Humoral immune response and safety of SARS-CoV-2 vaccination in very early onset inflammatory bowel disease.

Children with very early onset inflammatory bowel disease (VEO-IBD) may respond differently to coronavirus disease 2019 (COVID-19) immunization compared to healthy children or other patients with IBD. We recruited children with VEO-IBD <6 years of age and younger following receipt of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Demographics, IBD characteristics, medication use, adverse events (AEs) and IBD exacerbations were collected. Blood draws (optional) were obtained for measurement of antireceptor binding domain (RBD) IgG antibodies following vaccination. Of 41 participants, none required emergency department visit or hospitalization due to AE, and only one experienced IBD exacerbation. Detectable antibody was present in 19/19 participants who provided blood sample; 6/7 participants (86%) had durable humoral response 12 months postvaccination. Children with VEO-IBD experience robust humoral immune response to COVID-19 immunization. Severe AEs were rare. These findings provide reassurance that children with VEO-IBD respond well and safely to SARS-CoV-2 vaccination.

Long-Term Effectiveness and Durability of COVID-19 Vaccination Among Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.

Whole Foods Introduction Associated With Symptomatic Anastomotic Ulceration in Children With Short Bowel Syndrome.

OBJECTIVES: Anastomotic ulceration (AU) is a rare but life-threatening complication of pediatric short bowel syndrome (SBS). AUs may be challenging to detect and refractory to treatment. This study aimed to identify features associated with symptomatic bleeding AUs in children with SBS and factors that may impact resolution of bleeding. The relationship between dietary changes and symptomatic anastomotic hemorrhage was also explored. METHODS: We conducted a retrospective chart review of 381 patients cared for in the Intestinal Rehabilitation Program at our center from 2013 to 2022. Patients with symptomatic AUs were identified based on at least 1 endoscopic procedure showing AUs and evidence of clinically significant gastrointestinal bleeding. We collected patient demographics, clinical characteristics, dietary history, radiologic imaging, and histopathology. We used descriptive statistics to identify patterns of presentation. RESULTS: AUs were identified in 22 patients who were followed for a median duration of 2.9 years after anastomotic ulcer identification. AUs uniformly evolved years after the initial anastomosis (median 3.2 years). Characteristics included bowel stricture (4/22), small bowel-colon anastomosis (19/22), partial colectomy (17/22), and an increase in whole foods fraction (12/18). Bleeding resolved with operative intervention in the majority with anastomotic stricture (3/4). Recurrent bleeding was common in those without stricture (13/18). In a subset of patients without stricture, whole food reduction was associated with improvement or resolution of bleeding (5/6). CONCLUSIONS: We observed a higher proportion of patients with AUs who responded to surgical intervention in the subset of children with definitive anastomotic strictures versus those without, suggesting that careful characterization of intestinal anatomy may be critical to predicting response to therapy. We also observed that bleeding from AU typically first manifested within 1 year of a shift from elemental or hydrolyzed enteral formula to a whole food-based diet (including commercial blenderized feeds), which may indicate that components of the enteral diet play a role in the pathogenesis of AU. Further studies are needed to validate these hypotheses.

Low Rates of Breakthrough COVID-19 Infection After SARS-CoV-2 Vaccination in Patients With Inflammatory Bowel Disease.

We demonstrate low rates of breakthrough coronavirus disease 2019 (COVID-19) infection and mild course of illness following severe acute respiratory syndrome coronavirus 2 vaccination in a large cohort of inflammatory bowel disease patients. Residence in southern United States and lower median anti-receptor binding antibody level were associated with development of COVID-19.

Humoral Immune Response and Safety of SARS-CoV-2 Vaccination in Pediatric Inflammatory Bowel Disease.

