Severe Influenza-Related Outcomes in Patients with Inflammatory Bowel Disease on Immunosuppressive Therapy: A Propensity-Matched Cohort Analysis

Severe Influenza-Related Outcomes in Patients with Inflammatory Bowel Disease on Immunosuppressive Therapy: A Propensity-Matched Cohort Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Severe Influenza-Related Outcomes in Patients with Inflammatory Bowel Disease on Immunosuppressive Therapy: A Propensity-Matched Cohort Analysis Mohamed Eldesouki, Ahmed Ibrahim, Omar Alkasabrah, Eslam Mohamed, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7936452/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Mar, 2026 Read the published version in Digestive Diseases and Sciences → Version 1 posted 7 You are reading this latest preprint version Abstract Background Patients with moderate-to-severe inflammatory bowel disease (IBD) often require immunosuppressive therapy to achieve and maintain remission; however, the impact of these medications on influenza risk and the severity of influenza-related complications remains inadequately characterized. Methods Using the TriNetX U.S. Analytics Network, adults (≥ 18 years) with Crohn’s disease or ulcerative colitis during the 2022–2023 influenza season were identified. Patients were stratified by disease activity into two cohorts: (1) moderate-to-severe/active IBD, defined by elevated inflammatory markers, initiation of corticosteroids or a new biologic or small-molecule agent, or documented IBD-related symptoms or complications within the prior six months; and (2) mild/inactive IBD, defined by the absence of these features and no recent immunosuppressive therapy. Propensity score matching (1:1) was used to balance baseline characteristics, and Cox proportional hazards models were applied to estimate hazard ratios for influenza-related outcomes. Results After propensity score matching, each group had 22,784 patients. The incidence of influenza diagnosis was significantly higher in the moderate-to-severe/active IBD group (HR 1.41; 95% CI, 1.30–1.52). Hospitalization rates were also increased (HR 2.05; 95% CI, 1.89–2.23), as were influenza-related complications (HR 1.36; 95% CI, 1.23–1.51). ICU admissions (HR 1.51; 95% CI, 1.33–1.72) and mechanical ventilation (HR 1.68; 95% CI, 1.32–2.13) were both more frequent in the moderate-to-severe/active IBD group. Use of antiviral medications was higher among those in this cohort (HR 1.60; 95% CI, 1.22–2.10), and overall mortality was modestly increased (HR 1.17; 95% CI, 1.02–1.35). Subgroup analysis revealed the highest risk among patients on corticosteroids, followed by JAK inhibitors and anti–IL-23 agents. Conclusion Patients with moderate-to-severe/active IBD had more severe influenza-related outcomes compared with mild/inactive controls. Improving vaccine uptake and prompt evaluation of upper respiratory symptoms during influenza seasons are key to reducing influenza-related risks in immunosuppressed patients with IBD. Inflammatory bowel disease Immunosuppressive therapy Influenza Biologic agents Disease activity Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Influenza remains a significant global health burden, causing substantial morbidity and mortality worldwide with annual seasonal influenza epidemics resulting in an estimated 290,000-650,000 deaths globally [ 1 ]. Although seasonal influenza can cause a mild, self-limited illness, it may also lead to complications such as pneumonia and acute respiratory distress syndrome, particularly in high-risk populations including young children, pregnant women, older adults, and immunocompromised individuals [ 2 , 3 ]. Among over 121,000 patients hospitalized with confirmed influenza across nine seasons (2010 through 2018), approximately 5.5% died, with the majority of deaths occurring in individuals aged 65 and older and those with underlying medical comorbidities [ 4 ]. Patients with inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are considered a particularly vulnerable population due to their underlying immune dysregulation and frequent use of immunosuppressive therapies [ 5 ]. The chronic inflammatory nature of IBD itself can compromise immune function and commonly used treatments like steroids, immunomodulators, and advanced therapies can further suppress the body’s immune responses [ 6 , 7 ]. This dual burden of disease-related and treatment-induced immunosuppression places patients with IBD at increased risk for infections including opportunistic infections, specifically when multiple immunosuppressive agents are used concurrently [ 8 ]. This risk is highly notable for viral infections, as these therapies can impair both innate and adaptive immune responses necessary for effective viral clearance [ 9 ]. Although prior studies have demonstrated that patients with IBD are at greater risk of influenza infection and related complications, including hospitalization and extended hospital stays, most available literature have compared patients with IBD to the non-IBD population, rather than exploring variations in outcomes within IBD patients themselves [ 10 , 11 ]. Furthermore, limited data exist on the influence of newly approved biologic and small-molecule agents on influenza-related outcomes during recent influenza seasons [ 12 ]. To address these gaps, we conducted a propensity-matched analysis comparing influenza incidence and severity between patients with moderate-to-severe/active and mild/inactive IBD during the 2022–2023 influenza season and performed subgroup analyses to evaluate the influence of specific immunosuppressive therapies on influenza-related outcomes. METHODS Data Source This retrospective cohort study analyzed data from the TriNetX U.S Analytics Network Platform, a multicenter database that includes de-identified electronic health records of 66 Health Care Organizations (HCOs) with over 120 million patients across the United States. Health care organizations included in the TriNetX dataset are a mix of academic medical centers collecting data from their main and satellite hospitals, as well as outpatient clinics. The TriNetX platform allows for comparison between cohorts while accounting for potential confounders, using a propensity score matching (PSM) model. A rigorous quality assurance process ensures data integrity during the extraction from electronic health records (EHRs). Patients’ records were identified using International Classification of Diseases, Ninth or Tenth Edition, Clinical Modification (ICD-9-CM or ICD-10-CM) codes for patients’ diagnoses, International Classification of Diseases, Tenth Edition, Procedure Coding System (ICD-10-PCS), and Current Procedural Terminology (CPT©) codes for procedures, Logical Observation Identifiers Names and Codes (LOINC codes) for laboratory tests, RxNorm and Veteran Affairs (VA) codes for medication use, and TriNetX codes for physical measurements and laboratory data. Since the data are publicly available and deidentified, this study is exempt from approval by the Institutional Review Board (IRB). The de-identification process, as stipulated by the Health Insurance Portability and Accountability Act Privacy Rule (HIPAA), is meticulously executed at the network level by a qualified expert within the TriNetX framework. To ensure patient confidentiality and regulatory adherence, patient counts fewer than 10 are subject to automatic data suppression. Data were accessed on TriNetX from June 15th, 2025, through July 5th, 2025. TriNetX platform was previously applied and validated for investigating influenza as well as other viral respiratory infections within the US [ 13 – 16 ]. Study participants and cohorts Adult patients (≥ 18 years) with a documented diagnosis of either CD (ICD-10: K50) or UC (ICD-10: K51) between October 1, 2022, and March 31, 2023, were eligible for inclusion. Two cohorts were constructed based on disease activity and treatment profiles. Cohort 1 (moderate to severe/active IBD): Patients were classified as having moderate to severe/active disease if they had evidence of an IBD flare within the 6 months preceding the qualifying diagnosis. Activity was defined by the presence of any of the following: elevated inflammatory markers (C-reactive protein [CRP] ≥ 10 mg/L, erythrocyte sedimentation rate [ESR] ≥ 20 mm/h, or fecal calprotectin ≥ 250 µg/g); initiation of systemic corticosteroids, new biologics or small-molecule agents (e.g., infliximab, adalimumab, vedolizumab, ustekinumab, tofacitinib, ozanimod, and upadacitinib) ; IBD-related symptoms or complications (e.g., rectal bleeding, intestinal obstruction, fistula). Cohort 2 (mild/inactive IBD): Patients were classified as having mild/inactive disease if they had no new corticosteroids, immunomodulator, or biologic therapy, no laboratory evidence, of active inflammation or recent complications during the same baseline period. This design is consistent with prior research, where patients with clinically active IBD were defined using recent prescriptions for steroids, or biologics and/or documented IBD-related complications or hospitalization [ 17 – 19 ] (Fig. 1 ). Study outcomes Outcomes were assessed