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I NTERFERON GAMA RELEASE ASSAYS (IGRA)

I NTERFERON GAMA RELEASE ASSAYS (IGRA). Dr Zayre Erturan I.U. I stanbul Medical Faculty Dep . of M edical Microbiology. I have no conflicts of interests to disclose. TST versus in- vitro assays. Measurement of induration. Measurement of INF  production.

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I NTERFERON GAMA RELEASE ASSAYS (IGRA)

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  1. INTERFERON GAMA RELEASE ASSAYS (IGRA) DrZayreErturan I.U. IstanbulMedicalFaculty Dep. of MedicalMicrobiology

  2. I havenoconflicts of intereststodisclose

  3. TST versus in-vitroassays Measurement of induration Measurement of INFproduction Anderson P, et al. Lancet 2000; 356:1099

  4. Advantages/disadvantagesof IGRAsover TST TSTIGRA Setting of test in vivo in vitro internalcontrolsnoyes Cross-reactivitywith BCG yesno Cross-reactivitywith NTM yesno Interpretation of test subjectiveobjective Boostingeffectyesno Number of visitstwoone Time requiredforresult 48-72 h 16-24 h Test costlowhigh Laboratoryrequirement not existexist Drawingblood no yes except M. marinum, M. szulgai, M. kansasii, Richeldi L. Am J RespirCritCareMed 2006; 174:736 M. flavescensNahid P. ProcAmThoracSoc 2006;3: 10 ECDC guidance

  5. QuantiFERON –TB Gold In-TUBE (QFT-GIT) (CellestisLtdAustralia) T-SPOT. TB ( Oxford Immunotec, UK)

  6. www.cellestis.com

  7. InterpretationCriteriaforQuantiFERON-TB Gold InTube Test Positive Negative Indeterminate www.cellestis.com

  8. T-SPOT. TB – Application www.oxfordimmunotec.com

  9. T SPOT.TB-Interpretation Indeterminate Nil control Either (Panel A-Nil) or (Panel B-Nil) ≥ 8 spots Either (Panel A-Nil) or (Panel B-Nil) ≥ 8 spots positive positive Panel A:ESAT 6 Both (Panel A-Nil) and ( Panel B-Nil) ≤ 4 spots Both (Panel A-Nil) and ( Panel B-Nil) ≤ 4 spots Panel B:CFP 10 negative Indeterminate Positivecontrol borderline www.oxfordimmunotec.com

  10. Differences in TSPOT. TB and QFT-GIT T-SPOT. TB QFT-GIT Antigens ESAT-6, CFP-10 ESAT-6, CFP-10, TB 7.7 Readoutunits INF- spot-formingcells International units of INF- Technological platform ELISpot ELISA Test’ssubstratePBMC Wholeblood OutcomemeasureNumber of INF -producingT cellsSerum concentration of INF- ReadoutsystemEnumeration of spotsbynakedeye, Measurement of opticaldensity magnifying lens, orautomatedcounterusingautomatedreader Lab. Procedurescounting , separatingandIncubation of bloodcollection dispersing of PBMCstubes, noadditionalprocedure

  11. Interpretation of IGRA results • Positive M. tuberculosisinfectionlikely  latent/ active ? • Negative M. tuberculosisinfectionunlikely, but cannot be excluded • Indeterminate  ? lowmitogen, highnilvalues - Incorrectsamplecollecting, handling, incubationordelay of processing - other «technical» factors - poorpatientimmunfunction  test should be repeated •Borderline  test should be repeated

  12. IGRA Guidelines • 25 countries, 2 supranationalorganizations  33 guidelines/positionpapers USA (CDC, AAP), Canada, UK, Brazil, (France), Spain, Italy, (Germ)any, Austria,Portugal, Irland, Switzerland, Netherlands, Denmark, Norway, Finland, (CzechRepublic), Slovakia, (Poland), Bulgaria, Croatia, SaudiArabia,Avustralia, South Korea, Japan WHO, ECDC. Pai M. Int J TuberclLungDis 2010 ;14: 64 Denkinger CM et al . CMI 2011; 17: 806 www.tbevidence.org

