What are the presentation, risk factors, diagnosis, and treatment options for a patient with suspected Histoplasma infection, particularly those with a history of exposure to contaminated soil or bird droppings and immunocompromised individuals?

Histoplasmosis: Presentation, Risk Factors, Diagnosis, and Treatment

Clinical Presentation

Histoplasmosis presents with highly variable manifestations depending on immune status and disease burden, ranging from asymptomatic infection to life-threatening disseminated disease.

Acute Pulmonary Histoplasmosis

• Fever, chills, headache, myalgia, cough, and chest pain are the hallmark symptoms 1
• Respiratory symptoms occur in approximately 50% of patients 2
• Most infections remain asymptomatic in immunocompetent hosts 3

Disseminated Histoplasmosis

• Fever, fatigue, weight loss, hepatosplenomegaly, and lymphadenopathy are the dominant features 2, 1
• Pancytopenia may be present 4
• Chest imaging often reveals a miliary pattern 4
• This form predominantly affects immunocompromised patients, particularly those with HIV and CD4+ counts <150 cells/µL 5

CNS Histoplasmosis

• Fever, headache, seizures, and mental status changes characterize neurological involvement 2
• Mortality reaches 20-40% despite treatment 6
• Single or multiple enhancing brain or spinal cord lesions may be visible on imaging 6

Risk Factors

Environmental Exposures

HIV-infected persons with CD4+ counts <150 cells/µL must avoid high-risk activities including creating dust when working with surface soil, cleaning chicken coops contaminated with droppings, disturbing areas with bird or bat droppings, demolishing old buildings, and exploring caves 5, 6.

• Histoplasma capsulatum thrives in soil contaminated with bat guano and bird excreta 6, 1
• Cave exploration represents a particularly high-risk activity, as demonstrated by recent outbreak investigations 7
• Specific environmental conditions—moderate climate, humidity, and excrement-enriched soil—create microfoci of concentrated fungal presence 1

Host Factors

• Immunocompromised patients, especially those with CD4+ counts <150 cells/µL, face greatest risk for disseminated disease 5, 6
• Patients with centrilobular emphysema are highly susceptible to progressive pulmonary infection 2
• Both immunocompromised and immunocompetent individuals can be affected, though severity differs markedly 2

Geographic Distribution

• Endemic regions include the Ohio and Mississippi River valleys in the United States 1
• Other endemic areas span parts of Central and South America, Africa, Asia, and the Caribbean 1
• Travelers to endemic areas face infection risk based on exposure intensity and immune status 1

Diagnosis

Rapid Diagnostic Testing

Urine antigen detection is the preferred first-line diagnostic test, demonstrating 95% sensitivity in disseminated histoplasmosis and achieving 93% sensitivity when combined with serum antigen testing 5, 2.

• Serum antigen testing shows 85% sensitivity in disseminated cases but poor sensitivity for localized pulmonary infection 5, 2
• A positive antigen test yields a posttest probability of 98% in immunocompromised patients with suspected histoplasmosis 2
• Overall antigen detection demonstrates 81.4% sensitivity with 98.3% specificity across all forms 2
• Antigen levels >16 pg/mL have 88% positive predictive value for moderate-to-severe disease requiring amphotericin B therapy 2

Definitive Diagnosis

Tissue biopsy with fungal stains (Grocott methenamine silver or periodic acid-Schiff) remains the gold standard, demonstrating characteristic 2-4 µm budding yeast forms 2, 5, 6.

• Blood cultures have approximately 50% sensitivity in advanced HIV, but lysis-centrifugation method improves yield 6
• Fungal cultures from blood, bone marrow, or respiratory secretions are positive in >85% of cases but require 2-4 weeks 2, 5
• Serological testing is most useful for chronic pulmonary histoplasmosis but unreliable in severe immunosuppression 6, 2

Diagnostic Pitfalls to Avoid

• Antigen detection is not available in many European centers, requiring high clinical suspicion in non-endemic areas 4
• Clinicians may focus on tuberculosis given suggestive imagery, missing the diagnosis 4
• Conventional blood cultures without specialized fungal culture requests may miss the diagnosis 2

Treatment

Severe Disseminated Disease

For severe disseminated histoplasmosis, liposomal amphotericin B at 3.0 mg/kg daily for 1-2 weeks until clinical improvement, followed by itraconazole 200 mg three times daily for 3 days then 200 mg twice daily for at least 12 months, is the treatment of choice 5, 2, 6.

