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    Original Investigation
    November 8, 2019

    Association of Intestinal Alkaline Phosphatase With Necrotizing Enterocolitis Among Premature Infants

    Author Affiliations
    • 1Department of Pediatrics and Neonatology, Louisiana State University School of Medicine, Children’s Hospital of New Orleans, New Orleans
    • 2Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine and Health Sciences Center, New Orleans
    • 3Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis Children’s Hospital, St Louis, Missouri
    • 4Department of Biostatistics, Louisiana State University School of Public Health, New Orleans
    JAMA Netw Open. 2019;2(11):e1914996. doi:10.1001/jamanetworkopen.2019.14996
    Key Points español 中文 (chinese)

    Question  Unlike candidate biomarkers inclusive for all forms of systemic inflammation, can dysfunction in host management of microbiota have a high positive predictive value as a biomarker for necrotizing enterocolitis?

    Findings  In this diagnostic study of 136 premature infants, high amounts of intestinal alkaline phosphatase protein in stool and low intestinal alkaline phosphatase enzyme activity were associated with diagnosis of necrotizing enterocolitis. There was no association of intestinal alkaline phosphatase measures with non–gastrointestinal tract infections.

    Meaning  Measuring the inability of intestinal alkaline phosphatase to maintain host-microbiota homeostasis can potentially guide decisions for personalized care and treatment when an infant is most susceptible to developing necrotizing enterocolitis.


    Importance  Necrotizing enterocolitis (NEC) in preterm infants is an often-fatal gastrointestinal tract emergency. A robust NEC biomarker that is not confounded by sepsis could improve bedside management, lead to lower morbidity and mortality, and permit patient selection in randomized clinical trials of possible therapeutic approaches.

    Objective  To evaluate whether aberrant intestinal alkaline phosphatase (IAP) biochemistry in infant stool is a molecular biomarker for NEC and not associated with sepsis.

    Design, Setting, and Participants  This multicenter diagnostic study enrolled 136 premature infants (gestational age, <37 weeks) in 2 hospitals in Louisiana and 1 hospital in Missouri. Data were collected and analyzed from May 2015 to November 2018.

    Exposures  Infant stool samples were collected between 24 and 40 or more weeks postconceptual age. Enrolled infants underwent abdominal radiography at physician and hospital site discretion.

    Main Outcomes and Measures  Enzyme activity and relative abundance of IAP were measured using fluorometric detection and immunoassays, respectively. After measurements were performed, biochemical data were evaluated against clinical entries from infants’ hospital stay.

    Results  Of 136 infants, 68 (50.0%) were male infants, median (interquartile range [IQR]) birth weight was 1050 (790-1350) g, and median (IQR) gestational age was 28.4 (26.0-30.9) weeks. A total of 25 infants (18.4%) were diagnosed with severe NEC, 19 (14.0%) were suspected of having NEC, and 92 (66.9%) did not have NEC; 26 patients (19.1%) were diagnosed with late-onset sepsis, and 14 (10.3%) had other non–gastrointestinal tract infections. For severe NEC, suspected NEC, and no NEC samples, median (IQR) fecal IAP content, relative to the amount of IAP in human small intestinal lysate, was 99.0% (51.0%-187.8%) (95% CI, 54.0%-163.0%), 123.0% (31.0%-224.0%) (95% CI, 31.0%-224.0%), and 4.8% (2.4%-9.8%) (95% CI, 3.4%-5.9%), respectively. For severe NEC, suspected NEC, and no NEC samples, median (IQR) enzyme activity was 183 (56-507) μmol/min/g (95% CI, 63-478 μmol/min/g) of stool protein, 355 (172-608) μmol/min/g (95% CI, 172-608 μmol/min/g) of stool protein, and 613 (210-1465) μmol/min/g (95% CI, 386-723 μmol/min/g) of stool protein, respectively. Mean (SE) area under the receiver operating characteristic curve values for IAP content measurements were 0.97 (0.02) (95% CI, 0.93-1.00; P < .001) at time of severe NEC, 0.97 (0.02) (95% CI, 0.93-1.00; P < .001) at time of suspected NEC, 0.52 (0.07) (95% CI, 0.38-0.66; P = .75) at time of sepsis, and 0.58 (0.08) (95% CI, 0.42-0.75; P = .06) at time of other non–gastrointestinal tract infections. Mean (SE) area under the receiver operating characteristic curve values for IAP activity were 0.76 (0.06) (95% CI, 0.64-0.86; P < .001), 0.62 (0.07) (95% CI, 0.48-0.77; P = .13), 0.52 (0.07) (95% CI, 0.39-0.67; P = .68), and 0.57 (0.08) (95% CI, 0.39-0.69; P = .66), respectively.

    Conclusions and Relevance  In this diagnostic study, high amounts of IAP protein in stool and low IAP enzyme activity were associated with diagnosis of NEC and may serve as useful biomarkers for NEC. Our findings indicated that IAP biochemistry was uniquely able to distinguish NEC from sepsis.