Home-based guided hypnotherapy for children with functional abdominal pain and irritable bowel syndrome in primary care: study protocol for a randomised controlled trial.

INTRODUCTION: Children often present to primary care with functional abdominal pain (FAP) or irritable bowel syndrome (IBS), and around half still have abdominal complaints 1 year later. Hypnotherapy is an evidence-based treatment that is used in specialist care, but it lacks evidence in primary care. This study will investigate the (cost) effectiveness of home-based guided hypnotherapy for children with FAP or IBS in primary care. METHODS AND ANALYSIS: We report the design of a pragmatic randomised controlled trial among children aged 7-17 years, diagnosed with FAP or IBS by their general practitioner (GP), with assessments over 12 months. The control group will receive care as usual (CAU) by their GP (eg, communication, education and reassurance), while the intervention group will receive CAU plus 3 months of home-based guided hypnotherapy via a website. The primary outcome will be the proportion of children with adequate relief from abdominal pain/discomfort at 12 months, analysed on an intention-to-treat basis. Secondary outcomes will include the adequacy of pain relief at 3 and 6 months, pain/discomfort severity, pain frequency and intensity, daily functioning and impact on function, anxiety and depression, pain beliefs, sleep disturbances, school absence, somatisation, and healthcare use and costs. We must include 200 children to determine a 20% difference in those with adequate relief (55% control vs 75% intervention). ETHICS AND DISSEMINATION: The Medical Ethics Review Committee of the University Medical Center Groningen, the Netherlands, approved this study (METc2020/237). The results will be disseminated to patients, GPs and other stakeholders via email, a dedicated website, peer-reviewed publications and presentations at national and international conferences. We plan to collaborate with the Dutch Society of GPs to implement the results in clinical practice. TRIAL REGISTRATION NUMBER: NCT05636358.

Test Strategies to Predict Inflammatory Bowel Disease Among Children With Nonbloody Diarrhea.

OBJECTIVES: We evaluated 4 diagnostic strategies to predict the presence of inflammatory bowel disease (IBD) in children who present with chronic nonbloody diarrhea and abdominal pain. METHODS: We conducted a prospective cohort study including 193 patients aged 6 to 18 years who underwent a standardized diagnostic workup in secondary or tertiary care hospitals. Each patient was assessed for symptoms, C-reactive protein (>10 mg/L), hemoglobin (<-2 SD for age and sex), and fecal calprotectin (≥250 µg/g). Patients with rectal bleeding or perianal disease were excluded because the presence of these findings prompted endoscopy regardless of their biomarkers. Primary outcome was IBD confirmed by endoscopy or IBD ruled out by endoscopy or uneventful clinical follow-up for 6 months. RESULTS: Twenty-two of 193 (11%) children had IBD. The basic prediction model was based on symptoms only. Adding blood or stool markers increased the AUC from 0.718 (95% confidence interval [CI]: 0.604-0.832) to 0.930 (95% CI: 0.884-0.977) and 0.967 (95% CI: 0.945-0.990). Combining symptoms with blood and stool markers outperformed all other strategies (AUC 0.997 [95% CI: 0.993-1.000]). Triaging with a strategy that involves symptoms, blood markers, and calprotectin will result in 14 of 100 patients being exposed to endoscopy. Three of them will not have IBD, and no IBD-affected child will be missed. CONCLUSIONS: Evaluating symptoms plus blood and stool markers in patients with nonbloody diarrhea is the optimal test strategy that allows pediatricians to reserve a diagnostic endoscopy for children at high risk for IBD.

Exploring the Challenges of Implementing a Web-Based Telemonitoring Strategy for Teenagers With Inflammatory Bowel Disease: Empirical Case Study.

