20

INFECTIOUS DISEASES
JOHN A. MOLINARI, PHD
MICHAEL GLICK, DMD

BACTERIAL INFECTIONS

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 significant factor in social life.1 This was not an uncommon sentiment 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 identified as contributors to the emergence and re-emergence of
infectious disease, as follows:2

Tuberculosis
Legionella

PROTOZOAL INFECTION:
CRYPTOSPORIDIUM
Microbial Characteristics
Epidemiology and Transmission
Clinical Syndrome
Treatment and Control

VIRAL INFECTIONS
Hepatitis C Virus
HIV Infection

1. Changes in human demographics and behavior

2. Advances in technology and changes in industry practices
3. Economic development and changes in land use patterns
4. Dramatic increases in volume and speed of international travel and commerce
5. Microbial adaptation and change
6. Breakdown of public health capacity required to handle 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 immunodeficiency virus
(HIV) disease.3 HIV and other emerging and re-emerging
infectious diseases are recognized as significant 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

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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 established, whereas others are emerging and may become important sources of both contamination and transmission in dental 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.

Principles of Medicine

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

BACTERIAL INFECTIONS

1990

25,701

1992

26,673

Tuberculosis

1993

25,313

1994

24,361

1995

22,860

1996

21,337

1997

19,851

1998

18,361

1999

16,607

2000

12,942

There is a well-known phrase that states, The more things

change, the more they stay the same. This expression continues to apply to tuberculosis (TB), a widespread infectious disease 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; transmission modes of Mycobacterium tuberculosis, occupational
infection risks associated with health care, and airborne-hazard 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 worldwide 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
significant 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, documenting 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 predictions 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

CDC. Reported tuberculosis in the United States, 2000. Surveillance Reports; 2001.

the 1985 figure. 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 Mycobacterium contains a variety of species, ranging 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 characterized 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 structure also allows the bacteria to survive outside a hosts body,
suspended in airborne microdroplet nuclei for extended periods 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 infection 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

Infectious Diseases

mycobacterial source are the most important considerations

for infection. The overwhelming majority of primary human
infections involve inhalation of mycobacteria-laden respiratory microdroplets.13,14 The diameter of these aerosolized
droplets ranges from 1 to 5 microns. Dispersal of M. tuberculosis occurs via these droplets as a result of coughing, sneezing, 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 contaminated by droplets from a person with TB predisposes others
to infection. This rationale is illustrated by the fact that people 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 predisposes the lungs as primary infection sites, with the potential for subsequent dissemination to other tissues. Cross-infection or spread of tubercle bacilli does not result from casual
or sporadic exposure.
Onset of clinical disease is characterized by gradual infiltration 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 significant role in controlling the extent and severity of resultant disease.15,16 It is important to remember that most people infected with M. tuberculosis develop a positive type IV
hypersensitive skin test reaction when challenged (Figure 203) 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

FIGURE 20-1 Sequence of infection from a Mycobaterium tuberculosisladen microdroplet in a susceptible person.

527

FIGURE 20-2 Chest radiograph of lungs in a patient with primary

symptomatic tuberculosis. Multiple areas of disease are visible, with radiographic evidence of chronic granulomatous tubercles.

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 different states depending on the extent of M. tuberculosis exposure and resistance of the patient. These include (1) asymptomatic 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
influences disease onset and progression.

FIGURE 20-3 Positive 48-hour skin test following purified protein derivative intradermal challenge of a person with primary asymptomatic tuberculosis. No evidence of clinical disease was present, and the patient
remained asymptomatic following a prolonged course of isoniazid
chemotherapy.

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Principles of Medicine

Asymptomatic Primary Tuberculosis. Individuals may be

infected with M. tuberculosis without apparent clinical manifestations. 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 primary tuberculosis, M. tuberculosis is spread via the lymphatics to cause granulomatous inflammation in both the lung
periphery and hilar nodes, and it is accompanied by respiratory symptoms. The usual result is one of healing and development of cell-mediated immunity. The Ghon complex, a
remnant of this infection, most often occurs in infants and
children and is comprised of small calcified lung nodules and
lymphadenopathy of the hilar lymph nodes.
Progressive Primary Tuberculosis. A much more serious disease 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, resulting in miliary tuberculosis; (2) via the respiratory tissues,
inducing a bronchopneumonia; or (3) through the gastrointestinal 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 without 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 disease is thought to be due to the activation of persistent bacteria in the tubercles of a previous infection, which become activated by some alteration in host resistance. Infection is
characterized by tubercle formation, caseation, fibrosis, 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 systemic 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

FIGURE 20-4 Cervical tuberculosis lymphadenitis (scrofula) secondary

to pulmonary tuberculosis in a 16-year-old male.

(Figure 20-5) and in tooth extraction sites, and may even affect
the tongue and floor 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) development of a positive delayed hypersensitivity (tuberculin) skin
reaction to purified 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 provide evidence for suspicion of TB (Table 20-2).
RISK FACTORS

The re-emergence of M. tuberculosis infection as a significant

US public health problem appears to be the result of a combination of changing host susceptibility factors and declining
societal conditions for particular population groups. Among

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)

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Infectious Diseases

FIGURE 20-5 Partially calcified oral tuberculosis localized in the soft

tissue at the angle of the mandible.

FIGURE 20-6 Oral tuberculosis in the soft tissue of mandible.

the most frequently noted risk factors is infection with

HIV.1923 The suppressive effect of HIV infection on cellmediated 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, malnutrition, and crowding, especially in larger US cities, have
exacerbated the potential for the spread of TB (Table 20-3).13

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), initiation 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 cornerstone 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, pyrazinamide, and ethambutol are the most frequently applied
drug combinations unless a specific instance of mycobacterial resistance is noted.25,26 Hepatotoxicity is a frequent
adverse effect noted with prolonged administration of
antimycobacterial chemotherapy.
Unfortunately, a major complication preventing successful elimination of acid-fast organisms in TB patients is noncompliance 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 throughout the world.2730

TREATMENT

Prior to the advent of antimicrobial chemotherapy, approximately 50% of persons with active TB died within 2 years after

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

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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 isolates 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 children. 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 provided new opportunities for vaccine development. Ongoing
efforts are being directed at using combinations of established
approaches to vaccine composition, with newer deoxyribonucleic 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 confirmation of M. tuberculosis transmission in institutional 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 suppression of cellular immune defenses. As more clinical data
and scientific input were obtained from health care and public sources, the CDC incorporated that information in updated
draft recommendations. The finalized 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 minimizing 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 administrative and infection control practice for the range of possible 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 fight TB in the Workplace
submitted a request to Occupational Safety and Health

Principles of Medicine

Administration (OSHA) in December 1992 to issue national

enforcement guidelines to protect workers against M. tuberculosis 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 recommendations and guidelines would not be fully implemented or enforced appropriately in many workplaces. The
final OSHA-proposed rule incorporated many of the components of the 1994 CDC guidelines but also added a number of
mandatory regulations that have stirred considerable controversy within the CDC, among numerous hospital-based infection-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-recommended facility TB risk assessment protocol; (3) additional
respirator fit-testing requirements; (4) more frequent skintesting 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 population groups, and HCWs and other employees who come into
contact with persons manifesting active TB may have significantly increased infection risks above that of the general population. 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 economically feasible for affected workplaces. Few OSHA proposals 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 standard 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 outbreak of legionnaires disease in a Philadelphia hotel housing the 1976 American Legion convention. As a result of the
first reports of sudden severe pneumonia among conventioneers, multiple epidemiologic groups were rapidly mobilized in an effort to determine both the cause(s) and contributory factors responsible for the 221 total cases and 34
illness-associated deaths.36
MICROBIAL CHARACTERISTICS

When the elusive etiologic bacterium was eventually isolated in 1977, using lung tissue from patients in the

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Infectious Diseases

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)

Philadelphia epidemic, it became apparent that the aerobic

gram-negative bacillus represented a previously unrecognized species. Table 20-5 summarizes representative bacteriologic features of this organism.3739
One of the early surprises stemming from these studies
was that L. pneumophila had actually first been isolated from
the blood of a patient with respiratory illness in 1947.40
Improved more-sensitive research technologies provided better 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 manmade 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, causing 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. pneumophila. However, the species is remarkably chlorine tolerant. This feature appears to allow for microbial survival during 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 destructive enzymes have been associated with the pneumonia caused
by L. pneumophila. The acute inflammatory infiltration 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 pneumoniainducing conditions in that the bacteria are not transmitted
from person to person but from contaminated environmental reservoirs. Evidence accumulated from outbreaks of the
disease and experimental investigations suggests that
Legionella species may be passed to susceptible hosts via multiple 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 exceptionally 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 destruction 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. pneumophila 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 significant 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 subsequently developed Pontiac fever and not been aware of it.
The second, more publicized, type of legionellosis is a
potentially life-threatening illness termed legionnaires disease. The incubation period (2 to 10 days) is longer than that
for Pontiac fever. An individual may abruptly exhibit fever,
chills, headache, and other nonspecific signs of acute infection. Subsequently, multisystem involvement becomes evident with pneumonia as the pathognomonic feature.52 If
untreated, this form of severe pneumonia can result in a 15%

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TABLE 20-6 Clinical Conditions Caused by Legionella

Conditions
Characteristic

Legionnaires Disease

Pontiac Fever

Epidemiology
Attack rate

< 5%

> 90%

Person-to-person spread
Clinical manifestations
Incubation period

No

No

210 d

12 d

Clinical features

Pneumonia is dominant feature; spectrum from mild

cough to stupor with multisystem failure; cough
initially mild; only slightly productive

Acute self-limiting influenza-like illness; no pneumonia;

fever, malaise, myalgia, chills, and headache are
predominant symptoms

Course

Requires antibiotic therapy (eg, erythromycin)

Self-limiting

Mortality

1520%; higher if diagnosis is delayed

< 1%

or higher patient mortality rate (see Tables 20-6 and 20-8).

Legionnaires disease in healthy immunocompetent persons
appears infrequently because of efficient innate and specific
host defenses. Most patients diagnosed with legionnaires disease 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 identified
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 treatment of legionnaires disease. Timely appropriate chemotherapy 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 communityacquired pneumonia who are suspected of having L. pneumophila legionnaires disease.56,57 Antibiotic therapy is not
indicated for patients diagnosed with Pontiac fever because of
the self-limiting nature of the infection.

PROTOZOAL INFECTION:
CRYPTOSPORIDIUM
Although first isolated and identified in 1907,58 the protozoan
genus Cryptosporidium was 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 persons 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 classification to be accomplished via disparate criteria, including phylogeny, epidemiology, and clinical manifestations. Protozoa
such as Plasmodium, Entamoeba, and Trypanosoma have long
been recognized as leading causes of human disease and mortality 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 infection with subsequent progression to AIDS, has also been
related to significant increases in other protozoan infections,
such as those caused by Cryptosporidium species.6065

TABLE 20-7 Characteristics of Pontiac Fever

Acute self-limiting influenza-like illness

TABLE 20-8 Characteristics of Legionnaires Disease

24- to 48-hour incubation period

Early influenza-like symptomsinitial cough

Malaise, myalgia, fever, chills, headache

2- to 10-day incubation period

> 90% of those exposed develop symptoms

Chest pain may be prominent

Only symptomatic treatment necessary

Pneumonia is dominant finding

Complete recovery within 1 wk

Spectrum from mild cough to stupor with multisystem failure

Most cases undiagnosed

Treatment: erythromycin and other macrolides

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Infectious Diseases

The type-species of this genus is C. parvum, which measures 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 municipal 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 waterborne organisms in that they are highly resistant to the chlorine treatments used in municipal water facilities. In addition,
they are difficult to filter 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 evidence of contamination. Unfortunately, accumulated data
suggest that Cryptosporidium is found in numerous municipal 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 outbreaks have been demonstrated over the past 20 years. With
the development of better detection techniques, some important epidemiologic features have become apparent (Table 209). 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 accumulate, so have the number of cryptosporidiosis cases with
life-threatening acute diarrhea, mostly seen in immunocompromised 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 persons with AIDS to be among the most susceptible immunocompromised 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 filtration 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 immunocompromised patients. 68 Other instances of waterborne

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.

