Treatment and Workup of Disseminated Histoplasmosis
Immediate Treatment Based on Disease Severity
For immunocompromised patients with severe disseminated histoplasmosis, initiate liposomal amphotericin B at 3-5 mg/kg IV daily for 1-2 weeks until clinical improvement, then transition to itraconazole 200 mg three times daily for 3 days followed by 200 mg twice daily to complete at least 12 weeks of total therapy. 1, 2
Defining Severe Disease
Severe disease is indicated by any of the following criteria 3:
- Temperature >39°C (>102°F)
- Systolic blood pressure <90 mm Hg
- pO2 <70 torr or respiratory insufficiency requiring ventilatory support
- Weight loss >5%
- Karnofsky performance score <70
- Hemoglobin <10 g/dL
- Neutrophil count <1000 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 system dysfunction
Amphotericin B Formulation Selection
Liposomal amphotericin B is superior to amphotericin B deoxycholate, demonstrating 88% vs 64% response rates and 2% vs 13% mortality in AIDS patients with disseminated disease. 2, 4 Amphotericin B lipid complex (5 mg/kg/day) is an acceptable alternative due to lower cost. 1, 2 Standard amphotericin B deoxycholate (0.7-1.0 mg/kg/day) can be used but has higher nephrotoxicity. 3
Mild to Moderate Disease
For patients not requiring hospitalization with mild symptoms, itraconazole alone is appropriate: 200 mg three times daily for 3 days, then 200 mg twice daily for 12 weeks. 3, 1, 2 The liquid formulation is preferred over capsules due to superior absorption. 1
Diagnostic Workup
Primary Diagnostic Tests
Obtain urine and serum Histoplasma antigen testing immediately—this is the most sensitive rapid diagnostic method. 3
- Urine antigen: 95% sensitive in disseminated disease 3
- Serum antigen: 85% sensitive in disseminated disease 3
- Antigen is detectable before culture positivity and antibody formation 3
Additional Diagnostic Studies
Obtain blood cultures, bone marrow cultures, and cultures from any involved sites—positive in >85% of disseminated cases but require 2-4 weeks. 3 Fungal stains of blood smears or tissues provide rapid diagnosis but sensitivity is <50%. 3
Serologic antibody testing is positive in approximately two-thirds of AIDS patients but rarely helpful for acute diagnosis. 3 In immunosuppressed patients, antibody tests may be undetectable. 3
CNS Involvement Evaluation
If CNS histoplasmosis is suspected, obtain CSF for 3:
- Histoplasma antigen (positive in 40-70%)
- Antibody testing (positive in 70-90%)
- Fungal culture (positive in only 20-60%)
The highest diagnostic sensitivity is achieved by testing CSF for all three parameters. 3
Cross-Reactivity Warning
Histoplasma antigen can cross-react with blastomycosis, paracoccidioidomycosis, and Penicillium marneffei infections. 3
Special Treatment Considerations
CNS Histoplasmosis
For confirmed meningitis, continue amphotericin B for 12-16 weeks (not 1-2 weeks), followed by lifelong maintenance therapy with itraconazole. 3 Some guidelines suggest amphotericin B for 3 months then fluconazole for 12 months, but itraconazole is preferred based on efficacy data. 3
Adjunctive Corticosteroid Therapy
For patients with respiratory complications or hypoxemia, add methylprednisolone 0.5-1.0 mg/kg IV daily (maximum 80 mg) during the first 1-2 weeks. 1, 2 Concurrent itraconazole is mandatory to prevent progressive infection from corticosteroid-induced immunosuppression. 1, 2
HIV-Infected Patients
Do not delay antiretroviral therapy due to concerns about immune reconstitution inflammatory syndrome (IRIS)—it is rare and generally not severe in histoplasmosis. 1 Outcomes are significantly better in patients receiving antiretroviral therapy (100% vs 47% response rate). 1
Lifelong suppressive therapy with itraconazole 200 mg daily is mandatory to prevent relapses in HIV patients with disseminated disease. 3, 1, 2 Without maintenance therapy, relapse rates approach 90% in immunocompromised patients. 3
Critical Monitoring Requirements
Itraconazole Serum Levels
Measure itraconazole blood levels after at least 2 weeks of therapy to ensure adequate drug exposure. 1, 2 Target concentration is ≥1 µg/mL (ideally trough level). 3, 1, 2 Monitor in cases of suspected treatment failure, concern about compliance or absorption, or use of medications that reduce itraconazole solubility or accelerate metabolism. 3
Histoplasma Antigen Monitoring
Monitor antigen in serum and urine during therapy and for 12 months after completing treatment. 1 Antigen concentrations decline with effective treatment at rates of 0.2 units/week in urine and 0.3 units/week in serum. 3 An increase in antigen (>2-4 units) indicates relapse. 3, 1
Hepatic Function Monitoring
Measure hepatic enzymes before starting azole therapy, then recheck at 1,2, and 4 weeks, then every 3 months during treatment. 2 Asymptomatic transaminase increases occur in 1-13% of patients receiving azoles; rare cases of fatal hepatitis have been reported. 3
Common Pitfalls to Avoid
Itraconazole Absorption Issues
Itraconazole capsules require high gastric acidity and must be taken with food or cola. 2 Do not use in patients taking antacids, H2 blockers, or proton pump inhibitors due to severely impaired absorption. 2 The liquid formulation avoids this problem. 1
Drug Interactions
Carefully evaluate potential drug interactions before initiating azole therapy due to cytochrome P-450 inhibition. 3 Cardiac toxicity has been reported with concomitant terfenadine or astemizole use. 3
Fluconazole as Primary Therapy
Avoid fluconazole as primary therapy—it is less effective than itraconazole (64% vs 85% response rate) and resistance can develop. 3, 2 Fluconazole 800 mg daily is only acceptable when itraconazole cannot be tolerated. 3, 1 Even at high doses (400-800 mg daily), fluconazole remains inferior. 3
Amphotericin B Nephrotoxicity
Permanent nephrotoxicity is related to cumulative amphotericin B dose. 3 Ameliorate nephrotoxicity by administering 0.9% saline IV over 30 minutes before each amphotericin B infusion. 3
Treatment Failure Options
For treatment failures, posaconazole 800 mg/day has been successful in HIV patients whose previous therapies failed. 1 Voriconazole has been used in some cases but has in vitro cross-resistance with fluconazole. 1
Pregnancy Considerations
Amphotericin B is preferred in pregnant women, especially during the first trimester, due to embryotoxicity and teratogenicity of itraconazole. 1