Journal of Clinical Medicine Article Performance of Screening Strategies for Latent Tuberculosis Infection in Patients with Inflammatory Bowel Disease: Results from the ENEIDA Registry of GETECCU Sabino Riestra 1, * , Carlos Taxonera 2 , Yamile Zabana 3 , Daniel Carpio 4 , María Chaparro 5 , Jesús Barrio 6 , Montserrat Rivero 7 , Antonio López-Sanroman 8 , María Esteve 3 , Ruth de Francisco 1 , Guillermo Bastida 9 , Santiago García-López 10 , Miriam Mañosa 11 , María Dolores Martin-Arranz 12 , José Lázaro Pérez-Calle 13 , Jordi Guardiola 14 , Fernando Muñoz 15 , Laura Arranz 16 , José Luis Cabriada 17 , Mariana Fe García-Sepulcre 18 , Mercè Navarro 19 , Miguel Ángel Montoro-Huguet 20 , Elena Ricart 21 , Fernando Bermejo 22 , Xavier Calvet 23 , Marta Piqueras 24 , Esther Garcia-Planella 25 , Lucía Márquez 26 , Miguel Mínguez 27 , Manuel Van Domselar 28 , Luis Bujanda 29 , Xavier Aldeguer 30 , Beatriz Sicilia 31 , Eva Iglesias 32 , Guillermo Alcaín 33 , Isabel Pérez-Martínez 1 , Valeria Rolle 1 , Andrés Castaño-García 1 , Javier P. Gisbert 5,† , Eugeni Domènech 11,† and on behalf of the ENEIDA registry from GETECCU ‡ 1 Gastroenterology Department, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain; ruthdefrancisco@gmail.com (R.d.F.); ipermar_79@hotmail.com (I.P.-M.); bioestadistica@ispasturias.es (V.R.); castaogarcia@gmail.com (A.C.-G.) 2 Gastroenterology Department, Hospital Clínico Universitario San Carlos, Instituto de Investigación del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain; carlos.taxonera@salud.madrid.org 3 Gastroenterology Department, Hospital Universitari Mútua Terrassa, Centro de Investigación Biomédica en Citation: Riestra, S.; Taxonera, C.; Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08221 Terrassa, Spain; yzabana@gmail.com (Y.Z.); Zabana, Y.; Carpio, D.; Chaparro, M.; mariaesteve@mutuaterrassa.cat (M.E.) 4 Gastroenterology Department, Complexo Hospitalario Universitario de Pontevedra, 36071 Pontevedra, Spain; Barrio, J.; Rivero, M.; dcarlop1@yahoo.es López-Sanroman, A.; Esteve, M.; de 5 Gastroenterology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Francisco, R.; et al. Performance of Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Screening Strategies for Latent Enfermedades Hepáticas y Digestivas (CIBERehd), 28006 Madrid, Spain; mariachs2005@gmail.com (M.C.); Tuberculosis Infection in Patients javier.p.gisbert@gmail.com (J.P.G.) with Inflammatory Bowel Disease: 6 Gastroenterology Department, Hospital Universitario Río Hortega, 47012 Valladolid, Spain; Results from the ENEIDA Registry of jbarrioa95@gmail.com 7 Gastroenterology Department, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, GETECCU. J. Clin. Med. 2022, 11, 3915. https://doi.org/10.3390/ Instituto de Investigación Sanitaria Valdecilla (IDIVAL), 37008 Santander, Spain; montserrat.rivero@scsalud.es 8 Gastroenterology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; jcm11133915 mibuzon@gmail.com 9 Gastroenterology Department, Hospital Universitari i Politecnic La Fe, Centro de Investigación Biomédica en Academic Editor: Marilena Durazzo Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 46026 Valencia, Spain; guille.bastida@gmail.com Received: 25 May 2022 10 Gastroenterology Department, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Accepted: 4 July 2022 Aragón (IISA), 50009 Zaragoza, Spain; sgarcia.lopez@gmail.com 11 Gastroenterology Department, Hospital Universitari Germans Trials i Pujol, Centro de Investigación Published: 5 July 2022 Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08916 Badalona, Spain; Publisher’s Note: MDPI stays neutral mmanosa.germanstrias@gencat.cat (M.M.); eugenidomenech@gmail.com (E.D.) with regard to jurisdictional claims in 12 Gastroenterology Department, Hospital Universitario La Paz, Instituto de Investigación Sanitaria del Hospital published maps and institutional affil- La Paz (IdiPAZ), 28046 Madrid, Spain; mmartinarranz@salud.madrid.org 13 Gastroenterology Department, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain; iations. jlperezc@fhalcorcon.es 14 Gastroenterology Department, Hospital Universitario de Bellvitge, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), 08907 Barcelona, Spain; jguardiola@bellvitgehospital.cat 15 Gastroenterology Department, Hospital Universitario de Salamanca, 37007 Salamanca, Spain; Copyright: © 2022 by the authors. jmunozn@gmail.com Licensee MDPI, Basel, Switzerland. 16 Gastroenterology Department, Hospital Nuestra Señora de la Candelaria, 38010 Tenerife, Spain; This article is an open access article lauraarranz@gmail.com distributed under the terms and 17 Gastroenterology Department, Hospital de Galdakao-Usansolo, 48960 Galdakao, Spain; jcabriada@gmail.com conditions of the Creative Commons 18 Gastroenterology Department, Hospital General Universitario de Elche, 03203 Alicante, Spain; Attribution (CC BY) license (https:// marifegarciasepulcre@gmail.com 19 Gastroenterology Department, Hospital Sant Joan Despí-Moisès Broggi, 08970 Barcelona, Spain; creativecommons.org/licenses/by/ 4.0/). mnavarrollavat@gmail.com J. Clin. Med. 2022, 11, 3915. https://doi.org/10.3390/jcm11133915 https://www.mdpi.com/journal/jcm 18Gastroenterology Department, Hospital General Universitario de Elche, 03203 Alicante, Spain; marifegarciasepulcre@gmail.com 19 Gastroenterology Department, Hospital Sant Joan Despí-Moisès Broggi, 08970 Barcelona, Spain; mnavarrollavat@gmail.com 20 Gastroenterology Department, Hospital San Jorge, 22004 Huesca, Spain; maimontoro@gmail.com J. Clin. Med. 2022, 11, 3915 2 of 12 21 Gastroenterology Department, Hospital Clinic i