbation of hepatitis B after discontinuation as well as headache, abdominal pain, diarrhea,
fatigue, and dizziness.
Telbivudine
The most recently approved agent, telbivudine is administered once daily,patients with moderate
or severe kidney disease require dosage adjustment. The adverse effect profile is comparable to
that observed with other nucleoside analogs.
Boceprevir andTelaprevir
The serine protease inhibitors boceprevir and telaprevirrepresent a remarkable advancement in
the treatment of hepatitis C. They are associated with substantial toxicity and adverse events,
drug interactions. Approximately half of patients receiving boceprevir experience anemia,
necessitating erythropoietinadministration. In addition to anemia, dysgeusia, neutropenia, and
thrombocytopenia are common with the use of boceprevir.
Telaprevir is associated with substantial pruritus and other rash, observed in over 50% of
patients.
Human interferons
These agents have antiviral, antitumor, and immunoregulatory properties.
Adverse effects are common and include bone marrow suppression,an influenza-like illness with
fever, chills, nausea, vomiting, headache, arthralgia, myalgias.Considering the poor tolerability
of interferon, only a minority of patients infected with hepatitis C are actually candidates for
therapy.
43
CHAPTER 2
Scarlet fever
Anca Georgescu
Scarlet fever is an acute infectious, endemic-epidemic disease, caused by the infection with
group A beta-hemolytic streptococcus (GABHS), clinically manifested by fever, enanthema and
characteristic exanthem, followed by desquamation.
Etiology
GABHS known as Streptococcus pyogenes due to the potential to cause suppurative
infections, is the only representative of the group A streptococci, according to Lancefields
classification. It is a sporulated, gram-positive cocci, arranged in piles or short chains, which on the
areas with blood, produces, around the colonies, complete hemolysis (beta).
The GABHS cells structure is complex, consisting of somatic components (capsule, cell
wall, cytoplasmic membrane, cytoplasm), expressing multiple antigens on its surface:
capsular antigens; the capsule is made up of hyaluronic acid, which opposes phagocytosis,
being a virulence factor; they are poorly antigenic, but have a role in pharyngeal colonization
cell wall antigens located in three layers:
- the inner layer, mucopeptidic (MP)
- the middle layer of polysaccharide nature protein C, according to which the streptococci in
19 Lancefield groups (AM) are classified
- the outer layer: contains the M protein, which confers type specificity, through its structural
variability (there are over 100 serotypes); it is the major virulence factor, through the
involvement in the process of bacterial attachment and the strong antiphagocytic effect, due to
binding to plasma fibrinogen
Both C and M proteins have structural and antigenic similarities to particular components of
human tissues (from the heart, synovial valves, kidney), having a crucial role in determining
the pathogenesis of post streptococcal diseases.
cytoplasmic proteins, with the role of cross-reactive antigens
On the other hand, GABHS produces and releases extracellular products, represented by
toxins and enzymes, with systemic toxic role and in the spread of infection. The most important
ones are: streptolysin O (strong antigen) and S, streptokinase (role in fibrinolysis) Spe-B cysteine
proteases (role in the production of toxic shock), hyaluronidase, DNase and pyrogenic exotoxins A,
B and C, which have a role in the destruction of cell membranes; they are highly immunogenic,
causing antitoxin antibodies and antitoxic immunity. In scarlet fever, the exotoxin (previously
known as erythrotoxin or erythrogenic toxin) is responsible for the rash..
Epidemiology
Scarlet fever is universally spread, but tends to predominate in areas with a temperate
climate, with predominant manifestation in the cold season. The source of infection is represented
by patients with scarlet fever or those with angina, or porting of GABHS.
The disease is commonly spread by airborne transmission, by direct contact or indirectly via
contaminated objects; in this case the gateway is the pharyngeal mucosa. The digestive transmission
is possible as well (through milk / milk contaminated with GABHS) and rarely the cutaneous one
through open, cutaneous or surgical wounds that serve as gateways ("the plague" scarlet fever).
44
The contagious effect of patients with scarlet takes 2-3 days in case of a correct treatment
with antibiotics; GABHS carriers retain this status for an indefinite period of time.
Responsiveness is general, but the disease prevails between children of 4-12 years old and
very rarely occurs in infants and elderly.
Immunity after scarlet fever is solid and lasting, conferred by eritrogen antitoxin antibodies,
so that reinfection with scarlet fever are extremely rare, produced by secretory serotypes of other
exotoxin type. However, reinfections with GABHS can be common, but with other types, the
antimicrobial immunity being serotype specific.
Pathogenesis
GABHS limits itself to the entrance gate - pharyngeal, rarely cutaneous or puerperal, where
after attachment multiplies and releases the toxins and enzymes mentioned above. Erythrogenic
exotoxin which is the one which broadcasts by blood, the streptococcus remaining stuck at the gate,
where produces inflammation with typical angina manifestation.
Exotoxin is responsible for specific manifestations of scarlet fever: exanthem followed by
desquamation, fever, digestive and neurological manifestations, which constitute the toxic
syndrome; hypertoxic forms of scarlet fever, with marked toxemia may lead to the installation of
the streptococcal toxic shock, being extremely serious, and s that can cause toxic complications by
damaging some of the organs (hepatitis, myocarditis, nephritis).
Septic syndrome of scarlet fever is caused by the streptococcal infection itself, GABHS
having the ability to spread in the neighboring tissues of the infectious outbreak, causing local
septic complications (adenitis, otitis, mastoiditis, sinusitis) or systemic ones (bacteremia,
septicemia), which are exceptional.
The immuno-allergic syndrome is the result of the occurence of cross-reactive antibodies
against streptococcal antigens at 14-21 days after the acute illness and can cause post-streptococcal
diseases. After the same period of time, the eritrogen antitoxin antibodies occur as well, which give
the specific antitoxic immunity against the scarlet fever.
Clinical picture
Incubation is from 1 to 10 days, on average 3-6 days.
The onset of the disease is typically sudden, even brutal, with 38-40 C fever, dysphagia,
headache, abdominal pain, vomiting; in severe forms agitation or delirium may occur when the
blood pressure lowers in hypertoxic forms.
Physical examination reveals pharyngotonsillar hyperemia, regional angulo-mandibular
lymphadenopathy (which persists), saburral tongue.
The pre eruptive period (the invasion period) is characterized by persistent changes from the
onset, in association with the pharyngeal enantema, consisting of angina and the changes that
constitute the lingual cycle.
Streptococcal angina during scarlet fever may have different aspects depending on the
enzyme equipment of GABHS:
erythematous angina, with an intense pharyngolaryngeal congestion being "red as a flame"
extended at the level of the tonsils, tonsillar pillars, lueta and the soft palate, where is suddenly
demarcated by the hard palate
erythematous pultaceous angina characterized by marked edema and erythema of the
tonsils, which have in their crypt a white-gray exudate
45
pseudomembranous angina the white-gray purulent deposits from the crypts confluents,
forming false membranes on the surface of the tonsils
necrotizing ulcerative Henoch angina, in which the affected area is the same with the
erythematous forms, but ulcers caused by tissue necrosis are present, these may be complicated by
local bleeding by the perforation of the blood vessela, which favors possible systemic
hematogenous disseminations; the general condition is profoundly affected, intensely fetid halitosis
is present; this severe form of angina is caused by strains of streptococci with increased virulence
gangrenous angina, determined by coinfection with anaerobes, most commonly by the
complication of the ulcerative necrotic forms; in these two severe forms, regional adenopathy is
important, intensely painful, extending laterocervical and submandibular; the prognosis is
unfavorable.
The lingual mucosa suffers a characteristic transformation, causing a lingual cycle of scarlet
fever, which is important for the diagnosis by the dynamic changes: on day 1, the tongue is white,
saburral; in days 2-3 desquamation starts from the top and sides of the tongue progressing to its
base, suggesting a lingual "V"; on days 4-5, the desquamated tongue has the pathognomonic aspect
of a "raspberry" due to lingual papillae which became prominent; subsequently the re-epithelization
gives the tongue the aspect of a lacquered, glossy mucosa - "cat tongue" that gradually fades until
days 10-12, when it normalizes.
The state period starts at 24-48 hours from the onset, with the advent of scarlet exanthema,
initially on the chest, extending in 24 hours on the trunk and limbs, where is proximally more
expressed; it respects the face, palms and plants. The exanthema consists of a diffuse erythema
with congestive micropapule giving the feeling of a rough skin at touch.
The facies has a characteristic aspect, slapped, with a contrasting perioral pallor with
flushing cheeks, called Filatovs mask.
At the level of the bending folds (axillary, inguinal, abdominal folds), haemorrhagic lines
are distinguished as a result of the microbleeds due to capillary fragility by the action of the
erythrotoxin, at mechanical stress places called Pastia-Grozovicis lines.
During the state period, fever and symptoms from the onset period are maintained, which
may be associated, in the absence of antibacterial therapy, to cardio-circulatory (tachycardia,
hypotension), hepatic (jaundice, hepatomegaly), renal (focal nephritis) , neuropsychological
(meningism, agitation, delirium) manifestations with a toxic mechanism.
The descuamation period occurs 1-2 weeks after onset and can last 2-3 weeks. The aspect
and intensity of the descuamation are significantly influenced by the early instituted antibiotic
treatment: squama, classic in glove flaps or fingers at the level of the extremities and furfuracea
aspect on the face and torso, are very discreet after proper therapy.
Clinical forms
depending on the severity of the disease
average, common shape - corresponds to the one described
benign forms: abortive, oligosymptomatic, forms without rash
severe, malignant forms:
- toxic form: hyperpyrexia, cyanotic or hemorrhagic exanthema, hypotension, tachycardia,
circulatory failure, oligo-anuria, shock, possibly fatal evolution
- septic form: necrotizing ulcerative angina, painful cervical adenitis, adenophlegmons,
septicemia
- toxico-septic form
depending on the aspect of the rash
miliary scarlet fever: rash covered by microvesicles
46
Treatment
Hygienic-dietary treatment
Patients with scarlet fever are hospitalized and they stay in bed for 7 days; the diet is hydro
lacto mellitus all through the febrile period.
Etiologic treatment
The preferred antibiotic is Penicillin G, in doses of 50,000 IU / kg in children and 2-6 million
IU / day in adult, for 7 days. Alternatively, Penicillin V can be used, in double doses prior to the
anterior ones, with an every 6 hours administration. In the case of an allergy to Penicillin,
generation I or II cephalosporins are recommended for 7 days, or macrolides (erythromycin,
clarithromycin, azithromycin) or clindamycin for 10 days. In ulceronecrotic and gangrenous forms,
the antibiotic spectrum will be broadened in order to cover the anaerobic flora (Clindamycin or
association with Metronidazole).
Pathogenetic treatment
In common forms NSAIDs are recommended (Ibuprofen) in the first 3-5 days after onset.
Severe, toxic forms requiring emergency administration of steroids (hydrocortisone hemisuccinate
47
48
Erysipelas
Anca Georgescu
Erysipelas is a particular form of infectious acute dermita caused by group A betahemolytic streptococci (all GABHS serotypes - the same species that produce scarlet fever),
characterized by the presence of a plaque with a tendency to expand in a febrile state.
Epidemiology
Erysipelas occurs sporadically, being spread across the globe, but its incidence is higher in
the cold and temperate areas and in winter, as well as other forms of streptococcal infections. It
commonly affects older people, adults and males.
The source of infection is represented by patients with streptococcal infections (scarlet
fever, angina, sinusitis, pyoderma, impetigo) and GABHS carriers. Sometimes the patient may
be the source of infection (endogenous infection).
The transmission of the disease occurs directly (direct contact or by airborne transmission)
or indirectly through contaminated objects.
Infectiousness is reduced. The disease is not followed by the installation of immunity, but
rather, by a tendency to relapse at the same location, through a hypersensitivity effect of the
tissue to streptococcal C polysaccharide but as well because of the particular place the infection
occurs on.
Pathogenesis
The gateway is represented by continuity solutions at the tegumentary level (abrasions,
wounds, varicose ulcers, de-epithelization, interdigital mycosis, insect bites) or at the mucosal
level (dacryocystitis, rhinitis), where, by contiguity, GABHS spreads to the adjacent tegument.
Characteristic to streptococci is multiplication and spreading via the intradermal lymphatic
vessels, that become the premises of the inflammatory process by the presence of cellular
infiltration and vasodilatation, which are associated with edema.
The propagation of infection is centrifugal, in oil slick, so that the intensity of the
inflammatory phenomena in erysipelas is more pronounced at the periphery of the plaque where
there is an inflammatory burelet, compared to its center, which becomes pale.
The intensity of the edema determines particular clinical forms (bullosa, blister) by
cleavage of the epidermis to the dermis, respectively an array of cellulite by edematous
infiltration of the hypodermis.
Repeated episodes of erysipelas, maintained by the local sensitization phenomenon, will
gradually cause an irreversible impairment of the lymphatic microcirculation, which will lead to
a chronic lymphoedema as their sequel, and progressively to elephantiasis. On the other hand,
the lymphoedema itself is a predisposing factor to relapses, as well as the chronic venous stasis
in the varicose disease in case of post-thrombotic syndrome and venous circulatory failure.
Clinical picture
The incubation is 1-7 days.
49
The onset is extremely sudden, brutal, with fever preceded by chills, changing in the
general condition of the patient, sometimes vomiting, abdominal pain, headache. The only
change at the physical examination is the painful adenopathy, detectable in the area to be
interested in the onset of the plaque; if the adenopathy is deep, it may not be palpable but the
patient experiences local pain. In some cases the gateway to the proximity of this region may be
detectable or even obvious.
The state period is installed after a few hours, even 1-2 days after onset, together with the
occurence of the erysipelatous dermal inflammation: it is unique, well-defined, with a tendency
to rapid expansion,with clear edges where the inflammatory burelet is highlighted; it is
characterized by the presence of characteristic signs of acute inflammation: rubor, dolor, calor,
and it is accompanied by a degree of induration and edema. In the acute phase, the color of the
plaque is red; on the hairy skin of the head, it is white to gray and in cardiacs it is cyanotic or
purple. The plaque is warm but not painful, patients feel only a local tension. The pain occurs in
case of septic complications (abscess, phlegmon) and it is present in the location of erysipelas of
the scalp or auricle.
Painful regional adenopathy is present, taking into consideration the lymph nodes that
lymphatically drain the affected area.
Associated clinical signs are fever, digestive and nervous disorders (agitation, delirium,
headache), impaired renal function (proteinuria, oliguria, hematuria).
The evolution of the erysipelatous inflammation is of 10-14 days, according to the correct
antibiotic treatment, and may be extended in particular forms or on important lymphedema.
Relapses occur in 20-25% of patients, predisposing factors being the aforementioned local ones
(see Pathophysiology) but general as well: diabetes, obesity, cirrhosis.
Clinical Forms
Depending on the location:
Facial erysipelas: has the characteristic appearance of a butterfly, including
symmetrically the cheeks and the nasal pyramid. The edema is usually important, and
determines hypodermic infiltration (cellulitis) and evident frontal and eyelid edema
(palpebral fissure closed). The gateway is usually endogenous - an inflammatory process
of the skin or mucosa of the face
Lower limb erysipelas: is the most common, tends to recurrences by maintaining the local
predisposing factors
Post-partum or post-abortion perigenital erysipelas: severe forms
Erysipelas umbilicus of the newborn: potentially fatal
Upper limb erysipelas: occurs in mastectomized patients for breast cancer who develop
chronic upper limb lymphedema after axillary dissection; has a tendency to frequent
relapses
Depending on the aspect of the dermal plaque:
Blister and bullous erysipelas are forms caused by the marked edema; the break of the
blisters followed by the leaking of the content of a yellowish fluid or sero-citrine, which
dries and forms meliceric crusts
Gangrenous erysipela:: occurs in severe forms, by by necrosis of the overlying epidermis
of the placard
Migratory erysipelas: at least one placard from the initial one
Erratic erysipelas: some placards tangent to the lymphangitis route formed from the
gateway towards the inflammatory adenitis
Serpiginous erysipelas: with imprecise edges, wavy extensions
50
Diagnosis
Positive diagnosis concerning erysipelas is mainly clinical (dermal erythematous plaque
with described characters, important infectious syndrome), epidemiological data is missing or are
uncertain and the available laboratory data are often nonspecific: ESR, fibrinogen, CRP,
leukocytosis with granulocytosis; bacteriological examination is possible only in blister or
bullous clinical forms, respectively from throat or nasal swab in endogenous infections.
Differential diagnosis is made with: solar erythema, stasis dermatitis, contact dermatitis,
erythema migrans of Lyme borreliosis, erysipeloid of Rosenbach, acute varicophlebitis and
thrombophlebitis, herpes zoster, allergic exanthema, staphylococcus erysipelas (unique purple
plaque, cold, painful, imprecisely defined, with severe evolution, determined by the
compromised venous microcirculation by intravascular multiplication of staphylococci which
tend to form septic thrombi at this level).
In the erysipelas of the face the differentiation from the ophthalmic zoster, microbial
eczema, cavernous sinus thrombosis, malignant staphylococcal infection of the face (facial
cellulitis with marked edema, necrotic foci, pustules) is necessary to be made.
Complications
The incidence of complications is determined by the accuracy and timeliness of the
antibacterial therapy.
Septic complications
- Local:
a. Superficial: bacterial superinfection (with staphylococci, Gram-negative
bacilli), superficial necrosis, gangrene
b. Profound: abscesses, phlegmons, necrotizing fasciitis, suppurative
lymphadenitis
c. General: septicemia, nephritis
Local complications: lymphangitis, elephantiasis
Venous complications: phlebitis, thrombophlebitis
Immune-allergic complications: acute diffuse glomerulonephritis, rheumatic fever
(the same as after scarlet fever, but they rarely occur)
Treatment
In most cases it is recommended for the patient to be hospitalized, in particular in the
forms located in the lower limbs, which require bed rest throughout the duration of the disease or
in more serious / recurrent / complicated forms. Mild episodes and uncomplicated forms can be
cared for at home, with respecting the rules of hygiene.
Diet is unrestricted after overcoming the febrile period, limiting the intake of salt and
protein in case of renal disease.
Etiological treatment. Penicillin G is the antibiotic of choice in the dose of 4-8 MU / day
(80-100.000UI/kgc/zi) intravenously for 7-10-14 days. In some more severe forms, possibly
complicated ones, the therapeutic response is best on the second and third generation ofd
cephalosporins. In forms that are treated at home, macrolides,clindamycin, aminopenicillin with
beta-lactamase inhibitors (Augmentin) are indicated. In case of bacterial superinfections, the
associate of a quinolone or a aminoglycoside to the therapy with penicillin may be necessary (for
infections with Gram-negative staphylococcus) and metronidazole for the superinfections bz
anaerobes (or monotherapy with clindamycin).
51
Pathogenetic treatment. In common forms NSAIDs are recommended while in the severe
ones, with marked edema, glucocorticoids will be recommended (hydrocortisone hemisuccinate
3-4 mg / kg / day) for 3-5 days.
Symptomatic treatment, painkiller
- Therapy:
- Locally- with weak antiseptic solutions (Rivanol10%)
- Treatment of the entrance gate (varicose ulcer, interdigital mycosis, rhinitis)
- Surgical treatment of deep septic complications
- Prophylaxis of deep venous thrombosis with low molecular weight,with heparin
52
MEASLES
Cristina Grbovan
DEFINITION
Measles is a highly contagious acute, exanthematous respiratory disease with a characteristic
clinical picture and a pathognomonic enanthem : Koplik, s spots, an eruption on the buccal
mucous membranes.
ETIOLOGIC AGENT
Measles virus is the only member of the genus Morbilivirus, part of the family
Paramyxoviridae. On electron microscopy, measles virions are pleomorphic spheres with usual
diameters ranging from 120 to 250 nm. Virions consist of two structures , an inner nucleocapsid
that is a coiled helix of protein and RNA that has a diameter of 17 nm, and an envelope, 10-12
nm thick.
EPIDEMIOLOGY
Measles is seen in every country in the world. Countries in which measles vaccine is widely used
have experienced a marked decrease in the incidence of disease. The introduction and use of
measles vaccine has also changed the age group in which measles occurs. Before use of the
vaccine the incidence of measles in the United States was highest in young children, and the
disease was uncommon in adolescents and rare in adults. After the vaccine was introduction and
clinical cases of measles became less common, unvaccinated children had a greater opportunity
to reach adolescence and young adulthood without an exposure to measles. When a large group
of susceptibles is congregated , as in a college, a miniepidemic of measles may occur.
PATHOGENESIS
Measles virus infects by invasions of the respiratory epithelium, and spreads via the bloodstream
to the reticuloendothelial system , from which it infects white blood cells, thereby establishing
infection of the skin, respiratory tract and other organs. Multinucleated gigant cells with
inclusion bodies in the nucleus and cytoplasm (Warthin-Finkeldey cells) are found in respiratory
and lymphoid tissues and are pathognomonic for measles. After infection, initial replication
occurs in the respiratory epithelium with local spread by lymphatics and a primary viremia 2-3
days after infection. A secondary viremia occurs 3-4 days later and lasts for up to 7 days. The
peak viremia coincides with the prodromal symptoms. The rash results from the immunologic
reaction between the virus antigens and host antibody, with involvement of capillary walls.
IMMUNITY
Immunity to measles following an attack of the disease appears to be lifelong. Following
measles vaccine, immunity is similarly of many years duration and probably lifelong.
CLINICAL MANIFESTATIONS
The incubation period of measles is 10-14 days; it is often somewhat longer in adults that in
children. A prodromal phase lasting several days begins after the incubation period and it is
manifested by :
Malaise
Increasing Fever
Anorexia
Conjunctivitis
53
Nasal discharge
usually begins on the face and proceeds down the body involving the
extremities , including palms and soles last.
Usually lasts about 5 days and starts to clear on the skin that was first
involved
The patients with measles is usually most ill during the first or second day of the rash.Several
days after the appearance of the rash the fever abates, and the patient begins to feel better. The
entire uncomplicated illness from late prodrome to resolution of fever and rash lasts 7-10 days;
cough may be the last symptom to disappear.
COMPLICATIONS
The complications of measles can be divided into three groups (according to the site involved):
1) The respiratory tract
2) The central nervous system (CNS)
3) The gastrointestinal tract
1) Respiratory tract involvement, manifested as :
-
Laryngitis
Croup
Otitis media
Pneumonia
2) Neurologic complications :
-
Convulsions
Encephalitis
diarrhea
DIAGNOSIS
54
Classic measles with cough, coryza, conjunctivitis, Koplik spots, and a maculopapular rash
beginning on the face is easily diagnosed clinically. Laboratory diagnosis of measles is helpful
when the clinician is unfamiliar with the illness due to the decline in cases of clinical measles
since introduction of measles vaccine.
Laboratory findings- lymphopenia and neutropenia are common in measles . Leukocytosis may
herald a bacterial suprainfection.
A specific diagnosis of measles can be made quickly by immunofluorescent staining of a smear
of respiratoy secretions for measles antigen . Measles virus can be demonstrated by culture or
polymerase chain reaction in respiratory secretions or urine. A serologic diagnosis by enzyme
immunoassay (EIA) cannot necessarily be made rapidly if acute and convalescentsphase serum
specimens are examined.
DIFFERENTIAL DIAGNOSIS
Includes:
Kawasaki disease
Scarlet fever
Infectious mononucleosis
Toxoplasmosis
Drug eruption
PREVENTION
The vaccine was used in the United States since 1963 and induces seroconversion in 95% of
recipients and probably confers lifelong protection. For the past three decades measles vaccine
has been available as the combination vaccine measles mumps-rubella (MMR). This vaccine
should be administered to children at 12-15 months of age. A second dose of MMR vaccine is
recommended for school age children. Approximately 10% of healthy vaccines develop a fever,
with temperature up to 39,4 C, 5-7 days after vaccination; this fever lasts 1-5 days and is
accompanied by a transient rash.
Measles vaccine is contraindicated :
TREATMENT
Therapy for measles is largely supportive and symptom based.
Patients with otitis media and pneumonia should be given standard antibiotics.
Patients with encephalitis need supportive care, including observation for increased intracranial
pressure.
55
RUBELLA
Cristina Grbovan
Rubella virus was first isolated in 1962 by Parkman, Beuscher, and Artenstein and by Weller
and Neva. Rubella virus is now classified in the Togaviridae family, based on its RNA
genome., icosahedral capsid, and lipoprotein envelope.
On electron microscopy rubella virus is roughly spherical. Its envelope, which has short surface
projections, has a diameter of about 60 nm. Inside is the nucleocapsid that has a diameter of
about 30 nm.
The rubella virus is relatively unstable and is inactivated by lipid solvents, trypsin, formalin,
ultraviolet light
EPIDEMIOLOGY
Rubella was not distinguished from certain other exanthematous infections clinically until the
late nineteenth century. Since postnatal rubella is such a mild illness, the disease was considered
to be of only minor importance for many years. However, in 1941 when Gregg recognized the
link between maternal rubella and certain congenital defects, a more complete picture of
ddisease due to rubella virus began to emerge.
The incidence of clinical cases of rubella is highest in the spring, and it has been traditionally
recognized to be most common in children 5 to 9 years.
Rubella is only a moderate contagious illness in contrast to measles.
Spread of Rubella
Rubella virus is spread in droplets that are shed from the respiratory secretions of infected
persons. Patients are most contagious when the rash is erupting, but they may shed virus from
the throat from 10 days before onset of the rash to 15 days after onset.
Patients with subclinical cases of illness may also transmit the infection to others.
Infants with congenital rubella shed large quantities of virus from body secretions for many
months. The babies continue to excrete rubella virus despite high titers of neutralizing antibody,
a puzzling phenomenon that has yet to be explained.
Persons who have received rubella vaccine do not transmit rubella to others, although the virus
may be isolated from the pharynx.
PATHOGENESIS
The incubation period of rubella ranges from 12 to 23 days, with an average of 18 days. Rubella
virus has been detected in leukocytes of patients as long as 1 week before the onset of symptoms
CLINICAL MANIFESTATIONS
Age is the most important determinant of severity of rubella. Postnatally acquired rubella is
generally an innocuous infection, and as is true for many virl illnesses, children are apt to have
milder disease than adults. In contrast, the fetus is at high risk to develop severe rubella with
long- lasting sequelae, if infected transplacentally during maternal rubella in early pregnancy.
POSTNATAL RUBELLA
Many if not cases of these infections are subclinical.
56
Of those patients who are symptomatic, children do not experience a prodromal phase, but adults
may have a prodrome of malaise, fever, and anorexia for several days. The major symptoms of
postnatal rubella are adenopathy, which may last several weeks, and rash.
The lymph nodes involved include:
Posterior cervical
Suboccipital chains
During the first 2 months of gestation the fetus has a 40 to 60 percent chance of
being affected, with an outcome of either multiple congenital defects and/or
spontaneous abortion.
During the third month of fetal life has been associated with a 30 to 35 percent
chance of developing a single defect such as deafness or congenital heart disease.
Fetal infection during the fourth months carries a 10 percent risk of a single
congenital defect.
Thrombocytopenic purpura
Hepatosplenomegaly
Bone lesions
Large anterior fontanelle
Meningoencephalitis
Generalized lymphadenopathy
Hemolytic anemia
The most common manifestations are deafness:
Cataract or glaucoma
Retinopathy
Patent ductus arterious
Pulmonary stenosis
Behavior disorders
Mental retardation
Microcephaly
Spastic diplegia
DIAGNOSIS
Since rubella is usually a mild disease with nonspecific symptoms, it is often difficult to
diagnose rubella clinically.
Routine laboratory studies are not helpful for diagnosis since the may reveal only a leukopenia
and atypical lymphocytes.
The laboratory diagnosis of rubella is most often made serologically. Hemagglutination
inhibition (HAI) is the most commonly used technique. It is sensitive and simple to perform, so
it is useful for determining whether a person is susceptible or immune to rubella. However ,
because this antibody is detected in high titer very soon after onset of rubella, the HAI test is not
always useful for diagnosis of acte rubella.
Antibody to rubella virus may also be measured by complement fixation (CF), a reliable but
less sensitive technique than HAI. Rubella antibody titers are not detectable by CF until 4 to 8
weeks after onset, so this technique may be most useful when testing acute and convalescent
serum specimens.
DIFERENTIAL DIAGNOSIS
The disease has been confused with other infections such as
Scarlet fever
Mild measles
Infectious mononucleosis
Toxoplasmosis
Roseola
Erythema infectiosum
Enteroviral infections
58
TREATMENT
Since postnatal rubella is such a mild infection in most instances no treatment is indicated. There
is not specific therapy, but for patients with fever and arthritis and/or arthralgia, treatment of
symptoms is indicated.
VACCINATION AGAINST RUBELLA
The rationale for use of the vaccine is to prevent congenital rubella .The vaccines, when properly
administered, produced a seroconversion rate of approximately 95 percent.
59
Definition:
Highly contagious infectious disease, specifically human, caused by varicella-zoster virus
(VZV), characterized by maculo-papulo-vesicular exanthema and enanthema, fever and malaise,
followed by persistent immunity.
Etiologic agent:
Varicella-zoster virus (VZV) = type 3 Human Herpesvirus, belonging to Herpesviridae
family, subfamily Alpha-Herpesvirinae. It has double-stranded DNA structure.
Epidemiology
Ubiquitous infection, with sporadic or epidemic evolution. In temperate regions, it registers
epidemic peaks during the cold season. The highest incidence is registered among children, but
adolescents or adult seronegative persons may develop the disease as well. Attack rate: 95-100%
among susceptible individuals exposed to VZV (extremely contagious).
Reservoir: specifically human patients suffering from varicella or herpes zoster (VZV is
present in the naso-pharingeal secretions in case of patients with chickenpox and inside vesicular
fluid in case of chickenpox and / or herpes zoster patients). Following primary infection, the
virus persists in latent form at the site of sensorial ganglia, including dorsal roots of spinal
nerves. The patient is not contagious during this stage, but it becomes contagious again when the
infection reactivates, following immune suppression and herpes zoster appears.
Contagiousness: beginning with the last 3-5 days of incubation, until the stage of crusts
(overall 14 days).
Transmission route: direct transmission - airborne, via respiratory droplets (from patients
with chickenpox) or by direct contact with vesicular fluid, or indirect transmission via recently
contaminated objects (from varicella or herpes zoster patients).
Susceptibility: general
Immunity: both humoral (IgM and IgG anti-VZV antibodies) and cellular, follows disease
or vaccination. Immunity following disease is durable, life-long. Duration of vaccination-related
immunity is yet to be established. However, VZV infection reactivation (herpes zoster) occurs
following immune suppression, as VZV persists in latent form inside sensorial ganglia. Infants
born to immune mothers are protected against VZV infection during their first 4-6 months of life
due to transplacental transfer of IgG anti-VZV antibodies from their mothers.
Pathogenesis
VZV penetrates into the human organism through naso-pharingeal and / or conjunctival
mucosa, with local replication, followed by infection of the reticulo-endothelial system and
60
bloodstream penetration (viremia). VZV thus reaches the skin and mucosa, where it causes cell
degeneration, with the appearance of multinucleate giant cells, with eosinofilic inclusions, as
well as various other organs (visceralization).
Clinical manifestations
The incubation period lasts for 10-21 days. Prodrome / Invasion (24-48 hours),
characterized by fever, malaise, myalgia and headache may be absent. Clinical manifestations
include a characteristic pruriginous rash, which evolves in several successive crops, each
accompanied by fever, appearing over a period of 3-5 days. Erythematous maculo-papules
evolve over hours into dew-drop-like vesicles, with erithematous base. Initially, the vesicular
fluid is clear, but it becomes cloudy due to local accumulation of polymorphonuclear cells, fibrin
and cellular detritus. The vesicles centers umbilicate and the vesicles scab. Subsequent crusts
will be discharged spontaneously. The exanthema is generalized, covering trunk, face, limbs and
scalp, and polymorphic lesions at various stages of evolution may be found on the same skin
region (macula-papules, vesicles, crusts) It is accompanied by enanthema rash covering the
oro-pharinx, genital and sometimes conjunctival mucosa (aphtous lesions). In peculiar cases, e.g.
immunocompromised patients, severe forms of disease may occur, with hemorrhagic, bullous
or necrotic exanthema.
Clinical forms:
-
Varicella mitigate
Ordinary form
Hemorrhagic form
Bullous form
Necrotic form
Adults may develop more severe clinical forms than children. Severe forms of disease are
encountered in immunocompromized patients (congenital or acquired immune suppression, e.g.
HIV infection, malignancy, connective tissue disorders, diabetes mellitus, immunosuppressive
therapy, transplant recipients).
Perinatal varicella, occurring in newborns from mothers who developed chicken pox
within the first 5 days before or 2 days after delivery, is usually a severe form, as the newborn
did not benefit from transplacental antibodies transfer from his mother and is therefore not
protected against VZV infection).
Positive diagnosis
Based on:
-
multinucleate giant cells. VZV isolation in cell cultures is rarely necessary, usually for
research purposes.
Differential diagnosis
-
Complications
Bacterial secondary infection of skin lesions (with Streptococcus / Staphylococcus strains)
the most frequent complication (poor hygiene), requiring antibiotic therapy.
Respiratory complications: varicella pneumonia, tracheo-bronchitis, bacterial pneumonia
due to superinfection. Varicella pneumonia with possible subsequent respiratory failure,
presents nodular infiltrates and interstitial pneumonitis on chest X-ray. It has peculiar severe in
pregnant women.
Central nervous system complications: meningitis, encephalitis, mielitis, Guillain-Barre
syndrome. Usually occurring following the first week of disease. Reye syndrome consists of a
fatty liver degeneration associated with encephalopathy following acetyl-salicylate (aspirin) use
in patients with VZV infection.
Other complications: corneal lesions, nephritis, hepatitis, myocarditis, bleeding diathesis.
Chickenpox in pregnant women: may cause spontaneous abortion, premature birth or
malformations. VZV is teratogenic it may cause central nervous system and limb
malformations, as well as skin lesions with remnant scars.
Treatment
Isolation: at home in mild cases. Hospitalization is compulsory in severe clinical forms or
immunocompromised subjects. Skin and clothes hygiene is required in order to prevent bacterial
secondary infections of skin lesions. Secondary bacterial infection of skin lesions or scratching
may lead to the development of permanent scars and should therefore be avoided. Diet should be
light, with good hydration, and rich in vitamins. Antihistaminic drugs are used to fight pruritus,
antipyretic substances to fight fever. Aspirin and aspirin derivatives is prohibited in chickenpox
due to the risk of Reye syndrome.
Etiologic treatment is indicated in immunosuppressed hosts, severe forms of disease or
complications. However, adolescents and adults are known to develop more severe forms than
children and may benefit from etiologic therapy. Acyclovir is a nucleosidic analogue (guanine
derivative) that inhibits DNA polymerase and thus viral replication. It can be administered in
doses of 30 mg/kg/day orally or via intravenous route, divided into 3-5 doses, for 5-7 days. In
case of renal function impairment, acyclovir doses must be reduced. Valacyclovir, famciclovir
and brivudine may also be used. Iv immunoglobulin administration is useful in severe cases or
immunocompromised patients. In case of neurological complications (meningitis, encephalitis),
62
63
Definition
Acute infectious disease, caused by a reactivation of varicella-zoster virus (VZV)
infection, subsequent to immune suppression, characterized by dermatomal vesicular rash,
usually accompanied by neuropathic pain.
