The Use of Fecal Calprotectin Testing in Paediatric Disorders: A Position Paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee

Abstract

Objectives: The aim of the study was to review the evidence regarding the clinical use and value of fecal calprotectin (FC) measurements in different gastrointestinal disorders in children.; Methods: A literature search was conducted in the PubMed, MEDLINE, EMBASE, and Cochrane databases until October 31, 2019. Subtopics were identified and each assigned to individual authors.; Results: A total of 28 recommendations were voted on using the nominal voting technique. Recommendations are given related to sampling, measurement methods, and results interpretation. The 14 authors anonymously voted on each recommendation using a 9-point scale (1 strongly disagree to 9 fully agree). Consensus was considered achieved if at least 75% of the authors voted 6, 7, 8, or 9.; Conclusions: Consensus was reached for all recommendations. Limitations for the use of FC in clinical practice include variability in extraction methodology, performance of test kits as well as the need to establish local reference ranges because of the influence of individual factors, such as age, diet, microbiota, and drugs. The main utility of FC measurement at present is in the diagnosis and monitoring of inflammatory bowel disease (IBD) as well as to differentiate it from functional gastrointestinal disorders (FAPDs). FC, however, has neither utility in the diagnosis of infantile colic nor to differentiate between functional and organic constipation. A rise in FC concentration, may alert to the risk of developing necrotizing enterocolitis and help identifying gastrointestinal involvement in children with Henoch-Schönlein purpura. FC measurement is of little value in Cow's Milk Protein Allergy, coeliac disease (CD), and cystic fibrosis. FC does neither help to distinguish bacterial from viral acute gastroenteritis (AGE), nor to diagnose Helicobacter Pylori infection, small intestinal bacterial overgrowth (SIBO), acute appendicitis (AA), or intestinal polyps. (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)24:393–398.; Fagerhol MK. Nomenclature for proteins: is calprotectin a proper name for the elusive myelomonocytic protein? Clin Mol Pathol 1996; 49:M74–M79.; Sorg C. The calcium binding proteins MRP8 and MRP14 in acute and chronic inflammation. Behring Inst Mitt 1992; (91):126–137.; Dale I, Brandtzaeg P, Fagerhol MK, et al. Distribution of a new myelomonocytic antigen (L1) in human peripheral blood leukocytes: immunofluorescence and immunoperoxidase staining features in comparison with lysozyme and lactoferrin. Am J Clin Pathol 1985; 84:24–34.; Steinbakk M, Naess-Andresen C, Fagerhol M, et al. Antimicrobial actions of calcium binding leucocyte L1 protein, calprotectin. Lancet 1990; 336:763–765.; Lasson A, Stotzer P, Öhman L, et al. The intra-individual variability of faecal calprotectin: a prospective study in patients with active ulcerative colitis. J Crohn Colitis 2014; 9:26–32.; Haisma SM, van Rheenen PF, Wagenmakers L, et al. Calprotectin instability may lead to undertreatment in children with IBD. Arch Dis Child 2019; 105:996–998.; Johne B, Fagerhol MK, Lyberg T, et al. Functional and clinical aspects of the myelomonocyte protein calprotectin. Mol Pathol 1997; 50:113–123.; Hanai H, Takeuchi K, Iida T, et al. Relationship between fecal calprotectin, intestinal inflammation, and peripheral blood neutrophils in patients with active ulcerative colitis. Dig Dis Sci 2004; 49:1438–1443.; Røseth A, Kristinsson J, Fagerhol M, et al. Faecal calprotectin: a novel test for the diagnosis of colorectal cancer? Scand J Gastroenterol 1993; 28:1073–1076.; Tibble J, Teahon K, Thjodleifsson B, et al. A simple method for assessing intestinal inflammation in Crohn's disease. Gut 2000; 47:506–513.; van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ 2010; 341:c3369.; Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2018; 66:516–554.; Røseth A, Fagerhol M, Aadland E, et al. Assessment of the neutrophil dominating protein calprotectin in feces: a methodologic study. Scand J Gastroenterol 1992; 27:793–798.; Calafat M, Cabré E, Mañosa M, et al. High within-day variability of fecal calprotectin levels in patients with active ulcerative colitis: what is the best timing for stool sampling? Inflamm Bowel Dis 2015; 21:1072–1076.; Kristensen V, Lauritzen T, Jelsness-Jørgensen L, et al. Patient-performed extraction of faecal calprotectin. Clin Chem Lab Med 2016; 54:1357–1363.; Røseth AG, Aadland E, Jahnsen J, et al. Assessment of disease activity in ulcerative colitis by faecal calprotectin, a novel granulocyte marker protein. Digestion 1997; 58:176–180.; Tøn H, Brandsnes Ø, Dale S, et al. Improved assay for fecal calprotectin. Clin Chim Acta 2000; 292:41–54.; Shulman RJ, Eakin MN, Czyzewski DI, et al. Increased gastrointestinal permeability and gut inflammation in children with functional abdominal pain and irritable bowel