within an 180-day observation window following the index event, which was defined based on the earliest occurrence of qualifying diagnostic or treatment criteria for each cohort. The following outcomes were evaluated: Incidence of laboratory-confirmed or clinically diagnosed influenza, identified via ICD-10 codes (J09–J11) and laboratory markers for influenza virus A and B RNA or antigen presence. Use of antiviral medications, including oseltamivir, zanamivir, and baloxavir, based on RxNorm codes. Occurrence of influenza-related complications, including pneumonia (J12–J18), acute bronchitis (J20), sepsis (A41.89), myocarditis (I51.4), encephalopathy (G93.40), and acute respiratory distress syndrome (J80). Hospitalization, defined by inpatient services (CPT code 1013659). This outcome excluded patients with prior hospitalizations in the pre-index period. Intensive care unit (ICU) admissions, captured through critical care procedure codes (CPT:1013729). Mechanical ventilation, identified via CPT and ICD-10-PCS codes for assisted ventilation procedures (e.g., 5A1935Z–5A1955Z). Corticosteroid exposure, measured by prescriptions for prednisone, methylprednisolone, and hydrocortisone. All-cause mortality. Statistical analysis All statistical analyses were performed using TriNetX built-in function analytic tool, R’s survival package v3.2-3. Following cohort definition, a 1:1 PSM algorithm was applied using greedy nearest-neighbor matching without replacement, balancing baseline covariates including age, sex, race/ethnicity, and relevant clinical comorbidities. Standardized mean differences (SMD) were calculated to assess post-matching balance, with values < 0.1 indicating acceptable covariate balance. For each outcome, time-to-event data were analyzed using the Kaplan–Meier method. Survival curves were compared using the log-rank test, and hazard ratios (HR) with 95% CIs were calculated using Cox proportional hazards models. Patients were censored at the last recorded clinical encounter. Proportional hazards assumptions were assessed using standard diagnostics provided by the platform. For continuous outcomes, the mean and standard deviation were reported, and between-group differences were evaluated using t-tests. For categorical lab outcomes, proportions of positive, negative, and unknown results were compared. Analyses were stratified by outcome-specific settings: for example, hospitalization analyses excluded patients with prior admissions, whereas mortality analyses included all eligible patients. All hypothesis tests were two-tailed with a significance threshold of p < 0.05. RESULTS Baseline characteristics of the Study cohorts In the 2022–2023 influenza season, a total of 56,212 were identified in the moderate to severe/active IBD, and 50,467 in the mild/inactive IBD cohort with nearly 30% of patients in each age group. Before PSM, the mean age of the active cohort was 46.9, and 52.9 in the mild/inactive IBD cohort. Females represented 52.3% of the moderate to severe/active IBD, and 54.7% of the mild/inactive IBD. White individuals were 75.4% of the moderate to severe/active group vs. 77% in the mild/inactive group. Following PSM, each group included 22,784 patients with the mean age of 49 ± 19 years, The two cohorts were evenly matched regarding demographics, underlying comorbidities, and lifestyle features (Table 1 ). Table 1 Patient baseline characteristics before and after Propensity score matching Baseline characteristics Before matching Std. Diff. After matching Std. Diff. Mild/Inactive IBD N = 50,467 Moderate to severe/active IBD N = 56,212 Mild/Inactive IBD N = 22,784 Moderate to severe/Active IBD N = 22,784 Age (yrs, mean ± SD) 52.9 ± 18.4 46.9 ± 18.7 0.324 49.8 ± 18.8 49.1 ± 18.7 0.033 18–40 years, n (%) 12,623 (25.0%) 20,229 (36.0%) 0.240 7,278 (31.9%) 7,388 (32.4%) 0.010 40–60 years, n (%) 15,316 (30.3%) 16,404 (29.2%) 0.026 6,726 (29.5%) 6,744 (29.6%) 0.002 ≥ 60 years, n (%) 20,850 (41.3%) 16,480 (29.3%) 0.253 7,781 (34.2%) 7,644 (33.5%) 0.013 Demographics Female, n (%) 27,622 (54.7%) 29,372 (52.3%) 0.050 12,094 (53.1%) 11,965 (52.5%) 0.011 White, n (%) 38,879 (77.0%) 42,359 (75.4%) 0.040 17,295 (75.9%) 17,192 (75.5%) 0.011 Black or African American, n (%) 4,568 (9.1%) 5,390 (9.6%) 0.018 2,151 (9.4%) 2,186 (9.6%) 0.005 Asian, n (%) 1,053 (2.1%) 1,334 (2.4%) 0.019 552 (2.4%) 579 (2.5%) 0.008 Hispanic or Latino, n (%) 2,021 (4.0%) 2,817 (5.0%) 0.049 1,193 (5.2%) 1,196 (5.2%) 0.001 Comorbidities Tobacco use, n (%) 1,439 (2.9%) 2,420 (4.3%) 0.078 788 (3.5%) 791 (3.5%) 0.001 Diabetes mellitus, n (%) 4,261 (8.4%) 4,328 (7.7%) 0.027 1,891 (8.3%) 1,833 (8.0%) 0.009 Essential hypertension, n (%) 9,315 (18.5%) 10,291 (18.3%) 0.004 4,183 (18.4%) 4,161 (18.3%) 0.002 Hyperlipidemia, n (%) 4,561 (9.0%) 5,122 (9.1%) 0.003 2,055 (9.0%) 2,073 (9.1%) 0.003 Overweight and obesity, n (%) 3,036 (6.0%) 4,273 (7.6%) 0.063 1,530 (6.7%) 1,494 (6.6%) 0.006 Chronic kidney disease, n (%) 1,977 (3.9%) 2,591 (4.6%) 0.034 968 (4.2%) 985 (4.3%) 0.004 Ischemic heart diseases, n (%) 2,455 (4.9%) 2,738 (4.9%) < 0.001 1,077 (4.7%) 1,078 (4.7%) < 0.001 Heart failure, n (%) 1,169 (2.3%) 1,449 (2.6%) 0.017 535 (2.3%) 531 (2.3%) 0.001 HIV, n (%) 130 (0.3%) 100 (0.2%) 0.017 57 (0.3%) 47 (0.2%) 0.009 Influenza risk and influenza-related complications Patients in the moderate to severe/active IBD cohort had a mean follow-up duration of 173 ± 30 days, whereas those in the mild/inactive IBD cohort were followed up for 163 ± 49 days. The risk of developing influenza was higher in patients with moderate to severe/active IBD compared to those with mild/inactive IBD (7.1% vs. 4.9%; HR, 1.41; 95% CI, 1.30–1.52, p < 0.001). The risk of influenza-related hospitalization was (9.5% vs. 4.6%; HR, 2.05; 95% CI, 1.89–2.23, p < 0.001) Influenza-related complications were significantly higher in the moderate to severe/active IBD cohort (4.0% vs 2.9%; HR, 1.36; 95% CI, 1.23 − 1.51; p < 0.001). ICU admissions (2.7% vs 1.7%; HR, 1.51; 95% CI, 1.33–1.72; p < 0.001) and mechanical ventilation (0.8% vs 0.5%; HR, 1.68; 95% CI, 1.32–2.13; p < .001) were more frequent in the moderate to severe/active IBD group compared to the mild/inactive group. The rates of antiviral medications (0.6% vs 0.4%; HR, 1.60; 95% CI, 1.22 − 2.10; p = 0.001) were significantly higher among moderate to severe/active IBD cohort patients. Overall mortality was slightly higher in the moderate to severe/active IBD cohorts (1.1% vs 0.9%; HR 1.17, 95% CI 1.02–1.35; p = 0.01) ( Table 2 , Fig. 2 ). Table 2 Comparison of the outcomes between the Moderate to Severe/Active and Mild/Inactive IBD cohorts Outcome Moderate to Severe/Active IBD N = 22,784 Mild/Inactive IBD N = 22,784 HR (95% CI) P value Follow-up duration (days, mean, SD) 173 (30) 163 (49) - - Influenza risk, n (%) 1,623 (7.1%) 1,125 (4.9%) 1.41 (1.30–1.52) < 0.001 Hospitalization, n (%) 1,663 (9.5%) 848 (4.6%) 2.05 (1.89–2.23) < 0.001 Influenza complications, n (%) 916 (4.0%) 652 (2.9%) 1.36 (1.23–1.51) < 0.001 Antiviral medication use, n (%) 140 (0.6%) 84 (0.4%) 1.60 (1.22–2.10) 0.001 Risk of ICU admission, n (%) 608 (2.7%) 390 (1.7%) 1.51 (1.33–1.72) < 0.001 Mechanical ventilation, n (%) 180 (0.8%) 104 (0.5%) 1.68 (1.32–2.13) < 0.001 Overall mortality, n (%) 252 (1.1%) 213 (0.9%) 1.17 (1.02 − 1.35) 0.01 Subgroup analysis by immunosuppressive medications Subgroup analysis was associated with a significantly higher influenza risk in patients with moderate to severe/active IBD than patients with mild/inactive IBD across all included immunosuppressive classes (all p < 0.001). The largest relative increase was observed with steroids (HR 1.62, 95% CI 1.53–1.72; 7.77% vs 4.61%), followed by JAK inhibitors (HR 1.53, 1.43–1.63; 7.27% vs 4.55%), anti-IL-23 agents (HR 1.52, 1.43–1.63; 7.23% vs 4.54%), anti-IL-12/23 agents (HR 1.47, 1.38–1.57; 6.98% vs 4.54%), and anti-TNF agents (HR 1.46, 1.37–1.56; 6.84% vs 4.47%) (Table 3 , Fig. 3 ). Table 3 Hazard ratios of the flu risk after different immunosuppressive medications Variables Flu Risk in Moderate to Severe/Active IBD Flu Risk in Mild/Inactive IBD HR (95% CI) P value Steroids 2,864 (7.77) 1,700 (4.61) 1.62 (1.53–1.72) < 0.001 JAK inhibitors 2,355 (7.27) 1,475 (4.55) 1.53 (1.43–1.63) < 0.001 Anti-IL-23 agent 2,350 (7.23) 1,475 (4.54) 1.52 (1.43–1.63) < 0.001 Anti-IL-12/23 2,379 (6.98) 1,545 (4.54) 1.47 (1.38–1.57) < 0.001 Anti-TNF 2,415 (6.84) 1,578 (4.47) 1.46 (1.37–1.56) < 0.001 DISCUSSION Patients with moderate to severe/active IBD frequently require immunosuppressive therapies, including corticosteroids, biologics, and small-molecule agents, to control disease activity and prevent flares [ 20 , 21 ]. Although immunosuppression is a recognized risk factor for infections [ 22 ], the extent to which recent immunosuppressive exposure contributes to severe influenza-related outcomes in the IBD population remains insufficiently characterized [ 5 , 23 ]. In this large real-world study, patients with moderate to severe/active IBD were associated with a higher risk of influenza infection (51%), hospitalizations (105%), influenza-related complications (36%), and ICU admission (51%) when compared with those with