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Pathogen:
Histoplasma capsulatum, a fungus endemic to the south-central U.S. and South America, and found in soil contaminated by bird droppings or other organic material. After inhalation, the spores germinate into the yeast form. Patients with compromised immune systems, e.g. AIDS with CD4+ counts < 100 cells/mm3, are particularly susceptible in endemic areas.
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Sites of Infection:
Wide-spread dissemination occurs in most patients, most frequently in the lungs and less frequently in the skin and G.I. system.
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Symptoms:
Fever, weight loss, nodular or ulcerative skin lesions, respiratory complaints, anemia, and enlargement of the liver, spleen, and lymph nodes.
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Diagnosis:
By blood or bone marrow culture, biopsy of involved tissue, or detection of 11 capsulatum variety capsulatum polysaccharide antigen detection in urine, serum, bronchioalveolar lavage, or CSF. Antigen levels can be followed to monitor therapy and diagnose relapse. Antigen levels are obtained at the Histoplasmosis Reference Laboratory in Indianapolis, Indiana (800-HISTO-DG).
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Treatment Results:
Amphotericin B and itraconazole are approved for the treatment of histoplasmosis. Long-term maintenance therapy is required to prevent relapse of disseminated histoplasmosis following initial induction treatment in patients with AIDS. Due to the absorption variability of itiraconazole it is recommended that blood levels be monitored 2-4 hours after dosing during the second week of treatment and every 3 months thereafter. Ideally, itraconazole blood levels of 2 µg/ml should be achieved for induction and 1 µg/ml for maintenance. Itraconazole levels can be obtained at the Histoplasmosis Reference Laboratory in Indianapolis, Indiana (800-HISTO-DG).
Wheat et al. enrolled 59 patients in a study (ACTG 120) of open-label itraconazole for the treatment and prevention of relapse of acute histoplasmosis. All subjects received 300 mg PO twice daily for 3 days followed by a 12 week course (200 mg twice daily). Fifty of 59 (85%) patients responded to treatment (clearance of fungermia) and were continued on itraconazole maintenance treatment (200 to 400 mg PO daily) for at least one year. Of the nine non-responders, six failed treatment, two experienced toxicity, one was lost to follow-up.
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Maintenance Treatment:
Itraconazole is the maintenance treatment of choice for histoplasmosis. Forty-two AIDS patients with disseminated histoplasmosis were treated with open-label itraconazole (ACTG 120) for the prevention of relapse of acute histoplasmosis (Hecht et al.). AU subjects initially received induction therapy with amphotericin B followed by itraconazole 200 mg PO twice daily. The median duration of follow-up was 109 weeks (range, 4 to 134 weeks), and the median survival-time was 98 weeks (range, 4 to >134 weeks). 39/42 patents responded to treatment.(no clinical relapses) at the 200 mg/day dose. One patient withdrew from the study due to toxicity (hypokalemia). Histoplasma blood and urine antigen levels decreased in all patients except one.
Norris et al. found fluconazole 100-400 mg to be moderately effective and a reasonable choice in patients who were given induction therapy with amphotericin B and who could not take itraconazole because of drug interactions, malabsorption or side effects.
McKinsey et al. concluded that long-term, biweekly maintenance therapy with amphotericin B (50 mg IV every two weeks) was well tolerated and effective in preventing relapse of histoplasmosis in HIV-infected subjects.
A double-blind randomized study (MSG 28) is underway to compare itraconazole (200 mg daily) with placebo for the prophylaxis of-histoplasmosis in HIV positive people with CD4 counts below 150/mm3.
REFERENCES:
McKinsey DS et al. Histoplasmosis in patients with 'AIDS: efficacy of maintenance amphotericin B therapy. Amer Jrnl Mod 92: 225-227,1992.
McKinsey DS et al. Histoplasmosis in AIDS: incidence and risk factors. Abstract #PBO604, Intl Conf AIDS, Yokohama, 1994.
Norris et al. Prevention of relapse of histoplasmosis with fluconazole in patients with the acquired immunodeficiency syndrome. Amer Jrnl Med 96: June, 1994.
Wheat et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Amer Jrnl Med 98:55-9,1995. Wheat et al. Prevention of relapse of histoplasmosis With itraconazole in patients with the acquired immunodeficiency syndrome. Ann Int Med 11 g(g): 610-6,1993.
OTHER REPORTS:
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Hecht F et al. Itraconazole maintenance treatment for histoplasmosis in AIDS: prospective multi-center trial. 35th ICAAC, Abstract #1200, San Francisco, 1995.
Smith D et al. The pharmacokinetics of oral itraconazole in AIDS patients VII Intl Conf AIDS, Florence. Vol 2:225(W.B.2174),1991.
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