Histoplasmosis Workup

Updated: Sep 15, 2020
  • Author: Jazeela Fayyaz, DO; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Laboratory Studies

CBC count

Mild anemia may be present in chronic pulmonary histoplasmosis. In acute progressive disseminated histoplasmosis, pancytopenia occurs in 70-90% of patients, with a platelet count less than 70,000. Pancytopenia may occur at a lower rate in chronic, progressive, disseminated histoplasmosis.

Alkaline phosphatase and lactate dehydrogenase

Alkaline phosphatase levels are elevated in acute progressive disseminated histoplasmosis and chronic pulmonary histoplasmosis. [19]

Marked elevations in lactate dehydrogenase levels may be seen in AIDS patients with disseminated histoplasmosis. [20, 21]

Sputum cultures

Positive yields occur in approximately 15% patients with acute pulmonary histoplasmosis. Culture results are positive in 60-85% of specimens from patients with chronic pulmonary histoplasmosis. [19]

Blood cultures

Blood cultures should be performed in all patients. Results are positive in 50-70% of patients with progressive disseminated histoplasmosis. [19] Results are rarely positive in patients with other types of histoplasmosis.

Complement-fixing antibodies

Titer is considered positive at reciprocal dilutions greater than 1:8. A titer with dilutions greater than 1:32 suggests active histoplasmosis infection. Cross-reactivity with antigens from Blastomyces dermatitidis and Coccidioides immitis may cause a false-positive test result. False positive tests may also occur in persons with lymphoma, tuberculosis, or sarcoidosis. [12]

Positive results are expected in 5-15% of cases of acute pulmonary infection 3 weeks after exposure. This figure increases to 75-95% at 6 weeks in cases of symptomatic infection. Test results usually normalize over months, with resolution of infection.

Test results may remain positive in 70-90% of cases associated with chronic pulmonary histoplasmosis or chronic progressive disseminated histoplasmosis. [15]

Immunoprecipitating antibodies

This test detects antibodies to 2 glycoproteins, H and M. Anti-M antibody is detected in 50-80% of patients and remains elevated for years. Anti-H antibody is detected in only 10-20% of patients and becomes undetectable within 6 months in the absence of continued infection. Anti-H antibody is more specific for active histoplasmosis. [19]

Serum and urine antigen detection  [22]

These are useful in individuals who are immunocompromised when antibody production may be impaired.

Detection rates in cases of acute progressive disseminated histoplasmosis are 68% with serum assay and 65% with urine assay. With both urine and serum specimens, antigen was detected in 83%. Lower detection rates are observed in acute or chronic pulmonary histoplasmosis. [11]

Cross-reactivity with Blastomyces and Coccidioides species causes false-positive results. Cross-reactivity may occur in 90% of blastomycosis cases. [23]

Some patients with acute histoplasmosis may have high serum levels of angiotensin-converting enzyme. [24] This may cause a diagnostic confusion with sarcoidosis, particularly if the patient with histoplasmosis also has hilar adenopathy.

Urine antigen levels may be used to follow the patient's course. [12]

In making the diagnosis of progressive disseminated histoplasmosis, blood cultures, blood antigen, urine antigen, and Histoplasma immunodiffusion and complement fixation should be obtained. [15]

Third-generation antigen assays have increased sensitivity of antigenemia to almost 100% of disseminated histoplasmosis. [23]

Antigenuria can be detected in as many as 92% of cases with disseminated histoplasmosis, 83% with acute histoplasmosis, 30% with subacute histoplasmosis, and 88% with chronic pulmonary histoplasmosis. [23]

Negative results do not exclude histoplasmosis, and repeated testing is advised with progressive illness if the initial test results are negative. [23]


Imaging Studies

Chest radiography

In acute pulmonary histoplasmosis, findings on chest radiography are usually normal. Occasionally, hilar and mediastinal nodes are enlarged. Patchy infiltrates, predominately in the lower lung fields, may be present. In cases of exposure to high inoculum, diffuse pulmonary involvement correlates with a reticular nodular or miliary pattern on chest radiography. Cavitations are rarely present.

