Histoplasmosis

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Histoplasmosis

Mahreen Ameen and Wanda Sonia Robles

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(From Lebwohl, M.G., 2003. The Skin and Systemic Disease: A Color Atlas, 2nd edn. Churchill Livingstone, with permission of Elsevier.)

Histoplasmosis is an endemic mycosis caused by a dimorphic fungus, Histoplasma capsulatum, of which there are two varieties that are pathogenic to humans. The most common variety worldwide is H. capsulatum var. capsulatum, which is highly endemic in the US, particularly in the Mississippi and the Ohio valleys. H. capsulatum var. duboisii is endemic only in Central and West Africa (where it coexists with H. capsulatum var. capsulatum), and it is therefore sometimes referred to as African histoplasmosis The infection is usually contracted through inhalation of spores in dry soil or bird or bat droppings. Disease progression and severity depend on the intensity of exposure to H. capsulatum and host immunity. There is a wide clinical spectrum of disease. Acute pulmonary disease is the most common presentation, and most cases are either asymptomatic or mild and self-limiting. Chronic pulmonary histoplasmosis, usually occurring in patients with underlying lung disease, produces cavities, progressing to pulmonary fibrosis. Hematogenous dissemination occurs within the first few weeks but resolves with the development of cell-mediated immunity to H. capsulatum. Progressive disseminated histoplasmosis occurs in the immunocompromised. Patient groups at risk include those with AIDS, hematological malignancies, on immunosuppressive therapy (including corticosteroids and tumor necrosis factor antagonists), transplant recipients, and infants. Disseminated histoplasmosis is an AIDS-defining illness. It is usually a reactivation of prior infection and a sign of advanced immunosuppression, generally occurring in those with CD4 counts <150 cells/mm3.

Disseminated histoplasmosis can involve any organ, most commonly presenting with hepatosplenomegaly and mucocutaneous lesions. Molluscum-like papules, nodules or ulcerative lesions affect the skin, and are usually localized to the face, upper chest, and arms. Oropharyngeal ulcers affect the buccal mucosa, tongue, gingiva, lips, pharynx, and larynx. Histoplasmosis may also present to the dermatologist as a cause of erythema multiforme or erythema nodosum. Rarely, primary cutaneous lesions may arise from direct inoculation.

Management strategy

Pulmonary histoplasmosis in the acute phase usually resolves spontaneously and only requires treatment if symptoms persist for more than 1 month. Oral itraconazole is the treatment of choice for mild to moderate histoplasmosis. Severe pulmonary infection, disseminated histoplasmosis, and infection in the immunocompromised, particularly in association with AIDS, should be treated with amphotericin B (AmB) formulations (AmB deoxycholate, liposomal AmB or AmB lipid complex). The lipid formulations carry a lower risk of nephrotoxicity but are more expensive. Treatment is commenced with amphotericin until there is clinical improvement, and then stepped down to oral itraconazole. Fluconazole and ketoconazole are second-line alternatives to itraconazole. Ketoconazole carries higher risks of adverse effects than the other azoles. The new triazoles, voriconazole and posaconazole demonstrate in vitro activity against H. capsulatum, and have been successfully used in individual cases for different forms of histoplasmosis infection.

Patients with AIDS-related histoplasmosis who undergo antiretroviral treatment have better outcomes than those who are not treated with antiretrovirals. Some clinicians defer commencement of antiretroviral therapy until there is a reduction in fungal burden to avoid precipitating immune reconstitution inflammatory syndrome (IRIS). However, IRIS is a rare complication of histoplasmosis and is not usually severe. Therefore, others advocate early antiretroviral therapy to improve cellular immunity, a key defence against H. capsulatum.

Specific investigations

The gold standard method for diagnosing histoplasmosis is the isolation of H. capsulatum from culture. The use of several specimens (sputum, bronchoalveolar lavage, skin lesions, blood, bone marrow or liver) for culture will increase the yield. Culture is highly specific but is limited by slow growth, and plates must be kept for as long as 12 weeks. Blood culture using the lysis-centrifugation system is more rapid and increases sensitivity. Histopathology is also more rapid but its sensitivity is <50% in patients with disseminated disease, and even lower in pulmonary histoplasmosis. Biopsy specimens may demonstrate the distinctive 2–4 µm oval, narrow-based budding yeasts of H. capsulatum. Serological tests are rapid but may be falsely negative in immunosuppressed patients, and during the first 2 months following exposure while antibodies are still developing. In addition, elevated antibody titers persist for several years following initial infection. Antigen detection is a rapid means of diagnosis in patients with disseminated disease. Sensitivity is greater with urine than with other body fluids (plasma, bronchoalveolar lavage fluid or cerebrospinal fluid). Antigen quantitation enables treatment response to be monitored.

In disseminated disease, general laboratory tests reveal pancytopenia, hyperbilirubinemia, elevated liver enzymes, and serum lactate dehydrogenase levels.