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 centers, hospitals, and households is probably much more common 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. parvum to infect and colonize a variety of
mammals has also led to investigation of suggested animal-toperson 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 confirmed an outbreak in children in
1994 traced to fresh-pressed apple cider unknowingly contaminated with animal feces, contaminated hands were also thought
to have substantially contributed to oocyst cross-infection.76

Clinical Syndrome
The complex C. parvum life cycle occurs within a single host.77
Symptoms of cryptosporidiosis may develop within 2 to 10
days after a person has swallowed environmentally contaminated 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 protracted and severe in immunocompromised hosts, however, as
extensive dehydration and weight loss may occur over a prolonged period of longer than 2 weeks. In some cases, multiple
intravenous infusions of fluids are required to replace body
fluids lost owing to diarrhea. Even after symptoms of cryptosporidiosis diminish or disappear, the patient can still transmit infectious parasites to others for months via contaminated
stools (fecal-oral transmission). Infected individuals with debilitated 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 experimental 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 filtration techniques, and other efficient procedures are under investigation.

534

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 documented occupational risks for HBV over a three-decade
period, significant voids from other potentially serious hepatitis challenges continue to require definition. Although the routine 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 hepatitis that could not be attributed to any known microorganism.79,80 Since diagnosis of this type of hepatitis was based on
abnormal liver function in the absence of positive blood markers 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 identified prior to recognition and characterization of its
viral etiology. These included blood transfusion, parenteral
drug use, health care worker exposure in clinical settings, sexual transmission from a person with a history of hepatitis, and
low socioeconomic status. Significant 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 (antiHCV) 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 classified 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 ability 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
genome8385 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 approximate both worldwide infection prevalence and HCV incidence

Principles of Medicine

in various geographic areas, in an attempt to better define infection 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 persistent chronic hepatitis C infection, and thus are classified 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 persons (5 to 10%) of 3,000,000 who received transfusions developed 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 contact 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 population.91,92 A summary of these and other epidemiologic estimates is presented in Table 20-12. In recent years, other serologic 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 prevalence rate, which is over four times that of the general population. 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 efficient,
modes of viral exposure. In summary, transmission data still
strongly implicate parenteral exposure as the primary mechanism for HCV transmission.
SEROLOGY

In May 1990, the US Food and Drug Administration (FDA)

licensed two anti-HCV screening tests.96 Almost immediately, blood donation centers began testing for HCV infection

Picornaviridae; non-enveloped
single-stranded RNA

1540 d

Usually acute

Not present

Fecal-oral; poor sanitation

No

None reported

0.10.2

Anti-HAV

Family characteristics

Incubation period

Onset

Prodome: arthritis/rash

Transmission

Carrier state

Possible manifestations

Mortality rate (%)

Homologous immunity

Anti-HBsAg

12; higher in adults > 40 yr

Hepatocellular carcinoma;
cirrhosis

Yes (510%)

Parenteral; sexual contact;

perinatal; other secretions
(eg, saliva)

Sometimes

Usually insidious

50180 d

Hepadnaviridae; doublestranded DNA

Hepatitis B Virus (HBV)

Not defined

12

Hepatocellulalr carcinoma;
cirrhosis

Yes (> 85%)

Usually parenteral; sexual

contact less common;
perinatal

Sometimes

Usually insidious

15 mo

Flaviviridae; enveloped
single-stranded RNA

Hepatitis C Virus (HCV)

Anti-HBsAg

220

Hepatocellular carcinoma;
cirrhosis

Yes

Usually parenteral; sexual

contact less common

Unknown

Usually acute

2190 d

Satellite; non-enveloped
single-stranded RNA

Hepatitis D Virus (HDV)

Anti-HEV

12 in gen population;
20 in pregnant women

None reported

No

Fecal-oral; waterborne
(common in developing
countries)

Not present

Usually acute

29 wk

Caliciviridae; RNA

Hepatitis E Virus (HEV)

Adapted from Krugman S. Viral hepatitis: A, B, C, D, and Einfection. Pediatr Rev 1992;13:203; Molinari JA. Hepatitis C virus infection. Hepatitis C virus infection. Dent Clin North Am 1996;40:30925.
DNA = deoxyribonucleic acid; HBsAg = hepatitis B surface antigen; NA = not applicable; RNA = ribonucleic acid.

Hepatitis A Virus (HAV)

Feature

TABLE 20-10 Comparison of Major Microbiologic and Clinical Features of Hepatitis Viruses

Anti-HGV

NA

None reported

Yes

Parenteral; perinatal frequent

co-infection with HCV

NA

Acute disease spectrum

unknown

NA

Flaviviridae; RNA

Hepatitis G Virus (HGV)

Infectious Diseases
535

536

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.

Principles of Medicine

administered to patients. In addition, false-positive test

results are possible for those donors with certain
immunopathologic conditions, such as hypergammaglobulinemia, liver disease, or autoimmune connective-tissue disorders.98 More recently, blood tests have used other recombinant 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.

Most cases are mild to asymptomatic.

PATHOGENESIS

Many cases still have no risk factors.

Presentation of viral hepatitis in patients ranges from asymptomatic 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 manifestations of acute viral hepatitis, symptomatologies may vary
in intensity; yet they can be strikingly similar in their spectrum, 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

HCV = hepatitis C virus; HIV = human immunodeficiency virus; IV = intravenous.

as a component of their routine donor screening. In a noteworthy 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 undetected through screening, and their blood subsequently

TABLE 20-12 Estimated Average Prevalence of Hepatitis C Virus Infection in the United States*
Infection
Prevalence of
Persons with

Prevalence
Characteristic

Persons with hemophilia treated with products made before 1987

Range %

Characteristic (%)

87

7490

< 0.01

79

7286

0.5

Injection-drug users
Current

No data

Persons with abnormal alanine aminotransferase levels

History of prior use

15

1018

Chronic hemodialysis patients

10

064

50

616

1049

34

22

29

12

52

110

17

5
0.1

Persons with multiple sex partners (lifetime)

Persons reporting a history of sexually transmitted diseases

Persons receiving blood transfusions before 1990

59

Infants born to infected mothers

025

0.1

Men who have sex with men

General population

1.8

218

1.52.3

NA

Health care workers

12

Pregnant women

1.5

Military personnel

0.3

0.20.4

0.5

Volunteer blood donors

0.16

NA = not applicable.
*By various characteristics and estimated prevalence of persons with these characteristics in the population.

537

Infectious Diseases

TABLE 20-13 Tests for Hepatitis C Virus Infection

Test/Type

Applications

Comments

Hepatitis C virus antibody (anti-HCV)

EIA (enzyme immunoassay);
supplemental assay (ie, recombinant
immunoblot assay [RIBA])

Indicates past or present infection but does

not differentiate between acute, chronic,
or resolved infection
All positive EIA results should be verified
with supplemental assay

Sensitivity 97%
EIA alone has low positive-predictive value in lowprevalence populations

HCV RNA (hepatitis C virus ribonucleic acid)

Qualitative tests *: reverse transcriptase
polymerase chain reaction (RT-PCR)
amplification of HCV RNA by in-house
or commercial assays (eg, Amplicor HCV)

Detect presence of circulating HCV RNA

Monitor patients on antiviral therapy

Detect virus as early as 12 wk after exposure

Detection of HCV RNA during course of infection might
be intermittent; single negative RT-PCR is not conclusive
False-positive and false-negative results might occur

Quantitative tests *: RT-PCR amplification

of HCV RNA by in-house or commercial
assays (eg, Amplicor HCV Monitor)
Branched-chain DNA (bDNA) assays
(eg, Quantiplex HCV RNA Assay)

Determine concentration of HCV RNA

Might be useful for assessing the likelihood of
response to antiviral therapy

Less sensitive than qualitative RT-PCR

Should not be used to exclude the diagnosis of HCV
infection or to determine treatment end point

Genotype *: several methodologies available

(eg, hybridization, sequencing)

Group isolates of HCV on the basis ofgenetic

differences into 6 genotypes and > 90 subtypes
With new therapies, length of treatment
might vary based on genotype

Genotype 1 (subtypes 1a and 1b) most common in United

States and associated with lower response to
antiviral therapy

No clinical utility

Cannot distinguish between subtypes

Dual infections often observed

Serotype*: EIA based on immunoreactivity

to synthetic peptides (eg, Murex HCV
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 [-20C or -70C]; frozen samples should be shipped on dry ice).

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 clinically, 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 hepatitis 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 hepatitis C can present with few initial clinical manifestations of
liver disease and remain so as inactive viral carriers, or persistent viral infection can predispose a person later to
increased risk for hepatic failure and hepatocellular carcinoma. 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 transfusion or intravenous drug use. High-risk sexual activity
may also be a factor.
At the present time, the demonstration and characterization 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 infection with natural active immunity from one who has developed 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 etiology spurred intense occupational-risk investigations by clinical 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 published even before cloning of the virus was accomplished.
Multiple investigations documented HCV transmission to
health care workers and to other patients following percutaneous accidents involving blood (Table 20-14).102106

538

Principles of Medicine

TABLE 20-14 Modes of Transmission of Hepatitis C Virus in

Health Care Settings
Accidental needlesticks
Blood splashes into eyes
Blood transfusion (incidence declining rapidly)
Association with contaminated immune globin
Organ/tissue transplantation
Infected cardiac surgeon to patients
Infected patient to anesthesia assistant to other patients
Patient to patient via colonoscope

Relatively few studies have looked at HCV transmission in

dental treatment facilities. Initial reports showed oral surgeons
had a significantly higher incidence of positive anti-HCV
results than did general dentists and the general population,
owing to greater potential exposures to blood.107 These and
other data have been summarized by Cleveland and colleagues.108 When taken together, accumulated findings suggest
that although hepatitis C remains a bloodborne infection of
occupational concern, the long-term application of universal
infection-control precautions targeting HBV as the most infectious bloodborne pathogen has significantly lowered the dental providers risks for contracting HCV infection.
The most hazardous type of exposure that can increase the
possibility of HCV acquisition is an on-the-job needlestick
injury. A second primary characteristic of HCV risks to health
care workers is related to the virus life cycle and the titers of
infectious particles in blood. HCV is present in concentrations ranging from only a few virions to 100,000 or more particles per milliliter of a patients blood. Although this reinforces HCVs position as being a greater occupational
infectious risk than HIV, the concentrations fall far below those
routinely seen in HBV-infected persons. Thus, the substantially
lower HCV titer in blood offers less opportunity for occupational transmission per exposure incident. Table 20-15 puts
this into perspective by summarizing potential transmission
risks to health care workers for HBV, HIV, and HCV, by comparing viral concentrations found in blood and calculated
infection rates following needlestick accidents.109

TABLE 20-15 Risks of Transmission to Health Care Workers

Concentration/mL
Pathogen

HBV

of Serum/Plasma

1,000,000100,000,000

Transmission Rate (%)*

6.030.0

HCV

101,000,000

2.76.0

HIV

101,000

0.30

Adapted from Lanphear BP.109

HBV = hepatitis B virus, HCV=hepatitis C virus; HIV = human immunodeficiency
virus.
*As a result of a needlestick accident.