mild/inactive disease. Among specific immunosuppressive therapy, the highest risks were observed with corticosteroids (62% increase), followed by JAK inhibitors and anti-IL-23 agents (both around 53%). These results are consistent with prior literature indicating that patients with IBD requiring immunosuppressive therapy are particularly susceptible to respiratory viral infections. Stobaugh and colleagues reported elevated odds of hospitalization for influenza-related pneumonia among patients with UC [ 24 ]. Similarly, Tinsley et al., analyzing data of over 140,000 patients from the MarketScan database, found that individuals with IBD had a 54% higher risk of influenza compared to non-IBD controls, along with a significantly increased likelihood of hospitalization for influenza-related illness [ 10 ]. Notably, both studies compared patients with IBD to the general population without IBD, whereas our study focused exclusively on individuals with IBD, comparing those recently exposed to immunosuppressive therapy to those who were not. The agreement in observations across these studies supports the notion that the elevated risk of infection and complications is at least partly driven by immunosuppressive therapy. In the current study, the highest risk of influenza was observed in the subgroup taking steroids. This is similar to the previous study by Tinsley et al., reporting that systemic corticosteroids were the only medication class independently associated with increased influenza risk in IBD compared to non-IBD patients [ 10 ]. While their analysis did not find a significant association with other immunosuppressive agents, our results expand on this by demonstrating that multiple classes including corticosteroids, JAK inhibitors, and IL-23 antagonists, are associated with an elevated risk of influenza and its related complications. Another large population-based cohort study in UK by Irving et al., reported that patients with IBD receiving systemic corticosteroids, immunotherapies, or biologics were at particularly increased risk of viral infections, while those on amino salicylates did not show the same susceptibility [ 23 ]. The heightened risk of severe influenza-related effects in IBD patients under immunosuppression is biologically plausible, given the suppression of both innate and adaptive immune responses by immunosuppressive drugs [ 25 ]. For instance, corticosteroids suppress T-cell activation and inflammatory signaling pathways, which might delay viral clearance and increase the eventual complication of pneumonia and sepsis [ 25 , 26 ]. Similarly, biologic agents and targeted small molecules used in IBD disrupt key immunologic pathways necessary for antiviral defense, thereby increasing susceptibility to influenza. Anti-TNF agents impair the activity of tumor necrosis factor-α, a cytokine central to the recruitment and activation of macrophages and dendritic cells, thus weakening early viral clearance and mucosal immunity [ 27 ]. IL-23 and IL-12/23 inhibitors block the IL-23/Th17 axis, which is essential for maintaining epithelial barriers and promoting antiviral responses through IL-17–mediated neutrophil recruitment. By inhibiting this pathway, these agents may reduce mucosal immune surveillance, increasing vulnerability to respiratory viruses [ 25 ]. JAK inhibitors interfere with intracellular signaling of multiple cytokine receptors, including those for interferons, which are pivotal in modulating the innate and adaptive immune response to viral pathogens. As such, their use can result in diminished antiviral signaling and impaired lymphocyte function [ 28 ]. Together, these immunosuppressive mechanisms help explain the elevated risk of influenza infection and complications observed across multiple drug classes in our cohort. Current guidelines and practices, including those from the American College of Gastroenterology (ACG), European Crohn’s and Colitis Organization (ECCO) and American Gastroenterological Association (AGA), recommend annual inactivated influenza vaccination for all patients with IBD on immunosuppression, ideally administered prior to the onset of the influenza season [ 29 – 31 ]. Our findings reinforce these recommendations, highlighting the increased vulnerability to severe influenza-related complications among patients treated with immunosuppressants within the preceding six months. However, a key challenge is that certain immunosuppressive therapies, particularly anti-TNF agents (alone or in combination with thiopurines) and JAK inhibitors, may attenuate serologic responses to the vaccine [ 32 ]. Nonetheless, vaccination still confers meaningful protection and should not be withheld [ 33 ]. In a randomized trial, by Caldera et al., IBD patients under anti-TNF monotherapy elicit significantly greater antibody levels when given the high-dose influenza vaccine compared to the standard dose, suggesting that immunogenicity can be optimized with dosing strategies [ 34 ]. On the other hand, biologics such as ustekinumab (anti–IL-12/23) have not been shown to impair vaccine-induced immune responses, and patients on these agents can mount adequate protection [ 35 ]. Despite guideline endorsements, vaccination uptake remains suboptimal among IBD patients due to limited provider recommendation, patient concerns about safety, and underappreciation of infection risks [ 36 ]. Given the elevated influenza burden and complications seen in immunosuppressed IBD populations, improving vaccine coverage and enhancing clinician–patient communication are essential components of prevention. Prompt initiation of antiviral therapy such as oseltamivir, zanamivir, or peramivir is critical for suspected or confirmed influenza cases in these high-risk individuals [ 29 , 33 ]. Our study builds on existing evidence by quantifying the direct impact of recent immunosuppressive therapy on influenza outcomes in IBD patients, revealing a detailed association with increased risks of hospitalization, ICU admission, and mortality. A major strength of this work is the use of a large, multi-institutional dataset combined with rigorous 1:1 PSM to control confounders, enabling robust comparisons between immunosuppressed and non-immunosuppressed IBD patients. Additionally, we provide real-world estimates of key clinical outcomes such as ICU admission, mechanical ventilation, and mortality. Limitations of the current study include lack of definitive IBD activity measures, instead, we relied on drug exposure and biomarkers like C-reactive protein, and this may have introduced residual confounding effect. Use of these administrative databases also presents risk of coding errors and limitations of the clinical data; we could not determine the severity of influenza at presentation and vaccination status remains uncertain while there may be unmeasured confounding such as adherence to medications. Future studies should be prospective, longitudinal studies, involving laboratory confirmed influenza, and utilize standardized measures of IBD activity including clinical measures, imaging studies, and laboratory assessments. Head-to-head comparisons of individual agents will be needed to identify which agents have the greatest risk of infection. Although the evaluation of effectiveness, and timing of vaccination in patients with IBD on immunosuppressive therapy will be crucial to provide personalized prevention strategies. CONCLUSION Patients with moderate to severe/active IBD receiving immunosuppressive therapy have a higher risk of influenza infection and severe complications, including hospitalization, ICU admission, and mortality, compared to those with mild/inactive IBD. These findings emphasize the importance of annual influenza vaccination and timely antiviral treatment in this vulnerable population. Improving vaccine uptake through better clinician–patient communication and careful management of immunosuppressive therapies during influenza seasons are key to reducing influenza-related risks in moderate to severe IBD patients. Declarations Sources of Support This research did not receive any specific grant from funding agencies Conflict of Interest The contributing authors have no financial, professional, personal, or other conflicts of interest to declare. Disclosures Dr. Farraye has served as a Consultant for Astellas, Avalo Therapeutics, Bausch, BMS, Braintree Labs, Fresenius Kabi, GI Reviewers, IBD Educational Group, Iterative Health, Janssen, Pharmacosmos, Pfizer, Sandoz Immunology, Viatris.He sits on a DSMB for Eli Lilly and Moon Lake Data availability Data are available from the TriNetX Research Network for authorized users through institutional access. Author Contribution Conceptualization – O.A. and M.E.Methodology – M.E and S.A.Formal Analysis – M.E and A.I.Writing – Original Draft: O.A and E.M.Writing – Review & Editing: O.A. , J.H. , F.F.Supervision: J.H. and F.F.All the authors reviewed and approved the final version of the manuscript. References Tyrrell CS, Allen JLY, Gkrania-Klotsas E. 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Histological remission in inflammatory bowel disease and risk of adverse pregnancy outcomes: A nationwide study. EClinicalMedicine. 