Data on the course of severe COVID-19 in inflammatory bowel disease (IBD) patients remains limited. We aimed to determine the incidence rate and clinical course of severe COVID-19 in the heavily affected South-Limburg region in the Netherlands.
All COVID-19 patients admitted to the only two hospitals covering the whole South-Limburg region between February 27, 2020 and January 4, 2021 were included. Incidence rates for hospitalization due to COVID-19 were determined for the IBD (n = 4980) and general population (n = 597,184) in South-Limburg.
During a follow-up of 4254 and 510,120 person-years, 20 IBD patients (0.40%; 11 ulcerative colitis (UC), 9 Crohn’s disease (CD)) and 1425 (0.24%) patients from the general population were hospitalized due to proven COVID-19 corresponding to an incidence rate of 4.7 (95% Confidence interval (CI) 3.0–7.1) and 2.8 (95% CI 2.6–2.9) per 1000 patient years, respectively (Incidence rate ratio: 1.68, 95% CI 1.08–2.62, p = 0.019). Median age (IBD: 63.0 (IQR 58.0–75.8) years vs. general population: 72.0 (IQR 62.0–80.0) years, p = 0.10) and mean BMI (IBD: 24.4 (SD 3.3) kg/m2 vs. general population 24.1 (SD 4.9) kg/m2, p = 0.79) at admission were comparable in both populations. As for course of severe COVID-19, similar rates of ICU admission (IBD: 12.5% vs. general population: 15.7%, p = 1.00), mechanical ventilation (6.3% vs. 11.2%, p = 1.00) and death were observed (6.3% vs. 21.8%, p = 0.22).
We found a statistically significant higher rate of hospitalization due to COVID-19 in IBD patients in a population-based setting in a heavily impacted Dutch region. This finding reflects previous research that showed IBD patients using systemic medication were at an increased risk of serious infection. However, although at an increased risk of hospitalization, clinical course of severe COVID-19 was comparable to hospitalized patients without IBD.
Citation: Creemers RH, Rezazadeh Ardabili A, Jonkers DM, Leers MPG, Romberg-Camps MJ, Pierik MJ, et al. (2021) Severe COVID-19 in inflammatory bowel disease patients in a population-based setting. PLoS ONE 16(10): e0258271. https://doi.org/10.1371/journal.pone.0258271
Editor: Valérie Pittet, Center for Primary Care and Public Health, SWITZERLAND
Received: June 5, 2021; Accepted: September 22, 2021; Published: October 5, 2021
Copyright: © 2021 Creemers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Given the use of human research participants data in this study, the data contain potentially identifying or sensitive patient information and are therefore not directly shared. Metadata of the ELVIS registry is available for interested researchers and data is available after approval of research proposals by the Ethics Committee of Zuyderland Medical Centre and ELVIS registry committee (contact: METC@zuyderland.nl).
Funding: The author(s) received no specific funding for this work.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AvB has served as speaker, adviser and/or principal investigator for AbbVie, Arandal, Arena, Celgene, Ferring, Galapagos, Janssen, MSD, Pfizer, Roche, Takeda, TEVA, and received research grants from TEVA, Eurostars funding, ZonMW, all outside the submitted work. MP reports grants and non-financial support from Falk Pharma, grants from European commission, grants from ZONMW (Dutch national research fund), grants and non-financial support from Takeda, grants and non-financial support from Johnson and Johnson, grants and non-financial support from Abbvie, non-financial support from Ferring, non-financial support from Immunodiagnostics, non-financial support from MSD, all outside the submitted work. DJ reports grants from Top Knowledge Institute (Well on Wheat), grants from Horizon 2020 DISCOvERIE, grants from NWO-CCC Partnership program (Carbokinetics), all outside the submitted work. ARA, RC, ML and MRC have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Abbreviations: CD, Crohn’s disease; COVID-19, Coronavirus disease 2019; CT-CORADS, CT coronavirus disease 2019 reporting and data system; IBD, Inflammatory bowel disease; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; UC, Ulcerative colitis
Millions of people, including patients with Inflammatory Bowel Diseases (IBD), have been affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The broad use of immunosuppressants and biologicals in IBD patients increases susceptibility to opportunistic or severe infections [1–3]. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 . Data on incidence and clinical course of severe COVID-19 compared to a general population remains relatively sparse [5–12]. Especially data from population-based settings in heavily affected regions are underrepresented.