BACKGROUND: We designed a telemonitoring strategy for teenagers with inflammatory bowel disease to prevent an anticipated disease flare and avert unplanned office visits and day care procedures. The strategy was evaluated in a randomized controlled trial that involved 11 Dutch pediatric gastroenterology centers, each using repeated symptom scores and stool calprotectin measurements. In the telemonitoring arm of the trial, teenagers (n=84) as well as their health providers were alerted to out-of-range results, and suggestions for change in therapy were offered. We demonstrated that the technology was a safe and cost saving alternative to health checks by the specialist at fixed intervals. OBJECTIVE: The aim of this study was to evaluate whether we could move our telemonitoring strategy from a demonstration project to one that is sustained within existing sites. METHODS: In this empirical case study, we used the nonadoption, abandonment, scale-up, spread, and sustainability (NASSS) framework to explore the challenges to implementing our strategy. The framework distinguishes 7 domains: (1) the illness, (2) the technology, (3) the value proposition, (4) the adopter system, (5) the organization, (6) the societal system, and (7) the time dimension. We summarized the challenges across all 7 domains and classified them as simple (+++), complicated (++), or complex (+). Technologies in which multiple domains are complicated have proven difficult to implement, whereas those with multiple complex domains may not even become mainstreamed. RESULTS: The technology that we used and the linked program (IBD-live) allowed us to select and target the teenagers who were most likely to benefit from a face-to-face encounter with their specialist (+++). The value proposition of the technology was clear, with a distinct benefit for patients and an affordable service model, but health providers had plausible personal reasons to resist (double data entry, ++). The organization was not yet ready for the innovation, as it requires a shift to new ways of working (+). We had no concerns about reimbursement, as Dutch health insurers agreed that screen-to-screen consultations will be reimbursed at a rate equivalent to face-to-face consultations (+++). Finally, the technology was considered easy to adapt and evolve over time to meet the needs of its users (+++). CONCLUSIONS: The challenges to be addressed are merely complicated (++) rather than complex (+), which means that our program may be difficult but not impossible to sustain within existing sites. After integrating the technology and its use with local workflows first, we believe that our telemonitoring strategy will be ready for sustained adoption. In contrast with what we did ourselves, we recommend others to use the NASSS framework prospectively and in real time to predict and explore the challenges to implementing new technologies.

No association between abdominal pain and Dientamoeba in Dutch and Belgian children.

OBJECTIVE: To study the association between Dientamoebafragilis colonisation and faecal calprotectin to see whether the parasite is a harmless commensal or a gut pathogen. DESIGN: Cross-sectional study of previously collected stool samples. SETTING AND PATIENTS: Two hundred stool samples originated from children aged 5-19 years with chronic abdominal pain and diarrhoea, who were seen in paediatric clinics in the Netherlands and Belgium and in whom somatic gastrointestinal disorders were excluded. Another 122 samples came from a healthy community-based reference population of the same age. All stool samples were analysed with real-time PCR for the detection of D. fragilis and with an ELISA for calprotectin-a biomarker of gastrointestinal inflammation. MAIN OUTCOME MEASURES: Prevalence of D. fragilis colonisation and results of stool calprotectin testing. RESULTS: D. fragilis was detected in 45% (95% CI 38% to 51%) of patients and in 71% (95% CI 63% to 79%) of healthy children. Median (IQR) concentrations of calprotectin in patients and healthy children with a positive PCR result were not different from those with a negative PCR result (40 (40-55) µg/g vs 40 (40-75) µg/g, respectively). CONCLUSION: Since D. fragilis colonisation is most prevalent in healthy children and is not associated with an increase in faecal calprotectin concentration, our data do not support the inference that D. fragilis is a pathogenic parasite. Routinely testing for D. fragilis in children with chronic abdominal pain should therefore be discouraged.

Predicting inflammatory bowel disease in children with abdominal pain and diarrhoea: calgranulin-C versus calprotectin stool tests.

OBJECTIVE: Calgranulin-C (S100A12) is a new faecal marker of inflammation that is potentially more specific for inflammatory bowel disease (IBD) than calprotectin, since it is only released by activated granulocytes. We compared calgranulin-C and calprotectin to see which of the two tests best predicted IBD in children with chronic abdominal pain and diarrhoea. DESIGN: Delayed-type cross-sectional diagnostic study. SETTING AND PATIENTS: Previously undiagnosed patients aged 6-17 years, who were seen in paediatric clinics in the Netherlands and Belgium, sent in a stool sample for analysis. Patients with a high likelihood of IBD underwent upper and lower endoscopy (ie, preferred reference test), while those with a low likelihood were followed for 6 months for latent IBD to become visible (ie, alternative reference test). We used Bayesian modelling to correct for differential verification bias. MAIN OUTCOME MEASURES: Primary outcome was the specificity for IBD using predefined test thresholds (calgranulin-C: 0.75 µg/g, calprotectin: 50 µg/g). Secondary outcome was the test accuracy with thresholds based on receiver operating characteristics (ROC) analysis. RESULTS: IBD was diagnosed in 93 of 337 patients. Calgranulin-C had significantly better specificity than calprotectin when predefined thresholds were used (97% (95% credible interval (CI) 94% to 99%) vs 71% (95% CI 63% to 79%), respectively). When ROC-based thresholds were used (calgranulin-C: 0.75 µg/g, calprotectin: 400 µg/g), both tests performed equally well (specificity: 97% (95% CI 94% to 99%) vs 98% (95% CI 95% to 100%)). CONCLUSIONS: Both calgranulin-C and calprotectin have excellent test characteristics to predict IBD and justify endoscopy. TRIAL REGISTRATION NUMBER: NCT02197780.

