Comprehensive, up-to-date information on HIV/AIDS treatment and prevention from the University of California San Francisco

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.

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 10⁵ particles per gram of soil.

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)

In patients with AIDS, histoplasmosis presents as a progressive disseminated infection in 95% of cases. The majority of AIDS patients with disseminated disease have CD4 counts <150 cells/µL, with a median CD4 count of 50 cells/µL.(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 6-19%.(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 (1-7%) 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/µL, 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 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)

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 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)

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.

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, 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 µg/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.

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)

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 µg/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)

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/µL. 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/µL. 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.

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/µL 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)