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

  Citation: Zabana, Y.; Marín-Jiménez, I.; Rodríguez-Lago, I.; Vera, I.; Martín-Arranz, M.D.; Guerra, I.; Gisbert, J.P.; Mesonero, F.; Benítez, O.; Taxonera, C.; et al. 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. J. Clin. Med. 2022,11, 421. https://doi.org/10.3390/ jcm11020421 Academic Editor: Hemant Goyal Received: 9 December 2021 Accepted: 6 January 2022 Published: 14 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 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 , Ángel Ponferrada-Díaz 15, 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 , Jordi Gordillo 22, Luis Bujanda 2,23,24, NoemíManceñido 25 , Teresa Martínez-Pérez 26, Alicia López 27, Cristina Rodríguez-Gutiérrez 28, Santiago García-López 29 , Pablo Vega 30, Montserrat Rivero 31 , Luigi Melcarne 32 , Maria Calvo 33 , Marisa Iborra 2,34 , Manuel Barreiro de-Acosta 35 , Beatriz Sicilia 36, Jesús Barrio 37 , JoséLázaro Pérez 38, David Busquets 39 , Isabel Pérez-Martínez 40 , MercèNavarro-Llavat 41 ,Vicent Hernández 42 , Federico Argüelles-Arias 43 , Fernando Ramírez Esteso 44, Susana Meijide 45, Laura Ramos 46 , Fernando Gomollón2,47 , Fernando Muñoz 48, Gerard Suris 49, Jone Ortiz de Zarate 50, JoséMaría Huguet 51 , Jordina Llaó52, Mariana Fe García-Sepulcre 53, Mónica Sierra 54 , Miguel Durà55, Sandra Estrecha 56, Ana Fuentes Coronel 57 , Esther Hinojosa 58, Lorenzo Olivan 59, Eva Iglesias 60, Ana Gutiérrez 2,61, Pilar Varela 62, Núria Rull 63, Pau Gilabert 64, Alejandro Hernández-Camba 65 , Alicia Brotons 66 , Daniel Ginard 67, Eva Sesé68, Daniel Carpio 69, Montserrat Aceituno 1,2 , JoséLuis Cabriada 4,5 , Yago González-Lama 6, Laura Jiménez 8,9, María Chaparro 2,10,11 , Antonio López-San Román12, Cristina Alba 13,14, Rocío Plaza-Santos 15 , Raquel Mena 16, Sonsoles Tamarit-Sebastián17 , Elena Ricart 2,18, Margalida Calafat 2,19, Sonsoles Olivares 20, Pablo Navarro 21 , Federico Bertoletti 22, Horacio Alonso-Galán23,24, Ramón Pajares 25, Pablo Olcina 26 , Pamela Manzano 1, Eugeni Domènech 2,19 , Maria Esteve 1,2 and on behalf of the ENEIDA registry of GETECCU † 1Hospital Universitari Mútua Terrassa, 08221 Terrassa, Spain; [email protected] (O.B.); [email protected] (M.A.); [email protected] (P.M.); [email protected] (M.E.) 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain; javier[email protected] (J.P.G.); [email protected] (A.J.L.); [email protected] (B.C.); [email protected] (M.M.); [email protected] (L.B.); [email protected] (M.I.); [email protected] (F.G.); [email protected] (A.G.); [email protected] (M.C.); [email protected] (E.R.); margalidasar[email protected] (M.C.); [email protected] (E.D.) 3Hospital Gregorio Marañón, 218007 Madrid, Spain; [email protected] 4Gastroenterology Department, Hospital Universitario de Galdakao, 48960 Galdakao, Spain; iago.r[email protected] (I.R.-L.); [email protected] (J.L.C.) 5Biocruces Bizkaia Health Research Institute, 48960 Galdakao, Spain 6Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain; [email protected] (I.V.); [email protected] (Y.G.-L.) 7Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] 8Hospital Universitario de Fuenlabrada, 28942 Fuenlabrada, Spain; [email protected] (I.G.); [email protected] (L.J.) 9Instituto de Investigación Hospital Universitario La Paz (IdiPaz), 28046 Madrid, Spain 10 Department of Gastroenterology, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain 11 Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain 12 Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; [email protected] (F.M.); [email protected] (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; [email protected] (C.T.); [email protected] (C.A.) 14 Instituto de Investigación del Hospital Clínico San Carlos [IdISSC], 28040 Madrid, Spain 15 Hospital Universitario Infanta Leonor, 28031 Madrid, Spain; [email protected] (Á.P.-D.); [email protected] (R.P.-S.) 16 Consorci Sanitari de Terrassa, 08227 Terrassa, Spain; [email protected] (M.P.); [email protected] (R.M.) 17 Hospital General de Tomelloso, 13700 Tomelloso, Spain; [email protected] 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; [email protected] (P.M.-M.); [email protected] (S.O.) 21 Hospital Clinic Universitari de Valencia, 46010 Valencia, Spain; [email protected] (M.B.-W.); [email protected] (P.N.) 22 Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; [email protected] (J.G.); [email protected] (F.B.) 23 Hospital Universitario Donostia, Instituto Biodonostia, 20014 San Sebastián, Spain; [email protected] 24 Universidad del País Vasco (UPV/EHU), 48940 Leioua, Spain 25 Hospital Universitario Infanta Sofía, 28703 San Sebastián de los Reyes, Spain; [email protected] (N.M.); [email protected] (R.P.) 26 Hospital Virgen de la Luz, 16002 Cuenca, Spain; [email protected] (T.M.