Version May 2024
INTRODUCTION — Histoplasmosis is the most prevalent endemic mycosis in the United States [1]. While most infections are asymptomatic or self-limited, some individuals develop acute pulmonary infections or severe disseminated infection [2-5].
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 patients without HIV" and "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV" and "Treatment of histoplasmosis in patients with HIV".)
PATHOGENESIS — Histoplasma capsulatum is a thermally dimorphic fungus, growing as a mold in the environment and as a yeast at 37°C. 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 to the adjacent lymph nodes and from there by hematogenous spread throughout the reticuloendothelial system (liver, spleen, lymph nodes, and bone marrow).
In patients with 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 as well as in peripheral white blood cells (picture 1).
T cell immunity plays the predominant role in recovery from histoplasmosis [6]. Once cellular immunity to Histoplasma develops, macrophages become activated to kill the organism. Cytokines including interleukin (IL)-12 and interferon (IFN)-gamma trigger macrophages to kill the fungus and halt progression of disease [7-9].
Failure to activate macrophage fungicidal capacity is likely the key defect in immunity to H. capsulatum in patients with disseminated histoplasmosis. In one study in mice with severe combined immunodeficiency, administration of exogenous IL-12 increased IFN-gamma, tumor necrosis factor (TNF)-alpha, and nitric oxide production in splenocytes, resulting in decreased colony counts of H. capsulatum and increased survival [10]; administration of IFN-gamma antibody eliminated the protective effect of IL-12 in this model. The important role of TNF-alpha and IFN-gamma in patients with histoplasmosis is substantiated by the occurrence of severe disease in those receiving TNF-alpha inhibitor therapy [11,12] and in hosts with IFN-gamma receptor deficiency [13,14].
These defense mechanisms are generally sufficient to control the infection in immunocompetent individuals, explaining the subclinical or self-limited course characteristic of acute histoplasmosis. 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 [2,3,15]. Individuals with underlying conditions such as AIDS, or who are receiving immunosuppressive medications that impair these defenses, are at risk for developing more severe, and often fatal, progressive forms of infection.
Reinfection and reactivation of infection — Reinfection can occur in patients who previously had documented histoplasmosis. In persons with impaired immunity or in those who have a massive reexposure to H. capsulatum, host defenses against this organism can be overwhelmed and disease can recur.
Reactivation of latent histoplasmosis can also occur in immunocompromised patients [15,16]. Presumably, viable organisms persist in the tissues following recovery from the initial (often asymptomatic) episode of histoplasmosis. Development of disseminated histoplasmosis in individuals who left the endemic area years before is thought to be caused by reactivation of these quiescent foci. The finding of a mitochondrial DNA pattern characteristic of Panamanian strains of H. capsulatum in five patients who had moved from Puerto Rico to New York City provides convincing evidence for reactivation [17].
Cases of progressive pulmonary or disseminated histoplasmosis occurring shortly after initiation of immunosuppressive therapy with TNF-alpha inhibitors [11,12,18] could represent worsening of smoldering infection exacerbated by recently intensified immunosuppression, newly acquired infection, or reactivation. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Histoplasmosis'.)
PATHOLOGY — Three types of tissue response have been described in disseminated histoplasmosis: diffuse histiocytosis, focal histiocytosis, and tuberculoid granulomas [2]. Histiocytosis refers to macrophage infiltration into the infected tissues. In comparison, infiltration of neutrophils, lymphocytes, and plasma cells are not usually noted in the tissues of patients with disseminated histoplasmosis. Granulomas are seen less often with disseminated infection than with other types of histoplasmosis and usually are seen in patients with lower fungal burdens (picture 2) [2].
Perivasculitis with necrosis can be seen on histopathological examination of biopsy material from patients with more severe infection. Heavy infections may also cause marked enlargement of the involved organs (eg, liver, spleen, adrenal glands, lymph nodes), occasionally displacing normal parenchymal cells and causing organ dysfunction. At autopsy, many patients with disseminated histoplasmosis demonstrate involvement of these organs, as well as gastrointestinal tract mucosa [2]. Autopsy experience is biased toward the severe end of the disease spectrum, however, and the extent of dissemination to various organs is not well documented in milder cases.
RISK FACTORS — Most patients with disseminated histoplasmosis have underlying conditions (eg, immunosuppressive disorders, HIV infection) or take medications, such as antirejection transplant medications and tumor necrosis factor (TNF)-alpha inhibitors, that impair their ability to defend against intracellular pathogens [5,15,19,20].
