BACKGROUND: Inflammatory Bowel Disease (IBD) is a collective term that refers to chronic inflammatory diseases involving the gastrointestinal (GI) tract. The most common forms of IBD include Crohn’s Disease (CD) and ulcerative colitis (UC). GOALS: The goal of this study is to compare baseline and one-year follow-up measures of anxiety, depression, and quality of life in children with newly diagnosed IBD. A secondary goal of this study is to determine if there are parallel changes in the psychologic parameters in the parents of these children over a similar one-year interval. METHODS: This prospective cohort study was conducted in the Center for Inflammatory Bowel Diseases at Boston Children’s Hospital (BCH). The parents and children with newly diagnosed IBD completed validated questionnaires about their disease at baseline (within six months of their diagnosis) and then again 12-18 months later. RESULTS: Baseline data were collected from 75 patients with IBD, and 15 of these patient/parent dyads have completed follow-up questionnaires. The incidence of anxiety and depression trended downwards after the first year, and overall quality of life trended upwards, indicating an improvement in a global state of adjustment. Measures of anxiety and depression, as well as the reported frequency and difficulty of adverse events, all decreased in parental responses after the first year. CONCLUSION: While a larger sample size is necessary to better assess changes in psychometrics over time, existing data suggests that parents manifest the most significant change in anxiety and depression over the course of the first year from diagnosis. Children appear to be less anxious and depressed at baseline. Further enrollment and data collection will permit a more definitive assessment of the relationship between patient and parent coping strategies. Ideally, the results of this ongoing study will determine if impaired parental coping lowers a patient’s quality of life, contributes to higher childhood anxiety and depression scores, and results in higher healthcare utilization.

BACKGROUND: Characterized as inflammation of the gastrointestinal tract, pediatric inflammatory bowel disease has become increasingly more prevalent throughout the world. Inflammatory bowel disease is chronic, and no definitive cure exists. Instead, patients aim to achieve remission from flair-ups. Adequate transition into adult gastrointestinal care has been shown to be critical for future patient outcomes. Hence, successful transition from pediatric to adult inflammatory bowel disease care plays an important role in maintaining patient wellbeing. Identifying factors that contribute to patient transition readiness may be able to improve the transition process. OBJECTIVE: To elucidate sociodemographic and disease related parameters that influence transition, synthesize models that can predict transition readiness, and make recommendations to improve the process. METHODS: As part of a larger quality improvement project conducted by Massachusetts General Hospital for Children, 274 patients with inflammatory bowel disease ranging from ages 12 to 27 were enrolled between June 2019 and October 2020. Sociodemographic information was gathered via chart review. The Abbreviated Pediatric Crohn’s Disease Activity Index, Disease Activity Index Score, and Physician Global Assessment were completed by patients and physicians to assess disease severity. Patients also completed PROMIS questionnaires to assess anxiety, depression, sleep disturbance and impairment. Patients completed the Transition Readiness Assessment Questionnaire to gauge transition readiness. Bivariate analyses were conducted to elucidate the relationships between sociodemographic information, disease related parameters, and transition readiness. Multivariate regressions were conducted to synthesize models aimed at predicting transition readiness. RESULTS: Females had significantly worse disease severity, mental health, and sleep quality compared to males. Poor sleep quality had a significant relationship with disease severity and mental health status. Females had significantly higher transition readiness scores compared to males. Older age had a significant relationship with greater transition readiness. More patient anxiety was significantly associated with weaker communication skills. Otherwise, no disease related parameters significantly correlated with transition readiness. Disease duration demonstrated a significant positive relationship with transition readiness, particularly for patients diagnosed between the ages of 10 – 17. Models synthesized to predict transition readiness demonstrated substantial variability in predictive value. CONCLUSION: Transitioning from pediatric to adult inflammatory bowel disease care is a complex process. Future research should be aimed at elucidating discrepancies in transition readiness between genders, and further understanding the role disease duration plays in the transition process. Providers should work towards incorporating structured transition programs and improving patients’ disease-related knowledge, as well as patient familiarity with logistical aspects of the current US healthcare system. / 2023-11-09T00:00:00Z

