Fecal Calprotectin, Chitinase 3-Like-1, S100A12 and Osteoprotegerin as Markers of Disease Activity in Children with Crohn’s Disease
Abstract
:1. Introduction
2. Methods
2.1. Patient Recruitment
2.2. Standard Serum Markers of Inflammation
2.3. Clinical Disease Assessment
2.4. Fecal Biomarker Measurement
2.5. Statistical Analysis
2.6. Ethics
3. Results
3.1. Background Characteristics
3.2. Fecal Biomarker Levels
3.3. Correlations between Fecal Biomarkers and Other Markers
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Day, A.S.; Ledder, O.; Leach, S.T.; Lemberg, D.A. Crohn’s and colitis in children and adolescents. World J. Gastroenterol. 2012, 18, 5862–5869. [Google Scholar] [CrossRef] [PubMed]
- Selvakumar, D.; Evans, D.; Coyte, K.Z.; McLaughlin, J.; Brass, A.; Hancock, L.; Cruickshank, S. Understanding the development and function of the gut microbiota in health and inflammation. Frontline Gastroenterol. 2022, 13, e13–e21. [Google Scholar] [CrossRef] [PubMed]
- IBD Working Group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: Recommendations for diagnosis—The Porto criteria. J. Pediatr. Gastroenterol. Nutr. 2005, 41, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Annese, V.; Daperno, M.; Rutter, M.D.; Amiot, A.; Bossuyt, P.; East, J.; Ferrante, M.; Götz, M.; Katsanos, K.H.; Kießlich, R.; et al. European evidence based consensus for endoscopy in inflammatory bowel disease. J. Crohn’s Colitis 2013, 7, 982–1018. [Google Scholar] [CrossRef] [Green Version]
- Day, A.S.; Leach, S.T.; Lemberg, D.A. An update on diagnostic and prognostic biomarkers in inflammatory bowel disease. Expert Rev. Mol. Diagn. 2017, 17, 835–843. [Google Scholar] [CrossRef]
- Musci, J.O.; Cornish, J.S.; Dabritz, J. Utility of surrogate markers for the prediction of relapses in inflammatory bowel diseases. J. Gastroenterol. 2016, 51, 531–547. [Google Scholar] [CrossRef]
- D’haens, G.; Ferrante, M.; Vermeire, S.; Baert, F.; Noman, M.; Moortgat, L.; Geens, P.; Iwens, D.; Aerden, I.; Van Assche, G.; et al. Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease. Inflamm. Bowel Dis. 2012, 18, 2218–2224. [Google Scholar] [CrossRef]
- Mao, R.; Xiao, Y.L.; Gao, X.; Chen, B.-L.; He, Y.; Yang, L.; Hu, P.-J.; Chen, M.-H. Fecal calprotectin in predicting relapse of in-flammatory bowel diseases: A meta-analysis of prospective studies. Inflamm. Bowel Dis. 2012, 18, 1894–1899. [Google Scholar] [CrossRef]
- Sherwood, R.; Walsham, N. Fecal calprotectin in inflammatory bowel disease. Clin. Exp. Gastroenterol. 2016, 9, 21–29. [Google Scholar] [CrossRef] [Green Version]
- Rugtveit, J.; Fagerhol, M.K. Age-Dependent Variations in Fecal Calprotectin Concentrations in Children. J. Pediatr. Gastroenterol. Nutr. 2002, 34, 323. [Google Scholar] [CrossRef]
- Jensen, M.D.; Kjeldsen, J.; Nathan, T. Fecal calprotectin is equally sensitive in Crohn’s disease affecting the small bowel and colon. Scand. J. Gastroenterol. 2011, 46, 694–700. [Google Scholar] [CrossRef] [PubMed]
- Sipponen, T.; Savilahti, E.; Kolho, K.L.; Nuutinen, H.; Turunen, U.; Färkkilä, M. Crohn’s disease activity assessed by fecal calprotectin and lactoferrin: Correlation with Crohn’s disease activity index and endoscopic findings. Inflamm. Bowel Dis. 2008, 14, 40–46. [Google Scholar] [CrossRef] [PubMed]
