What does a CD4‑cell count of 5 cells/µL and a positive cryptococcal antigen test indicate?

Severe AIDS-Defining Immunosuppression with Active or Impending Cryptococcal Disease

A CD4 count of 5 cells/µL with positive cryptococcal antigen indicates severe AIDS-defining immunosuppression with either active cryptococcal infection or imminent risk of cryptococcal meningitis, requiring urgent diagnostic lumbar puncture and immediate antifungal therapy. 1

Immediate Clinical Significance

This combination represents a medical emergency with extremely high mortality risk:

• Cryptococcal antigenemia at CD4 <100 cells/µL predicts 2-3 times higher mortality compared to CrAg-negative patients, with death rates of 22-75% within one year even with treatment 2, 3, 4
• At CD4 count of 5 cells/µL, the patient has virtually no functional cellular immunity and is at maximum risk for disseminated opportunistic infections 1
• Positive CrAg preceded symptomatic meningitis by a median of 22 days in prospective studies, meaning this patient may already have or will soon develop meningitis 1

Urgent Diagnostic Algorithm

Step 1: Immediate Lumbar Puncture (Do Not Delay)

Perform lumbar puncture immediately regardless of symptoms to determine if cryptococcal meningitis is already present: 1

• Send CSF for cryptococcal antigen, India ink stain, fungal culture, opening pressure
• 33% of patients with positive serum CrAg have asymptomatic meningitis at time of screening 5
• Opening pressure measurement is critical as elevated intracranial pressure is the primary cause of death 1

Step 2: Interpret Results and Initiate Treatment

If CSF is CrAg-positive or culture-positive (cryptococcal meningitis):

• Start liposomal amphotericin B (3-4 mg/kg/day IV) plus flucytosine (100 mg/kg/day in 4 divided doses) for induction therapy for at least 2 weeks 1
• Manage elevated intracranial pressure aggressively with serial therapeutic lumbar punctures to maintain opening pressure <20 cm H₂O 1
• Do NOT start antiretroviral therapy immediately—delay ART for 4-6 weeks after starting antifungal therapy to reduce risk of IRIS 1

If CSF is CrAg-negative (asymptomatic cryptococcal antigenemia):

• Start high-dose fluconazole 800 mg daily as preemptive therapy [5, @19@]
• This reduces progression to meningitis from 21.4% to 5.7% 5
• Consider repeating lumbar puncture if symptoms develop or CrAg titer is very high (>1:160) 4

Additional Critical Considerations at CD4 Count of 5 cells/µL

Prophylaxis for Other Opportunistic Infections

This patient requires immediate prophylaxis for multiple opportunistic infections: 1

• Pneumocystis jirovecii pneumonia (PCP): Start trimethoprim-sulfamethoxazole double-strength daily (CD4 <200 threshold far exceeded) 1
• Toxoplasma gondii: Same TMP-SMX regimen provides dual prophylaxis 1
• Mycobacterium avium complex (MAC): Start azithromycin 1200 mg weekly (CD4 <50 threshold exceeded) 1

Screening for Other Endemic Fungi

At CD4 <150 cells/µL, consider screening for: 1

• Histoplasmosis if patient resides in or has traveled to Ohio/Mississippi River Valleys or Latin America
• Disseminated histoplasmosis occurs almost exclusively at CD4 <150 cells/µL 1

Prognosis and Monitoring

• Even with optimal treatment, mortality remains 2.2 times higher in CrAg-positive versus CrAg-negative patients 5
• Monitor for immune reconstitution inflammatory syndrome (IRIS) when ART is eventually started 1
• Continue fluconazole maintenance therapy (200 mg daily) after completing induction/consolidation until CD4 >200 cells/µL for >6 months on ART 1

Common Pitfalls to Avoid

• Never delay lumbar puncture in CrAg-positive patients—asymptomatic meningitis is present in one-third of cases and requires different treatment 5
• Never start ART immediately in patients with active cryptococcal disease—this increases IRIS risk and mortality 1
• Never use fluconazole monotherapy if meningitis is confirmed—amphotericin B plus flucytosine is required for induction 1
• Never ignore elevated intracranial pressure—this is the primary cause of death and requires aggressive serial lumbar punctures 1
• Never assume the patient only has cryptococcosis—at CD4 of 5 cells/µL, multiple concurrent opportunistic infections are common 6