Etiology and pathogenesis
Varicella-zoster virus (VZV) - type 3 human herpes virus. Following primary infection
(chickenpox), VZV persists in latent form in the sensorial ganglia of the cranial or spinal nerves
(posterior root) of the human host. VZV infection reactivates in case of immune suppression of
various origins: chronic illnesses, (e.g. HIV infection, malignant lesions, connective tissue
disorders, immunosuppressive treatment, transplant recipients, diabetes mellitus), acute diseases,
trauma / surgery, psycho-emotional stress, physical or psychological effort. Rarely, herpes zoster
may be the consequence of massive exposure to VZV from an external source. In cases of
extreme immune suppression, severe clinical forms, including generalization (herpes zoster
varicellosus) may occur.
Epidemiology
VZV DNA was detected in vesicular fluid. The patient may transmit the disease by
direct contact with skin lesions or indirectly, by recently contaminated objects, to susceptible
(seronegative persons) which will subsequently develop chickenpox. Contagiousness lasts until
all vesicular lesions are crusted. Unlike chickenpox, which registers its highest incidence among
children, herpes zoster is more common among persons > 60 years-old, but it may occur in
immunocompromised hosts of any age.
Clinical manifestations
Unilateral vesicular exanthema, with dermatomal distribution, usually associated with
neuralgia. The initial erythematous maculopapular exanthema evolves into vesicles and then
scabs, after several days. Skin lesions usually evolve in one crop, so the exanthema is
monomorphic. As the basal membrane of the epidermis is altered, skin lesions usually result in
permanent pigmented scars, even in the absence of bacterial secondary infection or scratching.
Unlike chickenpox, dermitic rash is accompanied by pain, not pruritus. In case of generalization
of skin lesions, similar to chickenpox rash (herpes zoster varicellosus), the initial dermatomeric
rash can still be distinguished due to the local richness of skin lesions. The average duration of
skin lesions is 10-14 days.
Neuropathic pain (zoster-associated neuralgia), due to acute neuritis, usually precedes
the appearance of the exanthema by several days up to one week and lasts for several weeks or
even months after the resolution of skin lesions (post-herpetic neuralgia PHN). It is described as
a burning sensation, paresthesia or severely disturbing pain. In rare cases, especially in young or
diabetic patients, neuralgia may be absent.
64
Clinical forms
-
Positive diagnosis
Mainly clinical.
-
Differential diagnosis
-
65
Treatment
Patients should either be isolated at home (mild cases) or hospitalized (severe cases,
complications). Isolation period should last for 10-14 days, until skin lesions have overpassed the
stage of crusts.
Etiologic (antiviral) treatment: acyclovir, a nucleosidic analogue which inhibits DNApolymerase and viral replication. It can be administered orally: 5x800 mg/day in adult patients,
for 7-10 days, or via intravenous route, in severe or complicated cases: 30 mg/kg/day, divided
into 3 doses, for 7 days. Valcyclovir, a prodrug of acyclovir, 3x1g/day 7-10 days orally, or
famciclovir, a prodrug of penciclovir, administered orally 3x500 mg/day for 7-10 days, are also
useful. Acyclovir doses must be modified according to the parameters of the renal function
(creatinine clearance). Acyclovir resistance, due to the impairment of timidine-kinase, a viral
enzyme which phosphorilates acyclovir into its active form, may be extended to famciclovir and
valacyclovir. Brivudine may represent a therapeutic alternative.
Acyclovir topical administration (ophthalmic ointment) is recommended in herpes
zoster keratitis. Corticosteroids are recommended in case of central nervous system
complications and / or uveitis, but only accompanied by antiviral treatment.
The management of PHN (post-herpetic neuralgia) is particularly difficult. It requires
non-narcotic or narcotic analgesics, ranging from natrium metamisole, paracetamol
(acetaminophen), NSAIDs, to narcotic derivatives. Lidocaine patches, amitriptyline
hydrochloride, pregabalin and gabapentin are frequently used substances. Group B vitamins may
be helpful in reducing the course of PHN.
Prophylaxis
Zoster vaccine (containing 18 times the amount of viral antigen contained by Oka antivaricella vaccine) administered to aged subjects (> 60 years old) was reported to reduce the
incidence of herpes zoster by 50% compared to patients who had not received vaccination, by
boosting cell-mediated immune response.
66
MUMPS
Cristina Grbovan
Definition
Mumps is an acute viral infection whose most distinctive feature is swelling of one or both
parotid glands. Involvement of other salivary glands, the meninges the pancreas, and the gonads
also is common. The disease is benign and self-limited, one-third of the persons having
subclinical infection. Meningitis and epididymoorchitis represent the two most important of the
less frequent manifestations of this disease. As the characteristic of many viral infections,
mumps in the postpubertal p erson is usually a more severe illness than in children and more
commonly leads to extrasalivary gland involvement.
Etiologic agent
Mumps virus , is a member of the Paramyxovirus genus of the Paramyxoviridae family which
includes the following genera : paramyxovirus (mumps, parainfluenza, and Newcastle disease
virus), morbillivirus (measles) and pneumovirus (respiratory syncytial virus.)
EPIDEMIOLOGY
Before widespread vaccination, the incidence of mumps was highest in the winter and spring,
with epidemics every 2-5 years. In the prevaccine era 50% of children aged 4-6 years and 90%
of children aged 14-15 years had positive serology of mumps. One attack of mumps usually
confers lifelong immunity. Long- term immunity is also associated with immunization.
PATHOGENESIS
The virus is naturally transmitted via direct contact, droplet nuclei, or fomites and enteres
through the nose or mouth. More intimate contact is needed to transmit mumps than either
measles or varicella. Replication of the virus in the epithelium of the upper respiratory tracts
leads to viremia, which is followed by infection of glandular tissues and/or the central nervous
system (CNS).
CLINICAL MANIFESTATIONS
The incubation period of mumps generally ranges from 14-18 days with extremes of 7 and 23
days.
The prodromal symptoms are nonspecific and include:
Low-grade fever
Anorexia
Malaise
Headache
Myalgia
Within a day the patients complains of an earache, and tenderness can be elicited by palpation of
the ipsilateral parotid.
Trismus may result from the parotitis, and the patient may have difficulty
with pronunciation and mastication.
67
The submaxillary and sublingual glands are involved less often than the parotid and are almost
never involved alone.
Epididymoorchitis is the most common extrasalivary gland manifestation in the adult man. It
develops in 20-30% of postpubertal men undergoing mumps infection and is bilateral in one of
six of those with testicular involvement. Gonadal involvement may precede parotitis or occur as
the only manifestation of mumps.
The onset is abrupt
chills
headache
vomiting
testicular pain
warmth
swelling
Headache
Vomiting
Fever
Nuchal rigidity
Cerebellar ataxia
Facial palsy
Transverse myelitis
Guillain-Barre syndrome
Migratory polyarthritis
Thyroididtis
Mastitis
Hepatitis
Thrombocytopenia
Prostatitis
DIAGNOSIS
In the majority of instances, the diagnosis of mumps is made on the basis of a history of
exposure and on the presence of parotid sweeling and tenderness accompanied by mild to
moderate constitutional symptoms.
The white blood cell and differential counts in mumps are normal, or there may be a mild
leukopenia with a relative lymphocytosis. When meningitis, orchitis, or pancreatitis is
present, leukocytosis with a shift to the left is most commonly encountered.
Serum amylase level is elevated in the presence of parotitis and may remain abnormal for
2-3 weeks.
Highly sensitive enzyme-linked immunosorbent assays are useful for serologis diagnosis
of mumps and for determination of susceptibility to the disease.
COMMENTS
Systemic infections
Mumps
Coxsackievirus infection
HIV infection
In HIV positive-children
antiretroviral therapy
69
receiving
no
Cat-scratch disease
Sygren, s syndrome
Uremia
Diabetes mellitus
Drugs
Thiouracil, Phenylbutazone
Unilateral Parotitis
Ductal obstruction duo to stones or strictures
Parotid cyst
Parotid tumor
Therapy
-Therapy of mumps parotitis is limited by symptomatic and supportive measures.
-The administration of analgesics and the application of warm or cold compress to the parotid
area may be helpful.
-Intravenous fluid administration is indicated for those patients with meningitis and pancreatitis
who have persistent vomiting.
PREVENTION
Live attenuated mumps vaccine induces antibodies that protect the recipient against infection in
95% of cases. Mumps vaccine is usually administered as part of the measles-mumps-rubella
(MMR) vaccine at the age 12-15 months and again at 4-12 years of age.
As with most other live virus vaccines, mumps vaccine should not be administered to:
Pregnant women
70
WHOOPING COUGH
Carmen Chiriac
Contagiousness period: 7 days after infectious contact + 4 weeks after onset. Its duration
is reduced to 10 days in cases receiving antibiotic therapy. Maximum attack rate is achieved
during the catarrhal period of the disease, high: 90 % among unimmunized family contacts.
Receptivity is general newborns may get sick immediately after birth, because the
immunoglobulins transmitted from mother do not cross the placenta.
Immunity after disease is durable. Re-infection is possible, with another type of
Bordetella. It is more serious in girls than boys.
Pathogenesis
The germ is not invasive, it attaches to the ciliated epithelial cells in the nasopharynx,
tracheobronchial mucosa, determining local inflammation, irritation of vagal nerve terminations
with initiation of cough reflex-phase of bronchogenic cough. On a cortical level, a dominant
focus of arousal is created (neurogenic period): cough sets off at sensory stimuli. The toxins
released by Bordetella are dispersed in the organism. Systemic manifestations (lymphocytosis)
are the result of toxin activity. The pathogenesis of neurologic events, such as seizures and
encephalopathy, is influenced by:
-
toxic factors
- hypoxic factors by coughing fits with apnea
- hemorrhagic factors
- allergic factors: sensitized at the nucleoprotein complex of coccobacillus.
Clinical manifestations
Pertussis is a prolonged coughing illness, the clinical manifestations vary by age. Pertussis is
most often seen in preschool and school-age children.
The average incubation period: 7-10 days
Catarrhal phase the: week 1-2. It is indistinguishable from the common cold and is characterized
by the following: - high contagiousness
- duration 7-14 days
- ordinary catarrh of respiratory airways
- hyperemic conjunctiva
- mild fever
The cough: initially ordinary. At the end of the catarrhal stage it becomes mainly nocturnal,
spastic and accompanied by vomiting. It is not influenced by symptomatic therapy.
Paroxysmal stage: duration 2-4 weeks. Paroxysmal episodes consist of: aura (the child
anticipates the access), sudden inspiration followed by (5-10) spasmodic expiratory bursts,
expiratory pause (face is congested and cyanotic), resumption: deep prolonged wheezing
inspiration. There may be several cycles of prolonged inspiration and jerky expiratory bursts.
Sputum expectoration is difficult: slimy mucus, accompanied by vomiting. During paroxysmal
episode, the patients face is congested, livid, eyes are injected. He may develop ulceration of
lingual frenum.
The number of paroxysmal episodes within 24 hours:
-
Differential diagnosis
-
-Early treatment of pertussis is very important. If treatment for pertussis is started early in the
course of illness, during the first 1 to 2 weeks before coughing paroxysms occur, symptoms may
be lessened.
-Isolation at home or at hospital
-Diet: fractioned meals in reduced amounts
-Antimicrobial treatment: Erythromycin, 40-50 mg/kg/day, Clarithromycin, Azithromycin,
Ampicillin, Cotrimoxazole
Pathogenic treatment: cough tranquilizers, antihistamines, oxygen therapy, assisted breathing,
postural drainage, aspiration of respiratory secretions, vitamins. Bacterial superinfections:
antibiotics therapy Encephalitis: cerebral edema control, anticonvulsants.
Prophylaxis
Regarding patients and contacts:Compulsory to declare
Isolation of contacts, 7-10 days prophylactic course of antibiotics
The best way to prevent pertussis is to get vaccinated. There are vaccines for infants, children,
preteens, teens and adults. The childhood vaccine is called DTaP (a combination vaccine that
protects against three diseases: diphtheria, tetanus and pertussis).
The development of acellular pertussis vaccines have replaced whole-cell pertussis vaccine.The
acellular pertussis vaccines are less reactogenic than whole-cell pertussis vaccine and may be
used for booster immunization in older childrens and adults. The pertussis booster vaccine for
adolescents and adults contains also protection against tetanus, diphtheria and pertussis.
74
EPSTEIN-BARR VIRUS
(INFECTIOUS MONONUCLEOSIS)
Cristina Grbovan
Cervical adenopathy, usually symmetric, is precent in 80-90 percent of the patients. Posterior
adenopathy is most common, but submandibular and anterior adenopathy are quite frequent as
well, and axillary and inguinal adenopathy also occur.
Abdominal examination may detect hepatomegaly in 10- 15 percent of the cases. Splenomegaly
is present in about one-half of the cases, and is usually maximal at the beginning of the second
week of illness and regresses over the next 7-10 days.
COMPLICATIONS
The vast majority of patients with infectious mononucleosis recover uneventfully.
Hematologic complications:
Thrombocytopenia
Splenic rupture is a rare but dramatic complication of infectious mononucleosis. The incidence
of rupture is highest in the second or third week of illness, but may be the first sign of infectious
mononucleosis.
Neurologic complications:
Aseptic meningitis
Encephalitis
Guillain-Barre syndrome
Bell s palsy
Transverse myelitis
Hepatic complications:
Cardiac complications:
Pericarditis
Myocarditis
Pulmonary complications:
Clinical Course
The vast majority of cases of infectious mononucleosis resolve spontaneously over a 2- to 3
week period. The sore throat is usually maximal for 3-5 days and then gradually resolves over
the course of a week to 10 days. Patients remain febrile for 10-14 days, but in the last 5-7 days ,
the fever is usually low grade and associated with little morbidity.
LABORATORY DIAGNOSIS
Hematologic Findings
The central hematologic manifestation of the illness is the circulating lymphocytosis. At
presentation, a relative and absolute mononuclear lymphocytosis is found in about 70 percent of
76
the cases. The lymphocytosis peaks during the second or third week of illness, and monocytes
and lymphocytes account for 50-70 percent of total white cell counts of 12-18 000/mm3.
Higher white cell counts are not uncommon, and occasional cases manifest 30-50 000
leukocytos/mm3 .
Atypical lymphocytes are the hematologic hallmark of infectious mononucleosis , and account
for about 30 percent of the differential count at the height of the atypical lymphocytosis.
Syndromes in which Atypical lymphocytosis may be found
Cytomegalovirus infections
Toxoplasmosis
Rubella
Roseola
Mumps
Drug reactions
A relative and absolute neutropenia is evident in 60-90 percent of the cases. In most cases, the
neutropenia is mild, with total granulocyte counts of 2000-3000/mm3 .
Thrombocytopenia is also common , and 50 percent of the patients in one series manifested
platelet counts of 140 000/mm3.
Heterophile Antibodies, originally described by Paul and Bunnell as sheep erythrocyte
agglutinins, are present in about 90 percent of the cases at some point during the illness. Beef
erythrocyte hemolysins and agglutinating antibodies to horse, goat and camel erythrocytes are
also demonstrable in infectious mononucleosis.
Heterophile antibodies may be demonstrable at the onset of illness or may appear later in the
course of illness.
EBV-Specific Antibodies
In addition to the transient heterophile antibodies, infection with EBV results in the development
of virus specific antibodies. Antibodies to viral capsid antigen (VCA) measured by
immunofluorescence arise early in the course of the illness and are demonstrable at presentation
in the majority of cases. IgG antibodies to VCA are usually present at titers of 80 or greater on
the first visit to a physician. On the other hand, IgM antibodies to VCA are sensitive and specific
for infectious mononucleosis but are difficult to measure.
Antibodies to EBNA appear late in the course of all cases of infectious mononucleosis and
persist for life. The appearance of EBNA antibodies in a patient who was previously VCA
positive and EBNA negative, is strong evidence of recent EBV infection.
Detection of EBV
Epstein-Barr virus may be cultured from oropharyngeal washings or from circulating
lymphocytes of 80-90 percent of the patients with infectious mononucleosis. Cultivation of the
virus is, however, not routinely in most diagnostic virology laboratories. Rapid diagnostic
77
techniques based on DNA hybridization or monoclonal antibody techniques are currently under
development.
DIFERENTIAL DIAGNOSIS
Toxoplasma
HIV
Hepatitis viruses
rubella
lymphoma or leukemia
TREATMENT
Treatment of infectious mononucleosis is largely supportive since more than 95 percent of the
patients recover uneventfully without specific therapy. Contact sports or heavy lifting should be
avoided during the first 2-3 weeks of illness, especially splenomegaly is present.
Aspirin or acetaminophen, are helpful in relieving the sore throat and in suppressing the fever.
Corticosteroids are often advocated, but their use in uncomplicated illness is still controversial.
Most infectious disease consultants prefer not to administer corticosteroids in this self-limited
disease of certain specific indications.
Corticosteroids are generally used in the following situations:
1) Impending airway obstruction
2) Severe thrombocytopenia
3) Hemolytic anemia
4) CNS involvement
5) Myocarditis
6) Pericarditis
Acyclovir has had no significant clinical impact on IM in controlled trialls. Acyclovir, at
a dosage of 400-800 mg five times daily, has been effective for the treatment of oral hairy
leukoplakia.
78
Diphtheria
Iringo Kezdi
Diphtheria is an acute disease manifested by both local infection of the upper respiratory tract
and the systemic effects of a toxin, which are most notable in the heart and peripheral nerves.
ETIOLOGY
The etiologic agent, C. diphtheriae is the principal human pathogen of the Corynebacterium
group, an aerobic gram-positive bacillus with irregular shape. C. diphtheria strains are divided
into three biotypes (mitis, gravis, intermedius). As referring to the toxin synthesis, there are
toxin-producing and non-producing strains. Diphtheria toxin is the primary virulence factor of
C.diphtheriae, the structural gene, tox, being carried by a family of bacteriophages. Under the
action of heat (40 C) or formalin 4%, the toxin may be transformed after a month in anatoxin,
an untoxic but immunizing substance. In nature, C. diphtheria is only rarely an invasive
organism; it is encountered in the respiratory tract, in wounds or on the skin of infected persons
in normal carriers. It is spread by droplets or by contact to susceptible individuals; the bacilli
then grow on mucous membranes or skin abrasions and those that are toxigenic start producing
toxin.
PATHOLOGY
All human tissues may suffer by the toxin because all human cells have receptor sites.
Accordingly, there is no specific target organ for the toxin, but clinical consequences generally
result from myocardial and neural abnormalities. Death often results from cardiac failure, but
necrotic and often hemorrhagic lesions are usually found in many organ. Except from the local
site of infection, the lesions are sterile. Diphtheria toxin is absorbed into the mucous membranes
and causes destruction of epithelium and a superficial inflammatory response. Locally, toxin
induces tissue necrosis, leukocyte response and formation of a tough, adherent pseudomembrane
composed of a mixture of fibrin, dead cells and bacteria-commonly over the tonsils, pharynx, or
larynx. Any attempt to remove the pseudomembrane results in bleeding. The diphtheria bacilli
within the membrane continue to produce toxin actively. This is absorbed and leads to distant
toxin damage, particularly parenchymatous degeneration, fatty infiltration and necrosis in heart
muscle, liver, kidneys (tubular necrosis), and adrenals, sometimes accompanied by important
hemorrhage. The toxin also produces nerve damage (neuronal demyelination), resulting often in
paralysis of the soft palate, eye muscles, or extremities. Wound or skin diphtheria occurs chiefly
in the tropics. A membrane may form on an infected wound that fails to heal. However,
absorption of toxin is usually slight, the small amount of toxin promotes development of
antitoxin antibodies, so that the systemic effects are negligible. There are 2 phases of diphtheria:
the initial local presentation as a severe pharyngitis with tough membranes that can cause
suffocation and a late systemic phase caused by the effects of the circulating exotoxin on tissues
of the host. Nondiphtheriacorynebacteria produce localized or systemic diseases principally by
colonizing foreign bodies introduced into the human tissue (prosthetic valves, catheters, etc).
CLINICAL FINDINGS
Incubation period is usually less than 1 week.
Pharyngitis. The initial form of diphtheria manifests as an infection of upper respiratory tract.
During the onset period that is abrupt, symptoms like malaise, sore throat, anorexia, fever
79
appear, as a result of the substantial systemic absorption of toxin. Physical exam includes
erythema of the posterior pharynx, followed by the development of a pseudomembrane, that is
usually asymmetric and extend, to involve the soft palate and uvula. As the membrane spreads,
the patient may develop significant oedema of the submandibular areas and the anterior neck
with the lymphadenopathy giving a characteristic bull neck appearance. Laryngeal
diphtheriacan occur as a result of membrane extension, or may be the only site of infection,
manifested by: hoarseness, stridor, dyspnea that may need intubation or tracheostomy. Nasal
diphtheria presents with purulent and serosanguinolent discharge. Cutaneos infection often
appears as a secondary infection of a previous wound (pustule, ulcer and oedematous rolled
borders that may evolve as a chronic non-healing ulcer). Other organ involvement includes: ears,
conjunctiva, cornea. The disease may progress if enough toxin enters the bloodstream, causing
severe prostration, striking pallor, rapid pulse, stupor and coma. The absorbed toxin can also
cause delayed damage at distant sites.
COMPLICATIONS
1. Cardiovascular complications
Myocarditis may occur in the second week of evolution early myocarditis ( 20-65% of
patients): progressive weakness, dispnea, congestive heart failure, muffled heart sounds, gallop
rhytm, and circulatory collapse, conduction disturbances (prolongation of PR interval, complete
atrioventricular block), and sometimes cardiac arrest.
Late myocarditis occurs between the third and fourth week of illness withmilder clinical
findings.
2. Neurologic complications
a. Palatal paralysis begins 1-2 weeks after the onset of symptoms, followed by paralysis of
swallowing and involvement of the other cranial nerves.
b. Oculomotor paralysis later ( weeks 4-5th), there may be difficulties with vision (paralysis of
accommodation)
c. Peripheral polyneuritis with a glove-and-stocking distribution of motor and sensory loss may
resemble Guillain-Barre syndrome (weeks 7-10). All of these manifestations tend to subside in a
few weeks and sometimes months, or may evolve with ascending syndrome (Landry) which is
lethal.
LABORATORY TESTS
1. Isolation of C. diphtheria from different specimens such as swabs from the nose, throat, or other
suspected lesions that must be obtained before antimicrobial drugs are administered ( culture on
Loeffler or Pai agar and cysteine tellurate). Any diphtheria-like organism culture must be
submitted to a virulence test before the bacteriologic diagnosis of diphtheria is definite.
Biotyping and toxigenicity testing has not been maintained in all countries. Toxin production
may be demonstrated in vivo by the guinea pig lethality test, or by the more rapid Elek test in
vitro.
2. Stained smears show beaded rods in typical arrangement.
DIAGNOSIS
The presence of an asymmetric grey, adherent membrane with lymph node enlargement and soft
tissue swelling, in a toxic-looking person is suggestive for diphtheria. Several predisposing
factors will make the diagnosis more likely:
- an unimmunized patient or who has not received the recommended booster immunizations;
- a history of contact with a diphtheria case;
80
81
INFLUENZA
Andrea Incze
Definition
Influenza is a moderate or severe infectious disease produced by the influenza viruses. It can
affect the upper and lower respiratory tract, it is accompanied by severe systemic symptoms
(fever, myalgia, weakness, headache). It can be endemic, or cause epidemics, pandemics, with a
peak in winter.
Etiologic agent
Influenza viruses belong to the family of Orthomyxoviruses, they are RNA viruses. There are 3
separate types of viruses, A, B and C, classified based on the characteristics of nucleoprotein
(NP) and matrix (M) antigens.
Each type, subtype and strain of influenza virus has similar morphology. The shape of the virion
is either spherical or elongated. The structure of the virus consists of:
-
the matrix protein (M) surrounds the nucleocapsid, and provides the stability of the
virion
these are surrounded by the envelope, a double-layer lipid structure, covered with
projections on its surface
Based on the structure of hemagglutinin (H) and neuraminidase (N) antigens influenza A is
further subtyped. There are 16 H subtypes and 9 N subtypes. All of the H subtypes can be found
in avian influenza viruses, however, only H1, 2, and 3 were associated with influenza epidemics
in humans. Regarding the N subtypes, only subtype 1 and 2 were associated with human
epidemics.
Influenza B and C viruses do not have subtype designations, because there are no antigen
variations in case of influenza virus C, and these variations are minor in case of influenza virus
B.
The designation of the influenza virus consists of:
-
geographic origin
isolate number
type of H and N
82
Influenza epidemics have a rapid onset, reach their peak in 2-3 weeks, last for 2-3 months and
subside abruptly. Influenza epidemics occur during the winter in the temperate zones, although
rarely they can occur during the warm months also. In the tropics they can occur during the
whole year. Rapid transport facilities contribute to the widespread of influenza to geographic
areas that are at a long distance.
The last influenza pandemic started in March 2009, ended in August 2010 (according to WHO).
It was caused by an A/H1N1 virus, which was a recombinant between a North American swine
virus and a Eurasian swine virus. The new virus was antigenically different from the A/H1N1
viruses that had circulated in the years before 2009, thus vaccines elaborated against the
circulating A/H1N1 strains were not efficient. A new vaccine was elaborated against the
A/California/07/2009/H1N1 virus. This virus was sensitive to the neuraminidase inhibitors
(oseltamivir and zanamivir), but resistant to amantadine and rimantadine. The clinical illness did
not differ from that caused by seasonal influenza A virus. Severe forms appeared in children,
young adults, pregnant women and patients with comorbidities.
Avian influenza is transmitted to humans through direct contact with infected poultry, in case of
poultry outbreaks of influenza. Human to human transmission is possible in case of close,
prolonged unprotected contact, but is very rare. According to CDC reports, since November
2003, 600 sporadic human cases of avian influenza have been noted, with a mortality rate of
60%.
Influenza B causes less extensive epidemics than influenza A, and the disease is milder. It affects
communities, such as schools, institutions for elderly, and the army. Reyes syndrome was
described as the most important complication of B influenza.
Influenza C causes mainly upper respiratory symptoms, it affects rarely the lower respiratory
tract, and there are many asymptomatic infections.
Pathogenesis
Influenza virus infects the organism through the respiratory epithelium. The ciliated columnar
epithelial cells become infected, and the infection can spread towards the alveolar cells,
macrophages, and mucous gland cells also. This process can be prevented by the action of
secretory IgA, nonspecific nucleoproteins that attach to the virus, and mechanic action of the
mucociliary apparatus.
Neuraminidase (N) reduces the viscosity of the mucosal layer, and uncovers the hemagglutininreceptors. The next step is viral-cellular fusion, followed by intracellular penetration. The virus
replicates in the cell within 4-6 hours, the newly formed virions leave the host cell, and the
infected cells are destroyed due to viral replication and apoptosis. The new virions infect other
epithelial cells, thus in a few hours a great number of respiratory epithelial cells are destroyed,
and desquamated. An inflammatory mononuclear infiltrate and edema appears in the submucosal
layer.
Although the systemic symptoms (headache, fever, myalgias) are prominent in influenza, the
virus has rarely been detected in extrapulmonary areas.
The immune response of the host consists of serum antibody production (antibodies against
hemagglutinin seem to be the most important), local secretory IgA antibodies, antigen-specific
and antigen-nonspecific cellular immune response (TCD4+, TCD8+, NK cells), interferons. In
most of the patients viral shedding stops in 2-5 days after the onset of disease, when the antibody
level is still low. Therefore it was supposed that interferon, cell-mediated immune response and
nonspecific inflammatory responses are responsibile for the recovery.
84
Clinical manifestations
The incubation is short, 3-4 days. The disease starts with severe, abruptly onset general
symptoms: fever with shivering and sweating, discomfort, prostration, arthralgia, myalgias, and
headache. The fever is high, 38-41C, lasts 2-3 days, until 1 week. The persistence of fever
above a week is sign of complication.
The respiratory tract symptoms are sore throat, cough, substernal discomfort. Tracheitis,
laryngitis, croup, otitis, sinusitis, conjunctivitis can also occur.
Vomiting, diarrhea, shortness of breath can also be present.
Ocular symptoms are present: burning of the eyes, photophobia, and pain at the movement of the
eyes.
As the general symptoms subside, the respiratory symptoms become more prominent.
Physical findings are minimal: hyperemic face and conjunctivae, dry skin, nasal discharge,
enlarged cervical lymph nodes, wheezes, rhonchi, scattered rales can sometimes be heard on
chest examination.
Dyspnea, hyperpnea, cyanosis, diffuse rales, and pulmonary consolidation are signs of
complications.
Patients recover from uncomplicated influenza in a week, however, cough may persist 1-2
weeks. Postinfluenzal asthenia may persist for several weeks.
Complications
The elderly, children under 2 years, pregnant women and patients with comorbidities such as
chronic cardiac, renal or pulmonary disorders, hemoglobinopathies, immunosuppression,
diabetes mellitus are prone to have complications.
Pulmonary complications
Pneumonia can be primary viral pneumonia, secondary bacterial pneumonia, or the mix of the
former two.
Viral pneumonia is characterized by a progressive worsening of influenza, with dyspnea,
cyanosis, hypoxia, bloody sputum, diffuse infiltrates on the chest X-ray, acute respiratory
distress syndrome. There is an important inflammatory reaction, necrosis and hemorrhage at the
level of alveoli.
In secondary bacterial pneumonia fever reappears after an afebrile period, cough, purulent
sputum, signs of consolidation can be found. The etiologic agents can be Streptococcus
pneumoniae, Staphylococcus aureus, Haemophylus influenzae.
In case of mixed pneumonia the involvement of the lung might be less extensive, compared to
viral pneumonia. The chest examination and X-ray reveals patchy infiltrates or consolidation.
Other pulmonary complications: croup, bronchiolitis (especially in children), worsening of
chronic pulmonary obstructive disease, exacerbation of asthma.
Extrapulmonary complications
Reyes syndrome, which appears in case of Aspirin administered to children with influenza
(especially B).
85
determination of the type of virus (A, B, C), and hemagglutinin subtype: with specific
antisera, detection of or neuraminidase activity rapid tests
Serologic tests: comparison of acute and convalescent antibody titers (during the acute illness
and after 10-14 days) 4x or greater titers are diagnostic
Nonspecific laboratory tests
-
the leucocyte count can be low early in illness, normal or slightly elevated later
Differential diagnosis
Influenza should be differentiated from:
86
acute febrile diseases in the invasion period (eg. measles, brucellosis, leptospirosis,
meningitis)
streptococcal pharyngitis
bacterial penumonia
Treatment
Etiologic treatment
Neuraminidaze inhibitors:
-
Side effects:
-
M2 protein inhibitors (membrane ionic channel): Amantadine, rimantadine are no longer used
due to the multiple resistant strains, their use may be reconsidered in case of sensitive strains.
Antibiotics should be used in case of bacterial superinfection.
Pathogenetic and symptomatic therapy:
Antivirals are not needed in the treatment of uncomplicated influenza. These cases are isolated
and treated at home. In this case NSAIDs (with the exception of Aspirin, which might lead to
Reye syndrome) should be used.
Codeine-based therapy can be applied against cough.
Rest and appropriate hydration are important.
In severe cases it is essential to maintain oxygenation, to treat the patient in an intensive care
unit, to provide respiratory and hemodynamic support.
Prophylaxis
Vaccination with inactivated or live attenuated vaccines can be applied.
Most of the vaccines are inactivated, derived from influenza A and B influenza strains that
circulated during the previous season. They provide 50-80% protection.
The vaccines might have side effects: fever, systemic symptoms, local reaction at the vaccination
site, allergic reaction (in case of egg-sensitivity), Guillain-Barr syndrome (rarely).
It is recommended to vaccinate the persons, who are elderly, have comorbidities, are
immunosuppressed, and their contacts, healthcare personnel.
Vaccination should be applied in the autumn, before the influenza outbreak, and should be
administered annually.
A live, attenuated vaccine is available, that can be given to the age group 5-49 years, and is
highly protective (92%).
87
Antivirals can be used as chemoprophylaxis. Oseltamivir and zanamivir can be given at half the
therapeutic dose, however, amantadin and rimantadin are not recommended, due to resistance.
Chemoprophylaxis is used in unvaccinated persons with high risk for influenza. It can be used in
vaccinated persons also, has an additive effect to the inactivated vaccine, but it should not be
administered closer than 2 weeks after the administration of live attenuated vaccine.
References:
1. Mandell GL, Bennett JE, Dolin R Principles and practice of infectious diseases, 6th
Edition, 2005, Elsevier
2. Kasper DL, Fauci A - Harrisons Infectious diseases, 2010, McGraw Hill Medical
3. Cupsa A Boli infecioase transmisibile, 2007, Editura Medical Universitar Craiova
4. Bannister B, Gillespie S, Jones J Infection Microbiology and Management 3rd Edition,
2006, Blackwell Publishing, London
5. http://www.cdc.gov/flu/avianflu/h5n1-people.htm
6. http://www.who.int/influenza/gisrs_laboratory/terminology_ah1n1pdm09/en/index.html
88
rhinoviruses
adenoviruses
parainfluenza viruses
human metapneumoviruses
coronaviruses
enteroviruses
influenza viruses
pharyngitis
laryngitis
croup (laryngotracheobronchitis)
tracheitis
bronchitis
bronchiolitis
pneumonia
Rhinovirus infections
Etiologic agent
89
Rhinoviruses are the etiological agents of about 50% of the common cold cases. They are RNA
viruses and take part of the Picornaviridae family.
Epidemiology
Rhinovirus infections are more frequent in lower age groups. Children under the age of 6
introduce the infection into their families, with a subsequent spread of the infection among
family members.
There is a higher seasonal incidence in the autumn and spring in temperate areas.
Rhinoviruses are transmitted through contact with infected secretions, such as infectious droplets
suspended in the air, infected surfaces, hand to hand contact. Close physical contact is needed in
order to transmit the virus.
Studies have demonstrated that lack of sleep, fatigue and exposure to cold do not facilitate the
appearance of illness caused by rhinovirus, but stress might conduct to the disease.
There are multiple serotypes of rhinoviruses that circulate together. Despite the presence of
multiple neutralizing antibodies in adults, further infections can still occur.
Pathogenesis
Rhinoviruses enter the human organism through the nasal mucosa, which becomes hyperemic,
edematous, with a mucoid discharge. On the second and third day large quantities of virus are
produced at this level.
In 8hours - 2days after the nasal inoculation clinical symptoms appear. Virus shedding begins
shortly before or together with the onset of symptoms.
Immunity develops after infection, however not in every individual. In case of massive
inoculation infection with the same serotype is possible despite the presence of antibodies.
Clinical manifestations
The symptoms that characterize the common cold are present: rhinorrhea, sneezing, nasal
congestion, sore throat, cough, hoarseness. Systemic symptoms (fever, headache) are mild and
uncommon. The recovery is spontaneous after 4-9 days. Lower respiratory tract might be
affected in children.
Complications
-
otitis
sinusitis
Diagnosis
Etiologic diagnosis cannot be made based on the clinical symptoms.
