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GASTROENTEROLOGY / CLINICAL RESEARCH
Novel scoring system for early diagnosis of necrotizing enterocolitis: integrating clinical and laboratory data with urinary caveolin-1 levels
1
Doctoral Program in Medical Science, Faculty of Medicine, Brawijaya University, Indonesia
2
Department of Pediatrics, Faculty of Medicine, Brawijaya University/Saiful Anwar General Hospital, Indonesia
3
Department of Pediatrics, Faculty of Medicine, University of Indonesia/Dr. Cipto Mangunkusumo General Hospital, Indonesia
4
Department of Clinical Microbiology, Faculty of Medicine, Brawijaya University/Saiful Anwar General Hospital, Indonesia
5
Department of Clinical Pathology, Faculty of Medicine, Brawijaya University/Saiful Anwar General Hospital, Indonesia
Submission date: 2023-06-21
Final revision date: 2023-09-21
Acceptance date: 2023-10-05
Online publication date: 2023-11-16
Corresponding author
Brigitta I.R.V. Corebima
Doctoral Program in Medical Science, Faculty of Medicine, Brawijaya University, Jalan Veteran, 65145, Malang, East Java, Indonesia
Doctoral Program in Medical Science, Faculty of Medicine, Brawijaya University, Jalan Veteran, 65145, Malang, East Java, Indonesia
Arch Med Sci 2024;20(2):444-456
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Necrotizing enterocolitis (NEC) poses a significant threat to preterm infants, with nonspecific early manifestations complicating timely diagnosis. Therefore, this study aimed to develop a novel scoring system for early diagnosis of NEC, incorporating clinical and laboratory data with urinary caveolin-1 levels.
Material and methods:
A single-center prospective cohort study was conducted at a tertiary hospital in East Java, Indonesia. NEC diagnosis was established by Bell’s criteria and proven gut dysbiosis. Urinary levels of claudin-2, caveolin-1, and epidermal growth factor (EGF) were assessed as potential indicators of tight junction disruption. The selected urine biomarker cutoff value was determined using symbolic classification analysis and combined with clinical and laboratory parameters from Bell’s criteria to create an NEC scoring system, validated with the Aiken index. Sensitivity and specificity analyses were performed.
Results:
Thirty-four neonates, comprising NEC, preterm non-NEC, and term infants, were included. qPCR analysis highlighted elevated Klebsiella, Lactobacillus, Clostridium, and Bacteroides levels in NEC patients, indicating a gut dysbiosis trend. Among 3 biomarkers, caveolin-1 ≥ 17.81 ng/dl on day 3 demonstrated 72.86% negative predictive value and 87.50% positive predictive value. The combined scoring system which comprised abdominal cellulitis, distension, radiology, advanced resuscitation at birth, prematurity or low birthweight, platelet count, sepsis, orogastric retention, metabolic acidosis and caveolin-1 findings exhibited an AUC of 0.922 (95% CI: 0.81–1.00, p < 0.001), with ≥ 1.81 as the cutoff, offering 93% sensitivity and 94% specificity.
Conclusions:
Urine caveolin-1 on day 3 signifies enterocyte tight junction damage and the acute phase of NEC in premature infants. The proposed scoring system demonstrates good performance in predicting NEC incidence in preterm infants.
Necrotizing enterocolitis (NEC) poses a significant threat to preterm infants, with nonspecific early manifestations complicating timely diagnosis. Therefore, this study aimed to develop a novel scoring system for early diagnosis of NEC, incorporating clinical and laboratory data with urinary caveolin-1 levels.
Material and methods:
A single-center prospective cohort study was conducted at a tertiary hospital in East Java, Indonesia. NEC diagnosis was established by Bell’s criteria and proven gut dysbiosis. Urinary levels of claudin-2, caveolin-1, and epidermal growth factor (EGF) were assessed as potential indicators of tight junction disruption. The selected urine biomarker cutoff value was determined using symbolic classification analysis and combined with clinical and laboratory parameters from Bell’s criteria to create an NEC scoring system, validated with the Aiken index. Sensitivity and specificity analyses were performed.
