Article Text
PDF
Abstract
Introduction Incidence of inflammatory bowel disease (IBD) is increasing in childhood and treatment increasingly targets mucosal healing. Monitoring bowel inflammation requires endoscopy or MRI enterography which are invasive, expensive and have long waiting lists.
We aim to examine the feasibility of a non-invasive monitoring tool—bowel ultrasound (BUS)—in children with IBD and explore correlations with inflammatory markers and disease activity measures. Some BUS criteria have been found to correlate with these markers; however, this has not been validated in children.
We aim to examine the feasibility of BUS for monitoring inflammation in this population; highlighting useful parameters for this purpose. We aim to inform a larger scale randomised controlled trial using BUS.
Methods and analysis This prospective observational feasibility study will be carried out over 24 months at the Noah’s Ark Children’s Hospital for Wales, Cardiff; with the endpoint recruitment of 50 participants. Children aged 2–18 years with a modified Porto criteria diagnosis of IBD will be included.
Patients without IBD or who have previously undergone IBD-related surgery will be excluded; as will families unable to give informed consent.
Ultrasound scan images and reports will be collected, as well as laboratory results and clinical outcomes.
The primary aim will assess the feasibility of targeted BUS for disease monitoring; including recruitment statistics. The secondary aims will involve data collection and correlation analysis for targeted ultrasound parameters, biomarkers, disease activity scores and prediction of changes in treatment. The statistical methods will include: feasibility metrics, descriptive statistics, cross-tabulation and χ2 analysis, correlation analysis, regression analysis.
Ethics and dissemination Ethical approval is granted by NHS Research Ethics Committee. The sponsor is Cardiff and Vale University Health Board. We will publish the results in a peer-reviewed medical journal.
Trial registration number NCT05673278.
- Paediatric gastroenterology
- Gastrointestinal imaging
- Inflammatory bowel disease
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
STRENGTHS AND LIMITATIONS OF THIS STUDY
Ultrasound is a ubiquitous, relatively inexpensive tool, currently underutilised in the paediatric population. Study methodology could, therefore, be readily replicated at other specialist gastroenterology centres.
The study is non-invasive, with ultrasound measurement being the only deviation from normal clinical care. No additional blood tests or stool samples will be taken for research purposes.
We aim to recruit a total of 50 participants, which would make NIMBUS one of the largest studies evaluating ultrasound monitoring in paediatric inflammatory bowel disease.
The NIMBUS study will be conducted at a single specialist gastroenterology centre.
Serial ultrasound measurements may be beneficial in research and clinical settings. If one-off scans are feasible and correlate with other non-invasive markers, further work could explore scan parameters over time. Feasibility parameters within this work will inform progression to larger randomised controlled trial.
Introduction
Inflammatory bowel disease (IBD) is increasingly diagnosed in the paediatric population globally, with rising incidence noted across international cohorts.1 The aims of treatment involve the control of inflammation and symptoms through bringing about remission, while maintaining the lowest possible medication burden.2 3 Controlling inflammation has a positive impact on growth, nutrition, decrease in surgical rates and reduction of long-term morbidity.4 5
The long-term goal of treatment is bringing about mucosal (or transmural) healing, which can be monitored through multiple parameters, the gold standard being ileocolonoscopy and tissue biopsy. Other methods for monitoring bowel inflammation include MRI enterography, laboratory markers of inflammation (C-reactive protein(CRP) and faecal calprotectin), disease scores (Paediatric Crohn’s Disease Activity Index, PCDAI and Paediatric Ulcerative Colitis Activity Index, PUCAI for Crohn’s disease and ulcerative colitis (UC), respectively) and patient reports of symptoms. Subjective symptom reporting does not accurately correlate with bowel inflammation, hence treatment cannot be guided on this alone.6 Moreover, inflammatory markers in isolation have low sensitivity and provide little information about disease severity and extent.7 Current practice involves the integration of these methods to guide treatment.
In children, these procedures require general anaesthesia. While direct visualisation and tissue sampling offers the highest quality of clinical information, endoscopic procedures can pose multiple problems including anaesthetic risk, local trauma and perforation. Moreover, endoscopic procedures and three-dimensional imaging are costly and have significant waiting lists.8 As a result of these disadvantages, there is a movement in current gastroenterology research, particularly in an adult population, to explore the use of non-invasive techniques such as ultrasound to monitor IBD.
