IRIS

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IRIS

• Dr Gulshan Bhatia MRCP(UK) DTMH
• Medical Director Santa Clara County TB Clinic
• Division of Infectious Diseases
• Santa Clara County Health and Hospital System

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IRIS Immune Reconstitution Inflammatory Syndrome
Delan McCullagh
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IRIS

• What is it
• How do you recognize it
• Who gets it
• How do you treat it
• Can you avoid it?

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IRIS

• Pathological Inflammatory response and
  paradoxical clinical deterioration as a result of
  HAART related immune recovery or reconstitution
  in HIV infected persons
• Also referred to as Immune Restoration Disease or
  Immune Recovery Syndrome
• 40 of cases reported through 2002 occurred in
  the context of mycobacterial infections and HIV
• Also seen in the context of CMV, Cryptococcal
  Disease and other OIs
• Recognized in HIV seronegative persons
  experiencing immune recovery
• Equivalent to the paradoxical responses seen in
  patients with TB who are HIV negative ( 2-23 ),

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IRIS Proposed Diagnostic criteria

• Major Criteria
• Atypical presentation of OI or tumours in pts on
  HAART
• Exaggerated Inflammatory response
• Fever, painful lesions
• Atypical Inflammatory Response In affected
  tissues
• Granulomas,Suppuration,Necrosis
• Progression of organ dysfunction or enlargement
  of pre existing lesions after definite clinical
  improvement with specific OI therapy and
  exclusion of toxicity prior to starting HAART
• Tuberculomas, Worsenng Kaposis, New onset CMV
  retinitis or CMV uveitis,
• Reduction in Plasma HIV RNA by gt 1 log 10 copies
  /ml
• Minor Criteria
• Increase in CD4
• Increase in specific immune response to the
  pathogen
• Spontaneous resolution of disease without
  specific therapy with continued anti retroviral
  therapy

French et al 2004
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Immune reconstitution inflammatory syndrome (IRIS)

• Case Definition
• A paradoxical deterioration in clinical status
  after initiating highly active antiretroviral
  therapy (HAART) attributable to the recovery of
  the immune response to latent or subclinical
  infectious or non-infectious processes

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IRIS

• Worsening of original disease
• No evidence of bacteriological relapse or
  recurrence
• May have high fevers must exclude concomitant
  disease
• Related to start of ARV not to OI Rx
• Often prolonged
• NB not always the case

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Risk factors for IRIS
Host susceptibility
Microbial antigens
CD4lt 50
Adapted from French et al, 2004
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Risk Factors for IRIS

• Advanced HIV disease - CD4 counts lt50
• Unrecognized Opportunistic infection or high
  microbial burden
• Early initiation of HAART
• ARV naïve
• Immune recovery with rapid fall in HIV RNA
• Genetic factors which can be pathogen specific
• Mycobacteria TNF-3082, IL6 174G
• Herpes virus - HLA- B44, -A2, -DR2,
  IL12B3UTR1

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Antiretroviral Therapy Improves Qualitative and
Quantitative Immune Defects
Migueles, Buenos Aires 2003
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ART and the treatment of OIs
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ART with subclinical infection
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Paradoxical Reactions in Tuberculosis

• Well recognized phenomenon for decades
• Lymphadenitis (12 25 ),
• 1 6 months post initiation of therapy
• Pulmonary disease, central nervous system-new
  tuberculomas, fevers, ARDS
• 75 have worsening of original lesions
• Often required steroids
• Due to intensification of the cell mediated
  immune response and conversion of TST
• Concomitant rise in TNF levels

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IRIS in TB and HIV Coinfected patients

• Reported initially around 1998
• Paradoxical reactions have been seen in TB prior
  to HIV thus IRIS phenomena in coinfected pts may
  have been under reported
• 29 - 36 coinfected pts on TB Rx and HAART
  develop clinically apparent IRIS
• Radiologic deterioration in 46

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Paradoxical reactions or IRIS in Tuberculosis
andHIV Co-infection

• More frequent in HIV than HIV patients
• 36 (12/33) Narita M, et al. AJRCCM 1998158157.
• 32 (6/19) Navas E, et al. ICAAC, 1999.
• 6 (6/82) Wendel K, et al Chest
  2001120193.
• 30.2 (26/86) Shelburne S, et al AIDS 2005
  19399
• Associated with restoration of TST reactivity

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IRIS TB HIV

• 27 papers 86 cases
• Majority of cases of IRIS occurred in pts who
  were being treated for TB when HAART initiated
• Duration of TB Rx median 2 months prior to
  IRIS presentation
• Duration of HAART median 1month prior to IRIS
  presentation
• 50 with undetectable HIV RNA at time of IRIS
• Median CD4 205 from nadir of 51 ( 26 103 )

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IRIS - HIV and TBreported cases in the literature

• Fever
• Worsening Lymphadenopathy (71)
• Increasing respiratory distress
• Deterioration of parenchymal lung disease (28)
• New effusions, ascites, abscesses
• Hypercalcaemia, ARF

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Management of IRIS
NO GOOD DATA

• Diagnostic Dilemmas
• Immune Reconstitution Syndrome
• Relapse
• Drug Toxicity
• New Disease Process

• Therapeutic Dilemmas
• Stop or continue ART
• Stop or change OI therapy
• Add immunosuppressives

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IRIS - HIV and TB

• THERAPY
• HAART interrupted in 15 of cases
• Adjunctive therapy
• Corticosteroids (26)
• Thalidomide
• Pentoxyfylline
• NSAIDS
• Surgery to drain abscesses
• Supportive care

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Prevention

• Screen all patients with advanced HIV disease for
  underlying or subclinical infections before
  starting HAART
• Significant problem in developing world
• Treat OI appropriately and try to delay HAART for
  a 1-2 months
• Risk of other OI and continued immunosuppression
  vs IRIS
• Recognize that the highest risk occurs in pts
  with CD4lt50 and HIV viral load gt100 000 who have
  a rapid response to ARV