A Healthcare Physician Can Be Trained to Perform Intestinal Ultrasound in Children With Inflammatory Bowel Disease

ABSTRACT Objectives: Training healthcare physicians to perform intestinal ultrasound (IUS) during outpatient visits with equal accuracy as radiologists could improve clinical management of IBD patients. We aimed to assess whether a healthcare-physician can be trained to perform IUS, with equal accuracy compared with experienced radiologists in children with iBD, and to assess inter-observer agreement. Methods: Consecutive children, 6 to 18 years with IBD or suspicion of IBD, who underwent ileo-colonoscopy were enrolled. iUS was performed independently by a trained healthcare-physician and a radiologist in 1 visit. Training existed of an international training curriculum for IUS. Operators were blinded for each other's IUS, and for the ileocolonoscopy. Difference in accuracy of IUS by the healthcare-physician and radiologist was assessed using areas under the ROC curve (AUROC). Inter-observer variability was assessed in terminal ileum (TI), transverse colon (TC) and descending-colon (DC), for disease activity (ie, bowel wall thickness [BWT] >2 mm with hyperaemia or fat-proliferation, or BWT >3 mm). Results: We included 73 patients (median age 15, interquartile range [IQR]:13–17, 37 [51%] female, 43 [58%] with Crohn disease). AUROC ranged between 0.71 and 0.81 for the healthcare-physician and between 0.67 and 0.79 for radiologist (P > 0.05). Inter-observer agreement for disease activity per segment was moderate (K: 0.58 [SE: 0.09], 0.49 [SE: 0.12], 0.52 [SE: 0.11] respectively for TI, TC, and DC). Conclusions: A healthcare- physician can be trained to perform IUS in children with IBD with comparable diagnostic accuracy as experienced radiologists. The interobserver agreement is moderate. Our findings support the usage of IUS in clinical management of children with IBD.


What Is Known
Inflammatory bowel disease is a relapsing and remitting condition, that requires regular monitoring of disease activity. Intestinal ultrasound is increasingly used to monitor disease activity in children with inflammatory bowel disease.

What Is New
By following a currently existing training curriculum, an unexperienced health care physician can be trained to perform intestinal ultrasound with equal diagnostic accuracy as a radiologist. Inter-observer agreement for intestinal ultrasound was moderate in our cohort. P atients with inflammatory bowel disease (IBD) need to be monitored frequently in order to detect disease relapses timely. Currently, an ileocolonoscopy is the reference standard method to detect disease activity. this is, however, an invasive method that is associated with significant distress, especially in the paediatric population. For this reason, paediatric gastroenterologists have a high threshold for performing ileocolonoscopy and mostly rely on noninvasive monitoring, using clinical indices, biomarkers in blood (eg, CRP) and stools (eg, faecal calprotectin) to guide clinical management. These biomarkers have important limitations though, as their accuracy is limited and their results do not give information on disease location and extension (1). Intestinal ultrasound (IUS) has evolved as an additional modality in the monitoring of IBD to overcome the limitations of conventional biomarkers and is increasingly used in clinical practice. A practical obstacle for its use is, however, the need for a radiologist or US technician to perform IUS. Training nonradiologist healthcare physicians-such as gastroenterologists and paediatricians-to perform a point-ofcare IUS (POCUS) during the outpatient clinic visit with equal accuracy as a radiologist would allow for a broader implementation ofIUS and could improve clinical decision-making (2). Because of a lack of evidence, however, there is currently no consensus on how to train healthcare physicians (3). Several surveys show that this poses a barrier for paediatricians for learning to perform POCUS, and resistance from the radiology department to support POCUS because of this lack of evidence is part of this barrier (4)(5)(6)(7). Comparing the diagnostic performance of a trained healthcare physician to a paediatric radiologist might help in eliminating this barrier. In this study, we assessed whether a trained healthcare physician can perform IUS, with an accuracy that is equal to an experienced paediatric radiologist. Our primary aim was to compare diagnostic performance of IUS by a trained healthcare physician and a paediatric radiologist, using ileocolonoscopy as reference standard. Our secondary outcome was the interobserver variability between both observers in children diagnosed with or suspected of IBD.

METHODS
This study was part of an ongoing study on the diagnostic test accuracy of IUS in paediatric IBD (the RAINBOW-study). The RAINBOW-study is a prospective cross-sectional study in 2 tertiary care centres in Amsterdam, the Netherlands. Consecutive patients, aged 6 to 18 years old who underwent an ileocolonoscopy for diagnosis or follow-up of IBD between August 2019 and June 2021 were enrolled. Patients with ongoing gastroenteritis or with history of surgical resection were excluded.

