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Risk of adverse outcomes in inflammatory bowel disease patients infected with SARS-CoV-2: a systematic review and meta-analysis

Background Between people with and without inflammatory bowel disease (IBD), there was no statistically significant difference in the probability of contracting the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the risk of adverse outcomes in IBD patients after virus infection remains unclear. Methods Eligible studies conducted from January 1, 2020 to March 17, 2022 were obtained by searching PubMed, Embase, and Web of Science. Information was collected in tables from the included studies. Random-effects and fixed-effects models were used as measures for the pooled estimates. All data were estimated by R version 4.1.3. Results Twenty-four studies were included. The risk ratio (RR) of adverse outcomes in COVID-19 patients with IBD increased by 32% (RR 1.32; 95% CI 1.06–1.66) relative to COVID-19 patients without IBD. The RR of mortality was higher in COVID-19 patients with IBD from Europe (RR 1.72; 95% CI 1.11–2.67) than in those that were not from Europe (RR 1.00; 95% CI 0.79–1.26; χ2 = 4.67; P = 0.03). Patients with ulcerative colitis were at higher risk of adverse outcomes after SARS-CoV-2 infection than patients with Crohn’s disease patients (RR1.38; 95% CI 1.27–1.50). The IBD drugs treatment was associated with the risk of adverse outcomes, the pooled odds ratio (OR) of mesalazine (1.79; 95% CI 1.59–2.02), immunomodulators (1.30; 95% CI 1.10–1.53), and anti-TNF (0.47; 95% CI 0.41–0.53) were assessed. Conclusion COVID-19 patients with IBD had an increased risk of adverse outcomes than those without IBD, whereas anti-TNF treatment might reduce the risk. Supplementary Information The online version contains supplementary material available at 10.1007/s00384-022-04265-w.


Introduction
The coronavirus disease 2019 (COVID-19) has exerted the most significant impact on human health among the epidemics in the last 100 years [1,2]. As of May 29, 2022, more than 526 million people had been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and over six million died due to the virus [3]. Preliminary studies have shown that advanced age, being male, high BMI, and pre-existing chronic diseases increase the risk of developing adverse forms and fatal outcomes [4,5]. The entry of SARS-CoV-2 into host cells depend on the interactions of viral spike protein and angiotensin-converting enzyme 2 (ACE-2) [6,7]. Thus, high ACE-2 expression levels in intestinal epithelial cells and SARS-CoV-2 may cause intestinal symptoms or results in poor prognosis in patients with chronic intestinal diseases [8][9][10][11].
Inflammatory bowel disease (IBD) refers to a group of disabling chronic and immune-mediated inflammatory disorders including ulcerative colitis (UC) and Crohn's disease (CD) and is associated with human immune system [12]. In 2017, approximately 6.8 million patients with IBD were recorded worldwide [13], including 2 million from Europe and 1.5 million from North America [14]. Notably, ACE-2 expression increases in patients with IBD, particularly in the colonic tissue of patients with UC [8,15], which might enable SARS-CoV-2 infection and cause poor outcomes Long Chen and Kai Hu these authors contributed equally. 1 3 [16]. The intestine might serve as an entry point for serious COVID-19 complications, such as endotoxemia and thrombosis [17]. In addition, a significant proportion of patients with IBD are treated with IBD drugs, including mesalazine, corticosteroids, immunomodulators (IMs), and anti-TNF, which may be associated with low immunity in patients and increased risk of COVID-19 infection and adverse outcomes [18][19][20][21].
Given these premises, a much-debated question is whether patients with IBD are at increased risk of being infected by COVID-19 and developing adverse outcomes [22][23][24][25][26][27]. Currently, the world is going through massive waves of infections by the omicron and delta variants of SARS-CoV-2, and the vast majority of people seem to be susceptible to the omicron variant [28]. Although the virulence of this variant has weakened and disease severity has been reduced through vaccination [29], the vast waves of omicron infections have indicated increasing number of adverse outcomes [28], especially in people with underlying diseases [30][31][32]. Therefore, focusing on adverse outcomes, such as hospitalization, intensive care unit (ICU), and mortality in COVID-19 patients with IBD in the context of high infectivity of SARS-CoV-2 is critical.
To date, the risk of adverse outcomes in patients with IBD after SARS-CoV-2 infection is contradictory in different studies [25][26][27]33], and a meta-analysis assessed this risk in COVID-19 patients with and without IBD has not been conducted. Therefore, we performed the meta-analysis. Then, the association between adverse outcomes and IBD drug treatment in COVID-19 patients with IBD was explored.

Selection criteria
We used the PECO strategy (patient, exposure, comparison, outcome) in constructing research questions and searching evidence. The meta-analysis adopted the following inclusion criteria: (a) prevalence of adverse outcomes in COVID-19 patients with and without IBD can be calculated; (b) prevalence of adverse outcomes in patients suffering from different types of IBD (UC and CD) and infected with SARS-CoV-2 can be calculated; or (c) provided medication status (mesalazine, corticosteroids, IMs, and anti-TNF) in adverse and mild cases.
Adverse outcomes were defined as requiring hospitalization, invasive ventilation, or intensive care unit (ICU) admission, or death [34], and mild outcomes were defined as presenting with mild or no symptoms of COVID-19 and without adverse outcomes. The study included cross-sectional, cohort, case-control, and case series studies. Animal experiments, literature without complete original data and no access to original data, and single case reports were excluded.

