Histoplasmosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Around 90% of infections are asymptomatic or result in a mild influenza-like illness.[11] For immunocompetent patients with mild flu-like symptoms, in the appropriate epidemiologic setting, the diagnosis of histoplasmosis may be obvious.

For other patients presenting with more persistent respiratory symptoms or for immunocompromised patients however, comprehensive evaluation that includes history, physical exam, and assessment of clinical, radiologic, and laboratory evidence of dissemination should be sought.

History

A thorough social and occupational history should be obtained. Histoplasma capsulatum is endemic to the Ohio, Mississippi, and Missouri River valleys in the US, as well as to Central and South America.[3][4][16] Cave exploring, close proximity to bird roosts or bats, demolition and excavation, and gathering and cutting wood are all associated with infection. This information will assist in establishing the amount of exposure to the fungal spores, although an exposure history is not always present in affected individuals. In light of increasing spread of this organism outside its current geographic boundaries, a diagnosis of histoplasmosis should be considered in the appropriate clinical context even in the absence of a typical travel history.[6]

The patient may have a drug history or comorbid condition that may contribute to an immunocompromised state.

The patient may have an underlying lung disease (e.g., emphysema). Chronic lung disease is a risk factor for the development of chronic pulmonary histoplasmosis.[26][27]

Because of its high morbidity and mortality, the possibility of disseminated fungal infection should be considered early in the disease course of patients with underlying impaired cellular immunity (e.g., AIDS/HIV infection, chronic immunosuppressive therapy such as tumor necrosis factor (TNF)-alpha antagonists and corticosteroids), neutropenia, age <2 years, chronic lung disease, and graft-versus-host disease, as well as stem cell and solid organ transplant recipients.[19][20][21]

Physical exam

Latent asymptomatic pulmonary histoplasmosis

This is clinically silent and may be discovered only incidentally on biopsy or autopsy, when localized granulomas may be detected in the lungs.

Acute respiratory histoplasmosis (symptoms <4 weeks)

Patients present with flu-like symptoms (e.g., fever, headache, malaise, abdominal pain, weight loss, dry or nonproductive cough, chest pain, fatigue, arthralgias).[1]
Findings on examination are usually unremarkable. Chest auscultation may be normal; scattered crackles and bronchial breathing may be heard in some patients.

Acute respiratory histoplasmosis (symptoms >4 weeks)

Symptoms persisting for >4 weeks may indicate that the patient is developing progressive disseminated disease, which may be arrested by effective therapy.
In patients with more severe respiratory symptoms, distant breath sounds may be heard during auscultation over a lung cavity.

Chronic pulmonary histoplasmosis

This occurs in patients with underlying lung disease (e.g., emphysema).
Infiltration of the upper lobes of one or both lungs can occur with cavitation.
The most common manifestations are productive cough, weight loss, fevers, malaise, and possibly hemoptysis.
Chronic pulmonary disease resembles tuberculosis and can worsen over months or years.

Mediastinal histoplasmosis

Results from involvement of mediastinal lymph nodes, which coalesce to form mass-like lesions.
Often asymptomatic, though symptoms can result from impingement on mediastinal structures such as the esophagus and bronchus.
Fibrosis of the mediastinum can occur as a late complication in some patients, with associated invasion of vital structures.

Disseminated histoplasmosis

Occurs primarily in immunocompromised patients, especially in patients with HIV infection.[1]
Impaired cellular immunity from primary immunodeficiency, or secondary to TNF-alpha antagonists or immunosuppressive therapy, increases the risk of progressive, disseminated, life-threatening histoplasmosis.[14][18]
Fever is the most common symptom; however, headache, anorexia, weight loss, and malaise are frequent complaints.
Extrapulmonary manifestations can be varied, including skin lesions, hepatosplenomegaly, abnormal liver enzymes, pancytopenia, gastrointestinal involvement, and a sepsis-like syndrome.[2]
Central nervous system dissemination of the disease may present as a brain lesion or meningitis.
In patients with advanced HIV/AIDS, histoplasmosis pneumonia usually occurs in conjunction with disseminated disease and presents with symptoms of pulmonary infection that are more acute and more severe than those seen in other patient groups.

