key: cord-0978606-2um2wbcs authors: Ludvigsson, Jonas F.; Axelrad, Jordan; Halfvarson, Jonas; Khalili, Hamed; Larsson, Emma; Lochhead, Paul; Roelstraete, Bjorn; Simon, Tracey G.; Söderling, Jonas; Olén, Ola title: Inflammatory bowel disease and risk of severe COVID‐19: A nationwide population‐based cohort study in Sweden date: 2021-03-11 journal: United European Gastroenterol J DOI: 10.1002/ueg2.12049 sha: 3c17913a0fe40082ffb63ff43ac5c554e08a0878 doc_id: 978606 cord_uid: 2um2wbcs BACKGROUND: There are concerns that individuals with chronic immune‐mediated diseases are at increased risk of COVID‐19 and related severe adverse outcome, including intensive care admission or death. We aimed to explore the absolute and relative risk of severe COVID‐19 in inflammatory bowel disease (IBD). METHODS: This population‐based cohort study used nationwide registers in Sweden, with 67,292 individuals with a diagnosis of IBD 1969–2017 (Crohn's disease, n = 21,599; ulcerative colitis: n = 43,622; IBD‐unclassified: n = 2071) and alive on 1 February 2020. Patients with IBD were matched to up to five controls from the general population (n = 297,910). Cox regression estimated hazard ratios (HRs) for (i) hospital admission with laboratory‐confirmed COVID‐19 as the primary diagnosis, and (ii) severe COVID‐19 (composite outcome consisting of (a) COVID‐19 intensive care admission, or (b) death from COVID‐19 or (c) death within 30 days of COVID‐19 hospital admission), were calculated. Analyses were conditioned on age, sex, calendar period, and county and adjusted for other comorbidities. RESULTS: Between 1 February and 31 July 2020, 179 (0.27%) IBD patients and 500 (0.17%) general population controls were admitted to hospital with COVID‐19 (adjusted HR [aHR] = 1.43; 95% CI = 1.19–1.72). The corresponding numbers for severe COVID‐19 was 65 (0.10%) and 183 (0.06%; aHR = 1.11; 95% CI = 0.81–1.52). Adjusted HRs were similar in Crohn's disease and ulcerative colitis. In a propensity score‐matched model taking comorbidity into account until 2016, the increased risk for COVID‐19 hospital admission remained (aHR = 1.32; 1.12–1.56), but there was no increased risk of severe COVID‐19 (aHR = 1.12; 0.85–1.47). CONCLUSIONS: While individuals with IBD were more likely to be admitted to hospital for COVID‐19 than the general population, the risk of severe COVID‐19 was not higher. Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the gastrointestinal (GI) tract that includes Crohn's diseases (CD) and ulcerative colitis (UC). 1 Its incidence worldwide is increasing. 2 IBD has been linked to an increased risk of death from infections both in adulthood [3] [4] [5] (hazard ratio [HR] in Sweden = 2.1; 95% CI = 1.9-2.4) 6 and in childhood (HR = 6.3; 95% CI = 2.1-16.9), 7 potentially due to underlying chronic inflammation, malnutrition and the impact of long-standing immunosuppressive medication exposure. Coronavirus disease 2019 (COVID- 19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 8 During spring, Sweden had no general lockdown and a high mortality rate from COVID-19. 9 While early COVID-19 reports focused on severe respiratory and cardiovascular aspects, 10 recent studies have also reported GI manifestations, 10, 11 such as diarrhea (7.7%) 12 and abdominal pain (2.7%). 12 Recently, Aziz et al. 13 reviewed the literature on IBD and risk of COVID-19. Among 9177 IBD patients in six studies, only 32 patients (0.3%; 95% CI = 0.1%-0.5%) had confirmed COVID-19. The low cumulative incidence of COVID-19 may suggest that IBD patients are not at increased risk of COVID-19, but the reviewed studies did not include general population controls and did not allow for the calculation of relative risks. In a recent Danish study, Attauabi et al. 14 report that IBD patients undergoing testing for COVID-19 were less often positive (2.5%) than in the overall population (3.7% positivity). Derikx et al. 15 reported a lower risk of incident COVID-19, but a higher risk of COVID-19 hospital admission in IBD patients, but their study did not adjust for sex, age or other confounders. In a US multicentre research network study, Singh et al. 16 retrieved data from 31 healthcare organisations. IBD patients with COVID-19 were no more likely to attain the composite outcome of hospital admission or death within 30 days following a diagnosis of COVID-19 compared to non-IBD-patients with COVID-19 (relative risk = 0.93; 95% CI = 0.68-1.27). This is consistent with smaller well-characterised studies from IBD centres. 