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Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series
Immune Reconstitution Inflammatory SyndromeDr. G. Manoharan, M.D., Medical Director, I-TECH India
22
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
3
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.
44
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
5
Case studies
IRIS
77
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
88
Case Study 1 (continued)
Prior to treatment After 2 months of ATT
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
99
Case Study 1 (continued)
After 2 months of ATTInitiated on ART also
3 weeks after ART (d4T+3TC+EFV)
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
1010
Case Study 1 (continued)
3 weeks after ART After treatment
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
1111
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
1212
•6th March 2006
•CD4 166
•16th May 2006
•CD4 199
•31st May 2006
Source: Dr.Manoharan, I-TECH
1313
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
1414
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
1515
Case Study- 3 (continued)
Source: GHTM,Chennai
1616
Case Study- 3 (continued)
Source: GHTM,Chennai
17
Case Study- 3 (continued)
What is the clinical diagnosis?
18
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%
19
Case Study- 3 (continued)
September 2007 November 2007.
20
Case Study- 3 (continued)
Jan. 2008
Feb. 2008.
21
Final diagnosis
Probable IRIS- dilated cardiomyopathy
Pathogenesis
IRIS
2323
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
24
PML-IRIS:Pathogenesis
B
C
D
A
25
MRI pictures of PMLN-IRIS
26
Increase in PPD specific T-cells
27
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
2828
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
2929
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
3030
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
3131
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
3232
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
3333
Onset of IRIS
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
3434
HAART & HIV RNA Levels
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
3535
IRIS & Non-IRIS Response to HAART
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
3636
Clinical Spectrum
Heterogeneous
Onset; early/delayed
Atypical symptoms; generalized/local
Varying severity
Infectious agents/site of infection
3737
Differential Diagnosis
Opportunistic infections
Drug resistance organisms
Drug side effects
Risk factors
IRIS
39
French: AIDS, Volume 18(12).August 20, 2004.1615-1627
40
Risk of TB-IRIS
AIDS 2007, 21:335–341
4141
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.
4242
Management
Temporary cessation of ART has to be considered if potentially life threatening forms of IRIS develop
43
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
4444
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
4646
Illustration 1
Before ART: 3.6.2004
4 Months after: 11.10.2004
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
4747
Illustration 2
Before ART
11 weeks after
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
4848
Illustration 3
10 weeks after
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
4949
Illustration-4
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
5050
Illustration 5
Source: CMC, Vellore
5151
IRIS CMV (Cytomegalovirus)
Source: Graeme Meintjes, HIV service, GF jooste Hospital, Department of Medicine, UCT
52
IRIS-Microsporidiosis
Multiple granulomas on hyperemic peritoneal wall
Granulomas over the peritoneum & the hyperemic bowel
Thank you!Next session: December 4th, 2008
Listserv: [email protected]: [email protected]
Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series
Next session: December 4th, 2008Mark Micek
Operations Research