Immune reconstitution syndrome management

This presentation gives the appropriate management of clients with IRIS

1. Immune reconstitution inflammatory syndrome (IRIS) BY E. Chauluka

2. Learning Objectives By the end of the session participants should be able: Describe IRIS Explain the risk factors of IRIS Explain the management of IRIS Integrated ART- PMTCT-TB Training- Session 40 2

3. Immune Reconstitution Potent ARV therapy blocks viral replication and prevents the destruction of CD4 T cells. This shifts the balance toward CD4 T cell regeneration and improvement in immune function. CD4 T cell counts increase. Antigen-specific immune responses are restored.

4. Immune Reconstitution The bottom line is that patients who respond to ART have improved immune function and are at lower risk for the development of opportunistic infections.

5. Is immune reconstitution always beneficial?

6. Immune Reconstitution Inflammatory Syndromes (IRIS): Immune Reconstitution Paradox: Recovery in the function of the immune system with ART can promote an inflammatory reaction to antigens that were previously not recognized by the immune system. This inflammatory reaction can sometimes lead to worsening of a current or latent opportunistic infection. The onset of IRIS often occurs 2-8 weeks after initiation of ARV therapy but can occur earlier or later.

7. IRIS: Risk F actors Shorter interval between TB treatment (or Cryptococcal meningitis treatment) and ART initiation Patients who start ART with very advanced AIDS are at a higher risk of developing IRIS. Recent / concurrent treatment for TB or cryptococcal meningitis Disseminated diseases Low baseline CD4 and high baseline VL Rapid, large CD4/VL response to ART Integrated ART- PMTCT-TB Training- Session 40 7

8. IRIS: Triggering Antigens In IRIS, the flaring of specific immune responses to microbial antigens occurs in the setting of improving immunity after the initiation of effective ART. IRIS may represent either an appropriate inflammatory response that was previously masked by severe immune deficiency or a pathological exaggerated inflammatory reaction. Inciting antigens may be from an active infection (replicating microorganisms) or from the remnants of a treated infection (microbial debris) or latent infection. IRIS is also associated with autoimmune disorders or malignancies such as Kaposi’s sarcoma and lymphoma .

9. Pathogens associated with IRIS Mycobacterium avium Mycobacterium tuberculosis Mycobacterium leprae Cryptococcus neoformans Pneumocystis jiroveci Histoplasma capsulatum Hepatitis B virus Hepatitis C virus Varicella-zoster virus Cytomegalovirus BK Virus Parvovirus B19 JC virus Papilloma virus HHV-8 (KS)

10. Clinical Presentation IRIS can occur as early as a few days after starting ARV therapy. In patients with baseline CD4+ T-cell counts below 50 cells/mm3, most events will happen within the first 8 weeks of therapy. Late IRIS with symptom onset after more than 1 year of ARVs have been described. Patients typically become ill in the setting of improving virologic and immunological measures. IRIS may be mistaken for a new opportunistic infection, but it can sometimes be distinguished by an atypical manifestation, such as localized inflammation where one would expect disseminated disease. IRIS may also present as paradoxical worsening of a known opportunistic infection. Depending on the site and activity of the immunologic response, the severity of clinical symptoms can vary widely from mild to life-threatening events.

11. IRIS Case Definition Evidence of clinical response to ART with: On ART Infectious or Inflammatory condition within 6 months of ART initiation Symptoms can not be explained by either: Newly acquired infection Expected clinical course of a previously recognized and successfully treated infectious agent Treatment failure Side effects of ART. Complete ART non-compliance

12. IRIS Associated with Crytococcal Meningitis IRIS may be associated with cryptococcal meningitis following initiation of ART. Upon initiation of ART, ≈25% of CM patients experience IRIS with increases in headache, intracranial pressure, signs of inflammation, and in ≈25%, serious complications include loss of vision, cranial nerve palsies, reduced cognition and death.

13. IRIS Management Evidence-based treatment recommendations are lacking. Identify the inciting pathogen and treat it. Most cases of IRIS are managed without stopping ARVs. In severe cases, treatment options include stopping ARVs, steroids, NSAIDS, and surgical treatment (for example drainage of abscesses).

