Histoplasmosis is disease caused by the fungusHistoplasma capsulatum, which is common in the south-central United States, South America, central Africa, southeast Asia and Australia but very rare in the United Kingdom. It is found in soil contaminated by bird droppings or other organic material.

It is caught by breathing in the spores which then sprout into a yeast form. It is not transmitted from person to person. In people with damaged immune systems the yeast is able to grow in the bloodstream and spread to the lungs and skin, and occasionally elsewhere in the body. Over 90% of people with AIDS diagnosed with histoplasmosis have CD4 cell counts below 100 cells/mm³.

Symptoms and diagnosis

Histoplasmosis can cause fever, weight loss, sores on the skin, breathing problems and swelling of the liver, spleen and lymph nodes. It commonly affects the bone marrow causing shortages of red blood cells (anaemia), some white blood cells (leukopenia) and platelets (thrombocytopenia). It also affects the skin and the central nervous system, and, less frequently, the heart and the eye.

It is diagnosed by growing the fungus from bone marrow samples or using the H. capsulatum polysaccharide antigen detection test on a sample of urine or blood serum.

Treatment and prophylaxis

Histoplasmosis is treated in two phases: induction (initial treatment of the acute infection) and maintenance (ongoing treatment to prevent recurrence).

Itraconazole (Sporanox) taken orally is an effective induction treatment for mild to moderate cases of histoplasmosis. In severe cases, intravenous amphotericin B (Fungizone) may be used. It has unpleasant side-effects such as fevers, chills, kidney damage and bone marrow suppression. A lipid (fat-coated) form of amphotericin B (AmBisome / Abelcet / Amphocil) is more effective against histoplasmosis than the standard formulation, and less toxic (Johnson 2002). People treated with either form of intravenous amphotericin B are admitted to hospital for 14 to 21 days until induction treatment by infusion is over. Due to individual variation in absorption of amphotericin B, drug levels should be monitored.

Fluconazole (Diflucan) is less active against histoplasmosis than itraconazole and amphotericin B but is considered an alternative induction regimen (Wheat 2002). It may be used in people with low blood levels of itraconazole or when side-effects or drug interactions mean amphotericin B or itraconazole cannot be used.

Maintenance treatment with 200mg of itraconazole daily will be necessary for life in the absence of immune reconstitution due to highly active antiretroviral therapy (HAART). However, there is evidence that people with sustained immune recovery can safely stop itraconazole maintenance therapy (Sued 2002). An alternative maintenance treatment, of amphotericin B infusions once weekly, is less well studied. Fluconazole (800mg daily) is another alternative maintenance option.

Use of itraconazole or fluconazole to prevent fungal infections including histoplasmosis is not generally recommended. However, preventive therapy (prophylaxis) against histoplasmosis may be indicated for people with CD4 cell counts below 100 cells/mm³ who live in areas where fungal infections are common or who work in high risk occupations, such as farming, gardening and labouring.

Research into induction and maintenance

Due to the absorption variability of itraconazole 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 2µg/ml should be achieved for induction and 1µg/ml for maintenance.

Wheat (2001b) compared the efficacy of liposomal amphotericin B and itraconazole for the treatment of disseminated histoplasmosis in people with AIDS in terms of clinical, blood culture and antigen responses. The clinical response was 86% in the liposomal amphotericin B arm (n=51) and 85% with itraconazole arm (n=59). Of the patients with positive blood cultures at enrollment, 85% of the liposomal amphotericin B group became negative at 2 weeks compared with 53% of the itraconazole group (p=0.0008). Median antigen levels also fell significantly in the amphotericin group.

Wheat (2002) compared the efficacy of itraconazole and fluconazole in separate groups of patients with histoplasmosis. Clinical response rates were equivalent (itraconazole 85% vs fluconazole 74%) but negative fungal blood cultures at week 4 were more likely in itraconazole recipients (92.3%) compared with fluconazole recipients (61.9%, p = 0.017). Antigen concentrations fell by a similar amount at weeks 4 and 12.

