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Immune Reconstitution Inflammatory Syndrome (IRIS) is a paradoxical worsening of pre-existing infections or unmasking of subclinical infections, triggered by restoration of immune function in immunocompromised patients, especially following initiation of antiretroviral therapy (ART) in HIV or withdrawal of immunosuppressants in autoimmune conditions.

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https://www.youtube.com/watch?v=p5RIcbLBTQQ

Pathophysiology

IRIS results from:

A rapid recovery of immune responses (within days)
Heightened pro-inflammatory cytokine release
Exaggerated host inflammatory reaction to existing pathogens (e.g., JC virus, Mycobacteria)

![Schematic representing the concept of immune reconstitution inflammatory syndrome (IRIS). Primary diseases in which non-HIV IRIS can occur, potential triggers of the recovery from the immune deterioration state and corresponding IRIS events are illustrated. CMV, cytomegalovirus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TB, tuberculosis; TNF, tumor necrosis factor.

Sueki H, Mizukawa Y, Aoyama Y. Immune reconstitution inflammatory syndrome in non‐HIV immunosuppressed patients. The Journal of Dermatology. 2017;45(1):3-9. doi:10.1111/1346-8138.14074](attachment:34882818-c32b-4c37-a850-d9cb280de633:jde14074-fig-0001-m.jpg)

Schematic representing the concept of immune reconstitution inflammatory syndrome (IRIS). Primary diseases in which non-HIV IRIS can occur, potential triggers of the recovery from the immune deterioration state and corresponding IRIS events are illustrated. CMV, cytomegalovirus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TB, tuberculosis; TNF, tumor necrosis factor.

Sueki H, Mizukawa Y, Aoyama Y. Immune reconstitution inflammatory syndrome in non‐HIV immunosuppressed patients. The Journal of Dermatology. 2017;45(1):3-9. doi:10.1111/1346-8138.14074

Types of IRIS

Type	Description
Paradoxical IRIS	Worsening of a known, treated infection (e.g., TB, cryptococcal meningitis)
Unmasking IRIS	New clinical presentation of a previously subclinical infection
PML-IRIS	Focal inflammation in areas of JC virus–induced demyelination after immune restoration
MS/NMOSD rebound	Disease flare after withdrawal of immunosuppressants (e.g., stopping natalizumab)

Risk Factors

Factor	Details
Advanced immunosuppression	HIV with CD4 < 50 cells/mm³
High pathogen burden	TB, JC virus, Cryptococcus
Rapid immune recovery	Initiation of HAART or withdrawal of natalizumab/rituximab
Early ART during opportunistic infection	May trigger IRIS in AIDS patients

Clinical Features

Typically occurs within days to weeks of immune restoration

Manifestation	Example
Neurologic	PML-IRIS: worsening hemiparesis, visual symptoms, seizures
Respiratory	Worsening pulmonary TB symptoms or new infiltrates
CNS infection	Cryptococcal IRIS: headache, increased ICP, meningitis-like symptoms
Constitutional	Fever, malaise, weight loss, lymphadenopathy

Symptoms mimic infection relapse, but cultures/PCR may be sterile.