Objective. To explore fecal calprotectin levels in pediatric ulcerative colitis (UC) in relation with the validated clinical activity index PUCAI. Methods. This study included all 37 children (median age 14 years) with UC who had calprotectin measured (PhiCal ELISA Test) by the time of PUCAI assessment at the Children's Hospital of Helsinki in a total of 62 visits. Calprotectin values <100？μg/g of stool were considered as normal. The best cut-off value of each measure to predict 3-month clinical outcome was derived by maximizing sensitivity and specificity. Results. In clinically active disease (PUCAI ≥ 10), calprotectin was elevated in 29/32 patients (91% sensitivity). When in clinical remission, 26% (8/30) of the children had normal calprotectin but 7 (23%) had an exceedingly high level (>1000？μg/g). The best cut-off value for calprotectin for predicting poor outcome was 800？μg/g (sensitivity 73%, specificity 72%; area under the ROC curve being 0.71 (95%CI 0.57–0.85)) and for the PUCAI best cut-off values >10 (sensitivity 62%, specificity 64%; area under the ROC curve 0.714 (95%CI 0.58–0.85)). Conclusion. The clinical relevance of somewhat elevated calprotectin during clinical remission in pediatric UC is not known and, until further evidence accumulates, does not indicate therapy escalation. 1. Introduction Neutrophil-derived markers, such as fecal calprotectin or lactoferrin, have proven to correlate well with mucosal inflammation of ulcerative colitis (UC) at a rho range of 0.6–0.8 [1–4]. Fecal level of these markers reflects the mucosal influx of inflammatory cells in the gut. When the level of these markers is low, the presence of active inflammation in the colon is unlikely [3, 5–8]. The probability of 1-year remission in UC children with normal calprotectin may be as high as 75% [9]. On the other hand, in UC (and unlike in Crohn’s disease), clinical judgment of symptoms also correlates well with endoscopic appearance, at a range of rho 0.7–0.8 [10], and clinical assessment also predicts well clinical outcomes in both adult [11] and pediatric severe UC [12]. Recently, we showed that calprotectin levels rarely decline completely during therapy with glucocorticoids or TNF-α-antagonist agents suggesting ongoing inflammation in the majority [13, 14]. The PUCAI is the validated pediatric ulcerative colitis activity index showing good correlation with endoscopic disease activity [15–17]. The index is based on item scores reflecting the clinical situation within the last two days and may thus be used in the acute setting [15]. In acute severe colitis,
References
[1]
S. K. Bunn, W. M. Bisset, M. J. C. Main, and B. E. Golden, “Fecal calprotectin as a measure of disease activity in childhood inflammatory bowel disease,” Journal of Pediatric Gastroenterology and Nutrition, vol. 32, no. 2, pp. 171–177, 2001.
[2]
S. K. Bunn, W. M. Bisset, M. J. C. Main, E. S. Gray, S. Olson, and B. E. Golden, “Fecal calprotectin: validation as a noninvasive measure of bowel inflammation in childhood inflammatory bowel disease,” Journal of Pediatric Gastroenterology and Nutrition, vol. 33, no. 1, pp. 14–22, 2001.
[3]
R. B. Canani, G. Terrin, L. Rapacciuolo et al., “Faecal calprotectin as reliable non-invasive marker to assess the severity of mucosal inflammation in children with inflammatory bowel disease,” Digestive and Liver Disease, vol. 40, no. 7, pp. 547–553, 2008.
[4]
A. Diamanti, F. Colistro, M. S. Basso et al., “Clinical role of calprotectin assay in determining histological relapses in children affected by inflammatory bowel diseases,” Inflammatory Bowel Diseases, vol. 14, no. 9, pp. 1229–1235, 2008.
[5]
R. B. Canani, L. Rapacciuolo, M. T. Romano et al., “Diagnostic value of faecal calprotectin in paediatric gastroenterology clinical practice,” Digestive and Liver Disease, vol. 36, no. 7, pp. 467–470, 2004.
[6]
T. R. Walker, M. L. Land, A. Kartashov et al., “Fecal lactoferrin is a sensitive and specific marker of disease activity in children and young adults with inflammatory bowel disease,” Journal of Pediatric Gastroenterology and Nutrition, vol. 44, no. 4, pp. 414–422, 2007.
[7]
T. Aomatsu, A. Yoden, K. Matsumoto et al., “Fecal calprotectin is a useful marker for disease activity in pediatric patients with inflammatory bowel disease,” Digestive Diseases and Sciences, vol. 56, no. 8, pp. 2372–2377, 2011.