First-line therapies

imageAmphotericin B B
imageItraconazole B

Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome.

AIDS Clinical Trial Group, Wheat J, Hafner R, Korzun AH, Limjoco MT, Spencer P, Larsen RA, et al. Am J Med 1995; 98: 336–42.

Another open study. Itraconazole 300 mg twice daily for 3 days followed by 200 mg twice daily was given for 12 weeks. Of 59 patients, 50 responded well to therapy. Five withdrew from the study because of progressive infection. One died within the first week of therapy, and two withdrew because of adverse effects. Resolution of systemic symptoms occurred after a median of 3 weeks in the less severely affected, and 6 weeks in moderately severe cases. Fungemia cleared after a median period of 1 week.

Itraconazole demonstrates efficacy in the treatment of mild disseminated histoplasmosis in patients with AIDS. For patients with moderately severe or severe histoplasmosis, amphotericin B is the drug of first choice which can be switched to itraconazole after clinical improvement.

Literature review and case histories of Histoplasma capsulatum var. duboisii infections in HIV-infected patients.

Loulergue P, Bastides F, Baudouin V, Chandenier J, Mariani-Kurkdjian P, Dupont B, et al. Emerg Infect Dis 2007; 13: 1647–52.

African histoplasmosis caused by H. capsulatum var. duboisii is much rarer than histoplasmosis caused by var. capsulatum, and its association with HIV infection is rarely reported. This article reports three such cases successfully treated, initially with amphotericin B which was subsequently switched to itraconazole. No clinical trials or efficacy studies have been performed for African histoplasmosis, and therefore its treatment is usually extrapolated from the guidelines of the Infectious Diseases Society of America established for histoplasmosis due to var. capsulatum.

Second-line therapies

imageKetoconazole B
imageFluconazole B
imagePosaconazole D
imageVoriconazole D

Treatment of blastomycosis and histoplasmosis with ketoconazole. Results of a prospective randomized clinical trial.

Dismukes WE, Cloud G, Bowles C, and the National Institute of Allergy and Infectious Diseases Mycoses Study Group. Ann Intern Med 1985; 103: 861–72.

A trial evaluating efficacy and toxicity of low-dose (400 mg/day) and high-dose (800 mg/day) oral ketoconazole. Among 19 patients with chronic cavitary histoplasmosis treated for 6 months or more, both regimens were equally effective (success rate, 84%). In 20 patients with localized or disseminated histoplasmosis treated for 6 months or more, low-dose treatment was more effective (100% vs 57%). The success rate for all patients treated for 6 months or more was 85%. Adverse effects were commoner with the high-dose. Ketoconazole is effective for non-life-threatening histoplasmosis in immunocompetent patients. Because of the higher frequency of side effects associated with the high dose, the authors suggested that therapy should be initiated at the lower dose.

With the availability of better tolerated and new generation azoles, there are no recent studies evaluating ketoconazole therapy for histoplasmosis. However, it is still a drug that is commonly used in endemic settings, because of its availability and low cost.

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, Wheat J, MaWhinney S, Hafner R, McKinsey D, Chen D, Korzun A, et al. Am J Med 1997; 103: 223–32.

An open-label trial to assess efficacy and safety of fluconazole in patients with AIDS and mild to moderate disseminated histoplasmosis. The initial protocol of fluconazole 1200 mg on day 1 followed by 600 mg daily for 8 weeks demonstrated a high failure rate of 50%. The therapy schedule was revised to 1600 mg on day 1 followed by 800 mg daily for 12 weeks, and then maintenance therapy with 400 mg daily for at least 1 year. Seven patients failed to respond to induction therapy with progression of histoplasmosis leading to death in one patient. Two withdrew due to liver toxicity; 73% (36/49 patients) responded but 30.5% (11/36) subsequently relapsed and one died. On the basis of historical comparison, maintenance therapy to prevent relapse with fluconazole 400 mg daily was less effective than itraconazole 200–400 mg daily or amphotericin B 50 mg weekly.

Fluconazole may have a role in the treatment of non-AIDS-related histoplasmosis. However, this study demonstrated a comparatively poor efficacy rate even with high-dose fluconazole induction therapy, and an unacceptably high relapse rate with maintenance therapy.

Treatment of histoplasmosis in pregnancy

Azoles are teratogenic and therefore amphotericin B is recommended. Women of childbearing age who are being treated with azoles need to use effective contraception during treatment and for 2 months after the drug is stopped.

Immunosuppressed patients may require lifelong suppressive therapy with itraconazole (200 mg daily) if immunosuppression cannot be reversed. For those on long-term itraconazole therapy, drug level needs to be measured 2 weeks after initiation of treatment.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Histoplasmosis

Mahreen Ameen and Wanda Sonia Robles

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(From Lebwohl, M.G., 2003. The Skin and Systemic Disease: A Color Atlas, 2nd edn. Churchill Livingstone, with permission of Elsevier.)

