Download Immune reconstitution inflammatory syndrome

Welcome to UW I-TECH HIV/AIDS
Clinical Seminar Series
Immune Reconstitution Inflammatory Syndrome
Dr. G. Manoharan, M.D., Medical Director, I-TECH India
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.
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(4)
(4) AIDS 2005 Mar 4;19(4):399-406.
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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5
Case studies
IRIS
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
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Case Study 1 (continued)
After 2 months of ATT
Initiated on ART also
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
After treatment
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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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
Source: Dr.Manoharan, I-TECH
•31st May 2006
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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)
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Source: GHTM,Chennai
Case Study- 3 (continued)
Source: GHTM,Chennai
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Case Study- 3 (continued)
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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Case Study- 3 (continued)
September 2007
November 2007.
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Case Study- 3 (continued)
Feb. 2008.
Jan. 2008
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Final diagnosis
Probable IRIS- dilated cardiomyopathy
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Pathogenesis
IRIS
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
23
PML-IRIS:Pathogenesis
A
C
B
D
24
MRI pictures of PMLN-IRIS
25
Increase in PPD specific T-cells
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Categories of IRIS
Categories
Antigen target
Infectious-unmasking
Infectious-paradoxical
Viable replicating infective
antigen
Dead or dying organisms
Auto immune
Host
Malignancies
Possible tumor or
associated pathogen
Range of antigens
Other inflammatory
conditions
Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Receiving
Antiretroviral Therapy Pathogenesis, Clinical Manifestations and Management
Devesh J. Dhasmana, Keertan Dheda, Pernille Ravn, Robert J. Wilkinson and Graeme Meintjes;
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Drugs 2008; 68 (2): 191-208
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 Biopsy demonstrating well formed
antiretroviral treatment
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; 29
Samuel A. Shelburne, Martin Montes and Richard J.Hamill
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
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Source: Battegay and Drechsler; Current Opinion in HIV and AIDS; 2006, 1; 56-61
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 31
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 HIVinfected Adults and Adolescents Including Postexposure Prophylaxis. May 2007
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Onset of IRIS
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Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
HAART & HIV RNA Levels
34
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
IRIS & Non-IRIS Response to HAART
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Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
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
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Risk factors
IRIS
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.
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Additional slides
Illustrations
Illustration 1
4 Months after:
11.10.2004
Before ART: 3.6.2004
Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai
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Illustration 2
11 weeks after
Before ART
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
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IRIS-Microsporidiosis
Granulomas over the
peritoneum & the
hyperemic bowel
Multiple granulomas on
hyperemic peritoneal wall
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Thank you!
Next session: December 4th, 2008
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Welcome to UW I-TECH HIV/AIDS
Clinical Seminar Series
Next session: December 4th, 2008
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Operations Research