1. Immune Reconstitution Inflammatory Syndrome
Dr.G.Manoharan
Medical Director, I-TECH India
Introduce the session to the participants; HAART improves the quality of life, improves the immune function, decreases OIs and
mortality. But the start of HAART also presents few clinical issues like ARV drug toxicities and the occurrence of problems due to immune restoration. These problems, the so called IRIS, IRS, Immune restoration disease, usually occur within few weeks to months after the start of HAART.

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. 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

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
Notes: IRIS-TB, PNEUMONITIS-RIGHT LOWER LOBE
Before ART:
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

10. Illustration 2 11 weeks after Before ART
Notes: IRIS-TB, LEFT LOWER LOBE CAVITY
Before ART
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

11. Illustration 3 10 weeks after
Notes: IRIS-TB, Left sided pleural effusion.
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

12. Illustration-4 Notes: IRIS-TB,Pericardial effusion
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

13. Illustration 5 Notes; IRIS-TB , supra scapular lymph node abscess
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 31st May 2006 Notes:
6th March 2006; Clear chest x-ray
16th March 2006; Infiltrations and patchy opacities involving the mid and lower zones of the lungs on both sides.
31st March 2006; The infiltrations and the patchy opacity cleared.
Source: Dr.Manoharan, I-TECH
31st May 2006

18. Immune reconstitution inflammatory syndrome
Patients Started on ART
2330
Immune reconstitution syndrome
302
Source: GHTM, Chennai

19. 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:

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, ;
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
Notes: 57 patients developed IRIS in this study. The duration between the Initiation of HAART and the diagnosis of IRIS is depicted in the above graph. The median time between the start of HAART and the diagnosis of IRIS was 46 days, with the shortest time being 3 days and the longest 658 days. Presentation was within 60days for 34 (60%) and within 90 days for 41 (72%) of beginning HAART. There were no significant differences between the underlying opportunistic disease and the time to onset of IRIS ( DATA NOT SHOWN) after commencing HAART.
Source: AIDS 2005, Vol 19 No4 ; , Samuel A. Shelburne et al

25. HAART & HIV RNA Levels
Notes; The HIV-1 RNA levels were analysed at the following intervals from the time of initiating HAART: 1-90days, days, AND days. Patients who developed IRIS had more marked reductions in HIV-1 RNA levels both initially and persistently vs patients who did not develop IRIS (P <0.001)
Source: AIDS 2005, Vol 19 No4 ; , Samuel A. Shelburne et al

26. IRIS & Non-IRIS Response to HAART
Notes; The CD4 levels were analysed at the following intervals from the time of initiating HAART: 1-90days, days, and days. The CD4 response did not differ significantly during the first interval, but by the time of the second and third interval the patients who developed IRIS had more marked increase CD4 levels vs patients who did not develop IRIS.
Source: AIDS 2005, Vol 19 No4 ; , Samuel A. Shelburne et al

27. Clinical Spectrum Heterogeneous Onset; early/delayed
Atypical symptoms; generalized/local
Varying severity
Infectious agents/site of infection
Notes: The clinical presentation of IRIS is heterogeneous. It depends on various host factors and also depends on the involved pathogen. Symptoms of IRIS can occur early, within a few days after the start of ART or late IRIS with onset after 1 year. IRIS may be mistaken for new OI, but can be differentiated by its atypical clinical features. Depending on the site of involvement and the nature of the infectious agent, the clinical features differ. The severity may vary from mild symptomatology to sometimes life threatening clinical event. The inflammatory response can result in a spectrum of clinical presentations ranging from clinical worsening of a treated OI, atypical appearance of an unrecognized OI to even auto immune disorders such as Grave’s disease. More than 20 infectious agents have been described as causes for IRIS.

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)
Notes: showing features of ascites, hepaotmegaly, and cervical lymphadenopathy.
Source: GHTM,Chennai

31. Case Study 3 (continued)
Notes: CXR-PA before the start of HAART and 9 months after ; showing features of dilated cardiomyopathy with features of CCF.
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, ;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
Notes: A 41 year old black Kenyan male with known HIV infection presented to our emergency clinic with breathlessness 2 weeks after the commencement of HAART. He had previously tested HIV positive in 1991, following an episode of oral candidiasis. Since that time he had remained well with no other opportunistic infections, and his CD4 count had been consistently above 450 cells x 106/l, while his viral load was less than copies/ml. However, after an absence of 1 year, in April 2000, he returned to the HIV clinic for further management. Routine investigation at that time revealed a normal chest radiograph (as in this slide) but his CD4 count had dropped to 121 cells x 106/l (12%) with an elevated viral load of copies/ml. Clinical examination at this time was normal. In view of his low CD4 count he started HAART using two nucleoside reverse transcriptase inhibitors (AZT 300 mg twice daily and 3TC 150 mg twice daily) with a non-nucleoside reverse transcriptase inhibitor (efavirenz 600 mg at night). In addition, he was given co-trimoxazole (960 mg once daily) as prophylaxis against Pneumocystis carinii pneumonia (PCP). He tolerated this regimen extremely well and reported greater than 95% adherence.

39. Case Study 4 (continued)
Chest x ray 2 weeks after commencing HAART
Demonstrates the presence of widespread miliary shadowing
Notes: Fourteen days later he returned to the clinic with a 2 day history of fevers and night sweats, and a 24 hour history of worsening shortness of breath. His CD4 count had increased to 298 cells x 106/l (19%) and his viral load had successfully fallen to copies/ml. It was noted that he desaturated on exercise breathing air from 96% to 89%. A chest radiograph taken at this time revealed gross abnormality with evidence of widespread miliary shadowing (fig 2). A provisional diagnosis of community acquired pneumonia or PCP was made, and he was treated with intravenous antibiotics (benzylpenicillin 1.2 g 4 hourly and clarithromycin 500 mg four times daily) and high dose intravenous co-trimoxazole (120 mg/kg per day).

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
Notes: Over the next 12 hours he developed worsening respiratory failure. An arterial blood gas on air indicated a pH 7.38, PaO2 4.2 kPa, PaCO2 4.9 kPa. He was, therefore, transferred to the intensive care unit for mechanical ventilation, and intravenous corticosteroids (hydrocortisone 100 mg four times daily) were added into his treatment regimen. A Swan Ganz catheter was inserted, and a pulmonary wedge pressure of 14 mm Hg was noted. Over the next 4 days he continued to be ventilated and required increasing amounts of positive pressure support. During this period his chest radiograph revealed increased alveolar shadowing in keeping with his clinical deterioration (fig 3).

41. Case Study 4 (continued)
Normal chest x ray 3 weeks after discharge
Notes: He underwent a fibreoptic bronchoscopy with bronchoalveolar lavage. This yielded no evidence for PCP; however, acid fast bacilli were seen on the direct smear. His therapy was therefore changed, and he was commenced on quadruple antituberculous therapy with pyrazinamide (2 g once per day), rifampicin (600 mg once per day), isoniazid (300 mg once per day), and ethambutol (1200 mg once per day). Over the next 7 days his clinical condition slowly improved and his ventilatory requirements lessened, to the point where he was extubated and returned to the medical ward.
Three weeks after admission he was fit enough for discharge. At this stage his chest radiograph had markedly improved (fig 4) with clearance of the shadowing. Subsequent, microbiological culture indicated fully sensitive Mycobacterium tuberculosis.