Infection control precautions against bloodborne disease

have correctly focused on prevention of hepatitis B transmission in health care facilities, in large part because of the high
HBV concentrations that can be reached in the blood of
infected patients and the high potential of infection after exposure to certain contaminated body fluids. With regard to
hepatitis C, sizable volumes of HCV-contaminated blood, such
as those used for blood transfusion, can readily cause infection.
Despite apparent lower risks from sharps, however, HCV infection carries with it the increased possibility of chronic liver disease. The progression from persistent viral infection to either
hepatic cirrhosis in about one-quarter of infected persons or
to hepatocellular carcinoma in others presents real challenges
to infection control for care providers.
HCV THERAPY AND PREVENTIVE APPROACHES

Preliminary studies began appearing in the literature in the mid1980s that suggested that a prolonged course of therapy with
interferon- could have beneficial effects for persons with
chronic hepatitis C.110,111 These beneficial effects occurred
rapidly during therapy, with alanine aminotransferase (ALT) levels eventually falling to within the normal range. Follow-up testing after completion of the regimen unfortunately found the
ALT decline to be transient in most of the patients. Later investigations involving larger numbers of HCV-infected persons led
to FDA approval of a recombinant form of this antiviral agent for
treatment of chronic hepatitis C in 1991.112 Additional studies
have attempted to further refine therapeutic dosages and drug
regimen intervals.113
Combination of chemotherapeutic agents has shown
promising results in recent years. Currently, a daily regimen of
interferon -2b plus ribavirin for 6 to 12 months has demonstrated a significant improvement in patient biochemical and
virologic responses when compared with interferon monotherapy. Approximately 50% of treated patients have a sustained
beneficial response, compared with response rates of 15 to 25%
using interferon alone.114 Future therapies will probably
include additional multidrug approaches, such as other forms
of interferon and specific HCV enzyme inhibitors.115
An effective vaccine for hepatitis C is not yet commercially
available. Multiple factors have hindered research efforts
directed at prophylactic strategies. Two principal factors are the
failure to define a protective host immune response against
HCV infection, and the antigenic heterogeneity described for
different viral strains. Until scientists ascertain how host resistance develops during recovery from hepatitis C, and against
what antigen(s) the immunity is directed, vaccine studies will
continue to be limited. At present, routine use of universal
precautions during patient care and anti-HCV screening of
potential blood donors appears to be successful in reducing
health care provider, patient, and public exposures.

HIV Infection
Since the early 1980s, HIV has been recognized as one of the
most devastating infectious diseases of the twentieth century. By the end of the century, almost 60 million people

Infectious Diseases

worldwide had been infected with the virus, and the rate of
infection continued unabated. 116 The vast majority of
exposed and at-risk individuals had no access to effective
medications to combat the virus or its associated opportunistic infections. Even in the early stage of the twenty-first
century, there are few indications that there soon will be any
effective and affordable vaccines or anti-HIV medications
available for most people afflicted by this disease. This chapter explores many different aspects of HIV disease and
emphasizes oral health considerations, which impact on the
overall health of HIV-infected individuals.
EPIDEMIOLOGY

In June and July of 1981, the Centers for Disease Control published two reports on several clusters of young homosexual
men who developed opportunistic infections that were chiefly
detected in severely immunodeficient individuals.117,118 It was
not clear what caused this apparent immunodeficiency, and
the disease was initially referred to as gay-related immune
deficiency, or GRID. Several theories focusing on the lifestyle
of homosexual and bisexual men were put forth to explain the
cause of this illness. However, soon after, it became clear that
there were other groups in society who also developed this
rapidly evolving disease and that the cause was most probably
an infectious pathogen and not sexual preference.119125
It became evident that finding a causative agent, developing an accurate test to detect this pathogen, and elucidating the
modes of transmission were imperative to slow down the
quickly expanding epidemic. The etiologic agent of this disease,
now termed human immunodeficiency virus, was recognized
within 2 years of the first reported cases.126,127 Due to the severe
immunosuppression observed in affected individuals, this disease was eventually given the name acquired immunodeficiency syndrome. The CDC quickly put a surveillance system
in place. This surveillance system was based on standard case
definitions. Due to the changing nature of this disease, the original case definition from 1985 was expanded in 1987 and again
in 1993 to better incorporate specific illnesses in different populations as well as reflect changes in infected individuals
immune status128 (Table 20-16). AIDS, the stage of HIV disease
when individuals start to develop opportunistic infections or
have severe immunosuppression, is a reportable condition in all
50 states, the District of Columbia, and the US territories. At the
time of this writing, HIV infection is not a reportable condition
in all states. The number of total accumulated cases of AIDS
and the rate of AIDS in the United States are reported by the
CDC on a biannual basis129 (Table 20-17). Although the number of total accumulated cases of AIDS changes over time, the
ranking of states and metropolitan areas remains fairly stable.
More important than the actual number of cases and rates is the
trend of change. The directions of these trends reflect the course
of the HIV epidemic. Between June 1999 and June 2000, there
were an additional 42,563 persons who developed AIDS in the
United States. However, this represented a decrease of 7.6% of
new cases from 1998 to 1999. Also, the rate of AIDS per 100,000
population decreased by 8.2%. A decrease of 8.6% in new cases

539

among males and a decrease of 3.4% in new cases among

females were noted for the same period. Thus, even though
new cases were reported, there was a marked decrease in the rate
of new AIDS cases. Taking into consideration that there are
between 40,000 to 50,000 new HIV infections annually in the
United States, the decreasing number of AIDS cases suggests
that infected individuals are remaining healthier and that the
disease is progressing more slowly over time. Since the introduction of more potent anti-HIV medications in the middle
1990s, an initial dramatic decrease in the rate of death of persons with AIDS has been observed (Table 20-18).129 However,
this trend has tapered off due to factors such as increased resistance to medications and patients reaching the limits of extending survival with these medications. By the end of the 1990s, it
was estimated that there were 650,000 to 900,000 HIV-infected
persons in the United States; approximately 500,000 of these
persons were aware of their HIV infection, and an estimated
335,000 of these received medical care.130
There are two different types of HIV: HIV-1 and HIV-2.
Both viruses cause immune deterioration and AIDS, but
HIV-2 has been associated with a more indolent course and
a less efficient transmission. The median time from infection
to AIDS has been reported to be approximately 10 years for
those infected with HIV-1 but almost 20 years for those with
HIV-2. The vast majority of HIV infections are caused by
HIV-1, except in particular geographic areas, such as the
western parts of Africa. Unless specified, HIV in this chapter refers to HIV-1.
Mainly through phylogenic analyses, it has been possible
to extrapolate that HIV-1, HIV-2, and the simian immunodeficiency virus (SIV) may have originated from the same
source in Africa and started to separate into different viruses
in the beginning of 1900s. It is not clear when HIV was introduced into the human host, but it likely happened in the 1920s
or 1930s, with a more rapid sustained spread around the mid1940s. The prevailing theory suggests that the human variant
of this immunodeficiency virus originated from different
types of primates. It is assumed that SIV from chimpanzees
(SIVCPZ) is the source of HIV-1, whereas HIV-2 originated
from monkeys, predominantly sooty mangabeys
(SIVSM).131,132 The earliest reported cases of AIDS in Europe
were observed in the 1950s; approximately 10 years later, AIDS
was reported in the United States. HIV is transmitted sexually
through contaminated blood and products, and vertically
from mother to child. It is important to realize that since the
recognition of HIV disease, the modes of transmission have
not changed and are not likely to change in the future.
Although extraordinary cases of HIV transmission by other
means have been reported, they are extremely rare or are
based on faulty documentation. There has never been any
documented case of occupational transmission of HIV from
patients to dental health care workers. In one celebrated case
from 1990, an HIV-infected dentist was implicated in transmitting the virus to several of his patients. Although this case
was thoroughly investigated by CDC and other agencies, how
the transmission occurred was never fully elucidated.133

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Principles of Medicine

TABLE 20-16 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS among
Adolescents and Adults
CD4+ T-Lymphocyte Categories

The lowest accurate CD4+ T-lymphocyte count should be used for classification purposes, even though more recent and possibly different counts may be available.
Clinical Categories

Clinical category A
Conditions:
Asymptomatic human immunodeficiency virus (HIV) infection
Persistent generalized lymphadenopathy (PGL)
Acute HIV infection with accompanying illness or history of acute HIV infection
Conditions listed in category B and category C must not have occurred.
Clinical category B
Symptomatic conditions in HIV-infected adolescents or adults that are not included in clinical category C and meet at least one of the following criteria: (a) the conditions
are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; (b) the conditions are considered by physicians to have a clinical course or to
require management that is complicated by HIV infection.
Examples of, but not limited to, the following conditions:
Bacillary angiomatosis
Candidiasis, oropharyngeal (thrush)
Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Constitutional symptoms, such as fever (38.5C) or diarrhea lasting > 1 mo
Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome
Idiopathic thrombocytopenia purpura
Listeriosis
Oral hairy leukoplakia
Pelvic inflammatory disease, particular if complicated by tubo-ovarian abscess
Peripheral neuropathy
Clinical category C
Conditions:
Candidiasis of bronchi, trachea, or lung
Candidiasis, esophageal
Cervical cancer, invasive
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (> 1 mo duration)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy, HIV related
Herpes simplex: chronic ulcer(s) (> 1 mo duration); or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal ( > 1 mo duration)
Kaposis sarcoma
Lymphoma, Burkitts (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium-intracellulare complex or Mycobacterium kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis carinii pneumonia
Pneumonia, recurrent
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis
Wasting syndrome due to HIV infection
Clinical Categories

CD4+ T Cells/mm3 or
CD4+ Percentage

A: Asymptomatic Acute HIV or PGL

B: Symptomatic, no A or C Conditions

C: AIDS-Indicator Conditions

500 or 29%
200499 or 1428%
< 200 or < 14%

A1
A2
A3*

B1
B2
B3*

C1*
C2*
C3*

Adapted from Centers for Disease Control and Prevention.128

* Expanded acquired immunodeficiency syndrome (AIDS) surveillance case definition.

541

Infectious Diseases

TABLE 20-17 Ranking of AIDS Cases and Rates per 100,000

Population*
Area of Residence

New York
California
Florida
Texas
New Jersey
Illinois
Puerto Rico
Pennsylvania
Georgia
Maryland

Total Cases

139,248
117,521
78,043
52,667
41,245
24,425
24,061
23,678
22,197
20,833

Area of Residence

Rates

District of Columbia
New York
Virgin Islands, US
Florida
Maryland
Puerto Rico
Delaware
Massachusetts
New Jersey
South Carolina

189.4
39.4
37.6
33.4
27.2
26.4
26.3
24.4
23.6
20.9

Metropolitan Area of Residence

New York, NY
Los Angeles, CA
San Francisco, CA
Miami, FL
Washington, DC
Chicago, IL
Houston, TX
Philadelphia, PA
Newark, NJ
Atlanta, GA
Metropolitan Area of Residence

New York, NY
Miami, FL
Fort Lauderdale, FL
San Francisco, CA
West Palm Beach, FL
Jersey City, NJ
Newark, NJ
Columbia, SC
Baltimore, MD
Washington, DC

Total Cases

117,792
42,394
27,567
23,521
22,321
21,173
18,735
18,348
16,739
15,524
Rates

68.1
58.3
56.9
52.6
50.5
43.2
40.3
39.7
35.9
35.8

Adapted from Centers for Disease Control and Prevention.129

*In the United States reported through June 2000.