Results:
Thirty-four neonates, comprising NEC, preterm non-NEC, and term infants, were included. qPCR analysis highlighted elevated Klebsiella, Lactobacillus, Clostridium, and Bacteroides levels in NEC patients, indicating a gut dysbiosis trend. Among 3 biomarkers, caveolin-1 ≥ 17.81 ng/dl on day 3 demonstrated 72.86% negative predictive value and 87.50% positive predictive value. The combined scoring system which comprised abdominal cellulitis, distension, radiology, advanced resuscitation at birth, prematurity or low birthweight, platelet count, sepsis, orogastric retention, metabolic acidosis and caveolin-1 findings exhibited an AUC of 0.922 (95% CI: 0.81–1.00, p < 0.001), with ≥ 1.81 as the cutoff, offering 93% sensitivity and 94% specificity.
Conclusions:
Urine caveolin-1 on day 3 signifies enterocyte tight junction damage and the acute phase of NEC in premature infants. The proposed scoring system demonstrates good performance in predicting NEC incidence in preterm infants.
REFERENCES (58)
2.
Alsaied A, Islam N, Thalib L. Global incidence of Necrotizing Enterocolitis: a systematic review and meta-analysis. BMC Pediatr 2020; 20: 344.
3.
Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. Necrotizing enterocolitis among neonates in the United States. J Perinatol 2003; 23: 278-85.
4.
Kaban RK, Rohsiswatmo R, Kautsar A, Sutrisno AA, Hikmahrachim HG, Hardiyanti N. Risk factors of necrotizing enterocolitis-related mortality in preterm neonates: a preliminary prospective study. Paediatr Indones 2022; 62: 186-91.
5.
Robinson JR, Rellinger EJ, Hatch LD, et al. Surgical necrotizing enterocolitis. Semin Perinatol 2017; 41: 70-9.
6.
Stey A, Barnert ES, Tseng CH, et al. Outcomes and costs of surgical treatments of necrotizing enterocolitis. Pediatrics 2015; 135: e1190-7.
7.
Sakellaris G, Partalis N, Dede O, et al. Gastrointestinal perforations in neonatal period: experience over 10 years. Pediatr Emerg Care 2012; 28: 886-8.
8.
Eicher C, Seitz G, Bevot A, et al. Surgical management of extremely low birth weight infants with neonatal bowel perforation: a single-center experience and a review of the literature. Neonatology 2012; 101: 285-92.
9.
Berkhout DJC, Klaassen P, Niemarkt HJ, et al. Risk factors for necrotizing enterocolitis: a prospective multicenter case-control study. Neonatology 2018; 114: 277-84.
10.
Li W, Huang X, Bi D. miRNA-21 plays an important role in necrotizing enterocolitis. Arch Med Sci 2022; 18: 406-12.
11.
Gane B, Bhat BV, Adhisivam B, et al. Risk factors and outcome in neonatal necrotising enterocolitis. Indian J Pediatr 2014; 81: 425-8.
12.
Lu Q, Cheng S, Zhou M, Yu J. Risk factors for necrotizing enterocolitis in neonates: a retrospective case-control study. Pediatr Neonatol 2017; 58: 165-70.
13.
Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33: 179-201.
14.
Duci M, Fascetti-Leon F, Erculiani M, et al. Neonatal independent predictors of severe NEC. Pediatr Surg Int 2018; 34: 663-9.
15.
Alexander KM, Chan SS, Opfer E, et al. Implementation of bowel ultrasound practice for the diagnosis and management of necrotising enterocolitis. Arch Dis Child 2021; 106: 96-103.
16.
Patel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res 2020; 88: 10-5.
18.
Maheshwari A, Schelonka RL, Dimmitt RA, et al. Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants. Pediatr Res 2014; 76: 100-8.
19.
