Journal of Clinical Medicine Article Nationwide COVID-19-EII Study: Incidence, Environmental Risk Factors and Long-Term Follow-Up of Patients with Inflammatory Bowel Disease and COVID-19 of the ENEIDA Registry Yamile Zabana 1,2, * , Ignacio Marín-Jiménez 3 , Iago Rodríguez-Lago 4,5 , Isabel Vera 6 , María Dolores Martín-Arranz 7 , Iván Guerra 8,9 , Javier P. Gisbert 2,10,11 , Francisco Mesonero 12 , Olga Benítez 1 , Carlos Taxonera 13,14 , 15 Ángel Ponferrada-Díaz , Marta Piqueras 16 , Alfredo J. Lucendo 2,11,17 , Berta Caballol 2,18 , Míriam Mañosa 2,19 , Pilar Martínez-Montiel 20, Maia Bosca-Watts 21 , 22 Jordi Gordillo , Luis Bujanda 2,23,24 , Noemí Manceñido 25 , Teresa Martínez-Pérez 26 , Alicia López 27 , Cristina Rodríguez-Gutiérrez 28 , Santiago García-López 29 , Pablo Vega , Montserrat Rivero 31 , Luigi Melcarne 32 , Maria Calvo 33 , 30 Marisa Iborra 2,34 , Manuel Barreiro de-Acosta 35 , Beatriz Sicilia 36 , Jesús Barrio 37 , José Lázaro Pérez 38 , David Busquets 39 , Isabel Pérez-Martínez 40 , Mercè Navarro-Llavat 41 ,Vicent Hernández 42 , Federico Argüelles-Arias 43 , Fernando Ramírez Esteso 44 , Susana Meijide 45 , Laura Ramos 46 ,  Fernando Gomollón 2,47 , Fernando Muñoz , Gerard Suris , Jone Ortiz de Zarate 50 , 48 49  José María Huguet 51 , Jordina Llaó 52 , Mariana Fe García-Sepulcre 53 , Mónica Sierra 54 , Citation: Zabana, Y.; Marín-Jiménez, Miguel Durà , Sandra Estrecha 56 , Ana Fuentes Coronel 57 , Esther Hinojosa 58 , 55 I.; Rodríguez-Lago, I.; Vera, I.; Lorenzo Olivan 59 , Eva Iglesias 60 , Ana Gutiérrez 2,61 , Pilar Varela 62 , Núria Rull 63 , Martín-Arranz, M.D.; Guerra, I.; Gisbert, J.P.; Mesonero, F.; Benítez, O.; Pau Gilabert 64 , Alejandro Hernández-Camba 65 , Alicia Brotons 66 , Daniel Ginard 67 , Taxonera, C.; et al. Nationwide Eva Sesé 68 , Daniel Carpio 69 , Montserrat Aceituno 1,2 , José Luis Cabriada 4,5 , COVID-19-EII Study: Incidence, Yago González-Lama 6 , Laura Jiménez 8,9 , María Chaparro 2,10,11 , Environmental Risk Factors and Antonio López-San Román 12, Cristina Alba 13,14, Rocío Plaza-Santos 15 , Raquel Mena 16, Long-Term Follow-Up of Patients Sonsoles Tamarit-Sebastián 17 , Elena Ricart 2,18 , Margalida Calafat 2,19 , with Inflammatory Bowel Disease Sonsoles Olivares 20 , Pablo Navarro 21 , Federico Bertoletti 22 , Horacio Alonso-Galán 23,24 , and COVID-19 of the ENEIDA Ramón Pajares 25 , Pablo Olcina 26 , Pamela Manzano 1 , Eugeni Domènech 2,19 , Registry. J. Clin. Med. 2022, 11, 421. Maria Esteve 1,2 and on behalf of the ENEIDA registry of GETECCU † https://doi.org/10.3390/ jcm11020421 1 Hospital Universitari Mútua Terrassa, 08221 Terrassa, Spain; olgabl27@gmail.com (O.B.); Academic Editor: Hemant Goyal maceituno1@hotmail.com (M.A.); hermisende@gmail.com (P.M.); mariaesteve@mutuaterrassa.cat (M.E.) 2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Received: 9 December 2021 28029 Madrid, Spain; javier.p.gisbert@gmail.com (J.P.G.); ajlucendo@hotmail.com (A.J.L.); Accepted: 6 January 2022 caballol@clinic.cat (B.C.); mmanosa.germanstrias@gencat.cat (M.M.); luis.bujanda@osakidetza.net (L.B.); Published: 14 January 2022 marisaiborra@hotmail.com (M.I.); fgomollon@gmail.com (F.G.); gutierrez_anacas@gva.es (A.G.); mariachs2005@gmail.com (M.C.); ericart@clinic.cat (E.R.); margalidasard.calafat@gmail.com (M.C.); Publisher’s Note: MDPI stays neutral eugenidomenech@gmail.com (E.D.) with regard to jurisdictional claims in 3 Hospital Gregorio Marañón, 218007 Madrid, Spain; drnachomarin@hotmail.com published maps and institutional affil- 4 Gastroenterology Department, Hospital Universitario de Galdakao, 48960 Galdakao, Spain; iations. iago.r.lago@gmail.com (I.R.-L.); jcabriada@gmail.com (J.L.C.) 5 Biocruces Bizkaia Health Research Institute, 48960 Galdakao, Spain 6 Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain; isabel.veramendoza@gmail.com (I.V.); ygonzalezlama@gmail.com (Y.G.-L.) 7 Hospital Universitario La Paz, 28046 Madrid, Spain; mmartina.hulp@salud.madrid.org Copyright: © 2022 by the authors. 8 Hospital Universitario de Fuenlabrada, 28942 Fuenlabrada, Spain; ivangm79@gmail.com (I.G.); Licensee MDPI, Basel, Switzerland. laujmarquez@gmail.com (L.J.) This article is an open access article 9 Instituto de Investigación Hospital Universitario La Paz (IdiPaz), 28046 Madrid, Spain distributed under the terms and 10 Department of Gastroenterology, Hospital Universitario de La Princesa, Universidad Autónoma de conditions of the Creative Commons Madrid (UAM), 28049 Madrid, Spain Attribution (CC BY) license (https:// 11 Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain creativecommons.org/licenses/by/ 12 Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; pacomeso@hotmail.com (F.M.); 4.0/). mibuzon@gmail.com (A.L.-S.R.) J. Clin. Med. 2022, 11, 421. https://doi.org/10.3390/jcm11020421 https://www.mdpi.com/journal/jcm J. Clin. Med. 2022, 11, 421 2 of 20 13 Hospital Clínico San Carlos, 28040 Madrid, Spain; ctaxonera.hcsc@salud.madrid.org (C.T.); cristina.alba@telefonica.net (C.A.) 14 Instituto de Investigación del Hospital Clínico San Carlos [IdISSC], 28040 Madrid, Spain 15 Hospital Universitario Infanta Leonor, 28031 Madrid, Spain; angelponmedicina@yahoo.es (Á.P.-D.); rocio_plaza@yahoo.es (R.P.-S.) 16 Consorci Sanitari de Terrassa, 08227 Terrassa, Spain; MPiqueras@cst.cat (M.P.); RMena@cst.cat (R.M.) 17 Hospital General de Tomelloso, 13700 Tomelloso, Spain; sonsolestamarit@hotmail.com 18 Hospital Clínic de Barcelona-IDIBAPS, 08036 Barcelona, Spain 19 Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain 20 Fundación Hospital Universitario Doce de Octubre, 28041 Madrid, Spain; pilarmarmon123@telefonica.net (P.M.-M.); sonsolesolivares@hotmail.com (S.O.) 21 Hospital Clinic Universitari de Valencia, 46010 Valencia, Spain; maiabosca@gmail.com (M.B.-W.); pnavarrocortes@gmail.com (P.N.) 22 Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; jgordillo@santpau.cat (J.G.); fbertoletti@santpau.cat (F.B.) 23 Hospital Universitario Donostia, Instituto Biodonostia, 20014 San Sebastián, Spain; horacio.alonsogalan@osakidetza.eus 24 Universidad del País Vasco (UPV/EHU), 48940 Leioua, Spain 25 Hospital Universitario Infanta Sofía, 28703 San Sebastián de los Reyes, Spain; nmancenido@gmail.com (N.M.); rpajaresvi@gmail.com (R.P.) 26 Hospital Virgen de la Luz, 16002 Cuenca, Spain; terechu.martinez@gmail.com (T.M.-P.); olcinapod@gmail.com (P.O.) 27 Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Hospital del Mar, 08003 Barcelona, Spain; alicialg84@gmail.com 28 Complejo Hospitalario de Navarra, 31008 Pamplona, Spain; cristina.rodriguez.gutierrez@cfnavarra.es 29 Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain; sgarcia.lopez@gmail.com 30 Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain; pablo.vega.villaamil@sergas.es 31 Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain; digrtm@humv.es 32 Hospital Universitari Parc Taulí, 08208 Sabadell, Spain; lmelcarne@tauli.cat 33 Hospital San Pedro-Logroño, 26006 Logroño, Spain; mciniguez@riojasalud.es 34 Hospital Universitario y Politécnico de la Fe de Valencia, 46026 Valencia, Spain 35 Hospital Clínico Universitario de Santiago, 15706 Santiago, Spain; manubarreiro@hotmail.com 36 Hospital Universitario de Burgos, 09006 Burgos, Spain; bsicilia4@gmail.com 37 Hospital Universitario Río Hortega (HURH), 47012 Valladolid, Spain; jbarrioa95@gmail.com 38 Hospital Universitario Fundación de Alcorcón, 28922 Alcorcón, Spain; jlperezc@fhalcorcon.es 39 Hospital Universitari de Girona Doctor Josep Trueta, 17007 Girona, Spain; dbusquets.girona.ics@gencat.cat 40 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; ipermar_79@hotmail.com 41 Hospital de Sant Joan Despí Moisès Broggi, 08970 Sant Joan Despí, Spain; merce.navarro@sanitatintegral.org 42 Hospital Álvaro Cunqueiro, 36213 Vigo, Spain; vicent.hernandez.ramirez@sergas.es 43 Hospital Universitario Virgen de la Macarena, Universidad de Sevilla, 41009 Sevilla, Spain; farguelles@telefonica.net 44 Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain; fernando.ramirez.est@gmail.com 45 Hospital Universitario de Cruces, 48903 Barakaldo, Spain; susana.meijidedelafuente@osakidetza.eus 46 Hospital Universitario de Canarias, 38320 San Cristobal de la Laguna, Spain; laura7ramos@gmail.com 47 Hospital Clínico Universitario “Lozano Blesa” and IIS Aragón, 50009 Zaragoza, Spain 48 Hospital Universitario de Salamanca, 37007 Salamanca, Spain; jmunozn@gmail.com 49 Hospital Universitari de Bellvitge, 08907 L’Hospitalet de Llobregat, Spain; tsuris@bellvitgehospital.cat 50 Hospital Universitario de Basurto, 48013 Bilbo, Spain; jone.ortizdezaratesagastagoitia@osakidetza.net 51 Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain; josemahuguet@gmail.com 52 Althaia Xarxa Assistencial Universitària de Manresa, 08243 Manresa, Spain; jllao@althaia.cat 53 Hospital Universitario de Elche, 03203 Elche, Spain; marifegarciasepulcre@gmail.com 54 Complejo Asistencial Universitario de León, 24071 León, Spain; msierra.ausin@gmail.com 55 Hospital Clínico de Valladolid, 47003 Valladolid, Spain; mdura@saludcastillayleon.es 56 Hospital Universitario Álava, 01009 Gasteiz, Spain; sandra.estrecha@gmail.com 57 Hospital Virgen de la Concha, 49022 Zamora, Spain; amfcoronel@gmail.com 58 Hospital de Manises, 46940 Manises, Spain; hinova200@gmail.com 59 Hospital Universitario San Jorge, 22004 Huesca, Spain; lorenolivan@gmail.com 60 Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, 14004 