What is Immune Reconstitution Inflammatory Syndrome (IRIS) in the context of HIV (Human Immunodeficiency Virus) and TB (Tuberculosis) coinfection?

What is Immune Reconstitution Inflammatory Syndrome (IRIS)?

IRIS is a paradoxical worsening of clinical symptoms, signs, or radiologic manifestations that occurs when antiretroviral therapy (ART) restores immune function in HIV-infected patients, resulting in an exaggerated inflammatory response to previously present infectious or non-infectious antigens. 1, 2

Pathophysiology

IRIS represents a dysregulated host inflammatory response that develops as the immune system reconstitutes following initiation of ART, characterized by a sudden and violent immune reaction with a cytokine storm involving TNF-α and IFN-γ. 2, 3 This overreaction occurs when immune competence is restored, particularly affecting macrophage function in clearing intracellular pathogens. 3

Timing and Incidence

• IRIS typically occurs within 3 to 6 months after initiating ART, with most cases presenting at a median of 29 days from HAART initiation (range: 4 to 186 days). 2, 4
• The overall incidence ranges from 6% to 39% depending on the population studied and burden of opportunistic infections. 2
• In tuberculosis-HIV coinfection specifically, the incidence is 7.6% in well-controlled studies, though other cohorts report 11% to 45%. 1, 5

Major Risk Factors

CD4+ count <50 cells/μL at ART initiation is the strongest predictor of IRIS development. 1, 2

Additional critical risk factors include:

• Early ART initiation (within 2 weeks after starting treatment for opportunistic infections) increases relative risk to 1.88 (95% CI, 1.31–2.69). 1
• Advanced immunosuppression with disseminated disease and high pathogen burden (>2 log10 CFU/mL mycobacteremia). 2
• Rapid viral load decline of more than 2.5 log at the time of IRIS compared with pre-HAART levels, with incrementally greater decreases directly correlating with increased IRIS risk. 4
• Boosted protease inhibitor-based regimens (OR = 7.41; P = 0.006) carry higher IRIS risk than other ART regimens. 4

Two Distinct Clinical Presentations

Paradoxical IRIS

Worsening of a known, treated infection after ART initiation despite appropriate antimicrobial therapy. 1, 6 This represents the majority of IRIS cases.

Unmasking IRIS

Previously subclinical or undiagnosed infection becomes clinically apparent after ART initiation. 1, 6 Whether this represents normal progression of untreated infection or true IRIS remains unclear. 1

Common Infectious Manifestations

Tuberculosis-IRIS (Most Common)

Clinical features include: 1, 2, 7

• High fevers and worsening respiratory symptoms
• Increase in size and inflammation of involved lymph nodes or new lymphadenopathy
• Expanding central nervous system (CNS) lesions
• Worsening of pulmonary parenchymal infiltrations
• New or increasing pleural effusions
• Development of intra-abdominal or retroperitoneal abscesses

Other Pathogens

• Cryptococcus neoformans: Increased intracranial pressure and worsening meningeal inflammation. 2
• Mycobacterium avium complex (MAC): Paradoxical worsening with fever, lymphadenitis, or other inflammatory manifestations despite appropriate antimycobacterial therapy. 2, 7
• CMV retinitis: Inflammatory worsening requiring ophthalmologic monitoring. 2

Severity Classification

When tuberculosis IRIS occurs: 1

• 69% of cases are mild to moderate in severity
• 31% require hospitalization
• More than half receive corticosteroids for management

Diagnostic Approach

IRIS is a diagnosis of exclusion. 1 You must systematically rule out:

1. Treatment failure from drug-resistant tuberculosis or other pathogens
2. New opportunistic infections (non-Hodgkin lymphoma, other infections)
3. Medication non-adherence or drug-drug interactions
4. Alternative inflammatory conditions

Only after excluding these causes can findings be attributed to IRIS. 1

Management Algorithm

Mild to Moderate IRIS

Continue both ART and antimicrobial therapy with addition of anti-inflammatory agents. 1, 2, 7

• Administer NSAIDs such as ibuprofen for symptomatic relief. 1, 2, 7
• Monitor closely for progression to severe disease. 2

Severe IRIS

Initiate corticosteroid therapy while continuing ART and antimicrobials. 1, 2, 7

• Prednisone 1.25 mg/kg/day (or 0.5-1.0 mg/kg/day depending on severity) for 2-6 weeks with gradual taper. 1, 2, 7
• In placebo-controlled trials, prednisone significantly reduced the need for hospitalization and surgical intervention. 1, 7
• Taper over 6-12 weeks or longer based on clinical response. 7

Procedural Interventions

For patients with worsening pleural effusions or abscesses, drainage may be necessary. 1

When to Modify ART

Do not discontinue ART unless life-threatening complications develop. 7 In general, development of IRIS does not worsen treatment outcomes for either tuberculosis or HIV infection, and most episodes can be managed symptomatically. 1

Critical Exception: CNS Tuberculosis

IRIS in patients with CNS tuberculosis may cause severe or fatal neurological complications. 1 For HIV-infected patients with tuberculous meningitis, ART is not initiated in the first 8 weeks of antituberculosis therapy. 1, 8 This represents the single most important exception to early ART initiation guidelines.

Prevention Strategies

Timing of ART Initiation Based on CD4 Count

For CD4 <50 cells/μL (non-CNS TB): Start ART within 2 weeks of tuberculosis treatment initiation to reduce mortality, accepting increased IRIS risk. 1, 2, 7

For CD4 ≥50 cells/μL: Initiate ART at 8-12 weeks after starting tuberculosis treatment. 1, 2

For CNS tuberculosis (any CD4 count): Delay ART for 8 weeks regardless of CD4 count. 7, 8

Additional Prevention Measures

• Screen and treat opportunistic infections before initiating ART when feasible. 2
• Ensure adequate antimicrobial therapy is established before introducing ART, particularly for MAC disease. 2
• For disseminated MAC disease, withhold ART until after the first 2 weeks of antimycobacterial therapy to reduce drug interactions, pill burden, and IRIS complications. 2

Monitoring Requirements

Monitor for new or worsening symptoms within the first 3-6 months after ART initiation. 2, 7 Track:

• CD4 count recovery
• HIV viral load suppression to confirm immune reconstitution
• Clinical response to antimicrobial therapy 2, 7

Common Pitfalls to Avoid

Do not mistake IRIS for treatment failure and unnecessarily change antimicrobial regimens. 7 This is the most common error in IRIS management.

Do not use corticosteroids for managing increased intracranial pressure in cryptococcal disease—this requires serial lumbar punctures for CSF drainage. 7

Avoid glucocorticoids in patients with Kaposi sarcoma, as they can cause significant disease flares. 7

Do not start ART and TB treatment simultaneously in CNS tuberculosis—this creates impossible-to-evaluate drug interactions and overlapping toxicities. 8