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Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV

Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV
Literature review current through: Jan 2024.
This topic last updated: Oct 17, 2022.

INTRODUCTION — Histoplasmosis is the most common endemic mycosis in patients with acquired immunodeficiency syndrome (AIDS) [1-3]. Although the risk of disease in patients with human immunodeficiency virus (HIV) has declined with effective antiretroviral therapy [4,5], it continues to cause severe morbidity and mortality in endemic areas, particularly in resource-limited settings [6].

The epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV will be reviewed here. The treatment of histoplasmosis in patients with HIV, as well as topic reviews that discuss histoplasmosis in patients without HIV, are found elsewhere. (See "Treatment of histoplasmosis in patients with HIV" and "Diagnosis and treatment of pulmonary histoplasmosis" and "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV" and "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Pathogenesis and clinical manifestations of disseminated histoplasmosis".)

EPIDEMIOLOGY

Geographic distribution − Histoplasmosis is found in temperate zones worldwide; specific endemic areas include the Mississippi and Ohio river valleys, the Caribbean, southern Mexico, certain parts of Central and South America, Africa, and Asia. In these regions, the fungus is found in high concentrations in soil contaminated with bird or bat excreta [7]. (See "Pathogenesis and clinical features of pulmonary histoplasmosis", section on 'Reservoir' and "Pathogenesis and clinical features of pulmonary histoplasmosis", section on 'Epidemiology'.)

Sources of infection − Transmission occurs via inhalation of Histoplasma capsulatum conidia from the soil. Thus, infection may be acquired through a multitude of activities (eg, demolition and construction, cleaning out old structures or chicken coops, spelunking, and gardening or handling of plants), which can lead to inhalation of the pathogen through contaminated soil [8-10]. Most primary cases of infection occur shortly after initial exposure; disseminated infection has also been described in patients living outside of endemic areas, suggesting endogenous reactivation of latent foci of infection that were acquired from previous travel or residence in endemic areas [8,11-13]. (See "Pathogenesis and clinical features of pulmonary histoplasmosis", section on 'Epidemiology'.)

Burden of disease − Early in the HIV epidemic, histoplasmosis occurred in 5 to 27 percent of patients with advanced HIV living in endemic areas of the United States [8]. Despite the risk of disease declining with effective antiretroviral therapy (ART) [4,5], histoplasmosis remains one of the most common infections among persons with HIV living in Latin America.

Risk factors − The major risk factor for developing histoplasmosis in persons with HIV is a CD4 count ≤150 cells/microL among untreated individuals. Other risk factors include occupations and activities associated with exposure to soil that contains bird or bat droppings [4]. ART is protective against histoplasmosis.

The importance of cellular immunity was demonstrated in one study of T-cell proliferative responses to Histoplasma antigens; in vitro data showed that T-cell proliferative responses were depressed in persons with HIV who had a history of histoplasmosis and CD4 counts ranging from 200 to 500 cells/microL compared with persons without HIV [14].

MICROBIOLOGY AND PATHOGENESIS — There are two varieties of H. capsulatum that infect humans: H. capsulatum var. capsulatum and H. capsulatum var. duboisii. The most common variety, H. capsulatum var. capsulatum, is found worldwide while H. capsulatum var. duboisii only exists in Africa [15].

This endemic fungus is thermally dimorphic; it exists as mold in the environment and as yeast at body temperature. Microscopically, H. capsulatum has hyaline, septate hyphae, with spherical, thick-walled tuberculate conidia and smaller microconidia (picture 1). In tissues, the organism appears as 2 to 4 micrometer oval, budding yeasts that can be found both inside and outside macrophages.

Infection with H. capsulatum occurs when the mold form is inhaled from contaminated soil or other material into the lungs. There, H. capsulatum converts into its yeast form and is ingested by macrophages. Macrophages then proceed to hematogenously spread the organism through the reticuloendothelial system (liver, spleen, lymph nodes, and bone marrow). CD4 cells play an important role in controlling primary infection [15]. When T cell immunity is impaired, the macrophages are not activated to kill the organisms, resulting in a suboptimal immune response and disseminated infection. Additional information on the pathogenesis of pulmonary and disseminated histoplasmosis is discussed elsewhere. (See "Pathogenesis and clinical features of pulmonary histoplasmosis", section on 'Pathogenesis' and "Pathogenesis and clinical manifestations of disseminated histoplasmosis", section on 'Pathogenesis'.)