Histoplasmosis is an endemic mycosis caused by a dimorphic fungus, Histoplasma capsulatum, of which there are two varieties that are pathogenic to humans. The most common variety worldwide is H. capsulatum var. capsulatum, which is highly endemic in the US, particularly in the Mississippi and the Ohio valleys. H. capsulatum var. duboisii is endemic only in Central and West Africa (where it coexists with H. capsulatum var. capsulatum), and it is therefore sometimes referred to as African histoplasmosis The infection is usually contracted through inhalation of spores in dry soil or bird or bat droppings. Disease progression and severity depend on the intensity of exposure to H. capsulatum and host immunity. There is a wide clinical spectrum of disease. Acute pulmonary disease is the most common presentation, and most cases are either asymptomatic or mild and self-limiting. Chronic pulmonary histoplasmosis, usually occurring in patients with underlying lung disease, produces cavities, progressing to pulmonary fibrosis. Hematogenous dissemination occurs within the first few weeks but resolves with the development of cell-mediated immunity to H. capsulatum. Progressive disseminated histoplasmosis occurs in the immunocompromised. Patient groups at risk include those with AIDS, hematological malignancies, on immunosuppressive therapy (including corticosteroids and tumor necrosis factor antagonists), transplant recipients, and infants. Disseminated histoplasmosis is an AIDS-defining illness. It is usually a reactivation of prior infection and a sign of advanced immunosuppression, generally occurring in those with CD4 counts <150 cells/mm3.

Disseminated histoplasmosis can involve any organ, most commonly presenting with hepatosplenomegaly and mucocutaneous lesions. Molluscum-like papules, nodules or ulcerative lesions affect the skin, and are usually localized to the face, upper chest, and arms. Oropharyngeal ulcers affect the buccal mucosa, tongue, gingiva, lips, pharynx, and larynx. Histoplasmosis may also present to the dermatologist as a cause of erythema multiforme or erythema nodosum. Rarely, primary cutaneous lesions may arise from direct inoculation.

Management strategy

Pulmonary histoplasmosis in the acute phase usually resolves spontaneously and only requires treatment if symptoms persist for more than 1 month. Oral itraconazole is the treatment of choice for mild to moderate histoplasmosis. Severe pulmonary infection, disseminated histoplasmosis, and infection in the immunocompromised, particularly in association with AIDS, should be treated with amphotericin B (AmB) formulations (AmB deoxycholate, liposomal AmB or AmB lipid complex). The lipid formulations carry a lower risk of nephrotoxicity but are more expensive. Treatment is commenced with amphotericin until there is clinical improvement, and then stepped down to oral itraconazole. Fluconazole and ketoconazole are second-line alternatives to itraconazole. Ketoconazole carries higher risks of adverse effects than the other azoles. The new triazoles, voriconazole and posaconazole demonstrate in vitro activity against H. capsulatum, and have been successfully used in individual cases for different forms of histoplasmosis infection.

Patients with AIDS-related histoplasmosis who undergo antiretroviral treatment have better outcomes than those who are not treated with antiretrovirals. Some clinicians defer commencement of antiretroviral therapy until there is a reduction in fungal burden to avoid precipitating immune reconstitution inflammatory syndrome (IRIS). However, IRIS is a rare complication of histoplasmosis and is not usually severe. Therefore, others advocate early antiretroviral therapy to improve cellular immunity, a key defence against H. capsulatum.

Specific investigations

The gold standard method for diagnosing histoplasmosis is the isolation of H. capsulatum from culture. The use of several specimens (sputum, bronchoalveolar lavage, skin lesions, blood, bone marrow or liver) for culture will increase the yield. Culture is highly specific but is limited by slow growth, and plates must be kept for as long as 12 weeks. Blood culture using the lysis-centrifugation system is more rapid and increases sensitivity. Histopathology is also more rapid but its sensitivity is <50% in patients with disseminated disease, and even lower in pulmonary histoplasmosis. Biopsy specimens may demonstrate the distinctive 2–4 µm oval, narrow-based budding yeasts of H. capsulatum. Serological tests are rapid but may be falsely negative in immunosuppressed patients, and during the first 2 months following exposure while antibodies are still developing. In addition, elevated antibody titers persist for several years following initial infection. Antigen detection is a rapid means of diagnosis in patients with disseminated disease. Sensitivity is greater with urine than with other body fluids (plasma, bronchoalveolar lavage fluid or cerebrospinal fluid). Antigen quantitation enables treatment response to be monitored.

In disseminated disease, general laboratory tests reveal pancytopenia, hyperbilirubinemia, elevated liver enzymes, and serum lactate dehydrogenase levels.

First-line therapies

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imageAmphotericin B B