BACKGROUND: Patients who have been diagnosed with Inflammatory Bowel Disease (IBD) present with increased risk of deficient vitamin D levels. Previous studies have demonstrated that these IBD patients who live in areas with lack of sun exposure are especially susceptible to becoming vitamin D deficient. Studies have also shown that the standard vitamin D dosing protocols have not proven effective in consistently improving vitamin D status. This failure is likely related to a combination of under-dosing and patient noncompliance. Vitamin D sufficiency is essential in the maintenance of both skeletal health and the immune system in children and adolescents. OBJECTIVES: The primary aim of this study is to investigate the safety and efficacy of administering an interval, high dose oral vitamin D supplementation in pediatric patients with IBD treated with Remicade. A secondary aim is to study the association between changes in serum 25OHD (25-hydroxyvitamin D3) levels and clinical and biochemical markers of IBD. The findings from this study will provide preliminary data for future studies using serial measurements of serum 25OHD levels to better articulate the optimal dosage for interval vitamin D supplementation in pediatric patients with IBD. METHODS: We identified and screened pediatric patients with IBD at Boston Children’s Hospital (BCH) with vitamin D deficiency (serum 25OHD level < 30 ng/mL). Vitamin D dosing was determined by a patient’s Remicade interval. Patients received either 50,000 international units (IU) of vitamin D3 (every 4-5 weeks) or 100,000 IU of vitamin D3 (every 6-8 weeks), concurrent with their Remicade infusion interval. Longitudinal data, including anthropomorphic measurements, serum chemistry labs, spot urine calcium to creatinine ratios, quality of life metrics, and surveys gauging dietary vitamin D intake and sunlight exposure, were collected throughout the study. RESULTS: Baseline vitamin D status in the 60 enrolled patients did not differ by gender, dosing group, diet, or diagnosis (Crohn disease, ulcerative colitis, or indeterminate colitis). Of the 57 patients for whom baseline and final serum 25OHD levels were available, there was a significant increase in total serum 25OHD levels from 22.53 ± 4.65 ng/mL to 29.91 ± 6.60 ng/mL, respectively. Similarly, increases in mean serum 25OHD levels were noted in both dosing formats and disease groups. Interestingly, there was no significant parallel impact of increased 25OHD levels on either disease activity or quality of life. There were no significant changes in serum calcium, phosphorous, and creatinine levels in response to changes in 25OHD levels. There were no reports of significant adverse events related to vitamin D supplementation. CONCLUSION: High dose, interval vitamin D supplementation improved vitamin D status from baseline in a majority of studied pediatric patients with IBD. The data suggest that this type of interval, high dose format is likely more effective than more traditionally once-daily dosing. Further studies are necessary to determine the optimal dosage regimens optimal in further increasing vitamin D status and to assess for its impact on clinical management.

Iron deficiency anemia (IDA) is the most common extraintestinal complication encountered in patients with Inflammatory Bowel Disease (IBD), and it is more prevalent in pediatric patients compared to adults (Rogler and Vavricka). The inflammation and blood loss from the disease impacts both the absorption and storage of iron in the body (Rogler and Vavricka). With the intent of establishing a standard of care for IDA treatment in patients with IBD, we conducted a prospective study of 104 consecutive pediatric patients to assess the safety and efficacy of intravenous (IV) iron therapy compared to oral therapy and no treatment, as well as the effects of iron therapy on patient quality of life. Efficacy was assessed by comparing the change in hemoglobin levels in the interval between admission to outpatient follow-up. The average time to the first ambulatory follow-up was 29.08 days. 69 patients received IV iron therapy, 17 patients received oral iron supplementation, and 18 patients had no treatment. Treatment with IV iron resulted in a statistically significant increase in hemoglobin levels (2.00 g/dL ± 1.57 g/dL, as mean ± standard deviation) from admission to the first follow-up ambulatory appointment (p < .0001). Patients receiving IV iron therapy also experienced a significantly greater mean increase in hemoglobin levels than those treated with oral iron (p = .0084) or no treatment (p = .0018). Further, patients treated with IV iron experienced a significant increase in their quality of life at follow-up compared to admission as measured by the Impact-III questionnaire (p = .0179). Our study illustrates the importance of screening pediatric patients with IBD for IDA and suggests that IV iron treatment is safe and more effective in raising hematologic and iron measures than orally- administered alternative options.

The role of histamine in chronic gastrointestinal diseases has been increasingly recognized in humans, but the role of histamine in the canine gastrointestinal tract has not been thoroughly investigated. The presence and distribution of all 4 histamine receptors (H1, H2, H3, and H4) in the stomach, duodenum, ileum, jejunum, and colon of healthy dogs were evaluated with a commonly employed immunohistochemistry technique using antibodies predicted to cross react with canine histamine receptors. All 4 histamine receptors were identified in the canine gastrointestinal tract, and differed in location and density within sections of the canine gastrointestinal tract. Antibody specificity was evaluated with Western blot. With the establishment of a method to study histamine receptors in the canine gastrointestinal tract, additional research to evaluate histamine receptors in dogs is warranted to further understand the pathophysiology and treatment of chronic canine enteropathies.