PATHOGENESIS

Early in the HIV epidemic, it was recognized that this disease

was caused by a virus that gradually destroyed a hosts immune
defenses, making virtually all infected individuals susceptible
to opportunistic infections. The particular immunodeficiency
in HIV disease was attributed to CD4+ lymphocyte depletion,
enabling the development of specific opportunistic infections
that were associated with a high degree of morbidity and mor-

tality. More than 20 years after the recognition of this disease

and its causative agents, it has been possible, with the help of
improved and new molecular biologic tools and methods, to
explain in more detail the pathogenesis of HIV disease.
HIV is a retrovirus harboring its genetic information in
two copies of a single-stranded RNA. The viral genome is contained within a protein core, which also contains the enzyme
reverse transcriptase. Surrounding the core particle is a lipid
membrane. Embedded within this membrane are two envelope glycoproteins, gp 41 and gp 120, both essential for the
recognition and binding of target cells. These two glycoproteins are subunits generated by the cleavage of the gp 160 precursor. HIV targets cells expressing CD4 molecules, particularly CD4+ T lymphocytes, monocytes, and macrophages,
taking advantage of the affinity between the viral gp 120 and
the cellular CD4 receptor. The binding of gp 120 to CD4 receptors causes a conformational change in gp 120, which exposes
and stabilizes a cellular chemokine receptor called CCR5.
These interactions activate gp 41, resulting in fusion of the
viral membrane with the cellular membrane, which allows the
viral RNA and reverse transcriptase to enter into the target cell.
The reverse transcriptase transcribes the viral RNA into DNA,
which integrates into the target cells genome. With the successful integration of viral DNA into the cellular genetic material, an infection has occurred.
HIV gains entry into the body directly through the blood
or at mucosal surfaces. The virus establishes itself within lymphoid tissues, where it replicates, makes itself available to the
cells of the immune system (such as T lymphocytes, monocytes, and macrophages), and slowly brings about destruction
of the lymphoid tissue. Mucosal surfaces have an abundance
of dendritic cells, such as Langerhans cells, that trap the virus
and enable the uptake of the virus into lymphoid aggregates
below the surface. Contact between mucosal surfaces and HIV
can result in infection of Langerhans cells after only a couple
of hours. Within a few days, the virus can be detected in
regional lymph nodes.
The rapid replication of HIV results in an initial viremia
causing seeding of the virus to lymphoid tissue throughout
the body. It is estimated that more than 10 billion virions, with
a half-life of approximately 1.6 days, are produced daily in
infected individuals.134,135 This continuous turnover of
viruses results in one-half of the circulating viruses being
replaced with newly formed virions every day. Furthermore,
almost 2 billion CD4+ lymphocytes are destroyed and
replaced every day.
Activated CD4+ lymphocytes express high levels of
chemokine receptors and are primary targets of HIV. However,
although these activated cells usually die within a few days, a
latent reservoir of HIV is established among CD4+ cells. An
extremely high viral titer can be detected in the blood during
the primary stage of HIV infection, but, over time, infectious
virions became undetectable in the plasma. The initial control
of viral replication is associated with antibody-dependent cellular cytotoxicity activity and HIV-specific cytotoxic T lymphocytes. However, neutralizing antibodies also develop.

542

Principles of Medicine

TABLE 20-18 Estimated Deaths and Rate of Change of Death of Persons with AIDS, in the United States
Measure

1993

1994

1995

1996

1997

1998

1999

Estimated number of deaths

45,381

49,869

50,610

37,787

21,923

17,930

16,273

+9.9

+1.5

25.3

42.0

18.2

9.2

Change (%)

Unfortunately, HIV replication is associated with a very high

mutation rate, resulting in a great genetic diversity of HIV quasispecies in individual patients.136 This heterogeneity increases
over time. Consequently, it is important to initiate viral suppression as early as possible after infection. This will accomplish
a decrease in viral diversity, resulting in more effective immune
control and less drug resistance. Even a single nucleotide change
in the HIV-1 transcriptase gene is enough to confer high levels
of drug resistance to particular anti-HIV medications.137
The hallmark of HIV disease is the progressive loss of
CD4+ lymphocytes. Without intervention, an average of 60 to
80 cells/mm3 are lost every year; this loss is highly variable and
occurs in periods of more stability and rapid decline.138 An
estimation of the plasma level of these cells (a CD4 cell count)
indicates an individuals immune status. Normal CD4 cell
counts are usually above 500 to 600 cells/mm3, whereas levels
below 200 cells/mm3 are considered to indicate severe immune
suppression. The lower the CD4 cell count, the more susceptible is a patient to develop opportunistic infections. As part of
the latest AIDS definition, a patient has an AIDS diagnosis
when the CD4 cell count drops below 200 cells/mm3 (see Table
20-16). At this level the patient is at very high risk of developing specific major opportunistic infections, such as
Pneumocystis carinii pneumonia (PCP), and prophylactic
medications are administered to ward off these infections.
Although the CD4 cell count was used for many years as a
marker for HIV disease progression, other biologic indicators,
such as the level of plasma viral RNA, or viral load, have since
proven to be more reliable and accurate.139 Today, CD4 cell
counts are mainly used to assess a patients immune status, to
determine when to institute antiretroviral medications, to
determine when to institute prophylaxis against opportunistic infections, and as an indicator for AIDS. Recent advances
in molecular biology have enabled detection of HIV RNA in
plasma and within different tissues.140 The most common
method used for clinical HIV care is reverse transcription coupled to the polymerase chain reaction (RT-PCR). This method
uses a PCR-based assay to assess the presence, as well as measure the quantity, of HIV RNA. Numerous retrospective studies have determined the progression of HIV disease, as well as
the prognosis, based on the quantity of plasma HIV-1 RNA139
(Table 20-19). Many of these studies show surprising consistency.141144 According to these studies, the risk for disease
progression and death is reduced by 30% when the viral load
is halved, by 55% with a four-fold reduction in viral load, and
by 65% with a 10-fold reduction in viral load.
As viral load significantly corresponds with changes in disease progression, this measure has also been used to assess

efficacy of antiretroviral medications.145 Effective drug therapy

is reflected in reduced viral loads; no or little viral load change
suggests less effective therapy. This association has created new
standards of care for patients with HIV. Acute HIV infection
occurs 2 to 6 weeks after exposure. During the acute stage of
the disease, affected individuals develop high plasma levels of
the virus. An antibody response can only be detected approximately 2 to 3 months after exposure. Twenty to 90% of
exposed individuals develop a self-limited nonspecific illness
characterized by fever, lymphadenopathy, myalgia, arthralgia,
sore throat, and occasional rashes and oral ulcerations. This illness has sometimes been described as a mononucleosis-like
syndrome and is referred to as the acute seroconversion syndrome or acute retroviral syndrome. Identification of individuals at this stage of the disease is important for several reasons. Of primary importance is the potential for further
transmission. As affected individuals have very high viral loads,
they are highly infectious and can unwittingly transmit the
virus to unsuspected partners.146 There is epidemiologic evidence that suggests that recently infected individuals are
responsible for a high percentage of transmissions.147
Evaluation of individuals during the acute retroviral syndrome
needs to include both a virologic test and an antibody test. A
positive HIV RNA test, together with a negative HIV-antibody
test, is diagnostic for primary HIV infection. Due to the possible false-positive result from an HIV RNA PCR-based assay,
a true positive result is considered when the viral load is above
100,000 copies/mL. Results below 5,000 copies/mL are more
likely to be false-positive than true positive.148
Another benefit of early recognition of HIV infection is the
potential to achieve viral suppression during this stage of the
disease. This may facilitate a more effective immune response
and diminish viral diversity. Institution of antiretroviral therapy during this stage of the disease has been shown to enhance
the immune systems ability to destroy infected cells and to
diminish CD4 cell depletion.149151
After the acute retroviral syndrome, most individuals
remain asymptomatic for many years. However, the deteriorating immune system eventually gives way, and opportunistic infections develop. Without treatment, the median time
from primary infection to AIDS is approximately 10 years.152
In most industrialized countries, individuals with HIV
have access to antiretroviral therapy. Consequently, the epidemiology of HIV disease has changed dramatically since the
mid-1990s. At that point, new and more potent antitretroviral medications were introduced that decreased the incidence
of opportunistic infections and death rate153 (see Tables 2018 and 20-20). Unfortunately, the rate of decline in the inci-

543

Infectious Diseases

TABLE 20-19 Prediction of Immune Deterioration, HIV Disease Progression, and AIDS by HIV-1 RNA
HIV-1 RNA Copies/mL

< 500
5013,000
3,00110,000
10,00130,000
> 30,000

Decrease in Yearly

Individuals Developing AIDS

Individuals Dying

CD4+ Cell Count/mm3

Within 6 Years (%)

Within 6 Years (%)

5.4
16.6
31.7
55.2
80.0

0.9
6.3
18.1
34.9
69.5

36.3
44.8
55.2
64.8
76.5

Adapted from Coffin JM.136

AIDS = acquired immunodeficiency syndrome; HIV-1 = human immunodeficiency virus type 1; RNA = ribonucleic acid.

dence of opportunistic infections, AIDS incidence, and AIDSrelated deaths has slowed down. These latest trends are most
probably related to the development of resistance to antiretroviral drugs, transmission of HIV-resistant strains, and
the inability to maintain complete viral suppression for
extended periods of time in all individuals. Furthermore, several new opportunistic syndromes have been described in
patients given antiretroviral medications.154 It is possible that
this phenomenon, termed reversal syndromes, is due to a
rebounding immune system that initially does not have the
same antigenic divergence as developing nave CD4+ lymphocytes. This immune dysfunction may facilitate the development of latent opportunistic infections or unmask an undiagnosed opportunistic infection.
Apparently, not all individuals exposed to HIV become
infected. Furthermore, the rate of HIV disease progression in
individuals is highly variable. Some infected persons may
progress from infection to AIDS within months, whereas others have no signs of opportunistic infections or immune suppression even after 15 to 20 years. Approximately 10% of HIVinfected persons progress to AIDS within the 2 to 3 years after
infection, whereas 10 to 17% of infected individuals may not
develop AIDS even 20 years after infection.155 Obviously, these
subgroups of infected persons are of great interest, as they
may provide invaluable information regarding the variables
associated with infection, progression, and even immunity to
HIV, and subsequent treatment.
Numerous studies have focused on the ability and inability
of HIV to enter into target cells, and the capability of the
immune system to rid the body of the virus. During the earliest stages of HIV infection, the virus particularly seeks out and

TABLE 20-20 Decrease in Rate of Opportunistic Infections in

HIV-Positive Individuals
Rate of Decrease
Disease

Pneumocystis carinii pneumonia

Mycobacterium avium-intracellulare complex
Esophageal candidiasis
Adapted from Kaplan JE et al.153

19921995

3.4
4.7
0.2

19961998

21.5
39.9
16.7

infects macrophages and memory T lymphocytes, using, in

addition to these cells CD4 receptors, the cells chemokine
receptors. The chemokine receptor used in these cells as a coreceptor for HIV is CCR5. At this stage of the disease it is common that the virus is referred to as macrophage-tropic, or Mtropic. M-tropic viruses do not have the ability to form
syncytia in vitro; they are therefore also referred to as nonsyncytia-inducing isolates. In addition, due to the viruss predilection for cells expressing CCR5, the virus is referred to as an R5
isolate. Investigations of chemokine receptors have indicated
that individuals with a homozygous mutation of CCR5 may be
almost completely resistant to HIV. This specific mutation has
been referred to as CCR5 32, indicating a characteristic 32
base-pair deletion in the gene encoding CCR5. Individuals with
a heterozygous mutation of CCR5 32, one normal and one
altered allele, tend to progress more slowly to AIDS and live
longer than individuals without this mutation.156,157
Furthermore, a promoter mutation in CCR5 has also been
associated with a slower progression to AIDS.158 Interestingly,
persons harboring these chemokine receptor changes do not
exhibit any pathologic effects due to these polymorphisms.
Unfortunately, very few individuals, approximately 1% of
Caucasians, exhibit homozygous deletion of the 32 base pair;
10% are heterozygotes. CCR5 32 is rare among Africans,
Native Americans, and East Asians.
All chemokine receptors have natural ligands, cytokines
that bind to the receptor. Three main cytokines have been
identified that bind to and block the CCR5 receptor: MIP-1, MIP-1- and RANTES. Interestingly, these cytokines are
generated by CD8+ T lymphocytes, which are cells that have
been implicated in releasing factors suppressing HIV infection.159 Selective blockage of CCR5 with these cytokines has
been shown to occur.
During the later stages of HIV disease, the virus predominantly infects T lymphocytes expressing CD4 receptors and a
chemokine co-receptor designated CXCR4. These T-tropic
viruses can cause multinucleated syncytia formation in vitro
and are therefore referred to as syncytia-inducing isolates
and X4 isolates. The use of the CXCR4 receptor by HIV is
associated with a more rapid depletion of CD4+ T lymphocytes and disease progression.160 Chemokines SDF-1- and
SDF-1- have been identified as ligands to CXCR4 and can
selectively inhibit T-tropic HIV-1 strains.

