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Immune Reconstitution Inflammatory Syndrome
Dr.G.Manoharan
Medical Director, I-TECH India
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Learning Objectives
Describe the historical picture of IRIS
Review case studies and illustrations related to IRIS
Define diagnostic criterias for IRIS
Explain clinical spectrum & differential diagnosis of IRIS
Discuss management of IRIS
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Historical Picture of IRIS
Paradoxical reactions among HIV-ve patients treated for Mycobacterium Tuberculosis infection
Inflammatory reactions occurring in patients on treatment for Mycobacterium Leprae
Recovery of immune cells following bone marrow transplantation or chemotherapy
Atypical, localized MAC Inflammatory responses in patients when they were treated with AZT monotherapy
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Immune Reconstitution Inflammatory Syndrome
Improved Cell Mediated Immunity with restoration of both memory and naïve CD4 cells
Increased CD4/CD8 cells detect hidden pathogens which were ignored with deficiency of immunity previously
Result in inflammatory process at the area of occult / sub-clinical infections
Usually improves with control of inflammation and specific treatment
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Case Study 1
7 yrs old HIV +ve male child, Presented with mediastinal TB & oral candidiasis
Mantoux Test : 0 mm
Sputum Smear AFB: Negative
CD4 : 84 Cells (4%)
ATT started
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Case Study 1 (continued)
Prior to treatment After 2 months of ATT
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Case Study 1 (continued)
After 2 months of ATT 3 weeks after ART (d4T+3TC+EFV)
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Case Study 1 (continued)
3 weeks after ART (d4T+3TC+EFV)
After treatment
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Illustration 1
Before ART: 3.6.2004
4 Months after: 11.10.2004
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Illustration 2
Before ART
11 weeks after
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Illustration 3
10 weeks after
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Illustration-4
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Illustration 5
Source: CMC, Vellore
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IRIS CMV (Cytomegalovirus)
Source: Graeme Meintjes, HIV service, GF jooste Hospital, Department of Medicine, UCT
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IRIS
Case Study 2
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Case Study 2
A 22 yrs old male HIV +ve since Feb.2000,on Cotrimoxazole prophylaxis, found to be eligible for ART on March06
ART was started on 8th March06
Presented with cough and grade 4 dyspnoea on 16th May 2006
Dramatic improvement with PCP therapeutic dose with steroids in 2 weeks time
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•6th March 2006
•CD4 166
•16th May 2006
•CD4 199
•31st May 2006
Source: Dr.Manoharan, I-TECH
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Immune reconstitution inflammatory syndrome
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72
81
85
3
3
OTHERS
HANSEN'S
CRYPTOCOCCOSIS
PCP
CMV RETINITIS
TUBERCULOSIS
HERPES ZOSTER
Patients Started on ART 2330
Immune reconstitution syndrome 302
Source: GHTM, Chennai
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Defining IRIS
Required criterion Supportive criterion
Worsening symptoms of inflammation/infection
Increase in cd4 cell count of > 25 cells/cu.mm
Temporal relationship with starting antiretroviral treatment
Biopsy demonstrating well formed granulomatous inflammation or unusually exuberant inflammatory response
Symptoms not explained by newly acquired infection or disease or the usual course of a previously acquired disease
> 1 log10 decrease in plasma viral load
Source: CID J 2006;(1 June) 42: 1639-46
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Defining IRIS
Proposed criteria for the diagnosis of IRIS
HIV positive
Receiving HAART Decrease in HIV-1 RNA level from baseline
Increase in CD4 cells from baseline(may lag HIV-1 RNA decrease)
Clinical symptoms consistent with inflammatory process
Clinical course NOT consistent with: Expected course of previously diagnosed OI
Expected course of newly diagnosed OI
Drug toxicity
Source: Journal of Antimicrobial Chemotherapy (2006) 57, 167-170; Samuel A. Shelburne, Martin Montes and Richard J.Hamill
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Defining IRIS: Major Criteria
Previous diagnosis of AIDS
Concurrent Antiretroviral Therapy; Increase in CD4 count and Decrease in plasma vireamia by > 1 log copies/ml
Atypical presentation of ‘opportunistic infection or tumor’ i.e. localized disease or
exaggerated inflammation or
atypical inflammatory response or
worsening of pre existing disease.
