Jan. 9, 2023
Updates in Intestinal Ultrasound
Chronic immune-mediated diseases of the small and large bowel, known as inflammatory bowel disease (IBD) are common, affecting more than 34,000 Albertans today. The investigation of symptoms related to IBD is challenging, because the entire bowel, particularly the small intestine is long (can be 7-8m) and therefore difficult to visualize directly with endoscopy. Cross-sectional imaging is increasingly used to indirectly evaluate the bowel and the surrounding structures that can be affected by the disease. Access to the safest diagnostic imaging modalities, such as magnetic resonance is challenging, and wait times are long (>6 months). In addition, these tests are difficult to undergo, with need for oral and intravenous contrast and with some, like CT they inpart radiation. As a result, the University of Calgary IBD Group was the first in North America, to start an innovative clinic using transabdominal, intestinal ultrasound (IUS) at the bedside to safely evaluate the bowel. Although Interest in growing globally, Calgary is the only site currently offering training to international experts in IBD from all over the world. This tool provides safe, accurate and timely information on the structure and function of the bowel, including bowel motility, helping physicians and patients understand the severity and extent of disease in a patient-centered manner, with emphasis on education and engagement.
Timely, accurate measures of inflammation in IBD during routine follow-up are essential to inform clinical-decisions to ensure patients reach the therapeutic target of intestinal healing. Attainment of these targets improves patient outcomes, such as reduced hospitalization, emergency room visits, and even surgery. In addition to these important outcomes, IBD care aims to enhance patient experience, improve patient quality of life, their productivity and reduce the limitations imparted by this chronic progressive disease. IUS offers a patient-centered, safe alternative means of monitoring patients routinely in clinic, so together these goals can be achieved in a patient-centered way.
The patient perspective
Although considered the gold standard measure of bowel inflammation, direct visualization of the small and large bowel with video endoscopy is challenging, it is costly, invasive and requires conscious sedation and a full day to prepare the bowel for testing. As a result, although important, patients prefer other, less difficult non-invasive yet accurate tests. A recently conducted, international qualitative study using patient focus groups, attempted to understand patient experience and preferences for disease monitoring among those with Crohn’s disease. The group was unanimous, wanting to have access to IUS in their center, given the ability to see their disease or lack thereof, with the physician who makes decisions about their care. Data published from Calgary demonstrates significant impact on timely clinical decision that improve disease control and limit invasive testing, particularly important during our recent global pandemic.
"Having ultrasounds available for patients like myself is a huge improvement. It’s quick, easy and much less invasive than getting a scope which many patients fear. Now I enjoy going to my appointments as we can take a look at my gut right there and make adjustments to my treatment plan as needed." as described by a patient.
Challenges and Obstacles
Despite the potential of IUS to transform routine, bedside monitoring of IBD in Canada, a number of challenges exist. First, performance of IUS requires specialized skill and training, with a steep learning curve. IUS training can be completed during IBD subspecialty fellowship, but most interested in IUS must accommodate training within their current active practice which is difficult. IUS machines are also expensive and require significant computing power for optimal resolution. Given the added time for IUS during clinic appointments, workflows need adjustment to optimize appropriate performance and time allocation. Finally, remuneration models are currently lacking, but several provinces are making progress with fees associated with clinic-based IUS which will facilitate provision in expert IBD centers.
Training and Dissemination
As the only site in North America currently accepting trainees, the University of Calgary hosts trainees from all over the world, including the Philippines, Uruguay, Cost Rica, Kuwait, Australia, the United Kingdom, United States and a number of regions in Canada. IUS is now available in most provinces in Canada, with many trainees getting their start here in Calgary. Dr. Hughie Fraser is a gastroenterologist who was the first to start an IUS-based clinic in the Maritimes, working just outside of Halifax. Dr. Kenneth Suarez an IBD specialist from Costa Rica who undertook training here in Calgary, is now working to implement IUS into clinical practice in Costa Rica and Latin America. "Understanding the bowel and IBD more comprehensively with IUS has helped me make decisions more efficiently and confidently in clinic. It also helps to show real-time objective information to our patients, making it easier for them to consider and accept our recommendations" Dr. Suarez explains.
Dr. Novak is a founding member of the International Bowel Ultrasound Group (IBUS), based in Berlin, Germany, who established the only credentialed training program for IBD-focused IUS monitoring in the world. The aim in Canada is to provide high quality, easy access IUS for both adults and children with IBD.
Research Needs and Highlights
monitoring clinical symptoms to targeting objective measurements on both endoscopic and cross-sectional imaging. Modalities such as IUS are rapidly
growing in use and are highly favoured for their cost-effectiveness, patient tolerance, and easy repeatability for frequent monitoring of response to therapy. Access to IUS is limited to certain centres in the world due to a variety of reasons including lack of training, remuneration, and less available evidence in comparison to the well-known CT (computed tomography) and magnetic resonance imaging (MRI) modalities. As a result, a main driver of research in IUS is to increase scientific evidence to support the use of IUS in both diagnosis and monitoring of IBD.