Ultrasound in IBD
Bowel ultrasound (BUS) is quick, reliable, accurate and acceptable to patients. It is readily available across district general and specialist children’s hospitals. No bowel preparation is required and images can be obtained at the bedside and reported instantaneously, allowing for contemporaneous decision-making. BUS is rarely undertaken in routine paediatric IBD practice, though may be employed in concern for acute surgical presentation or at diagnosis to visualise the small bowel. The vast majority of work utilising BUS has been undertaken in an adult population, and the tool is currently underutilised in children.9 10
BUS for monitoring has been shown to correlate with ileocolonoscopy and cross-sectional imaging in UC and Crohn’s among adult participants.11 12 BUS also offers the opportunity for patient and family engagement with their disease, through direct visualisation of inflammatory changes and discussion with scan technicians.13 Acceptability in the paediatric population is high, preferred over invasive techniques as well as regular blood and stool testing.14
Potential ultrasound measurements
There are multiple parameters that can measured using BUS. The most clinically useful measure is bowel wall thickness (BWT), which relates directly to gut inflammation.15 Colour Doppler has also been used to assess inflammation through hyperaemia of the bowel wall. This has been demonstrated to correlate with macroscopic endoscopy and gross surgical findings.16 Other measurable parameters of bowel inflammation are loss of colonic haustrations, visibility of bowel wall layers (stratification), mesenteric fat proliferation or fatty wrapping, motility in the TI and lymphadenopathy.17 In Crohn’s disease, it is also possible to visualise complications of longer-term inflammation including stricturing disease, fistulae and abscesses.18 19
Activity scores
There is scope to combine ultrasound parameters into standardised activity scores. Several scores have been evaluated in adult populations, using the above measurements. However, study design has often been suboptimal, with little standardisation between centres.19 Research in a paediatric population looking at standardised indices is lacking.
The Simple Paediatric Activity Ultrasound Score has been developed by Kellar et al integrating BWT, hyperaemia and inflammatory fat wrapping into a standardised score for pIBD. High scores demonstrated sensitivity of 100% (95% CI 90% to 100%) and specificity of 95% (95% CI 83% to 99.3%) for predicting active disease visualised on endoscopy.13 A US score for paediatric ulcerative colitis has been developed by Civitelli et al, which demonstrated correlation with clinical (r=0.94) and endoscopic (r=0.90) disease activity (p<0.001).20 A paediatric Crohn’s disease intestinal ultrasound score has also been developed by van Wassenaer et al demonstrating high sensitivity and specificity for inflammation.21 These scores have been developed in single centres and populations, and therefore, require external validation.
Assessing disease response
BUS also has potential for therapeutic monitoring when used serially over time, demonstrating potential for integration of BUS into routine follow-up for children and young people with IBD. The addition of regular BUS to disease surveillance would allow real-time, direct visualisation and measurement of bowel inflammation, providing useful information to inform the need to increase or decrease treatment.
Specific measurements from BUS taken early in presentation may have a role in predicting response to treatment. As a result, BUS could provide an accurate measure of disease control and also provide information regarding the need to escalate treatment, and further work is required to evaluate its implementation in this way.22
Study rationale
The use of BUS in adult patients with IBD during routine outpatient contact and during inpatient admission with acute symptoms has been demonstrated to be a useful tool in quantifying inflammation. In conjunction with patient symptom reporting, disease activity score and inflammatory markers this modality may offer sufficient information to escalate, de-escalate or even predict response to treatment in a paediatric population.
Targeted BUS potentially offers a reliable, accurate, cost-effective and non-invasive alternative to ileocolonoscopy or MR enterography. If widely accepted, training of paediatric gastroenterologists could allow for immediate, objective information to be collected in clinic, alongside or in place of bloods, faecal calprotectin or endoscopy. This study will provide assessment of the feasibility of this measure and inform further study into the clinical utility of BUS. We will also aim to assess whether specific parameters such as BWT and Doppler flow correlate with inflammatory markers, calprotectin and disease activity scores in a paediatric population and which parameters can be reasonably measured. Additionally, this study will provide assessment of BUS as a predictor of treatment escalation, symptoms or complications following ultrasound study.
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the applicable regulatory requirement(s).
Study schedule
The NIMBUS feasibility study will be undertaken according to the timeline outlined in table 1.
Gantt chart demonstrating NIMBUS (Non-Invasive Monitoring through Bowel Ultrasound) feasibility study timeline
Study objective and purpose
Primary aim
To examine the feasibility and utility of targeted BUS for disease monitoring in a paediatric cohort with IBD.