17 Still, none of these studies calculated relative risks for incident or severe COVID-19 in IBD versus matched general population controls. Additionally, most previous research has largely been limited to IBD referral centres, has not accounted for socioeconomic factors and lacked analyses according to IBD subtypes. In this nationwide cohort study, we aimed to investigate whether patients with IBD and its subtypes are at increased risk of hospital admission for COVID-19 or severe COVID-19. In Sweden, healthcare is tax-funded and universal. All residents receive a unique personal identity number allowing for register linkages. 18 The current study was restricted to study participants alive on 1 February 2020. The Swedish Patient Register began in 1964, became nationwide in 1987 and added nonprimary outpatient care in 2001. 19 Diagnoses are coded according to international classification of disease (ICD) codes. For IBD we required ≥1 ICD code for IBD (see Table E1 ), and a GI histopathology record that showed inflammation or was designated as IBD by the pathologist (Table E1) . Histopathology information was retrieved from the ESPRESSO study. 20 This study is based on all computerised GI histopathology records at any of Sweden's 28 pathology departments between 1965 and April 2017. It encompasses 2.1 million individuals. The combination of ICD codes and histopathology to define IBD has been used previously and has a positive predictive value of 95% (95% CI = 89%-99%). 21 Patient Register data on IBD were available up until 31 December 2016, and histopathology data up until 10 April 2017. Date of diagnosis was equal to the second of the two records. According to the first relevant ICD code, IBD patients were furthermore divided into subtypes (CD vs. UC vs. IBD unclassified; Table E1 ). For each individual with IBD, we selected up to five controls from the general population. Controls were matched on age, sex, calendar period and county at time of first GI biopsy. Controls were IBD-free at study entry and were censored if they developed IBD during follow-up). We also examined the risk of COVID-19 in IBD patients compared to unaffected full siblings. In spring 2020, Swedish Ethics Review Boards and government agencies were urged to facilitate COVID-19-related research. A fast track was created that allowed researchers to update existing cohorts with data on deaths and hospital care for COVID-19 (until 31 July 2020) as well as data on death dates (until 31 July 2020). The ESPRESSO cohort was updated accordingly, but the extra ethical permit did not include update of non-COVID-19-related information. For that reason, our data on comorbidity were limited to the original data retrieval for the ESPRESSO cohort (up until 31 December 2016). We retrieved the following comorbidity data from the Patient Register (hospital-based inpatient and outpatient care): cardiovascular disease including thromboembolic disease, diabetes mellitus, chronic obstructive pulmonary disease, end-stage renal disease, alcohol use disorders including alcohol-related liver disease, obesity/ dyslipidaemia, obstructive sleep apnoea, cancer and psychiatric disease (Table E2) . We retrieved data on education as a proxy for socioeconomic status (education, was divided into ≤9, 10-12 and ≥13 years in full time education 22 ) as well as country of birth (Nordic vs. not Nordic countries). 23 In Sweden, it is compulsory to report any positive COVID-19-test to the Swedish Public Health Agency. We had two main outcomes (i) hospital admission with laboratoryconfirmed COVID-19 as the primary diagnosis (ICD-10: U07.1), and (ii) severe COVID-19 (a composite outcome defined as: (a) COVID-19 intensive care admission, or (b) death due to COVID-19 or (c) death within 30 days of diagnosed COVID-19 (U07.1)). Data on COVID-19specific deaths were obtained through the Cause of Death register 24 (Table E3) . Secondary outcomes were (iii) the above combined (iv) all-cause mortality (COVID-19 or non-COVID- 19) Follow-up started on 1 February 2020, and ended with death, record of COVID-19 (according to our outcome definitions) or 31 July 2020. LUDVIGSSON ET AL. Cox regression conditioned on matching factors (age, sex, county and calendar year) was used to estimate hazard ratios (HRs) for COVID-19. We then adjusted for comorbidities at index date (date of IBD diagnosis, being the second of either an IBD ICD code or the GI histopathology report) and the equivalent date in controls. Our adjusted model also included data on education and country of birth. We performed subgroup analyses for hospital admission for laboratory verified COVID-19 and for severe COVID-19 according to follow-up (monthly intervals), sex, age at IBD diagnosis (<18, 18-<40, 40-<60, 60+ years), year of diagnosis (1969-1989, 1990-1999, 2000-2009, 2010-2017) , IBD subtype (CD, UC, IBD unclassified), country of birth and level of education. Rematching using a propensity score model To test the robustness of our findings, we carried out a second analysis where IBD patients were matched to non-IBD general population controls 1:5 on birth year, sex, county and a nearest neighbour propensity score algorithm allowing a maximum caliper width 26 of 0.2 of the pooled standard deviation of the logit of the propensity score. 