-P.); [email protected] (P.O.) 27 Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Hospital del Mar, 08003 Barcelona, Spain; [email protected] 28 Complejo Hospitalario de Navarra, 31008 Pamplona, Spain; cristina.rodriguez.gutierr[email protected] 29 Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain; [email protected] 30 Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain; [email protected] 31 Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain; [email protected] 32 Hospital Universitari Parc Taulí, 08208 Sabadell, Spain; [email protected] 33 Hospital San Pedro-Logroño, 26006 Logroño, Spain; [email protected] 34 Hospital Universitario y Politécnico de la Fe de Valencia, 46026 Valencia, Spain 35 Hospital Clínico Universitario de Santiago, 15706 Santiago, Spain; manubarreir[email protected] 36 Hospital Universitario de Burgos, 09006 Burgos, Spain; [email protected] 37 Hospital Universitario Río Hortega (HURH), 47012 Valladolid, Spain; [email protected] 38 Hospital Universitario Fundación de Alcorcón, 28922 Alcorcón, Spain; [email protected] 39 Hospital Universitari de Girona Doctor Josep Trueta, 17007 Girona, Spain; dbusquets.gir[email protected] 40 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; [email protected] 41 Hospital de Sant Joan DespíMoisès Broggi, 08970 Sant Joan Despí, Spain; mer[email protected]g 42 Hospital Álvaro Cunqueiro, 36213 Vigo, Spain; [email protected] 43 Hospital Universitario Virgen de la Macarena, Universidad de Sevilla, 41009 Sevilla, Spain; [email protected] 44 Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain; fernando.ramir[email protected] 45 Hospital Universitario de Cruces, 48903 Barakaldo, Spain; [email protected] 46 Hospital Universitario de Canarias, 38320 San Cristobal de la Laguna, Spain; [email protected] 47 Hospital Clínico Universitario “Lozano Blesa” and IIS Aragón, 50009 Zaragoza, Spain 48 Hospital Universitario de Salamanca, 37007 Salamanca, Spain; [email protected] 49 Hospital Universitari de Bellvitge, 08907 L’Hospitalet de Llobregat, Spain; [email protected] 50 Hospital Universitario de Basurto, 48013 Bilbo, Spain; [email protected] 51 Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain; [email protected] 52 Althaia Xarxa Assistencial Universitària de Manresa, 08243 Manresa, Spain; [email protected] 53 Hospital Universitario de Elche, 03203 Elche, Spain; marifegarciasepulcr[email protected] 54 Complejo Asistencial Universitario de León, 24071 León, Spain; [email protected] 55 Hospital Clínico de Valladolid, 47003 Valladolid, Spain; [email protected] 56 Hospital Universitario Álava, 01009 Gasteiz, Spain; [email protected] 57 Hospital Virgen de la Concha, 49022 Zamora, Spain; [email protected] 58 Hospital de Manises, 46940 Manises, Spain; [email protected] 59 Hospital Universitario San Jorge, 22004 Huesca, Spain; lor[email protected] 60 Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, 14004 Cordoba, Spain; [email protected] 61 Hospital General Universitario de Alicante, 03010 Alicante, Spain 62 Hospital Universitario de Cabueñes, 33394 Gijón, Spain; [email protected] J. Clin. Med. 2022,11, 421 3 of 20 63 Hospital Universitario Son Llàtzer, 07198 Palma, Spain; [email protected] 64 Hospital de Viladecans, 08840 Viladecans, Spain; [email protected] 65 Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; dr[email protected] 66 Hospital Vega Baja de Orihuela, 03314 Alicante, Spain; [email protected] 67 Hospital Universitario Son Espases, 07120 Palma, Spain; [email protected] 68 Hospital Universitari Arnau de Vilanova de Lleida, 25198 Lleida, Spain; [email protected] 69 Complexo Hospitalario de Pontevedra, 36071 Pontevedra, Spain; [email protected] *Correspondence: [email protected] † 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 under 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 immunosuppressive 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 comorbidities), 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 population 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 comorbidities were specifically registered: cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, heart disease, stroke, diabetes mellitus, arterial hypertension, dyslipidaemia, 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, social 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, cyclosporine, 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 epidemiological 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 physician 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 outcomes 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 respiratory 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 