Immune Reconstitution

Inflammatory Syndrome
Dr.G.Manoharan
Medical Director, I-TECH India
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

2
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

3
Immune Reconstitution
Inflammatory Syndrome
Improved Cell Mediated Immunity with
restoration of both memory and nave 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

4
 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

5
Case Study 1 (continued)

Prior to treatment After 2 months of ATT

Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai 6

Case Study 1 (continued)

3 weeks after ART

After 2 months of ATT
(d4T+3TC+EFV)

Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai 7

Case Study 1 (continued)

3 weeks after ART After treatment

(d4T+3TC+EFV)

Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai 8

Illustration 1

4 Months after:
11.10.2004

Before ART: 3.6.2004

Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai 9

Illustration 2

11 weeks after

Before ART

Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai 10

Illustration 3

10 weeks after

Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai 11

Illustration-4

Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai 12

Illustration 5

Source: CMC, Vellore

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IRIS CMV (Cytomegalovirus)

Source: Graeme Meintjes, HIV service, GF jooste Hospital, Department of Medicine, UCT

14
IRIS
Case Study 2
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

16
6th March 2006 16th May
2006
CD4 166
CD4 199

Source: Dr.Manoharan, I-TECH

31st May 2006 17

Immune reconstitution inflammatory
syndrome
Patients Started on ART 2330

Immune reconstitution syndrome 302

Source: GHTM, Chennai

18
 Defining IRIS
Required criterion Supportive criterion
Worsening symptoms of Increase in cd4 cell count of > 25
inflammation/infection cells/cu.mm

Temporal relationship with starting Biopsy demonstrating well formed

antiretroviral treatment 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; 20

Samuel A. Shelburne, Martin Montes and Richard J.Hamill
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

21
Source: Battegay and Drechsler; Current Opinion in HIV and AIDS; 2006, 1; 56-61
Defining IRIS: Minor Criteria
Increase in CD4 cell count
Increase in measured specific immune
response
Spontaneous resolution of symptoms
without specific therapy

22
Source: Battegay and Drechsler; Current Opinion in HIV and AIDS; 2006, 1; 56-61
Practical Definition: NACO
Occurrence or manifestations of new
OIs within six weeks to six months after
initiating ART; with increase in CD4
count
Indias National AIDS Control Organization,
Antiretroviral Therapy Guidelines for HIV-
infected Adults and Adolescents Including Post-
exposure Prophylaxis. May 2007

23
Onset of IRIS

24
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
HAART & HIV RNA Levels

25
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
IRIS & Non-IRIS Response to HAART

26
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
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

28
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

29
Case Study 3 (continued)

30
Source: GHTM,Chennai
Case Study 3 (continued)

Source: GHTM,Chennai

31
Differential Diagnosis
Opportunistic infections
Drug side effects

32
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
33
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.

34
Management
Temporary cessation of ART has to be
considered if potentially life threatening forms
of IRIS develop

35
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.

36
Additional slides
Case Study 4
Normal chest x ray before commencing HAART

38
Case Study 4 (continued)
Chest x ray 2 weeks after commencing
HAART
Demonstrates the presence of widespread
miliary shadowing

39
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

40
Case Study 4 (continued)
Normal chest x ray 3 weeks after discharge

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