Clinical Guide > Comorbidities and Complications > Histoplasmosis


January 2011

Chapter Contents


Histoplasmosis is caused by Histoplasma capsulatum, a fungus that thrives in soil contaminated by droppings from birds and bats. In the United States, H. capsulatum is found most often along the Ohio and Mississippi River Valleys, in the central, mid-Atlantic, and south-central states, and from Alabama to southwest Texas. In highly prevalent areas, such as Indianapolis and Kansas City, more than 80% of the population has been exposed to Histoplasma through inhalation of airborne infectious elements. Histoplasmosis also is found in the Canadian provinces of Quebec and Ontario, Puerto Rico, Mexico, Central and South America, Africa, East Asia, and Australia.

The initial infection in most cases either produces no symptoms or manifests only as a mild flulike illness. However, immunosuppressed individuals may develop disseminated disease. Progressive disseminated histoplasmosis often represents a reactivation of latent infection, occurs late in the course of HIV disease (the CD4 count usually is <150 cells/µL), and is an AIDS-defining illness. Pulmonary histoplasmosis (without dissemination) may occur in people with higher CD4 counts. Within endemic areas, histoplasmosis accounts for 5% of opportunistic infections among patients with AIDS. In hyperendemic areas, the prevalence of histoplasmosis may reach 25% among AIDS patients. The incidence of histoplasmosis in the United States has declined with the use of effective antiretroviral therapy (ART).

Common clinical features that may be associated with histoplasmosis are shown in Table 1.

S: Subjective

Histoplasmosis may be difficult to diagnose because the symptoms are nonspecific. In addition, clinicians may not suspect this diagnosis in low-prevalence areas.

Patients may experience fever, weight loss, fatigue, cough, and shortness of breath. They also may develop skin lesions, adenopathy, central nervous system (CNS) changes, oropharyngeal ulcers, nausea, diarrhea, and abdominal pain. Symptoms usually begin several weeks before patients present for care. On occasion, histoplasmosis presents abruptly as a sepsis-like syndrome.

Ask the patient about possible exposures, but note that absence of reported exposures does not rule out histoplasmosis. The following activities are associated with significant risk of exposure:

Table 1. Common Clinical Manifestations of Histoplasmosis

Symptom GroupPercentage of CasesExamples
  • Weight loss
  • Fever
  • Fatigue
  • Splenomegaly
  • Hepatomegaly
  • Diarrhea
  • Abdominal pain
  • Pneumonia
  • Pneumonitis
  • Anemia
  • Leukopenia
  • Thrombocytopenia
  • Meningitis, cerebritis
  • Encephalopathy
  • Focal parenchymal lesions
  • Hypotension
  • Respiratory insufficiency
  • Renal or hepatic failure
  • Disseminated intravascular coagulopathy
  • High fever
  • Follicular, pustular, maculopapular, or erythematous lesions

O: Objective

Measure vital signs and document fever.

Perform a complete physical examination, with special attention to the lymph nodes, lungs, abdomen, skin, and neurologic system.

Common findings include enlargement of the liver, spleen, and lymph nodes. Skin lesions and oropharyngeal ulcers may be seen.

A: Assessment

A partial differential diagnosis includes the following:

P: Plan

Diagnostic Evaluation


Treatment consists of two phases: induction and chronic maintenance. Treatment should be continued for at least 12 months.

Mild to moderate disseminated histoplasmosis without CNS involvement

Severe disseminated histoplasmosis

Severe infection requires IV induction therapy with a lipid formulation of amphotericin; standard amphotericin is less effective and is associated with more adverse effects, but may be used as an alternative.

Histoplasma meningitis

Amphotericin B must be used because itraconazole has poor penetration into the CNS:

Pulmonary histoplasmosis in patients with CD4 counts of >350 cells/µL

Manage as for non-immunocompromised patients.

See "Potential ARV Interactions," below, regarding azoles.

Long-term suppressive therapy

Long-term therapy must be given to prevent relapse after 12 months of initial treatment; this typically consists of itraconazole 200 mg PO once daily. Fluconazole 800 mg once daily is less effective but can be used as an alternative for patients who cannot tolerate or cannot obtain itraconazole. Voriconazole and posaconazole appear to be effective. (See "Potential ARV Interactions," below, regarding azoles.)

Few data support the discontinuation of chronic maintenance therapy. One small study sponsored by the AIDS Clinical Trials Group demonstrated safety in discontinuing suppressive itraconazole therapy for patients who met the following criteria: had completed >1 year of itraconazole therapy, negative blood cultures, Histoplasma serum antigen <2 units, CD4 counts >150 cells/µL, and had been on ART for ≥6 months. Therefore, per U.S. Centers for Disease Control and Prevention (CDC) guidelines, discontinuing suppressive therapy for any patient who meets these criteria can be considered.

Monitoring and relapse

Monitor either serum or urine Histoplasma antigen, as well as clinical status, to evaluate response to therapy; a rise in the antigen level suggests relapse of histoplasmosis. A drug level of itraconazole should be measured at least once during therapy as absorption of this drug can be erratic.

In cases of treatment failure, both voriconazole and posaconazole have been successful in a few case reports; if treatment failure is suspected, an infectious disease specialist should be consulted.

Primary Prophylaxis

Currently, there are no studies that prove any survival benefit in using primary prophylaxis; however, for patients with CD4 counts of <150 cells/µL, prophylaxis with itraconazole 200 mg PO once daily can be considered for high-risk patients (e.g., those with occupational exposure and those who reside in hyperendemic regions). HIV-infected patients with CD4 counts of ≤150 cells/µL should be educated about precautions for avoiding exposure.

Primary prophylaxis can be discontinued if the CD4 count remains >150 cells/µL for 6 months on effective ART; prophylaxis should be restarted if the CD4 count drops to ≤150 cells/µL.

Potential ARV Interactions

Note that azoles (particularly itraconazole, posaconazole, and voriconazole) may interact with certain protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and other medications); some combinations are contraindicated.

Patient Education