Performance of fecal S100A12 as a novel non-invasive diagnostic biomarker for pediatric inflammatory bowel disease: a systematic review and meta-analysis

Witarto, Bendix Samarta; Visuddho, Visuddho; Witarto, Andro Pramana; Sampurna, Mahendra Tri Arif; Irzaldy, Abyan

doi:10.1016/j.jped.2023.03.002

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REVIEW ARTICLE • J. Pediatr. (Rio J.) 99 (5) • 2023 • https://doi.org/10.1016/j.jped.2023.03.002 copy

Performance of fecal S100A12 as a novel non-invasive diagnostic biomarker for pediatric inflammatory bowel disease: a systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective:

The incidence and prevalence of inflammatory bowel disease (IBD) in pediatric patients are increasing. Currently, the diagnostic method for IBD is inconvenient, expensive, and difficult. S100A12, a type of calcium-binding protein, detected in the feces of patients with IBD has recently been suggested as a promising diagnostic tool. Hence, the authors aimed to evaluate the accuracy of fecal S100A12 in diagnosing IBD in pediatric patients by performing a meta-analysis.

Methods:

The authors performed a systematic literature search in five electronic databases for eligible studies up to July 15, 2021. Pooled diagnostic accuracies of fecal S100A12 were analyzed as the primary outcomes. Secondary outcomes were standardized mean difference (SMD) of fecal S100A12 levels between IBD and non-IBD groups and a comparison of diagnostic accuracies between fecal S100A12 and fecal calprotectin.

Results:

Seven studies comprising 712 children and adolescents (474 non-IBD controls and 238 IBD cases) were included. Fecal S100A12 levels were higher in the IBD group than in the non-IBD group (SMD = 1.88; 95% confidence interval [CI] = 1.19-2.58; p < 0.0001). Fecal S100A12 could diagnose IBD in pediatric patients with a pooled sensitivity of 95% (95% CI = 88%–98%), specificity of 97% (95% CI = 95%–98%), and area under the receiver operating summary characteristics (AUSROC) curve of 0.99 (95% CI = 0.97–0.99). Fecal S100A12 specificity and AUSROC curve values were higher than those of fecal calprotectin (p < 0.05).

Conclusion:

Fecal S100A12 may serve as an accurate and non-invasive tool for diagnosing pediatric IBD. © 2023 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

KEYWORDS
Diagnosis; Feces; Inflammatory bowel diseases; Pediatrics; S100A12; Sensitivity and specificity