Provincial, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain; ericart@clinic.cat 22 Gastroenterology Department, Hospital Universitario de Fuenlabrada, Instituto de Investigación Sanitaria 20 Hospital La Paz (IdiPaz), Gastroenterology 28942 Madrid, Department, HospitalSpain; fbermejos1@gmail.com San Jorge, 22004 Huesca, Spain; maimontoro@gmail.com 23 Gastroenterology Department, Hospital Universitari ParciTaulí, Sabadell, 08208 Centro Sabadell, 21 Gastroenterology Department, Hospital Clinic Provincial, IDIBAPS, deSpain; Investigación Biomédica en xavier.calvet.c@gmail.com Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain; ericart@clinic.cat 24 Depàrtament de Medicina, Universitat Autònoma 22 Gastroenterology Department, Hospitalde Barcelona, 08208 Universitario Sabadell, Spain de Fuenlabrada, Instituto de Investigación Sanitaria 25 CIBERehd—Instituto de Salud Carlos III, 28029 Madrid, Spain Hospital La Paz (IdiPaz), 28942 Madrid, Spain; fbermejos1@gmail.com 26 Gastroenterology Department, 23 Gastroenterology Consorcio Hospital SanitarioUniversitari de Terrasa, 08227 Barcelona, Spain; de Medicina Universitat Department, Parc Taulí, Depàrtament piqueras72@gmail.com Autònoma de Barcelona, Sabadell, CIBERehd, 08208 Sabadell, Spain; xavier.calvet.c@gmail.com 27 Gastroenterology Department, Hospital de la Santa Sanitario Creu i Sant 24 Gastroenterology Department, Consorcio de Pau, 08041 Terrasa, Barcelona, 08227 Spain; Barcelona, Spain; piqueras72@gmail.com egarciapl@santpau.cat 25 Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; 28 Gastroenterology Department, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques, egarciapl@santpau.cat 08003 Barcelona, Spain; lmarquez@parcdesalutmar.cat 26 Gastroenterology Department, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques, 29 Gastroenterology Department, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain; 08003 Barcelona, Spain; lmarquez@parcdesalutmar.cat miguel.minguez@uv.es 27 Gastroenterology Department, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain; 30 Gastroenterology Department, Hospital Universitario de Torrejón, 28850 Madrid, Spain; miguel.minguez@uv.es manuelvandomselaar@yahoo.com 28 Gastroenterology Department, Hospital Universitario de Torrejón, 28850 Madrid, Spain; 31 Gastroenterology Department, Hospital Universitario de Donostia/Biodonostia, manuelvandomselaar@yahoo.com Universidad del País Vasco (UPV/EHU), 29 Gastroenterology Department,Centro HospitaldeUniversitario Investigaciónde Biomédica en Red de Donostia/Biodonostia, Enfermedades Hepáticas Universidad dely País Digestivas (CIBERehd), 20014 Vasco (UPV/EHU), CentroSan de Sebastián, Spain; Investigación Biomédica en Red de Enfermedades luis.bujandafernandezdepierola@osakidetza.net Hepáticas y Digestivas (CIBERehd), 20014 San Sebastián, Spain; 32 Gastroenterology Department, Hospital Universitario de Girona Dr Josep Trueta, 17007 Girona, Spain; luis.bujandafernandezdepierola@osakidetza.net doctoraldeguer@yahoo.es 30 Gastroenterology Department, Hospital Universitario de Girona Dr Josep Trueta, 17007 Girona, Spain; 33 Gastroenterology Department, Hospital Universitario de Burgos, 09006 Burgos, Spain; doctoraldeguer@yahoo.es bsicilia4@gmail.com 31 Gastroenterology Department, Hospital Universitario de Burgos, 09006 Burgos, Spain; bsicilia4@gmail.com 34 Gastroenterology Department, Hospital Reina Sofía, IMIBIC, 14004 Córdoba, 32 Gastroenterology Department, Hospital Reina Sofía, IMIBIC, 14004Spain; evaiflores@gmail.com Córdoba, Spain; evaiflores@gmail.com 35 Gastroenterology Department, 33 Gastroenterology Hospital Clínico de Málaga, 29010 Málaga, Spain; galcainm@hotmail.com Department, Hospital Clínico de Málaga, 29010 Málaga, Spain; galcainm@hotmail.com * Correspondence: sriestram7@gmail.com * Correspondence: sriestram7@gmail.com † These authors † These contributed equally to equally authors contributed this work. to this work. ‡ Membership of the ENEIDA ‡ Membership of theisENEIDA providedisin the Supplementary provided Materials. Materials. in the Supplementary Abstract:Abstract: (1) Aims:(1)Patients receivingreceiving Aims: Patients antitumor necrosis necrosis antitumor factor (anti-TNF) therapy are factor (anti-TNF) at risk therapy areofat risk of developing tuberculosis (TB), usually due to the reactivation of a latent TB infection developing tuberculosis (TB), usually due to the reactivation of a latent TB infection (LTBI). LTBI (LTBI). LTBI screening and treatment screening decreases and treatment the riskthe decreases of TB. riskThis study of TB. Thisevaluated the diagnostic study evaluated performance the diagnostic performance of of different LTBI screening different strategies LTBI screening in patients strategies with inflammatory in patients with inflammatory bowelbowel disease (IBD).(IBD). disease (2) Meth- (2) Methods: ods: Patients in the Spanish ENEIDA registry with IBD screened for LTBI between Patients in the Spanish ENEIDA registry with IBD screened for LTBI between January 2003 January 2003 and and Jan- January 2018 were included. The diagnostic yield of different strategies (dual screening uary 2018 were included. The diagnostic yield of different strategies (dual screening with tuberculin with tuber- culin skin testtest skin [TST] [TST] and and interferon- ‫ ץ‬-release interferon- -release assay assay [IGRA], [IGRA], two-step two-step TST,TST, and andearlyearly screening screening performed at performed at 12 least least 12 months months beforebefore starting starting biological biological treatment) treatment) was analyzed. was analyzed. (3) Results: (3) Results: Out ofOut 7594ofscreened 7594 screened patients, 1445 (19%; 95% CI 18–20%) had