Cordoba, Spain; evaiflores@gmail.com 61 Hospital General Universitario de Alicante, 03010 Alicante, Spain 62 Hospital Universitario de Cabueñes, 33394 Gijón, Spain; trastoy@hotmail.com J. Clin. Med. 2022, 11, 421 3 of 20 63 Hospital Universitario Son Llàtzer, 07198 Palma, Spain; nrull@hsll.es 64 Hospital de Viladecans, 08840 Viladecans, Spain; pgilabert.hv@gencat.cat 65 Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; dr.alejandrohc@gmail.com 66 Hospital Vega Baja de Orihuela, 03314 Alicante, Spain; aliciabbrotons@gmail.com 67 Hospital Universitario Son Espases, 07120 Palma, Spain; daniel.ginard@ssib.es 68 Hospital Universitari Arnau de Vilanova de Lleida, 25198 Lleida, Spain; eseseabi@gmail.com 69 Complexo Hospitalario de Pontevedra, 36071 Pontevedra, Spain; daniel.carpio.lopez@sergas.es * Correspondence: yzabana@gmail.com † All Co-authors are part of ENEIDA. Abstract: We aim to describe the incidence and source of contagion of COVID-19 in patients with IBD, as well as the risk factors for a severe course and long-term sequelae. This is a prospective observational study of IBD and COVID-19 included in the ENEIDA registry (53,682 from 73 centres) between March–July 2020 followed-up for 12 months. Results were compared with data of the general population (National Centre of Epidemiology and Catalonia). A total of 482 patients with COVID-19 were identified. Twenty-eight percent were infected in the work environment, and 48% were infected by intrafamilial transmission, despite having good adherence to lockdown. Thirty-five percent required hospitalization, 7.9% had severe COVID-19 and 3.7% died. Similar data were reported in the general population (hospitalisation 19.5%, ICU 2.1% and mortality 4.6%). Factors related to death and severe COVID-19 were being aged ≥ 60 years (OR 7.1, 95% CI: 1.8–27 and 4.5, 95% CI: 1.3–15.9), while having ≥2 comorbidities increased mortality (OR 3.9, 95% CI: 1.3–11.6). None of the drugs for IBD were related to severe COVID-19. Immunosuppression was definitively stopped in 1% of patients at 12 months. The prognosis of COVID-19 in IBD, even in immunosuppressed patients, is similar to that in the general population. Thus, there is no need for more strict protection measures in IBD. Keywords: COVID-19; SARS-CoV-2; inflammatory bowel disease 1. Introduction The COVID-19 pandemic hit Spain at the end of February 2020 and is far from un- der complete control. Data on affected cases and mortality are continuously updated [1]. There is evidence that patients suffering from inflammatory bowel disease (IBD) have a greater risk for infections, some of them opportunistic, mainly favoured by immunosup- pressive treatment [2–4]. For that reason, experts on IBD, worried by the potential severity of COVID-19 in these patients, recommended, during the initial phases of the pandemic, that whenever possible, starting immunosuppressants should be delayed and treatment deescalated [5–7]. Notwithstanding this information, more than one year after the start of the pandemic, factors related to deleterious prognosis of COVID-19 in patients with IBD are essentially the same as those of the general population (mainly older age and comor- bidities), whereas those on immunosuppressants do not appear to have a greater risk for severe COVID-19, except for corticosteroids [8]. In this sense, the international self-reported registry SECURE-IBD (https://covidibd.org (accessed on 24 August 2021)) has provided valuable clinical and therapeutic information [9]. Nevertheless, retrospective studies and registries have important limitations, such as reporting bias, over- or underrepresentation of the more severe cases of COVID-19, and the possibility of including confounding factors that may influence the results. In addition, some studies have reported a low incidence of COVID-19 in patients with IBD [10], suggesting that IBD and the type of immunosuppressants administered for disease control do not represent risk factors for COVID-19. However, few of these studies are population based and do not address important environmental epidemiological risk factors, such as variability in the incidence of the infection in different regions within the same country. Neither do they address factors that may facilitate the infection, such as J. Clin. Med. 2022, 11, 421 4 of 20 occupational risk, or those that may reduce the risk, as they may be specific isolation measures that could be recommended to a particular diseased population [10–16]. Likewise, the impact of COVID-19 on patients with IBD in the long term has not yet been explored. The present study (COVID-19-EII study) was conducted 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) [17]. The aims of the present study were (1) to describe the incidence of COVID-19 in the ENEIDA registry, the geographical distribution of the infection compared with the distribution in the general Spanish popula- tion and exposure factors that may favour or prevent the infection (occupational risk and lockdown measures) during the first wave of the pandemic and (2) to describe the clinical characteristics and the disease course, including a 12-month follow-up after COVID-19. 2. Materials and Methods 2.1. Design This was an observational prospective cohort study (COVID-19-EII) within the Spanish ENEIDA IBD registry. It included all patients with IBD who had COVID-19 between March and July 2020 (in the first wave) from the participant centres. 2.2. Study Population The potential population was all patients with IBD registered in ENEIDA. Patients with COVID-19 were identified by an active search from their IBD unit (systematically addressing all the patients with IBD from the unit by email or phone call) or by direct notification from the patient itself, the family physician, the emergency department or the hospitalisation unit. 2.3. Data Collection A prospective module hosted on the ENEIDA platform was specially designed for this study. Data collected included clinical baseline characteristics such as type of IBD, date of IBD diagnosis and Montreal’s classification [18], extraintestinal manifestations, family history of IBD and smoking behaviour at time of infection. The following comor- bidities were specifically registered: cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, heart disease, stroke, diabetes mellitus, arterial hypertension, dys- lipidaemia, neoplasia, congestive heart failure, dementia, HIV, rheumatological disease or immune-mediated disease. Charlson’s index [19] was also calculated. We decided to explore both individual comorbidities and the Charlson comorbidity score, as these two approaches examine different aspects of comorbidity and are complementary. Variables measuring the exposure risk to SARS-CoV-2 included occupational risk (such as health care workers, teachers, basic services as supermarket cashiers, market clerks or pharmacy workers, police and firepersons, workers of closed institutions, veterinaries, animal control workers or conservation and forest technicians), compliance with lockdown measures, so- cial distancing and the route of contagion. At the time of COVID-19 diagnosis, IBD activity was evaluated using the Harvey-Bradshaw index [20] or partial Mayo score [21]. The IBD therapeutic regimen was registered at the time of infection and up to 3 and 12 months before it: systemic steroid treatment, aminosalicylates, immunosuppressants (thiopurines, cy- closporine, methotrexate, tacrolimus and tofacitinib) and biologics (anti-TNF, vedolizumab and ustekinumab). Regarding COVID-19, the data collected included symptoms associated with the infection at the time of diagnosis, diagnostic procedures and specific treatment. The variables registered 3 and 12 months after COVID-19 were IBD activity and COVID-19 sequelae, both physical and psychological. To assess the impact of COVID-19 on IBD treatment, any change in medical therapy, including withdrawal of immunosuppression, both definitive and temporary, was collected during follow-up. J. Clin. Med. 2022, 11, 421 5 of 20 2.4. Definitions COVID-19 diagnosis was based on a typical clinical picture consisting of fever (>38 ◦ C), respiratory symptoms (cough and/or dyspnoea), anosmia or dysgeusia within the epi- demiological setting. COVID-19 was considered confirmed by a positive diagnostic test including polymerase chain reaction (PCR) taken by nasopharyngeal swab or serology (IgM or IgG) for SARS-CoV-2. COVID-19 was considered probable in patients with a typical clinical picture but negative or lacking diagnostic tests. Asymptomatic patients with positive PCR or serology were not included. It was considered that any patient had a good compliance with the lockdown measures when maintaining social distance by staying at home almost exclusively since 14 March 2020, the date the Spanish government ordered a total lockdown to prevent the spread of SARS-CoV-2. Sequelae due to COVID-19 were any sign or symptom that the patient and/or physi- cian considered related directly to COVID-19 and that was present at 3 and 12 months after infection. 