544

Use of these chemokine receptors is not exclusive, and

about 40% of HIV-positive individuals use CXCR4 instead of,
and sometimes in addition to, CCR5.161 These viral isolates
are referred to as R5X4. Unfortunately, several other
chemokine receptors are involved in HIVs selection of target
cells, increasing the complexity of all HIVtarget cell interactions (Table 20-21).161163
MEDICAL TREATMENT

A better understanding of the pathogenesis of HIV disease has,

in recent years, changed many of the treatment paradigms for
infected individuals during the course of their illness. The
recognition that there exist different individual responses to
HIV infection, and even resistance, has provided clues to intervention strategies based on more accurate predictions of disease
progression. Furthermore, better knowledge of the mechanisms
for viral entry into target cells, integration, transcription, and
subsequent viral replication has enabled a more varied and
focused treatment strategy. Although the mainstay of HIV therapy is based on trying to slow down viral replication with antiretroviral medications, an important part of treatment for
patients with HIV disease is also the prevention and treatment
of opportunistic infections. HIV-infected individuals therefore
take many different medications, some which impact on oral
health and provision of dental care (Table 20-22).
The first antiretroviral drug was introduced in 1997. This
medication, AZT or zidovudine (ZDV), belongs to a group of
medications called nucleoside reverse transcriptase inhibitors
(NRTIs). These medications competitively inhibit the reverse
transcriptase from converting the viral RNA into viral DNA.
Other nucleoside analogues are abacavir (ABC), didanosine
(ddI), lamivudine (3TC), stavudine (d4T), and zalcitabine
(ddC). A similar group of medications that also inhibits reverse
transcriptase is the non-nucleoside reverse transcriptase
inhibitors (NNRTIs). NNRTIs include efavirenz (EFV),
delaviridine (DLV), and nevirapine (NVP). In the mid-1990s,
a new class of antiretroviral medications was introduced
protease inhibitors. These powerful medications prevent the
breakdown of viral proteins into appropriate building blocks

TABLE 20-21 Characteristics of Individuals with Slow Disease

Progression
Attenuated virus
Reduced replication kinetics
Low viral load
Effective cellular immune response
Strong HIV-1specific cytotoxic T lymphocytes
Effective antibody-dependent cellular cytotoxicity
Increased levels of CD8+ T lymphocytes
Increased divergence of the CD4+ T-lymphocyte repertoire, possibly due to
exposure to greater viral diversity
Polymorphisms and inhibition/blockage of chemokine receptors
Homozygote CCR5- 32 genotype
Heterozygote CCR5- 32 genotype
Inhibition/blockage by MIP-1-, MIP-1-, RANTES generated by CD8+ T cells
Data from Berger EA et al;161 Learmont J et al;162 Klein MR et al.163

Principles of Medicine

for viral replication. Included in these medications are amprenavir (APV), indinavir (IDV), nelfinavir (NFV), ritonavir
(RTV), and saquinavir (SQV). Due to the high level of toxicity and the rapid development of drug resistance, antiretroviral medications are given as double or triple therapy. This
combination therapy is referred to as highly active antiretroviral therapy, or HAART. Antiretroviral therapy is usually instituted when a patients CD4 cell count drops below a critical
value and/or when a patients viral load exceeds a critical level.
These predetermined values vary as better scientific information regarding the pathogenesis of HIV disease is elucidated
and depending on how patients react and respond to new and
better combinations of medications.
Prophylaxis against opportunistic infections is instituted
according to a patients immune status. Usually patients with
CD4 cell counts below 200 cells/mm3 are considered for prophylaxis to prevent Pneumocystis carinii pneumonia, and, at
even lower levels, prophylaxis is instituted against various fungal and mycobacterial infections. Knowledge about the type of
medications used to treat and prevent opportunistic infections helps the dental provider to attain additional insight into
a patients health status.
ORAL HEALTH CONSIDERATIONS

Oral health considerations for persons infected with HIV focus

on provision of dental care and oral conditions associated with
their underlying disease.164166 An appropriate work-up for an
HIV-infected patient needs to ascertain a patients overall
health, immune status, prognosis, presence and history of
opportunistic infections, risk for developing more severe
opportunistic infections and oral lesions, current medications,
and chance for long-term survival (Figure 20-7). The patient
may be able to provide all necessary information, but it is
appropriate to have the patient sign a consent form that
enables the provider to obtain more medical information from
the patients primary care physician (Figure 20-8).
As a general rule, no dental modifications are required for
patients based on their HIV status. Most individuals presenting for outpatient dental care are sufficiently healthy to tolerate all types of dental procedures, ranging from scaling to
implants.167 Also, numerous studies have indicated that
patients with HIV disease are not more susceptible to complications after dental care, regardless of CD4 cell count.168,169
As with other medically complex patients, the major concerns are impaired hemostasis, susceptibility to dentally
induced infections, drug actions and interactions, and the
patients ability to withstand the stress and trauma of dental
procedures. Few patients present with increased bleeding tendencies, unless they have concomitant liver disease or idiopathic thrombocytopenic purpura.170 Even when patients
CD4 cell counts are very low, they are not more susceptible to
dentally induced bacteremia. Thus, there are no indications for
routine use of antibiotic prophylaxis based on patients HIV
status. However, patients with neutrophil counts below 500 to
750 cells/mm3 require antibiotic prophylaxis. Furthermore,
some patients may be at an increased risk for developing sub-

545

Infectious Diseases

TABLE 20-22 Impact of Treatments for HIV Infection

Drug Name*

Type of Drug

Adverse Effects of Significance for Dentists

Co.

12

(+)-calanolide A*

NNRTI

Dysgeusia

3TC or lamivudine, Epivir; also

in Combivir and Trizivir

NRTI

Peripheral neuropathy

Abacavir (ABC), Ziagen;

also in Trizivir

NRTI

Associated with liver damage

IBT

Not known

Aldesleukin or interleukin-2
(IL-2), Proleukin

IBT

Not known

Amprenavir (APV), Agenerase

PI

Associated with hyperglycemia, dygeusia, and paraoral tingling sensations

Do not use with the following medications: midazolam, triazolam,
ergotamine, tricyclic antidepressants, vitamin E
Avoid use with the following medications: erythromycin, benzodiazepine,
or itraconazole

AZT or zidovudine, Retrovir;

also in Combivir and Trizivir

NRTI

Associated with seizures, rapid, uncontrollable eye movements, decreased

coordination, liver damage, and peripheral neuropathy

BCH-10652* or dOTC*

NRTI

None

ABC, see abacavir

AG1661* or HIV-1 Immunogen*
or Salk vaccine*, Remune*
Agenerase, see amprenavir

APV, see amprenavir

Bis(POC) PMPA*, see tenofovir

disoproxil fumarate*
BMS-232632*

PI

Not known

Capravirine* (CPV)
Coactinon*, see emivirine*

NNRTI

Dysgeusia

Combivir combination of
zidovudine + lamivudine

NRTI

Associated with liver damage and peripheral neuropathy

Coviracil*, see emtricitabine*

and FTC*
CPV*, see capravirine*
Crixivan, see indinavir
d4T or stavudine, Zerit

NRTI

Peripheral neuropathy

DAPD*

NRTI

Not known

13

ddC or zalcitabine, Hivid

NRTI

Associated with oral ulcerations, liver damage, and peripheral neuropathy

11

ddI or didanosine, Videx or Videx

EC (delayed-release capsules)

NRTI

Associated with xerostomia, liver damage, and peripheral neuropathy

Do not take the following medications within 2 hours of ddI: tetracycline,
doxycycline, minocycline, and ciprofloxacin
Take the following medications at least 2 hours before ddI: ketoconazole
and itraconazole

Delaviridine (DLV), Drescriptor

NNRTI

Do not use with orange and cranberry juice

Do not use with the following medications: clarithromycin, dapsone,
ergotamine, alprazolam, midazolam, triazolam, carbamazepine,
phenobarbital, and cimetidine

DMP-450*

PI

Not known

13

DOTC* or BCH-10652*

NRTI

Not known

NNRTI

Associated with confusion, abnormal behavior, or hallucinations

Do not use together with the following medications: midazolam and triazolam

Didanosine, see ddI

DLV, see delaviridine

Drescriptor, see delavirdine

Droxia, see hydroxyurea
Efavirenz (EFV), Sustiva

Continued

546

Principles of Medicine

TABLE 20-22 Impact of Treatments for HIV Infection (Continued)

Type of Drug

Adverse Effects of Significance for Dentists

Co.

Emivirine* (EMV), Coactinon*

NNRTI

Not known

13

Emtricitabine* or FTC*, Coviracil*

NNRTI

Not known

13

PI

11

Drug Name*

EFV, see efavirenz

EMV*, see emivirine*

Epivir, see lamivudine or 3TC
Fortovase, see saquinavir (soft gel cap)
FTC*, see emtricitabine*
GW-420867X*

NNRTI

Not known

GW-433908* or VX-175*

PI

Associated with hyperglycemia, dysgeusia, and paraoral tingling sensations

Do not use with the following medications: midazolam, triazolam, ergotamine,
tricyclic antidepressants, or vitamin E
Avoid use together with the following medications: erythromycin,
benzodiazepine, or itraconazole

HIV-1 Immunogen* or Salk

vaccine* or AG1661*Remune*

IBT

Not known

CI

Oral ulcerations; associated with bleeding and bruising

Indinavir (IDV), Crixivan

PI

Do not use with the following medications: midazolam, triazolam, or ergotamine

Avoid use with the following medications: ketoconazole and dexamethasone

Interleukin-2 (IL-2), or
aldesleukin, Proleukin

IBT

Not known

Lamivudine or 3TC, Epivir; also

in Combivir and Trizivir

NRTI

Peripheral neuropathy

Lopinavir + ritonavir, Kaletra

PI

Associated with hyperglycemia

Do not use with the following medications: midazolam or triazolam
Avoid use with metronidazole

Nelfinavir (NFV), Viracept

PI

Do not use with the following medications: midazolam, triazolam, or ergotamine

Nevirapine (NVP), Viramune

NNRTI

Associated with liver damage

PI

Not known

PI

Do not use with the following medications: ergotamine, diazepam, midazolam,

triazolam, meperidine, piroxicam, or propoxyphene
Avoid use with the following medications: phenobarbital, dexamethasone,
or metronidazole

Salk vaccine* or HIV-1 Immunogen*

or AG1661*, Remune*

IBT

Not known

Saquinavir (SQV) (HGC)

(hard gel cap), Invirase

PI

Associated with liver damage, peripheral neuropathy, and oral ulcerations

Do not use with the following medications: midazolam, triazolam, or ergotamine
Avoid use with the following medications: clarithromycin, phenobarbital,
carbamazepine, dexamethasone, ketoconazole, itraconazole, or clindamycin

Hivid, see zalcitabine or ddC

HU, see hydroxyurea
Hydroxyurea (HU), Droxia
IDV, see indinavir
10

Invirase, see saquinavir (hard gel cap)

Kaletra, see lopinavir + ritonavir

NFV, see nelfinavir

Norvir, see ritonavir
NVP, see nevirapine
PNU-140690* or tipranavir*
Proleukin, see aldesleukin or
interleukin-2
Remune,* see HIV-1 Immunogen*
or Salk vaccine* or AG1661*
Retrovir, see zidovudine
Ritonavir (RTV), Norvir; also
in Kaletra

RTV, see ritonavir

11

Continued

547

Infectious Diseases

TABLE 20-22 Impact of Treatments for HIV Infection (Continued)

Drug Name*

Type of Drug

Adverse Effects of Significance for Dentists

Co.