The development of validated scoring indices on all forms of diagnostic imaging is a key componentof developing treatment targets in IBD and following efficacy of therapies in both clinical practice and trials. More specifically, both Dr. Novak and Dr. Lu as principal investigators of individual grants have received over $5.5 million dollars in combined grant funding from the Leona M and Harry B Helmsley Foundation.
Dr. Novak is leading an international study with 16 centres developing a validated IUS scoring index evaluating response to treatment in a prospective trial entitled USE-IT: Ultrasound Score To Evaluate Inflammation And Treatment Response In Crohn’s Disease. Additionally, Dr. Lu is leading the development of an IUS index for small bowel Crohn’s disease strictures (fibrostenosis) to devise clear definitions of strictures and treatment response at certain time points for use during clinical trials. In fibrostenosis, the bowel wall undergoes scarring (fibrosis) leading to narrowing (strictures) and eventual blockage. At this time, the integration of IUS into clinical trials is dependent on the development of these validated indices and both Dr. Novak and Dr. Lu with their teams are the drivers of these large international initiatives.
Upcoming areas in IUS also include defining if transmural healing and early IUS normalization improve long term outcomes. One of the greatest advantages of IUS is its ease of repeatability every 12 weeks that will allow for more rapid adjustments in therapy if necessary. Patient engagement is also an important area of study where Dr. Novak's qualitative research conducted in the USA, Canada, Australia and the UK, found that they wanted to help guide monitoring choices and didn't always have the chance. Although access to IUS in clinics is limited, patients believed this should be more widely available.
SPOTLIGHT: Precision Medicine and Translational Research
In the field of translational research and precision medicine, Dr. Lu is leading the study of proteomic biomarkers combined with IUS to improve the diagnosis of fibrosis in patients with CD prior to overt stricture formation. In other words, as CD is progressive with no cure, asymptomatic patients with active deposition of fibrosis in early fibrostenosis not yet visualized on endoscopy, or diagnostic imaging are at risk of treatment delays and progressive bowel damage. Therefore, timely detection of disease behavior is paramount to improving CD outcome. Despite the revolutionary addition of biologic therapies over the past two decades, surgical resection estimates either remain unchanged, or have shifted from emergent to more elective procedures. Existing predictive tools for strictures lack the ability for clinicians to personalize therapy and identify those with early fibrosis, which may be contributing to this dilemma. Diagnostic imaging with MRI or IUS are first line investigations to diagnose CD strictures1. This is a paradigm shift where it is now widely recognized that endoscopy for diagnosis is limited due to its ability to only examine the inner most bowel wall layer, its invasiveness, and inability to traverse through a narrowing.
To address this unmet need, Dr. Lu and her co-investigators, Dr. Simon Hirota and Dr. Tony Dufour, are using proteomics technology to develop a simple, clinical diagnostic blood test to precisely identify those who have a stricture in CD. As proteins are ubiquitous in disease, proteomics has exceptional promise for biomarker discovery as it can detect and quantify thousands of proteins simultaneously. Dr. Lu’s aim is to provide a diagnostic protein panel that will guide physicians to personalize treatment decisions, where earlier biologic therapy may be introduced or earlier surgical resection may be beneficial. In addition, a subset of patients with inflammatory (non-stricture) phenotype will transform to the fibrostenotic phenotype over time. These changes are unpredictable and provide Dr. Lu the opportunity to utilize IUS to closely monitor the transformation of the bowel combined with a protein panel to detect fibrosis prior to overt stricture formation. Overall, this signature protein panel may make medicine more personalized for the patient by guiding timing of medication initiation or cessation, and preventing unnecessary prolonged use of one therapy in favor of surgical approaches to improve quality of life.
Proteomics analysis of blood or tissue samples yields thousands of proteins as potential candidates for deciphering between stricture and non-stricture CD subtypes. The use of machine learning, a form of artificial intelligence, is an integral component to developing predictive tools to incorporate both proteomics and imaging data. With Dr. Lu’s results and stricture imaging database, she is working with machine learning experts to develop a validated web-based calculator that is efficient and easy to use by clinicians to predict when patients will form strictures after diagnosis and following surgery. Precision medicine tools to stratify patients into low and high risk are absolutely necessary to assist physicians to transform current diagnostic strategies, optimize therapy, and to inform shared decision making with patients.
References: (1) Rimola J, Torres J, Kumar S, et al. Recent advances in clinical practice:advances in cross-sectional imaging in inflammatory bowel disease. Gut . 2022