Risk of COVID-19 Infection After Full Immunization in Patients With Inflammatory Bowel Disease on Treatment: A Research Network Analysis

Background: Acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an issue in treating patients with Inflammatory Bowel Disease (IBD) due to concerns for infection risk and poor post-vaccination antibody response. We examined the potential impact of IBD treatments on SARS-CoV-2 infection rates after full immunization against COVID-19. Methods: Patients who received vaccines between January 2020 and July 2021 were identified. The post-immunization Covid-19 infection rate at 3 and 6 months was assessed in IBD patients receiving treatment. The infection rates were compared to patients without IBD. Results: The total number of IBD patients was 143,248; of those (n=9405), 6.6% were fully vaccinated. In IBD patients taking biologic agents/small molecules, no difference in Covid-19 infection rate was found at 3 (1.3% vs. 0.97%, p=0.30) and 6 months (2.2% vs. 1.7%, p=0.19) when compared to non-IBD patients. No significant difference in Covid-19 infection rate was found among patients receiving systemic steroids at 3 (1.6% vs. 1.6%, p=1) and 6 months (2.6% vs. 2.9%, p=0.50) between the IBD and non-IBD cohorts. Conclusions: The COVID-19 immunization rate is suboptimal among IBD patients (6.6%). Vaccination in this cohort is under-utilized and should be encouraged by all healthcare providers.


Introduction
Multiple medical societies have published vaccine guideline recommendations for patients with Inflammatory Bowel Disease (IBD) [1][2][3][4]; however, despite these guidelines, the vaccination rate among IBD patients has been meager. It is estimated that among IBD patients, only 43.5% received influenza immunization, 24.1% pneumococcal vaccination, 48.3% Hepatitis B vaccination, 43.8% Measles, Mumps, Rubella (MMR) vaccine, 43% DTaP, 2.1% herpes zoster, and 3.4% Human papillomavirus (HPV) vaccination [1][2]. The current COVID-19 pandemic is a significant challenge for patients with IBD. Recent studies have shown that the outcomes of patients with IBD and COVID-19 infection compared to Covid-19 infection in the general population are similar [3][4]. Three vaccines have received full approval from the US Food and Drug Administration in the US. These are efficacious and safe in preventing Covid-19 infection [5][6][7][8][9]. Hadi et al. identified 3,866 IBD patients who received immunization against COVID-19; of these, 113 patients reported adverse events (2.03%), which is a similar and comparable rate among patients without IBD (relative risk [RR], 2.50; 95% Q6 confidence interval [CI], 2.07-3.00) [8]. Additionally, medical societies such as the British Society of Gastroenterology IBD Section and IBD Clinical Research Group strongly recommended the Covid-19 vaccine for patients with IBD [9]. This study examines the COVID-19 immunization rate and the potential impact of IBD treatments on Covid-19 infection rates after receiving full immunization.
This article was previously presented as a meeting abstract at the 2022 AASLD Annual Scientific Meeting From Nov 4-8, 2022.