CLINICAL PRESENTATION

Spectrum and time course of disease — Histoplasmosis can range from asymptomatic infection to life-threatening disseminated disease. In the immunocompetent host and in patients with HIV and CD4 counts >150 cells/microL, histoplasmosis usually presents as a mild self-limiting pulmonary illness [3,16] (see "Pathogenesis and clinical features of pulmonary histoplasmosis", section on 'Clinical manifestations'). Patients with HIV and CD4 counts ≤150 cells/microL usually develop acute disseminated histoplasmosis, characterized by fevers and weight loss [15]. Isolated pulmonary involvement without dissemination in patients with advanced HIV is rare, occurring in less than 5 percent of cases [2,8].

Histoplasmosis-associated immune reconstitution inflammatory syndrome is uncommon, but unusual manifestations such as splenic infarction and ulcerative skin lesions have been reported in patients who had recently started antiretroviral therapy (ART) [17]. (See 'Immune reconstitution inflammatory syndrome' below.)

Incubation period ranges from one to three weeks, although some infections in patients with advanced HIV are due to reactivation of a latent infection.

Clinical signs and symptoms — Most patients with advanced HIV will present with acute disseminated histoplasmosis. Common extrapulmonary sites of involvement include liver, spleen, gastrointestinal tract, bone marrow, adrenal glands, skin, and the central nervous system (CNS). With the exception of bone marrow, osseous involvement is rare with H. capsulatum var. capsulatum but was frequently observed with var. duboisii infections [18].

Clinical symptoms and signs are varied and depend on the organs affected. Common symptoms include fever, night sweats, fatigue, weight loss, nausea, vomiting, cough, and dyspnea [3,8,16,19-23]. Diarrhea and headache are less common. Presence of headache should prompt suspicion for meningitis. Further details on the clinical presentation of histoplasmosis within each organ are discussed in detail elsewhere. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis", section on 'Clinical manifestations'.)

Physical examination often demonstrates hepatosplenomegaly and lymphadenopathy. Skin and mucosal lesions can occur (picture 2) and are indicative of disseminated disease. Cutaneous lesions may be more common in Brazil than in the United States [6,24] and in H. capsulatum var. duboisii infections [18]; these variant clinical manifestations may be related to genetic differences in the causative organisms from the respective geographic locations [24].

Patients with advanced HIV can also present with severe, life-threatening infection characterized by shock, acute respiratory distress, hepatic and renal failure, altered mental status, disseminated intravascular coagulation, and reactive hemophagocytic syndrome [8,19,20,22]. Mortality can be as high as 50 percent in patients with advanced HIV, despite appropriate therapy [21,25]. Such life-threatening infections tend to occur in patients who are not on ART and are less commonly seen with the widespread use of ART.

Laboratory abnormalities — Laboratory abnormalities can vary depending on which organs are involved but generally include pancytopenia secondary to bone marrow involvement [16] and elevated alkaline phosphatase; aminotransferases are often only mildly elevated. Hyperkalemia and hyponatremia are suggestive of adrenal involvement. Elevated creatinine can be seen in patients with acute kidney injury and is a poor prognostic sign [1,3,16]. Nonspecific markers of inflammation, such as lactate dehydrogenase, ferritin, erythrocyte sedimentation rate, and C-reactive protein are often elevated [6].

If meningitis is present, cerebrospinal fluid (CSF) findings are often similar to patterns seen in other fungal etiologies (eg, 50 to 500 predominantly mononuclear white cells, low glucose level, and mildly elevated protein level). CSF findings may be altered in patients presenting with isolated focal CNS lesions or vascular CNS abnormalities. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis", section on 'Central nervous system disease'.)

Radiographic manifestations — As with clinical signs and symptoms and laboratory abnormalities, radiographic manifestations vary based on which organ systems are involved. Pulmonary infiltrates are seen in 40 to 50 percent of patients with advanced HIV and disseminated histoplasmosis and are commonly characterized by diffuse interstitial or reticulonodular infiltrates (image 1) [11]. Focal infiltrates, which are common in acute pulmonary histoplasmosis, are rare in disseminated histoplasmosis. Other less common findings include pleural effusions, mediastinal adenopathy, cavitary disease, and calcified granulomas [8,19]. In one case series, chest radiographic abnormalities were reported in 50 to 70 percent of patients with advanced HIV and disseminated infection [19]. Occasionally, the initial radiograph may be normal.

Computed tomography imaging of the abdomen may demonstrate hepatosplenomegaly and enlarged adrenals with necrosis in the central area.

