How should cryptococcal meningitis be diagnosed and treated in an immunocompromised patient, such as one with advanced HIV infection?

Cryptococcal Meningitis in Immunocompromised Patients

For cryptococcal meningitis in advanced HIV infection, initiate amphotericin B deoxycholate (0.7–1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) for at least 2 weeks, followed by fluconazole consolidation (400 mg/day) for 8 weeks, then maintenance fluconazole (200 mg/day) for at least 12 months. 1

Diagnostic Approach

All immunocompromised patients with suspected cryptococcosis require:

• Serum cryptococcal antigen (CrAg) testing using lateral flow assay, which has >95% sensitivity and specificity 2
• Blood cultures for Cryptococcus species—up to 75% of HIV-associated cryptococcal meningitis cases have positive blood cultures 1, 3
• Lumbar puncture with CSF analysis including opening pressure measurement, cell count, protein, glucose, India ink stain, fungal culture, and CSF CrAg 1, 2
• Opening pressure is elevated (>20 cm H₂O) in up to 75% of HIV patients with cryptococcal meningitis 1

In HIV-infected individuals with CD4+ counts <200 cells/µL, lumbar puncture and CSF testing are especially critical, as the overwhelming majority of cryptococcal disease occurs with CD4+ counts <50 cells/µL 4, 3

A positive serum CrAg is almost invariably present in CNS disease (97% sensitivity), but a negative serum CrAg does not exclude disseminated infection 4, 2

Treatment Algorithm for HIV-Associated Cryptococcal Meningitis

Induction Phase (Minimum 2 Weeks)

Preferred regimen:

• Amphotericin B deoxycholate 0.7–1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally (divided every 6 hours) for at least 2 weeks 1
• Lipid formulations of amphotericin B (liposomal AmB 3–4 mg/kg/day IV or AmB lipid complex 5 mg/kg/day IV) should be substituted in patients with or predisposed to renal dysfunction 1

Alternative regimens (in descending order of preference):

• Amphotericin B deoxycholate or lipid formulation alone for 4–6 weeks 1
• Amphotericin B deoxycholate 0.7 mg/kg/day IV plus fluconazole 800 mg/day orally for 2 weeks 1
• Fluconazole ≥800 mg/day (1200 mg/day favored) plus flucytosine 100 mg/kg/day orally for 6 weeks 1

Consolidation Phase (8 Weeks)

Fluconazole 400 mg (6 mg/kg) per day orally for a minimum of 8 weeks after completing induction therapy 1

Maintenance Phase (≥12 Months)

Fluconazole 200 mg per day orally for at least 12 months 1

Maintenance therapy may be safely discontinued when:

• CD4+ count >100 cells/µL sustained for ≥3 months 1
• Undetectable or very low HIV RNA level 1
• At least 12 months of antifungal therapy completed 1
• Reinstitute maintenance therapy if CD4+ count decreases to <100 cells/µL 1

Critical Management of Elevated Intracranial Pressure

Elevated intracranial pressure is the primary cause of morbidity and mortality in cryptococcal meningitis and requires aggressive management 1

For opening pressure >25 cm H₂O:

• Perform therapeutic lumbar puncture removing sufficient CSF to reduce opening pressure by 50% or to <20 cm H₂O 1
• Repeat daily lumbar punctures until opening pressure stabilizes at <20 cm H₂O 1

For persistently elevated pressure despite frequent lumbar drainage:

• Consider insertion of a ventriculoperitoneal (VP) shunt 1
• VP shunts can be placed during active infection as long as effective antifungal therapy has been initiated prior to placement 1

Avoid acetazolamide and corticosteroids for routine management of elevated intracranial pressure, as they have not been shown to improve outcomes and may worsen fungal clearance 1

Timing of Antiretroviral Therapy (ART)

Initiate HAART 2–10 weeks after commencement of initial antifungal treatment 1

This delayed initiation reduces the risk of immune reconstitution inflammatory syndrome (IRIS) while allowing time for CSF sterilization 1

Risk factors for IRIS include:

• More severe cryptococcal disease including fungemia 1
• Extremely low CD4+ cell count 1
• Lack of CSF sterilization at week 2 1
• Introduction of HAART during early induction therapy 1
• Rapid initial decrease in HIV viral load 1

Management of IRIS

IRIS can present as "unmasking" (cryptococcal symptoms first appear after starting HAART) or "paradoxical" (worsening during treatment of known cryptococcosis) 1

For minor IRIS manifestations:

• No need to alter direct antifungal therapy 1
• Minor manifestations resolve spontaneously in days to weeks 1

For major complications (CNS inflammation with increased intracranial pressure):

• Consider corticosteroids 0.5–1.0 mg/kg/day of prednisone equivalent, or dexamethasone at higher doses for severe CNS signs and symptoms 1
• A 2–6-week corticosteroid taper is a reasonable starting point, given with concomitant antifungal therapy 1
• Continue aggressive management of elevated intracranial pressure with therapeutic lumbar punctures 1

Special Considerations for Solid Organ Transplant Recipients

For CNS disease in transplant recipients:

• Use lipid formulations of amphotericin B (liposomal AmB 3–4 mg/kg/day IV or ABLC 5 mg/kg/day IV) plus flucytosine 100 mg/kg/day for at least 2 weeks 1
• Amphotericin B deoxycholate should be used with caution due to risk of nephrotoxicity and is not recommended 1
• If induction therapy does not include flucytosine, consider lipid formulation amphotericin B for at least 4–6 weeks 1

Immunosuppression management:

• Sequential or stepwise reduction of immunosuppressants, lowering corticosteroid dose first 1
• Taper gradually rather than stop abruptly to reduce risk of IRIS and allograft loss 4
• Calcineurin inhibitors possess intrinsic anti-cryptococcal activity and should be reduced after corticosteroids 4

Common Pitfalls to Avoid

Never assume isolated disease in an immunocompromised patient—disseminated disease is common when cryptococcosis occurs in HIV-infected patients, with virtually any organ potentially involved 1, 3

Do not mistake IRIS for treatment failure—many times IRIS is considered treatment failure and new antifungal regimens are considered when the essential issue is immune reconstitution 1

Avoid starting HAART too early (<2 weeks) after antifungal initiation, as this increases IRIS risk 1

Do not neglect serial monitoring of intracranial pressure—elevated pressure is the primary cause of death and requires daily therapeutic lumbar punctures until controlled 1

Baseline fluconazole resistance can reach up to 12% in non-HIV immunocompromised patients, which is an important consideration for relapses or suboptimal responses 5