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Screening for tuberculosis and the use of a borderline zone for the interpretation of the interferon-? release assay (IGRA) in Portuguese healthcare workers. PDF

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NienhausandCostaJournalofOccupationalMedicineandToxicology2013,8:1 http://www.occup-med.com/content/8/1/1 RESEARCH Open Access Screening for tuberculosis and the use of a borderline zone for the interpretation of the γ interferon- release assay (IGRA) in Portuguese healthcare workers Albert Nienhaus1,2* and José Torres Costa3 Abstract Introduction: The effect ofusing a borderline zone for theinterpretation of theinterferon-γ release assay (IGRA) on thepredictionof progression to active tuberculosis (TB) in healthcare workers(HCW) is analysed. Methods: Datafrom a published study on TB screening inPortugueseHCW is reanalysed using a borderline zone for theinterpretation of the IGRA.Testing was performed withtheQuantiFERON-TB Gold In-Tube (QFT). The borderline zone for the QFT was defined as interferon (INF)in QFT≥0.2 to <0.7 IU/mL. An X-ray was performed when theIGRA was positive (≥0.35 IU/mL) or typical symptoms were present. Sputum analysis was performed according to the X-ray or the presence of typical symptoms. Results: The cohort comprised2,884 HCW with a QFT that could be interpreted. In1,780 (61.7%) HCW, the QFT was <0.2 IU/mL.A borderline result was found in 341(11.8%)and a QFT >0.7 IU/mL in763 (26.3%) HCW. Fifty-seven HCW had a TB in their medical history, eight had a TB atthe time of screening and progression to active TB was observed infour HCW.Twoout of eight HCW (25%) with active TB atthe time of screening had a QFT result falling intothe borderline zone.One out of four HCW (25%) who progressed towards active TB after being tested with QFT had QFT results falling intothe borderline zone. A second IGRA was performed in 1,199 HCW. In total, 292 (24.4%) HCW had atleast one of the two IGRA results pertaining to the borderline zone. Conclusion: Using a borderline zone for the QFT from 0.2to 0.7 IU/mL should be administered with care, as active TB as well as progression to active TB might be overlooked. Therefore, theborderline zone should be restricted to populations witha low TB risk only. Keywords: Interferon-γrelease assay, Tuberculosis,Healthcare workers Introduction IGRA remain unanswered. This is particularly true for the Screening healthcare workers (HCW) for latent tubercu- interpretationoftheIGRAintheserialtestingofHCW. losisinfection(LTBI)andactivetuberculosis(TB)isfunda- Three reviews have covered the topic of IGRAvariabi- mental in infection control programmes in hospitals [1]. lity in the serial testing of HCW so far [11-13]. All three Meanwhile, the interferon-γ release assay (IGRA) is widely came to the conclusion that the reversion of positive used for TB screening in HCW [2-10]. Nevertheless, some IGRA results to negative results occurs more often than questionsconcerningtheinterpretationoftheresultsofthe conversion from negative to positive IGRA results. And more importantly,theprobability ofconversion orrever- sion depends on the quantitative results of the first *Correspondence:[email protected] 1UniversityMedicalCenterHamburg-Eppendorf,InstituteforHealthServices IGRA. Therefore, a borderline zone might be helpful in ResearchinDermatologyandNursing,Martinistrasse52,20246,Hamburg, order to separate real conversions and reversions in Germany 2InstitutionforStatutoryAccidentInsuranceandPreventionintheHealth IGRAfrom variationcaused bychance. andWelfareServices,Hamburg,Germany Fulllistofauthorinformationisavailableattheendofthearticle ©2013NienhausandCosta;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsofthe CreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse, distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. NienhausandCostaJournalofOccupationalMedicineandToxicology2013,8:1 Page2of5 http://www.occup-med.com/content/8/1/1 