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)
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.)
|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 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)
|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/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.
|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/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)