Immune reconstitution inflammatory syndrome — Immune reconstitution inflammatory syndrome (IRIS) associated with histoplasmosis is very rare. As an example, in one retrospective study of 22 patients with histoplasmosis-associated IRIS, the incidence was 0.74 cases per 1000 person-years, median CD4 cell count at the time of ART initiation was 54 cells/microL, and median time to IRIS symptoms onset after ART initiation was 11 days [26]. Fever, diarrhea, and lymphadenopathy were the most common presenting signs and symptoms of IRIS associated with histoplasmosis. (See "Immune reconstitution inflammatory syndrome".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of disseminated histoplasmosis varies depending on the organ systems involved but generally includes both infectious and noninfectious entities that present with a similar constellation of clinical signs and symptoms (eg, fever, weight loss, hepatosplenomegaly, lymphadenopathy, and pancytopenia).

Tuberculosis − Tuberculosis is the leading infection to consider in the differential diagnosis of histoplasmosis. Often tuberculosis infection and histoplasmosis can coexist in the same patient and is commonly reported in Latin America [25,27,28]. Therefore, diagnostic evaluation for both infections is indicated. Histoplasmosis and tuberculosis can be very difficult to distinguish based on clinical presentation and laboratory/imaging data alone and almost always require culture or histopathology data for diagnosis. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis", section on 'Diagnosis' and "Diagnosis of pulmonary tuberculosis in adults", section on 'Patients with HIV infection'.)

Other endemic fungi – Other endemic fungi, such as blastomycosis, coccidioidomycosis, paracoccidioidomycosis, and talaromycosis, can also present as a disseminated infection in a patient with advanced HIV infection who lives or has traveled to an area endemic for these other fungi. The endemic fungi can be difficult to differentiate from each other. Skin lesions are most common with blastomycosis or talaromycosis while mucous membrane lesions are more frequently seen in histoplasmosis and paracoccidioidomycosis. Histoplasmosis, paracoccidioidomycosis, and talaromycosis involve the reticuloendothelial system, resulting in hepatosplenomegaly and pancytopenia, signs that are uncommon in blastomycosis and coccidioidomycosis. (See "Clinical manifestations and diagnosis of blastomycosis", section on 'Immunocompromised hosts' and "Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis", section on 'Immunocompromised hosts' and "Diagnosis and treatment of Talaromyces (Penicillium) marneffei infection", section on 'Diagnosis' and "Primary pulmonary coccidioidal infection", section on 'Clinical manifestations' and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Clinical manifestations'.)

Disseminated cryptococcosis – Disseminated cryptococcosis can present similarly to disseminated histoplasmosis, with skin lesions, hepatomegaly, lymphadenopathy, and adrenal disease. Serum cryptococcal antigen is usually positive in patients with advanced HIV and disseminated cryptococcosis. (See "Cryptococcus neoformans infection outside the central nervous system", section on 'Diagnosis'.)

Multicentric Castleman disease – Multicentric Castleman disease (MCD) presents with multicentric lymphadenopathy, cytopenias, fevers, weight loss, and occasionally organ failure due to the hyperinflammatory response. Hypergammaglobulinemia is common in MCD while absent in histoplasmosis. MCD is typically diagnosed by histopathology. (See "HHV-8/KSHV-associated multicentric Castleman disease", section on 'Diagnostic evaluation' and "HHV-8-negative/idiopathic multicentric Castleman disease", section on 'Evaluation'.)

Sarcoidosis – Sarcoidosis can present very similarly to histoplasmosis, with fevers, weight loss, fatigue, lymphadenopathy, transaminitis, diffuse pulmonary infiltrates, and hepatomegaly. Splenomegaly and pancytopenia are uncommon. In general, infectious causes (including histoplasmosis) should be excluded prior to making the diagnosis of sarcoidosis. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Testing for tuberculosis and other infections'.)

Malignancy – Hematologic malignancies (eg, lymphomas) can often present similarly to histoplasmosis, with fevers, weight loss, pancytopenias, and lymphadenopathy. Kaposi sarcoma can occasionally manifest with gastrointestinal symptoms or respiratory symptoms that may mimic the symptoms of histoplasmosis. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)

DIAGNOSTIC EVALUATION

When to suspect histoplasmosis — Timely diagnosis of histoplasmosis warrants a high index of clinical suspicion. Disseminated histoplasmosis should be suspected in patients with HIV and a current CD4 count ≤150 cells/microL who lived or are living in a histoplasmosis-endemic area and present with clinical manifestations consistent with disseminated histoplasmosis, such as:

Fevers and weight loss

Cough and/or dyspnea

Skin and/or mucosal membrane lesions

Nausea, vomiting, and abdominal pain

Hepatosplenomegaly and/or lymphadenopathy

Pancytopenia

Other symptoms depending on organ system involved

Approach to diagnosis — Diagnostic testing should not be delayed if histoplasmosis is suspected. For patients in whom disseminated histoplasmosis is suspected, we suggest sending serum and urine Histoplasma antigen and fungal blood cultures using the lysis-centrifugation technique. Examination of tissues or body fluids for fungi using special stains (eg, Giemsa stain for bone marrow aspirates, methenamine silver stain for tissue specimens (picture 3C)) and culture of any available tissue or fluid specimens (eg, bone marrow aspirate, lymph node aspirate, skin biopsy tissue) should be performed (picture 1).