In a recent Swedish population-based study, IBD patients were at an increased risk of hospitalization for COVID-19 compared to the general population, even after adjusting for comorbidities . Remarkably, the subsequent risk for intensive care unit (ICU) admission or death was comparable with a low absolute risk of severe COVID-19 in IBD patients . To guide vaccination strategies against SARS-CoV-2, it is crucial to exactly delineate populations at risk for a severe course of COVID-19.
South-Limburg is a border region in the Southeast of the Netherlands with 597,184 inhabitants enclosed by Germany and Belgium . All regional inpatient care is provided by two hospitals: Zuyderland Medical Centre, a large general district hospital, and Maastricht University Medical Centre+. During the COVID-19 pandemic, the second highest COVID-19 mortality rate (144.7 per 100,000) in the Netherlands (96.0 national average) has been reported for this region .
This report aimed to expand the current knowledge on severe COVID-19 in the IBD population by calculating the incidence rate and examining the clinical course of severe COVID-19 compared to the regional population in a population-based setting in South-Limburg.
Materials and methods
Patient cohorts and follow-up
The IBD-cohort comprised all patients in the South-Limburg region with an IBD diagnosis at February 27th 2020 in either one of the only two hospitals covering this region. Due to lockdown and travel limitations all regional COVID-19 patients were treated in these hospitals. The total IBD population in South-Limburg is currently estimated at 4980 patients.
As control population, the total number of inhabitants in the South-Limburg region on February 27th, 2020 (n = 597,184) were included. Population data were obtained from the Dutch Central Bureau of Statistics (CBS) .
Both populations were observed from February 27th, 2020, date of first confirmed COVID-19 diagnosis in the Netherlands, until January 4th, 2021, the start date of COVID-19 vaccinations in the Netherlands.
Outcome and definitions
This study had two main outcomes: (1) incidence rate of severe COVID-19 was calculated for both IBD patients and the regional population. All IBD patients from the South Limburg region who were admitted for COVID-19-related complaints were included. For the regional population, data on COVID-19 hospitalization were obtained from The Dutch National Institute for Public Health and Environment (RIVM) which publishes daily updated metadata.
(2) To compare clinical course of severe COVID-19 in IBD patients with comparators, baseline characteristics and data on the course of severe COVID-19 were collected for all severe COVID-19 cases in Zuyderland Medical Centre. For this outcome, severe COVID-19 was defined as a confirmed COVID-19 diagnosis (i.e., COVID-19 associated symptoms and either a positive SARS-CoV-2 polymerase chain reaction or CT-CORADS score (≥4)) requiring hospitalization, and/or resulting in ICU admission or death. All patients admitted to Zuyderland Medical Centre were prospectively registered in the Zuyderland COVID-19 Registry (ELVIS). After inclusion, patients with IBD in their medical history were identified based on the ICD-10 codes.
This study was approved by the Ethics Committee of Zuyderland Medical Centre (Z2020171). All COVID-19 patients admitted to Zuyderland MC were registered in the ZuydErLand COVID-19 regiStry (ELVIS). All patients in the ELVIS registry received written information about the registry as well as an opt-out form in case they did not want to participate. None of the patients included in this study objected to participation. This opt-out mechanism was approved by the Ethics Committee of Zuyderland Medical Centre.
