1. Immune Reconstitution Inflammatory Syndrome (IRIS)
HAIVN
Harvard Medical School AIDS Initiative in Vietnam
Peds Module 2, 2010

2. Outline of Presentation
Definition of IRIS
Pathogenesis of IRIS
Clinical presentation of IRIS
IRIS due to TB, Hepatitis B, CMV
Diagnosis of IRIS
Management of IRIS

3. Learning objectives
At the end of this presentation, the trainee will be able to describe:
The two forms of the Immune Reconstitution Inflammatory Syndrome (IRIS)
The etiological agents and syndromes of IRIS
The management of IRIS
Commonly encountered forms of IRIS

4. IRIS: Definition IRIS = IRD: Immune Restoration Disease
IRIS: symptoms or signs consistent with an inflammatory and/or atypical presentation of OIs or tumors
Is not a side effect of ARV,
Occur after initiation, reintroduction, or change of ARV
In patients who have evidence of viral load suppression.
Definition IRIS: Immune Reconstitution Inflammatory Syndrome Risk Factors and Treatment Implications
Yukari C. Manabe, MD,*† James D. Campbell, MD, MS,‡ Emily Sydnor, MD,† and Richard D. Moore, MD, MHS†§
J Acquir Immune Defic Syndr _ 2007

5. IRIS: Definition
IRIS is a pattern of diseases presenting soon after the initiation of ARV.
Typically, it occurs in the first 2-12 weeks after starting ARV.
IRIS is a “paradoxical” overreaction against a foreign antigen (alive or dead) in patients starting ARV.

6. IRIS: Pathogenesis
IRIS is secondary to immunological changes after ARV:
Rapid and potent suppression of HIV viraemia +
Abundant microbial antigen (alive or dead) promotes a greater immune response when it encounters suddenly increased numbers of functionally active antigen-specific cells.
Immune reconstitution inflammatory syndrome in HIV
Marc Lipman and Ronan Breen. Current Opinion in Infectious Diseases 2006, 19:20–25

7. IRIS: Clinical presentations
IRIS in patients already receiving therapy for an OI at the time at which ARV is initiated. Clinical deterioration of the disease: “paradoxical reaction”.
IRIS may trigger the presentation of an OI that was sub-clinical prior ARV: “unmasking IRIS”.
Immune reconstitution disease: recent developments and implications forantiretroviral treatment inresource-limitedsettings
Stephen D. Lawna,b and Martyn A. Frenchc,d Current Opinion in HIV and AIDS 2007, 2:339–345

8. IRIS: Clinical presentations
Inflammatory response that causes the unexpected worsening of the patient’s condition.
Often there is no detectable evidence of the underlying pathogen.
Mycobacterium Tuberculosis accounts for 1/3 of all IRIS events.
BCG vaccine: very common in infants

9. Common Pathogens All infections have been reported to cause IRIS
Mycobacteria:
TB and MAC, BCG in children
Fungal:
Cryptococcosis, PCP, histoplasmosis, Penicilliosis
Viral:
CMV, VZV, HBV, HCV
Parasites:
Strongyloides stercoralis, cryptosporidium
Cryptococcus: increased mortality rate. Some patients with an initial or recurrent episode of crypto meningitis during the first weeks of ARV. CSF: more prominent inflammatory cell reaction in patients on ARV. Often CSF sterile culture for crypto

10. IRIS Risk factors Low CD4 count before starting ARV
Rapid reduction in HIV viral load with ARV
High pathogen load at the beginning of ARV, i.e. starting ARV therapy in the setting of an active OI
High number of prior OIs
Minor criteria: increase in CD4 count.
High pathogen load at the beginning of ARV, i.e. starting ARV therapy in the setting of an active OI: delaying ARV until the antigen load has been reduced by anti-microbial therapy will reduce the incidence of IRIS…………but more risks of further AIDS events. What is the best moment to start ARV in co-infected patients, especially with low CD4 counts, remain to be established
Minor criteria: increase in CD4 count. Absolute CD4 T-cell increase did not correlate with increasing risk for IRIS. CD4+ T-cell increases are not found in all patients with IRIS. Immune Reconstitution Inflammatory Syndrome. Risk Factors and Treatment Implications
Yukari C. Manabe, MD,*† James D. Campbell, MD, MS,‡ Emily Sydnor, MD,† and Richard D. Moore, MD, MHS†§
J Acquir Immune Defic Syndr _ 2007

11. IRIS TB
Worsening of signs and symptoms of TB in patients being started on anti-TB chemo-therapy
Described in the pre-HIV era but appear to be more frequent in HIV-infected patients
Occur in 7 to 36% of patients
More frequently when HAART is started within 2 months of beginning anti-TB treatment
Occur in 7 to 36% of patients: data are very different because no very clear clinical definitions of IRIS.

