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Histoplasmosis
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Epidemiology

Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. In the United States, infection is common in several regions where the disease is endemic, especially the Ohio and Mississippi River Valleys. It is also endemic in Latin America, including Puerto Rico. Among persons with HIV infection residing in areas in which histoplasmosis is endemic, symptomatic disease occurs at an annual incidence approaching 5%. Environmental exposure, positive Histoplasma serology, and a CD4+ count ≤150 cells/µL are associated with an increased risk for symptomatic illness (613McKinsey DS, Spiegel RA, Hutwagner L, et al. Prospective study of histoplasmosis in patients infected with human immunodeficiency virus: incidence, risk factors, and pathophysiology. Clin Infect Dis 1997;24:1195-203.).

Virtually all cases of primary histoplasmosis are acquired by inhalation of microconidia from the mycelial phase of the organism. Asymptomatic dissemination of infection beyond the lungs is common and cellular immunity is critical in controlling infection. Reactivation of a silent focus of infection that was acquired years earlier can occur when cellular immunity wanes and is the presumed mechanism for disease occurrence in nonendemic areas. The incidence of symptomatic histoplasmosis in patients with HIV infection appears to have declined since the use of potent ART.

Clinical Manifestations

Disseminated histoplasmosis usually occurs in patients with CD4+ counts ≤150 cells/µL (614Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-74.). Common clinical manifestations include fever, fatigue, weight loss, hepatosplenomegaly, and lymphadenopathy (615Sarosi GA, Johnson PC. Disseminated histoplasmosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1992;14(Suppl 1):S60-7.). Cough, chest pain, and dyspnea occur in approximately 50% of patients (614Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-74.). CNS, gastrointestinal, and cutaneous manifestations occur in a smaller percentage (670Karimi K, Wheat LJ, Connolly P, et al. Differences in histoplasmosis in patients with acquired immunodeficiency syndrome in the United States and Brazil. J Infect Dis 2002;186:1655-60.), and <10% of patients experience shock and multi-organ failure. Other anatomic sites are less commonly involved. Patients with CNS histoplasmosis typically experience fever, headache, and, if brain involvement is present, seizures, focal neurological deficits, and changes in mental status (614Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-74., 616Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005;40:844-52.). Gastrointestinal disease usually is manifested by diarrhea, fever, abdominal pain, and weight loss (617Assi M, McKinsey DS, Driks MR, et al. Gastrointestinal histoplasmosis in the acquired immunodeficiency syndrome: report of 18 cases and literature review. Diagn Microbiol Infect Dis 2006;55:195-201.). For patients with CD4+ counts >300 cells/µL, symptoms and signs of histoplasmosis are often limited to the respiratory tract.

Diagnosis

Detection of Histoplasma antigen in blood or urine is a sensitive method for rapid diagnosis of disseminated histoplasmosis but is insensitive for pulmonary infection. Antigen is detected in the urine of 95% and serum of 85% of AIDS patients with disseminated histoplasmosis (618Williams B, Fojtasek M, Connolly-Stringfield P, Wheat J. Diagnosis of histoplasmosis by antigen detection during an outbreak in Indianapolis, Ind. Arch Pathol Lab Med 1994;118:1205-8.). In patients with severe disseminated histoplasmosis, peripheral blood smears can show the organisms engulfed by WBCs. Histopathologic examination of biopsy material from involved tissues demonstrates the characteristic 2-4 µm budding yeast and can provide a rapid diagnosis.

H. capsulatum can be cultured from blood, bone marrow, respiratory secretions, or other involved sites in >85% of patients with AIDS, but organisms might require several weeks to grow (614Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-74., 618Williams B, Fojtasek M, Connolly-Stringfield P, Wheat J. Diagnosis of histoplasmosis by antigen detection during an outbreak in Indianapolis, Ind. Arch Pathol Lab Med 1994;118:1205-8.). Serologic tests are less useful than antigen assays in AIDS patients with disseminated histoplasmosis, but might be helpful in patients who have intact immune responses.

