Symptomology following mRNA vaccination against SARS-CoV-2.

Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination.

Is synoptic operative reporting necessary for Crohn's disease surgery? Variability in surgical reports across inflammatory bowel disease referral centres.

AIM: Ileocolic resection (ICR) is the most commonly performed operation in Crohn's disease (CD) patients. The surgical report is a vital tool for accessing information to gauge a patient's long-term prognosis and guide treatment decisions. Dictated narrative reports are the traditional method for surgical documentation but often lack essential information. The objective was to assess the quality of operation note in CD patients undergoing ICR. METHOD: This was a multi-institutional retrospective cohort collaborative study involving four tertiary inflammatory bowel disease referral centres in the USA and Canada. The patients were consecutive CD patients undergoing ICR between 2014 and 2020. There were no interventions. The main outcome measures were the variability and frequency of 28 critical items in the operation note. RESULTS: An analysis of 400 consecutive operation reports in four institutions (n = 100/institution) revealed significant variability in almost all variables. The initial surgical approach and wound protector use were the most consistently or frequently reported across all inflammatory bowel disease centres. The limitation was that this was a retrospective cohort study with inevitable selection bias. CONCLUSIONS: This study highlights the need for synoptic reporting in CD patients undergoing ICR.

Postvaccination Symptoms After SARS-CoV-2 mRNA Vaccination Among Patients With Inflammatory Bowel Disease: A Prospective, Comparative Study.

BACKGROUND: Vaccine hesitancy is prevalent among people with IBD, in part due to insufficient evidence regarding comparative safety of vaccines in this population. METHODS: We conducted a nationwide comparative study of postvaccination symptoms among those with IBD and health care workers (HCWs) without IBD. Symptom frequency, severity, and duration were measured. Continuous and categorical data were analyzed using Wilcoxon rank-sum and Fisher's exact test. Regression analysis was used to adjust for confounding variables. RESULTS: We had 2910 and 2746 subjects who completed a survey after dose 1 (D1) and dose 2 (D2) respectively (D1: HCW = 933, IBD = 1977; D2: HCW = 884, IBD = 1862). Mean age was 43 years, 67% were female, and 23% were nonwhite; 73% received BNT162b2 (Pfizer) including almost all HCWs and 60% of IBD patients. Most postvaccine symptoms were mild and lasted ≤2 days after both doses in both groups. Health care workers experienced more postvaccination symptoms overall than IBD patients after each dose (D1: 57% vs 35%, P < .001; D2: 73% vs 50%, P < .001). Gastrointestinal symptoms were noted in IBD more frequently after D1 (5.5% vs 3%, P = .003) but not after D2 (10% vs 13%, P = .07). Inflammatory bowel disease subjects who received mRNA-1273 (Moderna) reported more overall symptoms compared with BNT162b2 (57% vs 46%, P < .001) including gastrointestinal symptoms (12% vs 8%, P = .002) after D2. CONCLUSIONS: People with IBD had fewer postvaccination symptoms following the first 2 doses of SARS-CoV-2 mRNA vaccines than HCWs. Among those with symptoms, most symptoms were mild and of short duration.

Those with inflammatory bowel disease (IBD) reported fewer postvaccination symptoms relative to non-IBD health care workers. Local and systemic symptoms were generally mild and lasted less than 2 days in both populations. The data are reassuring with considerable vaccine hesitancy.

Ileal Paneth Cell Phenotype is a Cellular Biomarker for Pouch Complications in Ulcerative Colitis.

BACKGROUND & AIMS: Biomarkers that integrate genetic and environmental factors and predict outcome in complex immune diseases such as inflammatory bowel disease (IBD; including Crohn's disease [CD] and ulcerative colitis [UC]) are needed. We showed that morphologic patterns of ileal Paneth cells (Paneth cell phenotype [PCP]; a surrogate for PC function) is one such cellular biomarker for CD. Given the shared features between CD and UC, we hypothesized that PCP is also associated with molecular/genetic features and outcome in UC. Because PC density is highest in the ileum, we further hypothesized that PCP predicts outcome in UC subjects who underwent total colectomy and ileal pouch-anal anastomosis (IPAA). METHODS: Uninflamed ileal resection margins from UC subjects with colectomy and IPAA were used for PCP and transcriptomic analyses. PCP was defined using defensin 5 immunofluorescence. Genotyping was performed using Immunochip. UC transcriptomic and genotype associations of PCP were incorporated with data from CD subjects to identify common IBD-related pathways and genes that regulate PCP. RESULTS: The prevalence of abnormal ileal PCP was 27%, comparable to that seen in CD. Combined analysis of UC and CD subjects showed that abnormal PCP was associated with transcriptomic pathways of secretory granule maturation and polymorphisms in innate immunity genes. Abnormal ileal PCP at the time of colectomy was also associated with pouch complications including de novo CD in the pouch and time to first episode of pouchitis. CONCLUSIONS: Ileal PCP is biologically and clinically relevant in UC and can be used as a biomarker in IBD.

