Overview of histoplasmosis

Author: Rene Kurowski, Michael Ostapchuk
Date: Dec 15, 2002

Histoplasmosis is an endemic infection in most of the United States. Disseminated disease is rare but can be fatal if untreated. This article presents the manifestations, diagnosis, and treatment of histoplasmosis, beginning with the case of an immunocompetent child who developed disseminated disease.

Illustrative Case

A six-year-old boy was referred to a pediatric infectious disease clinic after a three-week history of fever, mild nonproductive cough, pallor, and fatigue. His oral temperature was 40.6[degrees]C (105.1[degrees]F), and he had occasional rigors, emesis, and night sweats.

Outpatient work-up revealed interstitial pneumonitis on chest radiograph; pancytopenia (platelet count, 72,000 per mm3 [72 3 109 per L]; hemoglobin, 8.9 g per dL [89 g per L]); and mildly abnormal results on liver function tests. Blood cultures, febrile agglutinins, and an infectious mononucleosis screen were all negative. Despite the use of antibiotics, the patient's disease progressed, leading to his referral to the infectious disease clinic and admittance to the children's hospital for further evaluation.

The patient's previous medical history was unremarkable. He lived on a farm in Kentucky with his parents and two siblings, and there was no known history of ill contacts, nearby construction, contact with birds or bats, recent travel, ingestion, tick bite, or other exposures. His family history was noncontributory.

At presentation he was found to be well developed and well nourished but very pale, and he appeared ill. He was tachycardic and tachypneic, with an axillary temperature of 39.1[degrees]C (102.4[degrees]F). His abdomen was severely distended, with liver and spleen palpable to just above the pelvic brim. Laboratory findings revealed worsening pancytopenia and liver function. A chest radiograph showed diffuse, fine, nodular interstitial prominence and superior mediastinal widening.

On admission, a computed tomography (CT) scan of the chest revealed diffuse miliary pulmonary infiltrates without mediastinal mass or lymphadenopathy (Figure 1). Bone marrow examination showed no evidence of malignancy. Empiric therapy for tuberculosis and histoplasmosis was initiated. Fungal elements consistent with Histoplasma capsulatum were later identified on bone marrow slides, and bone marrow cultures eventually revealed moderate growth of H. capsulatum. Urine antigen and serologic assays for histoplasmosis were positive. Testing for human immunodeficiency virus (HIV) was negative.

The antitubercular drug regimen was discontinued, and oral itraconazole was added to the amphotericin therapy. After showing marked improvement, the boy was discharged from the hospital on day 9. Amphotericin therapy was continued for a total of 16 days and itraconazole for six months. The patient also received six weeks of potassium supplementation for amphotericin-related hypokalemia. Within three months of discharge he was asymptomatic, with a normal physical examination. At six months, his urine antigen level was still elevated but significantly decreased. Antigen levels are usually monitored until results are negative but, because this patient was doing well enough after three months of itraconazole therapy, he was released to the care of a pediatrician. Further questioning revealed that the patient had been exposed to debris removed from the ventilation system when the heater was started for the winter. The heating ducts may have held fungal spores propagated by bats living in a chimney.


H. capsulatum is a dimorphic fungus found in the temperate zones of the world; it is highly endemic in the Ohio and Mississippi river valleys of the United States. (1) An estimated 40 million people in the United States have been infected with H. capsulatum, with 500,000 new cases occurring each year. (2) The mycelial form of H. capsulatum is found in the soil, especially in areas contaminated with bird or bat droppings, which provide added nutrients for growth. Infections in endemic areas are typically caused by wind-borne spores emanating from point sources such as bird roosts, old houses or barns, or activities involving disruption of the soil such as farming and excavation. (3) H. capsulatum infection is not transmissible through person-to-person contact.


