Coccidioidomycosis is caused C. posadasii or C. immitis. These sibling species were recognized by genotyping and phylogenetic analyses. However, they are phenotypically indistinguishable, cause similar clinical manifestations, and are not differentiated in the clinical laboratory. Coccidioidomycosis is endemic in well-circumscribed semiarid regions of the southwestern United States, Central America, and South America. Infection is usually self-limited, and dissemination is rare but always serious, and it may be fatal. Clinical and environmental isolates of Coccidioides have revealed that the two species are not equally distributed within the endemic regions. Although there is some overlap, C. immitis is largely confined to California, whereas C. posadasii predominates in Arizona, Texas, and South America.

Morphology and Identification

 Most infections are probably due to C. posadasii. However, since the two species cannot be readily identified in the laboratory and since the clinical manifestations are the same with either C. immitis or C. posadasii, only the former, more familiar species name will be used in this chapter.

On most laboratory media, C. immitis produces a white to tan cottony colony. The hyphae form chains of arthroconidia (arthrospores), which often develop in alternate cells of a hypha. These chains fragment into individual arthroconidia, which are readily airborne and highly resistant to adverse environmental conditions (Figure 1A). These small arthroconidia (3 × 6 µm) remain viable for years and are highly infectious. Following their inhalation, the arthroconidia become spherical and enlarge, forming spherules that contain endospores (see Figure 1B). Spherules can also be produced in the laboratory by cultivation on a complex medium.

Fig1. occidioides species and Coccidioidomycosis. A: In culture at ambient temperatures, C. posadasii produces hyaline, septate hyphae, and arthroconidia. 400×. B: Large spherules containing endospores can be seen in this section of lung tissue. H&E 200×.

In histologic sections of tissue, sputum, or other specimens, the spherules are diagnostic of C. immitis. At maturity, the spherules have a thick, doubly refractile wall and may attain a size of 80 µm in diameter. The spherule becomes packed with endospores (2–5 µm in size). Eventually, the wall ruptures to release the endospores, which may develop into new spherules (see Figure 1B).

Antigenic Structure

Two clinically useful antigens are available. Coccidioidin is an antigen preparation extracted from the filtrate of a liquid mycelial culture of C. immitis. Spherulin is produced from a filtrate of a broth culture of spherules. In standardized doses, both antigens elicit positive delayed skin reactions in infected persons. They have also been used in a variety of serologic tests to measure serum antibodies to C. immitis.

Pathogenesis and Clinical Findings

Inhalation of arthroconidia leads to a primary infection that is asymptomatic in 60% of individuals. The only evidence of infection is the development of serum precipitins and conversion to a positive skin test within 2–4 weeks. The precipitins will decline, but the skin test often remains positive for a lifetime. The other 40% of individuals develop a self-limited influenza-like illness with fever, malaise, cough, arthralgia, and headache. This condition is called valley fever, San Joaquin Valley fever, or desert rheumatism. After 1–2 weeks, about 15% of these patients develop hypersensitivity reactions, which present as a rash, erythema nodosum, or erythema multiforme. On radiographic examination, patients typically show hilar adenopathy along with pulmonary infiltrates, pneumonia, pleural effusions, or nodules. Pulmonary residua occur in about 5%, usually in the form of a solitary nodule or thin walled cavity (Figure 2).

Fig2. Chest radiograph of a patient with coccidioidomycosis revealing enlarged hilar lymph nodes and a cavity in the left lung.

Less than 1% of persons infected with C. immitis develop secondary or disseminated coccidioidomycosis, which is often debilitating and life-threatening. The risk factors for systemic coccidioidomycosis include heredity, sex, age, and compromised cell-mediated immunity. The disease occurs more frequently in certain racial groups. In decreasing order of risk, these are Filipinos, African Americans, Native Americans, Hispanics, and Asians. There is clearly a genetic component to the immune response to C. immitis. Males are more susceptible than females, with the exception of women who are pregnant, which may relate to differences in the immune response or a direct effect of sex hormones on the fungus. For example, C. immitis has estrogen-binding proteins, and elevated levels of estradiol and progesterone stimulate its growth. The young and the aged are also at greater risk. Because cell-mediated immune responses are required for adequate resistance, patients with AIDS and other conditions of cellular immunosuppression are at risk for disseminated coccidioidomycosis.

Some individuals develop a chronic but progressive pulmonary disease with multiplying or enlarging nodules or cavities. Dissemination will usually occur within a year after the primary infection. The spherules and endospores are spread hematogenously or by direct extension. A number of extrapulmonary sites may be involved, but the most frequent organs are the skin, the bones and joints, and the meninges. There are distinctive clinical manifestations associated with C. immitis infections in each of these and other areas of the body.

Dissemination occurs when the immune response is inadequate to contain the pulmonary foci. In most persons, a positive skin test signifies a strong cell-mediated immune response and protection against reinfection. However, if such individuals become immunocompromised by taking cytotoxic drugs or by disease (eg, AIDS), dissemination can occur many years after primary infection (reactivation disease). Coccidioidomycosis in AIDS patients often presents with a rapidly fatal diffuse reticulonodular pneumonitis. Because of the radiologic overlap between this disease and Pneumocystis pneumonia and the different therapies for these two entities, it is important to be aware of the possibility of coccidioidal pneumonia in AIDS patients. Blood cultures are often positive for C. immitis.

