INT J TUBERC LUNG DIS 18(4):413–420 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0589
Added value of interferon-gamma release assays in screening for tuberculous infection in the Netherlands C. G. M. Erkens,* A. G. Dinmohamed,*† M. Kamphorst,‡ S. Toumanian,§ R. van Nispen-Dobrescu,¶ M. Alink,# N. Oudshoorn,** M. Mensen,†† S. van den Hof,*‡‡ M. Borgdorff,††§§ S. Verver*‡‡ *KNCV Tuberculosis Foundation, The Hague, †Erasmus Medical Center, Rotterdam, ‡Public Health Service Rotterdam Rijnmond, Rotterdam, §GGD Twente, Enschede, ¶GGD Brabant Zuidoost, Eindhoven, #GGD Zuid Limburg, Heerlen, **GGD Den Haag, Den Haag, ††Public Health Services Amsterdam, Amsterdam, ‡‡Department of Global Health and Amsterdam Institute for Global Health and Development, Academic Medical Centre, University of Amsterdam, Amsterdam, §§University of Amsterdam, Clinical Epidemiology and Biostatistics, Amsterdam, The Netherlands SUMMARY B A C K G R O U N D : Interferon-gamma release assays (IGRAs) are reported to be more specific for the diagnosis of latent tuberculous infection (LTBI) than the tuberculin skin test (TST). The two-step procedure, TST followed by an IGRA, is reported to be costeffective in high-income countries, but it requires more financial resources. O B J E C T I V E : To assess the added value of IGRA compared to TST alone in the Netherlands. M E T H O D S : Test results and background data on persons tested with an IGRA were recorded by the Public Municipal Health Services in a web-based database. The number of persons diagnosed with LTBI using different screening algorithms was calculated. R E S U LT S : In those tested with an IGRA, at least 60% of persons who would have been diagnosed with LTBI
based on TST alone had a negative IGRA. Among those with a TST reaction below the cut-off for the diagnosis of LTBI, 13% had a positive IGRA. For 41% of persons tested with an IGRA after TST, the IGRA influenced whether or not an LTBI diagnosis would be made. C O N C L U S I O N : With the IGRA as reference standard, a high proportion of persons in low-prevalence settings are treated unnecessarily for LTBI if tested with TST alone, while a small proportion eligible for preventive treatment are missed. Incremental costs of the two-step strategy seem to be balanced by the improved targeting of preventive treatment. K E Y W O R D S : cost-effectiveness; public health resources; latent tuberculous infection; interferon-gamma release assay
THE NETHERLANDS is a low tuberculosis (TB) incidence country, with an incidence of 6 cases per 100 000 population in 2011. For more than two decades, targeted diagnosis and treatment of latent tuberculous infection (LTBI) has been an important component of TB control efforts. Target groups for LTBI case finding are listed in the Appendix.* From 1993 to 2011, 35 088 persons diagnosed with LTBI were notified and 27 308 (78%) started treatment. However, the low positive predictive value of the tuberculin skin test (TST) when used in populations with a low likelihood of infection has posed a challenge for the accurate diagnosis of LTBI. Before the introduction of interferon-gamma release assays (IGRAs), skin tests with antigens of common non-
tuberculous mycobacteria were often used in addition to TST to confirm LTBI. The specificity of IGRAs is higher than that of the conventional TST for the diagnosis of LTBI in immune-competent individuals,1–5 while the sensitivity is comparable. Several cost-effectiveness studies support the use of IGRAs in high-income countries, with TST followed by an IGRA being the more cost-effective strategy.6–11 In 2007, IGRA was introduced in the Netherlands for LTBI diagnosis. A two-step procedure using an IGRA as a confirmatory test in the case of TST 5 mm was applied per international recommendations.12 As the use of an IGRA would claim considerable resources from the TB control budget, it was decided that the added value of IGRAs in different target populations for LTBI screening in the Netherlands should be evaluated prospectively. The specific objectives were 1) to evaluate the adoption of the
*The appendix is available in the online version of this article, at http://www.ingentaconnect.com/content/ iuatld/ijtld/2014/00000018/00000004/00000008
Correspondence to: C G M Erkens, KNCV Tuberculosis Foundation, PO Box 146, 2501C The Hague, The Netherlands. Tel: (þ31) 704 167 222. Fax: (þ31) 703 358 4004. e-mail: [email protected] Article submitted 13 August 2013. Final version accepted 4 December 2013.
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two-step test strategy with the TST and an IGRA in TB control practice; 2) to determine the impact of the use of an IGRA in terms of numbers of persons diagnosed with LTBI and eligible for preventive treatment, compared to the use of the TST alone; and 3) to estimate the overall incremental costs for TB control as well as the incremental cost per LTBI diagnosis.
METHODS Of the 25 Public Municipal Health Services (PMHS) with a TB control unit, 19 participated in the study and contributed data on all individuals screened with an IGRA from 1 January 2008 to 31 December 2010. Demographic characteristics, comorbidity, bacille Calmette-Gu´erin (BCG) vaccination status, past and recent exposure, and results of TST (purified protein derivative RT23, 0.1 ml intracutaneous, Statens Serum Institute, Copenhagen, Denmark) and IGRA were entered directly in a central web-based database by the PMHS or retrieved from the electronic client register of the PMHS by dedicated registrars. Data were checked for duplicates, completeness and consistency. If inconsistent, the client registry was rechecked and data corrected. The final database was anonymised before analysis. Incomplete records, records of persons examined for active TB and records with unknown or indeterminate IGRA results were excluded from the analysis. Ethical approval was not required, as this was a non-experimental evaluation study using anonymous data. In April 2011, information from the PMHS on LTBI test policy and protocols, target groups for IGRA, how the IGRA was financed, perceived obstacles and the total number of TSTs and IGRAs performed during the study period was collected. The main outcome measure for added value of an IGRA was defined as the number and percentage of persons with a change in LTBI diagnosis based on the IGRA result for the following two categories of cases: 1) those with a positive IGRA, who would not have been eligible for preventive treatment on the basis of the TST reaction. This group included persons BCGvaccinated after infancy and those with a TST reaction below the cut-off value for the diagnosis of LTBI per national TST guidelines (Appendix Table). 2) Those with a negative IGRA who would have been eligible for preventive treatment on the basis of the TST reaction per national TST guidelines. Changes in the diagnosis of LTBI were calculated for the various target groups for LTBI screening and stratified according to the reported PMHS test policy. We also calculated the incremental cost of testing with IGRA alone and IGRA after TST 5 mm or after TST 10 mm compared with TST alone. The number of persons tested with an IGRA was based on the
proportion of persons tested with IGRAs after TST by the PMHS that follow the national recommendations. The costs of screening and preventive treatment were based on estimates from a study by Kik et al.13,14 All analyses were performed using IBM SPSS Statistics, version 19 (IBM Corporation, Armonk, NY, USA).
RESULTS Level of adoption of the two-step strategy per the national IGRA guidelines At the time of the survey, all 19 PMHS participating in the study used an IGRA mainly as a confirmatory test in a two-step procedure with TST. Of these, 5 used IGRA per the national recommendations (Appendix Table) on a routine basis, 5 used a locally adapted version of the national recommendations, and 9 used an IGRA only in cases when the TB physician doubted the accuracy of the diagnosis based on TST reaction. The locally adapted guidelines used a cut-off of 10 mm instead of 5 mm for the initial TST, or used IGRAs only in specific target groups, e.g., BCG-vaccinated contacts of infectious TB patients. Ten PMHS did not use IGRA in persons with a TST conversion, defined as an increase in TST reaction of 10 mm within a period of 2 years. Nine PMHS excluded specific groups from LTBI diagnosis, in particular persons with a presumed high likelihood of previous infection, such as immigrants from endemic areas, persons born before 1945, and persons who were previously TST-positive. PMHS that did not follow the national guidelines reported that limitations in the possibilities of financing IGRAs were the main reason for their limited use. Five PMHS partially paid for the cost of the IGRA from the PMHS budget, while other PMHS claimed the costs from the client’s insurance. PHMS tested in total 91 334 persons using the TST and 4497 with an IGRA (Table 1). PMHS performed 16% of the TSTs and 40% of the IGRAs per the national guidelines. Overall, 4.9 persons were tested using IGRAs for every 100 persons tested using TST. The actual proportion of persons tested using IGRAs after TST was lower, as on average 12% of the persons tested using IGRAs were not tested using TST. Added value of IGRA testing During the study period, a total of 4295 records were registered in the database. After data cleaning, the final database included 3789 records of individuals evaluated for LTBI (Figure). In 97% of the cases, the IGRA was performed using QuantiFERONw-TB Gold (Cellestis, Carnegie, VIC, Australia) and 3% with T-SPOTw.TB (Oxford Immunotec, Abingdon, UK). On average, 27% of the persons tested were IGRA-positive; 35 were diagnosed with active TB, of whom 9 were IGRA-negative (Table 2). Of 1054 persons diagnosed with LTBI by the clinician, 93%
Added value of IGRA in LTBI diagnosis
Table 1
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Number of IGRAs performed in relation to the number of TSTs in participating PMHS centres, 2008–2010 Persons tested, n†
PMHS testing policy* National policy, TST cut-off 5 mm Local policy, TST cut-off 10 mm No protocol, ad hoc use of IGRAs Total
TST (col %) 15 22 54 91
014 319 001 334
(16) (24) (59) (100)
IGRA (col %) 1821 1183 1493 4497
(40) (26) (33) (100)
IGRA /100 TST
Valid records in IGRA database n
12.1 5.3 2.8 4.9
1324 1256 1209 3789
*The local protocol at the PMHS may have changed over the study period. Cases are assigned to the protocol category at the time of the performance of the test. † Source: Client PMHS registers. IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; PMHS ¼ Public Municipal Health Service.
