What is the management approach for patients at risk of Immune Reconstitution Inflammatory Syndrome (IRIS) due to an infection?

Management of Patients at Risk for IRIS

For patients at risk of IRIS, continue both antiretroviral therapy (ART) and antimicrobial treatment for the underlying infection unless life-threatening complications develop, while initiating NSAIDs for mild-to-moderate symptoms and corticosteroids for severe manifestations. 1

Risk Stratification

Identify high-risk patients before initiating ART:

• CD4+ count <50 cells/μL represents the single most important risk factor for developing IRIS 1
• Early ART initiation within 2 weeks of starting opportunistic infection treatment significantly increases IRIS risk 1
• Disseminated disease with high pathogen burden (e.g., >2 log10 CFU/mL mycobacteremia) elevates risk 2
• Advanced immunosuppression at baseline predicts higher IRIS incidence 1

Timing of ART Initiation to Minimize IRIS Risk

The timing of ART initiation should be stratified by CD4 count and type of infection:

For Tuberculosis Coinfection:

• CD4 <50 cells/μL: Start ART within 2 weeks of tuberculosis treatment initiation to reduce mortality, accepting increased IRIS risk 2, 1
• CD4 ≥50 cells/μL: Delay ART until 8-12 weeks after starting tuberculosis treatment 2, 1
• Tuberculous meningitis: Defer ART for the first 8 weeks of antituberculosis therapy regardless of CD4 count 2

For Disseminated MAC Disease:

• Treatment-naïve patients: Withhold ART until after the first 2 weeks of antimycobacterial therapy to reduce drug interactions, pill burden, and IRIS complications 2
• Already on ART: Continue and optimize ART unless drug interactions preclude safe concomitant use 2

For CMV Disease:

• Retinitis, gastrointestinal disease, or pneumonitis: Initiate ART without delay, as no data suggest adverse effects on these manifestations 2
• Neurologic CMV disease: Consider delaying ART until clinical improvement occurs due to potential localized morbidity from inflammatory reactions 2

Clinical Recognition of IRIS

IRIS typically manifests within 3-6 months after ART initiation, though timing varies by pathogen 1:

• Tuberculosis IRIS: High fevers, worsening respiratory symptoms, enlarging or new lymphadenopathy, expanding CNS lesions, worsening pulmonary infiltrates, new or increasing pleural effusions, intra-abdominal or retroperitoneal abscesses 2, 1
• MAC IRIS: Paradoxical worsening despite appropriate antimycobacterial therapy with fever, lymphadenitis, or other inflammatory manifestations 2, 1
• Cryptococcal IRIS: Increased intracranial pressure and worsening meningeal inflammation 1

Critical caveat: Exclude tuberculosis treatment failure from drug-resistant disease, non-adherence, or another opportunistic infection (e.g., non-Hodgkin lymphoma) before attributing symptoms to IRIS 2

Treatment Algorithm for IRIS

Mild-to-Moderate IRIS:

• Continue both ART and antimicrobial therapy for the underlying infection 1
• Initiate NSAIDs (e.g., ibuprofen) for symptomatic relief 2
• Monitor closely for progression 1

Severe IRIS:

• Administer prednisone 0.5-1.0 mg/kg/day (equivalent to 20-40 mg oral prednisone daily for most adults) 1
• Alternative dosing from tuberculosis IRIS data: prednisone 1.25 mg/kg/day significantly reduced hospitalization and surgical intervention needs 2
• Duration: 2-6 weeks (or 4-8 weeks per some guidelines) with gradual taper 2, 1
• Continue ART and antimicrobial therapy unless life-threatening complications mandate temporary discontinuation 1

Specific Interventions:

• Worsening pleural effusions or abscesses: Perform drainage procedures as needed 2
• Increased intracranial pressure from cryptococcal IRIS: Therapeutic lumbar punctures may be required 1

Prevention Strategies

• Screen and treat opportunistic infections before initiating ART when feasible 1
• Optimize timing of ART initiation based on CD4 count and type of infection as outlined above 2, 1
• Ensure adequate antimicrobial therapy is established before introducing ART, particularly for MAC disease 2
• Consider prophylaxis: Co-trimoxazole prophylaxis reduces morbidity and mortality in HIV-infected patients with newly diagnosed tuberculosis 2

Monitoring Requirements

• Clinical assessment: Monitor for new or worsening symptoms within the first 3-6 months after ART initiation 1
• Laboratory monitoring: Track CD4 count recovery and viral load suppression 1
• Pathogen-specific monitoring:
  • MAC: Repeat blood cultures at 4-8 weeks only if clinical response is inadequate 2
  • CMV retinitis: Ophthalmologic examination after induction therapy completion, at 1 month, then monthly while on treatment 2
  • Tuberculosis: Clinical and radiographic assessment for paradoxical worsening 2

Common Pitfalls to Avoid

• Do not discontinue ART for mild-to-moderate IRIS – the mortality benefit of ART outweighs IRIS morbidity in most cases 1
• Do not delay corticosteroids for severe IRIS – early intervention reduces hospitalization and surgical needs 2
• Do not assume all clinical worsening is IRIS – always exclude treatment failure, drug resistance, and new opportunistic infections first 2
• Do not use clarithromycin doses >1 g/day for MAC treatment, as this increases mortality 2