Transplant recipients — Solid organ transplantation is a risk factor for disseminated histoplasmosis [21-23]. Infection in solid organ transplant recipients can occur as a new infection by inhalation of conidia or by reactivation of quiescent disease. Infection can also be transmitted from the transplant donor [24-26]. This was illustrated in a report of two kidney transplant recipients who developed disseminated histoplasmosis eight and nine months after transplantation. The recipients lived in different states from one another, neither of which were endemic regions, had never traveled to endemic areas, and had no prior serologic evidence of exposure to the fungus [24]. Both received cadaveric kidneys from the same donor who had serum antibody titers of 1:16 by complement fixation, and their isolates of H. capsulatum had identical patterns by both polymerase chain reaction and DNA analysis, reflecting transmission from the organs. (See 'Reinfection and reactivation of infection' above and "Infection in the solid organ transplant recipient", section on 'Donor-derived infections'.)
In a multicenter study of 152 cases of histoplasmosis in solid organ transplant recipients over an eight-year period, 81 percent had disseminated disease and 28 percent of patients had severe histoplasmosis requiring intensive care unit admission [22]. The median time from transplantation to diagnosis was 27 months, but 34 percent of patients were diagnosed during the first year after transplantation.
Histoplasmosis appears to be rare among hematopoietic cell transplant recipients [26-30].
Tumor necrosis factor-alpha inhibitors — TNF-alpha inhibitors, including infliximab, etanercept, adalimumab, and others, are an increasingly reported cause of disseminated histoplasmosis in patients with rheumatoid arthritis, inflammatory bowel disease, and other diseases treated with these agents [11,12,18,31-33]. Histoplasmosis in this patient population is further discussed elsewhere. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Histoplasmosis'.)
HIV infection — Although HIV infection is a significant risk factor for disseminated histoplasmosis, the risk of disease has declined in the United States with effective antiretroviral therapy [34]. However, histoplasmosis remains a major problem in persons with HIV in Latin America [35,36]. Detailed discussions of histoplasmosis in patients with HIV are found elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV" and "Treatment of histoplasmosis in patients with HIV".)
Other risk factors — Other risk factors that predispose to disseminated histoplasmosis include primary and acquired cellular immunodeficiency, receipt of other immunosuppressive medications, such as glucocorticoids, and extremes of age. At least one report noted that risk also may be increased during pregnancy [37].
A separate group of patients, most of whom are middle-aged to older men, may develop chronic disseminated histoplasmosis and have no known underlying immunosuppression [2]. In these patients, unidentified defects in cellular immunity likely explain their inability to control the infection. (See 'Clinical manifestations' below.)
CLINICAL MANIFESTATIONS
Time course and spectrum of disease — The clinical manifestations of disseminated histoplasmosis, as well as the timing of presentation, vary based on the host's immune function and the degree of exposure to the fungus [2,4]. Patients may present shortly after the exposure or years later and rarely may experience asymptomatic periods interrupted by symptomatic relapses [2]. Disseminated histoplasmosis occurs in two classically described forms (acute and chronic) based upon the time course of the illness [2]. The term progressive disseminated histoplasmosis often refers to severe disease involving multiple organ systems, usually among immunocompromised patients.
●Acute infection – Acute infection is mostly seen in infants and heavily immunocompromised hosts, such as persons with advanced HIV. Patients with acute infection present with fever, fatigue, hepatosplenomegaly, and pancytopenia. Diarrhea and dyspnea occur less commonly. Unusual manifestations, including splenic infarction and ulcerative skin lesions occurring within three months of initiating antiretroviral therapy have been reported in a few patients with HIV and have been attributed to immune reconstitution inflammatory syndrome [38]. (See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV" and "Immune reconstitution inflammatory syndrome".)
Severely immunocompromised patients can also present with overwhelming infection manifested by shock, respiratory distress, hepatic and renal failure, obtundation, and coagulopathy [15]. These manifestations were more common early in the AIDS epidemic. After the introduction of potent antiretroviral therapy, severe acute disseminated histoplasmosis in patients with HIV is seen less often.
●Chronic infection – Chronic infection has been described primarily in immunocompetent older adults. Patients with chronic histoplasmosis often present with pancytopenia, hepatosplenomegaly, oropharyngeal lesions, and symptoms and signs of adrenal gland dysfunction. They may have skin lesions and gastrointestinal involvement, and they often are ill for weeks to months before the diagnosis is made.
Not all patients with disseminated histoplasmosis can be placed neatly into these two distinct syndromes. Patients who have H. capsulatum documented at even one extrapulmonary site, such as extrathoracic lymphadenopathy or isolated central nervous system (CNS) infection, are classified as disseminated histoplasmosis [39]. Many of these patients do not have the findings noted above but rather have findings related to the predominant organ involved [39]. A review of disseminated histoplasmosis comparing immunocompetent with immunocompromised patients noted that patients who were immunocompetent were less likely to have fever and gastrointestinal manifestations, but night sweats, respiratory symptoms, and skin lesions were similar in both groups. Oropharyngeal lesions and symptoms and laboratory findings suggesting adrenal insufficiency were not found in that series [39].