- Sidler, M.A.; Leach, S.T.; Day, A.S. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm. Bowel Dis. 2008, 14, 359–366. [Google Scholar] [CrossRef] [PubMed]
- Day, A.S.; Ehn, M.; Gearry, R.B.; Lemberg, D.A.; Leach, S.T. Fecal S100A12 in Healthy Infants and Children. Dis. Markers 2013, 35, 295–299. [Google Scholar] [CrossRef] [PubMed]
- Kaiser, T.; Langhorst, J.; Wittkowski, H.; Becker, K.; Friedrich, A.W.; Rueffer, A.; Dobos, G.J.; Roth, J.; Foell, D. Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome. Gut 2007, 56, 1706–1713. [Google Scholar] [CrossRef] [Green Version]
- Däbritz, J.; Langhorst, J.; Lügering, A.; Heidemann, J.; Mohr, M.; Wittkowski, H.; Krummenerl, T.; Foell, D. Improving Relapse Prediction in Inflammatory Bowel Disease by Neutrophil-Derived S100A12. Inflamm. Bowel Dis. 2013, 19, 1130–1138. [Google Scholar] [CrossRef] [PubMed]
- Karl, J.; Wild, N.; Tacke, M.; Andres, H.; Garczarek, U.; Rollinger, W.; Zolg, W. Improved Diagnosis of Colorectal Cancer Using a Combination of Fecal Occult Blood and Novel Fecal Protein Markers. Clin. Gastroenterol. Hepatol. 2008, 6, 1122–1128. [Google Scholar] [CrossRef] [PubMed]
- De Voogd, F.A.E.; Gearry, R.B.; Mulder, C.J.; Day, A.S. Osteoprotegerin: A novel biomarker for inflammatory bowel disease and gastrointestinal carcinoma. J. Gastroenterol. Hepatol. 2016, 31, 1386–1392. [Google Scholar] [CrossRef] [Green Version]
- Pang, T.; Leach, S.T.; Katz, T.; Day, A.S.; Ooi, C.Y. Fecal Biomarkers of Intestinal Health and Disease in Children. Front. Pediatr. 2014, 2, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nahidi, L.; Leach, S.T.; Sidler, M.A.; Levin, A.; Lemberg, D.A.; Day, A.S. Osteoprotegerin in pediatric Crohn’s disease and the effects of exclusive enteral nutrition. Inflamm. Bowel Dis. 2011, 17, 516–523. [Google Scholar] [CrossRef]
- Skinner, A.; Lerer, T.; Wyzga, N.; Viswanathan, A.; Sylvester, F. S1225 Fecal Osteoprotegerin: A Marker for Pediatric Ulcera-tive Colitis At Diagnosis—A Pilot Study. Gastroenterology 2008, 134, A-205. [Google Scholar] [CrossRef]
- Mizoguchi, E. Chitinase 3-Like-1 Exacerbates Intestinal Inflammation by Enhancing Bacterial Adhesion and Invasion in Colonic Epithelial Cells. Gastroenterology 2006, 130, 398–411. [Google Scholar] [CrossRef] [PubMed]
- Eurich, K.; Segawa, M.; Toei-Shimizu, S.; Mizoguchi, E. Potential role of chitinase 3-like-1 in inflammation-associated carcinogenic changes of epithelial cells. World J. Gastroenterol. 2009, 15, 5249–5259. [Google Scholar] [CrossRef] [PubMed]
- Levine, A.; Koletzko, S.; Turner, D.; Escher, J.C.; Cucchiara, S.; de Ridder, L.; Kolho, K.-L.; Veres, G.; Russell, R.K.; Paerregaard, A.; et al. The ESPGHAN Revised Porto Criteria for the Diagnosis of Inflammatory Bowel Disease in Children and Adolescents. J. Pediatr. Gastroenterol. Nutr. 2014, 58, 795–806. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Daperno, M.; D’Haens, G.; Van Assche, G.; Baert, F.; Bulois, P.; Maunoury, V.; Sostegni, R.; Rocca, R.; Pera, A.; Gevers, A.; et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: The SES-CD. Gastrointest. Endosc. 2004, 60, 505–512. [Google Scholar] [CrossRef]