2.5. Outcomes To assess the disease course and clinical evolution of COVID-19, the following out- comes were registered and analysed: hospitalisation due to COVID-19, intensive care unit (ICU) admission, sequelae, severe COVID-19 and death. Severe COVID-19 was considered a composite variable that included ICU admission and/or use of active amines and/or res- piratory distress and/or invasive oxygen therapy and/or death [22]. Cases with systemic inflammatory response syndrome were also registered. Data on outcomes of our study were compared to those registered on the SECURE-IBD registry (accessed on 24 August 2021) [9], considered the worldwide IBD registry on COVID-19. These outcomes were also compared to those of the general population taking into account data from Catalonia [23]. 2.6. Ethical Considerations The Scientific Committee of ENEIDA approved the study on 16 March 2020. It was also approved by the Ethics Committee of Hospital Universitari Mútua Terrassa (coordinating centre). Informed consent was obtained from all subjects. The patients were not identified by name in the publication, and no one, except the investigators of this study, had access to their local data, in accordance with the local Law of Personal Data Protection. 2.7. Statistical Analysis Quantitative variables were compared with Student’s t test and the Mann–Whitney test, and the results are expressed as the means (±standard deviation) or median (±interquartile range (IQR) 25–75 percentiles). Quantitative variables were compared using Student’s t test for parametric data and the Mann–Whitney test for nonparamet- ric data, while qualitative variables were compared using the Chi2 test or Fisher’s exact test, as appropriate. Univariate and multivariate logistic binary regression analyses were performed to explore the variables related to the need for hospitalisation, ICU admission, se- vere COVID-19, death and sequelae found at the 3- and 12-month follow-ups. The intensity of the significant associations was measured by calculating the OR and its 95% confidence interval. The multivariate models included significant variables in univariate analysis at the p < 0.1 level. In addition, for the outcomes with a small number of events (death and ICU admission), only the 2 most significant covariates in the univariate analysis were included. As the use of aminosalicylates was more frequent in patients with ulcerative colitis (UC) than in Crohn’s disease (CD), the model was adjusted to UC diagnosis when this drug was independently associated with a specific outcome. Due to the great variability in the incidence of COVID-19 between the Spanish territo- ries, the number of cases of both IBD and the general population are shown per province. Data on COVID-19 incidence in the general population as well as the age at COVID-19 diagnosis, age of hospitalized patients (including ICU admission) and age of patients with J. Clin. Med. 2022, 11, 421 6 of 20 fatal outcomes were obtained from the National Centre of Epidemiology (CNE) [24,25]. The age- and sex-standardised incidence of every outcome in the IBD cohort was obtained based on all the patients actively followed in each participant centre of ENEIDA. 3. Results A total of 73 out of the 86 centres adhered to the ENEIDA registry at the time of the study and decided to participate. This registry had, at that moment, 60,512 patients actively followed-up (data as for 15 July 2020), with 53,682 coming from the 73 participating centres (89% of the whole registry). Finally, 482 cases of COVID-19 were reported (251 males (52%); median 52 years (IQR: 42–61); cumulative incidence of 8.97 per 1000 patients with IBD, taking into account the population at risk from the participating centres). Ten centres that agreed to participate did not register any COVID-19 cases during the study period, despite being aware. 3.1. Clinical Baseline Characteristics Tables 1 and 2 show the most important clinical characteristics of the patients regarding IBD at the time of COVID-19 diagnosis. The activity of the disease and treatment are provided separately for UC and CD (Table 2). Notably, 80% of patients were in remission, and 9% had moderate–severe disease activity. Regarding IBD treatment at the time of the infection, 42% of the patients were on aminosalicylates, 5.4% were receiving systemic steroids, 36% were receiving immunosuppressants, 36% were receiving biologics and 12% were receiving combination therapy. Eleven percent of the patients required steroids within the 3 months before COVID-19 diagnosis. Table 1. Clinical baseline characteristics regarding inflammatory bowel disease with COVID-19. Clinical Characteristics Cases n = 482 Gender Male 251 (52) Female 231 (48) Age at COVID-19 diagnosis 52 years (IQR 42–61) IBD duration at COVID-19 diagnosis 12 years (IQR 6–19) Type of IBD, n (%) Crohn’s disease 247 (51) Ulcerative colitis 221 (46) Unclassified colitis 14 (2.9) Ulcerative colitis extent (%) E1 43 (19) E2 80 (36) E3 98 (44) Crohn’s disease location, n (%) L1 114 (46) L2 43 (17) L3 88 (36) L4 (isolated) 3 (1.2) Crohn’s disease behaviour, n (%) B1 144 (58) B2 71 (29) B3 47 (19) Perianal 59 (24) B1 + perianal 29 (12) B2 + perianal 18 (7.3) B3 + perianal 20 (8.1) J. Clin. Med. 2022, 11, 421 7 of 20 Table 1. Cont. Clinical Characteristics Cases n = 482 Extraintestinal manifestation, n (%) 125 (26) Family history of IBD, n (%) 64 (13) Smoking behaviour, n (%) Active 53 (11) Former smoker 137 (28) Never smoker 268 (56) IQR: interquartile rate, IBD: inflammatory bowel disease, L1: ileal, L2: colonic, L3: ileocolonic, L4: upper gastrointestinal tract; B1: inflammatory behaviour, B2: stricturing behaviour, B3: penetrating behaviour. Table 2. Inflammatory bowel disease activity and treatment at time of COVID-19 diagnosis. IBD (Total) Crohn’s Disease Ulcerative Colitis p-Value * n = 482 n = 247 n = 221 IBD Activity at COVID-19 Diagnosis Clinical remission 385 (80) 200 (81) 173 (78) 0.35 Active disease 97 (20) 47 (19) 48 (22) 0.35 Mild 53 (11) 26 (10.5) 26 (12) Moderate 42 (8.7) 21 (8.5) 20 (9) Severe 2 (0.4) 0 2 (0.9) IBD treatment None, n (%) 62 (13) 37 (15) 23 (10.4) 0.15 5-aminosalicylates, n (%) 202 (42) 49 (20) 143 (65) <0.0001 Oral (oral and topic) 197 (41) 49 (20) 138 (62) Topical (exclusive) 5 (1) 0 5 (2.3) Monotherapy 131 (27) 31 (12) 91 (41) Systemic steroids 3 months before 53 (11) 30 (12) 21 (9.5) 0.36 COVID-19 (oral or intravenous), n (%) Systemic steroids, n (%) 26 (5.4) 16 (6.4) 8 (3.6) 0.37 Immunosuppressants 113 (23) 65 (26) 56 (25) 0.03 (in monotherapy), n (%) Azathioprine 90 (19) 54 (22) 46 (21) 0.04 Mercaptopurine 8 (1.7) 4 (1.6) 2 (0.9) 0.16 Cyclosporine 1 (0.2) 0 1 (0.4) 0.96 Methotrexate 9 (1.9) 6 (2.4) 3 (1.3) 0.06 Tacrolimus 1 (0.2) 1 (0.4) 0 1 Tofacitinib 4 (0.8) 0 4 (1.8) 0.10 Biologics 117 (22) 72 (29) 35 (16) 0.04 (in monotherapy), n (%) Anti-TNF 71 (15) 42 (17) 19 (8.6) <0.0001 Vedolizumab 25 (5.2) 12 (4.8) 13 (5.9) 0.75 Ustekinumab 21 (4.3) 18 (7.3) 3 (1.3) 0.001 Combotherapy, n (%) 59 (12) 45 (18) 14 (6.3) 0.02 Anti-TNF plus thiopurines 37 (7.7) 28 (11) 9 (4.1) 0.02 Anti-TNF plus methotrexate 9 (1.9) 6 (2.4) 3 (1.3) 0.62 Vedolizumab plus thiopurines 5 (1) 4 (1.6) 1 (0.4) 0.73 Vedolizumab plus methotrexate 1 (0.2) 0 1 (0.4) 0.78 Ustekinumab plus thiopurines 5 (1) 5 (2) 0 0.55 Ustekinumab plus methotrexate 2 (0.4) 2 (0.8) 0 0.98 * Comparison between Crohn’s disease and ulcerative colitis. IBD: inflammatory bowel disease; TNF: tumour necrosis factor. Vedolizumab plus thiopurines 5 (1) 4 (1.6) 1 (0.4) 0.73 Vedolizumab plus methotrexate 1 (0.2) 0 1 (0.4) 0.78 Ustekinumab plus thiopurines 5 (1) 5 (2) 0 0.55 Ustekinumab plus methotrexate 2 (0.4) 2 (0.8) 0 0.98 J. Clin. Med. 2022, 11, 421 * Comparison between Crohn’s disease and ulcerative colitis. IBD: inflammatory bowel disease; 8 of 20 TNF: tumour necrosis factor. Forty-four percent had at least one comorbidity, and 64% had a Charlson score of one Forty-four percent had at least one comorbidity, and 64% had a Charlson score of or more. The most frequent comorbidity was arterial hypertension (22% (106/482)), one or more. The most frequent comorbidity was arterial hypertension (22% (106/482)), followed by dyslipidaemia (15% (74/482)) and immune-mediated diseases (11% (53/482)) followed by dyslipidaemia (15% (74/482)) and immune-mediated diseases (11% (53/482)) otherthan other thanIBD IBD(Supplementary (SupplementaryTable TableS1). S1). 3.2. Geografical 3.2. GeograficalDistribution DistributionofofCOVID-19 COVID-19 and and Epidemiological EpidemiologicalRisk RiskFactors FactorsofofExposure Exposure Thegeographical The geographicaldistribution distributionofofcases casesisisshown shownininFigure Figure1A, 1a, allowing allowing aa comparative comparative approach with the incidence of COVID-19 in the Spanish general population approach with the incidence of COVID-19 in the Spanish general population (Figure (Figure1B). 1B). Figure 1. Geographic distribution of COVID-19 cases in the ENEIDA registry and comparison with Figure 1. Geographic distribution of COVID-19 cases in the ENEIDA registry and comparison with the general Spanish population in the first wave of the pandemic. the general Spanish population in the first wave of the pandemic. The majority of cases were reported in ENEIDA centres of the communities of Madrid The majority of cases were reported in ENEIDA centres of the communities of and in those of the metropolitan area of Barcelona (red colour), where there is also the high- Madrid est and inof proportion those of theIBD certified metropolitan units [26].area These of Barcelona two regions (red havecolour), where population the highest there is also density in Spain (844 and 743 inhabitants per km , respectively, as of Januarythe the highest proportion of certified IBD units [26]. 