Incidence rates were calculated as the ratio between COVID-19 hospitalizations (events) and patient-years of follow-up (time). Difference between incidence rates was assessed by calculating the incidence rate ratio using the ‘Exact Poisson Method’ . Baseline characteristics are presented as means with standard deviations (SD) or medians with interquartile range (IQR) for normal or non-normal distributed numerical variables respectively, and as number of patients with corresponding percentage for categorical variables. Independent samples t-test or Mann-Whitney U test was used for comparison of numerical variables and Chi-square test for categorical variables. Statistical analyses were conducted using SPSS (Version 26.0). A two-sided P value ≤0.05 was considered statistically significant.
Incidence rate of severe COVID-19
During a follow-up of 4254 person-years, 20 IBD patients (0.40%; 11UC, 9CD) were hospitalized in the South-Limburg region due to COVID-19 corresponding to an incidence rate of 4.7 (95% Confidence interval (CI) 3.0–7.1) per 1000 person-years. During the same period, in the general population 1425 patients (0.24%) were admitted to the hospital with COVID-19 during 510,120 person-years yielding an incidence rate of 2.8 (95% CI 2.6–2.9) per 1000 person-years and translating to an incidence rate ratio of 1.68 (95% CI 1.08–2.62, p = 0.019) for IBD versus the general population (Table 1).
Outcome of severe COVID-19
Out of 870 patients hospitalized for severe COVID-19 in the Zuyderland MC, 16 patients had IBD (10 UC, 6 CD). Baseline characteristics for the study population are presented in Table 2. Median age and BMI at admission were comparable between the IBD population and comparators. A lower, but statistically non-significant, burden of comorbidities (Charlson comorbidity index (CCI) ≥4 37.5% vs. 56.7%) was registered in the IBD population.
As for clinical course of severe COVID-19, rates of oxygen support, ICU admission, and mechanical ventilation did not differ between IBD patients versus matched time frame comparators without IBD. Furthermore, no statistically significant difference in death rate date was observed (Table 2).
In the present study, we aimed to investigate the incidence rate and clinical outcomes of severe COVID-19 for the IBD population. We observed a statistically significant increase in hospitalization rates due to COVID-19 in a population of 4980 IBD patients when compared to the general population in South-Limburg. This finding reflects previous research in a large population based nationwide cohort study that showed that IBD patients using systemic medication were at an increased risk of serious infections . It is important to note that although we demonstrated an increased risk of hospitalization, the risk of a serious course of COVID-19 was not different in the IBD population compared to the matched time frame comparator population without IBD.
Epidemiological data and disease outcome data on severe COVID-19 in IBD patients from the Netherlands and Denmark have previously been reported [7, 8]. In these studies, SARS-CoV-2 testing data from the general population were compared with data on symptomatic COVID-19 in IBD patients, likely to overrepresent the number of cases in the general population. In another recent population-based study from Sweden, it was assessed whether IBD patients were at an increased risk of severe COVID-19 . In the latter study, patients were identified at hospital admission, and IBD patients were matched with general population controls, therefore enabling more precise risk estimations. Reported incidence rates were 5.4 (95%CI 4.6–6.2), and 3.4 (95%CI 3.1–3.7) per 1000 patient years for COVID-19 hospital admissions in the IBD population and matched controls, respectively. In the present study, similar incidence rates for COVID-19 hospitalization (IBD: 4.7, 95%CI 3.0–7.1 vs. Comparators: 2.8, 95%CI 2.6–2.9) were observed.
Regarding the course of severe COVID-19, baseline patient characteristics of both groups did not differ. Interestingly, BMI, a well-established risk factor for worse disease outcome, was not different between the two groups and equal to the Dutch average [17, 18]. On post-hoc analysis, BMI of patients requiring ICU admission was significantly higher compared to non-ICU patients in both groups (mean BMI 25.8 (SD: 4.6) vs mean BMI 23.9 (SD: 4.8), p<0.001), confirming the importance of BMI as a risk factor for severe COVID-19. Additionally, the clinical course of severe COVID-19 was comparable between IBD patients and comparators, as reported before in different settings [19–22].