LTBI. Immunomodulator patients, 1445 (19%; 95% CI 18–20%) had LTBI. Immunomodulator (IMM) treatment at screening (IMM) treatment at screening decreased decreased the probability the probability of detecting of detecting LTBILTBI (20%(20% vs. 17%, vs. 17%, p = 0.001). p = 0.001). Regarding Regarding screen- screening strategies, ing strategies, LTBI was LTBImorewasfrequently more frequently diagnosed diagnosed by dual screening by dual screening than by than by a single a singlestrategy screening screening (IGRA, OR strategy 0.60; (IGRA, 95%OR CI0.60; 95% CIp0.50–0.73, 0.50–0.73, p < 0.001; < 0.001; TST, TST, OR 0.76; ORCI 95% 0.76; 95% CIp0.66–0.88, 0.66–0.88, < 0.001). pTwo-step < 0.001). TST Two-increased step TSTthe increased the diagnostic yield of a single TST by 24%. More cases of LTBI diagnostic yield of a single TST by 24%. More cases of LTBI were diagnosed by early screening were diagnosed by early than screening than by by routine routine screening screening beforeanti-TNF before starting starting anti-TNF agents (21% agents [95%(21% [95% CI 20–22%] CI 20–22%] vs. 14% [95% CI vs. 14% 13–16%], [95% CI 13–16%], p < 0.001).p The < 0.001). Thediagnostic highest highest diagnostic performance performance for LTBI for LTBI (29%) (29%) was was obtained byob- combining tained by combining early early and and TST/IGRA TST/IGRA dual screeningdual screening strategies strategies in patients in patients without IMM. (4):without IMM. (4): Conclusions: Both early Conclusions: Both early screening and TST/IGRA dual screening strategies significantly screening and TST/IGRA dual screening strategies significantly increased diagnostic performance increased diagnostic forperformance LTBI in patients for with LTBIIBD, in patients with IBD, with optimal with optimal performance achievedperformance when theyachieved when in the are used together they are absence used together of IMM. in the absence of IMM. Keywords: inflammatory bowel disease; latent tuberculosis infection; tuberculin skin test; interferon gamma release assays 1. Introduction Inflammatory bowel diseases (IBD) make up a group of chronic inflammatory condi- tions including Crohn’s Disease (CD), Ulcerative Colitis (UC) and unclassified colitis (IBD J. Clin. Med. 2022, 11, 3915 3 of 12 unclassified). Treatment with antitumor necrosis factor biologics (anti-TNFs) is important for controlling inflammatory activity in these patients. Patients receiving anti-TNF therapy are at risk of developing tuberculosis (TB), usually due to the reactivation of a latent TB infection (LTBI). Following the first report of this treatment-related complication [1], several scientific societies and international organizations published guidelines for the screening and treatment of LTBI in patients receiving biological treatment [2]. The adherence to these recommendations led to a decrease, but not the complete disappearance, in the number of cases of active TB [3–5]. Active TB still occurs, probably due to inadequate compliance with the screening recommendations [6], the limitations of immunodiagnostic tests [7] and the occurrence of de novo infections [4]. Recently, the risk of active TB during anti-TNF treatment has been related to the local epidemiology of TB and, additionally, it has been reported that up to 70% of cases occur in patients with negative baseline LTBI screening [8]. The low sensitivity of LTBI screening tests (tuberculin skin test (TST) and the interferon- γ-release assay (IGRA)) when performed under immunosuppressive therapies [7,9] has been posed as one of the potential factors that increase the risk of active TB during anti- TNF treatment. Different strategies have been developed to improve the performance of immunodiagnostic tests. Early screening, performed ideally at inflammatory bowel disease (IBD) diagnosis or in the absence of immunosuppressive drugs [9,10], increases its sensitivity for detecting LTBI. Adding a second TST seven to 14 days after a first negative test increases the LTBI diagnostic yield by 5–25% [10–12]. Finally, dual screening (TST plus IGRA) also increases the sensitivity for detecting LTBI compared to a single screening test (TST or IGRA), in patients with rheumatic diseases [13,14] or IBD [12]. However, there is a lack of studies assessing the best strategies in different clinical settings. The European Crohn’s and Colitis Organisation (ECCO) recommends adapting LTBI diagnostic and treatment strategies to the local TB epidemiology in anti-TNF candidates [15]. In 2018 Spain was considered, for the first time, a country with a low incidence of TB (9.4 cases/100,000 inhabitants/year), according to WHO criteria [16], although with wide variations in incidence among different Spanish regions [17]. In 2014, it was estimated that the prevalence of LTBI in Spain was 15% (95% CI 6.3–27%) [18], whereas the data reported for IBD patients was highly variable (13–34%) [10–12]. Taking these data into account, the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) published its updated recommendations for the screening and treatment of LTBI in 2021 [19] and recommended single screening (TST) for immunocompetent patients and dual screening (TST/IGRA) for immunocompromised patients. The main objective of this study was to describe the prevalence and risk factors of LTBI and to evaluate the diagnostic yield of different LTBI screening strategies (TST/IGRA dual screening, single screening, two-step TST, routine screening and early screening) in a large database of IBD patients. 