Updated May 20, 2014.

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Definition: Histoplasmosis (also known as “Cave Disease” and “Ohio Valley Disease”) is a potentially fatal fungal disease with worldwide distribution, although it is particularly endemic in the central and eastern parts of the United States, Latin Americam and East Africa.  

Symptoms of the disease vary, although it primarily affects the lungs. Extrapulmonary or disseminated histoplasmosis (i.e., histoplasmosis presenting outside the lungs) is classified by the U.S.

Centers for Disease Control and Prevention (CDC) as an AIDS defining condition.

With the advent of combination antiretroviral therapy (cART), histoplasmosis incidence has declined steadily in the developed world since the mid-1990s.

In the U.S., around 500,000 people are infected annually, although it most often presents with mild to moderate pulmonary symptoms which are either self-limiting or require minimal drug intervention. In many cases, there are no symptoms at all.

However, individuals with suppressed immune systems—particularly HIV-infected people with CD4 counts below 150 cells/ML—are more likely to have chronic complications ranging from recurrent pneumonia to pulmonary vessel obstruction.

If left untreated, the mortality rate from chronic pulmonary histoplasmosis can be as high as 50%. By contract, the mortality rate from untreated, chronic disseminated histoplasmosis is over 90%.

Causal Agents

Histoplasmosis is caused primarily by the fungus Histoplasma capsulatum, while Histoplasma var duboisii is the fungal isolate described solely in Africa.

H. capsulatum is commonly found in areas with persistently moist soil and high acidity levels, particularly those which contain either bird droppings or bat guano. The most endemic regions for H. capsulatum in the U.S. are the Ohio or Mississippi river valleys, while H. var duboisii is most commonly found in the caves of southern and East Africa.

Modes of Transmission

Histoplasmosis is acquired by inhaling the spores (microconidia) of H. capsulatum or H. var duboisii, where they are lodged inside the alveoli of the lungs. There, the microconidia are transformed into yeast cells, which can then can distributed throughout the body through the lymphatic system.

Histoplasmosis is not contagious and cannot be spread from human-to-human. Histoplasmosis can occasionally be acquired by ingesting contaminated soil or droppings, although this is less common.

No vaccine is available for histoplasmosis.

Symptoms of Histoplasmosis

Clinical manifestations of H. capsulatum infection generally begin anywhere from three to 14 day after exposure.

Symptoms from acute pulmonary histoplasmosis are usually self-limiting and present in only about 1% of infected individuals. The symptomatology is similar to that of an acute pneumonia, with fever, dry coughing, malaise, headache, and chest discomfort most commonly noted. Improvement is usually prompt, often requiring little or no treatment, although fatigue can persist for several months in some.  

In about 5% of acute pulmonary cases, additional complications may be noted, including:

• Rash (most often in young women)
• Muscle pain (myalgia) and/or joint pain (arthralgia)
• Swollen lymph glands (lymphadenopathy)
• Audible crackling  in the lungs (rales)
• Chills
• Acute respiratory distress

Some patients may progress to chronic cavitary pulmonary histosplasmosis, although this generally occurs in the elderly, in patients with pre-existing emphysema, or individuals with severe immunosuppression who have had previous or pre-existing pulmonary infection. Fibrosis (scarring) and subsequent necrosis (death) of lung tissue can result in the formation of large, persistent cavities.

Symptoms of chronic cavitary pulmonary histoplasmosis include:

• Night sweats
• Weight loss/anorexia
• Cough with sputum (occasionally blood-stained or bloody)
• Shortness of breath or “breath hunger” (dyspnea)

Pericarditis (or the inflammation of the sac surrounding the heart) can also occur on rare occasion, most predominantly in younger patients.

Patients with AIDS, transplant recipients, and infants with immature immune systems are at greatest risk for the development of chronic depressive disseminated histoplasmosis. Without the presence of T lymphocytes to activate a defensive immune response, the infection can be readily spread to other organs through lymphatic circulation.

Chronic depressive disseminated histoplasmosis can involve every organ system, either with widespread dissemination throughout multiple organs or a focal disease of a single organ. By and large, however, this stage of infection would most commonly present with:

• Gastrointestinal tract involvement, with intermittent pain and severe diarrhea
• Neurological complications, including chronic meningitis and encephalopathy
• Possible ocular involvement, including scarring of the retina and visual impairment
• Addison’s disease (a chronic adrenal condition), albeit occurring less frequently

Chronic depressive disseminated histoplasmosis can also occur in the elderly, although symptoms generally develop over the course of months (compared to the rapid disease progression seen in the severely immunosuppressed).

Diagnosis of Histoplasmosis

Diagnosis of histoplasmosis is supported by the presentation of clinical features and symptomatology, and can confirmed by the analysis of blood, urine, bone marrow, cerebrospinal fluid, or other bodily fluids.

Methods of diagnosis may include:

• Fungal cultures (which are considered confirmed diagnoses, but can often take up to four weeks)
• Urinary and blood antigen tests (which have specificity of 95% and 85% respectively)
• Serum antibody tests (although less accurate in patients with AIDS)
• Fungal staining (although this is considered less accurate than either antigen or culture testing)

In nearly 40% of cases, a secondary opportunistic infection will accompany histoplasmosis. Therefore, additional tests are generally performed to exclude (or confirm) infections that may have similar presentation to histoplasmosis, including pneumocystic jirovecii pneumonia (PCP), tuberculosis, mycobacterium avium complex (MAC), lymphoma, etc.

Treatment of Histoplasmosis

In the majority of immunocompetent patients, histoplasmosis will resolve with little to no treatment.

Antifungal medications are used to treat severe cases of acute histoplasmosis, as well as all cases of chronic and disseminated disease. The antifungal itraconazole is commonly prescribed in patients with acute, persistent infection, while amphotericin B is considered the drug of choice for immunosuppressed individuals with severe disease.

In the latter event, treatment is prescribed in both an induction and maintenance phase. An induction course of amphotercin B is generally prescribed for 1-2 weeks, followed by maintenance course of itraconazole to prevent relapses. Lifelong suppressive therapy with itraconazole may be indicated in immunosuppressed patients if immunosuppression cannot be reversed.

Fluconazole, commonly used for other fungal infections, is generally prescribed only in cases of itraconazole or amphotericin intolerance.

Prophylaxis with itraconazole may be also recommended in patients with CD4 counts under 150 cells/mL in areas where H. capsulatum or H. van duboisii is endemic.

Pronunciation:

• his-toe-plas-MOE-sus

Also Known As:

• “Caves Disease”
• “Caver’s Disease”
• Darling Disease
• Hystoplasmosis
• “Ohio Valley Disease”
• Presumed Ocular Histoplasmosis Syndrome (POHS)
• Reticuloendotheliosis
• “Spelunker’s Lung”

<sub>Sources:

U.S. Centers for Disease Control and Prevention (CDC). “Appendix A – AIDS Defining Conditions.” Atlanta, Georgia; last reviewed November 20, 2008.

Bohse, M. and Woods, J. “Surface Localization of Yps3P Protein Histoplasma Capsulatum.” Eukaryot Cell. April 2005; 4(4): 685-693. 

Kaufman, C. “Histoplasmosis: a Clinical and Laboratory Update.”Clinical Microbiology Review. January 2007: 20(1):115-132. 

Wheat, L.; Freifield, A.; Kleiman, M.; et al. “Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America.”Clinical Infectious Diseases. 2007; 45(7):807-825.

Wheat, L.; Connolly-Stringfield, P.; Baker, R.; et al. “Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature.”Medicine. November 1990; 69(6): 361-374.</sub>