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

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

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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.

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