Characterizing Regionalization of Inflammatory Bowel Disease Hospitalizations and Operations in Washington State.

BACKGROUND: Hospitalizations for inflammatory bowel disease (IBD) are a major contributor of healthcare utilization. We assessed IBD hospitalizations and surgical operations in Washington State to characterize regionalization patterns. METHODS: We identified a cohort of hospitalizations for Crohn's disease (CD) or ulcerative colitis (UC) from 2008 to 2019 using Washington State's Comprehensive Hospital Abstract Reporting System (CHARS). Hospitalizations were characterized by emergent or elective acuity and whether an operation or endoscopic procedure was performed. Facility volume and distance travelled by patients were used to determine regionalization. RESULTS: There were 20,494 IBD-related hospitalizations at 95 hospitals: 13,585 (66.3%) with CD and 6,909 (33.7%) with UC. Emergencies accounted for 78.2% of all IBD-related hospitalizations and did not differ between CD (78.3%) and UC (77.9%) (p = 0.54). Surgery was performed during 10.3% and endoscopy during 30.6% of emergent hospitalizations. 72.0% of emergent hospitalizations occurred at 22 facilities, while 71.1% of elective hospitalizations were concentrated at 9 facilities. Operations were performed during 78.5% of elective hospitalizations, and five hospitals performed 69% of all elective surgery. Laparoscopic surgery increased in both emergent (17% to 52%, p < 0.001) and elective operations (18% to 42%, p < 0.001) from 2008 to 2019. CONCLUSIONS: In Washington State, most IBD hospitalizations were emergent, which were decentralized and typically non-operative. By contrast, most elective admissions involved surgery and were centralized at a few high-volume centers. Further understanding the drivers behind IBD hospitalizations may help optimize emergent medical and elective surgical care at a state level.

Obesity and inflammatory bowel disease: diagnostic and therapeutic implications.

PURPOSE OF REVIEW: The review summarizes our current understanding of how obesity impacts diagnostic studies and therapies used in inflammatory bowel disease (IBD) as well as the safety and efficacy of medical and surgical weight loss therapies in the obese IBD patient. RECENT FINDINGS: Many of the diagnostic tools we rely on in the identification and monitoring of IBD can be altered by obesity. Obesity is associated with increased acute phase proteins and fecal calprotectin. It can be more difficult to obtain and interpret cross sectional imaging of obese patients. Recent studies have also shown that common therapies used to treat IBD may be less effective in the obese population and may impact comorbid disease. Our understanding of how best to measure obesity is evolving. In addition to BMI, studies now include measures of visceral adiposity and subcutaneous to visceral adiposity ratios. An emerging area of interest is the safety and efficacy of obesity treatment including bariatric surgery in patients with IBD. A remaining question is how weight loss may alter the course of IBD. SUMMARY: The proportion of obese IBD patients is on the rise. Caring for this population requires a better understanding of how obesity impacts diagnostic testing and therapeutic strategies. The approach to weight loss in this population is complex and future studies are needed to determine the safety of medical or surgical weight loss and its impact on the course of disease.

The microbiota in inflammatory bowel disease: current and therapeutic insights.

Inflammatory bowel disease is a heterogeneous group of chronic disorders that result from the interaction of the intestinal immune system with the gut microbiome. Until recently, most investigative efforts and therapeutic breakthroughs were centered on understanding and manipulating the altered mucosal immune response that characterizes these diseases. However, more recent studies have highlighted the important role of environmental factors, and in particular the microbiota, in disease onset and disease exacerbation. Advances in genomic sequencing technology and bioinformatics have facilitated an explosion of investigative inquiries into the composition and function of the intestinal microbiome in health and disease and have advanced our understanding of the interplay between the gut microbiota and the host immune system. The gut microbiome is dynamic and changes with age and in response to diet, antibiotics and other environmental factors, and these alterations in the microbiome contribute to disease onset and exacerbation. Strategies to manipulate the microbiome through diet, probiotics, antibiotics or fecal microbiota transplantation may potentially be used therapeutically to influence modulate disease activity. This review will characterize the factors involved in the development of the intestinal microbiome and will describe the typical alterations in the microbiota that are characteristic of inflammatory bowel disease. Additionally, this manuscript will summarize the early but promising literature on the role of the gut microbiota in the pathogenesis of inflammatory bowel disease with implications for utilizing this data for diagnostic or therapeutic application in the clinical management of patients with these diseases.

