key: cord-0745671-ogs77s5s
authors: Derikx, Lauranne A A P; Lantinga, Marten A; de Jong, Dirk J; van Dop, Willemijn A; Creemers, Rob H; Römkens, Tessa E H; Jansen, Jeroen M; Mahmmod, Nofel; West, Rachel L; Tan, Adriaan C I T L; Bodelier, Alexander G L; Gorter, Moniek H P; Boekema, Paul J; Halet, Eric R C; Horjus, Carmen S; van Dijk, Maarten A; Hirdes, Meike M C; Epping Stippel, Ludger S M; Jharap, Bindia; Lutgens, Maurice W M D; Russel, Maurice G; Gilissen, Lennard P L; Nauta, Sjoukje; van Bodegraven, Adriaan A; Hoentjen, Frank
title: Clinical Outcomes of Covid-19 in Patients with Inflammatory Bowel Disease: A Nationwide Cohort Study
date: 2020-10-20
journal: J Crohns Colitis
DOI: 10.1093/ecco-jcc/jjaa215
sha: ccccb7a784893c235ab7bc2e4b6b06e0d8a4e57d
doc_id: 745671
cord_uid: ogs77s5s

BACKGROUND AND AIMS: The COVID-19 risk and disease course in inflammatory bowel disease (IBD) patients remains uncertain. Therefore, we aimed to assess the clinical presentation, disease course and outcomes of COVID-19 in IBD patients. Second, we determined COVID-19 incidences in IBD patients and compared this with the general population. METHODS: We conducted a multicenter, nationwide IBD cohort study in the Netherlands and identified patients with COVID-19. First, we assessed the COVID-19 disease course and outcomes. Second, we compared COVID-19 incidences between our IBD study cohort and the general Dutch population. RESULTS: We established an IBD cohort of 34,763 patients. COVID-19 was diagnosed in 100/34,763 patients (0.29%). 20/100 patients (20%) had severe COVID-19 defined as admission to the intensive care unit, mechanical ventilation, and/or death. Hospitalization occurred in 59/100 (59.0%) patients and 13/100 (13.0%) died. All patients who deceased had comorbidities and all but one were > 65 years. In line, we identified > 1 comorbidity as an independent risk factor for hospitalization (OR 4.20, 95% CI 1.58-11.17, p = 0.004). Incidences of COVID-19 between the IBD study cohort and the general population were comparable (287.6 (95% CI 236.6-349.7) versus 333.0 (95% CI 329.3-336.7) per 100,000 patients, respectively; p = 0.15). CONCLUSIONS: Of 100 cases with IBD and COVID-19, 20% developed severe COVID-19, 59% was hospitalized and 13% died. A comparable COVID-19 risk was found between the IBD cohort (100/34,763 = 0.29%) and the general Dutch population. The presence of > 1 comorbidities was an independent risk factor for hospitalization due to COVID-19.

M a n u s c r i p t COVID-19 can affect all individuals while older patients and patients with co-existing illnesses, such as diabetes and hypertension, are at increased risk. 2 Mortality from COVID-19 is estimated at 1.5% to 3%. 3 Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract characterized by a variety of symptoms such as abdominal pain and (hemorrhagic) diarrhea. It is thought to be the result of an overactive mucosal immune response against gut microorganisms in genetically susceptible individuals. Many patients use immune modifying medical therapies to control IBD, but these drugs also come with an increased risk of (opportunistic) infection. 4 Consequently, IBD patients on immunosuppressive medical therapy may encounter an increased COVID-19 infection risk. Moreover, the upregulation of ACE2 in IBD patients facilitating the entry and replication of SARS-CoV-2 may further increase the COVID-19 risk. 1, 5 By contrast, immunosuppressive therapy may also have a potential benefit on clinical outcomes in COVID-19 since it may suppress not only mucosal inflammation but also the SARS-CoV-2 driven systemic inflammatory immune response. 1 A c c e p t e d M a n u s c r i p t Manuscript Doi: 10 .1093/ecco-jcc/jjaa215 11 Given these anticipated effects of SARS-CoV-2 infection, IBD and immunosuppressive medication, the COVID-19 risk and disease course in IBD patients remains uncertain. Some studies assessed clinical characteristics and the disease course of COVID-19 in IBD patients. [6] [7] [8] [9] [10] [11] [12] [13] In general, these reports identified a similar disease course and similar risk factors associated with a worse COVID-19 outcome compared to the general population. [8] [9] [10] [11] However, most of these studies were limited by small cohorts and harbor reporting or selection bias. 11, 14 Moreover, incidence data are lacking in most studies.

