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INFECTIOUS DISEASES
JOHN A. MOLINARI, PHD
MICHAEL GLICK, DMD
In the early 1960s, Sir MacFarlane Burnet proclaimed, One
can think of the middle of the twentieth century as the end
of one of the most important social revolutions in history,
the virtual elimination of the infectious disease as a signifi-
cant factor in social life.
1
This was not an uncommon sen-
timent among the medical community and resulted in a
decrease in awareness, research, and funding to combat
emerging, re-emerging, and drug-resistant infections.
Consequently, the medical community was ill prepared
when diseases thought to be conquered, and new diseases,
started to emerge in the 1980s and 1990s. In a recent report
from the Institute of Medicine, six major factors were iden-
tified as contributors to the emergence and re-emergence of
infectious disease, as follows:
2
1. Changes in human demographics and behavior
2. Advances in technology and changes in industry prac-
tices
3. Economic development and changes in land use pat-
terns
4. Dramatic increases in volume and speed of interna-
tional travel and commerce
5. Microbial adaptation and change
6. Breakdown of public health capacity required to han-
dle infectious diseases
Although the number of deaths from infectious diseases
has decreased dramatically in the United States during the
twentieth century, there was a temporary increase between
1980 and 1995, mainly due to human immunodeciency virus
(HIV) disease.
3
HIV and other emerging and re-emerging
infectious diseases are recognized as signicant health hazards
and have become the focus of many federal and academic
health initiatives. Efforts in controling infectious diseases have
addressed sanitation and hygiene, vaccination, the use of
BACTERIAL INFECTIONS
Tuberculosis
Legionella
PROTOZOAL INFECTION:
CRYPTOSPORIDIUM
Microbial Characteristics
Epidemiology and Transmission
Clinical Syndrome
Treatment and Control
VIRAL INFECTIONS
Hepatitis C Virus
HIV Infection
antibiotics and other antimicrobial medications, and improved
technology in detection and monitoring. Oral health care
providers are not excluded from these efforts, as many of these
endeavors impact directly on dental care.
This chapter highlights a few infectious diseases that are of
importance to dentistry. Some of these diseases are well estab-
lished, whereas others are emerging and may become impor-
tant sources of both contamination and transmission in den-
tal settings. Oral health care providers need to be able to assess
and evaluate patients who are carriers of infectious diseases
with the purpose of providing appropriate and safe dental care.
BACTERIAL INFECTIONS
Tuberculosis
There is a well-known phrase that states, The more things
change, the more they stay the same. This expression contin-
ues to apply to tuberculosis (TB), a widespread infectious dis-
ease scourge traced back to the earliest of centuries. As a result
of a resurgence of TB cases in the United States during the
1980s, attention refocused on the factors associated with the
observed reversal of a previous declining disease trend; trans-
mission modes of Mycobacterium tuberculosis, occupational
infection risks associated with health care, and airborne-haz-
ard infection control precautions.
48
Despite dramatic
improvements in public health measures associated with M.
tuberculosis infection and disease, such as living conditions,
nutrition, and antimicrobial chemotherapy, that resulted in an
observed dramatic decline in the incidence of TB in the United
States and certain other countries during the past century, TB
remains a major public health concern for much of the worlds
population.
9,10
Evidence supporting this statement includes
the following:
1. TB is the most common cause of death from a single
microbial agent.
2. TB is responsible for almost 1 in 4 preventable deaths
in the world.
3. The World Health Organization estimates that world-
wide there are approximately 20 million active TB cases.
4. Approximately 3 million people die each year from
TB, with 80% of this total occurring in developing
countries.
In short, many problems associated with tuberculosis as a
signicant world health problem 100 years ago remain as this
debilitating illness continues to be an even greater infectious
disease concern at the end of the twentieth century.
The United States witnessed a dramatically different pattern
of TB incidence from much of the rest of the world, docu-
menting a three-decade decline through to 1984 (Table 20-1).
Based on that rate of decline, the Centers for Disease Control
and Prevention (CDC) projected that TB would be eliminated
within the United States by the year 2010. These optimistic pre-
dictions were quietened in 1985, when the number of reported
cases showed a smaller decrease compared to the previous 2
years. In 1986, the number of reported cases actually exceeded
526 Principles of Medicine
the 1985 gure. This trend continued until the peak year of
1992 (26,673 cases). With the development and institution of
appropriate infection control policies and procedures aimed at
minimizing airborne spread of M. tuberculosis, continued
decrease in new TB cases has been noted in each subsequent
year.
11,12
ETIOLOGY AND PATHOGENESIS
The genus Mycobacteriumcontains a variety of species, rang-
ing from human pathogens to relatively harmless organisms.
As the major cause of TB, a chronic communicable disease, M.
tuberculosis is by far the most historically prominent member
of this group of bacteria. In addition to their very slow growth
on special enriched media, these aerobic slender rods are char-
acterized by their acid-fast staining feature. The unusually
high lipid content of the cell wall confers the organisms with
an ability to strongly retain a red dye (carbolfuchsin) after
treatment with an acid-alcohol solution. This unique struc-
ture also allows the bacteria to survive outside a hosts body,
suspended in airborne microdroplet nuclei for extended peri-
ods of time.
Contrary to a perception believed through the ages, M.
tuberculosis is not a highly contagious bacterium. It does not
synthesize potent exotoxins or extracellular enzymes, and it is
not surrounded by an antiphagocytic capsule. Onset of infec-
tion appears to be related to the ability of tubercle bacilli to
multiply within host cells and tissues while at the same time
resisting host defenses. Infection with M. tuberculosis typically
requires prolonged close contact of a susceptible host with an
infectious source. The closeness of the contact with
aerosolized bacilli and the degree of infectivity of the
TABLE 20-1 Summary of Reported Cases of Tuberculosis in the
United States by Year
Year Total Number of Cases
1954 79,775
1967 45,647
1970 37,137
1975 33,989
1980 27,749
1985 22,201
1986 22,768
1990 25,701
1992 26,673
1993 25,313
1994 24,361
1995 22,860
1996 21,337
1997 19,851
1998 18,361
1999 16,607
2000 12,942
CDC. Reported tuberculosis in the United States, 2000. Surveillance Reports; 2001.
Infectious Diseases 527
mycobacterial source are the most important considerations
for infection. The overwhelming majority of primary human
infections involve inhalation of mycobacteria-laden respira-
tory microdroplets.
