Journal of Clinical Medicine Article Risk Factors for COVID-19 in Inflammatory Bowel Disease: A National, ENEIDA-Based Case–Control Study (COVID-19-EII) Yamile Zabana 1,2, * , Ignacio Marín-Jiménez 3 , Iago Rodríguez-Lago 4 , Isabel Vera 5 , María Dolores Martín-Arranz 6 , Iván Guerra 7 , Javier P. Gisbert 2,8,9 , Francisco Mesonero 10 , Olga Benítez 1 , Carlos Taxonera 11 , Ángel Ponferrada-Díaz 12 , Marta Piqueras 13 , Alfredo J. Lucendo 2,9,14 , Berta Caballol 2,15 , Míriam Mañosa 2,16 , Pilar Martínez-Montiel 17 , Maia Bosca-Watts 18 , Jordi Gordillo 19 , Luis Bujanda 2,20 , Noemí Manceñido 21 , Teresa Martínez-Pérez 22 , Alicia López 23 , Cristina Rodríguez-Gutiérrez 24 , Santiago García-López 25 , Pablo Vega 26 , Montserrat Rivero 27 , Luigi Melcarne 28 , María Calvo 29 , Marisa Iborra 2,30 , Manuel Barreiro de Acosta 31 , Beatriz Sicilia 32 , Jesús Barrio 33 , José Lázaro Pérez Calle 34 , David Busquets 35 , Isabel Pérez-Martínez 36 , Mercè Navarro-Llavat 37 , Vicent Hernández 38 , Federico Argüelles-Arias 39 , Fernando Ramírez Esteso 40 , Susana Meijide 41 , Laura Ramos 42 , Fernando Gomollón 2,43 , Fernando Muñoz 44 , Gerard Suris 45 , Jone Ortiz de Zarate 46 , José María Huguet 47 , Jordina Llaó 48 , Mariana Fe García-Sepulcre 49 , Mónica Sierra 50 , Miguel Durà 51 , Sandra Estrecha 52 , Ana Fuentes Coronel 53 , Esther Hinojosa 54 , Lorenzo Olivan 55 , Eva Iglesias 56 , Ana Gutiérrez 2,57 , Pilar Varela 58 , Núria Rull 59 , Pau Gilabert 60 , Alejandro Hernández-Camba 61 , Alicia Brotons 62 , Daniel Ginard 63 , Eva Sesé 64 , Daniel Carpio 65 , Montserrat Aceituno 1,2 , José Luis Cabriada 4 , Yago González-Lama 5 , Laura Jiménez 7 , María Chaparro 2,8,9 , Citation: Zabana, Y.; Marín-Jiménez, Antonio López-San Román 10 , Cristina Alba 11 , Rocío Plaza-Santos 12 , I.; Rodríguez-Lago, I.; Vera, I.; Raquel Mena 13 , Sonsoles Tamarit-Sebastián 14 , Elena Ricart 2,15 , Margalida Calafat 2,16 , Martín-Arranz, M.D.; Guerra, I.; P. Sonsoles Olivares 17 , Pablo Navarro 18 , Federico Bertoletti 19 , Horacio Alonso-Galán 20 , Gisbert, J.; Mesonero, F.; Benítez, O.; Ramón Pajares 21 , Pablo Olcina 22 , Pamela Manzano 1 , Eugeni Domènech 2,16 , Taxonera, C.; et al. Risk Factors for Maria Esteve 1,2 and on behalf of the ENEIDA Registry of GETECCU † COVID-19 in Inflammatory Bowel Disease: A National, ENEIDA-Based 1 Hospital Universitari Mútua Terrassa, 08221 Terrassa, Spain Case–Control Study (COVID-19-EII). 2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), J. Clin. Med. 2022, 11, 7540. https:// 28029 Madrid, Spain doi.org/10.3390/jcm11247540 3 Hospital Gregorio Marañón and Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Academic Editor: Andrew Day Complutense de Madrid, 28040 Madrid, Spain 4 Hospital Universitario de Galdakao and Biocruces Bizkaia Health Research Institute, 48960 Galdakao, Spain 5 Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain Received: 18 September 2022 6 Hospital Universitario La Paz and Instituto de Investigación Sanitaria La Paz (IdiPaz), Universidad Accepted: 12 December 2022 Published: 19 December 2022 Autónoma de Madrid (UAM), 28046 Madrid, Spain 7 Hospital Universitario de Fuenlabrada, 28942 Fuenlabrada, Spain Publisher’s Note: MDPI stays neutral 8 Department of Gastroenterology, Hospital Universitario de La Princesa, Universidad Autónoma de with regard to jurisdictional claims in Madrid (UAM), 28006 Madrid, Spain 9 Instituto de Investigación Sanitaria Princesa (IIS-Princesa), 28006 Madrid, Spain published maps and institutional affil- 10 Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain iations. 11 Hospital Clínico San Carlos, Instituto de Investigación del Hospital Clínico San Carlos [IdISSC], 28040 Madrid, Spain 12 Hospital Universitario Infanta Leonor, 28031 Madrid, Spain 13 Consorci Sanitari de Terrassa, 08227 Terrassa, Spain Copyright: © 2022 by the authors. 14 Hospital General de Tomelloso and Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Licensee MDPI, Basel, Switzerland. 13700 Tomelloso, Spain This article is an open access article 15 Hospital Clínic de Barcelona-IDIBAPS, 08036 Barcelona, Spain distributed under the terms and 16 Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain 17 Fundación Hospital Universitario Doce de Octubre, 28041 Madrid, Spain conditions of the Creative Commons 18 Hospital Clinic Universitari de Valencia, 46010 Valencia, Spain Attribution (CC BY) license (https:// 19 Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain creativecommons.org/licenses/by/ 4.0/). J. Clin. Med. 2022, 11, 7540. https://doi.org/10.3390/jcm11247540 https://www.mdpi.com/journal/jcm J. Clin. Med. 2022, 11, 7540 2 of 14 20 Hospital Universitario Donostia and Instituto Biodonostia, Universidad del País Vasco (UPV/EHU), 20014 Donostia, Spain 21 Hospital Universitario Infanta Sofía, 28703 San Sebastián de los Reyes, Spain 22 Hospital Virgen de la Luz, 16002 Cuenca, Spain 23 Hospital del Mar and Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain 24 Complejo Hospitalario de Navarra, 31008 Pamplona, Spain 25 Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain 26 Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain 27 Hospital Universitario Marqués de Valdecilla and IDIVAL, 39008 Santander, Spain 28 Hospital Universitari Parc Taulí, 08208 Sabadell, Spain 29 Hospital San