Anke Heida

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 studys 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.

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 &mgr;g/g), 91% of IBDoc–Quantum Blue results were within the predefined limits of agreement (±100 &mgr;g/g), and 71% of IBDoc–ELISA results were in agreement. At the high range of calprotectin level (≥500 &mgr;g/g), 81% of IBDoc–Quantum Blue results were within the predefined limits of agreement (±200 &mgr;g/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 &mgr;g/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).

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

BackgroundTo 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/designA 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.DiscussionWeb-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 registrationDutch Trial Register identifier: NTR3759 (registered 29 December 2012)

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

ABSTRACT 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 &mgr;g/g) endoscopic and histological abnormalities were not seen. We propose to refrain from endoscopy when stool calprotectin levels are normal.

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 physicians 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

Abstract 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.

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 .

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.

Standardizing Fecal Calprotectin Monitoring in Asymptomatic Patients with Inflammatory Bowel Disease

1. Heida A, Park KT, van Rheenen PF. Clinical utility of fecal calprotectin monitoring in asymptomatic patients with inflammatory bowel disease: a systematic review and practical guide. Inflamm Bowel Dis. 2017;23: 894–902. 2. Ferreiro-Iglesias R, Barreiro-de Acosta M, Otero Santiago M, et al. Fecal calprotectin as predictor of relapse in patients with inflammatory bowel disease under maintenance infliximab therapy. J Clin Gastroenterol. 2016;50:147–151. 3. Mooiweer E, Severs M, Schipper ME, et al. Low fecal calprotectin predicts sustained clinical remission in inflammatory bowel disease patients: a plea for deep remission. J Crohns Colitis. 2015;9:50–55. 4. Gisbert JP, Bermejo F, Perez-Calle JL, et al. Fecal calprotectin and lactoferrin for the prediction of inflammatory bowel disease relapse. Inflamm Bowel Dis. 2009;15:1190–1198. 5. Walkiewicz D, Werlin SL, Fish D, et al. Fecal calprotectin is useful in predicting disease relapse in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:669–673.1. Heida A, Park KT, van Rheenen PF. Clinical utility of fecal calprotectin monitoring in asymptomatic patients with inflammatory bowel disease: a systematic review and practical guide. Inflamm Bowel Dis. 2017;23: 894–902. 2. Ferreiro-Iglesias R, Barreiro-de Acosta M, Otero Santiago M, et al. Fecal calprotectin as predictor of relapse in patients with inflammatory bowel disease under maintenance infliximab therapy. J Clin Gastroenterol. 2016;50:147–151. 3. Mooiweer E, Severs M, Schipper ME, et al. Low fecal calprotectin predicts sustained clinical remission in inflammatory bowel disease patients: a plea for deep remission. J Crohns Colitis. 2015;9:50–55. 4. Gisbert JP, Bermejo F, Perez-Calle JL, et al. Fecal calprotectin and lactoferrin for the prediction of inflammatory bowel disease relapse. Inflamm Bowel Dis. 2009;15:1190–1198. 5. Walkiewicz D, Werlin SL, Fish D, et al. Fecal calprotectin is useful in predicting disease relapse in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:669–673.