HIV Immune Reconstitution Inflammatory Syndrome
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Direct answer
Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical worsening of a known opportunistic infection — or the abrupt unmasking of a subclinical one — within 2 to 8 weeks (occasionally months) of starting antiretroviral therapy, as the recovering immune system generates inflammatory responses against antigens it had been too depleted to fight. In India the commonest culprit is tuberculosis, followed by cryptococcal meningitis, Pneumocystis pneumonia, herpes zoster, CMV disease and Kaposi sarcoma. Management is to treat the opportunistic infection, continue ART in most cases, and add corticosteroids (for example prednisolone 0.5–1.5 mg/kg per day tapering over weeks) for moderate-to-severe inflammatory disease, with ART interruption reserved for life-threatening IRIS.
What you must remember
- Two flavours: paradoxical IRIS (known, treated OI worsening after ART) and unmasking IRIS (new OI presenting floridly as immunity returns) — the distinction is standard exam phrasing.
- Timing window: typically 2–8 weeks after ART initiation, earlier with integrase-inhibitor-based regimens because of rapid viral load fall.
- Highest-risk profile: baseline CD4 below 50–100 cells/microlitre, high viral load, dissemination of the OI, and short interval between starting OI treatment and starting ART.
- TB-IRIS is the Indian prototype: fever returning, lymph nodes enlarging and maturing, lesions of disseminated TB flaring, or cold abscesses appearing on ART.
- Steroid evidence: the Meintjes trial showed prednisolone around 1.5 mg/kg for 2 weeks then 0.75 mg/kg for 2 weeks reduced paradoxical TB-IRIS severity — the number to quote.
- Cryptococcal IRIS is the dangerous one: raised intracranial pressure mimics treatment failure; manage pressure plus steroids cautiously and never stop antifungals abruptly.
- ART timing rules that trade off against IRIS: in TB coinfection start ART within 2 weeks of TB treatment when CD4 is under 50; in cryptococcal meningitis delay ART about 4–6 weeks to avoid fatal IRIS.
How to work through a ward scenario
A 29-year-old with CD4 40 and disseminated tuberculosis started antitubercular therapy; four weeks later ART (tenofovir-lamivudine-dolutegravir) was added; ten days after that he returns with return of evening fever, expanding cervical nodes, one of which is fluctuant, and new respiratory symptoms. Reason in sequence. First, define the event: worsening of a diagnosed, on-treatment OI within weeks of ART is paradoxical TB-IRIS by definition — but confirm it is not something else: check adherence, send sputum for smear and, where feasible, Xpert for rifampicin resistance, blood culture, and C-reactive protein; IRIS is inflammatory, not microbiological failure, so smears may show scanty or no bacilli. Second, grade severity: enlarging nodes with a cold abscess that needs aspiration is moderate disease; respiratory compromise or pericardial involvement would be severe. Third, treat: continue both ATT and ART in moderate disease, aspirate the abscess for comfort and diagnosis, and add prednisolone 1.5 mg/kg for two weeks tapering over the next two to four weeks per the Meintjes-derived schedule, with gastric and glucose precautions. Fourth, reassure and monitor: most TB-IRIS settles over 4–8 weeks without stopping ART; stopping ART is reserved for life-threatening cases because interruption breeds resistance. Fifth, learn the prevention for the next patient: this man's CD4 of 40 made IRIS near-inevitable — earlier HIV diagnosis and timely ART starting at higher CD4 counts is the only real prophylaxis.
Where students slip
The trap is labelling every post-ART fever as IRIS, which excuses sloppy thinking: differential always includes OI treatment failure, drug resistance, a new OI, drug fever from ATT or ART, and sepsis — the exam stem usually plants one of these. The second slip is stopping ART reflexively; the disciplined answer is continue, treat the OI, add steroids for severity. The third is prophylaxis confusion: there is no drug that reliably prevents IRIS in general (prophylactic-prednisolone evidence is limited), so the prevention mark belongs to early ART initiation and, for cryptococcal disease, the deliberate delay of ART.
Frequently asked questions
What distinguishes unmasking from paradoxical IRIS?
Paradoxical IRIS worsens an already-diagnosed opportunistic infection on treatment after ART starts; unmasking IRIS reveals a previously occult infection with florid inflammation as immunity recovers.
What is the typical time window for IRIS after starting ART?
Two to eight weeks in most cases, though presentations as late as six months occur, particularly with integrase-inhibitor regimens that suppress viral load quickly.
When are corticosteroids indicated in IRIS?
For moderate-to-severe paradoxical IRIS, chiefly tuberculosis: prednisolone about 1.5 mg/kg daily for 2 weeks tapering over the next weeks, grounded in the Meintjes randomised trial.
How does cryptococcal IRIS manifest and how is it managed?
Recurrent headache and raised intracranial pressure after ART despite antifungal therapy; managed with therapeutic lumbar punctures, continued antifungals, cautious steroids, and rarely ART interruption in life-threatening cases.
Why is ART delayed in HIV-associated cryptococcal meningitis?
Early ART precipitates fatal central nervous system IRIS; starting ART about 4–6 weeks into antifungal therapy balances that risk against uncontrolled HIV disease.