What is the difference between paradoxical and unmasking Immune Reconstitution Inflammatory Syndrome (IRIS) in patients with Human Immunodeficiency Virus (HIV) initiating Antiretroviral Therapy (ART)?

Paradoxical vs Unmasking IRIS in HIV Patients

Paradoxical IRIS occurs when a patient on treatment for a known opportunistic infection experiences worsening of symptoms after starting ART, while unmasking IRIS represents the new appearance of a previously subclinical or undiagnosed infection that becomes clinically apparent after ART initiation. 1, 2

Paradoxical IRIS

Definition and Clinical Presentation:

• Paradoxical IRIS manifests as temporary exacerbation of symptoms, signs, or radiographic manifestations in patients who have already been diagnosed and are receiving treatment for an opportunistic infection, occurring after ART initiation despite good clinical and bacteriologic response to antimicrobial therapy 3
• The patient must have experienced initial improvement on treatment for the underlying infection before ART was started 2
• Common manifestations include recurrence of fever, enlarged or new lymph nodes, worsening respiratory symptoms, appearance of cavitation on chest x-ray, expanding CNS lesions, worsening pulmonary infiltrates, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses 3, 1

Key Distinguishing Feature:

• The critical distinction is that the opportunistic infection was already known and under treatment before ART initiation 2
• Clinical deterioration occurs paradoxically despite appropriate antimicrobial therapy and immune reconstitution 3, 4

Unmasking IRIS

Definition and Clinical Presentation:

• Unmasking IRIS represents the progression of subclinical or asymptomatic infection to clinical disease after ART initiation 2
• The infection was not previously diagnosed and becomes clinically apparent only after immune reconstitution begins 1, 2
• Patients present with new symptoms and signs of an opportunistic infection they did not have (or did not know they had) before starting ART 5

Key Distinguishing Feature:

• The infection was undiagnosed and untreated at the time of ART initiation 2
• The newly restored immune system "unmasks" a previously silent infection by mounting an inflammatory response against it 4, 2

Shared Risk Factors

Both forms of IRIS share common risk factors:

• CD4+ count <50 cells/μL at ART initiation significantly increases risk 3, 1
• Early ART initiation (within 2 weeks) after starting treatment for opportunistic infections 3, 1
• Advanced immunosuppression with disseminated disease 1
• High pre-treatment HIV viral load (>5 log10 copies/mL) 6

Timing Considerations

• Both paradoxical and unmasking IRIS typically occur within 3-6 months after initiating ART, though timing varies by pathogen 1, 4
• The syndrome can develop as early as a few days to as late as 6 months post-ART initiation 6

Common Infectious Causes

For Both Types:

• Mycobacterium tuberculosis is the most common cause, presenting with high fevers, worsening respiratory symptoms, and lymphadenopathy 3, 1
• Cryptococcus neoformans manifests with increased intracranial pressure and worsening meningeal inflammation 1
• Mycobacterium avium complex (MAC) causes paradoxical worsening despite appropriate antimycobacterial therapy 1, 5
• Herpes viruses (HSV, VZV) and other opportunistic pathogens 4, 7

Critical Diagnostic Pitfall

The most important clinical distinction is determining whether the patient was already diagnosed and on treatment for the opportunistic infection before ART initiation (paradoxical) versus presenting with a new infection after ART started (unmasking). 2

• Before attributing symptoms to IRIS, you must exclude other causes including treatment failure from drug-resistant organisms, medication non-adherence, drug interactions, and new opportunistic infections 3
• This requires repeat cultures, drug susceptibility testing, and thorough evaluation for alternative diagnoses 3

Management Approach (Same for Both Types)

Mild to Moderate IRIS:

• Continue both ART and antimicrobial therapy unless life-threatening complications develop 1, 8
• Initiate NSAIDs such as ibuprofen for symptomatic relief 3, 1

Severe IRIS:

• Administer prednisone 0.5-1.0 mg/kg/day (or 1.25 mg/kg/day for tuberculosis IRIS) for 2-6 weeks with gradual taper 3, 1, 8
• For life-threatening manifestations (uncontrollable fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, sepsis-like syndrome), hospitalization and corticosteroids are indicated 3
• Drainage may be necessary for worsening pleural effusions or abscesses 3

Rare Occurrence: "Double IRIS"

• Patients can rarely develop both unmasking and paradoxical IRIS simultaneously or sequentially, though this remains uncommon in clinical practice 5
• This occurs when a patient develops unmasking IRIS for one infection while simultaneously experiencing paradoxical IRIS for another previously treated infection 5