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Emerging Infectious Diseases
Volume 2, Number 2, April-June 1996

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Synopsis

Emerging Disease Issues and Fungal Pathogens Associated with HIV Infection

Neil M. Ampel, M.D.
University of Arizona College of Medicine, Tucson Veterans Affairs Medical
Center, Tucson, Arizona, USA

Abstract:
Fungal diseases are increasing among patients infected with human
immunodeficiency virus (HIV) type 1. Infections due to Candida and
Cryptococcus are the most common. Although mucocutaneous candidiasis can be
treated with oral antifungal agents, increasing evidence suggests that
prolonged use of these drugs results in both clinical and microbiologic
resistance. The optimal therapy for cryptococcal meningitis remains
unresolved, although initial treatment with amphotericin B, followed by
life-long maintenance therapy with fluconazole, appears promising. Most
cases of histoplasmosis, coccidioidomycosis, and blastomycosis occur in
regions where their causative organisms are endemic, and increasing data
suggest that a significant proportion of disease is due to recent
infection. Aspergillosis is increasing dramatically as an opportunistic
infection in HIV-infected patients, in part because of the increased
incidence of neutropenia and corticosteroid use in these patients.
Infection due to Penicillium marneffei is a rapidly growing problem among
HIV-infected patients living in Southeast Asia. Although the advent of oral
azole antifungal drugs has made primary prophylaxis against fungal diseases
in HIV-infected patients feasible, many questions remain to be answered
before the preventive use of antifungal drugs can be advocated.

Over the last decade, the incidence of fungal infections has increased
dramatically. The human immunodeficiency virus (HIV) type 1 epidemic
accounts for a large share of this increase. This article is not a general
guide to the diagnosis or treatment of fungal diseases but rather a review
of emerging disease issues in regard to these infections among HIV-infected
patients. The infections discussed include candidiasis; cryptococcosis; the
endemic mycoses histoplasmosis, coccidioidomycosis, and blastomycosis;
aspergillosis; and penicilliosis. In addition, the role of preventive
therapy for fungal infections in HIV-infected patients is assessed. Fungal
pathogens and their most common manifestations in HIV-infected patients are
listed separately (Table).

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    Table. Common fungal pathogens in HIV
  infection and their most frequent clinical
                  syndromes
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     Organism          Clinical syndrome
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 Candida          Thrush, vaginal
 albicans         candidiasis, esophageal
                  candidiasis

 Cryptococcus
 neoformans       Meningitis

 Histoplasma      Disseminated infection
 capsulatum       with fever and weight loss

 Coccidioides     Diffuse and focal
 immitis          pulmonary disease

                  Localized pulmonary
 Blastomyces      disease and disseminated
 dermatitidis     infection, including
                  meningitis

 Aspergillus      Pulmonary disease with
 fumigatus        fever, cough, and
                  hemoptysis

                  Fever alone or with
 Penicillium      pulmonary infiltrates,
 marneffei        lymphadenopathy, or
                  cutaneous lesions
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Candidiasis

Mucocutaneous candidiasis is one of the most common manifestations of HIV
infection. In one prospective study, 84% of HIV-infected patients had
oropharyngeal colonization by Candida species on at least one occasion, and
55% developed clinical thrush (1). While other yeasts may occasionally
cause clinical disease, Candida albicans is the organism isolated from most
patients (1, 2). Candida species normally colonize the gastrointestinal
tract of healthy adults, and most infections in HIV-infected patients are
endogenously acquired. In some cases, candidal strains can be transmitted
from person to person (1). During the course of HIV infection, patients
appear to be colonized with one or a few dominant strains, which tend not
to change over time. Powderly and colleagues isolated the same strain of C.
albicans in 11 of 17 patients with recurrent yeast infection, by DNA probe
analysis (2). In another study, using contour-clamped homogeneous electric
field electrophoresis, Sangeorzan et al. found that 60% of patients were
colonized with one dominant strain of C. albicans. In 74% of these
patients, recolonization with the same strain occurred after antifungal
therapy (1). Using biotyping and restriction fragment length polymorphism
analysis of 25S ribosomal DNA, Whelan and colleagues found that strains of
C. albicans isolated from 24 patients with AIDS were not significantly
different from strains from 23 patients without HIV infection (3). Thus,
the candidal strains causing disease in patients with HIV infection appear
to be the same as those colonizing patients without HIV infection and, in
most patients, do not change over time.

