20/11/2014

Histoplasmosis and HIV Infection

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Histoplasmosis and HIV Infection

HIV InSite Knowledge Base Chapter
March 2006
Erika M. Young, DO, Indiana University School of Medicine
Mitchell Goldman, MD, Indiana University School of Medicine
Related Resources

Introduction

Related Know ledge Base Chapters

Journal Articles

Epidemiology

Guidelines and Best Practices

Online Books and Chapters
Slide Sets

Mycology

Links

Clinical Presentation

Laboratory Findings

Radiographic Findings

Diagnosis
Cultures
Antigen Detection
Fungal Staining
Serologic Tests
Differential Diagnosis
Treatment
Amphotericin B
Itraconazole
Fluconazole
Ketoconazole
Caspofungin
Voriconazole
Posaconazole
Treatment of Central Nervous System Histoplasmosis

Discontinuation of Maintenance Therapy

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Prevention of Histoplasmosis

References

Tables
Table 1.

Treatment of Disseminated Histoplasmosis in Persons with HIV Infection

Introduction
Histoplasmosis is the most common of the endemic mycoses in patients with AIDS.(1) Disseminated histoplasmosis (DH) initially was
reported in patients with AIDS in 1982 (2) and was added to the U.S. Centers for Disease Control and Prevention (CDC) AIDS case definition
in 1987.(3) Histoplasma capsulatum var capsulatum primarily affects those living in the valleys of the Ohio and Mississippi rivers in the United
States, and those living in Latin America. H capsulatum var duboisii is described only in Africa. Precise reasons for the endemic distribution
are not clear, but are thought to include the moderate climate, humidity, and soil characteristics.(4) Activities that disturb soil are associated
with exposure to H capsulatum. Air currents then can carry these spores for miles, exposing individuals without contact to the contaminated
site.(4)
In the United States, histoplasmosis has been diagnosed in 2-5% of the HIV-positive population. Significantly higher rates of infection have
been described in geographic regions where this infection is endemic. During an outbreak that occurred in Indianapolis between 1988 and
1995, histoplasmosis was the presenting illness in 26% of patients with AIDS.(5,6) In patients with advanced HIV infection, histoplasmosis
almost always is manifested by signs of progressive disseminated disease, as opposed to the asymptomatic or limited pulmonary infection
observed in the majority of healthy individuals exposed to H capsulatum.(6) Following the advent of effective antiretroviral therapy (ART),
evidence suggests a decrease in the incidence of histoplasmosis in people with AIDS.

Epidemiology
Although H capsulatum has been detected in many areas of the world, the most endemic region is the Ohio and Mississippi river valleys. The
conditions that favor the growth of this fungus in soil are a mean temperature ranging from 22 C to 29 C, an annual precipitation of 35-50
inches, and a relative humidity of 67-87%. The organism typically is found within 20 cm of the surface in soil that is acidic, has high nitrogen
content, and is moist. Bird and bat excrement enhances the growth of H capsulatum in soil by accelerating sporulation. In areas where birds
roost, the fungus is found where the bird excrement is decaying and mixed with soil. In such areas, infectious particles can exceed 10 5
particles per gram of soil.

Mycology
Infection is established after inhalation of H capsulatum microconidia into the lungs. Once inhaled, the microconidia rapidly convert to the
yeast phase within the lung parenchyma. It is thought that the yeast are phagocytized by macrophages within the lung in an attempt to
clear the infection.(7) The macrophages then carry the organism to regional lymph nodes, and then throughout the reticuloendothelial
system within 14-21 days of the initial exposure. Macrophages from HIV-infected individuals, particularly those with lower CD4 counts,
manifest defective activity in their interaction with H capsulatum.(8) In those with intact immune function, an inflammatory response occurs
at the site of infection, with either caseating or noncaseating granuloma formation. Yeast may remain viable in the granuloma for extended
periods of time.
In the vast majority of patients with a normally functioning immune system, the infection is brought under control with few if any clinical
symptoms. In patients with a poorly functioning cell-mediated immunity, such as those with HIV infection and a low CD4 count, the infection
ensues and widely disseminates. In some individuals, such as those residing in nonendemic areas with only a distant history of residing in
an endemic area, DH represents a reactivation of an old infection, presumably due to breakdown of a granuloma associated with a
weakening immune system. For those individuals who develop symptomatic DH while residing in an endemic area, disseminated disease
may represent a newly acquired infection or a reactivation of an old infection.(7,9)