Postvaccination Symptoms After a Third Dose of mRNA SARS-CoV-2 Vaccination in Patients With Inflammatory Bowel Disease: Results From CORALE-IBD.

BACKGROUND: The safety of a third dose of SARS-CoV-2 mRNA vaccination in patients with inflammatory bowel disease is unknown. METHODS: We compared symptoms following a third SARS-CoV-2 mRNA vaccine dose with symptoms after the second dose in IBD. RESULTS: The study group included 594 patients (70% female, 58% BNT162b2). Overall, 41% reported symptoms after a third dose. Symptom frequency and severity were lower after the third dose relative to the second dose for every organ system, except for gastrointestinal symptoms which were marginally worse. CONCLUSION: The frequency and severity of symptoms after a third mRNA vaccine dose are generally similar or milder than after a second dose for most organ systems.

The postvaccination symptom profile in patients with IBD is unknown after a third mRNA COVID vaccine dose. In a cohort of 594 subjects with IBD, we demonstrated that 41% experienced any symptoms after a third dose, the vast majority of which were mild and lasted less than 2 days. Symptoms after third dose were less frequently reported than after the second dose.

Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis.

The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and noninflamed samples from patients with inflammatory bowel disease (IBD) undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF/CFTR signaling axis in the adult intestine and identify epithelial cell-derived TNF as an upstream regulator of mucin homeostasis.

Watchful Waiting After Radiological Guided Drainage of Intra-abdominal Abscess in Patients With Crohn's Disease Might Be Associated With Increased Rates of Stoma Construction.

Background: Management of spontaneous intra-abdominal abscess (IAA) in patients with Crohn's disease (CD) with radiologically guided percutaneous drainage (PD) was debated. Methods: This is a secondary analysis from a multicenter, retrospective cohort study of all the patients with CD who underwent PD followed by surgery at 19 international tertiary centers. Results: Seventeen patients (4.8%) who did not undergo surgery after PD were compared to those who had PD followed by surgical intervention 335/352 (95.2%). Patients who had PD without surgery were those with longer disease duration, more frequently had previous surgery for CD (laparotomies/laparoscopies), enteric fistula, on steroid treatment before and continue to have it after PD. Patients who had PD without subsequent surgical resection had a higher risk of stoma construction at later stages 8/17 (47.1%) versus 90/326 (27.6%) (P < .01). Patients with PD with no subsequent surgery had numerically higher rates of abscess recurrence 5/17 (29.4%) compared to those who had PD followed by surgery 45/335 (13.4%) the difference was not statistically significant (P = .07). Conclusions: Even with the low number of patients enrolled in this study who had PD of IAA without subsequent surgery, the findings indicate a markedly worse prognosis in terms of recurrence, length of stay, readmission, and stoma construction. Watchful waiting after PD to treat patients with spontaneous IAA might be indicated in selected patients with poor health status or poor prognostic factors.

Differences in SARS-CoV-2 Vaccine Response Dynamics Between Class-I- and Class-II-Specific T-Cell Receptors in Inflammatory Bowel Disease.

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vß gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.

Exploring the perioperative outcomes of a sample of successful adopters of transanal total mesorectal excision (taTME) during the learning phase.

BACKGROUND: Transanal total mesorectal excision can be a technically challenging operation to master. While many early adopters have reported adequate outcomes, others have failed to reproduce these results. There are contradicting data on oncologic outcomes during the learning phase of this technique. Thus, our objective was to perform a multicentered assessment of oncological outcomes in patients undergoing transanal total mesorectal excision during the learning phase in a sample of successful adopting centers. METHODS: Surgeons from 8 centers with experience in the management of rectal cancer were invited to participate. The initial 51 consecutive benign and malignant cases of the participating units were retrospectively reviewed, but only 366 cancer cases were included in the analysis. Procedures were divided into implementation (ie, the first 10 cases) and postimplementation (ie, case 11 on onwards) groups, and the main outcome was the incidence of local recurrence. RESULTS: The overall prevalence of local recurrence was 4.1% at a median follow-up of 35 months (interquartile range 20.3-44.2); among implementation and postimplementation groups local recurrence was 7.5% and 3.1%, respectively, and the rate of local recurrence was observed to be nearly 60% lower in the postimplementation group (hazard ratio [95% confidence interval] = 0.43 [0.26-0.72]) Total mesorectal excision specimens were complete or nearly complete in 87.7% of cases, and the circumferential and distal margins were clear in 93.2% and 92.6%, respectively CONCLUSION: Local recurrence rate was low during the learning phase of the transanal total mesorectal excision in a sample of rectal cancer surgeons with acceptable surgical and oncologic outcomes. Both the prevalence and rate of local recurrence were markedly lower in the postimplementation phase, indicating improvement as experience accumulated.