Interaction of obesity and inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of unknown etiology that is thought to result from a combination of genetic, immunologic and environmental factors. The incidence of IBD has been increasing in recent decades, especially in developing and developed nations, and this is hypothesized to be in part related to the change in dietary and lifestyle factors associated with modernization. The prevalence of obesity has risen in parallel with the rise in IBD, suggesting a possible shared environmental link between these two conditions. Studies have shown that obesity impacts disease development and response to therapy in patients with IBD and other autoimmune conditions. The observation that adipose tissue produces pro-inflammatory adipokines provides a potential mechanism for the observed epidemiologic links between obesity and IBD, and this has developed into an active area of investigative inquiry. Additionally, emerging evidence highlights a role for the intestinal microbiota in the development of both obesity and IBD, representing another potential mechanistic connection between the two conditions. In this review we discuss the epidemiology of obesity and IBD, possible pathophysiologic links, and the clinical impact of obesity on IBD disease course and implications for management.

The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions.

We discuss the tripartite pathophysiological circuit of inflammatory bowel disease (IBD), involving the intestinal microbiota, barrier function, and immune system. Dysfunction in each of these physiological components (dysbiosis, leaky gut, and inflammation) contributes in a mutually interdependent manner to IBD onset and exacerbation. Genetic and environmental risk factors lead to disruption of gut homeostasis: genetic risks predominantly affect the immune system, environmental risks predominantly affect the microbiota, and both affect barrier function. Multiple genetic and environmental 'hits' are likely necessary to establish and exacerbate disease. Most conventional IBD therapies currently target only one component of the pathophysiological circuit, inflammation; however, many patients with IBD do not respond to immune-modulating therapies. Hope lies in new classes of therapies that target the microbiota and barrier function.

GUTSS: An Alignment-Free Sequence Comparison Method for Use in Human Intestinal Microbiome and Fecal Microbiota Transplantation Analysis.

BACKGROUND: Comparative analysis of gut microbiomes in clinical studies of human diseases typically rely on identification and quantification of species or genes. In addition to exploring specific functional characteristics of the microbiome and potential significance of species diversity or expansion, microbiome similarity is also calculated to study change in response to therapies directed at altering the microbiome. Established ecological measures of similarity can be constructed from species abundances, however methods for calculating these commonly used ecological measures of similarity directly from whole genome shotgun (WGS) metagenomic sequence are lacking. RESULTS: We present an alignment-free method for calculating similarity of WGS metagenomic sequences that is analogous to the Bray-Curtis index for species, implemented by the General Utility for Testing Sequence Similarity (GUTSS) software application. This method was applied to intestinal microbiomes of healthy young children to measure developmental changes toward an adult microbiome during the first 3 years of life. We also calculate similarity of donor and recipient microbiomes to measure establishment, or engraftment, of donor microbiota in fecal microbiota transplantation (FMT) studies focused on mild to moderate Crohn's disease. We show how a relative index of similarity to donor can be calculated as a measure of change in a patient's microbiome toward that of the donor in response to FMT. CONCLUSION: Because clinical efficacy of the transplant procedure cannot be fully evaluated without analysis methods to quantify actual FMT engraftment, we developed a method for detecting change in the gut microbiome that is independent of species identification and database bias, sensitive to changes in relative abundance of the microbial constituents, and can be formulated as an index for correlating engraftment success with clinical measures of disease. More generally, this method may be applied to clinical evaluation of human microbiomes and provide potential diagnostic determination of individuals who may be candidates for specific therapies directed at alteration of the microbiome.

Low Level Engraftment and Improvement following a Single Colonoscopic Administration of Fecal Microbiota to Patients with Ulcerative Colitis.