Laboratory diagnosis:
-
isolation of the virus from nasal secretions in tissue culture (it is rarely applied)
detection of serum antibody (it has no diagnostic value due to the many serotypes)
Treatment
There is no etiologic (antiviral) treatment.
Pathogenic and symptomatic therapy: nonsteroidal anti-inflammatory drugs (NSAIDs),
antihistamines, hydration, cough suppressants, nasal decongestants.
Antibiotics are recommended only in case of bacterial superinfection.
Prevention
Intranasal interferon is efficient, however causes local irritation.
In order to reduce the transmission rate appropriate hand washing, covering coughs and sneezes
with disposable nasal tissues, and environmental decontamination is useful.
Adenovirus infections
Etiologic agent
Adenoviruses are DNA viruses that belong to the genus Mastadenovirus. They can cause acute
respiratory infections and conjunctivitis.
Epidemiology
Adenoviruses cause infection especially in childhood, infancy and among the military recruits.
Neonates in most of the cases receive maternal antibodies that provide protection until the age of
6 months.
The route of transmission is the same as that of rhinoviruses, but adenoviruses can be transmitted
by fecal-oral route or inoculation into the conjunctiva also.
There are many serotypes of adenoviruses. Immunity after infection is serotype-specific, and
incomplete.
Pathogenesis
Adenoviruses can cause:
a. lytic infection in human epithelial cells that conducts to virus multiplication at high level and
cell death
b. latent, chronic infection in lymphoid cells (for example in the tonsils), with a low level of
virus multiplication and cell death, that can be overcome by cell multiplication
c. oncogenic transformation with the viral DNA integrated in the structure of the cellular DNA.
In this case viral DNA replicates together with the cellular DNA, with no new virion production.
In respiratory tract infections adenoviruses migrate from the upper towards the lower segments
of the respiratory tract, however they can reach the respiratory tract by the means of viraemia
also. Gastrointestinal infections might be associated to respiratory tract infections. In this case
the virus is swallowed, and can be isolated from the stool.
The immune response is based upon the production of IgA at the level of mucosa and serum
antibodies.
91
Clinical manifestations
Adenoviruses can cause several types of clinical manifestations, such as:
-
acute laryngotracheitis
epidemic keratoconjunctivitis
hemorrhagis cystitis
infantile diarrhea
intussusception in children
encephalitis, meningoencephalitis
Diagnosis
Adenovirus infection can be suspected based on epidemiological and clinical data.
Laboratory diagnosis:
-
cytopathic changes
immunofluorescence
in
tissue
culture,
identification
of
the
virus
with
Treatment
There is no etiologic therapy, only symptomatic and pathogenic treatment can be used.
Prevention
Parenteral vaccines containing live attenuated or inactivated virus were used, but given up
because of the oncogenic character of the virus in animal models. Live attenuated oral vaccines
were used among the military recruits, with no availability of the vaccine in the last decade.
General methods such as current disinfection in hospitals, appropriate disinfection of the
swimming pools, health education can be applied.
92
Diagnosis
Epidemiologic and clinical data are not sufficient for the diagnosis.
93
Laboratory diagnosis:
-
PCR assays
serologic diagnosis - the antibody level is determined from acute and convalescent
sera
Treatment
The therapy is symptomatic and pathogenic. Antibiotics are used in case of bacterial
superinfection. Severe cases need hospitalization, in case of acute respiratory distress
epinephrine aerosols, systemic and aerosolized glucocorticoids and humidified oxygen are given.
There is no antiviral therapy, however ribavirin was used in immunosuppressed patients.
Prevention
There is no vaccine available, general preventive methods should be applied.
temporary protection appears, and the disease is milder. The musosal IgA, serum antibodies and
cell-mediated immunity have a role in protection.
Clinical manifestations
HRSV causes a wide spectrum of diseases:
-
pneumonia
bronchiolitis
tracheobronchitis
The disease has a mild form in the beginning, with low fever, cough, rhinorrhea, wheezing,
followed by recovery. In severe cases tachypnea, dyspnea, hypoxia appears, with wheezing,
rhonchi and rales at the physical examination. Hyperexpansion, infiltrates can be seen on the
chest radiograph.
Severe forms appear in premature infants, in those with congenital heart disease, or in the
immunosuppressed. The elderly can develop severe HRSV pneumonias.
Diagnosis
Epidemiologic findings can facilitate the diagnosis (outbreaks of severe respiratory diseases
among infants).
Laboratory diagnosis:
-
serologic tests: comparison of the antibody levels of acute and convalescent sera
Treatment
Treatment is symptomatic, in case of hypoxia oxygen, hydration, antibronchospastic agents are
given. In severe hypoxia mechanic ventilation is needed.
Aerosolized ribavirin may be efficient in severe diseases in infants.
Prevention
In premature infants, children with cyanotic heart disease or bronchopulmonary dysplasia who
are younger than 2 years anti-HRSV immunoglobulin can be administered every month. In
pediatric wards protective barriers for the conjunctivae and disposable gloves should be used.
Epidemiology
Infection affects the children at early ages, and they develop antibodies until the age of 5 years.
Other age groups, elderly people, and immunosuppressed patients can also be affected.
Two genotypes circulate in parallel.
Clinical manifestations
HMPV affects the upper and lower respiratory tract, croup, bronchiolitis, pneumonia might
develop. In older children and adults the infection can be asymptomatic, or a common cold might
appear. Pneumonia can be present in the elderly. Severe diseases appear in the
immunosuppressed patients.
Diagnosis
Laboratory diagnosis:
-
Treatment
Treatment is symptomatic and pathogenetic.
Prevention
There are no specific preventive methods.
Coronavirus infections
Etiologic agent
Coronaviruses are RNA viruses that are part of the Coronaviridae family. They have 3 antigenic
groups, and infect a wide range of animals. Coronaviruses from serogroups 1 and 2 infect
humans also. The coronavirus responsible for the severe acute respiratory syndrome (SARSCoV) belongs to serogroup II.
SARS-CoV survives 1-2 days on dry surfaces at room temperature, in pathological products it
can survive for 21 days at low temperatures. It is sensitive to heat and disinfectants.
Epidemiology
Human coronavirus infections are ubiquitary, they occur usually in childhood. They produce the
symptoms of common cold, and appear more frequently in the cold months.
In 2002-2003 there was a pandemic due to SARS-CoV. It had animal origins, the natural host
was the horseshoe bat, and the outbreak started in southern China due to human contacts with
infected partially domesticated animals (such as the palm civet).
96
In contrast with other viruses, after crossing the border between species the virus was transmitted
very efficiently among humans. The virus was transmitted at high rates by persons with severe
disease, whereas those with asymptomatic infections seemed not to transmit it. Therefore the
outbreak could be controlled by correctly applied preventive measures. It affected more than
8000 people in 28 countries, with a 9.5% fatality rate.
The route of transmission was fecal-oral, respiratory through aerosols, and by the means of
wastewater.
Pathogenesis
Coronaviruses that cause common cold symptoms infect the epithelial cells of the nasopharynx,
replicate there, with subsequent local inflammatory response.
SARS-CoV penetrates the cells of the respiratory tract, with subsequent systemic infection. It
was detected in the stool, blood, urine, kidneys, CSF. The viral load increases progressively until
the 10th day of the illness, after that it decreases in parallel with the appearance of antibodies.
Despite of the decrease of viral load the symptoms can still worsen in this period. This might
suggest an immunpathologic mechanism of the lesions in the lung.
Hyaline membranes are formed in the alveoli, with descuamation of the pneumocytes, and there
is a mononuclear interstitial infiltrate. Giant cells are also present.
In the patients sera elevated levels of inflammatory cytokines and chemokines were detected.
Necrosis of the white pulp of the spleen and generalized arteritis of the small vessels were
described.
Clinical manifestations
The incubation period is 2-7 days, can be prolonged until 20 days. The symptoms are nonspecific
in the beginning: fever, myalgia, headache, malaise. The chest x-ray shows peripheral and
inferior interstitial infiltrates. After a short, transient recovery fever reappears with dry cough
and dyspnea, and in 25% of patients diarrhea develops. The radiological findings evolve to
bilateral multifocal infiltrates. The symptoms can progress towards adult respiratory distress
syndrome (ARDS) and multiorgan dysfunction. Illness is severe in the elderly, patients with
chronic diseases, pregnant women, however it is less severe in children.
Non-SARS coronaviruses produce common cold, in military recruits lower respiratory tract
disease, pneumonia in infants.
Diagnosis
Epidemiological data: contact with confirmed or suspect cases of SARS in the last10 days before
the onset of symptoms, travel history in the affected geographic regions.
Clinical data: the presence of fever, chills, myalgias, headache, malaise, dyspnea, acute
respiratory distress.
Laboratory findings in SARS:
-
isolation of the virus on cell cultures (from respiratory secretion, urine, stool, blood)
97
RT-PCR (from respiratory secretions and blood in the early phases, from stool and
urine in the later phases of illness)
98
CHAPTER 3
Central nervous system infections
Brndua ilea
Acute meningitis
Meningitis is the most common and important infection of the central nervous system (CNS)
being a severe disease with high mortality, requiring urgent diagnosis and immediate treatment.
Etiology
Theoretically, any agent can affect the leptomeninges, causing meningitis. But meningitis is a
rare disease occuring whenever infectious agents with specific pathogenic qualities meet
vulnerable organisms most likely due to favorable factors: immunological, age-related or
external conditions. Infectious agents that can cause meningitis are listed in Table I. The most
common meningitis is the viral one caused by enteroviruses (80%) and of the bacterial ones the
most frequent are produced by pneumococcus, meningococcus, Haemophylus influenzae (70% Fig. 1). Other etiologies are less frequent (Table II), depending on predisposing factors (Table
III).
Viruses
DNA viruses:
Herpes viruses
RNA viruses
Enteroviruses
Polio,
Coxsackie
unclassified
ECHO,
AND
Togaviruses: rubella
Myxoviruses: mumps,
measles, influenza and
parainfluenza
Arenaviruses:
Armstrong virus
Rhabdoviruses: rabies
Retroviruses: HIV
Bacteria
Mycobacterium
tuberculosis
Spirochetes
Borrelia,
leptospire
Fungi
Cryptococcus
neoformans, Candida
Protozoa
Toxoplasma
Plasmodium
falciparum
Treponema,
gondii,
Various species
Metazoans Cysticercus
cellulosae,
Angiostrongylus
cantonensi
Table I - Agents involved in the etiology of infectious meningitis
New born and <2 months
Adults
Elderly
Congenital
defects Staphylococcus aureus,
(spina
bifida, epidermidis
meningomyelocele,
Gram negative bacilli
congenital fistulas)
100
Acquired defects
(posttraumatic,
postsurgical)
Streptococcus
pneumoniae
Haemophylus influenzae
Neisseria meningitidis
(otitis,
sinusitis,
Streptococcus
pneumoniae
Haemophylus influenzae
Staphylococcus aureus
Anaerobes
Group B Streptococcus
Listeria monocytogenes
Herpes simplex 2
Staphylococcus aureus,
epidermidis
Gram negative
Anaerobes bacteria
Neisseria meningitidis
Asplenia
Streptococcus pneumoniae
Streptococcus pneumoniae
Neutropenia
Gram-negative
bacilli,
staphylococci, pneumococci
pathogenic
digestive
path
(enteroviruses),
Nervous path: olfactory nerve (herpes simplex), peripheral nerves (rabies virus, polio)
Clinical manifestations:
Meningitis being the infection of leptomeninges, is commonly associated with the following
syndromes:
infectious syndrome
meningean syndrome
encephalitic syndrome
102
Infectious syndrome includes signs such as fever, chills, myalgia, malaise, high fever and
relative bradycardia with a possible diphasic evolution.
The meningean syndrome is based on symptoms whose intensity are related in part to the degree
of ICH: headache (continuous, violent, accompanied by rachialgia), jet vomiting, photophobia,
and physical signs: cutaneous hyperesthesia, vasomotor disorders, signs of menigean irritation.
Signs of meningean irritation specific to the disease are caused by the inflammation of the
meninges that surround the spinal nerve roots. In meningitis rachialgia is so intense that the
patient takes antalgic positions,"gun cock" position, head is in extension and knees are flexed
(lateral decubitus) and sitting in "tripod position" (lying on the bed with his hands behind the
trunk).
Signs of muscle contraction are:
stiff neck: the examiner trying to make passive flexion of the head on the trunk,
limitation or incapacity is noticed.
Bruzinski 1: the lower limbs in extension, forced passive flexion of the head leads to
flexion of legs on thighs
Brudzinski 2: the lower limbs in extension,triple flexion of the leg produces a similar
response in the contralateral limb
ICP is the result of constant equilibrium established between the volume of cerebral blood
volume, the volume of nerve mass and the volume of CSF. The increase in volume of one of the
components mentioned leads to ICH syndrome with pathophysiological consequences such as
cerebral ischemia and cerebral herniation.
ICH clinical symptoms:
headache, exacerbated by standing or head movements
vomiting jet, drowsiness, bradycardia, disturbances of consciousness, seizures.
ICH meningitis syndrome is based on:
ICH syndrome accompanies meningitis and it can be objectively detected in advanced forms by
fundus examination by papillary edema and stasis. The presence of the latter warns against spinal
puncture because of the risk of brain substance migration.
Encephalitic syndrome
103
exacerbated forms usually bacterial meningitis associated with infectious and toxic
syndrome with high mortality rate due to the encephalitis component and lesions of the
vital organs (eg meningococcemia with purpura fulminans Waterhouse-Friderichsen
syndrome)
acute forms, classical ones violent onset while the health status seems perfect
apparently, infectious and meningean syndrome
attenuated forms - often of viral etyology, the infectious syndrome is modest and signs of
meningeal irritation are absent or discrete. Diagnosis is validated by lumbar puncture.
subtle forms - may go undiagnosed, being spontaneous and having rapid remission,
usually of viral etiology.
Diagnosis
Diagnosis of meningitis constitutes a major clinical emergency, subject to starting immediately
the etiological therapy. Positive diagnosis has two major objectives:
Diagnosis of meningitis as such shall be based on clinical data (presence of infectious syndrome
of HIC, meningeal signs of brain damage) and laboratory confirmation of meningitis by
examination of CSF obtained by spinal puncture:
a. examination begins right from puncture by assessing the appearance of CSF and pressure of
elimination. The jet flow of CSF points to high pressure of CSF, confirming the suspicion of
meningitis. Normal aspect or hipotension do not invalidate the diagnosis of meningitis.
b. Laboratory examination of CSF consists of:
104
existing cell count in CSF (pleocytosis). Any increase above 5/mm indicates an
inflammation. The number of these cells can be indicative in diagnosis:
- between 10-1500 elements - viral etiology, fungal, leptospirosis etc..
- between 200-400 items - specific etiology (TB) or protozoal
- thousands or tens of thousands - bacterial etiology
cultures performed at the patients bedside or in the laboratory under sterile conditions on
blood agar, Chocolat, Mueller-Hinton, Loewenstein, Sabouraud
immunological examination is designed to detect bacterial antigens in CSF: countercurrent immuneelecxtrophoresis (CIE), latex agglutination test, ELISA technique,
immunofluorescent techniques, the detection of specific DNA sequences in CSF by
means of gene amplification (PCR)
virological exam: performed in virology laboratories, aiming to isolate and identify the
virus in CSF
Other laboratory tests in meningitis: lung X-ray examination, ENT examination, CT scan, MRI,
EEG route. A special mention should be blood culture which is mandatory in patients with
bacterial or fungal meningitis.
Meningitis
CSF
type
appearance
Normal
CSF
Clear
Bacterial Cloudy
Meningitis
Cytology
Bacteriological
Biochemical
Proteins Glucose Chloride
<45mg%
glucose
Approx.
700mg%
Much
Much
Normal
increased + decreased or low
++
TB
Clear,
200-600 elem / Positive
stain Much
Much
Meningitis xantochrome mm 3 small and Ziehl-Nielsen
increased + decreased
medium-sized
+++
Lwenstein +
Low
mononuclear
lymphocytes
Viral
Clear,
meningitis opalescent
Moderately N
increased +
+
N
or
higher
Fungal
Clear
Meningitis
meningeal reaction - slight inflammatory reaction with early changes of CSF (10-100
lymph / mm3). May occur in many acute infectious diseases.
Intracerebral hemorrhage,subarachnoid
insolation (sun-stroke)
cerebral thrombophlebitis
Post-puncture syndrome
Complications
The most common complications occurring in bacterial and fungal meningitis are correlated with
age, germ virulence, immune system conditions, related diseases, early onset and correct
treatment.
Early complications:
septic shock
seizures
cerebral vasculitis
hydrocephalus (fig. 5)
brain abscess
Late complications:
mental retardation
motor deficit
deafness, blindness
epilepsy
Treatment
A correct treatment in acute meningitis requires the following:
possibility to monitor antibiotic levels in CSF for an efficient antibacterial titer at this
level
7%
2%
2%
S. pneumoniae
33%
18%
29%
N. meningitidis
Group B
Streptococcus
E. coli
H. Influenzae
Alti bacili gram
negativi
107
Fig. 5 - Hydrocephalus
Meningococcal disease
(Epidemic cerebrospinal meningitis)
Meningococcal disease is a major clinical manifestation of infection with Neisseria meningitidis,
which can take the following forms fulminant meningococcemia (purpura fulminans),
nasopharyngitis and healthy carrier of meningococ.
Etiology
Neisseria meningitidis (meningococcus) is a Gram negative diplococci, aerobes, 0.6 to 1 micron
with typical alignment (the "beans" that fit the concave side) of different sizes and extracellular
location, but frequently intracellular, belongs to the Neisseria type of Neisseriaceae family (Fig.
50). Meningococcus is a pretentious germ, he develops only on blood cultures (Socol agar,
serum agar). The medium used universally is Mueller-Hinton. Meningitis is extremely fragile in
external environment being destroyed rapidly by cold, heat, dryness. The optimum temperature
for growth is 36-37 C. To obtain the culture it is necessary that from the sampling point to the
thermostat, the cerebrospinal fluid (CSF, and so on) to be transported at 37 C.
Classification
After the antigen 12 serogroups structures have been identified A, B, C, E, H, I, K, L, X, Y, Z
and W-135. Identification is made with specific antisera. The most common meningococcal
disease is caused by the serotypes A, B, C and Y. In Africa and Europe the epidemic type is
represented by meningococci of group A, while groups B and C produce epidemics elsewhere
sporadically, meningococii of other groups are less virulent and of lesser importance.
Meningococii contain strong endotoxin (lipopolysaccharide) with pathogenic role in
meningococcal purpura and other clinical manifestations.
Epidemiology
Meningococcal infection is spread across the globe. Infections occur sporadically throughout the
year, but with a higher incidence in winter and spring.
108
The source of infection is only the human being: meningococci carriers and patients with
meningococcal nasopharyngitis disease.
Transmission is by direct contact through infected Pflugge droplets or indirectly through recently
contaminated objects.
Contagiousness is high, but virulence is generally weak and variable, which explains the low
number of disease compared with those infected.
Susceptability to infection is general, maximum at children decreasing with age.
Immunity. Based on studies it is known that there is a group meningococcal immunity expressed
by serum bactericidal activity and the presence of agglutinins and complement fixers antibodies.
Immunity is achieved through group polysaccharide antigen vaccines.
Pathogenesis
The gate for meningitis is nasopharynx and respiratory mucosa. An inapparent infection usually
follows or meningococcal nasopharyngitis. Overcoming the body's defense may result in
bacteremia, possibly followed by dissemination of meningococci in the form of metastases in
different organs and tissues: skin, meninges, joints, endocard, lung. Serum bactericidal activity
against meningococci belong to IgM fraction and this fraction deficit favors dissemination. Thus
meningococcal septicemia is produced; injuries that occur are predominantly vascular wall lesion
with vascular necrosis and thrombosis, resulting large petechiae and hemorrhagic areas. The
most severe form is fulminant meningococcemia with Waterhouse-Friderichsen syndrome in
which there is bleeding into the adrenal glands and death occurs in 24 hours. In most cases of
Waterhouse-Friderichsen syndrome microthrombi have been found in large numbers,
particularly in the kidney, liver, lung, choroid plexus.
Disseminated intravascular coagulation (DIC) is today considered a major pathogenic factor in
producing rapid death in meningococcemia. The syndrome can be detected by indentifying the
following: thrombocytopenia (20.000-30.000/mm3), increased prothrombin time (over 15
seconds). A consumptive coagulopathy with significant deficiency of coagulation factors (V,
VII, VIII and X) is noted. Intravascular microtrombi are formed causing difficulties in
microcirculation and a generalized bleeding diathesis.
Responsible for producing Waterhouse-Friderichsen syndrome is meningitis endotoxin. Against
meningococcal antigen sensitization phenomena may occur as fever, arthritis and vasculitis with
exanthematic aspect.
Complement is an important component of resistance against meningococcal illness. A decrease
in complement function is noted in the forms of invasive infection. Genetic deficiencies of
complement C3, C5, C7, C8 favor recurrent meningococcal meningitis. Another contributing
factor is gender, the disease being more common in males.
Clinical manifestations
Clinical manifestations of meningococcal infection are varied. The disease can occur in the
following forms: pharyngitis, sepsis or meningitis.
Meningococcal nasopharyngitis is the most common manifestation of meningococcal infection,
bacteriological exam contributes to identify the etiology by isolating meningococci. They have a
considerable epidemiological importance.
Meningococcal sepsis (meningococcemia). In its acute state it usually presents itself as the
worst option being extremely virulent, although chronic forms may exist as well.
109
Acute meningococcemia. Onset is sudden with fever, chills, myalgia, arthralgia. The patient
becomes apathetic, hallucinating or becomes comatose. The skin develops a rash with dark red
spots as closed, bleeding, unevenly distributed (Fig. 8). In severe cases with vascular thrombosis
the aspect is that of necrotic appearance or gangrene of the skin. Meningococii can be isolated by
culture from eruptive elements. The patient presents arthralgia or suppurative arthritis, herpes
labialis, splenomegaly.
In 20-30% of cases, these clinical manifestations are identified as meningoencephalitis.
Sudden onset of Meningococcemia. Onset is brutal with bacterial shock, massive purpura wide
spread bleeding. The patient may be febrile or hypothermic, in shock, with pallor, cyanosis,
tachycardia, hypotension, dizziness, agitation, coma. DIC is present most often manifested by
large gastrointestinal and cutaneous areas of bleeding. Death can occur quickly within a few
hours. (Fig. 9)
Chronic meningococcemia. Rare for meningococcemia evidenced by repeated fevers, chills,
arthralgia, headache, petechiae and purpura on the skin nodules. The clinical picture may suggest
vasculitis or collagen.
Meningococcal disease. Incubation: 2-5 days.
Onset: sudden, with chills, high fever, headache, nausea, vomiting, convulsions, coma.
The patients condition. The patient presents the picture of an acute meningitis: persistent fever,
headache, delirium, agitation, cutaneous hyperesthesia, photophobia, drowsiness, stupor. The
position of the patient is usually in the "cock of the rifle" patient showing signs of muscle
stiffness (stiffness of neck, Kerning signs, positive Brudzinski). Frequently there is an oral or
peribucal expanded herpes. Children have a characteristic cry ("encephalitic cry"), frequent
seizures, bulging fontanelle. CSF is high, turbid, purulent, containing hundreds or thousands of
cells / mm3, most neutrophils and intra-and extracellular meningococci identified on smears
(blue methylene, Gram). Neutrophilic leukocytosis are found in blood.
Clinical Forms
attenuated form
pneumonia
pericarditis
Arthritis
endocarditis
conjunctivitis.
Complications
110
Meningococcal disease is part of the list of contagious diseases with compulsory admission. For
family contacts and close contacts chemoprophylaxis with one of the following antibacterial
substances is recommended:
Rifampicin 600 mg / day in adults, 5 days
Spiramycin, 2g/day in adults, 50 mg / kg / day in children, 5 days
sulfonamides only if there is clear evidence of sensitivity of meningococci to this class
Specific prophylaxis. Lately we obtained effective vaccines against group A,C meningococcal
infection, which is administered in a single dose subcutaneously or intradermally.
Pneumococcal Meningitis
Definition
Pneumococcal meningitis is a type of meningitis with the extremely severe evolution due to
Streptococcus pneumoniae. It can be primary (in this case nasopharyngeal entry gate ) or
secondary to pneumococcal outbreaks or parameningeal (ORL). Patients with splenectomy, head
trauma, chronic diseases (cirrhosis, diabetes), fistulas with subarachnoid communication, the
elderly are especially susceptible.
The onset is usually sudden with an infectious syndrome, intracranial hypertension phenomena,
brain damage and rapidly evolving to coma, seizures, focal neurological signs.
Diagnosis is supported by CSF examination, Gram positive cocci in diplo are detected,
lanceolated, coated, extracellular and positive cultures as well (fig. 10, 11). Pneumococcus can
be identified in blood cultures.
The evolution of the disease is severe, since there are frequent relapses because of uncared for
fistula. The most common complications are hydrocephalus, subdural empyema, vasculitis. The
death rate, despite treatment, is 30% especially in the elderly.
Treatment is primarily etiologic because of additional issues such as:
112
Deposits of fibrin in early stages which leads to decreased access of antibiotics and of
active concentrations below the necessary bactericidal level;
Cefotaxime at a dose of 6-8 g / day for adults and 100 mg / kg / day for children;
Antibacterial treatment duration is at least 10 days, preferably 14 days depending on the clinical,
biological constants and changes in CSF.
Pathogenetic treatment is performed by administering anti-inflammatory steroids: hydrocortisone
hemisuccinate, dexamethasone, solumedrol.
Depletion therapy is oral mannitol, furosemide.
Symptomatic treatment: anti-pyretic, analgesic and neuroroborant.
Prophylaxis
In addition to the prevention of pneumococcal infection particular attention is given to cases of
patients with high risk due to favorable conditions. In patients with relapses of chronic diseases
splenectomised vaccination with polyvalent (Pneumovax) is recommended because it includes
23 of the most common and pathogenic serotypes.
Diagnosis is based on historical data supported by clinical and CSF examination where small
pleomorphic Gram negative cocobacilli have been detected as well as positive cultures. (Fig. 12,
13)
Treatment
A reconsideration of the etiologic treatment has been necessary in recent years triggered by
strains resistant to Ampicillin and Chloramphenicol in 30-40% of cases. Prior to antibiogram in
case of suspicion it is recommended to begin treatment with one of the following thirdgeneration cephalosporin: Ceftriaxone (100 mg / kg / day iv) ceftazidime, cefotaxime, ampicillin
(100 - 200 mg / kg / day iv) Amoxicillin. Added to these the cortisone, depleted, symptomatic
therapy is recommended as well. Antibacterial treatment duration is 14 days.
Prophylaxis
A vaccine (antihaemophilus influenzae type B) is currently available on the market, with
parenteral administration and satisfactory immunogenicity. Unfortunately immune reaction is
estimated to be effective only for children over the age of 1.5 years.
Nonspecific measures target children's communities by avoiding access of pharyngeal carriers,
especially in care units with chronic illness or immunological deficiencies.
Man is infected by eating or contact with sick animals or inhalation of contaminated dust.
The real incidence of the disease in humans is unknown because of the large number of
unapparent infections. The most frequent infection period is summer. It generally affects
immunosuppressed persons.
Positive diagnosis is established on the basis of epidemiological, clinical data and confirmation
is possible by isolating the germ of CSF from blood cultures, throat swabs, conjunctival
secretions.
Identification of isolated germ is carried out by immunofluorescence, ELISA technique.
Treatment
Moncytogenes Listeria generally responds to Ampicillin, Cotrimoxazole, Chloramphenicol. It is
usually resistant to cephalosporins and polimyxin. In such cases bi-therapy with Ampicillin and
Cotrimoxazole is recommended as well as anti-inflammatory steroids, depleted, symptomatic
therapy.
Staphylococcal meningitis
It is a particularly severe form of meningitis in adults, elderly, newborn.
Etiology
Staphylococci (staphs) are Gram-positive cocci, aerobes, immobile, non-sporing that are
arranged charactheristically in "piles", "bunches", both in pathological products and in solid
cultures. (Fig. 16, 17)
Staphylococcus species is divided into: Staphylococcus aureus, epidermidis and saprophyticus.
From a clinical point of view the pathogenetic classification is more important since it creates
two categories:
Staphylococci coagulase producers (highly pathogenic);
Coagulase-negative staphylococci (except pathogens: S. epidermidis, S. saprofiticus).
Positive diagnosis requires clinical examination of an array of staphylococcal sepsis or by
identifying a vulnerable entry gate. Bacteriological laboratory confirmation is given by viewing
staph in CSF and especially the cultivation of CSF, blood or metastatic foci.
Treatment
115
116
Electronic microscopy
Diagnosis is supported by anamnesis, confirmed by clinical and laboratory data (CSF, blood
culture), blood culture, latex agglutination, ELISA serology, PCR (Fig. 21).
Etiological treatment involves the combination of ampicillin (100 - 200 mg / kg / day iv) with
aminoglycosides (gentamicin, netilmicin - 5-7 mg / kg / day iv) or third-generation
cephalosporins, and vancomycin phosphomycine rifampicin in cases of intolerance to beta
lactams.
Pathogenetic treatment is carried out with anti-inflammatory steroids, depleting, symptomatic
drugs.
The treatment duration is of at least 14 days depending on the clinical status and laboratory
results.
118
The hematogenus path during primary infection (in children), if it is generalized (miliary
TB);
Clinical manifestations
Incubation is long, a few weeks in its reactive forms, but it can be shorter, of only a few days in
the primary disseminated forms, especially in immunocompromised bodies.
The onset is insidious. It takes 2-4 weeks until the onset of the meningean syndrome, during
which the patient accuses headache, fatigue, loss of appetite, drowsiness, low fever.
State of patient while illness is in progress: infectious syndrome is moderate; meningean
syndrome is gradually increasing in intensity. The stiffness of the neck becomes extreme
119
("wooden backhead"), the clinical manifestations are predominantly the result of the encephalitic
syndrome. The patient is drowsy, confused, exhausted, cranial nerve palsies may occur
(especially abducens, oculomotor), globe bladder, pyramidal motor deficits. HIC syndrome is
most often present.
Laboratory data: blood examination may be normal, and CSF has the following features:
clear or xantocrom;
hypertension;
increased albuminorachia;
low chloride;
fibrin coated.
Cultures become slowly positive in 4-6 weeks, and Ziehl-Nielsen stained smear may reveal acidalcolo-resistant bacilli. Supporting diagnosis can be made based on fluorescent staining of
smears, detection of mycobacterial antibodies in CSF, Lowenstein culture, mycobacterial
detection of DNA fragments in the CSF by PCR (Fig. 22).
Laboratory tests can support the diagnosis namely: lung X-ray examination may reveal miliar
aspect or pulmonary modifications, fundus examination may detect the presence of choroidal
tuber and cerebral CT scan may reveal brain edema, hydrocephalus, cerebral softening zone.
Positive diagnosis is supported by epidemiological data (history of TB contact,
immunocompromised diseases), clinical data, prolonged meningean syndrome, encephalitic
syndrome, CSF aspect.
Differential diagnosis is carried out taking into account, such as:
Treatment
Etiological treatment is established as early as possible at the slightest suspicion, by associating
the first 4 major anti-tuberculosis preparations:
This regimen can be modified over time in two cases: in case of therapeutic inefficiency or by
analysing the isolated bacillus or in case of some forms of intolerance or adverse reactions. In
these situations the solution is to resort to the use of alternative anti-TB drugs such as
ciprofloxacin, capreomycin.
Duration of daily administration is 3 months, after which an intermittent dosing schedule 3 days /
week (3/7) or 2 days / week (2/7) is recommended, the dose is thereafter appropriately modified,
for a period of up to 9 months.
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Viral meningitis
The feature that distinguishes viral meningitis from other types of meningitis is the particular
way of evolution, namely the tendency to spontaneous healing. The pattern of the evolution of
viral meningitis includes:
the invasion phase lasts a few days (3-7 days), thereby being obviously different from
bacterial meningitis, tuberculosis, fungal;
the inflammatory syndrome with meningeal irritation is prevalent, while ICH syndrome
and encephalitis syndrome are diminished or absent.
Sodium diet.
Clinical Forms
Fungal meningitis
Etiology
More than one species may be involved: Cryptococcus neoformans, Candida albicans,
Histoplasma capsulatum. These agents have in common the fact that they attack
immunocompromised organisms immunocompromised (AIDS, lymphoma, cancer,
immunological diseases).
Pathogenesis
In the absence of the defense capacity of the body, fungi can become invasive, moving from
colonization to systemic forms. Brain lesions are located mainly basal, fibrin coated, causing
vascular, necrotic injury, cloasonation and obstructions.
Clinical manifestations:
Onset: usually insidious. Moderate meningeal syndrome, the encephalitic syndrome when
present is severen and an indication of increased severity. The clinical manifestations are
determined by the ICH syndrome is often dominated by ICH and neurological (extreme
headache, nausea, vomiting, photophobia, bradycardia, cranial nerve impairment, convulsions,
paralysis).
Diagnosis
Examination is based on the CSF: clear, hypo-or hypertension, cellular elements 400-600
lymphocytes / mm 3 , proteinorachia greatly increased, glicorachia low. Giemsa stained smears,
China ink can identify fungi. The culture medium used for fungi is Sabouraud medium. For the
determination of the fungal antigens latex agglutination technique is used.
Etiologic treatment
Amphotericin B in progressive dose administered IV, 0,1 - 0,3 mg / kg / day, 2-3 weeks.
Flucytosine 150 mg / day orally, and IV.
Fluconazole 200-800 mg / day, 4 weeks iv then po.
Pathogenetic treatment
Anti-inflammatory, symptomatic treatment, depleting drugs.
123
References:
1. Bartlett J. Pocket Book of Infectious Disease Therapy. Lippincott Williams & Wilkins,
2002;167-270.
2. Bartlett J. Pocket Book of Infectious Disease Therapy. Lippincott Williams & Wilkins,
2007;120-240.
3. Chiotan M. Boli infecioase. Ed. Naional, 2002; 149-200.
4. Gilberd D, Moellering R, Eliopoulos G, Sande MA. The Sanford Guide to Antimicrobial
5. Gopa B Green, Ian S Harris, Grace Lin. Manual de terapeutic medical Washinghton
Lippincott Williams & Wilkins, Ed. Medical, Ediia 31, 2006; 358-399.
6. Koedel U, Scheld WM, Pfister HW. Pathogenesis and pathophysiology of pneumococcal
124
ENCEPHALITIS
Carmen Chiriac
Definition.
Encephalitis represents an inflammation of the brain parenchyma, characterized by focal or
diffuse neuro-psychic symptoms. Encephalitis is distinct to meningitis although on clinical
evaluation both of them have similar manifestations: headache, photophobia, neck stiffness.
Enchephalitis is also distinct to cerebritis which appears in the stage preceding the formation of a
brain abscess and implies a bacterial infection with massive destruction of the brain tissue.
Most frequently, encephalitis is a viral infection, injuring the brain parenchyma in various
degrees, of mild to severe gravity. Patients with encephalitis may also suffer from meningitis
meningoencephalitis, lesions of the spinal cord - encephalomyelitis, or lesions of the spinal nerve
roots encephalomyelo-radiculitis.
Etiology.