Efficacy of Home Telemonitoring versus Conventional Follow-up: A Randomized Controlled Trial among Teenagers with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Conventional follow-up of teenagers with inflammatory bowel diseases [IBD] is done during scheduled outpatient visits regardless of how well the patient feels. We designed a telemonitoring strategy for early recognition of flares and compared its efficacy with conventional follow-up. METHODS: We used a multicentre randomized trial in patients aged 10-19 years with IBD in clinical remission at baseline. Participants assigned to telemonitoring received automated alerts to complete a symptom score and send a stool sample for measurement of calprotectin. This resulted in an individual prediction for flare with associated treatment advice and test interval. In conventional follow-up the health check interval was left to the physician's discretion. The primary endpoint was cumulative incidence of disease flares. Secondary endpoints were percentage of participants with a positive change in quality-of-life and cost-effectiveness of the intervention. RESULTS: We included 170 participants [84 telemonitoring; 86 conventional follow-up]. At 52 weeks the mean number of face-to-face visits was significantly lower in the telemonitoring group compared to conventional follow-up [3.6 vs 4.3, p < 0.001]. The incidence of flares [33 vs 34%, p = 0.93] and the proportion of participants reporting positive change in quality-of-life [54 vs 44%, p = 0.27] were similar. Mean annual cost-saving was €89 and increased to €360 in those compliant to the protocol. CONCLUSIONS: Telemonitoring is as safe as conventional follow-up, and reduces outpatient visits and societal costs. The positive impact on quality-of-life was similar in the two groups. This strategy is attractive for teenagers and families, and health professionals may be interested in using it to keep teenagers who are well out of hospital and ease pressure on overstretched outpatient services. TRIAL REGISTRATION: NTR3759 [Netherlands Trial Registry].

Reference values of fecal calgranulin C (S100A12) in school aged children and adolescents.

BACKGROUND: Calgranulin C (S100A12) is an emerging marker of inflammation. It is exclusively released by activated neutrophils which makes this marker potentially more specific for inflammatory bowel disease (IBD) compared to established stool markers including calprotectin and lactoferrin. We aimed to establish a reference value for S100A12 in healthy children and investigated whether S100A12 levels can discriminate children with IBD from healthy controls. METHODS: In a prospective community-based reference interval study we collected 122 stool samples from healthy children aged 5-19 years. Additionally, feces samples of 41 children with suspected IBD (who were later confirmed by endoscopy to have IBD) were collected. Levels of S100A12 were measured with a sandwich enzyme-linked immunosorbent assay (ELISA) (Inflamark®). The limit of detection was 0.22 µg/g. RESULTS: The upper reference limit in healthy children was 0.75 µg/g (90% confidence interval: 0.30-1.40). Median S100A12 levels were significantly higher in patients with IBD (8.00 µg/g [interquartile range (IQR) 2.5-11.6] compared to healthy controls [0.22 µg/g (IQR<0.22); p<0.001]). The best cutoff point based on receiver operating characteristic curve was 0.33 µg/g (sensitivity 93%; specificity 97%). CONCLUSIONS: Children and teenagers with newly diagnosed IBD have significantly higher S100A12 results compared to healthy individuals. We demonstrate that fecal S100A12 shows diagnostic promise under ideal testing conditions. Future studies need to address whether S100A12 can discriminate children with IBD from non-organic disease in a prospective cohort with chronic gastrointestinal complaints, and how S100A12 performs in comparison with established stool markers.

Agreement Between Home-Based Measurement of Stool Calprotectin and ELISA Results for Monitoring Inflammatory Bowel Disease Activity.