2022;53:101722. doi: 10.1016/j.eclinm.2022.101722 Lichtenstein GR, Loftus EV, Afzali A, et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol. 2025;120(6):1225–64. doi: 10.14309/ajg.0000000000003465 Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019;114(3):384–413. doi: 10.14309/ajg.0000000000000152 Handley G, Hand J. Adverse Effects of Immunosuppression: Infections. Handb Exp Pharmacol. 2022;272:287–314. doi: 10.1007/164_2021_550 Irving PM, de Lusignan S, Tang D, et al. Risk of common infections in people with inflammatory bowel disease in primary care: a population-based cohort study. BMJ Open Gastroenterol. 2021;8(1). doi: 10.1136/bmjgast-2020-000573 Stobaugh DJ, Deepak P, Ehrenpreis ED. Hospitalizations for vaccine preventable pneumonias in patients with inflammatory bowel disease: a 6-year analysis of the Nationwide Inpatient Sample. Clin Exp Gastroenterol. 2013;6:43–9. doi: 10.2147/ceg.S42514 Zhang M, Bai X, Cao W, et al. The Influence of Corticosteroids, Immunosuppressants and Biologics on Patients With Inflammatory Bowel Diseases, Psoriasis and Rheumatic Diseases in the Era of COVID-19: A Review of Current Evidence. Front Immunol. 2021;12:677957. doi: 10.3389/fimmu.2021.677957 Tsai MJ, Yang KY, Chan MC, et al. Impact of corticosteroid treatment on clinical outcomes of influenza-associated ARDS: a nationwide multicenter study. Ann Intensive Care. 2020;10(1):26. doi: 10.1186/s13613-020-0642-4 Shale M, Czub M, Kaplan GG, et al. Anti-tumor necrosis factor therapy and influenza: keeping it in perspective. Therap Adv Gastroenterol. 2010;3(3):173–7. doi: 10.1177/1756283x10366368 Adas MA, Alveyn E, Cook E, et al. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18(3):253–61. doi: 10.1080/1744666X.2022.2014323 Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8(6):443–68. doi: 10.1016/j.crohns.2013.12.013 Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline Update: Preventive Care in Inflammatory Bowel Disease. Am J Gastroenterol. 2025;120(7):1447–73. doi: 10.14309/ajg.0000000000003541 Caldera F, Kane S, Long M, et al. AGA Clinical Practice Update on Noncolorectal Cancer Screening and Vaccinations in Patients With Inflammatory Bowel Disease: Expert Review. Clin Gastroenterol Hepatol. 2025;23(5):695–706. doi: 10.1016/j.cgh.2024.12.011 Liu Z, Alexander JL, Yee Eng K, et al. Antibody Responses to Influenza Vaccination are Diminished in Patients With Inflammatory Bowel Disease on Infliximab or Tofacitinib. J Crohns Colitis. 2024;18(4):560–9. doi: 10.1093/ecco-jcc/jjad182 Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa. Clin Infect Dis. 2019;68(6):895–902. doi: 10.1093/cid/ciy874 Caldera F, Hillman L, Saha S, et al. Immunogenicity of High Dose Influenza Vaccine for Patients with Inflammatory Bowel Disease on Anti-TNF Monotherapy: A Randomized Clinical Trial. Inflamm Bowel Dis. 2020;26(4):593–602. doi: 10.1093/ibd/izz164 Doornekamp L, Goetgebuer RL, Schmitz KS, et al. High Immunogenicity to Influenza Vaccination in Crohn's Disease Patients Treated with Ustekinumab. Vaccines (Basel). 2020;8(3). doi: 10.3390/vaccines8030455 Nakafero G, Grainge MJ, Card T, et al. Uptake, safety and effectiveness of inactivated influenza vaccine in inflammatory bowel disease: a UK-wide study. BMJ Open Gastroenterol. 2024;11(1). doi: 10.1136/bmjgast-2024-001370 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 06 Mar, 2026 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 12 Dec, 2025 Reviews received at journal 09 Dec, 2025 Reviewers agreed at journal 06 Nov, 2025 Reviewers invited by journal 28 Oct, 2025 Editor assigned by journal 24 Oct, 2025 Submission checks completed at journal 24 Oct, 2025 First submitted to journal 23 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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1","display":"","copyAsset":false,"role":"figure","size":399198,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of the study cohorts\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7936452/v1/3923c90e740e512d3cffff62.jpeg"},{"id":95502530,"identity":"00826496-1520-453c-bebe-f5404bcb2425","added_by":"auto","created_at":"2025-11-10 05:36:47","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":262182,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the hazard ratios comparing the outcomes between the Moderate to Severe/Active and Mild/Inactive IBD cohorts\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7936452/v1/11ffe6783ad2a096e14ff787.jpeg"},{"id":95529257,"identity":"e5b4e854-59aa-449f-a1a4-c8c0966cafe9","added_by":"auto","created_at":"2025-11-10 10:16:56","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":136084,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the hazard ratios of the flu risk for different immunotherapy medications\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7936452/v1/96098ee3b3d896845c3a0c97.jpeg"},{"id":104250812,"identity":"6cc1a8fd-7d17-4a1d-8e15-219666c49766","added_by":"auto","created_at":"2026-03-09 16:09:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1698273,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7936452/v1/f2f62eae-9540-4f29-a7be-cc9d44377de1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Severe Influenza-Related Outcomes in Patients with Inflammatory Bowel Disease on Immunosuppressive Therapy: A Propensity-Matched Cohort Analysis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eInfluenza remains a significant global health burden, causing substantial morbidity and mortality worldwide with annual seasonal influenza epidemics resulting in an estimated 290,000-650,000 deaths globally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although seasonal influenza can cause a mild, self-limited illness, it may also lead to complications such as pneumonia and acute respiratory distress syndrome, particularly in high-risk populations including young children, pregnant women, older adults, and immunocompromised individuals [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Among over 121,000 patients hospitalized with confirmed influenza across nine seasons (2010 through 2018), approximately 5.5% died, with the majority of deaths occurring in individuals aged 65 and older and those with underlying medical comorbidities [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePatients with inflammatory bowel disease (IBD), including Crohn\u0026rsquo;s disease (CD) and ulcerative colitis (UC), are considered a particularly vulnerable population due to their underlying immune dysregulation and frequent use of immunosuppressive therapies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The chronic inflammatory nature of IBD itself can compromise immune function and commonly used treatments like steroids, immunomodulators, and advanced therapies can further suppress the body\u0026rsquo;s immune responses [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This dual burden of disease-related and treatment-induced immunosuppression places patients with IBD at increased risk for infections including opportunistic infections, specifically when multiple immunosuppressive agents are used concurrently [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This risk is highly notable for viral infections, as these therapies can impair both innate and adaptive immune responses necessary for effective viral clearance [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough prior studies have demonstrated that patients with IBD are at greater risk of influenza infection and related complications, including hospitalization and extended hospital stays, most available literature have compared patients with IBD to the non-IBD population, rather than exploring variations in outcomes within IBD patients themselves [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, limited data exist on the influence of newly approved biologic and small-molecule agents on influenza-related outcomes during recent influenza seasons [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. To address these gaps, we conducted a propensity-matched analysis comparing influenza incidence and severity between patients with moderate-to-severe/active and mild/inactive IBD during the 2022\u0026ndash;2023 influenza season and performed subgroup analyses to evaluate the influence of specific immunosuppressive therapies on influenza-related outcomes.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData Source\u003c/h2\u003e\u003cp\u003eThis retrospective cohort study analyzed data from the TriNetX U.S Analytics Network Platform, a multicenter database that includes de-identified electronic health records of 66 Health Care Organizations (HCOs) with over 120\u0026nbsp;million patients across the United States. Health care organizations included in the TriNetX dataset are a mix of academic medical centers collecting data from their main and satellite hospitals, as well as outpatient clinics. The TriNetX platform allows for comparison between cohorts while accounting for potential confounders, using a propensity score matching (PSM) model. A rigorous quality assurance process ensures data integrity during the extraction from electronic health records (EHRs).