Abd Elhaleem MH, Abd Elmotaleb GS, Abd ELmonaem ER, Ahmed OS. Diagnostic role of transforming growth factor beta level in necrotizing enterocolitis in extremely low birthweight infants. Benha J Appl Sci 2021; 5: 121-4.
20.
Agakidou E, Agakidis C, Gika H, Sarafidis K. Emerging biomarkers for prediction and early diagnosis of necrotizing enterocolitis in the era of metabolomics and proteomics. Front Pediatr 2020; 8: 602255.
21.
Blackwood BP, Wood DR, Yuan CY, et al. Urinary claudin-2 measurements as a predictor of necrotizing enterocolitis: a pilot study. J Neonatal Surg 2015; 4: 43.
22.
Wang K, Tao G, Sun Z, Sylvester KG. Recent potential noninvasive biomarkers in necrotizing enterocolitis. Gastroenterol Res Pract 2019; 2019: 8413698.
23.
Ares G, Buonpane C, Sincavage J, Yuan C, Wood DR, Hunter CJ. Caveolin 1 is associated with upregulated claudin 2 in necrotizing enterocolitis. Sci Rep 2019; 9: 4982.
24.
Griffiths V, Al Assaf N, Khan R. Review of claudin proteins as potential biomarkers for necrotizing enterocolitis. Ir J Med Sci 2021; 190: 1465-72.
25.
Khailova L, Dvorak K, Arganbright KM, Williams CS, Halpern MD, Dvorak B. Changes in hepatic cell junctions structure during experimental necrotizing enterocolitis: effect of EGF treatment. Pediatr Res 2009; 66: 140-4.
26.
Luettig J, Rosenthal R, Barmeyer C, Schulzke JD. Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. Tissue Barriers 2015; 3: e977176.
27.
Itallie CMV, Anderson JM. Caveolin binds independently to claudin-2 and occludin. Ann NY Acad Sci 2012; 1257: 103-7.
28.
Warner BW, Warner BB. Role of epidermal growth factor in the pathogenesis of neonatal necrotizing enterocolitis. Semin Pediatr Surg 2005; 14: 175-80.
29.
Marchiando AM, Shen L, Graham WV, et al. Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo. J Cell Biol 2010; 189: 111-26.
30.
Lueschow SR, Boly TJ, Jasper E, Patel RM, McElroy SJ. A critical evaluation of current definitions of necrotizing enterocolitis. Pediatr Res 2022; 91: 590-7.
31.
Mahendradhata Y, Trisnantoro L, Listyadewi S, Soewondo P, Marthias T. The Republic of Indonesia Health System Review. vol. 7. 2017: Asia Pacific Observatory on Health System and Policies, WHO-SEARO; 2017.
32.
Pammi M, Cope J, Tarr PI, et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome 2017; 5: 31.
33.
Pennington EC, Javid PJ, Sullins V, Mueller C, Hunter CJ. Ethical dilemmas in the management of infants with necrotizing enterocolitis totalis. J Pediatr Surg 2022; 57: 329-34.
34.
Kang H. Sample size determination and power analysis using the G*Power software. J Educ Eval Health Prof 2021; 18: 17.
35.
Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods 2009; 41: 1149-60.
36.
Kurupati P, Chow C, Kumarasinghe G, Poh CL. Rapid detection of Klebsiella pneumoniae from blood culture bottles by real-time PCR. J Clin Microbiol 2004; 42: 1337-40.
37.
Enderle JL, Miller AL, Pyles RB. Quantification of bacterial uropathogens in preclinical samples using real-time PCR assays. Curr Microbiol 2014; 68: 220-6.
38.
Bergmark L, Poulsen PHB, Al-Soud WA, Norman A, Hansen LH, Sørensen SJ. Assessment of the specificity of Burkholderia and Pseudomonas qPCR assays for detection of these genera in soil using 454 pyrosequencing. FEMS Microbiol Lett 2012; 333: 77-84.
39.