Diet is a key factor in the development and progression of Inflammatory Bowel Disease (IBD). A variety of diets have been studied with IBD patients. This cross-sectional survey identified current healthcare practitioner views on different diets and their efficacy with IBD patients. Diets were rated on awareness, compliance, and contributors to success by participants (n = 181). Frequencies were conducted, and ANOVA with Duncan pairwise comparison or chi-square analysis were used to determine significant differences. Most participants (96%) and 98% of registered dietitians (RD) considered using diet to help treat IBD patients. RDs perceived the low fiber or low residue diet easiest for patient compliance (4.2 ± 1.0, P < .05), and the specific carbohydrate diet hardest for patient compliance (2.4 ± 1.4). Initial and follow up consultations with a RD significantly contributed to patient success across all diets, and greater involvement from the RD may solve issues with compliance.

Background Reported outcomes for colorectal cancer associated with Inflammatory Bowel Disease are inconsistent. We compared survival outcomes in colorectal cancer patients with and without Inflammatory Bowel Disease using a population-based cohort and elicited prognostic factors associated with survival Methods Adult patients with a diagnosis of colorectal cancer in 2007-2015 were identified from the Ontario Cancer Registry. Those with Inflammatory Bowel Disease were detected via the validated Ontario Crohn’s and Colitis Cohort. Primary outcome measure was overall survival from time of colorectal cancer diagnosis until the date of death. Secondary outcome measures included treatments received and publicly-provided health care costs. Results Colorectal cancer was diagnosed in 67,137 with Inflammatory Bowel Disease present in 783 (1.2%). The Inflammatory Bowel Disease-associated colorectal cancer patients were younger at diagnosis (median range 55-59 vs 70-74, p<0.001). Five-year survival in Inflammatory Bowel Disease-associated patients was 56.4% (95% CI 52.6-59.9) and 57.0% (95% CI 56.6-57.4) in sporadic colorectal cancer (p=0.8). Inflammatory Bowel Disease was a significant predictor of death (Hazard Ratio=1.45, 95% CI 1.29-1.63, p<0.001) after adjusting for other variables. In patients under 50, 5-year survival was significantly (p<0.001) reduced in the Inflammatory Bowel Disease population (56.8%, 95% CI 49.4-63.5) compared with the sporadic colorectal cancer population (71.4%, 95% CI 70.0-72.7). Similar results were observed in those 50-64 years old. Conclusion Young patients (<65) with Inflammatory Bowel Disease-associated colorectal cancer have worse survival outcomes than young (<65) patients with sporadic colorectal cancer. These findings inform prognostication and may direct future research for this high-risk population. / Thesis / Master of Science (MSc) / Background Reported outcomes for colorectal cancer associated with Inflammatory Bowel Disease are inconsistent. We compared survival outcomes in colorectal cancer patients with and without Inflammatory Bowel Disease using a population-based cohort and elicited prognostic factors associated with survival Methods Adult patients with a diagnosis of colorectal cancer in 2007-2015 were identified from the Ontario Cancer Registry. Those with Inflammatory Bowel Disease were detected via the validated Ontario Crohn’s and Colitis Cohort. Primary outcome measure was overall survival from time of colorectal cancer diagnosis until the date of death. Secondary outcome measures included treatments received and publicly-provided health care costs. Results Colorectal cancer was diagnosed in 67,137 with Inflammatory Bowel Disease present in 783 (1.2%). The Inflammatory Bowel Disease-associated colorectal cancer patients were younger at diagnosis (median range 55-59 vs 70-74, p<0.001). Five-year survival in Inflammatory Bowel Disease-associated patients was 56.4% (95% CI 52.6-59.9) and 57.0% (95% CI 56.6-57.4) in sporadic colorectal cancer (p=0.8). Inflammatory Bowel Disease was a significant predictor of death (Hazard Ratio=1.45, 95% CI 1.29-1.63, p<0.001) after adjusting for other variables. In patients under 50, 5-year survival was significantly (p<0.001) reduced in the Inflammatory Bowel Disease population (56.8%, 95% CI 49.4-63.5) compared with the sporadic colorectal cancer population (71.4%, 95% CI 70.0-72.7). Similar results were observed in those 50-64 years old. Conclusion Young patients (<65) with Inflammatory Bowel Disease-associated colorectal cancer have worse survival outcomes than young (<65) patients with sporadic colorectal cancer. These findings inform prognostication and may direct future research for this high-risk population.

The mucosal immune system encompasses a wide array of interactions that work in concert to protect an individual from harmful agents while retaining tolerance to molecules, microbes, and self-antigens that present no danger. The upheaval in the regulation-response balance is a critical aspect in both infectious and immune-mediated disease. To understand this balance and methods of its restoration, iterative and integrative modeling cycles on the pathogenesis of disease are necessary. In this thesis, I present three studies highlighting phases of a systems immunology cycle. Firstly, the thesis provides a description of the construction of a computational ordinary differential equation based model on the host-pathogen-microbiota interactions during Clostridium difficile infection and the use of this model for the development of the hypothesis that host-antimicrobial peptide production may correlate with increased disease severity and promote increased recurrence. Secondly, it provides insight into the necessity of trans-disciplinary analysis for the understanding of novel molecular targets in disease through the immunometabolic regulation of CD4+ T cell by NLRX1 in inflammatory bowel disease. Third, it provides the assessment of novel therapeutics in disease through the evaluation of LANCL2 activation in influenza virus infection. In total, the computational and experimental strategies used in this dissertation are critical foundational pieces in the framework of precision medicine initiatives that can assist in the diagnosis, understanding, and treatment of disease. / Ph. D.

