Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Histoplasmosis   Epidemiology    Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum and occurs in 2%--5% of patients with AIDS who reside in areas in the United States where the disease is endemic (e.g., the Midwest and Puerto Rico) and who are not receiving ART. In areas where the disease is not endemic, it most often occurs among those who have previously lived in an area where the disease is endemic. Histoplasmosis is acquired by inhalation of microconidia of the mycelial phase of the organism, but reactivation of latent infection might be a mechanism for disease in certain patients. Disseminated histoplasmosis usually occurs among persons with CD4+ T lymphocyte counts <150 cells/µL; localized pulmonary histoplasmosis might occur among persons with CD4+ T lymphocyte counts >300 cells/µL. The incidence of histoplasmosis appears to have declined with the use of potent ART. Clinical Manifestations The most common clinical presentation of histoplasmosis among patients with AIDS is disseminated multiorgan disease. Patients usually have fever, fatigue, and weight loss; respiratory tract symptoms of cough, chest pain, and dyspnea might occur in up to 50% of patients . Symptoms and signs might be limited to the respiratory tract for those with higher CD4+ T lymphocyte counts and localized pulmonary histoplasmosis. Septic shock syndrome occurs in <10% of patients. CNS, gastrointestinal, and cutaneous manifestations each occur in <10% of cases, and other sites might be less commonly involved. Diagnosis Detection of Histoplasma antigen in blood or urine is a sensitive method for rapid diagnosis of disseminated histoplasmosis but insensitive for pulmonary infection. Antigen is detected in the urine of 95% and serum of 85% of patients with disseminated histoplasmosis and might be present in bronchoalveolar lavage fluid or CSF of patients with pulmonary or meningeal involvement. Fungal stain of blood smears or tissues also might yield a rapid diagnosis, but the sensitivity is <50%. H. capsulatum can be isolated from blood, bone marrow, respiratory secretions or localized lesions in >85% of cases, but isolation can take 2--4 weeks . Serologic tests are positive in approximately two thirds of cases but are rarely helpful in the acute diagnosis of histoplasmosis disease. Diagnosis of meningitis poses added difficulties. Fungal stains are usually negative, and CSF cultures are positive in no more than half of cases . Antigen or anti-Histoplasma antibodies can be detected in the CSF in up to 70% of cases. Among certain patients, none of these tests are positive, and a presumptive diagnosis of Histoplasma meningitis might be appropriate if the patient has disseminated histoplasmosis and findings of CNS infection not explained by another cause. Treatment Recommendations Patients with severe disseminated histoplasmosis who meet one or more selected criteria (temperature >102oF [>39oC], systolic blood pressure <90 mm Hg, pO2 <70 torr, weight loss >5%, Karnofsky performance score <70, hemoglobin <10 g/dL, neutrophil count <1000 cells/µL, platelet count <100,000 cells/µL, aspartate aminotransferase >2.5 times normal, bilirubin or creatinine >2 times normal, albumin <3.5 g/dL, coagulopathy, presence of other organ system dysfunction, or confirmed meningitis) should be treated with intravenous amphotericin B, either the deoxycholate formulation or liposomal amphotericin B, for the first 3--10 days until they clinically improve  (AI). In a randomized clinical trial, liposomal amphotericin B was more effective than the standard deoxycholate formulation, inducing a more rapid and more complete response, lowering mortality, and reducing toxicity (BI). Intravenous itraconazole 200 mg/day after an initial higher dose induction period might be used for persons who cannot tolerate amphotericin B (BIII). Patients responding well after completion of initial amphotericin B therapy for 3--10 days might be switched to oral therapy with itraconazole capsules to complete 12 weeks of treatment and then placed on maintenance treatment  (AII). Itraconazole solution would be logical to use, but no trials document efficacy and tolerability in this setting. Fluconazole 800 mg daily is less effective than itraconazole (373), but is recommended as an alternative if patients cannot tolerate itraconazole (CII). For persons with confirmed meningitis, amphotericin B should be continued for 12--16 weeks, followed by maintenance therapy (AII). Fluconazole has been recommended previously among HIV-1--uninfected persons with meningitis following amphotericin B; however, because of the data documenting efficacy of itraconazole in persons with HIV-1 disease and nonmeningeal histoplasmosis, itraconazole should be used in this setting (AII). Among persons with mild illness, therapy with itraconazole capsules for 12 weeks is recommended (AII). Acute pulmonary histoplasmosis in an HIV-1--infected patient with intact immunity, as indicated by a CD4+ T lymphocyte count >500 cells/µL, might not require therapy and should be managed in a similar way to infection in an otherwise noncompromised host (370) (AIII). Prevention of Recurrence Patients who complete initial therapy for histoplasmosis should be administered lifelong suppressive treatment (i.e., secondary prophylaxis or chronic maintenance therapy) with itraconazole 200 mg twice daily (AI). Certain specialists recommend serum levels be tested to ensure free itraconazole concentrations of at least 1 mg/mL or free plus hydroxylated metabolite of 2 µg/mL. The metabolite also has antifungal activity. Although patients might be at low risk for recurrence of systemic mycosis when their CD4+ T lymphocyte counts increase to >100 cells/µL in response to ART, the number of patients who have been evaluated is insufficient to warrant a recommendation to discontinue secondary prophylaxis in this setting. Special Considerations During Pregnancy Treatment is the same as for nonpregnant adults. Because fluconazole is teratogenic in high doses in animal studies and itraconazole is teratogenic in high doses among rats and mice, as with other invasive fungal infections, amphotericin B should be substituted for itraconazole or fluconazole (if indicated) in the first trimester (BIII).