IGRA 2,889 Undetermined IGRA 5 (< 1%) Determined IGRA 2,884 IGRA negative IGRA borderline IGRA positive 1,780 (61.7%) 34.1 (11.8%) 763 (26.5%) Figure1Flowchartofstudypopulation. Two IGRA are commercially available: the ELISA- exclude active TB and to assess their pre-employment W based QuantiFERON -TB Gold In-Tube (QFT) and the status. Depending on the risk assessment, the examin- W ELISPOT-based T-SPOT.TB . So far, a borderline zone ation is repeated annually or every other year. HCW is recommended for the T-SPOT.TB by the Centers for with close contact to patients in the infection and TB Disease Control and Prevention (CDC) as well as the wards are considered to be at a high risk, workers with European Centers for Disease Control and Prevention regular contact to patients in the other wards are con- (ECDC) [14,15]. However, this recommendation is based sidered to be at a medium risk and workers with no on two rather small studies [16,17] and so far no con- regular patient contact and no contact with biological sensus has been reached regarding the definition of such material are considered to be at a low risk. After unpro- aborderlinezonefor theQFT. tected contact with an infectious patient, co-worker or Therefore, we reanalysed our data concerning TB and material,screening isperformedaswell. progression towards activeTB in HCW screened with the Since January 2007, screening has been performed QFT[18], using a borderline zone from 0.2to <0.7IU/mL using the IGRA. A chest X-ray is performed in order to forthespecificINF-γrelease. exclude active pulmonary disease when the IGRA is positive and in HCW with symptoms. For the IGRA, the Methods QuantiFERON-TBW Gold In-Tube assay (Cellestis Lim- All workers at the Hospital São João are offered TB ited, Carnegie, Australia) is used. Thiswhole-blood assay screening according to guidelines from the CDC [1]. uses overlapping peptides corresponding to ESAT-6, Upon starting employment, all workers are examined to CFP-10 and a portion of the tuberculosis antigen TB7.7 Table1ResultsofIGRAandTBinHCW TB QFTresults Total Negative Borderline Positive <0.2IU/mL 0.2–<0.7IU/mL ≥0.7IU/mL n % N % n % n % TBinhistory 16 28.1 15 26.3 26 45.6 57 2.0 ActiveTBatscreening 0 - 2 25.0 6 75.0 8 0.3 ProgressiontoactiveTB 0 - 1 25.0 3 75.0 4 0.1 NoTB 1,764 62.7 323 11.5 728 25.9 2,815 97.6 All 1,780 61.7 341 11.8 763 26.5 2,884 100.0 NienhausandCostaJournalofOccupationalMedicineandToxicology2013,8:1 Page3of5 http://www.occup-med.com/content/8/1/1 Table2ConversionandreversionratesdependingontheuseofaborderlinezoneandtheINF-γconcentrationofthe firstQFT FirstQFT SecondQFT Total <0.2IU/mL 0.2–<0.7IU/mL ≥0.7IU/mL n % n % n % n % <0.2IU/mL 588 82.0 73 10.2 56 7.8 717 59.8 0.2–<0.35IU/mL 24 35.3 18 26.5 26 38.2 68 5.7 0.35–<0.7IU/mL 48 45.7 21 20.0 36 34.3 105 8.8 ≥0.7IU/mL 45 14.6 46 14.9 218 70.6 309 25.8 All 705 58.8 158 13.2 336 28.0 1199 100.0 (Rv2654). Stimulation of the antigenic mixture occurs activeTB afterapositiveIGRA.Outofthe57HCW with within the tube used to collect blood. The tubes were an active TB in their history, 16 (28.1%) had a negative incubated overnight at 37°C before centrifugation, and IGRA and 15(26.3%) had anIGRAresultthatpertainsto INF-γ release is measured by ELISA according to the the borderline zone (Table 1). None of the HCW with a manufacturer’s protocol. All assays performed met the negativeIGRAresultwasdiagnosedwithactiveTBduring manufacturer’s quality control standards. The test is screening, or developed active TB during the follow-up considered positive when INF-γ is ≥0.35 IU/mL after period. Two HCW out of eight (25%) with active TB at correctionfor thenegative control. the time of screening had IGRA results falling into the For this analysis, a borderline zone from 0.2 to borderline zone. One HCW out of four (25%) who pro- <0.7 IU/mL was assumed, as proposed by a multicentre gressed towards activeTB after a positive IGRA result in analysisofserialQFTtestinginHCW[19].Therefore,a