Histoplasma capsulatum

Histoplasma capsulatum

Histoplasma capsulatum is a dimorphic fungus, which exists as a mold in the environment and as a yeast at body temperature. It is a soil-based fungus associated with bird and bat droppings. Human exposure occurs via inhalation of fungal spores. Human-to-human transmission does not occur. 

While endemic in the Ohio and Mississippi River valleys, cases of histoplasmosis have been documented throughout the entire continental United States. H. capsulatum is also endemic in Central and South America, sub-Saharan Africa, and South/Southeast Asia. 

Following inhalation of spores, H. capsulatum is engulfed by macrophages in the reticuloendothelial system. Most patients with acute pulmonary histoplasmosis are asymptomatic or have mild, self-limited cough. These infections usually remain undiagnosed. Patients who inhale a large number of spores may progress to pneumonia and mediastinal or hilar lymphadenopathy. Most of them will recover regardless of treatment. Risk factors for developing disseminated histoplasmosis include HIV with a CD4 count less than 150/uL, immunosuppressive medications, hematologic malignancies, and solid organ transplantation. Patients with disseminated histoplasmosis typically have fever, fatigue, weight loss, and shortness of breath. Common laboratory results include anemia, thrombocytopenia, leukopenia, and elevated transaminases and lactate dehydrogenase. Disseminated histoplasmosis is fatal if left untreated. 

 The differential diagnosis of disseminated histoplasmosis includes tuberculosis, cryptococcus, coccidiomycosis, blastomycosis, malignancy, and sarcoidosis. Serum and urine tests for H. capsulatum antigen are the tests of choice for the diagnosis of disseminated histoplasmosis. Histoplasma antigen can be detected in the urine of >90% of patients and in the serum in 80% of patients who have disseminated histoplasmosis. A confirmed case of histoplasmosis is defined as a serum or urine test positive for H. capsulatum, regardless of a person's symptoms.

Serial antigen testing is helpful in monitoring response to therapy. Both urine and serum antigen levels decrease during therapy. Failure to decrease may indicate treatment failure. Antigen levels increase in 90% of patients who relapse. Antigen levels should be measured before treatment is initiated, at 2 weeks, at 1 month, and then approximately every 3 months during therapy. Antigen levels should continue to be monitored for at least 6 months after therapy is discontinued. 

At MiraVista Diagnostics, the reference interval for both serum and urine H. Capsulatum antigen is no antigen detected. Positive Results for both urine and serum antigen range from 0.20 ng/mL to 20.00 ng/mL Results above 20.00 ng/mL are reported as “Above the Limit of Quantification. ” 

Cross-reactivity with other fungal infections, including Blastomyces dermatitidis, may occur.

Serologic detection of antibody to H. capsulatum is less sensitive than antigen testing, especially in immunosuppressed patients. Antibody testing is of limited usefulness in endemic regions where many individuals test positive. 

Histoplasmosis can also be rapidly diagnosed by PCR. Acceptable specimens include sputum, bronchoalveolar fluid, bronchial washing, bone marrow, spinal fluid and other body fluids. 

Antibody tests can be performed on serum or cerebrospinal fluid. Both complement fixation and immunodiffusion assays are available. Complement fixation measures total antibodies against both mycelial (mold) and yeast components of H. capsulatum and has higher sensitivity but lower specificity than immunodiffusion. Detection of antibodies to both H and M antigens is consistent with active infection. Detection of antibody to only the M antigen is seen in both current and past infection. Antibody to only H antigen is seldom seen and is not diagnostically useful. 

References

Mazi PB et al. The geographic distribution of dimorphic mycoses in the United States for the modern era. Clin Infect Dis. 2023;76(7):1295-1301. 

Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007;20:115–32. 

Kauffman CA. Histoplasmosis. Clin Chest Med. 2009;30(2):217-225. 

Azar MM, Loyd JL, Relich RF, Wheat LJ, Hage CA: Current concepts in the epidemiology, diagnosis, and management of Histoplasmosis syndromes. Semin Respir Crit Care Med. 2020 Feb;41(1):13-30.

Wheat LJ, et al. Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America, Clinical Infect Dis 2007;45:807-25.

Ghai RR, Sajewski ET, Blass M, et al. Cave-Associated Histoplasmosis Outbreak Among Travelers Returning from Costa Rica — Georgia, Texas, and Washington, December 2024–January 2025. MMWR Morb Mortal Wkly Rep 2025;74:289–292.