<p dir="ltr">Approximately 2.39 million Americans suffer from inflammatory bowel disease (IBD), an autoimmune disorder that is characterized by chronic inflammation of the gastrointestinal (GI) tract. Current treatment options for IBD, which are limited, include oral medications, surgery, and supportive care. These therapeutics often times are not effective and are associated with high toxicity. Thus, there is a pressing clinical need for a therapy that can be delivered both locally and precisely, while also having an improvement in efficacy and lower toxicity.</p><p dir="ltr">This study introduces three novel microrobot designs fabricated using stereolithography (SLA) 3D printing, which aims to address the challenges seen in IBD treatment. The microrobots utilize a reservoir design to encapsulate the drug for an on-demand release, allowing for improved control and precision. The SLA microrobots were evaluated for cytotoxicity as well as drug release capabilities. We were able to demonstrate a local release of a protein on-demand at a biologically relevant temperature. The integration of microrobots in IBD therapy has the capability to significantly improve patient outcomes and quality of life, offering a more efficient and less toxic treatment approach.</p>

Noncanonical NF-KB is an alternative NF-KB pathway that is critically involved in the development and maturation of the adaptive immune system. As such, it has typically been studied in B and T cell biology without application to complex organ systems such as the gut. The following work explores the contribution of noncanonical NF-KB to inflammatory and neoplastic disease in the gastrointestinal (GI) system, as well as the effects of its loss on GI health. Chapter 1 opens with an overview of gastrointestinal homeostasis and inflammation, with emphasis on the particular diseases studied in this body of work. Chapter 2 focuses on a review of noncanonical NF-KB function and components, as well as its applications in inflammatory bowel disease (IBD), a quintessential example of disruption of intestinal homeostasis. In Chapter 3 we determine the role of noncanonical NF-KB in allergic disease of the upper gastrointestinal tract, namely a novel model of the disease eosinophilic esophagitis. Our studies revealed that loss of NF-KB-inducing kinase (NIK), the bottleneck molecule in noncanonical NF-KB signaling, results in targeted esophageal inflammation, remodeling, and gene expression changes that are comparable to the human disease. In Chapter 4, we examine the role of noncanonical NF-KB in inflammatory bowel disease using biopsy samples from human IBD patients, and compare the expression of various components of the pathway to inflammation status and treatment response. Noncanonical NF-KB is upregulated in IBD patients, and also appears to be specifically upregulated in patients that have lost response to anti-TNF inhibitors, which are potent drugs that are widely used to treat IBD. In Chapter 5 we focus on NIK and its effects on stem cell function, growth, and inflammation-induced cancer in the gut. Loss of NIK in mice results in alterations in colonic stem cell function and changes in colonic microbiome, which predisposes them to the development of inflammation-induced carcinogenesis. Indeed, in human patients with colorectal cancer, noncanonical NF-KB is also suppressed. Overall, we have discovered multiple novel roles of noncanonical NF-KB signaling at multiple levels in the gut and in the context of a variety of diseases, and have greatly expanded the current body of knowledge as to the functions and effects of this pathway. / Ph. D. / The gastrointestinal system has a complex set of checks and balances to maintain overall health. If factors involved in the promotion or suppression of inflammation, the regulation of growth, or the prevention of tumor formation become dysregulated, there can be catastrophic consequences for the human body. The aim of this work is to investigate a pathway called noncanonical NF-κB in the development of various diseases in the GI tract. Noncanonical NF-κB is not a well understood pathway and to date has mostly been studied in the context of white blood cell development. However, we discovered that noncanonical NF-κB has several very important functions in the GI tract that have implications in conditions such as inflammatory bowel disease and colorectal cancer. First we explored the role of noncanonical NF-κB in the upper GI tract, namely the esophagus, and found that this signaling pathway is critically involved in the movement of white blood cells called eosinophils to the esophagus, resulting in throat inflammation in both mouse models and human patients. Secondly, we determined that this same pathway also has effects in the lower GI tract. Human patients with inflammatory bowel disease, especially those who develop resistance to popular medications, see an upregulation of this pathway in their colon tissue. Loss of this pathway in the colons of mice also causes changes in growth of the colonic epithelium, and predisposes them to the formation of colon cancer. Interestingly, in human colon cancer patients, we also see similar changes in expression of genes associated with this pathway. Overall, we have found many new and exciting roles for this underappreciated pathway in the gut.