key: cord-0921906-zhymwxv3
authors: Ellul, Pierre; Revés, Joana; Abreu, Bárbara; Chaparro, María; Gisbert, Javier P; Allocca, Mariangela; Fiorino, Gionata; Barberio, Brigida; Zingone, Fabiana; Pisani, Anthea; Cassar, David; Michalopoulos, George; Mantzaris, Gerassimos; Koutroubakis, Ioannis; Karmiris, Konstantinos; Katsanos, Konstantinos; Ďuricova, Dana; Burisch, Johan; Madsen, Gorm Roager; Maaser, Christian; Arebi, Naila; Orfanoudaki, Eleni; Milivojevic, Vladimir; Buisson, Anthony; Avedano, Luisa; Leone, Salvo; Torres, Joana
title: Implementation and short-term adverse events of anti-SARS-CoV-2 vaccines in Inflammatory Bowel Disease patients: an international web-based survey
date: 2022-01-17
journal: J Crohns Colitis
DOI: 10.1093/ecco-jcc/jjac010
sha: 10890c2c6a756d205895f07f73f498c234c40ed8
doc_id: 921906
cord_uid: zhymwxv3

INTRODUCTION: Anti-SARS-CoV-2 vaccines clinical trials did not include patients with immune-mediated conditions such as inflammatory bowel disease (IBD). We aimed to describe the implementation of anti-SARS-CoV-2 vaccination among IBD patients, patients’ concerns and side-effect profile of the anti-SARS-CoV-2 vaccines using real-world data. METHODS: An anonymous web-based self-completed survey was distributed in 36 European countries between June and July 2021. The results of the patient characteristics, concerns, vaccination status and side-effect profile were analysed. RESULTS: 3272 IBD patients completed the survey, 79.6% had received at least one dose of anti-SARS-CoV-2 vaccine, and 71.7% had completed the vaccination process. Patients over 60 years old had a significantly higher rate of vaccination (p<0.001). Patients’ main concerns before vaccination were the possibility of having worse vaccine-related adverse events due to their IBD (24.6%), an IBD flare after vaccination (21.1%) and reduced vaccine efficacy due to IBD or associated immunosuppression (17.6%). After the first dose of the vaccine, 72.4% had local symptoms and 51.4% had systemic symptoms (5 patients had non-specified thrombosis). Adverse events were less frequent after the second dose of the vaccine and in older patients. Only a minority of the patients were hospitalized (0.3%), needed a consultation (3.6%) or had to change IBD therapy (13.4%) after anti-SARS-CoV-2 vaccination. CONCLUSION: Although IBD patients raised concerns about the safety and efficacy of anti-SARS-CoV-2 vaccines, the implementation of vaccination in those responding to our survey was high and the adverse events were comparable to the general population, with minimal impact on their IBD.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel RNA coronavirus that is known to cause acute respiratory syndrome, pneumonia and multi-organ failure.(1) This ensuing public health crisis has triggered the need for a massive global vaccination campaign, with effective vaccination against SARS-CoV-2 entailing not only the protection against the morbidity and mortality caused by the disease, but also a reversal of its associated social-economic burden.

The promising clinical trials and subsequent roll-out of the BNT162b2 (Pfizer/BioNTech), ChAdOx1 nCoV-19 (Oxford/AstraZeneca), mRNA-1273 (Moderna) and JNJ-78436735 (Johnson and Johnson) vaccines have heralded a step towards the control of the pandemic. (2) (3) (4) . However, some individuals with pre-existing conditions, such as Inflammatory Bowel Disease (IBD) patients, were excluded from the original anti-SARS-CoV-2 vaccines developmental trials and, therefore, uncertainties remain, regarding their safety and efficacy in this specific patient population. Nevertheless, international societies have published recommendations for the vaccination of these patients. (5, 6) Regarding efficacy, some studies have shown that IBD patients may have a sub-optimal response to vaccination. Patients taking anti-tumour necrosis factor (anti-TNF) drugs are considered to have a decreased immune response to other vaccines, such as those administered for influenza and viral hepatitis. (7, 8) Two recent studies have raised a concern that infliximab-treated patients may have lower seroprevalence of anti-SARS-CoV2 antibodies and lower seroconversion rates either after infection or after the first dose of the vaccine, when compared to vedolizumab-treated patients. (9, 10) Few studies have investigated potential causal relationship between anti-SARS-CoV-2 vaccine administration and disease flare-up in IBD patients, although some reassurance can A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac010 be found in the extrapolation of data from the administration of other vaccines to IBD patients. (9) However, further studies are needed to clarify the concerns and willingness of IBD patients to get vaccinated, the impact of anti-SARS-CoV2 vaccination in IBD patients' management, as well as the impact of IBD medication on vaccination safety.