Saquinavir (SQV) (SGC)

(soft gel cap), Fortovase

PI

Associated with liver damage, peripheral neuropathy, and oral ulcerations

Do not use with the following medications: midazolam, triazolam, or ergotamine
Avoid use with the following medications: clarithromycin, phenobarbital, carbamazepine
dexamethasone, ketoconazole, itraconazole, or clindamycin

11

NRTI

Peripheral neuropathy

EI

Not known

14

Tenofovir disoproxil fumarate*

(TDF)

NtRTI

Not known

Tipranavir* or PNU-140690*

PI

Not known

SVX-175* or GW-433908*

PI

Associated with hyperglycemia, dygeusia, and paraoral tingling sensations

Do not use with the following medications: midazolam, triazolam, ergotamine,
tricyclic antidepressants, or vitamin E
Avoid use with the following medications: erythromycin, benzodiazepine,
or itraconazole

Zalcitabine or ddC, Hivid

NRTI

Associated with oral ulcerations, liver damage, and peripheral neuropathy

11

NRTI

Associated with seizures, rapid uncontrollable eye movements, decreased

coordination, liver damage, and peripheral neuropathy

SQV, see saquinavir

Stavudine or d4T, Zerit

Sustiva, see efavirenz

T-20*
TDF*, see tenofovir disoproxil
fumarate*

Trizivir, see abacavir + zidovudine

+lamivudine
Videx, see didanosine or ddI
Videx EC, see didanosine or ddI
Viracept, see nelfinavir
Viramune, see nevirapine

ZDV, see zidovudine

Zerit, see stavudine or d4T
Ziagen, see abacavir
Zidovudine (ZDV) or AZT,
Retrovir; also in Combivir
and Trizivir

CI = cellular inhibitor; EI = entry inhibitor (also fusion inhibitor); IBT = immune-based therapy; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside
reverse transcriptase inhibitor; NtRTI = nucleotide reverse transcriptase inhibitor; PI = protease inhibitor.
*Drug not approved by US Food and Drug Administration.
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.

acute bacterial endocarditis if they are former intravenous

drug users.171
Most side effects from medications used to treat HIV disease are associated with xerostomia. Drug interactions with
medications commonly used in a dental setting also exist (see
Table 20-22). Patients with HIV disease have been shown to
survive longer and are therefore more susceptible to develop
complications, particularly from drug side effects. A trend suggesting increased frequency of cardiovascular disease has been
noticed and should be considered in patients who have taken
protease inhibitors for long periods of time.
Treatment planning for HIV-positive patients needs to
address numerous considerations. The vast majority of
patients have some degree of xerostomia, ranging from very
mild to severe. Thus, when performing simple restorative pro-

cedures or fabricating fixed or removable prosthodontics, the

type of restorative material, long-term use, and maintenance
of a restoration need to be taken into consideration.
ORAL LESIONS

There are no oral lesions that are unique to HIV-infected individuals. All lesions found among HIV-positive patients also
occur with other diseases associated with immune suppression. It is therefore not surprising to find a clear correlation
between the appearance of oral lesions and a decreased
immune system. Several lesions such as oral candidiasis, oral
hairy leukoplakia, necrotizing ulcerative periodontal disease,
and Kaposis sarcoma are strongly suggestive of impaired
immune response with CD4 cell counts below 200
cells/mm3.172174 Using oral lesions for markers of immune

548

Principles of Medicine

Date:

Name and address of person permitted to disclose information:

Personal and demographic data (including other care providers):

...............................................................................................................................

Chief complaint:

...............................................................................................................................

History of chief complaint:

Name and address of individual or organization to which the disclosure is to

be made:

Past medical history (including last visit to primary care provider):

...............................................................................................................................

HIV test with dates:

...............................................................................................................................

First HIV test

Last negative HIV test
First positive HIV test

Name and address of patient:

...............................................................................................................................

Reason for HIV test:

...............................................................................................................................

Risk factor(s) for HIV:

Purpose of disclosure:

History of HIV disease (illnesses, signs and symptoms):

CD4 cell count with dates:
Initial count
Lowest count
Latest count

...............................................................................................................................
...............................................................................................................................
Information to be disclosed:
...............................................................................................................................
...............................................................................................................................

Viral load and dates:

Highest rate
Lowest rate
Latest rate
Complete blood cell count with a differential:

I, ........................................................, hereby give my permission for the above

mentioned individual and/or organization/hospital/clinic/laboratory to disclose
pertinent medical records to the individual/organization listed above.
I further understand that I may revoke this consent at anytime. Unless revoked
earlier by me, this consent expires .........................................................................

Medications with dosage and schedules:

Antiretrovirals
Anti-infectives

Patient signature: ..................................................... Date...................................

Other
Witness signature: ................................................... Date...................................
Allergies and drug sensitivity:
Hepatitis (type and status):

FIGURE 20-8 Consent for transmittal of HIV-related information.

Sexually transmitted diseases (type and status):

Tuberculosis (date of test[s] and present status):
Tobacco use (history and present status):
Alcohol use (history and present status):
Recreational drug use (history and present status):

FIGURE 20-7

HIV-relevant history questionnaire.

suppression and HIV disease progression is important and

can impact on medical intervention and treatment strategies.
T-lymphocyte depletion renders affected individuals more
susceptible to fungal infections, viral infections, and neoplastic growth. Some immune surveillance is also diminished,
enabling bacterial infections to flourish. Thus, it is not surprising to find oral infections of these types in patients with
HIV disease.
Fungal Infections. Candidiasis. Intraoral candidiasis,175,176 which is mainly caused by Candida albicans, is the
most common oral manifestation in patients with HIV disease. Although it is not in itself pathognomonic for HIV disease, oral candidiasis may be an indication of immune dete-

Infectious Diseases

549

rioration.177 A tentative diagnosis of oral candidiasis is usually based on clinical appearance but should be confirmed by
laboratory tests. These tests include cytologic smears with
potassium hydroxide, biopsy for periodic acidSchiff and
Gram staining for tissue infiltration by spores and hyphae, or
culture.178 In general, oral candidiasis has four different clinical presentations, as follows:
1. Pseudomembranous candidiasis, or thrush. This condition is a common type of oral candidiasis. It manifests
as white or yellowish single or confluent plaques that
can easily be rubbed off from the oral mucosa (Figure
20-9). It is found on all oral surfaces and may leave an
erythematous or even bleeding underlying mucosa.
Most patients are not aware of the presence of this form
of candidiasis as pseudomembranous candidiasis is
predominantly asymptomatic. The condition is noticed
most commonly when CD4 cells counts drop below
400 cells/mm3.
2. Erythematous or atrophic candidiasis. This condition appears on any mucosal surface as a reddish
macular lesion, atrophic patches, or depapillation on
the dorsum of tongue (Figure 20-10). Erythematous
candidiasis may be present alone or in combination
with the pseudomembranous type. Patients may
complain of an occasional burning sensation in the
mouth. Long-standing lesions may even present as
mucosal ulcerations.
3. Hyperplastic or chronic candidiasis. This form of candidiasis is relatively uncommon and is found mainly in
persons who are severely immunocompromised.
Hyperplastic candidiasis, manifesting as white or discolored plaques that may be solitary or confluent and
cannot be wiped off the mucosa, may be confused with
oral hairy leukoplakia when located on the tongue only
(Figure 20-11). Complaints of a burning sensation, dysphagia, and a feeling of having a large piece of cotton
in the mouth are not unusual. This type of oral candidiasis is often present with esophageal candidiasis.

FIGURE 20-9 Pseudomembranous candidiasis (thrush) on the hard

and soft palate in a patient with HIV disease. These white plaques can be
wiped off, leaving an erythematous mucosa.

FIGURE 20-10 Erythematous or atrophic candidiasis on the hard

palate. These erythematous lesions are usually asymptomatic.

4. Angular cheilitis. This condition, which is predominantly a mixed infection involving C. albicans and
Staphyloccocus aureus, manifests itself as red fissures
originating from the labial commissures of the mouth
(Figure 20-12). Angular cheilitis may be present with
intraoral candidiasis. Concurrent oral dryness also is
not uncommon. Angular cheilitis has been associated
with vitamin B deficiency and decreased vertical
dimension of occlusion from either periodontal disease or ill-fitting dentures. Therefore, it is important to
address concurrent conditions as antifungal treatment
is instituted.

FIGURE 20-11 Hyperplastic or chronic candidiasis on the soft and

hard palate of a severely debilitated HIV-infected patient. These lesions cannot be wiped off and do not respond well to topical antifungal medications.
This type of candidiasis is almost exclusively seen in patients with extremely
low CD4 cell counts and diminished salivary flow.

550

Principles of Medicine

FIGURE 20-12 A, Angular cheilitis is commonly caused by Candida albicans. This lesion usually manifests with an ulcer at the corner of the mouth,
with erythematous fissures radiating from the ulcer. A pseudomembrane sometimes covers the ulcers. B, Treatment with topical antifungal medications and
antibiotics, for bacterial superinfections, is usually efficacious.

Treatment of oral candidiasis includes topical and systemic

antifungal medications. Appropriate treatment should be instituted to reduce symptoms ranging from localized discomfort
to significant dysphagia. Topical therapies include mouth
rinses, troches, ointments, and creams. These formulations
should be used concurrently with systemic agents to resolve the
infection when there is a risk of esophageal candidiasis. Since
there is a high sucrose content in these preparations, which
predisposes patients to develop dental caries, a strict oral
hygiene program and daily flouride treatment should be instituted while the patient is taking topical antifungal medications. Topical antifungal therapies are most efficacious in
patients with CD4 counts above 150 to 200 cells/mm3. In
patients with atrophic candidiasis, troches should be used with
care since they may aggravate existing ulcerations through
mechanical abrasion against the lesions.179
Common topical treatments include nystatin oral suspension (100,000 units/mL; 10 mL swished and swallowed four to
five times per day) and nystatin troche (dissolved in the mouth
four to five times per day). Ointments and creams such as 1%
clotrimazole ointment, 2% ketoconazole cream, or nystatin
cream are efficacious in treating angular cheilitis.
The efficacy of systemic antifungal medications may be
significantly reduced by impaired gastric acid secretion and by
drug interactions with medications such as rifampin.
Furthermore, there exists a potential for liver toxicity that
needs to be addressed. Common systemic antifungals include
ketoconazole (200 mg tablets; one tablet twice a day with
food), fluconazole (100 mg tablets; 200 mg on day 1, followed
by 100 mg daily for 14 days),4 and itraconazole (100 mg tablets;
200 mg daily with food). Resistance to fluconazole has been
reported to occur in patients with severe immune deficiency.
Treatment of patients who are resistant to fluconazole with a
combination of fluconazole and terbinafine has been successful.180 It is also possible to increase the fluconazole dosage to
600 to 700 mg/d in order to improve efficacy. Another

approach to treat fluconazole-resistant fungal infections is to

add a topical medication such as clotrimazole troches. This is
successful if the resistance is owing to the emergence of
Candida krusei, a species resistant to fluconazole but susceptible to clotrimazole. Protease inhibitor therapy has been associated with a decreased incidence of oral candidiasis.177,181
This is owing mainly to improved immune status but may
also be a direct result of the protease inhibitors.
Deep-Seated Infections. Intraoral manifestations of deepseated fungal infections, caused by Cryptococcus neoformans,
Histoplasma capsulatum, Geotrichum candidum, and
Aspergillus spp, are uncommon and are usually an indication
of a disseminated disease.182,183 Intraoral lesions associated
with cryptococcosis, histoplasmosis, and aspergillosis have
been reported as being ulcerative, nodular, or necrotic in
nature, whereas geotrichosis lesions are described as being
pseudomembranous. Since oral lesions of this category are
nonspecific, definitive diagnosis requires histologic verification. Treatment of these lesions is usually reserved for intravenous amphotericin B.
Viral Infections. Although there are no specific oral lesions
caused by HIV infection, a patient can display oral manifestations as an early sign of HIV infection. Such oral symptoms
may include nonspecific oral ulcerations, sore throat, exudative pharyngitis, and oral candidiasis during the initial acute
infection state.179 These nonspecific manifestations disappear
after the acute phase.
Herpesvirus. Oral herpes simplex virus (HSV) presents both
as a local and a disseminated infection. The presence of intraoral HSV-associated lesions is usually the result of recurrent
infections caused by reactivation of latent viruses. This lesion
is not specifically related to HIV; it is also a fairly common
occurrence among non-HIV infected individuals. However,

