Types of IRIS in HIV
There are two distinct types of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients: unmasking IRIS and paradoxical IRIS. 1
The Two Forms of IRIS
1. Unmasking IRIS
- Definition: Occurs when a previously undiagnosed, subclinical opportunistic infection (OI) becomes clinically apparent after initiating antiretroviral therapy (ART)
- The infection was present but asymptomatic before ART
- The recovering immune system "unmasks" the hidden infection with an inflammatory presentation 1, 2
Common pathogens in unmasking IRIS include:
- Disseminated Mycobacterium avium complex (MAC) disease
- Tuberculosis
- Cytomegalovirus retinitis
- Pneumocystis pneumonia
- Kaposi sarcoma 1
2. Paradoxical IRIS
- Definition: Characterized by clinical worsening or recurrence of a previously diagnosed and treated OI after ART initiation
- The patient was already receiving treatment for the infection
- Despite appropriate antimicrobial therapy, symptoms paradoxically worsen due to immune recovery 1, 2
Clinical Context and Timing
Both forms of IRIS typically occur in patients who:
- Initiate ART at low CD4 cell counts (typically <100 cells/μL)
- Experience immune recovery after starting therapy
- Have unmasking IRIS present with a significantly longer time interval between ART initiation and IRIS onset compared to paradoxical IRIS 3
Clinical Significance
Both types of IRIS can cause considerable morbidity and occasionally mortality 1. The most frequently implicated pathogens are mycobacteria (both tuberculosis and MAC), with tuberculosis and cryptococcosis being particularly well-documented causes 1, 4.
Important Clinical Pitfall
Patients can rarely develop both types simultaneously - termed "double IRIS" - where unmasking IRIS of one pathogen occurs concurrently with paradoxical IRIS of another previously treated infection 5. While uncommon, clinicians must remain vigilant for this possibility when managing complex cases.
Risk Stratification
Severe mycobacterial IRIS may present with features overlapping hemophagocytic lymphohistiocytosis (HLH), characterized by:
- Hemoglobin <9.2 g/dL (best pre-ART predictor)
- Hyperferritinemia at IRIS onset
- Elevated CXCL9 and sCD25 levels 6
These patients require more aggressive and prolonged immunosuppressive therapy, typically with corticosteroids for extended durations (median >20 weeks) 6.