In HIV-infected patients, candidiasis is virtually always mucocutaneous,
involving the oropharynx, the esophagus, and the vagina. HIV infection by
itself is not associated withthe syndrome of disseminated candidiasis,
which is characterized by candidemia, endophthalmitis, and multiple organ
involvement. The precise immunologic processes that control candidal
infection in HIV-infected patients are not known. However, mucocutaneous
candidiasis is clearly related to the development of clinical cellular
immunodeficiency. In fact, oropharyngeal candidiasis is an independent
predictor of immunodeficiency in patients with AIDS (4). Moreover, a CD4
lymphocyte count < 200/ l is a major risk factor for the development of
clinical thrush in HIV-infected persons (1).

Although oropharyngeal candidiasis is frequent in men, recurrent vaginal
candidiasis is a common early manifestation of HIV infection in women. The
location and severity of candidiasis in women with HIV infection appear to
be closely associated with the degree of cellular immunodeficiency, based
on the peripheral blood CD4 lymphocyte count. In a study of 66 women,
mucocutaneous candidiasis developed in more than half of the women over a
median of 14 months of follow-up; vaginal candidiasis, with a mean CD4
lymphocyte count of 506/l, developed only in 10, while oropharyngeal
candidiasis, with a mean count of 230/l developed in 16, and esophagitis,
with a mean count of 30/l developed in nine (5).

Mucocutaneous candidiasis can be treated either topically or with systemic
antifungal agents (1, 6), but such therapy does not eradicate colonization
(1). Recently, several reports have noted the failure of azole drugs,
particularly fluconazole, to treat recurrent cases of oropharyngeal
candidiasis (1, 7). While factors such as diminishing cellular immunity,
drug interactions, or decreased drug absorption may account for some of
these treatment failures, increasing evidence suggests that Candida
organisms are developing drug resistance.

In the past, a lack of consensus on the methods for performing antifungal
susceptibility tests made it difficult to establish whether clinical
failure of antifungal therapy was due to resistance of the organism.
However, the National Committee for Clinical Laboratory Standards (NCCLS)
has now developed reference methods allowing for uniform testing of yeast
isolates (8). Using an NCCLS method, Sangeorzan et al. found that the MIC
of fluconazole for Candida isolates increased over time among patients who
had received fluconazole compared with those who received clotrimazole.
Clinical resistance to fluconazole was associated with an increased MIC
required by the isolate as well as the patients low CD4 lymphocyte count
(1). These data strongly suggest that continued use of antifungal agents,
particularly fluconazole, leads to both clinical treatment failure and
antifungal resistance, especially in highly immunodeficient patients.

Cryptococcosis

A rare disease before the HIV epidemic, cryptococcosis was identified very
early in the epidemic as one of the most common life-threatening infections
in AIDS patients (9). However, issues regarding its epidemiology and
therapy remain unresolved.

A single species, Cryptococcus neoformans, is responsible for virtually all
clinical cases of cryptococcosis. The species exists in two varieties,
neoformans and gattii, which inhabit different ecologic niches. C.
neoformans var. neoformans has been isolated in many parts of the world
from numerous sites, most frequently from soil containing high amounts of
dried bird excreta, particularly of pigeons and chickens. It has long been
presumed that inhalation of soil contaminated with such excreta is the most
likely source of cryptococcal infection. However, few data support this
hypothesis. In contrast, the only known environmental source of C.
neoformans var. gattii is the river red gum tree (Eucalyptus
camaldulensis), which grows in rural Australia. Although infection due to
var. neoformans is worldwide, cases due to var. gattii have only been
identified in tropical and subtropical regions, including areas where E.
camaldulensis is not found (10).

Virtually all instances of cryptococcosis among HIV-infected persons have
been caused by var. neoformans. The ubiquity of var. neoformans in the
environment may be making exposure and subsequent infection likely;
however, no clear link has ever been established between environmental
sources of C. neoformans and the development of cryptococcosis in patients
with HIV infection (10). In a recent study, Varma and colleagues, using
genomic probe analysis, could not find a direct link between environmental
sources of C. neoformans and infection in patients with AIDS or a unique
strain of C. neoformans that was infecting these patients (11). Suppression
of cellular immunity appears to be a critical factor in the development of
cryptococcosis in HIV-infected patients, with the development of disease
relating directly to the risk for AIDS and to the CD4 lymphocyte count (12,
13).

