key: cord-1028408-v7vjidq5
authors: Bezzio, Cristina; Armuzzi, Alessandro; Furfaro, Federica; Ardizzone, Sandro; Milla, Monica; Carparelli, Sonia; Orlando, Ambrogio; Caprioli, Flavio Andrea; Castiglione, Fabiana; Viganò, Chiara; Ribaldone, Davide Giuseppe; Zingone, Fabiana; Monterubbianesi, Rita; Imperatore, Nicola; Festa, Stefano; Daperno, Marco; Scucchi, Ludovica; Ferronato, Antonio; Pastorelli, Luca; Balestrieri, Paola; Ricci, Chiara; Cappello, Maria; Felice, Carla; Fiorino, Gionata; Saibeni, Simone
title: Therapies for inflammatory bowel disease do not pose additional risks for adverse outcomes of SARS‐CoV‐2 infection: an IG‐IBD study
date: 2021-10-25
journal: Aliment Pharmacol Ther
DOI: 10.1111/apt.16663
sha: dba77dd98966b20fa77883474e316355c38c1469
doc_id: 1028408
cord_uid: v7vjidq5

BACKGROUND: Older age and comorbidities are the main risk factors for adverse COVID‐19 outcomes in patients with inflammatory bowel disease (IBD). The impact of IBD medications is still under investigation. AIMS: To assess risk factors for adverse outcomes of COVID‐19 in IBD patients and use the identified risk factors to build risk indices. METHODS: Observational cohort study. Univariable and multivariable logistic regression was used to identify risk factors associated with pneumonia, hospitalisation, need for ventilatory support, and death. RESULTS: Of the 937 patients (446 with ulcerative colitis [UC]) evaluated, 128 (13.7%) had asymptomatic SARS‐CoV‐2 infection, 664 (70.8%) had a favourable course, and 135 (15.5%) had moderate or severe COVID‐19. In UC patients, obesity, active disease and comorbidities were significantly associated with adverse outcomes. In patients with Crohn's disease (CD), age, obesity, comorbidities and an additional immune‐mediated inflammatory disease were identified as risk factors. These risk factors were incorporated into two indices to identify patients with UC or CD with a higher risk of adverse COVID‐19 outcomes. In multivariable analyses, no single IBD medication was associated with poor COVID‐19 outcomes, but anti‐TNF agents were associated with a lower risk of pneumonia in UC, and lower risks of hospitalisation and severe COVID‐19 in CD. CONCLUSION: The course of COVID‐19 in patients with IBD is similar to that in the general population. IBD patients with active disease and comorbidities are at greater risk of adverse COVID‐19 outcomes. IBD medications do not pose additional risks. The risk indices may help to identify patients who should be prioritised for COVID‐19 re‐vaccination or for therapies for SARS‐CoV‐2 infection.

Over the past year, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world. 1 Research into the pathology of SARS-CoV-2-induced coronavirus disease 2019 (COVID- 19) has revealed that the immune system plays two crucial roles in the infection: it controls viral replication in the early stage, and it overproduces pro-inflammatory cytokines in patients who go on to develop severe disease. 2 Thus, physicians who care for patients with immune-mediated inflammatory diseases (IMID) are concerned about the impact that COVID-19 could have on these patients.

Like all IMIDs, the two main types of inflammatory bowel disease (IBD), namely ulcerative colitis (UC) and Crohn's disease, are characterised by an abnormal functioning of the innate and adaptive immune systems, leading to a chronic, progressive condition. From emerging data, the incidence and prevalence of SARS-CoV-2 infection in IBD patients are not different from those in the general population. [3] [4] [5] [6] [7] Additionally, the prevalence of adverse COVID-19 outcomes, namely pneumonia, hospitalisation, intensive care unit admission and death, appears to be similar to that in the general population. [4] [5] [6] [7] [8] [9] Numerous studies that investigated risk factors for adverse COVID-19 outcomes in IBD patients concordantly found similarities with those in the general population, namely older age [6] [7] [8] [9] [10] [11] [12] and presence of comorbidities. 3, 6, [8] [9] [10] 12, 13 However, in the assessment of IBD-related factors, discordant results were obtained. For example, some studies reported that disease activity was a risk factors for adverse outcomes of SARS-CoV-2 infection, 9, 12 while other studies identified treatment with corticosteroids, 8, 11, 14 aminosalicylates, 11, 13 and thiopurines (alone or in combination with anti-TNFα agents) 13 as risk factors. These discrepancies may be due to insufficient numbers of cases or differences in epidemiological methodology.