The most common etiology of encephalitis is viral. The most important viruses that might
determine sporadic encephalitides are the herpetic viruses:herpes simplex virus (HSV) 1 and 2,
varicella-zoster virus (VZV), Epstein-Barr virus (EBV), enteroviruses (includes Coxackieviruses,
Echoviruses, enterovirus 71) the measles virus, influenza viruses, mumps virus, rubella virus.
These viruses are transmitted by interpersonal contact. An important category of encephalitides
is due to the group of arboviruses, transmitted to humans by means of some vectors: ticks,
mosquitoes. Rabies is a particular form of encephalitis due to the rabies virus transmitted by
animal bite.
The bacterial etiology is not very common, implying species of Mycoplasma, rickettsi,Borrelia
burgdorferi. Other etiologic agents could be fungi, protozoa or prions.
Classification of encephalitides
-
lesions)
- encephalomyelitis (brain and spinal cord lesions)
- encephalo-myelo-radiculo-neuropathy
spinal cord / peripheral nerves lesions)
(brain
Pathogenesis
1. Direct invasive mechanism Primary, viral encephalitis
The virus replicates at the entrance gate: respiratory tract(e.g.measles virus), digestive tract
(e.g.enteroviruses) or skin(e.g.arboviruses) and produce a local infection, followed by
dissemination via bloodstream (viremia),leading to invasion and replication in the Central
Nervous System (CNS).The arboviruses probable enter the CNS via cerebral
capillaries,determining vascular endothelial cell infection,preceding infection of the neural
parenchyma.
Rabies virus and polioviruses gain acces to the CNS trough neuronal networks.
When the virus across the blood-brain barrier, the virus can infect the neural cells, with resultant
disruption in cell functioning,neuronal death, perivascular congestion, hemorrhage, and a diffuse
inflammatory response that disproportionately affects gray matter over white matter. Certain
viruses have a particularly tropism to a specific brain area due to neuron cell membrane receptors
found only in specific portions of the brain, with more intense focal pathology in these areas.
Herpes simplex virus has predilection for the inferior and medial temporal lobes.
2. The indirect immune-mediated mechanism Post-infectious encephalitis(ADEM)
that follows an infection,most common :measles,varicella,rubella,mums and mor recent were
involved influenza A and B viruses,hepatitis viruses,Mycoplasma. The pathogenic mechanism
generates immune, inflammatory reactions with demyelination, perivascular mononuclear
inflammatory infiltrates(T cells,macrophages),after a delay of 1-4 weeks.Postvaccination cases
of ADEM are rare with the newer vaccines now in general use.
3. Chronic encephalitis the etiology of slow virus infections, such as subacute
sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML), is
poorly understood, appear in a few months or years after the accute viral infection. SSPE is a
chronic degenerative disease of, more common in older children / teenagers who have suffered
from measles before the age of 2 years.
Prion-induced encephalitis: Creutzfeldt-Jakob disease, Kuru disease, Gerstman syndrome, fatal
familial insomnia.
The prions proteinaceous infectious particles, totally free of nucleic acids, which do not
stimulate the production of antibodies. They are a 100 times smaller than the smallest known
viruses. In mammals, they reproduce by the selection of the normal cellular prion protein (PrPc)
and the stimulation of the transformation into its isoform (PrPSc). Each different conformation of
PrPsc is associated with a different type of prion disease. In animals, they produce scrapie, a
denomination coming from the English verb to scrape = to scratch, to rub, to graze.
Humans can catch prion disease in several ways: from contaminated food, iatrogenically
(neurosurgical interventions, cornea transplant) or genetically transmitted.
Creutzfeldt-Jakob disease described in the year 1921 is characterized by a deep alteration of the
intellect, memory, social conduct, temporo-spatial disorientation. It appears in persons with ages
over 60 years, having a progressive evolution, with myoclonia, blindness, insanity. Death occurs
after a few months. Diagnosis is confirmed histopathologically by detecting PrPSc inside brain
parenchyma.
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encephalitic syndrome:
- consciousness disorders (confusion, behavior troubles, agitation, personality
changes, hallucinations, lethargy, coma)
Positive diagnosis
Encephalitis is one of the most challenging pathology for clinicians to diagnose and manage. The
etiology of many cases of encephalitis remain undiagnosed.
Epidemiological and clinical data, complementary examinations should be performed.
The initial laboratory testing include a complete blood count,test of renal and hepatic
function,cogulation studies.Serum electrolyte levels are usually normal unless dehydration is
present; The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the result
of hypothalamic dysfunction. The serum glucose level should be determined to rule out
confusion due to treatable hypoglycemia and to compare with the cerebrospinal fluid (CSF)
glucose value.
CSF examination should be performed in all cases of encephalitis, except for cases with severely
increased intracranial pressure (ICP). It allows differentiation from a possible purulent
meningitis. It generally reveals a minimum pleocytosis of 10-100/mm3, lymphocytes, moderate
or inconstant elevation of CSF proteins. However, CSF may be normal!
Isolation of the pathogen agent from the CSF:
-
antigen detection
determination of IgM specific antibodies from CSF and serum
Polymerase Chain Reaction (PCR) technique:high sensitivity and specificity for
identifying a specific viral etiology:herpes simplex virus (HSV-DNA), varicella-zoster
virus (VZV-DNA), JC virus, Epstein Barr virus (EBV-DNA)
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Treatment.Acyclovir,10mg/kg every 8 hours,14-21 days is the durg of choise for the treatment of
HSV encephalitis.
Prognosis.Several factors influence the prognosis of HSVE,including patient age,level of
consciousness,duration of clinical encephalitis before initiation of acyclovir therapy.
Classification of Arboviruses
-
Togaviridae
Bunyaviridae
Reoviridae
Flaviviridae
Pathogenesis: after the bite from an infected mosquito,the virus replicates in the local
tissue,lymph nodes-primary viremia.Dissemination of virus to the reticuloendothelial system
results in a secondary viremia that allows the virus to invade the CNS and other organs.
130
Clinical manifestations
Many patients describe prominent GI symptoms, especially vomiting and diarrhea. Nonspecific
symptoms may include sore throat, myalgias, and arthralgias
Onset acute: fever, headache, myalgia, quick progress to coma. Concomitantly, patients
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CHAPTER 4
LEPTOSPIROSIS
Cristina Grbovan
Leptospirosis is an acute generalized infectious disease, characterized by extensive vasculitis,
caused by spirochetes of the genus Leptospira. Infections are most commonly caused by
Leptospira interogans, of which more than 200 serovars infect humans. It is primarily a disease
of wild and domestic mammals; humans are infected only occasionally through direct or indirect
contact with animals. People become infected by exposure to animal urine or urine-contaminated
surface water.
MICROBIOLOGY
Leptospires are finely coiled, motile spirochetes, approxiomately 0,1 um in with by 6-20 um in
length, with bent or hooked ends. Leptospires survive for days or weeks in warm, damp, slightly
alkaline conditions
EPIDEMIOLOGY
Leptospirosis is a zoonosis of worldwide distribution, affecting many species of wild and
domestic mammals. Most cases occur in young adult men, and the peak incidence is in summer
and early fall. Indirect contact with infected animals, via water or soil contaminated with
infected urine, is a more common cause of human infection than direct contact animal contact.
Occupational exposure (farmers, veterinarians, abattoir workers) and recreational exposure
(campers, swimmers) are common. Worldwide rats are the most common source of human
infection.
The serotypes found most commonly in human infection include:
Canicola
Icterohaemorrhagiae
Pomona
Autumnalis
Grippotyphosa
Hebdomidis
Ballum
Australis
PATHOGENESIS
Leptospira penetrate intact mucous membranes and abraded skin and disseminate widely via the
bloodstream.The major clinical manifestations of disease result from infection of capillary
endothelial cells leading to vasculitis. Symptoms develop 7 to 12 days after exposure. Most
patients have an abrupt onset of a self-limited, 4-to 7-day anicteric illness characterized by fever,
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headache, myalgias, chills, cough, chest pain,neck stiffness, and/or prostration. An estimated
10% of patients will present with jaundice, hemorrhage, renal failure, and/or neurologic
dysfunction (Weil, s disease).
CLINICAL MANIFESTATIONS
Classically, leptospirosis has been considered a biphasic illness.
Symptoms and Signs of leptospirosis:
Headache(93%-97%)
Spenomagaly (5%-25%)
Oliguria (10%)
Cough (10%)
Jaundice (1,5%-6%)
Many patients with mild disease will not have symtoms of the secondary immune phase of
illness, and patients with very severe disease will have a relentless progression from onset of
illness to jaundice renal failure, hemorrhage, hypotension, and coma. The illness is biphasic in
about half of patients with relapse occurring approximately 1 week after resolution of initial
febrile illness. A late complication is anterior uveits, seen in up 10% of patients month to years
after convalescence.
DIAGNOSIS
Leptospirosis most often manifests as a nonspecific flulike illness, so recognition of
epidemiologic risk factors is essential. Epidemiologic risks should be sought in patients with a
flulike illness, respiratory illness, aseptic meningitis, acute hepatitis, acute renal failure,
pericarditis, atrioventricular block, or anterior uveitis.
Laboratory findings of Leptospirosis
Renal failure-acute interstitial nephritis ; related findings range from urinary sediment
changes (leukocytes, erythrocytes, and hyaline or granular cats), mild proteinuria.
Peripheral leukocyte counts range from 3000 to 26 000/ul, with a left shift
Thrombocytopenia
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Jaundice with only 2-to-3 fold elevations in transaminases and alkaline phosphatases,
conjugated bilirubinemia
Abnormal chest radiographs; patchy alveolar pattern in lower lobes with or without
interstitial/alveolar hemorrhage
Electrocardiogram
atrioventricular block
abnormalities:
sinus
tachycardia,
myocarditis,
first-degree
A definite diagnosis of leptospirosis is based either on isolation of the organism from the patient
or seroconversion or a rise in antibody titer in the microscopic agglutation test (MAT). In cases
with strong clinical evidence of infection a single antibody titer of 1:200-1:800. Antibodies
generally do not reach detectable levels until the second week of illness. Although not species or
serovar specific, enzyme-liked immunsorbent assay (ELISA) kits to detect immunoglobulin M
(IgM) antibodies enable diagnosis during the first week of illness.
DIFFERENTIAL DIAGNOSIS
Influenza
Malaria
Rickettsioses
Enteric fever
Viral hepatitis
Hantavirus infections
THERAPY
Doxycycline 100 mg orally twice daily for 7 days started within 48 hours of illness,
decreased the duration of illness by 2 days in one study.
Supportive care and treatment of the hypotension, renal failure(including dialysis), and
hemorrhage than can complicate leptospirosis are crucial for a good outcome.
After penetrating intact mucous membranes or abraded skin, leptospires enter the blood stream
and are rapidly carried to all parts of the body , including the cerebrospinal fluid (CSF) and eye.
Jaundice, which occurs in the severe cases, is due primarily to hepatocellular dysfunction,
usually without necrosis. Hepatic damage is apparently subcellular , and leptospires are rarely
seen in the liver. Renal functional abnormalities may be profound and out of proportion to
histologic changes seen in the kidney. Renal failure is primarily a result of tubular lumen.
During the first week of infection, leptospires may be readily found in the CSE but meningeal
signs are absent. Later,when serum antibody appears, meningitis may develop.
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RABIES
Carmen Chiriac
Rabies is an acute viral infection of the central nervous system, with terminal evolution. Humans
are infected by the bite of an ill animal or which is in the period of incubation.
-
Victor Babe - proved the prophylactic efficiency of the anti-rabies serum (1889)
Etiology
The virus of rabies forms part of Lyssavirus genus, Rhabdoviridae family also including other
viruses: the vesicular stomatitis virus (VSV). The rabies virus is a virus of large size 180 mm,
having a long shape of a bullet.
The nucleocapsid is formed by monocatenary RNA. The lipoprotein cover presents external
projections with the function of attaching the virus to the host receivers.
The rabies virus is destroyed by ethers, soap, quaternary derivates of ammonium but it lasts for
years if frozen at -70C.
Epidemiology
Rabies is a zoonotic viral disease, specific to warm blood vertebrates, and accidentally it can be
transmitted to humans. It is spread worldwide, excepting the following geographical areas:
Antarctic, England, New Zeeland, Hawaii, Cyprus.
The rabies virus is kept in circulation by means of three natural cycles:
1) The sylvatic reservoir of rabies virus is represented by some salvage animals,
reservoirs of rabies virus: in Europe foxes, wolves (in the areas where they still
exist), badgers, otters, rats, mice, rabbits; in USA coyotes, skunks
2) Urban, canine rabies the rabies virus reservoir is represented by dogs, cats, rarely
horses, bovines, pigs.
3) Chiroptera virus (vampires, bats) which can be healthy carriers of rabies virus,
United States, Spain, Portugal.
The transmission to humans is done by the saliva of contaminated animals: bites or epidermalmucous with the spit of ill animals. There have also been reported cases by airborne transmission
(exposure to aerosols in labs or caves where thousands of bats survive) or post-transplant. The
cornea transplant represented the rabies source in eight cases. Exceptionally, the virus can be
transmitted by inhalation in the caverns populated by bats. The handling of death animals is also
dangerous.
The receptivity is general. The death is mortal. The virus is excreted by spit 5-7 days before the
appearance of clinical signs, during the period of disease, till death. The virus does not penetrate
the healthy skin. The inoculation of mucous membranes by smeary hands is possible.
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Pathogeny
The rabies virus penetrates the organism by a solution of teguments continuity: animal bite, by
mucous membranes, respiratory tract.
The rabies virus is multiplied at local level, mostly in the corrugated muscular cells. It crosses neuralmuscular junctions, attaches to acetylcholine receptors (their blocking restrains the attaching of the
rabies virus). The penetration of the rabies virus into the sensitive and motor neurons is followed by
an ascendant, centripetal migration along the axons of peripheral nerves with a speed of 100-400
mm/day towards the spinal cord, brain stem, central nervous system (CNS).
In the CNS, the rabies virus is multiplied exclusively within the gray substance where it causes more
neuronal malfunctions and less neuronal destruction. From the level of the CNS, the virus spreads
centrifugally along the peripheral nerves towards other tissues: salivary glands, lungs, liver, kidneys,
adrenal glands, muscles, teguments, heart. The rabies virus is multiplied in the acinar cells of the
salivary glands and excreted by saliva. The histopathological modifications are specific: minimal
mononuclear inflammatory infiltrates in leptomeninges, perivascular, microglial nodules (Babe
nodules). The parenchyma reveals intracytoplasmic eosinophil inclusions containing viral
nucleocapsids denominated Negri corpuscles (more spread in the Purkinje cells from the
cerebellum).
Clinical frame
The medium incubation period is between 20 and 90 days. The shortest incubation periods have
been described in case of multiple bites on face, scalp, neck and the longest incubation periods
have exceeded 1 year.
Two clinical forms of rabies at humans have been described: furious rabies and paralytic rabies.
Furious rabies
Prodrome: the period of invasion (prodromal) with the duration of 2-4 days reveals: asthenia,
anorexia, fever, psychomotor excitation with anxiety, agitation, irritability, insomnia, a
depressive state.
The ill person complains about paresthesias/pain at the place of the bite, progressively a state of
epidermal, diffuse hyperesthesia.
State of disease: it begins with hyperexcitability, defined agitation, the patient becomes hoarse,
shouts, talks a lot, is disoriented, has hallucinations. Hydrophobia and aerophobia determined by
the glottic spasm are frequent, pain during the attempt to swallow liquids (or when hearing
flowing water) or when an air current passes over the face of the patient. Dysphagia also occurs,
the patient salivates excessively, cannot swallow the saliva which creeps through the
commissures. Other symptoms are also present: fever, muscular fasciculations, mydriasis,
hypersudoration, localized or generalized convulsions. After the appearance of furious crises,
patients die in maximum 1-2 weeks.
Paralytic rabies
It begins with rachialgias, pareses, soft paralyses, initially in the region of the bite, they extend
afterwards, ascending similarly to the Landry ascendant paralytic syndrome. Intense pains of the
limbs, or muscular volumes are common, the mental status is progressively degraded. Unlike the
furious type, aerophobia, hydrophobia are not present. The cephalorachidian fluid (CRF) is
hypertensive, normal biochemical parameters, moderate pleocytosis (lymphocytes).
The paralytic form also evolves to death in about 6-30 days from the installation of coma.
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Evolution: Rabies is a fatal disease, although recently there have been communicated also cases
of cure.
Diagnosis
Epidemiological data: animal bite
Clinical data: pain / paresthesias at the level of the bitten canker, hydrophobia/aerophobia
neurological signs
Etiologic diagnosis: isolation of the rabies virus from tissues, saliva, cornea, mucous membranes
intracerebral inoculation in mice.
The virus detection by immunofluorescence (2 hour result) from: saliva, CRF, corneal imprint,
fragment of teguments. Specific neutralizing antibodies into serum can be detected a few days
after the release of symptoms. Some patients do not create antibodies. The specific antibodies in
CRF suggest rabies, no matter the immune status of the patient.
The detection of viral RNA into the saliva, CRF, tissues, by the technique RT-PCR is very
specific and sensitive. Post mortem, the highlight of Babe Negri corpuscles in AMMONs
horn cells.
Differential diagnosis
During the precocious phases of disease, rabies, having a sporadic progress, is difficult to be
distinguished by other encephalitides: herpetic encephalitis, and it benefits of a specific
treatment.
Warm season encephalitides determined by enteroviruses, arboviruses could determine problems
of differential diagnosis with rabies. The epidemiologic data, the identification of specific
viruses using the PCR technique in LRC, blood make a difference with respect to the diagnosis.
Paralytic rabies may give the impression of the Guillain-Barre syndrome, it must be
distinguished from poliomyelitis, encephalomyelitis anti-rabies tetanus post vaccination
(trismus), botulism (symmetrical paralyses, without sensorial disorders)
The rabies phobia exaggerated fear of rabies may cause similar symptoms to rabies, agitation,
hypersialorrhea. Persons affected by rabies phobia may give the impression of hydrophobia but
they cannot imitate aerophobia.
Treatment
At the present time there is no etiologic specific treatment. Triggered rabies: special measures
are necessary for the maintenance of vital functions, prevention and control of complications.
Recently, there have been a few attempts for antiviral treatment: Amantadin, Ribavirin,
Interferon, which failed.
Post-exposal prophylaxis
The plague with rabies potential:
-
Prophylaxis
1. The existence or absence of rabies in the zone where the animal comes from; 2. The
deepness and the extension of lesions (face, neck, extremities, most dangerous mucous
membranes rich in nervous fillets); 3. The known/unknown aggressor animal, signals of
rabies in the aggressor animal. All bat bites or plagues smeared by the saliva of a suspect
animal: immediate anti-rabies treatment.
Post-exposure anti-rabies treatment (World Health Organization WHO)
Category
II
III
Bites,
deep vaccination (face, Anti-rabies
serum
neck, genital organs, other parts of (immunoglobulins + vaccine)
body)
Healthy animal interruption of
vaccination after 5/10 days
Wild animals
Serum + complete vaccination
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Lyme borreliosis
Brndua ilea
Definition
It is defined as a natural focal infectious disease transmitted by ticks from the Ixodes class
produced by bacteria of the Borrelia type, clinically characterized by multisystem manifestations
with evolving stage and polymorphous clinical picture.
Etiology
Lyme borreliosis (LB) has a universal spread with endemic avolution or in small
outbreaks.
Based on the diversity of antigen surface protein (Ospa) seven kinds of antigens or
serotypes have been described. Bb sensu lato is classified into eight subspecies and two
genomic groups.
Using genetic and immunological criteria, three human pathogenic subspecies have been
identified as pathogenic for human beings:
Borrelia burgdorferi sensu stricto or OspA1 serotype strain 212 in Europe and B31 in the
U.S.
Spirochete Borrelia burgdorferi is a Gram-negative germ, with sizes between 4-30 metri
an average of 7 to 11 flagella at each end, mobile, microaerophilic, catalase negative,
which multiplies slowly at 30-37 C. Like all spirochetes it possess a cytoplasmic
membrane surrounded by protoplasmic cylinder, then the flagella and outer membrane.
Borrelia is longer and less coiled than other spirochetes. The external membrane has a
trilaminar structure and it is fluid.
Growth media used for spirochetes culture is liquid, complex, after the BarbourStoenner-Kelly (BSK) formula.
Epidemiology
The potential reservoir of infection are the animals that may be act as hosts for the vector
agent. It is a vast reservoir (for Ixodes persulcatus 240 different species and for Ixodes
ricinus over 300 species of animals: wild mammals, domestic birds, reptiles).
Various species of tick transmit spirochete Bb: primary (rodent - rodent, rodent domestic animal) and secondary (rodent - domestic animal - human accidental infection).
To transmit Bb infection more bites of infected arthropods are necessary, especially in the
case of the larval stage or the connection by arthropod bite and the host should be
extended at least of 24 hours.
In Romania Ixodine species are found in the following genres: hyalloma Ixodes,
Rhipicephalus, Dermacentor, Haemaphysalis, margaropus.
The main risk factor for Lyme borreliosis is permanent or temporary human presence in
areas with high tick infection with the spirochete Bb.
Given the nature of the reservoir of germs and vectors of Lyme borreliosis, people who
are at risk are forestry workers, staff working in agriculture, forestry, hunters,
veterinarians, hikers, people who visit nature where they meet both the source infection
as well as the specific vectors.
major external surface proteins - OSPA and OspB, specific but only rarely detected and
only in the tardive stage of infection (more than six months of evolution).
Pathogenesis
Once it goes beyond the skin, Bb penetrates in the blood stream and invades various
tissue compartments, thus generating systemic infection. Spirochete can migrate and at
derm level. The difficulty in isolating blood spirochete suggests that spirochetemia is
transient and low.
Experimental studies have shown that the BB is able to adhere to a variety of human
cells, such as endothelial cells, cells of the central nervous system (microglial cells,
Schwann cells) cardiac cells, synovium.
Spirochete attachment to host tissue cells is the step that initiates infection, this
attachment involves an interaction between glucosamin structures on the surface of host
cells and the three proteins: 67 kDa, 62 kDa and 41 kDa (flagelina).
Spirochetes multiply and disseminate in blood, causing damage to the ECM, representing
the clinical manifestation of early stage I being thus the primary stage of the disease.
Stage III, tardive, or tertiary, covers a period of months or years, if appropriate therapy is
not initiated. A persistent infection occurs which may affect: CNS osteoarticular,
cardiovascular system.
Spirochete adheres to endothelial cells, causing vascular lesions, large areas of localized
cerebral vasculitis and perivasculitis, heart, joints and skin.
140
Bb induces the production of cytokines (IL-1 - TNF-), which potentiates the intensity
of inflammation.
Impairment occurs only late to persons showing major histocompatibility complex HLA
DR4.
Clinical manifestations
The clinical manifestations are polymorphic, but the most common manifestations are cutaneous,
neurological, cardiac, joint, which fall into three stages illustrated below:
Early infection
Primary Stage
Tardive infection
The secondary
Multiple ECM
Benign
limphocitom
Tertiary stage
Acrodermatitis
atrophicans
cutaneous
chronical
Chronic
Early
neuroborreliosis Tardive neuroborreliosis
erythema
(radiculitis,
meningitis,
(chronic
progressive
migrans (ECM) encephalitis, myelitis)
encephalomyelitis,
delayed
polyneuropathy)
Charditis
Arthritis
Chronic Arthritis
141
During spirochetemia patients may show: general systemic manifestations (mild fever up to
38C, chills, myalgia, arthralgia, coryza, without local acute inflammatory phenomena) that
occur as a result of acute or subacute damage to vital organs (arthralgia , headache, dysphagia,
fatigue,
stiffness,
transient
meningeal
irritation
syndrome),
lymphadenopathy,
hepatosplenomegaly, cardiac arrhythmias, myositis, hepatitis, transient impairment of CNS
outside any determinations.
Cardiac manifestations
Cardithis due to BL shows conduction abnormalities, various degrees of atrioventricular
block, these being the most common.
AVB I, II, III
Conduction abnormalities
Tachyarrhythmias
Miopericarditis
Congestive
Joint damage was in the U.S. at the origin of the description of this disease that was
initially called "Lyme arthritis" (fig. 74). Involvement of the osteoarticular apparatus in the BL
can occur at any age but it is found with higher frequency in children, it can occur both at an
early stage and the late stage of the disease.
Ophthalmic Manifestations
Keratitis is one of the most common ocular manifestations occurring in the months or
years following the onset of the disease.
Infection of the central nervous system (CNS) and the peripheral nervous system (PNS)
caused by spirochete Bb has been defined as Lyme neuroborreliosis - NBL. Spirochete
142
was detected in the central nervous structures both in the acute and sub-acute stage of the
disease as well as in later stage, which is why a distinction between accute subacute
neuroborreliosis occuring in weeks or months (6-12 months) after contact with infected
arthropods and chronic neuroborreliosis affection occurring after a period of over 12
months, even years later after infection is necessary.
a decrease in cerebral blood perfusion has been noted particularly in the white
matter as demonstrated by functional neuroimaging techniques;
research studies in laboratories have shown many times that the spirochetes have a
preference share for oligodendrocytes;
in CNS disease vascular direct modifications, localized mainly at the SAC level
have been identified;
it has been demonstrated in patients with NBL, in both stages of the disease, the
aspect of toxic metabolic encephalopathy induced by lymphokines;
Meningitis is often associated with cranial neuritis (facial nerve VII) and with
radiculoneuritis, Bannwarth syndrome.
Acute Lyme encephalomyelitis. Cerebral parenchymal abnormalities are found in 2050% of North American patients with Lyme meningitis. The frequency of CNS
manifestations is generally low in Europe and almost always accompanied by pleocytosis
in CSF and peripheral cranial neuritis. Central lesions may occur alone or may be
associated with meningeal peripherals damage, representing clinical picture of acute
meningoencephalitis, meningoencephalomielitis, encephalomielo polyradiculoneuritis.
Cranial nerve lesions. The most common is peripheral nerve VII palsy unilateral or
bilateral. Other nerves may be involved, especially the trigeminal and oculumotor one.
average 30 days after the tick bite, the most common locations being the lower limbs,
upper cephalic extremity.
Peripheral motor injuries. Motor impairment is rare, being responsible for asymmetric
paralysis, most commonly proximal, located at the level of certain muscles responsible
for muscular atrophy. Prolonged evolution, sequelae are possible.
Polyneuropathy and neuropathic tardive sclerotic lesions. The most common symptoms
are called paresthesia, often intermittent, asymmetric, focal involving the upper and lower
limbs. A quarter of patients had carpal tunnel syndrome.
Psychiatric disorders in Lyme borreliosis. Psychiatric aspects have been described more
frequently in children and adolescents with spectacular remission subsequent to
antibacterial therapy. The most common mental disorder observed (70%) is depression.
Other possible problems: short-term memory loss, anxiety, panic attacks, personality
changes, paranoia, mood swings, psychotic episodes, etc..
Diagnosis
BL accurate diagnosis remains problematic at the moment until a diagnostic test "gold standard"
will be developed. BL and NBL diagnosis is currently based on serological methods, which are
far from being satisfactory, both in terms of sensitivity and specificity. Serological tests need to
be interpreted with caution, taking into account the epidemiological and clinical context. Various
methods currently used in the diagnosis of BL are summarized in the table below:
Microscopic examination
Serological methods
Culture
Immunohistology
Western blotting
T lymphocyte
method
proliferation
study
lymphocytic pleocytosis;
Dose / day
Amoxicillin
3x500 or 2x1000 mg mg
po
10 to 21
Azithromycin
500 mg
po
5-7
Doxycycline
2x100 mg
po
10 to 21
Cefuroxime axetil
2x500 mg
po
10 to 21
145
Penicillin V
3x1000 U
po
10 to 21
Dose / day
Ceftriaxone
2g
iv
14 to 21
Cefotaxime
3x2 g
iv
14 to 21
Penicillin G
3x3 MU
iv
14 to 21
Dose / day
Amoxicillin
14 to 30
Doxycycline
2x100 mg
po
14 to 21
Ceftriaxone
2g
iv
14 to 21
Cefotaxime
3x2 g
iv
14 to 21
NBL early
Tardive
NBL
Antibiotic
Dose
Administration
Duration (days)
Ceftriaxone
2g
iv
14 to 21
Cefotaxime
2g
iv
14 to 21
Penicillin G
3x3 MU
iv
14 to 21
Doxycycline
2x200 mg
po
14 to 21
Amoxicillin
/
2g
clavulanic acid
po
14 to 21
Ceftriaxone
2g
iv
30
Cefotaxime
2g
iv
30
Penicillin G
3x3 MU
iv
30
Doxycycline
2x200 mg
po
30
po
30
Amoxicillin
/
2g
clavulanic acid
Table VII - Treatment of Lyme neuroborreliosis
In case of pregnant women treatment of firmly diagnosed cases and suspicions as well, is
recommended. Treatment with Aminopenicillin, macrolides (azithromycin) is recommended in
cases of infection localized to the tegument and in cases with neurological determination
Ceftriaxone is advisable.
146
Duration of therapy in both BL and NBL is variable between 14-30 days, but it can be extended
up to six weeks, even months in trenant or relapsed cases.
Complications and prognosis in Lyme borreliosis
The risk of acute complications in BL and NBL is more reduced if antibacterial therapy is
instituted early to avoid progression from acute stage to the tardive stage of the disease.
In cases of early NBL with severe CNS SNP impairment in about 10% of cases were
notified motor sequelae, residual neurological clinical symptoms such as headache,
dizziness, paresthesia, myalgia, arthralgia, anxiety.
Prophylaxis
Doctors who have to decide on the therapeutic approach in case of patient stung by ticks
have three alternatives:
-
to appreciate the dynamics of serology (blood, CSF) immediately and then after 36 weeks, treating only if there are clinical signs of a serological infection.
Prophylactic therapy is recommended for all persons who are stung and from endemic areas of
BL. The most commonly used antibiotics are: Amoxicillin, Amoxicillin / clavulanic acid,
azithromycin both in children and adults.
Cyclins (Doxycycline) is the recommended antibiotic in ECM prophylaxis and impaired adult
with SNP. Prophylactic therapy duration is between 14-21 days.
Nonspecific prophylactic measures
Physical measures
physical measures refer to avoiding areas with high density of ticks, using appropriate
clothing to avoid skin-fixing of the tick, regular monitoring of the presence and removal
of any tick.
Chemical Control
It is made using:
-
acaricides sprayed powder in endemic areas, but they present limitations, namely:
environmental pollution, side effects, duration of action limited in time, high cost,
inability to use them for wildlife;
References:
1. Cifecu C, Hristea A. Borrelioza Lyme. Ed. Briliant, Bucureti, 1999; 100-125.
2. Cohen J, Opal SM, Powderly WG. Infectious Diseases, 3rd Edition, vol I, 2010,
464-474
3. Pilly E. Maladies Infectieuses et Tropicales, 19e ed. 2004; 402-417, 422-450.
4. ilea B. Borrelioza Lyme. Ed. University Press, Tg. Mure, 2008; 40-80.
5. ilea B. Patologie Infecioas. Fundamente de licen n medicin. . Ed.
University Press, Tg. Mure, 2009, 111-119
6. Wilske B. Microbiological Diagnosis in Lyme Borreliosis. J Med Int Microbiol,
2002; 33:114-119.
148
ANTHRAX
Iringo Kezdi
The disease anthrax is produced by the sporulating bacterium Bacillus anthracis, found in the soil
in many parts of the world. The spores from the infected animal carcasses can contaminate the
pasture for many decades and lead to sporadic outbreaks.
It is believed that the fifth and sixth plagues of Egypt, described in the Old Testament, were
probably caused by anthrax, and also the description of the black bane, which caused an
estimated 60.000 deaths in cattle in Europe in the 1600s, indicate that this was anthrax.
Two microbiologists, Robert Koch and Louis Pasteur both studied anthrax in the 1870s. Koch
demonstrated that the disease could be produced by the transfer of infected material from one
animal to another. He also demonstrated the ability of the bacillus to produce heat- resistant
spores, which had the ability to germinate and infect animals.
Pasteur, confirmed the germ theory of the disease and he also demonstrated in 1881, in a
famous public experiment, that cows, goats and sheep could be vaccinated by use of a live
attenuated skin. The current vaccine is a live vaccine made from an unencapsulated, avirulent but
toxigenic strain.
The common name is derived from the Greek name anthrakis, or coal, so named from the
black cutaneous lesions produced.
Epidemiology
The disease is naturally one of animals, particularly herbivores, who ingest spores on the grass
and from the environment. Until the advent of an effective vaccine, the disease was common in
cattle, sheep, goats, horses and pigs, but is now far rarer. Infections in humans were most
oftenassociated with the handing of an infected animal carcasses or hides. Wool sorter`s
disease was contracted by those handling infected fleeces or hides, often from inhaling spores
released in the processing of the fleeces or hides. Anthrax is still endemic in some parts of the
world, notably Africa, the Middle East, Asia and some parts of the US and Australia. Inhalation
anthrax is extremely rare under normal conditions.
As has been illustrated so clearly in the US recently, anthrax can be used as a weapon of terror. It
is one of the favored species for germ warfare, or bioterrorism, but in not necessarily an ideal
one. It is not highly pathogenic, requiring a large number of spores to produce infection by any
route. It is not transmitted from person-to-person other than in exceptional circumstances. The
spores need to be transmitted in a very fine aerosol to be highly effective. Resistance can be
developed experimentally to most of the current agents of choice, and it remains to be seen
whether widespread use of ciprofloxacin and doxycicline will create a selective pressure on the
organism.
Etiology
B. anthracis is a large (1-3mm), gram-positive, aerobic, rod-shaped, non-motile, sporulating
bacillus. The spores are thermostable. Like many other members of the genus Bacillus, the
spores are remarkably resistant and long-lived in the environment. The organism grows rapidly
on normal laboratory media (nutrient or blood agars) not needing any special cultural techniques,
but does not grow on Mac-Conkey agar. There are a number of mop=rphological distinguishing
149
characteristics; white-grey, flat or slightly convex, irregular round colonies with a ground-glass
appearance. A Medusa head colony is characteristic for B.anthracis. culture are not or very
slightly haemolytic, but not -haemolytic. In smears from infections, long chains may be formed
and a capsule is present. The capsule can be seen clearly using India Ink. The lack of motility
distinguishes B.anthracis from many other Bacillus species. Modern molecular techniques can be
used to confirm strains of B. anthracis. Multiplex PCR has been used in recent outbreaks and
immunohistochemical staining can be valuable. MIC determination showed recently the
following results: Susceptible strain to: Doxycycline, Ciprofloxacin, Amoxicillin, Penicillin G,
Rifampicin, Clarithromycin, Clindamycin, Vancomycin, Chloramphenicol.
Intermediate to: Erythromycin, Azithromycin, Ceftriaxone
Preliminary studies report the presence of a Class B cephalosporinase( constitutive) and the
possibility of an inducible penicillinase.
