key: cord-0815561-sux6gw51
authors: Hadi, Yousaf Bashir; Thakkar, Shyam; Shah-Khan, Sardar Momin; Hutson, William; Sarwari, Arif; Singh, Shailendra
title: COVID-19 vaccination is safe and effective in patients with inflammatory bowel disease: Analysis of a large multi-institutional research network in United States.
date: 2021-06-15
journal: Gastroenterology
DOI: 10.1053/j.gastro.2021.06.014
sha: d52ffc6373e237c65c87bc8747e87fad34190845
doc_id: 815561
cord_uid: sux6gw51

nan

In December 2020, the US Food and Drug Administration (FDA) issued Emergency Use Authorizations followed by interim recommendations for use for two mRNA-based vaccines (Pfizer-BioNTech and Moderna) for prevention of More than 300 million doses of COVID-19 vaccines have been administered in USA as of May, 2021. 2 Large clinical trials reported efficacy of the mRNA COVID-19 vaccines, 3 however, data for specific patient populations such as inflammatory bowel disease (IBD) is lacking. mRNA COVID-19 vaccines employ novel mechanisms of action that limit extrapolation of safety and efficacy data from other vaccines previously studied in IBD patients. Moreover, a recent study reported reduced antibody responses to COVID-19 vaccines in IBD patients on biologic therapies, 4 raising concerns regarding effectiveness. Safety of COVID-19 vaccines in IBD patients has not yet been investigated in detail.

We used TriNetX (Cambridge, MA, USA) research network to retrospectively analyze data from multiple institutions in the USA. Patients with diagnosis of IBD (Crohn's disease (CD) or Ulcerative Colitis (UC)) who received COVID-19 vaccination until April 30, 2021 were identified and included. Details of the database are described in supplementary file and previous studies. 5 J o u r n a l P r e -p r o o f Study definitions and selection criteria are detailed in supplementary file. Safety and efficacy of COVID-19 vaccination in patients with IBD was studied in comparison to general population (non-IBD) who received COVID-19 vaccination. Safety outcomes included immediate adverse events within 1 day, and adverse events of special interest purported by CDC (Acute Myocardial Infarction, Anaphylaxis, Facial nerve palsy, Coagulopathy, DVT, Pulmonary embolism, Guillain-Barré syndrome, Transverse-myelitis, Immune thrombocytopenia, Disseminated intravascular coagulation, Myocarditis/Pericarditis, Hemorrhagic/Non-hemorrhagic stroke, Appendicitis, Narcolepsy, Encephalomyelitis) up to 30-days after any dose of COVID-19 vaccination. 6 30-day all cause hospitalization rates after COVID-19 vaccination were also compared between IBD and non-IBD cohorts. Efficacy was assessed by comparing the rates of new COVID-19 diagnosis any time after receiving COVID-19 vaccination. Time-to-event analysis was performed using Log-Rank tests. IBD and non-IBD groups were also compared using 1:1 propensity-score matching (PSM) based on demographic variables and comorbidities detailed in Supplemental file. Steroid prescriptions at 30 day follow up were compared between vaccinated and non-vaccinated IBD patients in matched and unmatched analyses.

Subgroup analysis based on type of IBD (UC/CD), and medications (biologics and/or immunomodulators) was also performed. Patient counts <10 were obfuscated to safeguard protected health information. Detailed methodology can be found in the Supplementary file.

A total of 864,575 patients who received COVID-19 vaccination during study period were identified. Of these, 5,562 patients had a prior diagnosis of IBD (2933 UC, 2629 CD). Mean age of IBD patients was 57.3+17.5 years and majority were females (59.67%) ( Table 1) . 2939 patients (52.84%) were on biologics/thiopurines before vaccination. One vaccine dose was administered in 1822 IBD patients, and 3740 IBD patients received two doses. Pfizer and Moderna vaccines were administered to 3104 and 762 IBD patients respectively, while manufacturer was not specified in the remaining patients. There was no difference in steroid prescription at one month follow up in vaccinated and unvaccinated IBD patients in unmatched (6.26% vs 6.92%, RR:0.90, 95%CI:0.81-1.01) and

propensity-score matched analysis (6.26% vs 6.44%, RR:0.97, 95%CI:0.84-1.12).