Clinical Presentation
In patients with AIDS, histoplasmosis presents as a progressive disseminated infection in 95% of cases. The majority of AIDS patients with

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disseminated disease have CD4 counts <150 cells/L, with a median CD4 count of 50 cells/L.(6) Patients with disseminated disease usually
present with complaints of fever, weight loss, and malaise over a period of several weeks. In about half of cases, vague respiratory
symptoms are reported.(6)
The most common clinical findings include fever, hepatomegaly, splenomegaly, and generalized lymphadenopathy. In a review of 3 reported
case series, fever was reported in 19-81%, hepatomegaly in 19-26%, splenomegaly in 12.5-31%, and generalized lymphadenopathy in 619%.(5,6) A syndrome resembling septicemia has been well described: patients present with hypotension, adult respiratory distress
syndrome, hepatic failure, renal failure, and disseminated intravascular coagulation. The syndrome appears to represent a late
manifestation of DH, occurring in patients who did not seek medical care early in the course of the illness or in whom the diagnosis was not
considered initially.(10) Such presentations are reported in about 13% of AIDS patients with histoplasmosis.(6)
Skin involvement occurs in up to 10% of cases in the United States.(10) Skin manifestations are protean, ranging from papules to ulcers to
erythema multiforme. Cutaneous presentations may vary based on geographic location. In a review comparing the clinical manifestations of
HIV-infected patients with DH from Brazil with those from the United States, skin lesions were present in the majority of Brazilian cases
(66%), and often were quite extensive when compared with those from the United States, where skin manifestations were less common (17%) and associated with fewer lesions.(11) Based on nuclear gene typing, it appears that genetic differences between the H capsulatum
isolates recovered from these 2 regions may account for the observed clinical differences.(11)
Gastrointestinal involvement may occur in up to 10% of cases. The most common manifestations include diarrhea, vague abdominal pain,
and fever. Intestinal obstruction and perforation have been reported. Lesions may occur anywhere along the intestinal tract, but most often
occur in the small intestine and colon. Gastrointestinal involvement appears to be more common in Brazil.(11)
Neurologic complications have been reported in up to 20% of patients.(5,6) These complications include encephalopathy, lymphocytic
meningitis, and focal parenchymal lesions in the brain or spinal cord. Frequent symptoms include headache and fever. Patients often
demonstrate mental status changes, and 10-30% of patients will have focal neurologic findings. Historically, neurologic involvement has
carried a worse prognosis (6); however, in 2 recent prospective studies reviewing factors associated with severe disease and death,
neurologic involvement was not a significant factor.(1,12)
Adrenal insufficiency is uncommon, though it has been a recognized manifestation of DH.(13) Failure to diagnose adrenal insufficiency could
lead to a fatal outcome despite appropriate antifungal therapy. Rare clinical manifestations include pleuritis, pancreatitis,(6) prostatitis, and
retinitis. Factors associated with severe DH (shock, respiratory failure, and death) have included black race, dyspnea on presentation,
hemoglobin <9.5 g/dL, thrombocytopenia <100,000 platelets/L, activated partial thromboplastin time (aPTT) >45 seconds, alkaline
phosphatase (ALP) >2.5 times normal, aspartate aminotransferase (AST) >2.5 times normal, total bilirubin >1.5 mg/dL, serum albumin
concentration <3.5 g/dL, serum creatinine >2.1 mg/dL, and an elevated lactate dehydrogenase (LDH) >2 times the upper limit of normal.
(1,12)
Patients who experience immunologic improvement on ART, as demonstrated by an increase in CD4 counts, may develop opportunistic
infections that differ from the typical presentation. These events, referred to as immune reconstitution inflammatory syndromes (IRIS), are
characterized by focal inflammatory histopathology (see chapter "Clinical Implications of Immune Reconstitution in AIDS"). Clinical
manifestations of histoplasmosis-associated IRIS have included elevations of hepatic enzymes, hepatic abscesses, lymphadenitis, arthritis,
uveitis, and intestinal obstruction.(14,15,16).

Laboratory Findings
Laboratory abnormalities in DH are nonspecific. Most commonly observed findings include leukopenia, anemia, and thrombocytopenia,
suggesting infiltration of the bone marrow. An elevated ALP may suggest infiltration of the liver. A markedly elevated serum LDH may be a
clinical clue to the diagnosis of DH in patients with AIDS.(17) A serum ferritin level >10,000 ng/mL also is suggestive of DH in the AIDS
population.(18)

Radiographic Findings
In patients with severely suppressed immune systems, histoplasmosis rarely causes focal infiltrates; rather, a diffuse interstitial or
reticulonodular pattern most often occurs.(6,13,19) The radiographic pattern often resembles those of Pneumocystis jiroveci (formerly carinii)
pneumonia (PCP) or miliary tuberculosis, and patients often are coinfected with these organisms. Mediastinal lymphadenopathy, which is
seen in the majority of cases of histoplasmosis in those with intact immune systems, is seen in <20% of cases complicating AIDS.(20) In one
study of patients with AIDS and DH, half had normal chest radiographs.(20) Of those with abnormal radiographs, the most common finding
was a pattern of diffuse nodular opacities.

Diagnosis
Diagnosis of DH requires both a high index of suspicion and an awareness of the use and limitations of the available mycologic and serologic
tests.(10)

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Cultures
In AIDS patients with DH, H capsulatum can be isolated readily from blood (91% sensitivity) and bone marrow (90% sensitivity).(6) In
addition, H capsulatum can be isolated from respiratory secretions, lymph nodes, localized lesions, and cerebrospinal fluid (CSF). Although
culture is the gold standard for diagnosis, isolation can take up to 4 weeks, and therefore is impractical as a criterion for treatment initiation.

Antigen Detection
Detection of H capsulatum antigen in body fluids permits rapid diagnosis of DH. In patients with HIV infection, antigen is detected in urine in
95% of cases of DH and serum in 85%.(21) For this reason, a urinary antigen test, in addition to the serum test, should be performed on all
patients with suspected DH. In addition, antigen may be detected in bronchoalveolar lavage fluid or CSF in patients with pulmonary or
meningeal involvement, respectively. In addition to assisting in the initial diagnosis of histoplasmosis, the urinary antigen levels can be used
to monitor response to therapy and to diagnose relapsed infection.(22) False-positive antigen tests have been described in patients with
blastomycosis, paracoccidioidomycosis, and Penicillium marneffei infections.(22) The antigen test is available through MiraVista Diagnostics
(Indianapolis, IN).

Fungal Staining
Fungal staining of tissue sections, peripheral blood smears, or buffy coat preparations also provide rapid diagnosis. Fungal stains of tissues
are positive in less than half of DH cases (21); the sensitivity of this test therefore is less than that of culture or antigen detection.

Serologic Tests
In patients with intact immune systems, antibodies develop at high levels within 4-6 weeks in most symptomatic Histoplasma infections and
are useful for diagnosis in those patients. Rarely, however, do serologic tests provide the diagnosis in patients with AIDS.(10) Indeed, a
major limitation of the serologic tests is that, even in the presence of active infection, they often are negative in immunosuppressed
patients, especially patients with AIDS.

Differential Diagnosis
The differential diagnosis most commonly includes other opportunistic processes, such as PCP, disseminated Mycobacterium avium complex
infection, miliary tuberculosis, and lymphoma.
Histoplasmosis may be accompanied by a second opportunistic infection in as many as 38% of cases.(6) It is important, therefore, to
consider additional infectious processes in a patient with DH that is unresponsive to appropriate antifungal therapy.

