Testing Algorithm for Histoplasmosis

When to consider testing for histplasmosis

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Overview

Histoplasmosis is a fungal infection that often presents as community-acquired pneumonia (CAP) in primary and urgent care settings. It is endemic in parts of the U.S. and the world.

Histoplasmosis cannot be reliably distinguished from other causes of respiratory illness by signs or symptoms alone. Thus, patients are commonly misdiagnosed; in some instances, over half of patients may receive inappropriate antibacterial drugs.¹

Consider testing patients with community-acquired pneumonia who:

• Live in or recently traveled to an endemic area (maps below) and
• Have not improved with at least one course of empiric antibiotics.

Visual algorithm

If a patient lives in or has traveled to a histoplasmosis-endemic area and has:

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A flowchart to show the diagnosis of histoplasmosis

1a. CAP of unknown etiology not responding to a course of empiric antibiotics

or

1b. Initial CAP visit if:

1. Notable exposure to bird or bat droppings (cave or demolition/remodeling exposure; note that many patients do not recall a specific exposure) OR
2. Chest X-ray showing new nodules or lymphadenopathy OR
3. Link to known histoplasmosis outbreak

2. Consider enzyme immunoassay (EIA) urine antigen and immunodiffusion (ID) or complement fixation (CF) serum antibody testing

1. Antigen or antibody positive
   1. Probable acute pulmonary histoplasmosis
2. Antigen and antibody negative
   1. Consider alternative diagnosis
   2. High degree of suspicion
      1. Consider consulting infectious disease or pulmonology
      2. Retest
         1. Repeat antibody testing, since testing may be negative early in illness, or order sputum or bronchoalveolar lavage (BAL) culture and microscopy.
         2. Retest is negative
            1. Consider alternative diagnosis
         3. Retest is positive
            1. Probable acute pulmonary histoplasmosis
3. Note: in the first two weeks of infection, false-negative tests may occur with antigen testing. Depending on availability, serum antibody testing for Histoplasma can be considered to increase sensitivity, particularly if clinical suspicion is high; however, a positive serum antibody test may indicate previous infection. Enzyme immunoassay (EIA or ELISA) antigen testing is typically considered first because of a quicker turnaround and higher sensitivity; however, it has a high rate of cross-reactivity with Blastomyces. Immunodiffusion and complement fixation antibody tests can be used if EIA is not available or if clinicians want to rule out blastomycosis or other fungal diseases.

Show Text Description

Approximate histoplasmosis-endemic areas

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Approximate area with Histoplasma in the US

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Approximate area with Histoplasma in the world

These areas include central and eastern United States, especially around the Ohio and Mississippi River Valleys

Globally, Histoplasmosis is endemic in parts of South and Central America, Africa, Asia and Europe.

Additional considerations

Clinicians may also consider testing for histoplasmosis on an initial presentation of community-acquired pneumonia when patients have any of the following features:

• Notable exposure to bird or bat droppings (e.g., entered cave, demolition/remediation of building with extensive droppings); be aware most patients do not recall such exposures
• Chest X-ray demonstrating new nodules or lymphadenopathy
• Link to known histoplasmosis outbreak

Disease can occur in both immunocompetent and immunocompromised persons. Travel-associated disease is common, and climate change may be influencing the geographical range of Histoplasma; thus, cases can be found in all regions across the United States.

How to test for histoplasmosis

We recommend ordering enzyme immunoassay (EIA) urine antigen tests. Clinicians may consider obtaining a serum specimen to test concurrently for antibody by immunodiffusion (ID) or complement fixation (CF) which may increase sensitivity of diagnosis; false positives from previous infection can occur, but antibody positivity typically wanes within three years after infection. If these tests are negative, clinicians should consider alternative diagnoses. If a high degree of suspicion remains despite negative initial testing, a clinician may consider ordering (or repeating) antibody testing since tests may be negative early in illness. At this point, clinicians might also consider ordering a sputum or bronchoalveolar lavage (BAL) culture and microscopy. Consultation with specialists in infectious diseases or pulmonology may be considered when a high degree of suspicion remains as well.

Histoplasma antigen and antibody tests have extensive cross-reactivity with Blastomyces. Both infections are treated the same way in most forms.

Clinicians should refer to the Infectious Diseases Society of America's histoplasmosis treatment guidelines or an infectious disease physician when determining therapy after a positive result.

Additional Resources

• Clinical Testing Guidance for Coccidioidomycosis, Histoplasmosis, and Blastomycosis in Patients With Community-Acquired Pneumonia for Primary and Urgent Care Providers | Clinical Infectious Diseases | Oxford Academic (oup.com)
• Webinar Thursday, September 21, 2023 – Algorithms for Diagnosing the Endemic Mycoses Blastomycosis, Coccidioidomycosis, and Histoplasmosis (cdc.gov)
• Three Cases of Community-Acquired Pneumonia (medscape.com)