\u003c/p\u003e\u003cp\u003ePatients\u0026rsquo; records were identified using International Classification of Diseases, Ninth or Tenth Edition, Clinical Modification (ICD-9-CM or ICD-10-CM) codes for patients\u0026rsquo; diagnoses, International Classification of Diseases, Tenth Edition, Procedure Coding System (ICD-10-PCS), and Current Procedural Terminology (CPT\u0026copy;) codes for procedures, Logical Observation Identifiers Names and Codes (LOINC codes) for laboratory tests, RxNorm and Veteran Affairs (VA) codes for medication use, and TriNetX codes for physical measurements and laboratory data.\u003c/p\u003e\u003cp\u003eSince the data are publicly available and deidentified, this study is exempt from approval by the Institutional Review Board (IRB). The de-identification process, as stipulated by the Health Insurance Portability and Accountability Act Privacy Rule (HIPAA), is meticulously executed at the network level by a qualified expert within the TriNetX framework. To ensure patient confidentiality and regulatory adherence, patient counts fewer than 10 are subject to automatic data suppression. Data were accessed on TriNetX from June 15th, 2025, through July 5th, 2025. TriNetX platform was previously applied and validated for investigating influenza as well as other viral respiratory infections within the US [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy participants and cohorts\u003c/h3\u003e\n\u003cp\u003eAdult patients (\u0026ge;\u0026thinsp;18 years) with a documented diagnosis of either CD (ICD-10: K50) or UC (ICD-10: K51) between October 1, 2022, and March 31, 2023, were eligible for inclusion. Two cohorts were constructed based on disease activity and treatment profiles. Cohort 1 (moderate to severe/active IBD): Patients were classified as having moderate to severe/active disease if they had evidence of an IBD flare within the 6 months preceding the qualifying diagnosis. Activity was defined by the presence of any of the following: elevated inflammatory markers (C-reactive protein [CRP]\u0026thinsp;\u0026ge;\u0026thinsp;10 mg/L, erythrocyte sedimentation rate [ESR]\u0026thinsp;\u0026ge;\u0026thinsp;20 mm/h, or fecal calprotectin\u0026thinsp;\u0026ge;\u0026thinsp;250 \u0026micro;g/g); initiation of systemic corticosteroids, new biologics or small-molecule agents (e.g., infliximab, adalimumab, vedolizumab, ustekinumab, tofacitinib, ozanimod, and upadacitinib) ; IBD-related symptoms or complications (e.g., rectal bleeding, intestinal obstruction, fistula). Cohort 2 (mild/inactive IBD): Patients were classified as having mild/inactive disease if they had no new corticosteroids, immunomodulator, or biologic therapy, no laboratory evidence, of active inflammation or recent complications during the same baseline period. This design is consistent with prior research, where patients with clinically active IBD were defined using recent prescriptions for steroids, or biologics and/or documented IBD-related complications or hospitalization [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eStudy outcomes\u003c/h3\u003e\n\u003cp\u003eOutcomes were assessed within an 180-day observation window following the index event, which was defined based on the earliest occurrence of qualifying diagnostic or treatment criteria for each cohort.\u003c/p\u003e\u003cp\u003eThe following outcomes were evaluated:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eIncidence of laboratory-confirmed or clinically diagnosed influenza, identified via ICD-10 codes (J09\u0026ndash;J11) and laboratory markers for influenza virus A and B RNA or antigen presence.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eUse of antiviral medications, including oseltamivir, zanamivir, and baloxavir, based on RxNorm codes.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOccurrence of influenza-related complications, including pneumonia (J12\u0026ndash;J18), acute bronchitis (J20), sepsis (A41.89), myocarditis (I51.4), encephalopathy (G93.40), and acute respiratory distress syndrome (J80).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eHospitalization, defined by inpatient services (CPT code 1013659). This outcome excluded patients with prior hospitalizations in the pre-index period.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIntensive care unit (ICU) admissions, captured through critical care procedure codes (CPT:1013729).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMechanical ventilation, identified via CPT and ICD-10-PCS codes for assisted ventilation procedures (e.g., 5A1935Z\u0026ndash;5A1955Z).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eCorticosteroid exposure, measured by prescriptions for prednisone, methylprednisolone, and hydrocortisone.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAll-cause mortality.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using TriNetX built-in function analytic tool, R\u0026rsquo;s survival package v3.2-3. Following cohort definition, a 1:1 PSM algorithm was applied using greedy nearest-neighbor matching without replacement, balancing baseline covariates including age, sex, race/ethnicity, and relevant clinical comorbidities. Standardized mean differences (SMD) were calculated to assess post-matching balance, with values\u0026thinsp;\u0026lt;\u0026thinsp;0.1 indicating acceptable covariate balance. For each outcome, time-to-event data were analyzed using the Kaplan\u0026ndash;Meier method. Survival curves were compared using the log-rank test, and hazard ratios (HR) with 95% CIs were calculated using Cox proportional hazards models. Patients were censored at the last recorded clinical encounter. Proportional hazards assumptions were assessed using standard diagnostics provided by the platform. For continuous outcomes, the mean and standard deviation were reported, and between-group differences were evaluated using t-tests. For categorical lab outcomes, proportions of positive, negative, and unknown results were compared. Analyses were stratified by outcome-specific settings: for example, hospitalization analyses excluded patients with prior admissions, whereas mortality analyses included all eligible patients. All hypothesis tests were two-tailed with a significance threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eBaseline characteristics of the Study cohorts\u003c/h2\u003e\u003cp\u003eIn the 2022\u0026ndash;2023 influenza season, a total of 56,212 were identified in the moderate to severe/active IBD, and 50,467 in the mild/inactive IBD cohort with nearly 30% of patients in each age group. Before PSM, the mean age of the active cohort was 46.9, and 52.9 in the mild/inactive IBD cohort. Females represented 52.3% of the moderate to severe/active IBD, and 54.7% of the mild/inactive IBD. White individuals were 75.4% of the moderate to severe/active group vs. 77% in the mild/inactive group. Following PSM, each group included 22,784 patients with the mean age of 49\u0026thinsp;\u0026plusmn;\u0026thinsp;19 years, The two cohorts were evenly matched regarding demographics, underlying comorbidities, and lifestyle features (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient baseline characteristics before and after Propensity score matching\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eBaseline characteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eBefore matching\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eStd. Diff.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eAfter matching\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eStd. Diff.\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMild/Inactive IBD \u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;50,467\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eModerate to severe/active IBD \u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;56,212\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMild/Inactive IBD \u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;22,784\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eModerate to severe/Active IBD \u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;22,784\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (yrs, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e52.9\u0026thinsp;\u0026plusmn;\u0026thinsp;18.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e46.9\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.324\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e49.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e49.1\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.033\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u0026ndash;40 years, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12,623\u0026nbsp;(25.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20,229\u0026nbsp;(36.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.240\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7,278\u0026nbsp;(31.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7,388\u0026nbsp;(32.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.010\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e40\u0026ndash;60 years, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15,316 (30.