Ultrasound
The 2 IUS examinations were performed consecutively at the radiology department, on the same day, the day before, or at most within 7 days of the reference standard, by 1 trained healthcare physician (training is described in detail below) and 1 of 3 paediatric radiologists (all > 12 years of experience). All operators were blinded for each other's IUS results, for the outcome of the reference standard and for clinical disease activity parameters.
Patients were asked to take no solid food, carbonated beverages and milk for 4 hours before the US examination, as recommended by the ESPR/ESGAR guideline (8). The IUS examinations were performed with a Philips EPIQ 5 machine (Philips Healthcare, Best, the Netherlands), using a convex probe (2-9 MHz, C9-2, Philips Healthcare) for general screening and a linear probe (4-12 MHz, L12-4, Philips Healthcare) for measurements. The following bowel measurements were performed: bowel wall thickness (BWT) in millimetre (mm), measured from the lumen/mucosa interface to the muscularis/serosa interface in a noncontracted bowel loop, next to a haustration at the most severely inflamed part of every bowel segment. BWT was measured twice in the longitudinal plane and twice in the cross-sectional plane and the mean of these 4 measurements was used. For the RAINBOW-study, we performed measurements of the jejunum, ileum, terminal ileum, cecum, ascending-, transverse-, descending-, sigmoid colon and rectum; however, for this sub-study, we limited our analyses to the terminal ileum (TI) and the descending colon (DC), as these are 2 of the most prevalent disease locations forrespectively paediatric Crohn disease (CD) and ulcerative colitis (UC) and both have a relatively fixed anatomic position. In addition, we included the transverse colon in the analyses, as the anatomical position is more variable and we wanted to investigate the effect of this variable anatomic position on the interobserver analyses. The TI was identified near the psoas muscle and iliac vessels, just proximal of the ileocecal valve. The TC was identified caudally from the stomach. The DC was identified on the lateral left side of the abdomen. Other measurements included: bowel wall perfusion using colour Doppler (yes [ie, spots or more] or no, velocity rate: þ/-10 cm/seconds), and presence of mesenteric fat proliferation, or so-called 'fatty wrapping' (yes or no). In addition, presence of complications (stenosis, fistula, and abscesses) were noted.
All measurements were noted on a prepiloted scoring form during the examinations and all operators received an instruction before the training on how to score.

Training of Physician
The healthcare physician (E.W.) was a physician working at the Department of Paediatric Gastroenterology, with no previous experience in performing ultrasound examinations. She followed the curriculum of the International Bowel Ultrasound Group, which consists of an introductory hands-on workshop, a 4-week part time hands-on training in an expertise centre and an advanced workshop including a final test (9). The 4-week hands-on training was followed at the Amsterdam IBD clinic and at the Gastroenterology Department of the Städtisches Klinikum Lüneburg, Germany. She performed 100 IUS examinations under the supervision of experienced ultrasonographers before the start of the study. In addition, she performed 20 IUS examinations at the Paediatric Radiology Department to gain experience with paediatric patients.

Reference Standards
The ileocolonoscopies were performed by the paediatric gastroenterologists of the participating centres and were videotaped. The videotapes were centrally read by 1 experienced paediatric gastroenterologist (B.K.) who was blinded for the IUS result. Disease activity was scored by the Simple Endoscopic Score forCD (SES-CD) (10) in case of CD and with the Mayo endoscopic sub score in case of UC.

Statistical Analyses
For the primary outcome, the difference in diagnostic performance of the healthcare physician and the paediatric radiologist was assessed by comparing areas under the receiver operating characteristics curve (AUROC) in all 3 segments using MedCalc (2021 MedCalc Software Ltd). The definition of disease activity assessed by IUS was a BWT >2 mm, in combination with at least 1 other sign of inflammation, or in case of a BWT >3 mm, with or without other signs of inflammation. For the SES-CD we used the cut-off ! 1 per segment as abnormal and for the Mayo score ! 1.
For interobserver agreement, Bland-Altman plots were used to display agreement on BWT. In addition, we categorized BWT in normal (0-2 mm), mildly increased (2-3 mm) and strongly increased (>3 mm). These categories were based on a systematic review on IUS measurements in healthy children (11) and on a systematic review on IUS in children with IBD (12). Foragreement in assessing disease activity, we used the definition of an abnormal IUS described above. Kappa statistics were used for dichotomous variables and weighted Kappas for ordinal variables. Kappa values were judged as follows: < 0.0: poor; k 0.0 to 0.20: slight; 0.21 to 0.40: fair; 0.41 to 0.60: moderate; 0.61 to 0.80: substantial; >0.80: almost perfect (13). In case of continuous variables, systematic differences were assessed using the Wilcoxon signed ranked test

Ethical Considerations
Informed consent was obtained from all patients ages between 12 and 18 years and all care givers of patients aged < 16 years. The study has been approved by the Institutional Review Board (number of approval: K1 B2019450) and complied to the Declaration of Helsinki.

RESULTS
We included a total of 73 patients between August 2019 and June 2021. The patient demographics are displayed in Table 1. The TI and TC could be measured by the healthcare physician in all cases and the DC was not identified in 1 case. The DC could be identified by the paediatric radiologist in all cases, and the TI and TC could not be identified in 1, respectively, 2 cases. In the TI, abscesses, fistula and stenosis were noted, respectively, 1, 0, and 3 times by the health care physician, and respectively, 1, 1, and 2 times by the paediatric radiologist. All complications were confirmed by MRE except for the stenosis in 1 patient who did not undergo MRE imaging. In other segments, neither of the operators noted complications.

