A 32-year-old man from Delhi presents with a 3-month history of progressive fatigue, fever, and oral candidiasis. He is newly diagnosed with HIV-1 infection with a CD4 count of 85 cells/µL and viral load of 450,000 copies/mL. He is started on a combination antiretroviral regimen. Two weeks after initiating therapy, he develops severe fever, lymphadenopathy, and hepatosplenomegaly. His CD4 count has risen to 120 cells/µL. Which of the following is the most likely diagnosis?

Explanation

## Immune Reconstitution Inflammatory Syndrome (IRIS) **Key Point:** IRIS is a paradoxical clinical deterioration that occurs in the first weeks to months after initiating antiretroviral therapy (ART) in patients with severe immunosuppression (CD4 <50 cells/µL), characterized by an exaggerated inflammatory response to previously controlled or subclinical infections. ### Clinical Features of IRIS - **Timing:** 2–12 weeks after ART initiation (most commonly 2–4 weeks) - **CD4 nadir:** Typically occurs in patients with CD4 <50 cells/µL at baseline - **Presentation:** Fever, lymphadenopathy, hepatosplenomegaly, worsening of pre-existing opportunistic infections (OIs) - **Paradox:** CD4 count rises, but clinical condition temporarily worsens ### Pathophysiology 1. ART suppresses viral replication → CD4 count recovery begins 2. Restored immune function mounts exaggerated inflammatory response to: - Antigens from previously controlled pathogens (MAC, CMV, TB, PCP) - Residual pathogen burden - Immune dysregulation and elevated pro-inflammatory cytokines ### Types of IRIS | Type | Mechanism | Examples | |------|-----------|----------| | **Unmasking IRIS** | Immune response to previously undiagnosed OI | TB, PCP, CMV, MAC | | **Paradoxical IRIS** | Worsening of known OI despite ART | TB-IRIS (most common) | ### Management - **Mild IRIS:** Continue ART; supportive care; NSAIDs - **Severe IRIS:** Corticosteroids (prednisone 1–2 mg/kg/day, taper over 4–12 weeks) - **Do NOT discontinue ART** — this worsens outcomes - Treat underlying OI if present **High-Yield:** IRIS is a diagnosis of exclusion — must rule out treatment failure, drug toxicity, and new/progressive OIs before attributing symptoms to IRIS. **Clinical Pearl:** The CD4 count *rising* while symptoms *worsen* is the hallmark of IRIS and distinguishes it from treatment failure or new OI. [cite:Harrison 21e Ch 197]