The ongoing SARS-CoV-2 vaccination program has also raised an important clinical question about the eligibility of IBD patients for priority access to primary vaccination and booster doses. On one hand, this decision could be supported by evidence of a lower serological response to vaccines or natural infection, related to either IBD itself 15 or IBD therapies, namely anti-TNF agents. 16, 17 On the other hand, if priority access is granted to people at higher risk of adverse COVID-19 outcomes, should this apply to some or all IBD patients? To answer this question, this observational study investigated risk factors for adverse COVID-19 outcomes in a large, nation-wide cohort of IBD patients, and used multivariable analyses to build indices to identify patients at the relatively highest risk. The risk indices may help to identify patients who should be prioritised for COVID-19 re-vaccination or for therapies for SARS-CoV-2 infection. entered into an electronic database accessible to participating centres.

Analyses were conducted using SPSS Statistical Software (v. 13.0, IBM). Differences in quantitative variables at baseline between UC and CD patients were tested for significance using the t test.

Associations between the type of IBD and categorical variables (baseline characteristics and symptoms of COVID-19) were tested for significance using the chi-square test. A two-tailed P < 0.05 was indicative of statistical significance.

Risk factors for moderate-to-severe COVID-19 outcomes were identified by logistic regression with univariable and multivariable analyses. Multivariable analyses were adjusted for confounding factors that could simultaneously impact upon another variable and the outcome (eg elderly patients are uncommonly prescribed anti-TNF agents, so the use of these drugs was adjusted for age). Confounding factors were selected according to the literature [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] and to reports by the Italian national health service on causes of death from COVID-19

in the general population and in IBD patients. 21 The confounding factors selected to adjust the regression analyses were therefore age, comorbidities, IMID and disease activity. Logistic regression was also used to assess the impact of medications on COVID-19 outcomes.

Variables that were retained in the multivariable analyses at P < 0.05 were used to build an index for the risk of moderate-to-severe COVID-19 in IBD patients. The coefficients from the multivariable analysis were used to assess the weight of each variable retained in the model and to calculate the index. We tested the sensitivity, specificity, and positive and negative likelihood ratios of this index using the clinical data from our population. ROC curve analysis was used to set the most sensitive and specific cut-off to identify IBD patients with infection by SARS-CoV-2 at risk of moderate-to-severe COVID-19.

We enrolled 937 IBD patients with a confirmed SARS-CoV-2 infection ( (2.7%) died. The rates of all adverse COVID-19 outcomes, but death, were significantly higher in UC patients than in CD patients ( Figure S1 ).

In UC patients, the variables found to be predictive of moderate or severe outcomes at univariable analysis were age (per unit increase, P < 0.001), active disease of any severity (P = 0.001), obesity (P < 0.001), arterial hypertension (P = 0.01), and CCI (per unit increase, P < 0.001) (Table S2) . At multivariable analysis, active disease (P < 0.001), obesity (P < 0.001), and CCI (P < 0.001) were significantly associated with a moderate or severe outcome. Univariable analyses in CD patients identified age (P < 0.001), obesity (P = 0.008), IMID (P < 0.001), and CCI (P < 0.001) as associated with moderate or severe outcomes, while multivariable analysis indicated age (P = 0.01), obesity (P = 0.02), and IMID

Regression analyses were repeated looking specifically at the risk of COVID-19-related pneumonia ( Table 2) . For UC patients, univariable analyses identified age ≥60 years, active disease of any severity, obesity, hypertension and CCI ≥2 as associated with the risk of pneumonia, and multivariable analyses found that active disease (OR = 1.88), obesity (OR = 23.76), and CCI ≥2 were associated with the risk of pneumonia. For CD patients, age ≥60 years, obesity, concomitant IMID, and a CCI ≥2 were significantly associated with pneumonia in the univariable analysis, whereas in the multivariable analysis only obesity (OR = 6.54) and concomitant IMID (OR = 3.52)

were associated with the risk of pneumonia.