syndrome. J Pediatr 2008; 153:646–650.; Olafsdottir E, Aksnes L, Fluge G, et al. Faecal calprotectin levels in infants with infantile colic, healthy infants, children with inflammatory bowel disease, children with recurrent abdominal pain and healthy children. Acta Paediatr 2002; 91:45–50.; Kolho KL, Alfthan H, Hamalainen E. Effect of bowel cleansing for colonoscopy on ecal calprotectin levels in pediatric patients. J Pediatr Gastroenterol Nutr 2012; 55:751–753.; Fagerberg UL, Lööf L, Merzoug RD, et al. Fecal calprotectin levels in healthy children studied with an improved assay. J Pediatr Gastroenterol Nutr 2003; 37:468–472.; Radillo O, Pascolo L, Martelossi S, et al. Fecal calprotectin: diagnostic accuracy of the immunochromatographic CalFast Assay in a pediatric population. J Clin Lab Anal 2016; 30:500–505.; Labaere D, Smismans A, Van Olmen A, et al. Comparison of six different calprotectin assays for the assessment of inflammatory bowel disease. United Eur Gastroenterol J 2014; 2:30–37.; Acevedo D, Salvador MP, Girbes J, et al. Fecal calprotectin: a comparison of two commercial enzymoimmunoassays and study of fecal extract stability at room temperature. J Clin Med Res 2018; 10:396–404.; Vinding KK, Elsberg H, Thorkilgaard T, et al. Fecal calprotectin measured by patients at home using smartphones--a new clinical tool in monitoring patients with inflammatory bowel disease. Inflamm Bowel Dis 2016; 22:336–344.; Malickova K, Janatková I, Bortlík M, et al. Calprotectin levels in patients with idiopathic inflammatory bowel disease comparison of two commercial tests. Epidemiol Mikrobiol Imunol 2008; 57:147–153.; Hessels J, Douw G, Yildirim DD, et al. Evaluation of Prevent ID and Quantum Blue rapid tests for fecal calprotectin. Clin Chem Lab Med 2012; 50:1079–1082.; Dhaliwal A, Zeino Z, Tomkins C, et al. Utility of faecal calprotectin in inflammatory bowel disease (IBD): what cut-offs should we apply? Frontline Gastroenterol 2015; 6:14–19.; Delefortrie Q, Schatt P, Grimmelprez A, et al. Comparison of the Liaison® Calprotectin kit with a well-established point of care test (Quantum Blue — Bühlmann-Alere®) in terms of analytical performances and ability to detect relapses amongst a Crohn population in follow-up. Clin Biochem 2016; 49:268–273.; Sherwood RA. Faecal markers of gastrointestinal inflammation. J Clin Pathol 2012; 65:981–985.; Heida A, Knol M, Kobold AM, et al. Agreement between home-based measurement of stool calprotectin and ELISA results for monitoring inflammatory bowel disease activity. Clinical Gastroenterology and Hepatology 2017; 15:1742.e2–1749.e2.; Kristensen V, Lauritzen T, Jelsness-JØrgensen L, et al. Validation of a new extraction device for measuring faecal calprotectin in inflammatory bowel disease, and comparison to established extraction methods. Scand J Clin Lab Invest 2015; 75:355–361.; Kristensen V, Malmstrøm GH, Skar V, et al. Clinical importance of faecal calprotectin variability in inflammatory bowel disease: intra-individual variability and standardisation of sampling procedure. Scand J Gastroenterol 2016; 51:548–555.; Bourdillon G, Biskou O, MacKinder M, et al. The routine use of fecal calprotectin in clinical pediatric practice: almost there or still issues to address? Am J Gastroenterol 2013; 108:1811–1813.; Prell C, Nagel D, Freudenberg F, et al. Comparison of three tests for faecal calprotectin in children and young adults: a retrospective monocentric study. BMJ Open 2014; 4:e004558.; Konikoff MR, Denson LA. Role of fecal calprotectin as a biomarker of intestinal inflammation in inflammatory bowel disease. Inflamm Bowel Dis 2006; 12:524–534.; Joshi S, Lewis SJ, Creanor S, et al. Age-related faecal calprotectin, lactoferrin and tumour M2-PK concentrations in healthy volunteers. Ann Clin Biochem 2010; 47:259–263.; Oord T, Hornung N. Fecal calprotectin in healthy children. Scand J Clin Lab Invest 2014; 74:254–258.; Li F, Ma J, Geng S, et al. Fecal calprotectin concentrations in healthy children aged 1-18 months. PLoS One 2015; 10:e0119574.; Zhu Q, Li F, Wang J, et al. Fecal calprotectin in healthy children aged 1-4 years. PloS One 2016; 11:e0150725.; Song JY, Lee YM, Choi YJ, et al. Fecal calprotectin level in healthy children aged less than 4 years in South Korea. J Clin Lab Anal 2017; 31:e22113.; Davidson F, Lock RJ. Paediatric reference ranges for faecal calprotectin: a UK study. Ann Clin Biochem 2017 54:214–218.; Roca M, Rodriguez Varela A, Donat E, et al. Fecal calprotectin and eosinophil-derived neurotoxin in healthy children between 0 and 12 years. J Pediatr Gastroenterol Nutr 2017; 65:394–398.; Peura S, Fall T, Almqvist C, et al. Normal values for calprotectin in stool samples of infants from the population-based longitudinal born into life study. Scand J Clin Lab Invest 2018; 78:120–124.; Zoppelli L, Guttel C, Bittrich HJ, et al. Fecal calprotectin concentrations in premature infants have a lower limit and show postnatal and gestational age dependence. Neonatology 2012; 