2 These two regions have 2021highest [27]) population density in Spain (844 and 743 inhabitants per and register the highest incidence of COVID-19 in the general population. km 2, respectively, as of January 2021Compared [27]) and register the highest to the Spanish incidence population of COVID-19 in March 2020 [24],in the the general median population. age of IBD cases Compared to the Spanish population in March 2020 [24] , the median age of IBD cases was similar: 52 years old (IQR, 42–61) in patients with IBD vs. 54 years old (IQR, 39–70) in wasgeneral the similar:population. 52 years old (IQR,considering When 42–61) in patients specific with IBD vs. outcomes, 54 yearstrend a similar old (IQR, 39–70) in was observed: the age of hospitalised patients with IBD was 59 years old (IQR, 50–72) vs. 66 years was the general population. When considering specific outcomes, a similar trend old observed: (IQR, 51–79) theinage the of hospitalised general patients population, andwith IBDofwas the age 59 years was ICU/death old (IQR, 50–72) 72 years old vs. 66 (IQR, years old (IQR, 51–79) in the general population, and the age of ICU/death 57–80) in patients with IBD vs. 70 years old (IQR, 59–80 years) in the general population was 72 years old (IQR, 57–80) Regarding in factors risk patients forwith IBD vs.almost COVID-19, 70 yearshalfold of (IQR, 59–80 declared the patients years) ingood the general adher- population ence to lockdown measures (48% (229/482)). The circumstances that ensured an appropriate domiciliary lockdown were having preventive sick leave (31% (71/229)), being retired (26% (60/229)), doing telecommuting (18% (42/229)) and being unemployed (6.6% (15/229)). Table 3 summarizes the risk for SARS-CoV-2 infection related to occupational risk. J. Clin. Med. 2022, 11, 421 9 of 20 Table 3. Epidemiological factors of SARS-CoV-2 infection and occupational risk. Route of Contagion, n (%) Unknown 242 (50) Intrafamilial transmission 108 (22) Occupational 96 (20) Travel 8 (1.7) Occupational Risk, n (%) 133 (28) Healthcare 85 (18) Basic services (supermarket cashiers, market clerks, 18 (3.7) pharmacy) Education 15 (3) Police and fireperson 5 (1) Closed institutions 2 (0.4) Veterinary, animal control worker or conservation and 4 (0.8) forest technician Almost one-third of the patients had a job position considered as posing a high risk of infection, which was the main cause for not having proper adherence to lockdown measures. Health care professions were the most frequent occupational hazard (18% (85/482). Table 4 shows the relationship between infection and occupational risk in patients with and without good adherence to a total lockdown. Table 4. Relationship between the route of contagion and occupational risk in patients with and without a total lockdown. Patients with Total Patients without Risk Variable Lockdown Total Lockdown p-Value (n = 229) (n = 225) Route of contagion, n (%) Intrafamilial transmission 70 (31) 38 (17) 0.001 Infection on March 2020 47 (20) 26 (12) 0.007 Infection on April–July 2020 23 (10) 12 (5.3) 0.034 Occupational 19 (8.3) 77 (34) <0.0001 Infection on March 2020 19 (8.2) 48 (21) <0.0001 Infection on April–July 2020 0 29 (13) <0.0001 Travel 3 (1.3) 5 (2.2) 0.69 Infection on March 2020 3 (1.3) 5 (2.2) 0.69 Infection on April–July 2020 - - Unknown 137 (60) 105 (47) 0.005 Infection on March 2020 83 (36) 69 (31) 0.167 Infection on April–July 2020 54 (24) 36 (16) 0.003 Occupational risk, n (%) Occupational risk (all) 38 (17) 92 (41) <0.0001 Healthcare 18 (7.9) 65 (29) <0.0001 Despite declaring good adherence, patients became infected mainly by intrafamilial transmission, particularly during the first 2 weeks (March 2020) after the Spanish govern- ment established lockdown. 3.3. COVID-19 Diagnosis and Treatment Symptoms of COVID-19 diagnosis can be found in Supplementary Table S2, with fever (69% (336/482)) and cough (63% (305/482)) as the most frequently observed symptoms. Di- J. Clin. Med. 2022, 11, 421 10 of 20 arrhoea was reported in 26% (126/482) of patients, with no significant differences between patients with active or inactive IBD. Supplementary Table S3 includes the tests performed for COVID-19 diagnosis. Notably, 90% of IBD patients had a diagnostic test performed, whether PCR (80% (388/482)) or SARS-CoV-2 serology (35% (167/482)). Only 49 patients did not have any diagnostic test performed. It is also important to emphasize that 28% of patients (85/301) had a positive PCR after one or more negative PCRs, with no difference between immunosuppressed and non-immunosuppressed patients (19% vs. 21%, p = 0.67). COVID-19 treatment followed the trend used and recommended by health authorities at that time. It included chloroquine/hydroxychloroquine in 41% (198/482), antibiotics in 38% (182/482), antivirals in 18% (88/482), systemic corticosteroids in 12% (58/482) and biologic therapy in 2.9% (14/482) (tocilizumab in 1.7% (8/482), interferon in 1.2% (6/482) and anakinra in 0.2% (1/482)). Antifungal therapy was used in 1.9% (9/482), vasoactive amines in 1.2% (6/482) and invasive oxygen therapy in 2.9% (14/482) of the patients (one patient received invasive oxygen therapy in a conventional floor due to occupation limitations of the ICU). 3.4. Outcomes Patients attended their primary care facility in 55% of the cases (266/482), received emergency room assistance in 52% (251/482) and required hospitalisation due to COVID in 35% (167/482). Eleven patients (0.2%) required IBD-related hospitalisation during the study period. Twenty-four patients had respiratory distress (4.9%), 56 (12%) presented with systemic inflammatory response syndrome upon admission and 6.4% (31/482) presented with systemic inflammatory response syndrome during hospitalisation. Thirteen (2.5%) required ICU admission, 38 (7.9%) fulfilled the criteria of severe COVID-19 and 21 patients died during the study. Of those who died, 18 (3.7%) died due to COVID-19 and 3 due to causes other than COVID-19, 2 of them during the first wave of the pandemic (one case with signet-ring cell adenocarcinoma of digestive origin and one case of pulmonary neoplasia) and the third 9 months after COVID-19 infection due to urinary sepsis. Only one death occurred outside the hospital (80-year-old female with inactive ileal CD treated with oral aminosalicylates). Compared to the general population in Spain, the severe outcomes were similar, with a mortality proportion of 4.6% and ICU requirement proportion of 2.1% with a slightly lower proportion of patients requiring hospitalisation (19.5%) [23]. Univariate and multivariate analyses of factors associated with hospitalisation, ICU ad- mission, severe COVID-19 and death are detailed in Supplementary Tables S4–S7. In that case, predictive factors for hospitalisation due to COVID-19 were being 50 years of age or more (OR 2.09, 95% CI 1.3–3.4), having at least one comorbidity (OR 2.28, 95% CI 1.4–3.6) and being treated with steroids for IBD within the 3 months before COVID-19 diagnosis (OR 1.3, 95% CI 1.1–1.6). Predictors for ICU admission were having a Charlson score of at least 2 (OR 5.4, 95% CI 1.5–20.1) and the use of aminosalicylates (OR 4.6, 95% CI 1.2–17). However, when adjusted for diagnosis, the effect of aminosalicylates disappeared (OR 3.6, 95% CI 0.85–15.2, p = 0.08). Independent risk factors related to death due to COVID-19 were being 60 years of age or more (OR 7.1, 95% CI 1.8–27.4) and having at least 2 comorbidities (OR 3.9, 95% CI 1.3–11.6). The only predictor for severe COVID-19 was being 60 years of age or more (OR 4.59, 95% CI 1.3–15.9), while having CD with an inflammatory behaviour was protective for this outcome (OR 0.29, 95% CI 0.09–0.89). There were no differences in the proportion of hospitalisation, ICU admission, severe COVID-19 or death between patients found under active search (18% of the centres) vs. those that were found by direct notification from the patient itself, the family physician, the emergency department or the hospitalisation unit (data not shown). The proportion of patients under specific IBD treatment, taking into account each predefined outcome, is shown in Table 5. J. Clin. Med. 2022, 11, 421 11 of 20 Table 5. Outcome of the COVID-19-EII cohort and treatment administered. The results are compared with those reported in the SECURE-IBD cohort (as for 24 August 2021) [9] ¶ . A. Outcomes Hospitalised ICU Admission Severe COVID-19 Death COVID-19-EII SECURE-IBD COVID-19-EII SECURE-IBD COVID-19-EII SECURE-IBD COVID-19-EII SECURE-IBD Outcome n = 482 n = 6438 n = 482 n = 6438 n = 482 n = 6438 n = 482 n = 6438 n = 168 n = 977 n = 13 n = 38 * n = 257 ** n = 18 n = 104 (35%) (15%) (2.6%) n = 184 (2.8%) (7.8%) (3.9%) (3.7%) (1.6%) B. Treatment taking into account each specific outcome OUTCOMES DRUG Total Hospitalised ICU Severe COVID-19 Death COVID-19-EII SECURE-IBD COVID-19-EII SECURE-IBD COVID-19-EII SECURE-IBD COVID-19-EII * SECURE-IBD ** COVID-19-EII SECURE-IBD Cohort n = 482 n = 6438 n = 168 n = 977 n = 13 n = 184 n = 38 n = 257 n = 18 n = 104 5-aminosalicylates, 202 (42) 1924 (30) 79 (47) 411 (42) 10 (77) 81 (44) 24 (63) 118 (46) 9 (50) 53 (51) Alone 131 (27) - 52 (31) - 5 (38) - 16 (42) - 6 (33) - With other IBD 71 (15) - 27 (16) - 5 (28) - 8 (21) - 3 (17) - drugs Systemic steroids 26 (5.4) 414 (6.4) 11 (6.5) 146 (15) 1 (7.7) 41 (22) 4 (10.5) 53 (21) 1 (5.6) 28 (27) Thiopurines 108 (22) 551 (8.6) 38 (23) 114 (12) 3 (23) 26 (14) 5 (13) 33 (13) 1 (5.6) 11 (10.6) (monotherapy) Methotrexate 9 (1.9) 49 (0.8) 4 (2.4) 13 (1.3) 1 (7.7) 1 (0.5) 2 (5.3) 3 (1.2) 1 (5.6) 2 (1.9) (monotherapy) Anti-TNF (monotherapy) 71 (15) 2082 (32) 11 (6.5) 178 (18) 2 (15) 24 (13) 3 (7.9) 31 (12) 2 (11) 10 (9.6) Anti-TNF in 0 combotherapy 46 (9.5) 636 (9.9) 20 (12) 91 (9.3) 17 (9) 2 (5.3) 21 (8.2) 2 (11) 6 (5.8) Vedolizumab 30 (6.2) 706 (11) 15 (8.9) 94 (9.6) 0 21 (11) 4 (10.5) 28 (10.9) 2 (11) 9 (8.6) Ustekinumab 28 (5.8) 602 (9) 6 (3.6) 50 (5.1) 1 (7.7) 9 (4.9) 1 (2.6) 11 (4.3) 1 (5.6) 5 (4.8) Tofacitinib 4 (0.8) 103 (1.6) 2 (1.2) 12 (1.2) 0 4 (2.2) 0 4 (1.5) 0 1 (0.9) ICU: intensive care unit, TNF: tumour necrosis factor. ¶ Brenner EJ, Ungaro RC, Colombel JF, Kappelman MD. SECURE-IBD Database Public Data, https://covidibd.org/current-data/ accessed on 24 August 2021. * Severe COVID-19 for the COVID-19-EII study: composite of intensive care unit admission and/or use of active amines and/or respiratory distress and/or invasive oxygen therapy and/or death. ** Severe COVID-19 for the SECURE-IBD registry: composite of intensive care unit admission and/or use of ventilator and/or death. J. Clin. Med. 2022, 11, 421 12 of 20 There were no differences in any outcomes between patients with probable or con- firmed COVID-19 (data not shown). To compare the results of the present study with those of the SECURE-IBD (accessed on 24 August 2021) [9], the results of the two cohorts are provided in the same table. In Supplementary Table S8, we show the incidence of adverse outcomes of COVID-19 in patients with IBD, taking into account sex and age. Of note, being ≥50 years old increases the incidence of the reported adverse outcomes from 3 to 7, with a greater frequency in males than in females. 3.5. Follow-Up IBD treatment and the presence of sequelae related to COVID-19 at the 3- and 12-month follow-up are described in Table 6. Table 6. Sequelae at 3- and 12-months of COVID-19 and the impact of the infection on changes in therapeutic regimens for IBD. 3 Months Follow-Up 12 Months Follow-Up (n = 462) (n = 451) COVID-19 sequelae, n (%) 65 (14) 72 (15) Psychologic sequelae, n (%) 20 (4.3) 15 (3.3) Physical sequelae, n (%) 55 (12) 67 (15) Asthenia 21 (4.5) 22 (4.8) Myalgia/Arthralgia 7 (1.5) 3 (0.7) Anosmia 4 (0.9) 7 (1.5) Dyspnoea 4 (0.9) 6 (1.3) Odynophagia 2 (0.4) 2 (0.4) Dysgeusia 2 (0.4) 2 (0.4) Hair loss 1 (0.2) 1 (0.2) Pulmonary fibrosis 1 (0.2) 3 (0.6) Bronchial hyperreactivity 1 (0.2) 1 (0.2) Deep venous thrombosis/pulmonary 1 (0.2) 1 (0.2) thrombosis Headache 1 (0.2) 6 (1.3) Obstructive pulmonary disease 1 (0.2) 3 (0.6) Paraesthesia 1 (0.2) 3 (0.6) Wegener’s vasculitis - 1 (0.2) Immunosuppression withdrawal, n (%) 65 (14) 6 (1.3) Transient 58 (13) 1 (0.2) Definitive 7 (1.5) 5 (1.1) De-escalation from combo to 13 (2.9) 1 (0.2) monotherapy Patients requiring Immunosuppression 12 (2.6) 43 * (9.5) initiation or modification, n (%) Systemic corticosteroids 1 (0.2) 7 (1.6) Thiopurines 2 (0.4) 5 (1.1) Methotrexate 0 1 (0.2) Anti-TNF 5 (1) 18 (4) Vedolizumab 1 (0.2) 7 (1.6) Ustekinumab 2 (0.4) 12 (2.7) Tofacitinib 1 (0.2) 6 (1.3) * Some patients required more than one new immunosuppressant (combined or sequential); therefore, this number expresses the total number of patients that required immunosuppression initiation/modification from 3 to 12 months after COVID-19. IBD = inflammatory bowel disease; TNF: tumour necrosis factor. Only 13% of patients had short-term immunosuppression withdrawal due to COVID- 19 (12% partial and 1.4% definitive), and only 1% kept their withdrawal of immunosup- pression in the long term. At the 3-month follow-up, 65 patients (13%) presented COVID-19 sequelae, of which 4% (20/482) were psychological and 11% (55/482) were physical (Table 6). At the 12-month Only 13% of patients had short-term immunosuppression withdrawal due to COVID-19 (12% partial and 1.4% definitive), and only 1% kept their withdrawal of immunosuppression in the long term. J. Clin. Med. 2022, 11, 421 At the 3-month follow-up, 65 patients (13%) presented COVID-19 sequelae, of which 13 of 20 4% (20/482) were psychological and 11% (55/482) were physical (Table 6). At the 12-month follow-up, 72 patients (15%) were considered to have sequelae, of which 3.1% (15/482) were psychological follow-up, and(15%) 72 patients 14% (67/482) were physical. were considered to haveThe most frequent sequelae, of whichphysical sequelae 3.1% (15/482) were asthenia, myalgia/arthralgia and anosmia. The only predictive were psychological and 14% (67/482) were physical. The most frequent physical sequelaefactor for having physical sequelaemyalgia/arthralgia were asthenia, at the 3-month follow-up was theThe and anosmia. useonly of steroid treatment predictive factorfor forIBD within having the physical sequelae at the 3-month follow-up was the use of steroid treatment for IBDNo 3 months before COVID-19 (OR 1.4, 95% CI 1.07–1.7) (Supplementary Table S9). predictive within thefactor for physical 3 months sequelae(OR before COVID-19 was1.4, found 95% atCIthe long-term 1.07–1.7) follow-up (12 (Supplementary months) Table S9). (Supplementary No predictive factorTableforS10). Only physical one patient sequelae reported was found at theSARS-CoV-2 reinfection long-term follow-up 6 months (12 months) after the index diagnosis. (Supplementary Table S10). Only one patient reported SARS-CoV-2 reinfection 6 months after the index diagnosis. IBD activity both at COVID-19 diagnosis and at 3- and 12-month follow-ups is shown IBD2. in Figure activity both atofCOVID-19 Two-thirds diagnosis patients (68%, and atremained 330/482) 3- and 12-month follow-ups in remission is shownthe throughout in Figure study period. 2. Two-thirds of patients (68%, 330/482) remained in remission throughout the study period. Figure 2.2. Figure Inflammatory Inflammatorybowel boweldisease diseaseactivity activityat atCOVID-19 COVID-19 diagnosis and 3- diagnosis and 3-and and12-month 12-monthfollow-up. follow-up. 4.4.Discussion Discussion WeWe report report the thelargest cohort largest of patients cohort with IBD of patients withandIBD symptomatic COVID-19 COVID-19 and symptomatic prospec- tively recruited with a one-year follow-up after infection. This is a national, prospectively recruited with a one-year follow-up after infection. This is a national, multicentre study that was multicentre study conducted that waswithin the ENEIDA conducted within project and included the ENEIDA project482 andpatients includedwith482 COVID-19 among 53,682 patients with IBD, giving a cumulative incidence of 8.97 per patients with COVID-19 among 53,682 patients with IBD, giving a cumulative incidence 1000. These data are in the upper limit of the wide range of incidence previously de- of 8.97 per 1000. These data are in the upper limit of the wide range of incidence previously scribed [10,14,28], ranging from 0.95 [29] to 100 per 1000 [15]. The universal access to described [10,14,28], ranging from 0.95 [29] to 100 per 1000 [15]. The universal access to health care within the National Health System in Spain (less than 3% of IBD patients with health privatecare within the insurance National never Health use public System services in Spain [30]) (less and the than 3% of adherence of most IBD patients centres with to private insurancecertification the nationwide never use public services programme [30])[26] in IBD andprovide the adherence of most homogeneity tocentres to the the cohort, nationwide minimizingcertification potential biasprogramme in the clinicalincharacteristics. IBD [26] provide We didhomogeneity to compara- not calculate the the cohort, minimizing tive incidencepotential bias between of COVID-19 in the clinical the IBD characteristics. We did from cohort and data obtained not the calculate generalthe comparative incidence population because the of COVID-19 of identification between the cases did IBD not usecohort and the same data obtained methodology. from the However, it is clearly observed in Figure 1 that the number of cases with COVID-19 and IBD is the highest in areas with the highest incidence of infection. The high variability in incidence between relatively close geographical areas was also observed, with a maximum in those areas with the highest population density. We decided to exclude asymptomatic patients, J. Clin. Med. 2022, 11, 421 14 of 20 as there was no policy for a universal testing in our patients nor in the general population during the first wave. Therefore data on asymptomatic patients with IBD and positive SARS-CoV-2 test are scarce and can imply a selection bias. It has been suggested that patients with IBD are at lower risk of having COVID- 19, and most studies support this assertion [10,31–35]. However, only a few of these studies performed in Denmark and Sweden were population based [36,37], which is how differences in the incidence of infection between population groups should be addressed. In our cohort, we recorded the influence of occupational risk, lockdown strategies and other risk factors, in addition to IBD treatment, that may have influenced, either increasing or decreasing, the risk of contagion. We observed, for example, that one-third of infected patients received special protection measures such as sick leave simply because they were considered a risk group. However, many patients became infected, perhaps because they were infected early before mandatory lockdown or through close family-infected contact. Lockdown has been demonstrated