Pathogenesis
Naturally acquired anthrax in humans is generally due to contact with infected animals or their
carcasses. Although fatal human disease may occur, B. anthracis is not highly virulent, and in
spite of its previous prevalence in the environment and in animals, human infections were not
common and are now rare. Virulence is associated with encapsulated strains and death is caused
by toxins, that produce massive haemorrhagia and shock. The most common form of the disease
is cutaneous, which is frequently self-limiting. To produce the serious form of inhalation
anthrax, a large number of spores, greater than 2000, and possibly 5-10.000, are necessary to
establish an infection. The organisms do not multiply in the lungs but are carried by alveolar
macrophages to the mediastinal lymph nodes where the spore germinate and multiply. From this
focus they are able to spread rapidly throughout the body. Three toxins are produced by
B.anthracis all thermolabile proteins; a protective antigen (PA), an oedema factor (OF), a lethal
factor (LF). The individual toxins have no adverse effects, they need to combine to produce the
characteristic toxicity seen in the disease. They target the macrophages and have little effect on
other cells. The protective antigen binds to receptors to the macrophage cell-surface protease.
This produces a cell-bound C-terminal 63kDa protein (PA63). This cleaved portion, A63, has
high affinity binding sites for the other two toxins. The bound complex enters the cell by
receptors mediated endocytosis. The OF toxin has calcium and calmodulin-dependent
adenylatecyclase activity. The LF toxin is a protease that interferes with the protein kinase signal
transduction pathway. The assembled toxin has powerful proteolytic activity, which causes the
eventual death of the macrophage. The release of cytokines, including IL-1 and TNF, from the
damaged macrophages is believed to cause the damage to the blood clotting system and to
contribute to the septic shock and oedema. The genome of B.anthracis has been sequenced
recently and considerable advances have also been made in understanding the mode of of action
of toxins. The plasmids coding for toxins (pX01) and the capsule-associated plasmids (pX02)
have also been identified and sequenced.
Clinical manifestations
Cutaneous form is the commonest form of the disease, occurring in up to 95% of cases.
Incubation period is 3-10 days. It is seen most often on the face, hands, forearms and
neck since infection is generally from handling infected material. The organisms, usually
spores, invade from a skin abrasion or cut. After germination of the spores, the vegetative
bacilli multiply locally and a small, visible papule, appears. Several days later a vesicle or
ring of vesicles develops (4-6 cm). This discharges clear with surrounding oedema. In
most cases cutaneous anthrax is self-limited, the lesion resolving within 10 days. In some
150
cases systemic anthrax may develop (malignant edema), but unless therapy is initiated
very late, by which time extensive toxin production has occurred, the disease responds
very well to chemotherapy. Painful, regional adenopathy may persist even after
successful therapy. In untreated cases the death rate can reach 20%, but is less than 1%
when treated.
Inhalation anthrax is rarer, compromising only approximately 5% of all cases. Once
established, this is a far more serious disease with a high death rate. Incubation period is
3-5 days. Initial symptoms are insidious and flu-like, generally mild and non-specific. In
the second phase there is acute respiratory distress, sepsis and an acute
haemorrhagicmediastinal widening. X-ray symptoms can be confused with those of
tuberculosis. Blood culture may be positive at this stage, and if the disease has progressed
to this stage, it is frequently fatal as toxin production has already advanced and therapy
can thus be ineffective.
Gastro-intestinal anthrax is even rarer and is contracted by consuming large number of
spores, which infect the intestinal tract or the oesophagus. The illness may present as an
acute abdomen, bloody diarrhea or cholera-like syndrome.
Meningitis is a rare complication of any form of anthrax, and is generally fatal since, by
the time it is diagnosed, toxin production is well advanced. It evolves with hemorrhagic
CSF.
Laboratory diagnosis
-
Differential diagnosis
-
Treatment
Most strains of B.anthracis are susceptible to a wide range of antibacterial agents. The organism
was traditionally highly susceptible to penicillin and, until recently, this was the drug of choice.
Wild-type strains often produce a constitutive cephalosporinase. Penicillin-resistance has been
noted, albeit rarely, in wild-type strains and, in addition, strains with resistance to penicillin are
believed to have been engineered durong the cold war era. For these reasons, the first choice is
now generally a fluoroquinolone, (ciprofloxacin), although other FQ are probably also effective.
Most authorities still recommend that therapy be switched to a penicillin (penicillin G, penicillin
151
152
Tetanus
Iringo Kezdi
Tetanus is a disease of the nervous system characterized by persistent tonic spasm, with violent
brief exacerbations. The onset is acute and the spasm almost always commences in the muscles
of the neck and jaw, causing trismus, and involves the muscles of the trunk more than those of
the limbs.
Etiology
Clostridium tetani is an obligate anaerobic rod that in young culture stains is gram positive, but
after 24 hours of incubation Grams stain is negative. The organism is found commonly in soil
samples around the world, especially in warmer climates. It is isolated from the intestinal tract of
animals and from human excrement. The mature C.tetani organism develops a terminal round
spore creating a tennis racket appearance and producing tolerance to extremes of
environmental conditions. Two exotoxins, tetanospasmin and tetanolysin, are released by some
strains of the organism while it is actively dividing. The role of tetanolysin is unknown ( it is
presumed that can disrupt cell membranes). Tetanospasmin disseminates from the infected site of
entry, to neuromuscular junctions, by intraaxonal transport, in the central nervous system. The
organism remains localized in the anaerobic tissue environment.
Pathophysiology
Tetanospasmin act at three levels: central motor control, autonomic function and neuromuscular
junction.
The 150 kD peptide tetanospasmin inhibits release of inhibitory neurotransmitters gaminobutyric acid (GABA) and glycine. The resulting imbalance in the central nervous system
predisposes the patient to reflex spasms. The process involves three steps:
-binding to the presynaptic membrane
-translation of the toxin to the active site
-induction of paralysis
Tetanospasmin disinhibits sympathetic reflexes at the spinal level, so the hyperadrenergic
findings do not depend on hypothalamic or brain stem dysfunction. The clinical effects of
tetanospasmin may persist for 4-6 weeks.
Clinical manifestations
Tetanus can occur in patients with gangrene, burns, decubitus ulcers, septic abortions,
intramuscular injections, dental infections, penetrating eye injuries, and umbilical stump
infections.
The incubation period range from 3 to 30 days (11 days). The disease has four forms:
1. Generalized tetanus is the most frequent form of the disease.
a. The most commonly presenting sign is trismus (inability to open the mouth) caused
by the rigidity of the masseter muscles. Among the first symptoms are also the
stiffness in the neck, or jaw, difficulties in swallowing and back or shoulder stiffness.
153
The initial symptoms of generalized tetanus tend to descend from the head to the
skeletal muscles of the trunk and extremities.
b. Risussardonicus is another characteristic sign
c. The typical generalized spasm resembles decorticate posturing, consisting of: sudden
tonic contraction of muscles causing opisthotonus, flexion and adduction of the arms
and extension of the lower extremities. Other positions are orthotonus and
pleurosthotonus
d. Generalized spasms can involve abdominal, diaphragmatic, and laryngeal muscles,
causing apnea and necessitating endotracheal intubation. During these spasms
patients do not lose consciousness, and sustained skeletal muscle contractions are
extremely painful. Tetanic contractions are powerful enough to cause fractures of the
spine and long bones.
e. Autonomic dysfunction is the leading cause of death in tetanus patients. This
syndrome includes: labile hypertension, tachycardia, irregularities of cardiac rhythm,
peripheral vascular constriction, profuse sweating, pyrexia, and sometimes
development of hypotension (signs which are present toward the end of the first
week, or during the second). The disease may continue to increase in intensity for 1014 days, recovery requiring about 4 weeks.
2. Localized tetanus may develop in persons who are partially immunized to tetanospasmin.
Muscle rigidity depends on the location of injury, which could involve agonists,
antagonists and fixators. The muscles are painful, and deep tendon reflexes are enhanced.
3. Cephalic tetanus: -facial paresis is usually present
-ophtalmoplegic tetanus when there is a paresis of the IIIrd, IVth, and VIth
cranial nerves
4. Neonatal tetanus occurs when the mother lacks immunity; usually follows an infection of
the umbilical stump. Infant is unable tu suck, typical opisthotonic posture occurring later.
Rating scales for tetanus severity
Table 1.Veronesi scale
Veronesi scale
Incubation period < 7 days
Period of onset* < 48 hours
High-risk portal of entry (surgical, abortion, etc)
Generalized tetanus
Core temperature above 40C
Tachycardia (heart rate>120 in adults, >150 in neonates
Score one point for each
*period from the first symptom to the first reflex spasm
Table 2. Severity and prognosis
Score*
Severity
Mortality
154
0-1
Mild
< 10%
2-3
Moderate
10-20%
Severe
20-40%
5-6
Very severe
>50%
Symptoms
Mild
Moderate
Severe
Marked rigidity,
compromise/apnea
frequent
generalized
spasms,
disphagia,
respiratory
Diagnosis
The average annual incidence of tetanus in the world is about 1 million cases. Due to its rarity,
the initial clinical symptoms may be missed and the diagnosis may not be made until a
generalized tetanic spasm occurs. Diagnosis is established in the presence of a portal of entry,
trismus, tonic contraction, sudden spasms and a descending manner of contraction progression.
Wounds are classified as clean or tetanus prone. The latter are more than 6 hours old;
contaminated with dirt, feces, soil or saliva; or involve tissue with poor vasculature. Diabetic
foot infections are commonly polymicrobial and contain necrotic tissue classifying them as
tetanus prone. The diagnosis of tetanus cannot depend on wound cultures because cultures are
positive for c.tetani in only 32-50% of cases. In addition, isolation of C. tetani is inconsequential
in immune patients. The lack of a defined wound does not exclude the diagnosis of tetnus. A
protective titer antitetanus antibodies may help to exclude diagnosis, but only in retrospect.
Differential diagnosis
Trismus in tetanus must be distinguished by: alveolar ridge abscess, temporomandibular
joint arthritis, tonsillitis;
Spasms and rigidity must be distinguished by: generalized convulsive status epilepticus,
strychnine intoxication, tetany precipitated by hipocalcemia, meningitis, encephalitis,
brain hemorrhage;
Local tetanus- with transverse myelitis
Complications
1. Respiratory dysfunction: atelectasias, apnea (phrenic and laryngeal neuropathy),
pneumonia
2. Cardiovascular complications: cardiomiopathy
155
157
CHAPTER 5
ENTEROVIRUS INFECTIONS
Nina incu
Etiologic agents
Enteroviruses = single-stranded RNA viruses, which belong to the Enterovirus genus in the
Picornaviridae family. Their denomination came from their ability to replicate inside the human
digestive tract, but they are responsible for a wide variety of diseases apart from infectious
gastroenteritis: herpangina, hand-foot-and-mouth disease, exanthem, acute hemorrhagic
conjunctivitis, pneumonia, pleurodinia, central nervous system infections (meningitis /
encephalitis, paralysis), myocarditis / pericarditis.
65 human serotypes have been identified so far:
-
Poliovirus 3 serotypes
Susceptibility: general
Immunity: serotype-specific humoral immunity IgM antibodies appear 1-3 days after contact
with the virus and last for 2-3 months, IgG antibodies initially appear about 10 days after contact
with the virus and persist for life, but are targeted against the specific serotype which caused the
infection. Infection with other viral serotypes is possible.
Pathogenesis
Enteroviruses penetrate into the human body via the digestive or upper respiratory tract
(pharynx). Following replication at the entrance gate, in submucosal lymphatic tissues,
enteroviruses penetrate into the bloodstream and cause minor viremia, which results in the
infection of the reticulo-endotelial system, where the virus continues to replicate (liver, spleen,
bone marrow). From these sites, virions are again discharged into the bloodstream, causing a
second, clinically manifest, major viremia. In most cases, immune mechanisms are able to
contain the infection before the second phase of major viremia, which leads to subclinical
forms of infection.
Clinical entities
Enterovirus infections may cause a wide range of clinical manifestations. Disregarding
poliovirus, for which a distinct chapter is reserved, Coxsackievirus and Echovirus infections may
involve the gastro-intestinal and respiratory tracts, the central nervous system, eyes, kidney,
myocardium and pericardium. Clinical entities characterised by fever and exanthema may also
be the result of enterovirus infections.
The incubation period for most cases of enterovirus infections range between 2-14 days, with an
average duration of incubation beneath 7 days.
Herpangina. It is usually caused by group A coxsackievirus, particularly serotypes 1-10, 16, 22.
Rare etiologic agents could be group B coxsackievirus serotypes 1-5 and echoviruses and
enterovirus 71. Clinical manifestations include acute onset, fever, sore throat, odynophagia,
possibly associated with vomiting, myalgia, headache. The characteristic enanthem consists of 24 mm vesicles on erythematous base, distributed on the soft palate, uvula, tonsilary pillars,
sometimes on the posterior pharyngeal wall, with subsequent ulcerations. Acute lymphonodular
pharyngitis, caused by group A coxsackievirus serotype 10, is regarded as a clinical variant of
herpangina, with small yellowish nodules (formed by lymphocytes) situated on the soft palate
and uvula, without consecutive ulceration.
Pleurodinia (Bornholm disease). It is actually o myositis usually caused by group B
coxsackievirus, serotypes 1-6, less often by group A coxsackivirus or echoviruses. Clinical
manifestations consist of acute, knifelike spasmodic pain in the chest (adults) or upper abdomen
(children), with 15-30 minutes duration, accompanied by fever peaks, which resolve along with
the pain. Physical examination reveals pleural rub and local tenderness to palpation of the
involved muscles, but chest X-ray is negative.
Pneumonia more frequent in children, it can be caused by echovirus serotypes 6, 7, 9, 11, 12,
19, enterovirus 71, but also group A or B coxsackievirus. Respiratory symptoms concur to
interstitial or patchy bronchopneumonia features on chest X-ray.
Other respiratory diseases caused by enteroviruses are: choryza, laringo-tracheo-bronchitis,
croup and bronchiolitis.
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Nonspecific febrile illness (summer grippe) the most frequent enterovirus-associated clinical
entity, with flu-like symptoms fever, coryza, sore throat, cough; it occurs during the summer
early autumn warm season. It resolves spontaneously, within 3-7 days.
Exanthems. Enteroviruses produce a broad range of exanthems, accompanied by fever,
resembling those encountered in rubella, measles, scarlet fever, roseola infantum, herpetic or
allergic rash and even petechial exanthema.
Hand-foot-and-mouth disease is most often caused by coxsackievirus A16, although other
serotypes of coxsackievirus group A 4-7, 9-10, group B 2-5, echovirus 18 and enterovirus 71 are
also known to produce the disease. Clinical manifestations include fever, vesicles and ulcerations
in the oral cavity and skin lesions, consisting of erythematous papules and clear vesicles
surrounded by erythema distributed characteristically on the hand, feet and sometimes gluteal
regions. The etiologic agent can be isolated from the vesicular fluid.
Aseptic meningitis most frequently caused by group B coxsackievirus serotypes 1-5 and
echovirus serotypes 4, 6, 7, 9, 11, 13, 16, 18, 19, 30, 33, less often by group A coxsackievirus
type 2, 4, 7, 9 and 10. Enteroviruses are reported as the most frequent cause of aseptic meningitis
in children and young adults, evolving especially during the warm season. Clinical
manifestations include fever, chills, headache, vomiting, photophobia, neck stiffness and other
meningeal sings, sometimes accompanied by other clinical symptoms that indicate an
enterovirus infection: herpangina, diarrhea, rash, myocaditis. CSF analysis reveals pleocytosis:
initially polymorphonuclears prevale (differential diagnosis with bacterial meningitis), but
lymphocytes become dominant usually after 24 hours. Total CSF cell count is usually below
1000 cells/L, glucose CSF levels are normal, protein CSF levels are slightly elevated. Prognosis
is usually good, with clinical recovery after one week.
Encephalitis enteroviral infection account for about 10-20% cases of viral encephalitis. Most
cases appear in children and young adults, during the warm season. Coxsackievirus B2, B5, A9,
echovirus serotypes 6, 9 and enterovirus 71 have been incriminated more frequently. Mental
status impairment, ranging from disorientation to coma, seizures, cerebellar ataxia and
sometimes paresis are present. A severe form brainstem encephalitis, caused more frequently
by enterovirus 71 implies cardio-respiratory malfunction of central origin. CSF alterations
resemble those from enteroviral aseptic meningitis. Imaging and electroencephalogram may
reveal various generalized or localized abnormalities. Prognosis is good in most cases, although
fatal outcome and lifelong sequelae have been reported as well.
Other central nervous system infections. Paralysis (poliomyelitis-like flaccid motor paralysis)
may be the result of enterovirus 71 or coxsackievirus A7. Less frequent etiologic agents could be
coxsackievirus A4, A9, B1-B5, echovirus serotypes 6, 9. The course of the disease is less severe
than in poliomyelitis. Guillain-Barre syndrome has also been depicted associated to
coxsackievirus A2, A5, A9 and echovirus 6, 22. Chronic meningitis or encephalitis has been
reported in patients with hypo- or agammaglobulinemia infected with enterovirus.
Acute hemorrhagic conjunctivitis. It is usually caused by enterovirus 70, which evolves in
epidemic outbreaks, but coxsackievirus A24 has also been reported as etiologic agent. The most
common route of transmission is direct inoculation of mucosa via contaminated hands or fomites
(towels, handkerchiefs). Clinical manifestations include pain, foreign body sensation in the eye,
eyelid oedema, serous or seromucoid discharge, subconjunctival haemorrhages, with 7-10 days
duration. Upon physical examination, small follicles are found on the tarsal conjunctiva. Corneal
erosions and punctuate keratitis may sometimes be seen. Signs initially manifest unilaterally, but
they rapidly involve the contralateral eye. Fever and malaise appear in about 20% cases.
Myocarditis and pericarditis most commonly encountered as a unitary entity
myopericarditis. Enteroviruses are responsible for > 50% cases of viral myopericarditis.
Coxsackievirus A4, A9 and A16, B1-B5 and echovirus serotypes 6, 9, 11, 22 are most frequently
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involved. The virus reaches the myocardium via bloodstream and induces an inflammatory local
immune response, which may persist for months. Myocyte destruction is a consequence of both
the virus and the inflammation. Myopericarditis is more frequent among adolescents and young
adults. Clinical signs and symptoms imply fever, malaise, chest pain, cardiac arrhythmias
(tachyarrhytmias, various degrees of cardiac block), dyspnea and, in case of pericardial
involvement sharp pain in the precordial area, exacerbated by recumbent position, pericardial
friction rub on cardiac auscultation. Cardiomegaly and congestive heart failure may appear.
Serum myocardial enzymes are increased. Electrocardiogram reveals ST-segment and T-wave
abnormalities, while echocardiography may depict dilation of cardiac cavities or reduction of
ejection fraction. Recovery implies interstitial fibrosis and myocyte loss. Long-term sequelae are
present in 1/3 adult patients, including cardiomegaly, chronic congestive heart failure and
persistent echocardiographic changes. Dilated cardiomyopathy and chronic constrictive
pericarditis may occur.
Gastro-enteritis. Both coxsackie and echovirus, especially echovirus serotypes 11, 14, 18 have
been incriminated in cases of non-bacterial gastro-enteritis, characterised by fever, vomiting and
diarrheic stools.
Generalized neonatal disease. It may be the result of vertical transmission of enterovirus in the
perinatal period (maternal infection during the last week of pregnancy) or infection acquired
during the first month of life (either from an infected mother or during nosocomial outbreaks in
nurseries). Although many enterovirus serotypes produce the same clinical manifestations in
newborns as in older patients, some serotypes cause a severe, generalized disease of the
newborn, particularly coxsackievirus group B serotypes 1-5, echovirus saerotype 11. Group A
coxsackievirus serotypes 3, 9, 16 and echovirus serotypes 4-6, 7, 9, 12, 14, 16, 18, 19-21, 31 are
less frequently encountered. Generalized disease of the newborn includes myocarditis, hepatitis,
encephalitis and respiratory distress syndrome, sometimes with fatal outcome.
Other clinical entities have also been depicted in association with enterovirus infections: acute
nephritis, acute arthritis, parotitis, orchitis, polymyositis. Group B Coxsackievirus has been
isolated from the pancreas of several children diagnosed with type 1 diabetes mellitus, but, so
far, there is no confirmed correlation between enteroviruses and this metabolic condition.
However, acute pancreatitis has been depicted in association with group B coxsackievirus type
1-5 and echovirus serotypes 6, 11, 22 and 30.
Positive diagnosis
Epidemiologic and clinical data are rarely suggestive for enterovirus infections. Clinically
distrinct entities, such as hand-foot-and-mouth disease or herpangina are exceptions. Enterovirus
infections may be suspected in case of epidemic outbreaks, by contact with other confirmed
cases.
Laboratory findings
Serologic tests detect the presence of anti-enterovirus IgM antibodies after 1-3 days from contact
with enterovirus, which last for 1-3 months, and of IgG antibodies, which appear > 10 days from
the infective contact with lifelong duration. Anti-enterovirus antibodies are serotype-specific.
Neutralizing and complement-fixating titers of antibodies can be determined. Dynamic
serological tests should be performed, detecting antibody titers at 4 weeks-distance.
Enteroviruses can be isolated in cell cultures (monkey kidney cell lines, human embryonic
fibroblasts, human rhabdomyosarcoma cell lines), by characteristic cytopathic effect, or into
suckling mice. Thus, enteroviruses can be isolated from the throat, faeces, CSF or blood.
PCR (polymerase chain reaction) detects the presence of enteroviral RNA genome in blood,
CSF, stool, naso-pharyngeal samples or from tissues.
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Treatment
So far, no antiviral medication has been licensed for enterovirus infections. Iv administration of
immunoglobulin containing high anti-enterovirus antibodies titers can be used in
agammaglobulinemic patients, newborns with severe generalized neonatal disease or in other
patients with severe forms of illness, including central nervous system infections.
Treatment is supportive: symptomatic, anti-inflammatory medication, bed rest. Meningitis
encephalitis requires corticosteroids, depletion, neuronal trophic medication, group B vitamins.
Patient isolation can be performed either at home in mild cases or by hospitalization in severe
forms of illness.
Prophylaxis
Apart from poliovirus, there is no vaccination against other enterovirus infections. Good
hygiene, hand washing, use of gloves and masks help prevent enterovirus transmission
(especially nosocomially). Enteric precautions should be maintained for about 1 week after the
onset of the disease. Overcrowding should be avoided.
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POLIOMYELITIS
Nina incu
Definition
Acute infectious and contagious systemic disease caused by poliovirus (an enterovirus), with
diverse clinical manifestations, ranging from asymptomatic infection to paralyitic poliomyelitis
and even death.
polios = gray, myelos = marrow (Greek): involves gray matter neurons (especially the
anterior horns of the spinal cord).
Etiology
Poliovirus genus Enterovirus, family Picornaviridae. It has single stranded RNA structure,
proteic capside and no lipidic envelope, which makes it resistant in acidic environments, such as
the human stomach. It may resist for several days at room temperature, several weeks at 4C and
is not destroyed by alcohol, ether, chloroform and usual detergents. It is inactivated by
formaldehyde, ionizing radiations and phenol.
Poliovirus can be cultivated in HeLa cell lines or monkey kidney cell cultures.
Poliovirus has 3 known serotypes:
- Type 1 (Brunhilde) most frequently involved in severe, paralytic forms of
disease
- Type 2 (Lansing) usually causing asymptomatic infections
- Type 3 (Leon) rarely encountered
Epidemiology
In 1988, World Health Organisation (WHO) set poliomyelitis eradication until the year 2000 as
major goal. The introduction of anti-poliovirus vaccination significantly decreased the number of
cases of poliomyelitis. However, in spite of general availability of anti-poliovirus vaccination,
the disease is not yet eradicated worldwide, as cases are still reported, especially in the subSaharan region and south-east Asia. In Romania, poliomyelitis is considered eradicated illness,
although the possibility of import cases in travellers returning from endemic areas cannot be
excluded.
Reservoir: human. It consists of patients infected with poliovirus, either developing a clinical
manifest disease or apparently healthy carriers of virus. Persons recently vaccinated with oral
live-attenuated vaccine (OPV) shed the virus through their faeces and may be source of infection
for unimmunized contacts.
Contagiousness: high. The period of contagiousness begins from the last ( 5) days of
incubation and last for about 8 weeks after the clinical onset of the disease. Poliovirus can be
isolated from the oropharynx for about 3 weeks and from the faeces for about 8-12 weeks after
the onset of the disease.
Transmission route: both airborne, through naso-pharyngeal droplets, and via faecal-oral route,
by contact with faeces, contaminated hands, food and / or water. About 1 million infective doses
are eliminated within 1 gram of faeces.
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Susceptibility: general, among unimmunized contacts. However, only a minority develop the
paralytic form of disease, asymptomatic infection and minor illness are more frequent.
Immunity: Infection with one poliovirus serotype confers type-specific lifelong immunity, but
does not protect against infections with different serotypes. Immunity following vaccination with
trivalent vaccine lasts for about 5 years. Secretory IgA antibodies appear in the oropharynx and
intestinal tract after 1-3 weeks from OPV. IgG serum antibodies develop after OPV or IPV.
Breastfed infants born to immune mothers benefit of protection against poliovirus infection due
to the passage of mothers antibodies during their first 3-4 months of life.
Pathogenesis
Poliovirus penetrates into the organism via the oropharynx or digestive tract. After infecting the
epithelial cells of the digestive mucosa, it replicates inside local lymphoid structures: tonsils and
Peyers patches (the intestinal stage of infection). It subsequently disseminates to the
reticuloendothelial system via minor viremia and, in most patients, infection is limited at this
stage by antibody formation (asymptomatic disease). Bloodstream dissemination follows
replication inside the reticuloendothelial system (major viremia), corresponding to clinical
phenomena characterising the minor illness. If infection is contained at this stage, without
involving the central nervous system (CNS), the patient develops a form of abortive
poliomyelitis (4-8% cases of infection).
CNS impairment (CNS invasion stage), resulting in paralytic poliomyelitis, may be the result of
dissemination via neuronal pathways or from bloodstream; occurs in 1-2% cases. The poliovirus
receptor is found at the site of neuromuscular junctions, which suggested that poliovirus reaching
the junction during viremia may travel from muscles to the anterior horns of the spinal cord via
long axons composing the peripheral nerve fibres.
Poliovirus affects the motor and autonomic neurons from the gray matter of the spinal cord
(especially the anterior horns), but also from cranial nerves nuclei from the brainstem,
(especially medulla oblongata and pons). Apart from neuronal destruction, inflammatory lesions
were depicted, consisting of leukocyte infiltrates, oedema and vasculitis, that persist for months.
Muscle denervation and atrophy are the result of neuronal degeneration, with the formation of
glial scars in the place of destroyed neurons.
Several factors may influence the development of paralytic poliomyelitis, apart from strain
virulence: age, immune status, pregnancy, trauma. Tonsillectomy predisposes to bulbar paralytic
poliomyelitis and reduces the duration of the incubation period. Intramuscular injections are
prohibited as they favour the onset of muscle paralysis.
Clinical manifestations
About 95% cases of infection are asymptomatic. 4-8% cases are abortive forms of poliomyelitis.
1-2% cases involve CNS.
The classic evolution of poliomyelitis is biphasic and includes several stages:
Incubation: average: 9-12 days (ranging from 5 to 35 days). Incubation period is shortened in
case of tonsillectomy (< 1 week).
Minor illness: duration: 2-3 days. The patient complains of fever, headache, vomiting,
abdominal pain, sore throat, respiratory symptoms, without any neurological signs. It resembles
flu and may be misdiagnosed. In abortive poliomyelitis, the course of infection ends at this
stage.
Latency period: a 3-5 day symptom-free period.
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Major illness: temperature raise, followed by a pre-paralytic phase, which lasts for 1-2 days,
resembling aseptic meningitis: headache, vomiting, neck stiffness, pleocytosis of the CSF, with
minimum elevation of CSF protein levels (cyto-albuminologic dissociation). Pronounced
myalgias, hyperesthesia, paresthesia, muscle spasms and fasciculations precede the onset of the
paralytic stage by 1-2 days. Signs and symptoms are characteristic for the peripheral motor
neuron syndrome. Flaccid paralysis occurs, with asymmetrical distribution. Lower limb muscles
are more frequently interested than upper limb muscles and proximal muscles of the limbs are
more frequently affected that distal muscle groups. Deep tendon reflexes are hyperactive at the
beginning, than become absent. Abdominal and thoracic muscle paralysis may occur as well.
Paralysis of the respiratory muscles intercostals and diaphragm may cause respiratory arrest..
Paralysis progression extends during hours or days and stops after fever remission.
Lesions of autonomic neurons translate into circulatory troubles, cold extremities, perspiration,
urinary retention due to urinary bladder paralysis.
In bulbar forms, the involvement of neurons belonging to cranial nerves (especially IX and X)
leads to dysphonia, dysphagia, sometimes dyspnea. Facial palsy is possible. Alteration of the
cardio-circulatory brainstem centres may be fatal.
Consciousness troubles are uncommon, except for polioencephalitis. Sensory deficits are not
characteristic for poliomyelitis; they impose differential diagnosis with Guillain-Barre syndrome.
Recovery stage: begins 10-14 days after the onset of the disease and lasts for months or years,
though most reversible lesions disappear in one month. Partial recovery of the motor functions
may take place in various amounts. About two thirds of patients remain with lifelong sequelae.
Stage of sequelae: lifelong; it is characterised by definitive limb paralysis and muscle atrophies
due to denervation. Deformations of the limbs, pelvis or spine are common, especially since
paralysis is asymmetrical and involves either only the extensors or only the flexors of one limb.
Since the opposite muscle group maintains its tone, various vicious positions may be acquired.
Equinovarus foot, valgus deformity, scoliosis may occur. Failure to grow of one limb, while the
controlateral limb develops normally leads to the apparent shortening of one limb.
Postpoliomyelitis syndrome: appears 20-40 years after the initial episode of poliomyelitis. It s
characterised by newly established weakness, muscle atrophy, fatigue, pain, usually in the same
muscle groups involved in the initial episode of disease, rarely extending to previously healthy
muscle groups. The cause is considered to be the progressive loss of motor units innerving
muscle groups already impaired during the initial course of the disease (motor units that had
taken over the function of previously destroyed neurons) and not an infection reactivation. It
affects 20-30% patients. Disease severity and rate of progression is not comparable to those from
the initial episode of poliomyelitis.
Clinical forms
Non-paralytic forms:
- Asymptomatic forms 90-95% cases
- Abortive poliomyelitis includes only minor disease 4-8% cases
- Polio meningitis aseptic meningitis (initial cyto-albuminological dissociation in
the CSF, followed by albumin-cytological dissociation)
Paralytic forms:
- Spinal paralytic poliomyelitis the most frequent paralytic form paralysis of the
limb muscles (monoplegia, hemiplegia, paraplegia, quadriplegia), of the abdominal
or thoracic muscles, including respiratory muscles, paralysis of neck muscles
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spino-encephalitic,
bulbo-encephalitic,
with
According to the age of patients: infants may develop polioencephalitis or severe forms more
often than adults.
Vaccine-associated poliomyelitis follows OPV
Positive diagnosis
-
Epidemiologic data:
vaccination history.
Laboratory findings: Poliovirus can be isolated from the oropharynx, faeces and
CSF by PCR technique or cultivated on HeLa / monkey kidney cell cultures. For
epidemiologic purpose, it is important to identify the viral strain as wild-type, OPV
or vaccine-derived poliovirus. Serological tests, performed 4 weeks apart, detect an
increase in neutralizing or complement-fixation titres of IgM antibodies. CSF is
clear, characteristic for aseptic meningitis, with lymphocytic pleocytosis, but
slightly elevated or normal protein levels (cyto-albuminological dissociation), with
normal glucose levels. Poliovirus can be identified from the CSF by PCR or
cultivation on cell lines. However, lumbar puncture should be avoided, as it may
exacerbate the course of illness.
Minor disease: DDx with flu and other respiratory virus infections
Major disease paralytic stage: DDx with other enterovirus infections (enterovirus
71), West-Nile infection, vaccine-associated myelitis, brain haemorrhage, botulism,
post-dyphteric paralysis, spinal cord compression, Guillain-Barre syndrome
(symmetrical, bilateral, ascending paralysis, sensation impairment, albumincytological dissociation in the CSF: elevated CSF albumin level without significant
pleocytosis)
Complications
-
Treatment
No etiologic antiviral treatment has been discovered so far. Case management implies supportive
methods. Hospitalization and careful monitoring is required during the acute phase of paralytic
poliomyelitis. Severe forms of disease require hospitalisation in an intensive care unit. Bed rest
is compulsory during this stage, with no exercise. Intramuscular injections are prohibited, as they
may exacerbate neurological symptoms. Hot moist packs are applied to involved muscle groups.
Pain relievers, sedatives, group B vitamins may be of help.
Mechanical ventilation is necessary in case of paralysis of respiratory muscles: tracheal
intubation and positive pressure ventilation. Postural drainage and secretion aspiration is useful
in patients with bulbar forms of poliomyelitis, with accumulation of secretions in their airways.
Physical therapy begins in the recovery phase and may last for years. Sometimes surgery is
necessary to correct vicious positions or limb abnormalities.
Prognosis
Mortality in paralytic forms of poliomyelitis was reported to be of 5-10% during polio epidemics
and even more increased in bulbar forms of disease. Lifelong sequelae are frequent in paralytic
forms, characterised by limb paralysis and muscle atrophy, usually accompanied by vicious
positions of the limbs due to asymmetric muscle involvement.
Prophylaxis
Two types of anti-polio vaccine have been available.
Live-attenuated oral poliovirus vaccine (Sabin) OPV contains strains of poliovirus attenuated
by multiple successive passages in monkey kidney cell cultures and selection of mutant strains
with low virulence. It is administered orally and induces local, gastro-intestinal immunity,
reflected by local appearance of IgA anti-poliovirus antibodies after 1-3 weeks from vaccination.
IgG antibodies appear as well. Trivalent vaccine is used (effective against all 3 serotypes of
poliovirus). However, as it contains a live-attenuated viral strain, one must bear in mind the risk
of developing vaccine-associated poliomyelitis following administration of oral (live-attenuated)
vaccine. It is about 1 case/2.5 million doses among immunocompetent subjects and 2000 times
higher among immunosuppressed individuals, disease occurring both in vaccinated persons and
their contacts, as vaccinated persons shed poliovirus through their faeces (up to 6 weeks) and
naso-pharingeal secretions (up to 3 weeks). The replication of the live-attenuated viral strain
inside the digestive tract may lead to mutations and transformation into a virulent strain that may
cause disease. Intramuscular injections are prohibited during the first months following OPV
vaccination as these manoeuvres increase the risk of vaccine-associated poliomyelitis.
Intercurrent diarrheal diseases reduce the efficacy of OPV. Like other live-attenuated vaccines,
OPV is prohibited in immunocompromised hosts.
Inactivated poliovirus vaccine (Salk) IPV is obtained by formalin-inactivation of viral strains.
It does not cause vaccine-associated poliomyelitis. It induces IgG antibody formation.
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While industrialized countries mostly use IPV, OPV is administered at large scale in less
developed regions. Nowadays, IPV is used in Romania. Four doses are recommended in children
at the age of 2 months, 4 months, 6-18 months and 4-6 years.
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Introduction
Acute infectious diarrheal diseases are the second worldwide regarding their frequency,
following the acute respiratory illnesses. In children under 5 years diarrhea appears 2-3 times per
year in developed countries, whereas in developing countries in can have a frequency of 10-18
episodes per year. In Asia, Africa, and Latin America diarrhea is a leading cause of morbidity
and mortality in children.