Byun R, Nadkarni MA, Chhour KL, Martin FE, Jacques NA, Hunter N. Quantitative analysis of diverse Lactobacillus species present in advanced dental caries. J Clin Microbiol 2004; 42: 3128-36.
40.
Song Y, Liu C, Finegold SM. Real-time PCR quantitation of Clostridia in feces of autistic children. Appl Environ Microbiol 2004; 70: 6459-65.
41.
Converse RR, Blackwood AD, Kirs M, Griffith JF, Noble RT. Rapid QPCR-based assay for fecal Bacteroides spp. as a tool for assessing fecal contamination in recreational waters. Water Res 2009; 43: 4828-37.
42.
Datcu R, Gesink D, Mulvad G, et al. Vaginal microbiome in women from Greenland assessed by microscopy and quantitative PCR. BMC Infect Dis 2013; 13: 480.
43.
Haarman M, Knol J. Quantitative real-time PCR assays to identify and quantify fecal Bifidobacterium species in infants receiving a prebiotic infant formula. Appl Environ Microbiol 2005; 71: 2318-24.
44.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods San Diego Calif 2001; 25: 402-8.
45.
Wagner S, Kronberger G, Beham A, et al. Architecture and design of the HeuristicLab Optimization Environment. In: Advanced Methods and Applications in Computational Intelligence. Klempous R, Nikodem J, Jacak W, Chaczko Z (eds.). Springer International Publishing, Heidelberg 2014; 197-261.
46.
Morrow AL, Lagomarcino AJ, Schibler KR, et al. Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants. Microbiome 2013; 1: 13.
47.
Corebima BIRV, Handono K, Barlianto W, et al. Risk factors of necrotising enterocolitis among 28-34 weeks preterm neonates at a Tertiary Care Hospital, East Java, Indonesia. Med J Malaysia 2023; 78: 458-65.
48.
Stout G, Lambert DK, Baer VL, et al. Necrotizing enterocolitis during the first week of life: a multicentered case-control and cohort comparison study. J Perinatol 2008; 28: 556-60.
49.
Corebima BIRV, Rohsiswatmo R, Gayatri P, Patole S. Fecal human -defensin-2 (hBD-2) levels and gut microbiota patterns in preterm neonates with different feeding patterns. Iran J Microbiol 2019; 11: 151-9.
50.
Li X, Xing M, Zhang Y, Yang M. Therapeutic effect of Lactobacillus reuteri DSM 17938 on feeding intolerance in preterm infants. Arch Med Sci 2023. DOI: https://doi.org/10.5114/aoms/1....
51.
Milani C, Duranti S, Bottacini F, et al. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota. Microbiol Mol Biol Rev 2017; 81: e00036-17.
52.
Abdulkadir B, Aisha AS, Abdulqadir I, et al. Necrotizing enterocolitis associated with dysbiosis of preterm gut microbiome: a review. Bayero J Pure Appl Sci 2018; 11: 195-7.
53.
Magne F, Gotteland M, Gauthier L, et al. The Firmicutes/Bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients 2020; 12: 1474.
54.
Jia Q, Yu X, Chang Y, et al. Dynamic changes of the gut microbiota in preterm infants with different gestational age. Front Microbiol 2022; 13: 923273.
55.
Liu L, Ao D, Cai X, et al. Early gut microbiota in very low and extremely low birth weight preterm infants with feeding intolerance: a prospective case-control study. J Microbiol 2022; 60: 1021-31.
56.
Harris MC, D’Angio CT, Gallagher PR, Kaufman D, Evans J, Kilpatrick L. Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality. J Pediatr 2005; 147: 462-8.
57.
Fox J, Thacker L, Hendricks-Muñoz K. Early detection tool of intestinal dysfunction: impact on necrotizing enterocolitis severity. Am J Perinatol 2015; 32: 927-32.
58.
Khalak R, D’Angio C, Mathew B, et al. Physical examination score predicts need for surgery in neonates with necrotizing enterocolitis. J Perinatol 2018; 38: 1644-50.
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