2. Methods This is a retrospective, descriptive, multi-center study, conducted in patients included in the ENEIDA registry. ENEIDA is a nationwide Spanish database of IBD patients pro- moted by GETECCU, which is a non-profit association whose mission is to improve the lives of people with IBD by promoting excellence in health care, teaching and research and influencing political and social initiatives. [20]. The registry was approved by the Ethics Committee of each participating center and all patients gave their informed con- sent. The study was approved by the ENEIDA Scientific Committee and, at the time of the data extraction (January 2018), the registry included 31,827 patients from 33 centres (Supplementary Membership of the ENEIDA). 2.1. Study Population and Definitions We included all patients who had been screened for LTBI from January 2003 (the date of the publication of the first GETECCU recommendations for LTBI screening in IBD patients) [21] to January 2018. Those patients who had previously been diagnosed J. Clin. Med. 2022, 11, 3915 4 of 12 with active TB or LTBI were excluded. We considered that a patient had undergone LTBI screening when a TST and/or IGRA had been performed and/or a recent contact with a bacilliferous subject was identified. In patients with more than one LTBI screening test recorded in the database, the result of the first screening was taken into account to evaluate the frequency of LTBI. A patient was considered to have LTBI if there was a positive result in either screening test (positive IGRA and/or TST > 5 mm), when there were lesions suggestive of an old TB infection on a chest X-ray (calcified nodes or nodules, pleural apical thickening, fibrous tracts), or when recent contact with a bacilliferous TB patient was identified [19]. 2.2. Performance of Tests and Screening Strategies for Latent Tuberculosis Infection We analyzed the overall frequency of LTBI, as well as the diagnostic yield per single test (IGRA or TST). We also evaluated the association of a positive screening with demographic and clinical variables including gender, age at diagnosis of IBD, age at LTBI screening, type of IBD, smoking habit, use of immunomodulators (IMM) (thiopurines, methotrexate or calcineurinics) and anti-TNF (Infliximab, adalimumab or golimumab) at screening, autonomous community of residence (Madrid, Aragón, Asturias, Canarias, Cantabria, Castilla-León, Catalonia, Basque country, Valencia), country of origin (classified according to WHO criteria as high, intermediate or low incidence of TB) [14] and the year in which the screening was performed. Subsequently, we evaluated the diagnostic yield of different screening strategies. First, we compared TST/IGRA dual screening to single screening (TST or IGRA); secondly, we evaluated the strategy of a second TST (two-step TST) in patients with a negative first TST. Finally, we compared early screening (considered as when screening tests were performed at least 12 months before starting biological treatment) to routine screening (when tests were done in the three months before initiating biological treatment). 2.3. Statistical Analysis Categorical variables are reported as absolute and relative frequencies (number, per- centage, and 95% confidence interval). Continuous variables are expressed as the mean and standard deviation or median and interquartile range (IQR), as appropriate. The initial comparability between groups was analyzed with the chi square test or Fisher’s exact test for qualitative variables and with the Student’s t test or median test for quantitative data. To assess the performance of different tests and diagnostic strategies for LTBI, we used a logistic regression model (with the presence of LTBI as a dependent variable and the independent variables mentioned in the previous section). To assess the performance of TST/IGRA dual screening compared to a single screening, we used a logistic regression model (the presence of LTBI as a dependent variable, while leaving only the screening strategy as a separate variable). To evaluate the performance of early compared to rou- tine screening, the diagnostic yield was calculated for each strategy and compared using a difference estimation test for proportions. Crude and adjusted odds ratios with their respective 95% confidence intervals (CIs) were reported. A p-value of <0.05 was considered to be statistically significant. In addition, the non-inferiority criterion was evaluated for subgroup analysis comparisons showing a non-significant trend. The non-inferiority cri- terion was not met for any comparisons if the lower limit of the 95% CI was lower than the pre-specified non-inferiority criterion of ≤0.65. All analysis were performed with R software version 4.0.2. 3. Results In total, 7594 IBD patients screened for LTBI between January 2003 and January 2018 were included. The demographic and clinical characteristics of patients are summarized in Table 1. J. Clin. Med. 2022, 11, 3915 5 of 12 Table 1. Clinical and demographic characteristics of the cohort of patients with IBD who were screened for LTBI. Number of patients screened for LTBI, n 7594 Male gender, n (%) 3988 (53) Age at diagnosis of IBD, years, mean (±SD) 36.3 ± 15.2 Type of IBD, n (%) - Crohn’s disease 4622 (61) - Ulcerative colitis 2813 (37) - IBD unclassified 159 (2) Smoking status, n (%) - ever 3677 (48) - never 3377 (45) - unknown 540 (7) Age at LTBI screening, years, mean (± SD) 45.2 ± 15.2 Time between diagnosis of IBD and screening, years, 2.09 (0.19–10.46) median (IQR) IMM at screening, n (%) 2143 (28) Azathioprine 1703 Mercaptopurine 185 Methotrexate 146 Other IMM 109 Anti-TNF at screening, n (%) 369 (4.9) Country of origin with TB incidence ≥ 40 294 (3.9) LTBI: latent tuberculosis infection; IBD: inflammatory