Presentation on theme: "Tuberculosis and the Immune Reconstitution Inflammatory Syndrome (IRIS) Bob Colebunders."— Presentation transcript:
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’
4 PathogenesisIncreased lymphoproliferative response to mycobacterium antigens in vitroRestoration of cutaneous response to TuberculinIncreased [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)IndiaKumarasamy et al: IRIS of 15.2 cases per 100 patient-yearsPatel 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 treatmentDisseminated, extra-pulmonary diseaseLow base line CD4 countRise in CD4 %Fall in viral loadHigh 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
19 Prognosis Breton et al: 16 cases of TB/IRIS: 5 ‘severe’ complications Splenic ruptureCompressive lymphadenopathyUreteric obstructionNarita et al: The study found a 6-fold increased risk of subsequent TB relapse in patients who experienced IRIS during early TB treatment.
22 Differential diagnosis Side effects of the antiretroviral treatmentDrug feverTB infection not responding to standard anti-TB treatmentOther concomitant infectionFailure of HAART (late IRIS)
23 Proposed criteria for the diagnosis of IRIS in HIV patients on antiretroviral therapy French et al
24 Major criteriaAtypical presentation of ‘opportunistic infections or tumours’ in patients responding to antiretroviral therapyDecrease 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 antigensSpontaneous 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 infiltratesor 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 ofLarge adenopathiesAbscessesMiliary TB with large nodulesCavity formation
28 “Confirmed” TB IRIS Same definition as suspected TB IRIS but multi drug resistant TB excludedanda satisfactory virological response to ART
29 Diagnostic investigations AFB may be be present or absentViable organisms despite TB treatment since > 2 months may suggest treatment failureTuberculin skin testing88% of IRIS negative33% of non-IRIS negative
31 Recommendations to prevent TB IRIS Exclude TB before starting antiretroviral therapyTreat first the TB and start antiretroviral treatment only once the patient has clinically improved, is tolerating very well his TB treatmentIncrease awareness about TB IRIS
32 Treatment recommendations TB treatment should be continuedExclude treatment failureEnsure adequate treatmentEnsure adherence to ATTConsider drug resistance
33 Treatment recommendations DrainageAdding prednisolone/NSAIDS may be beneficialContinue HAART in most casesConsider stopping ARV’s if life threatening?
34 Research questions? Propose definition of IRIS Validate clinical definition of IRISIncidence 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 issuesHow 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 methodsCohort studiesRandomised clinical trials