Sub-group analysis revealed no difference in 30-day adverse events of special interest after COVID-19 vaccination between IBD patients with and without biologic and/or immunomodulator use (2.2%vs1.67%; RR:1.32, 95%CI 0.85-2.06) and between patients with CD and UC (2.07%vs1.98%; RR:1.04, 95%CI:0.70-1.54). No difference in steroid use after vaccination was found between patients with and without biologic and/or immunomodulator use (6.55%vs5.28%; RR:1.24, 95%CI:0.97-1.59) and between patients with CD and UC (6.37%vs6.16%; RR:1.03, 95%CI:0.83-1.29). <10 patients on biologics and/or immunomodulators were diagnosed with COVID-19 after vaccination. Immediate adverse events after vaccination were rare in both cohorts. Incidence of Adverse Events of Special Interest in IBD patients after COVID-19 vaccination was small and similar to a matched cohort of non-IBD patients. Furthermore, there was no signal towards increased steroid need in vaccinated patients when compared to unvaccinated IBD patients. Thus, we conclude that the benefits of COVID-19 vaccination in IBD patients probably outweigh the minimal risks.

There is some concern that IBD patients, especially those using immunosuppressive medications, may be at risk of sub-optimal vaccine response. 4 We found that the incidence of COVID-19 in IBD patients after vaccination is very low, including patients on immunosuppressive agents, and is similar to non-IBD population. Further studies including a larger cohort with longer follow-up duration are needed.

Our study has several limitations inherent to retrospective studies based on electronic health record data. However, several factors lend strength to our conclusions, including first large realworld data on IBD patients undergoing vaccinations. Our study findings are reassuring and support the continued use of these vaccines in patients with IBD. J o u r n a l P r e -p r o o f TriNetX (Cambridge, MA, USA) is a multiinstitutional cloud-based research network. It allows real-time access to de-identified data from participating institutions to end users.

De-identified data on the network is collected and aggregated from participating healthcare organizations in real time, which can then be analyzed using statistical and analytical tools available on the network. TriNetX platform obtains data directly from Electronic Health Records (EHRs), and this data includes demographic characteristics, clinical diagnoses, medical procedures, laboratory investigations available for patients, medications, and other clinical variables including vital signs and presenting complaints etc. The platform can also extract facts directly from clinical documents available in EHRs through its Natural Language Processing (NLP) system that is then transformed into standard clinical terminologies.

The healthcare organizations (HCOs) that are included in the TriNetX platform are mostly large academic heathcare centers comprising more than one facility and include both tertiary care centers and satellite healthcare clinics. HIPAA compliance is ensured by the platform by including either de-identified data or a Limited Data Set depending on the participating HCO. TriNetX obfuscates patient ages more than 90 and patient counts less than 10 to ensure anonymity.

Western IRB has granted a waiver to TriNetX as a federated network. West Virginia University Clinical and Translational Science Institute (WVU CTSI) manages the TriNetX platform at West Virginia University.

First COVID-19 Vaccines Receiving the US FDA and EMA Emergency Use Authorization

Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine

Serological response to mRNA COVID-19 vaccines in IBD patients receiving biological therapies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Coronavirus disease

vaccine, mRNA-LNP, spike protein, preservative free, 30 mcg/0.3mL dosage, diluent reconstituted, for intramuscular use

Immunization administration by intramuscular injection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Coronavirus disease [COVID-19]) vaccine, mRNA-LNP, spike protein, preservative free, 30 mcg/0.3mL dosage, diluent reconstituted

Immunization administration by intramuscular injection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Coronavirus disease [COVID-19]) vaccine, mRNA-LNP, spike protein, preservative free, 30 mcg/0.3mL dosage, diluent reconstituted

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Coronavirus disease

vaccine, mRNA-LNP, spike protein, preservative free, 100 mcg/0.5mL dosage, for intramuscular use