bowel disease; SD: standard deviation; IQR: interquartile range; IMM: immunomodulator; anti-TNF: antitumor necrosis factor; TB: tuberculosis. Overall, 1445 patients (19%; 95% CI 18–20%) were diagnosed with LTBI. The frequency of LTBI, regarding the tests performed for screening and the use of IMM at the time the screening was performed, are shown in Table 2. In 369 patients, the first LTBI screening collected in ENEIDA was performed during anti-TNF treatment; LTBI was less frequently detected among patients taking anti-TNF than in patients without such treatment (12% [95% CI 8.6–16%] vs. 19% [95% CI 19–20%], respectively; p < 0.001). Table 2. Frequency of LTBI and results of the screening methods. Patients Screened, Patients with LTBI, p Value * n n (%) [95% CI] Any test of LTBI ** 7594 1445 (19) [18–20] - no IMM at screening 5451 1086 (20) [19–21] 0.001 - IMM at screening 2143 359 (17) [15–18] TST 6028 965 (16) [15–17] - no IMM at screening 4234 736 (17) [16–19] <0.001 - IMM at screening 1794 229 (13) [11–14] IGRA 2982 386 (13) [12–14] - no IMM at screening 2208 314 (14) [13–16] <0.001 - IMM at screening 774 72 (9.3) [7.4–12] Chest X-ray 2365 55 (2.3) [1.8–3] Recent contact with 7594 213 (2.8) [2.5–3.2] baciliferous subject LTBI: latent tuberculosis; CI: confidence interval; IMM: immunomodulator; TST: tuberculin skin test; IGRA: inter- feron gamma release assay; * p value comparing results of screening performed during IMM and no IMM therapy; ** TST and/or IGRA positive and/or abnormal chest X-ray and/or recent contact with baciliferous subject. J. Clin. Med. 2022, 11, 3915 6 of 12 Table 3 shows the factors associated with detecting LTBI. Age at screening, male gender, smoking habit, autonomous community of residence, year in which the screening was performed, origin in countries with a high incidence of active TB (≥40 cases/105 inhabitants/year), and lack of IMM and anti-TNF treatment at screening, were all associated with higher rates of detected LTBI. Table 3. Factors associated with diagnosis of LTBI in patients with IBD. Univariable Analysis Multivariable Analysis Odds Ratio 95% CI p Odds Ratio 95% CI p Gender Female Reference Reference Male 1.22 1.09–1.37 0.001 1.21 1.07–1.37 0.002 Age at TB screening, 1.04 1.03–1.04 <0.001 1.04 1.04–1.04 <0.001 years Type of IBD IBD-unclassified Reference Reference Ulcerative colitis 0.84 0.57–1.25 0.37 0.78 0.52–1.19 0.23 Crohn’s disease 0.88 0.60–1.31 0.50 0.89 0.60–1.36 0.58 Smoking status Never Reference Reference Ever 1.58 1.40–1.78 <0.001 1.53 1.35–1.74 <0.001 Unknown 1.02 0.79–1.30 0.86 0.87 0.66–1.13 0.29 IMM at TB screening No Reference Reference Yes 0.80 0.70–0.91 0.001 0.81 0.70–0.93 0.004 Anti-TNF at TB screening No Reference Reference Yes 0.55 0.39–0.75 <0.001 0.56 0.40–0.77 <0.001 Geographical area Madrid Reference Reference Aragón 0.89 0.68–1.14 0.35 0.93 0.71–1.21 0.60 Asturias 0.96 0.73–1.26 0.79 1.14 0.86–1.50 0.36 Canarias 0.69 0.39–1.13 0.16 0.58 0.32–0.97 0.050 Cantabria 1.34 1.08–1.67 0.009 1.39 1.10–1.75 0.005 Castilla-León 1.49 1.23–1.80 <0.001 1.94 1.58–2.38 <0.001 Catalonia 1.26 1.08–1.48 0.003 1.51 1.28–1.79 <0.001 Basque country 0.69 0.46–1.01 0.07 0.81 0.53–1.19 0.30 Valencia 0.58 0.44–0.74 <0.001 0.66 0.50–0.86 0.002 TB incidence in country of origin Low/intermediate Reference Reference High 2.15 1.67–2.77 <0.001 3.51 2.67–4.60 <0.001 Year of TB screening 0.97 0.96–0.99 0.002 0.93 0.91–0.94 <0.001 CI: confidence interval; TB tuberculosis; IBD: inflammatory bowel disease; IMM: immunomodulator; anti-TNF: antitumor necrosis factor. When we exclude patients undergoing anti-TNF at screening (n = 369) from the logistic regression analysis, the factors associated with LTBI diagnosis were the same as for the general cohort (Supplementary Table S1). Overall, LTBI was more common in men than in women (21% vs. 17%, p = 0·01), al- though these differences were only observed in people over 55 years of age (Supplementary Table S2). Since 2003, a progressive decrease in LTBI frequency (slope: −1.6; 95% CI −2.2 to −1.0; p = 0.013) was observed (Supplementary Figure S1). Moreover, a decreasing use of TST and an increasing use of IGRA were observed over time. While TST and IGRA were performed in 91% and 22% of the screenings performed from 2009 to 2011, these figures were 63% and 62%, respectively, in the 2015–2017 period. J. Clin. Med. 2022, 11, 3915 7 of 12 3.1. Latent Tuberculosis Infection Screening Strategies 3.1.1. TST/IGRA Dual Screening In total, 1471 and 6068 patients were screened using a dual or a single screening strategy, respectively. Overall, the likelihood of a positive screening was significantly higher with the dual screening strategy than with a single screening. The probability of diagnosing LTBI with a single IGRA decreased by 40% (OR: 0.60; 95% CI 0.50–0.73, p < 0.001), and, in the case of a single TST, this probability decreased by 24% (OR: 0.76; 95% CI 0.66–0.88, p < 0.001), compared to TST/IGRA dual screening (Table 4). Significant differences were maintained for the subgroup of patients without IMM treatment. In the subgroup of patients with IMM treatment, a non-significant trend was observed towards a lower sensitivity of a single IGRA (p = 0.2) and of a single TST (p = 0.2) when compared with dual screening, with none of the single tests achieving the non-inferiority criterion compared to TST/IGRA dual testing (Table 4). In patients screened with both TST and IGRA (n = 1471), concordance between tests was low (kappa 0.49; 95% CI 0.42–0.55). Table 4. Performance of screening strategies for the diagnosis of LTBI in patients with IBD. All Patients Patients without IMM Patients with IMM LTBI, OR (95% CI); LTBI, OR (95% CI); LTBI, OR (95% CI); N N N n (%) p-Value n (%) p-Value n (%) p-Value Dual vs. single test TST and IGRA 1471 342 (23) Reference 1032 260 (25) Reference 439 82 (19) Reference 0.76 (0.66–0.88); 0.73 (0.62–0.86); 0.76 (0.64–1.12); only TST 4557 852 (19) 3202 632 (20) 1355 220 (16) <0.001 <0.001 0.2 * 0.60 (0.50–0.73); 0.55 (0.45–0.68); 0.84 (0.52–1.12); only IGRA 1511 234 (16) 1176 184 (16) 335 50 (15) <0.001 <0.001 0.2 * 2 step TST vs. 1 step TST 1 step TST 6028 802 (13) Reference 4234 618 (15) Reference 1794 184 (10) Reference 1.24 (1.12–1.37); 1.23 (1.09–1.39); 1.28 (1.04–1.60); 2 step TST 6028 965 (16) 4234 736 (17) 1794 229 (13) <0.001 <0.001 0.038 Early vs. routine screening Early 4365 913 (21) Reference 3523 758 (22) Reference 842 155 (18) Reference 0.63 (0.53–0.74); 0.57 (0.45–0.72); 0.78 (0.60–1.03); Routine 1421 203 (14) 729 99 (14) 588 104 (15) <0.001 <0.001 0.08 * Dual vs. single test in early and in routine screening Early screening 4365 3523 842 TST and IGRA 801 226 (28) Reference 643 188 (29) Reference 158 38 (24) Reference 0.65 (0.54–0.78); 0.65 (0.53–0.79); 0.65 (0.43–1.01); only TST 2632 535 (20) 2089 442 (21) 543 93 (17) <0.001 <0.001 0.05 * 0.50 (0.39–0.62); 0.47 (0.36–0.60); 0.65 (0.36–1.14); only IGRA 932 152 (16) 791 128 (16) 141 24 (17) <0.001 <0.001 0.14 * Routine screening 1421 729 692 TST and IGRA 335 48 (14) Reference 187 25 (13) Reference 148 23 (16) Reference 1.04 (0.73–1.49); 1.11 (0.68–1.86); 0.95 (0.58–1.61); only TST 881 130 (15) 417 47 (15) 464 69 (15) 0.9 0.7 * 0.8 * 0.83 (0.49–1.38); 0.75 (0.36–1.51); 0.96 (0.44–2.02); only IGRA 205 25 (12) 125 13 (10) 80 12 (15) 0.5 * 0.4 * 0.9 * LTBI: latent tuberculosis infection; IMM: immunomodulator; TST: tuberculin skin test; IGRA: interferon gamma release assay. * Comparisons showing a non-significant trend in which the non-inferiority criterion was evaluated. 3.1.2. Screening with Two-Step TST (Booster) Eight hundred and two out of 6028 patients (13%) had a first positive TST (one-step strategy). A second TST was performed on 2332 of the 5226 patients (45%) with a first negative TST and was positive in 163 (6%). The two-step TST strategy increased the likelihood of detecting LTBI by 24% (OR 1.24; 95% CI 1.12–1.37, p < 0.001) (Table 4). 3.1.3. Early Screening In total, 4365 and 1421 patients were screened using an early or routine screening strategy, respectively. Overall, LTBI was diagnosed more frequently using early than routine screening (21% vs. 14%, p < 0.001). Routine screening was associated with a 37% reduction in the likelihood of detecting LTBI vs. early screening (OR 0.63; 95% CI 0.53–0.74; J. Clin. Med. 2022, 11, 3915 8 of 12 <0.001) (Table 4). Significant differences remained for the subgroup of patients without IMM. In the subgroup of patients on IMM treatment, a non-significant trend was observed towards a lower LTBI detection capacity of routine screening compared to early screening (OR 0.78; 95% CI 0.60–1.03; p = 0.08) (Table 4). 3.1.4. Interactions between Early Screening and Dual Screening Strategies The highest LTBI detection capacity (188 of 643 patients [29%]) was obtained with the association of the early screening and TST/IGRA dual screening strategies in patients without IMM (Table 4). 3.1.5. Probability of LTBI according to Demographic, IMM Use, and Screening Strategy Table 5 shows the probability of detecting LTBI according to gender, smoking status, IMM use at screening, screening strategy used and origin in a country with a high or inter- mediate/low incidence of TB. Thus, the probability of LTBI ranged from 53% (men, ever smoker and origin in a country with a high incidence of TB, when a dual and early screening was used while without IMM) to 8% (women, never smoker and origin in a country with an intermediate/low incidence, when a single IGRA screening was used while on IMM). The results obtained when patients receiving anti-TNF treatment at the time of LTBI screening were excluded are similar to those of the overall series (Supplementary Table S3). Table 5. Probability (%) of LTBI according to gender, smoking status, immunomodulator use at screening, strategy of screening (dual versus single, early versus routine) and origin in a country with a high or intermediate/low incidence of tuberculosis. Men Women IGRA and TST IGRA TST IGRA and TST IGRA TST No With No With No With No With No With No With IMM IMM IMM IMM IMM IMM IMM IMM IMM IMM IMM IMM Ever 53 50 41 38 46 43 48 46 37 34 41 39 High smoked TB incidence Never 41 38 30 28 34 32 37 34 27 25 30 28 Early smoked screening Ever 31 29 22 20 25 23 27 25 19 17 22 20 Low/intermediate smoked TB incidence Never 22 20 15 13 17 16 19 17 13 12 15 14 smoked Ever 43 41 32 30 37 34 39 37 29 26 33 30 High smoked TB incidence Never 32 30 23 21 26 24 28 26 20 18 23 21 Routine smoked screening Ever Low/intermediate 23 22 16 15 19 17 20 19 14 13 16 15 smoked TB incidence Never 16 15 11 10 13 11 14 13 9 8 11 10 smoked IGRA: interferon gamma release assay; TST: tuberculin skin test; IMM: immunomodulator; TB: tuberculosis. 