What are the risks, diagnosis, and treatment for histoplasmosis infections?

Histoplasmosis: Risk Factors, Diagnosis, and Treatment

Risk Factors for Infection

HIV-infected persons with CD4+ counts <200 cells/µL should avoid high-risk activities including disturbing surface soil, cleaning heavily contaminated chicken coops, working beneath bird-roosting sites, demolishing old buildings, and exploring caves. 1

High-Risk Populations

• Immunocompromised patients are at greatest risk, particularly those with CD4+ T-lymphocyte counts <150 cells/µL for disseminated disease 1, 2
• HIV/AIDS patients with advanced disease represent the highest risk group 2
• Transplant recipients on immunosuppressive therapy are highly susceptible 3
• Patients with centrilobular emphysema commonly develop progressive pulmonary infection 1, 4
• Extremes of age (very young and elderly) carry increased risk 4

Environmental Exposures

• Bird and bat excrement in soil accelerates fungal sporulation and creates concentrated "microfoci" of organism 4
• Air currents can carry spores for miles, exposing individuals unaware of contaminated sites 4
• Geographic location matters: endemic areas include Ohio and Mississippi River valleys in the US, parts of Central and South America, Africa, and Asia 4

Diagnostic Approach

Tissue biopsy with fungal stains (Grocott methenamine silver or periodic acid-Schiff) is the gold standard for diagnosis, but Histoplasma antigen detection in urine or serum provides the most rapid diagnosis for disseminated disease. 2

Antigen Testing (First-Line for Disseminated Disease)

• Urine antigen is positive in 95% of disseminated cases 1
• Serum antigen is positive in 85% of disseminated cases 1
• Sensitivity is poor for localized pulmonary infection 1
• Useful for monitoring treatment response 2

Culture Methods

• Blood, bone marrow, or respiratory secretions yield positive cultures in >85% of cases 1
• Lysis-centrifugation method improves blood culture sensitivity 2
• Specialized fungal cultures should be specifically requested, as conventional blood cultures often miss the diagnosis 2
• Takes 2-4 weeks for isolation 1

Histopathology

• Fungal stains of blood smears or tissues provide rapid diagnosis but sensitivity is <50% 1
• Tissue biopsy remains the definitive diagnostic method 2

Serologic Testing

• Positive in approximately two-thirds of cases 1
• Most useful for chronic pulmonary histoplasmosis but less reliable in immunocompromised patients 2
• Rarely helpful for acute diagnosis 1

CNS Disease Diagnosis

• CSF fungal stains are usually negative 1
• CSF cultures are positive in no more than 50% of cases 1
• CSF antigen or antibodies can be detected in up to 70% of cases 1
• Presumptive diagnosis is appropriate if disseminated histoplasmosis exists with unexplained CNS findings 1

Testing NOT Recommended

• Routine skin testing with histoplasmin is not predictive of disease and should not be performed 1
• Routine serologic screening in endemic areas is not indicated 1

Treatment Recommendations

Severe/Disseminated Disease

For severe disseminated histoplasmosis (defined by fever >102°F, hypoxemia, hypotension, significant weight loss, or organ dysfunction), liposomal amphotericin B is superior to standard amphotericin B deoxycholate, inducing more rapid response, lower mortality, and reduced toxicity. 1, 2

Initial Therapy

• Liposomal amphotericin B for 1-2 weeks (or 3-10 days) until clinical improvement 1, 2
• Alternative lipid formulations of amphotericin B may be used if liposomal formulation is unavailable 2
• Amphotericin B deoxycholate can be used in patients at low risk for nephrotoxicity 2, 5
• Intravenous itraconazole 200 mg/day after initial higher-dose induction may be used for those who cannot tolerate amphotericin B 1

Step-Down Therapy

• Switch to oral itraconazole after clinical improvement to complete 12 weeks total treatment 1, 2
• Continue maintenance therapy with itraconazole 200 mg twice daily lifelong after completing initial treatment 1
• Fluconazole 800 mg daily is less effective than itraconazole but recommended as alternative if itraconazole cannot be tolerated 1

CNS Histoplasmosis

• Amphotericin B for 12-16 weeks followed by maintenance therapy 1
• Itraconazole for at least 1 year after amphotericin B 2

Mild-to-Moderate Disease

• Itraconazole 200 mg once daily for 6-12 weeks is recommended 1, 2
• Monitor itraconazole blood levels after at least 2 weeks of therapy to ensure adequate drug exposure 1, 2
• Check levels 2-4 hours post-dose in cases of suspected treatment failure, compliance concerns, absorption issues, or drug interactions 1

Acute Pulmonary Histoplasmosis

• No treatment needed for typical self-limited cases in immunocompetent patients 1
• Consider itraconazole 200 mg once daily for 6-12 weeks if no clinical improvement after 1 month of observation 1
• Treat immediately if diffuse radiographic involvement with hypoxemia is present 1
• Fever persisting ≥3 weeks may indicate progression to disseminated disease requiring treatment 1

Chronic Pulmonary Histoplasmosis

• Always requires treatment 1
• Itraconazole is the drug of choice 1

Special Populations

HIV-Infected Patients

• Do not withhold antiretroviral therapy due to concerns about immune reconstitution inflammatory syndrome, which is rare and usually not severe 2
• Prophylaxis with itraconazole is recommended for patients with CD4+ counts <100 cells/µL in hyperendemic areas (≥10 cases per 100 patient-years) or with high occupational exposure 1, 2
• Lifelong suppressive therapy with itraconazole 200 mg twice daily after acute treatment 1

Pregnant Women

• Avoid itraconazole during pregnancy due to embryotoxicity and teratogenicity in animal studies 1
• Amphotericin B is preferred, especially during first trimester 1
• Effective birth control should be recommended to all HIV-infected women on azole therapy 1

Children

• Lifelong suppressive therapy is a reasonable option after acute episode due to risk of disseminated infection 1

Conditions NOT Requiring Treatment

• Acute self-limited syndromes 1
• Mild acute pulmonary histoplasmosis in immunocompetent patients 1
• Rheumatologic syndromes 1
• Pericarditis 1
• Histoplasmoma 1
• Broncholithiasis 1
• Fibrosing mediastinitis 1

Important Caveats

• Granulomatous mediastinitis with obstruction should be considered for treatment, especially with elevated ESR or complement fixation titers >1:32, though efficacy is unproven 1
• Most patients recover without therapy, making the decision to treat versus observe critical 1
• Amphotericin B is specifically indicated for progressive, potentially life-threatening fungal infections and should not be used for noninvasive disease 5