were IGRA-positive. IGRA positivity increased with the likelihood of infection, defined by level of recent exposure (Table 2) and size of TST reaction (TST ,5 mm: 8%; TST 5–10 mm: 10%; TST 10–14 mm: 18%; and TST .15 mm: 47%). Of 3352 persons tested using the TST, 1899 (57%) had a TST reaction above the cut-off point for diagnosis of LTBI using TST alone. In this group, 1155 (61%) persons were IGRA-negative. Of 1453 persons with a TST reaction below the TST cut-off point for LTBI, 192 (13%) were IGRA-positive. Of 437 persons tested with an IGRA alone, 100 (23%) were IGRA-positive (Table 3). The IGRA was positive among respectively 44%, 43% and 30% of TSTpositive persons per the national recommendations, those who used a local protocol and those who used ad hoc IGRAs. The percentage of persons with a change of diagnosis LTBI when using a two-step
strategy for TST and IGRA was 41% overall, 48% in persons who tested after possible exposure and 38% in TB contacts (Table 4). Incremental costs of IGRAs and the two-step strategy The number of LTBI cases and the incremental costs of IGRA per LTBI case for a cohort of 10 000 persons tested for LTBI are presented in Table 5. The incremental cost per LTBI case diagnosed with an IGRA alone, or using a two-step strategy with TST 5 mm and 10 mm as a cut-off, was respectively E1428, E124 and E43. If the IGRA test cost drops to E30, the incremental costs would be respectively E519, E9 and -E55 (data not shown). Comparing the two-step screening strategies, the incremental cost of finding an extra LTBI case with a TST cut-off point at 5 mm instead of 10 mm is E750. Assuming a lifetime risk of activation of 10%, an effectiveness of
Figure Study population. *Cut-off for LTBI as defined in TST guideline 2005, see Appendix Table. IGRA ¼ interferon-gamma release assay; TB ¼ tuberculosis; LTBI ¼ latent tuberculous infection; TST ¼ tuberculin skin test.
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Table 2
Characteristics of persons tested with IGRAs and test results, 2008–2010 IGRA-negative
IGRA-positive
Total
n
Row %
n
Row %
n
Column %
Total National policy, TST cut-off 5 mm Local policy, TST cut-off 10 mm No protocol, ad hoc use of IGRAs
2753 930 853 970
73 77 68 73
1036 279 403 354
27 23 32 27
3789 1209 1256 1324
100 32 33 35
Sex Male Female
1115 1634
67 77
554 481
33 23
1669 2115
44 56
Age, years ,5 5–14 15–29 30–44 45
25 79 1114 682 846
89 73 77 69 71
3 42 327 313 344
11 27 23 31 29
28 121 1441 995 1190
1 3 38 26 31
Country of origin Born in The Netherlands Foreign-born
1866 887
78 63
516 520
22 37
2382 1407
63 37
Number of years in endemic area 0 .0–11 12 Unknown
1909 319 268 263
77 69 52 79
581 141 246 70
23 31 48 21
2490 460 514 333
66 12 14 9
BCG status No BCG BCG before first year of age BCG after infancy BCG status unknown
1361 158 835 399
78 61 66 77
390 101 428 117
22 39 34 23
1751 259 1263 516
46 7 33 14
Reason for examination Baseline measurement (no known recent TB exposure)* Source investigation Contact investigation Screening before immune-suppressive therapy/immune suppression Health care worker screening Visitors to endemic areas after visit Visitors to endemic areas before visit Other
393 82 1359 28 358 263 159 111
79 75 67 60 81 87 80 72
106 28 677 19 82 41 40 43
21 25 33 40 19 13 20 28
499 110 2036 47 440 304 199 154
13 3 54 1 4 12 8 5
691 921 386 755
77 81 68 64
208 219 180 429
23 19 32 36
899 1140 566 1184
24 30 15 31
TST reaction, mm 0–4 5–9 10–14 15
118 521 1072 705
92 90 82 53
10 56 242 628
8 10 18 47
128 577 1314 1333
3 15 35 35
TST result per guidelines‡ Positive (above cut-off) Negative (below cut-off) No TST
1155 1261 337
61 87 77
744 192 100
39 13 23
1899 1453 437
50 38 12
Final diagnosis§ No LTBI Recent LTBI Remote LTBI Active TB No diagnosis, further examination planned
2596 57 21 9 70
100 7 12 26 74
10 818 158 26 24
0 93 88 74 26
2606 875 179 35 94
69 23 5 1 2
Likelihood of infection† Low exposure Possible exposure Probable exposure High exposure
*Includes health care workers or other contact groups eligible for LTBI screening before potential exposure, for whom a baseline measurement would indicate whether a positive test result after potential exposure could be attributed to recent exposure. † High exposure: close contacts of sputum smear-positive TB patients; probable exposure: other contacts of TB patients; possible exposure: persons with possible exposure outside the context of contact investigation (professional contacts and visitors after visits to high-endemic areas); low exposure: persons with no or unlikely exposure (professional contacts and visitors before visits to high-endemic areas). ‡ Cut-off point for LTBI as defined in 2005 TST guidelines, see Appendix Table. § Based on operational data. ´ IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; BCG ¼ bacille Calmette-Guerin; TB ¼ tuberculosis; LTBI ¼ latent tuberculous infection.
DISCUSSION
*Cut-off for LTBI as defined in the 2005 TST guidelines, see Online Supplementary Table. IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; LTBI ¼ latent tuberculous infection; PMHS ¼ Public Municipal Health Service.
1324 1256 1209 3789
35 33 32 100
5/52 0/26 5/50 10/128
(10) (0) (10) (8)
35/331 5/77 16/169 56/577
(11) (6) (9) (10)
90/380 74/452 78/482 242/1314
(24) (16) (16) (18)
179/339 314/652 135/342 628/1333
(53) (48) (39) (47)
223/503 342/803 179/593 744/1899
(44) (43) (30) (39) (20) (20) (27) (23) 45/222 10/49 45/166 100/437
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preventive treatment of 70% and a treatment completion rate of 85%, the incremental cost per TB case averted of the two-step strategy with a TST cut-off 5 mm would be E12 605 (data not shown). Using a two-step approach with TST 5 mm or 10 mm, respectively 86% and 360% of the cost of IGRA screening is recouped through the reduction in LTBI diagnosis and the associated costs for preventive treatment in comparison with LTBI diagnosis and treatment on the basis of TST alone.
National policy, TST cut-off 5 mm Local policy, TST cut-off 10 mm No protocol, ad hoc use of IGRAs Total
TST 15 mm TST 10–14 mm Column %
TST 0–4 mm
TST 5–9 mm
IGRA-positive, n/N (%)
Number of records in study population PMHS testing policy
Table 3
Percentage of IGRA-positive individuals in study population by TST induration size
IGRA-database study population
IGRA only, no TST
TST cut-off for LTBI*
Added value of IGRA in LTBI diagnosis
The IGRA was negative in 61% of those who would have been diagnosed with LTBI on the basis of TST alone. Furthermore, 13% of all persons with a reaction below the TST cut-off point for LTBI diagnosis were diagnosed with LTBI on the basis of a positive IGRA. Overall, for 41% of all persons tested with an IGRA after TST, the IGRA result would have consequences for individual case management in terms of LTBI diagnosis and preventive treatment. The estimated incremental cost of the national policy to use IGRA as a confirmatory test for LTBI diagnosis is E124 per person with LTBI diagnosed. If the cost of the IGRA test can be reduced to E30, the incremental cost will be negligible. IGRAs were used on an ad hoc basis, and a positive TST was not routinely confirmed using an IGRA in nearly 60% of the population targeted for LTBI screening during the study period. Financial constraints were mentioned by half of the PMHS centres as the main barrier to IGRA use according to the then prevailing recommendations. Other barriers were lack of confidence in the added value of IGRAs when TST was ,10 mm or clearly positive (e.g., TST reaction .15 mm in nonvaccinated TB contacts), and/or in case of a TST conversion. Our study provides evidence that, in a large proportion of these LTBI cases, overdiagnosis is likely. Moreover, our data show that those using financial constraints as an argument for not using an IGRA do not take the cost savings of unnecessary treatment into consideration. Based on these results, we therefore conclude that under operational conditions in a low-prevalence country, the twostep procedure is a feasible and cost-saving strategy. Furthermore, it avoids unnecessary testing with IGRAs, which poses an extra demand on limited public health resources. Two regional TB services claimed that the TST cutoff of 5 mm was too sensitive, given the high likelihood of a negative IGRA in BCG-vaccinated persons with a TST ,10 mm. For reasons of efficiency, they preferred a higher cut-off of 10 mm for the confirmatory test with an IGRA. Using a higher cut-off of TST 10 mm is indeed a cheaper strategy, and is actually cost-saving in our estimates.