[8]
P. Henderson, A. Casey, S. J. Lawrence et al., “The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease,” The American Journal of Gastroenterology, vol. 107, no. 6, pp. 941–949, 2012.
[9]
T. Sipponen and K. L. Kolho, “Faecal calprotectin in children with clinically quiescent inflammatory bowel disease,” Scandinavian Journal of Gastroenterology, vol. 45, no. 7-8, pp. 872–877, 2010.
[10]
D. Turner, C. H. Seow, G. R. Greenberg, A. M. Griffiths, M. S. Silverberg, and A. H. Steinhart, “A systematic prospective comparison of noninvasive disease activity indices in ulcerative colitis,” Clinical Gastroenterology and Hepatology, vol. 7, no. 10, pp. 1081–1088, 2009.
[11]
A. Gustavsson, G. J？rnerot, E. Hertervig et al., “Clinical trial: colectomy after rescue therapy in ulcerative colitis-3-year follow-up of the Swedish-Danish controlled infliximab study,” Alimentary Pharmacology and Therapeutics, vol. 32, no. 8, pp. 984–989, 2010.
[12]
D. Turner, D. Mack, N. Leleiko et al., “Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response,” Gastroenterology, vol. 138, no. 7, pp. 2282–2291, 2010.
[13]
K. L. Kolho, T. Raivio, H. Lindahl, and E. Savilahti, “Fecal calprotectin remains high during glucocorticoid therapy in children with inflammatory bowel disease,” Scandinavian Journal of Gastroenterology, vol. 41, no. 6, pp. 720–725, 2006.
[14]
A. H？m？l？inen, T. Sipponen, and K.-L. Kolho, “Infliximab in pediatric inflammatory bowel disease rapidly decreases fecal calprotectin levels,” World Journal of Gastroenterology, vol. 17, pp. 5166–5171, 2011.
[15]
D. Turner, A. R. Otley, D. Mack et al., “Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study,” Gastroenterology, vol. 133, no. 2, pp. 423–432, 2007.
[16]
D. Turner, J. Hyams, J. Markowitz et al., “Appraisal of the pediatric ulcerative colitis activity index (PUCAI),” Inflammatory Bowel Diseases, vol. 15, no. 8, pp. 1218–1223, 2009.
[17]
D. Turner, C. H. Seow, G. R. Greenberg, A. M. Griffiths, M. S. Silverberg, and A. H. Steinhart, “A systematic prospective comparison of noninvasive disease activity indices in ulcerative colitis,” Clinical Gastroenterology and Hepatology, vol. 7, no. 10, pp. 1081–1088, 2009.
[18]
D. Turner, S. T. Leach, D. Mack et al., “Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response,” Gut, vol. 59, no. 9, pp. 1207–1212, 2010.
[19]
G. T. Ho, H. M. Lee, G. Brydon et al., “Fecal calprotectin predicts the clinical course of acute severe ulcerative colitis,” American Journal of Gastroenterology, vol. 104, no. 3, pp. 673–678, 2009.
[20]
J. E. Lennard-Jones, “Classification of inflammatory bowel disease,” Scandinavian Journal of Gastroenterology, Supplement, vol. 24, no. 170, pp. 2–6, 1989.
[21]
K. L. Kolho, H. Alfthan, and E. H？m？l？inen, “Effect of bowel cleansing for colonoscopy on fecal calprotectin levels in pediatric patients,” Journal of Pediatric Gastroenterology and Nutrition, vol. 55, no. 6, pp. 751–753, 2012.
[22]
J. F. Colombel, P. Rutgeerts, W. Reinisch et al., “Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis,” Gastroenterology, vol. 141, no. 4, pp. 1194–1201, 2011.
[23]
K. F. Fr？slie, J. Jahnsen, B. A. Moum, and M. H. Vatn, “Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort,” Gastroenterology, vol. 133, no. 2, pp. 412–422, 2007.
[24]
D. Turner, C. M. Walsh, E. I. Benchimol et al., “Severe paediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy,” Gut, vol. 57, no. 3, pp. 331–338, 2008.
[25]
R. Shaoul, M. Sladek, D. Turner et al., “Limitations of fecal calprotectin at diagnosis in untreated pediatric Crohn's disease,” Inflammatory Bowel Diseases, vol. 18, no. 8, pp. 1493–1497, 2012.