102:68–74.; Josefsson S, Bunn SK, Domellof M. Fecal calprotectin in very low birth weight infants. J Pediatr Gastroenterol Nutr 2007; 44:407–413.; Kapel N, Campeotto F, Kalach N, et al. Faecal calprotectin in term and preterm neonates. J Pediatr Gastroenterol Nutr 2010; 51:542–547.; Campeotto F, Kalach N, Lapillonne A, et al. Time course of faecal calprotectin in preterm newborns during the first month of life. Acta Paediatr 2007; 96:1531–1533.; Yang Q, Smith PB, Goldberg RN, et al. Dynamic change of fecal calprotectin in very low birth weight infants during the first month of life. Neonatology 2008; 94:267–271.; Nissen AC, van Gils CE, Menheere PP, et al. Fecal calprotectin in healthy term and preterm infants. J Pediatr Gastroenterol Nutr 2004; 38:107–108.; Soto-Méndez MJ, Romero-Abal ME, Aguilera CM, et al. Associations among inflammatory biomarkers in the circulating, plasmatic, salivary and intraluminal anatomical compartments in apparently healthy preschool children from the western highlands of Guatemala. PloS One 2015; 10:e0129158.; Soto-Mendez MJ, Romero-Abal ME, Schumann K, et al. Normative fecal calprotectin concentrations in guatemalan preschoolers are high relative to children reported elsewhere. J Pediatr Gastroenterol Nutr 2017; 64:238–244.; Hestvik E, Tumwine JK, Tylleskar T, et al. Faecal calprotectin concentrations in apparently healthy children aged 0-12 years in urban Kampala, Uganda: a community-based survey. BMC Pediatr 2011; 11:9.; Liu J, Sheng X, Hu Y, et al. Fecal calprotectin levels are higher in rural than in urban Chinese infants and negatively associated with growth. BMC Pediatr 2012; 12:129.; Lee YM, Min C, Choi YJ, et al. Delivery and feeding mode affects fecal calprotectin levels in infants <7 months old. Early Hum Dev 2017; 108:45–48.; Dorosko SM, MacKenzie T, Connor RI. Fecal calprotectin concentrations are higher in exclusively breastfed infants compared to those who are mixed-fed. Breastfeed Med 2008; 3:117–119.; Li F, Ma J, Geng S, et al. Comparison of the different kinds of feeding on the level of fecal calprotectin. Early Hum Dev 2014; 90:471–475.; Savino F, Castagno E, Calabrese R, et al. High faecal calprotectin levels in healthy, exclusively breast-fed infants. Neonatology 2010; 97:299–304.; Selimoglu MA, Temel I, Yildirim C, et al. The role of fecal calprotectin and lactoferrin in the diagnosis of necrotizing enterocolitis. Pediatr Crit Care Med 2012; 13:452–454.; Campeotto F, Butel MJ, Kalach N, et al. High faecal calprotectin concentrations in newborn infants. Arch Dis Child Fetal Neonatal Ed 2004; 89:F353–F355.; Rougé C, Butel M, Piloquet H, et al. Fecal calprotectin excretion in preterm infants during the neonatal period. PLoS One 2010; 5:e11083.; Poullis A, Foster R, Shetty A, et al. Bowel inflammation as measured by fecal calprotectin: a link between lifestyle factors and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2004; 13:279–284.; Hawkey CJ, Ell C, Simon B, et al. Less small-bowel injury with lumiracoxib compared with naproxen plus omeprazole. Clin Gastroenterol Hepatol 2008; 6:536–544.; Goldstein J, Eisen G, Lewis B, et al. Small bowel mucosal injury is reduced in healthy subjects treated with celecoxib compared with ibuprofen plus omeprazole, as assessed by video capsule endoscopy. Aliment Pharmacol Ther 2007; 25:1211–1222.; Kuramoto T, Umegaki E, Nouda S, et al. Preventive effect of irsogladine or omeprazole on non-steroidal anti-inflam atory drug-induced esophagitis, peptic ulcers, and small intestinal lesions in humans, a prospective randomized controlled study. BMC Gastroenterol 2013; 13:85.; Shah AA, Thjodleifsson B, Murray FE, et al. Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen. Gut 2001; 48:339–346.; Smecuol E, Sanchez MIP, Suarez A, et al. Low-dose aspirin affects the small bowel mucosa: results of a pilot study with a multidimensional assessment. Clin Gastroenterol Hepatol 2009; 7:524–529.; Poullis A, Foster R, Mendall MA, et al. Proton pump inhibitors are associated with elevation of faecal calprotectin and may affect specificity. Eur J Gastroenterol Hepatol 2003; 15:573–574.; Cohen M. Proton pump inhibitors may cause elevation in faecal calprotectin levels. Br J Gen Pract 2016; 66:350.; Kim SY, Lee NM, Yun SW, et al. Influence of proton pump inhibitor therapy on intestinal inflammation assessed by fecal calprotectin in pediatric patients. Korean J Pediatr 2019; 62:400–404.; Tibble JA, Sigthorsson G, Foster R, et al. High prevalence of NSAID enteropathy as shown by a simple faecal test. Gut 1999; 45:362–366.; Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Diseases of the Colon & Rectum 1995; 38:1311–1321.; Aalto K, Lahdenne P, Kolho K. Fecal calprotectin in juvenile idiopathic arthritis patients related to drug use. Pediatr Rheumatol Online J 2017; 15:9.; Maiden L, Thjodleifsson B, Theodors A, et al. A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroenterology 2005; 128:1172–1178.; Kolho K, Korpela K, Jaakkola T, et