What is the recommended diagnostic workup and treatment for a patient suspected of having histoplasmosis, particularly one with a history of exposure to bird or bat droppings, or an immunocompromised individual presenting with symptoms such as fever, cough, and fatigue?

Histoplasmosis Workup

Diagnostic Approach

For suspected histoplasmosis, immediately obtain urine and serum Histoplasma antigen testing, as urine antigen is positive in 95% of disseminated cases and provides the most rapid diagnosis. 1

Initial Diagnostic Testing

• Urine antigen testing is the preferred first-line diagnostic test, detecting antigen in 95% of disseminated histoplasmosis cases 2, 1
• Serum antigen testing is positive in 85% of disseminated cases but has poor sensitivity for localized pulmonary infection 2, 1
• Blood cultures using the lysis-centrifugation method yield positive results in >85% of cases, though isolation requires 2-4 weeks 2, 1
• Fungal stains (Grocott methenamine silver or periodic acid-Schiff) of blood smears or tissues provide rapid diagnosis but have <50% sensitivity 2, 1

Tissue Diagnosis

• Tissue biopsy with fungal stains is the gold standard for definitive diagnosis, as recommended by the Infectious Diseases Society of America 1
• Histopathologic examination demonstrates characteristic 2-4 µm budding yeast forms 2
• Request specialized fungal cultures rather than conventional blood cultures, which frequently miss the diagnosis 1

Serologic Testing

• Serologic tests are positive in approximately two-thirds of cases but are rarely helpful for acute diagnosis 2
• Most useful for chronic pulmonary histoplasmosis in immunocompetent patients 1
• Less reliable in immunocompromised patients 1

CNS Involvement Evaluation

• For suspected CNS histoplasmosis, perform lumbar puncture showing lymphocytic pleocytosis, elevated protein, and low glucose 2, 3
• CSF fungal stains are usually negative, and cultures are positive in <50% of cases 2
• Histoplasma antigen or antibodies in CSF are detected in up to 70% of cases and are diagnostic 2, 1
• A presumptive diagnosis is appropriate if disseminated histoplasmosis is present with CNS findings unexplained by other causes 2

Clinical Assessment for Disease Severity

Severe Disease Criteria (Requiring IV Amphotericin B)

Patients meeting one or more of the following criteria have severe disease 2:

• Temperature >102°F (>39°C)
• 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 other organ dysfunction
• Confirmed meningitis

Risk Stratification by Immune Status

• Disseminated disease typically occurs in patients with CD4+ counts <150 cells/µL 2, 3
• Localized pulmonary disease may occur in patients with CD4+ counts >300 cells/µL 2, 3
• Immunocompetent patients with low-level exposure typically have self-limited disease 3

Treatment Recommendations

Severe Disseminated Histoplasmosis

Initiate 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. 2, 1

• Liposomal amphotericin B is superior to amphotericin B deoxycholate, inducing more rapid response, lower mortality, and reduced toxicity 2, 1
• Alternative lipid formulations (ABLC at 5.0 mg/kg daily) may be substituted due to cost or tolerability 2, 1
• Amphotericin B deoxycholate can be used in patients at low risk for nephrotoxicity 1

Mild-to-Moderate Disseminated Histoplasmosis

• Itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily is appropriate initial therapy 2, 1
• The liquid formulation is preferred due to better absorption and fewer food interactions 2
• Monitor blood levels after at least 2 weeks of therapy to ensure adequate drug exposure 1
• Continue for 6-12 weeks for mild-to-moderate disease 1

CNS Histoplasmosis

• Liposomal amphotericin B at 5 mg/kg daily for 4-6 weeks, followed by itraconazole 200 mg two or three times daily for at least 1 year and until resolution of abnormal CSF findings 2, 1

Special Populations

Pregnancy

• Amphotericin B should be used in the first trimester to avoid teratogenicity with itraconazole 2, 1
• Itraconazole is embryotoxic and teratogenic 1

HIV-Infected Patients

• Do not withhold antiretroviral therapy due to concerns about immune reconstitution inflammatory syndrome, which is rare and usually not severe 1
• Lifelong suppressive therapy with itraconazole is recommended for patients with CD4+ counts <100 cells/µL 1
• Maintenance therapy can be discontinued if CD4+ counts rise to >150 cells/µL for 6 months on ART 2

Prevention Strategies

High-Risk Activity Avoidance

HIV-infected persons with CD4+ counts <150 cells/µL should avoid 2, 1:

• Creating dust when working with surface soil
• Cleaning chicken coops contaminated with droppings
• Disturbing areas contaminated with bird or bat droppings
• Cleaning, remodeling, or demolishing old buildings
• Exploring caves

Primary Prophylaxis

• Itraconazole 200 mg daily can be considered for patients with CD4+ counts <150 cells/µL who have occupational exposure or live in hyperendemic areas (>10 cases/100 patient-years) 2
• Discontinue prophylaxis once CD4+ counts are >150 cells/µL for 6 months on ART 2

Occupational Protection

• N95 respirators or higher should be used during cleanup of areas with bat or bird droppings, not standard surgical masks 4, 5

Critical Diagnostic Pitfalls

• Do not confuse pigeon exposure with histoplasmosis risk—pigeon droppings are associated with psittacosis (Chlamydia psittaci), not histoplasmosis 4
• Histoplasmosis is associated with bat droppings and chicken coops, not pigeons 4, 5
• Always obtain travel history to endemic areas (Ohio/Mississippi River valleys, Central America, caves) 4, 6
• Consider environmental exposures including mold and infected birds in immunocompromised patients 6