Gastrointestinal disease — Gastrointestinal disease manifestations are uncommon. Involvement may occur all along the gastrointestinal tract but most often involves the colon or ileum, especially the ileocecal area. Clinical symptoms include nausea, vomiting, and diarrhea; clinical findings include ulcerations resembling inflammatory bowel disease and polypoid masses resembling cancer (image 1) [2,5]. Less common presentations include painful ulcerative mouth lesions with heaped up borders resembling malignancy, dysphagia, esophagitis, abdominal pain, gastrointestinal bleeding, and colonic perforation.
Subclinical gastrointestinal involvement is much more common; approximately 70 percent of patients with disseminated histoplasmosis have involvement of the gastrointestinal tract at autopsy [2]. Histologic examination reveals infected macrophages in the lamina propria.
Patients with fever and intestinal lesions on colonoscopy who are from endemic areas or who have a history of possible exposure to H. capsulatum should be evaluated for histoplasmosis. Care must be taken to exclude histoplasmosis as the cause for ulcerative bowel disease before initiating immunosuppressive therapy, especially with TNF-alpha inhibitors [40]. (See "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV", section on 'Diagnosis of disseminated histoplasmosis'.)
Skin involvement — Skin lesions are seen much more frequently in persons with advanced HIV [41-43]. The lesions seen include nodules, papules, plaques, ulcers, vesicles, pustules, abscesses, and generalized dermatitis (picture 3). Less common manifestations include exfoliative erythroderma, necrotizing vasculitis, cellulitis, panniculitis, petechiae, purpura, and ecchymoses.
H. capsulatum is present on fungal stains of skin biopsy specimens of lesions in most cases of HIV-associated disseminated histoplasmosis [44]. Diagnosis of skin involvement can be difficult because organisms may primarily be seen extracellularly and pathologic findings may resemble leukocytoclastic vasculitis [45]. Presence of an infiltrate composed of macrophages that are heavily infected with H. capsulatum is a characteristic finding on histopathology; granulomas are uncommon.
Adrenal involvement — Overt adrenal insufficiency is found in less than 10 percent of cases, although adrenal involvement is common in autopsied cases [2]. Adrenal involvement may be unilateral or bilateral (image 2). The adrenal sinusoids may be diffusely involved or may have focal collections of infected macrophages in the medulla, zona reticularis of the cortex, or corticomedullary junction. Perivasculitis may be a prominent feature, causing thrombosis and infarction of the adrenal gland and adrenal insufficiency. Thus, clinicians should consider histoplasmosis in patients with adrenal masses or adrenal insufficiency and should consider adrenal insufficiency in patients with disseminated histoplasmosis who present with electrolyte abnormalities (high serum potassium levels and low serum sodium levels), orthostatic hypotension, and/or hypoglycemia.
Central nervous system disease — Studies report CNS involvement in 5 to 20 percent of cases of disseminated histoplasmosis, with higher incidence in patients with underlying immunosuppressive disorders [5,46,47]. Clinical presentations include meningitis with other symptoms of disseminated histoplasmosis, isolated chronic meningitis, cerebral vasculitis with stroke syndrome, focal brain lesions, encephalitis, and localized involvement of the spinal cord [46]. Histoplasmosis should be considered in the differential diagnosis of patients who are from endemic areas or who have a history of possible exposure to H. capsulatum and present with chronic meningitis, focal brain or spinal cord lesions, or encephalitis [48]. (See "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV", section on 'Special considerations for diagnosing meningitis'.)
Endocarditis — Endocarditis is a rare manifestation of H. capsulatum infection [49-53] and is often difficult to diagnose. Symptoms typically last for weeks to months before the diagnosis is made. H. capsulatum can affect native and prosthetic valves, as well as aortic grafts [54].
In a multicenter study of 14 persons with proven Histoplasma endocarditis diagnosed over a 10-year period, 10 had an infected prosthetic aortic valve, three had an infected native mitral valve, and one had an infected left atrial myxoma [53]. Diagnosis was delayed a median of seven weeks; blood cultures yielded the organism in only six patients, but 11 had a positive serum or urine Histoplasma antigen assay. Mortality was 22 percent with death occurring from two days to two months after diagnosis.
A literature review of 61 cases of H. capsulatum endocarditis diagnosed from 1945 to 2020 compared native and prosthetic valve endocarditis [55]. Thirty-six patients had native valve endocarditis, with 58 percent involving the aortic valve; 25 patients had prosthetic valve endocarditis, with 76 percent involving the aortic valve. Symptoms were present for a mean of 10 months for native valve endocarditis and six months for prosthetic valve endocarditis. Embolic complications occurred equally often in native valve and prosthetic valve endocarditis. The mean case fatality rate was 88 percent prior to 1970 compared with 21 percent after 1970.
