Histoplasmosis is an infection that occurs from breathing in the spores of the fungus Histoplasma capsulatum.

Causes Histoplasmosis is a fungal infection. It occurs throughout the world. In the United States, it is most common in the southeastern, mid-Atlantic, and central states.

Histoplasma fungus grows as a mold in the soil. You may get sick when you breathe in spores produced by the fungus. Soil that contains bird or bat droppings may have larger amounts of this fungus. The threat is greatest after an old building is torn down or in caves.

Having a weakened immune system increases your risk for getting or reactivating this disease. Very young or very old people, or those with AIDS, cancer, or an organ transplant have more severe symptoms.

People with chronic lung disease (such as emphysema and bronchiectasis) are at higher risk of a more severe infection.

Symptoms Most people have no symptoms, or only have a mild flu-like illness.

If symptoms do occur, they may include:

Fever and chills Cough and chest pain that gets worse when breathing in Joint pain Mouth sores Red skin bumps called erythema nodosum, most often on the lower legs

The infection may be active for a short period of time, and then the symptoms go away. Sometimes, the lung infection may become long-term (chronic). Symptoms include:

Chest pain and shortness of breath Cough, possibly coughing up blood Fever and sweating In a small number of patients, histoplasmosis may spread throughout the body, causing irritation and swelling (inflammation) in response to the infection. Symptoms may include:

Chest pain from swelling in the lining around the heart (pericarditis) Headache and neck stiffness from swelling in the covering of the brain and spinal cord High fever Exams and Tests Histoplasmosis is diagnosed by:

Biopsy of the lung, skin, liver, or bone marrow Blood or urine tests to detect histoplasmosis proteins or antibodies Cultures of the blood, urine, or sputum (this test provides the clearest diagnosis of histoplasmosis, but results can take 6 weeks) To help diagnose this condition, your doctor may perform:

Bronchoscopy Chest CT scan Chest x-ray Spinal tap to look for signs of infection in cerbrospinal fluid (CSF) Treatment

Most of the time, this infection goes away without treatment.

If you are sick for more than 1 month or are having trouble breathing, your doctor may prescribe medication. The main treatment for histoplasmosis is antifungal drugs. Amphotericin B, itraconazole, and ketoconazole are the usual treatments.

Antifungals may need to be given through a vein, depending on the form or stage of disease. Some of these medicines can have side effects. Sometimes, long-term treatment with antifungal drugs may be needed. You may need to take these medications for up to 1 to 2 years.

Outlook (Prognosis) The outlook depends on how severe the infection is, and the patient's health. Some people get better without treatment. An active infection will usually go away with antifungal medicine, but there may be scarring left inside the lung.

The death rate is higher for people with untreated widespread (disseminated) histoplasmosis whose immune system is not working well.

Possible Complications Scarring in the chest cavity may trap:

The major blood vessels carrying blood to and from the heart The heart itself The esophagus (food pipe) The lymph nodes Enlarged lymph nodes in the chest (called mediastinal granulomas) may press on body parts such as the esophagus and blood vessels of the lungs.

When to Contact a Medical Professional Call your health care provider if you live in an area where histoplasmosis is common, and you develop flu-like symptoms, chest pain, cough, and shortness of breath. While there are many other illnesses that have similar symptoms, you may need to be tested for histoplasmosis.

Prevention Histoplasmosis may be prevented by reducing exposure to dust in chicken coops, bat caves, and other high-risk locations. Wear masks and other protective equipment if you work in these environments.

Alternative Names Ohio River Valley fever; Fibrosing mediastinitis Pathophysiology H capsulatum in the saprobic state grows in the mycelial form. Macroconidia and microconidia are produced on the hyphae of mycelium and are converted to the yeast form under temperature-controlled regulation. The aerosolization of conidia and mycelial fragments from contaminated soil results in alveolar deposition via inhalation.

The host defense includes the fungistatic properties of neutrophils and macrophages. T lymphocytes are crucial in limiting the extent of infection. Susceptibility to dissemination is increased markedly with impaired cellular host defenses.