OBJECTIVE: Fecal microbiota transplantation (FMT) is an investigational treatment for diseases thought to involve alterations in the intestinal microbiota including ulcerative colitis (UC). Case reports have described therapeutic benefit of FMT in patients with UC, possibly due to changes in the microbiota. We measured the degree to which the transplanted microbiota engraft following FMT in patients with UC using a donor similarity index (DSI). METHODS: Seven patients with mild to moderate UC (UC disease activity index scores 3-10) received a single colonoscopic administration of FMT. Metagenomic sequence data from stool were analyzed using an alignment-free comparison tool, to measure the DSI, and a phylogenetic analysis tool, to characterize taxonomic changes. Clinical, endoscopic, histologic, and fecal calprotectin outcome measures were also collected. RESULTS: One of 5 patients from whom sequencing data were available achieved the primary endpoint of 50% donor similarity at week 4; an additional 2 patients achieved 40% donor similarity. One patient with 40% donor similarity achieved clinical and histologic remission 1 month after FMT. However, these were lost by 2-3 months, and loss correlated with a decrease in DSI. The remaining patients did not demonstrate clinical response or remission. Histology scores improved in all but 1 patient. No patients remained in remission at 3 months after FMT. CONCLUSIONS: Following a single colonoscopic fecal transplant, a DSI of 40-50% is achieved in about two-thirds of recipients. This level of engraftment correlated with a temporary clinical improvement in only 1/5 patients. Larger sample sizes could further validate this method for measuring engraftment, and changes in transplant frequency or method might improve microbiota engraftment and efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01742754.

Increased body mass index is associated with earlier time to loss of response to infliximab in patients with inflammatory bowel disease.

BACKGROUND: Obesity is an emerging problem in the care of inflammatory bowel disease (IBD) patients and has been associated with a diminished response to adalimumab. Whether obesity influences the response to infliximab (IFX) is not known. METHODS: A retrospective cohort of 124 subjects with IBD initiating IFX, naive to biologic therapy, was identified. Subjects were stratified according to their weight and body mass index (BMI). The primary outcome was the first occurrence of an IBD flare defined as dose escalation of IFX, corticosteroid use, discontinuation of IFX, hospitalization, or surgery. Multivariable logistic regression was performed considering body mass and BMI as categorical and continuous variables. RESULTS: Obese (BMI > 30 kg/m) patients with Crohn's disease were more likely to have an IBD flare than nonobese patients (adjusted hazard ratio [HR]: 3.03, P < 0.001); overweight (BMI > 25 kg/m) patients with ulcerative colitis trended toward a similar observation (HR: 9.68, P = 0.06). When considered as continuous variables, increasing mass and BMI were associated with earlier IBD flare in both Crohn's disease (adjusted HR: 1.06 per unit increase in BMI [P = 0.02] and 1.02 per kg increase in body mass [P = 0.02]) and ulcerative colitis (adjusted HR: 1.3 per unit increase in BMI [P = 0.01] and 1.11 per kg increase in body mass [P = 0.004]). CONCLUSIONS: Increased body weight is associated with an earlier time to loss of response to IFX in Crohn's disease and ulcerative colitis, a novel finding given that IFX is the only antitumor necrosis factor agent whose dosing reflects increased body weight.

The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation?

One hypothesis for the etiology of inflammatory bowel disease is that an altered or pathogenic microbiota causes inflammation in a genetically susceptible individual. Understanding the microbiota's role in the pathogenesis of the disease could lead to new IBD treatments aimed at shifting the bacteria in the gut back to eubiosis. Probiotics have some efficacy in the treatment of ulcerative colitis (UC), but our current repertoire is limited in potency. Fecal microbiota therapy (FMT) is an emerging treatment for several gastrointestinal and metabolic disorders. It has demonstrated efficacy in treating refractory Clostridium difficile infection, and there are case reports of FMT successfully treating UC. Further clinical studies are justified, and could be complemented by mouse models of fecal transplantation, in which variables can be controlled and manipulated.

Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines.