ttest 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 ttest for parametric data and the Mann–Whitney test for nonparametric 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, severe 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 territories, 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 1and 2show 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) n= 482 Crohn’s Disease n= 247 Ulcerative Colitis n= 221 p-Value * 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 COVID-19 (oral or intravenous), n(%) 53 (11) 30 (12) 21 (9.5) 0.36 Systemic steroids, n(%) 26 (5.4) 16 (6.4) 8 (3.6) 0.37 Immunosuppressants (in monotherapy), n(%) 113 (23) 65 (26) 56 (25) 0.03 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 (in monotherapy), n(%) 117 (22) 72 (29) 35 (16) 0.04 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. J. Clin. Med. 2022,11, 421 8 of 20 Forty-four percent had at least one comorbidity, and 64% had a Charlson score of 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)) other than IBD (Supplementary Table S1). 3.2. Geografical Distribution of COVID-19 and Epidemiological Risk Factors of Exposure The geographical distribution of cases is shown in Figure 1A, allowing a comparative approach with the incidence of COVID-19 in the Spanish general population (Figure 1B). J. Clin. Med. 2022, 11, x FOR PEER REVIEW 8 of 21 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. Forty-four percent had at least one comorbidity, and 64% had a Charlson score of 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)) other than IBD (Supplementary Table S1). 3.2. Geografical Distribution of COVID-19 and Epidemiological Risk Factors of Exposure The geographical distribution of cases is shown in Figure 1a, allowing a comparative approach with the incidence of COVID-19 in the Spanish general population (Figure 1B). 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 majority of cases were reported in ENEIDA centres of the communities of Madrid and in those of the metropolitan area of Barcelona (red colour), where there is also the highest proportion of certified IBD units [26]. These two regions have the highest population density in Spain (844 and 743 inhabitants per km2, respectively, as of January 2021 [27]) and register the highest incidence of COVID-19 in the general population. 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 the general population. When considering specific outcomes, a similar trend was observed: the age of hospitalised patients with IBD was 59 years old (IQR, 50–72) vs. 66 years old (IQR, 51–79) in the general population, and the age of ICU/death was 72 years old (IQR, 57–80) in patients with IBD vs. 70 years old (IQR, 59–80 years) in the general population 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 majority of cases were reported in ENEIDA centres of the communities of Madrid and in those of the metropolitan area of Barcelona (red colour), where there is also the highest proportion of certified IBD units [ 26 ]. These two regions have the highest population density in Spain (844 and 743 inhabitants per km 2 , respectively, as of January 2021 [ 27 ]) and register the highest incidence of COVID-19 in the general population. 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 the general population. When considering specific outcomes, a similar trend was observed: the age of hospitalised patients with IBD was 59 years old (IQR, 50–72) vs. 66 years old (IQR, 51–79) in the general population, and the age of ICU/death was 72 years old (IQR, 57–80) in patients with IBD vs. 70 years old (IQR, 59–80 years) in the general population Regarding risk factors for COVID-19, almost half of the patients declared good adherence 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 3summarizes 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, pharmacy) 18 (3.7) Education 15 (3) Police and fireperson 5 (1) Closed institutions 2 (0.4) Veterinary, animal control worker or conservation and forest technician 4 (0.8) 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. Risk Variable Patients with Total Lockdown (n= 229) Patients without Total Lockdown (n= 225) p-Value 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 government 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 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 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 Supplementary 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, research 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, Ferring, 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 education 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. 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