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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 Delan McCullagh

IRIS
Immune Reconstitution Inflammatory Syndrome
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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 Kaposi’s, New onset CMV retinitis or
CMV uveitis,
– Reduction in Plasma HIV RNA by > 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

Microbial Host
antigens susceptibility

CD4< 50

Adapted from French et al, 2004 8

 Risk Factors for IRIS
• Advanced HIV disease - CD4 counts <50
• 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-308*2, IL6 – 174*G
– Herpes virus - HLA- B44, -A2, -DR2, IL12B3’UTR*1

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 Antiretroviral Therapy Improves
Qualitative and Quantitative Immune
Defects
Immune suppression/deficiency

Qualitative/functio Quantitative Impaired

immune defects pathogen
HIV Immune nal immune defects
OI
-specific
replication activation Response to recall CD4 counts
antigens
immunity

Immune Reconstitution
HAART

Qualitative/function Quantitative immune

al immune defects defects Improved Improved
HIV Immune pathogen- immune
Reversal of anergy Redistribution, death (HIV-, specific
replication activation control
activation-induced),
Lymphocyte immunity
production (peripheral
proliferative capacity
expansion and thymic)

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Migueles, Buenos Aires 2003
 ART and the treatment of OIs

Patient with OI
Treated with
ART

Asymptomatic Return of
New
immune original
Symptoms
recovery symptoms

Medication
Relapse IRIS New OI IRIS
Side-effects

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 ART with subclinical infection
ART in
advanced
HIV disease

Asymptomatic
Immune IRIS
recovery
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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 and
HIV Co-infection
• More frequent in HIV+ than HIV – patients

– 36% (12/33) Narita M, et al. AJRCCM 1998;158:157.

– 32% (6/19) Navas E, et al. ICAAC, 1999.
– 6% (6/82) Wendel K, et al Chest 2001;120:193.
– 30.2% (26/86) Shelburne S, et al AIDS 2005; 19:399

• 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 TB
reported 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 Therapeutic Dilemmas

• Immune • Stop or continue ART
Reconstitution • Stop or change OI
Syndrome therapy
• Relapse • Add
• Drug Toxicity immunosuppressives
• New Disease
Process

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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

CD4<50 and HIV viral load >100 000 who have a
rapid response to ARV

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