What is the recommended diagnostic workup and treatment regimen for pulmonary cryptococcosis in immunocompetent versus immunocompromised adults, including severe disease and pregnancy?

Treatment of Pulmonary Cryptococcosis

For immunocompetent adults with mild-to-moderate pulmonary cryptococcosis, treat with fluconazole 400 mg daily orally for 6-12 months; for immunosuppressed patients with similar disease severity, use the same regimen but always perform lumbar puncture first to exclude CNS involvement. 1

Initial Diagnostic Workup

Immunocompetent Patients

• Lumbar puncture can be avoided in normal hosts with asymptomatic pulmonary nodule or infiltrate, no CNS symptoms, and negative or very low serum cryptococcal antigen 1
• Obtain serum cryptococcal antigen testing in all cases 2
• Perform chest imaging to characterize extent of disease 2
• Consider observation without treatment for truly asymptomatic patients with resected lesions and negative/very low antigen 2

Immunosuppressed Patients

• Lumbar puncture is mandatory to rule out asymptomatic CNS involvement, as meningitis alters dose and duration of therapy 1, 2
• Obtain blood cultures and serum cryptococcal antigen 3
• Perform chest imaging 3
• Assess for dissemination to other sites 2

Treatment Algorithm by Disease Severity

Mild-to-Moderate Disease (No Diffuse Infiltrates)

Immunocompetent patients:

• Fluconazole 400 mg daily orally for 6-12 months 1, 2
• Alternative agents if fluconazole unavailable/contraindicated: itraconazole 200 mg twice daily, voriconazole 200 mg twice daily, or posaconazole 400 mg twice daily 1, 2
• Do not continue therapy based solely on persistent positive serum antigen titers 1, 2

Immunosuppressed patients (including HIV):

• Fluconazole 400 mg (6 mg/kg) daily orally for 6-12 months 1, 2
• For HIV patients on HAART with CD4 >100 cells/μL and cryptococcal antigen ≤1:512 (not increasing), consider stopping maintenance fluconazole after 1 year 1

Severe Disease (ARDS, Diffuse Infiltrates, or CNS/Disseminated Disease)

Treat identically to CNS cryptococcosis:

• Induction: Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally (divided into 4 doses) for at least 2 weeks 3, 2
• Consolidation: Fluconazole 400 mg daily for 8 weeks 3
• Maintenance: Fluconazole 200-400 mg daily for 6-12 months 3
• Consider corticosteroids if ARDS occurs in context of immune reconstitution inflammatory syndrome (IRIS) 1

High Fungal Burden Without CNS Disease

For cryptococcemia or antigen titer ≥1:512:

• Treat as CNS disease with amphotericin B-based induction therapy 1, 3

For single-site disease with negative CNS evaluation and no fungemia:

• Fluconazole 400 mg daily for 6-12 months 1

Special Populations

Pregnant Women

• For limited, stable pulmonary disease: Close follow-up during pregnancy, defer fluconazole until after delivery 1
• For severe/disseminated disease: Amphotericin B deoxycholate or liposomal amphotericin B, with or without flucytosine (Category C, weigh risk/benefit) 1
• Avoid fluconazole in first trimester; use cautiously in second/third trimesters only if continuous therapy essential 1
• Monitor for IRIS in postpartum period 1

Children

• Fluconazole 6-12 mg/kg/day orally for 6-12 months for pulmonary disease 1
• For severe disease: Amphotericin B 1 mg/kg/day IV plus flucytosine 100 mg/kg/day orally for 2 weeks, then consolidation 1

Transplant Recipients

• Prefer liposomal amphotericin B over deoxycholate formulation due to concurrent nephrotoxic immunosuppressants 3
• Monitor for drug interactions with calcineurin inhibitors 3

Critical Management Considerations

Monitoring During Therapy

• Monitor renal function, electrolytes, and complete blood count in patients receiving amphotericin B 3
• Check flucytosine peak serum levels (target <75 μg/mL) to prevent bone marrow toxicity 3
• Serial chest imaging to assess response 4, 5

Surgical Indications

• Consider surgery for diagnosis when non-invasive methods insufficient 2
• Persistent radiographic abnormalities and symptoms not responding to antifungal therapy after adequate treatment duration 1, 2
• Large lesions (≥3 cm) with mass effect 2

Common Pitfalls and How to Avoid Them

Diagnostic Errors

• Failing to perform lumbar puncture in immunosuppressed patients can miss asymptomatic meningitis, which may precede neurological symptoms by weeks 1, 2, 6
• Misdiagnosing as lung cancer or tuberculosis due to similar radiographic appearance 5, 7
• Inadequate culture observation time—Cryptococcus may require up to 14 days for growth 6

Treatment Errors

• Using persistently positive serum antigen titers as sole criterion to continue therapy in immunocompetent patients—this is incorrect 1, 2
• Inadequate treatment duration leading to relapse 7, 8
• Starting antiretroviral therapy too early in HIV patients (delay 2-10 weeks to reduce IRIS risk) 3

Treatment Failure

• Defined as lack of clinical improvement after 2 weeks or relapse after initial response 3
• Switch to or restart amphotericin B-based therapy 3
• Consider higher doses of liposomal amphotericin B (4-6 mg/kg/day) 3
• Obtain MIC testing for azole resistance, particularly in Asia-Pacific region where fluconazole resistance reported 9
• Voriconazole combined with liposomal amphotericin B may be effective for fluconazole-resistant cases 9