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Table 4 Change of LTBI diagnosis based on TST and IGRA results in different target groups for screening IGRA Positive n
TST cut-off for LTBI*
TB contacts (high and probable exposure) Above 538 Below 92 Total 630
Change of diagnosis LTBI Negative n
Total n
n
%
606 592 1198
1144 684 1828
606 92 698
53 13 38
Health care workers baseline examination (before possible exposure) and visitors before visit to endemic areas (low risk of exposure) Above 81 211 292 211 72 Below 50 306 356 50 14 Total 131 517 648 261 40 Health care workers and visitors after visit to endemic areas (possible exposure) Above 72 268 340 Below 32 253 285 Total 104 521 625 Other target groups (low risk of exposure) Above 53 Below 18 Total 71 Total persons tested with TST Above Below Total
744 192 936
268 32 300
79 11 48
70 110 180
123 128 251
70 18 88
57 14 35
1155 1261 2416
1899 1453 3352
1155 192 1347
61 13 40
*Per national TST guidelines (Online Appendix). LTBI ¼ latent tuberculous infection; TST ¼ tuberculin skin test; IGRA ¼ interferon-gamma release assay.
However, the additional cost of the screening strategy with TST 5 mm is within the limits of a costeffective public health intervention.16,17 Our study confirms that the chance of a positive IGRA increases with level of exposure and size of TST reaction, irrespective of BCG vaccination status (Table 3). However, even among close contacts of infectious TB patients with a TST induration of .15
mm, the agreement between TST and IGRA was lower than 60% (data not shown). This suggests that in all cases, IGRAs are of considerable added value, as the negative predictive value (NPV) of IGRAs is regarded as being very high.18 The highest added value for IGRAs was observed in travellers and health care workers without documented exposure who were tested serially. Similar data were found among
Table 5 Cost estimation of LTBI screening strategies in a cohort of 10 000 persons compared with screening with TST alone and 100% acceptance of preventive treatment Baseline test Costs*
Costs/person E
TST E
TST, 10 100 000 IGRA 60 Preventive treatment 250 LTBI diagnoses, n 445† Estimated number of false-positive LTBI diagnoses, n# 89 Cost of preventive treatment 111 250 Cost of preventive treatment in false-positive LTBI 22 250 Total cost of screening and preventive treatment 211 250 Increase total cost of screening with IGRAs Incremental costs of IGRAs per LTBI diagnosis Total treatment costs saved Incremental costs of IGRAs compensated through savings on preventive treatment, % Incremental cost of IGRAs with cut-off TST 5 mm compared to 10 mm Incremental cost of IGRAs per extra LTBI detected
Screening strategy All IGRA E
TST 5 mm þ IGRA E
TST 10 mm þ IGRA E
600 000
100 000 72 000
100 000 54 000
330‡ 3 82 500 825 682 500 471 250 1428 28 750 6
78 250 38
*Cost estimation per Kik et al.14 † Number based on observed number of TSTs cut-off for LTBI per national TST guidelines. ‡ Based on the observed number of IGRA-positives and TST 5 mm and estimated extra LTBI among persons with TST,5 mm. § Based on the observed number of IGRA-positives and TST 5 mm. ¶ Based on the observed number of IGRA-positives and TST 10 mm. # Based on specificity for TST 5 mm of 80% and for IGRA 99%.15 LTBI ¼ latent tuberculous infection; TST ¼ tuberculin skin test; IGRA ¼ interferon-gamma release assay.
33
312§ 3 000 780 000 750 124 250 86
69 223 11 42 27
276¶ 3 000 690 000 750 43 250 360 000 750
Added value of IGRA in LTBI diagnosis
military personnel in the Netherlands.19 However, in health care workers the value of IGRAs is also questioned due to the false conversions, reversions and variations over time observed in many studies.20 Moreover, in a situation with a high likelihood of infection, the NPV of the IGRA will be lower than in a situation with low expected prevalence. It is not clear to what extent the national policy to base LTBI diagnosis on IGRA results leads to under-treatment of persons at risk of developing TB. Scientific evidence on the predictive value of IGRAs for the development of TB is still scarce. In 2009, a prospective study in foreign-born close contacts of highly infectious TB patients showed that the risk for TST- or IGRApositive immigrant contacts of developing active TB within the next 2 years was 3%. This study showed that in this particular target group of individuals with a higher likelihood of previous M. tuberculosis infection, the NPV of the IGRA for the progression to active TB was lower than that of the TST. Other studies in different target populations yielded heterogeneous results.21–23 We have therefore decided to link the cohort to the national TB surveillance system to observe whether persons in our database develop TB within 2 years after testing. National surveillance data on annual LTBI notifications show a likely effect of the introduction of IGRAs.24 The number of native Dutch persons diagnosed and treated for LTBI has decreased considerably, while the number of foreign-born individuals with a higher risk of recent exposure has increased. These trends support our hypothesis that the use of IGRAs enables improved targeting of preventive treatment to those most at risk for development of active TB. The routine setting of our study led to some study limitations. The population in this evaluation study was not a random selection of those screened for LTBI, as IGRAs were not systematically used per national recommendations in all participating PMHS centres. However, we believe that PMHS results per national recommendations are most representative and least subject to selection bias. For the analysis of the added value of IGRAs, we defined eligibility for preventive treatment on the basis of TST reaction, level of recent exposure, the susceptibility of the person to develop TB when infected and IGRA positivity. However, the physician’s decision to offer preventive treatment will normally be based on medical history and assessment of these three components, which have not been captured in detail in this study. Only 69% of individuals with a positive IGRA in our study population were actually offered preventive treatment (data not shown). The numbers of persons eligible for preventive treatment may therefore have been overestimated. Furthermore, in practice, 7% of those diagnosed with LTBI by a physician were
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IGRA-negative. In these cases, the IGRA did not have an added value for diagnosis. On the basis of our study findings, the Committee of Practical Tuberculosis Control advised national authorities in 2011 to allow public use of IGRAs. As of July 2013, the PMHS can claim the material costs of IGRA use from the client’s health care insurance. Inappropriate financial barriers for IGRA use per the professional guidelines have thus been cleared.
