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

DelanMcCullagh

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?

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 > 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

Frenchetal2004
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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

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
antigens

Host
susceptibility

CD4< 50

Adapted from French et al, 2004

Risk Factors for IRIS

Advanced HIV disease - CD4 counts <50
Unrecognized Opportunistic infection or high
microbial burden
Early initiation of HAART
ARV nave
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,
IL12B3UTR*1
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Antiretroviral Therapy Improves

Qualitative and Quantitative Immune
Defects
Immune suppression/deficiency

HIV
replication

Immune
activation

Qualitative/functio
nal immune defects

Quantitative
immune defects

Response to recall
antigens

CD4 counts

Impaired
pathogen
-specific
immunity

OI

Immune Reconstitution
HAART

HIV
replication

Immune
activation

Qualitative/function
al immune defects

Quantitative immune
defects

Reversal of anergy

Redistribution, death (HIV-,

activation-induced),
production (peripheral
expansion and thymic)

Migueles, Buenos Aires 2003

Lymphocyte
proliferative capacity

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Improved
pathogenspecific
immunity

Improved

immune
control

ART and the treatment of OIs

Patient with OI
Treated with
ART
Asymptomatic
immune
recovery

Relapse

Return of
original
symptoms

New
Symptoms

IRIS

New OI

Medication
Side-effects

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IRIS

ART with subclinical infection

ART in
advanced
HIV disease
Asymptomatic
Immune
recovery

IRIS
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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 systemnew 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
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

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