Author, Year	Study Location	Study Design	Population Characteristics	IBD Diagnostic Criteria	Fecal S100A12 Assay	Sample Size				Age^a a Data are presented in mean ± SD.	AUC (95% CI)	Cut-Off
						Non-IBD	IBD
						Non-IBD	CD	UC	IBDU
de Jong et al., 2006³⁴34 de Jong NS, Leach ST, Day AS. Fecal S100A12: a novel noninvasive marker in children with Crohn’s disease. Inflamm Bowel Dis. 2006;12:566–72.	Australia	Case-control	Case: Children diagnosed with IBD at the hospital Control: Healthy children from families of hospital staff	Standard criteria with clinical, endoscopic, histological, and imaging findings	In-house ELISA	25	22	1	0	8.98 ± 4.28	0.98	10 mg/kg (pre-defined)
Sidler et al., 2008³⁵35 SidlerMA, Leach ST, Day AS. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm Bowel Dis. 2008;14:359–66.	Australia	Cross-sectional	Children presenting with GI symptoms who were suspected of having organic bowel disease, which required further examination Case: Diagnosed with IBD Control: Diagnosed other than IBD	Standard criteria with clinical, endoscopic, histological, and imaging findings	In-house ELISA	30	30	1	0	11.11 ± 3.52	0.99 (0.97–1.01)	10 mg/kg (pre-defined)
Heida et al., 2017³⁶36 Heida A, Kobold AC, Wagenmakers L, De Belt K van, Rheenen PF. Reference values of fecal calgranulin C (S100A12) in school aged children and adolescents. Clin Chem Lab Med. 2017;56:126–31.	Netherlands	Case-control	Case: Children diagnosed with IBD at the hospital Control: Healthy school children	European Society for Pediatric Gastroenterology Hepatology and Nutrition	Inflamark® ELISA	122 (one outlier was excluded from accuracy analysis)	21	19	1	12.24 ± 3.73	0.97 (0.93–1.00)	0.75 mg/g (pre-defined)
Heida et al., 2018³⁷37 Heida A, Van De Vijver E, Van Ravenzwaaij D, Van Biervliet S, Hummel TZ, Yuksel Z, et al. Predicting inflammatory bowel disease in children with abdominal pain and diarrhoea: calgranulin-C versus calprotectin stool tests. Arch Dis Child. 2018;103:565–71.	Netherlands and Belgium	Cross-sectional	Children presenting with persistent diarrhea for > 4 weeks or chronic/recurrent abdominal pain Case: Diagnosed with IBD Control: Diagnosed other than IBD	IBD Risk Stratifier (Endoscopy with biopsy or clinical follow-up)	Inflamark® ELISA	244	52	39	2	N/A	N/A	0.75 mg/g (pre-defined)
Pham et al., 2010³⁸38 Pham M, Leach ST, Lemberg DA, Day AS. Subclinical intestinal inflammation in siblings of children with crohn’s disease. Dig Dis Sci. 2010;55:3502–7.	Australia	Case-control	Case: Children diagnosed with CD at the hospital Control: Same control population as Sidler et al., 200,8³⁵35 SidlerMA, Leach ST, Day AS. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm Bowel Dis. 2008;14:359–66.	Standard criteria with clinical, endoscopic, histologi-cal, and imaging findings	In-house ELISA	30	13	0	0	N/A	N/A	N/A
Ehn, 2011³⁹39 Ehn M. Levels of fecal S100A12 in Normal Children and Children with Inflammatory Bowel disease [doctorate thesis]. Uppsala, Sweden: Uppsala University; 2011.	Sweden	Case-control	Case: children diagnosed with IBD at the hospital Control: Healthy children from outpatient clinic, pediatric ward, or family of hospital staff	Standard criteria	In-house ELISA	38	7	0	3	5.08 ± 5.15	N/A	N/A
Nylund et al., 2011⁴⁰40 Nylund CM, D’Mello S, Kim MO, Bonkowski E, Dabritz J, Foell D, et al. Granulocyte macrophage-colony-stimulating factor autoantibodies and increased intestinal permeability in crohn disease. J Pediatr Gastroenterol Nutr. 2011;52:542–8.	United States	Case-control	Case: Children diagnosed with CD at the hospital Control: Healthy children from local communities	Standard diagnostic criteria with clinical, endoscopic, and radiographic findings	Double sandwich ELISA	15	27	0	0	N/A	N/A	N/A

Diagnostic Accuracy Parameter	Fecal S100A12					Fecal Calprotectin						Comparison Result
Diagnostic Accuracy Parameter	Number of Studies	Total Sample	Pooled Value	95% CI	SE	Author, Year	Number of Studies	Total Sample	Pooled Value	95% CI	SE	Z	p
Sensitivity	4	608	95%	88%–98%	2.55	Henderson et al., 2014¹⁷17 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;109:637–45.	8	715	97.8%	94.7%–99.6%	1.25	0.99	0.32
Specificity			97%	95%–98%	0.77				68.2%	50.2%–86.3%	9.21	3.12	0.002^a a p < 0.05.
AUC			0.99	0.97–0.99	0.01	Holtman et al., 2017³³33 Holtman GA, Lisman-van Leeuwen Y, Day AS, Fagerberg UL, Henderson P, Leach ST, 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 Pediatr. 2017;171:984–91.	6	593	0.95	0.93–0.98	0.01	2.91	0.004^a a p < 0.05.

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[1] * Corresponding author. E-mail: mahendra.tri@fk.unair.ac.id (M.T. Sampurna).