13,14
The diameter of these aerosolized
droplets ranges from 1 to 5 microns. Dispersal of M. tubercu-
losis occurs via these droplets as a result of coughing, sneez-
ing, or even speaking. Microdroplet nuclei are small enough
to bypass protective host bronchial mucocilliary defenses,
leading to mycobacteria subsequently replicating in both free
alveolar spaces and within phagocytic cells (Figure 20-1).
Repeated prolonged exposure to air that has been contami-
nated by droplets from a person with TB predisposes others
to infection. This rationale is illustrated by the fact that peo-
ple who live in the same home with an infected individual, or
close friends or co-workers who routinely breathe the same
mycobacteria-contaminated air from an undiagnosed or
untreated person with pulmonary TB, have a high risk of
acquiring infection. The organisms oxygen requirement pre-
disposes the lungs as primary infection sites, with the poten-
tial for subsequent dissemination to other tissues. Cross-infec-
tion or spread of tubercle bacilli does not result from casual
or sporadic exposure.
Onset of clinical disease is characterized by gradual inl-
tration of neutrophils, macrophages, and T lymphocytes.
Distinctive granulomatous TB lesions called tubercles may
appear anywhere in the lung parenchyma; however, they are
most evident in the periphery (Figure 20-2). Because TB is the
prototype microbial infection for inducing protective cellular
immunity, the immunocompetence of the affected host plays
a signicant role in controlling the extent and severity of resul-
tant disease.
15,16
It is important to remember that most peo-
ple infected with M. tuberculosis develop a positive type IV
hypersensitive skin test reaction when challenged (Figure 20-
3) but do not progress to clinical disease. For those infected
individuals who develop clinical symptoms, fatigue, malaise,
weight loss, night sweats, and fever are most commonly noted
in addition to positive chest radiograph manifestations.
Pulmonary manifestations most frequently are chest pain,
bloody sputum, and the presence of a prolonged productive
cough of greater than 3 weeks duration.
Initial mycobacterial infection may progress to several dif-
ferent states depending on the extent of M. tuberculosis expo-
sure and resistance of the patient. These include (1) asympto-
matic primary tuberculosis, (2) symptomatic primary
tuberculosis, (3) progressive primary tuberculosis, and (4)
reactivation tuberculosis. A major risk factor for progression
of initial infection with tubercle bacilli to more severe disease
stages is the absence of an adequate host acquired cellular
immune response to mycobacterial antigens. The ability of an
infected individual to develop dual cellular and humoral
immune responses against M. tuberculosis antigens thus greatly
inuences disease onset and progression.
FIGURE 20-1 Sequence of infection from a Mycobaterium tuberculo-
sisladen microdroplet in a susceptible person.
FIGURE 20-2 Chest radiograph of lungs in a patient with primary
symptomatic tuberculosis. Multiple areas of disease are visible, with radi-
ographic evidence of chronic granulomatous tubercles.
FIGURE 20-3 Positive 48-hour skin test following puried protein deriv-
ative intradermal challenge of a person with primary asymptomatic tuber-
culosis. No evidence of clinical disease was present, and the patient
remained asymptomatic following a prolonged course of isoniazid
chemotherapy.
Asymptomatic Primary Tuberculosis. Individuals may be
infected with M. tuberculosis without apparent clinical mani-
festations. When skin tested, individuals with asymptomatic
primary tuberculosis display a positive tuberculin reaction
indicating that they have been infected and have developed
cell-mediated immunity against the bacteria. This protective
immune response prevents the continued multiplication and
dissemination of the bacteria, but it does not destroy all of the
bacteria present. The remaining bacteria are sequestered
within tubercles in the affected tissues and may be the source
of bacteria that initiate reactivation tuberculosis.
Symptomatic Primary Tuberculosis. In symptomatic pri-
mary tuberculosis, M. tuberculosis is spread via the lymphat-
ics to cause granulomatous inammation in both the lung
periphery and hilar nodes, and it is accompanied by respira-
tory symptoms. The usual result is one of healing and devel-
opment of cell-mediated immunity. The Ghon complex, a
remnant of this infection, most often occurs in infants and
children and is comprised of small calcied lung nodules and
lymphadenopathy of the hilar lymph nodes.
Progressive Primary Tuberculosis. A much more serious dis-
ease may develop in those individuals who are less resistant to
tubercle bacilli. In these patients, microorganisms may spread
throughout the body either (1) by means of the blood, result-
ing in miliary tuberculosis; (2) via the respiratory tissues,
inducing a bronchopneumonia; or (3) through the gastroin-
testinal tract as a result of the organisms being coughed up. In
miliary tuberculosis, foci of infection occur in distant organs
and tissues but most frequently develop in the meninges, lungs,
liver, and renal cortex. Although cell-mediated immunity may
develop in some patients, others may not react (anergy) when
skin tested with tuberculin protein preparations. Anergic
patients have a poor prognosis for recovery and often die with-
out rapid treatment.
Reactivation Tuberculosis. Reactivation tuberculosis occurs
in individuals who have developed primary tuberculosis and
who are asymptomatic, but who still carry the bacteria within
tubercles. These patients exhibit positive tuberculin skin tests
and thus demonstrate cellular immunity. Reactivation of dis-
ease is thought to be due to the activation of persistent bacte-
ria in the tubercles of a previous infection, which become acti-
vated by some alteration in host resistance. Infection is
characterized by tubercle formation, caseation, brosis, and
further extension of the lesion. Progression may advance into
a bronchus, leading to cavitation of the lung and secretion of
an infectious sputum.
ORAL MANIFESTATIONS
Oral manifestations of tuberculosis occur in approximately
3% of cases involving long-standing pulmonary and/or sys-
temic infection.
17,18
The bacteria can infect oral tissues and
lymph nodes (scrofula) (Figure 20-4). Within the oral cavity,
lesions can occur in the soft tissues and supporting bone
528 Principles of Medicine
(Figure 20-5) and in tooth extraction sites, and may even affect
the tongue and oor of the mouth (Figure 20-6).
When reviewing this information, it becomes apparent
that progression of infection with tubercle bacilli to more
severe disseminated stages occurs in the absence of adequate
cellular immunity to infection. Thus, the ability of an
infected individual to develop a dual immune response
against M. tuberculosis antigens greatly influences disease
onset and progression. These crucial protective responses are
(1) acquired immunity to infection and (2) development of
tuberculin hypersensitivity.