To determine progress to randomised controlled trial (RCT) using a ‘traffic light system’, data for specific feasibility measures will be collected. These criteria have been set to examine the viability of completing a larger, main trial within the site, population and anticipated budget. Thresholds for percentage scores have been set for ‘red’ (where issues in this area cannot be overcome; ‘amber’ (where issues may be remedied in this area); and ‘green’ (where no concerning issues are identified).23 Recruitment and technical logistics of ultrasound parameter measurement will inform future larger research studies into BUS in pIBD. The below areas are defined to determine feasibility of further study:
To identify the proportion of eligible patients approached who consent to the study.
To identify the proportion of patients for whom biomarker and clinical outcome data are available.
To assess compliance with attendance for ultrasound scans.
To identify which ultrasound parameters are measurable.
To assess barriers to obtaining high-quality ultrasound images and visualising predefined ultrasound parameters.
Secondary aims
To examine associations of targeted ultrasound parameters with inflammatory and nutritional biochemical markers and faecal calprotectin.
To examine whether there are any associations with targeted BUS and disease activity scores.
To examine whether targeted BUS in children with IBD is predictive of changes in management or disease course.
To develop a suitable framework for a full health economic evaluation in future RCT.
To examine links between blood and stool tests (inflammatory, nutritional biochemical markers and faecal calprotectin) already used for monitoring disease with ultrasound in children and young people with IBD.
To evaluate associations between scores used to rate disease activity in paediatric IBD and ultrasound scan results.
To examine whether there are correlations between BUS findings and clinical outcomes up to 12 months after scan, noting whether ultrasound findings predict treatment escalation, complications or changes in management.
Methods and analysis
Study setting and design
This is an observational prospective feasibility study. The study will be conducted at the single centre of the Noah’s Ark Children’s Hospital for Wales. The singular intervention is the use of one-off ultrasound scan. If fulfilling outlined feasibility criteria, this project will inform a large RCT, using serial ultrasound measures within recruited patients.
Subject selection
Recruitment sites—all inpatient and outpatient areas within the Noah’s Ark Children’s Hospital for Wales. Main sites will be Starfish outpatient department as well as Children’s Investigation unit as outpatients attend for infusions. Ward inpatients will also be eligible for inclusion.
Fifty children visiting hospital for routine clinical appointments (clinic, infusions, endoscopy, etc) or admitted with sequelae of IBD or ‘flare’.
Inclusion and exclusion criteria are outlined in table 2.
Inclusion and exclusion criteria for NIMBUS (Non-Invasive Monitoring through Bowel Ultrasound) feasibility study
Recruitment and consent
Eligible patients will be identified by clinical team from inpatient and outpatient lists, endoscopy and infusion schedules and from existing database of current paediatric patients with IBD. Potential recruits will be checked with the research team for eligibility and appropriateness for recruitment. Any eligible children will be provided the patient information sheet and invite letter (age matched/appropriate). Consent can be achieved after allowing young people and their families adequate time to review information provided (>24 hours). Should potential recruits have been approached via email or post through the invite letter and information sheet, and adequate time has been allotted for review of this information, then participants can complete consent on the same day as ultrasound scan. Consent or assent (for a child) will be on an age specific consent form. Initial recruitment proforma case reporting form (CRF) to be completed at time of consent.
Withdrawal of subjects
Parents and child have the option to opt out of recruitment at any stage. Children and parents have the right to withdraw their child at any point in the study. Participants or their parents who request will have all research data destroyed for their child. Any data collected up until the point of withdrawal will be kept and analysed. In addition, the investigating team may discontinue a participant from the study at any time if the investigating team considers it necessary for any reason.
Outcomes to be measured
Primary feasibility measures.
BUS (images, report, completed scoring system, barriers to obtaining high-quality images).
Routine disease scores—PCDAI or PUCAI depending on disease subtype.
Routine blood results (C-reactive protein (CRP), White cell count (WCC), erythrocyte sedimentation rate (ESR), albumin, ferritin).
Routine stool sample calprotectin results.
Medications at time of scan and at follow-up.
Subsequent changes in management following BUS.
Weight and height.
Blood tests and faecal calprotectin will be recorded from the routine clinical measurements when taken at hospital episodes. No additional blood tests or stool samples will be taken for research purposes. The study schedule is outlined in figure 1.