CONCLUSION We conclude that IGRAs reduce the number of unnecessary preventive treatments of LTBI in the Netherlands; at the same time, the use of IGRAs also increases the number of persons eligible for preventive treatment. This results in better targeted preventive treatment of tuberculous infection. The two-step strategy of TST, followed by IGRA, reduces incremental costs, while these costs are at least partially compensated by a reduction in the cost of preventive treatment. In high-income, low TB prevalence settings, diagnosis of LTBI should preferably be based on the TST in combination with an IGRA. Acknowledgements This work was supported by the Netherlands Organisation for Health Research and Development, The Hague (ZonMw, Grant number: 50-50800-98-106) and KNCV Tuberculosis Foundation, The Hague, The Netherlands. Conflict of interest: none declared
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APPENDIX Table
TST and IGRA guidelines for LTBI diagnosis in target groups for LTBI screening 2005 TST guidelines
Indication for LTBI case finding and screening method*
TST cut-off for prophylaxis
2010 IGRA guidelines
Screening method†‡
Indication for prophylaxis
Contact investigation (high exposure ¼ close and casual contacts of sputum smear-positive index patient; probable exposure ¼ other contacts) BCG after infancy
All BCG-vaccinated
CXR immediately after diagnosis of index patient and single TST after window period (8 weeks)
Close contacts of sputum smear-positive TB patient: TST 15 mm
CXR in two rounds (immediately after diagnosis of index patient and after 3 months)
All other contacts: no target group for LTBI screening and prophylaxis
All close contacts: CXR immediately after diagnosis of index patient and serial or single TST after window period, followed by IGRA when TST 5 mm
Positive IGRA
Positive IGRA
BCG before age of 1 year* CXR immediately after diagnosis of index patient and single TST
Close contact: TST 10 mm Other contact: TST 15 mm
All other contacts: single TST after window period, followed by IGRA when TST 5 mm
Positive IGRA
5 years: TST 10 mm
5 years; CXR immediately after diagnosis of index patient and serial TST after window period, followed by IGRA when TST 5 mm , 5 years; as for those aged 5 years, but IGRA when TST 5 mm and TST , 10 mm (all child contacts)
Positive IGRA
Non-BCG-vaccinated* Close contacts CXR immediately after diagnosis of index patient and serial TST in two rounds immediately after diagnosis of index patient and after window period (8 weeks) Other contacts
,5 years: TST 10 mm Primary prophylaxis if TST , 10 mm†
Serial TST in two Other contact: TST 15 mm rounds or single TST after window period Immune-compromised individuals CXR and serial TST in two rounds
TST 10 mm or positive IGRA: primary prophylaxis during the window period if close contacts TST , 5 mm§ or IGRA-negative§
As for BCG-vaccinated contacts and child contacts ,5 years
Positive IGRA
Regardless of BCG status: TST and IGRA if TST ,5 mm
TST 5 mm or positive IGRA Primary prophylaxis during the window period if close contact and TST,5 mm or negative IGRA§
TST 10 mm or TST 15 mm (TST cut-off based on history and likelihood of infection)
Regardless of BCG status: CXR and TST,# followed by IGRA when TST 5 mm
Positive IGRA and high likelihood of recent infection
No target group for LTBI screening and prophylaxis
Regardless of BCG status: CXR and TST,# followed by IGRA when TST 5 mm
Positive IGRA and high likelihood of recent infection
TST 15 mm and likelihood of recent infection
Regardless of BCG status: TST followed by IGRA when TST 5 mm
Positive IGRA and high likelihood of recent infection
No target group for LTBI screening and prophylaxis
Regardless of BCG status: TST followed by IGRA when TST 5 mm
Positive IGRA and high likelihood of recent infection
TST 5 mm Close contact: primary prophylaxis if TST ,5 mm†
Source investigation (possible exposure)¶ No BCG or BCG in infancy CXR and single TST
BCG after infancy CXR
Baseline measurement (low exposure)** No BCG or BCG in infancy TST
BCG after infancy CXR
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Table
Continued 2005 TST guidelines
Indication for LTBI case finding and screening method*
TST cut-off for prophylaxis
2010 IGRA guidelines
Screening method†‡
Indication for prophylaxis
Possible TB exposure (health care worker, travellers) (possible exposure) No BCG or BCG in infancy TST TST 10 mm BCG after infancy CXR
Regardless of BCG status: TST followed by IGRA when TST 5 mm
Positive IGRA
No target group for LTBI prophylaxis
Screening before immunosuppressive therapy (immune-competent individual) (low exposure)‡ CXR and TST
Prophylaxis/anti-tuberculosis treatment of inadequately treated TB and likelihood of infection in the past BCG after infancy: TST 10 Regardless of BCG status: CXR, TST mm and IGRA if TST , 10 mm No BCG or BCG in infancy: TST 5 mm
TST 10 mm or positive IGRA
All indications HIV-infected and other immunocompromised individuals (low exposure)‡ CXR and TST
Prophylaxis/anti-tuberculosis treatment of inadequately treated TB and likelihood of infection in the past TST 5 mm CXR, TST and IGRA if TST , 5 mm
TST 5 mm or positive IGRA
*Individuals born before 1 January 1945 or living .12 years in a TB-endemic country (.50 per 100 000 population). No target group for LTBI screening with TST to detect recent infection with M. tuberculosis. † If previous TST 5 mm and IGRA-negative or unknown: IGRA only. ‡ Including persons born before 1 January 1945 or living .12 years in a TB-endemic country. § Primary prophylaxis is discontinued when second TST ,5 mm (and/or IGRA) in individuals with a reliable immune response at the end of the latency period (8 weeks after last exposure to infection). ¶ Performed in TB patients likely to be recently infected in the Netherlands with no identified source case. # TST is performed to identify co-infected individuals, who may lead to the putative source case. **Includes travellers and health care workers or other contact groups eligible for serial LTBI screening after potential exposure, for whom a baseline measurement would indicate whether a positive test result after potential exposure could be attributed to recent exposure. ´ TST ¼ tuberculin skin test; IGRA ¼ interferon-gamma release assay; LTBI ¼ latent tuberculous infection; BCG ¼ bacille Calmette-Guerin; CXR ¼ chest X-ray; HIV ¼ human immunodeficiency virus; TB ¼ tuberculosis.
Added value of IGRA in LTBI diagnosis
iii
RESUME C O N T E X T E : Les tests de lib´eration de l’interf´eron gamma (IGRA) sont r´eput´es d’ˆetre plus sp´ecifiques pour le diagnostic d’une infection tuberculeuse latente (LTBI) que le test cutan´e a` la tuberculine (TST). La proc´edure en deux e´ tapes de la TST suivie par l’IGRA est r´eput´ee rentable dans les pays a` hauts revenus, mais elle n´ecessite davantage de ressources financi`eres. O B J E C T I F : Evaluer la valeur ajout e´ e de l’IGRA compar´ee a` la TST seule aux Pays-Bas. M E´ T H O D E S : Les services de sant´e publics municipaux (PMHS) ont enregistr´e les r´esultats des tests et les donn´ees de contexte des personnes test´ees avec l’IGRA dans une base de donn´ees en ligne. Le nombre de personnes chez qui une LTBI a e´ t´e diagnostiqu´ee grace ˆ aux diff´erents tests de d´epistage a e´ t´e calcul´e. R E´ S U LT A T S : Chez les patients test´es par IGRA, au
moins 60% des patients qui auraient eu un diagnostic de LTBI bas´e sur la TST seule avaient un IGRA n´egatif. Parmi ceux qui avaient une r´eaction TST en-dessous du seuil de diagnostic de LTBI, 13% avaient un test IGRA positif. Pour 41% des personnes test´ees par IGRA apr`es TST, le r´esultat de l’IGRA influen¸cait la confirmation du diagnostic de LTBI. C O N C L U S I O N : En utilisant l’IGRA comme test de r´ef´erence, une proportion e´ lev´ee de personnes vivant dans des zones de faible pr´evalence est inutilement trait´ee pour LTBI si le diagnostic est e´ tabli sur la TST seule, alors qu’une faible proportion de personnes justiciables d’un traitement pr´eventif est oubli´ee. Le cout ˆ marginal de la strat´egie en deux temps semble donc compense´ par un meilleur ciblage du traitement pr´eventif. RESUMEN
M A R C O D E R E F E R E N C I A : Se ha notificado que las pruebas de liberacion ´ de interferon ´ gama (IGRA) son ma´s espec´ıficas en el diagnostico ´ de la infeccion ´ tuberculosa latente (LTBI) que la prueba cuta´nea de la tuberculina (TST). El procedimiento diagnostico ´ en dos etapas que consiste en una reaccion ´ TST seguida de una IGRA ha demostrado ser una estrategia rentable en los pa´ıses con altos ingresos, pero precisa ma´s recursos economicos. ´ O B J E T I V O : Evaluar el valor agregado de la IGRA al compararla con la TST exclusiva en los Pa´ıses Bajos. M E´ T O D O S : Los servicios municipales publicos ´ de salud registraron en una base de datos en internet los resultados de las pruebas y los datos generales de las personas en quienes se practico´ la IGRA. Se calculo´ el numero ´ de personas con diagnostico ´ de LTBI mediante diferentes algoritmos de deteccion. ´ R E S U L T A D O S : De las personas examinadas con la
IGRA, como m´ınimo 60% de los casos que se hubiesen diagnosticado como LTBI con base en una TST exclusiva obtuvo un resultado negativo en la IGRA. En las personas con una reaccion ´ TST por debajo el umbral diagnostico ´ de la LTBI, 13% presento´ una prueba positiva de IGRA. En 41% de las personas examinadas con la IGRA despu´es de la TST, el resultado de la IGRA influyo´ sobre la decision ´ diagnostica ´ de LTBI. ´ N : Al considerar la IGRA como referencia, CONCLUSIO una alta proporcion ´ de personas reciben tratamiento innecesario por LTBI cuando se utiliza la TST exclusivamente en un entorno con baja prevalencia y se pasa por alto una pequena ´ de casos con ˜ proporcion indicacion ´ de tratamiento preventivo. Al parecer el incremento en el costo de la estrategia en dos etapas, se compensa con la optimizacion ´ de la seleccion ´ de casos que reciben el tratamiento preventivo.