Wheat (2001) studied treatment failure in HIV-infected people with histoplasmosis. Treatment failure due to drug resistance was more likely with fluconazole than intraconazole.

Johnson (2002) enrolled 81 people with histoplasmosis into a study of liposomal amphotericin B (Ambisome) (3mg/kg/day) vs standard amphotericin B. 64% of 22 people treated with amphotericin B responded to treatment compared with 88% of 51people receiving liposomal amphotericin B. Death was more common among those on standard treatment (3 vs 1). Infusion-related side effects and kidney toxicity occurred among 63% and 37% of the amphotericin B group, respectively, and among 25% and 9% of patients treated with liposomal amphotericin B.

Sued (2002) reported on 39 people with moderate to severe histoplasmosis who had sustained immune recovery due to long-term antiretroviral therapy. Median CD4 count at the time of ceasing prophylaxis was 266. After an average follow-up time of 20 months (range 1-52 months), no cases of relapse had occurred.

Wheat (1995) enrolled 59 patients in ACTG 120, a study of itraconazole (300 mg by mouth twice a day for 3 days followed by 200mg by mouth twice a day for 12 weeks) as treatment for acute histoplasmosis. 50/59 (85%) patients responded to treatment (clearance of fungæ­©a) and were continued on itraconazole maintenance therapy (200 to 400mg/day) for at least one year. Of the 9 non-responders, 6 failed treatment, 2 experienced toxicity and 1 was lost to follow-up.

Wheat (1994) conducted an open-label study (ACTG 174) of fluconazole (1600mg on the first day followed by 800mg/day for 12 weeks, then 400mg/day maintenance therapy) for histoplasmosis. 37/50 participants responded to induction therapy. 12/37 participants who entered maintenance therapy failed. The study was closed by the interim monitoring team when they found a difference in failure rate of people receiving itraconazole in ACTG 120 (5%) compared with fluconazole-treated people in ACTG 174 (33%).

Hecht (1997) studied maintenance therapy for mild-moderate histoplasmosis in 46 HIV-infected people. 200mg itraconazole once daily or 400mg once daily. Only two people had a relapse over 87 weeks follow-up, one due to poor adherence and another due to a drug interaction with rifampicin. Survival at one year was 73%. Five people stopped treatment due to drug toxicity.

McKinsey (1989) concluded that long-term, intermittent maintenance therapy with amphotericin B (50-80mg intravenously every 2 weeks) was effective and well tolerated. 63% of patients developed catheter-related complications.

Wheat (1993) enrolled 42 patients with proven disseminated histoplasmosis in ACTG 084, a study of itraconazole (200mg by mouth twice daily) for maintenance treatment. No relapse occurred in 30/32 patients followed for longer than 52 weeks (mean follow-up of 76 weeks); 2/32 withdrew from study, one from toxicity.

Norris (1994) found fluconazole (400mg daily) 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.

Hajjeh (2001) conducted a multi-centre case control study of 92 people with histoplasmosis between 1996-1999 and 252 controls. 89% of cases were men, 55% were black, 85% had a CD4 count below 100 cells/microL, 87% were hospitalised, and 12% died. Treatment with antiretroviral therapy and/or triazole drugs was associated with a decreased risk of histoplasmosis. A history of herpes infection or other chronic conditions was associated with a poor outcome. Preventive therapy with triazoles for people who take part in high-risk activities that involve frequent exposure to soil, who have CD4 counts below 100 cells/microL, and who live in areas where histoplasmosis is endemic was suggested.

Research into prevention of histoplasmosis

Takeda (2003) retrospectively studied 77 HIV-infected people with disseminated histoplasmosis and 41 randomly selected HIV-positive people without histoplasmosis. The histoplasmosis group had a lower average CD4 count (95 versus 165) and were significantly less likely not to be taking antiretroviral therapy. People with histoplasmosis had more fever (p < 0.001), skin lesions (p = 0.007), cough (p = 0.013), and serum lactate dehydrogenase levels were higher (p < 0.001). 80% of patients with hepatomegaly had histoplasmosis. The authors stated that antiretroviral therapy protected against histoplamosis and death due to histoplasmosis.