INTRODUCTION: Children with inflammatory bowel disease (IBD) may respond differently to COVID-19 immunization as compared with healthy children or adults with IBD. Those younger than 12 years receive a lower vaccine dose than adults. We sought to describe the safety and humoral immune response to COVID-19 vaccine in children with IBD. METHODS: We recruited children with IBD, ages 5-17 years, who received ≥ 2 doses of the BNT162b2 vaccine by a direct-to-patient outreach and at select sites. Patient demographics, IBD characteristics, medication use, and vaccine adverse events were collected. A subset of participants had quantitative measurement of anti-receptor binding domain IgG antibodies after 2-part immunization. RESULTS: Our study population included 280 participants. Only 1 participant required an ED visit or hospitalization because of an adverse event. Of 99 participants who underwent anti-receptor binding domain IgG antibody measurement, 98 had a detectable antibody, with a mean antibody level of 43.0 µg/mL (SD 67) and a median of 22 µg/mL (interquartile range 12-38). In adjusted analyses, older age ( P = 0.028) and antitumor necrosis factor monotherapy compared with immunomodulators alone ( P = 0.005) were associated with a decreased antibody level. Antibody response in patients treated with antitumor necrosis factor combination vs monotherapy was numerically lower but not significant. DISCUSSION: Humoral immune response to COVID-19 immunization in children with IBD was robust, despite a high proportion of this pediatric cohort being treated with immunosuppressive agents. Severe vaccine-related AEs were rare. Overall, these findings provide a high level of reassurance that pediatric patients with IBD respond well and safely to SARS-CoV-2 vaccination.

Dietary fiber-based regulation of bile salt hydrolase activity in the gut microbiota and its relevance to human disease.

Complications of short bowel syndrome (SBS) include malabsorption and bacterial overgrowth, requiring prolonged dependence on parenteral nutrition (PN). We hypothesized that the intolerance of whole food in some SBS patients might be due to the effect of dietary fiber on the gut microbiome. Shotgun metagenomic sequencing and targeted metabolomics were performed using biospecimens collected from 55 children with SBS and a murine dietary fiber model. Bioinformatic analyses were performed on these datasets as well as from a healthy human dietary intervention study. Compared to healthy controls, the gut microbiota in SBS had lower diversity and increased Proteobacteria, a pattern most pronounced in children on PN and inversely correlated with whole food consumption. Whole food intake correlated with increased glycoside hydrolases (GH) and bile salt hydrolases (BSH) with reduced fecal conjugated bile acids suggesting that dietary fiber regulates BSH activity via GHs. Mechanistic evidence supporting this notion was generated via fecal and plasma bile acid profiling in a healthy human fiber-free dietary intervention study as well as in a dietary fiber mouse experiment. Gaussian mixture modeling of fecal bile acids was used to identify three clinically relevant SBS phenotypes. Dietary fiber is associated with bile acid deconjugation likely via an interaction between gut microbiota BSHs and GHs in the small intestine, which may lead to whole food intolerance in patients with SBS. This mechanism not only has potential utility in clinical phenotyping and targeted therapeutics in SBS based on bile acid metabolism but may have relevance to other intestinal disease states.

Factors Affecting Initial Humoral Immune Response to SARS-CoV-2 Vaccines Among Patients With Inflammatory Bowel Diseases.

INTRODUCTION: Although an additional coronavirus disease 2019 vaccine dose for immunocompromised persons has been recommended in some countries, further data to guide vaccination strategies for patients with inflammatory bowel disease (IBD) are urgently needed. We sought to identify factors affecting initial humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among patients with IBD. METHODS: In this prospective cohort of SARS-CoV-2 immunized patients with IBD, we evaluated associations between participant age, sex, vaccine type, medication use, and the presence of a detectable antireceptor binding domain antibody and quantitative antibody level. RESULTS: In total, 1,909 participants were included (1,123, 692, and 94 received BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively) of whom 96% achieved a positive antibody response. On multivariable analysis, factors associated with lack of antibody response were older age (P = 0.043), BNT162b2 vs mRNA-1273 (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.0-3.9), and combination therapy with anti-TNF and 6MP, azathioprine, or methotrexate (OR 4.2, 95% CI 2.4-7.3). The use of 5-aminosalicylate or sulfasalazine (OR 0.3, 95% CI 0.1-0.8) and ustekinumab (OR 0.2, 95% CI 0.05-0.8) was associated with decreased odds of lacking antibody response. DISCUSSION: Most patients with IBD mount an initial response to SARS-CoV-2 vaccination; however, older patients and those treated with anti-TNF and immunomodulator have blunted responses and may benefit the most from an additional vaccine dose. Patients treated with other classes of immunosuppressive medications have more robust initial immune responses to vaccination. These data should inform key decisions about patient selection for additional coronavirus disease 2019 vaccine doses in patients with IBD.