Definition
Diarrhea is defined as passing 3 or more watery stools, or one or more bloody stools per day.
The average stool weight is 100 g per day, whereas diarrhea is defined as at least 200 g of stool
output per day.
Severe diarrhea is characterized by one or more of the following: volume depletion, fever, 6 or
more stools per day, the illness lasting above 48 hours, and immunosuppression.
Classification
Classification regarding the duration of diarrhea
Regarding its duration diarrhea can be classified as:
-
viruses
bacteria
parasites
fungi
penetrating mechanism:
o distal small bowel is affected
o the microorganisms penetrate the epithelial layer via the phagocytes, and
disseminate throughout the body, causing enteric fever
o
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A great number of microorganisms are ingested with every meal, neutralized by the defense
mechanisms of the normal host. The elements of the host defense are:
Gastric acid
The acidic pH (<4) of the stomach destroys the majority of enteric pathogens. Neutralization of
this barrier by antiacid medication might conduct to enteric bacterial and parasitic infections.
In order to pass this barrier a great inoculum of pathogens is needed (for example: 108 organisms
of Vibrio cholerae).
Some microorganisms can survive gastric acidity such as rotavirus, which is stable in acid
environment, and some parasites, their process of excystation is facilitated by the low pH.
Personal hygiene
The acquisition of an enteric infection depends on the number of pathogens ingested. The
exception is Shigella, which can be transmitted with only 10-100 organisms, and cysts of certain
parasites.
The route of transmission of enteric pathogens is oral in most of the cases. Therefore the supply
of uncontaminated water and appropriate sanitary facilities play an important role in the
prevention of diarrhea.
Normal flora
The intestine is inhabited by a large number of bacteria, 99% of which is anaerobic (1011
organisms per gram of normal feces Bacteroides, Clostridium, peptostreptococci, peptococci
and others). These bacteria produce volatile fatty acids and provide acidic pH, which prevents
colonization of the bowels by enteric pathogens.
Infants who have not developed yet their normal flora, or persons receiving antibiotics that cause
a loss of normal flora, are more likely to have infections with enteric pathogens. A single dose of
antibiotic can eradicate the protective effect of normal flora.
Intestinal motility
Gut motility and diarrhea helps the host to get rid of the intestinal pathogens. Antimotility drugs
administered in bacterial diarrhea might worsen the outcome, and conduct to bacteremia in some
cases.
Immunity
Cellular and humoral immunity play an important role in protection from enteric infections.
Humoral immunity consists of systemic IgM and IgG, and local secretory IgA.
The first line defense is the mucosal immune system. Bacterial antigens are bound to the luminal
surface of the M cells in the distal small bowel and they are presented to the subepithelial
lymphoid cells. As a result sensitized lymphocytes (plasma cells) are produced, these spread
throughout the mucosa, and produce secretory IgA.
Breast-feeding has a protective role through the antibody, lactoferrin, lysozyme, phagocyte,
lactose, low pH, low protein, low phosphate and oligosaccharide-fraction content of the human
milk.
Host genotype and age
Host genotype and age influence the susceptibility to colonization with enteric pathogens. For
example persons with blood group O are more susceptible to cholera, shigellosis, and norovirus
infection, whereas those with blood group A to giardiasis. Infections with enteroaggregative E.
coli are associated with a polymorphism in the interleukin 8 gene.
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Rotavirus and enteropathogenic E. coli infections affect young children especially. This is
related to age-specific changes of intestinal mucosa, cell surface factors, microbial flora,
environmental exposure, and specific immune factors.
Microbial factors
Inoculum size
There is a certain number of microorganisms that has to be ingested in order to cause disease.
This number can be low (10-1000 bacteria or cysts) for Shigella, enterohemorrhagic E. coli,
Giardia lamblia and Entamoeba, or high (105-108) in the case of Vibrio cholerae.
Adherence
By adhering to the intestinal walls microorganisms can avoid the effect of peristaltism, they can
colonize the mucosa.
Microorganisms adhere to the specific receptors of the intestinal cells through specific surface
structures, such as pili, fimbiriae, or other adherence factors (adhesins). Examples of
microorganisms using adherence factors: Vibrio cholerae, enterotoxigenic and enteropathogenic
and enterohemorrhagic E. coli.
Enterotoxin production
The enterotoxins act on the secretory mechanisms of the mucosa. They activate the adenilate or
guanilate-cyclase enzymes of the eneterocytes, which results in cyclic AMP or GMP formation.
These cyclic nucleotides activate the water and electrolyte secretion, which conducts to watery
diarrhea. Examples of enterotoxin-producing microorganisms: Vibrio cholerae, enterotoxigenic
E. coli.
Cytotoxin production
Cytotoxins inhibit the protein synthesis of intestinal epithelial cells, which conducts to cell
destruction. As a result of this disentery syndrome appears, characterized by bloody stools with
inflammatory cells (frequent low quantities of mucous-purulent-bloody stools associated with
abdominal cramps and tenesmus). Examples of cytotoxin-producing microorganisms:
Clostridium difficile, Vibrio parahaemolyticus, Enteropathogenic E. coli, some types of
Salmonella, Shigella dysenteriae type 1, and Shiga-toxin producing E. coli. The last two produce
a verotoxin, which conducts to hemolytic-uremic syndrome and hemorrhagic colitis.
Neurotoxins are produced by microorganisms outside the host, which are ingested. This is the
case of food poisoning. For example the staphylococcal and Bacillus cereus toxins act on the
central nervous system, and produce vomiting.
Invasion
Many microorganisms can adhere to and invade the intestinal epithelial cells. This conducts to
the destruction of the epithelial cells and dysentery syndrome. The bacteria multiply in the cells,
destroy the cells and spread to adjacent cells. An important local inflammatory reaction appears.
The subsequent systemic invasion is rare however it might appear in the immunocompromised
patients. Examples of invasive microorganisms: Shigella, enteroinvasive E. coli, Salmonella.
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Penetration
Some microorganisms can penetrate the intact intestinal mucosa, without local destruction. They
multiply in the phagocytes found in Peyers patches or intestinal lymph nodes. Afterwards they
produce systemic invasion, manifested as enteric fever syndrome, characterized by fever,
headache, relative bradycardia, abdominal pain, splenomegaly, and leukopenia. Examples of
penetrating microorganisms: Salmonella typhi and paratyphi, Salmonella cholerae suis, Yersinia
enterocolitica.
Mature epithelial cell destruction
Mature epithelial cells are infected and destroyed in viral intestinal infections. However
destruction does not affect the cells of the intestinal cryptae. As a result the structure of intestinal
vili is destroyed, and the absorption of the fluids altered. Water and electrolyte loss occurs
therefore the stools are watery, although rarely they might be also bloody.
Clinical manifestations
Diarrhea can be easily recognized based on the presence of frequent soft stools associated or not
with abdominal cramps, tenesmus. However, it is not easy to establish the etiology of diarrhea.
Complications
Dehydration and electrolyte loss are frequent acute complications of diarrhea.
Chronic complications can follow an acute episode of diarrhea. Chronic diarrhea can be caused
by: lactase deficiency, small bowel bacterial overgrowth, malabsorbtion syndromes.
Inflammatory bowel disease can be exacerbated by an acute infectious diarrhea.
Reactive arthritis (Reiters syindrome) can appear following infection with invasive
microorganisms (Salmonella, Shigella, Campylobacter).
Hemolytic-uremic syndrome, manifested with hemolytic anemia, thrombocytopenia and renal
failure can appear in case of verotoxin producing microorganisms (Shigella dysenteriae type 1,
enterohemorrhagic E. coli).
Diagnosis
History
Historical data has to be obtained about:
-
the presence / absence of fever (fever means either invasive disease, or it can result
from an infection outside the intestinal tract)
abdominal pain:
o severe in inflammatory processes (Shigella, Campylobacter)
o painful cramps caused by electrolyte loss: in cholera
o bloating: lambliasis
o appendicitis-like syndrome: Yersinis enterocolitica
tenesmus (painful rectal spasms with the sensation of defecation, but little passage of
stool): proctitis (shigellosis, amebiasis)
vomiting:
o toxin-mediated illness
o food poisoning
o systemic illness
o bowel obstruction
contacts presenting the same symptoms: food poisoning, the food can be examined
Physical examination
Severe disease has to be identified: high fever, toxic syndrome, dehydration.
Dehydration can be mild, moderate or severe:
-
mild dehydration: thirst, dry mouth, decreased urine output, decreased axillary sweat,
slight weight loss (5%)
moderate dehydration: orthostatic fall of blood presure, decreased skin turgor, sunken
eyes, sunken fontanelle (in infants), moderate weight loss (5-10 %)
Laboratory evaluation
Test for fecal leukocytes
A thin smear of stool is prepared on a glass slide, a drop of methylene blue is added, and it is
examined. Fecal lactoferrin is a marker of the fecal leukocytes. Its evaluation is more sensitive,
and avalilable in latex agglutination and ELISA formats.
The presence of neutrophils suggests an invasive or cytotoxic mechanism, although it can be
present in ulcerative colitis and Crohns disease, also.
The absence of leukocytes suggests noninflammatory diarrhea, which can be either infectious
(enterotoxin-produced, viral, parasitic) or noninfectious (tumors, immunosuppression).
Gram stained smear from stool
It is useful in case of staphylococcal diarrhea and cholera. It cannot be used to distinguish the
Gram negative microorganisms.
174
Cultures
Stool culture: The stool sample has to be obtained before the initiation of antibiotic therapy.
Negative stool culture does not exclude the bacterial etiology of an acute diarrhea. Indications to
perform stool cultures are: dysenteric syndrome, feverish diarrhea lasting > 3 days, diarrhea
outbreaks, travelers diarrhea, diarrhea following antibiotic therapy, immunosuppressed patients.
In case of food poisoning cultures have to be made from vomiting and the food also.
Blood cultures are useful in the case of typhoid fever, and invasive diarrhea (Salmonella,
Yersinia enterocolitica, Campylobacter spp.)
Detection of specific pathogens
The useful tests to detect viruses as the cause of diarrhea are: latex agglutination (rotavirus),
ELISA tests and PCR (norovirus).
Parasites can be detected by performing native and coloured smears, either from stool or from
the duodenal fluid, or from intestinal biopsy. At least three specimens should be examined.
If there is a suspicion of cholera, stool should be cultured on TCBS (thiosulfate-citrate-bile saltssucrose) agar.
In case of Clostridium difficile: the toxins A and B have to be detected in stool, by latex
agglutination, or ELISA tests.
Differential diagnosis
Acute infectious diarrhea has to be differentiated from:
-
toxic diarrhea (intoxication with mushrooms, ciguatoxin and scombrotoxin from fish
or seafood, heavy metals such as lead, mercury)
food allergy
psychogenic diarrhea
neoplasms
Treatment
In most cases of infectious diarrhea an etiologic diagnosis is not necessary or available, due to
the time consuming diagnostic approaches, therefore the therapy is empirical. It is focused on
adequate rehydration, diet, symptomatic therapy. Most of acute infectious diarrheas are self
limited and do not require antimicrobial therapy.
Most of the patients with diarrhea are treated at home. Hospital admission is necessary in cases
of severe dehydration and certain diseases with epidemiologic risk (dysentery, cholera, typhoid
fever).
175
The diet is rich in liquids (tea, rice soup, vegetable soup with salt and glucose, plain water).
Boiled rice, boiled pasta, followed by boiled meat and vegetables, toast, non fermented cheese
can be consumed, in small, frequently administered quantities. It is advisable to avoid milk,
juices, alcohol, coffee, vegetables with high cellulose content (beans, peas), potatoes, fruits,
sweets, other foods that are not easily digested.
Breast-feeding should be maintained in infants, however in case of formula fed infants lactosefree formulas have to be used.
Rehydration is the most important therapeutic action. Oral rehydration solutions are effective in
mild and moderate dehydration. The World Health Organization recommends oral rehydration
solutions that contain 3.5 g sodium chloride, 2.5 g sodium bicarbonate, 1.5 g potassium chloride
and 20 g glucose per liter of water.
In case of vomiting or in severe dehydration intravenous rehydration is necessary. Physiological
saline, 5% glucose, Ringers lactate solutions can be used.
Antidiarrheic therapy such as loperamide is recommended only in watery diarrhea. It is
contraindicated in invasive diarrhea, dysentery syndrome, due to its lowering effect on the bowel
movements. This facilitates the invasion of microorganisms, and their entrance into the systemic
circulation.
Intestinal adsorbents such as Bismuth subsalicylate, Pectin, Kaolin and Diosmectite can be
used.
Probiotics facilitate the recolonization of intestines with lactobacilli, which modify the local pH,
and create unfavorable conditions for pathogenic microorganisms.
Antimicrobial therapy is recommended in enteric fever, dysentery, diarrhea caused by
Clostridium difficile, cholera. The recommendation is debated in case of diarrhea produced by
Campylobacter, Yersinia, Aeromonas, and E. coli.
Antimicrobial therapy can be either empirical or specific. Many antibiotics can be used:
fluoroquinolones (ciprofloxacin, levofloxacin), 2nd and 3rd generation cephalosporins,
azithromycin, erythromycin, trimethoprim-sulfamethoxazole, rifaximin (not recommended in
dysentery), furazolidone, doxycycline. The duration of antimicrobial therapy is 3-5 days.
Examples of antimicrobial therapy according to specific agents:
-
Prophylaxis
Individual and comunitary hygiene has to be improved in order to reduce the fecal-oral
transmission of enteric microorganisms.
176
Travelers should eat only cooked food, avoid raw vegetables, salads and unpeeled fruit, drink
only boiled or treated water, and avoid ice. Prophylactic antimicrobial therapy is recommended
for travelers only if they are immunosuppressed (rifaximine, trimethoprim-sulfamethoxazole,
quinolones).
Rotaviral infections can be prevented by vaccination. A live attenuated oral vaccine is available,
that has to be administered in 2 doses to infants aged between 6-24 months.
References
1. Mandell GL, Bennett JE, Dolin R Principles and practice of infectious diseases, 6th
Edition, 2005, Elsevier
2. Kasper DL, Fauci A - Harrisons Infectious diseases, 2010, McGraw Hill Medical
3. Cupsa A Boli infecioase transmisibile, 2007, Editura Medical Universitar Craiova
4. Gantz NM, Brown RB, Berk SL, Myers JW Manual of clinical problems in infectious
disease, 5th Edition, 2006, Lippincott, Williams & Wilkins
5. Szalka A, Timr L, Ludwig E, Mszner Zs Infektolgia, 2005, Medicina Knyvkiad,
Budapest
6. Chiotan M Boli infecioase, 2002, editura Medical Naional, Bucureti
7. http://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm13353
9.pdf
177
In some cases there is no sign of disease, only a transient carrier state. If the process is not
limited to the intestines, bacteria can pass into the lymphatic and systemic circulation. Metastatic
foci can appear in case of bacteremia.
Clinical manifestations
Gastroenteritis is characterized by nausea, vomiting, diarrhea, with an incubation of 6-48 hours.
Abdominal cramps, fever can also occur. The stools are of moderate volume, loose, nonbloody,
but they might be bloody, dysenteric or watery. Symptoms mimicking appendicitis might appear.
Diarrhea is self limited, antimicrobial treatment is recommended only in the immunosuppressed
patients and extreme ages. The carriage state lasts 4-5 weeks, or > 1 year in case of chronic
carriage.
Bacteremia appears in 5% of diarrheal diseases, and 5% of these develop septic metastases.
These are more common in S. choleraesuis and S. Dublin infection, and at extreme ages or
immunosuppression. Endocarditis, arteritis can occur as a result of bacteremia.
Non-typhoidal Salmonellae can cause intraabdominal infections, such as hepatic, splenic
abscesses, cholecystitis. These are facilitated by gallstones, hepatobiliary tract abnormalities,
abdominal neoplasms, and sickle cell anemia.
Other infections:
-
bone, joint and soft tissue infections: osteomyelitis, septic arthritis (facilitated by
sickle cell disease, hemoglobinopathies, preexisting bone disease)
179
Antimicrobial agents used in therapy are: ciprofloxacin (2x500 mg/day), levofloxacin (500
mg/day once daily), azithromycin (500 mg/day once daily), trimethoprim-sulfamethoxazole,
amoxicillin, ceftriaxone, ampicillin.
There are resistant strains to trimethoprim-sulfamethoxazole, chloramphenicol, ceftriaxone,
fluoroquinolones.
The duration of antimicrobial therapy of gastroenteritis is 48-72 hours-7-10 days, or in case of
immunosuppression 7-14 days. In AIDS patients with Salmonella bacteremia the duration of
therapy is longer, 1-2 weeks iv therapy followed by 4 weeks of oral fluoroquinolones. Those
who relapse should receive long term suppressive therapy. In case of endocarditis or arteritis the
duration of therapy is 6 weeks. In case of extraintestinal nonvascular infections the duration of
therapy is 2-4 weeks. Surgical treatment is required in some cases.
Chronic carriers should receive a prolonged antibiotic course.
Prophylaxis
Every step of food production should be monitored. Contaminated food has to be pasteurized,
irradiated or cooked properly.
The infections have to be reported to the Public Health Authority to prevent larger outbreaks.
Limited usage of antibiotics in humans and animals might prevent the emergence of multidrogresistant Salmonella.
180
Typhoid fever is a human systemic disease caused by Salmonella typhi or paratyphi serotypes A,
B, or C, characterized by fever, splenomegaly, typhoid state, and rose spots, with severe,
potentially fatal evolution.
Etiologic agent
Salmonella typhi has a somatic antigen (O), flagellar antigen (H induces specific antibodies,
which are determined by the Widal reation), virulence (Vi) antigen, with antiphagocytic
characteristics.
The microorganism is resistant in the environment, can survive at low temperatures for long
periods of time. Salmonella typhi is destroyed by common disinfectants.
Epidemiology
The hosts of Salmonella typhi and paratyphi A, B, and C are exclusively human. The source of
infection is the ill person or healthy carrier.
The disease is transmitted through fecal-oral route, directly, or indirectly, through contaminated
food, water or objects. Sexual transmission is possible between homosexuals. The infection of
health care workers is possible through contact with ill persons or processing clinical specimens
or cultures.
Receptivity is general, the immunity is relative, does not provide protection in case of massive
reinfection.
Outbreaks of enteric fever are related to poor sanitation and lack of clean drinking water.
Sporadic cases may appear in travelers.
Multidrug-resistant strains of Salmonella typhi have emerged, which are resistant to
chloramphenicol, ampicillin, trimethoprim, ciprofloxacin.
Pathogenesis
Salmonella typhi and paratyphi passes the intestinal epithelium through the M cells within
Peyers patches at ileocecal level. Subsequently they are phagocytosed by macrophages,
however they survive within macrophages. Then they disseminate throughout the body in
macrophages via the lymphatics. This is the first, transient bacteremia. They colonize the
reticuloendothelial tissues such as liver, spleen, lymph nodes, bone marrow. The patient has no
fever and few symptoms in this phase (incubation).
Salmonellae are taken up by the tissular macrophages, multiply within them, and in 1-3 weeks a
secondary bacteremia occurs, with the spread of infection to another organs, such as the
gallbladder, biliary tract, and reinfect the Peyers patches of the ileon. The secondary bacteremia
is continuous, low quantities of microorganisms are continuously released into circulation. As a
consequence intestinal lesions appear such as necrosis of Peyers patches, followed by
ulceration. The symptoms of the disease start in parallel with the secondary bacteremia.
The endotoxin of Salmonella typhi plays a major role also, it enhances the inflammatory
response at the microbial multiplication sites, pyrogenic molecules and inflammatory cytokines
181
are produced. The delirious attitude called typhoid state, myocarditis, and leucopenia are caused
by the endotoxin.
Clinical manifestations
Incubation lasts for 10-14 days.
The initial symptoms appear progressively, the fever increases progressively during 5-7 days,
there is severe, persistent headache, insomnia, fatigue, myalgias, anorexia. Rarely starts the
disease abruptly with high fever.
Prolonged fever is the most important symptom, which lasts up to 4 weeks.
Typhoid state appears, called muttering delirium or coma vigil, which is characterized by a
delirious attitude, dreaming, the patient touches imaginary objects, rarely insomnia, psychosis.
At the end of first week a rash appears, rose spots, pink maculae situated on the abdomen, basis
of the chest, it resolves in 2-5 days. Salmonella can be cultured from these lesions.
Digestive syndrome is characterized by anorexia, nausea, vomiting, and coated, dry tongue
(parrot tongue). Ulcerative angina (Duguet angina) may be present. The abdomen is
meteoristic, with diffuse pain, especially in the right iliac fossa, where bowel movements can be
observed. The stool can be diarrheic (yellow-green stool), or can be normal, or constipation may
be present.
Hepatosplenomegaly may be present.
Cardio-vascular symptoms: relative bradycardia (discordant with fever), hypotension.
Other symptoms: bronchitis, oliguria, albuminuria, cylindruria, hematuria, encephalitis, coma.
In the absence of treatment this phase lasts 2-3 weeks. After this fever lowers progressively,
during a weeks period.
Convalescence lasts 2-4 weeks, but relapse is possible during this period.
Clinical forms
There are mild, moderate, atypical and severe forms.
Other clinical forms:
-
encephalytic form
hemorrhagic form
cholera-like form
Complications
Neurological complications are encephalitis, meningitis, polyradiculoneuritis.
Digestive complications are:
-
intestinal bleeding
bowel perforation
Both are life threatening, require rapid fluid replacement and surgical intervention.
Cardiovascular complications: myocarditis, thrombophlebitis, arteritis
182
leucopenia, lymphocytosis
Specific findings:
-
isolation of Salmonella typhi from: blood cultures (1st week), bone marrow cultures,
stool cultures, urine cultures, cultures from the rose spots, cultures from bile,
intestinal secretions (obtained by non-invasive duodenal string test), abscesses
serologic tests: paired sera (acute and convalescent) are sampled to evaluate the antiO anti-H (Widals test) and anti-Vi antibodies
Differential diagnosis
Other diseases that cause prolonged fever have to be differentiated: sepsis, endocarditis,
brucellosis, tuberculosis, malaria, mononucleosis, leptospirosis, neoplasias, malignant
hemopathies, chronic inflammatory diseases
Diseases with typhoid state: exanthematic typhus, recurrent fever, meningoencephalitis have to
be differentiated.
Treatment
In typhoid fever prompt antibiotic therapy is mandatory. Ciprofloxacin (2x200 mg IV/day 7-10
days), levofloxacin (750 mg PO or IV/day 7-10 days) Ceftriaxone (2 gram IV/day 7-14
days), azithromycin (1 gram PO 1st dose, than 500 mg PO/day for 5-7 days), chloramphenicol
4x500 mg PO or IV/day 14 days), amoxicillin, trimethoprim-sulfamethoxazole can be used.
The patient has to be admitted to the hospital. Complete bed rest is recommended.
In severe forms with neurologic manifestation or shock corticosteroid therapy (Dexamethasone)
is recommended.
Cholecystectomy and antimicrobial therapy for 10-14 days is recommended in case of gallstone
in chronic carriers. In case of normal gallbladder the antimicrobial therapy lasts for 4-6 weeks in
chronic carriers. Amoxicillin, ciprofloxacin or trimethoprim-sulphametoxazole can be used.
Prophylaxis
183
Ill patients are isolated in hospital. They can be released after 21 days of normal body
temperature, but only after 3 negative stool cultures were obtained.
Persons working in risky areas such as public alimentation, day care centers are allowed to return
to work only after 3 months. The carriers must not be employed in risky areas.
It is important to provide adequate sewage disposal and water supplies.
Three vaccines are available, an oral live attenuated, a parenteral, that contains purified Vi
polysaccharide, and a killed whole cell vaccine. The travelers vaccination is recommended.
Persons who have intimate or household contact with carriers, or laboratory workers who
frequently deal with Salmonella typhi, should be vaccinated.
References:
1. Kasper DL, Fauci A - Harrisons Infectious diseases, 2010, McGraw Hill Medical
2. Cupsa A Boli infecioase transmisibile, 2007, Editura Medical Universitar Craiova
3. Szalka A, Timr L, Ludwig E, Mszner Zs Infektolgia, 2005, Medicina Knyvkiad,
Budapest
4. Rebedea I Boli infecioase, 2000, Editura Medical Bucureti
5. Gilbert DN, Moellering RC, Eliopoulos GM, Chambers HF, Saag MS The Sanford
Guide to Antimicrobial Therapy, 41st Edition, 2011, Antimicrobial Therapy Inc., USA
184
PARATYPHOID FEVER
The etiologic agents of paratyphoid fever are Salmonella paratyphi A, B or C. The disease
resembles typhoid fever, with slight differences according to each etiologic agent.
In paratyphoid fever A the intestinal lesions are rare and superficial therefore the digestive
complications are rare.
In paratyphoid fever B the incubation period is shorter than in typhoid fever, the onset is rapid,
the rose spots appear in greater numbers, and diarrhea is more prominent. The course of disease
is shorter, with fewer complications.
In paratyphoid fever C the clinical manifestations are severe, and the patients might have
jaundice and encephalitis. However there are no intestinal lesions.
Diagnosis and therapy are similar as in typhoid fever. The Widal reaction shows the presence of
anti-Salmonella paratyphi A, B, respective C antibodies.
185
SHIGELLOSIS
Andrea Incze
Definition
Shigellosis or dysentery is an acute infectious diarrheal disease caused by Shigella spp.,
characterized by fever, tenesmus and bloody mucopurulent stools.
Etiologic agent
Shigellae are non-spore forming, imobile gram-negative bacteria. They are members of the
Enterobacteraiceae, and genetically related to E. coli.
There are 4 serogroups of Shigella:
-
Epidemiology
Dysentery is present worldwide.
The reservoir of infection is represented by persons with acute or chronic infection, and healthy
carriers. Higher primates can also be reservoirs of infection.
The transmission is by fecal-oral route, via unwashed hands. Contaminated water, food, or flies
can play a role in the transmission. Shigella can survive in food, causing food-borne infections.
Sexual transmission is also possible among homosexual men.
The receptivity is general. Morbidity and mortality rates are higher among children below 10
years. Infants may be protected during breastfeeding.
Shigellae are resistant to the low pH of the stomach, therefore the inoculum required to produce
infection is low (10-100 bacilli).
Pathogenesis
Shigella invades the mucosa of distal ileon and colon. The microorganism spreads from cell to
cell after crossing the epithelial barrier through M cells (specialized translocating epithelial
cells). This conducts to inflammation and necrosis, focal ulcerations that can reach the
submucosal layer.
Shigella dysenteriae type 1 produces a neurotoxin (Shiga toxin), which increases the severity of
the disease. Other shigellae produce enterotoxins which alter the hydro-electrolyte transport, and
conduct to intraluminal fluid accumulation.
Systemic invasion is rare, it occurs only in infants, in case of immunodepression, and
malnutrition.
186
Clinical manifestations
The incubation period lasts 1-8 days.
The initial manifestations are high fever, diffuse or lower abdominal pain, watery diarrhea,
malaise, anorexia, tenesmus. At this stage the small intestine is affected.
The manifestations of dysentery follow: small volumes of bloody mucopurulent stools with
tenesmus and abdominal cramps. In this stage the distal colon and rectum is affected.
The disease is self-limited in most of the cases, and resolves within 1 week.
Complications
Dysentery can be life-threatening in malnourished children below 5 years.
Bacteremia can occur in malnourished and immunosuppressed patients.
Dehydration can be present, it can be severe also. However dehydration is not a major feature in
dysentery. Other metabolic complications such as hyponatremia, hyopglycemia can occur.
Neurologic symptoms may appear in young children: meningism, seizures, confusion, delirium,
coma, and headache. Very rare complications: meningitis, toxic encephalopathy.
Hemolytic uremic syndrome is characterized by hemolytic anemia (hemoglobin <8g/dl),
thrombocytopenia (<60000/ l) and acute renal failure leukemoid reactions (leukocyte number
50000/l).
Local complications are rectal prolapse, intussusception, toxic megacolon (the inflammation
reaches the colonic smooth-muscle layer and causes paralysis, dilatation peritonitis), and
intestinal perforations.
Reiters syndrome can appear as postinfectious immunologic complication, manifested as a
reactive arthritis weeks or months after shigellosis. It appears especially in patients with
histocompatibility antigen HLA-B27, and only following Shigella flexneri infection. The
arthritis can be associated with conjunctivitis and urethritis.
Diagnosis
Epidemiological data can reveal contact with ill persons or healthy carriers.
Clinical data consist of the presence of dysentery syndrome, although shigellosis can evolve
without dysentery syndrome also.
Laboratory diagnosis:
-
Non-specific findings:
o test for fecal leukocytes: neutrophil predominance
o blood leukocyte count: can be normal, low or elevated (leukemoid reactions
occur in infections with Shigella dysenteriae type 1)
Specific findings:
o isolation and identification of Shigella from stool
pigs
conducts
to
o PCR: high sensitivity test that can detect Shigella from stool
Differential diagnosis
The following diseases should be differentiated from shigellosis:
-
Treatment
The patients with dysentery have to be admitted to hospital. Diet, rehydration and symptomatic
therapy should be applied. Antimotility agents have to be avoided. Although mild cases respond
well to this therapy, antimicrobial therapy shortens the course of disease, and facilitates the
sterilization of the intestine.
Antimicrobial therapy:
-
188
Prophylaxis
Patients with shigellosis have to be isolated in hospital, and the cases are reported to the Public
Health Authorities. Patients can be released from hospital only after obtaining 3 negative
cultures form stool. Stool cultures have to be repeated in the following 3 months.
Hand washing before handling food, after defecation and after handling childrens feces is
important.
References:
1. Mandell GL, Bennett JE, Dolin R Principles and practice of infectious diseases, 6th
Edition, 2005, Elsevier
2. Kasper DL, Fauci A - Harrisons Infectious diseases, 2010, McGraw Hill Medical
3. Cupsa A Boli infecioase transmisibile, 2007, Editura Medical Universitar Craiova
4. Szalka A, Timr L, Ludwig E, Mszner Zs Infektolgia, 2005, Medicina Knyvkiad,
Budapest
5. Bannister B, Gillespie S, Jones J Infection Microbiology and Management 3rd Edition,
2006, Blackwell Publishing, London
6. Gilbert DN, Moellering RC, Eliopoulos GM, Chambers HF, Saag MS The Sanford
Guide to Antimicrobial Therapy, 41st Edition, 2011, Antimicrobial Therapy Inc., USA
189
CHOLERA
Andrea Incze
Definition
Cholera is an acute infectious diarrheal disease, caused by Vibrio cholerae, characterized by high
quantities of watery diarrhea, vomiting, subsequent severe dehydration, muscle cramps, and
possibly death.
Etiologic agent
Vibrio cholerae has 200 serogroups, classified based on the structure of the lipopolysaccharide O
antigen. They are divided into 2 groups: those with O1 antigen, and without O1 antigen (non-O1
Vibrio cholerae). Non O1 serogroups cause only sporadic outbreaks, serogroup O1 causes
epidemics. Serogroup O139 can also cause epidemics.
Serogroup O1 is divided into 2 biotypes: classical and El Tor. These biotypes are divided into 3
serotypes: Inaba, Ogawa and Hikojima.
The disease can be produced only by toxin-producing strains from groups O1 and O139.
A specific medium, TCBS (thiosulfate-citrate-bile salts-sucrose) agar is used for inoculation.
Vibrio cholerae is destroyed by heat, gastric acid, and disinfectants. Biotype El Tor is more
resistant in the environment than the classical biotype.
Epidemiology
The natural habitat of V. cholerae is coastal salt waters. Humans become infected incidentally.
After being infected they spread the infection. Ill persons with symptomatic or oligosymptomatic
disease, convalescent and healthy carriers can be sources of infection. The carrier phase is longer
(3-4 months) in case of biotype El Tor.
The route of transmission is fecal-oral, especially through the consumption of contaminated
water or food.
The infectious dose is high (108-1011 bacteria) however it decreases in case of hypochlorhydria or
antiacid consumption (106 bacteria).
The receptivity is general, higher in children, although they can have asymptomatic forms more
frequently.
Secretory IgA seems to be responsible for immunity. Breastfed children have a passive
immunity, through secretory IgA from milk, and do not develop severe cholera. There is no
cross-immunity between groups O1 and O139.
Cholera is either endemic, or appears in epidemics, or pandemics. Since 1817 seven global
pandemics were noted. Biotype El Tor caused the last one. It was believed that V. cholerae O139
was the cause of the 8th pandemic, however, it did not spread outside Asia. War or other
circumstances that conduct to the breakdown of public health measures facilitate the spread of
cholera.
Many geographic areas are affected in the present, such as: the Indian subcontinent, Asia, Africa,
Latin America.
190
Pathogenesis
A large inoculum dose is needed in order to pass the gastric barrier. Subsequently Vibrio
cholerae traverses the intestinal mucous layer with the help of proteases. It colonizes the small
intestine, adheres through a pilus, and produces a toxin. The diarrhea is toxin-mediated.
The toxin has 2 components: subunit A (enzymatic activity) and subunit B (binding activity).
Subunit A activates the adenylate cyclase, and as a result intracellular cyclic AMP concentration
increases, conducting to intraluminal sodium and chloride secretion. Water moves passively
along. When the quantity of secreted water exceeds the resorbtive capacity of the intestine,
diarrhea appears.
The quantity of diarrhea is high, about 1 liter per hour, that conducts to severe dehydration,
acidosis, shock.
Clinical manifestations
Incubation may last 1-5 days.
The initial symptoms have sudden onset, with painless watery diarrhea and vomiting.
The volume of the stools increases rapidly, they are frequent, 20-50 per day, watery, profuse, the
aspect resembles rice-water, with sweet, inoffensive odor.
Fever usually is absent.
Muscular cramps appear due to electrolyte loss.
The signs of mild, moderate or severe dehydration are present. (Table 1.)
Finding
Mild dehydration
Moderate
dehydration
Severe dehydration
Loss of fluid
Thirst
Moderate
Intense
Very intense
Mental status
Normal
Normal
Normal
or
somnolence, coma
Pulse rate
Moderate tachycardia
Very rapid
Normal
Weak
Feeble or impalpable
Respiration
Normal
Deep
Blood pressure
Normal
Orthostatic
hypotension
Very low
Skin elasticity
Retracts rapidly
Retracts slowly
Eyes
Normal
Sunken
Very sunken
Voice
Normal
Hoarse
Not audible
Urine quantity
Normal
Oliguria
Oligoanuria, anuria
191
Clinical forms
There are mild, moderate and severe forms of cholera.
Cholera may have the form of a common gastroenteritis.
Cholera sicca is a very severe form characterized by important fluid loss and paralytic ileus. The
fluids may not be eliminated through diarrhea or vomiting, and the patient dies within hours.
Another severe form is the typhoidic form, with high fever and rapidly lethal evolution.
Complications
The complications that can occur in cholera are:
-
shock
acidosis
hypoglycemia
bacterial superinfections
Diagnosis
Epidemiological data reveal residence or travel in endemic or epidemic geographical areas, or
contact with ill persons or cholera carriers.
Clinical data show afebrile abundant watery diarrhea with rice-water aspect and rapid
dehydration.