DIAGNOSIS
A diagnosis of infection with M. tuberculosis relies on (1) devel-
opment of a positive delayed hypersensitivity (tuberculin) skin
reaction to puried protein derivative (PPD), a mycobacterial
antigen isolated from bacterial cultures, and (2) demonstration
of acid-fast mycobacteria in clinical specimens. Information
obtained while collecting a patients medical history can pro-
vide evidence for suspicion of TB (Table 20-2).
RISK FACTORS
The re-emergence of M. tuberculosis infection as a signicant
US public health problem appears to be the result of a com-
bination of changing host susceptibility factors and declining
societal conditions for particular population groups. Among
FIGURE 20-4 Cervical tuberculosis lymphadenitis (scrofula) secondary
to pulmonary tuberculosis in a 16-year-old male.
TABLE 20-2 Patient History Prompting Suspicion of Active
Tuberculosis
1. Productive cough (> 3 wk) pulmonary tuberculosis
2. Other symptoms (eg, fever, chills, night sweats, fatigue)
3. Extrapulmonary tuberculosis (occurs in 15% of cases)
4. Patients with tuberculosis and HIV infection4075% have extrapulmonary
tuberculosis and pulmonary tuberculosis
5. History of tuberculosis exposure and/or previous tuberculosis infection
(active disease)
Infectious Diseases 529
the most frequently noted risk factors is infection with
HIV.
1923
The suppressive effect of HIV infection on cell-
mediated immunity increases host susceptibility to a variety
of microbial pathogens that are normally controlled by these
defense mechanisms. It should be noted, however, that current
information does not suggest HIV-infected persons are more
susceptible to M. tuberculosis infection, but they can present
with earlier clinical manifestations of the disease. Increased
immigration of people to the United States from countries
with high TB prevalence rates adds to the reservoir for
mycobacterial transmission.
24
Unfortunately, funding for TB
research, screening programs, and epidemiologic tracking
lagged in the 1980s as attention focused on other infectious
diseases, such as those caused by herpesviruses, hepatitis B,
and HIV/acquired immunodeficiency syndrome (AIDS).
These factors, together with documented societal tragedies
such as increased parenteral drug abuse, homelessness, mal-
nutrition, and crowding, especially in larger US cities, have
exacerbated the potential for the spread of TB (Table 20-3).
13
TREATMENT
Prior to the advent of antimicrobial chemotherapy, approxi-
mately 50% of persons with active TB died within 2 years after
onset of symptoms.
24
Regimens of multiple antibiotics are
currently used to treat patients with active TB to ensure tissue
penetration and minimize emergence of resistant organisms.
General guidelines for appropriate TB chemotherapy include
necessity for long-term treatment interval (up to 2 years), ini-
tiation of treatment if sputum smear is positive for acid-fast
bacilli, and patient compliance (a major factor in determining
chemotherapy success).
Isoniazid (INH) is the antimycobacterial therapy corner-
stone and is included in all routine drug regimens. People who
develop a positive tuberculin skin reaction but do not have
active disease, as well as close contacts of patients who develop
TB, are placed on INH for 6 months to 1 year.
For treatment of patients with active TB, combinations of
three or more drugs are chosen based on the nature and site
of disease (Table 20-4). In addition to INH, rifampin, pyra-
zinamide, and ethambutol are the most frequently applied
drug combinations unless a specific instance of mycobacte-
rial resistance is noted.
25,26
Hepatotoxicity is a frequent
adverse effect noted with prolonged administration of
antimycobacterial chemotherapy.
Unfortunately, a major complication preventing success-
ful elimination of acid-fast organisms in TB patients is non-
compliance to the prolonged drug regimens. Patients often
notice a substantial decline in symptoms within a few weeks
of therapy and prematurely discontinue their medications.
Consequently, bacterial strains causing multidrug-resistant
tuberculosis (MDR-TB) have emerged and spread through-
out the world.
2730
FIGURE 20-5 Partially calcied oral tuberculosis localized in the soft
tissue at the angle of the mandible.
FIGURE 20-6 Oral tuberculosis in the soft tissue of mandible.
TABLE 20-3 Persons at High Risk for Contracting Tuberculosis
1. Persons with HIV infection
2. Persons with close contacts with infectious patients
3. Persons with medical conditions that increase risk of contracting TB
4. Persons from countries with high rates of TB
5. Persons in low-income populations
6. Alcoholics
7. Intravenous drug abusers
8. Prisoners
9. Nursing home residents
10. Health care workers in certain work settings (local risk)
TB = tuberculosis
TABLE 20-4 Chemotherapy for Tuberculosis
Combination therapy: usually 34 drugs to prevent resistance, chosen from the
following: isoniazid, rifampin, ethambutol, rifabutin, streptomycin, pyrazinamide
Prolonged therapy6 mo minimum indicated for slow growth rate of bacteria,
increasing incidence of Mycobacterium tuberculosis drug resistance
TUBERCULOSIS VACCINES
Bacille Calmette-Gurin (BCG), an attenuated strain of
Mycobacterium bovis, has been used for more than 80 years to
protect humans against TB. The original mycobacterial iso-
lates were responsible for causing TB in cattle. Calmette and
Guerin attenuated these bacteria by culturing, passaging, and
maintaining them in specialized growth media for more than
10 years. Humans began receiving the BCG preparations in
1921, with resultant protection observed in vaccinated chil-
dren. Most countries currently vaccinate children against TB,
and this preventive approach has been shown to result in a 60
to 80% reduction in disease in treated individuals.
31
Unfortunately, the vaccine is much less effective in adults, for
reasons that are still unexplained. With adults comprising the
major sources of infection, the expected worldwide success of
the BCG vaccine has not been accomplished. The successful
sequencing of the complete M. tuberculosis genome has pro-
vided new opportunities for vaccine development. Ongoing
efforts are being directed at using combinations of established
approaches to vaccine composition, with newer deoxyri-
bonucleic acid (DNA) technologies that look at the roles of
host and mycobacterial genetic factors, to better ascertain the
development of protective immune responses.
32
ORAL HEALTH CONSIDERATIONS
The risk of TB transmission from patients to dental care
providers is considered to be minimal.