Conversion from the mycelial to the pathogenic yeast form occurs intracellularly. After phagocytosis by macrophages, the yeast replicates in approximately 15-18 hours. Despite fusion with lysosomes, multiplication continues within the phagosomes. Proposed theories suggest that the yeasts may produce proteins that inhibit the activity of lysosomal proteases.

As the host immunity response develops, yeast growth ceases within 1-2

weeks after exposure. Cytokines systemically activate the fungistatic activity of macrophages against intracellular yeasts. With further maturation of the cell-mediated response, delayed-type hypersensitivity to histoplasmal antigens occurs (3-6 wk after exposure). Approximately 85-90% of individuals who are immunocompetent produce a positive response to skin antigen test for Histoplasma species.[2] Over weeks to months, the inflammatory response produces calcified fibrinous granulomas with areas of caseous necrosis.

Clinical manifestations of histoplasmosis appear with continued exposure to large inocula. The initial pulmonary infection may disseminate systemically, with hematogenous spread, and produce extrapulmonary manifestations. Hematogenous spread to regional lymph nodes may occur through the lymphatics or the liver and spleen. Progressive disseminated histoplasmosis is rare in adult hosts who are immunocompetent. Systemic spread usually occurs in patients with impaired cellular immunity and typically involves the CNS, liver, spleen, and rheumatologic, ocular, and hematologic systems.

Previous Next Sectio Pathophysiology Etiology: Histoplasma capsulatum Transmission: Inhalation Sources (infection often with heavy cleaning of source) Soil contaminated with bird and bat droppings Old houses (especially attics) Farms (especially barns and chicken coops) Infection course Initial phase (controlled by Macrophages) Fungus spores inhaled into lung alveoli Travel to lymph nodes at hilum and mediastinum Spreads from lung, lymph to liver, Spleen, marrow Second phase (controlled by cellular immunity)

Occurs 10-14 days after spore inhalation Infected sites necrose, caseate, and fibrose Calcified granulomas form within a few years Disseminated infection if cellular immunity defect Risks for disseminated infection Infants and young children Intense exposure to airborne spores Immunocompromised patients HIV with CD4 <200 Lymphoma Immunosuppressant medication (e.g. Corticosteroid) Epidemiology Consider in immunocompromised patients Undifferentiated fever Pneumonia Mucocutaneous disease United States Incidence: 500,000 new cases per year Endemic Areas (Ohio and Mississippi river valleys) Southeast Mid-Atlantic Central States Endemic in some cities Indianapolis Kansas City Houston

Symptoms and Signs: Acute Pulmonary Histoplasmosis Symptoms Most cases are asymptomatic or mild Fever Non-productive Cough Dyspnea Headache Malaise Diaphoresis Weight loss Signs Hepatomegaly Splenomegaly Adenopathy Erythema Nodosum Erythema Multiforme Symptoms and Signs: Chronic Pulmonary Histoplasmosis Exaggerated immune response to fungal antigens Typical patient is middle aged white male with COPD Symptoms (Similar to Tuberculosis) Productive cough Fever Night Sweats Symptoms and Signs: Disseminated Histoplasmosis Most patients (80%) are immunocompromised Symptoms

Fever (most common) Headache Weight loss Cough (<50% of cases) Abdominal cramps, Diarrhea, Melena (rare) Signs Hepatomegaly Splenomegaly Lymphadenopathy Jaundice Ulcerative lesions in nose, mouth, Larynx (25%) Imaging: General Necrotizing granulomata Chest XRay (see below) PET Scan is diagnostic Imaging: Chest XRay Acute Pulmonary Histoplasmosis Usually normal Hilar Adenopathy Pneumonitis involving lower lung fields Chronic Pulmonary Histoplasmosis Calcified fibronodular apical infiltrates Underlying Emphysematous changes No adenopathy Disseminated Histoplasmosis Discrete Pulmonary Nodules or miliary pattern