  13. Main approachesacrosstheguidelines 1. Two-stepapproach: TST first, followedby IGRA 2. IGRA only 3. Either TST or IGRA

  14. IGRAs in thediagnosis of active TB Meta-analysis of studies in low-andmiddle-incomecountries: HIV (+) HIV (-) sensitivity T-SPOT-TB %76 % 83 QFT-GIT %60 %69 specificityT-SPOT -TB %52 %61 QFT-GIT %50 %52 MetcalfeJZ et al. J InfectDis2011;15(suppl 4): 110

  15. IGRAs in the diagnosis of active TB • Meta-analysisof studies in high-and low- TB incidencecountries: T-SPOT-TB QFT-GIT sensitivity%81 %80 specificity %59 % 79 Sester M et al. EurRespir J 2011; 37:100

  16. IGRAs in the diagnosis of active TB - WHO: recommendsagainsttheuse of IGRAsforactive TB in lowandmiddleincomecountries STAG-TB report of the 10th meeting, WHO Geneva 2010 - ECDC: IGRAsshould not replacedstandarddiagnosticmethods. However, in certainclinicalsituationsIGRAscouldcontributesupplementaryinformation as part of thediagnosticwork-up. ECDC guidance, Stockholm 2011

  17. Recommendationsforactive TB Denkinger CM et al. ; CMI 2011; 17:806

  18. IGRAs in contact investigation in adults Specificity of IGRAs %96-100 NPVforprogressionto TB within 2 years T-SPOT TB %97.8 QTF GIT %99.8 PPV forprogression 10% in UK ( 2/20 TB cases/IGRA+ve) 14% in Germany (6/41) 8% in Austria (3/36) 2-3% in Holland (6/181)

  19. IGRAs in contact investigation in adults •  Only a fewstudiesassessingthePPV forprogression of IGRAs • Studydesignvariedwidely thepresentedvaluesareuncertain • Lownumber of studiesandsmallstudypopulations insufficient • statisticalpower • it is not possibletomake a valid general statement • High NPV forprogressionmeasuredforIGRAs an individualwith a • negative IGRA resultwillmostlikely not develop TB disease in thefuture However, studiesonlycovered a smallnumber of individualsandwere restrictedtofollow –upperiods of upto 2 years Diel R ve ark. ERJ 2011; 37: 88 (TBNET/ECDC sistematicRev&Metaan. ) ECDC guidance, Stockholm 2011

  20. Rangaka M et al. Lancet Infect Dis 2012; 12:45

  21.  IGRA and TST weresimilarwiththerespecttothe risk of TB • pooled IRR : 2.11(1.29-3.46) for IGRA, • 1.60(0.94-2.72) for TST •  IGRAsand TST have • weak but similarpredictivevalueandmay not help ID • those at highest risk of progressiontodisease •  PPVfor TB in IGRA positiveindividualsis low(5%) similar • tothe TST • Rangaka M et al. LancetInfectDis 2012; 12:45

  22. IGRAs in contact investigation in adults • A combination of TST/IGRA and risk factorinformationmay be morehelpful Web – basedalgorithm • www.tstin3d.com •  TST size •  IGRA result •  Country of birth •  BCG status • recentcontactwith • active TB • Conditions • - PPV - risk of development of active TB after 2 years - cummulative risk of active TB uptotheage of 80 The online TST/IGRA Interpreter

  23. Recommendationsforcontactinvestigation in adults Denkinger CM et al. ; CMI 2011; 17:806

  24. IGRAs in contactinvestigation in children  Limited data on theuseforthediagnosis of LTBI in childrenespecially in veryyoungchildren Recentmeta-analyses TST andIGRAshavesimilaraccuracyforthedetection of TB infectionorthediagnosis of disease in children Mandalakas AM et al. Int J TubercLungDis 2011; 15: 1018 Machingaidze S et al. Pediatr InfectDis J 2011, 30: 694 Sun L et al. FEMS ImmunolMedMicrobiol 2011; 63: 165