al. Fecal microbiota in pediatric inflammatory bowel disease and its relation to inflammation. Am J Gastroenterol 2015; 110:921–930.; Quince C, Ijaz UZ, Loman N, et al. Extensive modulation of the fecal metagenome in children with Crohn's disease during exclusive enteral nutrition. Am J Gastroenterol 2015; 110:1718–1729.; Mendall MA, Chan D, Patel R, et al. Faecal calprotectin: factors affecting levels and its potential role as a surrogate marker for risk of development of Crohn's Disease. BMC Gastroenterol 2016; 16:126.; Levine A, Turner D, Pfeffer Gik T, et al. Comparison of outcomes parameters for induction of remission in New Onset Pediatric Crohn's Disease: evaluation of the Porto IBD Group “Growth Relapse and Outcomes with Therapy”(GROWTH CD) Study. Inflamm Bowel Dis 2014; 20:278–285.; Holtman GA, Lisman-van Leeuwen Y, Day AS, et al. Use of laboratory markers in addition to symptoms for diagnosis of inflammatory bowel disease in children: a meta-analysis of individual patient data. JAMA Pediatri 2017; 171:984–991.; Sridhar M, Kesavelu D. Fecal calprotectin as a screening marker for inflammatory bowel disease. Indian Pediatr 2019; 56:249–250.; Chen CC, Huang JL, Chang CJ, et al. Fecal calprotectin as a correlative marker in clinical severity of infectious diarrhea and usefulness in evaluating bacterial or viral pathogens in children. J Pediatr Gastroenterol Nutr 2012; 55:541–547.; Zijlstra M, Pluimakers V, Nikkels P, et al. Elevated faecal calprotectin does not differentiate between inflammatory bowel disease and a juvenile polyp. J Pediatr Gastroenterol Nutr 2016; 62:e22–e23.; Olafsdottir I, Nemeth A, Lorinc E, et al. Value of fecal calprotectin as a biomarker for juvenile polyps in children investigated with colonoscopy. J Pediatr Gastroenterol Nutr 2016; 62:43–46.; Degraeuwe PL, Beld MP, Ashorn M, et al. Faecal calprotectin in suspected paediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2015; 60:339–346.; Henderson P, Anderson NH, Wilson DC. The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2014; 109:637–645.; Sipponen T, Kolho K. Fecal calprotectin in diagnosis and clinical assessment of inflammatory bowel disease. Scand J Gastroenterol 2015; 50:74–80.; Yang Z, Clark N, Park KT. ffectiveness and cost-effectiveness of measuring fecal calprotectin in diagnosis of inflammatory bowel disease in adults and children. Clin Gastroenterol Hepatol 2014; 12:253.e2–262.e2.; Kolho K, Raivio T, Lindahl H, et al. Fecal calprotectin remains high during glucocorticoid therapy in children with inflammatory bowel disease. Scand J Gastroenterol 2006; 41:720–725.; Bunn SK, Bisset WM, Main MJ, et al. Fecal calprotectin as a measure of disease activity in childhood inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2001; 32:171–177.; Bunn SK, Bisset WM, Main MJ, et al. Fecal calprotectin: validation as a noninvasive measure of bowel inflammation in childhood inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2001; 33:14–22.; Shaoul R, Sladek M, Turner D, et al. ESPGHAN Porto IBD GroupLimitations of fecal calprotectin at diagnosis in untreated pediatric Crohn's disease. Inflamm Bowel Dis 2012; 18:1493–1497.; Aomatsu T, Yoden A, Matsumoto K, et al. Fecal calprotectin is a useful marker for disease activity in pediatric patients with inflammatory bowel disease. Dig Dis Sci 2011; 56:2372–2377.; Aggarwal V, Day AS, Connor S, et al. Role of capsule endoscopy and fecal biomarkers in small-bowel Crohn's disease to assess remission and predict relapse. Gastrointest Endosc 2017; 86:1070–1078.; Klang E, Kopylov U, Eliakim R, et al. Diffusion-weighted imaging in quiescent Crohn's disease: correlation with inflammatory biomarkers and video capsule endoscopy. Clin Radiol 2017; 72:798.e7–798.e13.; Sipponen T, Savilahti E, Kärkkäinen P, et al. Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti-TNF-alpha therapy for Crohn's disease. Inflamm Bowel Dis 2008; 14:1392–1398.; Canani RB, Terrin G, Rapacciuolo L, et al. Faecal calprotectin as reliable non-invasive marker to assess the severity of mucosal inflammation in children with inflammatory bowel disease. Dig Liver Dis 2008; 40:547–553.; Diamanti A, Colistro F, Basso M, et al. Clinical role of calprotectin assay in determining histological relapses in children affected by inflammatory bowel diseases. Inflamm Bowel Dis 2008; 14:1229–1235.; Fagerberg UL, Loof L, Lindholm J, et al. Fecal calprotectin: a quantitative marker of colonic inflammation in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007; 45:414–420.; Hradsky O, Ohem J, Mitrova K, et al. Fecal calprotectin levels in children is more tightly associated with histological than with macroscopic endoscopy findings. Clin Lab 2014; 60:1993–2000.; Sipponen T, Kolho K. Faecal calprotectin in children with clinically quiescent inflammatory bowel disease. Scand J Gastroenterol 2010; 45:872–877.; van Rheenen PF. Role of fecal calprotectin testing to predict relapse in teenagers with inflammatory bowel disease who report