Laboratory diagnosis
Non-specific findings
-
elevated hematocrit
Specific findings
-
serologic tests: antibodies appear in the 4th-6th day, the titer lowers in 2-3 months,
except in the healthy carriers
192
Differential diagnosis
Cholera can be differentiated from other acute infectious diarrheas, toxic diarrheas, meningitis
(in children).
Treatment
The patient has to be admitted to the hospital.
The most important is to replace rapidly the fluid, electrolyte, and base losses.
Rehydration with oral rehydration solutions (ORS) can be used. If they are not available, WHO
recommends a substitute made of teaspoon salt and 6 level teaspoons of sugar dissolved in a
liter of potable water.
In case of severe vomiting or severe dehydration intravenous rehydration is needed. The total
fluid deficit can be replaced in 4 hours, half within the first hour. Ringers lactate is
recommended. Potassium replacement is needed.
Antimicrobial therapy:
-
erythromycin: 4x500 mg /day for 3 days in adults or 40 mg/kg/day tid, for 3 days in
children
193
References:
1. Mandell GL, Bennett JE, Dolin R Principles and practice of infectious diseases, 6th
Edition, 2005, Elsevier
2. Kasper DL, Fauci A - Harrisons Infectious diseases, 2010, McGraw Hill Medical
3. Cupsa A Boli infecioase transmisibile, 2007, Editura Medical Universitar Craiova
4. Szalka A, Timr L, Ludwig E, Mszner Zs Infektolgia, 2005, Medicina Knyvkiad,
Budapest
5. Rebedea I Boli infecioase, 2000, Editura Medical Bucureti
6. Gilbert DN, Moellering RC, Eliopoulos GM, Chambers HF, Saag MS The Sanford
Guide to Antimicrobial Therapy, 41st Edition, 2011, Antimicrobial Therapy Inc., USA
194
Botulism
Iringo Kezdi
Botulism is a paralytic illness caused by the neurotoxin produced by the bacterium C.botulinum.
Botulism begins with cranial nerve paralysis, including diplopia, dilated and fixed pupils,
dysarthria, dysphagia, and dry throat. Paralysis first affects the cranial nerves, then the skeletal
muscles; untreated intoxications can lead to dense flaccid paralysis, respiratory failure, and
death.
Etiology
Members of genus Clostridium are gram-positive, anaerobic bacilli. C.botulinum and closely
related organisms produce toxins designated as types A, B, C, D, E, F and G. Human botulism is
most commonly caused by types A, B and E. Type E is associated with foods of marine or
freshwater origin. The toxins causing this disease are among the most potent bioactive
substances known (the oral lethal dose for humans is 0.05-0.5 microgrames). C.botulinum spores
are ubiquitous. Safe food preservation methods destroy spores or inhibit their germination and
growth. Conditions that promote germination and growth of C.botulinum spores include absence
of oxygen (anaerobic conditions), low acidity (pH>4.6), temperatures>39F, and high moisture
content.
Pathogenesis
There is four clinical type of botulism:
1.Foodborne botulism- characterizes infection in adults and older children and is caused
by the ingestion of food contaminated with preformed botulinum toxin. From the upper
small intestine the toxin pass into the bloodstream and binds irreversibly to the following
sites:
Receptors on cholinergic nerve fibers at a neuromuscular junction
Postganglionic parasympathetic nerve endings
Autonomic ganglia
The toxins enter the nerve endings and irreversibly interfere with the release of acetylcoline.
2. Wound botulism results from spore germination and toxin production in contaminated
wounds with subsequent systemic absorption of toxin.
3. Infant botulism results from the ingestion of spores that germinate and produce toxin in
the infants gastrointestinal tract.
4. Infectious botulism develops after ingestion of spores, followed by toxin production
in gastrointestinal tract.
Clinical manifestations
The latent period is typically 12-36 hours, but can range from 6 hours to 10 days. Pacients are
afebrile in the absence of complications. The symptoms are:
195
In wound botulism gastrointestinal signs usually do not occur. Muscle tone permits
differentiation from tetanus.
Infant botulism is manifested with lethargy, weak cry, decreased sucking, ptosis and
constipation.
Symptoms and signs of botulism are reversible, but cranial nerve dysfunction and mild
autonomic dysfunction may persist for more than a year.
Complications include otitis media, aspiration pneumonia, respiratory distress syndrome.
Laboratory diagnosis
Detection and identification of botulinum toxin in blood, feces and in the food
consumed before onset of illness. Mouse bioassay consist on intraperitoneally
inoculation of above mentioned extracts (positive test:death within 24-48 hours of all
mice except those protected by the polyvalent and type-specific antisera and those
receiving inocula that have been heat-treated).
Isolation of C.botulinum from the stool
CSF is normal
Differential diagnosis
The disease that may be confused with botulism are: tick-borne encephalitis, diphtheria,
poliomyelitis, Guillain-Barre syndrome, myasthenia gravis, food poisoning or other etiology.
For infant botulism differential diagnosis includes: sepsis, dehydration, pneumonia, Epstein-Barr
infection, diphtheria, congenital myasthenia gravis, muscular dystrophy, hypothyroidism,
metabolic and toxic conditions which may produce weakness and hypotonia.
Therapy
1. Supportive care, nutritional support
2. Prevention of nosocomial pulmonary and urinary tract infection
3. Trivalent botulinum antitoxin (neutralize only circulating toxin) must be administrated
as early as possible, with a test for the hypersensitivity.
-for cutaneous testing: 0.1 ml antitoxin in 1/100 physiologic saline dilution,
intracutaneously
- for ocular testing: one drop of antitoxin in a 1/10 dilution of physiologic saline (PS) is
instilled in one eye with a control drop of PS in the other eye (lacrimation and
conjunctivitis occurred after 10-30 minutes is evidence of hypersensitivity)
- anaphylaxis should be treated with epinephrine hydrochloride, steroids or ACTH
196
Antitoxin must be give intravenously, in one vial (if there are no signs of hypersensitivity).
Hypersensitivity reactions must be averted through the use of human botulism immune globulin.
Botulism antitoxin desensitization: with serial subcutaneous injections of antitoxin in 20 minute
intervals
4.
5.
6.
7.
Guanidine hydropchloride
High-dose penicillin therapy is generally given
Antibiotics if there are complications
Debridement of the wound
When foodborne botulism is suspected, clinicians and public health investigators should inquire
about the preparation and eating of foods preserved by any home method (e.g., canning, pickling,
curing and fermenting). C.botulinum spores are not killed by boiling at 100C. The toxin is heatlabile, so it may be inactivated by boiling of foods before consumption. Mortality rate is 25-30%.
197
CHAPTER 6
Acute Viral Hepatitis
Anca Georgescu
Generalities
Acute viral hepatitiss are systemic infections that affect mainly the liver through inflammation.
They are still a major public health problem due to high morbidity and mortality rates in spite of
the existence of efficient vaccines against the two most frequent etiologic agents: Hepatitis A
Virus (HAV) and Hepatitis B Virus (HBV); the resulting health costs are high and the treatment
resources are limited.
Five different viruses are accounting for more than 90% of the hepatitis infections: HAV, HBV,
Hepatitis C Virus (HCV), Hepatitis D Virus (HDV) and Hepatitis E Virus (HEV). While HBV is
a DNA virus, the rest of these are RNA viruses.
This etiologic diversity leads to complex antigenic properties, diverse pathologies, different
evolutions; the clinical picture is however similar for all types of hepatitis. The clinical specter
spans from asymptomatic infections to extremely severe and rapid evolutions but the main public
health burden is due to the possibility of evolution towards chronic infections with B, C and D
viruses and the risk of developing hepatocellular carcinoma.
Etiology
HAV is belongs to the Hepatovirus genus of the Picornaviridae family; it was initially classified
as an Enterovirus to which it however displays differences of structure, it has a slower
replication and does not induce cytopathic effects.
It is a RNA non-enveloped virus with icosahedric symmetry. The capsid has 4 polypeptidic
units, VP1 to VP4 that are bearing the antigenic determinants. The viral genome is a single
stranded positive RNA molecule with a single open reading frame (ORF) and 3 coding regions
(P1, P2, P3). Although there are 7 genotypes HAV cross-reacts antigenically: it displays a single
serotype and a single major epitope: (Ag HAV).
HAV does not induce cytopathic effect, is slowly replicating on cell lines; although it can be
cultivated in vitro, this technique is not of diagnostic use; in vivo, it replicates strictly in the
liver; it can be detected in the liver, bile and the feces by the end of the incubation period.
HAV is thermostable and resistant to acids and organic solvents; it remains viable in the feces
several hours at room temperature. It is inactivated by boiling for one minute, intense
chlorination, autoclaving, UV exposure and formaldehyde.
HBV is a type 1 hepadnavirus that belongs to the Hepadnaviridae family alongside distinct
genera that induce hepatitis in mammals and birds.
HBV has three morphologic forms that circulate in the serum of infected patients:
-
42 nm spheric particles, 100-1000 times less frequent, that represent the complete virions
(Dane particles).
The complete virion consists of a lipid envelope and the core (nucleocapsid)
The envelope embeds the surface antigen HBsAg that has three forms: Large, Medium and
Small. The Large peptide displays several epitopes: a (which is present in all strains) d/y and w/r,
respectively; their combination defines the 8 subtypes and 8 genotypes (A-H) that have distinct
geographical distribution and differ in terms of chronic evolution vs. clearance of the virus. The
A (adw) and D (ayw) genotypes predominate in Europe.
The viral nucleocapsid (core) is 27 nm large, is localized in the nucleus of the hepatocyte and
consists of:
-
HBc AG: it is located strictly in the hepatocyte and cannot be detected in the blood, it
is highly immunogenic, eliciting anti-HBc Ac
HBe Ag: it is the soluble form of HBc Ag. It is a replication marker, its presence
indicates high infectivity; it is transiently present early in the infection; its clearance
indicates recovery but its persistence for more than 3 months is predictive for chronic
evolution.
HBV DNA: its presence in blood accounts for the contamination risk; it is small
(3200 ntd), asymmetric, closed and circular, partially double stranded. The negative
strands codes for 4 overlapping ORFs (Fig. 1):
o S: it codes for the major surface protein (HBs) that mediates the attachment of
the virion on the hepatocyte and the penetration and other 2 surface proteins
(Medium: pre-S2+S, Large: preS1+preS2+S)
o P codes for the DNA polymerase
o C codes for HBcAg and HBeAg (pre-C segment)
o X codes the HBxAg
The DNA polymerase intervenes in the viral replication that occurs in the liver and in the
lymph nodes. HBV and the other hepadnaviruses are unique among DNA viruses because
this enzyme mediates a replication process that includes reverse transcription of the RNA
very much like it is performed by retroviruses.
HCV is the only member of the Hepacavirus genus of the Flaviviridae family. Prior to its
identification it was known as posttransfusional hepatitis virus and the disease as non-A nonB hepatitis.
It is a single stranded positive RNA virus, with a diameter of 55 nm. A single ORF coding for
structural (C, E1, E2, p7) and nonstructural (NS2-NS5) proteins is flanked by 5 and 3
untranslated regions (UTR). The viral genome does not integrate in the host genome.
The viral envelope is lypoproteic and it embeds two proteins, E1 and E2 that have a role in the
attachment of the virus to the cell surface.
Genetic variation is a major characteristic of HCV; there are 6 genotypes, more than 50 subtypes
and all are quasispecies. This diversity is generated by a high mutation rate during viral nucleic
acid replication. The effects of variability are of major consequence:
199
The most accurate diagnostic test is detection of HCV RNA by molecular techniques (PCR). The
Simmonds classification of HCV by sequencing the 5 UTR and NS5 describes 6 genotypes (16) and 12 subtypes. This classification correlates with the response to interferon (IFN) treatment
and with evolution; the 1b genotype is associated with high levels of viremia, higher rate of
chronic infections and liver carcinoma and poor to average response to IFN; in contrast, the
genotypes 2a and 3a have a 100% response rate to treatment.
HDV is a single stranded circular negative RNA virus; it is spherical with a 35-37 nm diameter.
It is defective: the presence of HBV is required for HDV pathogenic effects to be elicited.
It has an envelope that has AgHBs embedded and a core-like structure which associates the viral
genome with HDAg, the only protein coded by the viral RNA.
There are two forms of HDAg: the large P27 inhibits RNA replication and stimulates viral
assembly and export while the small form, P24, initiates the rolling-circle mechanism of the viral
genome replication independently of the HBV replication. These particular replicative
properties alongside the defective character of HDV lead to its classification as a subviral
particle within the Deltavirus genus.
HDV replicates exclusively in the liver cells. It is characterized by a high genetic variability with
effects that are incompletely understood; the major genotypes are IA, IB, II and III.
HEV belongs so the Hepevirus of the Hepeviridae family. It structure and epidemiology are
similar to HAV: a diameter of 32-34 nm, icosahedric symmetry, unenveloped, a single stranded
RNA genome with 5 ORFs: ORF1 codes for the nonstructural proteins that are involved in
replication; ORF2 codes for the structural proteins of the nucleocapsid and ORF3 codes for a
protein with unknown function.
There are one HEV serotype and 5 genotypes, 4 of which are pathogenic in humans and have
distinct geographic distributions. Animal reservoirs are involved in the endemicity of this viral
infection.
The virus is detected in the liver, bile and the feces were it is excreted at the end of the
incubation period. The IgM and IgG responses are very rapid but transient; the viral titers decline
in 9-12 weeks. There are no standardized tests for the routine diagnostic of HEV. The virus is
unstable at cold (-70C) but it resists to acids and alkali.
Epidemiology
Viral hepatitis A
The HAV infection is widely spread through the world with sporadic or endemic/epidemic
evolution, with autumn-winter seasonality and a periodicity of outbursts of about 5 years through
accumulation of receptive population.
200
The proportion of immunize adults has decreased in developed countries as a result of better
sanitation conditions in childhood; the infection is associated with fecal-oral transmission, direct
contact or through contaminated food or water. This route of transmission is still highly
prevalent in poor countries. Intrauterine transmission has not been demonstrated; parenteral
transmission is an exception due to the short period of viremia (10 days before and after the
clinical onset). There have been cited severe epidemics in recipients of coagulation factors.
The source of infection is exclusively the diseased patient weather with or without clinical
symptoms. HAV is detected in the feces starting two weeks after the infective contact until two
weeks after the clinical onset but the infectivity diminishes markedly after the apparition of
icterus; fecal excretion of the virus can last for 8 weeks and even longer in children and
immunocompromised hosts. There is no chronic excretion of HAV.
Humans are universally susceptible to HAV but no more than 40-50% of the infected persons
develop clinical symptoms; these are more frequent and more severe in the elder children and
adults. Anicteric, asymptomatic infections are quite frequent in children. There is solid, lifelong
post infection immunity.
Viral Hepatitis B
Although the HBV infection is globally spread with a human reservoir of more than 350 million
carriers its prevalence varies substantially in different geographic regions. It is only 0.5-1% in
Western Europe and the USA as compared with 5-10-20% in Far East Asia. The prevalence in
Romania is 3-5% with slight zonal variations and a decrease after a vaccination program for the
newborns was introduced.
The source of infection is represented by the patients with acute or chronic disease and the
carriers. HBV is detectable in the blood and in most of the body fluids: saliva, sperm both
sources of infection as well as in milk, genital secretions, tears, CSF.
There are several transmission routes:
-
Transfusions
o Non-medical interventions
Vertical perinatal:
o In utero: it accounts for 10% of the vertical transmission cases; the risk
when the pregnant woman is infected during the last three months of
pregnancy; in mothers that are carriers of HBsAg the risk is correlated
201
with the presence of HBeAg (90% risk when it is present vs. 10% when it
is absent).
o Intrapartum the most frequent route of infection
o Postpartum the risk of transmission during breastfeeding has not been
documented enough
The persons at risk of acquiring HBV infection are:
-
Medical staff
Viral Hepatitis C
The HCV infection is universal but unevenly distributed. The human reservoir is increasing
despite the fact that the infecting dose is smaller than for HBV and the blood and blood products
have been controlled rigorously after the 80s.
The reservoir is strictly human, it includes acutely and chronically infected (symptomatic or
asymptomatic) patients; an estimated total of 170 million people carry the virus.
The routes of transmission for HCV are:
-
The perinatal transmission is extremely rare; it seems that the risk correlates with
the mothers viral load; breastfeeding does not increase the risk of transmission.
The sexual and perinatal transmission routes account for 5% of transmissions which is sensibly
less than the HBV transmission.
There is universal receptivity to HCV. The role of the post infection immunity is unclear: antiHCV antibodies signify history of infection but are not necessarily protective.
202
Viral Hepatitis D
The reservoir of infection for D hepatitis is represented by the persons with double infection
HBV-HDV.
The routes of transmission are identical with those of HBV, most commonly the parenteral route
after multiple transfusions and in IV drug users followed by the sexual transmission. The vertical
transmission is less common.
The receptive population is the HBV receptive population HBV and HBV can be
simultaneously transmitted and persons chronically infected with HBV (HDV superinfections).
The HDV infection can be endemic or sporadic in correlation with the high or low prevalence of
the HBV infection.
Viral Hepatitis E
This form of hepatitis is more common in Asia, India, Africa and Central America where its
prevalence can reach 40 %. The epidemiology is very similar to HAV due to its enteric way of
transmission. The infection is prevalent mainly in young adults although there is general
receptivity and it can propagate by interhuman transmission. The infection is sporadic in
Western countries affecting mainly people travelling in endemic regions; the antibody
prevalence is about 2%.
The source of infection is the infected person whether with manifest or atypical clinical forms;
virus excretion in the feces is short (2 weeks). There is much argument about the existence of an
animal reservoir (pigs, rodents).
Fecal-oral transmission is mediated by food (mainly sea food) or water. There is also vertical
transmission and pregnant women are infected during the last trimester of pregnancy.
The immunity is limited, reinfections are possible.
Pathogenesis
Viral Hepatitis A
HAV is orally ingested and the first round of replication is in the oropharynx, salivary glands
and the bowel where it can be recovered at this time. Multiplication in the epithelial cells of the
small intestine is follow by transport by way of the port vein to the liver where another round of
replication occurs in hepatocytes and Kupfer cells. Transcription of RNA is followed by
synthesis of the viral proteins that are assembled into new capsids then virions in the cytoplasm;
the virions are excreted in the bile ducts without cell destruction HAV lacks cytopathic effect.
HAV is transported through the bile to the feces or can infect new target cells.
The intrahepatic replication is accompanied by viremia that last from week 2 post infection until
week 2 after the onset of symptoms (1 week after the apparition of icterus)
The hepatic lesions are the result of immunologic mechanisms induced by expression of viral
antigens on the surface of hepatocytes; NK (natural Killer) cells and CTL (cytotoxic T cells) are
involved in viral clearance through cytokine and interferon action.
The humoral immunity is limiting the infection and achieves viral clearance; IgM antibodies
appear concomitantly with the clinical onset, during fecal excretion of the virus, and last for 6
months, being thus a marker for current or recent infection; IgG antibodies follow, are
predominant during convalescence and through long life persistence protect against reinfection.
203
Detectable at 1-12 weeks, 2-6 weeks prior to cytolysis and clinical onset
HBsAb
204
Appear after HBsAg clearance; the interval between the two events is
called serologic window
early apparition, 1-2 weeks after HBsAg, weeks or months before HBsAb
HBeAg
Denotes viral replication, are associated with DNA viral load and Dane
particle
HBeAc
active immune response the immune reactive stage, clinically manifest, followed almost
always by healing and clearance of the virus and none of the mentioned complications.
In contrast to this typical evolution of the hepatitis with HBV, the chronic evolution is
announced by the lack of clearance of the HBsAg after 6 months and the lack of HBsAb; only
HBcAb IgG can be detected and HBV DNA is detectable in the serum and in the hepatocytes.
The peak of infectivity is during the replicative stage when virions, viral DNA and HBeAg can
be detected in the serum. The nonreplicative stage follows after the seroconversion in the e
system; at this point the viral DNA is integrated in the hepatocyte genome and only altered
virions are circulating in the periphery; this stage is of inactive carrier. Reversion to the previous
stage is sometimes possible.
Viral Hepatitis C
Infection with HCV is followed after 1-2 weeks by viremia that is at is highest initially then
varies; when the evolution is toward chronic infection the viremia persists after cytolysis
decreases but it correlates with the severity of the hepatic lesions thus indicating poor prognosis.
HCV replication occurs in the hepatocytes with no direct cytopathic effect but also in monocytes
and lymphocytes. The mechanism of the hepatic lesion is by immune response cell mediated
and by cytokines with antiviral effect released by the T lymphocytes. The degree of response by
CD8 cytotoxic lymphocytes correlates with the healing rate, their being present in high titers
indicates favorable prognosis. NK Lymphocytes contribute to controlling the infection. The
effect of these immune mechanisms in controlling the HCV infection is quite often transient;
evolution to persistent infection occurs in 70-85% of the cases. Persistent infection is caused by
suboptimal response of the adaptive immunity as a result of the variability of the virus
(quasispecies) and by the downregulating of the innate immunity (interferon) by the viral
proteins.
The risk of chronicization in HCV hepatitis is influenced by viral factors (genotype 1b high
viremia) and host factors (HIV, HBV coinfections, alcoholism, male gender) and immune
response variations.
Viral Hepatitis D
The hepatic lesions in HDV hepatitis is through direct cytopathic effect through blocking the
host cell protein expression. The immune response is however also playing a role in chronic
infections.
HDV is a defective virus that cannot be transmitted in the absence of HBV. The interaction of
the two viruses leads to higher severity of the hepatitis. There are two types of interaction:
A. HDV-HBV coinfection leading to severe acute hepatitis and biphasic clinical,
biological and histologic pictures; healing is possible but the evolution is more severe
than in hepatitis with HBV only
B. HDV superinfection: severe acute hepatitis occurs in a HBV carrier, liver failure and
fulminant evolution occur in 10% of cases; with chronic evolution, 75% of the
patients progress towards cirrhosis.
206
Viral Hepatitis E
HEV has fecal-oral transmission very much like HAV; ingestion of the virus is followed by
primary replication in the cells of the small intestine and consequently in the liver. The hepatic
lesion is induced by the immune system HEV lacks cytopathic effects.
The humoral immune response is prompt: HEV IgM antibodies are detectable at the onset of the
clinical stage and usually disappear 2-3 months after the acute illness although they can persist
for 2 years and more; the IgG antibodies appear two weeks after the onset of the disease and
persist in small titers for months and up to 10 years without conferring protection against
reinfection.
HEV RNA can be detected in the serum and feces at 4-6 weeks after the onset of the disease.
Clinical picture
The onset of acute hepatitis follows an incubation period that varies according to the etiology. It
is shorter in the forms with fecal-oral transmission: 20-45 days (4 weeks) for HAV, 14-60 days
(5-6 weeks) for HEV; the HBV and HDV hepatitises have an average incubation of 8-12 weeks
(30-180 days at the extremes) and HCV hepatitis has 7 week incubation on average with a very
large variability (15-160 days).
The prodromal (anicteric) stage is polymorphic as symptomatology: it is dominated by systemic
manifestations, unspecific and with varying intensities, that begin 1-2 weeks before icterus and
are often associated with digestive symptoms; the latter are receding with the onset of icterus.
Among the systemic manifestations:
Unspecific digestive syndrome, with anorexia, reduced olfactory and taste
sensitivity, flatulence. When this is the main clinical picture at the beginning it is
a clinical staple of acute hepatitis with digestive onset; the symptoms subside
when icterus appears.
The general infectious symptoms are fever 38-39C (mainly in hepatitis with
enteric transmission), myalgia, asthenia, fatigue, headaches, photophobia.
Common cold syndrome, cough, angina in the pseudoinfluenza syndrome
Small joint arthralgia, nocturnal and symmetric sometime with rash or purpura;
serum sickness-like symptoms occur in 10% of the patients with HBV and 5% of
the patients with HCV and are associated with the infectious syndrome. Pseudorheumatic symptoms occur more frequently in HBV hepatitis (30-70%); Gianotti
syndrome (papular acrodermatitis) is a particular form in children that consists of
papulovesicular skin rash of the face and chest and generalized adenopathy
Neuropsychiatric manifestations: severe asthenia, drowsiness of insomnia,
depression, restlessness, apathy are characteristics of the neuropsychiatric onset
Atypical manifestations: colic, abrupt apparition of icterus can mimic acute
surgical abdomen
Hyper chrome urines and discolored stools appear 2-5 days before icterus.
On clinical examination painful hepatomegaly (10%), and often splenomegaly and adenopathy
(5%) can be detected mainly in children.
The prodrome lasts for 5-7 in HAV hepatitis, 1-4 days in HEV hepatitis and 2-3 weeks in HBV
hepatitis. In HCV hepatitis the symptoms are very faint and are often ignored by the patient.
207
ECG
late
phase
modifications,
Young and adult patients with HBV account for half of the cases of
fulminant hepatitis; the frequency is low, higher when HBV-HDV
confection or chronic hepatitis C are present
Laboratory diagnostic
The positive diagnosis relies on complex laboratory investigations that reflect the pathology of
the disease:
Hepatic cytolysis:
o The increase in serum transaminases (AST, ALT) is frequently substantial
(20-30 fold), already in the prodromal stage and precedes the jaundice and
reverses gradually during convalescence; their levels do not correlate with the
severity of the hepatic injury
The biliary retention syndrome
o The serum bilirubin (both fractions) increases; jaundice can be observed
when it reaches 4-5 mg/dl
o Higher bilirubin levels (>20 mg/dl) that persist are correlating with severe
forms
209
Proconvertin
Viral hepatitis D
Serology: anti HDV IgM antibodies are detectable after the clinical onset and persist for along
time; they are followed by a serological window and then IgG antibodies.
Virological diagnostic consists of detecting Ag HDV in the serum by immunofluorescence the
second week after infection and during 3 weeks. HDV RNA can be detected in serum by PCR
and signifies viral replication and infectiveness.
Viral hepatitis E
The IgM anti-HEV antibodies appear 4 weeks after infection and persist for 3 month; their
detection signifies acute infection. The same is true for IgE anti-HEV antibodies.
Virological diagnostic is made by detecting HEV antigen in the serum and stools (although
shedding of virus in the stool is limited to a short period); the first viral marker to be detected is
HEV RNA and it persists for approx. 6 weeks.
Prognostic
Viral hepatitis A
The otherwise healthy patients that develop this form of disease recover completely with no
sequels. Elder age, preexisting chronic liver disease and hypo or agammaglobulinaemia are
predisposing factors for more severe evolution, with mortality of 0.1-1%, sometimes through
fulminant evolution.
Viral hepatitis B
The rate of complete recovery after the HBV infection is 95-99% in adults that are otherwise
healthy; it is estimated that only 1% of immune competent people do not eliminate the HBsAg
after an acute infection. Severe forms are more frequent in elderly patients and when other
pathology is associated: alcoholic liver disease, other chronic hepatopathies, and diabetes. The
mortality in HBV acute hepatitis is 1% and severe prognosis is announced by liver failure or
very high hepatic cytolysis.
Viral hepatitis C
The HCV acute hepatitis is milder than HBV hepatitis; asymptomatic and anicteric forms are
much more frequent but the chronic evolution is extremely frequent, 85-90%, and they lead to
cirrhosis in 50% of cases.
HBV-HDV coinfection
The mortality associated to this coinfection is not higher than that of HBV infection (5%) and the
risk of evolution to chronic infection is also low.
211
early stages of disease a diet rich in lacto-vegetarian diet is better tolerated but the diet will
become unrestricted afterwards with the exception of hepatotoxic agents (alcohol); hepatotoxic
drugs and those that are metabolized in the liver or are cholestatic are also to be avoided. The
patients with prolonged gastric intolerance who cannot feed orally most receive parenteral
support glucose and caloric supplements
Etiologic treatment is not generally recommended in acute hepatitis with the exception of cases
that are not selflimited thus being at risk for chronic evolution. There are studies that document
the usefulness of nucleoside analogues of reverse transcriptase in severe hepatitis with HBV and
monotherapy with alfa interferon in HCV hepatitis by inducing a sustained virologic response
and preventing chronic evolution.
The symptomatic medication includes:
Supportive treatment
Treatment of constipation and meteorism
Treatment of insomnia
Antiemetics
Treatment of dislypemia when chronic liver disease is associated
Hepatotropic agents: they have no proven effect on the clinical or virologic
recovery
Treatment of associated diseases (ulcer, gastritis, duodenitis, parasitosis,
nutritional disorders)
Choleretics, muscle relaxants, cholestyramine,
antihistamines in the cholestatic forms
ursodeoxycholic
acid,
Corticotherapy is not recommended during acute viral hepatitis because immune suppression
favors viral multiplication, persistent antigenemia and chronic evolution. It is indicated in
particular cases:
Severe, fulminant cases, when the prothrombin index is below 50% (there is no
consensus though)
Correction of hypoglycemia
Other radical (and costly) therapeutic measures did not prove their efficacy in improving
the survival rate. Among these, hemoperfusion, extracorporeal circulation,
plasmapheresis
Prophylaxis
Unspecific measures
Specific measures:
Active prophylaxis:
o HAV vaccination with highly immunogenic inactivated virus
o HBV vaccination recombinant vaccines with very good efficacy; they induce
anti-HBs antibodies
214
CHAPTER 7
Sepsis
Brndua ilea
Definition
Septicemia is a disease caused by various etiologic agents which have an evolution that involves
fever without any tendency to withdraw, while its severity is progressive and the the clinical
manifestation are amplified and complicated, with an important lethal risk.
The classical acception of systemic bacterial infections, the following steps are defining:
1. The entry gate for a pathogen agent (skin, respiratory, digestive, etc..)
2. Establishment of an initial foci - the place, often located near the entrance gate, where
the pathogen multiplies in the body and from where it disseminates in the body with
its exo and endotoxins.
3. Hematogenous dissemination - the germs start from the primary foci and spread in
various other places in the body. It is an essential step and at the same time, the main
manifestation of the disease, being maintained through participation and secondary
foci;
4. Formation of septic metastatic foci secondary to grafting germs involved in
circulation. These secondary foci, originating in the embolized vascular wall will
remain connected with the vessel, in this way they will continue to introduce new
quantities of germs in circulation. The secondary foci maintain and amplify the
presence of germs in the blood.
The existence of septic metastatic foci, differentiates septicemia from bacteremia (simply
discharging the germs from the entry gate or from the primary foci without repercussions in
terms of the illness progress);
5. seriously impairing the patients status by two major consequences:
The authors tend to simplify the concept, proposing the term "sepsis" for all situations of
uncontrolled infection by defense mechanisms of the body, these carrying the same risk factor in
terms of evolution.
During amplification several developmental stages can be detected:
SIRS (Systemic Inflammatory Response Syndrome) There are four criteria:
215
tachycardia> 90 / min.
tachypnea> 20/min.
Infection/Trauma (SIRS)
Sepsis
Severe Sepsis
tachycardia> 90 / min.
tachypnea> 20/min.
Sepsis is defined as SIRS occurred in the context of infection, the defining criteria are valid for
SIRS plus clinical evidence of infection. (Fig. 2)
Infection/Trauma
Sepsis
Severe sepsis
SIRS
SIRS with infection
process confirmed or suspected
Fig. 2 - Sepsis, definition
Severe sepsis is defined as sepsis plus one of the following criteria:
hypoxemia defined as PCO2 / FiO2 <280 intubated patient as PAO2 <75mmHg or the
need to administer an anesthetic gas containing more than 40% O2 artificially ventilated
patient
Infection/Trauma
Sepsis
Severe sepsis
SIRS
SEPSIS with one or
more organ impairment:
cardiovascular
renal
respiratory
liver
haematologic
CNS
Metabolic acidosis
SHOCK
Refractory hipotension
Septic shock is considered a special case in severe sepsis, having as a criteria for defining
those described above.
The criteria used to define various organ deficiencies are those proposed by Knaus (see
Table XXIV)
Insufficient organ
Cardiovascular
AV <55/min
BP <80mmHg
tachycardia or recent atrial fibrillation
pH <7.25 with PaCO2 <50mmHg
Respiratory
Renal
Hematologic
WBC <1000/mm 3
HT <20%
PLT <20.000/mm 3
217
SNC
Hepatic
Epidemiology
Although the incidence of severe systemic infections might be expected to decrease due to
improvement of preventive measures and of potentially active therapy in localized infections,
such tendency is not however evident. On the contrary in the U.S. an increase with 39%. in the
incidence of severe sepsis in 2000 compared to 1990. Some of the major causes of this
phenomenon are:
Currently in the U.S., are reported over 750,000 cases of sepsis annually, every day 500
patients die from sepsis. The average age is around 58, and considering gender men are more
often affected. (Fig. 4)
the germs with good antigen ability are capable to determine the formation of protective
antibodies (in such a context the development will be self-limiting, even in the presence
of bacteremia stages or in the case of secondary metastasis the case of Salmonellelor
Typhi and Paratyphi that develops typhoid fever).
Romania
42%
Enterobacteria
29.5%
Pseudomonas
10.04%
Bacteroides fragilis
0.91%
Other GNB
56%
Staphylococcus aureus
28.76%
Staphylococcus albus
12.32%
Streptococcus viridans
4.5%
Pneumococcus
4.5%
Enterococci
5.02%
1.76%
Fungi
2%
Polymicrobial infections
sepsis in iv drug addicts with opportunistic germs mostly of the saprophyte germs
(Staphylococcus epidermidis, corynebacteria) or intestinal bacteria;
Pathogenesis
Specific key stages in the evolution of sepsis are evident from its definition:
The entry gate of the germ functions as a primary pathogen, its identification therefore,
represents a diagnostic with an indicative value, even retroactively: based on the location and the
conditions in which the infection occurs certain etiologies can be detected. For example, the skin
entry gate suggests the involvement of staphylococci, genitourinary location - aerobic Gramnegative bacilli or enterococci, a genital entry gate especially in the case of a septic abortion,
towards the aerobic and anaerobic germs, etc..
Primary septic sites
Primary infection sites are usually located in close proximity to the entry gate (in case of
soft tissue phlegmon subsequent to infected penetrating wounds of limbs, the case of parametritis
formed after postabortum endometritis etc.) or in its vicinity on the lymph circuit
(adenophlegmon satellites of entry gate ).
Dissemination of germs from the primary septic site is possible in several ways:
by erosion of the walls of small veins trapped in the focus of inflammation, thrombosis at
that level, directly exposed to germs (staphylococci secret coagulase) or by means of
other local mechanisms, infected thrombi detach intermittently and being spread in the
general circulation will embolize distantly usually at the level of vascular bifurcation in
the systemic circulation or in the pulmonary vascular circulation.
primitive lymphatic
adenophlegmons);
through depleted circulating macro-and microphage. These cells incorporate germs for
phagocitosis but they are unable to perform the germs lysis due to the depletion of
lysosomes or the required energy resources so that once entering circulation, they will
end up releasing the viable germs in other places outside the primary infection site
(process revealed in staphylococci).
path
and
subsequently
hematogenous
(in
the
case
of
The most affected site in metastasis is the lung (clinically manifest in over 40-60% of
cases) because the alveolar capillary network, is a veritable "filter" in the way of septic thrombi.
The prevalence and dissemination of secondary sites in the body, affecting the viscera including meningocerebral and soft parts of the body the clinical manifestations worsen.