Treatment
DH is a progressive infection in patients with AIDS, necessitating treatment if the diagnosis is strongly suspected or confirmed.
Treatment of DH in patients with AIDS is divided into 2 phases: the induction phase and maintenance phase (Table 1). Therapy in the
induction phase is directed at controlling the clinical manifestations of the disease, and the recommended duration is 12 weeks. The
maintenance phase is directed at preventing relapse. Prior to the availability of effective ART, the rate of relapse without maintenance
therapy was 80%.(6) Accordingly, lifelong antifungal maintenance therapy was recommended for patients with AIDS and histoplasmosis.
With the availability of more potent ART, discontinuation of antifungal maintenance therapy after 12 months of total antifungal therapy
appears to be safe in patients who have sustained immunologic improvement on ART.(23) (See "Discontinuation of Maintenance Therapy"
below.)
The primary choices for induction therapy in moderate to severe disease include amphotericin B in either the standard deoxycholate
formulation or a lipid formulation; for milder disease, induction therapy can be accomplished with itraconazole.(24) Maintenance therapy
most commonly is completed with itraconazole.(24-26) Optimal treatment for central nervous system (CNS) histoplasmosis is unknown, but
an aggressive approach is recommended because of the likelihood of poor outcome.(4) (See "Treatment of Central Nervous System
Histoplasmosis" below.)

Amphotericin B
Amphotericin B therapy is the treatment of choice for patients with AIDS who are admitted to the hospital with moderate to severe
histoplasmosis.(5) In particular, a patient with presumptive or confirmed DH presenting with hypotension, hypoxemia, mental confusion,

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severe hematologic cytopenias, or significant hepatic laboratory abnormalities should be treated with an amphotericin B as induction
therapy. Standard amphotericin B deoxycholate should be administered at a dosage of 0.7-1 mg/kg per day; the lipid amphotericin products
are administered at a dosage of 3-5 mg/kg per day. In the past, lipid formulations were reserved for patients experiencing renal toxicity. A
randomized controlled trial comparing the conventional deoxycholate formulation of amphotericin B with liposomal amphotericin B for
induction therapy in AIDS patients with moderate to severe histoplasmosis demonstrated clinical success in 64% of those treated with
amphotericin B deoxycholate compared with 88% success in those receiving liposomal amphotericin B.(27) Mortality rates during induction
were higher in patients treated with amphotericin B deoxycholate than in those receiving liposomal amphotericin B. Nephrotoxicity occurred
in only 9% of the patients treated with liposomal amphotericin B compared with 33% of patients treated with conventional amphotericin B.
For these reasons, liposomal amphotericin B is preferred for more severe DH. However, the cost of lipid formulations may limit their
availability.
Most patients respond quickly to amphotericin B, with improvement in fever within 7 days of therapy in 80% of patients,(6) and clearance of
fungemia within 14 days in 85% of patients. After a patient has responded clinically to amphotericin B-containing products, transition to
itraconazole can be considered to complete a 12-week course of induction therapy.

Itraconazole
A multicenter nonrandomized prospective trial was performed to evaluate itraconazole for the treatment of mild DH in patients with AIDS.
Patients with CNS involvement and severe clinical manifestations were excluded. In this study, 85% of those patients receiving therapy
responded.(24) Treatment failures occurred in those patients with more severe illness. Resolution of fever occurred in a median of 3 weeks.
(24) The recommended dosage for induction therapy is 300 mg orally twice daily for 3 days followed by 200 mg orally twice daily for 12
weeks. Following successful induction therapy, maintenance therapy with itraconazole (200-400 mg orally daily) should be given.(26) As
successful therapy requires adequate serum concentrations of itraconazole, it is recommended that itraconazole levels be monitored in this
patient group. Itraconazole levels can be drawn after 7 days of therapy, with a targeted therapeutic level of >=2 g/mL.(24)
Although significant levels of itraconazole are not attained in CSF, itraconazole use has been associated with both successes and failures
when used as maintenance therapy for H capsulatum meningitis (see "Treatment of Central Nervous System Histoplasmosis" below).
Itraconazole absorption in the stomach varies; itraconazole in the capsule preparation requires an acidic environment for absorption.
Patients with HIV infection may have decreased acid secretion, secondary to HIV gastropathy. Therapeutic concentrations with the capsule
preparation may not be achieved in these patients. Absorption of the commercially available oral solution formulation of itraconazole is not
dependent on stomach acidity and may be used in place of the capsule in these circumstances. Of additional concern are those medications
metabolized by the cytochrome P450 3A4 enzyme, as is itraconazole. Such medications have the potential for pharmacokinetic interaction
with itraconazole and its major metabolite, hydroxyitraconazole. Elevated and potentially toxic levels of other medications can result from
inhibition of metabolism when itraconazole is coadministered. Elevated serum levels of indinavir have been reported with itraconazole
coadministration, and significantly reduced levels of itraconazole have been reported when itraconazole was coadministered with lopinavir.
(28) Although not all potential interactions have been studied, there is potential for mutual inhibition of metabolism between itraconazole
and protease inhibitors.(29) Before prescribing itraconazole, potential drug interactions should be reviewed. Patients treated with
itraconazole should be monitored for adverse reactions attributable to possible drug-drug interactions. In addition, serum itraconazole
concentrations should be monitored, and consideration should be given to monitoring protease inhibitor concentrations if a significant
interaction is likely.

