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COVID-19 and Outcomes in Patients With Inflammatory Bowel Disease: Systematic Review and Meta-Analysis

Abstract Background Our understanding of coronavirus disease 2019 (COVID-19) and its implications for patients with inflammatory bowel diseases (IBD) is rapidly evolving. We performed a systematic review and meta-analysis to investigate the epidemiology, clinical characteristics, and outcomes in IBD patients with COVID-19. Methods We searched PubMed, EMBASE, Cochrane Central, Clinicaltrials.gov, Web of Science, MedRxiv, and Google Scholar from inception through October 2020. We included studies with IBD patients and confirmed COVID-19. Data were collected on the prevalence, patient characteristics, pre-infection treatments for IBD, comorbidities, hospitalization, intensive care unit (ICU), admission, and death. Results Twenty-three studies with 51,643 IBD patients and 1449 with COVID-19 met our inclusion criteria. In 14 studies (n = 50,706) that included IBD patients with and without COVID-19, the prevalence of infection was 1.01% (95% confidence interval [CI], 0.92-1.10). Of IBD patients with COVID-19, 52.7% had Crohn’s disease, 42.2% had ulcerative colitis, and 5.1% had indeterminate colitis. Nine studies (n = 687) reported outcomes according to IBD therapy received. Compared with patients on corticosteroids, those on antitumor necrosis factor (anti-TNF) therapy had a lower risk of hospitalization (risk ratio [RR], 0.24; 95% CI, 0.16-0.35; P < .01; I2 = 0%) and ICU admission (RR, 0.10; 95% CI, 0.03-0.37; P < .01) but not death (RR, 0.16; 95% CI, 0.02-1.71; P = .13; I2 = 39%). Compared with patients on mesalamine, those on antitumor necrosis factor therapy had a lower risk of hospitalizations (RR, 0.37; 95% CI, 0.25-0.54), ICU admissions (RR, 0.20; 95% CI, 0.07-0.58), and death (0.21; 95% CI, 0.04-1.00). Comparing patients on immunomodulators vs mesalamine or anti-TNF therapy, there was no difference in these outcomes. Conclusions The prevalence of COVID-19 in IBD patients was low. Use of corticosteroids or mesalamine was significantly associated with worse outcomes, whereas use of anti-TNFs was associated with more favorable outcomes. Further investigation clarifying the mechanisms of these disparate observations could help identify risk and adverse outcome-mitigating strategies for patients with IBD.


Introduction
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus that caused the coronavirus disease 2019 (COVID- 19) outbreak. In December 2019, the first reported case of SARS-CoV-2 presented as pneumonia of unknown etiology in Wuhan, Hubei province, China. 1,2 Since then, it has spread rapidly leading to a large number of infections and deaths worldwide. The World Health Organization (WHO) declared a pandemic state that led to various national and international authorities to impose restrictions, including total lockdown, to prevent the spread of the virus. 3 The infection with the virus ranges from asymptomatic to a wide range of clinical manifestations including fevers, chills, gastrointestinal manifestations, pneumonia, respiratory distress, and death. As of July 2021, there were over 190 million cases with over 4 million deaths worldwide. In the United States alone, there are over 600,000 deaths due to  Inflammatory bowel diseases (IBD), predominantly comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, idiopathic, immune-mediated inflammatory disorders of the digestive tract affecting nearly 3 million Americans and over 3 million people in Europe. [5][6][7] The pathogenesis of both CD and UC is thought to be driven by dysregulated immune response towards gut mucosa and intestinal flora in a genetically susceptible host. 7 Treatment of IBD is aimed at controlling an overactive immune response, which may involve use of immune modifying therapies including immunomodulators or biologic drugs. Many of these treatments are associated with known increased risks of infections, potentially posing an increased risk of infection with SARS-CoV-2, as well. 8 Since the beginning of the pandemic, immunocompromised individuals were deemed at risk of acquiring the infection and possibly a more severe form of it. 9 However, the actual risk of infection or development of COVID-19 in these at-risk patients with IBD or those on immunosuppressive treatments for IBD is not clear. Additionally, it is not known whether any dose adjustments are appropriate to mitigate these risks without altering the maintenance of remission leading to complications from the disease. 8,10 Throughout the ongoing COVID-19 pandemic, the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has provided guidance on the management of IBD, such as the encouragement to continue biologic therapies and only temporarily holding them when infected. 10 However, as more data emerge, our understanding on COVID-19 and its clinical implications in IBD are rapidly evolving. We performed a systematic review and metaanalysis to investigate the evolving epidemiology, clinical characteristics, therapeutic options, and outcomes in IBD patients with COVID-19.