Added value of interferon-gamma release assays in screening for tuberculous infection in the Netherlands C. G. M. Erkens,* A. G. Dinmohamed,*† M. Kamphorst,‡ S. Toumanian,§ R. van Nispen-Dobrescu,¶ M. Alink,# N. Oudshoorn,** M. Mensen,†† S. van den Hof,*‡‡ M. Borgdorff,††§§ S. Verver*‡‡ *KNCV Tuberculosis Foundation, The Hague, †Erasmus Medical Center, Rotterdam, ‡Public Health Service Rotterdam Rijnmond, Rotterdam, §GGD Twente, Enschede, ¶GGD Brabant Zuidoost, Eindhoven, #GGD Zuid Limburg, Heerlen, **GGD Den Haag, Den Haag, ††Public Health Services Amsterdam, Amsterdam, ‡‡Department of Global Health and Amsterdam Institute for Global Health and Development, Academic Medical Centre, University of Amsterdam, Amsterdam, §§University of Amsterdam, Clinical Epidemiology and Biostatistics, Amsterdam, The Netherlands SUMMARY B A C K G R O U N D : Interferon-gamma release assays (IGRAs) are reported to be more specific for the diagnosis of latent tuberculous infection (LTBI) than the tuberculin skin test (TST). The two-step procedure, TST followed by an IGRA, is reported to be costeffective in high-income countries, but it requires more financial resources. O B J E C T I V E : To assess the added value of IGRA compared to TST alone in the Netherlands. M E T H O D S : Test results and background data on persons tested with an IGRA were recorded by the Public Municipal Health Services in a web-based database. The number of persons diagnosed with LTBI using different screening algorithms was calculated. R E S U LT S : In those tested with an IGRA, at least 60% of persons who would have been diagnosed with LTBI
based on TST alone had a negative IGRA. Among those with a TST reaction below the cut-off for the diagnosis of LTBI, 13% had a positive IGRA. For 41% of persons tested with an IGRA after TST, the IGRA influenced whether or not an LTBI diagnosis would be made. C O N C L U S I O N : With the IGRA as reference standard, a high proportion of persons in low-prevalence settings are treated unnecessarily for LTBI if tested with TST alone, while a small proportion eligible for preventive treatment are missed. Incremental costs of the two-step strategy seem to be balanced by the improved targeting of preventive treatment. K E Y W O R D S : cost-effectiveness; public health resources; latent tuberculous infection; interferon-gamma release assay
THE NETHERLANDS is a low tuberculosis (TB) incidence country, with an incidence of 6 cases per 100 000 population in 2011. For more than two decades, targeted diagnosis and treatment of latent tuberculous infection (LTBI) has been an important component of TB control efforts. Target groups for LTBI case finding are listed in the Appendix.* From 1993 to 2011, 35 088 persons diagnosed with LTBI were notified and 27 308 (78%) started treatment. However, the low positive predictive value of the tuberculin skin test (TST) when used in populations with a low likelihood of infection has posed a challenge for the accurate diagnosis of LTBI. Before the introduction of interferon-gamma release assays (IGRAs), skin tests with antigens of common non-
tuberculous mycobacteria were often used in addition to TST to confirm LTBI. The specificity of IGRAs is higher than that of the conventional TST for the diagnosis of LTBI in immune-competent individuals,1–5 while the sensitivity is comparable. Several cost-effectiveness studies support the use of IGRAs in high-income countries, with TST followed by an IGRA being the more cost-effective strategy.6–11 In 2007, IGRA was introduced in the Netherlands for LTBI diagnosis. A two-step procedure using an IGRA as a confirmatory test in the case of TST 5 mm was applied per international recommendations.12 As the use of an IGRA would claim considerable resources from the TB control budget, it was decided that the added value of IGRAs in different target populations for LTBI screening in the Netherlands should be evaluated prospectively. The specific objectives were 1) to evaluate the adoption of the
*The appendix is available in the online version of this article, at http://www.ingentaconnect.com/content/ iuatld/ijtld/2014/00000018/00000004/00000008
Correspondence to: C G M Erkens, KNCV Tuberculosis Foundation, PO Box 146, 2501C The Hague, The Netherlands. Tel: (þ31) 704 167 222. Fax: (þ31) 703 358 4004. e-mail: [email protected] Article submitted 13 August 2013. Final version accepted 4 December 2013.
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two-step test strategy with the TST and an IGRA in TB control practice; 2) to determine the impact of the use of an IGRA in terms of numbers of persons diagnosed with LTBI and eligible for preventive treatment, compared to the use of the TST alone; and 3) to estimate the overall incremental costs for TB control as well as the incremental cost per LTBI diagnosis.
METHODS Of the 25 Public Municipal Health Services (PMHS) with a TB control unit, 19 participated in the study and contributed data on all individuals screened with an IGRA from 1 January 2008 to 31 December 2010. Demographic characteristics, comorbidity, bacille Calmette-Gu´erin (BCG) vaccination status, past and recent exposure, and results of TST (purified protein derivative RT23, 0.1 ml intracutaneous, Statens Serum Institute, Copenhagen, Denmark) and IGRA were entered directly in a central web-based database by the PMHS or retrieved from the electronic client register of the PMHS by dedicated registrars. Data were checked for duplicates, completeness and consistency. If inconsistent, the client registry was rechecked and data corrected. The final database was anonymised before analysis. Incomplete records, records of persons examined for active TB and records with unknown or indeterminate IGRA results were excluded from the analysis. Ethical approval was not required, as this was a non-experimental evaluation study using anonymous data. In April 2011, information from the PMHS on LTBI test policy and protocols, target groups for IGRA, how the IGRA was financed, perceived obstacles and the total number of TSTs and IGRAs performed during the study period was collected. The main outcome measure for added value of an IGRA was defined as the number and percentage of persons with a change in LTBI diagnosis based on the IGRA result for the following two categories of cases: 1) those with a positive IGRA, who would not have been eligible for preventive treatment on the basis of the TST reaction. This group included persons BCGvaccinated after infancy and those with a TST reaction below the cut-off value for the diagnosis of LTBI per national TST guidelines (Appendix Table). 2) Those with a negative IGRA who would have been eligible for preventive treatment on the basis of the TST reaction per national TST guidelines. Changes in the diagnosis of LTBI were calculated for the various target groups for LTBI screening and stratified according to the reported PMHS test policy. We also calculated the incremental cost of testing with IGRA alone and IGRA after TST 5 mm or after TST 10 mm compared with TST alone. The number of persons tested with an IGRA was based on the
proportion of persons tested with IGRAs after TST by the PMHS that follow the national recommendations. The costs of screening and preventive treatment were based on estimates from a study by Kik et al.13,14 All analyses were performed using IBM SPSS Statistics, version 19 (IBM Corporation, Armonk, NY, USA).
RESULTS Level of adoption of the two-step strategy per the national IGRA guidelines At the time of the survey, all 19 PMHS participating in the study used an IGRA mainly as a confirmatory test in a two-step procedure with TST. Of these, 5 used IGRA per the national recommendations (Appendix Table) on a routine basis, 5 used a locally adapted version of the national recommendations, and 9 used an IGRA only in cases when the TB physician doubted the accuracy of the diagnosis based on TST reaction. The locally adapted guidelines used a cut-off of 10 mm instead of 5 mm for the initial TST, or used IGRAs only in specific target groups, e.g., BCG-vaccinated contacts of infectious TB patients. Ten PMHS did not use IGRA in persons with a TST conversion, defined as an increase in TST reaction of 10 mm within a period of 2 years. Nine PMHS excluded specific groups from LTBI diagnosis, in particular persons with a presumed high likelihood of previous infection, such as immigrants from endemic areas, persons born before 1945, and persons who were previously TST-positive. PMHS that did not follow the national guidelines reported that limitations in the possibilities of financing IGRAs were the main reason for their limited use. Five PMHS partially paid for the cost of the IGRA from the PMHS budget, while other PMHS claimed the costs from the client’s insurance. PHMS tested in total 91 334 persons using the TST and 4497 with an IGRA (Table 1). PMHS performed 16% of the TSTs and 40% of the IGRAs per the national guidelines. Overall, 4.9 persons were tested using IGRAs for every 100 persons tested using TST. The actual proportion of persons tested using IGRAs after TST was lower, as on average 12% of the persons tested using IGRAs were not tested using TST. Added value of IGRA testing During the study period, a total of 4295 records were registered in the database. After data cleaning, the final database included 3789 records of individuals evaluated for LTBI (Figure). In 97% of the cases, the IGRA was performed using QuantiFERONw-TB Gold (Cellestis, Carnegie, VIC, Australia) and 3% with T-SPOTw.TB (Oxford Immunotec, Abingdon, UK). On average, 27% of the persons tested were IGRA-positive; 35 were diagnosed with active TB, of whom 9 were IGRA-negative (Table 2). Of 1054 persons diagnosed with LTBI by the clinician, 93%
Added value of IGRA in LTBI diagnosis
Table 1
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Number of IGRAs performed in relation to the number of TSTs in participating PMHS centres, 2008–2010 Persons tested, n†
PMHS testing policy* National policy, TST cut-off 5 mm Local policy, TST cut-off 10 mm No protocol, ad hoc use of IGRAs Total
TST (col %) 15 22 54 91
014 319 001 334
(16) (24) (59) (100)
IGRA (col %) 1821 1183 1493 4497
(40) (26) (33) (100)
IGRA /100 TST
Valid records in IGRA database n
12.1 5.3 2.8 4.9
1324 1256 1209 3789
*The local protocol at the PMHS may have changed over the study period. Cases are assigned to the protocol category at the time of the performance of the test. † Source: Client PMHS registers. IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; PMHS ¼ Public Municipal Health Service.
were IGRA-positive. IGRA positivity increased with the likelihood of infection, defined by level of recent exposure (Table 2) and size of TST reaction (TST ,5 mm: 8%; TST 5–10 mm: 10%; TST 10–14 mm: 18%; and TST .15 mm: 47%). Of 3352 persons tested using the TST, 1899 (57%) had a TST reaction above the cut-off point for diagnosis of LTBI using TST alone. In this group, 1155 (61%) persons were IGRA-negative. Of 1453 persons with a TST reaction below the TST cut-off point for LTBI, 192 (13%) were IGRA-positive. Of 437 persons tested with an IGRA alone, 100 (23%) were IGRA-positive (Table 3). The IGRA was positive among respectively 44%, 43% and 30% of TSTpositive persons per the national recommendations, those who used a local protocol and those who used ad hoc IGRAs. The percentage of persons with a change of diagnosis LTBI when using a two-step
strategy for TST and IGRA was 41% overall, 48% in persons who tested after possible exposure and 38% in TB contacts (Table 4). Incremental costs of IGRAs and the two-step strategy The number of LTBI cases and the incremental costs of IGRA per LTBI case for a cohort of 10 000 persons tested for LTBI are presented in Table 5. The incremental cost per LTBI case diagnosed with an IGRA alone, or using a two-step strategy with TST 5 mm and 10 mm as a cut-off, was respectively E1428, E124 and E43. If the IGRA test cost drops to E30, the incremental costs would be respectively E519, E9 and -E55 (data not shown). Comparing the two-step screening strategies, the incremental cost of finding an extra LTBI case with a TST cut-off point at 5 mm instead of 10 mm is E750. Assuming a lifetime risk of activation of 10%, an effectiveness of
Figure Study population. *Cut-off for LTBI as defined in TST guideline 2005, see Appendix Table. IGRA ¼ interferon-gamma release assay; TB ¼ tuberculosis; LTBI ¼ latent tuberculous infection; TST ¼ tuberculin skin test.
