What opportunistic infections are associated with a CD4 (Cluster of Differentiation 4) count less than 200 cells/mm^3?

Opportunistic Infections with CD4 Count <200 cells/mm³

When CD4 counts fall below 200 cells/mm³, patients face significantly elevated risk for Pneumocystis pneumonia (PCP) and require immediate prophylaxis, while additional opportunistic infections emerge at progressively lower thresholds, with toxoplasmosis at <100 cells/mm³, disseminated Mycobacterium avium complex (MAC) at <50 cells/mm³, and cytomegalovirus (CMV) disease at <100-150 cells/mm³. 1

Primary Opportunistic Infections by CD4 Threshold

CD4 <200 cells/mm³

• Pneumocystis jiroveci pneumonia (PCP) is the sentinel opportunistic infection at this threshold and requires immediate initiation of prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) double-strength once daily 1, 2
• Bacterial pneumonia remains common at any CD4 level, with Streptococcus pneumoniae and Haemophilus influenzae as primary pathogens, though risk increases substantially below 200 cells/mm³ 2
• Oropharyngeal candidiasis becomes increasingly common and itself serves as an indication for PCP prophylaxis even if CD4 count is >200 cells/mm³ 1
• Cryptococcal meningitis risk increases, though peak incidence occurs at lower CD4 counts 1

CD4 <100 cells/mm³

• Toxoplasmic encephalitis becomes a major concern in patients with positive Toxoplasma IgG serology, requiring immediate prophylaxis initiation 1, 3
• Cryptococcosis (particularly cryptococcal meningitis) incidence rises significantly at this threshold 1
• CMV retinitis risk begins to increase, with peak incidence below 50 cells/mm³ 1

CD4 <50 cells/mm³

• Disseminated Mycobacterium avium complex (MAC) becomes a primary concern and requires prophylaxis with azithromycin or clarithromycin 1
• CMV disease (retinitis, colitis, esophagitis) incidence peaks at this profoundly immunosuppressed state 1
• Histoplasmosis and coccidioidomycosis risk increases substantially in endemic areas 1

Critical Management Algorithm

Immediate Actions for CD4 <200 cells/mm³

1. Initiate PCP prophylaxis immediately with TMP-SMX double-strength (160mg/800mg) once daily, which also provides protection against toxoplasmosis and bacterial infections 1, 2, 3
2. Check Toxoplasma IgG serology if not previously documented—if positive and CD4 <100 cells/mm³, the TMP-SMX regimen already provides adequate prophylaxis 1, 3
3. Assess for active opportunistic infections including fever >100°F for ≥2 weeks, unexplained weight loss, or thrush, which increase suspicion for active OIs 1, 2
4. Start or optimize antiretroviral therapy (ART) immediately, as immune reconstitution is the definitive treatment 2

Additional Prophylaxis Based on CD4 Thresholds

• CD4 <100 cells/mm³ with positive Toxoplasma IgG: TMP-SMX double-strength daily provides dual coverage for PCP and toxoplasmosis 1, 3
• CD4 <50 cells/mm³: Add MAC prophylaxis with azithromycin 1200mg weekly or clarithromycin 500mg twice daily 1
• For sulfa-allergic patients: Use dapsone 100mg daily for PCP (plus pyrimethamine 50mg weekly and leucovorin 25mg weekly for toxoplasmosis if IgG positive and CD4 <100) 1, 3

Geographic and Special Considerations

Mycobacterium tuberculosis can occur at any CD4 count but risk increases dramatically below 300 cells/mm³, with atypical presentations becoming more common at lower counts 1, 2

In endemic areas, consider risk for histoplasmosis and coccidioidomycosis particularly when CD4 <100 cells/mm³, though no routine primary prophylaxis is recommended 1

Common Pitfalls to Avoid

• Never delay PCP prophylaxis while waiting for CD4 count confirmation if clinical suspicion is high (presence of thrush, unexplained fever, or known recent CD4 <200) 1, 2
• Do not use aerosolized pentamidine for toxoplasmosis prophylaxis, as it provides no protection against toxoplasmic encephalitis despite preventing PCP 3
• Avoid fluoroquinolone monotherapy in patients with CD4 <200 without excluding tuberculosis first, as this can mask TB diagnosis and promote resistance 2
• Do not discontinue prophylaxis prematurely—CD4 must remain >200 cells/mm³ for at least 3 consecutive months on ART before safely stopping PCP prophylaxis 1
• Remember that bacterial pneumonia remains the most common pneumonia at any CD4 level and should always be covered empirically with beta-lactam plus macrolide, never macrolide monotherapy due to drug-resistant S. pneumoniae 2

Mortality Impact

Failure to prescribe prophylaxis is associated with significantly increased mortality even in the combination ART era, with the greatest absolute benefit in patients with CD4 <50 cells/mm³, where prophylaxis lowers mortality from 33.5 to 6.3 per 100 person-years 4

Approximately 75% of AIDS-defining illnesses occur when CD4 count is below 200 cells/mm³, emphasizing the critical importance of this threshold for prophylaxis initiation 5