1. Tuberculosis and the Immune Reconstitution Inflammatory Syndrome (IRIS)
Bob Colebunders

2. Definition
‘a paradoxical inflammatory reaction against a foreign antigen (alive or dead) in patients who have started antiretroviral therapy and who have undergone a reconstitution of their immune responses against this antigen’

3. Names Immune reconstitution inflammatory syndrome (IRIS)
Immune restoration disease (IRD)
Paradoxical reactions

4. Pathogenesis
Increased lymphoproliferative response to mycobacterium antigens in vitro
Restoration of cutaneous response to Tuberculin
Increased [Il-6], activation markers (CD38)
Associated with TNFA-308*1, IL6-174*G

5. Incidence TB/IRIS Europe and USA Narita et al 36% (Miami, 1998)
Wendel et al 11% (Baltimore 2001)
Breen et al 29% (London, 2004)
Breton et al 43% (Paris, 2004)

6. Incidence TB/IRIS Africa India Breton et al: 41%
No cases in TB/DOT study in South Africa (20 patients only)
India
Kumarasamy et al: IRIS of 15.2 cases per 100 patient-years
Patel et al: TB IRIS more often in patients with active TB at the start of HAART than in those without active TB at the start of HAART (11 [8.73] vs. 3 [2.32%], respectively; p = ).

7. Risk factors for TB/IRIS
Starting ARV’s within 6 weeks of TB treatment
Disseminated, extra-pulmonary disease
Low base line CD4 count
Rise in CD4 %
Fall in viral load
High bacillary burden?

8. Types of TB IRIS Patient unknown to have TB at the start of HAART
Patient on TB treatment before or at the start of HAART

9. Timing of IRIS Mean of 15 days after starting HAART
Up to months (years)
Syndrome lasts for days

10. TB IRIS

11. TB IRIS

12. TB IRIS

13. TB IRIS

14. TB IRIS

18. TB IRIS

19. Prognosis Breton et al: 16 cases of TB/IRIS: 5 ‘severe’ complications
Splenic rupture
Compressive lymphadenopathy
Ureteric obstruction
Narita et al: The study found a 6-fold increased risk of subsequent TB relapse in patients who experienced IRIS during early TB treatment.

20. MRI: TB abscess spinal cord

21. Cryptococcal meningitis treated with HAART, bilateral blindness: fundoscopy: bilateral papiloedema: IRIS?

22. Differential diagnosis
Side effects of the antiretroviral treatment
Drug fever
TB infection not responding to standard anti-TB treatment
Other concomitant infection
Failure of HAART (late IRIS)

23. Proposed criteria for the diagnosis of IRIS in HIV patients on antiretroviral therapy
French et al

24. Major criteria
Atypical presentation of ‘opportunistic infections or tumours’ in patients responding to antiretroviral therapy
Decrease in plasma HIV RNA level by 1log10 copies/mL

25. Minor criteria Increased blood CD4 T-cell count after HAART
Increase in an immune response specific to the relevant pathogen, e.g. DTH response to mycobacterial antigens
Spontaneous resolution of disease without specific antimicrobial therapy or tumour chemotherapy with continuation of anti-retroviral therapy anti-retroviral therapy

26. “Suspected TB IRIS”: a TB patient who after starting HAART develops either
New persistent fevers (temperature >38.6°C) which last for more than 1 week without an identifiable source (e.g., urine and sputa testing, and other procedures when clinically indicated) or reason (e.g. an allergic reaction)
or marked worsening or emergence of intrathoracic lymphadenopathy, pulmonary infiltrates
or worsening or emergence of cervical adenopathies/abscesses, or worsening of other tuberculous lesions or manifestations, such as cutaneous peritoneal or central nervous system (CNS) inflammatory pathology.

27. “Suspected TB IRIS”: a patient who after starting HAART develops TB characterised by the formation of
Large adenopathies
Abscesses
Miliary TB with large nodules
Cavity formation

28. “Confirmed” TB IRIS Same definition as suspected TB IRIS but
multi drug resistant TB excluded
and
a satisfactory virological response to ART

29. Diagnostic investigations
AFB may be be present or absent
Viable organisms despite TB treatment since > 2 months may suggest treatment failure
Tuberculin skin testing
88% of IRIS negative
33% of non-IRIS negative

31. Recommendations to prevent TB IRIS
Exclude TB before starting antiretroviral therapy
Treat first the TB and start antiretroviral treatment only once the patient has clinically improved, is tolerating very well his TB treatment
Increase awareness about TB IRIS

32. Treatment recommendations
TB treatment should be continued
Exclude treatment failure
Ensure adequate treatment
Ensure adherence to ATT
Consider drug resistance

33. Treatment recommendations
Drainage
Adding prednisolone/NSAIDS may be beneficial
Continue HAART in most cases
Consider stopping ARV’s if life threatening?

34. Research questions? Propose definition of IRIS
Validate clinical definition of IRIS
Incidence of TB IRIS in different populations?
Predictors/risk factors for IRIS?
Morbidity and mortality (cause of early deaths?)
What are the potential long term consequences?

35. How to diagnose TB IRIS?
What are the clinical manifestations of TB IRIS in adults and children?
Are there immunological markers or other simple laboratory parameters that could help to diagnose TB IRIS?
How useful is it to perform a tuberculin skin test prior to the start of ARVs and to repeat it when there is a suspicion of IRIS?

36. What is the pathophysiology of TB IRIS (early and late forms of IRIS)?

37. How to treat TB IRIS? Corticosteroids (dose, duration)?,
NSAIDs? thalidomide?…
Aspiration of abscesses?
Should HAART be stopped? When?
Should the management of early and late TB IRIS be different?

38. How to prevent/avoid IRIS?
When is the optimal moment HAART should be started in a HIV/TB co infected patient?
TB prophylaxis to avoid IRIS?
Corticosteriod therapy able to prevent the development of TB IRIS?

39. Operational issues
How to diagnose TB IRIS clinically at the primary health level?
When should a health care worker at the primary health care level refer a patient or call for advice?

40. Research methods
Cohort studies
Randomised clinical trials