Pathogenesis and clinical manifestations of disseminated histoplasmosis
- Joseph Wheat, MD
Joseph Wheat, MD
- Owner and Director
- MiraVista Diagnostics
- Carol A Kauffman, MD
Carol A Kauffman, MD
- Section Editor — Fungal Infections
- Professor of Internal Medicine
- University of Michigan Medical School
- Veterans Affairs Ann Arbor Healthcare System
Histoplasmosis is the most prevalent endemic mycosis in the United States . While most infections are asymptomatic or self-limited, some individuals develop acute pulmonary infections or severe and progressive disseminated infection [2-5]. Progressive disseminated histoplasmosis occurs in about one in 2000 patients with acute infection [2,5,6].
Although hematogenous dissemination probably occurs in most patients during the acute infection before cellular immunity develops, progressive illness is unusual except in the host with altered immunity and those at the extremes of age [2,3,6]. The diagnosis of disseminated histoplasmosis requires a high index of suspicion, recognition of the common modes of presentation, and familiarity with the appropriate diagnostic tests.
The pathogenesis of disseminated histoplasmosis, risk factors for dissemination, and clinical features of the infection will be reviewed here. The diagnosis and treatment of this infection and the manifestations of localized pulmonary histoplasmosis are discussed separately. (See "Diagnosis and treatment of disseminated histoplasmosis in HIV-uninfected patients" and "Pathogenesis and clinical features of pulmonary histoplasmosis".)
Histoplasma capsulatum is a thermally dimorphic fungus, growing as a mold in the environment and as a yeast at 37ºC. Infection develops when Histoplasma microconidia are inhaled into the lungs, where they change into the yeast form. Neutrophils, macrophages, lymphocytes, and natural killer (NK) cells are attracted in response to the infection. As in tuberculosis, macrophages assist in spreading the organism via lymphatics and the blood to the adjacent lymph nodes and throughout the reticuloendothelial system (liver, spleen, lymph nodes, adrenal glands, and bone marrow).
In patients with progressive disseminated infection, macrophages are typically engorged with yeasts, supporting the important role of intracellular proliferation of the organism. Organisms are confined to macrophages but less commonly can be seen within the tissue spaces. The organisms can occasionally be seen in peripheral white blood cells in patients with disseminated infection (picture 1).
- Chu JH, Feudtner C, Heydon K, et al. Hospitalizations for endemic mycoses: a population-based national study. Clin Infect Dis 2006; 42:822.
- Goodwin RA Jr, Shapiro JL, Thurman GH, et al. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore) 1980; 59:1.
- Sathapatayavongs B, Batteiger BE, Wheat J, et al. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine (Baltimore) 1983; 62:263.
- Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007; 20:115.
- Assi MA, Sandid MS, Baddour LM, et al. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Medicine (Baltimore) 2007; 86:162.
- 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.
- Deepe GS Jr, Bullock WE. Histoplasmosis: a granulomatous inflammatory response. In: Basic Principals and Clinical Correlates, Gallin JI, Goldstein IM, Snyderman R (Eds), Raven, New York 1988. p.733.
- Horwath MC, Fecher RA, Deepe GS Jr. Histoplasma capsulatum, lung infection and immunity. Future Microbiol 2015; 10:967.
- Garfoot AL, Rappleye CA. Histoplasma capsulatum surmounts obstacles to intracellular pathogenesis. FEBS J 2016; 283:619.
- Woods JP. Revisiting old friends: Developments in understanding Histoplasma capsulatum pathogenesis. J Microbiol 2016; 54:265.
- Zhou P, Sieve MC, Tewari RP, Seder RA. Interleukin-12 modulates the protective immune response in SCID mice infected with Histoplasma capsulatum. Infect Immun 1997; 65:936.
- Hage CA, Bowyer S, Tarvin SE, et al. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis 2010; 50:85.
- Vergidis P, Avery RK, Wheat LJ, et al. Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases. Clin Infect Dis 2015; 61:409.
- Zerbe CS, Holland SM. Disseminated histoplasmosis in persons with interferon-gamma receptor 1 deficiency. Clin Infect Dis 2005; 41:e38.
- Lionakis MS, Netea MG, Holland SM. Mendelian genetics of human susceptibility to fungal infection. Cold Spring Harb Perspect Med 2014; 4.
- Davies SF, Khan M, Sarosi GA. Disseminated histoplasmosis in immunologically suppressed patients. Occurrence in a nonendemic area. Am J Med 1978; 64:94.