The diagnosis of meningitis can be difficult. A lymphocytic pleocytosis is usually associated with elevated protein and low glucose. Fungal stains are usually negative, and CSF cultures are positive in a minority of cases (619Wheat J. Current diagnosis of histoplasmosis. Trends Microbiol 2003;11:488-94.). Histoplasma antigen or anti-Histoplasma antibodies can be detected in CSF in up to 70% of cases and either is diagnostic. For some patients, none of these tests are positive, and a presumptive diagnosis of Histoplasma meningitis is appropriate if the patient has disseminated histoplasmosis and findings of CNS infection not explained by another cause.

Preventing Exposure

Although HIV-infected persons living in or visiting areas in which histoplasmosis is endemic cannot completely avoid exposure, those whose CD4+ counts are ≤150 cells/µL should avoid activities known to be associated with increased risk (CIII). Such activities include creating dust when working with surface soil; cleaning chicken coops that are contaminated with droppings; disturbing areas contaminated with bird or bat droppings; cleaning, remodeling, or demolishing old buildings; and exploring caves (CIII).

Preventing Disease
Initiating Primary Prophylaxis

Data from a prospective, randomized, controlled trial indicate that itraconazole can reduce the frequency of histoplasmosis among patients who have advanced HIV infection and who live in areas in which histoplasmosis is highly endemic (594McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999;28:1049-56.). However, no survival benefit was observed among persons receiving itraconazole.

Prophylaxis with itraconazole at a dose of 200 mg daily can be considered for patients with CD4+ counts ≤150 cells/µL who are at high risk because of occupational exposure or who live in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years) (CI).

Discontinuing Primary Prophylaxis

If used, primary prophylaxis can be discontinued once peripheral blood CD4+ counts are >150 cells/µL for 6 months in patients on potent ART (BIII). Prophylaxis should be restarted if the CD4+ counts fall to ≤150 cells/µL (CIII).

Treatment of Disease

Patients with moderately severe to severe disseminated histoplasmosis should be treated with an IV lipid formulation of amphotericin B for ≥2 weeks (or until they improve clinically) followed by oral itraconazole (200 mg three times daily for 3 days and then 200 mg twice daily for a total of >12 months) (AI) (620Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002;137:105-9., 621Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000;30:688-95.).

In a randomized clinical trial, liposomal amphotericin B at 3.0 mg/kg daily was more effective than standard amphotericin B deoxycholate at 0.7 mg/kg daily (620Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002;137:105-9.), inducing a more rapid and more complete response, lowering mortality, and reducing toxicity. Substitution with ABLC at 5.0 mg/kg daily may be an alternative because of cost or tolerability (CIII).

In patients with less severe disseminated histoplasmosis, oral itraconazole at 200 mg three times daily for 3 days followed by 200 mg twice daily is appropriate initial therapy (AII) (622Wheat J, Hafner R, Korzun AH, et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Med 1995;98:336-42.). The liquid formulation of intraconazole is preferred, owing to better absorption and fewer food interactions.

For persons with confirmed meningitis, liposomal amphotericin B should be administered as initial therapy for 4-6 weeks at a dosage of 5 mg/kg daily. This should be followed by maintenance therapy with itraconazole at a dose of 200 mg two or three times daily for a total of ≥1 year and until resolution of abnormal CSF findings (AII) (616Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005;40:844-52.).

Posaconazole has been reported in some salvage studies to be of some benefit (623Restrepo A, Tobon A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect 2007;54:319-27.). Fluconazole has limited to no activity against histoplasmosis and should not be used. The role of other azoles, including voriconazole, is not clear. Voriconazole should be used cautiously with HIV PIs and efavirenz. No published data exist regarding the use of echinocandins for treating patients with histoplasmosis.

Acute pulmonary histoplasmosis in an HIV-infected patient with intact immunity, as indicated by a CD4+ count >300 cells/µL, should be managed in a manner similar to that used for a nonimmunocompromised host (AIII) (621Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000;30:688-95.).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Serial monitoring of serum or urine for Histoplasma antigen is useful for determining response to therapy. A rise in level is suggestive of a relapse (AIII). Because absorption of itraconazole can be erratic, serum itraconazole levels should be obtained at least once in all patients to ensure adequate absorption (AIII). The serum concentration should be >1 µg/mL, ideally drawn for reasons of consistency as a trough level after at least 7 days on the current regimen. Itraconazole solution is recommended over the capsule formulation because absorption is improved, but this has not been studied specifically in AIDS patients.

