Immune Reconstitution Inflammatory Syndrome

Dysregulated, hyper-inflammatory state that occurs due to an abrupt shift from an anti-inflammatory and immunosuppressed state to a pro-inflammatory state.

Although IRIS can occur in any patient seeing a recovery of suppressed immune function, the disease was originally described in HIV patients commencing HAART who paradoxically developed opportunistic infections, and most of the evidence relates to this population.

Diagnosis requires both improving immunologic function and one of either:

Epidemiology and Risk Factors

IRIS is also known as: immune recovery disease, immune reconstitution disease, immune reconstitution syndrome, immune restoration disease, and immune rebound illness.

Early papers also described it variably as: paradoxical immune activation, immune restitution vitritis (for the ocular variants), paradoxical inflammatory flares, partial immune restoration and pathogen associated inflammatory disease.

Factors influencing incidence and severity of IRIS in HIV include:

  • Severity of CD4 lymphopenia
  • Severity of existing opportunistic infection
  • Certain previous opportunistic infections
    • C. neoformans
      Cryptococcal meningitis.
    • P. jirovecii
      PJP.
    • TB
    • M. avium complex
    • CMV
      • Retinitis
    • HSV
    • VZV
    • Hepatitis
  • HIV viral load prior to commencing HAART
  • Rapid response to HAART

Pathophysiology

Underlying mechanisms are not fully understood, but include a rapid ↑ in immune function including:

  • Rapid change in T-helper responses
  • ↑ Lymphocyte proliferation
  • Pathogen specific delayed-hypersensitivity

Aetiology

IRIS requires both recovery from an immunosuppressed state and a precipitant:

  • Immunosuppressed states
    • Commencement of HAART for HIV
      IRIS occurs most commonly in the first six months of treatment. May occur in up to 30% of patients, though risk is lower if patients commence HAART prior to significant decline in CD4 counts.
    • Withdrawal of immunosuppression in solid organ transplant
    • Post-partum
      Risk in 3-6 weeks post-partum, as the immunosuppressed state of pregnancy resolves.
    • Resolution of Neutropenia
    • Withdrawal of TNF antagonists
  • Precipitant
    • Latent/opportunistic infections
      Classically:
      • TB
      • Mycobacterium avium
      • CMV
      • HSV
      • Hepatitis viruses
      • Cryptococcus neoformans
      • Pneumocystis jirovecii
    • Autoimmune diseases
      SLE, RA.

Clinical Features

Relate to the presenting symptoms of the precipitating illness.

Diagnostic Approach and DDx

Diagnosis is made clinically:

  • Improvement in immunological function
    • From a suitable nadir of immunosuppression
      • In HIV/AIDS a CD4 nadir of <100 cells/µl is usually required (or <200 for TB)
    • Adequate return of function

Differential is broad, and includes:

  • Progression of opportunistic infection for another reason
  • New opportunistic infection
  • Drug toxicity

Management

  • Treat underlying cause
  • Consider altering immunotherapy
  • Symptomatic relief

Specific therapy:

  • Pharmacological
    • Continue or consider adjusting HAART
    • Immunosuppression
      • Corticosteroids
        • Prednisolone 0.5-1mg/kg/day
      • Infliximab

Complications

  • ↑ HAART resistance
  • ↓ HAART compliance

Prognosis

Varies depending on the organ involvement:

  • Majority of cases are mild and self-limiting
  • CNS or pulmonary involvement may lead to death or severe neurological morbidity.

References

  1. Thapa S, Shrestha U. Immune Reconstitution Inflammatory Syndrome. [Updated 2022 May 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. 
  2. Wolfe C. Immune reconstitution inflammatory syndrome. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Accessed December 14, 2022.
  3. Nelson, Ann Marie, Yukari C. Manabe, and Sebastian B. Lucas. “Immune Reconstitution Inflammatory Syndrome (IRIS): What Pathologists Should Know.” Seminars in Diagnostic Pathology, Seminars Issue on HIV-related Disease, 34, no. 4 (July 1, 2017): 340–51. .
  4. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.