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Table 2
Characteristics of persons tested with IGRAs and test results, 2008–2010 IGRA-negative
IGRA-positive
Total
n
Row %
n
Row %
n
Column %
Total National policy, TST cut-off 5 mm Local policy, TST cut-off 10 mm No protocol, ad hoc use of IGRAs
2753 930 853 970
73 77 68 73
1036 279 403 354
27 23 32 27
3789 1209 1256 1324
100 32 33 35
Sex Male Female
1115 1634
67 77
554 481
33 23
1669 2115
44 56
Age, years ,5 5–14 15–29 30–44 45
25 79 1114 682 846
89 73 77 69 71
3 42 327 313 344
11 27 23 31 29
28 121 1441 995 1190
1 3 38 26 31
Country of origin Born in The Netherlands Foreign-born
1866 887
78 63
516 520
22 37
2382 1407
63 37
Number of years in endemic area 0 .0–11 12 Unknown
1909 319 268 263
77 69 52 79
581 141 246 70
23 31 48 21
2490 460 514 333
66 12 14 9
BCG status No BCG BCG before first year of age BCG after infancy BCG status unknown
1361 158 835 399
78 61 66 77
390 101 428 117
22 39 34 23
1751 259 1263 516
46 7 33 14
Reason for examination Baseline measurement (no known recent TB exposure)* Source investigation Contact investigation Screening before immune-suppressive therapy/immune suppression Health care worker screening Visitors to endemic areas after visit Visitors to endemic areas before visit Other
393 82 1359 28 358 263 159 111
79 75 67 60 81 87 80 72
106 28 677 19 82 41 40 43
21 25 33 40 19 13 20 28
499 110 2036 47 440 304 199 154
13 3 54 1 4 12 8 5
691 921 386 755
77 81 68 64
208 219 180 429
23 19 32 36
899 1140 566 1184
24 30 15 31
TST reaction, mm 0–4 5–9 10–14 15
118 521 1072 705
92 90 82 53
10 56 242 628
8 10 18 47
128 577 1314 1333
3 15 35 35
TST result per guidelines‡ Positive (above cut-off) Negative (below cut-off) No TST
1155 1261 337
61 87 77
744 192 100
39 13 23
1899 1453 437
50 38 12
Final diagnosis§ No LTBI Recent LTBI Remote LTBI Active TB No diagnosis, further examination planned
2596 57 21 9 70
100 7 12 26 74
10 818 158 26 24
0 93 88 74 26
2606 875 179 35 94
69 23 5 1 2
Likelihood of infection† Low exposure Possible exposure Probable exposure High exposure
*Includes health care workers or other contact groups eligible for LTBI screening before potential exposure, for whom a baseline measurement would indicate whether a positive test result after potential exposure could be attributed to recent exposure. † High exposure: close contacts of sputum smear-positive TB patients; probable exposure: other contacts of TB patients; possible exposure: persons with possible exposure outside the context of contact investigation (professional contacts and visitors after visits to high-endemic areas); low exposure: persons with no or unlikely exposure (professional contacts and visitors before visits to high-endemic areas). ‡ Cut-off point for LTBI as defined in 2005 TST guidelines, see Appendix Table. § Based on operational data. ´ IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; BCG ¼ bacille Calmette-Guerin; TB ¼ tuberculosis; LTBI ¼ latent tuberculous infection.
DISCUSSION
*Cut-off for LTBI as defined in the 2005 TST guidelines, see Online Supplementary Table. IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; LTBI ¼ latent tuberculous infection; PMHS ¼ Public Municipal Health Service.
1324 1256 1209 3789
35 33 32 100
5/52 0/26 5/50 10/128
(10) (0) (10) (8)
35/331 5/77 16/169 56/577
(11) (6) (9) (10)
90/380 74/452 78/482 242/1314
(24) (16) (16) (18)
179/339 314/652 135/342 628/1333
(53) (48) (39) (47)
223/503 342/803 179/593 744/1899
(44) (43) (30) (39) (20) (20) (27) (23) 45/222 10/49 45/166 100/437
417
preventive treatment of 70% and a treatment completion rate of 85%, the incremental cost per TB case averted of the two-step strategy with a TST cut-off 5 mm would be E12 605 (data not shown). Using a two-step approach with TST 5 mm or 10 mm, respectively 86% and 360% of the cost of IGRA screening is recouped through the reduction in LTBI diagnosis and the associated costs for preventive treatment in comparison with LTBI diagnosis and treatment on the basis of TST alone.
National policy, TST cut-off 5 mm Local policy, TST cut-off 10 mm No protocol, ad hoc use of IGRAs Total
TST 15 mm TST 10–14 mm Column %
TST 0–4 mm
TST 5–9 mm
IGRA-positive, n/N (%)
Number of records in study population PMHS testing policy
Table 3
Percentage of IGRA-positive individuals in study population by TST induration size
IGRA-database study population
IGRA only, no TST
TST cut-off for LTBI*
Added value of IGRA in LTBI diagnosis
The IGRA was negative in 61% of those who would have been diagnosed with LTBI on the basis of TST alone. Furthermore, 13% of all persons with a reaction below the TST cut-off point for LTBI diagnosis were diagnosed with LTBI on the basis of a positive IGRA. Overall, for 41% of all persons tested with an IGRA after TST, the IGRA result would have consequences for individual case management in terms of LTBI diagnosis and preventive treatment. The estimated incremental cost of the national policy to use IGRA as a confirmatory test for LTBI diagnosis is E124 per person with LTBI diagnosed. If the cost of the IGRA test can be reduced to E30, the incremental cost will be negligible. IGRAs were used on an ad hoc basis, and a positive TST was not routinely confirmed using an IGRA in nearly 60% of the population targeted for LTBI screening during the study period. Financial constraints were mentioned by half of the PMHS centres as the main barrier to IGRA use according to the then prevailing recommendations. Other barriers were lack of confidence in the added value of IGRAs when TST was ,10 mm or clearly positive (e.g., TST reaction .15 mm in nonvaccinated TB contacts), and/or in case of a TST conversion. Our study provides evidence that, in a large proportion of these LTBI cases, overdiagnosis is likely. Moreover, our data show that those using financial constraints as an argument for not using an IGRA do not take the cost savings of unnecessary treatment into consideration. Based on these results, we therefore conclude that under operational conditions in a low-prevalence country, the twostep procedure is a feasible and cost-saving strategy. Furthermore, it avoids unnecessary testing with IGRAs, which poses an extra demand on limited public health resources. Two regional TB services claimed that the TST cutoff of 5 mm was too sensitive, given the high likelihood of a negative IGRA in BCG-vaccinated persons with a TST ,10 mm. For reasons of efficiency, they preferred a higher cut-off of 10 mm for the confirmatory test with an IGRA. Using a higher cut-off of TST 10 mm is indeed a cheaper strategy, and is actually cost-saving in our estimates.
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Table 4 Change of LTBI diagnosis based on TST and IGRA results in different target groups for screening IGRA Positive n
TST cut-off for LTBI*
TB contacts (high and probable exposure) Above 538 Below 92 Total 630
Change of diagnosis LTBI Negative n
Total n
n
%
606 592 1198
1144 684 1828
606 92 698
53 13 38
Health care workers baseline examination (before possible exposure) and visitors before visit to endemic areas (low risk of exposure) Above 81 211 292 211 72 Below 50 306 356 50 14 Total 131 517 648 261 40 Health care workers and visitors after visit to endemic areas (possible exposure) Above 72 268 340 Below 32 253 285 Total 104 521 625 Other target groups (low risk of exposure) Above 53 Below 18 Total 71 Total persons tested with TST Above Below Total
744 192 936
268 32 300
79 11 48
70 110 180
123 128 251
70 18 88
57 14 35
1155 1261 2416
1899 1453 3352
1155 192 1347
61 13 40
*Per national TST guidelines (Online Appendix). LTBI ¼ latent tuberculous infection; TST ¼ tuberculin skin test; IGRA ¼ interferon-gamma release assay.