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16,404 (29.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.026\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6,726 (29.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6,744 (29.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;60 years, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20,850 (41.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16,480 (29.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.253\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7,781 (34.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7,644 (33.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDemographics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27,622 (54.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29,372 (52.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.050\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12,094\u0026nbsp;(53.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11,965\u0026nbsp;(52.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38,879 (77.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42,359 (75.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.040\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17,295 (75.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e17,192\u0026nbsp;(75.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlack or African American, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4,568 (9.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5,390 (9.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2,151 (9.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2,186 (9.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAsian, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,053 (2.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,334 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e552 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e579 (2.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHispanic or Latino, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,021 (4.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2,817 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.049\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1,193 (5.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,196 (5.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTobacco use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,439 (2.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2,420 (4.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.078\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e788 (3.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e791 (3.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes mellitus, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4,261 (8.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4,328 (7.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.027\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1,891 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,833 (8.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEssential hypertension, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9,315 (18.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10,291 (18.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4,183 (18.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4,161 (18.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHyperlipidemia, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4,561 (9.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5,122 (9.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2,055 (9.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2,073 (9.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOverweight and obesity, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,036 (6.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4,273 (7.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.063\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1,530 (6.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,494 (6.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic kidney disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,977 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2,591 (4.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.034\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e968 (4.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e985 (4.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIschemic heart diseases, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,455 (4.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2,738 (4.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1,077 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,078 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeart failure, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,169 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,449 (2.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e535 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e531 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHIV, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e130 (0.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100 (0.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e57 (0.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e47 (0.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInfluenza risk and influenza-related complications\u003c/h3\u003e\n\u003cp\u003ePatients in the moderate to severe/active IBD cohort had a mean follow-up duration of 173\u0026thinsp;\u0026plusmn;\u0026thinsp;30 days, whereas those in the mild/inactive IBD cohort were followed up for 163\u0026thinsp;\u0026plusmn;\u0026thinsp;49 days. The risk of developing influenza was higher in patients with moderate to severe/active IBD compared to those with mild/inactive IBD (7.1% vs. 4.9%; HR, 1.41; 95% CI, 1.30\u0026ndash;1.52, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The risk of influenza-related hospitalization was (9.5% vs. 4.6%; HR, 2.05; 95% CI, 1.89\u0026ndash;2.23, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) Influenza-related complications were significantly higher in the moderate to severe/active IBD cohort (4.0% vs 2.9%; HR, 1.36; 95% CI, 1.23 \u0026minus;\u0026thinsp;1.51; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). ICU admissions (2.7% vs 1.7%; HR, 1.51; 95% CI, 1.33\u0026ndash;1.72; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and mechanical ventilation (0.8% vs 0.5%; HR, 1.68; 95% CI, 1.32\u0026ndash;2.13; p\u0026thinsp;\u0026lt;\u0026thinsp;.001) were more frequent in the moderate to severe/active IBD group compared to the mild/inactive group. The rates of antiviral medications (0.6% vs 0.4%; HR, 1.60; 95% CI, 1.22 \u0026minus;\u0026thinsp;2.10; p\u0026thinsp;=\u0026thinsp;0.001) were significantly higher among moderate to severe/active IBD cohort patients. Overall mortality was slightly higher in the moderate to severe/active IBD cohorts (1.1% vs 0.9%; HR 1.17, 95% CI 1.02\u0026ndash;1.35; p\u0026thinsp;=\u0026thinsp;0.01) \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of the outcomes between the Moderate to Severe/Active and Mild/Inactive IBD cohorts\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eModerate to Severe/Active IBD\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;22,784\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMild/Inactive IBD\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;22,784\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHR\u003c/p\u003e\u003cp\u003e(95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFollow-up duration (days, mean, SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e173 (30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e163 (49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfluenza risk, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,623 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,125 (4.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.41\u0026nbsp;(1.30\u0026ndash;1.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospitalization, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,663 (9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e848 (4.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.05 (1.89\u0026ndash;2.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfluenza complications, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e916 (4.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e652 (2.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.36 (1.23\u0026ndash;1.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAntiviral medication use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e140 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e84 (0.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.60 (1.22\u0026ndash;2.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRisk of ICU admission, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e608 (2.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e390 (1.