The appropriate therapy for cryptococcal meningitis in HIV-infected
patients is unsettled at this time. The combination of amphotericin B plus
flucytosine for 4 to 6 weeks has been considered standard for patients
without HIV infection. However, concern about increased toxicity and
decreased efficacy (12) has led to a reconsideration of this regimen in
HIV-infected patients.

Several studies have examined the use of oral fluconazole in lieu of
amphotericin B for initial therapy of cryptococcal meningitis in patients
with HIV infection. Larsen and colleagues studied 21 patients and found
that amphotericin B plus oral flucytosine resulted in fewer clinical
failures and faster cryptococcal clearance of the cerebrospinal fluid than
fluconazole alone (14). A large collaborative trial compared results with a
relatively low dose of intravenous amphotericin B to those with oral
fluconazole and found no significant difference in the overall mortality
rate (15). However, in this trial, the early mortality rate, defined as
death within the first 2 weeks of therapy, was slightly higher, and time to
first negative CSF culture was somewhat longer among patients in the
fluconazole group.

The recurrence of cryptococcosis, even after initial therapy has rendered
the CSF culture sterile, is extremely common in HIV-infected patients (16);
continued antifungal therapy appears to reduce the risk for recurrence (12,
16). Fluconazole in daily doses has been shown to be effective in
preventing relapse (16) and is superior to amphotericin B in weekly doses
(17).

Current information suggests that therapy for cryptococcal meningitis in
HIV-infected patients should begin with amphotericin B, with or without
flucytosine. Suppressive therapy with fluconazole should be given
subsequently to prevent a relapse. When available, the results of a study
sponsored by the Mycoses Study Group and AIDS Clinical Treatment Group of
the National Institute of Allergy and Infectious Diseases, National
Institutes of Health, should clarify these issues.

Histoplasmosis, Coccidioidomycosis, and Blastomycosis

Unlike candidiasis and cryptococcosis, infections caused by Histoplasma
capsulatum, Coccidioides immitis, and Blastomyces dermatitidis are acquired
in specific geographic regions. Infections due to these fungi were not
initially associated with HIV infection because the HIV epidemic in the
United States began in the large urban areas of the East and West Coasts,
outside the areas in which these fungi are endemic. As HIV infection spread
to the Midwest, where histoplasmosis and blastomycosis are endemic, and to
the Southwest, where coccidioidomycosis occurs, these fungi became
recognized as major opportunistic agents.

Histoplasmosis

H. capsulatum var. capsulatum causes infection worldwide and is the
organism most associated with disease in HIV-infected patients. A few cases
of histoplasmosis in HIV-infected patients have been due to H. capsulatum
var. duboisii (18), which is found in tropical Africa. In the Western
Hemisphere, infection is concentrated in the easternUnited States but is
also found in the Caribbean as well as in Central and South America. H.
capsulatum var. capsulatum is typically isolated from soil contaminated
with avian or bat excreta, and a number of epidemics among persons without
HIV infection have been associated with disruption of contaminated soil.

Most cases of histoplasmosis in patients with HIV infection have occurred
within the recognized area for endemic H. capsulatum in North America, the
Ohio and Mississippi River valleys. However, within that area, great
variability has been seen in the incidence of disease, with most cases
being reported from a single city, Indianapolis, Indiana (19, 20). Since
1978, Wheat has recorded several outbreaks of histoplasmosis in that city,
mostly centered in areas where active construction led to soil disruption.
In the most recent outbreak, patients with AIDS accounted for more than 50%
of the culture-proven cases of histoplasmosis (21); these data suggest that
many of these cases represent new infection due to recent exposure rather
than reactivation of latent disease.

Cases of histoplasmosis and HIV-infection have also been reported well
outside the recognized histoplasmosis-endemic areas (22, 23). In some
instances, these cases represent reactivation of infection acquired during
residence in or travel to disease-endemic regions. In other instances, they
appear to represent acute infection after disruption of microfoci of H.
capsulatum that exist outside the recognized disease-endemic areas (19).