Histoplasmomas are healed pulmonary lesions that appear as residual nodules on chest radiography. These coin lesions usually are 1-4 cm in diameter. When yeast forms are present in the core, continued fibrosis in response to the yeast antigens adds to the fibrotic capsule, slowly enlarging the lesions.

Hilar lymphadenopathy is rare in chronic pulmonary histoplasmosis, although calcified nodes from prior healed infections may be present. Cavitations, predominantly in the upper lobes, are present in 90% of patients. Underlying emphysematous changes are common. Progressive fibrotic scarring is present in long-standing cases.

In chronic progressive disseminated histoplasmosis, chest radiography findings usually do not reveal any active pulmonary disease.

In acute progressive disseminated histoplasmosis, hilar lymphadenopathy with diffuse nodular infiltrates is common, occurring in 50% of patients. Findings on chest radiography are normal in 33% of patients initially, but radiographs may reveal pulmonary involvement as the disease progresses. [15]

CT scanning

Head CT scanning is useful in detecting the presence of cerebral histoplasmosis prior to performing a lumbar puncture.

Abdominal CT scanning is useful if adrenal involvement is suspected, especially with subacute progressive disseminated histoplasmosis, which results in adrenal infection in 80% of patients. Bilateral adrenal enlargement usually is detectable. [11]


Transthoracic or transesophageal echocardiography may be helpful if valvular involvement is suspected; endocarditis with Histoplasma species is rarely associated with positive blood cultures.


Other Tests

Pulmonary function testing

Use pulmonary function testing to determine the extent of pulmonary involvement by evaluating the degree of restrictive defect, the presence of a small airway obstruction, the extent of diffusion impairment, and the presence of hypoxemia.

Monitor the progression of pulmonary disease in patients with chronic pulmonary histoplasmosis.



Procedures that may be necessary in the diagnosis of histoplasmosis include the following:

  • Lumbar puncture: If CNS involvement is suspected, consider performing a lumbar puncture to evaluate for other possible CNS infections or lesions. Always perform CT scanning prior to lumbar puncture to evaluate for masses or bleeding that may complicate the lumbar procedure.

  • Lavage: Lavage may be required for histiologic evaluation and to obtain cultures to make the diagnosis. A 2010 study showed that bronchoalveolar lavage has a sensitivity of 96.8% in detecting antigen for histoplasmosis. [25]

  • Thoracentesis: This procedure may be required if the presence of pleural fluid is causing respiratory distress.

  • Tissue biopsy: Obtaining tissue from pulmonary lesions and lymph nodes by bronchoscopy, percutaneous needle biopsies, or rarely, thoracoscopy may be required to make the diagnosis. Results of biopsy of oropharyngeal ulcers are usually diagnostic. [26]

  • Pericardiocentesis: Cultures of pericardial fluid are rarely diagnostic.


Histologic Findings

Tissue biopsy results may reveal the presence of yeast forms in tissue through hematoxylin and eosin staining. Using the Grocott-Gomori methenamine-silver procedure, yeast may be detected in areas of caseation necrosis from histoplasmomas and calcified lymph nodes. Yeast forms in circulating neutrophils and monocytes are rarely detected using Wright-Giemsa staining. Most biopsies do not reveal organisms.

See the images below.

Thoracic histoplasmosis. Gomori methenamine silver Thoracic histoplasmosis. Gomori methenamine silver staining performed on lung tissue shows the yeast phase of histoplasmosis.
Thoracic histoplasmosis. A transbronchial biopsy w Thoracic histoplasmosis. A transbronchial biopsy was performed. Pathologic examination of the specimen revealed multiple noncaseating granulomas present diffusely.
Thoracic histoplasmosis. Another image of the yeas Thoracic histoplasmosis. Another image of the yeast phase of histoplasmosis.