14. TB-IRIS Recurrent, new or worsening TB symptoms, signs and/or radiological findings Incidence: 8-45% 1-4 weeks up to years after ART initiation Fever is the most common manifestation Lawn 2005, Shelburne 2005, Breton 2004, Narita 1998, Michailidis 2005, Ollala 2002, Breen 2004, Kumarasamy 2004 Integrated ART- PMTCT-TB Training- Session 40 14

15. TB-IRIS Signs and symptoms include: New or worsening symptoms Fever Pulmonary infiltrates / Worsening CXR findings Pleural effusions Lymph node enlargement or ‘cold abscess’ TB Meningitis or tuberculoma Usually sputum culture negative Integrated ART- PMTCT-TB Training- Session 40 15

16. Differential diagnosis of clinical worsening after ART initation Cryptococcal meningitis Kaposi Sarcoma MDR-TB These should be ruled out before making a diagnosis of TB IRIS Integrated ART- PMTCT-TB Training- Session 40 16

17. TB-IRIS Nodes Peripheral lymph nodes – Typically culture negative , may be AFB stain+; often with caseous liquefaction (& drainage) Integrated ART- PMTCT-TB Training- Session 40 17

18. Resolving with TB treatment; ARV’s were continued Integrated ART- PMTCT-TB Training- Session 40 18

19. Management of TB IRIS Before starting ART, counsel TB patients about the possibility of a temporary worsening of symptoms If a patient develops IRIS while on anti-TB treatment and ART: Seek the advice of a senior ART provider No need to stop or change TB or ARV treatment Confirm patient’s adherence to all medications Admit severe cases to the hospital Exclude other OIs; consider MDR-TB, non-adherence and drug reaction Integrated ART- PMTCT-TB Training- Session 40 19

20. Use of Steroids for IRIS Indications for giving steroids: Respiratory failure TB Meningitis / Tuberculoma(s) Severe symptoms, e.g., airway compression due to massive LN enlargement Guidelines recommend steroids for life-threatening TB-IRIS Watch for side effects of steroids Integrated ART- PMTCT-TB Training- Session 40 20

21. Use of Steroids for IRIS (2) Give Dexamethasone or Prednisolone Dexamethasone 8 to 16 mg/day BID, or Prednisolone 1 mg/kg body wt OD Treat for 14 – 21 days at full dose After 14-21 days, rapidly taper the steroids over a 10-14 day period while monitoring for recurrence and/or worsening of symptoms Integrated ART- PMTCT-TB Training- Session 40 21

22. Key points Assess patient adherence Do not change TB or ART regimens Consider possible TB treatment failure if the patient worsens after receiving one or more months of anti-TB treatment Rule-out other OIs Most cases of IRIS are self-limited Integrated ART- PMTCT-TB Training- Session 40 22

23. Why is so much IRIS seen in Africa? IRIS occurs most often in patients with advanced HIV disease and severe immunosuppression. Because of limited availability of ART in Africa, treatment is often reserved only for patients with advanced disease. Opportunistic infections associated with IRIS, such as tuberculosis and cryptococcal meningitis, occur frequently in Africa. Limited diagnostic capabilities in resource poor regions may impair the diagnosis of alternative etiologies, such as a second opportunistic infection. The diagnosis of IRIS is often invoked when no other definitive diagnosis is found.

24. IRIS Clinical deterioration in the initial period of immune recovery as a result of inflammatory reactions to antigens or organisms An over-aggressive response of the immune system caused by a sudden recovery on ART IRIS appears as a severe bout / worsening of HIV related diseases TB, Crypto. meningitis, Herpes zoster, KS Hepatitis, thyroiditis IRIS : Diagnosis by exclusion Integrated ART- PMTCT-TB Training- Session 40 24

25. Key facts A minority of patients may get worse in the first 6 months after starting ART Most common causes: Untreated (undiagnosed) HIV-related disease (mainly TB) Poor adherence to ART Drug-resistant TB (if on TB treatment) IRIS : I mmune R econstitution I nflammatory S yndrome Integrated ART- PMTCT-TB Training- Session 40 25