Histoplasmosis

Background

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 consider 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 are associated with significant risk of exposure:

  • Residence or travel in endemic areas (see above); in the United States, particularly the Ohio and Mississippi River Valleys
  • Occupational history of farming or construction/remodeling
  • Hobbies that involve contact with caves, bird roosts or nests, or farm areas
  • Contact with soil having a high organic content and undisturbed bird droppings, such as that found around old chicken coops and bird roosts
Table 1. Common Clinical Manifestations of Histoplasmosis
Symptom GroupPercentage of CasesExamples
Constitutional
95%
  • Weight loss
  • Fever
  • Fatigue
Gastrointestinal
>10%
  • Splenomegaly
  • Hepatomegaly
  • Diarrhea
  • Abdominal pain
Respiratory
50-60%
  • Pneumonia
  • Pneumonitis
Hematologic
>50%
  • Anemia
  • Leukopenia
  • Thrombocytopenia
Neurologic
15-20%
  • Meningitis, cerebritis
  • Encephalopathy
  • Focal parenchymal lesions
Septic
10-20%
  • Hypotension
  • Respiratory insufficiency
  • Renal or hepatic failure
  • Disseminated intravascular coagulopathy
  • High fever
Dermatologic
<10%
  • 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:

  • Other deep-seated fungal infections, such as cryptococcosis and coccidioidomycosis
  • Mycobacterial disease (Mycobacterium tuberculosis or Mycobacterium avium complex)
  • Pneumocystis pneumonia
  • Lymphoma

P: Plan

Diagnostic Evaluation

  • The H. capsulatum antigen test is sensitive and specific. The test is most sensitive for urine samples (>95% in disseminated disease), but can be used on serum (>85% sensitive in disseminated disease), bronchial fluids, or cerebrospinal fluid (CSF) specimens. Results may be obtained in a few days' time. Urine antigen levels can be used to monitor the response to therapy.
  • Cultures of blood, bone marrow, and specimens from other sources have reasonable sensitivity (about 85%), but obtaining results may take several weeks.
  • Wright stain of the buffy coat of a blood specimen may reveal intracellular organisms.
  • Biopsies of lymph nodes, liver, cutaneous lesions, and lungs may be diagnostic in up to 50% of cases; bone marrow can be stained with methenamine silver to show the organism within macrophages.
  • Meningitis can be challenging to diagnose. Diagnostically, Histoplasma antigen or anti-Histoplasma antibodies can be detected in CSF in up to 70% of cases, whereas results for cultures are often negative. Nonspecific findings in the CSF include elevated protein and low glucose as well as a lymphocytic pleocytosis. A diagnosis of Histoplasma meningitis should be considered if the patient has known disseminated disease and other more common etiologies of meningitis have been ruled out.
  • Lactate dehydrogenase (LDH) and ferritin, although not specific, may be markedly elevated in disseminated disease.
  • Complete blood count and chemistry panels may show pancytopenia, elevated creatinine, or abnormal liver function.

Treatment

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

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.

  • Induction therapy (≥2 weeks or clinically improved):
    • Preferred: Liposomal amphotericin B lipid formulation 3 mg/kg IV QD
    • Alternatives: Amphotericin B lipid complex or amphotericin B cholesteryl sulfate complex 3 mg/kg IV QD
  • Maintenance therapy: After ≥2 weeks of therapy or improvement of the patient's clinical status, therapy may be switched to itraconazole 200 mg PO TID for 3 days, then BID for at least 12 months of therapy. Liquid formulation of itraconazole is preferred.

Histoplasma meningitis

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

  • Induction therapy: Liposomal amphotericin B 5 mg/kg QD for 4-6 weeks
  • Maintenance therapy: Itraconazole 200 mg PO BID or TID for ≥12 months and until abnormal CSF findings resolve

Mild to moderate disseminated histoplasmosis without CNS involvement

  • Induction and maintenance therapy: Itraconazole 200 mg PO TID for 3 days followed by itraconazole 200 mg BID for ≥12 months; liquid formulation of itraconazole is preferred

Pulmonary histoplasmosis in patients with CD4 counts of >300 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; preferred therapy consists of itraconazole 200 mg PO QD. Fluconazole 800 mg QD 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 guidelines, discontinuing suppressive therapy for any patient who meets these criteria can be considered. Suppressive therapy should be restarted if the CD4 count drops to <150 cells/µL.

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 after 2 weeks of therapy as absorption of this drug can be erratic and interactions are expected between itraconazole and some ARVs.

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, prophylaxis with itraconazole 200 mg PO QD can be considered for high-risk patients whose CD4 counts are <150 cells/µL (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 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

There may be significant drug-drug interactions between certain systemic antifungals, (particularly itraconazole, voriconazole, and posaconazole) and ritonavir-boosted protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), elvitegravir/cobicistat, or maraviroc. Some combinations are contraindicated and others require dosage adjustment of the ARV, the antifungal, or both, and/or monitoring of drug levels. Check for adverse drug interactions before prescribing. See relevant tables in the U.S. Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, or consult with an expert.

Patient Education

  • Histoplasmosis is not transmitted from person to person, so isolation is not necessary.
  • Patients should take all their medications exactly as prescribed by their health care provider.
  • Even with maintenance therapy, relapses can occur. Patients should contact their provider immediately if symptoms worsen.
  • Persons with histoplasmosis should be treated with antiretroviral therapy.
  • The azoles may cause birth defects. Women who are taking azole medications should avoid pregnancy. In addition, itraconazole and other azoles interact with some antiretrovirals and other medications; patients should tell their provider if they begin taking any new medications while receiving itraconazole.

References

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly