Observational Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2019; 25(10): 1266-1277
Published online Mar 14, 2019. doi: 10.3748/wjg.v25.i10.1266
Consecutive fecal calprotectin measurements for predicting relapse in pediatric Crohn’s disease patients
Alice Jane Foster, Matthew Smyth, Alam Lakhani, Benjamin Jung, Rollin F Brant, Kevan Jacobson
Alice Jane Foster, Matthew Smyth, Alam Lakhani, Benjamin Jung, Rollin F Brant, Kevan Jacobson, Division of Gastroenterology, Hepatology and Nutrition, British Columbia Children’s Hospital, Vancouver, BC V6H 3V4, Canada
Alice Jane Foster, Matthew Smyth, Alam Lakhani, Benjamin Jung, Kevan Jacobson, Pediatrics, B.C. Children’s Hospital Research Institute, Vancouver, BC V6H 3V4, Canada
Alice Jane Foster, Matthew Smyth, Alam Lakhani, Rollin F Brant, Kevan Jacobson, Pediatrics, British Columbia children’s Hospital, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
Rollin F Brant, Department of Statistics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
Kevan Jacobson, Department of Cellular and Physiological Sciences, Faculty of Medicine, Vancouver, BC V6T 1Z3, Canada
Author contributions: Foster AJ and Jacobson K designed the study; Foster AJ, Smyth M, Lakani A, and Jacobson K performed the research; Foster AJ, Jung B, Brant RF and Jacobson K analyzed and interpreted the data; Foster AJ and Jacobson K wrote the manuscript with critical input from Jung B, Brant RF, Smyth M, and Lakani A.
Supported by an unrestricted grant from the Lutsky Foundation; Abbvie pharmaceuticals provided initial funding to purchase the Buhlmann ELISA kits.
Institutional review board statement: The study was reviewed and approved by the University of British Columbia Clinical Research Ethics Board and the British Columbia Children’s and Women’s Research Review Committee (H12-03533).
Informed consent statement: All study participants or their legal guardian provided informed written consent prior to study enrolment.
Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Kevan Jacobson, FRCP (C), MD, Doctor, Professor, Senior Scientist, Division of Gastroenterology, Hepatology and Nutrition, British Columbia children’s Hospital, 4480 Oak Street, Room K4-181, Vancouver, BC V6H 3V4, Canada. kjacobson@cw.bc.ca
Telephone: +1-6048752332 Fax: +1-6048753244
Received: December 5, 2018
Peer-review started: December 6, 2018
First decision: January 6, 2019
Revised: January 16, 2019
Accepted: January 18, 2019
Article in press: January 18, 2019
Published online: March 14, 2019
Research background

Inflammatory bowel disease (IBD) is a chronic relapsing intestinal inflammatory disorder requiring ongoing monitoring to optimize care. It has become increasing evidence that sustained remission reduces the likelihood of complicated disease. Consequently the incorporation of effective monitoring tools is required to assess disease activity allowing for the escalation of therapy in a timely manner. Fecal calprotectin (FC) has been studied in disease diagnosis and response to therapy but there is limited data evaluating its role in disease relapse in pediatric IBD patients in clinical remission. In the present prospective pediatric IBD study, we show that routine serial FC measurements are a valuable predictor of symptomatic relapse.

Research motivation

The motivation of the study was to evaluate the utility of FC as a predictive marker of disease relapse and in doing so reinforce the use of this strategy in clinical practice. Moreover adopting the strategy outlined in the paper will hopefully lead to better monitoring of disease activity with early optimization of therapy reducing the likelihood of fully blown clinical flare ups. Further research will need to look at the utility of this monitoring strategy and the role and relationship to endoscopic monitoring of disease activity and mucosal healing.

Research objectives

The main objective was to evaluate the accuracy of serial FC measurements to predict clinical flares in pediatric Crohn’s disease (CD) patients on maintenance anti-tumor necrosis factor therapy and in clinical remission. The realization of this objective infers that serial FC done 3-monthly should be incorporated into clinical practice. Future research should also evaluate whether this strategy improves the quality of care, patient outcomes and costs to health care systems.

Research methods

This was a prospective observational study where serial FC levels were measure in pediatric patients with IBD in clinical remission on Remicade. The responsible clinicians were blinded to the FC results. Patient characteristics included age, sex, age of diagnosis, disease location and behaviour, other medications (both IBD and non-IBD related), IBD-related surgeries, time from diagnosis to infliximab start, and infliximab infusion dosing and interval were collected. The PDCAI was recorded at each visit. FC levels were measure by ELISA within 4-mo of sample extraction. Standard statistical methodology was used. Continuous variables are presented using median values and interquartile range (IQR) and Wilcoxon signed-rank test was used to compare differences between patients who relapsed and remaining in clinical remission. Categorical data are presented as percentages. Kaplan-Meier survival curves (time-to-event data) are used for biomarkers [FC, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin]. One predictor logistic regression and receiver operating characteristic (ROC) curve analyses for biomarkers were used to evaluate the cumulative incidence of flares in a 2-wk time window around (before or after) 3 and 6 mo after the FC and a 4-wk window around 12 mo after the FC. Specificity, sensitivity and optimal threshold values of FC were determined from ROC curve analysis.

Research results

Of the 62 patients prospectively enrolled, 53 were analyzed; 68% were male and median follow-up time 1.5 years. A total of 205 stool samples were collected and analyzed (mean of 4 stool samples per patient). Symptomatic relapse was recorded in 18 (34%) patients (mean time from enrolment to clinical flare 7.1 mo, range, 1.5-15 mo). Baseline FC level in the symptomatic relapse group was higher than those remaining in clinical remission [median 723 μg/g (IQR 283-1758) vs 244 μg/g (IQR 61-627), P = 0.02]. The median FC level at the visit prior to relapse was 765 μg/g (IQR 504-1800). Time to clinical relapse curves calculated for the first year of the study using baselines FC levels < or ≥ 250 μg/g showed a significant differences in relapse rates in patients with FC < 250 μg/g compared to those with levels ≥ 250 μg/g (P = 0.004). In addition, FC had good accuracy in predicting clinical disease relapse within 3 mo of collection with a ROC value of 0.86 [95% confidence interval (CI) 0.781-0.937]. Treatment decisions were based on clinical symptoms and standard biomarkers of inflammation (ESR and CRP) and thus did not reflect the potential benefit of the FC result. Consequently prospective evaluation of sequential FC testing is required to evaluate the short and long-term benefits on disease remission and outcome.

Research conclusions

FC had good accuracy in predicting clinical disease relapse within 3 mo of collection with a ROC value of 0.86 (95%CI: 0.781-0.937). Prospective monitoring with proactive intervention with either endoscopy assessment of disease activity and extent and, or optimization of medical therapy will reduce the likelihood of clinical flares, reduce the risk of complication and improve patient outcomes. FC is a useful biological tool to evaluate disease activity in patients in clinical remission on a biological agent. The Pediatric CD Activity Index (PCDAI) is not sensitive enough to monitor disease activity in children with CD. The addition of FC monitoring improves the quality of care for children with IBD. Regular 3-monthly FC monitoring should be incorporated into clinical practice. However it is important to follow the trend in level and not rely on a single level. That 3-monthly FC monitoring is a good addition to currently available biomarkers of inflammation. That FC is a good predictor of clinical relapse. That 3-monthly FC monitoring detects patients who will experience a symptomatic flare of disease. The inclusion of regular 3-monthly FC monitoring into clinical practice. The addition of FC monitoring will improves the quality of care and outcomes for children with IBD.

Research perspectives

Such studies are important to do. Colonoscopy should be included as an endpoint. A treatment decision can be made based on the FC result with subsequent determination whether the change had positive benefit (i.e., normalization of FC level and evidence of mucosal healing at colonoscopy). To prospective evaluate sequential FC testing and to determine the short and long-term benefits on disease remission, quality of life, patient outcome and related health care-costs. To define the relationship between FC monitoring and endoscopic monitoring of disease activity and mucosal healing. To determine the best cut off for FC for patients in remission. Prospective interventional studies with clearly defined FC levels, endoscopic score and treatment strategies with clearly defined primary and secondary outcomes (i.e., disease in steroid free remission, disease biochemical remission, and mucosal healing).