Methods
We conducted a systematic review with a predefined protocol in accordance with the Cochrane Handbook and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 11

Search Strategy
We searched PubMed, EMBASE, Cochrane Central, Clinicaltrials.gov, Web of Science, MedRxiv, and Google Scholar from inception through October 2020 to identify studies that had IBD patients with confirmed COVID-19. The medical subject heading (MeSH) terms used were coronavirus disease 19, COVID-19, SARS-CoV-2, inflammatory bowel disease, ulcerative colitis, Crohn's disease, IBD, UC, CD, in conjunction with operators AND or OR. Studies from search results were uploaded to Covidence for screening and inclusion. Two investigators independently screened titles and abstracts of the studies and included them for full-text review. Subsequently, full text studies were reviewed independently by 1 reviewer, with confirmation and review by another reviewer. Conflicts were resolved through adjudication by consensus discussion with a third reviewer.

Selection Criteria
All studies and case series that met the following criteria were included: (1) any adult patient with a confirmed diagnosis of IBD; and (2) any patient in the study population with a confirmed COVID-19 diagnosis with positive diagnostic test. Literature reviews, systematic reviews and/or meta-analyses, studies that included pediatric population (younger than 18 years old), and editorials were excluded. There were no language or geographic restrictions.

Data Extraction
Data were independently abstracted by 2 authors. Data were collected for first author of the study, year of publication, study design, country of origin, number of participants, total number of patients with IBD, total number of IBD patients with COVID-19, patient demographics (age, sex), type of IBD, comorbidities, active smoking, ongoing treatment for IBD at the time of COVID-19 infection (eg, corticosteroids, 5-aminosalicylate , immunomodulator, biologic therapy), symptom at presentation, treatment offered for COVID-19, and clinical outcomes (hospitalizations, intensive care unit [ICU] admissions, or deaths). Case reports were included in the initial search but were excluded in the metaanalyses.

Assessment of Study Quality
All included studies were cohort, nonrandomized studies. Hence, the Newcastle-Ottawa Scale (NOS) was used to assess the quality of the studies. The NOS score ranged from 0 to 9 based on 8 items that included selection (representativeness of the exposed cohort, selection of nonexposed cohort, ascertainment of exposure, the demonstration that outcome of interest was not present at the start of study); comparability (comparability of the cohort on the basis of design or analysis); and outcome (assessment of outcome, whether follow-up was long enough for outcomes to occur, adequacy of follow-up cohorts). For each criterion fulfilled, 1 star can be awarded to the study in question, except for comparability where a maximum of 2 stars can be awarded. The NOS score of 6 and higher were high-quality studies, and 3 and lower were low-quality studies.

Statistical Analysis
The prevalence of COVID-19 infections was estimated using the total number of COVID-19 infections divided by the total number of individuals. Studies that reported only COVID-19-positive patients were excluded from prevalence estimations. Meta-analyses using random effects models were performed to compare therapeutic classes (corticosteroids, 5-ASA, immunomodulator, biologic agent) and their relative risk of the primary outcomes (hospitalization, ICU admission, death). For comparability within the same study population, each meta-analysis only included studies that fully reported data on the compared medications and particular outcome of interest. Heterogeneity was assessed qualitatively and quantitatively using χ 2 and I 2 statistics. An I 2 <25% was considered low heterogeneity, 25% to 50% moderate heterogeneity, and >50% substantial heterogeneity. Statistical analyses were performed using R 4.0 and RevMan 5.4.

Study Characteristics
The PRISMA flowchart of the search results is detailed in the Figure 1. A total of 5393 articles were identified through the search with PubMED Medline resulting in 260 results, Embase with 339 results, Cochrane Central with 6 results, Clinicaltrials.gov with 13, Web of Science with 116, MedRxiv with 29, and Google Scholar with 4630-results out of which the first 200 were saved for screening. After excluding duplicates, 468 were included for title and abstract review, and 85 studies were included for full-text review. After full-text review, an additional of 39 studies were excluded ( Figure 1). Finally, 41 studies were included for abstraction, including the SECURE-IBD registry and 18 individual case reports that were not included in the meta-analysis.

Patient Demographics and Characteristics
A total of 23 studies with 51,643 IBD patients and 1449 with confirmed COVID-19 met our inclusion criteria (Table  1). Additionally, there were 18 case reports with a total of 19 IBD patients with confirmed COVID-19 cases (Table 1).  and Outcomes in Patients With Inflammatory Bowel Disease: Systematic Review and Meta-Analysis
Subgroup meta-analysis comparing thiopurines and methotrexate did not reveal any differences in risk of hospitalization, ICU admission, or death; although the comparisons were limited by sparse data (Supplementary Figure 4). Data on ustekinumab and vedolizumab were sparse, so metaanalysis could not be performed.

Heterogeneity
In the meta-analyses, there was no evidence of significant statistical heterogeneity, and most had low to moderate degree of heterogeneity, except for substantial heterogeneity (I 2 = 65%) in the comparison between immunomodulators and corticosteroids for the outcome of death. Qualitatively, included studies were similar in demographics; however, study population was heterogenous from different parts of the world. All included studies were retrospective and were similar in methodologies.