33
Responding to reports
and conrmation of M. tuberculosis transmission in institu-
tional settings occurring the 1980s, the CDC developed a series
of guidelines for prevention of the spread of TB in health care
environments. Special emphasis within the document was
directed at the heightened TB risks for those persons living
with HIV infection or AIDS as a result of virus-induced sup-
pression of cellular immune defenses. As more clinical data
and scientic input were obtained from health care and pub-
lic sources, the CDC incorporated that information in updated
draft recommendations. The nalized document released in
1994 provided the following:
1. Guidance for assessing potential TB risks in a variety of
health care facilities
2. Detailed description of administrative procedures,
infection control practices, engineering controls, and
respiratory personal equipment appropriate for mini-
mizing airborne microbial transmission
3. Suggestions for ongoing health care worker (HCW)
training and education.
34
Specific considerations for dentistry were delineated
within this document and provided wellthought out admin-
istrative and infection control practice for the range of possi-
ble dental exposure categories.
The efforts of the CDC have been very effective, yet they
represent only one component of the governmental response
to the public health threat posed by mycobacterial infection
and TB. The Labor Coalition to ght TB in the Workplace
submitted a request to Occupational Safety and Health
530 Principles of Medicine
Administration (OSHA) in December 1992 to issue national
enforcement guidelines to protect workers against M. tuber-
culosis exposure. This was followed by the coalition of labor
unions petitioning OSHA in 1993 to develop a permanent set
of rules to protect workers (mostly in patient care facilities)
from occupational TB transmission. Serious concern was
expressed by these groups about the emergence of cases of
MDR-TB, along with the contention that nonmandatory rec-
ommendations and guidelines would not be fully imple-
mented or enforced appropriately in many workplaces. The
nal OSHA-proposed rule incorporated many of the compo-
nents of the 1994 CDC guidelines but also added a number of
mandatory regulations that have stirred considerable contro-
versy within the CDC, among numerous hospital-based infec-
tion-control professionals, and infection-control groups. A
few of the areas of contention include (1) overstatement of the
current TB risk to HCWs in lieu of the effectiveness of the 1994
CDC TB control guidelines; (2) elimination of the CDC-rec-
ommended facility TB risk assessment protocol; (3) additional
respirator t-testing requirements; (4) more frequent skin-
testing requirements for employees, including TB skin testing
within 30 days of job termination; and (5) increased facility
costs to implement new regulations.
OSHAs rationale for mandatory TB controls stemmed
from the assessment that TB is still endemic in certain popu-
lation groups, and HCWs and other employees who come into
contact with persons manifesting active TB may have signi-
cantly increased infection risks above that of the general pop-
ulation. The agency also made a preliminary determination
that the portions of the standard directing engineering, work
practice, and administrative controls, respiratory protection,
training, and medical surveillance are technologically and eco-
nomically feasible for affected workplaces. Few OSHA pro-
posals for worker protection in any American workplace have
sparked as much debate and resistance as the proposed rules
regarding tuberculosis. The issue may have been resolved in
favor of continuing the successful adherence to the 1994 CDC
guidelines in early 2001, but the Institute of Medicine then
published a report that critically reviewed the proposed stan-
dard and found numerous problems with some of mandatory
aspects of the legislation.
35
Legionella
Scientists, clinicians, and the public officially became
acquainted with Legionella pneumophila as a result of the out-
break of legionnaires disease in a Philadelphia hotel hous-
ing the 1976 American Legion convention. As a result of the
first reports of sudden severe pneumonia among conven-
tioneers, multiple epidemiologic groups were rapidly mobi-
lized in an effort to determine both the cause(s) and contrib-
utory factors responsible for the 221 total cases and 34
illness-associated deaths.
36
MICROBIAL CHARACTERISTICS
When the elusive etiologic bacterium was eventually iso-
lated in 1977, using lung tissue from patients in the
Infectious Diseases 531
Philadelphia epidemic, it became apparent that the aerobic
gram-negative bacillus represented a previously unrecog-
nized species. Table 20-5 summarizes representative bacte-
riologic features of this organism.
3739
One of the early surprises stemming from these studies
was that L. pneumophila had actually rst been isolated from
the blood of a patient with respiratory illness in 1947.
40
Improved more-sensitive research technologies provided bet-
ter cultural and serologic methodologies for isolation and
characterization. As a result, scientists began to appreciate (1)
the ubiquity of L. pneumophila and related species in man-
made waterborne environments, (2) the role of this bacterial
species as one of the three most common microbial etiologies
of community-acquired pneumonia, and (3) the multiple
forms of disease that can develop in immunocompetent and
immunocompromised individuals. L. pneumophila serogroup
1 is still the most clinically important pathogenic species, caus-
ing the overwhelming majority of illnesses after exposure to
contaminated water.
MAJOR HABITATS
Legionella species are found extensively in natural bodies of
water. Most samples from colonized rivers, lakes, and other
sources typically contain only low concentrations of L. pneu-
mophila. However, the species is remarkably chlorine toler-
ant. This feature appears to allow for microbial survival dur-
ing treatment procedures, leading to subsequent entrance and
proliferation in water distribution systems.
Multiple studies have shown that the presence of amebae
and other waterborne microbes offers L. pneumophila a unique
opportunity for initial parasitism, leading to ultimate survival
and proliferation. Amebae appear to serve as primary natural
hosts for the bacteria in man-made water environments such
as water distribution systems.
4143
This intracellular parasitic
characteristic allows the legionellae to thrive and replicate,
protected from adverse external surroundings. When the
infected amebae die and lyse, both the water source and other
susceptible single-cell organisms are then exposed to a much
higher concentration of Legionella.
CLINICAL SYNDROME
Clinical conditions caused by L. pneumophila and other
Legionella species are grouped under the term legionellosis.
With regard to virulence factors, neither exotoxins nor destruc-
tive enzymes have been associated with the pneumonia caused
by L. pneumophila. The acute inammatory inltration and
febrile nature of clinical illness appear to be consistent with the
biologic manifestations of released endotoxin in tissues.
MODES OF TRANSMISSION
Legionella infections differ from other kinds of pneumonia-
inducing conditions in that the bacteria are not transmitted
from person to person but from contaminated environmen-
tal reservoirs. Evidence accumulated from outbreaks of the
disease and experimental investigations suggests that
Legionella species may be passed to susceptible hosts via mul-
tiple routes: aspiration, aerosolization, and instillation into
the lungs. Aspiration of contaminated water appears to be the
major means of human infection.
44
In one study, passage of
microorganisms via this mechanism appeared to be excep-
tionally serious in patients after surgery for head and neck
cancer because of the patients frequency of aspiration of
fluids.