Fluconazole
Except in cases of CNS involvement, fluconazole therapy should be reserved for patients who are intolerant of both amphotericin and
itraconazole. In a nonrandomized prospective trial, the relapse rate with fluconazole treatment approached 47% at 1 year in patients with
AIDS and mild to moderately severe histoplasmosis.(30) In addition, the development of fluconazole-resistant histoplasmosis has been
observed in patients on fluconazole therapy.(31) Patients treated with fluconazole therefore should be monitored closely for signs of
relapse (see "Treatment of Central Nervous System Histoplasmosis" below).(4)

Ketoconazole
Because of high relapse rates, ketoconazole is not a recommended treatment option for AIDS patients with DH.(6)

Caspofungin
The echinocandin caspofungin does not appear to have adequate activity against H capsulatum in a murine model and, therefore, should not
be used for histoplasmosis.(32)

Voriconazole
Although voriconazole has significant in vitro activity against H capsulatum,(33) and may achieve reasonably high concentrations in CSF, the
agent appears to be less well tolerated than itraconazole and is not recommended for routine treatment of histoplasmosis.

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Posaconazole
Posaconazole, an investigational triazole, was highly effective at reducing the fungal burden and appeared as effective as amphotericin B
and more effective than itraconazole in an immunocompromised murine model.(34) In an open-label trial, 7 patients--3 of whom were HIV
positive--received posaconazole as salvage therapy for histoplasmosis after failing therapy with amphotericin B, fluconazole, itraconazole, or
voriconazole. Successful outcomes were seen in 6 of these cases, including 1 case of DH-related meningitis.(35)

Treatment of Central Nervous System Histoplasmosis

The treatment of CNS histoplasmosis has been inadequately studied. In animal studies, liposomal amphotericin B achieved higher
concentrations in the brain than did conventional amphotericin B or the amphotericin B lipid complex preparation (36); however, neither the
lipid preparation nor conventional amphotericin B achieves detectable concentrations in the CSF,(37) and neither has been evaluated in the
treatment of Histoplasma meningitis. That said, the current recommendation for treatment of meningitis or focal CNS histoplasmosis in
advanced HIV infection includes induction therapy with the liposomal amphotericin B at a dosage of 3-5 mg/kg daily for 6-12 weeks.(38)
Following successful induction therapy, maintenance therapy with fluconazole 600-800 mg daily then can be given for at least 1 year.(38)
Itraconazole at a dosage of 200 mg 2 or 3 times daily also may be considered as maintenance therapy as long as adequate serum levels
can be achieved (>2 g/mL).(38) For patients who fail to respond or who relapse despite appropriate therapy, one of the newer or
investigational triazole agents (eg, voriconazole or posaconazole) should be considered.(38) If all else fails, amphotericin B can be
administered directly into the ventricles, cisterna magna, or lumbar subarachnoid space.(4,39)

Discontinuation of Maintenance Therapy

A prospective observational study was conducted to assess the safety of stopping maintenance therapy for DH in 32 HIV-positive patients
responding to ART.(23) Patients eligible for the study were on antifungal therapy for at least 12 months and ART for 6 months prior to
enrollment with CD4 counts >=150 cells/L. In 24 months of follow-up, no relapses were observed. A similar study was completed in
Argentina in 39 patients also with CD4 counts >=150 cells/L. No relapses were observed in 16 months of follow-up.(40) Discontinuation of
antifungal maintenance therapy therefore appears to be safe for HIV-infected patients with treated DH if sustained immunologic
improvement is seen while on ART.