Pedro-Logroño, 26006 Logroño, Spain 30 Hospital Universitario y Politécnico de la Fe de Valencia, 46026 Valencia, Spain 31 Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain 32 Hospital Universitario de Burgos, 09006 Burgos, Spain 33 Hospital Universitario Río Hortega (HURH), 47012 Valladolid, Spain 34 Hospital Universitario Fundación de Alcorcón, 28922 Alcorcón, Spain 35 Hospital Universitari de Girona Doctor Josep Trueta, 17007 Girona, Spain 36 Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain 37 Hospital de Sant Joan Despí Moisès Broggi, 08970 Sant Joan Despí, Spain 38 Hospital Álvaro Cunqueiro, 36312 Vigo, Spain 39 Hospital Universitario Virgen de la Macarena, Universidad de Sevilla, 41009 Sevilla, Spain 40 Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain 41 Hospital Universitario de Cruces, 48903 Barakaldo, Spain 42 Hospital Universitario de Canarias, 38320 La Laguna, Spain 43 Hospital Clínico Universitario “Lozano Blesa” and IIS Aragón, 50009 Zaragoza, Spain 44 Hospital Universitario de Salamanca, 37007 Salamanca, Spain 45 Hospital Universitari de Bellvitge, 08907 L’Hospitalet de Llobregat, Spain 46 Hospital Universitario de Basurto, 48013 Bilbo, Spain 47 Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain 48 Althaia Xarxa Assistencial Universitària de Manresa, 08243 Manresa, Spain 49 Hospital Universitario de Elche, 03203 Elche, Spain 50 Complejo Asistencial Universitario de León, 24071 León, Spain 51 Hospital Clínico de Valladolid, 47003 Valladolid, Spain 52 Hospital Universitario Álava, 01009 Álava, Spain 53 Hospital Virgen de la Concha, 49022 Zamora, Spain 54 Hospital de Manises, 46940 Manises, Spain 55 Hospital Universitario San Jorge, 22004 Huesca, Spain 56 Hospital Universitario Reina Sofía de Córdoba and Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain 57 Hospital General Universitario de Alicante and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010 Alicante, Spain 58 Hospital Universitario de Cabueñes, 33394 Gijón, Spain 59 Hospital Universitario Son Llàtzer, 07198 Palma, Spain 60 Hospital de Viladecans, 08840 Viladecans, Spain 61 Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain 62 Hospital Vega Baja de Orihuela, 03314 Orihuela, Spain 63 Hospital Universitario Son Espases, 07120 Palma, Spain 64 Hospital Universitari Arnau de Vilanova de Lleida, 25198 Lleida, Spain 65 Complexo Hospitalario de Pontevedra, 36071 Pontevedra, Spain * Correspondence: yzabana@gmail.com † All Co-authors are part of ENEIDA. Abstract: (1) Scant information is available concerning the characteristics that may favour the acqui- sition of COVID-19 in patients with inflammatory bowel disease (IBD). Therefore, the aim of this study was to assess these differences between infected and noninfected patients with IBD. (2) This nationwide case–control study evaluated patients with inflammatory bowel disease with COVID-19 (cases) and without COVID-19 (controls) during the period March–July 2020 included in the ENEIDA of GETECCU. (3) A total of 496 cases and 964 controls from 73 Spanish centres were included. No differences were found in the basal characteristics between cases and controls. Cases had higher comorbidity Charlson scores (24% vs. 19%; p = 0.02) and occupational risk (28% vs. 10.5%; p < 0.0001) J. Clin. Med. 2022, 11, 7540 3 of 14 more frequently than did controls. Lockdown was the only protective measure against COVID-19 (50% vs. 70%; p < 0.0001). No differences were found in the use of systemic steroids, immunosuppres- sants or biologics between cases and controls. Cases were more often treated with 5-aminosalicylates (42% vs. 34%; p = 0.003). Having a moderate Charlson score (OR: 2.7; 95%CI: 1.3–5.9), occupational risk (OR: 2.9; 95%CI: 1.8–4.4) and the use of 5-aminosalicylates (OR: 1.7; 95%CI: 1.2–2.5) were fac- tors for COVID-19. The strict lockdown was the only protective factor (OR: 0.1; 95%CI: 0.09–0.2). (4) Comorbidities and occupational exposure are the most relevant factors for COVID-19 in patients with IBD. The risk of COVID-19 seems not to be increased by immunosuppressants or biologics, with a potential effect of 5-aminosalicylates, which should be investigated further and interpreted with caution. Keywords: COVID-19; SARS-CoV-2; inflammatory bowel disease; 5-aminosalicylates; immunosup- pression 1. Introduction Knowledge concerning the effect of the SARS-CoV-2 pandemic has grown exponen- tially. We previously published the largest cohort of patients with inflammatory bowel disease (IBD) and COVID-19 prospectively recruited with 12 months of follow-up in a national study [1]. A high percentage of patients in this cohort had occupational risk or were infected by intrafamilial transmission. We also confirmed that IBD does not worsen the COVID-19 prognosis, even with the use of immunosuppressants and biologics, as was shown elsewhere [2,3]. We demonstrated that COVID-19 affects neither the progno- sis of IBD nor its treatment during the acute phase of infection or in the long term. In this sense, severe COVID-19 in patients with IBD is mainly related to older age [4,5] and comorbidities [2,6,7], as it occurs in the general population. Investigations assessing factors that may favour the acquisition of COVID-19 in pa- tients with IBD (case–control studies of patients with IBD with or without COVID-19) are