Adenopathy rarely occurs Labs: Diagnosis Sputum Culture (Gold standard for definitive diagnosis) Requires 2-6 weeks of growth Test Sensitivity for disseminated Histoplasmosis: 85% Sensitivity chronic pulmonary Histoplasmosis: 85% Not sensitive for limited acute pulmonary disease Serologic Titers (positive if > 1:32) Sensitivity acute or chronic pulmonary disease: >98% Moderate sensitivity in disseminated disease: 71% False negatives False negatives in immunocompromised False negatives in first 6 weeks of infection False positives Histoplasmosis Infection within last 5 years Other fungus cross reactivity Blastomyces Aspergillus Fungal staining of Bone Marrow or tissue histopathology Bone Marrow in disseminated disease: 75% sensitivity Difficult to differentiate from other organisms Candida glabrata Pneumocystis carinii Histoplasma Antigen testing (Urine and serum antigens) High Test Sensitivity in disseminated disease (92%) Low sensitivity in acute and chronic pulmonary Histoplasmosis

Useful for monitoring treatment outcomes Skin Test Useless in diagnosing acute disease High false positive rate in endemic areas High false negative rate in disseminated and chronic Labs: Disseminated Histoplasmosis Liver Function Test abnormalities Complete Blood Count: Pancytopenia Anemia Leukopenia Complications: Acute pulmonary Histoplasmosis Mediastinal granuloma (Chest Pain, Hemoptysis) Pericarditis (Chest Pain, fever) - delayed response Arthritis (symmetric and polyarticular) Course Chronic pulmonary Histoplasmosis 33% stabilize or improve spontaneously Management Acute Pulmonary Histoplasmosis Severe disease First 2 weeks Amphotericin B 0.7 mg/kg/day Prednisone 20 mg qd Next 12 weeks Itraconazole dosed as in mild to moderate disease Mild to moderate disease

Itraconazole 200 mg qd to bid for 12 weeks Chronic Pulmonary Fibrosis Severe disease Start: Amphotericin B 0.7 mg/kg/day Next: Itraconazole as below for 12-24 months Moderate disease Itraconazole 200 mg PO qd to bid for 12-24 months Disseminated Histoplasmosis Severe disease Start: Amphotericin B 0.7 to 1.0 mg/kg/day Next: Itraconazole as below for 6-18 months Stop when urine and serum antigen <4 units Moderate disease Itraconazole 200 mg PO qd to bid for 6-18 months Continue Itraconazole for life if HIV positive References Kurowski (2002) Am Fam Physician 66(12):2247-52 Wheat (2000) Clin Infect Dis 30:688-95 Mocherla (2001) Semin Respir Infect 16(2):141-8 Pathogenesis of Histoplasma capsulatum.

Woods JP, Heinecke EL, Luecke JW, Maldonado E, Ng JZ, Retallack DM, Timmerman MM. Source

Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, WI 53706-1532, USA. jpwoods@facstaff.wisc.edu

Abstract

Histoplasma capsulatum is well adapted to be infectious and pathogenic for humans. As a soil fungus with no known requirement for interacting with a mammalian host as part of an obligate lifecycle, its plethora of strategies for successful pathogenesis is particularly remarkable. These features include the dimorphic mold-yeast transition, entry into host macrophages, subcellular localization, intracellular survival and proliferation during active infection, and persistence during clinically inapparent infection with the capacity for reactivation. To thrive within the harsh environment of a professionally phagocytic and antimicrobial host cell, H. capsulatum displays mechanisms for modulating its microenvironmental pH level, resisting host reactive oxygen and nitrogen intermediates and degradative enzymes, and withstanding nutrient starvation conditions, including acquisition of iron and calcium and biosynthesis of nucleic acid precursors. Attention has been focused on identifying virulence-associated phenotypic traits and genes that are differentially expressed under relevant conditions, such as yeast morphotype-specific genes and genes that are up-regulated during infection. These studies, together with the increasing ability to perform molecular genetic manipulations in this fungus, may yield novel antifungal drug or vaccine targets as well as elucidating pathogenic mechanisms.

Copyright 2001 by W.B. Saunders Company

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