Infectious Diseases

HSV infections among immunocompromised individuals

may be more severe and manifest differently than what is
noticed in immunocompetent patients. Although ulcerations
caused by HSV-1 and HSV-2 are clinically indistinguishable,
HSV-1 is more frequently associated with oral lesions.
However, oral lesions caused by HSV-2 appear to have a
higher recurrence rate and are associated with a higher incidence of resistance to acyclovir.164
HSV in the oral cavity manifests as single or coalescent
crops of vesicles with subsequent ulceration and healing. The
ulcers are small, shallow, and round to elliptical. In general,
recurrent HSV infections occur primarily on more keratinized
epithelium such as the gingiva. However, there are numerous
reports of oral ulcerations caused by HSV infections on
nonkeratinized epithelium in HIV-infected patients. HSVassociated ulcerations are usually accompanied by increased
pain during the acute stage, which can affect an individuals
nutritional intake. These ulcerations tend to heal in 7 to 10
days, although this may be extended in immunocompromised
patients. In this particular patient population, lesions tend to
be larger and occur with increased frequency. Furthermore, in
these patients, recurrent HSV may exhibit clinical signs and
symptoms that are similar to those of primary HSV infection,
such as malaise, cervical lymphadenopathy, and intensely
painful linear gingival erythema.164
Oral manifestations of HSV can be mistaken for other viral
infections such as Cytomegalovirus and varicella-zoster virus,
infection or for aphthous ulcers, and a definitive diagnosis
should be made based on the clinical history and laboratory
tests, such as cytologic staining for Tzanck cells, viral culture
from the ulcer, biopsy, or HSV-1 detection via monoclonal-antibody testing. Treatment for HSV-1 infections usually consists of
acyclovir (200 mg orally five times daily). Although famciclovir
can also be used, valacyclovir is a poor alternative because it may
cause severe side effects in immunocompromised patients.
Foscarnet may be used for resistant infections.184
Cytomegalovirus. Oral manifestation of Cytomegalovirus
(CMV) infection is only observed in patients with CD4 counts
below 100 cells/mm3. Lesions associated with CMV are nonspecific ulcerations that usually appear as a single ulcer, without preceding vesicles, on any oral mucosal tissue. These ulcers
are painful and tend to heal poorly. Differential diagnosis
should include recurrent aphthous ulcers and HSV-associated
lesions. A definitive diagnosis must include a biopsy specimen
that shows basophilic intranuclear inclusions of CMV, or CMV
identification via monoclonal-antibody assay or in situ
hybridization.185 A recommended regimen for intraoral
lesions is high-dose acyclovir therapy (800 mg orally five times
a day) for a minimum of 2 weeks. Oral manifestations of CMV
may be associated with disseminated disease, and the patient
needs to be evaluated for ophthamologic and other CMVassociated diseases once an oral diagnosis is confirmed.186
Epstein-Barr Virus. Epstein-Barr virus (EBV) infections have
been associated with numerous manifestations, including

551

infectious mononucleosis, Burkitts lymphoma, nasopharyngeal carcinoma, and oral hairy leukoplakia. Oral hairy leukoplakia was initially described in individuals with HIV disease,
but it has since been found in many other patient populations. This lesion may be present in all phases of HIV disease,
but it is most commonly found in individuals with CD4 cell
counts below 200 cells/mm3. It manifests as an asymptomatic
white lesion, most frequently with vertical hyperkeratotic striae
that are usually seen on the lateral borders of the tongue187
(Figure 20-13). The lesion may vary from linear striae to white
patches that cannot be wiped off, and they often have white
hyperkeratotic hairlike projections. Because of its clinical characteristics, differential diagnosis should include hyperplastic
candidiasis. Although it is not thought that Candida albicans
contributes to the clinical appearance of oral hairy leukoplakia,
C. albicans may be present in more than 50% of oral hairy
leukoplakia lesions. When definitive diagnosis of oral hairy
leukoplakia needs to be established, it is necessary to verify the
presence of EBV in the superficial layers of the involved epithelium. Owing to the significant association between this lesion
and HIV, a biopsy is necessary to rule out oral hairy leukoplakia in patients yet to be tested for HIV. In HIV-positive
individuals, an empiric diagnosis can be inferred when a clinical lesion resembling oral hairy leukoplakia does not respond
to antifungal medications.
It is important to assure the patient that the presence of
oral hairy leukoplakia has not been associated with person-toperson transmission of EBV.
Treatment of this lesion usually is not indicated unless the
patient complains of esthetic disfiguration or masticatory
functional impairment. Antiviral therapy (acyclovir 800 mg
orally five times a day) is effective to achieve resolution of the

FIGURE 20-13 Oral hairy leukoplakia is an asymtomatic white lesion,

caused by Epstein-Barr virus, that is usually found on the tongue. It is rare
to find this lesion on other sites in the oral cavity. The lateral borders of the
tongue are most commonly affected.

552

lesion within 2 weeks. Prophylactic therapy with 800 mg acyclovir per day may be necessary to prevent recurrence.
Varicella-Zoster Virus. There have been reports of
increased incidence of human varicella-zoster virus (HZV)
infections among HIV-infected persons, relative to increased
age and degree of immunosuppression. Complications associated with HZV in immunocompromised patients are common and can be severe, especially for those individuals with
CD4 counts fewer than 200 cells/mm3.188 Clinically, oral
HZV infection presents as vesicles that quickly rupture,
resulting in ulcerations. The ulcers are multiple, shallow,
and small, with an erythematous base, and are characteristically distributed unilaterally along a division of the fifth
cranial nerve. Patients frequently complain of pain, neuropraxia, and tenderness. Although clinical presentation is distinct for HZV infection, a definitive diagnosis should be
confirmed by laboratory tests such as histologic staining for
multinucleated giant cells with intranuclear inclusions,
direct immunofluorescence, and cytology smears taken from
the lesion.
Treatment usually is focused on supportive care and is centered on the prevention of postherpetic neuralgia and dissemination. High doses of oral acyclovir (800 mg orally five
times a day), famciclovir (500 mg orally three times a day), or
valacyclovir (500 mg orally three times a day) have been efficacious in treating HZV infection. Caution is needed when
using valacyclovir in severely immunosuppressed patients as
this medication has been associated with hemolysis in this
particular patient population. For greatly immunosuppressed
patients, intravenous acyclovir therapy may be more appropriate. Foscarnet also may be useful for acyclovir-resistant herpes zoster.189 It has been reported that there are high incidences of herpes zoster in patients shortly after they start
treatment with protease inhibitors, which might suggest a need
for prophylaxis for those at increased risk for developing herpes zoster infection.190

Principles of Medicine

Human Herpesvirus 8. Recently, human herpesvirus 8

(HHV8) has been linked to the etiology of Kaposis sarcoma
(KS).191 Most intraoral KS lesions are found on the hard and
soft palates, manifesting as red-blue or purple-blue macules or
nodules (Figure 20-14). The lesions are initially asymptomatic,
but due to trauma and secondary ulcerations, they can become
symptomatic as they get larger in size. Large lesions may interfere with the individuals ability to speak, swallow, and masticate. Lesions on the gingiva and tongue are also common;
however, extrapalatal lesions are associated with a more rapid
progression of KS, as well as HIV disease.
Oral KS is usually seen in patients with CD4 counts below
200 cells/mm3 but can be seen in all stages of HIV disease. The
macular lesions can be confused with physiologic pigmentation; a differential diagnosis should also include bacillary
(epithelioid) angiomatosis, lymphoma, and trauma.192 As KS
is an AIDS-defining lesion, a definitive diagnosis requires a
biopsy.
Treatment for KS includes radiation (800 to 2,000 rad),
surgical excision, and intralesional injections with chemotherapeutic agents such as vinblastine sulfate (0.1 mg/mm2 ) or
sodium tetradecyl sulfate (0.1 mg/mm2 ). Intralesional injections are most effective for small nodular lesions and as an
adjuvant to radiation. It is important to realize that most of
these treatments do not result in a cure but are used to reduce
the size and number of lesions.193 Recent studies show some
efficacy with antiangiogenesis agents, such as thalidomide, and
oral 9-cis retinoic acid.194 No antiherpetic medications have
shown any benefit as prophylaxis or treatment for KS.
Human Papillomavirus. Oral manifestations with papillomaviruses are similar to human papillomavirus (HPV)
infections at other sites. Infections with HPV may cause different distinct appearances, including oral squamous cell
papilloma, verruca vulgaris, focal epithelial hyperplasia, and
condyloma acuminatum (Figure 20-15). Each lesion has a
specific expression of an identified HPV genotype. Oral

FIGURE 20-14 A, Initial lesions of Kaposis sarcoma are usually found on the hard and soft palates. These lesions are commonly bluish-red macules.
B, Long-standing palatal lesions may become nodular and even ulcerative.

553

Infectious Diseases

FIGURE 20-15 Human papillomavirus has become more common in individuals whose immune system is undergoing changes, such as reconstitution
after severe CD4 cell depletion. Florid lesions may affect the lips (A) and intraoral mucosa (B).

squamous cell papillomas may present as exophytic pedunculated papules with a cauliflower-like appearance. Verruca
vulgaris (the common wart) is a firm, sessile, exophytic, and
whitish lesion. This form of HPV presentation also has a
hyperkeratinized superficial epithelium with a slight invagination of the center of the lesion. Focal epithelial hyperplasia (Hecks disease) may present as a single or multiple,
smooth or pebble-like, hyperplastic leukoplakic lesion. Focal
epithelial hyperplasia is commonly found on keratinized tissues such as the alveolar mucosa and the lips. Condyloma
acuminatum presents as small white-to-pink nodules with
a pebbled surface and is most commonly found on the soft
and hard palates and the tongue.195 The presence of HPVassociated lesions is not pathognomonic for HIV infection
or progression. However, an increase in the prevalence of
oral HPV infections among HIV-infected persons has been
reported since the introduction of protease inhibitors.
Although most of oral HPV manifestations are asymptomatic, unless lesions are induced by trauma, they can interfere
with mastication and may raise cosmetic concerns. Treatments
for HPV include surgical removal, laser ablation, cryotherapy,
and topical application of keratinolytic agents. For smaller
lesions, topical application of 25% podophyllum resin may be
used to reduce the size. A more novel approach has been the use
of intralesional injection of antiviral agents. Interferon- in
intralesional injections (1,000,000 IU/cm2 once weekly) and
subcutaneous injections (3,000,000 IU/cm2 twice weekly) have
been shown to be effective in long-term resolution of lesions.196
Bacterial Infection. Periodontal Disease. The most common oral manifestations of bacterial origin are associated
with periodontal conditions. These conditions are usually categorized by their clinical appearance and include linear gingival erythema (LGE), necrotizing ulcerative gingivitis
(NUG), and necrotizing ulcerative periodontitis (NUP). It
has also been noted that HIV-seropositive patients with previous periodontal disease may show faster rates of conventional periodontal deterioration as compared with those of

HIV-seronegative persons. Lamster and colleagues have suggested that the progression of periodontal disease in HIVinfected persons is dependent on the immunologic competency of the host and local host response to typical and
atypical microorganisms related to periodontal disease.197
Thus, the level of immune suppression, as demonstrated by
decreasing number of T-cell lymphocytes, in combination
with the degree of plaque accumulation, may explain these
conditions in HIV-infected patients.173
Linear gingival erythema is an atypical gingivitis that is
depicted as a 2 to 3 mm distinct band of fiery redness at the
marginal gingiva around the teeth (Figure 20-16). Such erythema is not proportional to the plaque accumulation and
seems to only affect the soft tissue, without any ulcerations,
increased pocket depths, or any attachment loss. Patients with
this condition are usually asymptomatic. The true prevalence
of LGE is difficult to determine due to variable diagnostic criteria that have been put forth.
Differential diagnosis should include a localized erythema
due to dry mucosa associated with mouth breathing, lichen
planus, mucous membrane pemphigoid, or an allergic reaction.
The most recent theory regarding the pathogenesis of this lesion
implicates subgingival candida infection as a possible cause.197

FIGURE 20-16 Linear gingival erythema of the gingival margin.