45
Aerosolization of contaminated water occurs from
such sources as humidifiers, nebulizers, and cooling tower air
conditioners. Because the organisms are resistant to destruc-
tion in moist environments, it is believed that exposure to
legionellae is common. Reports in the literature in recent
years have implicated potable water harboring L. pneu-
mophila as an important source of community-acquired
pneumonia. As a result, investigation of legionellosis cases
now includes examination of water supplies in patients
rooms, homes, and workplaces.
4648
CLINICAL FEATURES
Two disparate forms of clinical disease can develop after
Legionella infection. The most common manifestation,
known as Pontiac fever, presents as an acute influenza-like
illness without any evidence of pneumonia. There is a 24- to
48-hour incubation period, and many patients experience
fever, chills, malaise, and headaches. Patients typically
recover from this self-limiting illness within 7 to 10 days.
49
Although the attack rate for Pontiac fever among exposed
persons is high (Tables 20-6 and 20-7), many cases of
legionellosis are never diagnosed because symptoms are
either absent or mild.
Published reports suggest that dental professionals may
have a signicant occupational exposure to Legionella from
aerosolization of contaminated dental-unit water, resulting in
the formation of anti-Legionella antibodies.
50,51
Individuals
similarly exposed in a variety of environments may have sub-
sequently developed Pontiac fever and not been aware of it.
The second, more publicized, type of legionellosis is a
potentially life-threatening illness termed legionnaires dis-
ease. The incubation period (2 to 10 days) is longer than that
for Pontiac fever. An individual may abruptly exhibit fever,
chills, headache, and other nonspecic signs of acute infec-
tion. Subsequently, multisystem involvement becomes evi-
dent with pneumonia as the pathognomonic feature.
52
If
untreated, this form of severe pneumonia can result in a 15%
TABLE 20-5 Bacteriologic Characteristics of Legionella
pneumophila
Family: Legionellaceae
Morphology: gram-negative non-spore-forming motile unencapsulated bacilli
Physiology: aerobic and nutritionally fastidious; does not grow on standard
bacteriologic media; requires charcoal yeast extract at pH 6.9; L-cysteine
is essential nutrient
Ecology: natural habitat: rivers, lakes, streams, thermally polluted waters; can
survive water treatment processes; chlorine tolerant; proliferates in man-made
water habitats (cooling towers, water distribution systems)
or higher patient mortality rate (see Tables 20-6 and 20-8).
Legionnaires disease in healthy immunocompetent persons
appears infrequently because of efcient innate and specic
host defenses. Most patients diagnosed with legionnaires dis-
ease present with previous immunosuppressive disorders.
Investigation of nosocomially acquired legionnaires disease
suggests that patients recovering from surgery may be at
greatest risk of contraction.
5355
Other conditions identied
as legionellosis risk factors include advanced age, cigarette
smoking, chronic obstructive pulmonary disease, neoplasia,
and immunosuppressive therapy.
TREATMENT
Erythromycin was the historic antibiotic of choice for treat-
ment of legionnaires disease. Timely appropriate chemother-
apy can dramatically reduce the mortality rate of legionnaires
disease, with many patients showing signs of recovery within
3 to 5 days. With the advent of later-generation macrolides,
azithromycin has replaced erythromycin because of
azithromycins lower toxicity potential in a range of infected
patients.
52
Quinolones also have been shown to be effective
antimicrobial agents in studies of patients with community-
acquired pneumonia who are suspected of having L. pneu-
mophila legionnaires disease.
56,57
Antibiotic therapy is not
indicated for patients diagnosed with Pontiac fever because of
the self-limiting nature of the infection.
532 Principles of Medicine
PROTOZOAL INFECTION:
CRYPTOSPORIDIUM
Although rst isolated and identied in 1907,
58
the protozoan
genus Cryptosporidiumwas not associated with human disease
until 1976.
59
Only a few cases of cryptosporidiosis were
reported over the next few years, with those occurring in per-
sons having severely compromised immune defenses. Since
the early 1980s, however, Cryptosporidium parvum has
emerged as a major etiology of persistent diarrhea in people of
developing countries, of severe life-threatening diarrhea in
persons with AIDS and other immunosuppressive conditions,
and in previously healthy individuals, as well as an increasingly
serious threat to the safety of the US water supply.
Microbial Characteristics
Among the most common of human pathogens, the diversity
of members within the protozoa has required their classica-
tion to be accomplished via disparate criteria, including phy-
logeny, epidemiology, and clinical manifestations. Protozoa
such as Plasmodium, Entamoeba, and Trypanosoma have long
been recognized as leading causes of human disease and mor-
tality in many parts of the world. The dramatic increase in
numbers of individuals with less-than-adequate immune
defenses throughout the world, in part related to HIV infec-
tion with subsequent progression to AIDS, has also been
related to signicant increases in other protozoan infections,
such as those caused by Cryptosporidium species.
6065
TABLE 20-6 Clinical Conditions Caused by Legionella
Conditions
Characteristic Legionnaires Disease Pontiac Fever
Epidemiology
Attack rate < 5% > 90%
Person-to-person spread No No
Clinical manifestations
Incubation period 210 d 12 d
Clinical features Pneumonia is dominant feature; spectrum from mild Acute self-limiting inuenza-like illness; no pneumonia;
cough to stupor with multisystem failure; cough fever, malaise, myalgia, chills, and headache are
initially mild; only slightly productive predominant symptoms
Course Requires antibiotic therapy (eg, erythromycin) Self-limiting
Mortality 1520%; higher if diagnosis is delayed < 1%
TABLE 20-7 Characteristics of Pontiac Fever
Acute self-limiting inuenza-like illness
24- to 48-hour incubation period
Malaise, myalgia, fever, chills, headache
> 90% of those exposed develop symptoms
Only symptomatic treatment necessary
Complete recovery within 1 wk
Most cases undiagnosed
TABLE 20-8 Characteristics of Legionnaires Disease
Early inuenza-like symptomsinitial cough
2- to 10-day incubation period
Chest pain may be prominent
Pneumonia is dominant nding
Spectrum from mild cough to stupor with multisystem failure
Treatment: erythromycin and other macrolides
Infectious Diseases 533
The type-species of this genus is C. parvum, which mea-
sures approximately 2.5 m in diameter, about the same size
and shape as yeast cells. It is capable of infecting and causing
disease in both humans and mammals. The infectious form of
C. parvum is a thick-walled oocyst that is excreted in feces
from infected hosts. Oocysts are resistant to standard munic-
ipal chlorination procedures, and this feature is important in
distinguishing cryptosporidia from many other unicellular
waterborne organisms. Because the oocysts can be found in
numerous natural water sources, they can readily cause large
cryptosporidiosis outbreaks when water treatment is less than
optimal and community supplies become contaminated.
