Table Of ContentNienhausandCostaJournalofOccupationalMedicineandToxicology2013,8:1
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
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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
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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
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