The classic authors maintain that in case of sepsis an important role is played by the defense
capacity of the body. Thus it is stated that:
people with a very good defense capability neutralize infection even in the initial stages;
people with a low capacity for defense evolve to septic shock and death, without clinical
manifestations of sepsis, the fulminant infection evolving rapidly.
ORIGINS
EFFECTS
macrophage
TNF
IL 1
IL 2
IL 6
leukotrienes
lipoprotein
inhibitors
T lymphocytes, Nk
hipercatabolism
neutrophils
pyrogenic effect
endothelial cells
antitumor
lymphocyte proliferation
T, B and Nk
the
most
pyrogenic
auto-positive feedback
stimulating macrophage
B and T lymphocyte
stimulation
pyrogenic effect
Increased
pulmonary
vascular resistance
lymphocyte
macrophage
T lymphocyte
macrophage
T lymphocyte
arachidonic acid
221
lipase
important
syndrome
PGI2
(Prostacyclin)
TxA2
(Thromboxane)
arachidonic acid
arachidonic acid
PAF
platelets
(Platelet-activating
factor)
macrophages
interferon
T lymphocyte
collagen defect
free radical
granulocytes
vasodilation
antiplatelet
PGI2 antagonist
endothelials
Fibronectin
Endorphins
activation
aggregation
platelet
macrophage activation
increased
permeability
increased
pulmonary
vascular resistance
neutrophil degranulation
Macrophag activation
Nk activation
increases synthesis of IL
1 and TNF-
Low-swelling
toxic bacterial
toxic cell
Increased
permeability
capillary
capillary
222
triggering the coagulation cascade - by means of factor XII (Hagemann), which may
involve the triggering of DIC;
at the level of vascular endothelium directly assaulted (the action of germs and their
endotoxins) or indirectly, a large amount of nitric oxide will be released (NO) with
negative consequences on circulatory equilibrium (leading to vasoplegia, hiperpermeability leakage of capillary fluid in the tissues) and evolution towards shock.
Clinical manifestations
What is commonly referred to as incubation, considered to be the time spent between the
existence of the entry gate and the first general manifestations, is not precise because sepsis is
not a self-limiting cyclic model of evolution.
Depending on the size of the inoculum and pathogenicity germ, and the ability of the
body's defense, this interval can be of 1-2 days or weeks - months. The shortest incubation were
found in cases with genital entry gate because of septic endometritis postabortion caused
empirically by ingestion of various toxic substances or by the introduction of irritating materials
in the cervix. Extensive local necrosis allows a large area of the entry gate and high
pathogenicity - usually by bacterial association. Meanwhile, the bodies of young women in
question have the capacity to fight the infection so that the inflammatory syndrome is intense and
fast.
The onset is often sudden, with fever, chills, heat curve and may take different aspects
the septic type with large vesperal oscillations, - intermittent type, with unregulated variations
every hour or daily (known as "irregular fever ") can apparently become steady "the plateau
stage "- especially in cases of osteoarthritis or metastatic pleural empyema etc.
Other elements are added to the previous ones:
Skin: various rashes appear on the skin (macules, petechiae, bleeding blisters) of the
embolic type or painless nodules in the extremities (Osler nodes). Often the appearance is
pale or Teros due to vasoconstriction and anemia.
Sometimes there are local signs of vascular type (superficial thrombophlebitis with
inflammatory edema, rarely large arterial embolism with acute peripheral ischemia syndrome;
Neurological: may reveal stiff neck or signs of advanced meningeal irritation, inequalities
of tendon reflexes and skin hypotony or isolated paresis, tremor, lack of coordination,
focal neurological signs (microbial embolism) there may be visible signs of encephalitis
(sleepiness or agitation, delirium, etc..).
albuminuria,
The existence of inflammatory syndrome with accelerated ESR (over 100mm/hour) with
leukocytosis and neutrophilia - but leukopenia with neutropenia combination is common,
either due to lack of reactivity, or due to Gram-negative bacilli, leukopenia being the
expression of a toxic bone marrow inhibition. All other tests for inflammation show
much altered data (C-reactive protein, fibrinemia etc.).
Clinical Forms
From an evolutionary standpoint, there are supraacute forms rapidly evolving to
infectious shock and death within a few days of onset, acute forms (most of them) described
above, and subacute forms, metastatic manifestations being predominant.
Clinical types in terms of etiology and entry gate.
1. Skin sepsis with skin as entry gate is in most cases of staphylococcal etiology (staph
pathogen, aureus, hemolytic coagulase-positive or, more rarely, with pathogenic
staphylococci, coagulase-negative). This type is among the most severe because of
high pathogenicity (rapidly invasive embolizing germ, toxigenic, causing thrombosis,
with tissular destructive-necrotic action) (Fig. 7). It presents two clinical features that
allow etiologic diagnosis:
local high toxicity (frequently evolving to uterine necrosis) and general toxicity;
Urinary sepsis (urosepsis) - can be spontaneous, but more often occurs after ureterobladder instrumental explorations. The main cause are - Gram negative bacilli: Escherichia coli,
Enterobacter, Proteus, Pseudomonas. They frequently occur as a complication of diseases
resulting from prolonged immobilization.
Surgical sepsis it is rare, it is a cause of various complications due to digestive, genital
or cardiovascular interventions especially. It is usually monoetiologic with acute or subacute
development due to the normal practice of post-operative prophylactic antibiotic.
A special category is sepsis contracted in ICU services (post intubation maneuvers, vascular or
urinary catheterization, etc..) extremely severe, because of puriresistant germs to antibiotic
treatment.
Evolution and prognosis
In the absence of therapy, fatal sepsis evolves lethally in over 85-90% of cases.
Spontaneous healing is possible, in some cases, but not without sequelae.
Under complex treatment lethality has decreased around 14-17%, and in the personal
research mentioned above, we calculated a mortality rate of only 9.7% in the group of 327 adult
septicemia.
Lethality is higher at extreme ages (over 50-60%), in persons with immune deficiency
and in the cases presented or diagnosed too late. Mortality may also vary depending on the
etiology, it is higher in the case of Gram negative bacilli and sometimes Staph.
Diagnosis
There are two stages of diagnosis:
etiological diagnosis.
Positive diagnosis is easy when there is a full clinical picture but it may be more difficult
to establish in cases with subacute evolution or in a very early stage, before they show signs of
metastatic impairment.
Differential diagnosis requires the removal:
of other causes of high and persistent fever - typhoid fever, pneumonia, viral diseases
(complicated influenza) system diseases (collagen), lymphocyte and myeloproliferative
syndromes, neoplasms with fever, suppuration (abdominal, perirenal, pelvic), deep pelvic and
cerebral thrombophlebitis etc.
Etiologic diagnosis
It is an absolute must.
Guidance - but with great value in the choice of first-line therapy, the diagnosis has to
consider:
the condition in which the infection was contracted (in the hospital ICU ward, or
community - ie outpatient, home);
226
In order to isolate the causative agent as early as possible and - especially before the introduction
of antibiotic treatment the following procedures are required:
cultures (aerobic and anaerobic) from the primary foci and metastatic foci, if possible;
Coefficient of certainty is greater if the same germ is isolated from several cultures or if
the isolated germ comes from closed hematogenous foci.
After isolation and identification of the germ, antibiotics will be used for susceptibility to
antibiotics testing, both normal and backup by antibiograms and determination of MICs against
selected preparations.
Rapid methods of diagnosis:
a. capsular antigen determination by agglutination - Latex, counterimunelectrophoresis (for
Meningococcal, Pneumococcal H influenzae, cryptococcal)
b. determination of bacterial DNA by gene amplification methods (PCR)
c. determination of serum levels of procalcitonin, E-selectin, C-reactive protein
d. determining of the level of CD10 -which decreases in bacterial infections.
Treatment
Perhaps more than in other situations, a complex treatment is urgently required (etiologic,
pathogenetic rebalancing, symptomatic and hygienic-dietary treatment).
1. Etiological therapy, involves two steps:
spectrum;
- the route of administration will be, whenever possible, parenteral- especially IV
bolus - to ensure peak concentrations which will lead to high tissular concentrations.
The choice of antibiotic preparations should consider the following:
- etiological probability;
- statistical probability of the alleged germ sensitivity;
- bioavailability able to ensure effective concentrations in all tissular locations;
- the absence of contraindications due to sensitivity or other circumstances;
- lower toxicity per dose;
- availability for a lasting cure;
227
Germs covered
First-line antibiotics
Cutaneous
Urinary
BGN (Enterobacteriaceae)
Pulmonary
Digestive
Genital
Streptococcus
B/BGN/anaerobic
Ceftriaxone+AMG+Metronidazole
Ceftazidime+FQN+Metronidazole
Germs covered
Cutaneous
Methyl-R
Staphylococcus, Vancomycin and cefepime + AMG
Pseudomonas, other BGN
or FQN
Central
catheter
venous
First-line antibiotics
Vancomycin-4G
Amphotericin B
C3
Digestive Surgery
/ Pseudomonas / Candida
Fluconazole
Artificial
ventilation
Pseudomonas, other
Staphylococcus
Urinary
BGN,
Carbapenem + Vancomycin
Germ covered
First-line antibiotic
Agranulocytosis
Splenectomy
Pneumococcus / H influenzae
Ceftriaxone AMG
Multiple Myeloma
Pneumococcus
Aminopenicillin / Vancomycin
Iv Addiction
Alcoholism
Pneumococcus / Klebsiella
C3G
HIV
Pneumococcus / Salmonella
Carbapenem C4G
228
Scheme of choice
Alternative therapeutic
Amoxicylin/C3G + AMG
Vancomycin + AMG
The prosthetic
Vancomycin + AMG
the existence of remaining undrained septic foci. Evacuation of pus or serous exudate
will cause significant reduction of fever;
b)
remission of general condition and symptoms and of other elements characteristic to
systemic inflammatory response.
Laboratory:
a)
b)
checking the inhibitory efficiency level (IEL) or bactericidal level (IEB) in serum under
treatment.
Any amount of IEL of at least 8 offers therapeutical certainty (considering that it will be
able to provide effective concentrations in affected tissues, where the concentration is usually
lower than serum).
2. Pathogenetic therapy involves several aspects:
Ensuring the monitoring of vital functions in an ICU ward, knowing that the patients in a
state of severe sepsis syndrome can easily develop severe septic shock or MSOF
syndrome. Attention will be paid to balance the level of electrolytes, acid-base, and
nitrogen homeostasis;
diet will vary according to digestive tolerance, fluid and calories needed, depending on
the patient's age and fever;
control and maintenance of hygiene at the level of skin and mucous membranes, urinary
wells and transcutaneous venous lines etc.
Prophylaxis
The proper treatment of small wounds or infections of the skin and mucous membranes
mean prevention of sepsis. Basically, there are several possibilities:
- Visiting the doctor at the first small signs of local infection or signs of disease in the already
complicated situations;
- Counteracting the tendency to solve empirical localized infections (manual manouvres of
collections);
- Ensure asepsis and antisepsis, especially for people who manage medication (insulin-dependent
diabetes) or iv drug (increasing frequency situation in our country);
- Antibiotic prophylaxis in case of interventions with bleeding risk and bacteremia (dental
uterine curettage), especially in individuals at risk (valvular, cirrhotic, ethylic, splenectomised).
Administration will begin 12 hours before intervention and will be continued at least 2-3 days
afterwards;
References
1. Bartlett J. Pocket Book of Infectious Disease Therapy. Lippincott Williams &
Wilkins, 2007;120-240.
2. Bearden A, Safdar N. Prevention and Management of Health Care-Associated
Infections.Infectious Disease Special Edition. 2009; 12: 67-83.
3. Benea EO, Popescu C, Popescu G. Ghidul Angelescu. Terapie antimicrobian, 2004;
29-133.
4. Cohen J, Opal SM, Powderly WG. Infectious Diseases, 3rd Edition, vol I, 2010,
478-491
5. Chiotan M. Boli infecioase. Ed. Naional, 2002; 149-200.
6. Gilberd D, Moellering R, Eliopoulos G, Sande MA. The Sanford Guide to
Antimicrobial Therapy 37th ed. 2007; 167-190.
230
231
CHAPTER 8
INFECTION WITH THE HUMAN IMMUNODEFICIENCY VIRUS HIV
(HIV)
Carmen Chiriac
The acquired imunodeficiency syndrome (AIDS), consequence of the infection with HIV, has
been recognized in USA in 1981, when CDC reported 5 cases of pneumonia with Pneumocystis
jiroveci (carinii) diagnosed in homosexual patients (from Los Angeles) and 26 patients with
Kaposi sarcoma associated or not with pneumonia, in New York and Los Angeles. Subsequently,
similar cases have been reported in intravenous drug users, recipients of blood transfusions,
hemophiliacs.
Etiology
Human imunodeficiency virus (HIV) belongs to the Retroviridae family. Viruses belonging to
retroviruses, are defined by their way of replication: the reverse transcriptase enzyme
retranscribes the viral RNA into proviral DNA. According to the retroviruses pathogenesis we
may distinguish three subfamilies:
1. Oncoviruses: are the most widespread retroviruses, associated with tumors and
leukemias: HTLV1, HTLV2 (Human T-Cell Leukemia Virus)
2. Lentiviruses: are viruses which cause diseases with a lent evolution, pneumoniae,
neurological disorders and they are cythopathogenic in culture. HIV1 and HIV2
(Human Immunodeficiency Virus) belong to this subfamily. These two types of
viruses have been identified in 1983, respectively in 1986.
3. Spumaviruses: identified in numerous mammals but non-associated with a known
pathology, either in animals, or in human.
HIV Target Cells. Cells that have on their surface the CD4 receptor and one of the co-receptors
(CCR5, CXCR4).
-
Monocytes, macrophages
Langerhans cells
Romania: HIV 1 F
Asia: HIV 1 C, B, E
Epidemiology
1981 first AIDS case USA
1959 first serologic test which marks out antibody and HIV human serum in a patient
from Congo-Zair
1972 cases diagnosed with HIV infection in Uganda, Malawi
The first case of HIV infection reported in Europe was a Norwegian sailor infected
probably in 1966, deceased in 1976.
In Romania, the first AIDS case in adults has been diagnosed in 1985, in children in
1989.
Epidemiologic Process
1. Source of infection: persons infected with HIV
2. Modes of transmission of HIV infection
a). The sexual transmission of HIV is predominantly transmission rout worldwide.HIV is
transmitted by both heterosexual and homosexual contact. High viral concentrations are
found in blood and semen, in infected mononuclear cells or in free form. The virus
focuses in the semen due to certain genital infections, the number of leukocytes and
monocytes is high (sexually transmitted diseases). HIV has been demonstrated in vaginal
fluids also. There are a series of factors that favour the sexual transmission: lesions of
mucouses, of tegument. The risk of sexual transmission is significantly higher if the HIVseropositive partner is in an advanced stage of immunodeficiency.
b). Transmission by blood and blood products: HIV is transmitted by blood ,blood
products or transplanted tissue. Intravenous drug users, hemophiliacs, contaminated
blood recipients, medical staff, the tattoos and piercing consumers are exposed. Drug
users are exposed to HIV infection under the conditions in which drugs are administered
parenterally (intravenous, intramuscular,,muscling,, or subcutaneous,skin popping,,), the
risk grows proportionally with the injection duration, the number of partners with which
is made the exchange of accessories (syringes, needles, water in which drugs are
dissolved, filter).
The transmission of HIV via blood and blood products has been reduced on a global
scale.All blood donors are tested for HIV-1 via antibody tests, by ELISA technique,but
233
the risk is not completely eliminated.To identify donors who may be in the window of
seroconversion,PCR test is performed.
Persons so-called risk behavior:IV drug users,sexually active mans and women,persons
from hig-prevalence countries are excluded from blood donation.
c). Vertically transmission : HIV can be transmitted from the infected mother to her child,
intrauterine, during delivery, or by breastfeeding.The most important risk factor is viral
load of the mother during pregnancy, and at the time of delivery.The probability of
vertical transmission of HIV,in the absence of intervention, range from 15-25% in
developed country and 25-35% in developing countries.Since 1995,the mother to child
HIV transmission has been reduced to 1-2%,trough the prophylactic antiretroviral
therapy,elective caesarian section prior to the start of labor,avoinding the breastfeeding.
d).Occupationallyacquired HIV infection:the risk of HIV infection of health care
workers,laboratory personel, and others who work with HIV-containg materials-sharp
objects is small, estimated to be around 0,3.Exposures that is at risk to transmitted HIV
are : needlestick injury,cut with a sharp object,or contact of mucous membrane /nonintact
skin with blood or others potentially infectious body fluids.The use of antiretroviral drugs
as postexposure prophylaxis (PEP),decreases the risk of HIV infection.
Structural aspects of HIV
HIV-1 Genome is constituted of three regions named: gag, pol i env, which codify the internal
proteins of the virion, the enzymes necessary for viral replication and the surface proteins of the
virion. On each extremity of the viral DNA there is a sequence of variable length: Long Terminal
Repeat (LTR) that allows DNA integration under the form of provirus, into host cell genome and
contains promoter elements necessary to genes expression. Except the three classic genes, HIV
genome contains also two particular regions, located between pol and env genes, and
respectively in the extension of the env. gene. They contain six supplementary viral genes
named: tat, rev, vif, vpr, vpu-vpx and nef. Codified proteins by these supplementary genes are
involved in the regulation of viral proteins expression and implicitly in the viral replication.
HIV viral particles have a unique morphology: spherical with a 90-120 nm diameter
The envelope is constituted of a lipid bilayer crossed by two glycoproteins gp120, gp 41.
Nucleocapsid, dense, trapezoidal shape, contains: protein p24 (marker of viral replication), p17
Enzymatic equipment: reverse transcriptase, integrase, protease.
HIV Replication Cycle.
1. First step starts with binding and penetration inside host cell, gp120 binding to host
cell receptor-CD4 molecule, which is found predominantly on the surface of T helper
lymphocytes and macrophages. Fixation of gp20 is followed by the conformational
modification of gp120 that allows the recognition of V3a gp120 domain by other surface
molecules named co-receptors. The major co-receptors of HIV are CCR5 and CXCR4.
2. The second step is the reverse transcription: RNA genome is copied into proviral DNA
via reverse transcriptase
3. Integration of proviral DNA in the genome of the host cell due to the viral integrase
4. Transcription of proviral DNA in messenger RNA
5. Synthesis of viral proteins
6. Assembly and maturation of viral proteins via viral protease
234
HIV frequently modifies its genetic structure with the apparition of quasispecies:
lymphatic ganglia (elude the defense mechanisms of the host) and transform the HIV infection in
chronic infection.
Immune response of the host:
-
Viral Quantification
236
the viral load is a predictive factor of the disease evolution and the fundamental
parameter in therapeutic monitoring and HIV infection diagnosis at infants born
by a HIV-seropositive mother.
Antigen p24 detection (useful in the immunological window period few weeks
up to 3-6 months after infection)
Viral culture
Genotypation tests
Phenotypation tests
Legislation enforces appropriate counseling of the person who is to be tested: pretesting, post- testing counseling
Observance of confidentiality
Testing is recommended for: persons who personally demand the test, the person
belonging to the groups of risk (tuberculosis, sexually transmitted diseases),
compulsory testing of pregnant women
1. Acute stage: lasts a few weeks. 50-60% of patients present unspecific clinical manifestations
that realize a pseudo-influenza syndrome: fever, dysphagia, cephalalgia, myalgias, asthenia. The
most frequent relevant clinical signs are diarrhea, oral or genital ulcerations, adenopathies,
neurological events (meningitides, encephalitides, facial paralysis, peripheral neuropathy,
myelopathies). The manifestations disappear spontaneously in a few weeks (2-6 weeks) from
infecting contact. Retroviral acute syndrome (similar to infectious mononucleosis). The
symptoms persist a few weeks, gradually the immune response to HIV is developing, the
plasmatic viremy decreases. Biological manifestations: leukopenia, thrombocytopenia,
mononucleosis-like syndrome, moderate growth of transaminases, high plasmatic viral load, anti
HIV antibodies positive p24 antigen. Clinical severity is proven at persons whom have
neurological signs present in acute stage, and it is given a prognosis of risk of accelerated
evolution and HIV disease progression.
2. Asymptomatic stage (clinical)
Patient infected with HIV do not present clinical symptomatology or present unspecific
symptoms: fatigue, depression, memory disorders, progressive loss of weight. Viral replication
continues.
3. Chronic stage
Generalized lymphadenopathy: symmetric adenopathies with cervical, axyllary, submaxillary,
237
AIDS
Opportunistic infections
Tumors
Manifestations of SN
High viremy
Category B: HIV infection with symptoms that are directly attributable to HIV infection
(or a defect in T-cellmediated immunity) or that are complicated by HIV infection
These 3 categories are further subdivided on the basis of the CD4+ T-cell count, as follows:
Clinical categories
A asymptomatic, B symptomatic HIV
infection, C SIDA
1. 500
A1
B1
C1
2. 200 - 499
A2
B2
C2
3. < 200
A3
B3
C3
238
Late serious consequence of HIV infection is the AIDS stage. It is characterized by the
appearance of infectious and tumor opportunistic manifestations of vital risk, due to profound
depletion of immunity or as direct manifestations of the cytopathic effect of HIV.
Opportunistic infections indicating AIDS are in fact reactivations of prior chronic infections,
they may affect certain apparatuses and systems, or the entire body evolves chronically with
recrudescences and correlates itself with the degree of immunosuppression.
Currently there are two main circumstances associated to opportunistic infections.
Patients of whom HIV infection is unknown, is not treated, and at whom opportunistic infections
manifest themselves in an inaugural manner, late presenters patients.
A second category is represented by the HIV infected patients who find themselves in a
therapeutic failure, with a number of TCD4 cells <200/mm3.
INFECTIONS THAT INAUGURATE THE AIDS STAGE
Parasites
Agent
Localization
Pneumocystis jiroveci
Pneumonia
(carinii)
Toxoplasma gondii
Cryptosporidium
retina,
lungs,
Isospora belli
Fungi
Bacteria
Mycrosporidium
Candida
Cryptococcus
Nervous system
Histoplasma
Systemic dissemination
Aspergillus
Recurrent septicemias
Mycobacterii tuberculosis
M.Kansasii
complex
Viruses
Tumors
Cytomegalovirus
Herpes viruses
Papovavirus
tube,
239
The most important opportunistic manifestations, evocating the AIDS stage are the following:
Pneumonia with Pneumocystis jiroveci
Initially known as pneumonia with Pneumocystis carinii, name reserved to a species of
Pneumocystis that infects rodents, it constitutes the important opportunistic infection associated
with AIDS. Pneumocystis jiroveci fung ubiquitar (biologically close to protozoa) affects
organisms with cellular immunity deficiency either by reactivation of a latent infection, or by a
new exposure, realizing a hypoxemia inducing pneumonia.
Clinical manifestations install themselves progressively: non-productive cough, fever, dyspnea
of progressive intensity, thoracic pains. Sometimes the onset is abrupt-brutal with severe
tachypnea and cyanosis with the clinical picture of an acute respiratory insufficiency.
Diagnosis is realized via pulmonary radiography that reveals diffuse bilateral interstitial
infiltrates or infiltrative nodules, in severe forms are described cavities, bubbles, cysts. The
specific complication that may appear at a reduced number of patients is the pneumothorax.
The certainty diagnosis is realized by emphasizing the cystic forms of pneumocystis in the
bronchoalveolar lavage fluid or in the post induced expectoration sputum, by
immunofluorescence or specific Gomori staining.
As extrapulmonary manifestations are described: affection of lymphatic ganglia, spinal cord,
spleen, liver.
The election treatment consists in the administration of trimetoprim-sulfametoxazol, appropriate
doses, for 21 days. It is associated with corticosteroids, oxygen.
Pneumocystosis is associated with a smaller T CD4 number than 200 cells/mm.
For pneumocystosis prevention it is recommended to respect the prophylactic medication in
immunosuppressed patients.
Cryptococcosis
Cryptococcus is a fungus responsible of approximately 5 % of the disease associated to AIDS
stage. The most frequent manifestation is the meningitis or the subacute meningoencephalitis,
which start with fever, cephalalgia, consciousness disorders, convulsions, neurological signs of
infection focus.
The neurologic picture may be accompanied by systemic manifestations: pneumonia, cutaneous
lesions, ocular lesions.
Diagnosis is suggested by the clinical picture, confirmed by the detection of cryptococcal antigen
through the latex agglutination test in serum, cephalorachidian liquid, cultures on special media.
Treatment recommends Amphotericin B associated with Flucytosine followed by Fluconazol.
Prophylaxis with Fluconazol, is compulsory in patients who passed through the clinical disease
and have a smaller number of T CD4 than 50/mm.
Mycobacterium avium Complex infections
Infections caused by Mycobacterium avium Complex (MAC) are detected in patients without
antiretroviral therapy, deeply immunosuppressed, without appropriate prophylaxis.
The specific clinical manifestation is multiorganic dissemination. Typical symptoms include
fever, nocturnal perspirations, marked weight loss, asthenia, abdominal pain, diarrhea. It also
240
manifests within the immune reconstitution inflammatory syndrome (IRIS) characterized by fast
increase of T CD4 cells, after the initiation of antiretroviral therapy.
Other clinical manifestations of MAC dissemination, include pneumonia, pericarditis,
osteomyelitis, abscesses of teguments and subcutaneous tissue, genital ulcers, infections of the
central nervous system.
Diagnosis is confirmed by MAC isolation in cultures.
Bacteriemia is direct and final. Biopsy and cultures from suspected sites (lymphatic ganglia) may
also isolate mycobacteria.
Specific identification is realized by technical PCR.
Preferential treatment of MAC disseminated infection is Clarithromycin associated with
Etambutol and/or Rifabutin. As alternatives may be used parenterally fluorochinolone and
amikacina.
In parallel is initiated as soon as possible antiretroviral therapy.
Prophylaxis is initiated in patients with T CD4 values under 50/mm and consists in
administration of Azithromycin/ Clarithromycin or Rifabutin.
Cytomegalovirus Infection
Cytomegalovirus (CMV) is a frequent opportunist associated to infections in patients with AIDS.
The infection is realized through reactivation of latent focuses due to advanced
immunosuppression.
CMV Retinitis: is the most frequent clinical manifestation of the CMV infection. It evolves
unilateral or bilateral, peripheral or central. Peripheral lesions are characterized by scotomas or
visual field reduction, central retinal lesions are associated with diminishment of visual acuity.
CMV colitis evolves with fever, anorexia, loss of weight, abdominal pains, persistent diarrhea.
Potential complications are gastro-intestinal hemorrhage and perforation.
Esophagitis is manifested through odynophagia, retrosternal discomfort, fever.
Less frequent pneumonia may set off hypoxemia.
Neurologic disorders, with severe prognostic are frequent: encephaloventriculitis, dementia,
ascending poliradiculomyelopathy.
The certainty diagnosis consists in CMV detection by PCR technique.
The CMV antibodies titer is not very useful, a CMVIgG negative titer, does not exclude viremy.
Therapeutic options recommend valganciclovir, ganciclovir, cidofovir, foscarnet, antivirals that
are not lacking of side effects: neutropenia, trombocytopenia, nausea, diarrhea, renal
dysfunction.
Prophylaxis is recommended to patients with CMV retinitis and for those with T CD4 values <
100/mm3.
Cerebral toxoplasmosis
The most important opportunistic infection in HIV-infected patients remains cerebral
toxoplasmosis.Toxoplasma gondii is an intracellular parasite that infects birds,mammals and
humans.
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Cerebral toxoplasmosis occurs at CD4T cell count bellow 100cell/ul.The major signs include
focal neurological deficits such as paresis,speech problems,sensory loss.A febrile status with
headaches,confusion are also frequent signs.CT or MRI scan of haead should be performed in
every case of focal neurological deficit.
Progressive multifocal leukoencephalopathy (PML)
PML is a progressive demyelinating condition of advanced HIV disease caused by the John
Cunningham virus (JCV) and presents with focal neurological signs, changes in personality and
ataxia. The diagnosis is by MRI. There is no specific treatment and the patient usually dies
within six months unless effective ART is used. Some patients develop PML during combined
ART in the setting of immune reconstitution. Steroids may be useful in such cases.
Kaposi Sarcoma
Description of Kaposi sarcoma in young people, American homosexuals, constituted one of the
clinical events that signed the act of birth of AIDS disease. In AIDS evolution, Kaposi sarcoma,
an angioproliferative tumor associated to the infection with human Herpes virus 8 (HHV-8) takes
an aggressive evolution, with dissemination at the cutaneous-mucouse level, but visceral also,
difficult to treat.
Clinically, is characterized by the aspect of nodular lesions with lavender like colour,
disseminated on the face, neck, upper third of the body, limbs. Lesions may evolve at the level of
the oral cavity, palatine arch. Visceral dissemination is more frequent at the level of the digestive
tube and evolves often asymptomatically.
The pulmonary localization evolves with dyspnea, non-productive cough, sometimes
hemoptysis, pleurodynia.
Histopathological diagnosis is the certainty diagnosis. It may be associated to PCR technique
which documents the infection with HHV-8.
The treatment associates administration of recombinant interferon alpha in antiretroviral therapy.
Neurologic diseases In HIV infected persons,the neurologic manifestations are developed
primary by HIV itself, secondary,to opportunistic infections,or neoplasm. HIV-associated
neurocognitive disorder
is
the term used to describe a spectrum of
neurologic
manifestations,that are be classfified in three categories ,in the order of descending severity.
1.HIV- associated asymptomatic neurocognitive impairment (ANI)-the impairment does not
interfere with everyday functioning;
2.HIV-associated mild neurocognitive disorder(MND)-at least mild interference in daily
functioning
3.HIV-associated dementia(HAD)-marked acquired impairment in cognitive functioning
Antiretroviral Treatment
Specific treatment of HIV infection has achieved remarkable progresses since 1996 the year in
which the concept of extreme active therapy has been introduced, HAART (Highly Active
Antiretroviral Therapy), which consists in the association of antiretrovirals capable to achieve
the following challenges: clinical, lifespan prolongation and improvement of life quality,
virological: reduction of HIV viremy up to the lowest values possible having as purpose
prevention of infection progress and limitation of the HIV development resistance to
antiretroviral drugs.
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From an imunologic point of view, the antiretroviral therapy has as objective the restoration and
preservation of the immune system function, increasing the number of T CD4 lymphocytes to
values which inhibit the development of opportunistic infections. Efficient antiretroviral therapy,
has also an epidemiologic role, reduces the rate of transmission of the infection
Antiretroviral medication used currently contains substances that activate in different phases of
the viral replication cycle.
Nucleoside reverse transcriptase inhibitors have as mechanism of action inhibition of viral
reverse transcriptase, by replacing some of its nucleosides with others, inappropriate ones.
Through this mechanism the DNA synthesis fails.
Zidovudine (AZT, Retrovir) was the first synthesized medicine used in HIV treatment in 1987.
Subsequently have been also synthesized other substances with similar action.
Generic Name
FDA approval
Zidvudine ( AZT)
1987
Didanosine ( ddi)
1991
Zalcitabine ( ddC)
1992
Stavudine ( d4T)
1994
Lamivudine (3TC)
1996
2000
Tenofovir DF ( TDF)
2001
Entricitabina ( FTC)
2003
Abacavir/lamivudine
2004
Emtricitabine/tenofovir
2004
a). Non-nucleoside reverse transcriptase inhibitors are active molecules which also activate on
the reverse transcriptase, by direct and non-competitive binding, followed by alteration of its
function.
Non-nucleoside reverse transcriptase inhibitors
Name
Year of approval
Nevirapine
1996
Delaviridine
1997
Efavirenz
1998
Etravirine
2008
Rilpivirine
II B under study
Protease inhibitors
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1. HIV protease with a key role in the assembly of viral particles is a protein composed of
two identical symmetrical subunits of 99 amino acids, which delimitate in the central
position of the active site of the enzyme that cuts out the polyproteins produced at the end
of the viral replication cycle, in 9 subunits. The appearance of protease inhibitors
constitutes an incontestable event that has revolutionized the treatment of HIV infection.
Numerous clinical studies have proven the efficiency of the therapy with one or two
protease inhibitors in association with two reverse transcriptase inhibitors. Since 1996,
the protease inhibitors synthesis has developed very much.
Protease inhibitors
Name
Year of approval
Indinavir
1996
Ritonavir
1996
Saquinavir
1995
Nelfinavir
1997
Amprenavir
1999
Lopinavir/ritronavir
2000
Atazanavir
2003
Fosamprenavir
2003
Tipranair
2005
Darunaiviri
2. Fusion inhibitors, block the virus binding to the host cell through the competitive
inhibition mechanism activated at level gp41. The medicine used currently is enfuvirtide
(fuzeon) approved in 2003.
3. CCR5 co-receptors inhibitors, CCR5 antagonists have a potent antiviral activity both in
vitro and in vivo against a population of HIV-1 strains with tropism for CCR5 coreceptors, but not against the strains using CXCR4. The approved substance is called
Maraviroc and has demonstrated in several clinical trials, favorable results.
4. Integrase inhibitors
Raltegravir is the first integrase inhibitor approved to be used in the antiretroviral therapy of
experienced patients.
New class of antiretrovirals recently approved or under development for treatmentexperienced patients.
Class
Name
Antagonist CCR5
Maraviroc,
Integrase inhibitors
Raltegraviri, Elvitegraviri
Maturation inhibitors
A major obstacle in the therapys success is represented by the capacity of HIV virus to generate
genetic mutations. HIV resistance to antiretrovirals was reported for the first time in 1989 at
patients treated with zidovuzine. Therapy diversification, the HAART concept has generated
new mechanisms of resistance and implicitly the therapeutic failure.
On the other hand the pharmacokinetic profile of antiretroviral drugs intercrosses with the one
of other medications used in the patients management. Protease inhibitors are metabolized
through the inhibition of 3A4 enzyme of P-450 cytochrome. The inhibition of this enzyme has
important pharmacokinetic implications. The intervention which has revolutionized the use of
protease inhibitors was the administration of low doses of ritonavir that blocks the metabolism of
the other inhibitors favoring high concentrations of the latter for a longer period of time.
It is important that this aspect be known because the use of other medicines in HIV/AIDS
infected patients, including antifungals, antituberculous, oral contraceptives, anticonvulsivants,
methadone, hypolipemiant drugs (statins) interact with protease inhibitors in an unfavourable
manner.
Antiretroviral complex therapy has reduced morbidity and mortality by HIV infection, but
opened new chapters of pathology, as lipodystrophic syndrome, alteration of carbohydrate and
lipid metabolisms, mitochondrial toxicity, cardiovascular, osteoarticular disorder.
Prevention of HIV infection.
The most effective way to prevent transmission of HIV is education,counseling and behavior
modification.
When the HIV status of the partner is not know or the partner is HIV infected,use of condoms
can decrease the risk of HIV transmission.
To prevent transmission of HIV among IV drugs users,the most effective strategy is to stop the
use of injectabile drugs.
Transmission of HIV by blood and blood products has been decreased by screening of all blood
donors.
Prevention the transmission of HIV from mothers to child, consist in a lot of
methods:antriretroviral therapy for mother,and for child afters biths,caesarian section,the
avoidance of breastfeeding.
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