Impact of SARS-CoV-2 Vaccination on Inflammatory Bowel Disease Activity and Development of Vaccine-Related Adverse Events: Results From PREVENT-COVID.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 vaccination is recommended for all individuals with inflammatory bowel disease (IBD), including those on immunosuppressive therapies; however, little is known about vaccine safety and efficacy in these patients or the impact of vaccination on IBD disease course. METHODS: We evaluated coronavirus disease 2019 (COVID-19) vaccine-related adverse events (AEs) and the effect of vaccination on IBD disease course among participants in the PREVENT-COVID (Partnership to Report Effectiveness of Vaccination in populations Excluded from iNitial Trials of COVID) study, a prospective, observational cohort study. Localized and systemic reactions were assessed via questionnaire. Disease flare was defined by worsening IBD symptoms and change in IBD medications. Outcomes were stratified by vaccine type and IBD medication classes. RESULTS: A total of 3316 individuals with IBD received at least 1 COVID-19 vaccine. Injection site tenderness (68%) and fatigue (46% dose 1, 68% dose 2) were the most commonly reported localized and systemic AEs after vaccination. Severe localized and systemic vaccine-related AEs were rare. The mRNA-1273 vaccine was associated with significantly greater severe AEs at dose 2 (localized 4% vs 2%, systemic 15% vs 10%; P < .001 for both). Prior COVID-19 infection, female sex, and vaccine type were associated with severe systemic reactions to dose 1, while age <50 years, female sex, vaccine type, and antitumor necrosis factor and vedolizumab use were associated with severe systemic reactions to dose 2. Overall rates (2%) of IBD flare were low following vaccination. CONCLUSIONS: Our findings provide reassurance that the severe acute respiratory syndrome coronavirus 2 vaccine is safe and well tolerated among individuals with IBD, which may help to combat vaccine hesitancy and increase vaccine confidence.

The severe acute respiratory syndrome coronavirus 2 vaccine is safe and well tolerated among individuals with inflammatory bowel disease (IBD). Severe localized and systemic vaccine-related adverse events were rare, and rates of IBD flare were low (2%) following severe acute respiratory syndrome coronavirus 2 vaccination in a cohort of 3316 participants with IBD.

Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease.

The incidence and prevalence of pediatric inflammatory bowel disease (IBD) are rising worldwide, with a steep increase in children under 5 years of age. Compared to adult IBD, pediatric IBD presents with a more severe, aggressive phenotype and unique complications, notably growth impairment. Treatment goals include achieving intestinal healing, reaching growth potential, and optimizing quality of life, all while limiting drug toxicities. In the last 2 decades, the advent of anti-tumor necrosis factor (TNF) α agents has significantly increased the potential to reach these goals. However, nonresponse or loss of response to anti- TNFα agents is still encountered in approximately one-third of patients. Although the development of novel biologic therapies has offered new alternatives in recent years, the use of these therapies in the pediatric setting has been limited due to delayed approval. This article summarizes the key evidence for biologic agents currently used in the treatment of pediatric IBD and discusses challenges and barriers unique to pediatric drug development.

The Structure and Function of the Human Small Intestinal Microbiota: Current Understanding and Future Directions.

Despite growing literature characterizing the fecal microbiome and its association with health and disease, few studies have analyzed the microbiome of the small intestine. Here, we examine what is known about the human small intestinal microbiota in terms of community structure and functional properties. We examine temporal dynamics of select bacterial populations in the small intestine, and the effects of dietary carbohydrates and fats on shaping these populations. We then evaluate dysbiosis in the small intestine in several human disease models, including small intestinal bacterial overgrowth, short-bowel syndrome, pouchitis, environmental enteric dysfunction, and irritable bowel syndrome. What is clear is that the bacterial biology, and mechanisms of bacteria-induced pathophysiology, are enormously broad and elegant in the small intestine. Studying the small intestinal microbiota is challenged by rapidly fluctuating environmental conditions in these intestinal segments, as well as the complexity of sample collection and bioinformatic analysis. Because the functionality of the digestive tract is determined primarily by the small intestine, efforts must be made to better characterize this unique and important microbial ecosystem.

Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease.

BACKGROUND: Recent studies have shown that oral combination antibiotics may improve disease course in refractory inflammatory bowel disease (IBD). Here, we describe the use of combination oral antibiotics as salvage therapy in refractory ulcerative colitis (UC), Crohn's colitis, and IBD-unclassified (IBD-U) at a large pediatric IBD center. METHODS: Clinical response, disease activity indices, adverse events, and clinical outcomes were measured up to 1 year after antibiotic treatment in this retrospective cohort study of children with medically refractory IBD colitis. RESULTS: Sixty-three patients with refractory UC, Crohn's colitis, and IBD-U (median age [interquartile range {IQR}], 15.3 [11.2-16.5] years; median disease duration [IQR], 1.2 [0.41-4.6] years) received a combination of 3 or 4 oral antibiotics (most commonly amoxicillin, metronidazole, and either doxycycline or ciprofloxacin) for a median (IQR) of 29 (21-58) days. Thirty-four patients (54%) were deemed corticosteroid-refractory or -dependent, with the majority (62/63) having a previous or present loss of response or primary nonresponse to anti-tumor necrosis factor alpha (anti-TNFα) therapy. Use of combination antibiotics led to a significant decrease in median Pediatric Ulcerative Colitis Activity Index (PUCAI) score (IQR) from 55 (40-65) to 10 (0-40; P < 0.0001) over 3 ± 1 weeks, with 25/63 (39.7%) patients achieving clinical remission (PUCAI <10 points). The clinical benefits of oral antibiotics were independent of anti-TNFα therapy optimization. Among children entering clinical remission (n = 25), only 1 patient required surgery at 1-year follow-up, vs 10 patients in the nonresponder group. Negative predictors of response to combination antibiotics were exposure to doxycycline (odds ratio [OR], 0.25; 95% CI, 0.08-0.76) and PUCAI ≥65 at baseline (OR, 0.2; 95% CI, 0.05-0.74). CONCLUSIONS: Oral combination antibiotics appears to be an effective rescue and steroid-sparing therapy to induce remission in the short term in patients failing a biologic.

Clostridium Difficile, Colitis, and Colonoscopy: Pediatric Perspective.

PURPOSE OF THE REVIEW: Review tests available for detection of Clostridium difficile (C. Diff) induced disease, including when such tests should be done in children and how they should be interpreted. RECENT FINDINGS: Multiple tests are available for detecting disease due to C. diff. These include colonoscopy and stool analysis. Colonoscopy with biopsy is the most sensitive test for detecting the presence of colitis. The toxins produced by the C. diff. (toxin A, toxin B, and binary toxin) are the agents that cause injury and disease. Only toxin producing C. diff. Strains will cause disease. Binary toxin by itself is not thought to produce disease. Binary toxin causes disease in humans when present with toxin A and B producing bacteria, and has been implicated with fulminant life threatening disease. Stool analyses vary in sensitivity and specificity depending on the assay used. The presence of toxin producing strains of C diff. in the stool does not equate with disease. The presence of a toxin-producing bacteria or toxins (A or B) only equates with disease if diarrhea or a diseased colon (toxic megacolon, ileus, and sepsis) is present. Nucleic acid amplification testing (NAAT), when used in the stool from patients with diarrhea, appears to be the most efficient study to detect the gene that encodes for toxin A and B and thus to diagnose C. diff.-induced disease. Infants have a high carriage rate of C. diff. and are believed not to develop disease from it or its toxins. Infants should not be tested for C. difficile. The NAAT is most specific when done on patients with diarrhea with liquid stools. Testing for C. difficile should only be done on patients with diarrhea. One can assume that a patient who has no diarrhea and is not ill does not have C. diff.-induced disease. Treatment should be limited to patients with diarrhea who test positive for C. diff. toxin (A or B) or toxin-producing bacteria. Direct testing for binary toxin is not commercially available. Binary toxin is only thought to cause disease in humans when C. diff. toxin (A and B)-producing bacteria are present.