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Immune Reconstitution Inflammatory
Syndrome (IRIS)
Clinical Diagnosis/Features
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IRIS is a well recognized (but unknown MOA) condition
seen in AIDS or other immunosuppressed conditions
resulting in an overwhelming response to antigen as the
immune system begins to recover
Most commonly occurs with TB, M. avium, Cryptococcus,
CMV, VZV, EBV, and viral hepatitis
Up to 50% of patients with past history of treated
cryptococcus are at risk of developing IRIS after
initiation of ART
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Risk factors for cryptococcal IRIS include low initial CD4
HIV infection revealed by cryptococcal infection
Fungemia
Rise in absolute CD4 count not recognized as a risk factor
Clinical Diagnosis/Features
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Two types, early vs. late IRIS
Early type seen within the first few months of ART
representing response to occult infection
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Late “paradoxical” type reaction seen in up to 3 years
Occurs after successful past treatment
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Characterized by subclinical opportunistic infection
Unmasked by ART
Infectious/active pathogens are present on cultures
Symptomatic relapse after successful past treatment
Antigen driven immune activation
Sterile cultures
Either form can be related to serious morbidity and
mortality if not addressed and treated
Note that IRIS should not represent failure to ART, quite
the contrary, can be a marker of successful response to
ART
Immunopathogenesis
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Maintenance of immune
homeostasis is partially
regulated by CD4+CD25+ Tregulatory cells (T-regs)
Immunopathogenesis
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Immune dysregulation in
IRIS may occur from:
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Absence of functional Tregs
Lack of proper
costimulation (CTLA-4) to
self limit immune
responses
Biased cytokine profiles
from a limited pool of
adaptive immune cells
(anti-inflammatory vs.
inflammatory cytokine
balance)
Treatment
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Overall goal is to reduce antigenic
burden and address immunologic
response
Empiric treatment for inciting antigen is
presently recommended and directed at
pathogen of interest
Some studies argue for treatment of
aberrant immune response with
corticosteroids
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No studies yet to address use of other antiinflammatory methods such as
immunomodulation or use of biologics
References
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French, M. Immune reconstitution
inflammatory syndrome: A reappraisal.
Clinical Infectious Diseases. 2009; 48:101-7
Bonham, S., et al. Biomarkers of HIV immune
reconstitution inflammatory syndrome.
Biomark Med. 2008; 2(4):349-361
Sungkanuparph, S., et al. Timing of
Cryptococcal immune reconstitution
inflammatory syndrome after anti-retroviral
therapy in patients with AIDS and
cryptococcal meningitis. Acquired Immune
Deficiency Syndrome. 2007; 45:595-6
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