The 2023 Impact of Inflammatory Bowel Disease in Canada: COVID-19 and IBD

Abstract The COVID-19 pandemic had a monumental impact on the inflammatory bowel disease (IBD) community. At the beginning of the pandemic, knowledge on the effect of SARS-CoV-2 on IBD was lacking, especially in those with medication-suppressed immune systems. Throughout the pandemic, scientific literature exponentially expanded, resulting in clinical guidance and vaccine recommendations for individuals with IBD. Crohn’s and Colitis Canada established the COVID-19 and IBD Taskforce to process and communicate rapidly transforming knowledge into guidance for individuals with IBD and their caregivers, healthcare providers, and policy makers. Recommendations at the onset of the pandemic were based on conjecture from experience of prior viruses, with a precautionary principle in mind. We now know that the risk of acquiring COVID-19 in those with IBD is the same as the general population. As with healthy populations, advanced age and comorbidities increase the risk for severe COVID-19. Individuals with IBD who are actively flaring and/or who require high doses of prednisone are susceptible to severe COVID-19 outcomes. Consequently, sustaining maintenance therapies (e.g., biologics) is recommended. A three-dose mRNA COVID-19 vaccine regimen in those with IBD produces a robust antibody response with a similar adverse event profile as the general population. Breakthrough infections following vaccine have been observed, particularly as the virus continues to evolve, which supports receiving a bivalent vaccine booster. Limited data exist on the impact of IBD and its therapies on long-term outcomes following COVID-19. Ongoing research is necessary to address new concerns manifesting in those with IBD throughout the evolving pandemic.


INTRODUCTION: CROHN'S AND COLITIS CANADA'S COVID-19 & IBD TASKFORCE
Inflammatory bowel disease (IBD) affects more than 0.8% of the Canadian population in 2023 (1)(2)(3)(4).When the World Health Organization declared COVID-19 a global pandemic on March 11, 2020, immunocompromised individuals with IBD were initially considered vulnerable to infection and complication by SARS-CoV-2 (5).As the SARS-CoV-2 virus was novel, direct clinical evidence was lacking to inform healthcare providers and policy makers on guidance for immunocompromised individuals.Consequently, Crohn's and Colitis Canada developed the COVID-19 and IBD Taskforce on March 12, 2020 (6).The Taskforce included adult and paediatric gastroenterologists from across the country with infectious disease specialists, nurses, and patient representatives.This team met regularly to review the emerging evidence on the impact of COVID-19 on those with IBD to establish recommendations for the IBD community (6).
Expert reviews of population-level recommendations were tailored to the IBD community and communicated through website FAQs and infographics (6); a public-oriented burden report (7) with foci on additional special populations (e.g., pregnant people (8), pediatrics (8), seniors (9)), IBD medications (10), mental health (11), and access to care (12); and through a moderated, online webinar series.The one-to two-hour webinar recordings were then curated into threeto five-minute video clips to answer specific questions and uploaded to Crohn's and Colitis Canada's YouTube page (6).As of October 2022, Crohn's and Colitis Canada's webpage on COVID-19 has been viewed over 800,000 times, and the thirty webinars produced on COVID-19 and IBD were viewed over 81,000 times.
Crohn's and Colitis Canada's 2021 Impact of COVID-19 and IBD report synthesized the knowledge learned by the COVID-19 and IBD Taskforce (13).The purpose of this article is to provide up-to-date knowledge on the influence of COVID-19 on the IBD community.