- Hyams, J.S.; Ferry, G.D.; Mandel, F.S.; Gryboski, J.D.; Kibort, P.M.; Kirschner, B.S.; Griffiths, A.M.; Katz, A.J.; Grand, R.J.; Boyle, J.T.; et al. Development and validation of a pediatric Crohn’s disease activity index. J. Pediatr. Gastroenterol. Nutr. 1991, 12, 439–447. [Google Scholar] [CrossRef] [PubMed]
- Turner, D.; Griffiths, A.M.; Walters, T.D.; Seah, T.; Markowitz, J.; Pfefferkorn, M.; Keljo, D.; Otley, A.; LeLeiko, N.S.; Mack, D.; et al. Appraisal of the pediatric Crohn’s disease activity index on four prospectively collected datasets: Recommended cutoff values and clinimetric properties. Am. J. Gastroenterol. 2010, 105, 2085–2092. [Google Scholar] [CrossRef]
- Turner, D.; Griffiths, A.M.; Walters, T.D.; Seah, T.; Markowitz, J.; Pfefferkorn, M.; Keljo, D.; Waxman, J.; Otley, A.; LeLeiko, N.S.; et al. Mathematical weighting of the pediatric Crohn’s disease activity index (PCDAI) and comparison with its other short versions. Inflamm. Bowel Dis. 2012, 18, 55–62. [Google Scholar] [CrossRef]
- Leach, S.; Nahidi, L.; Tilakaratne, S.; Day, A.S.; Lemberg, D. Development and Assessment of a Modified Pediatric Crohn Disease Activity Index. J. Pediatr. Gastroenterol. Nutr. 2010, 51, 232–236. [Google Scholar] [CrossRef]
- Turner, D.; Ricciuto, A.; Lewis, A.; D’Amico, F.; Dhaliwal, J.; Griffiths, A.M.; Bettenworth, D.; Sandborn, W.J.; Sands, B.E.; Reinisch, W.; et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021, 160, 1570–1583. [Google Scholar] [CrossRef]
- Aomatsu, T.; Imaeda, H.; Matsumoto, K.; Kimura, E.; Yoden, A.; Tamai, H.; Fujiyama, Y.; Mizoguchi, E.; Andoh, A. Faecal chitinase 3-like-1: A novel biomarker of disease activity in paediatric inflammatory bowel disease. Aliment. Pharmacol. Ther. 2011, 34, 941–948. [Google Scholar] [CrossRef]
- Lopez, R.N.; Leach, S.T.; Lemberg, D.A.; Duvoisin, G.; Gearry, R.B.; Day, A.S. Fecal biomarkers in inflammatory bowel disease. J. Gastroenterol. Hepatol. 2017, 32, 577–582. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Şahin, B.S.G.; Keskindemirci, G.; Özden, T.A.; Durmaz, Ö.; Gökçay, G. Faecal calprotectin levels during the first year of life in healthy children. J. Paediatr. Child Health 2020, 56, 1806–1811. [Google Scholar] [CrossRef] [PubMed]
- Hestvik, E.; Tumwine, J.K.; Tylleskär, T.; Grahnquist, L.; Ndeezi, G.; Kaddu-Mulindwa, D.H.; Aksnes, L.; Olafsdottir, E. Faecal calprotectin concentrations in apparently healthy children aged 0–12 years in urban Kampala, Uganda: A community-based survey. BMC Pediatr. 2011, 11, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Soto-Méndez, M.-J.; Romero-Abal, M.-E.; Schümann, K.; Gil, Á.; Solomons, N.W. Normative Fecal Calprotectin Concentrations in Guatemalan Preschoolers Are High Relative to Children Reported Elsewhere. J. Pediatr. Gastroenterol. Nutr. 2017, 64, 238–244. [Google Scholar] [CrossRef] [PubMed]
- Leonardi, S.; Parisi, G.F.; Capizzi, A.; Manti, S.; Cuppari, C.; Scuderi, M.G.; Rotolo, N.; Lanzafame, A.; Musumeci, M.; Salpietro, C. YKL-40 as marker of severe lung disease in cystic fibrosis patients. J. Cyst. Fibros. 2016, 15, 583–586. [Google Scholar] [CrossRef] [Green Version]