IRIS has been reported uncommonly in patients with histoplasmosis (605Shelburne SA, Darcourt J, White AC, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005; 40:1049-52., 624Tobon AM, Agudelo CA, Rosero DS, et al. Disseminated histoplasmosis: a comparative study between patients with acquired immunodeficiency syndrome and non-human immunodeficiency virus-infected individuals. Am J Trop Med Hyg 2005;73:576-82., 625Nacher M, Sarazin F, El Guedj M, et al. Increased incidence of disseminated histoplasmosis following highly active antiretroviral therapy initiation. J Acquir Immune Defic Syndr 2006;41:468-70.). ART should not be withheld because of concern for the possible development of IRIS (AIII).

Management of Treatment Failure

Posaconazole solution at 800 mg daily was recently reported to be successful in three patients with HIV infection whose other previous therapies had failed (623Restrepo A, Tobon A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect 2007;54:319-27.). Voriconazole has been used in several transplant recipients and in one patient with AIDS who failed or could not tolerate therapy with other agents (626Al-Agha OM, Mooty M, Salarieh A. A 43-year-old woman with acquired immunodeficiency syndrome and fever of undetermined origin: disseminated histoplasmosis. Arch Pathol Lab Med 2006;130:120-3., 627Freifeld AG, Iwen PC, Lesiak BL, et al. Histoplasmosis in solid organ transplant recipients at a large Midwestern university transplant center. Transpl Infect Dis 2005;7:109-15.). Cross resistance between fluconazole and voriconazole has been noted in vitro (628Wheat LJ, Connolly P, Smedema M, et al. Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole. J Antimicrob Chemother 2006;57:1235-9.).

Preventing Recurrence

Long-term suppressive therapy with itraconazole (200 mg daily) should be administered for patients with severe disseminated or CNS infection (AII) and in patients who relapse despite receipt of appropriate therapy (CIII). Fluconazole 800 mg daily is less effective than itraconazole (CII) (629Hecht FM, Wheat J, Korzun AH, et al. Itraconazole maintenance treatment for histoplasmosis in AIDS: a prospective, multicenter trial. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:100-7.). The role of voriconazole and posaconazole is not clear, but both have been used successfully in patients with histoplasmosis (623Restrepo A, Tobon A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect 2007;54:319-27., 626Al-Agha OM, Mooty M, Salarieh A. A 43-year-old woman with acquired immunodeficiency syndrome and fever of undetermined origin: disseminated histoplasmosis. Arch Pathol Lab Med 2006;130:120-3.).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

An AIDS Clinical Treatment Group (ACTG)-sponsored study reported that discontinuing itraconazole was safe for patients who have been treated for histoplasmosis and who have a good immunologic response to ART (630Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004;38:1485-9.). In that trial, patients had received ≥1 year of itraconazole therapy, had negative blood cultures, Histoplasma serum antigen <2 units, CD4+ counts >150 cells/µL, and had been on ART for 6 months. No relapses were evident in 32 subjects who were followed for a median of 24 months (630Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004;38:1485-9.). Thus, discontinuing suppressive azole therapy appears to be safe for patients who meet the criteria described above (AI). Suppressive therapy should be resumed if the CD4+ count decreases to <150 cells/µL (BIII).

Special Considerations During Pregnancy

Because of their risk for teratogenicity, azoles should not be used during the first trimester of pregnancy (EII). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.

Prophylaxis to prevent first episode of opportunistic disease
PathogenIndicationFirst choiceAlternative
Histoplasma capsulatum infectionCD4+ count ≤150 cells/µL and at high risk because of occupational exposure or live in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years) (CI)Itraconazole 200 mg PO daily (CI)
Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents
Opportunistic infectionPreferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Histoplasma capsulatum infections

Preferred therapy for moderately severe to severe disseminated disease

Induction therapy (for 2 weeks or until clinically improved)
transparent gifgrey bulletLiposomal amphotericin B at 3 mg/kg IV daily (AI)
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Maintenance therapy
transparent gifgrey bulletItraconazole 200 mg PO tid for 3 days, then bid (AII)
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Preferred therapy for less-severe disseminated disease

Induction and maintenance therapy
transparent gifgrey bulletItraconazole 200 mg PO tid for 3 days, then 200 mg PO bid (AII)
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Duration of therapy: at least 12 months