Epidemiology: The Risk of COVID-19 among those with IBD is Similar to the General Population
The global pandemic was in part driven by the high transmission of SARS-CoV-2.Earlier in the pandemic, concern was raised that those with IBD might be at higher risk of being infected by SARS-CoV-2.The Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry is an international cohort study that recruited over 6000 individuals with IBD who were diagnosed with COVID-19 (14).Analyzing the waves of reporting into the SECURE-IBD registry showed similar patterns to the general population during the first year of the pandemic, which provided the first clues that having IBD or being immunosuppressed by therapies to treat IBD may not increase the risk of acquiring SARS-CoV-2 (15).Subsequently, a meta-analysis of seven observational studies showed that individuals with IBD had comparable rates of COVID-19 as the general population (pooled odds ratio [OR]: 0.47; 95% CI: 0.18, 1.26) (16).However, additional studies are necessary to assess whether the risk of SARS-CoV-2 was influenced by public health recommendations geared towards immunocompromised populations and adherence among those with IBD (6).Overall, the accumulating data consistently demonstrated that the risk of severe COVID-19 in the general population was similar to those with Crohn's disease or ulcerative colitis (16).Moreover, the risk factors associated with severe COVID-19, defined as hospitalization or death, were similar in those with IBD as compared to the general population: namely age and comorbidities (16)(17)(18)(19).Like the general population, seniors with IBD (particularly those with multiple comorbidities such as diabetes, cancer, and cardiovascular disease) were at the highest risk for hospitalization or death from SARS-CoV-2 infection (16)(17)(18).

Key Points
IBD Risk-Individuals on Prednisone were at Risk for Severe COVID-19 Outcomes Numerous studies assessed the risk of severe COVID-19 in relation to the medications used to treat IBD.By July 2020, the first 500 cases reported in SECURE-IBD provided clues on the risk of drugs on severe COVID-19 (20).In 2022, the largest study-including 6000 individuals with IBD from March 2020 to May 2021 (before widespread access to vaccines)-reported that those with IBD who were using anti-TNFs, vedolizumab, ustekinumab, or tofacitinib at the time of their infection with SARS-CoV-2 had a lower risk of hospitalization or death from COVID-19 (21).In contrast, those who experienced an active flare and required higher doses of oral prednisone (>20 mg/day), were more likely to experience severe outcomes of from COVID-19 (20)(21)(22).The risk of severe COVID-19 was particularly observed among individuals under the age of 50 who were flaring with IBD (22).Consequently, guidance to the IBD community consistently recommended to continue IBD therapies during the pandemic to avoid flaring from lack of adherence.Moreover, those with IBD who were flaring were recommended to isolate while on high doses of prednisone (10).Unlike medical therapy, the risk of severe COVID-19 is not specifically increased among those who had prior surgery for IBD (23).Among those with IBD who are at increased risk for severe COVID-19, treatment with Paxlovid (nirmatrelvir and ritonavir) reduced the risk of hospitalization as compared to those not treated with antiviral therapy (24).

Individuals with IBD Require Regular Booster Doses of SARS-CoV-2 Vaccines to Maintain Immunity
The approval of the first mRNA and nonreplicating viral vector vaccines against SARS-CoV-2 occurred in December 2020 (25).Throughout 2021, numerous studies were conducted to evaluate the serological response to different dose regimens of the COVID-19 vaccines among immunocompromised individuals with IBD.The largest serological study in people with IBD is CLARITY-IBD, which initially showed that the antibody response following a two-dose vaccine schedule is superior for mRNA vaccines compared to adenovirus vector vaccines, for those on vedolizumab compared to infliximab, and those on infliximab monotherapy versus those on concomitant immunomodulator therapy (26).The VIP study demonstrated a lower antibody response after two vaccine doses among those using infliximab and tofacitinib, those who receive a vector adenovirus vaccine compared to an mRNA, and those of advanced age (27).A meta-analysis of 46 studies in the IBD population confirmed high seroconversion (96%) after completing a two-dose vaccine series, with lower serological response in those on anti-TNF therapies, and a subsequent decay of antibodies over time (28).Adolescents with IBD mount a robust antibody response to a two-dose mRNA vaccine regimen (29,30).
A large prospective cohort study in Calgary, Alberta established the immunological efficacy of a three-dose mRNA vaccine series for those with IBD (31).Following the third vaccine dose, the seroconversion rate was 99.6% with a high geometric mean titer within eight weeks of the third dose; however, after eight weeks, antibody levels fell by approximately 12% (95% CI: 8%, 15%) per week (31).The independent factors associated with a reduced serological response were advanced age and use of oral prednisone at the time of the third vaccine dose (Figure 1) (31).Similarly, the CLARITY-IBD and VIP studies demonstrated robust serological responses following a third SARS-CoV-2 vaccine, though anti-TNF therapy and tofacitinib were associated with lower antibody levels (32,33).These data have led various jurisdictions to recommend a fourth vaccine dose, which has been associated with recapturing decaying antibody levels in those with IBD (34).Despite booster doses of SARS-CoV-2 mRNA vaccines advocated by Crohn's and Colitis Canada (35), data from Ontario indicated low uptake of a third vaccine dose in the IBD population in the pre-Omicron era (i.e., before December 2021) (36).