Patients with progressive disseminated histoplasmosis, the most common form
of disease among HIV-infected persons, usually have fever, malaise, and
weight loss over a period of weeks. Diagnosis is often established by
isolating the fungus from respiratory secretions, blood, or bone marrow,
but detecting Histoplasma capsulatum var. capsulatum polysaccharide antigen
(HPA) in the serum or urine is also helpful (19).

Amphotericin B therapy is usually effective for progressive disseminated
histoplasmosis in patients with HIV infection. Itraconazole may be useful
for less severe cases (24). However, relapses are extremely common when
therapy is stopped (19, 25), and maintenance therapy with intermittent
amphotericin B (25) or with itraconazole (26) is required to prevent this.
Fluconazole is less effective but can be used by those who cannot tolerate
amphotericin B or itraconazole (27). Urine and serum HPA levels decline
with successful therapy and can be useful in determining a patients
response to therapy as well as assessing a patient for relapse (26-28).

Coccidioidomycosis

Within the disease-endemic area (U.S. Southwest), coccidioidomycosis is one
of the most frequent opportunistic infections in persons with AIDS (29). In
a prospective study in Tucson, Arizona, active coccidioidomycosis developed
in 25% of a cohort of HIV-infected patients over a 41-month period (30).
The major risk for developing disease was immunosuppression, as manifested
by a CD4 lymphocyte count below 250/l, a diagnosis of AIDS, or anergy
indicated on control skin tests. Length of time in the disease-endemic
area, a history of prior coccidioidomycosis, and a positive coccidioidal
skin test were not associated with the development of active
coccidioidomycosis. These data suggest that most coccidioidomycosis cases
among HIV-infected persons in a disease-endemic area are recently acquired
and not due to reactivation of latent infection. However, as with
histoplasmosis, in a small number of HIV-infected patients, previously
acquired infection is reactivated, and clinical coccidioidomycosis develops
while the patient is residing outside the disease-endemic area (29).

Despite recent outbreaks of coccidioidomycosis in the San Joaquin Valley
and in Northridge, California (31, 32), most cases of coccidioidomycosis
among HIV-infected patients have been reported from Arizona, particularly
the metropolitan areas of Phoenix and Tucson (30, 33). Whether this
represents underreporting of disease in California or a true increase in
incidence in Arizona is unknown.

Most HIV-infected patients with coccidioidomycosis seek treatment for
pulmonary disease. In many, chest radiographs show a diffuse,
reticulonodular pattern. Approximately 70% of patients with this pattern
die within 1 month despite antifungal therapy (30, 33). In fact, this
radiographic pattern may mimic that seen with Pneumocystis carinii
pneumonia (34). Sites of dissemination frequently seen in patients without
HIV infection, such as skin, soft tissue, bone, joint, and meninges, appear
less common among patients with HIV infection (30, 33). Serologic tests can
be useful in diagnosing coccidioidomycosis in HIV-infected patients,
although they are more likely to have negative results than patients
without HIV infection (35). On the other hand, a positive coccidioidal
complement-fixation serologic test result in an HIV-infected patient, even
in the absence of clinical illness, predicts impending active
coccidioidomycosis (36).

Comparative trials regarding the therapy of coccidioidomycosis in
HIV-infected patients have not been carried out. For severe disease, such
as for diffuse, reticulonodular pneumonia, amphotericin B is recommended.
However, for less fulminant infection, fluconazole has been effective. As
with cryptococcosis and histoplasmosis, life-long maintenance therapy with
an oral azole is recommended, although relapses have occurred despite this.

Blastomycosis

Blastomycosis is the least common of the three endemic mycoses in North
America among patients with HIV infection; fewer than 25 cases have been
reported. Only recently has an environmental link been established for
infection, when the organism was isolated from riverbank soil in
association with an outbreak (37).

Pappas and colleagues have published the largest series of cases associated
with HIV infection, consisting of 15 patients from 10 medical centers (38).
Ten of the 15 cases were reported from sites within the known
disease-endemic area, the midwestern and southeastern United States, and
the other five patients had resided within the disease-endemic area at some
time before the diagnosis. Most patients were clinically immunodeficient at
the time of diagnosis and had either chronic pulmonary infection or disease
disseminated beyond the lungs, including meningitis. In all but one case,
the diagnosis was established by culture of B. dermatitidis, whereas
results of serologic tests, when performed, were uniformly negative. Both
amphotericin B and ketoconazole were used successfully as therapy in the
series.

