Immune Reconstitution Inflammatory Syndrome Dr. G. Manoharan, M.D., Medical Director, I-TECH India

Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series

Immune Reconstitution Inflammatory SyndromeDr. G. Manoharan, M.D., Medical Director, I-TECH India

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Learning Objectives

Describe the epidemiology and historical picture of IRIS

Review IRIS case studies

Review pathogenesis of IRIS

Define diagnostic criteria for IRIS

Explain the clinical spectrum & differential diagnosis of IRIS

Discuss management of IRIS

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IRIS- epidemiology

IRIS is recognized as a potential complication that can occur after potent ART.

The frequency of IRIS has not been reported conclusively, but it may be estimated to occur in 10% – 25% of patients who receive ART

23% – 25% of HAART responders developed one or more inflammatory syndromes consistent with IRIS in two large case series from Australia and London

Retrospective study of HIV-infected patients in Texas with history of MTB, MAC, and/or cryptococcal infection: 31% developed IRIS

similar rates of IRIS for each pathogen Ref: (1) French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected

patients with highly active antiretroviral therapy.HIV Med 2000; 1:107–15 (2) DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1–infected persons after initiation of highly

active antiretroviral therapy. Ann Intern Med 2000; 133:447–54.(3) Clin Infect Dis. 2006 Feb 1;42(3):418-27.(4) (4) AIDS 2005 Mar 4;19(4):399-406.

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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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Case studies

IRIS

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Case Study 1

7 yrs old HIV positive 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


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After 2 months of ATTInitiated on ART also

3 weeks after ART (d4T+3TC+EFV)


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3 weeks after ART After treatment


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Case Study - 2

A 22 yr old male HIV positive since Feb. 2000, on Cotrimoxazole prophylaxis, found to be eligible for ART in March 2006

08th March 06: Started on AZT,3TC and NVP

16th May 06: Presented with cough and grade 4 dyspnoea

Dramatic improvement with steroids and Cotrimoxazole (therapeutic dose) 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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Case Study - 3

Jan07: 10 yr old girl, sputum positive Pulmonary tuberculosis was started on Category -1 (Rifamycin, Isoniazid, Ethambutol and Pyrazinamide) anti-TB treatment and cotrimoxazole; body weight 10.5 kg

March.07: Body weight 11 kg; Hb 8.5gms% and CD4 (317) 9%; Sputum negative ; started on d4T, 3TC & EFV

Sept.07: Hospitalised

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Case study - 3 (continued)

Severe dyspnea, pedal edema, & cough

Dyspnoeic at rest, tachycardia, pitting pedal edema, cervical adenopathy; Body weight 15 kg

CVS: JVP elevated; S1,S2 heard well, S3+, systolic murmur +

Respiratory system: Basal rales at both lungs

Abdomen: Distended & Liver +

Hb:12.9gms% & CD4 33%, sputum negative for AFB

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Case Study- 3 (continued)

Source: GHTM,Chennai

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Source: GHTM,Chennai

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What is the clinical diagnosis?

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Case Study- 3 (continued) Clinical course – 8 months later…

May 2008

Weight: 18 Kg

Echo findings >> Moderate LV dysfunction, Mild MR, Mild Pulmonary Hypertension, No pericardial effusion, Ejection fraction 48%

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September 2007 November 2007.

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Jan. 2008

Feb. 2008.

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Final diagnosis

Probable IRIS- dilated cardiomyopathy

Pathogenesis

IRIS

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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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PML-IRIS:Pathogenesis

B

C

D

A

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MRI pictures of PMLN-IRIS

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Increase in PPD specific T-cells

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Categories of IRISCategories Antigen target

Infectious-unmasking Viable replicating infective antigen

Infectious-paradoxical Dead or dying organisms

Auto immune Host

Malignancies Possible tumor or associated pathogen

Other inflammatory conditions

Range of antigens

Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Receiving Antiretroviral Therapy Pathogenesis, Clinical Manifestations and ManagementDevesh J. Dhasmana, Keertan Dheda, Pernille Ravn, Robert J. Wilkinson and Graeme Meintjes; Drugs 2008; 68 (2): 191-208

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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

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


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IRIS & Non-IRIS Response to HAART


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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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Differential Diagnosis

Opportunistic infections

Drug resistance organisms

Drug side effects

Risk factors

IRIS

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French: AIDS, Volume 18(12).August 20, 2004.1615-1627

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Risk of TB-IRIS

AIDS 2007, 21:335–341

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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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Prevention of IRIS

Identify and treat OI’s before the initiation of ART, if possible

o How long should ART be deferred??

In patients with a recently treated OI, identify those at risk of “paradoxical” IRIS

o Low CD4 cell count

o Disseminated infection

o Genetic susceptibiltiy

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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

Illustrations

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Illustration 1

Before ART: 3.6.2004

4 Months after: 11.10.2004


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Illustration 2

Before ART

11 weeks after


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Illustration 3

10 weeks after


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Illustration-4


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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-Microsporidiosis

Multiple granulomas on hyperemic peritoneal wall

Granulomas over the peritoneum & the hyperemic bowel

Thank you!Next session: December 4th, 2008

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Immune Reconstitution Inflammatory Syndrome Dr. G. Manoharan, M.D., Medical Director, I-TECH India