What is immune reconstitution inflammatory syndrome (IRIS), including its timing after antiretroviral therapy initiation, risk factors, clinical presentation, diagnostic criteria, and recommended management?

Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS is a paradoxical worsening of clinical symptoms occurring when antiretroviral therapy restores immune function in HIV-infected patients, resulting in an exaggerated inflammatory response to previously present infectious antigens—most cases are mild to moderate and can be managed symptomatically with continuation of both ART and antimicrobial therapy, though severe cases require corticosteroids at prednisone 1.25 mg/kg/day. 1, 2

Definition and Pathophysiology

IRIS represents a dysregulated host inflammatory response that develops as the immune system reconstitutes following ART initiation. 1, 2 The syndrome manifests in two distinct forms:

• Paradoxical IRIS: Worsening of a known, previously treated opportunistic infection after ART initiation 3, 4
• Unmasking IRIS: Emergence of clinical manifestations from a previously subclinical or incubating infection that becomes apparent after immune restoration 1, 5

The pathophysiology involves partial recovery of immune function with exuberant inflammatory responses to antigenic stimuli, though the exact mechanisms remain incompletely understood. 4, 6

Timing and Incidence

• IRIS typically occurs within 3 to 6 months after initiating ART, though timing varies by underlying pathogen 2
• Overall incidence ranges from 6% to 39% depending on the population studied and burden of opportunistic infections 2
• In the STRIDE study of tuberculosis-HIV coinfection, IRIS occurred in 7.6% of patients 1

Major Risk Factors

The following factors significantly increase IRIS risk:

• CD4+ count <50 cells/μL at ART initiation is the strongest predictor 1, 2
• Early ART initiation within 2 weeks after starting treatment for opportunistic infections (relative risk 1.88,95% CI 1.31-2.69) 1, 2
• Advanced immunosuppression with disseminated disease and high pathogen burden 2
• Excellent virological response to ART with rapid viral load suppression 6

Clinical Presentation by Pathogen

Tuberculosis IRIS (Most Common)

Signs include: 1, 2

• High fevers and worsening respiratory symptoms
• Enlarging or new lymphadenopathy with increased inflammation
• Expanding CNS lesions
• Worsening pulmonary parenchymal infiltrations
• New or increasing pleural effusions
• Development of intra-abdominal or retroperitoneal abscesses

Cryptococcal IRIS

Manifests with increased intracranial pressure and worsening meningeal inflammation despite appropriate antifungal therapy. 2

Mycobacterium Avium Complex (MAC) IRIS

Presents as paradoxical worsening with fever, lymphadenitis, or other inflammatory manifestations despite appropriate antimycobacterial therapy. 2

Other Pathogens

Varicella zoster, herpesviruses, and CMV are frequently implicated. 4

Diagnostic Approach

IRIS remains a diagnosis of exclusion—you must systematically rule out other causes before attributing symptoms to IRIS. 1, 7

Essential Exclusions:

• Drug-resistant tuberculosis or treatment failure 1
• New opportunistic infections (non-Hodgkin lymphoma, other infections) 1
• Medication toxicity or drug interactions 6
• Disease progression from inadequate antimicrobial therapy 7

Diagnostic Criteria:

No laboratory test confirms IRIS. 7 Diagnosis requires:

• Temporal relationship to ART initiation (typically within 3-6 months) 2
• Evidence of immune recovery (rising CD4 count, decreasing viral load) 6
• Clinical or radiologic worsening of infectious manifestations 1
• Exclusion of alternative diagnoses 1

Management Algorithm

Mild to Moderate IRIS (69% of cases)

Continue both ART and antimicrobial therapy unless life-threatening complications develop. 1, 2

• Initiate NSAIDs (ibuprofen) for symptomatic relief 1, 2
• Provide supportive care and close monitoring 1
• Consider drainage for worsening pleural effusions or abscesses 1

Severe IRIS (31% of cases requiring hospitalization)

Administer prednisone 1.25 mg/kg/day (50-80 mg/day) for 2-4 weeks, then taper over 6-12 weeks or longer. 1, 2 This regimen significantly reduces hospitalization and surgical intervention needs in placebo-controlled trials. 1

• Continue ART and antimicrobial therapy during corticosteroid treatment 1
• Monitor for corticosteroid-related complications 2
• Extend taper duration if symptoms recur 1

Critical Exception: CNS Tuberculosis

Do NOT initiate ART in the first 8 weeks of antituberculosis therapy for patients with tuberculous meningitis or other CNS tuberculosis, even with CD4 <50 cells/μL. 1 Early ART initiation (within 2 weeks) in CNS tuberculosis is associated with increased adverse events and higher mortality due to severe or fatal neurological complications from IRIS. 1

Prevention Strategies

Timing of ART Initiation by Clinical Scenario:

For tuberculosis without CNS involvement:

• CD4 <50 cells/μL: Start ART within 2 weeks of tuberculosis treatment to reduce mortality, accepting increased IRIS risk 1, 2
• CD4 ≥50 cells/μL: Initiate ART at 8-12 weeks after starting tuberculosis treatment 1, 2

For cryptococcal meningitis:

• Initiate ART 2-4 weeks after starting antifungal therapy, ensuring clinical improvement with controlled intracranial pressure and negative CSF cultures 2

For disseminated MAC:

• Consider withholding ART until after the first 2 weeks of antimycobacterial therapy to reduce drug interactions and IRIS complications 2

For most other opportunistic infections:

• Start ART within 2 weeks of initiating treatment 2

Additional Prevention Measures:

• Screen and treat opportunistic infections before initiating ART when feasible 2
• Ensure adequate antimicrobial therapy is established before introducing ART 2
• Monitor closely during the first 3-6 months after ART initiation 2

Critical Pitfalls to Avoid

• Never delay ART indefinitely to avoid IRIS—mortality reduction from early ART outweighs IRIS risk in most scenarios 2
• Do not discontinue ART for mild-moderate IRIS—most episodes resolve with symptomatic management while continuing therapy 1
• Avoid early ART in CNS tuberculosis—this is the one exception where delayed ART (8 weeks) is mandatory due to mortality risk 1
• Do not attribute all clinical worsening to IRIS—systematically exclude treatment failure, drug resistance, and new infections first 1, 7
• Do not use corticosteroids empirically for mild cases—reserve for severe manifestations with evidence of benefit 1, 2