However, the additional cost of the screening strategy with TST 5 mm is within the limits of a costeffective public health intervention.16,17 Our study confirms that the chance of a positive IGRA increases with level of exposure and size of TST reaction, irrespective of BCG vaccination status (Table 3). However, even among close contacts of infectious TB patients with a TST induration of .15
mm, the agreement between TST and IGRA was lower than 60% (data not shown). This suggests that in all cases, IGRAs are of considerable added value, as the negative predictive value (NPV) of IGRAs is regarded as being very high.18 The highest added value for IGRAs was observed in travellers and health care workers without documented exposure who were tested serially. Similar data were found among
Table 5 Cost estimation of LTBI screening strategies in a cohort of 10 000 persons compared with screening with TST alone and 100% acceptance of preventive treatment Baseline test Costs*
Costs/person E
TST E
TST, 10 100 000 IGRA 60 Preventive treatment 250 LTBI diagnoses, n 445† Estimated number of false-positive LTBI diagnoses, n# 89 Cost of preventive treatment 111 250 Cost of preventive treatment in false-positive LTBI 22 250 Total cost of screening and preventive treatment 211 250 Increase total cost of screening with IGRAs Incremental costs of IGRAs per LTBI diagnosis Total treatment costs saved Incremental costs of IGRAs compensated through savings on preventive treatment, % Incremental cost of IGRAs with cut-off TST 5 mm compared to 10 mm Incremental cost of IGRAs per extra LTBI detected
Screening strategy All IGRA E
TST 5 mm þ IGRA E
TST 10 mm þ IGRA E
600 000
100 000 72 000
100 000 54 000
330‡ 3 82 500 825 682 500 471 250 1428 28 750 6
78 250 38
*Cost estimation per Kik et al.14 † Number based on observed number of TSTs cut-off for LTBI per national TST guidelines. ‡ Based on the observed number of IGRA-positives and TST 5 mm and estimated extra LTBI among persons with TST,5 mm. § Based on the observed number of IGRA-positives and TST 5 mm. ¶ Based on the observed number of IGRA-positives and TST 10 mm. # Based on specificity for TST 5 mm of 80% and for IGRA 99%.15 LTBI ¼ latent tuberculous infection; TST ¼ tuberculin skin test; IGRA ¼ interferon-gamma release assay.
33
312§ 3 000 780 000 750 124 250 86
69 223 11 42 27
276¶ 3 000 690 000 750 43 250 360 000 750
Added value of IGRA in LTBI diagnosis
military personnel in the Netherlands.19 However, in health care workers the value of IGRAs is also questioned due to the false conversions, reversions and variations over time observed in many studies.20 Moreover, in a situation with a high likelihood of infection, the NPV of the IGRA will be lower than in a situation with low expected prevalence. It is not clear to what extent the national policy to base LTBI diagnosis on IGRA results leads to under-treatment of persons at risk of developing TB. Scientific evidence on the predictive value of IGRAs for the development of TB is still scarce. In 2009, a prospective study in foreign-born close contacts of highly infectious TB patients showed that the risk for TST- or IGRApositive immigrant contacts of developing active TB within the next 2 years was 3%. This study showed that in this particular target group of individuals with a higher likelihood of previous M. tuberculosis infection, the NPV of the IGRA for the progression to active TB was lower than that of the TST. Other studies in different target populations yielded heterogeneous results.21–23 We have therefore decided to link the cohort to the national TB surveillance system to observe whether persons in our database develop TB within 2 years after testing. National surveillance data on annual LTBI notifications show a likely effect of the introduction of IGRAs.24 The number of native Dutch persons diagnosed and treated for LTBI has decreased considerably, while the number of foreign-born individuals with a higher risk of recent exposure has increased. These trends support our hypothesis that the use of IGRAs enables improved targeting of preventive treatment to those most at risk for development of active TB. The routine setting of our study led to some study limitations. The population in this evaluation study was not a random selection of those screened for LTBI, as IGRAs were not systematically used per national recommendations in all participating PMHS centres. However, we believe that PMHS results per national recommendations are most representative and least subject to selection bias. For the analysis of the added value of IGRAs, we defined eligibility for preventive treatment on the basis of TST reaction, level of recent exposure, the susceptibility of the person to develop TB when infected and IGRA positivity. However, the physician’s decision to offer preventive treatment will normally be based on medical history and assessment of these three components, which have not been captured in detail in this study. Only 69% of individuals with a positive IGRA in our study population were actually offered preventive treatment (data not shown). The numbers of persons eligible for preventive treatment may therefore have been overestimated. Furthermore, in practice, 7% of those diagnosed with LTBI by a physician were
419
IGRA-negative. In these cases, the IGRA did not have an added value for diagnosis. On the basis of our study findings, the Committee of Practical Tuberculosis Control advised national authorities in 2011 to allow public use of IGRAs. As of July 2013, the PMHS can claim the material costs of IGRA use from the client’s health care insurance. Inappropriate financial barriers for IGRA use per the professional guidelines have thus been cleared.
CONCLUSION We conclude that IGRAs reduce the number of unnecessary preventive treatments of LTBI in the Netherlands; at the same time, the use of IGRAs also increases the number of persons eligible for preventive treatment. This results in better targeted preventive treatment of tuberculous infection. The two-step strategy of TST, followed by IGRA, reduces incremental costs, while these costs are at least partially compensated by a reduction in the cost of preventive treatment. In high-income, low TB prevalence settings, diagnosis of LTBI should preferably be based on the TST in combination with an IGRA. Acknowledgements This work was supported by the Netherlands Organisation for Health Research and Development, The Hague (ZonMw, Grant number: 50-50800-98-106) and KNCV Tuberculosis Foundation, The Hague, The Netherlands. Conflict of interest: none declared
References 1 Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008; 149: 177–184. 2 Diel R, Goletti D, Ferrara G, et al. Interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis. Eur Respir J 2011; 37: 88–99. 3 Arend S M, Thijsen S F, Leyten E M, et al. Comparison of two interferon-gamma assays and tuberculin skin test for tracing tuberculosis contacts. Am J Respir Crit Care Med 2007; 175: 618–627. 4 Franken W P, Koster B F, Bossink A W, et al. Follow-up study of tuberculosis-exposed supermarket customers with negative tuberculin skin test results in association with positive gamma interferon release assay results. Clin Vaccine Immunol 2007; 14: 1239–1241. 5 Lalvani A, Richeldi L, Kunst H. Interferon gamma assays for tuberculosis. Lancet Infect Dis 2005; 5: 322–324; author reply 5–7. 6 Dheda K, van Zyl Smit R, Badri M, Pai M. T-cell interferongamma release assays for the rapid immunodiagnosis of tuberculosis: clinical utility in high-burden vs. low-burden settings. Curr Opin Pulm Med 2009; 15: 188–200. 7 Diel R, Nienhaus A, Loddenkemper R. Cost-effectiveness of interferon-gamma release assay screening for latent tuberculosis infection treatment in Germany. Chest 2007; 131: 1424– 1434. 8 Hardy A B, Varma R, Collyns T, Moffitt S J, Mullarkey C, Watson J P. Cost-effectiveness of the NICE guidelines for screening for latent tuberculosis infection: the QuantiFERON-
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TB Gold IGRA alone is more cost-effective for immigrants from high burden countries. Thorax 2010; 65: 178–180. Nienhaus A, Schablon A, Costa J T, Diel R. Systematic review of cost and cost-effectiveness of different TB-screening strategies. BMC Health Serv Res 2011; 11: 247. Pareek M, Watson J P, Ormerod L P, et al. Screening of immigrants in the UK for imported latent tuberculosis: a multicentre cohort study and cost-effectiveness analysis. Lancet Infect Dis 2011; 11: 435–444. Thijsen S F, van Rossum S V, Arend S, Koster B, Machiels A M, Bossink A W. The value of interferon gamma release assays for diagnosis infection with Mycobacterium tuberculosis during an annual screening of health care workers. J Occup Environ Med 2008; 50: 1207–1208. Drobniewski F, Cobelens F, Zellweger J P. Use of gammainterferon assays in low- and medium-prevalence countries in Europe: a consensus statement of a Wolfheze Workshop organised by KNCV/EuroTB, Vilnius, Lithuania, September 2006. Euro Surveill 2007; 12: E070726.2. Kik S V, Franken W P, Mensen M, et al. Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts. Eur Respir J 2010; 35: 1346–1353. Kik S V, Olthof S P, de Vries J T, et al. Direct and indirect costs of tuberculosis among immigrant patients in the Netherlands. BMC Public Health 2009; 9: 283. Flores L L, Steingart K R, Dendukuri N, et al. Systematic review and meta-analysis of antigen detection tests for the diagnosis of tuberculosis. Clin Vaccine Immunol 2011; 18: 1616–1627. Cartwright W S. Methods for the economic evaluation of health