full disease control. Inflamm Bowel Dis 2012; 18:2018–2025.; Kolho K, Turner D. Fecal calprotectin and clinical disease activity in pediatric ulcerative colitis. ISRN Gastroenterol 2013; 2013:Article ID 179024.; Turner D, Leach ST, Mack D, 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 2010; 59:1207–1212.; Foster AJ, Smyth M, Lakhani A, et al. Consecutive fecal calprotectin measurements for predicting relapse in pediatric Crohn's disease patients. World J Gastroenterol 2019; 25:1266-1277.; Kolho K, Sipponen T, Valtonen E, et al. Fecal calprotectin, MMP-9, and human beta-defensin-2 levels in pediatric inflammatory bowel disease. Int J Colorectal Dis 2014; 29:43–50.; Kopylov U, Rosenfeld G, Bressler B, et al. Clinical utility of fecal biomarkers for the diagnosis and management of inflammatory bowel disease. Inflamm Bowel Dis 2014; 20:742–756.; Heida A, Park K, 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.; Mosli MH, Zou G, Garg SK, et al. C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis. Am J Gastroenterol 2015; 110:802–819.; Kostakis ID, Cholidou KG, Vaiopoulos AG, et al. Fecal calprotectin in pediatric inflammatory bowel disease: a systematic review. Dig Dis Sci 2013; 58:309–319.; Ruemmele FM, Veres G, Kolho KL, et al. European Crohn's and Colitis Organisation, European Society of Pediatric Gastroenterology, Hepatology and NutritionConsensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis 2014; 8:1179–1207.; van Rheenen PF, Aloi M, Assa A, et al. The medical management of paediatric Crohn's disease: an ECCO-ESPGHAN Guideline Update. J Crohn's Colitis 2020; Oct 7:jjaa161.; Kolho K, Alfthan H. Concentration of fecal calprotectin in 11,255 children aged 0-18 years. Scand J Gastroenterol 2020; 55:1024–1027.; Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 2: acute severe colitis-an evidence-based Consensus Guideline From the European Crohn's and Colitis Organization and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 67:292–310.; Melmed GY, Dubinsky MC, Rubin DT, et al. Utility of video capsule endoscopy for longitudinal monitoring of Crohn's disease activity in the small bowel: a prospective study. Gastrointest Endosc 2018; 88:947–955.; Egea Valenzuela J, Pereñíguez López A, Pérez Fernández V, et al. Fecal calprotectin and C-reactive protein are associated with positive findings in capsule endoscopy in suspected small bowel Crohn's disease. Rev Esp Enferm Dig 2016; 108:394–400.; Hamalainen A, Sipponen T, Kolho KL. Infliximab in pediatric inflammatory bowel disease rapidly decreases fecal calprotectin levels. World J Gastroenterol 2011; 17:5166–5171.; Gerasimidis K, Nikolaou CK, Edwards CA, et al. Serial fecal calprotectin changes in children with Crohn's disease on treatment with exclusive enteral nutrition: associations with disease activity, treatment response, and prediction of a clinical relapse. J Clin Gastroenterol 2011; 45:234–239.; Grogan JL, Casson DH, Terry A, et al. Enteral feeding therapy for newly diagnosed pediatric Crohn's disease: a double-blind randomized controlled trial with two years follow-up. Inflamm Bowel Dis 2011; 18:246–253.; Frivolt K, Schwerd T, Werkstetter K, et al. Repeated exclusive enteral nutrition in the treatment of paediatric Crohn's disease: predictors of efficacy and outcome. Aliment Pharmacol Ther 2014; 39:1398–1407.; Copova I, Hradsky O, Zarubova K, et al. Fecal calprotectin is not a clinically useful marker for the prediction of the early nonresponse to exclusive enteral nutrition in pediatric patients with Crohn disease. Eur J Pediatr 2018; 177:1685–1693.; Logan M, Clark CM, Ijaz UZ, et al. The reduction of faecal calprotectin during exclusive enteral nutrition is lost rapidly after food re-introduction. Aliment Pharmacol Ther 2019; 50:664–674.; Levine A, Wine E, Assa A, et al. Crohn's disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial. Gastroenterology 2019; 157:440.e8–450.e8.; Svolos V, Hansen R, Nichols B, et al. Treatment of active crohn's disease with an ordinary food-based diet that replicates exclusive enteral nutrition. Gastroenterology 2019; 156:1354.e6–1367.e6.; Zubin G, Peter L. Predicting endoscopic Crohn's disease activity before and after induction therapy in children: a comprehensive assessment of PCDAI, CRP, and fecal calprotectin. Inflamm Bowel Dis 2015; 21:1386–1391.; Weinstein-Nakar I, Focht G, Church P, et al. ImageKids study groupAssociations among mucosal and transmural healing and fecal level of calprotectin in children with Crohn's disease. Clin Gastroenterolo Hepatol 2018; 16:1089.e4–1097.e4.; Walkiewicz D, Werlin SL, Fish D, et al. Fecal calprotectin is useful in predic ing disease relapse in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2008; 14:669–673.; Theede K, Holck S, Ibsen P, et al. Fecal calprotectin predicts relapse and histological mucosal healing in ulcerative colitis. Inflamm Bowel Dis 2016; 22:1042–1048.; Ferreiro-Iglesias R, Barreiro-de Acosta M, Lorenzo-Gonzalez A, et