scarce and needed [8]. Previous case–control studies either included COVID-19 patients from the general population as a control group [5], included a small proportion of COVID- 19 cases or were retrospective cohorts [9,10]. The incidence of COVID-19 in patients with IBD is low [11]. This finding does not mean necessarily that patients with IBD are less sus- ceptible to infection by SARS-CoV2, but could merely reflect special measures adopted in patients with a particular risk of infections [12]. Therefore, differences in factors that could influence the acquisition of COVID-19 must be assessed with the same type of population and under the same circumstances. This study complements the findings of our previous study [1] to define which characteristics favour or protect the occurrence of COVID-19 in IBD. Consequently, we sought to investigate, for the first time, two cohorts of patients with IBD, during the same time period and encompassing the first COVID-19 wave. The present study aimed to assess epidemiological, demographic, and clinical factors that could influence the acquisition of COVID-19 in a large cohort of infected patients with IBD compared with noninfected patients. 2. Materials and Methods 2.1. Design This study (COVID-19-EII study) was performed in the setting of the ENEIDA project, the Spanish registry of patients with IBD, promoted by the Spanish Working Group on Crohn’s disease and ulcerative colitis (GETECCU) [13]. ENEIDA is a prospectively main- tained database that at the moment of study initiation had 60,512 patients with active follow-up (15 July 2020) in 86 hospitals. A total of 73 hospitals with 53,682 patients regis- tered (89% of the entire database) accepted participation in this case–control study. J. Clin. Med. 2022, 11, 7540 4 of 14 2.2. Study Population Cases were all patients with COVID-19, diagnosed between March and July 2020 (during the first COVID-19 wave), who were identified by active search from their IBD unit (systematically addressing all the patients with IBD from each unit by email or phone call) or by direct notification from the emergency department, patient, family physician, or hospitalisation unit. Cases were matched with two controls (1:2) by age (±5 years), type of disease (Crohn’s disease [CD]/ulcerative colitis [UC]), sex, and centre. Both cases and controls came from the ENEIDA registry. 2.3. Definitions A patient with IBD was considered a case if a COVID-19 diagnosis was made, based on a typical clinical picture that included fever (>38 ◦ C), respiratory symptoms (cough and/or dyspnoea), dysgeusia or anosmia within the epidemiological setting. COVID-19 was confirmed by a positive diagnostic test including serology (IgM or IgG) or polymerase chain reaction (PCR) performed by nasopharyngeal swab for SARS-CoV-2. COVID-19 was considered probable in patients with a typical clinical picture but negative or lacking diagnostic tests. The control group comprised patients with IBD without a COVID-19 diagnosis, coming from the same centre, during the study period (March–July 2020). The fact of not having COVID-19 was confirmed clinically by each attending physician through direct consultation with the patient, as at that time serologic or PCR tests were performed only for highly suspicious cases. Asymptomatic patients with IBD with positive PCR or serology were excluded from the study and were considered to have been infected with SARS-CoV-2 but without suffering from COVID-19. Patients were considered to be in adequate compliance with the lockdown measures when they maintained social distance by staying almost exclusively at home since 14 March 2020, the date the Spanish government ordered a total lockdown to prevent the spread of SARS-CoV-2. 2.4. Data Collection A prospective module hosted on the ENEIDA registry was specifically designed for this study to avoid missing cases and was externally monitored to ensure the correct acquisi- tion of data. The data collected included clinical baseline characteristics such as date of IBD diagnosis and Montreal classification [14], type of IBD, family history of IBD, extraintestinal manifestations, and smoking behaviour at the time of infection. The following comorbidi- ties were specifically registered, taking into account the moment of inclusion in the study as the time frame: chronic renal failure, dementia, chronic obstructive pulmonary disease, HIV, stroke, heart disease, congestive heart failure, diabetes mellitus, dyslipidaemia, arterial hypertension neoplasia, cirrhosis, rheumatological disease and immune-mediated disease, allowing the calculation of the Charlson comorbidity score [15]. These variables were collected at the time of the study (March–July 2022). Variables measuring the exposure risk to SARS-CoV-2 included occupational risk (such as health care workers, basic services such as supermarket cashiers, market clerks or pharmacy workers, teachers, workers of closed institutions, police and firepersons, animal control workers, veterinarians, or conservation and forest technicians), compliance with lockdown measures, social distancing and the route of contagion. The IBD therapeutic regimen was registered during the study period and included 5-aminosalicylates (5-ASA), systemic steroid treatment, immunosuppressants (cyclosporine, methotrexate, thiopurines, tacrolimus and tofacitinib) and biologics (anti- TNF, vedolizumab, and ustekinumab). All the controls were selected after the completeness of the inclusion period of cases (15 July 2020). They were identified by only one investigator blinded to the other characteristics to avoid selection bias. J. Clin. Med. 2022, 11, 7540 5 of 14 2.5. Ethical Considerations Written informed consent was obtained from all the subjects before inclusion in the registry. The Scientific Committee of ENEIDA approved the study on March 2020. It was also approved by the Ethics Committee of Hospital Universitari Mútua Terrassa (coordinating centre). 