To systematically investigate the COVID-19 risk and disease course in IBD patients, we established a nationwide IBD cohort (n=34,763) in the Netherlands. We aimed to assess the clinical presentation, disease course and clinical outcomes of COVID-19 in this nationwide IBD cohort. Moreover, we determined the COVID-19 incidence in IBD patients and compared this with the general Dutch population.

We established a multicenter, retrospective cohort of IBD patients to study the incidence, disease course and clinical outcomes of COVID-19 in the Netherlands. To assess the disease course, we performed a nested case control study. Two academic and 18 non-academic hospitals participated in this study. Participating centers were primarily located in the central and southern provinces of the Netherlands as these regions reported the highest incidence of COVID-19 in the Netherlands.

Incidences of COVID-19 were compared between the IBD study cohort and the general Dutch population as reported by the Dutch National Institute for Public Health and the Environment

A c c e p t e d M a n u s c r i p t 

To assess the disease course and clinical outcomes of COVID-19 in IBD, we used the primary composite outcome severe COVID-19. This was defined as either a) admission to an intensive care unit (ICU), and/or b) the use of mechanical ventilation, and/or c) death. Previous studies used this outcome to assess disease severity of COVID-19 or other serious infectious diseases such as H7N9 infection. 2, 11 Our secondary outcome included the hospital admission rate of IBD patients due to COVID-19.

To compare the COVID-19 incidence between the IBD study cohort and the general population, we determined both the incidence of all reported COVID-19 cases and the hospitalization incidence due to COVID-19.

We identified patients in each participating hospital using Diagnosis Treatment Combinations (DTC).

DTCs are based on the International Classification of Disease (ICD), 10 th revision, and are the foundation of the healthcare payment system in the Netherlands. DTCs were previously used for validated and reliable identification of IBD patients in the Netherlands. 16 First, we performed from May 2019 until June 2020 in every participating center a DTC search including the terms "Crohn's disease" (DTC 601) or "ulcerative colitis" (DTC 602) to determine the size of the total IBD study cohort in each participating center. Second, we combined the terms "Crohn's disease" (DTC 601) or category 5 on chest computed tomography (CT). 18 We excluded patients who were diagnosed with IBD less than two weeks prior to COVID-19 diagnosis.

Demographic and clinical data were anonymously extracted from the electronic patient charts. related mortality rates were compared.

All analyses were performed with IBM SPSS statistical software package version 25 (Armonk, NY).

Descriptive statistics were used to describe baseline data and variables related to IBD and COVID-19.

Continuous variables are expressed as medians and interquartile range or mean and standard deviation, depending on distribution. Categorical variables were reported as frequencies with valid percentages. These are defined as the percentage of observations in a category out of the total number of non-missing responses in that category.

We performed explorative analyses with univariable and multivariable logistic regression on the To assess COVID-19 incidences in the IBD study cohort we first computed these incidences by dividing the number of new COVID-19 cases in a specified time period by the total IBD study cohort.

We computed both a COVID-19 incidence during four months (March 2020 -June 2020) and per two weeks. The 95% confidence intervals for a single proportion were counted for all incidences. Second, we compared incidences between the IBD study cohort and the general population in the corresponding regions using two by two tables at the Open Source of Epidemiologic Statistics for public health. 19 χ2 test or Fisher exact test (if expected cell counts were <5) were performed to compare incidences.

The study was approved by the Medical Ethics Review Committee region Arnhem -Nijmegen (Registration number 2020-6473). Subsequently, local approval was obtained in each participating hospital.

We established a multicenter IBD cohort of 34,763 patients (53.5% UC, 46.5% CD). In total, 100 of 34,763 IBD patients (0.29%) were diagnosed with COVID-19 ( 

Baseline characteristics of the 100 IBD patients with COVID-19 are shown in Table 1 A c c e p t e d M a n u s c r i p t Table 3 and Figure 1 show the four-month COVID-19 incidence per 100,000 individuals for both the IBD study cohort and the general population, stratified per participating center. The incidence of reported COVID-19 was comparable between the IBD study cohort (287.6 per 100,000 patients; 95%

confidence interval 236.6-349.7) and the general population (333.0 per 100,000 subjects; 95% confidence interval 329.3-336.7; p = 0.15). In line, incidences for all reported COVID-19 cases per two weeks in the IBD study cohort followed a similar course as in the general population with overlapping 95% confidence intervals ( Figure 2 ).