Diagnostic Accuracy
The AUROC for detecting disease activity for all 3 bowel segments are displayed in Figure 1. The ileum could not be intubated in 5 patients, and these were thus excluded from the analysis of the ileum. There was no significant difference in AUROC between the health care physician and the paediatric radiologist for TI

Bowel Wall Thickness
There was no significant difference between the BWT measurements of the healthcare physician and radiologist.  Figure 2, there was no systematic difference in BWT measurements, and for DC, the mean difference increased when mean BWT increased. The agreement in categorizing BWT (ie, 0-2, 2-3, > 3 mm) was fair for TI

Overall disease Activity
The agreement for assessing disease activity per segment was moderate for each segment

DISCUSSION
This study shows that a healthcare physician can be trained to perform an IUS in children with IBD with an equal accuracy compared with an experienced radiologist, by following a currently available training curriculum. These results further support the introduction of POCUS as monitoring tool for disease activity in children with IBD. This is the first study that performed a head-to-head comparison between a trained healthcare physician and an experienced radiologist with regard to IUS. The diagnostic accuracy of trained healthcare physician in performing IUS has been studied before, mostly in the adult IBD population (14,15). None of these studies, however, compared their results to those of an experienced radiologist. Equal diagnostic accuracy of IUS by healthcare physician compared with radiologists was shown in other intestinal disorders in children, such as the detection of intussusception and appendicitis (16,17). Adding POCUS as noninvasive monitoring tool for detection of IBD activity could alter clinical decision-making (2). On the basis of our results, IUS performed by a trained healthcare physician will not negatively impact diagnostic accuracy in comparison to radiologist-performed IUS. The AUROCs in our study were not optimal, however. To really determine the optimal use and diagnostic accuracy of IUS for local and overall disease, the most relevant IUS features and their cut-off values for detecting inflammation in paediatric IBD need to be determined (12).
A remarkable finding of our study was the moderate interobserver agreement on overall inflammation between the 2 raters (k: 0.49-0.58). This despite standardizing the assessment of our IUS examinations by using a pre-piloted scoring form and by training the raters before the start of the study. Other studies on inter-radiologist- (18)(19)(20) and inter-gastroenterologist (21,22) agreement for IUS suggested higher agreement levels (k: 0.60-0.96). A possible explanation could be that these analyses were based on assessments of previously stored images and not on realtime assessments. One other small study on real-time interobserver agreement of IUS between experienced nonradiologists in 15 adult patients with IBD demonstrated moderate to substantial agreement for most IUS items (s ¼ 0.41 -0.78) (23). A recently published study on real-time inter-observer agreement between gastroenterologists in 49 IBD patients demonstrated substantialto-near perfect agreement on the other hand (24). This underscores the relevance of standardization of the IUS procedure and  There are currently no standardized training guidelines for teaching healthcare physicians in paediatrics how to perform IUS (3). On the basis of our results, performing around 100 dedicated IUS examinations under supervision of both experienced healthcare physicians and radiologists, as part of the International Bowel Ultrasound Group curriculum is sufficient to reach an equal level as an experienced radiologist. Whether this also holds for other types of US, such as screening for appendicitis or intussusception, however, remains to be proven. In addition, the cost-benefit of training health care physicians might be different in centres with smaller IBD populations, where the efforts of following an IUS training and maintaining skills may not balance the benefits.
The strengths of this study are the short time interval between the 2 US examinations and the reference standard, the blinding of all operators, and the central reading procedure for the reference standard. Limitations are the inclusion of 3 different radiologists; although all 3 completed the paediatric radiology training and had > 12 years of experience, the inter-radiologist variability was not assessed and might have biased our results. In addition, we only assessed the diagnostic performance of 1 single healthcare physician, and learning curves may differ individually. More importantly, we used the SES-CD score as reference standard for CD patients, while this score is not validated as segmental score. The cut-off of > 1 value for the segmental SES-CD was chosen by the authors and considered as most appropriate, as this reflects any level of disease activity. Another limitation is the scoring system for the IUS, as to date, there is no consensus on which cut-off value to use when scoring an IUS in children with IBD, both for patients with CD and UC (12). In this study, we pooled results of both IBD entities; however, for studies into optimal use and diagnostic accuracy ofIUS, we advise to analyse both entities separately (12). Lastly, as we only used ileo-colonoscopy as reference for this study, we could not assess the small bowel proximal to the TI.
As non-radiologist POCUS is increasingly used in paediatric medicine (3), future research should focus on training of nonradiologists for other purposes as well. Moreover, more research is needed to determine the added clinical value of IUS in the treatment of children with IBD in addition to other frequently used biomarkers of disease activity, such as CRP and faecal calprotectin.

CONCLUSIONS
On the basis of our results, a healthcare physician can be trained to perform IUS in children with IBD with comparable diagnostic accuracy as an experienced radiologist. This supports the uptake of POCUS in the clinical management of children with IBD. Future research should demonstrate the clinical value of IUS in addition to other frequently used biomarkers of disease activity.