12. IRIS TB Factors complicating ARV and TB therapy:
Adherence to heightened pill burden
Overlapping drug toxicities
Drug/drug interactions

13. IRIS TB “Paradoxical reaction”:
Initial clinical response to TB treatment,
ARV introduction,
New persistent symptoms or signs of TB,
Adequate adherence to ARV and TB treatment.
For patients on TB treatment at the moment to start ARV:
Initial clinical response to TB treatment : cessation of fever, relief of pulmonary symptoms, decrease in lymph node size, termination of meningeal signs
New persistent symptoms or signs of TB : fevers without an identifiable source or reason, worsening or emergence of dypnoea, increase in lymph node size, development of abscesses, abdominal pain = ultrasound: abdominal adenopathies, CNS symptoms

14. IRIS TB Diagnosis “Paradoxical reaction”:
Chest X ray/Ultrasound: worsening or new lesions,
Good virological response,
Clear exclusion of other conditions:
TB treatment failure, resistant TB
others OI,
Malabsortion,
Drug reactions.
Chest X ray/Ultrasound: showing worsening or emergence of intra-thoracic adenopathy, pulmonary infiltrates, pleural effusions, abdominal lymph nodes
Good virological response: rapid and significant viral load decline at least > 1 log

15. IRIS TB Diagnosis “Unmasking IRIS”: Unapparent TB at the start of ARV
Insufficient clinical symptoms to justify TB treatment,
Chest X ray: normal
Patients with cough at least 3 sputum: AFB negative

16. IRIS TB Diagnosis “Unmasking IRIS”:
TB appeared within the first 6 months of ARV
Good virological response to ARV
Adequate adherence to ARV

17. CXR before ARV
CXR 3 weeks after ARV

18. 8 months old: Severe malnutrition Wt 5 kg; height 58cm
Hepatosplenomegaly
CD4 40.6%; 662 tb/mm3
PCR +
ARV: D4T/3TC/NVP
enlargement of the axillary lymph nodes.
Left Axillary LN = BCG disease

19. IRIS TB Differential diagnosis
For patients on TB treatment who develop IRIS after start ARV: “Paradoxical reaction”
Side effects of ARV
drug fevers
TB infection not responding to treatment
Resistant TB
Poor adherence to TB treatment
Other HIV or non-HIV related infections
IRIS is a diagnosis of exclusion !!!

20. Overlapping Side Effects of Antituberculosis and Antiretroviral Drugs

21. Overlapping Side Effects of Antituberculosis and Antiretroviral Drugs

22. IRIS in Thai children Between May 2002-2004 (3 hospital)
HIV-infected children enrolled: 153
ARV regimens:
D4T + 3TC + NVP: 81
D4T + 3TC + EFV: 72
Mean Age: 8 years old
Mean CD4 baseline: 5%
No active OI
Immune Reconstitution Syndrome After Highly ActiveAntiretroviral Therapy in Human ImmunodeficiencyVirus-Infected Thai Children
Thanyawee Puthanakit,
The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

23. IRIS in Thai children: results
153 enrolled children:
29 children (19%) had 32 episodes of IRIS
Median time: 4 weeks after ARV
IRIS:
Mycobacterial: 14 episodes (43%)
Atypical mycobacteria: 9
Mycobacterium Tuberculosis: 3
Mycobacterium Bovis: 2
Varicella-Zoster: 7 episodes
Mycobacterium diseases: localized infections ( Lymph nodes, subcutaneous tissues, lungs)
M Bovis: 2 patients with BCG vaccine years before
The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

24. IRIS in Thai children: results (cont’)
HSV: 7 episodes
Cryptococcus: 3
Guillain Barre: 1
The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

25. IRIS in Thai children: outcomes
One patient interrupted 8 weeks ARV during IRIS
3 patients died of IRIS or its complications
The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

26. IRIS in infants (South Africa)
Infants less than 24 months old: 169
ARV: D4T + 3TC + Aluvia
Median age: 8 months old
IRIS: 34 infants (21%)
Median time: 2 weeks post-ARV
BCG disease: 24/34 (71%)
Local reaction and/or ipsilateral axillary lymph node
Ipsilateral lymph nodes were the most common manifestation of the BCG
AIDS 2009, 23:1097–1107

27. IRIS in infants (South Africa)
Tuberculosis: 12 cases (6 co-infected with M. bovis)
Outcomes:
IRIS: 3/34 died (9%)
BCG disease: 2 cases
BCG and TB: 1 case
AIDS 2009, 23:1097–1107

28. IRIS Management Continuation of primary therapy against the pathogen,
Continuation of ARV,
Judicious use of anti-inflammatory agents,
To provide reassurance to the patients:
With appropriate management, IRIS usually does not alter the patients long-term prognosis.

29. IRIS Management
Corticosteroids (1mg/kg/day) might be necessary in case of severe symptoms:
Worsening of meningeal, cerebral or mediastinal disease with compression of vital structure,
Pain, prolonged fever.
In case of life-threatening forms of IRIS, stopping ARV temporarily could be considered.
* Rifampicin decrease 50% prednisolone concentrations

30. Managing ARV During IRIS
Continue ARV
Except in life-threatening situations
Adjust for anti-mycobacterial treatment
If rifampin is prescribed:
Switch NVP to EFV
Stop PIs and start EFV or a third NRTI, as appropriate
Super boosted PI

31. Summary and Key Points
Restoration of immunopathological response to antigens of opportunistic pathogens
subclinical infections
treated infections
Usually presents during the first weeks (2-12 weeks) of ARV
Less commonly presents after many months of ARV
The most common agent inducing IRIS in Vietnam is TB/BCG 28

32. Summary and Key Points IRIS is a diagnosis of exclusion
Treatment consists of antimicrobial + anti-inflammatory therapy or anti-inflammatory therapy alone
IRIS is NOT treatment failure: ARV therapy should be continued
The syndrome will be spontaneously resolved after months

33. Thank you!
Questions?