- Keath EJ, Kobayashi GS, Medoff G. Typing of Histoplasma capsulatum by restriction fragment length polymorphisms in a nuclear gene. J Clin Microbiol 1992; 30:2104.
- Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38:1261.
- Wheat LJ, Slama TG, Norton JA, et al. Risk factors for disseminated or fatal histoplasmosis. Analysis of a large urban outbreak. Ann Intern Med 1982; 96:159.
- Smith DK, Neal JJ, Holmberg SD. Unexplained opportunistic infections and CD4+ T-lymphocytopenia without HIV infection. An investigation of cases in the United States. The Centers for Disease Control Idiopathic CD4+ T-lymphocytopenia Task Force. N Engl J Med 1993; 328:373.
- Whitt SP, Koch GA, Fender B, et al. Histoplasmosis in pregnancy: case series and report of transplacental transmission. Arch Intern Med 2004; 164:454.
- Cuellar-Rodriguez J, Avery RK, Lard M, et al. Histoplasmosis in solid organ transplant recipients: 10 years of experience at a large transplant center in an endemic area. Clin Infect Dis 2009; 49:710.
- Assi M, Martin S, Wheat LJ, et al. Histoplasmosis after solid organ transplant. Clin Infect Dis 2013; 57:1542.
- Nieto-Ríos JF, Serna-Higuita LM, Guzman-Luna CE, et al. Histoplasmosis in renal transplant patients in an endemic area at a reference hospital in Medellin, Colombia. Transplant Proc 2014; 46:3004.
- Limaye AP, Connolly PA, Sagar M, et al. Transmission of Histoplasma capsulatum by organ transplantation. N Engl J Med 2000; 343:1163.
- Botterel F, Romand S, Saliba F, et al. A case of disseminated histoplasmosis likely due to infection from a liver allograft. Eur J Clin Microbiol Infect Dis 1999; 18:662.
- Kauffman CA, Freifeld AG, Andes DR, et al. Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET). Transpl Infect Dis 2014; 16:213.
- Peterson MW, Pratt AD, Nugent KM. Pneumonia due to Histoplasma capsulatum in a bone marrow transplant recipient. Thorax 1987; 42:698.
- Walsh TJ, Catchatourian R, Cohen H. Disseminated histoplasmosis complicating bone marrow transplantation. Am J Clin Pathol 1983; 79:509.
- Kauffman, CA. Endemic mycoses after hematopoietic stem cell or solid organ transplantation. In: Transplant Infections, 3rd edition, Bowden, R, Ljungman, P, Snydman, DR (Eds), Lippincott Williams and Wilkins, Philadelphia 2010. p.607.
- Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 2002; 46:2565.
- Hajjeh RA, Pappas PG, Henderson H, et al. Multicenter case-control study of risk factors for histoplasmosis in human immunodeficiency virus-infected persons. Clin Infect Dis 2001; 32:1215.
- Wheat J. Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol 1996; 7:7.
- Shelburne SA 3rd, Visnegarwala F, Adams C, et al. Unusual manifestations of disseminated Histoplasmosis in patients responding to antiretroviral therapy. Am J Med 2005; 118:1038.
- Kahi CJ, Wheat LJ, Allen SD, Sarosi GA. Gastrointestinal histoplasmosis. Am J Gastroenterol 2005; 100:220.
- Goulet CJ, Moseley RH, Tonnerre C, et al. Clinical problem-solving. The unturned stone. N Engl J Med 2005; 352:489.
- Cunha VS, Zampese MS, Aquino VR, et al. Mucocutaneous manifestations of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome: particular aspects in a Latin-American population. Clin Exp Dermatol 2007; 32:250.
- 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.
- Tobón 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.
- Cohen PR, Bank DE, Silvers DN, Grossman ME. Cutaneous lesions of disseminated histoplasmosis in human immunodeficiency virus-infected patients. J Am Acad Dermatol 1990; 23:422.
- Eidbo J, Sanchez RL, Tschen JA, Ellner KM. Cutaneous manifestations of histoplasmosis in the acquired immune deficiency syndrome. Am J Surg Pathol 1993; 17:110.
- Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system. A clinical review. Medicine (Baltimore) 1990; 69:244.
- Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005; 40:844.
- Bhatti S, Vilenski L, Tight R, Smego RA Jr. Histoplasma endocarditis: clinical and mycologic features and outcomes. J Infect 2005; 51:2.
- Gaynes RP, Gardner P, Causey W. Prosthetic valve endocarditis caused by Histoplasma capsulatum. Arch Intern Med 1981; 141:1533.