to be the most effective strategy precluding SARS-CoV-2 expansion [38–40], also in patients with IBD [41]. Thus, the low incidence of COVID-19 in IBD cohorts does not necessarily reflect a lower susceptibility to infection but a higher protection attitude towards IBD patients based on recommendations [6,42] or because they spontaneously adopt more rigorous self-protecting measures [43]. It has been shown that patients under biologic drugs perceive themselves to be at greater risk of SARS-CoV-2 infection, but, despite that, they do not perform more strict social distancing practices than patients with IBD without biologics or in remission [43]. However, in our cohort, only 49% exhibited good adherence to lockdown measures. Currently, data on the exposure environment of noninfected patients are very limited [44]. The study also showed that one-third of IBD patients with COVID-19 had occupational risks, mainly working in health care facilities. It has been reported that health care providers bore a great burden during the pandemic, as shown in data coming from Italy and China [22,45]. Nonetheless, we did not find that occupational risk or failure to meet lockdown measures were predictors for a worse evolution of COVID-19 in patients with IBD. The reported outcomes of COVID-19 are highly variable [10,28,33,36,46] and may depend on many factors, such as age, comorbidity, ethnicity, socioeconomic status and the quality of health care. In our cohort, as in others, the most important factors influ- encing outcomes were age and comorbidity. Thirty-five percent of the patients required hospitalisation, 7.9% had severe COVID-19, 2.5% required ICU admission and 3.7% died. These figures are similar to those extracted from the general population in Spain [23] (hos- pitalisation 19.5%, ICU 2.1% and mortality 4.6%) and are also identical to those reported in the first publication of SECURE-IBD, including the first 525 registered cases [8]. Age is known to be one of the most consistent risk factors for severe COVID-19 and death worldwide [47,48], both in the general population and in patients with IBD [10,49]. We found that patients 50 years old or older were at greater risk for hospitalization, while those 60 years old or older were more prone to severe COVID-19 or death due to COVID-19. Comorbidities have also been considered the other important risk factor for deleterious COVID-19 evolution, both in patients with IBD [16,29,33,36,46] and in the gen- eral population [22,50], and we also found consistent results in our cohort. Thus, differences in the percentages of parameters of the severity of COVID-19 between cohorts can be largely explained by these two factors, not only by themselves. The median age of patients in the initial SECURE-IBD cohort was 41 years versus 52 years in our cohort, and the percentage of comorbidities was 36% versus 44%, respectively. Data from SECURE-IBD accessed on 24 August 2021 [9], showed significantly improved outcomes compared to previous outcomes, with a fifty percent reduction in indicators of severity, including hospitalisation, severe COVID-19 and death (more than 70% of the patients were younger than 49 years). Although it can be speculated that improved knowledge of COVID-19 management may account for a better outcome over time, important selection bias accounting for differences in this type of registry cannot be ruled out. J. Clin. Med. 2022, 11, 421 15 of 20 The only protective factor for severe COVID-19 was CD with inflammatory behaviour. As this was found to be independent of IBD activity and treatment, we speculate that this is because this pattern has less disease burden, as it was also related to a shorter duration of the disease (11 years of disease in inflammatory IBD vs. 18 years in stricturing or penetrating disease, p < 0.0001). As stated previously, IBD-related immunosuppression has not been found to be a risk factor for severe COVID-19 or death [28,29,51]. Our cohort confirms that there is no relationship between anti-TNF or any other form of therapeutic immunosuppression and COVID-19 severity. Some authors suggested that the risk of hospitalisation is higher in patients under biologics, but this may reflect a precaution more than COVID-19 severity itself, as overall mortality related to COVID has not been demonstrated to be increased in ours and other previous studies [28,36,46,51,52]. This consistent evidence reinforces the message that biologics can be safely continued in most cases. The use of steroids in this pandemic has been controversial [53,54]. In contrast to SECURE-IBD [8], we did not find that current treatment with systemic steroids was related to a worse COVID-19 evolution, an outcome that we have previously found related to other relevant infections in patients with IBD [3]. This might be due to the small proportion of patients under this treatment (5.4%) or the type of schedule administered. However, the use of steroids three months before COVID-19 diagnosis was an independent risk factor for hospitalisation and physical sequelae (at the 3-month follow-up). This could be indirectly related to a probable active IBD that was challenging to treat and required the use of systemic steroids. Finally, we describe the evolution of patients at 3 and 12 months after COVID-19. Thirteen percent withdrew IBD medication during COVID-19. This is less than previously reported, ranging between 27% [15] and 34% [55]. This is certainly encouraging, as the first guidelines on the treatment of patients with IBD during the pandemic were very clear in recommending the withdrawal of immunosuppressants and biologics in infected individuals [6]. However, as our experience increased, it was assured that the inappropriate cessation of effective agents for IBD treatment due to unjustified fear of adverse events could lead to IBD relapse and then to the use of steroids or hospitalisation, thus increasing the risk of COVID-19 exposure and infection. The last outcome that we explored was COVID-19 sequelae, present in 13% at 3 months and 15% at 12 months in our cohort. The only predictive factor for having physical sequelae at the 3-month follow-up was the use of steroid treatment for IBD 3 months before COVID-19 (OR 1.4, 95% CI 1.07–1.7). It has been shown that severe sequelae were lower in patients with IBD when matched to non-IBD controls [49], so IBD does not seem to be a disease linked to more sequelae due to COVID-19. In contrast, a recent population-based Danish study has suggested that sequelae are a common phenomenon, affecting almost 44% of patients [56]. It has to be noted that this study accessed sequelae only in 222 of the 516 patients included and that they were self-reported sequalae, limiting the confirmation of a real effect that might be caused by COVID-19. In addition, another study found that patients with IBD, hospitalized due to COVID-19, have a greater risk of severe infections requiring further hospitalisation [57], a situation that has not been found in our cohort. Our study has several limitations to be aware of. First, only 18% of centres performed an active search of cases (82% of cases were collected by direct notification from the patient itself, the family physician, the emergency department or the hospitalisation unit, as stated in the Methods section). Thus, it is possible that very mild cases did not consult their IBD unit; thus, mild COVID-19 cases might be underrepresented. However, data on hospitalisa- tion, severe COVID-19, ICU admission and death from the general population are similar to our cohort and we did not find differences in specific outcomes between these two search- ing strategies; therefore, this bias is probably small. On the other hand, the majority of participant centres were certified IBD units that had open access to their outpatient clinics, nurse-led advice lines and/or emails for emergencies as mandatory quality criteria [26]. Sec- ond, this study, including only the first wave of an ongoing pandemic, is observational and cannot establish causation or account for unmeasured confounders. Finally, discovering the J. Clin. Med. 2022, 11, 421 16 of 20 real number of infected patients remains a global challenge because PCR or serology were not performed universally at the beginning and there is evidence of false negative results. This occurred in 10% of this cohort. Notwithstanding these issues, there are some important strengths. First, it has national coverage with active participation of almost 90% of the IBD units from the ENEIDA registry. However, the main strength relies on prospective data, collecting IBD activity, and other important variables. In addition, although nationwide series on COVID-19 and IBD have been published before [29,33], our study is the largest cohort of patients with IBD and COVID-19 with the longest follow-up after infection. 5. Conclusions In conclusion, we have shown that occupational risk and intrafamilial transmission are relevant epidemiological risk factors and that a high proportion of patients receive preventive sick leave. We have also demonstrated that IBD does not worsen COVID- 19 prognosis, even when immunosuppressants and biological drugs are used. Age and comorbidity are the most important prognostic factors for more severe COVID-19 in patients with IBD and are even more relevant than epidemiological risk factors such as occupational risk. Finally, COVID-19 is not a condition that affects the prognosis of IBD or its treatment, either in the short or the long term and is not a cause of significant sequelae in patients already suffering from IBD. Therefore, there is no need for more strict protection measures than those adopted for the general population. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/jcm11020421/s1, Table S1. Comorbidities; Table S2. Symptoms at COVID-19 diagnosis; Table S3. Tests performed for COVID-19 diagnosis; Table S4. Clinical characteristics and treatment for IBD in patients who required hospitalization; Table S5. Clinical characteristics and treatment for IBD in patients who required ICU admission; Table S6. Clinical characteristics and treatment for IBD in patients who died due to COVID-19; Table S7. Clinical characteristics and treatment for IBD in patients with severe COVID-19; Table S8. Incidence of adverse outcomes of COVID-19 patients in the ENEIDA registry; Table S9. Clinical characteristics and treatment for IBD in patients with 3-month physical sequelae; Table S10. Clinical characteristics and treatment for IBD in patients with 12-month physical sequelae. Author Contributions: Study design: Y.Z., I.M.-J., I.R.-L., M.E.; study conduction: Y.Z., P.M.; data collection: Y.Z., I.M.-J., 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. (Maria Calvo), M.I., M.B.d.-A., B.S., J.B., J.L.P., 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., P.M., E.D., M.E.; data analysis and interpretation: Y.Z., I.M.-J., I.R.-L., M.E.; manuscript drafting: Y.Z., I.M.-J., I.R.-L., M.E. All authors have read and agreed to the published version of the manuscript, including the authorship list. Funding: This study is funded by the Carlos III Health Institute (COV20/00227: Co-IP Dra. Maria Es- teve 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 (coordinat- ing 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 Supple- mentary Materials. J. Clin. Med. 2022, 11, 421 17 of 20 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, re- search support and consulting fees from Abbvie, Adacyte, Almirall, Amgen, Dr Falk, FAES Pharma, Ferring, Jannsen, MSD, Otsuka, Pfizer, Shire, Takeda and Tillotts. 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, Ferring, Dr. Falk 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, Shire Pharmaceuticals, Ferring, Dr. 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, Tillotts Pharma, Faes farma. 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, Fer- ring, Faes Farma, Shire Pharmaceuticals, Dr. 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 Dr. 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, Taked, Janssen, Ferring, Faes Pharma, Shire Pharmaceuticals, Dr Falk Pharma, Galapagos and Tillotts. 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, Dr. 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, Dr. 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 Dr Falk Pharma. JM. 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, Janssen, 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 educa- tion funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. 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 Dr. 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, and Tillotts. M. Esteve: has received support for conference attendance, speaker fees, research support and consulting fees from Abbvie, Ferring, Janssen, MSD, Otsuka, Pfizer, Takeda and Tillotts. I.V. era, I. Guerra, A. Ponferrada-Díaz, A. Lucendo, B. Caballol, M.Mañosa, P. Martínez-Montiel, M. Bosca-Watts, J. Gordillo, L. Bujanda, 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, M. Navarro-Llavat, 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, J. Clin. Med. 2022, 11, 421 18 of 20 R. Pajares, P. Olcina and P. Manzano have no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. References 1. John Hopkins University Coronavirus Resource Center. Coronavirus COVID-19 Global Cases. Available online: https:// coronavirus.juy.edu/map.html (accessed on 21 August 2021). 2. Kirchgesner, J.; Lemaitre, M.; Carrat, F.; Zureik, M.; Carbonnel, M.F.; Dray-Spira, R.; Carbonnel, F.; Dray-Spira, R. Risk of Serious and Opportunistic Infections Associated with Treatment of Inflammatory Bowel Diseases. Gastroenterology 2018, 155, 337–346. [CrossRef] [PubMed] 3. Zabana, Y.; Rodríguez, L.; Lobatón, T.; Gordillo, J.; Montserrat, A.; Mena, R.; Beltrán, B.; Dotti, M.; Benitez, O.; Guardiola, J.; et al. Relevant Infections in Inflammatory Bowel Disease, and Their Relationship with Immunosuppressive Therapy and Their Effects on Disease Mortality. J. Crohn’s Colitis 2019, 13, 828–837. [CrossRef] [PubMed] 4. Tinsley, A.; Navabi, S.; Williams, E.D.; Liu, G.; Kong, L.; Coates, M.D.; Clarke, K. Increased Risk of Influenza and Influenza-Related Complications among 140,480 Patients with Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2019, 25, 369–376. [CrossRef] [PubMed] 5. Rubin, D.T.; Feuerstein, J.D.; Wang, A.Y.; Cohen, R.D. AGA Clinical Practice Update on Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Expert Commentary. Gastroenterology 2020, 159, 350–357. [CrossRef] 6. Kennedy, N.A.; Jones, G.-R.; Lamb, C.A.; Appleby, R.; Arnott, I.; Beattie, R.M.; Bloom, S.; Brooks, A.J.; Cooney, R.; Dart, R.J.; et al. British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic. Gut 2020, 69, 984–990. [CrossRef] [PubMed] 7. Abreu, C. 1st Interview COVID-19 ECCO Taskforce. 2020. Available online: https://ecco-ibd.eu/images/6_Publication/6_8_ Surveys/1st_interview_COVID-19%20ECCOTaskforce_published.pdf (accessed on 2 August 2021). 8. Brenner, E.J.; Ungaro, R.C.; Gearry, R.B.; Kaplan, G.G.; Kissous-hunt, M.; Lewis, J.D.; Ng, S.C.; Rahier, J.; Reinisch, W.; Ruemmele, F.M.; et al. Corticosteroids, but Not TNF Antagonists, Are Associated with Adverse COVID-19 Outcomes in Patients with Inflammatory Bowel Diseases: Results from an International Registry. Gastroenterology 2020, 159, 481–491. [CrossRef] [PubMed] 9. Brenner, E.; Ungaro, R.; Colombel, J.; Kappelman, M. SECURE-IBD Database Public Data. Available online: https://covidibd. org/current-data/ (accessed on 24 August 2021). 10. Aziz, M.; Fatima, R.; Haghbin, H.; Smith, W.L.; Nawras, A. The incidence and outcomes of COVID-19 in ibd patients: A rapid review and meta-Analysis. Inflamm. Bowel Dis. 2020, 26, E132–E133. [CrossRef] 11. Mao, R.; Liang, J.; Shen, J.; Ghosh, S.; Zhu, L.-R.; Yang, H.; Wu, K.-C.; Chen, M.-H. Implications of COVID-19 for patients with pre-existing digestive diseases. Lancet Gastroenterol. Hepatol. 2020, 5, 425–427. [CrossRef] 12. Norsa, L.; Indriolo, A.; Sansotta, N.; Cosimo, P.; Greco, S.; D’Antiga, L. Uneventful course in IBD patients during SARS-CoV-2 outbreak in northern Italy. Gastroenterology 2020, 159, 371–372. [CrossRef] 13. Allocca, M.; Fiorino, G.; Zallot, C.; Furfaro, F.; Radice, S.; Danese, S.; Peyrin-biroulet, L. Incidence and patterns of COVID-19 among inflammatory bowel disease patients from the Nancy and Milan cohorts. Clin. Gastroenterol. Hepatol. 2020, 18, 2134–2135. [CrossRef] 14. Taxonera, C.; Sagastagoitia, I.; Alba, C.; Mañas, N.; Olivares, D.; Rey, E. 2019 novel coronavirus disease (COVID-19) in patients with inflammatory bowel diseases. Aliment. Pharmacol. Ther. 2020, 52, 276–283. [CrossRef] 15. Guerra, I.; Algaba, A.; Jiménez, L.; Aller, M.M.; Garza, D.; Bonillo, D.; Esteban, L.M.M.; Bermejo, F. Incidence, Clinical Characteristics, and Evolution of SARS-CoV-2 Infection in Patients with Inflammatory Bowel Disease: A Single-Center Study in Madrid, Spain. Inflamm. Bowel Dis. 2021, 27, 25–33. [CrossRef] 16. Rodríguez-Lago, I.; Ramírez de la Piscina, P.; Elorza, A.; Merino, O.; Ortiz de Zárate, J.; Cabriada, J.L. Characteristics and Prognosis of Patients with Inflammatory Bowel Disease during the SARS-CoV-2 Pandemic in the Basque Country (Spain). Gastroenterology 2020, 159, 781–783. [CrossRef] 17. Zabana, Y.; Panés, J.; Nos, P.; Gomollón, F.; Esteve, M.; García-Sánchez, V.; Gisbert, J.P.; Barreiro-de-Acosta, M.; Domènech, E. The ENEIDA registry (Nationwide study on genetic and environmental determinants of inflammatory bowel disease) by GETECCU: Design, monitoring and functions. Gastroenterol. Hepatol. 2020, 43, 551–558. [CrossRef] 18. Silverberg, M.S.; Satsangi, J.; Ahmad, T.; Arnott, I.D.; Bernstein, C.N.; Brant, S.R.; Caprilli, R.; Colombel, J.-F.; Gasche, C.; Geboes, K.; et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can. J. Gastroenterol. 2005, 19 (Suppl. A), 5–36. [CrossRef] 19. Huang, Y.Q.; Gou, R.; Diao, Y.S.; Yin, Q.H.; Fan, W.X.; Liang, Y.P.; Chen, Y.; Wu, M.; Zang, L.; Li, L.; et al. Charlson comorbidity index helps predict the risk of mortality for patients with type 2 diabetic nephropathy. J. Zhejiang Univ. Sci. B 2014, 15, 58–66. [CrossRef] 20. Harvey, R.F.; Bradshaw, J.M. A simple index of Crohn’s-disease activity. Lancet 1980, 1, 514. [CrossRef] 21. Lewis, J.D.; Chuai, S.; Nessel, L.; Lichtenstein, G.R.; Aberra, F.N.; Ellenberg, J.H. Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis. Inflamm. Bowel Dis. 2008, 14, 1660–1666. [CrossRef] [PubMed] J. Clin. Med. 2022, 11, 421 19 of 20 22. Guan, W.-J.; Ni, Z.-Y.; Hu, Y.; Liang, W.-H.; Ou, C.-Q.; He, J.-X.; Liu, L.; Shan, H.; Lei, C.-L.; Hui, D.S.C.; et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 2020, 382, 1708–1720. [CrossRef] [PubMed] 23. Alves-Cabratosa, L.; Comas-Cufí, M.; Blanch, J.; Martí-Lluch, R.; Ponjoan, A.; Castro-Guardiola, A.; Hurtado-Ganoza, A.; Pérez-Jaén, A.; Rexach-Fumaña, M.; Faixedas-Brunsoms, D.; et al. Persons with SARS-CoV-2 during the First and Second Waves in Catalonia (Spain): A Retrospective Observational Study Using Daily Updated Data. JMIR Public Heal. Surveill. 