Blood Level of Inter-Alpha Inhibitor Proteins Distinguishes Necrotizing Enterocolitis From Spontaneous Intestinal Perforation

Abstract

Objective To examine circulating levels of inter-alpha inhibitor protein (IaIp) in infants with necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP) and matched controls in order to assess the diagnostic accuracy of IaIp to differentiate NEC from SIP; and to compare receiver operating characteristics (ROC) of IaIp for NEC with C-reactive protein (CRP). Study design A p rospective, nested case control study of infants with feeding intolerance was carried out. Blood and clinical data were collected from 27 infants diagnosed with NEC or SIP and from 26 matched controls admitted to our unit. Infants with modified Bell's criteria stage 2 or higher were included as NEC. Clinical, radiological and/or surgical findings were used to identify infants with SIP. Controls were matched for gestational age, postnatal age, sex, and birth weight. Results Mean±SD IaIp blood levels were 147±38 mg/L, 276±67 mg/L and 330±100 mg/L in infants with NEC, SIP and matched controls, respectively (P<0.004 and P<0.01). ROC analysis to establish the predictive value of NEC demonstrated areas under curve of 0.98 and 0.63 for IaIp and CRP, respectively. Conclusions IaIp levels were significantly decreased in infants with NEC compared with SIP and matched controls. The diagnostic accuracy of IaIp for NEC was superior to that of CRP.

The Microbiome and Biomarkers for Necrotizing Enterocolitis: Are We Any Closer to Prediction?

“…Ng, et al, used genomics to differentiate the two entities, reporting both differentially expressed mRNA as well as micro-RNAs in the small bowel tissue of NEC and SIP compared with surgical control tissue (79, 80). Shah et al used a more clinically applicable serum biomarker to distinguish NEC from SIP, called inter-alpha inhibitor proteins (IaIps) (81). IaIps are serine protease inhibitors that act as negative acute phase reactants, consumed as they protect from damaging proteases that are released into circulation during acute inflammation (81).…”

“…Shah et al used a more clinically applicable serum biomarker to distinguish NEC from SIP, called inter-alpha inhibitor proteins (IaIps) (81). IaIps are serine protease inhibitors that act as negative acute phase reactants, consumed as they protect from damaging proteases that are released into circulation during acute inflammation (81). An earlier study reported that IaIp concentrations were significantly decreased in infants with NEC compared with controls at the time of disease diagnosis (82).…”

“…ROC analysis for NEC yielded an AUC of 0.98 (p<0.0001, 95% CI 0.84–0.99). However, in the week prior to disease onset, blood concentrations did not differ significantly between groups (81). This raises the possibility that there is only a very short interval between organ injury and clinical NEC, such that there would be a low likelihood of a very early in life biomarker.…”

Ontogeny of inter‐alpha inhibitor protein (IAIP) expression in human brain

“…Recent studies have also reported changes in the level of IAIPs after stroke (Kashyap et al, 2009) and Alzheimer's disease (Shi et al, 2019), suggesting that endogenous IAIPs may be integrally related to the pathogenesis of inflammatory-related brain disorders. In addition, systemic levels of IAIPs have been reported to be decreased in sepsis in neonates and adults (Chaaban et al, 2009;Degraeuwe & Nieman, 2010;Opal et al, 2007) and in necrotizing enterocolitis in neonates (Chaaban et al, 2010;Shah et al, 2017). Sepsis and necrotizing enterocolitis are both associated with impaired neurodevelopmental outcomes in premature infants (O'Shea, 2002;Stoll et al, 2004).…”

Necrotizing enterocolitis

“…Various specific proteins, including cytokines, measured in blood, urine, and stool, have been evaluated, but most have poor specificity for making an accurate diagnosis . However, blood inter‐alpha inhibitor proteins are able to distinguish NEC from SIP and NEC from matched controls with feeding intolerance . Another potentially useful biomarker may be intestinal fatty acid‐binding protein (I‐FABP) which displays high specificity, albeit moderate sensitivity .…”