4. Discussion To date, the best strategy for the LTBI screening of patients for whom biological treatment is planned remains unknown, and should always depend on the local epi- demiology of TB (incidence of active TB and prevalence of LTBI) [15]. In this study, the frequency of LTBI in a large cohort of Spanish patients with IBD was 19%, with a steady decline over a 15-year period (25% in 2003 to 18% in 2017). During this period, the inci- dence of active TB among the background Spanish population also dropped from 27 to 9.4 cases/105 inhabitants/year, leading Spain to become a country with a low incidence of TB (<10 cases/105 inhabitants/year) [22]. In our study, age, male gender, smoking status and being from countries with a high incidence of TB were independently associated with a higher frequency of LTBI, as was previously reported [23]. Moreover, we observed marked differences in LTBI prevalence between autonomous communities, some of which are geographically close. In this regard, an autonomous community with a higher proportion of people over the age of 65 (i.e., Castilla and León) or a larger immigrant population (i.e., Catalonia) may explain the higher frequency of LTBI in some regions [24]. J. Clin. Med. 2022, 11, 3915 9 of 12 ECCO recommends performing LTBI screening at the time of IBD diagnosis, before starting immunosuppressive therapy and, preferably, when a low inflammatory load is present [15]. At present, only a few patients will have the screening performed under these optimal conditions and no studies have analyzed the benefits of this strategy. The study evaluated in a real-life setting the sensitivity of early screening performed on patients for whom anti-TNF therapy was not foreseen compared with routine screening performed before the initiation of biological therapy, and we found that early screening markedly increased the likelihood of detecting LTBI in both UC and CD patients. It has been reported that the sensitivity of TST was lower when it was indicated as part of the mandatory screening for LTBI before the initiation of biological therapy, and this has been related to an increased use of steroids and IMM and to a higher systemic inflammatory load associated with active IBD [10]. Our results show for the first time that routine screening affects not only the sensitivity of TST, but also that of IGRA and TST/IGRA dual testing. Early screening increased LTBI diagnostic capacity by 43% in the cohort of patients who were not receiving IMM compared to routine screening, whereas this increase was smaller among patients on IMM. In the same way, the incremental benefit of TST/IGRA dual screening over single screening was more marked in those patients who were not receiving IMM than in those on IMM. The IMM subgroup analysis for the diagnostic performance of early screening and dual screening reinforces the evidence from the multivariate analysis that IMM had a pronounced negative effect on the diagnostic yield of screening tests for LTBI in all situations. In our study, the best diagnostic yield for LTBI was obtained with the simultaneous use of early and TST/IGRA dual screening strategies. The incremental benefit of dual testing was higher when combined with an early screening strategy compared to when routine screening was performed. This could be explained by the fact that, at that time, a greater proportion of patients with routine screening were receiving IMM drugs (44% vs. 19%). Therefore, the results of our study strongly support the need for LTBI screening when a patient is not receiving IMM therapy. The limitations of this study include its retrospective design, which prevented the analysis of the possible influence of corticosteroid treatment and the inflammatory load of IBD at the time of LTBI screening. Moreover, the sample sizes of some subgroup analyses may diminish the significance of our findings. In addition, our results should not be extrapolated to other geographical areas with a different local TB epidemiology. Conversely, the main strengths of the study are the inclusion of a large number of patients and the fact that information on LTBI screening strategies used in real life in a nationwide multi-center setting was systematically collected. In conclusion, in an area with an intermediate incidence of TB, both early screening and TST/IGRA dual screening strategies increased the performance of LTBI in patients with IBD. The sum of both strategies maximizes the probability of diagnosing LTBI. Since new cases of active TB still occur in IBD patients on biologic therapy despite preventive actions, it is crucial to screen patients early in the absence of IMM treatment and take advantage of the incremental benefit of associating diagnostic tests for LTBI. Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11133915/s1. Supplementary Membership of the ENEIDA. List of centres participating in the study; Supplementary Table S1. Factors associated with diagnosis of LTBI in IBD patients who were not undergoing anti-TNF treatment at screening; Supplementary Table S2. Frequency of latent tuberculosis infection among adult patients with inflammatory bowel disease according to age and gender; Supplementary Figure S1. Frequency of latent tuberculosis infection, positive result in tuberculin skin test and interferon gamma release assay, depending on the year in which screening was performed in Spanish patients with inflammatory bowel disease; Supplementary Table S3. Probability (%) of LTBI in IBD patients who were not undergoing anti-TNF treatment at screening according to gender, smoking status, immunomodulator use at screening, strategy of screening (dual versus single, early versus routine) and origin in a country with a high or intermediate/low incidence of tuberculosis. J. Clin. Med. 2022, 11, 3915 10 of 12 Author Contributions: Conceptualization, S.R., J.P.G. and E.D.; data curation, S.R.; formal analysis, S.R., C.T., Y.Z., D.C., M.C., V.R. and J.P.G.; funding acquisition, E.D.; investigation, S.R., J.B., M.R., A.L.-S., M.E., R.d.F., G.B., S.G.-L., M.M. (Miriam Mañosa), M.D.M.-A., J.L.P.-C., J.G., F.M., L.A., J.L.C., M.F.G.-S., M.N., M.Á.M.-H., E.R., F.B., X.C., M.P., E.G.-P., L.M., M.M. (Miguel Mínguez), M.V.D., L.B., X.A., B.S., E.I., G.A., A.C.