Since refusal to get vaccinated with anti-SARS-CoV-2 vaccines, due to fear of side effects or due to fear of getting vaccinated can compromises the entire public health vaccination campaign against SARS-CoV-2, we aimed to report on: (i) the implementation of anti-SARS-CoV-2 vaccination among IBD patients (ii) patients' concerns and fears before vaccination, and (iii) short-term adverse events (AEs) of the anti-SARS-CoV-2 vaccines in IBD patients.

We performed a multicentre European cross-sectional survey study, with the collaboration of the European Federation of Crohn's & Ulcerative Colitis Associations (EFCCA), IBD physicians and National Patient Associations where IBD patients were invited to participate.

No exclusion criteria were defined. An anonymous structured web-based self-completed questionnaire was developed using the Research Electronic Data Capture (REDCap) and made available in 9 different languages (English, Italian, German, Spanish, Portuguese, Danish, Czech, French, Greek). The survey was distributed by IBD physicians in outpatient clinics, and online with the collaboration of different national and international patients' association groups, including EFCCA to known IBD patients. Completion of the entire questionnaire was not compulsory.

Demographic data including patients' baseline characteristics, country of origin (stratified according to the geographical sub-regions of Europe, as defined by the EuroVoc)(10), smoking status, type of IBD (Crohn's disease (CD), Ulcerative Colitis (UC) or Undefined A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac010 IBD), disease activity (inactive vs active), current treatment and previous IBD-related surgery were collected. Vaccination status against SARS-CoV-2 was assessed, including the number of doses and the type of vaccine received. Vaccination against the Influenza virus was also evaluated as to understand the overall willingness for patients to get vaccinated.

Data regarding patients' fears and concerns related to vaccination were collected, alongside local and systemic adverse events (AE) after each dose of the vaccine and its impact on professional absenteeism. The impact of the vaccine on IBD, namely exacerbation of symptoms, need for consultation, hospitalization, therapy escalation, or need for treatment readjustment (including infusion re-scheduling) was also evaluated.

Descriptive analysis for baseline characteristics was performed. Continuous variables were described as mean and standard deviation or median and inter-quartile range, as appropriate. Categorical variables were expressed as frequencies with 95% Confidence Intervals (CI) and proportions. Univariable and multivariable logistic regression analysis was performed. A p-value<0.1 in univariate analysis was used to select variables to include in multivariable models. A p-value < 0.05 was considered statistically significant. Statistical analysis was performed using Stata package version 16.

Between June 2021 and July 2021, 3272 patients from 36 European countries answered the survey. Most patients had CD (58.1%), with a median patient age of 43 years (IQR 33-54).

There was a female predominance (60.4%), and most patients (69.4%) were from southern European countries. A description of patient participation by country of origin can be found in Supplementary Hesitancy and fear regarding vaccination seem to be associated with being female, aged over 60 years old, living in a central European country and being treated with corticosteroids, in a univariate analysis (table 2) . When adjusting these variables into a multivariable logistic regression model, all predictors remained significant except treatment with corticosteroids (table 3) .

At least one dose of any vaccine against SARS-CoV-2 was reported from 79. The prevalence of vaccination stratified by baseline characteristics, disease activity and medications used is shown in table 4. Older patients were almost three times more likely of being vaccinated (OR 2.98, 95% CI 2.20-4.03, p<0.001), as opposed to younger patients. An increased implementation of vaccination was observed in patients from western Europe (89,0%), compared to those from central and eastern Europe (71.9%). There was no association between the country of origin and the chance of being vaccinated (p=0.08).

Furthermore, there was no significant difference in the vaccination rate between patients with active disease and patients in clinical remission (80.2% vs 78.6%, p=0.26). Patients taking 5-ASA medications alone, one immunomodulator, corticosteroids or tofacitinib had lower rates of vaccination when compared to those who were not taking these medications (table 2) . The most frequent AE at the injection site was pain (65.5% and 40.9% after the 1 st and 2 nd dose, respectively) and the most frequent systemic symptoms were tiredness (36.5% and 31.6%, respectively), headache (20.3% and 17.7%, respectively) and muscle pain (18.2% and 17.3%, respectively) (table 6 and table 7 No further details about the type or severity of these self-reported thrombotic events were collected in the questionnaire. On logistic regression analysis, being on immunosuppressive treatment (either corticosteroids, biologic alone, immunomodulator alone, combination therapy or small molecules) seemed to be a predictor of the development of adverse effects of the vaccine (local AE: OR 1. Almost one-fifth (19.2%, 499/2594) of the patients had to miss work at least once due to vaccination-related AE.

Ninety-four patients (3.6%) had a consultation with their IBD physician following the first dose of the vaccine. In 73.4% of the cases, these consultations were requested by the patients in view of new onset of symptoms or concerns regarding interaction between IBD medication and the vaccine. The rest (26.6%) were previously planned and scheduled appointments. Following the second dose, the number of consultations was lower (2.95%, 53/1799), but more than a half were due to relapse of IBD (62.3%, 33/53). The most frequent symptoms were increased stool frequency (12.6%, 328/2594), feeling unwell (11.3%, 294/2594) and abdominal pain (10.0%, 260/2594). In more than half of the patients (67.5%, 872/1291) symptoms subsided on their own without needing any change in medication. 

