What are the signs and symptoms of Immune Reconstitution Inflammatory Syndrome (IRIS) and how is it managed?

Signs and Symptoms of Immune Reconstitution Inflammatory Syndrome (IRIS) and Its Management

Immune Reconstitution Inflammatory Syndrome (IRIS) presents with paradoxical worsening of symptoms and signs of an underlying infection despite appropriate antimicrobial therapy, occurring as a consequence of immune recovery, and should be managed with continued antimicrobial therapy plus anti-inflammatory agents for severe cases. 1

Clinical Presentation of IRIS

IRIS occurs in two main forms:

1. "Unmasking" IRIS: Previously subclinical infections become symptomatic after immune recovery begins 1
2. "Paradoxical" IRIS: Worsening of previously diagnosed and treated infections 1

Common Signs and Symptoms

• Systemic manifestations:

  • High fevers
  • Worsening of general condition
  • Weight loss
  • Fatigue 1

• Respiratory manifestations:

  • Worsening respiratory symptoms
  • Worsening of pulmonary parenchymal infiltrations
  • New or increasing pleural effusions 1

• Lymphatic manifestations:

  • Increase in size and inflammation of involved lymph nodes
  • New lymphadenopathy (peripheral, mediastinal, or abdominal) 1

• Central nervous system manifestations:

  • Expanding CNS lesions
  • Worsening of meningitis symptoms
  • Neurological deterioration 1

• Abdominal manifestations:

  • Abdominal pain
  • Development of intra-abdominal or retroperitoneal abscesses 1

• Other site-specific manifestations:

  • Pericarditis
  • Osteomyelitis
  • Skin or soft tissue abscesses
  • Genital ulcers 1

Risk Factors for IRIS

• Low baseline CD4+ cell count (<50 cells/μL) 1
• High viral load before treatment initiation 1, 2
• Rapid decrease in HIV viral load after starting ART 1
• Early initiation of ART after treatment for opportunistic infections 1
• High antigenic burden of opportunistic infection 2
• Previous opportunistic infections 1

Diagnostic Approach

IRIS is a diagnosis of exclusion. The following should be ruled out before attributing symptoms to IRIS:

• Treatment failure due to drug-resistant infection
• New opportunistic infection
• Drug toxicity
• Malignancy (e.g., non-Hodgkin lymphoma) 1

Key diagnostic features:

• Temporal relationship with ART initiation (typically within days to weeks)
• Evidence of immune recovery (increasing CD4+ count)
• Negative cultures from affected sites (in paradoxical IRIS) 1, 2
• Clinical or radiological evidence of inflammatory response 1

Management of IRIS

Management should be stratified based on severity:

For Mild to Moderate IRIS

• Continue antimicrobial therapy for the underlying opportunistic infection 1
• Continue antiretroviral therapy in most cases 1
• Add non-steroidal anti-inflammatory drugs such as ibuprofen for symptomatic relief 1

For Severe IRIS

• Corticosteroids are the mainstay of treatment for severe IRIS:
  • Prednisone 0.5-1.0 mg/kg/day (or equivalent) for major complications 1
  • For CNS inflammation with increased intracranial pressure, consider dexamethasone at higher doses 1
  • Duration typically 2-6 weeks with gradual taper 1

For Specific Complications

• For worsening pleural effusions or abscesses: Drainage may be necessary 1
• For CNS IRIS with increased intracranial pressure: More aggressive management with corticosteroids and possibly CSF drainage 1
• For TB-IRIS: In a placebo-controlled trial, prednisone 1.25 mg/kg/day significantly reduced the need for hospitalization or surgical procedures 1

Prevention Strategies

• Optimal timing of ART initiation:

  • For patients with CD4+ counts <50 cells/μL: Start ART within 2 weeks of opportunistic infection treatment (except for CNS infections) 1
  • For patients with CD4+ counts ≥50 cells/μL: Consider delaying ART to 8-12 weeks after opportunistic infection treatment 1
  • For patients with tuberculous meningitis: Delay ART until after 8 weeks of antituberculous therapy 1

• Treat opportunistic infections before starting ART when possible to reduce antigenic burden 3

Special Considerations

• CNS-IRIS: Particularly challenging to manage, especially with JC virus infections (PML), as there are no specific antimicrobials and corticosteroids may impair immune control of the infection 3

• Cryptococcal IRIS: Can present with increased intracranial pressure requiring aggressive management; VP shunts may be needed in cases of obstructive hydrocephalus 1

• TB-IRIS: Common with early ART initiation, particularly in those with CD4+ counts <50 cells/μL; may require corticosteroids for management 1

Remember that IRIS does not generally predict overall HIV treatment outcomes, and discontinuation of ART is not recommended as the benefits of treating HIV infection typically outweigh the risks associated with IRIS 4.