27 The logistic regression model included age, sex, education, Nordic country of birth and comorbidities on 31 December 2016. In this analysis, the IBD subtype was based on the last preceding ICD code. Due to lack of controls, the number of IBD-patients in this analysis (n = 67,099) was slightly lower than in the main analysis. To minimize the impact of unmeasured confounding we also compared IBD patients to their siblings. Finally, we also examined the risk of overall death in IBD patients admitted to hospital with COVID-19 versus controls admitted with COVID-19; as well as overall death in IBD patients and controls who had at some stage tested positive for COVID-19 (hospital admission not needed). All statistical analyses were performed using SAS (version 9.4) and STATA (version 16.0). This study was approved by the Stockholm Ethics Review Board (no: 2014/1287-31/4, with a COVID-19 specific amendment: 2020-02307). Since this study was based solely on registry data, the review board waived informed consent. 28 We identified 67,292 Individuals with a diagnosis of IBD between 1969 and 2017 (Crohn's disease, n = 21,599; ulcerative colitis: n = 43,622; IBD-unclassified: n = 2071) and 297,910 matched general population controls (Table 1 and Figure 1 ). Numbers were similar for the propensity score-matched model ( Figure E1 ). In the sibling analyses we compared 46,607 individuals with IBD and 81,393 siblings. The median age at IBD diagnosis (second of either ICD diagnosis or histopathology record) was 37.5 years (IQR = 25.7-51.6), with 6569 (9.8%) diagnosed before 18 years of age. Comorbidities were more common in IBD patients both before the index date (date of IBD diagnosis) and before start of follow-up (Table 1) . Characteristics, including IBD subtype, were similar in the rematched propensity-score cohort and in the sibling analyses (Tables E4 and E8) . We found increased risks of COVID-19 hospital admission in patients with IBD throughout follow-up (Table 3) IBD patients were also at a 21% increased risk of any COVID-19 (Table 2 ). In total, 811 (1.21%) IBD patients and 2890 (0.97%) controls had a record of any COVID-19 (Table 2) . In (Table 5 and Figure E3 ). Finally, restricting our sample to IBD patients and controls who were COVID-19 positive or admitted to hospital for COVID-19, IBD status was not associated with subsequent death (Tables E9 and E10 ). In this nationwide population-based cohort study, we observed an increased risk of hospital-admission for COVID-19 but no significant association with severe COVID-19 among more than 67,000 individuals with IBD. Results were similar for CD and UC, and were robust in sensitivity analyses after propensity score-matching and when comparing IBD patients to their siblings. Research on IBD and COVID-19 evolved from how to manage patients during the pandemic, 29 In the present study, and differing from earlier research, we neither restricted our population exclusively to IBD patients nor to patients who are COVID-19 positive. Rather, we took advantage of the Swedish national healthcare registers and compared IBD patients to general population controls. We found an increased risk of hospital admission for COVID-19, one of our two main outcomes. Despite this finding, the magnitude of the risk was small, in both absolute and relative terms. During the study period, one in 185 IBD patients was admitted to hospital for COVID-19 compared with one in 295 controls (or one in 249 comorbidity-matched controls). These incidence rates corresponded to a 43% increased risk of hospital admission for COVID-19, but importantly, this did not translate into an increased risk of severe COVID-19, defined as requirement for intensive care or death. Neither did we see an increased risk of death among IBD patients who were hospitalised with COVID-19. There could be several explanations for our findings. Viral SARS-COV-2 RNA has been detected in faecal samples, 37 Our sibling analyses enabled us to minimize confounding from shared risk factors such as genetics and environmental factors. Despite being based on more than 23,000 individuals with IBD, the sibling analysis had limited power. This likely explains the lack of statistical significance despite an aHR of 1.25 for COVID-19 hospital admission, which appears consistent with the increased risk seen in our main analysis. Our main limitation is the lack of data on medication 43 and IBD disease activity. We did not have data on endoscopy or faecal calprotectin. Other limitations include the lack of data on body mass index and smoking. These factors, especially body mass index (obesity) and hypertension, seem to be important