The significant public health, social, and economic impact caused by the COVID-19 pandemic has led to the rapid development of several vaccines against SARS-CoV-2 that are deemed to help control the burden caused by the disease. However, there have been some concerns regarding the use of anti-SARS-CoV-2 vaccines in IBD patients, not only related to their efficacy as highlighted by the CLARITY group, but also to their safety. (11, 12) Despite these fears, two recent studies have demonstrated that the majority of IBD patients were willing to get vaccinated, with vaccination intent being as high as 81%. (13, 14) . Furthermore, current guidance suggests that patients on immunosuppressants who In our study, we confirmed the achievement of this vaccination intent, with almost 80% of our study population having received at least one dose of the vaccine. The adherence to the anti-SARS-CoV-2 vaccine was even higher than the adherence to the Influenza vaccine in 2020 (53.3%). This may be explained by patients' awareness of the severity of COVID-19 A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac010 and the significant burden already caused by this pandemic, with the vaccine being considered a global solution to control the disease. Of those patients who did not get vaccinated, more than half (52.9%) said that SARS-CoV-2 vaccination was not offered to them and, therefore, does not directly reflect an unwillingness to be vaccinated. Rules for access to vaccination were different across countries, and in most areas, vaccination was prioritised for older people, those working in medical facilities, bearing serious co-morbidities and receiving immunosuppressive therapies.

In a multivariate logistic regression model, female gender, older age and being from a central European country were independent predictors of fear of being vaccinated. Older age is also consistent with the fact that at the time of the survey most countries were prioritising the older population. Despite this, global vaccination rates across all these groups were above 70% and 97% of the patients who received the vaccine would recommend vaccination to other IBD patients. A campaign led by the different stakeholders may be required to increase the uptake of the vaccine in the patient cohorts who are at higher risk of severe disease and ensure the uptake of the 3 rd dose of the vaccine in those who received the twodose mRNA vaccine series.

In our population of IBD patients, local and systemic AE were very similar, though slightly lower to those reported in the general population, with pain at the injection site being the most common local side effect and fatigue the most common systemic effect. (2, 3, 16) ( Table 7) Similarly to previous studies on the AE of anti-SARS-CoV-2 vaccines in the general population, we also demonstrated that younger patients experienced more AE to the vaccine when compared with older patients, although this difference was only statistically significant for local AE after the first dose of the vaccine and systemic AE after the second dose of the vaccine. (2, 3, 16) This may be explained by the higher immunological response that is probably mounted in younger patients, and that may lead to an increased frequency of AE. However, this does not seem to have compromised vaccination adherence. There A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac010 was a total of 5 cases of thrombosis, which occurred with three different types of vaccines.

As a limitation of our study, the clinical details of the thrombosis episodes and its consequences were not characterized. Interestingly, all five patients were considered to have active disease, three of them with mild activity and the other two with moderate activity.

Furthermore, we were unable to ascertain if these cases fulfilled the diagnostic criteria of vaccine-induced immune thrombotic thrombocytopenia (VITT). (17) Though on logistic regression analysis immunosuppressive treatment seemed to be a predictor of the development of AE of the vaccine, individual assessment of these therapies demonstrated that biological monotherapy was a predictor for the development of AE.

Further sub-analysis showed that this remained significant only for vedolizumab and ustekinumab. The presence of bias due to small sample size of patients on these medications cannot be excluded.

Regarding the impact of the anti-SARS-CoV-2 vaccine on IBD management, only a minority (3.6%) of the patients needed to consult their gastroenterologist after vaccination and in less than a half of those this was due to an IBD flare. Only 3 patients were hospitalized due to an IBD relapse after vaccination and there was a significant association between hospitalization and disease severity at the baseline (OR 4.23, 95%CI 1.09-16.41, p=0.04). Data from vaccine side-effects in the general population demonstrate that diarrhoea occurs in approximately 10% of the people who receive the vaccine and therefore, may be confused with exacerbation of the disease (2, 3, 16) .

Most of the patients did not have to change IBD medication after vaccination and only a minority (5.7%) had to escalate therapy. Nevertheless, almost 9% of the patients rescheduled their infusion. The reason for this was not clarified. A possible explanation could be that this was done as a preventive measure to be able to determine, if any symptoms were due to vaccination or secondary to infusion reactions. Our study has strengths and limitations. This is the largest study presenting data on anti-SARS-CoV-2 vaccination in IBD patients from different geographic locations, treated with different drug regimens. Our results are reassuring, with local and systemic AEs being very similar to those reported in the general population. Moreover, through this study, we were able to evaluate patients' concerns and vaccination adherence. Our major limitation relies on the fact that, being designed to be answered by patients, disease related features and disease activity were self-reported, which may have introduced some reporting bias. 

A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac010 

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