Study flow chart demonstrating the schedule of the NIMBUS (Non-Invasive Monitoring through Bowel Ultrasound) feasibility study. IBD, inflammatory bowel disease.
Disease activity scores (PCDAI or PUCAI) will be conducted following recruitment and throughout the study period and recorded for analysis. These scores would normally be calculated in routine practice.
Ultrasound scans will be performed after recruitment, are the main investigative part of the study and singular deviation from routine care. Studies will be undertaken by a single consultant paediatric radiologist, removing variation between operators. The ultrasound machine used for the study, a Canon Aplio i700 (with 14MHz and curvilinear 5–8 MHz probes), is currently used within the paediatric radiology department. Equipment is validated for bedside use by clinical engineering and in warranty. Scans will be performed as documented by Dollinger and Kayal, with initial global assessment of the bowel using a convex probe, before segmental analysis for IBD activity using high-frequency linear probe.24 Sigmoid, descending, ascending colon, cecum and terminal ileum will be assessed for the below criteria. Maximum numerical points total will be recorded for continuous variables within these segments as well as binary scores for parameters which can be defined as either present/absent. Parameter measurement will be made in line with International Bowel Ultrasound Group consensus guidance.25 An overall composite score of these parameters will be recorded.
Ultrasound studies will note key, predetermined criteria where possible:
I—BWT.
II—Colour Doppler signal.
III—Loss of wall layer stratification.
IV—Loss of haustration.
V—Fatty wrapping.
VI – Motility in terminal ileum (TI)
VII—Lymphadenopathy.
VIII—Abscess.
IX—Stricture.
+Image quality and factors influencing quality.
All measurements to be recorded on study CRF and entered into a database. Original proformas identifying patients will be held securely on site. Digital data containing scan images will be stored either on secure, encrypted memory sticks, physically at the Children and Young Adults Research Unit (CYARU) with access restricted to project team. This is to prevent the instantaneous upload of images to the clinical computer system where they might be visible to the clinical team. Digital data will be stored securely with access limited to the study team on National Health Service (NHS) computers.
Results of ultrasound scans will not be shared with clinical team unless deemed to require urgent medical or surgical management. This is to prevent influence of clinical decision making and subsequent integration of BUS into disease management. A standard operating procedure has been created for use in the event unexpected findings are noted on ultrasound scan.
We will record data collected at subsequent routine clinical appointments and extract disease activity scores over this time frame.
Measurements to be conducted in line with the methods formulated and validated by Cardiff and Vale University health board. All measurements to be collected by members of the study team who have had training and experience in the use of these tools in a standardised way. All ultrasound equipment will be prior to use according to health board policy.
Equipment required
Canon Aplio i700 machine ultrasound machine. This is currently used in paediatric radiology at Noah’s Ark Children’s Hospital for Wales and maintained by the health board. This machine is under contract and calibration with the manufacturer, who will be available in the event of device operational issues.
Height measure (all outpatient/inpatient departments).
Weighing scales (all outpatient/inpatient departments).
Patient and public involvement
Study design and documents have been reviewed by patients and families living with IBD. The project design aligns with priorities set out by the James Lind Priority Setting Alliance regarding IBD research and supports strategies of minimally invasive monitoring and proposes management which would decrease disruption to school and activity of children and young people—supported by charitable organisations such as Crohn’s In Childhood Research Association (CICRA) and Guts UK.
Definition of end of project
The primary data collection will be completed when the follow-up data at up to 12 months postultrasound has been collected for the final participant. The secondary endpoint will be completion of data entry, analysis and publication.
Statistics and data
Sample size considerations
Sample size (n=50) based on similar research work in this population and demographic as well as logistic factors within the Noah’s Ark Children’s hospital for Wales. In their 2019 meta-analysis of studies looking to compare ultrasound findings with MRI or ileocolonoscopy, van Wassenaer et al reported on 12 studies with numbers of participants ranging from 9 to 50.26 Practically, at the Noah’s ark Children’s Hospital for Wales there are approximately 250 children and young people with IBD managed by the paediatric gastroenterology team. The investigating team estimates that recruiting the desired number from this population will be feasible and within financial and time constraints of study, while having an adequate size to demonstrate the feasibility of ultrasound for monitoring tool in this group.
Statistical analysis
The primary feasibility metrics (recruitment, retention/follow-up) will be reported as point estimates alongside 95% CIs, and assessed against a traffic light progression criteria:
Recruitment rate (number screened and approached/number consented): >60% green, 30%–60% amber and <30% red.