Regarding hospitalisation (Table 2 ), in UC patients, age ≥60 years, active disease of any severity, obesity, hypertension and CCI ≥2 were found to be associated with risk in univariable analyses. In multivariable analyses adjusted for confounders, only active disease (OR = 1.92), obesity (OR = 22.8) and CCI ≥2 points (OR = 3.97) were found to be associated with the risk of hospitalisation. In CD patients, age ≥60 years, obesity, a concomitant IMID and CCI ≥2 were significantly associated with hospitalisation at the univariable analysis; at the multivariable analysis adjusted for confounders, only concomitant IMID (OR = 2.26) was found to be associated with the risk of hospitalisation.

A final analysis investigated the risk of severe COVID-19 outcomes (need for ventilatory support or death; Table 2 ). In UC patients, age ≥60 years, male sex, active disease of any severity, obesity, hypertension and CCI ≥2 were found to be associated with the risk of severe COVID-19; at the multivariable analyses adjusted for confounders, age ≥60 years (OR = 2.57), male sex (OR = 2.85), active disease (OR = 2.03), obesity (OR = 20.34), and CCI ≥2 (OR = 1.53) were associated with the risk of severe COVID-19.

In CD patients, age ≥60 years, obesity and CCI ≥2 were significantly associated with severe COVID-19 at univariable analyses; at multivariable analyses adjusted for confounders, only obesity (OR = 12.07) and CCI ≥2 (OR = 1.77) were associated with the risk of severe COVID-19.

These results are shown in Table 3 .

In the UC population, at univariable analysis, the use of anti-TNF agents was associated with significantly lower risks of COVID-19, pneumonia, and severe COVID-19. Similarly, in CD patients, the use of anti-TNF agents was associated with significantly lower risks of COVID-19, 

Based on the multivariable analyses for moderate-severe COVID-19 outcomes, we built two risk indices that sum the contributions of 

In this study, the majority of IBD patients had an asymptomatic (13.7%) or favourable course (70.8%) of SARS-CoV-2 infection.

However, UC patients were more likely than CD patients to have symptoms and to develop moderate or severe COVID-19. Among the 145 patients who had moderate or severe COVID-19, age ≥60 years, male sex, obesity, arterial hypertension and another concomitant IMID were risk factors for an adverse outcome. Considering variables related to IBD, disease activity of any severity was an additional risk factor, but no single IBD medication was found at multivariable analysis to be associated with adverse COVID-19 outcomes. On the contrary, anti-TNF agents were associated with a lower risk of pneumonia in UC patients and with lower risks of hospitalisation and severe COVID-19 in CD patients.

Overall, our findings confirm that the course of COVID-19 in IBD patients is similar to that observed in the general population. [3] [4] [5] [6] [7] Moreover, they confirm that the general risk factors for worse out- findings of previous studies. 8, 11, 13 Due to the small subgroup of patients in combination therapy with anti-TNF agents and immunosuppressants, we are not able to draw conclusions about its reported potential negative impact. 13 The potential protective role of anti-TNF agents could be due to their downregulation of ACE2 expression in the intestine, 22 their known effects on cytokine storms, 23 or to a general dampening of the inflammatory response during the hyperimmune phase of the infection. 2

Our study did not find an association between salicylates and COVID-19 outcomes, once confounders were eliminated through multivariable analysis. This finding is in apparent contrast to reports of an association between salicylate use and a negative course of SARS-CoV-2 infection from the SECURE-IBD international registry. 11, 13 This potential negative role of salicylates is a matter of debate: besides the theoretical plausibility, 24 it is possible that several biases led to this finding, including the fact that anti-TNF agents were used as a comparator. 25 Our study also did not find any impact of corticosteroids, in contrast to earlier studies where these drugs were negative factors for a worse outcome of COVID-19 with a possible dose-dependent effect. 8, 11, 14 

We gratefully thank Stefanos Bonovas for his contribution to the statistical analyses. Valerie Matarese provided scientific editing.

Guarantor of the article: Cristina Bezzio. 

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https://orcid.org/0000-0003-0076-8549Nicola Imperatore https://orcid.org/0000-0003-3230-6832Stefano Festa https://orcid.org/0000-0002-4635-3050Chiara Ricci https://orcid.org/0000-0002-0748-6600Simone Saibeni https://orcid.org/0000-0001-5677-2534