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.51 (1.33\u0026ndash;1.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e180 (0.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104 (0.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.68 (1.32\u0026ndash;2.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOverall mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e252 (1.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e213 (0.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.17 (1.02 \u0026minus;\u0026thinsp;1.35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eSubgroup analysis by immunosuppressive medications\u003c/h3\u003e\n\u003cp\u003eSubgroup analysis was associated with a significantly higher influenza risk in patients with moderate to severe/active IBD than patients with mild/inactive IBD across all included immunosuppressive classes (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The largest relative increase was observed with steroids (HR 1.62, 95% CI 1.53\u0026ndash;1.72; 7.77% vs 4.61%), followed by JAK inhibitors (HR 1.53, 1.43\u0026ndash;1.63; 7.27% vs 4.55%), anti-IL-23 agents (HR 1.52, 1.43\u0026ndash;1.63; 7.23% vs 4.54%), anti-IL-12/23 agents (HR 1.47, 1.38\u0026ndash;1.57; 6.98% vs 4.54%), and anti-TNF agents (HR 1.46, 1.37\u0026ndash;1.56; 6.84% vs 4.47%) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eHazard ratios of the flu risk after different immunosuppressive medications\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFlu Risk in Moderate to Severe/Active IBD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFlu Risk in Mild/Inactive IBD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSteroids\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2,864 (7.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1,700 (4.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.62 (1.53\u0026ndash;1.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJAK inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2,355 (7.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1,475 (4.55)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.53 (1.43\u0026ndash;1.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-IL-23 agent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2,350 (7.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1,475 (4.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.52 (1.43\u0026ndash;1.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-IL-12/23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2,379 (6.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1,545 (4.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.47 (1.38\u0026ndash;1.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-TNF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2,415 (6.84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1,578 (4.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.46 (1.37\u0026ndash;1.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003ePatients with moderate to severe/active IBD frequently require immunosuppressive therapies, including corticosteroids, biologics, and small-molecule agents, to control disease activity and prevent flares [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although immunosuppression is a recognized risk factor for infections [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], the extent to which recent immunosuppressive exposure contributes to severe influenza-related outcomes in the IBD population remains insufficiently characterized [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In this large real-world study, patients with moderate to severe/active IBD were associated with a higher risk of influenza infection (51%), hospitalizations (105%), influenza-related complications (36%), and ICU admission (51%) when compared with those with mild/inactive disease. Among specific immunosuppressive therapy, the highest risks were observed with corticosteroids (62% increase), followed by JAK inhibitors and anti-IL-23 agents (both around 53%).\u003c/p\u003e\u003cp\u003eThese results are consistent with prior literature indicating that patients with IBD requiring immunosuppressive therapy are particularly susceptible to respiratory viral infections. Stobaugh and colleagues reported elevated odds of hospitalization for influenza-related pneumonia among patients with UC [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Similarly, Tinsley et al., analyzing data of over 140,000 patients from the MarketScan database, found that individuals with IBD had a 54% higher risk of influenza compared to non-IBD controls, along with a significantly increased likelihood of hospitalization for influenza-related illness [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Notably, both studies compared patients with IBD to the general population without IBD, whereas our study focused exclusively on individuals with IBD, comparing those recently exposed to immunosuppressive therapy to those who were not. The agreement in observations across these studies supports the notion that the elevated risk of infection and complications is at least partly driven by immunosuppressive therapy.\u003c/p\u003e\u003cp\u003eIn the current study, the highest risk of influenza was observed in the subgroup taking steroids. This is similar to the previous study by Tinsley et al., reporting that systemic corticosteroids were the only medication class independently associated with increased influenza risk in IBD compared to non-IBD patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While their analysis did not find a significant association with other immunosuppressive agents, our results expand on this by demonstrating that multiple classes including corticosteroids, JAK inhibitors, and IL-23 antagonists, are associated with an elevated risk of influenza and its related complications. Another large population-based cohort study in UK by Irving et al., reported that patients with IBD receiving systemic corticosteroids, immunotherapies, or biologics were at particularly increased risk of viral infections, while those on amino salicylates did not show the same susceptibility [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe heightened risk of severe influenza-related effects in IBD patients under immunosuppression is biologically plausible, given the suppression of both innate and adaptive immune responses by immunosuppressive drugs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. For instance, corticosteroids suppress T-cell activation and inflammatory signaling pathways, which might delay viral clearance and increase the eventual complication of pneumonia and sepsis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Similarly, biologic agents and targeted small molecules used in IBD disrupt key immunologic pathways necessary for antiviral defense, thereby increasing susceptibility to influenza. Anti-TNF agents impair the activity of tumor necrosis factor-α, a cytokine central to the recruitment and activation of macrophages and dendritic cells, thus weakening early viral clearance and mucosal immunity [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. IL-23 and IL-12/23 inhibitors block the IL-23/Th17 axis, which is essential for maintaining epithelial barriers and promoting antiviral responses through IL-17\u0026ndash;mediated neutrophil recruitment. By inhibiting this pathway, these agents may reduce mucosal immune surveillance, increasing vulnerability to respiratory viruses [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. JAK inhibitors interfere with intracellular signaling of multiple cytokine receptors, including those for interferons, which are pivotal in modulating the innate and adaptive immune response to viral pathogens. As such, their use can result in diminished antiviral signaling and impaired lymphocyte function [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Together, these immunosuppressive mechanisms help explain the elevated risk of influenza infection and complications observed across multiple drug classes in our cohort.