al. Accuracy of consecutive fecal calprotectin measurements to predict relapse in inflammatory bowel disease patients under maintenance with anti-tnf therapy: a prospective longitudinal cohort study. J Clin Gastroenterol 2018; 52:229–234.; Molander P, Färkkilä M, Ristimäki A, et al. Does fecal calprotectin predict short-term relapse after stopping TNF(-blocking agents in inflammatory bowel disease patients in deep remission? J Crohn Colitis 2014; 9:33–40.; Pakarinen MP, Koivusalo A, Natunen J, et al. Fecal calprotectin mirrors inflammation of the distal ileum and bowel function after restorative proctocolectomy for pediatric-onset ulcerative colitis. Inflamm Bowel Dis 2009; 16:482–486.; Hukkinen M, Pakarinen MP, Merras-Salmio L, et al. Fecal calprotectin in the prediction of postoperative recurrence of Crohn's disease in children and adolescents. J Pediatr Surg 2016; 51:1467–1472.; Amil-Dias J, Kolacek S, Turner D, et al. IBD Working Group of ESPGHAN (IBD Porto Group)Surgical management of Crohn disease in children: guidelines from the paediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr 2017; 64:818–835.; Schoepfer AM, Lewis JD. Serial fecal calprotectin measurements to detect endoscopic recurrence in postoperative Crohn's disease: is colonoscopic surveillance no longer needed? Gastroenterology 2015; 148:889–892.; Hukkinen M, Pakarinen MP, Piekkala M, et al. Treatment of complex perianal fistulas with seton and infliximab in adolescents with Crohn's disease. J Crohn Colitis 2014; 8:756–762.; Benninga MA, Nurko S, Faure C, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 2016; 150:1443.e2–1455.e2.; Hyams JS, Di Lorenzo C, Saps M, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology 2016; 150:1456.e2–1468.e2.; Rhoads JM, Fatheree NY, Norori J, et al. Altered fecal microflora and increased fecal calprotectin in infants with colic. J Pediatr 2009; 155:823.e1–828.e1.; Rhoads JM, Collins J, Fatheree NY, et al. Infant colic represents gut inflammation and dysbiosis. J Pediatr 2018; 203:55.e3–61.e3.; Sung V, Collett S, de Gooyer T, et al. Probiotics to prevent or treat excessive infant crying: systematic review and meta-analysis. JAMA Pediatr 2013; 167:1150–1157.; Korterink J, Devanarayana NM, Rajindrajith S, et al. Childhood functional abdominal pain: mechanisms and management. Nat Rev Gastroenterol Hepatol 2015; 12:159–171.; Apley J, Naish N. Recurrent abdominal pains: a field survey of 1,000 school children. Arch Dis Child 1958; 33:165–170.; Flagstad G, Helgeland H, Markestad T. Faecal calprotectin concentrations in children with functional gastrointestinal disorders diagnosed according to the Pediatric Rome III criteria. Acta Paediatr 2010; 99:734–737.; Pieczarkowski S, Kowalska-Duplaga K, Kwinta P, et al. Diagnostic value of fecal calprotectin (S100 A8/A9) test in children with chronic abdominal pain. Gastroenterol Res Pract 2016; 2016:8089217.; Di Nardo G, Barbara G, Cucchiara S, et al. Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS. Neurogastroenterol Motil 2014; 26:196–204.; Diederen K, Hoekman D, Hummel T, et al. The prevalence of irritable bowel syndrome-type symptoms in paediatric inflammatory bowel disease, and the relationship with biochemical markers of disease activity. Aliment Pharmacol Ther 2016; 44:181–188.; Bremner A, Roked S, Robinson R, et al. Faecal calprotectin in children with chronic gastrointestinal symptoms. Acta Paediatr 2005; 94:1855–1858.; Mahjoub FE, Zahedi N, Ashjai B, et al. Role of fecal calprotectin in differentiating between Hirschsprung's disease and functional con tipation. Korean J Gastroenterol 2013; 62:288–291.; Osborne NJ, Koplin JJ, Martin PE, et al. HealthNuts InvestigatorsPrevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J Allergy Clin Immunol 2011; 127:668.e2–676.e2.; Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 2011; 128:e9–e17.; Sicherer SH. Epidemiology of food allergy. J Allergy Clin Immunol 2011; 127:594–602.; Rona RJ, Keil T, Summers C, et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol 2007; 120:638–646.; Koletzko S, Niggemann B, Arató A, et al. European Society of Pediatric Gastroenterology, Hepatology, and NutritionDiagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr 2012; 55:221–229.; Waligora-Dupriet A, Campeotto F, Romero K, et al. Diversity of gut Bifidobacterium species is not altered between allergic and non-allergic French infants. Anaerobe 2011; 17:91–96.; Beşer ÖF, Sancak S, Erkan T, et al. Can fecal calprotectin level be used as a markers of inflammation in the diagnosis and follow-up of cow's milk protein allergy? Allergy, Asthma Immunol Res 2014; 6:33–38.; Díaz M, Guadamuro L, Espinosa-Martos I, et al. Microbiota and derived parameters in fecal samples of infants with non-IgE cow's milk protein allergy under a restricted diet. Nutrients 2018; 10:1481.; Merras-Salmio L, Kolho K, Pelkonen AS, et al. Markers of gut mucosal inflammation and cow's milk specific immunoglobulins in non-IgE cow's milk allergy. Clin