Bivalent Vaccines are Recommended for those with IBD due to Breakthrough Infections
Prior to the Omicron variant becoming the dominant strain, before December 2021, breakthrough infections following the completion of a vaccine series in those with IBD were not common.In a large cohort study in the United States, completed before December 2021, only 1.7% of individuals with IBD reported COVID-19 more than one month after completing their vaccine series (37).Moreover, individuals with a breakthrough infection had lower mean antibody levels (37).Similarly, a meta-analysis conducted on studies prior to the Omicron era showed the pooled risk of breakthrough infections after two vaccine doses was ~1%, and the risk of breakthrough infections in those with IBD was similar to the general population (pooled relative risk [RR]: 0.60; 95% CI: 0.25, 1.42) (38).
Studies conducted during the Omicron wave (December 2021-present); however, have reported considerably higher breakthrough infection rates in those with IBD due to the highly infectious transmissibility and vaccine evasive subvariants of Omicron.The CLARITY-IBD study demonstrated that, during the Omicron wave, 15% of individuals with IBD experienced a breakthrough infection after a three-dose SARS-CoV-2 vaccine regimen (32).Although breakthrough infections occurred more commonly in those on infliximab compared to vedolizumab, antibody levels alone were not associated with protection from infection (32).These data suggest that those with IBD will likely benefit from bivalent vaccines (i.e., mRNA of native spike protein with subvariant: BA.1, BA.4, and/or BA.5).Moreover, a robust serological response to the bivalent vaccines has been shown in the IBD population (39), though the durability over time will need to be confirmed in future studies.

SARS-CoV-2 Vaccines are Safe in Those with IBD and do not Trigger a Flare of Disease Activity
Overall, the short-term adverse events to SARS-CoV-2 vaccines in those with IBD are similar to the general population.A cohort study from the US showed that the most commonly reported adverse events after receiving a vaccine were: injection site pain, fatigue, and malaise; the rate of reporting in those with IBD was not different than healthy controls (40).Adverse events were classified as mild and short-lived (i.e., less than two days).After the third dose of a vaccine, approximately 41% of people with IBD reported an adverse event.Most adverse events decreased in severity from second to third dose (40).The one exception was gastrointestinal symptoms, which were slightly worse after the third dose of the vaccine (40).However, a Canadian study on adverse events within 30 days of each vaccine dose documented no objective risk of flaring IBD within 30 days of receiving either the first, second, or third vaccine dose (41).

