Immune Reconstitution Inflammatory Syndrome

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

2. 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

3. 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

4. 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

5. 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 Case Study 1 Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

6. Case Study 1 (continued) Prior to treatment After 2 months of ATT Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

7. Case Study 1 (continued) 3 weeks after ART (d4T+3TC+EFV) After 2 months of ATT Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

8. Case Study 1 (continued) 3 weeks after ART (d4T+3TC+EFV) After treatment Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

9. Illustration 1 4 Months after: 11.10.2004 Before ART: 3.6.2004 Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

10. Illustration 2 11 weeks after Before ART Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

11. Illustration 3 10 weeks after Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

12. Illustration-4 Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

13. Illustration 5 Source: CMC, Vellore

14. IRIS CMV (Cytomegalovirus) Source: Graeme Meintjes, HIV service, GF jooste Hospital, Department of Medicine, UCT

15. IRIS Case Study 2

16. 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

17. 6th March 2006 • CD4 166 • 16th May 2006 • CD4 199 Source: Dr.Manoharan, I-TECH • 31st May 2006

18. Immune reconstitution inflammatory syndrome Source: GHTM, Chennai

19. Defining IRIS Source: CID J 2006;(1 June) 42: 1639-46

20. 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

21. 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

22. 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

23. 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

24. Onset of IRIS Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al

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

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

27. Clinical Spectrum • Heterogeneous • Onset; early/delayed • Atypical symptoms; generalized/local • Varying severity • Infectious agents/site of infection

28. 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

29. 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

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

31. Case Study 3 (continued) Source: GHTM,Chennai

32. Differential Diagnosis • Opportunistic infections • Drug side effects

33. 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

34. 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.

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

36. 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.

37. Additional slides

38. Case Study 4 Normal chest x ray before commencing HAART

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

40. 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

41. Case Study 4 (continued) • Normal chest x ray 3 weeks after discharge