When spores produced by the mycelial form of H. capsulatum become airborne, they are inhaled and deposited in alveoli. At normal body temperature (37[degrees]C [98.6[degrees]F]), the spores germinate into the yeast form of this dimorphic fungus and are ingested by pulmonary macrophages. The yeasts become parasitic, multiply within these cells, (3) and travel to hilar and mediastinal lymph nodes, where they gain access to the blood circulation that disseminates them to various organs. Macrophages throughout the reticuloendothelial system ingest and sequester the organism. (1)

About 10 to 14 days after exposure, cellular immunity develops, and macrophages become fungicidal and clear an immunocompetent host of infection. (4) Necrosis develops at the sites of infection in the lungs, lymph nodes, liver, spleen, and bone marrow, leading to caseation, fibrous encapsulation, calcium deposition and, within a few years of the primary infection, calcified granulomas. (1,4) Any defects in cellular immunity result in a progressive disseminated form of infection that can be lethal. (1)

Clinical Presentation


The majority of people with normal immunity who develop histoplasmosis manifest an asymptomatic or clinically insignificant infection (Table 1). (4,5) The most common abnormality on chest radiograph is a solitary pulmonary nodule. Cavitation is rare, but adenopathy (particularly hilar and mediastinal) is seen frequently. (1) acute pulmonary histoplasmosis Symptomatic illness is primarily caused by an intense exposure (e.g., cleaning an attic or a chicken coop), and the severity of disease is related to the number of spores inhaled. (1) Cellular immunity attained through previous exposure decreases the incidence and severity of symptomatic infections. Therefore, infants and children are affected more frequently than adults. (1)

Acute pulmonary histoplasmosis manifests as a diverse clinical spectrum ranging from a brief period of malaise to a severe, protracted illness (Table 1). (4,5) Common symptoms include fever, headache, nonproductive cough, chills, pleuritic chest pain, weight loss, malaise, myalgias, and sweats. With a larger inoculum, patients may exhibit dyspnea with hypoxia. The physical examination is frequently unremarkable; however, hepatosplenomegaly, adenopathy, erythema nodosum, and erythema multiforme can be encountered. (1,6)

Acute pulmonary infections are not typically associated with abnormalities on chest radiography. Single or multiple patches of airspace disease (particularly in the lower lung zones) are the most frequent abnormal findings.1 Hilar and mediastinal adenopathy is sometimes present, and more severe infections frequently show small diffuse pulmonary nodules. (1)

Mediastinal granuloma, pericarditis, and rheumatologic syndromes (i.e., arthritis) are possible sequelae following acute infections of pulmonary histoplasmosis (Table 1). (4,5) Actively inflamed mediastinal lymph nodes cause chest pain, cough, hemoptysis, and dyspnea because of airway or vascular compression, and the clinical course is extremely variable. (4,5) Pericarditis is caused by an immune reaction to histoplasma infection in mediastinal lymph nodes. (4,5) Patients present with chest pain and fever weeks to months after the pulmonary infection. (4) Despite the risk of hemodynamic compromise, long-term outcome is excellent.4,5 Arthritis may occur as an inflammatory reaction to the primary infection, and distribution is often symmetric and polyarticular. (4,5) Symptoms usually resolve spontaneously or following treatment with anti-inflammatory agents. Radiographs are normal. (4)


Chronic pulmonary histoplasmosis (Table 1) (4,5) is associated with preexisting abnormal lung architecture, especially emphysema, (1,3,6,7) and occurs most commonly in white, middle-aged men. (3) Symptoms (malaise, productive cough, fever, and night sweats) are similar to those of tuberculosis but are usually less severe. The progressive disease process that ends in necrosis and loss of lung tissue results from a hyperimmune reaction to fungal antigens rather than from the infection itself. (1,4)

Chest radiographs often reveal emphysematous lungs with apical bullae surrounded by segmental airspace disease. Progressive thickening of cavity walls and retraction of adjacent lung tissue occur over time, (1,3) but adenopathy is typically absent.


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RENE KUROWSKI, M.D., is assistant professor in the Department of Family and Community Medicine at the University of Louisville School of Medicine, Louisville, Ky., where she also completed a residency. Dr. Kurowski received her medical degree from Loma Linda University School of Medicine, Loma Linda, Calif.

MICHAEL OSTAPCHUK, M.S., is associate director of the Family Practice Residency Program at the University of Louisville School of Medicine, where he also completed a family practice residency. Dr. Ostapchuk received a medical degree from the University of Kentucky College of Medicine, Lexington, Ky., and completed a pediatric residency at East Carolina University School of Medicine, Greenville, N.C.

Address correspondence to Rene Kurowski, M.D., Department of Family and Community Medicine, University of Louisville, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202 (e-mail: r.kurowski@louisville.edu). Reprints are not available from the authors.

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