Other — Uncommon manifestations of disseminated histoplasmosis include [2,3]:
●Thrombotic microangiopathy [56].
●Hemophagocytic lymphohistiocytosis [57,58].
●Hypercalcemia due to calcitriol production by activated macrophages [59,60] (see "Hypercalcemia in granulomatous diseases"). Hypercalcemia may lead to the incorrect diagnosis of sarcoidosis [61].
●Chorioretinitis [62].
●Pleuritis [63].
●Pericarditis [64].
●Peritonitis [65].
●Pancreatitis and cholecystitis [66].
●Panniculitis [67].
●Mastitis [68].
●Osteomyelitis and septic arthritis of both native and prosthetic joints [69-71].
●Tenosynovitis [72].
●Prostatitis [73], epididymitis, or involvement of the penis or vagina [74-76].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Histoplasmosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: Histoplasmosis (The Basics)")
SUMMARY
●General – Histoplasmosis is the most prevalent endemic mycosis in the United States. Most infections are asymptomatic or self-limited, but some individuals develop acute pulmonary infections or severe and progressive disseminated infection. Severe illness is unusual except in the host with altered immunity and those at the extremes of age. (See 'Introduction' above.)
●Pathogenesis
•Histoplasma capsulatum is a thermally dimorphic fungus, growing as a mold in the environment and as a yeast at 37°C. Infection develops when Histoplasma microconidia are inhaled into the lungs, where they change into the yeast form. In patients with disseminated infection, macrophages are typically engorged with yeasts, supporting the important role of intracellular proliferation of the organism. (See 'Pathogenesis' above.)
•T cell immunity plays the predominant role in recovery from histoplasmosis. Once cellular immunity to Histoplasma develops, macrophages become activated to kill the organism. Failure to activate macrophage fungicidal capacity appears to be the key defect in immunity to H. capsulatum in patients with disseminated histoplasmosis. (See 'Pathogenesis' above.)
•Reinfection can occur in patients who previously had documented histoplasmosis. In persons with impaired immunity or in those with massive exposure, reexposure to H. capsulatum can overcome residual host defenses against this organism. Reactivation of latent histoplasmosis can also occur in immunocompromised patients. Presumably, viable organisms persist in the tissues following recovery from the initial episode of histoplasmosis. (See 'Reinfection and reactivation of infection' above.)
●Pathology – At autopsy, many patients with disseminated histoplasmosis demonstrate involvement of the liver, spleen, lymph nodes, bone marrow, adrenal glands, central nervous system (CNS), and gastrointestinal tract mucosa. (See 'Pathology' above.)
●Risk factors
•Most patients with disseminated histoplasmosis have underlying conditions that impair their ability to defend against intracellular pathogens. A variety of conditions have been found to predispose to disseminated histoplasmosis, including:
-HIV infection
-Primary immunodeficiency or other immunosuppressive disorders
-Immunosuppressive medications, such as glucocorticoids, antirejection therapies in solid organ transplant recipients, or tumor necrosis factor (TNF)-alpha inhibitor therapies
-Extremes of age (see 'Risk factors' above)
•A separate group of patients have chronic disseminated histoplasmosis and have no known underlying immunosuppression. In these patients, unidentified defects in cellular immunity likely explain their inability to control the infection. (See 'Risk factors' above.)
●Clinical manifestations
•The clinical manifestations of disseminated histoplasmosis as well as the timing of presentation vary based on host immunity and the degree of exposure to the fungus. Patients may present shortly after the exposure or years later and rarely may experience asymptomatic periods interrupted by symptomatic relapses. Disseminated histoplasmosis occurs in two forms, based upon the time course of the illness and the extent of infection:
-Acute infection, which is mostly seen in infants and heavily immunocompromised hosts
-Chronic infection, noted more often in older adults (See 'Time course and spectrum of disease' above.)
•Severely immunocompromised patients, such as those with AIDS or those receiving treatment with immunosuppressive medications, may present with overwhelming infection manifested by shock, respiratory distress, hepatic and renal failure, obtundation, and coagulopathy. (See 'Clinical manifestations' above.)
•Patients with chronic infection often present with pancytopenia, hepatosplenomegaly, hepatic enzyme elevation, and oropharyngeal lesions. Other sites include the skin, brain, and adrenal glands (image 3 and image 2 and figure 1). (See 'Clinical manifestations' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joseph Wheat, MD, who contributed to an earlier version of this topic review.
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