Treatment of Histoplasmosis

Introduction to Treatment

• The Centers for Disease Control and Prevention recommends liposomal amphotericin B as the first-line treatment for moderate to severe disseminated histoplasmosis in patients with HIV and severe immunosuppression (CD4 <150 cells/mm³) 1, 2
• Amphotericin B is the first-line treatment for moderate to severe histoplasmosis due to its superior efficacy in reducing mortality compared to azole antifungals, with liposomal formulations showing higher response rates and lower mortality than conventional formulations, as recommended by the Infectious Diseases Society of America 2

Treatment Regimens

• Liposomal amphotericin B has been shown to have a higher response rate (88% vs 64%) and lower mortality (2% vs 13%) compared to conventional amphotericin B formulation 2
• The recommended dose of liposomal amphotericin B is 3-5 mg/kg IV daily for at least 2 weeks or until clinical improvement 1, 2
• Initial therapy with liposomal amphotericin B (L-AmB) 3-5 mg/kg IV daily for 1-2 weeks, followed by step-down therapy with itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily, is recommended by the Infectious Diseases Society of America 3, 2, 4
• The IDSA recommends itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily for 12 weeks as the treatment of choice for patients not requiring hospitalization (AII recommendation) 5
• Itraconazole has shown 85-100% response rates in various studies 5

Special Considerations

• Antiretroviral therapy should be initiated as soon as possible after patient stabilization 2
• Coinfection with tuberculosis and histoplasmosis can occur in patients with HIV, especially in endemic areas, and the presence of positive bacilloscopy for tuberculosis does not exclude the need for investigation for histoplasmosis in patients with prolonged fever and adenomegaly 1, 2
• Patients with CD4+ counts <150 cells/μL in endemic areas should avoid creating dust when working with surface soil, cleaning chicken coops, disturbing areas contaminated with bird or bat droppings, cleaning, remodeling, or demolishing old buildings, and exploring caves, as advised by the Centers for Disease Control and Prevention (CDC) 1, 2

Diagnostic Approaches

• The detection of antigen in blood or urine is a sensitive method for rapid diagnosis of disseminated histoplasmosis 1
• Urine antigen testing has a sensitivity of 79.5% overall and 95% in disseminated disease, while serum testing alone has a sensitivity of 83.9% (general) and 85% (disseminated disease), according to the American Thoracic Society 6
• Combined urine and serum antigen testing significantly increases sensitivity to 93%, as recommended by the American Thoracic Society 6
• Serologic testing (antibodies) has a sensitivity that varies by immune status, with 80-95% sensitivity in immunocompetent patients with pulmonary disease, as reported by the American Thoracic Society 6
• Fungal culture, considered the gold standard, can be isolated from blood, bone marrow, respiratory secretions, or other involved sites, and the lysis-centrifugation blood culture method is preferred, with improved sensitivity over conventional blood cultures 3
• The following table summarizes the diagnostic approaches:

• Tissue biopsy with fungal stains showing characteristic morphology is diagnostic even with negative antigen tests, with sensitivity varying with disease burden and host immune status 3, 7

Renal Considerations

• In patients with severe disease, renal impairment is common due to multi-organ failure caused by severe histoplasmosis or nephrotoxicity of amphotericin B, but treatment with liposomal amphotericin B should be maintained due to the poor prognosis justifying the use of the most effective therapy despite nephrotoxicity 2
• Daily monitoring of renal function, electrolytes, complete blood count, and liver function tests is recommended during amphotericin B therapy, as advised by the Clinical Infectious Diseases guidelines and the MMWR Recommendations and Reports 2, 8

Treatment Duration and Monitoring

• Treatment duration should be at least 12 months for immunocompromised patients and at least 6 months for non-immunosuppressed patients, as recommended by the Infectious Diseases Society of America 3
• Antigen levels should be measured during therapy and for 12 months after therapy completion, with therapy continuing until Histoplasma antigen concentrations are <4 units in urine and serum, as recommended by the Clinical Infectious Diseases guidelines and the Infectious Diseases Society of America 2, 5, 4

Pregnancy and Lifelong Suppressive Therapy

• In pregnant women, amphotericin B formulations are preferred due to the teratogenicity of azoles, as advised by the Clinical Infectious Diseases guidelines and the Infectious Diseases Society of America 2, 3
• Lifelong suppressive therapy with itraconazole 200 mg daily may be necessary in immunocompromised patients if immunosuppression cannot be reversed, as recommended by the Infectious Diseases Society of America 2

Alternative Therapies

• Fluconazole is less effective, with relapse occurring in nearly one-third of patients who received fluconazole maintenance therapy 5
• In vitro resistance to fluconazole can develop during treatment 5
• The Infectious Diseases Society of America (IDSA) does not recommend rezafungin for the treatment of histoplasmosis due to lack of clinical evidence supporting its efficacy for this fungal infection 5, 2