By contrast, we found higher four-month incidence rates for hospital admissions due to COVID-19 in the IBD study cohort (177.2 per 100,000 patients; 95% confidence interval 137.7-228.1) compared to the general population (84.5 per 100,000 patients; 95% confidence interval (82.6-86.5); p < 0.01; Figure 3 ). Similarly, higher two weekly hospitalization incidence rates were found in the IBD study cohort at specific time points (4/3/2020 -17/3/2020, p = 0.01; 15/4/2020 -28/4/2020, p < 0.01; 27/5/2020 -9/6/2020, p =0.01; Figure 4 ).

In line with the reported COVID-19 incidence, we found comparable four-month COVID-19 related mortality rates between the IBD study cohort (37.3 per 100,000 patients; 95% confidence interval 21.9-64.0) and the general population (44.9 per 100,000 patients; 95% confidence interval 43.5-46.3; p = 0.51). Mortality rates per two weeks were comparable as well with overlapping confidence intervals ( Figure 5 ).

A c c e p t e d M a n u s c r i p t and death. 8, 11 In contrast, the SECURE-IBD study additionally identified use of either systemic corticosteroid or 5-ASA/sulfasalazine as risk factors for severe COVID-19. 11 This study was criticized given the reported high rate of anti-TNF use (43.4%), thereby potentially overestimating the effect of corticosteroids and 5-ASA treatment on COVID-19 severity. 21 In contrast, only 13.1% of IBD patients included in our study were treated with anti-TNF mono-or combination therapy during COVID-19

and potentially reflect a more representative cohort of IBD patients. As a result, this could explain why we did not identify use of any IBD-related medical therapy as a risk factor for severe COVID-19 or hospitalization. incidence between the IBD and general population (0.0025 versus 0.0017, respectively). 22 Similarly, a single center Spanish case series reported a cumulative incidence of COVID-19 infection of 630 per 100,000 IBD patients (12 out of 1912 IBD patients), compared to 660 per 100,000 for the total population of Madrid (43,877 cases in 6.7 million inhabitants). The authors found a comparable mortality ratio (OR 0.95, 95% CI: 0.84-1.06; p=0.36) as well. 10 Another retrospective study in Northern California in the United States showed that the prevalence of COVID-19 among IBD patients was similar to the prevalence in the general population in that region (3.0% vs 2.8%, respectively). 23 The authors of the latter papers suggested that IBD patients are not facing an increased risk for COVID-19 despite the use of immunosuppressive drugs, which was relatively high (average 37%) in both studies. 24 It should be noted that our cohort had a relatively low use of biologicals (16%) and none of the patients with severe COVID-19 used anti-TNF. These data support the hypothesis that IBD patients despite immune modulating therapies do not have an increased risk of COVID-19. Several factors may contribute to this observation, including awareness among physicians of potential COVID-19 risk during immunosuppression, and increased caution among IBD patients to isolate themselves from others in fear of contracting COVID-19.

Strengths of this study include its nationwide coverage by the large number of hospitals which cover 125 of the 355 municipalities (35.2%) of the country, including over 34,000 IBD patients. The participating centers were primarily located in the regions reporting the highest incidence of COVID-19. This large coverage including academic but mainly non-academic hospital allowed us to build a cohort that approximates the national IBD population, limiting selection bias. In addition, the most affected parts of the country were included, ensuring sufficient COVID-19 cases for statistical analysis. Finally, we were able to systematically identify COVID-19 patients as well as the total A c c e p t e d M a n u s c r i p t M a n u s c r i p t Forest plot comparing the reported COVID-19 incidence during 4 months between the IBD study cohort and general Dutch population NC, not computable

Reported COVID-19 incidence per 100,000 patients per two weeks for both the IBD study cohort and the general Dutch population in the corresponding region

Forest plot comparing the hospitalized COVID-19 incidence during 4 months between the IBD study cohort and general Dutch population NC, not computable

Hospitalized COVID-19 incidence per 100,000 patients per two weeks for both the IBD study cohort and the general Dutch population in the corresponding region 

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A c c e p t e d M a n u s c r i p t Manuscript Doi: 10 .1093/ecco-jcc/jjaa215 23 M a n u s c r i p t