The T-cell clonal response to SARS-CoV-2 vaccination in inflammatory bowel disease patients is augmented by anti-TNF therapy and often deficient in antibody-responders.

BACKGROUND: Vaccination against SARS-CoV-2 is a highly effective strategy to protect against infection, which is predominantly mediated by vaccine-induced antibodies. Postvaccination antibodies are robustly produced by those with inflammatory bowel disease (IBD) even on immune-modifying therapies but are blunted by anti-TNF therapy. In contrast, T-cell response which primarily determines long-term efficacy against disease progression,, is less well understood. We aimed to assess the post-vaccination T-cell response and its relationship to antibody responses in patients with inflammatory bowel disease (IBD) on immune-modifying therapies. METHODS: We evaluated IBD patients who completed SARS-CoV-2 vaccination using samples collected at four time points (dose 1, dose 2, 2 weeks after dose 2, 8 weeks after dose 2). T-cell clonal analysis was performed by T-cell Receptor (TCR) immunosequencing. The breadth (number of unique sequences to a given protein) and depth (relative abundance of all the unique sequences to a given protein) of the T-cell clonal response were quantified using reference datasets and were compared to antibody responses. RESULTS: Overall, 303 subjects were included (55% female; 5% with prior COVID) (Table). 53% received BNT262b (Pfizer), 42% mRNA-1273 (Moderna) and 5% Ad26CoV2 (J&J). The Spike-specific clonal response peaked 2 weeks after completion of the vaccine regimen (3- and 5-fold for breadth and depth, respectively); no changes were seen for non-Spike clones, suggesting vaccine specificity. Reduced T-cell clonal depth was associated with chronologic age, male sex, and immunomodulator treatment. It was preserved by non-anti-TNF biologic therapies, and augmented clonal depth was associated with anti-TNF treatment. TCR depth and breadth were associated with vaccine type; after adjusting for age and gender, Ad26CoV2 (J&J) exhibited weaker metrics than mRNA-1273 (Moderna) (p=0.01 for each) or BNT262b (Pfizer) (p=0.056 for depth). Antibody and T-cell responses were only modestly correlated. While those with robust humoral responses also had robust TCR clonal expansion, a substantial fraction of patients with high antibody levels had only a minimal T-cell clonal response. CONCLUSION: Age, sex and select immunotherapies are associated with the T-cell clonal response to SARS-CoV-2 vaccines, and T-cell responses are low in many patients despite high antibody levels. These factors, as well as differences seen by vaccine type may help guide reimmunization vaccine strategy in immune-impaired populations. Further study of the effects of anti-TNF therapy on vaccine responses are warranted.

Outcomes of Definitive Draining Seton Placement for Complex Anal Fistula in Crohn's Disease.

Definitive draining seton (DDS) alone is an accepted treatment for complex refractory anal fistulas in Crohn's disease (CD). We evaluated the long-term success of DDS in CD patients. DDS was defined as draining seton placed definitively for at least 12 months. Primary end point was clinical response (CR) defined as a lack of induration, pain, swelling, abscess recurrence, or unintended dislodgement. The study cohort of 23 patients had a median age of 29 (range; 9-61) years and included 14 males (61%). Reasons for DDS included anal stenosis (n = 9; 39%), active proctitis (n = 9; 39%), and/or anal canal ulceration (n = 9; 39%). Median number of setons was 2 (range; 1-6) and 65% had multiple fistula tracts. Almost all patients (n = 22; 96%) were on a biologic postoperatively. At 12-month follow-up, only 39% (n = 9) had a CR. The remaining 14 patients failed due to new abscess formation (n = 6; 26%), new fistula formation (n = 6; 26%), and seton dislodgement (n = 2; 9%). Six (26%) patients required fecal diversion. No patients required proctectomy. DDS for complex CD fistula results in a mediocre CR with many patients developing recurrent abscess/fistula or requiring diversion despite biologic therapy.

A Standardized Multimodal Analgesia Protocol Reduces Perioperative Opioid Use in Minimally Invasive Colorectal Surgery.