Interestingly, none of the IBD patients with severe COVID-19 were on biologicals when in fact a substantial proportion of IBD patients in our population currently use biologicals, in particular anti-tumour necrosis factor (TNF) agents such as infliximab and adalimumab. Since TNF is recognized as an important component of the cytokine response during the inflammatory phase, also known as the cytokine release syndrome (CRS), several studies have described the rationale for anti-TNF therapy in COVID-19 [23, 24]. Moreover, accumulating observational clinical data in IBD and other immune mediated inflammatory diseases (IMIDs) have highlighted the potential benefit of anti-TNF therapies as treatment for COVID-19 and have also led to initiation of various clinical trials that are currently investigating use of anti-TNF in COVID-19 . All in all, although cases were limited, the observation of no anti-TNF users among the IBD patients with severe COVID-19 in the current study further substantiates the potential protective role of anti-TNF agents in the pathophysiology of COVID-19.
Among the strengths of this study is the strict definition of severe COVID-19 applied to both the IBD population as well as the matched time frame comparators. Furthermore, the prospective ELVIS registry enabled detailed phenotyping of baseline and COVID-19 characteristics in both IBD patients and comparators, thus providing us with means to find signals that may be missed in larger retrospective cohorts based on selected cases. As therapeutic focus shifts from reducing symptoms of SARS-CoV-2 infection to preventing severe infection through vaccination, the presented data may be of help to identify most benefitting populations since IBD and treatment of it do not seem to worsen clinical course of severe COVID-19. Nevertheless, we recognize several limitations in this study, of which most important the limited number of severe COVID-19 cases. The limited number of cases prevented adjustment of incidence rates for demographic and clinical characteristics and sub-analyses to identify risk factors for severe COVID-19. Therefore, the statistical comparisons should be interpreted with care.
In conclusion, we found a statistically significant higher rate of hospitalization due to COVID-19 in IBD patients in a population-based setting in a heavily impacted Dutch region. This finding reflects previous population-based reports in which was shown that IBD patients using systemic medication are at an increased risk of serious infection, as contrasted with case-based analyses in larger series in which IBD did not seem to be a risk factor for contracting SARS-CoV-2 infection. However, despite increased rates of hospitalization, clinical course of COVID-19 was comparable to hospitalized patients without IBD.
The authors thank the Research Department (Bureau Wetenschappelijk Onderzoek, BWO), namely Anke Linssen, Esther Bergman, Christel Jacquot, Marijke Lemmens and Audrey Merry for data management of the ELVIS registry.
- 1. Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases. Gastroenterology. 2018;155(2):337–46.e10. pmid:29655835
- 2. Kucharzik T, Ellul P, Greuter T, Rahier JF, Verstockt B, Abreu C, et al. ECCO Guidelines on the Prevention, Diagnosis, and Management of Infections in Inflammatory Bowel Disease. Journal of Crohn’s and Colitis. 2021.
- 3. Hindryckx P, Novak G, Bonovas S, Peyrin-Biroulet L, Danese S. Infection Risk With Biologic Therapy in Patients With Inflammatory Bowel Disease. Clinical pharmacology and therapeutics. 2017;102(4):633–41. pmid:28699217
- 4. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine. 2020;382(18):1708–20. pmid:32109013
- 5. Singh AK, Jena A, Kumar-M P, Sharma V, Sebastian S. Risk and outcomes of coronavirus disease in patients with inflammatory bowel disease: A systematic review and meta-analysis. United European Gastroenterology Journal. 2021;9(2):159–76. pmid:33210980
- 6. Allocca M, Fiorino G, Zallot C, Furfaro F, Gilardi D, Radice S, et al. Incidence and Patterns of COVID-19 Among Inflammatory Bowel Disease Patients From the Nancy and Milan Cohorts. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association. 2020;18(9):2134–5. pmid:32360811
- 7. Derikx LAAP, Lantinga MA, de Jong DJ, van Dop WA, Creemers RH, Römkens TEH, et al. Clinical Outcomes of Covid-19 in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study. Journal of Crohn’s and Colitis. 2020;15(4):529–39.