Aspergillosis

Although disseminated aspergillosis was originally listed as an infection
at least moderately predictive of AIDS, it was removed from the list in
1984 because only three cases had been reported among 1,762 patients (39).
However, over the last 5 years, the number of cases of invasive
aspergillosis among HIV-infected patients has dramatically increased
(40-44); more than 75 cases now have been documented. The largest series,
containing 33 patients, was reported by Lortholary and colleagues from
France (43). All patients had AIDS and a median CD4 lymphocyte count of
27/l. About half the patients had the traditional risk factors for
invasive aspergillosis (neutropenia or corticosteroid use) at the time of
diagnosis. Culture of fluid from bronchoalveolar lavage was positive in all
cases in which it was done; A. fumigatus grew in 29 of 31 patients. In this
study, isolating the fungus from bronchoalveolar lavage fluid correlated
with histologic evidence of invasive aspergillosis in 14 of 15 patients.

In all series, the death rate has been extremely high despite therapy.
Intravenous amphotericin B has been used most often for treatment, but
itraconazole has been tried in some instances (40, 43). In a recent study
of the use of itraconazole for the treatment of invasive aspergillosis in a
variety of patients, therapy was unsuccessful in all 16 patients with AIDS
and aspergillosis (45). In seven of these, either toxicity to the drug
developedor clinical symptoms worsened while they were receiving
itraconazole; nine died, two directly of aspergillosis and seven of other
causes.

If the incidence of aspergillosis is increasing among HIV-infected
patients, the factors associated with this increase remain unclear. The
identified risk factors for aspergillosis have no doubt increased among
HIV-infected patients in the last decade with the use of such drugs as
zidovudine and ganciclovir, which are associated with neutropenia, and
corticosteroids for the treatment of severe Pneumocystis carinii pneumonia
and other conditions. Others have postulated that prior pneumonia, which
may result in diminished macrophage function (43) and contaminated air,
inhaled during marijuana smoking (40), may also play a role. Further
studies are needed to clarify this.

Penicilliosis

Piehl and colleagues reported the first case of infection due to
Penicillium marneffei in an AIDS patient in 1988 when they described a
patient in Chicago with persistent fever, anorexia, and a papular skin
rash. The patients travel history was not given. Blood, bone marrow,
sputum, and skin biopsy specimen cultures all grew P. marneffei. The
patient responded to therapy with amphotericin B, but relapsed once the
therapy was discontinued (46).

Since that report, the number of reported cases among HIV infected patients
has risen rapidly, particularly in association with the HIV epidemic in
Thailand. In a series of 80 patients reported by Supparatpinyo and
colleagues (47), most patients were men from the Chiang Mai province of
northern Thailand. The most common characteristic in these patients was a
generalized papular rash; some of the lesions had central ubilication
reminiscent of molluscum contagiosum. Diagnosis was usually established by
examining Wright-stained samples of bone marrow aspirates or touch smears
of skin biopsy specimens.

Treatment with amphotericin B has been successful in most patients.
Itraconazole and fluconazole may also be useful. The mortality rate appears
most related to a delay in diagnosis. Relapse is common once therapy is
stopped (48); therefore, antifungal therapy should be life-long in the
HIV-infected patient with penicilliosis.

In northern Thailand, penicilliosis is now the third most common
opportunistic infection (after tuberculosis and cryptococcosis) among
HIV-infected persons (48). Given that P. marneffei appears endemic in
Southeast Asia, penicilliosis can be expected to become an even larger
problem as the HIV epidemic continues to expand in this part of the world.

Prevention of Fungal Infections in HIV-Infected Patients

With the rise of fungi as opportunistic pathogens among patients infected
with HIV and with the success of preventive therapy for other opportunists,
such as P. carinii, primary prevention of fungal disease in HIV-infected
patients should be pursued. The goal of any such prevention would be to
increase both the length and the quality of the patients life.