Preferred therapy for meningitis

Induction therapy (4-6 weeks)
transparent gifgrey bulletLiposomal amphotericin B 5 mg/kg/day (AII)
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Maintenance therapy
transparent gifgrey bulletItraconazole 200 mg PO bid-tid for ≥1 year and until resolution of abnormal CSF findings (AII)
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Preferred therapy for long-term suppression therapy In patients with severe disseminated or CNS infection (AII) and in patients who relapse despite appropriate therapy (CIII)
transparent gifgrey bulletItraconazole 200 mg PO daily
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Alternative therapy for moderately severe to severe disseminated disease

Induction therapy (for 2 weeks or until clinically improved)
transparent gifgrey bulletAmphotericin B deoxycholate 0.7 mg/kg IV daily (BI)
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transparent gifgrey bulletAmphotericin B lipid complex 5 mg/kg IV daily (CIII)
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Maintenance therapy
same as "Preferred therapy"
Itraconazole levels should be obtained in all patients to ensure adequate absorption (AIII). Serum concentrations of itraconazole + hydroxyitraconazole should be >1 µg/mL

Itraconazole oral solution is preferred over capsule by certain specialists because of improved absorption

Acute pulmonary histoplasmosis in HIV-infected patients with CD4+ count >300 cells/µL should be managed as non-immunocompromised host (AIII)

References

594. McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999;28:1049-56.
605. Shelburne SA, Darcourt J, White AC, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005; 40:1049-52.
613. McKinsey DS, Spiegel RA, Hutwagner L, et al. Prospective study of histoplasmosis in patients infected with human immunodeficiency virus: incidence, risk factors, and pathophysiology. Clin Infect Dis 1997;24:1195-203.
614. Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-74.
615. Sarosi GA, Johnson PC. Disseminated histoplasmosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1992;14(Suppl 1):S60-7.
616. Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005;40:844-52.
617. Assi M, McKinsey DS, Driks MR, et al. Gastrointestinal histoplasmosis in the acquired immunodeficiency syndrome: report of 18 cases and literature review. Diagn Microbiol Infect Dis 2006;55:195-201.
618. Williams B, Fojtasek M, Connolly-Stringfield P, Wheat J. Diagnosis of histoplasmosis by antigen detection during an outbreak in Indianapolis, Ind. Arch Pathol Lab Med 1994;118:1205-8.
619. Wheat J. Current diagnosis of histoplasmosis. Trends Microbiol 2003;11:488-94.
620. Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002;137:105-9.
621. Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000;30:688-95.
622. Wheat J, Hafner R, Korzun AH, et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Med 1995;98:336-42.
623. Restrepo A, Tobon A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect 2007;54:319-27.
624. Tobon AM, Agudelo CA, Rosero DS, et al. Disseminated histoplasmosis: a comparative study between patients with acquired immunodeficiency syndrome and non-human immunodeficiency virus-infected individuals. Am J Trop Med Hyg 2005;73:576-82.
625. Nacher M, Sarazin F, El Guedj M, et al. Increased incidence of disseminated histoplasmosis following highly active antiretroviral therapy initiation. J Acquir Immune Defic Syndr 2006;41:468-70.
626. Al-Agha OM, Mooty M, Salarieh A. A 43-year-old woman with acquired immunodeficiency syndrome and fever of undetermined origin: disseminated histoplasmosis. Arch Pathol Lab Med 2006;130:120-3.
627. Freifeld AG, Iwen PC, Lesiak BL, et al. Histoplasmosis in solid organ transplant recipients at a large Midwestern university transplant center. Transpl Infect Dis 2005;7:109-15.
628. Wheat LJ, Connolly P, Smedema M, et al. Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole. J Antimicrob Chemother 2006;57:1235-9.
629. Hecht FM, Wheat J, Korzun AH, et al. Itraconazole maintenance treatment for histoplasmosis in AIDS: a prospective, multicenter trial. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:100-7.
630. Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004;38:1485-9.
670. Karimi K, Wheat LJ, Connolly P, et al. Differences in histoplasmosis in patients with acquired immunodeficiency syndrome in the United States and Brazil. J Infect Dis 2002;186:1655-60.
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