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Coccidioidomycosis

(San Joaquin Fever; Valley Fever)

By Sanjay G. Revankar, MD, Professor of Medicine and Director, Infectious Disease Fellowship Program, Division of Infectious Diseases, Wayne State University School of Medicine

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Coccidioidomycosis is a pulmonary or hematogenously spread disseminated disease caused by the fungi Coccidioides immitis and C. posadasii; 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 Overview of Fungal Infections and the Infectious Diseases Society of America’s Clinical Practice Guideline for the Treatment of Coccidioidomycosis.)

In North America, the endemic area for coccidioidomycosis includes

  • The southwestern US

  • Northern Mexico

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. Coccidioides also occurs in Utah, Nevada, and south-central Washington. About 30 to 60% of people who live in an endemic region are exposed to the fungus at some point during their life. In the US, 11,027 cases of coccidioidomycosis were reported in 2015.

Pathophysiology

Coccidioidomycosis is acquired by inhaling spore-laden dust. Thus, certain occupations (eg, farming, construction) and outdoor recreational activities increase risk. Epidemics can occur when heavy rains, which promote the growth of mycelia, are followed by drought and winds. 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, systemic dissemination, or both; focal lesions may form in almost any tissue, most commonly in skin, subcutaneous tissues, bones (osteomyelitis), joints, and meninges (meningitis).

Risk factors for coccidioidomycosis

Progressive coccidioidomycosis is uncommon in otherwise healthy people and more likely to occur in the following contexts:

  • HIV infection

  • Use of immunosuppressants

  • Advanced age

  • 2nd half of pregnancy or postpartum

  • Certain ethnic backgrounds (Filipino, African American, Native American, Hispanic, and Asian, in decreasing order of relative risk)

Symptoms and Signs

Primary coccidioidomycosis

Most patients with primary coccidioidomycosis are asymptomatic, but nonspecific respiratory symptoms resembling those of influenza, acute bronchitis, or, less often, acute pneumonia or pleural effusion sometimes occur.

Symptoms of primary coccidioidomycosis, 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 is uncommon in otherwise healthy people and occurs mainly in those who are immunocompromised. It 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

  • Cultures (routine or fungal)

  • Microscopic examination of specimens to check for C. immitis spherules

  • Serologic testing

Eosinophilia may be an important clue in identifying coccidioidomycosis.

The diagnosis of coccidioidomycosis 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. Because culturing Coccidioides can pose a severe biohazard to laboratory personnel, the laboratory should be notified of the suspected diagnosis.

Serologic testing for anticoccidioidal antibodies includes

  • Enzyme immunoassay, which is very sensitive and is commonly used to diagnose coccidioidomycosis

  • Immunodiffusion kit (to detect IgM or IgG antibodies)

  • Complement fixation (to detect IgG antibodies)

Titers 1:4 in serum are consistent with current or recent infection, and high titers ( 1:32) signify an increased likelihood of extrapulmonary dissemination. Complement fixation titers can be used to estimate disease severity; high titers suggest more severe disease. 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.

A urine antigen test may be useful for diagnosing coccidioidomycosis in immunocompromised patients with severe forms of the disease, including pneumonia and disseminated infection.

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

  • For mild to moderate disease, fluconazole or itraconazole

  • For severe disease, amphotericin B

(See also Antifungal Drugs.)

Patients with primary coccidioidomycosis and risk factors for severe or progressive disease should be treated.

Treatment for primary coccidioidomycosis is controversial in low-risk patients. Some experts give fluconazole because its toxicity is low and because even in low-risk patients, 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 itraconazole 200 mg po bid. Voriconazole 200 mg po or IV bid or posaconazole 400 mg po bid are alternatives but have not been well-studied.

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. Lipid formulations of amphotericin B are preferred over conventional amphotericin B. 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, given until the CD4 cell count is > 250/μL.

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 once/day. Treatment for meningeal coccidioidomycosis should be given lifelong.

Surgical removal of involved bone may be necessary to cure osteomyelitis.

When residual cavitary pulmonary lesions cause hemoptysis or are likely to rupture, surgery may be necessary.

Key Points

  • Coccidioidomycosis is a common fungal infection acquired by inhaling spore-laden dust.

  • It is endemic to the southwestern US and northern Mexico; disease also occurs in certain parts of Central and South America.

  • Most patients have an asymptomatic or mild pulmonary infection, but those who are immunocompromised or have other risk factors may develop severe, progressive pulmonary disease or disseminated infection (typically to skin, bone, or meninges).

  • Diagnose using culture, staining, and/or serologic testing.

  • For mild to moderate disease, use fluconazole or itraconazole.

  • For severe disease, use a lipid formulation of amphotericin B.

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Drugs Mentioned In This Article

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  • DIFLUCAN
  • NOXAFIL
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  • SPORANOX