2.6. Statistical Analysis Quantitative variables were correlated using the Mann–Whitney test for nonparametric data and Student’s t test for parametric data, while qualitative variables were compared using Fisher’s exact test or Chi2 test, when appropriate. Quantitative variables were compared using Student’s t test and the Mann–Whitney test, and the results were expressed as medians (± interquartile range (IQR) 25–75th percentiles). Multivariable analysis was performed using conditional logistic regression analysis for case–control studies (COXREG in SPSS), where the presence of COVID-19 was the dependent variable. Variables with p value ≤ 0.1 on univariate analysis were introduced into the model. Because 5-ASA was more frequently used in patients with UC than in those with CD, the model was adjusted for UC diagnosis. 3. Results Four hundred eighty-two cases with COVID-19 and nine hundred sixty-four controls without COVID-19 were included. The clinical characteristics of the patients with IBD and COVID-19 have been described previously in detail [1]. 3.1. Clinical Baseline Characteristics Table 1 shows the most important clinical characteristics of the cases and controls. Table 1. Clinical baseline characteristics regarding inflammatory bowel disease between cases and controls. B1: inflammatory behaviour, B2: stricturing behaviour, B3: penetrating behaviour; L1: ileal, L2: colonic, L3: ileocolonic, L4: upper gastrointestinal tract; E1: proctitis; E2: left colitis; E3: extensive colitis. IQR: interquartile rate; IBD: inflammatory bowel disease. Cases Controls Univariate Variable n = 482 n = 964 p-Value Male gender, n (%) 251 (52) 501 (52) 0.97 Age (years) Median (IQR) 52 (42–61) 53 (42–62) 0.75 Type of IBD, n (%) Ulcerative colitis 221 (46) 471 (49) Unclassified colitis 14 (2.9) 1 (0.1) 0.60 Crohn’s disease 248 (51) 492 (51) Crohn’s disease location, n (%) L1 114 (46) 232 (47) 0.79 L2 43 (17) 73 (15) 0.43 L3 88 (36) 186 (38) 0.48 L4 (isolated) 3 (1.2) 1 (0.2) 0.08 Crohn’s disease behaviour, n (%) B1 144 (58) 302 (31) 0.75 B2 71 (29) 147 (15) 0.72 B3 47 (19) 90 (9.3) 0.89 Perianal 59 (24) 164 (17) 0.85 Ulcerative colitis extent (%) E1 43 (19) 85 (17) E2 80 (36) 183 (37) 0.97 E3 98 (44) 203 (41) Extraintestinal manifestation, n (%) 125 (26) 247 (26) 0.98 Family history of IBD, n (%) 64 (13) 122 (25) 0.02 Smoking behaviour, n (%) Active smoker 53 (11) 160 (17) Ex-smoker 137 (28) 261 (27) 0.034 Never smoker 268 (56) 503 (52) Extraintestinal manifestation, n (%) 125 (26) 247 (26) 0.98 Family history of IBD, n (%) 64 (13) 122 (25) 0.02 Smoking behaviour, n (%) Active smoker 53 (11) 160 (17) 0.034 J. Clin. Med. 2022, 11, 7540 Ex-smoker 137 (28) 261 (27) 6 of 14 Never smoker 268 (56) 503 (52) Cases less Cases less frequently had aa family family history historyofofIBD IBD[13% [13%(64/482) (64/482) vs.vs. 25% 25%(122/964); p= (122/964); p0.02] andand = 0.02] hadhad a lower proportion a lower proportionof of active smokers active smokers[11%[11%(53/482) vs.vs. (53/482) 17%17%(160/964); p= (160/964); p0.034] than = 0.034] thethe than controls. controls. At least At leastone onecomorbidity comorbiditywaswasobserved observedinin43% 43%(206/482) (206/482) of ofcases casesandand36% 36%(344/964) (344/964) of controls of controls(p(p==0.01), 0.01),with with24%24%(114/482) (114/482) ofof cases cases and and 19% 19%(183/964) (183/964) of controls controls having having aa moderate–severe moderate–severeCharlson Charlsonscore score(score (scoreofofthree threeor ormore) more)(p (p== 0.02). 0.02). The The differences differences within within specific specificcomorbidities comorbiditiesare areshown shownin inFigure Figure11and andSupplementary SupplementaryTable TableS1.S1. Figure1. Figure 1. Comorbidities Comorbidities between between cases casesand andcontrols. controls. 3.2. Epidemiological Risk Factors of Exposure Table 2 summarizes the risk for COVID-19 related to occupational and epidemiological risk factors. Almost one-third of cases (28%) and 10% of controls (p < 0.0001) were at risk because of occupational exposure. Health care professions were the most frequent occupational hazard [18% (85/482)] among cases and involved 4.5% (44/964) of controls]. One hundred thirty-three cases were considered to have an occupational risk. Among them, 96 (78%) were infected during their working activity. Most of these infections [70% (67/96)] occurred in the first month of the pandemic in Spain (March 2020). Regarding other epidemiological risk factors for COVID-19, 44% of cases and 60% of controls (p = 0.154) declared good adherence to social distancing measures because of mandatory compliance, with no differences between groups. However, cases