Retention/follow-up rate (number consented/number providing outcome data): >80% green, 70%–80% amber and <70% red.
Availability rate of ultrasound scan attendance and specific parameters, that is, ability to obtain, for example ‘loss of bowel wall haustrations’ (number scanned/number providing outcome data): >80% green, 70%–80% amber and <70% red.
Descriptive statistics will be used to summarise the demographic and outcome variables of the children in all study periods. Subsequent analysis will be adjusted for potential confounding variables, for example, weight, height, diagnosis and gender.
Measured outcomes will be tested for normality in order to help determine the nature of analysis methods to be used. Normal plots will be used, with a cut-off value of p<0.05 accepted as evidence of a non-normal distribution.
For continuous data, if normally distributed, the mean and SD will be calculated. If not normally distributed, the median and IQR will be calculated. Categorical or binary variables will be summarised as frequency and percentage of total.
Cross-tabulation will be performed for categorical data. χ2 statistics, along with probability of chance observation, will be applied with a cut-off value of p<0.05 accepted as evidence of statistical significance. Box and whisker plots will be presented where appropriate.
T-tests or non-parametric tests will be employed for comparison of subgroups with a cut-off value of p<0.05 accepted as evidence of statistical significance. Correlation in continuous variables, that is, US parameters and biomarkers will be assessed with Spearman’s rank or Pearson’s correlation tests.
Multiple regression analysis may be considered to evaluate the ultrasound parameters with treatment outcome at up to 12 months, in relation to ultrasound severity score and other factors such as height, weight, diagnosis type and gender.
Review of data analysis methods was undertaken by a statistician in study development, and statistical support will be sought after data acquisition.
Data recording and record keeping
All study documents, in paper or electronic form, will be collected and retained in accordance with the data protection act 1998. This will be a secure location and utilised throughout the study period and after study end. All essential documents and original source documents will be retained until participants 25th birthday (or their 26th birthday if they were aged 17 years at the conclusion of treatment) according with C&VUHB policy.
All investigators and study site staff must comply with the requirements of the General Data Protection Regulation and Data Protection Act 2018 with regard to the collection, storage, processing and disclosure of personal information and will uphold the Act’s core principles.
Patient laboratory results, disease activity scores and ultrasound reports will be linked by secure study number and stored on NHS computers at the CYARU. Images from ultrasound scans will be stored on encrypted memory stick devices securely on site at the CYARU. Original proformas, which could identify patients, will be held securely on site. No identifiable information will be shared or published in any form.
Data will be securely stored on site at CYARU. Physical data will be stored in locked filing cabinets with access limited and controlled by project coordinator and chief investigator. Digital data will be stored on NHS computers within CYARU under password access controlled by CI and project co-ordinator. The CI will be responsible for data analysis and is the data custodian.
Data will be analysed by the CI and project core coordinator on site at Noah’s Ark Children’s hospital for Wales.
Ethics and dissemination
Health and Care Research Wales and Heath Research Authority approval was granted on 24 March 2023 following review by NHS Research Ethics Committee—23/WA/0028. The sponsor is Cardiff and Vale University Health Board. We will publish the results in a peer-reviewed medical journal and via websites and newsletters of Noah’s Ark Children’s Hospital, CYARU and CICRA.
Ethics statements
Patient consent for publication
Acknowledgments
The authors would like to thank Dr Tracy Coelho for undertaking scientific review of the study design and methodology and the team at the Children and Young Adult’s Research Unit (CYARU) in Cardiff for facilitating this work.
Footnotes
Contributors ZG is responsible for the day to day running and progress of this study, and to ensure the study is conducted as detailed in this protocol. EM will edit the protocol for publication. MOE will oversee the progress as chief investigator and AW will act as medical expert in paediatric gastroenterology. AE will act as medical expert in paediatric radiology. JA and MB at the University Hospital of Southampton have provided advice and guidance regarding study design and methodology. ZG and EM drafted the work and all authors reviewed the intellectual content critically and gave final approval of the version to be published.
Funding This research project is funded by the Noah’s Ark Children’s Hospital Charity and by the Crohn’s In Childhood Research Association (CICRA).
Disclaimer There are no plans to pay participants any money or provide any other benefits (Declaration of Helsinki requirement).
Competing interests JJA reports that he has received payment for being on the scientific advisory board of Orchard Therapeutics and is funded by an NIHR advanced Fellowship. The other authors have no conflicts of interest to declare.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.