What is the diagnostic workup and treatment for patients presenting with clinical findings suggestive of coccidioidomycosis?

Diagnostic Workup and Treatment for Coccidioidomycosis

For patients with suspected coccidioidomycosis, immediately order serological testing (EIA, immunodiffusion, or complement fixation) and obtain a chest radiograph, while recognizing that serology may be negative early in disease or in immunocompromised patients—in which case culture from respiratory specimens becomes essential for diagnosis. 1

Initial Diagnostic Approach

Essential Laboratory Testing

• Order serological testing first looking for IgM antibodies (appear 1-3 weeks after symptom onset) followed by IgG antibodies (appear 4-8 weeks later). 1
• Obtain quantitative complement fixation (CF) testing and repeat approximately every 12 weeks during treatment to monitor response. 1
• Critical caveat: Serologic tests may remain persistently negative despite active infection, particularly in immunocompromised patients with CD4+ counts <250 cells/µL. 1, 2

Culture and Histopathology

• Culture from any clinical site proves the diagnosis—Coccidioides grows on routine blood agar and Sabouraud dextrose agar at 25-30°C, with mycelial growth visible as early as 4-5 days (hold cultures up to 6 weeks). 1
• In patients sufficiently ill to warrant hospitalization or those with negative serology, culture of sputum or bronchoscopic specimens may provide the only means of diagnosis. 2
• Histopathology showing spherules or endospores is considered proven disease, even without positive culture. 1

Imaging Studies

• Obtain chest radiograph in all patients—look for dense infiltrates (often upper lobe), hilar or mediastinal adenopathy, consolidation and cavitation, or pleural effusion. 1, 2

Risk Stratification and Severity Assessment

Document High-Risk Factors Requiring Treatment

• Immunosuppression: High-dose corticosteroids (≥20 mg prednisone daily for ≥2 weeks), TNF inhibitors, organ transplant recipients, HIV infection with CD4+ <250 cells/µL. 2
• Pregnancy, especially third trimester. 2
• African or Filipino ancestry. 1
• Diabetes and cardiopulmonary comorbidities. 1

Severity Markers Mandating Antifungal Therapy

• Weight loss >10%. 1
• Night sweats >3 weeks duration. 1
• Infiltrates exceeding 50% of one lung or bilateral disease. 1
• CF titers ≥1:16. 1

Evaluation for Disseminated Disease

When to Perform Lumbar Puncture

• Obtain CSF sample from all patients with: sustained or worsening headache with altered mental status, unexplained nausea/vomiting, or new focal neurologic deficits. 2, 1
• Do not perform routine lumbar puncture in patients with uncomplicated pulmonary disease or even other sites of dissemination if CNS symptoms are absent. 2

CSF Findings in Coccidioidal Meningitis

• CSF shows low glucose, elevated protein (commonly >150 mg/dL), lymphocytic pleocytosis. 2, 1
• CF antibody frequently detected in CSF (30-60% initially positive), though culture is positive in <33% of cases. 2, 1

Screening for Extrapulmonary Foci

• Presence of skin lesions should prompt investigation for other extrapulmonary sites—as many as 90% of persons with cutaneous dissemination have other extrapulmonary foci. 3
• Tissue-destructive lesions are nearly always evident from focal signs and symptoms; their absence is strong evidence against disseminated infection. 2

Treatment Algorithm

Mild to Moderate Pulmonary Disease in Immunocompetent Patients

• Many patients with uncomplicated primary pulmonary infection require only periodic reassessment to demonstrate resolution, as 95% resolve spontaneously without antifungal therapy. 2
• Initiate treatment if severity markers are present (see above) or if symptoms persist beyond several weeks. 1
• Oral fluconazole 400-800 mg daily for 3-6 months for mild/moderate disease. 2
• Alternative: Itraconazole 200 mg twice daily (requires monitoring serum concentrations after 2 weeks to ensure adequate absorption). 2

Severe or Rapidly Progressive Disease

• Amphotericin B 0.5-0.7 mg/kg/day IV is the preferred initial therapy for patients with respiratory failure or rapidly progressive infection. 2, 4
• Intravenous liposomal amphotericin B (3 mg/kg daily) for 1-2 weeks followed by long-term oral fluconazole for severe infection. 2
• Continue amphotericin B until clinical improvement occurs, usually after 500-1,000 mg total dose. 2

Coccidioidal Meningitis

• Fluconazole 400-1,200 mg orally daily is the recommended initial therapy for most patients with normal renal function—there is no role for doses <400 mg daily in adults without substantial renal impairment. 2
• Fluconazole has been successful in approximately 80% of patients with coccidioidal meningitis. 2
• Intrathecal amphotericin B is the most accepted alternative but is toxic and requires specialist consultation. 2

Immunocompromised Patients

• All HIV-infected patients with clinical coccidioidomycosis and CD4+ <250 cells/µL require antifungal therapy. 2
• Continue antifungal therapy as long as CD4+ count remains <250 cells/µL. 2
• Immunocompromised individuals require prolonged treatment followed by long-term azole prophylaxis. 2

Duration and Monitoring

• Duration of therapy ranges from many months to years, and for some patients, chronic suppressive therapy is needed to prevent relapses. 2
• Lifelong suppressive therapy is required for patients who complete initial therapy for disseminated coccidioidomycosis using either fluconazole 400 mg daily or itraconazole 200 mg twice daily. 2
• Management should routinely include repeated patient encounters for 1-2 years to document resolution or identify complications early. 2

Critical Pitfalls to Avoid

• Do not rely solely on CF antibody titers to diagnose disseminated disease—while higher titers correlate with dissemination in groups, individual variability is substantial and tissue diagnosis is usually required. 1, 2
• Do not rule out coccidioidomycosis based on negative serology alone—antibody tests may remain negative despite active infection, especially early or in immunosuppressed patients. 1
• Do not assume positive serology equals disseminated disease—any positive antibody test usually indicates recent or active infection, but extrapulmonary lesions require direct evidence. 1
• In immunosuppressed patients, maintain higher clinical suspicion as serologic responses may be blunted. 1