Cryptosporidia are also unlike many other single-celled water-
borne organisms in that they are highly resistant to the chlo-
rine treatments used in municipal water facilities. In addition,
they are difcult to lter out because of their small size, and
thus they can escape the standard water treatment processes.
Epidemiology and Transmission
As awareness of the potential threat of cryptosporidiosis has
increased, so have efforts to investigate water sources for evi-
dence of contamination. Unfortunately, accumulated data
suggest that Cryptosporidium is found in numerous munici-
pal water supplies, public pools, nursing homes, and hospitals.
It is also highly infectious, with an inoculum of 30 to 100
oocysts capable of initiating infection.
66,67
Numerous out-
breaks have been demonstrated over the past 20 years. With
the development of better detection techniques, some impor-
tant epidemiologic features have become apparent (Table 20-
9). Most cases in the United States have occurred as a result
of environmental water contamination related to treatment
facility failures.
6871
As reports of the wide distribution of this pathogen accu-
mulate, so have the number of cryptosporidiosis cases with
life-threatening acute diarrhea, mostly seen in immunocom-
promised persons but also in previously healthy individuals. A
dramatic rise in the number of large outbreaks and individual
cases has been noted since 1982, corresponding to the early
days of the AIDS epidemic. Multiple reports have shown per-
sons with AIDS to be among the most susceptible immuno-
compromised groups.
6365
The largest documented outbreak occurred in 1993,
involving the entire city of Milwaukee, in which over 400,000
people became ill after drinking parasite-contaminated water.
Defective ltration of the citys water supply was determined
to be the prime factor responsible for the epidemic, which
resulted in the death of a number of severely immunocom-
promised patients.
68
Other instances of waterborne
C. parvum infection have been traced back to ingestion of
water from oocyst-contaminated swimming pools and
amusement park wave pools.
70
A second mode of parasite infection is person-to-person
spread. Fecal-oral transmission of oocysts within day care cen-
ters, hospitals, and households is probably much more com-
mon than accumulated statistics suggest.
7274
The route of
microbial passage can place child care workers, children in day
care facilities, and other health care providers, who come into
direct contact with feces while attending to cryptosporidiosis
patients, at increased risk for acquiring the infection.
The ability of C. parvumto infect and colonize a variety of
mammals has also led to investigation of suggested animal-to-
person cryptosporidiosis. Multiple investigations have shown
protozoal transmission from calves to humans, and these have
triggered intense study of potential risks for those persons
who have constant close contact on dairy farms.
75
The least proven risk factor for cryptosporidiosis involves
food. Although the CDC conrmed an outbreak in children in
1994 traced to fresh-pressed apple cider unknowingly contam-
inated with animal feces, contaminated hands were also thought
to have substantially contributed to oocyst cross-infection.
76
Clinical Syndrome
The complex C. parvumlife cycle occurs within a single host.
77
Symptoms of cryptosporidiosis may develop within 2 to 10
days after a person has swallowed environmentally contami-
nated water. The most common manifestations of C. parvum
infection are a profuse watery diarrhea, accompanied by fever,
severe abdominal cramping, and pain. Rapid dehydration of
patients is a major concern for physicians, as onset of diarrhea
can be quite sudden and can last for over 2 weeks.
Gastrointestinal symptoms abate in many patients with healthy
immune systems in about 2 weeks, although some may suffer
a relapse of the syndrome.
78
The infection is typically more pro-
tracted and severe in immunocompromised hosts, however, as
extensive dehydration and weight loss may occur over a pro-
longed period of longer than 2 weeks. In some cases, multiple
intravenous infusions of uids are required to replace body
uids lost owing to diarrhea. Even after symptoms of cryp-
tosporidiosis diminish or disappear, the patient can still trans-
mit infectious parasites to others for months via contaminated
stools (fecal-oral transmission). Infected individuals with debil-
itated immune systems can remain infectious much longer.
Treatment and Control
Currently, there is no generally accepted antimicrobial agent
available to treat cryptosporidiosis, and thus, supportive care
of patients remains the treatment of choice.
77
As expected,
this problem is a major area of research, with certain experi-
mental antibiotic regimens showing some promise. Because
the thick-walled oocyst portion of the C. parvum life cycle is
so resistant to chlorine, new approaches to control the spread
of these infectious particles are also being pursued. Reverse
osmosis, better ltration techniques, and other efcient pro-
cedures are under investigation.
TABLE 20-9 Epidemiology of Cryptosporidium Infection
C. parvum is a highly infectious enteric pathogen.
The protozoa are ubiquitous in many mammals.
Infections can occur worldwide.
It is the leading cause of persistent diarrhea in developing countries.
VIRAL INFECTIONS
Hepatitis C Virus
Traditional health care concerns about viral hepatitis focused
primarily on hepatitis B virus (HBV) from the late 1940s to the
early 1980s. Yet, despite accumulated evidence for the docu-
mented occupational risks for HBV over a three-decade
period, signicant voids from other potentially serious hepati-
tis challenges continue to require denition. Although the rou-
tine application of specific serologic tests was valuable in
screening and diagnosing infections caused by hepatitis A virus
(HAV) and HBV, a number of reports, written beginning in
1975, described a form of bloodborne post-transfusion hepati-
tis that could not be attributed to any known microorgan-
ism.
79,80
Since diagnosis of this type of hepatitis was based on
abnormal liver function in the absence of positive blood mark-
ers for HAV, HBV, and other viruses known to cause hepatitis,
the term non-A, non-B hepatitis(NANBH) was introduced.
Most of the risk factors associated with NANBH transmission
were identied prior to recognition and characterization of its
viral etiology. These included blood transfusion, parenteral
drug use, health care worker exposure in clinical settings, sex-
ual transmission from a person with a history of hepatitis, and
low socioeconomic status. Signicant advances in recombinant
DNA technology were instrumental in the later isolation and
cloning of the responsible microorganism in 1989the
hepatitis C virus (HCV).