Prevention of Histoplasmosis
The disturbance of soil and other materials associated with a high risk of exposure to H capsulatum should be avoided by all persons with
HIV infection. In particular, avoidance of accumulations of bird or bat droppings is prudent. Prior to the availability of effective ART, a trial
comparing itraconazole 200 mg daily with placebo enrolled patients with AIDS who had CD4 counts <150 mg/L and were living in endemic
areas.(41) This study demonstrated a 2-fold reduction in the incidence of histoplasmosis in the itraconazole group compared with those
receiving placebo.(41) There was no survival benefit, however, associated with itraconazole prophylaxis. During the study period, the
overall rate of histoplasmosis in the placebo arm was low. Although the cost-benefit analysis did not support a recommendation for
adopting itraconazole prophylaxis in clinical practice, for regions experiencing high rates of histoplasmosis (>5 cases per 100 patient-years),
itraconazole prophylaxis should be considered for those at risk for this infection.(4)

References
1. Wheat LJ, Chetchotisakd P, Williams B, Connolly P, Shutt K, Hajjeh R. Factors associated with severe manifestations of histoplasmosis
in AIDS. Clin Infect Dis 2000; 30:877-81.
2. Sathapatayavongs B, Batteiger BE, Wheat J, Slama TG, Wass JL. Clinical and laboratory features of disseminated histoplasmosis
during two large urban outbreaks. Medicine (Baltimore) 1983; 62:263-70.
3. Leads from the MMWR. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Jama 1987;
258:1143-5, 1149, 1153-4.
4. Wheat J, Sarosi G, McKinsey D, Hamill R, Bradsher R, Johnson P, Loyd J, Kauffman C. Practice guidelines for the management of
patients with histoplasmosis. Infectious Diseases Society of America. Clin Infect Dis 2000; 30:688-95.

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5. Johnson PC, Khardori N, Najjar AF, Butt F, Mansell PW, Sarosi GA. Progressive disseminated histoplasmosis in patients with acquired
immunodeficiency syndrome. Am J Med 1988; 85:152-8.
6. Wheat LJ, Connolly-Stringfield PA, Baker RL, Curfman MF, Eads ME, Israel KS, Norris SA, Webb DH, Zeckel ML. Disseminated
histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature.
Medicine (Baltimore) 1990; 69:361-74.
7. Wheat J. Endemic mycoses in AIDS: a clinical review. Clin Microbiol Rev 1995; 8:146-59.
8. Chaturvedi S, Frame P, Newman SL. Macrophages from human immunodeficiency virus-positive persons are defective in host defense
against Histoplasma capsulatum. J Infect Dis 1995; 171:320-7.
9. McKinsey DS, Spiegel RA, Hutwagner L, Stanford J, Driks MR, Brewer J, Gupta MR, Smith DL, O'Connor MC, Dall L. Prospective study of
histoplasmosis in patients infected with human immunodeficiency virus: incidence, risk factors, and pathophysiology. Clin Infect Dis
1997; 24:1195-203.
10. Wheat J. Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol 1996; 7:7-18.
11. Karimi K, Wheat LJ, Connolly P, Cloud G, Hajjeh R, Wheat E, Alves K, Lacaz Cd Cda S, Keath E. Differences in histoplasmosis in patients
with acquired immunodeficiency syndrome in the United States and Brazil. J Infect Dis 2002; 186:1655-60.
12. Couppie P, Sobesky M, Aznar C, Bichat S, Clyti E, Bissuel F, El Guedj M, Alvarez F, Demar M, Louvel D, Pradinaud R, Carme B.
Histoplasmosis and acquired immunodeficiency syndrome: a study of prognostic factors. Clin Infect Dis 2004; 38:134-8.
13. Wheat J. Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature. Medicine (Baltimore) 1997; 76:33954.
14. Bottaro E, Elsner B, Cassetti Y. Histoplasmosis y HAART: aparicion de adenomegalis durante el tratmiento. In: Program and abstracts
of the Third Argentinean Congress on AIDS; 1997; Mar de Plata, Argentina.
15. Shelburne SA, 3rd, Visnegarwala F, Adams C, Krause KL, Hamill RJ, White AC, Jr. Unusual manifestations of disseminated
Histoplasmosis in patients responding to antiretroviral therapy. Am J Med 2005; 118:1038-41.
16. Breton G, Adle-Biassette H, Therby A, Ramanoelina J, Choudat L, Bissuel F, Huerre M, Dromer F, Dupont B, Lortholary O. Immune
reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. Aids 2006; 20:119-21.
17. Corcoran GR, Al-Abdely H, Flanders CD, Geimer J, Patterson TF. Markedly elevated serum lactate dehydrogenase levels are a clue to
the diagnosis of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis 1997; 24:942-4.