On histologic examination, the coccidioidal lesions contain typical granulomas with giant cells and interspersed suppuration. A diagnosis can be made by finding spherules and endospores. The clinical course is often characterized by remissions and relapses.

Diagnostic Laboratory Tests

 A. Specimens and Microscopic Examination

 Specimens for culture include sputum, exudate from cutaneous lesions, spinal fluid, blood, urine, and tissue biopsies.

Materials should be examined fresh (after centrifuging, if necessary) for typical spherules. KOH or calcofluor white stain will facilitate finding the spherules and endospores (see Figure 1B). These structures are often found in histologic preparations stained with H&E, GMS, or PAS.

B. Cultures

Cultures on IMA or brain–heart infusion blood agar slants can be incubated at room temperature or at 37°C. The media can be prepared with or without antibacterial antibiotics and cycloheximide to inhibit contaminating bacteria or saprophytic molds, respectively. Because the arthroconidia are highly infectious, suspicious cultures are examined only in a biosafety cabinet (see Figure 1A). Identification must be confirmed by detection of a C. immitis-specific antigen, animal inoculation, or use of a specific DNA probe.

C. Serology

Within 2–4 weeks after infection, IgM antibodies to coccidioidin can be detected with a latex agglutination test. Specific IgG antibodies are detected by the immunodiffusion (ID) or complement fixation (CF) test. With resolution of the primary episode, these antibodies decline within a few months. In contrast, in disseminated coccidioidomycosis, the CF antibody titer continues to rise. Titers above 1:32 are indicative of dissemination, and their fall during treatment suggests improvement (Figure 3 and Table 1).

Fig3. In non-AIDS patients, the immunoglobulin G (IgG) antibody titers to coccidioidin are inversely related to the severity of coccidioidomycosis. IgM, immunoglobulin M. (Reproduced with permission from Ryan KJ, Ray CG [editors]: Sherris Medical Microbiology, 5th ed. McGraw-Hill, 2010, p 753. © McGraw-Hill Education.)

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

However, CF titers less than 1:32 do not exclude coccidioidomycosis. Indeed, only half of the patients with coccidioidal meningitis have elevated serum antibodies, but antibody levels in the cerebrospinal fluid are usually high. In AIDS patients with coccidioidomycosis, these serologic tests are often negative.

D. Skin Test

The coccidioidin skin test reaches maximum induration (≥5 mm in diameter) between 24 and 48 hours after cutaneous injection of 0.1 mL of a standardized dilution. If patients with disseminated disease become anergic, the skin test will be negative, which implies a very poor prognosis. Cross reactions with antigens of other fungi may occur. Spherulin is more sensitive than coccidioidin in detecting reactors. Reactions to skin tests tend to diminish in size and intensity years after primary infection in persons residing in endemic areas, but skin testing exerts a booster effect. Following recovery from primary infection, there is usually immunity to reinfection.

Treatment

In most persons, symptomatic primary infection is self-limited and requires only supportive treatment, although itraconazole may reduce the symptoms. However, patients who have severe disease require treatment with amphotericin B, which is administered intravenously. This regimen may be followed by several months of oral therapy with itraconazole. Cases of coccidioidal meningitis have been treated with oral fluconazole, which has good penetration of the central nervous system; however, long-term therapy is required, and relapses have occurred. The azoles are not more efficacious than amphotericin B, but they are easier to administer and associated with fewer and less severe side effects. The newer lipid emulsions of amphotericin B promise to deliver higher doses with less toxicity. Surgical resection of pulmonary cavities is sometimes necessary and often curative.

Epidemiology and Control

 The areas of endemicity for Coccidioides are semiarid regions, resembling the Lower Sonoran Life Zone. They include the southwestern states—particularly the San Joaquin and Sacramento Valleys of California, areas around Tucson and Phoenix in Arizona, the Rio Grande Valley—and similar areas in Central and South America. Within these regions, Coccidioides can be isolated from the soil and indigenous rodents, and the level of skin test reactivity in the population indicates that many humans have been infected. The infection rate is highest during the dry months of summer and autumn, when dust is most prevalent. A high incidence of infection and disease may follow dust storms. During an epidemic of coccidioidomycosis in the San Joaquin Valley of California in 1991–1993, the rate of coccidioidomycosis increased more than tenfold. Increased precipitation in the spring months of these years was suggested as an environ mental stimulus. However, since 1998, the incidence has risen another tenfold, and this increase cannot be attributed to population growth or improved diagnoses. Furthermore, recent reports have documented the spread of coccidioidomycosis to the northwestern states, including Washington, and in patients without a history of travel to the endemic areas.

The disease is not communicable from person to person, and there is no evidence that infected rodents contribute to its spread. Some measure of control can be achieved by reducing dust, paving roads and airfields, planting grass or crops, and using oil sprays.

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