Data extraction and quality assessment
First, two authors (CL and HK) independently analyzed the titles and abstracts to exclude irrelevant studies. Subsequently, the full texts of the included studies were further reviewed. In the case of any disagreement, a third reviewer was consulted (CC).
The following pieces of information were extracted from the included studies: first author, study name, type of study design, publication year, country, number of COVID-19 patients with IBD, number of adverse outcomes in patients with IBD, number of comparators (COVID-19 patients without IBD), number of comparators with adverse outcomes, type of IBD (UC and CD), demographic information (age, gender, and comorbidity), and ongoing IBD treatments, including mesalazine, corticosteroids, IMs (including azathioprine, mercaptopurine, and methotrexate), and anti-TNF. The Newcastle-Ottawa scale (NOS) was used in evaluating the quality of eligible studies [35]. Each study has a maximum score of nine (highest quality), and a NOS score of ≥ 6 indicated high quality.

Data analysis
The RR was used as a unified effect size for assessing the risk of adverse outcomes in COVID-19 patients with IBD and those without and in patients with UC or CD. And the odds ratio (OR) was used in estimating the association between IBD drugs and adverse outcomes. Random-effects models (I 2 > 50%) and common-effects models (I 2 ≤ 50%) 1 3 were used in estimating the pooled adjusted effect, and Q test and I 2 statistics were used in assessing heterogeneity among the studies. An I 2 value of < 25% demonstrated no heterogeneity among the studies, 25-50% indicated low heterogeneity, and > 50% indicated moderate-to-high heterogeneity. For subgroup analyses, the studies were stratified by region, the source of the population, gender, age, disease type, and sample size. We further conducted sensitivity analysis by sequentially eliminating each study to assess the stability of the results. Egger's test and funnel plots were used in evaluating publication bias.
A two-tailed P < 0.05 was considered statistically significant in all the analyses, which were performed with R version 4.1.3 and RStudio (the integrated development environment of R) with meta-packages.

Study selection and characteristics
The exclusion and inclusion processes for articles are presented in Fig. 1. A total of 2638 articles were identified in the databases. After duplicates were excluded, titles and abstracts of 2121 articles were screened, and full-text reading was performed in 223 studies. Finally, 24 articles met the inclusion criteria, and data from the SECURE-IBD registry were included (date of last update: January 25, 2022). Nine studies evaluated the risk of adverse outcomes in patients with IBD and COVID-19 and comparative population, and 14 studies evaluated the risk in patients with UC or CD. a total of 15 studies analyzed IBD drug exposure in adverse  and mild cases. Among these studies, 13 were conducted in European countries, seven in North American countries (six in the USA and one in Canada), three in Asia, and one in multiple healthcare organizations. Table 1 provides the included studies' main characteristics, including type of research, location, publication date, number of subjects, use of IBD drugs, comorbidities, types of inclusion criteria (a, b, and c), and NOS score. Among the included studies, 20 respected the NOS for good-quality research, and three case series and one cross-sectional study had unclear answers.

Risk of adverse outcomes in COVID-19 patients with IBD versus comparative population
Nine studies regarded IBD as the exposure factor in COVID-19 patients and adverse effects as outcomes [18,22,25,26,[36][37][38][39][40]. A total of 7280 COVID-19 patients with IBD and 635,363 COVID-19 patients without IBD served as the comparative populations, including a matched population adjusted for age, gender, and comorbidities and the general population in the same period. In the comparison of the risk of adverse outcomes in COVID-19 patients with IBD and comparators, the pooled RR was 1.32 (95% CI 1.06-1.66), and heterogeneity was high (I 2 = 81%; P < 0.01; Fig. 2). The results of Egger's test indicated no evidence of publication bias (P = 0.72). In subgroup analyses performed according to the source of comparators (matched and general population), the pooled RRs of adverse outcomes were 1.20 (95% CI 1.12-1.29; I 2 = 40%; P = 0.13) in the control population group and 1.74 (95% CI 0.87-3.50; I 2 = 77%; P = 0.04; Fig. 2) in the general population group.

Subgroup and sensitivity analyses
Subgroup analyses defined by age, region, sample size, source of comparators (control and general population), gender, and type of IBD were associated with the risk of adverse outcomes ( Table 2). In subgroup analyses of the source of the comparators, the pooled RR was 1.20 (95% CI 1.12-1.29) with mild heterogeneity (I 2 = 40%; P = 0.13) in the control population group, and the pooled RR was 1.74 (95% CI 0.87-3.50) with high heterogeneity (I 2 = 77%; P = 0.04) in the general population group. Therefore, the different sources of comparators may account for the high heterogeneity.
In sensitivity analysis, none of the individual studies led to a substantial change in pooled risk in the leave-one-out analysis removing one study in turn ( Supplementary Fig. 3).