presented more preventive sick leave than controls [15% (73/482) vs. 8.5% (82/964); p < 0.0001], but a lower proportion of telecommuting [9.1% (44/482) vs. 19% (182/964); p = 0.009] and unemployment [3.3% (16/482) vs. 9.8% (94/964); p = 0.003]. Likewise, cases performed a worse overall total lockdown since the start of the state of alarm [50% (239/482) vs. 70% (676/964); p < 0.0001]. As stated previously, most of the cases were infected in March 2020, despite having had a higher proportion of preventive sick leave at the beginning of the pandemic [64% (47/73) in March 2020 vs. 36% (26/73) in April–July 2020; p = 0.037]. J. Clin. Med. 2022, 11, 7540 7 of 14 Table 2. Lockdown and epidemiological risk factors between cases and controls. Cases Controls Univariate Variable n = 482 n = 964 p-Value Occupational risk, n (%) 133 (28) 101 (10.5) Healthcare 85 (18) 44 (4.5) Education 15 (3) 22 (2.3) Basic services (market clerks, supermarket <0.0001 18 (3.7) 28 (2.9) cashier, pharmacy) Police and fireperson 5 (1) 2 (0.2) Closed institutions 2 (0.4) 2 (0.2) Veterinary, animal control worker or 4 (0.8) 3 (0.3) conservation and forest technician Social distance measures since the start of 211 (44) 574 (60) 0.154 the state of alarm, n (%) Sick leave 73 (15) 82 (8.5) <0.0001 Retirement 60 (12) 191 (20) 0.348 Telecommuting 44 (9.1) 182 (19) 0.009 Unemployed 16 (3.3) 94 (9.8) 0.003 Others 18 (3.7) 25 (2.6) 0.016 Total lockdown since the start of the state of 239 (50) 676 (70) <0.0001 alarm, n (%) Sick leave AND total lockdown since the 73 (15) 82 (8.5) start of the state of alarm, n (%) Sick leave WITHOUT total lockdown since 95 (19) 11 (1) the start of the state of alarm, n (%) 3.3. Treatment of IBD and COVID-19 Table 3 compiles the treatment received for both cases and controls for the period of time between March and July 2020. Table 3. Differences in treatment for inflammatory bowel disease between cases and controls. Cases Controls Univariate Variable n = 482 n = 964 p-Value 5ASA, n (%) 204 (42) 332 (34) 0.003 Oral (oral and topic) 125 (26) 180 (19) <0.0001 Topical (exclusive) 6 (1) 18 (1.9) 0.051 Monotherapy 142 (29) 214 (22) 0.9 Systemic steroids, n (%) 26 (5.4) 35 (3.6) 0.06 Immunosuppressants (all), n (%) 319 (66) 611 (63) Immunosuppressants (in monotherapy), n 113 (23) 191 (20) (%) Azathioprine 90 (19) 160 (17) 0.39 Mercaptopurine 8 (1.7) 7 (0.7) Cyclosporine 1 (0.2) 1 (0.1) Methotrexate 9 (1.9) 11 (1.1) Tacrolimus 1 (0.2) 2 (0.2) Tofacitinib 4 (0.8) 6 (0.6) J. Clin. Med. 2022, 11, 7540 8 of 14 Table 3. Cont. Cases Controls Univariate Variable n = 482 n = 964 p-Value Biologics (all), n (%) 235 (49) 493 (51) Biologic (in monotherapy), n (%) 117 (22) 239 (25) Anti-TNF 71 (15) 134 (14) Vedolizumab 25 (5.2) 50 (5.2) Ustekinumab 21 (4.3) 52 (5.4) Combotherapy, n (%) 59 (12) 148 (15) 0.28 Anti-TNF plus thiopurines 37 (7.7) 85 (8.8) Anti-TNF plus methotrexate 9 (1.9) 28 (2.9) Vedolizumab plus thiopurines 5 (1) 11 (1.1) Vedolizumab plus methotrexate 1 (0.2) 3 (0.3) Ustekinumab plus thiopurines 5 (1) 15 (1.6) Ustekinumab plus methotrexate 2 (0.4) 6 (0.6) No differences were found in the use of immunosuppressants and/or biologics. There was a tendency for greater use of steroids in cases than in controls [5.4% (26/482) vs. 3.6% (35/964); p = 0.06]. The use of 5-ASA was more frequent in cases [42% (204/482)] than controls [34% (332/964); p = 0.003]. However, a difference was found in the use of 5-ASA between patients with CD [14% (106/738)] vs. those with UC [61% (420/693); p < 0.001]. 3.4. Risk Factors for COVID-19 in Patients with IBD Considering the differences found in the univariate analysis (Tables 1–3, Supplemen- tary Table S1), a multivariate model was conducted and is presented in Table 4. Table 4. Risk factors for symptomatic COVID-19 in inflammatory bowel disease patients. IBD: inflammatory bowel disease. * The cases and controls were paired based on age, sex, disease type and hospital of reference. Multivariate Analysis * Adjusted Hazard Ratio (95% Covariates p-Value Confidence Interval) Family history of IBD 1.15 (0.9–1.5) 0.291 Active smoking 0.74 (0.4–1.04) 0.647 Charlson score Mild (one–two) 1.2 (0.7–2.2) 0.518 Moderate (three–four) 2.7 (1.3–5.9) 0.011 Severe (five or more) 4.7 (1.7–12.7) 0.002 Occupational Risk 2.8 (1.8–4.4) <0.0001 Total lockdown since the start of the 0.1 (0.09–0.2) <0.0001 state of alarm Systemic steroids 1.6 (0.8–3.1) 0.203 5-aminosalycilates 1.7 (1.2–2.5) 0.004 Ulcerative colitis 0.6 (0.08–5.2) 0.688 A moderate (OR: 2.7; 95% CI: 1.3–5.9; p = 0.011) or severe (OR: 4.7; 95% CI: 1.7–12.7; p = 0.002) Charlson score, occupational risk (OR: 2.8; 95% CI: 1.8–4.4; p < 0.0001) and the use of 5-ASA (OR: 1.7; 95% CI: 1.2–2.5; p = 0.004) were independent risk factors for symptomatic COVID-19. Strict adherence to lockdown measures was the only factor protecting patients with IBD from contracting symptomatic infection for SARS-CoV2 (OR: 0.1; 95% CI: 0.09–0.2; p < 0.001). J. Clin. Med. 2022, 11, 7540 9 of 14 Because the use of 5-ASA produced conflicting results regarding its potential effect on the association with COVID-19 acquisition and severity [16–19], we also used an adjusted model considering the Charlson index, corticosteroids, immunomodulators and biologics. The adjusted OR of the use of 5-ASA between cases and controls remained significant after adjusting for these additional factors: 1.8 (95% CI: 1.3–2.2; p < 0.0001). 