Coccidioidomycosis

Robert Bercovitch and Antonino Catanzaro

INTRODUCTION

Coccidioidomycosis is an infection caused by the fungus Coccidioides. Inhalation is the main route of infection. Coccidioidomycosis causes a wide spectrum of pulmonary disease, including acute and chronic pneumonia, pulmonary nodules, and cavitary disease. Dissemination via the bloodstream can occur to any organ, including the lungs, but the most common sites of dissemination are skin and bone. Infection is common in endemic areas, and travelers to these areas are at risk for infection. Healthcare providers in endemic and nonendemic areas should be aware of the clinical manifestations, diagnosis, and management of coccidioidomycosis.

MICROBIOLOGY

In addition to Coccidioides immitis, a second species, Coccidioides posadii, has been identified. Although the two organisms are genetically distinct and geographically separated, there are no known differences in terms of the immune response or clinical disease. Coccidioides is a dimorphic fungus. It proliferates in the mycelial form during the rainy season and forms arthroconidia, the infectious spore, when the climate becomes hot and dry. Wind or soil disruption causes the arthroconidia to become airborne, and infection is caused when they are inhaled. Once inhaled, the arthroconidia undergoes transformation into a spherule. The spherule undergoes internal division, forming numerous endospores. With rupture of the spherule, endospores are released, each able to mature into a spherule. The findings of spherules and endospores on histology is characteristic of coccidioidomycosis.

EPIDEMIOLOGY

Coccidioides grows in the soil in endemic areas, including the lower Sonoran life zone (southern California, Arizona, Nevada, New Mexico, and Texas), and in northern Mexico and parts of Central and South America. Infection has been reported in nonendemic areas returning travelers or persons exposed to objects containing dust sent from an endemic area. Coccidioidomycosis outbreaks can follow natural disasters such as earthquakes, which can vigorously disturb soil and cause the release of arthroconidia. Construction can also disrupt soil and contribute to outbreaks.

CLINICAL PRESENTATION

The primary coccidioidal infection is asymptomatic in 60% of individuals; the remainder have a similar presentation to other causes of community-acquired pneumonia (CAP) with fever, chills, malaise, cough, dyspnea, chest pain, arthralgias, pharyngitis, and rash. In endemic areas, coccidioidomycosis is a common cause of CAP, with evidence of infection in up to 29% of patients presenting for evaluation of lower respiratory tract symptoms.

In general, physical findings in primary coccidioidomycosis are nonspecific. Signs of pulmonary parenchymal consolidation may be present and often are very localized and transient; pleural rubs are unusual. San Joaquin Valley Fever represents a characteristic symptom complex of primary coccidioidomycosis and classically includes erythema nodosum (with or without erythema multiforme), arthralgias, malaise, and fever. Skin manifestations are common in primary infection, occurring in approximately 5% of men and 25% of women. A fine erythematous maculopapular exanthem, toxic cutaneous erythema, is said to be very common but is an extremely evanescent, early event.

The chest X-ray is often abnormal, even in asymptomatic individuals, and infiltrates are observed in 80% of patients requiring hospitalization. The infiltrates vary widely in size, location, character, and duration. Hilar adenopathy occurs in 20% of cases and does not influence the prognosis unless it is persistent and accompanied by rising serologic titers. Pleural effusion is seen in less than 10% of symptomatic individuals; in most patients, the effusion is small (<1 L). Pleural effusions in coccidioidomycosis can be eosinophilic exudates.

Coccidioidomycosis is considered chronic or progressive when symptoms or signs of pulmonary involvement are present or increasing beyond 6 to 8 weeks. Manifestations of chronic pulmonary coccidioidomycosis may include acute progressive pneumonia that is usually symptomatic, chronic progressive pneumonia, pulmonary nodule or nodules, and pulmonary cavities. Coccidioidomas represent isolated residua of active pulmonary disease, and organisms have been cultured from lesions that remained unchanged for decades. Cavities may be thin-walled and often represent the initial radiographic manifestation of infection. The thin-walled cavities have a tendency to expand. Most coccidioidal cavities are clinically silent, but hemorrhage and rupture leading to bronchopleural fistulas can occur, although this is typically limited to the initial phase of the disease and related to necrotizing pneumonia. Occasionally, secondary bacterial infection of cavities can occur. Empyema may result and be either bacterial or fungal in etiology. In persistent pulmonary coccidioidomycosis, serologic evidence of activity (e.g., elevated complement fixation [CF] titers) may be absent but, when present, should raise the possibility of intrapulmonary dissemination.

A worse prognosis and an increased risk of dissemination may be indicated by the findings of (1) elevated CF titers, (2) pulmonary infiltrates or hilar or paratracheal adenopathy that persists more than 6 weeks, and (3) significant weight loss. Extrapulmonary dissemination is estimated to occur in less than 5% of symptomatic infections. The risk of dissemination is increased in patients with depressed cell-mediated immune (CMI) responses. Certain individuals appear predisposed to severe, prolonged, or disseminated infections. These include immunocompromised individuals, most notably those with AIDS; patients taking immunosuppressive drugs, particularly prednisone and tumor necrosis factor (TNF) antagonists; individuals of Black, Filipino, or American Indian extraction; and those in the last trimester of pregnancy. Age older than 55 carries a greater risk of continuing illness even after 1 year of treatment. Recently, mutations in the IL-12/IL-23/IFN pathway have been identified in certain individuals with disseminated coccidioidomycosis, but it is not known whether genetic polymorphisms in this axis underlie the ethnic differences in disseminated disease that have been observed.

The most frequent sites of dissemination are the skin, bones, soft tissues, and meninges; however, single- or multiple-mass lesions or abscesses may occur in any organ. Typical miliary lesions occur in 4% of cases. Cutaneous fistula formation from deep-seated lesions is common. Meningitis is the most ominous form of dissemination because of anatomic disruption that can lead to hydrocephalus, and because of the difficulty in getting drugs to the site of infection. There is some evidence that patients with facial lesions due to coccidioidomycosis have a greater risk for developing meningitis than patients who had lesions only on the body. This association may allow for earlier detection and treatment of coccidioidomycosis meningitis. If dissemination has occurred or is suspected, a careful evaluation of its extent should be undertaken, including analysis of the cerebrospinal fluid (CSF) for CF titer. CSF may be negative in 25% of cases on an initial examination. If clinical suspicion is high, a spinal tap should be repeated in 1 or 2 weeks. Bone scans are very useful in the search for subclinical sites of dissemination.

DIAGNOSIS

Coccidioidomycosis can be diagnosed by culture, histology, or serology. In addition, the presence of tissue eosinophilia, while nonspecific, should raise suspicion for coccidioidomycosis in the correct clinical context. Skin testing was performed frequently in the past to determine cellular immunity to Coccidioides. Unfortunately, the skin test reagent has been unavailable for a number of years, but it may be reintroduced.

The finding of spherules containing endospores on direct microscopy is considered pathognomonic for coccidioidomycosis. The organism can be detected on histopathology using standard hematoxylin–eosin (H&E), periodic acid Schiff (PAS), or Grocott methenamine silver (GMS) stains, with the GMS stain considered the most sensitive. Sputum samples can be prepared with potassium hydroxide (KOH) or calcofluour white (CFW), although these methods lack sensitivity.

Coccidioides can be cultured on a wide variety of culture media, including some bacterial media. Visible growth is usually evident by 4 to 5 days. Identification is usually by direct microscopy of the specimen, but a nucleic acid probe for rapid identification is also commercially available. In vitro drug susceptibility testing has not been shown to correlate with clinical response and is not routinely performed in clinical labs. Culture of Coccidioides

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