Identification of H. capsulatum by staining or culture confirms the diagnosis. A positive antigen test strongly supports the diagnosis, according to the European Organisation for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium diagnostic guidelines [29]. However, false positives can occur due to cross-reactivity with other endemic fungi (eg, blastomycosis, coccidioidomycosis, paracoccidioidomycosis). These tests are discussed in more detail below. Discussion of diagnostic evaluation of central nervous system (CNS) histoplasmosis is found elsewhere. (See "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV", section on 'Special considerations for diagnosing meningitis'.)

Antigen testing − We send urine and serum Histoplasma antigen as part of the initial diagnostic workup since it is the most sensitive test for the detection of disseminated histoplasmosis [16,30,31]. Antigen testing can be performed on urine, serum, bronchoalveolar lavage (BAL) fluid, and cerebrospinal fluid (CSF) [16]. Serum antigen can occasionally be positive when urine results are negative [30,32]. In one report, antigen was detected in patients with advanced HIV and disseminated histoplasmosis in the following samples: urine (97 percent), blood (83 percent), and CSF (67 percent) [8]. In another report, antigen testing was positive in 39 of 40 patients with HIV in urine and 36 of 37 patients in serum [16].

Histopathology − If tissue samples are available (eg, bone marrow or lymph node biopsy, mucocutaneous lesions), we perform periodic acid-Schiff or methenamine silver stains to evaluate for H. capsulatum. Laboratory evidence of granulomas with yeasts resembling Histoplasma spp in extrapulmonary tissues is consistent with disseminated disease (picture 3A-C) [33]. However, histopathologic examination of tissues using special stains requires additional facilities and a pathologist, tissue preparation can lead to a delay in diagnosis, and sensitivity is low.

Direct microscopy − Direct microscopy can be performed on a routine peripheral blood smear or a buffy coat preparation, as well as on other body fluids, such as bone marrow or lymph node aspirates. Visualization of the organism within macrophages on a Wright-stained peripheral blood smear allows for inexpensive and rapid identification and diagnosis of histoplasmosis, although the sensitivity is low (less than 10 percent) [16,34]. Bone marrow and lymph node aspirates can be stained with Wright, Giemsa, or May-Grünwald-Giemsa stains [35]. Visualization of budding yeast 2 to 4 micrometers in a body fluid is diagnostic of histoplasmosis; Histoplasma yeasts can occasionally be confused with Candida glabrata, Talaromyces marneffei, and amastigote forms of Leishmania [25].

Combining culture with direct microscopy increases the diagnostic yield. In a study of 36 persons with advanced HIV and suspected disseminated disease, the combination of blood culture plus examination of the peripheral smear by direct microscopy had a sensitivity of 88 percent for diagnosis [34].

Culture − Culture of blood, respiratory samples, or other tissues (eg, bone marrow) remains the "gold standard" for diagnosis (picture 1); however, cultures of H. capsulatum may take up to four to six weeks to grow and sensitivity depends on disease burden and type of specimen [25]. In one retrospective study of 46 patients with advanced HIV and disseminated disease, blood cultures using the lysis-centrifugation system were positive in 50 percent of patients [16]. In a study of 184 Colombian patients with HIV and histoplasmosis, 59 (32 percent) had positive tissue cultures, 22 (12 percent) had positive BAL cultures, 14 (7.6 percent) had positive skin scrapings cultures, 11 (6 percent) had positive sputum cultures, and 8 (4.3 percent) had positive whole blood cultures [36]. The reported diagnostic yield of BAL in patients with advanced HIV has varied, but one small study of 27 patients found the sensitivity of stain and culture using BAL fluid to be 70 percent and 89 percent, respectively [37]. The diagnostic yield of sputum in patients with advanced HIV has not been well studied.