Transl Allergy 2014; 4:8.; Baldassarre ME, Laforgia N, Fanelli M, et al. Lactobacillus GG improves recovery in infants with blood in the stools and presumptive allergic colitis compared with extensively hydrolyzed formula alone. J Pediatr 2010; 156:397–401.; Ataee P, Zoghali M, Nikkhoo B, et al. Diagnostic value of fecal calprotectin in response to mother's diet in breast-fed infants with cow's milk allergy colitis. Iran J Pediatr 2018; 28:e66172.; Winberg A, Nagaeva O, Nagaev I, et al. Dynamics of cytokine mRNA expression and fecal biomarkers in school-children undergoing a double-blind placebo-controlled food challenge series. Cytokine 2016; 88:259–266.; Seo S, Ahn SH, Ri S, et al. Elevated fecal calprotectin levels are associated with severity of atopic dermatitis in children. Asian Pac J Allergy Immunol 2018; 36:82–87.; Orivuori L, Mustonen K, de Goffau M, et al. High level of fecal calprotectin at age 2 months as a marker of intestinal inflammation predicts atopic dermatitis and asthma by age 6. Clin Exp Allergy 2015; 45:928–939.; Kukkonen K, Kuitunen M, Haahtela T, et al. High intestinal IgA associates with reduced risk of IgE-associated allergic diseases. Pediatr Allergy Immunol 2010; 21 (1 Pt I):67–73.; Biskou O, Gardner-Medwin J, Mackinder M, et al. Faecal calprotectin in treated and untreated children with coeliac disease and juvenile idiopathic arthritis. J Pediatr Gastroenterol Nutr 2016; 63:e112–e115.; Balamtekin N, Baysoy G, Uslu N, et al. Fecal calprotectin concentration is increased in children with celiac disease: relation with histopathological findings. Turk J Gastroenterol 2012; 23:503–508.; Shahramian I, Bazi A, Shafie-Sabet N, et al. A survey of fecal calprotectin in children with newly diagnosed celiac disease with villous atrophy. Shiraz E-Med J 2019; (In Press).; Rajani S, Huynh HQ, Shirton L, et al. A Canadian study toward changing local practice in the diagnosis of pediatric celiac disease. Cana J Gastroenterol Hepatol 2016; 2016:6234160.; Norkina O, Kaur S, Ziemer D, et al. Inflammation of the cystic fibrosis mouse small intestine. Am J Physiol Gastrointest Liver Physiol 2004; 286:G1032–G1041.; Smyth RL, Croft NM, O’Hea U, et al. Intestinal inflammation in cystic fibrosis. Arch Dis Child 2000; 82:394–399.; Werlin SL, Benuri-Silbiger I, Kerem E, et al. Evidence f intestinal inflammation in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2010; 51:304–308.; Bruzzese E, Raia V, Gaudiello G, et al. Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration. Aliment Pharmacol Ther 2004; 20:813–819.; Rumman N, Sultan M, El-Chammas K, et al. Calprotectin in cystic fibrosis. BMC Pediatr 2014; 14:133.; Dhaliwal J, Leach S, Katz T, et al. Intestinal inflammation and impact on growth in children with cystic fibrosis. J Pediatr Gastroenterol Nutr 2015; 60:521–526.; Garg M, Leach ST, Coffey MJ, et al. Age-dependent variation of fecal calprotectin in cystic fibrosis and healthy children. J Cyst Fibros 2017; 16:631–636.; Ellemunter H, Engelhardt A, Schuller K, et al. Fecal calprotectin in cystic fibrosis and its relation to disease parameters: a longitudinal analysis for 12 years. J Pediatr Gastroenterol Nutr 2017; 65:438–442.; Adriaanse MP, van der Sande, Linda JTM, et al. Evidence for a cystic fibrosis enteropathy. PloS One 2015; 10:e0138062.; Ooi CY, Syed SA, Rossi L, et al. Impact of CFTR modulation with ivacaftor on gut microbiota and intestinal inflammation. Sci Rep 2018; 8:1–8.; Sýkora J, Siala K, Huml M, et al. Evaluation of faecal calprotectin as a valuable non-invasive marker in distinguishing gut pathogens in young children with acute gastroenteritis. Acta Paediatr 2010; 99:1389–1395.; Duman M, Gencpinar P, Bicmen M, et al. Fecal calprotectin: can be used to distinguish between bacterial and viral gastroenteritis in children? Am J Emerg Med 2015; 33:1436–1439.; Czub E, Nowak JK, Moczko J, et al. Comparison of fecal pyruvate kinase isoform M2 and calprotectin in acute diarrhea in hospitalized children. Sci Rep 2014; 4:4769.; Shastri YM, Bergis D, Povse N, et al. Prospective multicenter study evaluating fecal calprotectin in adult acute bacterial diarrhea. Am J Med 2008; 121:1099–1106.; Swale A, Miyajima F, Roberts P, et al. Calprotectin and lactoferrin faecal levels in patients with Clostridium difficile infection (CDI): a prospective cohort study. PLoS One 2014; 9:e106118.; Barbut F, Gouot C, Lapidus N, et al. Faecal lactoferrin and calprotectin in patients with Clostridium difficile infection: a case–control study. Eur J Clin Microbiol Infect Dis 2017; 36:2423–2430.; Bustinduy AL, Sousa-Figueiredo JC, Adriko M, et al. Fecal occult blood and fecal calprotectin as point-of-care markers of intestinal morbidity in Ugandan children with Schistosoma mansoni infection. PLoS Negl Trop Dis 2013; 7:e2542.; Sorokman TV, Sokolnyk SV, Popelyuk AV, et al. Giardiasis in children: molecular genotyping, growth and calprotectin levels. Arch Balk Med Union 2019; 54:522–531.; Callahan MJ, Rodriguez