Study Quality
All included studies were assessed for quality using the NOS. Two studies scored 8 and above (high quality for assessing outcomes) and were included. 20,26 There were 4 studies with moderate quality that scored 7 points; of these, 3 were included. 15,18,34 There were 9 studies with low quality that scored 6 points; of these, 4 were included in the analyses. 12,19,30,31 Studies scoring 5 and lower were not included due to lack of outcome of interest (Table 3).

Discussion
This systematic review aimed to investigate the epidemiology and outcomes of COVID-19 among IBD patients. Across studies that provided data on patients with and without COVID-19, the pooled infection prevalence was 1%.
The prevalence is variable depending on a given time point, but to provide context, varied from 0.4% to 0.7% in earlier studies. 53,54 A third of IBD patients who contracted COVID-19 required hospitalization, and fewer than 4% required admission to the ICU. Mortality in this specific population was also low at 2.5%. Our study also found an association between use of 5-ASA compounds and increased risk of adverse outcomes, including hospitalization, ICU admission, and death. By contrast, use of biologic therapy was associated with lower risk of these adverse outcomes.
The SECURE-IBD trial recently showed that combination therapy and thiopurines may be associated with an increased risk of severe COVID-19; however, there was no significant difference in severe infections when comparing different classes of biologics. 55 With this anecdotal evidence from the SECURE-IBD registry, Feldman et al proposed to use anti- TNFs under clinical trials in patients who are at high risk of developing severe infection to prevent worse outcomes. 56 The findings from our meta-analysis is consistent with those published by Burke et al in January 2021, which states that the use of biologics is associated with preferable outcomes in patients with COVID-19 infection, most likely due to reduction in the cytokine storm. 53 Of patients receiving anti-TNFs, 12.9% required hospitalization, with less than 1% deaths. Hence, it appears safe to continue biologics in IBD patients who are in remission or in process of achieving remission. This would prevent disease-related adverse outcomes and possibly prevent loss of drug from the therapeutic armamentarium for the patient, as discontinuation and missed doses can lead to formation of antibodies. 57 The use of 5-ASA leading to worse clinical outcomes in IBD patients with COVID-19 is not well understood. The 5-ASA compounds act on peroxisome proliferator-activator gamma receptors (PPAR-y) to alleviate the ongoing inflammatory response. COVID-19 infection is typically accompanied by an aggressive inflammatory response, with the release of large amount of pro-inflammatory cytokines, known as the "cytokine storm." 58 This cytokine storm directly correlates with lung injury, multi-organ failure, and ultimately, unfavorable outcomes due to severe disease. 58,59 Although immunomodulators and biologic medications are linked to an increased risk of infections, their suppressive effect on the cytokines involved during inflammation in IBD might help suppress the hyperactivation of T cells and the cytokine storm that occurs during COVID-19. 60 Alternatively, it is possible that patients on biologic therapies have been much more cautious about infection precautions than those on less immunosuppressive therapies. In our recent multicenter survey of 323 adults with IBD during the COVID-19 pandemic, use of biologic therapy was associated with increased perception of risk and decreased activity when compared with those not on biologic therapy. 61 Additionally, reporting bias remains a concern for patients on 5-ASA, as these patients may not report mild/early symptoms of COVID-19 when compared with those on immunosuppressive medications such as anti-TNFs. These factors may have led to less outdoor activity, less physical interaction with others, and increased precautions with socializing in this subset of population.
This study is thus far the most extensive and up-to-date systematic review with meta-analysis evaluating the epidemiology and outcomes of IBD patients with COVID-19. We nonetheless acknowledge several limitations. First, not every study reported the outcome of interest. Second, we were unable to control for potential selection bias or unmeasured confounders, such as smoking, corticosteroid use, or med- ical practices. Third, at the time of the review, there were no randomized trials on medications with our outcomes of interest. Fourth, given that the SECURE-IBD registry aggregates data worldwide, there is a chance of data duplication, which cannot be eliminated. Some estimates may thus be inappropriately strengthened. However, the included studies are reported from a very diverse and heterogenous population from different parts of the world, which may inherently have different disease characteristics and outcomes based on the native population or regional practices. This diversity in study population improves generalizability of our findings.
In conclusion, the prevalence of COVID-19 in IBD patients was low; however, our ability to obtain an accurate denominator for global prevalence is limited due to limitations in available studies and their respective regions. The use of mesalamine was significantly associated with worse outcomes including higher hospitalization rates, ICU admissions, and deaths, though the use of anti-TNFs was associated with favorable hospitalization and mortality outcomes. Although more data are needed to clarify the validity of these differential effects, our findings at least indicate that anti-TNF therapy is not associated with increased risk of adverse outcomes, and in general, patients with IBD should continue their maintenance biologic therapies. No recommendations regarding mesalamine therapies can be made at this time until the significance is better understood. Further investigation clarifying the mechanisms of these disparate observations could help identify risk and adverse outcome-mitigating strategies for patients with IBD.

Supplementary Data
Supplementary data is available at Inflammatory Bowel Diseases online.