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

Infective

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

Auto-immune

Guillain-Barré Syndrome
Sarcoidosis

Malignant

Kaposi's Sarcoma
Non-Hodgkin Lymphoma

TB IRIS

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-years^jiapac1

Defnitions

French et al, 2004

Major criteria^french
- 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 patient^shelburne
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 IRIS^colebunders
- 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

Links

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
French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS. 2004; 18:1615–27. [PubMed: 15280772]
Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother. 2006; 57:167–70. [PubMed: 16354748]
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]
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