Coccidioidomycosis (Coccidioides Species)

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Chapter 232 Coccidioidomycosis (Coccidioides Species)

Epidemiology

Coccidioides spp. inhabit soil in arid regions. C. immitis is primarily found in California’s San Joaquin Valley. C. posadasii is endemic to southern regions of Arizona, Utah, Nevada, New Mexico, western Texas, and regions of Mexico and Central and South America.

Population migrations into endemic areas and increasing numbers of immunosuppressed persons have caused coccidioidomycosis to become an important health problem. Infection rates increased from 2000 to 2007. About 150,000 newly reported infections occur annually in the USA. Coccidioidin skin test positivity in 5-7 yr old students in a highly endemic area demonstrated a decline from 10% to 2% in a 58-yr period ending in 2000. During 2002, 153 children required hospitalization for coccidioidomycosis, and infection was fatal in 9% of cases.

Infection results from inhalation of spores. Incidence increases during windy, dry periods that follow rainy seasons. Seismic events, archaeological excavations, and other activities that disturb contaminated sites have caused outbreaks. Person-to-person transmission does not occur. Rarely, infections result from spores that contaminate fomites or grow beneath casts or wound dressings of infected patients. Infection has also resulted from transplantation of organs from infected donors and from mother to fetus or newborn. Visitors to endemic areas can acquire infections, and diagnosis may be delayed when they are evaluated in nonendemic areas. Spores are highly virulent, and Coccidioides spp. are potential agents of bioterrorism (Chapter 704).

Clinical Manifestations

The clinical spectrum (Fig. 232-1) encompasses pulmonary and extrapulmonary disease. Pulmonary infection occurs in 95% of cases and can be divided into primary, complicated, and residual infections. About 60% of infections are asymptomatic. Symptoms in children are milder than those in adults. The incidence of extrapulmonary dissemination in children approaches that of adults.

Dissseminated (Extrapulmonary) Infection

Clinically apparent dissemination occurs in 0.5% of patients. Its incidence is increased in infants; men; persons of Filipino, African, and Latin American ancestry; and in other Asians. Primary or acquired disorders of cellular immunity (Table 232-1) markedly increase the risk of dissemination.

Table 232-1 RISK FACTORS FOR POOR OUTCOME IN PATIENTS WITH ACTIVE COCCIDIOIDOMYCOSIS

PRIMARY INFECTIONS
Severe, prolonged (≥6 wk), or progressive infection
RISK FACTORS FOR EXTRAPULMONARY DISSEMINATION
Primary or acquired cellular immune dysfunction (including patients receiving tumor necrosis factor inhibitors)
Neonates, infants, the elderly
Male sex (adult)
Filipino, African, Native American, or Latin American ethnicity
Late-stage pregnancy and early postpartum period
Standardized complement fixation antibody titer >1:16 or increasing titer with persisting symptoms
Blood group B
HLA class II allele-DRBI*1301

Symptoms usually occur within 6 mo of primary infection and can follow directly. Prolonged fever, toxicity, skin lesions, subcutaneous and/or osseous cold abscesses, and laryngeal lesions can herald onset. Organism-specific skin lesions have a predilection for the nasolabial area and appear initially as papules, which evolve to form pustules, plaques, abscesses, and verrucous plaques. Biopsy of these lesions demonstrates spherules. Basilar meningitis is the most common manifestation and may be accompanied by ventriculitis, ependymitis, cerebral vasculitis, abscess, and syringomyelia. Headache, vomiting, meningismus, and cranial nerve dysfunction are often present. Untreated meningitis is almost invariably fatal. Bone infections account for 20-50% of extrapulmonary manifestations, are often multifocal, and can affect adjacent structures. Miliary dissemination and peritonitis can mimic tuberculosis.

Diagnosis

Nonspecific tests have limited usefulness. The complete blood count might show an elevated eosinophil count, and marked eosinophilia can accompany dissemination.

Serology

Serologic tests provide valuable diagnostic information but may be falsely negative early in self-limited infections and in immunocompromised patients. Three major methods are used, including EIA, complement fixation (CF), and immunodiffusion (ID). EIA and CF tests are best done in experienced reference laboratories.

Immunoglobulin M (IgM) specific antibody becomes measurable in 50% of infected patients 1 wk after onset and in 90% of infected patients by 3 wk. EIA is sensitive and can detect IgM and IgG antibody; it is less specific than other methods, and confirmation with ID or CF may be needed. IgG antibodies measured by CF appear between the 2nd and 3rd wk but can take several months; follow-up testing is needed if tests are negative and clinical suspicion persists. In the presence of CF titers of 1:2 or 1:4, a positive IDF test can help corroborate significance. IgG-specific antibody can persist for months, with titers elevated in proportion to the severity of illness. CF titers >1:16 are suggestive of dissemination. Direct comparison of the results of CF (IgG) antibody tests measured by different methodologies should be interpreted with caution. IgG antibody titers used to monitor disease activity should be tested concurrently with serum samples taken earlier in the illness using the same methodology.

C. immitis antibody is present in CSF in 95% of patients with meningitis and is usually diagnostic. Rarely, “spillover” in patients without meningitis but with high IgG titers in serum can be present in CSF. Isolation of Coccidioides from CSF culture of patients with meningitis is uncommon, although culture of large volumes of CSF may improve sensitivity.