18. Kirn DH, Fredericks D, McCutchan JA, Stites D, Shuman M. Marked elevation of the serum ferritin is highly specific for disseminated
histoplasmosis in AIDS. Aids 1995; 9:1204-5.
19. Schlech WF, 3rd, Wheat LJ, Ho JL, French ML, Weeks RJ, Kohler RB, Deane CE, Eitzen HE, Band JD. Recurrent urban histoplasmosis,
Indianapolis, Indiana, 1980-1981. Am J Epidemiol 1983; 118:301-12.
20. Conces DJ, Jr., Stockberger SM, Tarver RD, Wheat LJ. Disseminated histoplasmosis in AIDS: findings on chest radiographs. AJR Am J
Roentgenol 1993; 160:15-9.
21. Williams B, Fojtasek M, Connolly-Stringfield P, Wheat J. Diagnosis of histoplasmosis by antigen detection during an outbreak in
Indianapolis, Ind. Arch Pathol Lab Med 1994; 118:1205-8.
22. Wheat LJ, Connolly-Stringfield P, Kohler RB, Frame PT, Gupta MR. Histoplasma capsulatum polysaccharide antigen detection in
diagnosis and management of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome. Am J Med 1989;
87:396-400.
23. Goldman M, Zackin R, Fichtenbaum CJ, Skiest DJ, Koletar SL, Hafner R, Wheat LJ, Nyangweso PM, Yiannoutsos CT, Schnizlein-Bick CT,
Owens S, Aberg JA. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to
antiretroviral therapy. Clin Infect Dis 2004; 38:1485-9.
24. Wheat J, Hafner R, Korzun AH, Limjoco MT, Spencer P, Larsen RA, Hecht FM, Powderly W. Itraconazole treatment of disseminated
histoplasmosis in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trial Group. Am J Med 1995; 98:336-42.
25. Norris S, Wheat J, McKinsey D, Lancaster D, Katz B, Black J, Driks M, Baker R, Israel K, Traeger D, et al. Prevention of relapse of
histoplasmosis with fluconazole in patients with the acquired immunodeficiency syndrome. Am J Med 1994; 96:504-8.
26. Wheat J, Hafner R, Wulfsohn M, Spencer P, Squires K, Powderly W, Wong B, Rinaldi M, Saag M, Hamill R, Murphy R, Connolly-Stringfield
P, Briggs N, Owens S. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency
syndrome. Ann Intern Med 1993; 118:610-6.

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27. Johnson PC, Wheat LJ, Cloud GA, Goldman M, Lancaster D, Bamberger DM, Powderly WG, Hafner R, Kauffman CA, Dismukes WE. Safety
and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients
with AIDS. Ann Intern Med 2002; 137:105-9.

28. Crommentuyn KM, Mulder JW, Sparidans RW, Huitema AD, Schellens JH, Beijnen JH. Drug-drug interaction between itraconazole and
the antiretroviral drug lopinavir/ritonavir in an HIV-1-infected patient with disseminated histoplasmosis. Clin Infect Dis 2004; 38:e73-5.
29. U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and
Adolescents. October 6, 2005. Accessed March 3, 3006.
30. Wheat J, MaWhinney S, Hafner R, McKinsey D, Chen D, Korzun A, Shakan KJ, Johnson P, Hamill R, Bamberger D, Pappas P, Stansell J,
Koletar S, Squires K, Larsen RA, Cheung T, Hyslop N, Lai KK, Schneider D, Kauffman C, Saag M, Dismukes W, Powderly W. Treatment of
histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious
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