Materials And Methods
We identified patients aged 18 to 90 who received the BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson) cases between January 20, 2020, and July 1, 2021. The postimmunization Covid-19 infection rate was compared at 3 and 6 months between non-IBD versus IBD patients receiving treatment with biologic/small molecule, immunomodulators, systemic steroids, or other agents. Propensity-matched (PSM) was used to examine the cohorts to control for potential confounders. We queried TriNetx (Covid-19 research network), a collection of 66 healthcare organizations from 6 countries. The Trinetx Inc. (Cambridge, MA) database is a global federal research network that combines real-time data from electronic medical records. The platform combines international data sets in a user-friendly interface that allows users to query different cohorts. A total of 143,248 IBD cases were identified. The Covid-19 infections database was queried; see a description of codes (supplement 1). Patients with an ICD-10 diagnosis of IBD, as listed in supplement 1, were identified. Additionally, IBD patients were grouped by the treatment they received. Treatment groups were as follows: 1. Biologic/small molecule (Certolizumab, Ustekinumab, Infliximab, Adalimumab, Vedolizuman, Tofacitinib, Golimumab), 2. Immunomodulators (Methotrexate, Azathioprine), and 3. Systemic steroids. The TriNetX platform uses several descriptive statistics as frequencies with percentages for differing categorical variables and mean ± standard deviation for continuous measures. The baseline characteristics were compared using Pearson's chi-squared test for defined categorical variables. To account for possible differences in the cohorts, a 1:1 PSM was created for well-matched groups, as shown (tables 1-3). The 1:1 PSM uses a logistic regression from the Python libraries (NumPy and Sklearn). This platform compares the results to R for verification. The final step in the verification process uses the nearest neighbor function set to a tolerance level of 0.01 and a deference value >0.1. Mortality was determined by the difference in association using the Kaplan-Meier method and the statistical difference between the risk factors.    To understand if differing health conditions are affecting the outcomes of this study, a sensitivity analysis was performed to control for the possibility of residual confounders. The falsification endpoint of bleeding was used to see if there were possible confounders in each model.

FIGURE 3: IBD Patients on Systemic Steroids
The falsification endpoint of bleeding was used to see if there were possible confounders in each model. No difference in the falsification endpoint of any of the models was observed.

Discussion
The rapid spread of the COVID-19 pandemic has significantly impacted all aspects of medicine. The pandemic has also challenged the management of IBD, as many patients require immunomodulatory therapies that might weaken the immune system, leading to an increased risk of infections. Multiple studies have been done to evaluate whether IBD patients have an increased risk of developing COVID-19 infection than the general population; there have been contradicting results [10][11][12]. Nevertheless, the primary focus should remain improving IBD patients' quality of life by achieving appropriate control of symptoms and encouraging medication adherence during difficult times. Patients with IBD should be vaccinated against COVID-19 at the earliest opportunity, as recommended by international advisory committees, and vaccination should not be delayed because a patient is receiving immune-modifying therapies [13]. The speed with which Covid-19 vaccines have been developed and the lack of data on long-term safety have been cited as reasons patients may have reduced vaccine acceptance, as demonstrated by a survey of Italian patients [14][15]. Historically, vaccines are safe and efficacious in IBD patients; however, the rate of immunization in this population is poor. Lack of patient education and the importance of vaccination being overlooked by general practitioners have contributed to the vaccination disparity in this population [15]. Only 6.6% of IBD patients in our study had full COVID-19 immunization, even though multiple authors have demonstrated that COVID-19 immunization is safe among these patients [8][9]. The role of primary care physicians and gastroenterologists in promoting prompt immunization is, therefore, of vital importance. The disease-related immune disorder and the immunosuppression induced by medications are two mechanisms that potentially compromise the natural response to immunization and impact the immunogenicity in IBD patients and, therefore, potentially increase the risk of viral infections [2,[16][17]. Our study found that regardless of the treatment patients with IBD received, the rate of Covid-19 infection in IBD patients is similar to that of non-IBD patients; this trend has been expressed in the medical literature. A significant strength of our study is the use of an extensive database of 66 different healthcare facilities allowing us to include a large sample of 143,248 IBD patients and giving us a more representative sample with a diverse array of patients in the US and worldwide. Our study has some limitations due to the retrospective nature and the sizeable de-identified database nature of TriNetx; furthermore, patients who were not tested for Covid-19 and were asymptomatic could have been positive for COVID-19.

Conclusions
In conclusion, the Covid-19 immunization rate among IBD patients was suboptimal (6.6%). Additionally, no increased risk of Covid-19 infection post-vaccination in IBD patients on immunosuppression was noted. This suggests durable protection for at least 6 months post-vaccination, likely from appropriate antibody response after vaccination. An essential task in reducing IBD patients' hesitancy to be vaccinated against Covid-19 not only falls in the hands of primary care physicians or gastroenterologists but is also the responsibility of any healthcare provider involved in the care of this population.