risk factors for severe COVID-19. Neither were we able to explore the risk of COVID-19 according to UC/CD/IBD-U subtypes. Finally, we had no individual-based data on precautions undertaken by Swedish IBD patients during the pandemic, or on intubation during ICU care. In this cohort study of more 67,000 patients with IBD, we found a moderately increased risk of COVID-19 hospital admission but no increased risk of severe COVID-19. This study was supported by Karolinska Institutet. Jonas F. Ludvigsson coordinates a study on behalf of the Swedish IBD quality register (SWIBREG), that has received funding from Janssen corporation. Tracey G. Simon has served as a consultant to Aetion, for work unrelated to this manuscript. Ola Olén has been PI on projects at No additional data are available due to Swedish regulations. Researchers can apply from the data through the Swedish National Board of Health and Welfare, and the government agency Statistics Sweden. This study was approved by the Stockholm Ethics Review Board (no: 2014/1287-31/4, with a COVID-19 specific amendment: 2020-02307). Jonas F. Ludvigsson https://orcid.org/0000-0003-1024-5602 Inflammatory bowel disease Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of populationbased studies Mortality trends in Crohn's disease and ulcerative colitis: a population-based study in Quebec Mortality and causes of death in patients with inflammatory bowel disease: a nationwide register study in Finland Predictors and risks for death in a population-based study of persons with IBD in Manitoba Mortality in adult-onset and elderly-onset IBD: a nationwide register-based cohort study Increased mortality of patients with childhood-onset inflammatory bowel diseases, compared with the general population An interactive web-based dashboard to track COVID-19 in real time The first eight months of Sweden's COVID-19 strategy and the key actions and actors that were involved Clinical characteristics of coronavirus disease 2019 in China Current knowledge and research priorities in the digestive manifestations of COVID-19 AGA Institute rapid review of the gastrointestinal and liver manifestations of COVID-19, meta-analysis of international data, and recommendations for the consultative management of patients with COVID-19 The incidence and outcomes of COVID-19 in IBD patients: a rapid review and meta-analysis Prevalence and outcomes of COVID-19 among patients with inflammatory bowel disease -a Danish prospective population-based cohort study Clinical outcomes of covid-19 in patients with inflammatory bowel disease: a nationwide cohort study Risk of severe COVID-19 in patients with inflammatory bowel disease in United States. A multicenter research network study From the American Epicenter: coronavirus disease 2019 in patients with inflammatory bowel disease in the New York city metropolitan area The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research External review and validation of the Swedish national inpatient register Cohort profile: ESPRESSO (Epidemiology strengthened by histoPathology reports in Sweden) Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden The longitudinal integrated database for health insurance and labour market studies (LISA) and its use in medical research Registers of the Swedish total population and their use in medical research The Swedish cause of death register Review of 103 Swedish healthcare quality registries Optimal caliper width for propensity score matching of three treatment groups: a Monte Carlo study An introduction to propensity score methods for reducing the Effects of confounding in observational studies Ethical aspects of registry-based research in the Nordic countries Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel Care of the patient with IBD requiring hospitalization during the COVID-19 pandemic Inflammatory bowel disease management during the COVID-19 outbreak: the 10 do's and don'ts from the ECCO-COVID Taskforce British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study Incidence and patterns of COVID-19 among inflammatory bowel disease patients from the Nancy and milan cohorts but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry. Gastroenterology Baseline disease activity and steroid therapy stratify risk of COVID-19 in patients with inflammatory bowel disease. Gastroenterology Prolonged presence of SARS-CoV-2 viral RNA in faecal samples Detection of SARS-CoV-2 in different types of clinical specimens Evidence for gastrointestinal infection of SARS-CoV-2 Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study The new Swedish Prescribed Drug Register-opportunities for pharmacoepidemiological research and experience from the first six months Inflammatory bowel disease and risk of severe COVID-19: A nationwide population-based cohort study in Sweden