4. Discussion We showed that comorbidities and occupational risk were the two most relevant factors for having COVID-19 among patients with IBD in the ENEIDA cohort [13]. Thus, comorbidity is the most relevant risk factor as it is also related to harmful events due to COVID-19 [1,2,4–7]. Currently, data on the environmental exposure of noninfected patients are limited. Health care providers bore an enormous burden during the pandemic, as revealed in the data coming from Italy and China [20,21]. Almost one-third of cases and 10% of controls (p < 0.0001) had a job position considered to pose a high risk of infection and was the main cause for improper adherence to lockdown measures. Lockdown was demonstrated as the most effective strategy precluding SARS-CoV-2 expansion, also in patients with IBD [22]. Our study found that doing a strict lockdown was the only protective factor for COVID-19 in patients with IBD, regardless of their treatment. We also confirmed that immunosuppressive treatment does not expose the patient to a greater risk of contagion. Univariate analysis revealed a trend toward greater use of steroids in patients with IBD who were infected (p = 0.06). The use of steroids is critical for other relevant infections in patients with IBD [12]. However, this finding was not replicated in the multivariate analysis (p = 0.203). On the other hand, 5-ASA, irrespective of the type of IBD, was the only drug independently related to symptomatic COVID-19 in patients with IBD. The use of 5-ASA in patients with IBD and COVID-19 has shown conflicting results and is a debatable issue because the findings represent the first time that a nonimmunosup- pressive treatment considered “safe” regarding infection risk was found to be potentially involved in both the acquisition of and/or having severe COVID-19 [23]. The first report of a possible harmful effect of 5-ASA on the COVID-19 outcome came from the first two publications of the SECURE-IBD registry, where associations of 5-ASA with hospitalisation and other severe COVID-19 outcomes were described, even after several and restrictive sta- tistical analyses [17,24]. Nevertheless, the latest report [18] failed to show this relationship. The authors stated that the number of reported cases in the earliest assessments was too low to fully evaluate the association of 5-ASA in COVID-19 evolution. However, further analysis using a machine learning approach showed that 5-ASA was highly associated with COVID-19/IBD mortality [25], but this finding was not confirmed by another similar pre- dictive model [26]. Considering this information, researchers of the SECURE-IBD registry were very cautious and concluded that the association of 5-ASA and COVID-19 was likely due to reporting bias and/or reporting delays [18]. By contrast, several other studies did not find 5-ASA to be related to COVID-19 [3,27]. One of the few IBD-COVID-19 case–control studies performed using a design similar to ours demonstrated that the rate of COVID-19 was similar between patients treated under therapeutic immunosuppression or users of 5-ASA compared to those who were not [9]. A recent case–control study demonstrated that SARS-CoV-2 has no impact on IBD clinical activity in patients under biological therapy, with no difference in the incidence of SARS- CoV-2 infection between users and nonusers of 5-ASA [10]. In two other studies of the Veterans Affairs Health Care System, neither thiopurines nor anti-TNF was associated with an increased risk of COVID-19 in IBD [2], and both vedolizumab and corticosteroids were independently associated with SARS-CoV-2 infection [19]. They reported no harmful COVID-19 events with the use of 5-ASA. However, 5-ASA was used as the reference treatment and was considered the “safest” [19]. Finally, a meta-analysis of 24 studies [28] showed that the risk of hospitalisation, intensive care unit admission and mortality due to COVID-19 in patients with IBD was J. Clin. Med. 2022, 11, 7540 10 of 14 higher only in patients using steroids or 5-ASA. This meta-analysis speculated that the increased risk of COVID-19 infection related to 5-ASA might reflect a confounding factor due to the use of 5-ASA as a proxy for an underlying UC. In our cohort, although 5-ASA was used differentially between patients with UC or CD, the effect of 5-ASA was independently associated with COVID-19, even when considering the diagnosis of UC in the model. However, insufficient mechanistic data exist that link the use of 5-ASA and COVID-19. In fact, 5-ASA neither alters intestinal mucosal ACE-2 expression [29] nor changes SARS- CoV-2 infectivity [30]. On the other hand, 5-ASA exerts an anti-inflammatory effect in the colon by binding the peroxisome proliferator–activated receptor gamma (PPAR-γ). This receptor also increases the expression of ACE-2 and inhibits the expression of a transmem- brane serine protease (TMPRSS2) relevant for viral entry with ACE-2 internalization and could be a potential mechanism of 5-ASA favouring COVID-19 [31]. Our study has several limitations. First, we did not collect information on the disease activity of the controls at the time of inclusion in the study. Overall, the use of immuno- suppressive therapy between cases