Complications of COVID-19 in Those with IBD Include Mental Health Concerns and Possible Long COVID
Overall, the long-term complications of COVID-19 in those with IBD appear to be similar to the general population (42); though, high quality, longitudinal studies in the IBD population are lacking.Post acute COVID-19 syndrome (also known as long COVID-19) is a consideration for those with IBD as SARS-CoV-2 antigens may persists in intestinal mucosa for months after clearing the infection (43).Statistics Canada reported 14.8% of Canadians experience symptoms of long COVID three months after infection; populationbased data from Ontario indicated increased health services utilization following COVID-19; and individuals with long COVID demonstrate physiological changes (44,45).However, studies in the IBD population are necessary to assess if the risk is elevated of post acute COVID-19 syndrome (46).Irrespective of whether individuals with IBD are at additional risk of long COVID compared to the general population, overlapping long COVID and IBD places a significant burden on people living with IBD and the health systems.
Deterioration in mental health and elevated stress and anxiety impacted the IBD community as many feared worse outcomes from COVID-19 (11,47).Depressive symptoms and distress were exacerbated in those who experienced isolation in an attempt to shield themselves from exposure to SARS-CoV-2 (11,47).Furthermore, stress and anxiety were associated with worsening of gastrointestinal symptoms and disease activity (see also Graff et al. this volume) (48).Consequently, many individuals with IBD struggled with low health-related quality of life during the pandemic (49), which was also observed in children with IBD (50).

CONCLUSION
Crohn's and Colitis Canada's COVID-19 and IBD Taskforce synthesized the medical literature during the pandemic in order to communicate timely and insightful guidance to the IBD community.Over the last three years, since the onset of the pandemic, the knowledge on the impact of COVID-19 on those with IBD has expanded dramatically.The risk of COVID-19 among those with IBD is similar to the general population.Individuals with IBD had similar risk factors for severe COVID-19 as the general population, namely age and comorbidities.Those with IBD who flared and were administered prednisone were at risk for severe COVID-19 outcomes.Vaccines served as the primary preventative health measure.Individuals with IBD require at least a three dose

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Journal of the Canadian Association of Gastroenterology, 2023, Vol. 6, No. S2 SARS-CoV-2 vaccine regimen.In addition, bivalent vaccines are recommended due to breakthrough infections and immune-escaping variants of the virus.Importantly, SARS-CoV-2 vaccines are safe in those with IBD and do not trigger a flare of disease activity.Data on the long-term impact of COVID-19 in people with IBD are lacking.Despite actions to guide the IBD community through the pandemic, those with IBD struggled with mental health concerns and impaired quality of life during the pandemic.

KNOWLEDGE GAP & FUTURE RESEARCH DIRECTIONS
1.There is still work to be done to understand the impact of public health recommendations geared to immunocompromised populations on the risk of infection by SARS-CoV-2.

Figure 1
Figure 1 Average antibodies by time period relative to vaccine doses in a cohort of 556 individuals with IBD from Calgary, Alberta, Canada, grouped by IBD medication class.Adapted from Quan et al. 2023 (39).
Information provided in this article provides peace of mind and reassurance to patient partners, allowing them to make educated decisions about their physical and mental wellbeing.Patient partners encouraged greater access to mental health supports for pandemic-related isolation, stress, and anxiety that many individuals experienced.Partners recognized there were some individuals, such as those in active flares and/or on >20 mg/day of prednisone, who remain clinically vulnerable or who may experience increased vulnerability to worse COVID-19 outcomes if they contract the virus.Ongoing protection and advocacy efforts need to center around these clinically vulnerable individuals.It was recommended that individuals perform their own risk assessment based on the scientific information available.information on the pandemic and communicate this knowledge to the IBD community via online sites and webinar series.2. Crohn's and Colitis Canada can educate healthcare providers on the appropriate guidance of managing IBD throughout the pandemic, especially on the importance of receiving bivalent vaccines.3. Crohn's and Colitis Canada should continue to advocate to policymakers and health authorities during the pandemic for vulnerable immunocompromised individuals with IBD.This article appears as part of the supplement "The Impact of Inflammatory Bowel Disease in Canada in 2023", sponsored by Crohn's and Colitis Canada, and supported by Canadian Institutes of Health Research Project Scheme Operating Grant (Reference number PJT-162393).
POLICY IMPLICATIONS & KEY ADVOCACY OUTCOMES1.Crohn's and Colitis Canada's COVID-19 and IBD Taskforce served as an invaluable resource to synthesize rapidly evolving