the screening had an IGRA result that belongs in the QFT result of <0.2 IU/mL was considered negative, a borderline zone. Therefore, applying a borderline zone result of 0.2 to <0.7 IU/mL was considered borderline wouldhaverenderedthediagnosisofTBmoredifficultin andaresultof≥0.7IU/mLwasconsideredpositive. three (25%) HCW out of twelve in whom active TB was Data analysis was performed using SPSS, Version 14 observed. (SPSS Inc., Chicago, Illinois). All persons gave their A second IGRA was performed in 1,199 HCW. The informedconsentpriortotheirinclusioninthestudy.No averagetimespanbetweenthetwoIGRAwas13.5months additionaldatawascollectedforthepurposesofthestudy (range:0–44months,standarddeviation:8.5months).The and the analysis was performed using anonymous data. result of the first IGRA was <0.2 IU/mL in 717 (59.8%), Therefore, no endorsement by an ethics committee was andtheresultofthesecondIGRAwas<0.2IU/mLin705 required. (58.8%)HCW(Table2).ThenumberofHCWwithaposi- tiveIGRA(≥0.7IU/mL)increasedfrom309(25.7%)inthe Results first IGRA to 336 (28.0%) in the second IGRA. In total, The study population comprises 2,885 HCW (Figure 1). The IGRA was indeterminate in five HCW. 61.7% of the Table4Conversionandreversionratesdependingonthe HCW had a QFT result below the borderline zone useofaborderlinezoneandthetimespanbetweenthe (<0.2IU/mL).11.8%hadaresultfallingintotheborderline firstandsecondQFT zone and 25.9% of the HCW tested had a positive QFT Timebetweenfirst SecondQFT Total (≥0.7IU/mL).Fifty-seven(2.0%)HCWhadahistoryofac- andsecondQFT <0.2 0.2–<0.7 ≥0.7 tive TB. Active TB was diagnosed in eight HCW during IU/mL IU/mL IU/mL screening and four HCW showed progression towards n % n % n % n % FirstQFT<0.2IU/mL Table3ResultsofthefirstandsecondQFT(negative: <0.35IU/mL,positive:≥0.35IU/mL) <9months 167 83.1 22 10.9 12 6.0 201 100.0 First SecondQFT Total 9–<16months 263 89.5 19 6.5 12 4.1 294 100.0 QFT Negative Positive ≥16months 158 71.2 32 14.4 32 14.4 222 100.0 n % n % n % FirstQFT≥0.7IU/mL Negative 657 83.7 128 16.3 785 <9months 34 30.6 15 13.5 62 55.9 111 100.0 Positive 120 29.0 294 71.0 414 9–<16months 4 3.8 16 15.2 85 81.0 105 100.0 All 777 64.8 422 35.2 1,199 100.0 ≥16months 7 7.5 15 16.1 71 76.3 93 100.0 NienhausandCostaJournalofOccupationalMedicineandToxicology2013,8:1 Page4of5 http://www.occup-med.com/content/8/1/1 292(24.4%)HCWhadatleastoneofthetwoIGRAresults borderline zone for the QFT may be harmful, as was pertainingtotheborderlinezone(calculatedfromTable2). shownbyourdata. Aconversiondefinedastrespassingoftheborderlinezone To our dismay, we are not able to propose which TB from negative to positive was observed in 56 (7.8%) of the prevalencetheuseofaborderlinezonefortheQFTmight HCWwithanegative(<0.2IU/mL)firstIGRA.Areversion be usefulfor.Until today,dataon diseasedetection in TB analogous to this definition was observed in 45 (14.6%) of screenings of HCW and on disease prediction with the the HCW with a first IGRA result of ≥0.7 IU/mL. With a IGRA has been frustratingly sparse or non-existent. For simple dichotomous approach, conversion and reversion contact tracings, the situation is much better, as recent rateswereabouttwiceashighat16.3%and29.0%,respect- publications from two large studies from Germany and ively(Table3). the UK are available [23-25]. However, these studies did Withthetimebetweenthetwo IGRAtheprobabilityof not consider the use of a borderline zone. In the German a conversion (trespassing the borderline zone) increased contact tracing study [24], progression to active TB was, (Table 4). However, the increase was not monotonous. however, observed in close contacts with a positive QFT With less than nine months between the two IGRA, the resultofbetween0.35and0.7IU/mL.Therefore,forthese conversion rate was 6.0%, with nine to 16 months in be- contacttracings,theuseofaborderlinezonefortheQFT tween it was 4.1% and with ≥16 months it was 14.4% isnotadvisable,either. (Table 4). The reversion rate did decrease