DP, Taylor GA. CT of appendicitis in children. Radiology 2002; 224:325–332.; Rothrock SG, Pagane J. Acute appendicitis in children: emergency department diagnosis and management. Ann Emerg Med 2000; 36:39–51.; Allister L, Bachur R, Glickman J, et al. Serum markers in acute appendicitis. J Surg Res 2011; 168:70–75.; Ambe PC, Gödde D, Bönicke L, et al. Calprotectin could be a potential biomarker for acute appendicitis. J Transl Med 2016; 14:107.; Ambe PC, Orth V, Gödde D, et al. Improving the preoperative diagnostic accuracy of acute appendicitis. can fecal calprotectin be helpful? PloS One 2016; 11:e0168769.; Kharbanda AB, Rai AJ, Cosme Y, et al. Novel serum and urine markers for pediatric appendicitis. Acad Emerg Med 2012; 19:56–62.; Sarsu SB, Erbagci AB, Ulusal H, et al. The place of calprotectin, lactoferrin, and high-mobility group Box 1 protein on diagnosis of acute appendicitis with children. Indian J Surg 2017; 79:131–136.; Huckins DS, Simon HK, Copeland K, et al. A novel biomarker panel to rule out acute appendicitis in pediatric patients with abdominal pain. Am J Emerg Med 2013; 31:1368–1375.; Gonzalez Del Castillo J, Ayuso FJ, Trenchs V, et al. Diagnostic accuracy of the APPY1 Test in patients aged 2-20 years with suspected acute appendicitis presenting to emergency departments. Emerg Med J 2016; 33:853–859.; Benito J, Acedo Y, Medrano L, et al. Usefulness of new and traditional serum biomarkers in children with suspected appendicitis. Am J Emerg Med 2016; 34:871–876.; Sýkora J, Huml M, Siala K, et al. Paediatric Rome III criteria–related abdominal pain is associated with Helicobacter pylori and not with calprotectin. J Pediatr Gastroenterol Nutr 2016; 63:417–422.; Teixeira TF, Souza NC, Chiarello PG, et al. Intestinal permeability parameters in obese patients are correlated with metabolic syndrome risk factors. Clin Nutr 2012; 31:735–740.; Spagnuolo MI, Cicalese MP, Caiazzo MA, et al. Relationship between severe obesity and gut inflammation in children: what's next? Ital J Pediatr 2010; 36:66.; Verdam FJ, Fuentes S, de Jonge C, et al. Human intestinal microbiota composition is associated with local and systemic inflammation in obesity. Obesity (Silver Spring) 2013; 21:E607–E615.; Bartels RH, Chimwezi E, Watson V, et al. Hypoallergenic and anti-inflammatory feeds in children with complicated severe acute malnutrition: an open randomised controlled 3-arm intervention trial in Malawi. Sci Rep 2019; 9:2304.; Versloot CJ, Attia S, Bourdon C, et al. Intestinal pathogen clearance in children with severe acute malnutrition is unrelated to inpatient morbidity. Clin Nutr ESPEN 2018; 24:109–113.; Pergialiotis V, Konstantopoulos P, Karampetsou N, et al. Calprotectin levels in necrotizing enterocolitis: a systematic review of the literature. Inflammation Res 2016; 65:847–852.; Carroll D, Corfield A, Spicer R, et al. Faecal calprotectin concentrations and diagnosis of necrotising enterocolitis. Lancet 2003; 361:310–311.; Houston JF, Morgan JE. Question 2: can faecal calprotectin be used as an effective diagnostic aid for necrotising enterocolitis in neonates? Arch Dis Child 2015; 100:1003–1006.; Thuijls G, Derikx JP, van Wijck K, et al. Non-invasive markers for early diagnosis and determination of the severity of necrotizing enterocolitis. Ann Surg 2010; 251:1174–1180.; Pauley-Hunter RJ, Kunnath S, Wolff K, et al. Fecal calprotectin and pediatric juvenile polyps. J Pediatr Gastroenterol Nutr 2015; 60:e30–e31.; Teitelbaum JE, Adu-Darko MA. Fecal calprotectin in juvenile polyposis coli. J Clin Gastroenterol 2010; 44:593.; Cole CR, Frem JC, Schmotzer B, et al. The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses. J Pediatr 2010; 156:941.e1–947.e1.; Fundaro C, Fantacci C, Ansuini V, et al. Fecal calprotectin concentration in children affected by SIBO. Children 2011; 15:1328–1335.; Fernell E, Fagerberg UL, Hellström PM. No evidence for a clear link between active intestinal inflammation and autism based on analyses of faecal calprotectin and rectal nitric oxide. Acta Paediatr 2007; 96:1076–1079.; de Magistris L, Familiari V, Pascotto A, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr 2010; 51:418–424.; Kushak RI, Buie TM, Murray KF, et al. Evaluation of intestinal function in children with autism and gastrointestinal symptoms. J Pediatr Gastroenterol Nutr 2016; 62:687–691.; Kanik A, Baran M, Ince FD, et al. Faecal calprotectin levels in children with Henoch–Schönlein purpura: is this a new marker for gastrointestinal involvement? Eur J Gastroenterol Hepatol 2015; 27:254–258.; Teng X, Gao C, Sun M, et al. Clinical significance of fecal calprotectin for the early diagnosis of abdominal type of Henoch–Schonlein purpura in children. Clin Rheumatol 2018; 37:1667–1673.. Linking ISSN: 02772116. Subset: MEDLINE; Date of Electronic Publication: 20210401. Current Imprints: Publication: 1998- : Philadelphia, PA : Lippincott Williams & Wilkins; Original Imprints: Publication: [New York, N.Y.] : Raven Press, [c1982- <br />