Symptoms consistent with infectious/inflammatory condition
Symptoms not explained by normal course of previous or new OI or side effect of ART
Source: Battegay and Drechsler; Current Opinion in HIV and AIDS; 2006, 1; 56-61
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Defining IRIS: Minor Criteria
Increase in CD4 cell count
Increase in measured specific immune response
Spontaneous resolution of symptoms without specific therapy
Source: Battegay and Drechsler; Current Opinion in HIV and AIDS; 2006, 1; 56-61
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Practical Definition: NACO
“Occurrence or manifestations of new OIs within six weeks to six months after initiating ART; with increase in CD4 count”
India’s National AIDS Control Organization, Antiretroviral Therapy Guidelines for HIV-infected Adults and Adolescents Including Post-exposure Prophylaxis. May 2007
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Onset of IRIS
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
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HAART & HIV RNA Levels
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
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IRIS & Non-IRIS Response to HAART
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
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Clinical Spectrum
Heterogeneous
Onset; early/delayed
Atypical symptoms; generalized/local
Varying severity
Infectious agents/site of infection
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Case Study 3
Jan07 >> 10yrs old girl, sputum +ve Pulmonary tuberculosis was started on Category -1 anti TB treatment
Feb.07 >> 11 Kg body weight, Hb 8.5gms% & 9% CD4 , started on d4T,3TC & EFV
Sept.07 >>15 kg body weight, Hb:11.9gms, & 33% CD4, sputm –ve for AFB
Hospitalised
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Case study 3 (continued)
Exertional dyspnea, pedal edema, & cough
Dyspnoeic at rest, tachycardia, pitting pedal oedema, & cervical adenopathy
JVP elevated, S1 & S2 heard well, S3+; systolic murmur +
Distended abdomen & Liver +
Basal rales at both lungs
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Case Study 3 (continued)
Source: GHTM,Chennai
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Case Study 3 (continued)
Source: GHTM,Chennai
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Differential Diagnosis
Opportunistic infections
Drug side effects
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Risk factors
Risk factors at base line:
Lower CD4 count prior to start of ART
Higher HIV-1 RNA levels at base line
Initiating ART in close proximity to starting therapy for an OI
Response to therapy & the development of IRIS:
Rapid fall in HIV-1 RNA level during the first 3 months of therapy
Source: Journal of Antimicrobial Chemotherapy (2006) 57, 167-170;Samuel A. Shelburne, Martin Montes and Richard J.Hamill
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Management
Mild form (with ongoing ART) Observation
Localized IRIS (with ongoing ART) Local therapy such as minor surgical procedures for lymph
node abscesses
Most of the situations (with ongoing ART) Unmasking &/or Recognition of ongoing infections >>
Antimicrobial therapy to reduce the antigen load of the triggering pathogen;
Reconstituting immune reaction to non-replicating antigens >> no antimicrobial therapy. Short term therapy with corticosteroids or non-steroidal anti inflammatory drugs to reduce the inflammation.
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Management
Temporary cessation of ART has to be considered if potentially life threatening forms of IRIS develop
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Key Points
IRIS less likely to occur when ART is initiated early enough
HIV infected persons who come late in their disease course are at risk from IRIS
Clinicians need to know about this syndrome and its pathophysiology when working up the differential diagnosis of a wide variety of clinical symptoms in HIV-infected patients on ART
Important in countries where ART is prescribed for patients who already have advanced immunodeficiency.
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Additional slides
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Case Study 4
Normal chest x ray before commencing HAART
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Case Study 4 (continued)Chest x ray 2 weeks after commencing HAART
Demonstrates the presence of widespread miliary shadowing
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Case Study 4 (continued)
Chest x ray after the admission to the intensive care unit.
Demonstrates the presence of bilateral alveolar infiltrates compatible with ARDS
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Case Study 4 (continued)
Normal chest x ray 3 weeks after discharge