Since the availability of the oral azoles, using antifungal agents to
prevent fungal diseases in HIV-infected patients has become a promising
approach. However, several questions must be considered before antifungal
chemoprophylaxis is used (49). Is the prevalence of disease high enough to
make the drug useful in most patients? Is the efficacy of the drug in
preventing disease sufficient? Does the therapy induce the development of
drug resistance? Is the cost of the drug reasonable? Finally, does the drug
have an acceptable toxicity profile, and does it interact or interfere with
the metabolism of other drugs?

Few answers to these questions are available. In a recently published
prospective, randomized study comparing fluconazole to topical clotrimazole
(13), fluconazole was significantly better than clotrimazole in preventing
oropharyngeal and esophageal candidiasis as well as cryptococcal
meningitis. The benefit of fluconazole was greatest among patients whose
CD4 lymphocyte count was < 50/l. However, 10% of the patientshad at least
one episode of candidiasis while taking fluconazole, which suggests drug
resistance. Moreover, the overall and fungal-disease-related death rates
were no different between the two groups. Given the present data, further
studies will be needed before the issue of primary prevention of fungal
disease through chemoprophylaxis is settled (50).

Dr. Ampel is an associate professor of medicine at the University of
Arizona College of Medicine and director of HIV Clinical Services at the
Tucson Veterans Affairs Medical Center. His research focuses on the immune
response in coccidioidomycosis.

Address for correspondence:

Neil M. Ampel, M.D.
Medical Service (111), Veterans Affairs Medical Center, 3601 S. Sixth
Avenue, Tuscon, AZ 85713, USA
fax: 520-629-1861
e-mail: nampl@aol.com