Discussion
During the SARS-CoV-2 pandemic, IBD patients, as immune-mediated disease patients, should be treated more carefully than the general population. Until now, many patients with IBD did not receive or complete vaccines because of concerns about adverse reactions to vaccines, and the effectiveness of vaccines may wane more rapidly in patients with IBD [53][54][55]. Accumulating evidence of poor prognosis in patients with other diseases accompanied by IBD and increased risk of developing malignancies in these patients has been obtained, such as myocardial infarction and hematological malignancies [56][57][58]. Therefore, the risk of hospitalization, death, and other adverse outcomes in patients suffering from IBD and infected with SARS-CoV-2 should be an ongoing concern.
To the best of our knowledge, this study is the first metaanalysis to evaluate the risk of adverse outcomes between COVID-19 patients with and without IBD. In this study, we found that COVID-19 patients with IBD were at increased 1 3 risk for adverse outcomes than those without IBD. Furthermore, patients with UC have an increased risk than those with CD. Moreover, COVID-19 may intersect with the pathogenesis of IBD and extend treatment. As a result, mesalazine (5-ASA) and IMS treatment might be risk factors for adverse outcomes in COVID-19 patients with IBD.
By contrast, anti-TNF treatment might provide protection against the development of negative outcomes.
On subgroup analyses of the source of comparators (control and general population group), there is a pooled RR with low heterogeneity in control population group adjusted for age, gender, and comorbidities. Inconsistency in the distribution of these confounders may account for the heterogeneity.
The increased risk of adverse outcomes in patients with IBD may be associated with increased SARS-CoV-2 replication and imbalance of ACE-2 levels in the intestine. On the one hand, the intestines of IBD patients with high ACE-2 expression may provide favorable sites for virus replication. On the other hand, ACE-2 not only is a SARS-CoV-2 binding receptor but also acts as an enzyme in the renin-angiotensin system to reduce inflammatory response [59,60]. The renin-angiotensin system functions in inflammation, fibrosis, and cell proliferation in opposite roles regulated through two complementary pathways (classical and alternative) [61,62]. The ACE-2/Ang 1-7/MasR axis can reduce proinflammatory response and cytokine storm in the renin-angiotensin system [63]. Recent studies have revealed that the key enzymes of the system (ACE and ACE-2) were expressed and active in the human intestine [62,64]. As a result of binding to virus, ACE-2 in the guts of patients with IBD may be severely depleted [65], and this effect may result in an imbalance in the renin-angiotensin system that promotes fibrosis and inflammatory response and has negative effects.
Similarly, differences in ACE-2 expression levels in the guts of patients with UC or CD may account for differences in the risk of developing adverse outcomes. In contrast to the results of our study, UC patients without COVID-19 were not at increased risk of developing adverse outcomes in contrast to CD patients without COVID-19 [66,67]. These findings were consistent with the meta-analysis results. In addition to the above reason, UC patients may prefer 5-ASA [68], an IBD drug associated with high risk of developing adverse outcomes. In our study, 5-ASA and IMS treatments might be risk factors for adverse outcomes in COVID-19 patients with IBD. By contrast, anti-TNF treatment might protect against the development of negative outcomes. Notably, reduced small bowel but elevated colonic ACE-2 levels in IBD patients were associated with adverse outcomes but returned to normal after anti-TNF therapy [69]. Although evidence showing the risk of adverse outcomes in IBD patients treated wtih corticosteroids is insufficient, previous studies have shown that corticosteroids should be selected carefully [70,71].
Our study has some limitations. Nevertheless, it has offered a comprehensive review of the risk of adverse outcomes in IBD patients after being infected with SARS-CoV-2, in patients with UC or CD, and in patients using different IBD treatment drugs. First, many small case series were included in our meta-analysis, including four studies with quality not evaluated using the NOS. Second, heterogeneity in our meta-analysis was high, which is a general limitation of all published COVID-19 studies. Third, some studies showed data duplication in reporting adverse outcomes, such as hospitalization, ICU admission, and death. In these studies, the number of patients hospitalized or admitted to ICUs was the number of patients with adverse outcomes, and some patients who died but were not hospitalized may have been not included.
In conclusion, this systematic review and meta-analysis shows that COVID-19 patients with IBD have a higher risk of developing adverse outcomes than patients without IBD. The 5-ASA and IMS treatments may be associated with high risk of adverse outcomes in COVID-19 patients with IBD, whereas anti-TNF treatment can reduce this risk.
Author contribution LC and KH were responsible for the conception and design of the work and the drafting of the manuscript; LC, KH, and CC analyzed the data; QH, LZ, TA, YG, SC, GD revised the manuscript. All authors read and approved the final manuscript.
Funding This work was supported by the National Natural Science Foundation of China (82073618) and Epidemic Prevention and Control Research and Development projects in Henan Province (211100310900).