81
A initial diagnostic serologic assay
was also developed for detection of antibodies to HCV (anti-
HCV) produced by infected persons against a recombinant
viral antigen c100-3.
82
Later generations of more sensitive
immunoassays have been implemented since 1990. Currently,
at least six viral agents appear to account for the majority of
viral hepatitis cases (Table 20-10), with new information
emerging to expand this list.
VIROLOGY
HCV is a single-stranded positive-sense ribonucleic acid
(RNA) virus whose structure appears closely related to the
genera Flavivirus and Pestivirus. Because of the similarities to
these viral types, HCV is currently classied as a separate genus
in the family Flaviviridae. Detailed molecular biologic studies
have shown that different HCV strains can have substantial
differences in genome sequencing. These are due to the abil-
ity of the virus to mutate and modify surface components
during replication within an infected host. As a result, several
genotypes, or quasi-species, have been described that can
exhibit significant differences throughout the RNA
genome
8385
and contribute to the observed alarming high
rate of chronic infection.
EPIDEMIOLOGY AND TRANSMISSION
HCV has a primary bloodborne mode of transmission and is
a dominant cause of chronic liver disease throughout the world.
Data using anti-HCV as a marker have been used to approxi-
mate both worldwide infection prevalence and HCV incidence
534 Principles of Medicine
in various geographic areas, in an attempt to better dene infec-
tion and disease patterns.
86
Infection with HCV is also the most
common chronic bloodborne infection in the United States.
Current estimates range from 2.7 (1.3%) to 3.9 (1.8%) million
HCV-infected persons in the United States (Table 20-11).
87,88
Approximately 2.7 million people are thought to have per-
sistent chronic hepatitis C infection, and thus are classied as
potentially infectious viral carriers. Mortality in the United
States from all forms of hepatitis C infection is believed to
occur in 8,000 to 10,000 people each year. With the advent of
widespread use of anti-HCV assays and increased awareness of
documented risks and changing viral transmission patterns,
the incidence of new cases of acute hepatitis C has declined by
greater than 80% since 1989.
Statistics acquired during the 1970s and 1980s indicated
that parenteral NANBH was responsible for nearly 90% of
the reported US transfusion-associated hepatitis cases.
Accumulated data suggested that approximately 150,000 per-
sons (5 to 10%) of 3,000,000 who received transfusions devel-
oped acute NANBH.
89,90
With the advent of routine testing
using sensitive anti-HCV tests, however, the current risk for
acquiring transfusion-associated hepatitis C is 1/100,000 per
unit transfused.
91
According to CDC national surveillance
data, parenteral drug use was the most common risk factor
reported by patients with NANBH between 1990 and 1992.
Injection-drug use remains the primary risk factor for new
cases of HCV infection. In addition, persons with hemophilia
who routinely received factor VIII or IX before 1987 and
chronic hemodialysis patients have also been considered at
risk. Occasionally, health care workers who have frequent con-
tact with blood and personal contact with others who may be
infected have been documented to have an increased incidence
for hepatitis C compared with that of the general popula-
tion.
91,92
A summary of these and other epidemiologic esti-
mates is presented in Table 20-12. In recent years, other sero-
logic surveys have revealed a large previously undetected group
of persons at risk for HCV: military veterans, especially
Vietnam-era veterans. Testing at multiple Veterans
Administration (VA) hospitals found an 8 to 10% HCV preva-
lence rate, which is over four times that of the general popu-
lation. Other reports indicate that more than half of the
patients receiving liver transplants in VA medical centers were
diagnosed with HCV infections.
9395
Unfortunately, even with
improved epidemiologic tracking, published studies continue
to report that greater than 40% of the hepatitis C patients do
not have any identifiable risk factors.
91
Evidence of sexual
transmission and of perinatal passage from HCV-infected
mothers to their offspring suggest possible, but not efcient,
modes of viral exposure. In summary, transmission data still
strongly implicate parenteral exposure as the primary mech-
anism for HCV transmission.
SEROLOGY
In May 1990, the US Food and Drug Administration (FDA)
licensed two anti-HCV screening tests.
96
Almost immedi-
ately, blood donation centers began testing for HCV infection
Infectious Diseases 535
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as a component of their routine donor screening. In a note-
worthy positive outcome, the use of this radioimmunoassay
was found to yield positive anti-HCV results in 80 to 90% of
specimens from potential donors thought to be infectious for
HCV.
97
Unfortunately, false-negative results are possible at
early stages of HCV infection since development of
detectable antibody could be delayed for months post viral
infection. This prolonged delay in seroconversion suggests
that some potentially infectious donors could pass unde-
tected through screening, and their blood subsequently
536 Principles of Medicine
administered to patients. In addition, false-positive test
results are possible for those donors with certain
immunopathologic conditions, such as hypergammaglobu-
linemia, liver disease, or autoimmune connective-tissue dis-
orders.
98
More recently, blood tests have used other recom-
binant HCV synthetic peptide antigens, and these assays have
increased sensitivity and specificity (Table 20-13).
91
As a
result, the incidence of transfusion-associated hepatitis C
has become increasingly uncommon.
PATHOGENESIS
Presentation of viral hepatitis in patients ranges from asymp-
tomatic illness to a fulminant chronic form in which severe
sequelae and high mortality rates are seen. Many chronic
hepatitis carriers are also at increased risk for hepatocellular
carcinoma. For those individuals who develop icteric mani-
festations of acute viral hepatitis, symptomatologies may vary
in intensity; yet they can be strikingly similar in their spec-
trum, regardless of the etiology. Disease presentations may
include jaundice, malaise, fever, anorexia, nausea, abdominal
pain, dark (stormy,foamy) urine, chalky gray stools, rash,
and arthritis.
The clinical features of HCV infection can be variable, in
patterns reminiscent of those observed for other hepatitis
viruses. Less than one-third of HCV-infected individuals
TABLE 20-11 Hepatitis C Incidence in the United States
Approximately 3.9 million HCV-infected persons (1.8% of population)
4 times HIV infection incidence
2.7 million chronic potentially infectious carriers
10,000 HCV-related deaths/yr
80% decline in new cases since 1989
> 50% new cases related to IV-drug users
Incidence of transfusion cases is declining rapidly.
Most cases are mild to asymptomatic.
Many cases still have no risk factors.
HCV = hepatitis C virus; HIV = human immunodeciency virus; IV = intravenous.