Criteria defining severe disease include 5:

• Temperature >102°F
• Systolic blood pressure <90 mm Hg
• pO₂ <70 torr
• Weight loss >5%
• Karnofsky performance score <70
• Hemoglobin <10 g/dL
• Neutrophil count <1,000 cells/µL
• Platelet count <100,000 cells/µL
• AST >2.5 times normal
• Bilirubin or creatinine >2 times normal
• Albumin <3.5 g/dL
• Coagulopathy or confirmed meningitis

Liposomal amphotericin B is superior to amphotericin B deoxycholate, providing more rapid response and lower mortality 2, 6.

• Alternative lipid formulations of amphotericin B may be used if liposomal formulation is unavailable 6
• Amphotericin B deoxycholate can be used in patients at low risk for nephrotoxicity 6

Mild-to-Moderate Disease

Itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily for 6-12 weeks, is the treatment of choice for mild-to-moderate disease 6, 2, 5.

• Blood levels should be monitored after at least 2 weeks of therapy to ensure adequate drug exposure 2
• All immunocompromised patients with pulmonary histoplasmosis require treatment regardless of symptom severity 2

CNS Histoplasmosis

For CNS involvement, liposomal amphotericin B followed by itraconazole for at least 1 year is recommended, though outcomes remain poor with 20-40% mortality 2, 6.

• Amphotericin B 0.7-1 mg/kg/day to complete a 35 mg/kg total dose over 3-4 months has been used most often 6
• Fluconazole 800 mg daily might be continued for another 9-12 months after amphotericin B completion to reduce relapse risk 6
• Combining CSF antigen, antibody, and culture testing achieves highest diagnostic sensitivity 2

Asymptomatic Pulmonary Nodules

Isolated pulmonary nodules (histoplasmomas) in asymptomatic patients require no antifungal treatment, as they do not contain viable organisms and will not respond to antifungals 2.

Maintenance Therapy and Prophylaxis

Lifelong suppressive therapy with itraconazole 200 mg once or twice daily is recommended for HIV-infected patients who complete initial therapy 6.

• Prophylaxis with itraconazole 200 mg daily is recommended for HIV-infected patients with CD4+ counts <150 cells/µL who have occupational exposure or live in hyperendemic areas (≥10 cases per 100 patient-years) 5, 6
• Antigen levels should be monitored every 3-6 months during maintenance therapy and for 12 months after treatment completion 6, 2
• Amphotericin B 50 mg IV once weekly is an alternative for patients who cannot take itraconazole 6

Medications to Avoid

Fluconazole should not be used as first-line therapy due to lower success rates than itraconazole and emergence of resistance 2, 6.

• Fluconazole has reduced efficacy as chronic maintenance therapy 6
• Voriconazole is not routinely recommended 6

Special Populations

Pregnant Women

Amphotericin B is preferred for pregnant women, especially during the first trimester, due to embryotoxicity and teratogenicity of itraconazole in animal studies 2, 6.

• Effective birth control measures should be recommended to all HIV-infected women on azole therapy 6

HIV-Infected Patients

Antiretroviral therapy should not be withheld due to concerns about immune reconstitution inflammatory syndrome, which is rare and usually not severe 2.

• Disseminated histoplasmosis typically occurs with CD4+ counts <150 cells/µL 2
• Antibody testing has poor sensitivity (45%) in HIV/AIDS patients 2

Immunosuppressive Therapy

• Histoplasmosis secondary to tumor necrosis factor-α inhibitor therapy requires discontinuation of the TNF-α blocker during antifungal therapy 6
• After clinical response, immunosuppression might be reinstituted if antifungal treatment is administered for approximately 12 months and antigen test results are negative 6