and controls in our current study was similar; thus, we can assume that there were no significant differences in this respect. Second, we included only symptomatic cases infected with SARS-CoV2. At the time of the first wave, neither PCR nor serology testing was mandatory and was not performed universally, raising the possibility of someone with asymptomatic or mildly symptomatic COVID-19 disease be- ing considered a control. Finally, we must determine whether patients with IBD have a higher risk of contagion or a poorer COVID-19 outcome than the population of reference in population-based studies. However, our study has crucial strengths. First, the study had national coverage with active participation of almost 90% of the IBD units from the Spanish ENEIDA registry. The universal access to health care within the National Health System in Spain [32] and adherence of most centres to the nationwide certification programme in IBD [33] provided homogeneity to this cohort. Additionally, although national case–control studies series on COVID-19 and IBD have been published previously [2,7,10], our study is the largest cohort of patients with IBD both with and without COVID-19. 5. Conclusions In conclusion, we have shown that comorbidities and epidemiological risk factors are the most relevant aspects for COVID-19 in patients with IBD. We have also demonstrated that a strict lockdown is the only protective factor against the contagion. Finally, the potential impact of 5-ASA on SARS-CoV2 acquisition and COVID-19 severity should be confirmed or rejected in large-scale studies adjusted for potential effect modifiers and confounders to provide clear therapeutic recommendations. Presently, the risk–benefit of 5-ASA does not favour its withdrawal during the pandemic. Moreover, the findings of our study and others should be a warning not to assume certain apriorisms concerning the risk or harmlessness of certain drugs. The replacement of an effective therapeutic regimen in well-controlled patients by other drugs supposed to be less dangerous or total drug withdrawal may put patients at risk of severe decompensation. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/jcm11247540/s1, Table S1: Comorbidities between cases and controls. Author Contributions: Conceptualization, Y.Z., I.M.-J., I.R.-L. and M.E.; Methodology, Y.Z., I.M.-J. and M.E.; Formal analysis, Y.Z., I.M.-J., I.R.-L. and M.E.; Investigation, Y.Z., I.R.-L., I.V., M.D.M.-A., I.G., J.P.G., F.M. (Francisco Mesonero), O.B., C.T., Á.P.-D., M.P., A.J.L., B.C., M.M., P.M.-M., M.B.-W., J.G., L.B., N.M., T.M.-P., A.L., C.R.-G., S.G.-L., P.V. (Pablo Vega), M.R., L.M., M.C. (María Calvo), M.I., M.B.d.A., B.S., J.B., J.L.P.C., D.B., I.P.-M., M.N.-L., V.H., F.A.-A., F.R.E., S.M., L.R., F.G., F.M. (Fernando Muñoz), G.S., J.O.d.Z., J.M.H., J.L., M.F.G.-S., M.S., M.D., S.E., A.F.C., E.H., L.O., E.I., A.G., P.V. (Pilar Varela), N.R., P.G., A.H.-C., A.B., D.G., E.S., D.C., M.A., J.L.C., Y.G.-L., L.J., M.C. (María Chaparro), A.L.-S.R., C.A., R.P.-S., R.M., S.T.-S., E.R., M.C. (Margalida Calafat), S.O., P.N., F.B., H.A.-G., R.P., P.O. and E.D.; Resources, Y.Z.; Data curation, Y.Z., I.M.-J., I.R.-L. and Pamela Manzano; Writing—original draft, Y.Z.; Writing—review & editing, Y.Z., I.M.-J., I.R.-L., I.V., M.D.M.-A., I.G., J.P.G., F.M. (Francisco J. Clin. Med. 2022, 11, 7540 11 of 14 Mesonero), O.B., C.T., Á.P.-D., M.P., A.J.L., B.C., M.M., P.M.-M., M.B.-W., J.G., L.B., N.M., T.M.-P., A.L., C.R.-G., S.G.-L., P.V. (Pablo Vega), M.R., L.M., M.C. (María Calvo), M.I., M.B.d.A., B.S., J.B., J.L.P.C., D.B., I.P.-M., M.N.-L., V.H., F.A.-A., F.R.E., S.M., L.R., F.G., F.M. (Fernando Muñoz), G.S., J.O.d.Z., J.M.H., J.L., M.F.G.-S., M.S., M.D., S.E., A.F.C., E.H., L.O., E.I., A.G., P.V. (Pilar Varela), N.R., P.G., A.H.-C., A.B., D.G., E.S., D.C., M.A., J.L.C., Y.G.-L., L.J., M.C. (María Chaparro), A.L.-S.R., C.A., R.P.-S., R.M., S.T.-S., E.R., M.C. (Margalida Calafat), S.O., P.N., F.B., H.A.-G., R.P., P.O., E.D. and M.E.; Supervision, Y.Z. and P.M.; Project administration, Y.Z. and P.M.; Funding acquisition, Y.Z. and M.E. ENEIDA Registry of GETECCU: patients’ platform and data curation. All authors have read and agreed to the published version of the manuscript. Funding: This study was funded by the Carlos III Health Institute (COV20/00227: Co-IP Dra. Maria Esteve and Dra. Yamile Zabana), FEDER (Fondo Europeo de Desarrollo Regional) and supported by GETECCU. The ENEIDA Registry of GETECCU is supported by Takeda, Pfizer, Galápagos, AbbVie and Biogen. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Scientific Committee of ENEIDA on 16 March 2020. It was also approved by the Ethics Committee of Hospital Universitari Mútua Terrassa (coordinating centre). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: The data underlying this article are available in the article and in its online Supplementary Data. Acknowledgments: The authors would like to thank the centres that registered no cases during the study period but performed an active search of IBD patients with COVID-19: Hospital Sant Joan de Deu, Hospital Sant Jaume de Calella, Hospital de Castellón, Hospital Materno-Infantil de Málaga, Hospital de Granollers, Hospital Joan XXIII, Hospital Niño Jesús, Hospital de Cáceres, Hospital de Vic, and Complejo Hospitalario La Mancha Centro. Conflicts of Interest: Y. Zabana has received support for conference attendance, speaker fees, research support and consulting fees from AbbVie, Adacyte, Almirall, Amgen, Falk Pharma, FAES Pharma, Ferring, Janssen, Otsuka, Pfizer, Shire, Takeda, Galapagos, Boehringer Ingelheim and Tillots. I. Marín-Jiménez has received financial support for travelling and educational activities from or has served as an advisory board member to MSD, Pfizer, AbbVie, Amgen, Takeda, Janssen, Sandoz, Shire Pharmaceuticals, Faes Farma, Ferring, Falk Pharma, Tillotts Pharma, Kern Pharma, Fresenius, Chiesi, Galapagos, Gebro Pharma, and Otsuka Pharmaceutical. I. Rodríguez-Lago has received financial support for travelling and educational activities from or has served as an advisory board member to MSD, Pfizer, AbbVie, Takeda, Janssen, Tillotts Pharma, Roche, Celltrion, Ferring, Falk Pharma, Adacyte and Otsuka Pharmaceutical. MD Martín-Arranz has received fees as a speaker, consultant and advisory member for or has received funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Shire Pharmaceuticals, Tillots Pharma, and Faes Pharma. J. P Gisbert has served as speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene, Gilead/Galapagos, Ferring, Faes Farma, Shire Pharmaceuticals, Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma. F. Mesonero has served as a speaker or has received education funding or advisory fees from MSD, Abbvie, Takeda, Janssen, Pfizer, Kern Pharma, Ferring and Falk Pharma. O. Benítez has received financial support for travelling and educational activities from Janssen, Biogen and MSD. C. Taxonera has served as a speaker, consultant, and advisory board member for or has received research funding from MSD, AbbVie, Pfizer, Takeda, Janssen, Ferring, Faes Pharma, Shire Pharmaceuticals, Falk Pharma, Galapagos, and Tillots. M. Piqueras has received financial support or has served as speaker for Takeda, Abbvie and Janssen. N. Manceñido has been a consultant or speaker for Abbvie, Janssen, Takeda, Ferring, Chiesi, Falk Pharma and Tillotts Pharma. M. Rivero has served as a speaker, consultant and advisory member for Merck Sharp and Dohme, Abbvie, Pfizer, Takeda and Janssen. M. Barreiro has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma. F. Argüelles has received financial support for travelling and educational activities from or has served as an advisory board member to MSD, Pfizer, Abbvie, Amgen, Takeda, Janssen, Sandoz, Shire Pharmaceuticals, Ferring and Falk J. Clin. Med. 2022, 11, 7540 12 of 14 Pharma. J.M. Huguet has participated in educational activities, research projects, scientific meetings or advisory boards sponsored by Merck Sharp Dohme (MSD), Ferring, Abbvie, Janssen, Biogen, Sandoz, Kern Pharma, Faes Farma, Vifor Pharma and Takeda. A. Hernández-Camba has served as speaker, or has received education funding from AbbVie, Takeda, Kern Pharma, Pfizer, Janssen, Adacyte Therapeutics and Ferring. D. Ginard has received support for conference attendance, speaker fees, research support and consulting fees from Abbvie, Adacyte, Jannsen, Takeda, Sandoz, Ferring, Pfizer and Biogen. M. Aceituno has received educational grants from Ferring, Pfizer, Janssen and AbbVie. M. Chaparro has served as a speaker and consultant and has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Falk Pharma, Tillotts Pharma, Faes Pharma, Biogen and Gilead. H. Alonso-Galán has received financial support for travelling and educational activities from or has served as an advisory board member to Janssen, MSD, Abbvie, Takeda, Ferring, Pfizer and Falk Pharma. E. Domènech has served as a speaker, or has received research or education funding or advisory fees from AbbVie, Adacyte Therapeutics, Biogen, Celltrion, Gilead, Janssen, Kern Pharma, MSD, Pfizer, Roche, Samsung, Takeda, Galápagos and Tillots. M. Esteve has received support for conference attendance, speaker fees, research support and consulting fees from Abbvie, Ferring, Janssen, MSD, Otsuka, Pfizer, Takeda and Tillots. L. Bujanda has served as consultant or has received research funding from Ikan Biotech. M Bosca-Watts declares educational activities, research projects, scientific meetings and advisory boards sponsored by MSD, Ferring, Abbvie, Janssen, Biogen and Takeda. M. Navarro-Llavat has received support for conference attendance, speaker fees and research support from Abbvie, MSD, Takeda, Janssen, Ferring, Pfizer, and Biogen. I. Vera, I. Guerra, A. Ponferrada-Díaz, A. Lucendo, B. Caballol, M.Mañosa, P. Martínez-Montiel, J. Gordillo, T. Martínez-Pérez, A. López, C. Rodríguez, S. García-López, P. Vega, L. Melcarne, M. Calvo, M. Iborra, B. Sicilia, J. Barrio, JL. Pérez, D. Busquets, I. Martínez-Pérez, V. Hernández, F. Ramírez Esteso, S. Mejilde, L. Ramos, F. Gomollón, F. Muñoz, G. Suris, J. Ortiz de Zarate, J. Llaó, M. García-Sepulcre, M. Sierra, M. Durà. S. Estrecha, A. Fuentes Coronel, E. Hinojosa, L. Olivan, E. Iglesias, A. Gutiérrez, P. Varela, N. Rull, P. Gilabert, A. Brotons, E. Sesé, D. Carpio, JL Cabriada, Y. González-Lama, L. Giménez, A. López-San Román, C. Alba, R. Plaza-Santos, R. Mena, S. Tamarit-Sebastián, E. Ricart, M. Calafat, S. Olivares, P. Navarro, F. Bertoletti, R. Pajares, P. Olcina, and P. Manzano have no conflicts of interest. 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