TABLE 20-12 Estimated Average Prevalence of Hepatitis C Virus Infection in the United States*
Infection
Prevalence of
Prevalence
Persons with
Characteristic % Range % Characteristic (%)
Persons with hemophilia treated with products made before 1987 87 7490 < 0.01
Injection-drug users
Current 79 7286 0.5
History of prior use No data 5
Persons with abnormal alanine aminotransferase levels 15 1018 5
Chronic hemodialysis patients 10 064 0.1
Persons with multiple sex partners (lifetime)
50 9 616 4
1049 3 34 22
29 2 12 52
Persons reporting a history of sexually transmitted diseases 6 110 17
Persons receiving blood transfusions before 1990 6 59 6
Infants born to infected mothers 5 025 0.1
Men who have sex with men 4 218 5
General population 1.8 1.52.3 NA
Health care workers 1 12 9
Pregnant women 1 1.5
Military personnel 0.3 0.20.4 0.5
Volunteer blood donors 0.16 5
NA = not applicable.
*By various characteristics and estimated prevalence of persons with these characteristics in the population.
Infectious Diseases 537
manifest jaundice after receiving contaminated units of
blood.
99,100
They may appear healthy with normal liver
function and no pathologic sequelae, or develop acute
and/or chronic disease manifestations. Although acute
hepatitis C can resemble hepatitis A and hepatitis B clini-
cally, HCV infection often induces less hepatic inflammatory
reactions and thus usually manifests milder symptoms.
Serologic demonstration of anti-HCV often does not occur
for weeks to months after viral infection, thereby providing
a prolonged undetected period during which the patient
continues to be infectious. As occurs with HBV infection,
pathologic sequelae can occur in persons who have chronic
HCV infection, often with life-threatening ramifications.
Unfortunately, as many as 50% of long-term chronic hepati-
tis C cases may progress to chronic hepatitis C liver disease.
This develops far more often than the 5 to 10% carrier rate
observed with HBV infection. Persons with chronic hepati-
tis C can present with few initial clinical manifestations of
liver disease and remain so as inactive viral carriers, or per-
sistent viral infection can predispose a person later to
increased risk for hepatic failure and hepatocellular carci-
noma.
101
Patients with pre-existent immunosuppressive
conditions, such as those with HIV infection and others
undergoing kidney or liver transplantation, also have been
found to have higher hepatitis C morbidity. Transmission
here is most probably due to the patients potential to expe-
rience frequent parenteral exposure to HCV via blood trans-
fusion or intravenous drug use. High-risk sexual activity
may also be a factor.
At the present time, the demonstration and characteriza-
tion of a protective host immune response against HCV have
not been accomplished. Presence of anti-HCV in a persons
blood does not distinguish between cases of acute or chronic
hepatitis C, nor can a positive test for this immunoglobulin
discriminate between a person who has recovered from infec-
tion with natural active immunity from one who has devel-
oped chronic hepatitis C.
OCCUPATIONAL RISKS TO HEALTH CARE PROFESSIONALS
Health care workers are at risk for exposure to patient blood
and possible subsequent infection from bloodborne diseases,
such as those caused by members of the hepatitis virus group.
Early observation that a form of NANBH has a bloodborne eti-
ology spurred intense occupational-risk investigations by clin-
ical scientists. Accidental injuries from contaminated sharps
have been associated with resulting onset of both hepatitis B
and hepatitis C. Information describing occupational HCV
transmission in hospital settings was investigated and pub-
lished even before cloning of the virus was accomplished.
Multiple investigations documented HCV transmission to
health care workers and to other patients following percuta-
neous accidents involving blood (Table 20-14).
102106
TABLE 20-13 Tests for Hepatitis C Virus Infection
Test/Type Applications Comments
Hepatitis C virus antibody (anti-HCV) Indicates past or present infection but does Sensitivity 97%
EIA (enzyme immunoassay); not differentiate between acute, chronic, EIA alone has low positive-predictive value in low-
supplemental assay (ie, recombinant or resolved infection prevalence populations
immunoblot assay [RIBA]) All positive EIA results should be veried
with supplemental assay
HCV RNA (hepatitis C virus ribonucleic acid) Detect presence of circulating HCV RNA Detect virus as early as 12 wk after exposure
Qualitative tests *
: reverse transcriptase Monitor patients on antiviral therapy Detection of HCV RNA during course of infection might
polymerase chain reaction (RT-PCR) be intermittent; single negative RT-PCR is not conclusive
amplication of HCV RNA by in-house False-positive and false-negative results might occur
or commercial assays (eg, Amplicor HCV)
Quantitative tests *
:
RT-PCR amplication Determine concentration of HCV RNA Less sensitive than qualitative RT-PCR
of HCV RNA by in-house or commercial Might be useful for assessing the likelihood of Should not be used to exclude the diagnosis of HCV
assays (eg, Amplicor HCV Monitor) response to antiviral therapy infection or to determine treatment end point
Branched-chain DNA (bDNA) assays
(eg, Quantiplex HCV RNA Assay)
Genotype *
: several methodologies available Group isolates of HCV on the basis ofgenetic Genotype 1 (subtypes 1a and 1b) most common in United
(eg, hybridization, sequencing) differences into 6 genotypes and > 90 subtypes States and associated with lower response to
With new therapies, length of treatment antiviral therapy
might vary based on genotype
Serotype*: EIA based on immunoreactivity No clinical utility Cannot distinguish between subtypes
to synthetic peptides (eg, Murex HCV Dual infections often observed
Serotyping 16 Assay)
DNA = deoxyribonucleic acid; HCV = hepatitis C virus.
*Currently not approved by US Food and Drug Administration; lack standardization.
Samples require special handling (eg, serum must be separated within 24 h of collection and stored frozen [-20
C or -70
Pharmaceutical companies: 1-Abbott Laboratories; 2-Agouron Pharmaceuticals; 3-BioChem Pharma; 4-Boehringer Ingelheim ; 5-Bristol-Myers Squibb; 6-Chiron Corporation;
7-DuPont Pharmaceuticals; 8-Gilead Sciences; 9-Glaxo Wellcome; 10-Merck & Co.; 11-Roche Laboratories; 12-Sarawak Medichem; 13-Triangle Pharmaceuticals; 14- Trimeris.
TABLE 20-22 Impact of Treatments for HIV Infection (Continued)
Drug Name* Type of Drug Adverse Effects of Signicance for Dentists Co.