What is the difference between paradoxical and unmasking Immune Reconstitution Inflammatory Syndrome (IRIS) in patients with Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS)?

Difference Between Paradoxical and Unmasking IRIS

Paradoxical IRIS occurs when a known, previously treated opportunistic infection worsens after starting ART, while unmasking IRIS occurs when ART reveals a previously undiagnosed, subclinical infection that becomes clinically apparent. 1, 2

Paradoxical IRIS

Paradoxical IRIS represents clinical deterioration of a recognized and treated infection after ART initiation. 3, 4

Key Defining Features:

• The opportunistic infection was diagnosed and treatment initiated before ART 2, 4
• Clinical worsening occurs despite appropriate antimicrobial therapy that should be controlling the infection 1, 5
• Manifests as progression or appearance of new clinical and/or radiographic disease in patients with previously recognized infection 4

Common Clinical Presentations:

• Tuberculosis paradoxical IRIS presents with high fevers, worsening respiratory symptoms, enlarging or new lymphadenopathy, expanding CNS lesions, worsening pulmonary infiltrates, new or increasing pleural effusions, and intra-abdominal or retroperitoneal abscesses 3, 1
• Cryptococcal paradoxical IRIS manifests with increased intracranial pressure and worsening meningeal inflammation despite adequate antifungal therapy 1, 6
• MAC paradoxical IRIS shows fever, lymphadenitis, or other inflammatory manifestations despite appropriate antimycobacterial therapy 1

Timing and Risk Factors:

• Typically occurs within 3-6 months after ART initiation, though timing varies by pathogen 1
• Higher risk with CD4 count <50 cells/μL at ART initiation 1
• Early ART initiation (within 2 weeks) after starting opportunistic infection treatment increases risk 1
• In the STRIDE study, paradoxical tuberculosis IRIS occurred in 7.6% of patients, with 69% being mild-moderate severity and 31% requiring hospitalization 3

Unmasking IRIS

Unmasking IRIS occurs when ART initiation reveals a previously undiagnosed, subclinical opportunistic infection that becomes clinically apparent. 3, 2, 4

Key Defining Features:

• The infection was not recognized or treated before ART initiation 2, 4
• Represents progression of incubating, subclinical disease to overt clinical manifestations 3
• The infection becomes "unmasked" as immune function recovers 5, 6

Clinical Distinction:

• Unmasking IRIS involves tuberculosis symptoms and clinical manifestations becoming more pronounced after ART initiation in patients with previously unrecognized disease 3
• Whether this represents normal progression of untreated infection versus true IRIS remains debated 3
• Can reveal unexpected pathogens such as EBV-associated B-cell lymphoma or disseminated MAC 5, 6

Diagnostic Challenge:

• Requires excluding other causes including treatment failure from drug-resistant organisms or entirely new opportunistic diseases such as non-Hodgkin lymphoma 3
• The diagnosis is confirmed using clinical and laboratory data after excluding differential diagnoses and concomitant infections 5

Critical Management Differences

For Paradoxical IRIS:

• Continue both ART and antimicrobial therapy unless life-threatening complications develop 1
• For mild-moderate cases, initiate NSAIDs such as ibuprofen for symptomatic relief 1
• For severe manifestations, administer prednisone 0.5-1.0 mg/kg/day for 2-6 weeks with gradual taper 1, 7
• In tuberculosis IRIS, prednisone 1.25 mg/kg/day significantly reduced hospitalization and surgical intervention needs 1

For Unmasking IRIS:

• Initiate appropriate antimicrobial therapy for the newly diagnosed infection 5
• Continue ART while treating the unmasked infection 1
• Apply same anti-inflammatory strategies as paradoxical IRIS if severe inflammatory response develops 1

Prevention Strategies

• Screen and treat opportunistic infections before initiating ART when feasible to reduce paradoxical IRIS risk 1
• For patients with CD4 <50 cells/μL without CNS tuberculosis, start ART within 2 weeks of tuberculosis treatment to balance mortality reduction against IRIS risk 1, 7
• For patients with CD4 ≥50 cells/μL, initiate ART at 8-12 weeks after starting tuberculosis treatment 1
• For cryptococcal meningitis, defer ART initiation until 4-6 weeks after starting antifungal therapy to reduce IRIS risk 7

Important Clinical Pitfall

Both forms can occur simultaneously in the same patient - rare "double IRIS" cases have been reported where patients develop both unmasking IRIS (e.g., MAC) and paradoxical IRIS (e.g., cryptococcal meningitis) concurrently 6. This underscores the importance of maintaining high clinical suspicion for multiple opportunistic infections in severely immunosuppressed patients initiating ART.