BACKGROUND: The goal of this study was to assess the natural history of low-grade dysplasia (LGD) and its risk of progression in ulcerative colitis (UC) patients by prospective endoscopic surveillance. METHODS: Forty-two UC patients with LGD were followed prospectively using a uniform approach to surveillance colonoscopy with an average of 43 biopsies per exam. The interval between colonoscopies ranged from 3-12 months. Progression was defined as development of high-grade dysplasia (HGD) or cancer at subsequent colonoscopy or at colectomy. Univariate and multivariate analysis were performed to identify risk factors associated with progression. RESULTS: Patients were followed for an average of 3.9 years (range 1-13). Over that period 19% (8/42) of patients progressed to advanced neoplasia (two cancer, six HGD) while 17% (7/42) had persistent LGD and 64% (27/42) had indefinite dysplasia or no dysplasia at the end of follow-up. Multivariate analysis demonstrated that the number of biopsies with LGD at baseline was associated with an increased risk of progression to advanced neoplasia (relative risk [RR] 5.8, 95% confidence interval [CI]: (1.29-26.04). Among the 15 patients who underwent colectomy, four were found to have higher-grade neoplasia on their colectomy specimen than their preoperative colonoscopy, and these patients were more likely to be nonadherent with recommendations for colectomy. CONCLUSIONS: The majority (81%) of UC patients with LGD did not progress to higher grades of dysplasia during a 4-year follow-up. Patients with three or more biopsies demonstrating LGD at a single colonoscopy were at increased risk for progression to advanced neoplasia.

Novel diagnostic and prognostic modalities in inflammatory bowel disease.

Inflammatory bowel disease remains a complex disease with variable clinical presentations and often nonspecific symptoms. Physicians must rely on diagnostic tools for clarification of disease diagnosis and for guiding management of patients with established disease. Advances in radiologic imaging modalities facilitate early and accurate detection of luminal disease and extraluminal complications. The introduction and dissemination of small bowel capsule endoscopy and double-balloon enteroscopy permit detailed visualization and sampling of the mucosa throughout the entire bowel. Serologic biomarkers are evolving as a valuable tool to clarify diagnosis and stratify patients by disease phenotypes and patterns of behavior. Neutrophil-derived fecal biomarkers are emerging as useful surrogate markers of intestinal inflammation with the potential for a variety of clinical applications, but their application to clinical management has not yet been clarified.

Novel diagnostic and prognostic modalities in inflammatory bowel disease.

Inflammatory bowel disease remains a complex disease with variable clinical presentations and often nonspecific symptoms. Physicians must rely on diagnostic tools for clarification of disease diagnosis and for guiding management of patients with established disease. Advances in radiologic imaging modalities facilitate early and accurate detection of luminal disease and extraluminal complications. The introduction and dissemination of small bowel capsule endoscopy and double-balloon enteroscopy permit detailed visualization and sampling of the mucosa throughout the entire bowel. Serologic biomarkers are evolving as a valuable tool to clarify diagnosis and stratify patients by disease phenotypes and patterns of behavior. Neutrophil-derived fecal biomarkers are emerging as useful surrogate markers of intestinal inflammation with the potential for a variety of clinical applications, but their application to clinical management has not yet been clarified.

Identification of patients at increased risk for colorectal cancer in an open access endoscopy center.

GOALS: To determine whether patients referred for open access endoscopy (OAE) are being appropriately identified as "increased risk" or "average risk" for colorectal cancer (CRC) by referring physicians. BACKGROUND: OAE allows nongastroenterologists to schedule elective endoscopies without prior consultation with a gastroenterologist. It is unknown how accurately referring physicians identify CRC risk of such patients. METHODS: We retrospectively reviewed the records of outpatients referred to a single OAE center for screening or surveillance colonoscopy from July 1, 2001 to November 8, 2002. Before colonoscopy, a 3-question tool was used to stratify each patient as average risk or increased risk for CRC. CRC risk assessment was compared with the referring physician's indication for colonoscopy. Chi-square testing was used to compare the incidence of neoplastic polyps between average risk and increased risk patients. RESULTS: Two hundred eighty-eight patients met inclusion criteria. Referring physicians accurately identified 61% of 126 increased risk patients, including 13 of 19 patients (68%) with a personal history of CRC, 29 of 61 patients (48%) with a family history of CRC, 47 of 61 patients (77%) with a personal history of colonic polyps, and 0 of 8 patients (0%) who met clinical criteria for hereditary nonpolyposis colorectal cancer. Adenomatous polyps were found in 24% of average risk patients compared with 41% of increased risk patients (P<0.01). CONCLUSIONS: In an OAE system, referring physicians often fail to correctly identify patients at increased risk for CRC. Our 3-question tool for risk assessment helps to better identify patients at increased risk of CRC and can be used by gastroenterologists to stratify patients referred for OAE.