- 8. Attauabi M, Poulsen A, Theede K, Pedersen N, Larsen L, Jess T, et al. Prevalence and Outcomes of COVID-19 Among Patients With Inflammatory Bowel Disease—A Danish Prospective Population-based Cohort Study. Journal of Crohn’s and Colitis. 2020;15(4):540–50.
- 9. Singh S, Khan A, Chowdhry M, Bilal M, Kochhar GS, 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(4):1575–8.e4. pmid:32522507
- 10. Aziz M, Fatima R, Haghbin H, Lee-Smith W, Nawras A. The Incidence and Outcomes of COVID-19 in IBD Patients: A Rapid Review and Meta-analysis. Inflammatory Bowel Diseases. 2020;26(10):e132–e3. pmid:32619003
- 11. Taxonera C, Sagastagoitia I, Alba C, Mañas N, Olivares D, Rey E. 2019 novel coronavirus disease (COVID-19) in patients with inflammatory bowel diseases. Alimentary pharmacology & therapeutics. 2020;52(2):276–83. pmid:32359205
- 12. Axelrad JE, 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. Inflammatory Bowel Diseases. 2020;27(5):662–6.
- 13. Ludvigsson JF, Axelrad J, Halfvarson J, Khalili H, Larsson E, Lochhead P, et al. Inflammatory bowel disease and risk of severe COVID-19: A nationwide population-based cohort study in Sweden. United European Gastroenterology Journal. 2021;9(2):177–92. pmid:33704918
- 14. CBS. Regional Population Figures Netherlands https://opendata.cbs.nl/#/CBS/nl/dataset/70072ned/table?searchKeywords=bevolking Accessed on 23 April 2021: Statline; 2021 [updated 31 March 2021].
- 15. RIVM. COVID-19 metadata https://data.rivm.nl/covid-19/ Accessed on 1 April 2021 [updated Daily].
- 16. Sahai H, Khurshid A. Statistics in epidemiology: methods, techniques and applications. 1995.
- 17. Tartof SY, Qian L, Hong V, Wei R, Nadjafi RF, Fischer H, et al. Obesity and Mortality Among Patients Diagnosed With COVID-19: Results From an Integrated Health Care Organization. Ann Intern Med. 2020;173(10):773–81. pmid:32783686
- 18. Popkin BM, Du S, Green WD, Beck MA, Algaith T, Herbst CH, et al. Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships. Obesity Reviews. 2020;21(11):e13128. pmid:32845580
- 19. Kjeldsen J, Nielsen J, Ellingsen T, Knudsen T, Nielsen RG, Larsen MD, et al. Outcome of COVID-19 in hospitalized patients with chronic inflammatory diseases. A population based national register study in Denmark. Journal of Autoimmunity. 2021;120:102632. pmid:33812171
- 20. Attauabi M, Seidelin JB, Felding OK, Wewer MD, Vinther Arp LK, Sarikaya MZ, et al. Coronavirus disease 2019, immune-mediated inflammatory diseases and immunosuppressive therapies—A Danish population-based cohort study. J Autoimmun. 2021;118:102613. pmid:33592545
- 21. Brenner EJ, Ungaro RC, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, 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(2):481–91.e3. pmid:32425234
- 22. Gianfrancesco M, Yazdany J, Robinson PC. Epidemiology and outcomes of novel coronavirus 2019 in patients with immune-mediated inflammatory diseases. Current Opinion in Rheumatology. 2020;32(5). pmid:32675715
- 23. Feldmann M, Maini RN, Woody JN, Holgate ST, Winter G, Rowland M, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet (London, England). 2020;395(10234):1407–9. pmid:32278362
- 24. Robinson PC, Liew DFL, Liew JW, Monaco C, Richards D, Shivakumar S, et al. The Potential for Repurposing Anti-TNF as a Therapy for the Treatment of COVID-19. Med. 2020;1(1):90–102. pmid:33294881
- 25. Robinson PC, Richards D, Tanner HL, Feldmann M. Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment. Lancet Rheumatol. 2020;2(11):e653–e5. pmid:33521660