-G. and J.P.G.; methodology, S.R., I.P.-M., V.R. and E.D.; project administration, S.R.; software, S.R. and V.R.; supervision, S.R., J.P.G. and E.D.; writing—original draft, S.R., C.T., Y.Z., D.C. and M.C.; writing—review & editing, S.R., J.P.G. and E.D. All authors have read and agreed to the published version of the manuscript. Funding: The ENEIDA registry of GETECCU is supported by Biogen, Pfizer, Takeda, Galapagos and AbbVie. None of them had access to the clinical information or were involved in the present analysis. Institutional Review Board Statement: The study was conducted by the the Spanish Working Group of Crohn’s disease and Ulcerative Colitis (GETECCU) using aggregated patient data included in the ENEIDA database. The ENEIDA project was approved by research ethics committees in all participating centers (Ethic Committee of reference Hospital Clínic, Barcelona, code 2006/3155, June 17, 2019); all patients gave written informed consent before being enrolled in the ENEIDA registry. The study was carried out in accordance to the European General Data Protection Regulation (GDPR) 2016/679 and then Spanish Data Protection Organic Law 3/2018. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: Original data from this study will be provided upon reasonable request. Conflicts of Interest: S.R. has served as speaker, consultant, and advisory member for or has received research funding from MSD, AbbVie, Takeda, Janssen, Pfizer, Mylan, Biogen, Kern Pharma, Ferring, Faes Farma, Tillotts Pharma, Shire Pharmaceuticals, Dr. Falk Pharma and Adacyte Therapeutics. C.T. has served as a speaker, consultant, and advisory board member for MSD, AbbVie, Pfizer, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Galapagos, and Tillotts Pharma. Y.Z. has served as speaker, or has received research funding from AbbVie, MSD, Ferring, Amgen, Janssen, Pfizer, Dr Falk Pharma, Tillotts Pharma, Galapagos. D.C. has served as speaker, advisory member for or has received research funding from Takeda, Janssen, Pfizer, MSD, Kern Pharma, AbbVie, Amgen, Fresenius Kabi, Gilead, Faes Farma, Tillotts Pharma, Dr Falk Pharma, Ferring. M.C. has served as a speaker, or has received research or education funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, and Tillotts Pharma. M.E. reports grants and personal fees from AbbVie, Janssen, personal fees from Menarini, Takeda, Pfizer and Ferring outside the submitted work. R.F. has served as speaker or has received research funding from MSD, AbbVie, Takeda, Janssen, Kern Pharma, Tillotts Pharma and Dr. Falk Pharma. G.B. has received funding directly or indirectly from the pharmaceutical industry for the development of research projects and publications, to participate in scientific meetings or paid as a speaker by the following laboratories: Janssen, Pfizer, AbbVie, Takeda, Fresenius Kabi, MSD, Kern Pharma, Ferring, Faes Farma and Vifor Pharma. S.G-L. has served as a speaker, advisory member for or has received research funding from AbbVie, MSD, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals and Chiesi. M.M. has served as a speaker, consultant or has received research funding from AbbVie, Gilead, Janssen, MSD, Pfizer, Shire Pharmaceuticals, Faes Farma, Takeda, Tillotts Pharma. M.D.M-A. has received fees as a speaker, consultant an advisory member for o has received research funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Shire Pharmaceuticals, Tillotts Pharma, Faes Farma. J.L.P-C. has served as a speaker o has received research funding from Chiesi, Takeda y Janssen, Pfizer, Dr. Falk Pharma, Ferring and Faes Farma. F.M. has served as speaker, consultant, and advisory member for or has received research funding from MSD, AbbVie, Pfizer, Amgen, Mylan, Takeda, Janssen, Ferring, Faes Farma, and Tillotts Pharma. J.L.C. has served as consultant for, or received research funding from, MSD, Pfizer, Janssen, Takeda and Otsuka Pharma. M.F.G.-S. has served as a speaker or has received research or educational funding from MSD, AbbVie, Takeda and Janssen. E.R. has provided scientific advice/participated in medical meetings/received research funding from/received payment for presentations and advice from: MSD, Schering-Plough, Ferring, AbbVie, Takeda, Janssen, Fresenius Kabi, Pfizer. F.B. has served as a speaker, a consultant and advisory member for or has received research funding from MSD, AbbVie, Takeda, Janssen, Pfizer, Biogen, Amgen, Ferring, Faes Farma, Tillotts Pharma, Dr Falk Pharma, Chiesi, Gebro Pharma. X.C. has received grants for research from Abbott, MSD, Vifor Pharma fees for advisory boards form Abbott, MSD, Takeda, Pfizer, Janssen and Vifor Pharma and has given lectures for Abbott, MSD, Janssen, Pfizer, Takeda, Shire Pharmaceuticals and Allergan. M.P. has served as a speaker or has received J. Clin. Med. 2022, 11, 3915 11 of 12 research funding from AbbVie, Takeda and Janssen. E.G-P. has served as a speaker, or has received research or education funding or advisory fees from Faes Farma, Dr Falk Pharma, Ferring, AbbVie, MSD, Janssen, Takeda, Pfizer. M.M. has served as a speaker, a consultant an advisory member for or has received research funding from MSD, AbbVie, Janssen, Takeda and Allergan. B.S. has received support for conference attendance, speaker fees, research support and consulting fees of AbbVie, Dr Falk Pharma, Faes Farma, Ferring, Janssen, MSD, Pfizer, Shire Pharmaceuticals and Takeda. I.P-M. has served as speaker or has received research funding from Takeda, Janssen, AbbVie and Tillotts Pharma. A.C-G. has received research funding from Takeda, Janssen and AbbVie. 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