H. capsulatum is a dimorphic soil saprophyte that causes histoplasmosis, the most prevalent pulmonary fungal infection in humans and animals. In nature, H. capsulatum grows as a mold in association with soil and avian habitats, being enriched by alkaline nitrogenous substrates in guano. H. capsulatum and histoplasmosis, which is initiated by inhalation of the conidia, occur worldwide. However, the incidence varies considerably, and most cases occur in the United States. H. capsulatum received its name from the appearance of the yeast cells in histopathologic sections; however, it is neither a protozoan nor does it have a capsule.

Morphology and Identification

 At temperatures below 37°C, primary isolates of H. capsulatum often develop brown mold colonies, but the appearance varies. Many isolates grow slowly, and specimens require incubation for 4–12 weeks before colonies develop. The hyaline, septate hyphae produce microconidia (2–5 µm) and large, spherical thick-walled macroconidia with peripheral projections of cell wall material (8–16 µm) (Figure 1B). In tissue or in vitro on rich medium at 37°C, the hyphae and conidia convert to small, oval yeast cells (2 × 4 µm). In tissue, the yeasts are typically seen within macrophages, as H. capsulatum is a facultative intracellular parasite (see Figure 1A). In the laboratory, with appropriate mating strains, a sexual cycle can be demonstrated, yielding Ajellomyces capsulatus, a teleomorph that produces ascospores.

Fig1. Histoplasmosis and H. capsulatum. A: Small, oval yeast cells (2–4 µm) packed within macrophages. Giemsa’s stain. 1000×. B: In culture at ambient temperatures, H. capsulatum produces hyaline, septate hyphae bearing microconidia and large, spherical macroconidia. 400×.

Antigenic Structure

Histoplasmin is a crude but standardized mycelial broth culture filtrate antigen. After initial infection, which is asymptomatic in over 95% of individuals, a positive delayed type skin test to histoplasmin is acquired. Antibodies to both yeast and mycelial antigens can be measured serologically (Table 1). An uncharacterized polysaccharide antigen can be detected serologically in serum and other specimens (see Table 2).

Table1. Summary of Serologic Tests for Antibodies to Systemic Dimorphic Pathogenic Fungi

Table2. Laboratory Tests for Fungal Antigens in Clinical Specimens

Pathogenesis and Clinical Findings

After inhalation, the conidia develop into yeast cells and are engulfed by alveolar macrophages, where they are able to replicate. Within macrophages, the yeasts may disseminate to reticuloendothelial tissues, such as the liver, spleen, bone marrow, and lymph nodes. The initial inflammatory reaction becomes granulomatous. In over 95% of cases, the resulting cell-mediated immune response leads to the secretion of cytokines that activate macrophages to inhibit the intracellular growth of the yeasts. Some individuals, such as immunocompetent persons who inhale a heavy inoculum, develop acute pulmonary histoplasmosis, which is a self-limited flu-like syndrome with fever, chills, myalgias, headaches, and nonproductive cough. On radiographic examination, most patients will have hilar lymphadenopathy and pulmonary infiltrates or nodules. These symptoms resolve spontaneously without therapy, and the granulomatous nodules in the lungs or other sites heal with calcification.

Chronic pulmonary histoplasmosis occurs most often in men and is usually a reactivation process, the breaking down of a dormant lesion that may have been acquired years before. This reactivation is usually precipitated by pulmonary dam age such as emphysema.

Severe disseminated histoplasmosis develops in a small minority of infected individuals—particularly infants, the elderly, and the immunosuppressed, including AIDS patients. The reticuloendothelial system is especially apt to be involved, with lymphadenopathy, enlarged spleen and liver, high fever, anemia, and a high mortality rate without antifungal therapy. Mucocutaneous ulcers of the nose, mouth, tongue, and intestine can occur. In such individuals, histologic study reveals focal areas of necro sis within granulomas in many organs. The yeasts may be present in macrophages in the blood, liver, spleen, and bone marrow.

Diagnostic Laboratory Tests

 A. Specimens and Microscopic Examination

Specimens for culture include sputum, urine, scrapings from superficial lesions, bone marrow aspirates, and buffy coat blood cells. Blood films, bone marrow slides, and biopsy specimens may be examined microscopically. In disseminated histoplasmosis, bone marrow cultures are often positive. The small ovoid cells may be observed within macrophages in histologic sections stained with fungal stains, such as GMS or PAS, or in Giemsa-stained smears of bone marrow or blood (see Figure 1A).