Colorectal cancer and dysplasia in inflammatory bowel disease.

Both ulcerative colitis and Crohn's disease carry an increased risk of developing colorectal cancer. Established risk factors for cancer among patients with inflammatory bowel disease (IBD) include the younger age at diagnosis, greater extent and duration of disease, increased severity of inflammation, family history of colorectal cancer and coexisting primary sclerosing cholangitis. Recent evidence suggests that current medical therapies and surgical techniques for inflammatory bowel disease may be reducing the incidence of this complication. Nonetheless heightened vigilance and a careful, comprehensive approach to prevent or minimize the complications of invasive cancer are warranted in this unique cohort of patients. Current guidelines for the prevention and early detection of cancer in this high risk population are grounded in the concept of an inflammation-dysplasia-carcinoma sequence. A thorough understanding of the definition and natural history of dysplasia in IBD, as well as the challenges associated with detection and interpretation of dysplasia are fundamental to developing an effective strategy for surveillance and prevention, and understanding the limitations of the current approach to prevention. This article reviews the current consensus guidelines for screening and surveillance of cancer in IBD, as well as presenting the evidence and rationale for chemoprevention of cancer and a discussion of emerging technologies for the detection of dysplasia.

Pharmacoeconomics and quality of life of current and emerging biologic therapies for inflammatory bowel disease.

The development of biologic therapies for Crohn's disease and ulcerative colitis has profoundly affected the treatment of these diseases. The impact of these novel therapies has been tremendous in terms of their ability to cause clinical improvement in symptoms and endoscopic and histologic evidence of healing, as well as improvements in quality of life. However, the success of these new remedies comes with a significant price tag. In the current cost-containment environment of health care, it is essential to evaluate the impact of these novel and promising therapies on health care resource utilization, employment productivity, and quality of life. Despite the high cost of these new medications, they may result in a net cost savings through their ability to induce remission in the sickest of inflammatory bowel disease (IBD) patients, thereby averting the large expenditures associated with hospitalization and surgery. Likewise, by improving patients' physical symptoms, emotional well-being, and quality of life, biologic agents have the potential to reduce much of the unemployment, missed work, and disability through which IBD patients suffer. In a disease with an early age of onset and a chronic course with normal life expectancy, reducing morbidity and improving quality of life should be important measures of treatment success. Biologic therapies for IBD hold significant promise in this regard, allowing clinicians to achieve lasting remission in patients who are unresponsive to conventional therapies. Comparison of the costs and benefits of biologic therapies with conventional treatments for IBD is complicated by the need to assess the downstream effects of an intervention. For example, corticosteroids are inexpensive and very effective for induction of remission, but they come with significant long-term complications, such as osteoporosis, cataracts, impaired glucose tolerance, and poor wound healing, which must be taken into account when assessing their true cost as a maintenance medication. We do not yet have enough experience with biologic therapies to evaluate their potential to prevent or create future costs associated with adverse effects. However, as we move forward with our knowledge of biologic agents, an understanding of the economic and quality-of-life implications of these innovative therapies is crucial for patients, clinicians, and third-party payers alike.

Current and future therapies for inflammatory bowel disease.

The introduction of biologic agents to the therapeutic arsenal has dramatically impacted the way we treat patients with inflammatory bowel disease, allowing clinicians to achieve lasting remission in patients who are unresponsive to conventional therapies. New research continues to expand our understanding of the inflammatory cascade of ulcerative colitis and Crohn's disease, revealing a host of potential therapeutic targets for intervention. As we look toward the future in this rapidly developing field, we must learn how best to incorporate these new agents into the treatment algorithm to enhance or replace conventional therapies.