BACKGROUND: Multimodal analgesia protocols are becoming a common part of enhanced recovery pathways after colorectal surgery. However, few protocols include a robust intraoperative component in addition to pre-operative and post-operative analgesics. METHOD: A prospective cohort study was performed in an urban teaching hospital in patients undergoing minimally invasive colorectal surgery before and after implementation of a multimodal analgesia protocol consisting of pre-operative (gabapentin, acetaminophen, celecoxib), intraoperative (lidocaine and magnesium infusions, ketorolac, transversus abdominis plane block), and post-operative (gabapentin, acetaminophen, celecoxib) opioid-sparing elements. The main outcome measure was use of morphine equivalents in the first 24-h post-operative period. RESULTS: The study cohort (n = 71) included 41 patients before and 30 patients after implementation of a multimodal analgesia protocol. Mean age of the entire study cohort was 47 ± 19.7 years and 46% were male. Patients undergoing surgery post-multimodal analgesia vs. pre-multimodal analgesia had significantly lower use of IV morphine equivalents in first 24-h post-operative period (5.8 ± 6.4 mg vs. 22.8 ± 21.3 mg; p = 0.005) and first 48-h post-operative period (7.6 ± 9.4 mg vs. 42 ± 52.9 mg; p = 0.0008). This reduction in IV morphine equivalent use post-multimodal analgesia was coupled with improved pain scores in the post-operative period. Post-operative hospital length of stay, post-operative ileus, and overall complications were not significantly different between groups. CONCLUSIONS: Multimodal analgesia incorporating pre-operative, intraoperative, and post-operative opioid-sparing agents is an effective method for reducing perioperative opioid utilization and pain after minimally invasive colorectal surgery.

A Systematic Review of Unsystematic Total Ankle Replacement Wear Evaluations.

BACKGROUND: Numerous studies have reported the use of laboratory multistation joint simulators to successfully predict wear performance and functionality of hip and knee replacements. In contrast, few studies in the peer-reviewed literature have used joint simulation to quantify the wear performance and functionality of ankle replacements. We performed a systematic review of the literature on joint simulator studies that quantified polyethylene wear in total ankle arthroplasty. In addition to the quantified wear results, the load and motion parameters were identified and compared among the studies. METHODS: A search was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to identify articles reporting total ankle replacement polyethylene wear using joint simulators. RESULTS: Nine studies that used joint simulators and 1 study that used a computer simulation were found. Although all studies used physiological multidirectional motions (i.e., internal/external rotation, plantar flexion/dorsiflexion, anterior/posterior translation), there was large variability among the studies in the magnitudes of these motions. Among these studies, mean non-cross-linked polyethylene wear ranged from 3.3 ± 0.4 to 25.8 ± 3.1 mm per million cycles. In contrast, mean highly cross-linked polyethylene wear ranged from 2.1 ± 0.3 to 3.3 ± 0.4 mm per million cycles. The wide distribution in wear rates was attributable to the highly inconsistent kinematic parameters and loads applied as well as differences in implant design and materials. CONCLUSIONS: There is a severe lack of clinically applicable data on wear performance of total ankle replacements in the peer-reviewed literature. No universal set of kinematic load parameters has been established. Furthermore, only 2 of the published studies have validated their findings using independently derived data, such as retrieval analysis. These shortcomings make it difficult to compare findings as a function of design parameters and materials, or to draw clinically relevant conclusions from these simulations. More work is required to enhance the predictive capability of in vitro simulations of total ankle replacements. CLINICAL RELEVANCE: The results of joint wear simulator studies may not accurately represent in vivo wear of total ankle replacements. Joint simulator studies should establish that they are accurately replicating in vivo wear, thus enabling use of their predictive capabilities for new materials and designs.

No Pain, More Gain: Reduced Postoperative Opioid Consumption with a Standardized Opioid-Sparing Multimodal Analgesia Protocol in Opioid-Tolerant Patients Undergoing Colorectal Surgery.

The utility of opioid-sparing multimodal analgesia protocols (OSMMAPs) in opioid-tolerant (OT) patients is unknown. We sought to determine the impact of a standardized OSMMAP in OT versus opioid-naïve (ON) patients after major colorectal surgery. Consecutive patients undergoing surgery before (January 2015-March 2017) and after OSMMAP implementation (April 2017-March 2018) were identified from a single-institution prospective colorectal surgery registry. OT was defined by the presence of an opioid on the preadmission medication record. Opioid use (measured in oral morphine equivalents (OMEs)) and surgical outcomes were compared between OT and ON patients pre- and post-OSMMAP. The study cohort of 201 patients included 59 OT patients (25 pre- and 34 post-OSMMAP) and 142 ON controls (34 pre- and 108 post-OSMMAP). The median age was 47.5 years (IQR 32), and 50% were male. 185 patients (92%) had a laparoscopic/robotic resection and 16 (8%) open. There were statistically significant reductions in OME required post-OSMMAP on each postoperative day (days 1 to 4) and cumulative OME for both OT and ON patients. The reduction in opioid requirements was significantly larger in OT than ON patients. We present the first study highlighting a larger opioid usage reduction in OT than in ON patients after OSMMAP implementation.

The T-Cell Response to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease is Augmented with Anti-TNF Therapy.

T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.