Investigations

Chest x-ray

This should be performed in all patients. Even with mild disease, chest x-ray will assist in determining the extent of pulmonary involvement and help distinguish the disease from influenza and community-acquired pneumonia.
Calcified granulomas may be seen; these represent healed foci of previous infection with the fungus (focal infiltrates).
Unilateral or bilateral interstitial or reticulonodular infiltrates, nodules, mediastinal or hilar lymphadenopathy, and cavitary lesions are common findings. Pleural effusions are uncommon.
HIV-infected and immunocompromised patients with pulmonary histoplasmosis may present with diffuse bilateral reticulonodular infiltrates indistinguishable from pneumocystis pneumonia.[2] In both immunocompromised and immunocompetent patients, the presence of diffuse interstitial infiltrates on chest x-ray warrants evaluation for disseminated fungal histoplasmosis. [Figure caption and citation for the preceding image starts]: Chest x-ray of a patient with histoplasmosis, demonstrating bilateral diffuse reticulonodular infiltratesFrom the personal collection of Dr David L. Goldman [Citation ends].

Computed tomography (CT) scan

In immunosuppressed patients, where the index of suspicion for a fungal process is high and the chest x-ray is normal, a CT scan should be a part of the initial evaluation.
The CT scan will assist in determining the extent of dissemination.[Figure caption and citation for the preceding image starts]: Lung CT scan showing classic "snowstorm" appearance of acute histoplasmosisPublic Health Image Library, US Centers for Disease Control and Prevention [Citation ends].

Laboratory studies can serve as a basis for diagnosis with compatible clinical and radiographic findings. Each test has certain limitations that should be recognized before use. Samples may be taken from sputum, urine, serum, bronchoalveolar lavage (BAL), or cerebrospinal fluid (CSF). Usually sputum, urine, and serum are used, but if severe disease is indicated clinically and initial laboratory results are equivocal, then BAL and CSF samples may be used to confirm the diagnosis.

Culture

Fungal cultures are the gold standard test to confirm the diagnosis, but can be technically challenging and time consuming.[28]

Cultures are most useful in patients with chronic pulmonary histoplasmosis or disseminated disease. Patients with acute diffuse pneumonia and disseminated histoplasmosis have a high fungal burden; sputum fungal cultures are usually positive in 60% to 85% of cases.[29][30] By contrast, patients with acute localized pulmonary disease have a low fungal burden; in these patients, sputum culture has a sensitivity of only 15%.
The fungus grows slowly and may take up to 4 to 6 weeks to grow in culture. Samples may be taken from sputum or BAL.
In patients with disseminated disease (e.g., patients with AIDS), culture of the blood using lysis centrifugation bottles increases diagnostic sensitivity when compared with standard culture techniques. Bone marrow culture may also be useful in patients with disseminated disease.[25][Figure caption and citation for the preceding image starts]: Slant cultures growing Histoplasma capsulatum colonies on 2 different kinds of agarDr Lenore Haley, Public Health Image Library, US Centers for Disease Control and Prevention [Citation ends].
BAL culture has a sensitivity of 89% in patients with AIDS.[31]

Antigen detection: enzyme immunoassay

This test provides a rapid diagnosis and is based on the detection of H capsulatum galactomannan. It is useful for patients who are severely ill.[32] It can use samples of serum, urine, BAL, and CSF. Antigen testing of urine or serum is recommended for the rapid diagnosis of suspected disseminated and acute pulmonary histoplasmosis, for which rapid initiation of treatment is paramount to improve outcomes.[4][28][32][33][34][35]
Patients with acute diffuse pneumonia and disseminated histoplasmosis have a high fungal burden, and the urine antigen test is positive in 75% of patients.[29][30] By contrast, patients with acute localized pulmonary disease have a low fungal burden, and the urine antigen test is positive in only approximately 30% of patients.[36]
Sensitivity of antigen detection in urine is comparable to or better than in serum.[37] It is especially useful in making the diagnosis in immunocompromised patients or in those who are severely ill and may not have developed an antibody response.[36]
Antigen detection has a sensitivity of 85% and specificity of 92% in BAL specimens.[38] For patients with AIDS and disseminated histoplasmosis, the sensitivity of antigen detection in BAL fluid appears to be comparable with that in blood.[31]
Serum antigen levels decrease within the first 2 weeks of therapy, while urine antigen levels may persist in low concentrations for many months before they disappear.[39] Antigen levels can be used to monitor patients’ progress while they are receiving antifungal therapy; antigen levels decrease with effective therapy whereas an increase predicts relapse.[28]

