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Histoplasmosis
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Histoplasmosis is an endemic mycosis caused by a dimorphic fungus, H. 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 United States, 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 and later progression to pulmonary fibrosis. Haematogenous 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 acquired immunodeficiency syndrome (AIDS), hematological malignancies, those on immunosuppressive therapy (including corticosteroids and tumor necrosis factor [TNF] 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/mm 3 .
Disseminated histoplasmosis can involve every organ system, 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, which are thought to be a hypersensitivity response to the H. capsulatum antigen. Rarely, primary cutaneous lesions may arise from direct inoculation.
Management Strategy
Pulmonary forms of histoplasmosis in the acute phase usually resolve spontaneously and only require 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 AmB 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 defense 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-micrometer 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 titres persist for several years following initial infection. Antigen detection is a rapid means of diagnosis and can be useful in individuals who are immunocompromised when antibody production may be impaired. Sensitivity is greater with urine and plasma compared with other body fluids. Antigen quantitation enables treatment response to be monitored.
In disseminated disease, general laboratory tests will reveal a pancytopenia, hyperbilirubinemia, elevated liver enzyme and serum lactate dehydrogenase levels.
Histoplasmosis: up-to-date evidence-based approach to diagnosis and management
Hage CA, Azar MM, Bahr N, et al. Semin Respir Crit Care Med 2015; 36(5): 729–45.
This is a comprehensive and up-to-date review. Liposomal AmB is recommended for more severe cases and itraconazole for milder cases and ‘step-down’ therapy following response to AmB.
Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases
Vergidis P, Avery RK, Wheat LJ, et al. Clin Infect Dis 2015; 61(3): 409–17.
Disseminated histoplasmosis is a potential complication of anti-TNF-α therapy. This is a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between 2000 and 2011. The most commonly used biologic agent was infliximab (67.3%). Based on these data the authors recommend that antifungal therapy is administered for at least 12 months. Thereafter resumption of TNF-α blocker therapy appears safe. They also conclude that disease outcomes were generally favorable.
HIV-associated histoplasmosis: current perspectives
Myint T, Leedy N, Cari EV, et al. HIV AIDS 2020; 12: 113–25.
This review outlines the impact of HIV on the prevalence and clinical manifestations of histoplasmosis. It assesses the clinical trial data of drug therapies for histoplasmosis in HIV-infected individuals. It recommends that liposomal AmB is given for 1–2 weeks followed by itraconazole for at least 1 year until CD4 counts are above 150 cells/mm 3 , HIV viral load is below 400 copies/mL, and Histoplasma urine antigen is negative. Serum itraconazole level should be monitored to avoid drug toxicity. Antigen should be measured periodically to establish that treatment is effective and to assist in identifying relapse. IRIS should be considered in patients failing antifungal treatment.
Treating progressive disseminated histoplasmosis in people living with HIV
Murray M, Hine P. Cochrane Database Syst Rev 2020; 4(4): CD013594.
This review concluded that liposomal AmB was a better choice compared with deoxycholate AmB for treating disseminated histoplasmosis in people with HIV. They concluded that fluconazole performed poorly compared with other azoles.
Disseminated histoplasmosis in patients with AIDS in Panama: a review of 104 cases
Gutierrez ME, Canton A, Sosa N, et al. Clin Infect Dis 2005; 40(8): 1199–1202.
In this study from Panama, the authors report that prior to the spread of AIDS, disseminated histoplasmosis was rarely seen. Now it is often the first manifestation of AIDS in this region, and must be suspected in anyone with fever, respiratory symptoms, weight loss, diarrhea, and a CD4 cell count <100 cells/microliter. Of 104 patients with AIDS-related disseminated histoplasmosis, 100 (96%) received AmB deoxycholate induction therapy, most receiving 1 g in total before being switched over to oral itraconazole. Forty patients had therapy-related adverse effects with hypokalemia reported in 50% and an increased creatinine level in 43%.
Itraconazole therapy for blastomycosis and histoplasmosis
NIAID Mycoses Study Group; Dismukes WE, Bradsher RW Jr, Cloud GC, et al. Am J Med 1992; 93(5): 489–97.
This was a prospective, non-randomized, multicenter open trial where 37 patients with histoplasmosis received itraconazole 200–400 mg daily. After a median treatment period of 9 months, 81% ( n = 30) were cured. Treatment failure occurred only in those patients with chronic cavitary pulmonary disease. Minor adverse effects were experienced in 29% ( n = 25), requiring therapy withdrawal in only one patient.
Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome
AIDS Clinical Trial Group; Wheat J, Hafner R, Korzun AH, et al. Am J Med 1995; 98: 336–42.
A multicenter, non-randomized prospective trial. Itraconazole 300 mg twice daily for 3 days followed by 200 mg twice daily was given for 12 weeks. Evaluation of 59 patients showed that 50 (85%) 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 itraconazole-related adverse effects. Resolution of systemic symptoms occurred after a median of 3 weeks in the less severely affected, and 6 weeks in the 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, AmB is the drug of first choice, which can be switched to itraconazole after clinical improvement.
Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS
Johnson PC, Wheat LJ, Cloud GA, et al; US National Institute of Allergy and Infectious Diseases Mycoses Study Group. Ann Intern Med 2002; 137: 105–9.
A multicenter, randomized, controlled trial compared AmB deoxycholate with liposomal AmB for induction therapy of moderate-to-severe disseminated histoplasmosis in patients with AIDS. The trial demonstrated a higher response rate (88% vs. 64%) and lower mortality rate (2% vs. 13%) in patients who were treated with liposomal amphotericin ( n = 51) than with AmB deoxycholate ( n = 22). Infusion-related side effects were greater with AmB deoxycholate (63%) than with liposomal AmB (25%) ( p = 0.002). Nephrotoxicity was also higher with AmB deoxycholate (37%) than with liposomal AmB (9%) ( p = 0.003).
This study demonstrated that liposomal amphotericin is associated with higher efficacy, lower mortality, and better tolerance during induction treatment of disseminated histoplasmosis.
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