- Permain, J.; Appleton, L.; Ho, S.S.C.; Coffey, M.; Ooi, C.Y.; Keenan, J.I.; Day, A.S. Children With Cystic Fibrosis Have Elevated Levels of Fecal Chitinase-3-like-1. J. Pediatr. Gastroenterol. Nutr. 2022, 75, 48–51. [Google Scholar] [CrossRef]
- Vind, I.; Johansen, J.; Price, P.; Munkholm, P. Serum YKL-40, a potential new marker of disease activity in patients with inflammatory bowel disease. Scan. J. Gastroenterol. 2003, 38, 599–605. [Google Scholar]
- Buisson, A.; Vazeille, E.; Minet-Quinard, R.; Goutte, M.; Bouvier, D.; Goutorbe, F.; Pereira, B.; Barnich, N.; Bommelaer, G. Faecal chitinase 3-like 1 is a reliable marker as accurate as faecal calprotectin in detecting endoscopic activity in adult patients with inflammatory bowel diseases. Aliment. Pharmacol. Ther. 2016, 43, 1069–1079. [Google Scholar] [CrossRef] [Green Version]
Patients | 65 | |
---|---|---|
Male | 46 (70%) | |
Age at inclusion in years, median (IQR) | 12 (9–15) | |
Age at diagnosis in years, median (IQR) | 9 (6.5–12.5) | |
Disease duration in years, median (IQR) | 1 (0–3.5) | |
New diagnosis of CD | 32 (49%) | |
Disease location at diagnosis | ||
L1: Ileal | 15 (23%) | |
L2: Colonic | 16 (24%) | |
L3: Ileocolonic | 32 (49%) | |
L4a/b: Proximal from ileum | 31 (48%) | |
Crohn’s disease behavior at diagnosis | ||
B1: Nonstricturing and nonpenetrating | 61 (94%) | |
B2: Stricturing | 2 (3%) | |
B3: Penetrating | 2 (3%) | |
P: Perianal disease | 9 (14%) | |
Medication at enrolment | ||
Exclusive enteral nutrition | 9 (14%) | |
Aminosalicylates | 19 (29%) | |
Antibiotics | 5 (8%) | |
Corticosteroids | 2 (3%) | |
Thiopurines/Methotrexate | 21 (33%) | |
Biological | 4 (6%) | |
No medication | 23 (35%) | |
Disease activity at enrolment | ||
Remission (PCDAI < 10) | 26 (40%) | |
Mild (PCDAI 10–27.5) | 28 (43%) | |
Moderate (PCDAI ≥ 27.5–37.5) | 6 (9%) | |
Severe (PCDAI ≥ 37.5) | 5 (8%) | |
SES-CD at baseline | n = 20 | |
Inactive (0–2) | 2 (10%) | |
Mild (3–6) | 2 (10%) | |
Moderate (7–15) | 11 (55%) | |
Severe (>15) | 5 (25%) | |
Serum markers (medians and IQR) | ||
ESR (in mm/h) | n = 51 | 12 (8–21) |
CRP (in mg/L) | n = 56 | 3.0 (2.3–8.8) |
Albumin (in g/L) | n = 53 | 41 (39–44) |
Hematocrit (in L/L) | n = 59 | 0.38 (0.35–0.40) |
Platelets (×109/L) | n = 58 | 356 (295–445) |
FC µg/g | (IQR) | n | CHI3L1 ng/g | (IQR) | n | S100A12 µg/g | (IQR) | n | OPG pg/mL | (IQR) | n | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Overall levels | 784 | (180–2878) | 58 | 83 | (17–637) | 65 | 31 | (4–88) | 63 | 69 | (63–577) | 63 |
Gender | ||||||||||||
Female | 1344 | (131–2857) | 17 | 26 | (8–706) | 19 | 40 | (8–98) | 19 | 74 | (63–219) | 19 |
Male | 779 | (230–3640) | 41 | 89 | (17–621) | 46 | 26 | (3–78) | 44 | 66 | (63–824) | 44 |
p = 0.878 | p = 0.713 | p = 0.472 | p = 0.434 | |||||||||
Age at inclusion | ||||||||||||
≤6 years | 1952 | (495–2841) | 7 | 155 | (39–1696) | 9 | 65 | (60–84) | 9 | 219 | (63–2024) | 9 |
7–12 years | 456 | (98–1679) | 27 | 40 | (6–400) | 28 | 9 | (2–69) | 28 | 63 | (63–577) | 28 |
≥13 years | 1420 | (166–4616) | 24 | 99 | (17–759) | 28 | 26 | (7–116) | 26 | 81 | (63–867) | 26 |
p = 0.357 | p = 0.372 | p = 0.074 | p = 0.447 | |||||||||
Crohn’s disease location at diagnosis | ||||||||||||