with time from For the T-SPOT.TB, a borderline zone has already 30.6%to3.8%and7.5%,respectively. been proposed by the CDC and ECDC [14,15]. How- ever, as mentioned above, the recommendation is based Discussion on little data. As it was shown that the specificity of the This is the first study to report data on disease detection T-SPOT. TB is lower than the specificity of the QFT in TB screenings of HCW and on disease prediction with [26], an analogous approach to the QFT might not be theIGRAusingaborderlinezonefortheinterpretationof justified. the QFT. Applying a borderline zone, the conversion was The use of the IGRA for screening close contacts or reduced to 7.8%, which seems to be more realistic than HCWisendorsedinseveralnationalguidelines[15,27-29]. the 14.6% with a dichotomous approach, taking the rela- Taking the advantages of the IGRA over the tuberculin tivelyshortaveragetimespanbetweenthetwoIGRAinto skin test intoconsideration,this is well justified.However, consideration (mean: 13.5 months). The reversion rate is these guidelines lack the recommendation to systematic- reduced from 29.0% to 14.6%. Assuming that a latent TB ally evaluate the screenings in order to better understand infection (LTBI) is long lasting and immunologic theireffectiveness andefficiency andtheroleoftheIGRA responsestotheLTBIdonotchangerapidly,thelowerre- withintheseendeavours.Beforeconsensusontheuseofa versionratemightbemorerealistic,too. borderline zone for the QFT can be reached, more and However, introducing a borderline zone comes with a betterdataondiseasepredictionwiththeQFTisneeded. price. The QFT is less sensitive for activeTB and for the prediction of TB when a borderline zone is applied and a Competinginterest chest X-ray is not performed in those with a QFT result Theauthorsdeclarethattheydonothaveanydirectorindirectpersonal relationship,affiliationorassociationwithanypartywithwhomtheydealin withintheborderlinezone.Inourpopulationinparticular, theirday-to-dayworkthatwouldgiverisetoanyactualorperceived 25% of the activeTB cases detected would probably have competinginterest. sufferedfromdelayeddiagnosiswhenstrictlyapplyingthe borderline zone. As the positive predictive value of a la- Authors’contribution boratorytestincreases withthe prevalenceof the diseases JTCdesignedthestudy,performedthephysicalexaminationsandwas involvedindraftingthepaper.ANanalysedthedataandwrotethefirstdraft testedforandviceversa,itmightbesafetoassumethatin ofthepaper.Bothauthorsreadandapprovedthefinalmanuscript. apopulationwithaverylowprevalence,andthereforein- cidence, of activeTB, the application of a borderline zone Authordetails 1UniversityMedicalCenterHamburg-Eppendorf,InstituteforHealthServices is beneficial. Under these circumstances, the number of ResearchinDermatologyandNursing,Martinistrasse52,20246,Hamburg, X-rays and preventive chemotherapies is reduced, render- Germany.2InstitutionforStatutoryAccidentInsuranceandPreventioninthe ing the screening to likely be more efficient. The HCW HealthandWelfareServices,Hamburg,Germany.3FacultyofMedicine,Porto University,AlamedaProfessorHernâniMonteiro,Porto,Portugal. studies from the United States published recently might describetypicalcohortsthatwillprofitfromtheintroduc- Received:17December2012Accepted:25January2013 tion of a borderline zone for QFT. In these studies, the Published:28January2013 rates of positive QFT were low and reversion rates were high [20-22]. In parenthesis, it might be considered if TB References 1. JensenPA,LambertLA,IademarcoMF,RidzonR:Guidelinesforpreventing screeninginthesepopulationsisefficientatall.Inapopu- thetransmissionofmycobacteriumtuberculosisinhealthcaresettings. lation with a higher risk of TB, the introduction of a MMWR2005,54(RR-17):1–141. NienhausandCostaJournalofOccupationalMedicineandToxicology2013,8:1 Page5of5 http://www.occup-med.com/content/8/1/1 2. NienhausA,SchablonA,SianoB,leBacleC,DielR:Evaluationofthe 22. 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