Serology (antibody detection): immunodiffusion precipitin test

Antibody testing is recommended for immunocompetent patients with suspected pulmonary histoplasmosis.[28]
The result is positive in 90% of symptomatic patients with acute pulmonary histoplasmosis and nearly 100% with chronic pulmonary histoplasmosis. This test is relatively sensitive but has some limitations because of cross-reactivity.
Measurable antibodies appear 4 to 8 weeks after acute infection and last for 12 to 18 months. This may explain why serology may be negative initially but then positive 1 month later.
Background seropositivity in endemic areas is low; therefore, the immunodiffusion test has a high sensitivity and specificity even in endemic regions.[40]
The result is reported as the presence of M or H bands.[29] H and M antigens are glycoproteins released by the fungus. The M band is found in approximately 76% of patients with acute pulmonary histoplasmosis. The H band is seen in only 20% of infected patients but is associated with severe acute pulmonary histoplasmosis, disseminated infection, and cavitary disease.[29] The M band tends to persist longer than the H band. Its presence can be indicative of acute, chronic or resolved infection.
In patients with AIDS, the sensitivity of serologic tests, including the immunodiffusion test, is reduced to 70%.[2] Likewise, the sensitivity of serology is likely to be decreased in other conditions associated with immunosuppression (e.g., organ transplantation or chronic corticosteroid administration).

Serology (antibody detection): complement fixation assay

Antibody testing is recommended for immunocompetent patients with suspected pulmonary histoplasmosis.[28][32]
This test is quicker and more sensitive than the immunodiffusion test (95% versus 90%) but has a lower specificity due to cross-reactive antibodies induced by other mycotic infections (e.g., coccidioidomycosis, blastomycosis).[40]
It uses H capsulatum yeast and mycelial antigens.
Sensitivity may be decreased in immunocompromised individuals.[32]
Titers between 1:8 and 1:16 are considered low positive and must be interpreted in a clinical context. Titers ≥1:32 or a fourfold rise in titer are diagnostic of acute infection.[41]

Serology (antibody detection): enzyme immunoassay

Antibody testing is recommended for immunocompetent patients with suspected pulmonary histoplasmosis.[28][32]
Commercially available assay that provides quantitative measurement of histoplasmosis specific-immunoglobulin (Ig)G and IgM levels.

In one limited clinical study, this assay was reported to be more sensitive than both complement fixation assays and immunodiffusion assays in the diagnosis of acute pulmonary histoplasmosis.[42]

Combined use of this assay with antigen detection may enhance the diagnosis of acute pulmonary histoplasmosis.[32][42]

Limitations include cross-reactivity with antibodies to other fungi and decreased sensitivity in immunocompromised individuals.[32]

Complete blood count

The results will assist in confirming or rejecting the possibility of disseminated disease.
Immunocompetent patients with histoplasmosis pneumonia may demonstrate only mild anemia.
Patients with progressive disseminated histoplasmosis may have evidence of anemia, neutropenia, pancytopenia, and thrombocytopenia due to disseminated infection involving the reticuloendothelial system.

Liver function tests (LFTs)

These are helpful at baseline if treatment is to be azole antifungals, because of the drugs' risk of hepatotoxicity.
Elevated LFTs in the setting of histoplasmosis infection suggest the presence of disseminated disease.

Biopsy

Tissue should be obtained whenever possible to allow for histopathologic diagnosis via fungal stains and fungal culture.[4] On examination H. capsulatum appear as relatively small (2-4 microns), ovoid, intracellular yeast. Granulomatous inflammation may be caseating or non-caseating.

Periodic acid-Schiff or Grocott methenamine silver staining may be used.[4]

Sensitivity of histopathology will vary according to the burden of disease and degree of immunosuppression.[4][Figure caption and citation for the preceding image starts]: Methenamine silver stain revealing Histoplasma capsulatum fungi in lung tissue Dr Edwin P. Ewing, Jr., Public Health Image Library, US Centers for Disease Control and Prevention [Citation ends].[Figure caption and citation for the preceding image starts]: Histopathologic changes associated with histoplasmosis of the lungDr Martin Hicklin, Public Health Image Library, US Centers for Disease Control and Prevention [Citation ends].

Typical laboratory findings

Acute pulmonary histoplasmosis (symptoms <4 weeks)

Fungal burden is low. Enzyme immunoassay will detect urine antigen in approximately 30% of patients. Sputum culture has a sensitivity of approximately 15%. Serology is positive in most cases.

Acute pulmonary histoplasmosis (symptoms >4 weeks)

Fungal burden is high. Antigen testing and cultures are often positive. Serology may be negative initially but then positive 1 month later.

Chronic pulmonary histoplasmosis

Serology is positive in most cases and complement fixation titers are often high.

Disseminated disease

Sputum fungal cultures are positive in 60% to 85% cases. Serology is positive in most cases, though sensitivity may be adversely affected in immunocompromised patients. Antigen detection has a sensitivity of more than 90% for disseminated disease in immunocompromised patients.[43] Bone marrow examination may provide a rapid method of diagnosis in patients with disseminated disease, especially patients with AIDS.[25]

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