What is Immune Reconstitution Inflammatory Syndrome (IRIS)?

What is Immune Reconstitution Inflammatory Syndrome (IRIS)?

Immune Reconstitution Inflammatory Syndrome (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

Core Definition and Pathophysiology

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

• Paradoxical IRIS: Clinical deterioration of a known, treated opportunistic infection after starting ART, despite appropriate antimicrobial therapy 1
• Unmasking IRIS: Emergence of a previously subclinical or unrecognized infection that becomes clinically apparent after ART initiation 1, 3

The underlying mechanism involves restoration of pathogen-specific immune responses with excessive production of inflammatory cytokines (particularly TNF-α and IFN-γ), leading to a "cytokine storm" that causes tissue damage and clinical deterioration. 2, 4

Timing and Incidence

IRIS typically occurs within 3 to 6 months after initiating ART, though timing varies by the underlying pathogen. 1 The overall incidence ranges from 6% to 39% depending on the population studied and the burden of opportunistic infections. 1, 2

Major Risk Factors

The following characteristics significantly increase IRIS risk:

• CD4+ count <50 cells/μL at ART initiation 1
• High antigenic burden from active opportunistic infections 5
• Early ART initiation (within 2 weeks) after starting treatment for opportunistic infections 1
• Robust virologic response with rapid HIV viral load suppression 5
• Advanced immunosuppression with disseminated disease 1, 6

Common Infectious Manifestations

The most frequently implicated pathogens include:

• Mycobacterium tuberculosis: Presents with high fevers, worsening respiratory symptoms, enlarging lymph nodes, expanding CNS lesions, worsening pulmonary infiltrates, new or increasing pleural effusions, and intra-abdominal or retroperitoneal abscesses 1
• Cryptococcus neoformans: Manifests with increased intracranial pressure and worsening meningeal inflammation 6
• Mycobacterium avium complex (MAC): Shows paradoxical worsening despite appropriate antimycobacterial therapy 1
• Cytomegalovirus (CMV): Can cause retinitis or other end-organ disease 1, 2
• Kaposi sarcoma: Characterized by marked lesional swelling, increased tenderness, and peripheral edema 1
• Pneumocystis jirovecii: May worsen despite appropriate treatment 1
• Varicella zoster virus and other herpesviruses 2

Critical Diagnostic Considerations

IRIS is a diagnosis of exclusion. Before attributing clinical deterioration to IRIS, you must systematically rule out:

• Treatment failure from drug-resistant organisms (especially drug-resistant tuberculosis) 1
• New opportunistic infections (such as non-Hodgkin lymphoma) 1
• Medication non-adherence 6
• Drug toxicity or interactions 1

The diagnosis requires documented immune reconstitution (rising CD4 count, declining HIV viral load) concurrent with clinical worsening that cannot be explained by the natural progression of untreated disease or treatment failure. 1, 5

Management Principles

General Approach

For most patients with mild to moderate IRIS:

• Continue both ART and antimicrobial therapy unless life-threatening complications develop 1
• Initiate nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for symptomatic relief 1
• Provide supportive care including drainage of abscesses or pleural effusions when indicated 1

Corticosteroid Therapy

For severe IRIS manifestations, administer prednisone 0.5-1.0 mg/kg/day (or equivalent) for 2-6 weeks with gradual taper. 6 Specific evidence supports corticosteroids in:

• TB-IRIS: Prednisone 1.25 mg/kg/day significantly reduces hospitalization and need for surgical intervention 1
• Cryptococcal IRIS: Short-term corticosteroids (prednisone 20-40 mg daily for 4-8 weeks) reduce symptoms and morbidity 1, 6
• MAC-IRIS: Corticosteroids for moderate to severe symptoms that don't improve with NSAIDs 1

Critical Exception: Kaposi Sarcoma

Glucocorticoids are absolutely contraindicated in Kaposi sarcoma-associated IRIS because they stimulate Kaposi sarcoma spindle cells and can cause life-threatening disease exacerbation. 1 ART should not be delayed or discontinued unless life-threatening IRIS develops. 1

Special Consideration: CNS Tuberculosis

For patients with tuberculous meningitis and HIV infection, delay ART initiation until 8 weeks after starting antituberculosis therapy because early ART (within 2 weeks) increases adverse events and mortality from severe neurological IRIS complications. 1

Prevention Strategies

To minimize IRIS risk:

• Screen and treat opportunistic infections before initiating ART when feasible 1
• For patients with CD4 <50 cells/μL without CNS tuberculosis, start ART within 2 weeks of tuberculosis treatment to balance mortality reduction against IRIS risk 1
• For patients with CD4 ≥50 cells/μL, initiate ART at 8-12 weeks after starting tuberculosis treatment 1
• For cryptococcal meningitis, defer ART for 4-6 weeks after starting antifungal therapy 6

Prognosis

Despite causing considerable morbidity and occasional mortality, most IRIS episodes resolve with appropriate management and do not worsen long-term outcomes for HIV infection or the underlying opportunistic infection. 1 The development of IRIS may actually indicate a favorable immunologic response to ART with improved survival prospects. 7