Immune Reconstitution Inflammatory Syndrome

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• Immune Reconstitution Inflammatory Syndrome
• Dr. 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
  110715
• (2) DeSimone JA, Pomerantz RJ, Babinchak TJ.
  Inflammatory reactions in HIV-1infected persons
  after initiation of highly active antiretroviral
  therapy. Ann Intern Med 2000 13344754.
• Clin Infect Dis. 2006 Feb 142(3)418-27.
• (4) AIDS 2005 Mar 419(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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Source Dr.Rajasekaran, Superintendent,
GHTM,Chennai
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Case Study 1 (continued)
3 weeks after ART (d4T3TCEFV)
After 2 months of ATT Initiated on ART also
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Source Dr.Rajasekaran, Superintendent,
GHTM,Chennai
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Case Study 1 (continued)
3 weeks after ART
After treatment
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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
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• 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
• Hb12.9gms CD4 33, sputum negative for AFB

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Case Study- 3 (continued)
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Source GHTM,Chennai
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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 gtgt 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

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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-IRISPathogenesis
C
A
B
D
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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 IRIS
Categories 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
Management Devesh 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 gt 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
gt 1 log10 decrease in plasma viral load
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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

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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 gt 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
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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

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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

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

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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, 21335341
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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
  gtgt Antimicrobial therapy to reduce the antigen
  load of the triggering pathogen
• Reconstituting immune reaction to non-replicating
  antigens gtgt 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 OIs before the initiation of
  ART, if possible
• How long should ART be deferred??
• In patients with a recently treated OI, identify
  those at risk of paradoxical IRIS
• Low CD4 cell count
• Disseminated infection
• 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

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Illustration 1
4 Months after 11.10.2004
Before ART 3.6.2004
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Source Dr.Rajasekaran, Superintendent,
GHTM,Chennai
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Illustration 2
11 weeks after
Before ART
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Source Dr.Rajasekaran, Superintendent,
GHTM,Chennai
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Illustration 3
10 weeks after
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Source Dr.Rajasekaran, Superintendent,
GHTM,Chennai
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Illustration-4
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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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• Next session December 4th, 2008
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• Email DLinfo_at_u.washington.edu

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• Next session December 4th, 2008
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• Operations Research