2021, 8, e30006. [CrossRef] [PubMed] 24. ISC; CNE. Informe Sobre la Situación de COVID-19 en España. Informe COVID-19 no12, 20 Marzo, 2020. Available on- line: https://www.isciii.es/QueHacemos/Servicios/VigilanciaSaludPublicaRENAVE/EnfermedadesTransmisibles/Paginas/ -COVID-19.-Informes-previos.aspx (accessed on 2 August 2021). 25. CNE; ISC; ICI. COVID-19 en España. Available online: https://cnecovid.isciii.es/covid19/#provincias (accessed on 2 Au- gust 2021). 26. Barreiro-de Acosta, M.; Gutiérrez, A.; Zabana, Y.; Beltrán, B.; Calvet, X.; Chaparro, M.; Domènech, E.; Esteve, M.; Panés, J.; Gisbert, J.P.; et al. Inflammatory bowel disease integral care units: Evaluation of a nationwide quality certification programme. The GETECCU experience. United Eur. Gastroenterol. J. 2021, 9, 766–772. [CrossRef] 27. Instituto Nacional de Estadística (INE). Población por Provincias y Sexo. 2021. Available online: https://www.ine.es/jaxiT3 /Datos.htm?t=2852#!tabs-tabla (accessed on 2 September 2021). 28. Burke, K.E.; Kochar, B.; Allegretti, J.R.; Winter, R.W.; Lochhead, P.; Khalili, H.; Colizzo, F.P.; Hamilton, M.J.; Chan, W.W.; Ananthakrishnan, A.N. Immunosuppressive Therapy and Risk of COVID-19 Infection in Patients with Inflammatory Bowel Diseases. Inflamm. Bowel Dis. 2021, 27, 155–161. [CrossRef] 29. Khan, N.; Patel, D.; Xie, D.; Lewis, J.; Trivedi, C.; Yang, Y.-X. Impact of Anti-Tumor Necrosis Factor and Thiopurine Medications on the Development of COVID-19 in Patients with Inflammatory Bowel Disease: A Nationwide Veterans Administration Cohort Study. Gastroenterology 2020, 159, 1545–1546.e1. [CrossRef] 30. Chaparro, M.; Garre, A.; Núñez Ortiz, A.; Diz-Lois Palomares, M.T.; Rodríguez, C.; Riestra, S.; Vela, M.; Benítez, J.M.; Fernández Salgado, E.; Sánchez Rodríguez, E.; et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885. [CrossRef] [PubMed] 31. Khan, N.; Mahmud, N.; Trivedi, C.; Reinisch, W.; Lewis, J.D. Risk factors for SARS-CoV-2 infection and course of COVID-19 disease in patients with IBD in the Veterans Affair Healthcare System. Gut 2021, 70, 1657–1664. [CrossRef] 32. Ardizzone, S.; Ferretti, F.; Monico, M.C.; Carvalhas Gabrielli, A.M.; Carmagnola, S.; Bezzio, C.; Saibeni, S.; Bosani, M.; Caprioli, F.; Mazza, S.; et al. Lower incidence of COVID-19 in patients with inflammatory bowel disease treated with non-gut selective biologic therapy. J. Gastroenterol. Hepatol. 2021, 36, 3050–3055. [CrossRef] 33. Derikx, L.A.A.P.; Lantinga, M.A.; de Jong, D.J.; van Dop, W.A.; Creemers, R.H.; Römkens, T.E.H.; Jansen, J.M.; Mahmmod, N.; West, R.L.; Tan, A.C.I.T.L.; et al. Clinical Outcomes of Covid-19 in Patients with Inflammatory Bowel Disease: A Nationwide Cohort Study. J. Crohn’s Colitis 2020, 15, 529–539. [CrossRef] [PubMed] 34. Singh, S.; Khan, A.; Chowdhry, M.; Bilal, M.; Kochhar, G.S.; Clarke, K. Risk of Severe Coronavirus Disease 2019 in Patients with Inflammatory Bowel Disease in the United States: A Multicenter Research Network Study. Gastroenterology 2020, 159, 1575–1578.e4. [CrossRef] [PubMed] 35. Wetwittayakhlang, P.; Albader, F.; Golovics, P.A.; Bessissow, T.; Bitton, A.; Afif, W.; Wild, G.; Lakatos, P.L. Clinical Outcomes of COVID-19 and Impact on Disease Course in Patients with Inflammatory Bowel Disease. Can. J. Gastroenterol. Hepatol. 2021, 2021, 7591141. [CrossRef] 36. Attauabi, M.; Poulsen, A.; Theede, K.; Pedersen, N.; Larsen, L.; Jess, T.; Rosager Hansen, M.; Verner-Andersen, M.K.; Haderslev, K.V.; Berg Lødrup, A.; et al. Prevalence and Outcomes of COVID-19 Among Patients with Inflammatory Bowel Disease—A Danish Prospective Population-Based Cohort Study. J. Crohn’s Colitis 2020, 15, 540–550. [CrossRef] 37. Ludvigsson, J.F.; Axelrad, J.; Halfvarson, J.; Khalili, H.; Larsson, E.; Lochhead, P.; Roelstraete, B.; Simon, T.G.; Söderling, J.; Olén, O. Inflammatory bowel disease and risk of severe COVID-19: A nationwide population-based cohort study in Sweden. United Eur. Gastroenterol. J. 2021, 9, 177–192. [CrossRef] 38. Guzzetta, G.; Riccardo, F.; Marziano, V.; Poletti, P.; Trentini, F.; Bella, A.; Andrianou, X.; Del Manso, M.; Fabiani, M.; Bellino, S.; et al. Impact of a Nationwide Lockdown on SARS-CoV-2 Transmissibility, Italy. Emerg. Infect. Dis. 2021, 27, 267–270. [CrossRef] [PubMed] 39. Pan, A.; Liu, L.; Wang, C.; Guo, H.; Hao, X.; Wang, Q.; Huang, J.; He, N.; Yu, H.; Lin, X.; et al. Association of Public Health Interventions with the Epidemiology of the COVID-19 Outbreak in Wuhan, China. JAMA 2020, 323, 1915–1923. [CrossRef] [PubMed] 40. Lodyga, M.; Maciejewska, K.; Eder, P.; Waszak, K.; Stawczyk-Eder, K.; Dobrowolska, A.; Kaczka, A.; Gasiorowska,˛ A.; St˛epień- Wrochna, B.; Cicha, M.; et al. Social distancing during COVID-19 pandemic among inflammatory bowel disease patients. J. Clin. Med. 2021, 10, 3689. [CrossRef] [PubMed] 41. Allocca, M.; Chaparro, M.; Gonzalez, H.A.; Bosca-Watts, M.M.; Palmela, C.; D’Amico, F.; Zacharopoulou, E.; Kopylov, U.; Ellul, P.; Bamias, G.; et al. Patients with Inflammatory Bowel Disease Are Not at Increased Risk of COVID-19: A Large Multinational Cohort Study. J. Clin. Med. 2020, 9, 3533. [CrossRef] [PubMed] J. Clin. Med. 2022, 11, 421 20 of 20 42. Magro, F.; Rahier, J.F.; Abreu, C.; MacMahon, E.; Hart, A.; van der Woude, C.J.; Gordon, H.; Adamina, M.; Viget, N.; Vavricka, S.; et al. Inflammatory bowel disease management during the COVID-19 outbreak:The ten do’s and don’ts from the ECCO-COVID task force. J. Crohn’s Colitis 2020, 14, S798–S806. [CrossRef] 43. Bezzio, C.; Pellegrini, L.; Manes, G.; Arena, I.; Picascia, D.; Della Corte, C.; Devani, M.; Schettino, M.; Saibeni, S. Biologic therapies may reduce the risk of COVID-19 in patients with inflammatory bowel disease. Inflamm. Bowel Dis. 2020, 26, E107–E109. [CrossRef] 44. Iborra, I.; Puig, M.; Marín, L.; Calafat, M.; Cañete, F.; Quiñones, C.; González-González, L.; Cardona, G.; Mañosa, M.; Domènech, E. Treatment Adherence and Clinical Outcomes of Patients with Inflammatory Bowel Disease on Biological Agents during the SARS-CoV-2 Pandemic. Dig. Dis. Sci. 2021, 66, 4191–4196. [CrossRef] 45. The Lancet. COVID-19: Protecting health-care workers. Lancet 2020, 395, 922. [CrossRef] 46. Bezzio, C.; Saibeni, S.; Variola, A.; Allocca, M.; Massari, A.; Gerardi, V.; Casini, V.; Ricci, C.; Zingone, F.; Amato, A.; et al. Outcomes of COVID-19 in 79 patients with IBD in Italy: An IG-IBD study. Gut 2020, 69, 1213–1217. [CrossRef] 47. Williamson, E.J.; Walker, A.J.; Bhaskaran, K.; Bacon, S.; Bates, C.; Morton, C.E.; Curtis, H.J.; Mehrkar, A.; Evans, D.; Inglesby, P.; et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020, 584, 430–436. [CrossRef] 48. Nowak, J.K.; Lindstrøm, J.C.; Kalla, R.; Ricanek, P.; Halfvarson, J.; Satsangi, J. Age, Inflammation, and Disease Location Are Critical Determinants of Intestinal Expression of SARS-CoV-2 Receptor ACE2 and TMPRSS2 in Inflammatory Bowel Disease. Gastroenterology 2020, 159, 1151–1154.e2. [CrossRef] 49. Lukin, D.J.; Kumar, A.; Hajifathalian, K.; Sharaiha, R.Z.; Scherl, E.J.; Longman, R.S. Baseline Disease Activity and Steroid Therapy Stratify Risk of COVID-19 in Patients with Inflammatory Bowel Disease. Gastroenterology 2020, 159, 1541–1544.e2. [CrossRef] [PubMed] 50. Chan, J.F.-W.; Yuan, S.; Kok, K.-H.; To, K.K.-W.; Chu, H.; Yang, J.; Xing, F.; Liu, J.; Yip, C.C.-Y.; Poon, R.W.-S.; et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020, 395, 514–523. [CrossRef] 51. Axelrad, J.E.; Malter, L.; Hong, S.; Chang, S.; Bosworth, B.; Hudesman, D. From the American Epicenter: Coronavirus Disease 2019 in Patients with Inflammatory Bowel Disease in the New York City Metropolitan Area. Inflamm. Bowel Dis. 2020, 27, 662–666. [CrossRef] [PubMed] 52. Bataille, P.; Amiot, A.; Claudepierre, P.; Paris, N.; Neuraz, A.; Lerner, I.; Garcelon, N.; Rance, B.; Grisel, O.; Moreau, T.; et al. Letter: Severe COVID-19 infection and biologic therapies—A cohort study of 7 808 patients in France. Aliment. Pharmacol. Ther. 2020, 52, 1245–1248. [PubMed] 53. Shang, L.; Zhao, J.; Hu, Y.; Du, R.; Cao, B. On the use of corticosteroids for 2019-nCoV pneumonia. Lancet 2020, 395, 683–684. [CrossRef] 54. Zhou, W.; Liu, Y.; Tian, D.; Wang, C.; Wang, S.; Cheng, J.; Hu, M.; Fang, M.; Gao, Y. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Signal. Transduct. Target. Ther. 2020, 5, 18. [CrossRef] 55. Agrawal, M.; Brenner, E.J.; Zhang, X.; Colombel, J.-F.; Kappelman, M.D.; Ungaro, R.C.; Gearry, R.B.; Kalpan, G.G.; Kissous-Hunt, M.; Lewis, J.D.; et al. Physician Practice Patterns in Holding Inflammatory Bowel Disease Medications due to COVID-19, in the SECURE-IBD Registry. J. Crohns. Colitis 2021, 15, 860–863. [CrossRef] 56. Attauabi, M.; Dahlerup, J.F.; Poulsen, A.; Hansen, M.R.; Verner-Andersen, M.K.; Eraslan, S.; Prahm, A.P.; Pedersen, N.; Larsen, L.; Jess, T.; et al. Outcomes and long-term effects of COVID-19 in patients with inflammatory bowel diseases—A Danish prospective population-based cohort study with individual-level data. J. Crohn’s Colitis 2021, in press. [CrossRef] [PubMed] 57. Mertz, B.; Dijkstra, F.; Nielsen, J.; Kjeldsen, J. Post COVID-19 hospitalizations in patients with chronic inflammatory diseases—A nationwide cohort study. J. Autoimmun. 2021, 125, 102739.