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Coccidioidomycosis is a pulmonary or hematogenously spread disseminated disease caused by the fungus Coccidioides immitis; it usually occurs as an acute benign asymptomatic or self-limited respiratory infection. The organism occasionally disseminates to cause focal lesions in other tissues. Symptoms, if present, are those of lower respiratory infection or low-grade nonspecific disseminated disease. Diagnosis is suspected based on clinical and epidemiologic characteristics and confirmed by chest x-ray, culture, and serologic testing. Treatment, if needed, is usually with fluconazole, itraconazole, newer triazoles, or amphotericin B.
(See also the Infectious Diseases Society of America's Practice Guidelines for the Treatment of Coccidioidomycosis.)
In North America, the endemic area for coccidioidomycosis includes
The affected areas of the southwestern US include Arizona, the central valley of California, parts of New Mexico, and Texas west of El Paso. The area extends into northern Mexico, and foci occur in parts of Central America and Argentina.
Pathophysiology
Infections are acquired by inhaling spore-laden dust. Because of travel and delayed onset of clinical manifestations, infections can become evident outside endemic areas.
Once inhaled, C. immitis spores convert to large tissue-invasive spherules. As spherules enlarge and then rupture, each releases thousands of small endospores, which may form new spherules. Pulmonary disease is characterized by an acute, subacute, or chronic granulomatous reaction with varying degrees of fibrosis. Lesions may cavitate or form nodular-like coin lesions.
Sometimes disease progresses, with widespread lung involvement, dissemination, or both; focal lesions may form in almost any other tissue, most commonly in skin, subcutaneous tissues, bones (osteomyelitis), and meninges (meningitis). Progressive disease is more common among men and is more likely to occur in the following contexts:
Symptoms and Signs
Primary coccidioidomycosis
Most patients are asymptomatic, but nonspecific respiratory symptoms resembling those of influenza, acute bronchitis, or, less often, acute pneumonia or pleural effusion sometimes occur. Symptoms, in decreasing order of frequency, include fever, cough, chest pain, chills, sputum production, sore throat, and hemoptysis.
Physical signs may be absent or limited to scattered rales with or without areas of dullness to percussion over lung fields. Some patients develop hypersensitivity to the localized respiratory infection, manifested by arthritis, conjunctivitis, erythema nodosum, or erythema multiforme.
Primary pulmonary lesions sometimes leave nodular coin lesions that must be distinguished from tumors, TB, and other granulomatous infections. Sometimes residual cavitary lesions develop; they may vary in size over time and often appear thin-walled. A small percentage of these cavities fail to close spontaneously. Hemoptysis or the threat of rupture into the pleural space occasionally necessitates surgery.
Progressive coccidioidomycosis
Nonspecific symptoms develop a few weeks, months, or occasionally years after primary infection; they include low-grade fever, anorexia, weight loss, and weakness.
Extensive pulmonary involvement may cause progressive cyanosis, dyspnea, and mucopurulent or bloody sputum. Symptoms of extrapulmonary lesions depend on the site. Draining sinus tracts sometimes connect deeper lesions to the skin. Localized extrapulmonary lesions often become chronic and recur frequently, sometimes long after completion of seemingly successful antifungal therapy.
Untreated disseminated coccidioidomycosis is usually fatal and, if meningitis is present, is uniformly fatal without prolonged and possibly lifelong treatment. Mortality rates in patients with advanced HIV infection exceed 70% within 1 mo of diagnosis; whether treatment can alter mortality rates is unclear.
Diagnosis
Eosinophilia may be an important clue in identifying coccidioidomycosis. The diagnosis is suspected based on history and typical physical findings, when apparent; chest x-ray findings can help confirm the diagnosis, which can be established by fungal culture or by visualization of C. immitis spherules in sputum, pleural fluid, CSF, exudate from draining lesions, or biopsy specimens. Intact spherules are usually 20 to 80 μm in diameter, thick-walled, and filled with small (2 to 4 μm) endospores. Endospores released into tissues from ruptured spherules may be mistaken for nonbudding yeasts.
Serologic testing for anticoccidioidal antibodies using an immunodiffusion kit (for IgG and IgM antibodies) and complement fixation (for IgG antibodies) are the most useful tests. Titers ≥ 1:4 in serum are consistent with current or recent infection, and higher titers (≥ 1:32) signify an increased likelihood of extrapulmonary dissemination. However, immunocompromised patients may have low titers. Titers should decline during successful therapy. The presence of complement-fixing antibodies in CSF is diagnostic of coccidioidal meningitis and is important because CSF cultures are rarely positive.
Delayed cutaneous hypersensitivity to coccidioidin or spherulin usually develops within 10 to 21 days after acute infections in immunocompetent patients but is characteristically absent in progressive disease. Because this test is positive in most people in endemic areas, its primary value is for epidemiologic studies rather than for diagnosis.
Treatment
Treatment for primary coccidioidomycosis is controversial in low-risk patients. Some experts give fluconazole because its toxicity is low and there is a small risk of hematogenous seeding, especially to bone or brain. In addition, symptoms resolve more quickly in treated patients than in those who are not treated with an antifungal. Others think that fluconazole may blunt the immune response and that risk of hematogenous seeding in primary infection is too low to warrant use of fluconazole. High complement fixation titers indicate spread and the need for treatment.
Mild to moderate nonmeningeal extrapulmonary involvement should be treated with fluconazole ≥ 400 mg po once/day or voriconazole 200 mg po or IV bid. For severe illness, amphotericin B 0.5 to 1.0 mg/kg IV over 2 to 6 h once/day is given for 4 to 12 wk until total dose reaches 1 to 3 g, depending on degree of infection. Patients can usually be switched to an oral azole once they have been stabilized, usually within several weeks.
Patients with HIV- or AIDS-associated coccidioidomycosis require maintenance therapy to prevent relapse; fluconazole 200 mg po once/day or itraconazole 200 mg po bid usually is sufficient, and weekly IV amphotericin B may suffice for azole-intolerant patients. Lipid formulations of amphotericin B are preferred over conventional amphotericin B.
For meningeal coccidioidomycosis, fluconazole is used. The optimal dose is unclear; oral doses of 800 to 1200 mg once/day may be more effective than 400 mg/day. If amphotericin B is used, intrathecal injections are needed, either intraventricularly via a subcutaneous reservoir or intracisternally. Treatment for meningeal coccidioidomycosis must be continued for many months, probably lifelong. Surgical removal of involved bone may be necessary to cure osteomyelitis.
Last full review/revision April 2009 by Alan M. Sugar, MD
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