- Ellis ME, Al-Abdely H, Sandridge A, et al. Fungal endocarditis: evidence in the world literature, 1965-1995. Clin Infect Dis 2001; 32:50.
- Pierrotti LC, Baddour LM. Fungal endocarditis, 1995-2000. Chest 2002; 122:302.
- Riddell J 4th, Kauffman CA, Smith JA, et al. Histoplasma capsulatum endocarditis: multicenter case series with review of current diagnostic techniques and treatment. Medicine (Baltimore) 2014; 93:186.
- Dwyre DM, Bell AM, Siechen K, et al. Disseminated histoplasmosis presenting as thrombotic microangiopathy. Transfusion 2006; 46:1221.
- Koduri PR, Chundi V, DeMarais P, et al. Reactive hemophagocytic syndrome: a new presentation of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis 1995; 21:1463.
- Townsend JL, Shanbhag S, Hancock J, et al. Histoplasmosis-Induced Hemophagocytic Syndrome: A Case Series and Review of the Literature. Open Forum Infect Dis 2015; 2:ofv055.
- Walker JV, Baran D, Yakub N, Freeman RB. Histoplasmosis with hypercalcemia, renal failure, and papillary necrosis. Confusion with sarcoidosis.. JAMA 1977; 237:1350.
- Murray JJ, Heim CR. Hypercalcemia in disseminated histoplasmosis. Aggravation by vitamin D. Am J Med 1985; 78:881.
- Gulati M, Saint S, Tierney LM Jr. Clinical problem-solving. Impatient inpatient care. N Engl J Med 2000; 342:37.
- Macher A, Rodrigues MM, Kaplan W, et al. Disseminated bilateral chorioretinitis due to Histoplasma capsulatum in a patient with the acquired immunodeficiency syndrome. Ophthalmology 1985; 92:1159.
- Kilburn CD, McKinsey DS. Recurrent massive pleural effusion due to pleural, pericardial, and epicardial fibrosis in histoplasmosis. Chest 1991; 100:1715.
- Young EJ, Vainrub B, Musher DM. Pericarditis due to histoplasmosis. JAMA 1978; 240:1750.
- Reddy PA, Brasher CA, Christianson C, et al. Peritonitis due to histoplasmosis. Ann Intern Med 1969; 72:79.
- Patrick CC, Flynn PM, Henwick S, Pui CH. Disseminated histoplasmosis presenting as a cystic duct obstruction. Pediatr Infect Dis J 1992; 11:593.
- Pottage JC Jr, Trenholme GM, Aronson IK, Harris AA. Panniculitis associated with histoplasmosis and alpha 1-antitrypsin deficiency. Am J Med 1983; 75:150.
- Osborne BM. Granulomatous mastitis caused by histoplasma and mimicking inflammatory breast carcinoma. Hum Pathol 1989; 20:47.
- Darouiche RO, Cadle RM, Zenon GJ, et al. Articular histoplasmosis. J Rheumatol 1992; 19:1991.
- Jones PG, Rolston K, Hopfer RL. Septic arthritis due to Histoplasma capsulatum in a leukaemic patient. Ann Rheum Dis 1985; 44:128.
- Fowler VG Jr, Nacinovich FM, Alspaugh JA, Corey GR. Prosthetic joint infection due to Histoplasma capsulatum: case report and review. Clin Infect Dis 1998; 26:1017.
- Cucurull E, Sarwar H, Williams CS 4th, Espinoza LR. Localized tenosynovitis caused by Histoplasma capsulatum: case report and review of the literature. Arthritis Rheum 2005; 53:129.
- Zighelboim J, Goldfarb RA, Mody D, et al. Prostatic abscess due to Histoplasma capsulatum in a patient with the acquired immunodeficiency syndrome. J Urol 1992; 147:166.
- Kauffman CA, Slama TG, Wheat LJ. Histoplasma capsulatum epididymitis. J Urol 1981; 125:434.
- Sills M, Schwartz A, Weg JG. Conjugal histoplasmosis. A consequence of progressive dissemination in the index case after steroid therapy. Ann Intern Med 1973; 79:221.
- Jayalakshmi P, Goh KL, Soo-Hoo TS, Daud A. Disseminated histoplasmosis presenting as penile ulcer. Aust N Z J Med 1990; 20:175.
- Reinfection and reactivation of infection
- RISK FACTORS
- Transplant recipients
- Anti-TNF-alpha therapies
- HIV infection
- Cellular immunodeficiency
- CLINICAL MANIFESTATIONS
- Gastrointestinal disease
- Skin involvement
- Adrenal involvement
- Central nervous system disease
- INFORMATION FOR PATIENTS