References

  1. Sangeorzan JA, Bradley SF, He X, Zarins LT, et al. Epidemiology of
     oral candidiasis in HIV-infected patients: colonization, infection,
     treatment, and emergence of fluconazole resistance. Am J Med 1994;
     97:339-46.
  2. Powderly WG, Robinson K, Keath EJ. Molecular epidemiology of recurrent
     oral candidiasis in human immunodeficiency virus-positive patients:
     evidence for two patterns of recurrence. J Infect Dis 1993; 168:463-6.
  3. Whelan WL, Kirsch DR, Kwon-Chung KJ, Wahl SM, et al. Candida albicans
     in patients with the acquired immunodeficiency syndrome: absence of a
     novel or hypervirulent strain. J Infect Dis 1990; 162:513-8.
  4. Klein RS, Harris CA, Butkus Small C, Moll B, et al. Oral candidiasis
     in high-risk patients as the initial manifestation of the acquired
     immunodeficiency syndrome. N Engl J Med 1984; 311:354-8.
  5. Imam N, Carpenter CC, Mayer KH, Fisher A, et al. Hierarchical pattern
     of mucosal Candida infections in HIV-seropositive women. Am J Med
     1990; 89:142-6.
  6. Stevens DA, Greene SI, Lang OS. Thrush can be prevented in patients
     with acquired immunodeficiency syndrome and the acquired
     immunodeficiency syndrome-related complex: randomized, double-blind,
     placebo-controlled study of 100-mg oral fluconazole daily. Arch Intern
     Med 1991; 151:2458-64.
  7. Redding S, Smith J, Farinacci G, Rinaldi M, et al. Resistance of
     Candida albicans to fluconazole during treatment of oropharyngeal
     candidiasis in a patient with AIDS: documentation by in vitro
     susceptibility testing and DNA subtype analysis. Clin Infect Dis 1994;
     18:240-2.
  8. Rex JH, Pfaller MA, Rinaldi MG, Polack A, et al. Antifungal
     susceptibility testing. Clin Microbiol Rev 1993; 6:357-81.
  9. Dismukes WE. Cryptococcal meningitis in patients with AIDS. J Infect
     Dis 1988; 157:624-8.
 10. Levitz SM. The ecology of Cryptococcus neoformans and the epidemiology
     of cryptococcosis. Rev Infect Dis 1991; 13:1163-9.
 11. Varma A, Swinne D, Staib F, Bennett JE, et al. Diversity of DNA
     fingerprints in Cryptococcus neoformans. J Clin Microbiol 1995;
     33:1807-14.
 12. Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the
     acquired immunodeficiency syndrome. N Engl J Med 1989; 321:793-9.
 13. Powderly WG, Finkelstein D, Feinberg J, Frame P, et al. (NIAID AIDS
     Clinical Trials Group). A randomized trial comparing fluconazole with
     clotrimazole troches for the prevention of fungal infections in
     patients with advanced human immunodeficiency virus infection.
     N Engl J Med 1995; 332:700-5.
 14. Larsen RA, Leal MAE, Chan LS. Fluconazole compared with amphotericin B
     plus flucytosine for cryptococcal meningitis in AIDS: a randomized
     trial. Ann Intern Med 1990; 113:183-7.
 15. Saag MS, Powderly WG, Cloud GA, Robinson P, et al. (NIAID Mycoses
     Study Group and the AIDS Clinical Trials Group). Comparison of
     amphotericin B with fluconazole in the treatment of acute
     AIDS-associated cryptococcal meningitis. N Engl J Med 1992; 326:83-9.
 16. Bozzette SA, Larsen RA, Chiu J, Leal MAE, et al. A placebo-controlled
     trial of maintenance therapy with fluconazole after treatment of
     cryptococcal meningitis in the acquired immunodeficiency syndrome. N
     Engl J Med 1991; 324:580-4.
 17. Powderly WG, Saag MS, Cloud GA, Robinson P, et al. A controlled trial
     of fluconazole or amphotericin B to prevent relapse of cryptococcal
     meningitis in patients with the acquired immunodeficiency syndrome. N
     Engl J Med 1992; 326:793-9.
 18. Chandenier J, Goma D, Moyen G, Samba-Lefebvre MC, et al. [African
     histoplasmosis due to Histoplasma capsulatum var. duboisii:
     relationship with AIDS in recent Congolese cases]. Sante 1995;
     5:227-34.
 19. Wheat LJ, Connolly-Stringfield PA, Baker RL, Curfman MF, et al.
     Disseminated histoplasmosis in the acquired immune deficiency
     syndrome: clinical findings, diagnosis and treatment, and review of
     the literature. Medicine [Baltimore] 1990; 69:361-74.
 20. Wheat LJ, Slama TG, Zeckel ML. Histoplasmosis in the acquired immune
     deficiency syndrome. Am J Med 1985; 78:203-10.
 21. Wheat LJ. Histoplasmosis in Indianapolis. Clin Infect Dis 1992; 14
     (Suppl 1):S91-9.
 22. Huang CT, McGarry T, Cooper S, Saunders R, et al. Disseminated
     histoplasmosis in the acquired immunodeficiency syndrome: report of
     five cases from a nonendemic area. Arch Intern Med 1987; 147:1181-4.
 23. Salzman SH, Smith RL, Aranda CP. Histoplasmosis in patients at risk
     for the acquired immunodeficiency syndrome in a nonendemic setting.
     Chest 1988; 93:916-21.
 24. Wheat J, Hafner R, Korzun AH, Limjoco MT, et al. (AIDS Clinical Trials
     Group). Itraconazole treatment of disseminated histoplasmosis in
     patients with the acquired immunodeficiency syndrome. Am J Med 1995;