Immunization administration by intramuscular injection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Coronavirus disease [COVID-19]) vaccine, mRNA-LNP, spike protein, preservative free, 100 mcg/0.5mL dosage

Immunization administration by intramuscular injection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Coronavirus disease [COVID-19]) vaccine, mRNA-LNP, spike protein

COVID-19 diagnosis

Patients were identidfied by using International Classification of Diseases, Ninth Revision and tenth Revision, Clinical Modification (ICD-10-CM) codes as well as LOINC codes for positive laboratory tests discussed below. 1. ICD-10-CM codes U07.1 (COVID-19, virus identified), OR B34.2 (Coronavirus infection, unspecified), OR B97

This code is mapped to ICD-10 code B34.2 and B97.2, and it was exclude to prevent false positives because it is used as a catch all code sometimes for many viral infections

RdRp gene [Presence] in Respiratory specimen by NAA with probe detection 41458-1 SARS coronavirus RNA [Presence] in Unspecified specimen by NAA with probe detection 94309-2 SARS coronavirus 2 RNA [Presence] in Unspecified specimen by NAA with probe detection 94531-1 SARS Coronavirus 2 RNA panel -Respiratory specimen by NAA with probe detection 94506-3 SARS coronavirus 2 IgM Ab [Units/volume] in Serum or Plasma by Immunoassay 94500-6 SARS coronavirus 2 RNA [Presence] in Respiratory specimen by NAA with probe detection 94315-9 SARS coronavirus 2 E gene [Presence] in Unspecified specimen by NAA with probe detection. 94316-7 SARS-CoV-2 (COVID19) N gene [Presence] in Unspecified specimen by NAA with probe detection 94502-2 SARS-related coronavirus RNA [Presence] in Respiratory specimen by NAA with probe detection 3. Patient identification period was limited from

Patients with IBD were identified using the International Classification of Diseases, Ninth Revision and tenth Revision, Clinical Modification (ICD-10-CM) codes. Patients were included if they had encounters with a diagnosis of Ulcerative Colitis or Crohn's disease and were on an IBD specific medication. Identification criteria was based on study by

Crohn's disease OR K51.90: Ulcerative colitis, in conjunction with one of the following medication use history

Mycophenolate mofetil: 68149 Other agents

Unvaccinated IBD control group was identified using the same IBD case definition stated above. Patients were included if they did not have associated COVID vaccination code, and had a healthcare visit within the study duration

Recent trends in the prevalence of Crohn's disease and ulcerative colitis in a commercially insured US population

Patients were identified up to April 15, 2021. Study analysis was updated through May 31, 2021.COVID-19 vaccine administration was identified with the following criteria:Pfizer COVID-19 vaccine:Administration of first dose of COVID 19 vaccine per criteria defined above was considered the index event for the purposes of our study.

Immediate adverse effects of after vaccination J o u r n a l P r e -p r o o f Immediate adverse effects of vaccination were considered upto 1 day after administration of any dose of COVID-19 vaccine. 

Efficacy was assessed by comparing the rates of new COVID-19 diagnosis anytime after receiving the first dose of COVID-19 vaccination. Patients with COVID-19 diagnosis on the day of vaccination or prior to vaccination were excluded from this analysis.

IBD and non-IBD groups were compared using propensity-score matched analysis. One-to-one matching was performed based on age, gender, ethnicity, BMI, and comorbidities including hypertension, diabetes, chronic lower J o u r n a l P r e -p r o o f respiratory diseases, chronic kidney disease, ischemic heart disease. Propensity scores were generated using greedy nearest-neighbor algorithms with a caliper width of 0.1 pooled SD. Balance on covariates was assessed using standardized mean-difference, and absolute values > 0.1 were considered indicative of residual imbalance. Twosided alpha <0.05 was defined a-priori for statistical significance. TriNetX obfuscates patient counts when aggregate count is <10 to safeguard protected health information.

A sensitivity analysis was performed with 1:1 propensity score matching of only those patients with healthcare visits 1 month or more after the vaccine administration (to ensure more robust capture of follow up data/ adverse events etc, and to control/adjust for follow up). No difference in statistical significance was noted as shown in results of this analysis below.