B. Culture

Specimens are cultured in rich media, such as glucose cysteine-blood agar at 37°C and on SDA or IMA at 25–30°C. Cultures must be incubated for a minimum of 4 weeks. The laboratory should be alerted if histoplasmosis is suspected because special blood culture methods, such as lysis centrifugation or fungal broth medium, can be used to enhance the recovery of H. capsulatum. Because the mold form resembles saprobic fungi, the identification of H. capsulatum must be confirmed by in vitro conversion to the yeast form, detection of a species-specific antigen, or PCR testing for specific DNA sequences.

C. Serology

CF tests for antibodies to histoplasmin or the yeast cells become positive within 2–5 weeks after infection. CF titers rise during progressive disease and then decline to very low levels when the disease is inactive. With progressive disease, the CF titers are ≥ 1:32. Because cross-reactions may occur, antibodies to other fungal antigens are routinely tested. In the ID test, precipitins to two H. capsulatum-specific anti gens are detected: The presence of antibodies to the H antigen often signifies active histoplasmosis, while antibodies to the M antigen may arise from repeated skin testing or past expo sure (see Table 1).

One of the most sensitive tests is a radioassay or enzyme immunoassay for circulating polysaccharide anti gen of H. capsulatum (Table 2). Nearly all patients with disseminated histoplasmosis have a positive test for antigen in the serum or urine; the antigen level drops following successful treatment and recurs during relapse. Despite cross reactions with other mycoses, this test for antigen is more sensitive than conventional antibody tests in AIDS patients with histoplasmosis.

E. Skin Test

 The histoplasmin skin test becomes positive soon after infection and remains positive for years. It may become negative in progressive disseminated histoplasmosis. Repeated skin testing stimulates serum antibodies in sensitive individuals, interfering with the diagnostic interpretation of the serologic tests.

Immunity

Following initial infection, most persons appear to develop some degree of immunity. Immunosuppression may lead to reactivation and disseminated disease. AIDS patients may develop disseminated histoplasmosis through reactivation or new infection.

Treatment

Acute pulmonary histoplasmosis is managed with supportive therapy and rest. Itraconazole is the treatment for mild to moderate infection. In disseminated disease, systemic treatment with amphotericin B is often curative, though patients may need prolonged treatment and monitoring for relapses. Patients with AIDS typically relapse despite therapy that would be curative in other patients. Therefore, AIDS patients require maintenance therapy with itraconazole.

Epidemiology and Control

The incidence of histoplasmosis is highest in the United States, where the endemic areas include the central and eastern states and in particular the Ohio River Valley and portions of the Mississippi River Valley. Numerous out breaks of acute histoplasmosis have resulted from exposure of many persons to large inocula of conidia. These occur when H. capsulatum is disturbed in its natural habitat, that is, soil mixed with bird feces (eg, starling roosts and chicken houses) or bat guano (caves). Birds are not infected, but their excrement provides superb culture conditions for growth of the fungus. Conidia are also spread by wind and dust. The largest urban outbreak of histoplasmosis occurred in Indianapolis.

In some highly endemic areas, 80–90% of residents have a positive skin test by early adulthood. Many will have miliary calcifications in the lungs. Histoplasmosis is not communicable from person to person. Spraying formaldehyde on infected soil may destroy H. capsulatum.

In Africa, in addition to the usual pathogen, there is a stable variant, H. capsulatum var duboisii, which causes African histoplasmosis. This form differs from the usual disease by causing less pulmonary involvement and more skin and bone lesions with abundant giant cells that contain the yeasts, which are larger and more spherical.

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تحذير طبي من مرض شائع يزيد خطر الإصابة بنوعين من السرطان

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مواضيع ذات صلة

Coccidioidomycosis

Endemic Mycoses

Phaeohyphomycosis

Chromoblastomycosis

Mycetoma

Sporotrichosis

Superficial Mycoses

Cutaneous mycoses

Laboratory Diagnosis of Mycoses

General Properties, Virulence, and Classification of Pathogenic Fungi

Conventional Yeast identification methods

Commercially available yeast identification systems