     98:336-42.
 25. McKinsey DS, Gupta MR, Riddler SA, Driks MR, et al. Long-term
     amphotericin B therapy for disseminated histoplasmosis in patients
     with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med
     1989; 111:655-9.
 26. Wheat J, Hafner R, Wulfsohn M, Spencer P, et al. (NIAID Clinical
     Trials and Mycoses Study Group Collaborators). Prevention of relapse
     of histoplasmosis with itraconazole in patients with the acquired
     immunodeficiency syndrome. Ann Intern Med 1993; 118:610-6.
 27. Norris S, Wheat J, McKinsey D, Lancaster D, et al. Prevention of
     relapse of histoplasmosis with fluconazole in patients with the
     acquired immunodeficiency syndrome. Am J Med 1994; 96:504-8.
 28. Wheat LJ, Connolly-Stringfield P, Blair R, Connolly K, et al. Effect
     of successful treatment with amphotericin B on Histoplasma capsulatum
     variety capsulatum polysaccharide antigen levels in patients with AIDS
     and histoplasmosis. Am J Med 1992; 92:153-60.
 29. Jones JL, Fleming PL, Ciesielski CA, Hu DJ, et al. Coccidioidomycosis
     among persons with AIDS in the United States. J Infect Dis 1995;
     171:961-6.
 30. Ampel NM, Dols CL, Galgiani JN. Coccidioidomycosis during human
     immunodeficiency virus infection: results of a prospective study in a
     coccidioidal endemic area. Am J Med 1993; 94:235-40.
 31. Einstein HE, Johnson RH. Coccidioidomycosis: new aspects of
     epidemiology and therapy. Clin Infect Dis 1993; 16:349-56.
 32. CDC. Coccidioidomycosis following the Northridge
     EarthquakeCalifornia, 1994. MMWR 1994; 43:194-5.
 33. Fish DG, Ampel NM, Galgiani JN, Dols CL, et al. Coccidiodiomycosis
     during human immunodeficiency virus infection: a review of 77
     patients. Medicine [Baltimore] 1990; 69:384-91.
 34. Mahaffey KW, Hippenmeyer CL, Mandel R, Ampel NM. Unrecognized
     coccidioidomycosis complicating Pneumocystis carinii pneumonia in
     patients infected with the human immunodeficiency virus and treated
     with corticosteroids: a report of two cases. Arch Intern Med 1993;
     153:1496-8.
 35. Antoniskis D, Larsen RA, Akil B, Rarick MU, et al. Seronegative
     disseminated coccidioidomycosis in patients with HIV infection. AIDS
     1990; 4:691-3.
 36. Arguinchona HL, Ampel NM, Dols CL, Galgiani JN, et al. Persistent
     coccidioidal seropositivity without clinical evidence of active
     coccidioidomycosis in patients infected with human immunodeficiency
     virus. Clin Infec Dis 1995; 20:1281-5.
 37. Klein BS, Vergeront JM, Weeks RJ, Kumar UN, et al. Isolation of
     Blastomyces dermatitidis in soil associated with a large outbreak of
     blastomycosis in Wisconsin. N Engl J Med 1986; 314:529-34.
 38. Pappas PG, Pottage JC, Powderly WG, Fraser VJ, et al. Blastomycosis in
     patients with the acquired immunodeficiency syndrome. Ann Intern Med
     1992; 116:847-53.
 39. Jaffe HW, Selik RM. Acquired immunodeficiency syndrome: is
     disseminated aspergillosis predictive of underlying cellular
     deficiency? [letter]. J Infect Dis 1984; 149:829.
 40. Denning DW, Follansbee SE, Scolaro M, Norris S, et al. Pulmonary
     aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med
     1991; 324:654-62.
 41. Singh N, Yu VL, Rihs JD. Invasive aspergillosis in AIDS. South Med J
     1991; 84:822-6.
 42. Klapholz A, Salomon N, Perlman DC, Talavera W. Aspergillosis in the
     acquired immunodeficiency syndrome. Chest 1991; 100:1614-8.
 43. Lortholary O, Meyohas MC, Dupont B, Cadranel J, et al. (French
     Cooperative Study Group on Aspergillosis in AIDS). Invasive
     aspergillosis in patients with acquired immunodeficiency syndrome:
     report of 33 cases. Am J Med 1993; 95:177-87.
 44. Miller WT, Jr., Sais GJ, Frank I, Gefter WB, et al. Pulmonary
     aspergillosis in patients with AIDS: clinical and radiographic
     correlations. Chest 1994; 105:37-44.
 45. Denning DW, Lee JY, Hostetler JS, Pappas P, et al. NIAID Mycoses Study
     Group multicenter trial of oral itraconazole therapy for invasive
     aspergillosis. Am J Med 1994; 97:135-44.
 46. Piehl MR, Kaplan RL, Haber MH. Disseminated penicilliosis in a patient
     with acquired immunodeficiency syndrome. Arch Pathol Lab Med 1988;
     112:1262-4.
 47. Supparatpinyo K, Sirisanthana T. Disseminated Penicillium marneffei
     infection diagnosed on examination of a peripheral blood smear of a
     patient with human immunodeficiency virus infection. Clin Infect Dis
     1994; 18:246-7.
 48. Supparatpinyo K, Khamwan C, Baosoung V, Nelson KE, et al. Disseminated
     Penicillium marneffei infection in southeast Asia. Lancet 1994;
     344:110-3.
 49. Perfect JR. Antifungal prophylaxis: to prevent or not? Am J Med 1993;
     94:233-4.
 50. Powderly WG. Prophylaxis for HIV-related infections: a work in
     progress. Ann Intern Med 1996; 124:342-4.