McKinsey (1999) conducted a prospective, randomized, double-blind trial of nearly 300 HIV-infected people with advanced infection. Participants received itraconazole capsules (200 mg daily) or placebo. Failure of prophylaxis occurred in 19% of the itraconazole recipients and 29% of the placebo recipients (p = 0.004). Six invasive fungal infections occurred in the itraconazole group (4 histoplasmosis; 1 cryptococcosis; 1 aspergillosis) and 19 in the placebo group (10 histoplasmosis; 8 cryptococcosis; 1 aspergillosis) (p=0.0007). Time to onset of histoplasmosis and cryptococcosis was significantly delayed but no survival benefit was shown.

Nightingale (1992) routinely treated HIV-positive patients with CD4 counts below 68 with fluconazole 100mg/day to prevent disseminated fungal infections. 329 patients who received fluconazole prophylaxis were compared to an historical control of 337 patients with CD4 counts below 68 who did not receive prophylaxis. Development of histoplasmosis was equivalent in the two groups. One of 329 patients in the fluconazole group and 16/337 in the historical control no-treatment group developed cryptococcosis.

For other studies targeting disseminated fungal infections generally, see Cryptococcus in Symptoms and illnesses: A to Z of illnesses.

References

Hajjeh RA et al. Multicenter case-control study of risk factors for histoplasmosis in human immunodeficiency virus-infected persons. Clinical Infectious Diseases 32(8):1215-1220, 2001.

Johnson P et al. A multicenter randomized trial comparing amphotericin B (AmB) and lipsomal Amphotericin B (AmBisome, LAmB) as induction therapy of disseminated histoplasmosis (DH) in AIDS patients. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 232, 2000.

McKinsey DS et al. Long-term amphotericin B therapy for disseminated histoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). Annals of Internal Medicine 111(8):655-659, 1989.

McKinsey DS et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clinical Infectious Diseases 28(5):1049-1056, 1999.

Nightingale S et al. Primary prophylaxis with fluconazole against systemic fungal infections in HIV-positive patients. AIDS 6:191-194, 1992.

Norris S et al. Prevention of relapse of histoplasmosis with fluconazole in patients with the acquired immunodeficiency syndrome. American Journal of Medicine 96:504-508, 1994.

Prechter GC et al. Bronchoscopy in the diagnosis of pulmonary histoplasmosis. Chest 95:1033-1036, 1989.

Smith D et al. The pharmacokinetics of oral itraconazole in AIDS patients. Journal of Pharmacy and Pharmacology 44(7):618-9, 1992.

Sued O et al. Discontinuation of maintenance therapy for disseminated histoplasmosis: a study of 39 patients. Fourteenth International AIDS Conference, Barcelona, abstract ThPeC7476, 2002.

Takeda CFV et al. Disseminated histoplasmosis in persons infected with human immunodeficiency virus: a comparative study. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris (Antiviral Therapy 8:1), abstract 909, 2003.

Wheat LJ et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine 69:361-374, 1990.

Wheat et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. American Journal of Medicine 98:336-342, 1995.

Wheat J et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Annals of Internal Medicine 118:610-616, 1993.

Wheat L et al. Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group. American Journal of Medicine 103(3):223-32, 1997.

Wheat L et al. Emergence of resistance to fluconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome. Clinical Infectious Diseases 33(11):1910-1913, 2001.

Wheat L et al. Clearance of fungal burden during treatment of disseminated histoplasmosis with liposomal amphotericin B versus itraconazole. Antimicrobial Agents and Chemotherapy 45(8):2354-2357, 2001b.

Wheat LJ et al. Antigen clearance during treatment of disseminated histoplasmosis with itraconazole versus fluconazole in patients with AIDS. Antimicrobial Agents and Chemotherapy 46(1):248-250, 2002.