Imaging Procedures

During primary infection, chest radiography may be normal or demonstrate consolidation, single or multiple circumscribed lesions, or soft pulmonary densities. Hilar and subcarinal lymphadenopathy is often present (see Fig. 232-2). Cavities tend to be thin-walled (Fig. 232-3). Pleural effusions vary in size. The presence of miliary or reticulonodular lesions is prognostically unfavorable. Isolated or multiple osseous lesions are usually lytic and often affect cancellous bone. Lesions can affect adjacent structures, and vertebral lesions can impact the spinal cord.

Treatment

Based on the few rigorous clinical trials performed in adults and the opinions of experts in the management of coccidioidomycosis, consensus treatment guidelines have been developed (Table 232-2). Consultation with experts in an area of endemicity should be considered when formulating a plan of management.

Table 232-2 INDICATIONS FOR TREATMENT OF COCCIDIOIDOMYCOSIS IN ADULTS

INDICATION TREATMENT
Acute pneumonia, mild Observe without antifungal treatment at 1-3 mo intervals for ≥1 yr; some experts recommend antifungal treatment
Weight loss >10%; sweats >3 wk; infiltrates at least half of one lung or parts of both lungs; prominent or persistent hilar lymphadenopathy; CF titers >1:16; inability to work, symptoms >2 mo Treat with an azole daily for 3-6 mo, with follow up at 1-3 mo intervals for ≥1 yr
Uncomplicated acute pneumonia, special circumstances: immunosuppression, late pregnancy, Filipino or African ancestry, age >55 yr, other chronic diseases (diabetes, cardiopulmonary disease), symptoms >2 mo Treat with an azole daily for 3-6 mo, with follow up at 1-3 mo intervals for ≥1 yr
Treat with amphotericin B if in late pregnancy
Diffuse pneumonia: reticulonodular or miliary infiltrates suggest underlying immunodeficiency and possible fungemia, pain Treat initially with amphotericin B if significant hypoxia or rapid deterioration, followed by an azole for ≥1 yr
In mild cases, an azole for ≥1 yr
Chronic pneumonia Treat with an azole for ≥1 yr
Disseminated disease, nonmeningeal Treat with an azole for ≥1 yr except in severe or rapidly worsening cases for which amphotericin B is recommended
Disseminated disease, meningeal Treat with fluconazole (some add intrathecal amphotericin B) and treat indefinitely

CF, complement fixation.

Patients should be followed closely because late relapse can occur, especially in patients who are immunosuppressed or have severe manifestations. Treatment is recommended for all HIV-infected patients with active coccidioidomycosis and CD4 counts <250/µL. Following successful treatment, antifungals may be stopped if the CD4 count exceeds 250/µL. Treatment should be continued if the CD4 count remains less than 250/µL and should be given indefinitely in all HIV-infected patients with coccidioidal meningitis.

First-line agents include oral and intravenous preparations of fluconazole (6-12 mg/kg/day IV or PO) and itraconazole (5-10 mg/kg/day). Serum levels of itraconazole should be monitored.

Amphotericin B is preferred for initial treatment of severe infections. Amphotericin B deoxycholate is less costly than lipid formulations and is often well tolerated in children. Once a daily dose of amphotericin B deoxycholate of 1-1.5 mg/kg/day is achieved, the frequency of administration can be reduced to 3 times weekly. The recommended total dosage ranges from 15 mg/kg to 45 mg/kg and is determined by the clinical response. Lipid formulations of amphotericin are recommended for patients with impaired renal function, patients receiving other nephrotoxic agents, or if amphotericin B deoxycholate is not tolerated. Some experts prefer liposomal amphotericin to treat CNS infections because it achieves higher levels in brain parenchyma. Amphotericin B preparations do not cross the blood-brain barrier to effectively treat Coccidioides spp., but they can mask the signs of meningitis. Infections during pregnancy should be treated with amphotericin B, because the azoles are potentially teratogenic. Voriconazole and posaconazole have been used successfully as salvage therapy in infections failing the standard agents.

Primary Pulmonary Infection

Primary pulmonary coccidioidomycosis resolves in 95% of patients without risk factors for dissemination; antifungal therapy does not lessen the frequency of dissemination or pulmonary residua. When it is elected to defer antifungal therapy, visits are recommended as needed and at 3-6 mo intervals for 2 yr and as needed.

Patients with significant or prolonged symptoms are more likely to incur benefit from antifungal agents, but there are no established criteria upon which to base the decision. Commonly used indicators in adults are summarized in Table 232-2. A treatment trial in adults with primary respiratory infections examined outcomes of antifungal therapy prescribed on the basis of severity and compared them to an untreated group with less severe symptoms; complications occurred only in patients in the treatment group and only in those in whom treatment was stopped. If treatment is elected, a 3-6 mo course of fluconazole (6-12 mg/kg/day) or itraconazole (5-10 mg/kg/day) is recommended.

Disseminated Infection (Extrapulmonary)

For nonmeningeal infection (see Table 232-2), oral fluconazole and itraconazole are effective for treating disseminated coccidioidomycosis that is not extensive, is not progressing rapidly, and has not affected the CNS. Some experts recommend higher doses for adults than were used in clinical trials. A subgroup analysis showed a tendency for improved response of skeletal infections that were treated with itraconazole. Amphotericin B deoxycholate is used as an alternative, especially if there is rapid worsening and lesions are in critical locations. Voriconazole has been used successfully as salvage therapy. The optimal duration of therapy with the azoles has not been clearly defined. Late relapses have occurred after lengthy treatment and favorable clinical response.

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