Immune Reconstitution Inflammatory Syndrome (IRIS)

Immune Reconstitution Inflammatory Syndrome (IRIS) is a clinical worsening of an opportunistic infection or autoimmune condition that occurs as a result of the rapid restoration of pathogen-specific immunity following ART initiation in HIV-infected patients with advanced immunosuppression. The syndrome reflects a dysregulated immune response—after the immune system was unable to mount any inflammatory response, it suddenly responds to existing antigens (latent or treated infections), generating exaggerated inflammation and tissue damage.

IRIS is classified into two main types: paradoxical IRIS (worsening of an opportunistic infection that was diagnosed and treated before ART initiation, such as new pulmonary infiltrates in TB-IRIS or worsening cryptococcal meningitis with elevated intracranial pressure), and unmasking IRIS (clinical manifestation of a previously subclinical opportunistic infection, such as new disseminated MAC, CMV retinitis, or PML appearing weeks after ART start). The most common pathogens involved are Mycobacterium tuberculosis, Cryptococcus neoformans, Mycobacterium avium complex, CMV, JC virus (PML), Pneumocystis jirovecii, hepatitis B/C, herpes zoster, and Kaposi sarcoma.

Risk factors include very low pre-ART CD4 count (<100 cells/μL, especially <50), high baseline HIV viral load, rapid CD4 recovery, untreated opportunistic infection at ART start, and shorter interval between OI treatment and ART initiation. Diagnosis requires temporal association with ART initiation (typically 2-12 weeks), exclusion of treatment failure, drug toxicity, or new opportunistic infection unrelated to immune restoration. Management includes continuing ART unless life-threatening, optimizing OI treatment, anti-inflammatory therapy with NSAIDs or corticosteroids (prednisone 1-1.5 mg/kg for severe cases—proven benefit in TB-IRIS), and supportive care. Prevention involves screening for and treating opportunistic infections before ART, using ART regimens carefully chosen to minimize drug-drug interactions, and timing ART initiation appropriately (e.g., delay 4-8 weeks for cryptococcal meningitis, immediate for TB without CNS involvement).