BACKGROUND & AIMS: An increasing number of physicians use repeated measurements of stool calprotectin to monitor intestinal inflammation in patients with inflammatory bowel diseases (IBDs). A lateral flow-based rapid test allows patients to measure their own stool calprotectin values at home. The test comes with a software application (IBDoc; Bühlmann Laboratories AG, Schönenbuch, Switzerland) that turns a smartphone camera into a results reader. We compared results from this method with those from the hospital-based reader (Quantum Blue; Bühlmann Laboratories AG) and enzyme-linked immunosorbent assay (ELISA) analysis. METHODS: In a single-center comparison study, we asked 101 participants (10 years of age or older) in the Netherlands to perform the IBDoc measurement on stool samples collected at home, from June 2015 to October 2016. Participants then sent the residual extraction fluid and a fresh specimen from the same bowel movement to our pediatric and adult IBD center at the University Medical Center Groningen, where the level of calprotectin was measured by the Quantum Blue reader and ELISA analysis, respectively. The primary outcome was the agreement of results between IBDoc and the Quantum Blue and ELISA analyses, determined by Bland-Altman plot analysis. RESULTS: We received 152 IBDoc results, 138 samples of residual extraction fluid for Quantum Blue analysis, and 170 fresh stool samples for ELISA analysis. Spearman's rank correlation coefficient was 0.94 for results obtained by IBDoc vs Quantum Blue and 0.85 for results obtained by IBDoc vs ELISA. At the low range of calprotectin level (<500 µg/g), 91% of IBDoc-Quantum Blue results were within the predefined limits of agreement (±100 µg/g), and 71% of IBDoc-ELISA results were in agreement. At the high range of calprotectin level (≥500 µg/g), 81% of IBDoc-Quantum Blue results were within the predefined limits of agreement (±200 µg/g) and 64% of IBDoc-ELISA results were in agreement. CONCLUSIONS: Measurements of fecal levels of calprotectin made with home-based lateral flow method were in agreement with measurements made by Quantum Blue and ELISA, as long as concentrations were <500 µg/g. For patients with concentrations of fecal calprotectin above this level, findings from IBDoc should be confirmed by another method. (Netherlands Trial Registration Number: NTR5133).

Clinical Utility of Fecal Calprotectin Monitoring in Asymptomatic Patients with Inflammatory Bowel Disease: A Systematic Review and Practical Guide.

BACKGROUND: In asymptomatic patients with inflammatory bowel disease (IBD), "monitoring" involves repeated testing aimed at early recognition of disease exacerbation. We aimed to determine the usefulness of repeated fecal calprotectin (FC) measurements to predict IBD relapses by a systematic literature review. METHODS: An electronic search was performed in Medline, Embase, and Cochrane from inception to April 2016. Inclusion criteria were prospective studies that followed patients with IBD in remission at baseline and had at least 2 consecutive FC measurements with a test interval of 2 weeks to 6 months. Methodological assessment was based on the second Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. RESULTS: A total of 1719 articles were identified; 193 were retrieved for full text review. Six studies met eligibility for inclusion. The time interval between FC tests varied between 1 and 3 months. Asymptomatic patients with IBD who had repeated FC measurements above the study's cutoff level had a 53% to 83% probability of developing disease relapse within the next 2 to 3 months. Patients with repeated normal FC values had a 67% to 94% probability to remain in remission in the next 2 to 3 months. The ideal FC cutoff for monitoring could not be identified because of the limited number studies meeting inclusion criteria and heterogeneity between selected studies. CONCLUSIONS: Two consecutively elevated FC values are highly associated with disease relapse, indicating a consideration to proactively optimize IBD therapy plans. More prospective data are necessary to assess whether FC monitoring improves health outcomes.

Selecting children with suspected inflammatory bowel disease for endoscopy with the calgranulin C or calprotectin stool test: protocol of the CACATU study.

INTRODUCTION: The introduction of the faecal calprotectin (FC) test to screen children with chronic gastrointestinal complaints has helped the clinician to decide whether or not to subject the patient to endoscopy. In spite of this, a considerable number of patients without inflammatory bowel disease (IBD) is still scoped. Faecal calgranulin C (S100A12) is a marker of intestinal inflammation that is potentially more specific for IBD than FC, as it is exclusively released by activated granulocytes. OBJECTIVE: To determine whether the specificity of S100A12 is superior to the specificity of FC without sacrificing sensitivity in patients with suspected IBD. METHODS: An international prospective cohort of children with suspected IBD will be screened with the existing FC stool test and the new S100A12 stool test. The reference standard (endoscopy with biopsies) will be applied to patients at high risk of IBD, while a secondary reference (clinical follow-up) will be applied to those at low risk of IBD. The differences in specificity and sensitivity between the two markers will be calculated. ETHICS AND DISSEMINATION: This study is submitted to and approved by the Medical Ethics Review Committee of the University Medical Center Groningen (the Netherlands) and the Antwerp University Hospital (Belgium). The results will be disseminated through a peer-reviewed publication, conference presentation and incorporation in the upcoming National Guideline on Diagnosis and Therapy of IBD in Children. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02197780 .