Serology − Serologic tests are of limited value in the initial diagnosis of histoplasmosis since results may be delayed for up to two weeks. Standard serology, consisting of complement fixation and immunodiffusion tests, has a combined diagnostic yield of approximately 70 to 92 percent in patients with advanced HIV and histoplasmosis [30,36], although nonreactive serologic testing has also been described [8,36]. Immunodiffusion is less sensitive but more specific than complement fixation [36,38].

Postdiagnostic evaluation — Once diagnosis is made either by culture, pathology, or antigen testing results, patients who report neurologic symptoms (eg, headache, paresthesias) or demonstrate neurologic deficits on exam should be evaluated for CNS disease with brain magnetic resonance imaging and a lumbar puncture. If meningitis is present, CSF results reflect fungal meningitis.

Patients who did not have a Histoplasma urine antigen test sent prior to diagnosis should have one sent after the diagnosis is made, as it will be helpful to monitor response to therapy over time. (See "Treatment of histoplasmosis in patients with HIV", section on 'Monitoring of patients'.)

Evaluation for concurrent infections — As part of the diagnostic evaluation, we conduct a careful search for coinfections since patients with advanced HIV may be concurrently infected with multiple opportunistic pathogens. Common concurrent infections include typical bacterial pneumonia, tuberculosis, disseminated mycobacterium avium complex, pneumocystis pneumonia, and cryptococcal pneumonia or meningitis. (See "Overview of prevention of opportunistic infections in patients with HIV".)

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: Opportunistic infections in adults with HIV" and "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 AND RECOMMENDATIONS

Epidemiology − Histoplasmosis is the most common endemic mycosis in patients with advanced HIV, although the risk of disease has declined with effective antiretroviral therapy. A CD4 count ≤150 cells/microL is the main risk factor for histoplasmosis in patients with HIV. (See 'Epidemiology' above.)

Transmission − Transmission of Histoplasma occurs via inhalation of spores from the soil of endemic areas (eg, Mississippi and Ohio river valleys in the United States, the Caribbean, southern Mexico, certain parts of Central and South America, Africa, and Asia), which can lead to acute infection; some patients also develop disease many years after travel to an endemic area due to reactivation of latent foci. (See 'Epidemiology' above and 'Microbiology and pathogenesis' above.)

Clinical presentation

Spectrum of disease − Histoplasmosis can range from asymptomatic infection to life-threatening disseminated disease. Isolated pulmonary involvement without dissemination in patients with advanced HIV is rare. (See 'Spectrum and time course of disease' above.)

Disseminated disease − Patients with advanced HIV (CD4 count ≤150 cells/microL) usually develop acute disseminated histoplasmosis, characterized by fever, night sweats, weight loss, hepatosplenomegaly, elevated alkaline phosphatase and transaminases, and pancytopenia. Pulmonary infiltrates (eg, diffuse interstitial or reticulonodular infiltrates) are seen in 40 to 50 percent of patients with advanced HIV and disseminated histoplasmosis (image 1). (See 'Clinical signs and symptoms' above and 'Laboratory abnormalities' above and 'Radiographic manifestations' above.)

When to suspect histoplasmosis in patients with HIV

Disseminated histoplasmosis should be suspected in patients with HIV and CD4 counts ≤150 cells/microL who are from and/or living in a histoplasmosis-endemic area and present with clinical manifestations consistent with disseminated histoplasmosis, such as:

-Fevers and weight loss

-Cough and/or dyspnea

-Skin and/or mucosal membrane lesions (picture 2)

-Nausea, vomiting, and abdominal pain

-Hepatosplenomegaly and/or lymphadenopathy

-Pancytopenia

-Other symptoms depending on organ system involved (see 'When to suspect histoplasmosis' above)

Approach to diagnosis

For patients in whom disseminated histoplasmosis is suspected, we send serum and urine Histoplasma antigen, and fungal blood cultures. Examination of tissues or body fluids for fungi using special stains (eg, Giemsa stain for bone marrow aspirates, methenamine silver stain (picture 3C) for tissue specimens) and culture of any available tissue or fluid specimens (eg, bone marrow aspirate, lymph node aspirate, skin biopsy tissue) should be performed (picture 1). Laboratory evidence of granulomas with yeasts resembling Histoplasma in extrapulmonary tissues is consistent with disseminated disease (picture 3A-C). (See 'Approach to diagnosis' above.)

Other diagnostic tests include direct microscopy of a peripheral blood smear, bone marrow aspirate, or lymph node aspirate, and serology. Sensitivity of these tests is low. (See 'Approach to diagnosis' above.)

Identification of H. capsulatum by staining or culture confirms the diagnosis. A positive antigen test strongly supports the diagnosis. (See 'Approach to diagnosis' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

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