554

Treatments include improved oral home care and conventional dental scaling and root planing, along with the use of
chlorhexidine gluconate (0.12%) mouth rinses (15 mL
swished and expectorated twice a day) for up to 3 months.
Additionally, concomitant use of topical antifungal medications may be beneficial.
Manifestations of NUG and NUP are triggered by changes
in the immune status, most probably aggravated by intraoral
bacteria. The two entities may present as a continuum of the
same disease but also may appear as separate entities. NUG is
limited to the gingiva (Figure 20-17), whereas NUP is characterized by localized to generalized aggressive alveolar bone and
attachment destruction (Figure 20-18). Occurrence of NUG
has been associated with stress, anxiety, malnutrition, and smoking. Patients with NUG complain of spontaneous gingival bleeding and mild to moderate gingival pain. NUP is associated with
complaints of deep-seated bone pain, spontaneous gingival
bleeding, halitosis, and tooth mobility. Clinically, these conditions are presented with initial lesions of limited craterlike
necrosis of gingival papillae. When untreated, NUP may
progress at a rate of 1 to 2 mm of soft- and hard-tissue destruction per week. NUP is mostly seen with severe immune suppression, with CD4 counts below 100 cells/mm3.173
A definitive diagnosis is based on clinical evaluation and
radiologic evaluation with panoramic radiographs or specific
periapical dental radiographs. Specific laboratory tests may be
needed to rule out conditions and lesions such as bullous lesions
of benign mucous membrane pemphigoid, erythema multiforme, acute forms of leukemia, and major aphthous ulceration.
Treatment for both NUG and NUP consists of dbridement of necrotic soft and hard tissue, antibiotic therapy with
metronidazole or tetracycline (500 mg four times a day) for
a week, and a follow-up with scaling and dbridement.173
Due to the high risk for fungal infections in these patients, an
antifungal regimen may be prescribed together with the
antibiotics. Chlorohexidine gluconate (0.12%) mouth rinses
are recommended as maintenance therapy. Metronidazole
should be used with caution in patients who are taking
lopinavir and retonavir.

FIGURE 20-17 Necrotizing ulcerative gingivitis localized to the lower

first and second molars.

Principles of Medicine

Tuberculosis. Intraoral lesions associated with TB may present as single nonhealing caseating granulomatous ulcerations that are accompanied by deep-seated pain. The lesions
have been noted on the tongue, the palate, the buccal mucosa,
and the angles of the mouth.198 Diagnosis by clinical presentation alone is difficult and needs to be complemented
with demonstration of acid-fast TB bacilli within the
lesion.199 Treatment is locally palliative as an adjunct to systemic TB therapy.
Syphilis. Clinical presentation of syphilis includes chancres,
snail-track ulcers, and gumma formation.200 Chancres are
mostly asymptomatic indurated ulcers with a brown crusted
appearance that are usually seen on the lips, oral mucosa,
tongue, palate, and posterior pharyngeal wall. Secondary
syphilis is characterized by highly infectious mucosal ulcers
with an appearance of white lesions surrounded by an erythematous base. Frank ulceration is most common in tertiary
syphilis as a result of gummatous destruction. It is usually
seen on the palate and tongue.
Differential diagnosis should include herpetic cold sores,
deep-seated fungal infections, mycobacteria-associated ulcer,
malignant ulcers, and trauma. A definitive diagnosis is made
by dark-field microscopy that demonstrates the etiologic
agent, Treponema pallidum. Treatment is based on appropriate systemic antibiotic therapy.
Nonspecific Ulcerations. Necrotizing Stomatitis. Necrotizing
stomatitis is a localized acute painful ulcerative lesion on
mucosal surfaces overlying bone (Figure 20-19). This condition
eventually leads to necrosis of tissue and subsequent bone exposure. No specific microbial agent or mechanism has been linked
to its etiology. This condition is seen in patients with CD4 cells
fewer than 100 cells/mm3.168 Differential diagnosis includes
aphthous ulcer and NUP. Treatment consists of careful dbridement, local or systemic steroid therapy, antibiotics, and institution of a soft-tissue stent to protect the affected area from further trauma and for delivery of topical medications.201
Aphthous Ulcers. Recurrent aphthous ulcerations (RAUs)
are idiopathic oral ulcerations. There are three disease entities of RAUs: minor, major, and herpetiform. Diagnosis of
RAUs is a diagnosis of exclusion; the clinical impression
should be confirmed with histologic examination and by
response to treatment.179
Minor (recurrent) aphthous ulcerations are smaller than
10 mm in diameter, well-circumscribed, round, sometimes
covered by a yellow-gray pseudomembrane, and surrounded
by an erythematous halo. The erythematous halo may be
absent in severely immunocompromised patients due to their
lack of an intact inflammatory response. Minor aphthous
ulcerations are usually confined to the nonkeratinized oral
mucosa and tend to recur, often at the same site. Their duration is about 1 to 2 weeks, and healing occurs without scarring.
Minor aphthous ulcerations are prevalent in both nonHIVinfected populations and HIV-infected populations.

555

Infectious Diseases

FIGURE 20-18 Necrotizing ulcerative periodontitis of the lower anterior

region. A, Both gingival and alveolar bone are affected. B, Submandibular
lymphadenopathy can also be present.

Differential diagnosis includes recurrent HSV infection.

Treatment is focused to provide symptomatic relief. An analgesic mouth rinse, such as 2 to 4% viscous lidocaine solution
(10 mL swished and expectorated), is most commonly instituted for relief.
Major (recurrent) aphthous ulcerations are larger than 10
mm in diameter, well-circumscribed, round, and shallow or
deep with indurated margins (Figure 20-20). A gray
pseudomembrane covering the lesion may sometimes be present. Major aphthous ulcerations can occur on any area of the
oral mucosa. They are usually single ulcerations, but in
immunosuppressed individuals, groups of up to 10 lesions
have been observed. These ulcers tend to persist for more than
3 weeks and to heal with a scar formation. In patients with

FIGURE 20-19 Necrotizing stomatitis on the palatal area of the upper

first and second molars.

HIV, major aphthous ulcers have been associated with severe

immune suppression, with CD4 counts below 100 cells/mm3,
and are markers for HIV disease progression.202
Treatment for major aphthous ulcerations includes
administration of systemic corticosteroids. Topical formulations of clobetasol or fluocinonide gel applied directly to the
lesion, dexamethasone elixir mouth rinses (0.5 mg/5 mL),
and systemic administration of 60 to 80 mg of prednisone per
day for 10 days have been used successfully. For steroid-resistant patients, alternative therapy of 100 to 200 mg thalidomide may be used. Thalidomide needs to be used with caution because of its severe adverse side effects. However, despite
its severe side effects, thalidomide has been used with some
success to treat both oral and esophageal ulcerations.
Refractory cases may be treated with other agents including
colchicine or levamisole.203 Antibiotics and antifungal agents
may be used concurrently when appropriate to prevent bacterial or fungal superinfections.
Herpetiform ulcers are the least common type of aphthous ulcers. These ulcers are pinpoint (smaller than 1 mm in
diameter) and round, with perilesional erythema. They are
usually found in batches of up to 100, appearing on nonkeratinized mucosa such as the ventral surface of the tongue and
soft palate. Healing occurs without scarring. Treatments are
similar to those for minor aphthous ulcers and include symptomatic relief, suppression of the local pathologic immune
reaction, and treatment of any concomitant superinfection.
Drug-Induced Ulcerations. Several medications that are
frequently used for HIV-infected patients have been associated with the development of oral ulcerations.204206 These
medications include zidovudine, zalcitabine, foscarnet,
interferon, and ganciclovir.207 Drug-induced ulcerations are
mainly seen on nonkeratinized mucosa, but they tend to
affect keratinized mucosa in more severely immunocompromised patients.

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Principles of Medicine

A
FIGURE 20-20

B
A, Major aphthous ulcer in the retromolar region in an HIV-infected patient. B, The same major aphthous ulcer, after treatment.

Certain antiretroviral therapies induce neutropenia and

are thereby linked to the occurrence of oral ulcerations.
Administration of a growth factor such as granulocytemacrophage colony-stimulating factor has shown to be successful in resolving ulcerations associated with neutropenia.208
Xerostomia. Xerostomia, or dry mouth, is a subjective symptomatic complaint that is frequently noted by HIV-infected
patients. It has been reported that reduced salivary flow occurs
in 2 to 10% of HIV-infected individuals.207 However, the true
prevalence is 80 to 90% of all patients taking HAART. The
effect of oral dryness on quality of life is profound, and many
patients with severe xerostomia sometimes opt to change or
stop their antiretroviral medications in order to regain better
salivary functions.
The most common cause of decreased salivary flow in HIVinfected patients is side effects of pharmocotherapeutic agents.
Many medications, such as antiretroviral medications (including
nucleoside transcriptase inhibitors, protease inhibitors) as well as
antihistamines, anticholinergics, antihypertensives, decongestants, narcotic analgesics, and tricyclic antidepressants, have been
associated with xerostomia. In addition, xerostomia may be a
result of HIV-associated salivary gland disease in this population.
The parotid glands are most frequently affected; however, minor
salivary glands can also be affected by viral infection such as with
CMV.209 Another cause of reduced salivary flow is radiation therapy to the head and neck area, causing functional impairment of
salivary glands in the radiated area.
Treatment for xerostomia focuses on symptomatic relief by
encouraging patients to hydrate themselves frequently and to
minimize the intake of caffeine and alcohol, which act as
diuretics. Patients are also recommended to use commercially
available artificial saliva substitutes (Xero-lube, Sali-synt, Moistir, Orex) to achieve relief. The use of pilocarpine and
bethanechol to stimulate salivary flow can also be useful.

Ultimately, discontinuation or substitution of xerostomiainducing drugs may be necessary.

Oral Lesions in the Pediatric Population. HIV-infected children may also develop a spectrum of oral lesions. These lesions
can affect children more severely than adults and can be a significant source of pain with subsequent limitation of oral
intake of nutrition and medications.
The most common oral manifestation in immunocompromised children is candidiasis.210 The presence of oral candidiasis in HIV-infected infants, as well as other clinical symptoms,
is used as a clinical marker for disease progression in a prognosis-based clinical staging system. Clinical presentation of oral
candidiasis in the pediatric population is similar to that of the
adult population. Some reports suggest that erythematous candidiasis is more common than the pseudomembranous type in
HIV-infected children.211 A definitive diagnosis should be
accompanied by laboratory tests, as described previously.
Both topical and systemic treatment with antifungal medications can be used to treat oral candidiasis. Several reports
have shown that there are subtypes of Candida that are isolated in candidal lesions.211,212 Therefore, it is not unreasonable to determine a specific subtype of Candida and to
select a specific antifungal agent directed toward the subtype. A report has shown that fluconazole suspension (6
mg/kg loading dose followed by 3 mg/kg/d) has been highly
effective and is superior to routine nystatin rinses.213 In children who are fed by bottle, it is possible to place the antifungal medication inside the nipple, as well as to cover the
nipple with a thin layer of topical medication.
Several of the medications used by children are made to
taste better by the addition of sugar formulations, which also
make them syrupy and sticky. It is advisable to have children
rinse their mouths with water after administration of these
medications in order to reduce the incidence of tooth decay.

Infectious Diseases

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