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Added value of IGRA in LTBI diagnosis
i
APPENDIX Table
TST and IGRA guidelines for LTBI diagnosis in target groups for LTBI screening 2005 TST guidelines
Indication for LTBI case finding and screening method*
TST cut-off for prophylaxis
2010 IGRA guidelines
Screening method†‡
Indication for prophylaxis
Contact investigation (high exposure ¼ close and casual contacts of sputum smear-positive index patient; probable exposure ¼ other contacts) BCG after infancy
All BCG-vaccinated
CXR immediately after diagnosis of index patient and single TST after window period (8 weeks)
Close contacts of sputum smear-positive TB patient: TST 15 mm
CXR in two rounds (immediately after diagnosis of index patient and after 3 months)
All other contacts: no target group for LTBI screening and prophylaxis
All close contacts: CXR immediately after diagnosis of index patient and serial or single TST after window period, followed by IGRA when TST 5 mm
Positive IGRA
Positive IGRA
BCG before age of 1 year* CXR immediately after diagnosis of index patient and single TST
Close contact: TST 10 mm Other contact: TST 15 mm
All other contacts: single TST after window period, followed by IGRA when TST 5 mm
Positive IGRA
5 years: TST 10 mm
5 years; CXR immediately after diagnosis of index patient and serial TST after window period, followed by IGRA when TST 5 mm , 5 years; as for those aged 5 years, but IGRA when TST 5 mm and TST , 10 mm (all child contacts)
Positive IGRA
Non-BCG-vaccinated* Close contacts CXR immediately after diagnosis of index patient and serial TST in two rounds immediately after diagnosis of index patient and after window period (8 weeks) Other contacts
,5 years: TST 10 mm Primary prophylaxis if TST , 10 mm†
Serial TST in two Other contact: TST 15 mm rounds or single TST after window period Immune-compromised individuals CXR and serial TST in two rounds
TST 10 mm or positive IGRA: primary prophylaxis during the window period if close contacts TST , 5 mm§ or IGRA-negative§
As for BCG-vaccinated contacts and child contacts ,5 years
Positive IGRA
Regardless of BCG status: TST and IGRA if TST ,5 mm
TST 5 mm or positive IGRA Primary prophylaxis during the window period if close contact and TST,5 mm or negative IGRA§
TST 10 mm or TST 15 mm (TST cut-off based on history and likelihood of infection)
Regardless of BCG status: CXR and TST,# followed by IGRA when TST 5 mm
Positive IGRA and high likelihood of recent infection
No target group for LTBI screening and prophylaxis
Regardless of BCG status: CXR and TST,# followed by IGRA when TST 5 mm
Positive IGRA and high likelihood of recent infection
TST 15 mm and likelihood of recent infection
Regardless of BCG status: TST followed by IGRA when TST 5 mm
Positive IGRA and high likelihood of recent infection
No target group for LTBI screening and prophylaxis
Regardless of BCG status: TST followed by IGRA when TST 5 mm
Positive IGRA and high likelihood of recent infection
TST 5 mm Close contact: primary prophylaxis if TST ,5 mm†
Source investigation (possible exposure)¶ No BCG or BCG in infancy CXR and single TST
BCG after infancy CXR
Baseline measurement (low exposure)** No BCG or BCG in infancy TST
BCG after infancy CXR
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The International Journal of Tuberculosis and Lung Disease
Table
Continued 2005 TST guidelines
Indication for LTBI case finding and screening method*
TST cut-off for prophylaxis
2010 IGRA guidelines
Screening method†‡
Indication for prophylaxis
Possible TB exposure (health care worker, travellers) (possible exposure) No BCG or BCG in infancy TST TST 10 mm BCG after infancy CXR
Regardless of BCG status: TST followed by IGRA when TST 5 mm
Positive IGRA
No target group for LTBI prophylaxis
Screening before immunosuppressive therapy (immune-competent individual) (low exposure)‡ CXR and TST
Prophylaxis/anti-tuberculosis treatment of inadequately treated TB and likelihood of infection in the past BCG after infancy: TST 10 Regardless of BCG status: CXR, TST mm and IGRA if TST , 10 mm No BCG or BCG in infancy: TST 5 mm
TST 10 mm or positive IGRA
All indications HIV-infected and other immunocompromised individuals (low exposure)‡ CXR and TST
Prophylaxis/anti-tuberculosis treatment of inadequately treated TB and likelihood of infection in the past TST 5 mm CXR, TST and IGRA if TST , 5 mm
TST 5 mm or positive IGRA
*Individuals born before 1 January 1945 or living .12 years in a TB-endemic country (.50 per 100 000 population). No target group for LTBI screening with TST to detect recent infection with M. tuberculosis. † If previous TST 5 mm and IGRA-negative or unknown: IGRA only. ‡ Including persons born before 1 January 1945 or living .12 years in a TB-endemic country. § Primary prophylaxis is discontinued when second TST ,5 mm (and/or IGRA) in individuals with a reliable immune response at the end of the latency period (8 weeks after last exposure to infection). ¶ Performed in TB patients likely to be recently infected in the Netherlands with no identified source case. # TST is performed to identify co-infected individuals, who may lead to the putative source case. **Includes travellers and health care workers or other contact groups eligible for serial LTBI screening after potential exposure, for whom a baseline measurement would indicate whether a positive test result after potential exposure could be attributed to recent exposure. ´ TST ¼ tuberculin skin test; IGRA ¼ interferon-gamma release assay; LTBI ¼ latent tuberculous infection; BCG ¼ bacille Calmette-Guerin; CXR ¼ chest X-ray; HIV ¼ human immunodeficiency virus; TB ¼ tuberculosis.
Added value of IGRA in LTBI diagnosis
iii
RESUME C O N T E X T E : Les tests de lib´eration de l’interf´eron gamma (IGRA) sont r´eput´es d’ˆetre plus sp´ecifiques pour le diagnostic d’une infection tuberculeuse latente (LTBI) que le test cutan´e a` la tuberculine (TST). La proc´edure en deux e´ tapes de la TST suivie par l’IGRA est r´eput´ee rentable dans les pays a` hauts revenus, mais elle n´ecessite davantage de ressources financi`eres. O B J E C T I F : Evaluer la valeur ajout e´ e de l’IGRA compar´ee a` la TST seule aux Pays-Bas. M E´ T H O D E S : Les services de sant´e publics municipaux (PMHS) ont enregistr´e les r´esultats des tests et les donn´ees de contexte des personnes test´ees avec l’IGRA dans une base de donn´ees en ligne. Le nombre de personnes chez qui une LTBI a e´ t´e diagnostiqu´ee grace ˆ aux diff´erents tests de d´epistage a e´ t´e calcul´e. R E´ S U LT A T S : Chez les patients test´es par IGRA, au
moins 60% des patients qui auraient eu un diagnostic de LTBI bas´e sur la TST seule avaient un IGRA n´egatif. Parmi ceux qui avaient une r´eaction TST en-dessous du seuil de diagnostic de LTBI, 13% avaient un test IGRA positif. Pour 41% des personnes test´ees par IGRA apr`es TST, le r´esultat de l’IGRA influen¸cait la confirmation du diagnostic de LTBI. C O N C L U S I O N : En utilisant l’IGRA comme test de r´ef´erence, une proportion e´ lev´ee de personnes vivant dans des zones de faible pr´evalence est inutilement trait´ee pour LTBI si le diagnostic est e´ tabli sur la TST seule, alors qu’une faible proportion de personnes justiciables d’un traitement pr´eventif est oubli´ee. Le cout ˆ marginal de la strat´egie en deux temps semble donc compense´ par un meilleur ciblage du traitement pr´eventif. RESUMEN
M A R C O D E R E F E R E N C I A : Se ha notificado que las pruebas de liberacion ´ de interferon ´ gama (IGRA) son ma´s espec´ıficas en el diagnostico ´ de la infeccion ´ tuberculosa latente (LTBI) que la prueba cuta´nea de la tuberculina (TST). El procedimiento diagnostico ´ en dos etapas que consiste en una reaccion ´ TST seguida de una IGRA ha demostrado ser una estrategia rentable en los pa´ıses con altos ingresos, pero precisa ma´s recursos economicos. ´ O B J E T I V O : Evaluar el valor agregado de la IGRA al compararla con la TST exclusiva en los Pa´ıses Bajos. M E´ T O D O S : Los servicios municipales publicos ´ de salud registraron en una base de datos en internet los resultados de las pruebas y los datos generales de las personas en quienes se practico´ la IGRA. Se calculo´ el numero ´ de personas con diagnostico ´ de LTBI mediante diferentes algoritmos de deteccion. ´ R E S U L T A D O S : De las personas examinadas con la
IGRA, como m´ınimo 60% de los casos que se hubiesen diagnosticado como LTBI con base en una TST exclusiva obtuvo un resultado negativo en la IGRA. En las personas con una reaccion ´ TST por debajo el umbral diagnostico ´ de la LTBI, 13% presento´ una prueba positiva de IGRA. En 41% de las personas examinadas con la IGRA despu´es de la TST, el resultado de la IGRA influyo´ sobre la decision ´ diagnostica ´ de LTBI. ´ N : Al considerar la IGRA como referencia, CONCLUSIO una alta proporcion ´ de personas reciben tratamiento innecesario por LTBI cuando se utiliza la TST exclusivamente en un entorno con baja prevalencia y se pasa por alto una pequena ´ de casos con ˜ proporcion indicacion ´ de tratamiento preventivo. Al parecer el incremento en el costo de la estrategia en dos etapas, se compensa con la optimizacion ´ de la seleccion ´ de casos que reciben el tratamiento preventivo.
