Bhatia 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
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?
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
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
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
Antiretroviral Therapy Improves Qualitative and Quantitative Immune Defects

Immune suppression/deficiency
HIV replication
Immune activation
Qualitative/functio nal immune defects

Response to recall antigens
Quantitative immune defects

CD4 counts
Impaired pathogen -specific immunity
OI
Immune Reconstitution
HAART Qualitative/function al immune defects
Reversal of anergy Lymphocyte proliferative capacity
HIV replication
Immune activation
Quantitative immune defects

Redistribution, death (HIV-, activation-induced), production (peripheral expansion and thymic)
Improved pathogenspecific immunity
Improved
immune control
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Migueles, Buenos Aires 2003
ART and the treatment of OIs

Patient with OI Treated with ART
Asymptomatic immune recovery
Return of original symptoms
New Symptoms
Relapse
IRIS
New OI
Medication Side-effects
IRIS
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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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IRIS : Proposed Diagnostic criteria

Immune reconstitution inflammatory syndrome (IRIS)

Risk factors for IRIS

Adapted from French et al, 2004

Risk Factors for IRIS

Antiretroviral Therapy Improves Qualitative and Quantitative Immune Defects

Qualitative/functio nal immune defects

Quantitative immune defects

Impaired pathogen -specific immunity

Quantitative immune defects

Improved pathogenspecific immunity

ART and the treatment of OIs

Asymptomatic immune recovery

Return of original symptoms

ART with subclinical infection

Asymptomatic Immune recovery

Paradoxical Reactions in Tuberculosis

IRIS in TB and HIV Coinfected patients

Associated with restoration of TST reactivity

IRIS - HIV and TB

IRIS - HIV and TB

Treat OI appropriately and try to delay HAART for a 1-2 months

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