Immune Reconstitution Inflammatory Syndrome

Immune Reconstitution Inflammatory Syndrome (IRIS) is defined as worsening of a preexisting untreated or partially treated opportunistic infection or appearance of a previously unrecognized opportunistic infection following immune restoration of an immunocompromised individual. It is most commonly seen in HIV infected individuals following initiation of effective combination anti-retroviral therapy (cART). But it may also be seen in other causes of immunocompromised status including organ donor recipients

Types of IRIS

Paradoxical IRIS

Worsening of a previously treated or partially treated opportunistic infection

Unmasking IRIS

Manifestation of a previously unrecognized opportunistic infection

Etiological Classification


  • Bacterial
    • Mycobacterium Tuberculosis
    • Mycobacterium Avium Complex
    • Whipple's Disease
  • Viral
    • Cytomegalovirus
    • Viral Hepatitis
    • Progressive Multifocal Leucoencephalopathy (PMLE)
    • Herpes Zoster
  • Fungal
    • Pneumocystis
    • Cryptococcus
    • Histoplasma


  • Guillain-Barré Syndrome
  • Sarcoidosis


  • Kaposi's Sarcoma
  • Non-Hodgkin Lymphoma


Tuberculosis associated IRIS is the condition in which tubercular infection which has been previously unrecognized or which has been well-responding to treatment, but shows worsening of clinical condition after initiation of anti-retroviral therapy (ART). The symptoms may include —

  • Fever
  • Cough
  • Lymphadenopathy
  • Pleural effusion
  • X-ray abnormalities

TB IRIS is more common in the following conditions —

  • Advanced AIDS (CD4 < 50)
  • Disseminated TB / Extra-Pulmonary TB
  • Good response to ART
  • Early ART initiation

TB IRIS is usually seen within 1-3 months of ART initiation. It is usually self-limiting and mortality is rare. In India the incidence of TB IRIS is around 51.3/person-yearsjiapac1


French et al, 2004

  • Major criteriafrench
    • Atypical presentation of OI in ART responsive patient
      • Localized disease
      • Exaggerated inflammation
      • Atypical inflammation
      • Worsening after improvement with specific therapy after ART excluding toxicity / new diagnosis
    • Decreased plasma HIV RNA by > 1log10 copies/ml
  • Minor criteria
    • Increased CD4 after ART
    • Increased immune response to pathogen
    • Spontaneous resolution

Diagnosis requires any of the following —

  • Two major criteria
  • One major + two minor criteria

Shelburne et al, 2006

  • HIV infected patientshelburne
  • Receiving effective ART as evidenced by
    • Decreased HIV RNA from baseline
    • Increased CD4 from baseline
  • Consistent clinical symptoms
  • Inconsistent clinical course

Colebunders et al, 2006

  • Suspected TB IRIScolebunders
    • Initial clinical response to TB treatment
    • New clinical symptoms (no other identifiable cause)
      • Persistent fever, worsening dyspnea, stridor, increased lymph node size, abscess, abdominal pain, retroperitoneal lymph nodes (RPLN), central nervous system symptoms etc.
    • Adequate adherence to ART and ATD
  • Confirmed TB IRIS
    • Worsening radiologic findings
      • Intrathoracic lymphadenopathy, pulmonary infiltrates, pleural effusion, RPLN, hepatosplenomegaly
    • Response to ART, evidenced by any of the following
      • Virological response
      • Increased CD4
      • Tuberculin test negative to positive
      • Adequate adherence to ATD and ART
    • Exclusion of other conditions including
      • ATD failure
      • Concomitant infections, tumors or allergies
IRIS unmasking
Pre-ART and Post-ART chest x-ray showing unmasking TB IRIS (mediastinal lymph nodes)

Proposed definitions in resource limited settings

These definitions were proposed in a meeting at Kampala, Uganda in November, 2006 which was attended by 97 researchers from 16 countries on 6 continents. They were published in a paper in Lancet Infectious Disease in August, 2008.lancet1

Paradoxical TB IRIS

  • Antecedent criteria, requires both
    • TB diagnosis before starting ART
    • Initial response to ATD
  • Clinical criteria
    • Within 3 months of ART
    • One major or two minor (new/worsening)
    • Major criteria
      • Lymph node, abscess, focal involvement
      • Radiological finding
      • CNS TB
      • Serosistis
    • Minor criteria
      • Constitutional symptoms
      • Respiratory symptoms
      • Abdominal pain with peritonitis, hepatomegaly, splenomegaly or RPLN
  • Exclusion criteria
    • ATD failure
    • Poor adherence to ATD
    • Another OI or neoplasm
    • Drug toxicity or reaction

ART associated TB

  • Not receiving ATD when ART is initiated
  • Active TB diagnosed after ART initiation
  • TB diagnosis fulfils WHO criteria

Unmasking TB IRIS

  • Not receiving ATD when ART is initiated
  • Presents with active TB within 3 months of ART
  • And, one of the following
    • Heightened clinical manifestations
    • Paradoxical reaction after ATD

Management of TB IRIS

  • Continuation of ATD and ART
  • NSAIDS for symptomatic management
  • Corticosteroids for severe manifestations
  • Prednisolone 1mg/kg/day, in tapering dose


  1. Nisha Thambuchetty, Kayur Mehta, Karthika Arumugam, Umadevi G. Shekarappa, Jyothi Idiculla and Anita Shet. The Epidemiology of IRIS in Southern India: An Observational Cohort Study. Journal of the International Association of Providers of AIDS Care. 2017 Sep-Oct; 16(5): 475–480
  2. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS. 2004; 18:1615–27. [PubMed: 15280772]
  3. Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother. 2006; 57:167–70. [PubMed: 16354748]
  4. Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynen L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis. 2006; 10:946–53. [PubMed: 16964782]
  5. Graeme Meintjes, Stephen D Lawn, Fabio Scano, Gary Maartens, Martyn A French, William Worodria, Julian H Elliott, David Murdoch, Robert J Wilkinson, Catherine Seyler, Laurence, John, Maarten Schim van der Loeff, Peter Reiss, Lut Lynen, Edward N Janoff, Charles Gilks and Robert Colebunders. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infectious Disease. 2008 August ; 8(8): 516–523


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