L1: Ileal | 294 | (76–494) | 15 | 17 | (6–36) | 16 | 7 | (2–24) | 15 | 63 | (63–63) | 15 |
L2: Colonic | 1629 | (196–4346) | 13 | 194 | (24–1027) | 16 | 66 | (6–85) | 16 | 71 | (63–1014) | 16 |
L3: Ileocolonic | 1416 | (371–4572) | 29 | 226 | (29–996) | 32 | 40 | (7–119) | 31 | 143 | (63–856) | 31 |
p = 0.025 | p = 0.005 | p = 0.033 | p = 0.021 | |||||||||
L1: ileal | 294 | (76–494) | 15 | 17 | (6–36) | 16 | 7 | (2–24) | 15 | 63 | (63–63) | 15 |
L2/L3: (ileo)colonic | 1523 | (245–4527) | 42 | 226 | (27–996) | 48 | 56 | (7–116) | 47 | 94 | (63–857) | 47 |
p = 0.007 | p = 0.001 | p = 0.009 | p = 0.007 | |||||||||
Clinical disease activity * | ||||||||||||
Remission | 277 | (100–1576) | 24 | 23 | (8–149) | 26 | 13 | (3–73) | 25 | 63 | (63–495) | 25 |
Active disease | 1648 | (343–4527) | 34 | 227 | (27–1109) | 39 | 58 | (6–123) | 38 | 81 | (63–758) | 38 |
p = 0.012 | p = 0.013 | p = 0.164 | p = 0.288 | |||||||||
Clinical disease activity for patients with L1 ileal disease * | ||||||||||||
Remission | 98 | (30–294) | 7 | 15 | (6–24) | 8 | 3 | (2–10) | 7 | 63 | (63–63) | 7 |
Active disease | 475 | (256–2028) | 8 | 22 | (2–232) | 8 | 16 | (2–63) | 8 | 63 | (63–128) | 8 |
p = 0.014 | p = 0.645 | p = 0.336 | p = 0.867 | |||||||||
SES-CD | ||||||||||||
Inactive (0–2) | 98 | 1 | 43 | (2–43) | 2 | 1 | 1 | 63 | 1 | |||
Mild (3–6) | 30 | 1 | 1717 | (14–1717) | 2 | 107 | (10–107) | 2 | 364 | (63–364) | 2 | |
Moderate (7–15) | 1952 | (630–3640) | 9 | 155 | (27–776) | 11 | 60 | (12–116) | 10 | 63 | (63–225) | 10 |
Severe (>15) | 4482 | (2841–4482) | 3 | 776 | (125–2549) | 5 | 210 | (81–732) | 5 | 898 | (399–3439) | 5 |
p = 0.068 | p = 0.456 | p = 0.120 | p = 0.058 |
FC | CHI3L1 | S100A12 | OPG | |
---|---|---|---|---|
CHI3L1 | 0.83 | |||
S100A12 | 0.62 | 0.66 | ||
OPG | 0.68 | 0.60 | 0.48 | |
CRP | ns | 0.30 * | ns | ns |
ESR | 0.40 | 0.54 | ns | 0.40 |
Albumin | ns | ns | ns | ns |
Platelets | 0.45 | 0.60 | ns | 0.46 |
Haematocrit | ns | ns | ns | ns |
PCDAI | 0.40 | 0.38 | ns | ns |
modPCDAI | 0.42 * | 0.45 | 0.36 * | ns |
SES-CD | 0.57 * | ns | ns | 0.48 * |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Volkers, A.G.; Appleton, L.; Gearry, R.B.; Frampton, C.M.; de Voogd, F.A.E.; Peters van Ton, A.M.; Leach, S.T.; Lemberg, D.A.; Day, A.S. Fecal Calprotectin, Chitinase 3-Like-1, S100A12 and Osteoprotegerin as Markers of Disease Activity in Children with Crohn’s Disease. Gastrointest. Disord. 2022, 4, 180-189. https://doi.org/10.3390/gidisord4030017
Volkers AG, Appleton L, Gearry RB, Frampton CM, de Voogd FAE, Peters van Ton AM, Leach ST, Lemberg DA, Day AS. Fecal Calprotectin, Chitinase 3-Like-1, S100A12 and Osteoprotegerin as Markers of Disease Activity in Children with Crohn’s Disease. Gastrointestinal Disorders. 2022; 4(3):180-189. https://doi.org/10.3390/gidisord4030017
Chicago/Turabian StyleVolkers, Adriaan G., Laura Appleton, Richard B. Gearry, Christopher M. Frampton, Floris A. E. de Voogd, Annemieke M. Peters van Ton, Steven T. Leach, Daniel A. Lemberg, and Andrew S. Day. 2022. "Fecal Calprotectin, Chitinase 3-Like-1, S100A12 and Osteoprotegerin as Markers of Disease Activity in Children with Crohn’s Disease" Gastrointestinal Disorders 4, no. 3: 180-189. https://doi.org/10.3390/gidisord4030017