  25. Recommendationsforcontactinvestigation in children Denkinger CM et al. ; CMI 2011; 17:806

  26. IGRAsin Immunocompromisedpatients: HIV infected individuals J Acquir Immune Defic Syndr 2011; 56:230 •  Sensitivity of IGRAs in HIV infectedPatientswithcultureconfirmedTB: • T-SPOT-TB ( 72%)  QTF-GIT (61%) • Neither IGRA wasconsistentlymoresensitivethanthe TST • AgreementbetweenIGRAsand TST washigher in high-incomecountrieswere BCG –vaccinationwasusedlessfrequently •  IGRAsarelessaffectedby HIV-relatedimmunsuppressionthanthe TST, • but thedifferencesbetweenthetestsweresmall • IGRAsperformsimilarlytothe TST in identifying HIV-infectedindividualswhocouldbenefitfrom LTBI treatment

  27. Recommendationsfor HIV-infectedpopulations Denkinger CM et al. ; CMI 2011; 17:806

  28. IGRAs in Immunocompromised patients:individuals on TNF-inhibitortherapy • Screeningfor LTBI is recommendet in manycountriespriortostarting TNF-inhibitors • Onlyfewstudieshaveevaluatedtheperformance of IGRAs in screeningfor LTBI in thesepatients • No meta-analysis, tworeviews: Thecurrentevidencedoes not suggestsuperiority of IGRAsoverthe TST in identifyinglatent TB in individualswithimmune-mediatedinflammatorydisorders Winthrop KL et al. Int J AdvRheumatol 2010; 8: 43 Smith R et al. CurOpin in Rheumatology 2011; 23:377

  29. Recommendationsforpersons on TNF-inhibitortherapy Denkinger CM et al. ; CMI 2011; 17:806

  30. IGRAs in screening of immigrants ● Inlow-incidencecountries, a majority of the TB cases occuramongrecentimmigrants screening is a key componentfor TB control  A World BCG Atlas has beenpublished:www.bcgatlas.org Zwerling A et al. PLOS Med 2011; 8: e1001012 Detailedinformation on current/past BCG policies/practices forover 180 countries betterinterpretation of TST andIGRAs

  31. Recommendationsforscreening of immigrants Denkinger CM et al. ; CMI 2011; 17:806

  32. IGRAs in serialtesting of healthcareworkers Zwerling A et al. Thorax 2012; 67:62 • Theuse of IGRAsinstead of TST forone-time screeningmayresult in a lowerprevalence of positivetestsandfewerhealthcareworkerswhorequire LTBI treatment, particularly in low TB incidencesettings • Theuse of IGRAsforserialtesting optimal cut-offs? • conversions? • reversions?

  33. Recommendationsforserialtesting of healthcareworkers Denkinger CM et al. ; CMI 2011; 17:806

  34. Conclusions-1 ● Theuse of IGRAs is increasinglyrecommended, primarily in low-incidencesettings ● There is a considerablediversity in recommendations on how exactlyIGRAsshould be used ● Inhigh-incidenceandlow-resourcecountries, the TST is stillfavored as there is nostrongevidencethatIGRAsaresuperiortothe TST ● Inlow-incidenceandhigh-resourchesettings,thehigherspecificity of IGRAsandtheirlogisticaladvantagesseemtoenhancetheiradoptionandusage ● Onereasonfortheheterogeneityamongguidelines is thatconclusive data toinformtheseguidelineswereoftenlimited

  35. Conclusions-2 - IGRA and TST arebothimperfecttestswith a lowpredictive valueforactive TB andbetterpredictivetoolsarerequired

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