A Cross-Sectional Study on the Perceptions and Practices of Teenagers With Inflammatory Bowel Disease About Repeated Stool Sampling.

PURPOSE: Repeated stool sampling to monitor disease activity is increasingly used in teenagers with inflammatory bowel disease (IBD). Knowledge about their perceptions and practices regarding collection of feces will increase the success rate of this monitoring strategy. METHODS: We sent a survey to teenagers with IBD treated in an academic center. RESULTS: Seventy-two of 122 invited teenagers completed the survey (response rate 59%; median age 15 years (interquartile range, 13-17). Eighty-five percent reported that stool sampling is normally initiated with help of their parents or caretakers. Seventy-eight percent of respondents say that their parents assist with the placement of stool in the container. CONCLUSIONS: Teenagers do not feel embarrassed by the idea of stool sampling, but an active role of the parents or caretakers is an important prerequisite for maintaining a stool-based disease monitoring system. Autonomy in stool sampling is an essential skill required for a successful transition to adult-centered IBD care.

Avoid Endoscopy in Children With Suspected Inflammatory Bowel Disease Who Have Normal Calprotectin Levels.

In children with suspected inflammatory bowel disease, adding calprotectin stool testing to the screening strategy has been recommended to distinguish organic from nonorganic disease. In this cohort study with historical controls, we could not confirm that screening with stool calprotectin improves the diagnostic yield (ratio inflammatory bowel disease-positive endoscopies and total number of endoscopies); however, in patients with normal fecal calprotectin levels (<50 µg/g) endoscopic and histological abnormalities were not seen. We propose to refrain from endoscopy when stool calprotectin levels are normal.

Comparing the efficacy of a web-assisted calprotectin-based treatment algorithm (IBD-live) with usual practices in teenagers with inflammatory bowel disease: study protocol for a randomized controlled trial.

BACKGROUND: To prevent clinical relapse in teenagers with inflammatory bowel disease (IBD) there is a need to monitor disease activity continuously. Timely optimisation of medical treatment may nip a preclinical relapse in the bud and change the natural course of IBD. Traditionally, disease monitoring is done during scheduled visits, but this is when most teenagers report full control. IBD care could be more efficient if patients were seen at times of clinical need. This study aims to examine the effectiveness of a web-assisted calprotectin-based treatment algorithm (IBD-live) compared with usual practices in teenagers with IBD. METHODS/DESIGN: A randomized trial of web-based disease monitoring versus usual care is conducted at 10 Dutch IBD care centers. We plan to recruit 180 patients between 10- and 19-years old with quiescent IBD at baseline. Teenagers assigned to IBD-live will use the flarometer--an automatic cumulation of disease activity and fecal calprotectin measurements- to estimate probability of relapse. In case the flarometer indicates high risk the patient requires treatment intensification in accordance with national guidelines; low risk means that maintenance therapy is unchanged; and intermediate risk requires optimisation of drug adherence. Patients assigned to usual practice get the best accepted medical care with regular health checks. Primary outcome is the frequency of relapse at 52 weeks of follow-up. The diagnosis of relapse is based on a clinical activity index score >10 points necessitating remission induction therapy. Secondary outcomes include quality of life and cost-effectiveness. DISCUSSION: Web-assisted monitoring of disease activity with rapid access for those with acute relapse may allow teenagers to develop skills that are required of adult patients (including communication and self-determination). Similar monitoring systems have been introduced for teenagers with asthma and diabetes, with a positive effect on disease control, but the intervention has not been evaluated in teenagers with IBD. A randomized trial in adult patients with ulcerative colitis showed that a web-assisted treatment algorithm is feasible, safe and cost-effective. Results of the current trial are expected to have important implications for teenagers with IBD that incurs substantial health burdens and economic costs. TRIAL REGISTRATION: Dutch Trial Register identifier: NTR3759 (registered 29 December 2012).