\u003c/p\u003e\u003cp\u003eCurrent guidelines and practices, including those from the American College of Gastroenterology (ACG), European Crohn\u0026rsquo;s and Colitis Organization (ECCO) and American Gastroenterological Association (AGA), recommend annual inactivated influenza vaccination for all patients with IBD on immunosuppression, ideally administered prior to the onset of the influenza season [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Our findings reinforce these recommendations, highlighting the increased vulnerability to severe influenza-related complications among patients treated with immunosuppressants within the preceding six months. However, a key challenge is that certain immunosuppressive therapies, particularly anti-TNF agents (alone or in combination with thiopurines) and JAK inhibitors, may attenuate serologic responses to the vaccine [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Nonetheless, vaccination still confers meaningful protection and should not be withheld [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In a randomized trial, by Caldera et al., IBD patients under anti-TNF monotherapy elicit significantly greater antibody levels when given the high-dose influenza vaccine compared to the standard dose, suggesting that immunogenicity can be optimized with dosing strategies [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. On the other hand, biologics such as ustekinumab (anti\u0026ndash;IL-12/23) have not been shown to impair vaccine-induced immune responses, and patients on these agents can mount adequate protection [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite guideline endorsements, vaccination uptake remains suboptimal among IBD patients due to limited provider recommendation, patient concerns about safety, and underappreciation of infection risks [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Given the elevated influenza burden and complications seen in immunosuppressed IBD populations, improving vaccine coverage and enhancing clinician\u0026ndash;patient communication are essential components of prevention. Prompt initiation of antiviral therapy such as oseltamivir, zanamivir, or peramivir is critical for suspected or confirmed influenza cases in these high-risk individuals [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study builds on existing evidence by quantifying the direct impact of recent immunosuppressive therapy on influenza outcomes in IBD patients, revealing a detailed association with increased risks of hospitalization, ICU admission, and mortality. A major strength of this work is the use of a large, multi-institutional dataset combined with rigorous 1:1 PSM to control confounders, enabling robust comparisons between immunosuppressed and non-immunosuppressed IBD patients. Additionally, we provide real-world estimates of key clinical outcomes such as ICU admission, mechanical ventilation, and mortality. Limitations of the current study include lack of definitive IBD activity measures, instead, we relied on drug exposure and biomarkers like C-reactive protein, and this may have introduced residual confounding effect. Use of these administrative databases also presents risk of coding errors and limitations of the clinical data; we could not determine the severity of influenza at presentation and vaccination status remains uncertain while there may be unmeasured confounding such as adherence to medications. Future studies should be prospective, longitudinal studies, involving laboratory confirmed influenza, and utilize standardized measures of IBD activity including clinical measures, imaging studies, and laboratory assessments. Head-to-head comparisons of individual agents will be needed to identify which agents have the greatest risk of infection. Although the evaluation of effectiveness, and timing of vaccination in patients with IBD on immunosuppressive therapy will be crucial to provide personalized prevention strategies.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003ePatients with moderate to severe/active IBD receiving immunosuppressive therapy have a higher risk of influenza infection and severe complications, including hospitalization, ICU admission, and mortality, compared to those with mild/inactive IBD. These findings emphasize the importance of annual influenza vaccination and timely antiviral treatment in this vulnerable population. Improving vaccine uptake through better clinician\u0026ndash;patient communication and careful management of immunosuppressive therapies during influenza seasons are key to reducing influenza-related risks in moderate to severe IBD patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSources of Support\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe contributing authors have no financial, professional, personal, or other conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Farraye has served as a Consultant for Astellas, Avalo Therapeutics, Bausch, BMS, Braintree Labs, Fresenius Kabi, GI Reviewers, IBD Educational Group, Iterative Health, Janssen, Pharmacosmos, Pfizer, Sandoz Immunology, Viatris.He sits on a DSMB for Eli Lilly and Moon Lake\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available from the TriNetX Research Network for authorized users through institutional access.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization \u0026ndash; O.A. and M.E.Methodology \u0026ndash; M.E and S.A.Formal Analysis \u0026ndash; M.E and A.I.Writing \u0026ndash; Original Draft: O.A and E.M.Writing \u0026ndash; Review \u0026amp; Editing: O.A. , J.H. , F.F.Supervision: J.H. and F.F.All the authors reviewed and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTyrrell CS, Allen JLY, Gkrania-Klotsas E. 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BMJ Open Gastroenterol. 2024;11(1). doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmjgast-2024-001370\u003c/span\u003e\u003cspan address=\"10.1136/bmjgast-2024-001370\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Inflammatory bowel disease, Immunosuppressive therapy, Influenza, Biologic agents, Disease activity","lastPublishedDoi":"10.21203/rs.3.rs-7936452/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7936452/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePatients with moderate-to-severe inflammatory bowel disease (IBD) often require immunosuppressive therapy to achieve and maintain remission; however, the impact of these medications on influenza risk and the severity of influenza-related complications remains inadequately characterized.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eUsing the TriNetX U.S. Analytics Network, adults (\u0026ge;\u0026thinsp;18 years) with Crohn\u0026rsquo;s disease or ulcerative colitis during the 2022\u0026ndash;2023 influenza season were identified. Patients were stratified by disease activity into two cohorts: (1) moderate-to-severe/active IBD, defined by elevated inflammatory markers, initiation of corticosteroids or a new biologic or small-molecule agent, or documented IBD-related symptoms or complications within the prior six months; and (2) mild/inactive IBD, defined by the absence of these features and no recent immunosuppressive therapy. Propensity score matching (1:1) was used to balance baseline characteristics, and Cox proportional hazards models were applied to estimate hazard ratios for influenza-related outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAfter propensity score matching, each group had 22,784 patients. The incidence of influenza diagnosis was significantly higher in the moderate-to-severe/active IBD group (HR 1.41; 95% CI, 1.30\u0026ndash;1.52). Hospitalization rates were also increased (HR 2.05; 95% CI, 1.89\u0026ndash;2.23), as were influenza-related complications (HR 1.36; 95% CI, 1.23\u0026ndash;1.51). ICU admissions (HR 1.51; 95% CI, 1.33\u0026ndash;1.72) and mechanical ventilation (HR 1.68; 95% CI, 1.32\u0026ndash;2.13) were both more frequent in the moderate-to-severe/active IBD group. Use of antiviral medications was higher among those in this cohort (HR 1.60; 95% CI, 1.22\u0026ndash;2.10), and overall mortality was modestly increased (HR 1.17; 95% CI, 1.02\u0026ndash;1.35). Subgroup analysis revealed the highest risk among patients on corticosteroids, followed by JAK inhibitors and anti\u0026ndash;IL-23 agents.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePatients with moderate-to-severe/active IBD had more severe influenza-related outcomes compared with mild/inactive controls. Improving vaccine uptake and prompt evaluation of upper respiratory symptoms during influenza seasons are key to reducing influenza-related risks in immunosuppressed patients with IBD.\u003c/p\u003e","manuscriptTitle":"Severe Influenza-Related Outcomes in Patients with Inflammatory Bowel Disease on Immunosuppressive Therapy: A Propensity-Matched Cohort Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 05:36:42","doi":"10.21203/rs.3.rs-7936452/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-12T22:57:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-10T01:24:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"70128504100699219019742828504363673521","date":"2025-11-06T16:04:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-28T15:23:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-24T20:12:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-24T14:07:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2025-10-24T03:41:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c324df4e-7bed-4de1-9cea-411d7f81b954","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-09T16:05:00+00:00","versionOfRecord":{"articleIdentity":"rs-7936452","link":"https://doi.org/10.1007/s10620-026-09773-1","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2026-03-06 15:59:35","publishedOnDateReadable":"March 6th, 2026"},"versionCreatedAt":"2025-11-10 05:36:42","video":"","vorDoi":"10.1007/s10620-026-09773-1","vorDoiUrl":"https://doi.org/10.1007/s10620-026-09773-1","workflowStages":[]},"version":"v1","identity":"rs-7936452","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7936452","identity":"rs-7936452","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}