Mapping the New World of Necrotizing Enterocolitis (NEC): Review and Opinion

Abstract

A comprehensive review of necrotizing enterocolitis (NEC) is provided; including history, biological basis and frequently asked questions. In addition, a system of improved NEC classification is explained in detail (consisting of five NEC subsets and four NEC-like diseases), to aid the bedside clinician in therapy and prevention. The authors offer opinion for therapeutics in italics at the end of each definition.

Keywords: classification; necrotizing enterocolitis; neonate; premature infant.

Figure 1

Summation / consolidation of data about SIP and NEC, including time of presentation, percent mortality and incidence of disease stratified by gestational age. A: SIP, the left-sided y-axis equals day of onset indicated by point at the sphere centers. The sphere diameters indicate the percentage of the population of SIP who presented on that day of life (presented as estimated means based on multiple studies). The spheres are arrayed along the x-axis in the underlying graph to show the approximated gestational distribution. The percent mortality stratified by gestational age is indicated by the bars with the values indicated on the right-sided y-axis. B: NEC, left-sided y-axis equals day of onset indicated by the sphere centers. The sphere diameters indicate the percent of the population of NEC that presented on that day of life (mean for the gestational age group), and correlate with the x-axis below. The gray columns indicate the percent mortality (right side y-axis). On average, NEC can be seen to occur later in life at all gestational ages than SIP. NEC also has a higher mortality when compared across gestational strata. It is apparent in this comparison of SIP and NEC, that the timing of presentation, incidence and trends in mortality are different across gestational strata. Data for the extrapolations these figures are based upon are summarized data from references –. In cases where precise data was unavailable in the units needed (example, if the data was available by birth weight instead of gestational age), the data was extrapolated using the assumption that the population as a whole was appropriate for gestational age and the datasets were representative of the same disease entity. For example, in the case where pooled averages of two birth weight groups were the only data available for timing and incidence from a national dataset, gestational spread of a single center report was used to re-apportion the values into the gestational distribution shown (SIP). Likewise, two single center reports were used to overlay the timing of NEC onset onto the national dataset of incidence and mortality.

Figure 2

Schematic illustrating proposed differences in NEC risk between preterm and term intestine at the cellular level of the mucosa. At the top of the schematic, risk modifiers and their resultant effectors are shown in boxes. Immediately above the mucosa, bacteria are shown in appropriate abundance and in relation to the boxed narrative above and the corrected gestation time line below (indicated by the numbers in the intestinal epithelial cells). Innate immune system effectors of cellular apoptosis / necrosis can be seen at or after 32 weeks corrected gestation, consistent with Sartwell’s model of incubation. In the term intestine, adaptive immune constituents abrogate NEC risk via active modulation of lumenal flora and down regulation of the innate immune system. Abbreviations / legend: TLR4 (toll like receptor-4 – principle mediator of enterocyte apoptosis in NEC genesis), fMLP (a bacterial metabolite that acts as a chemoattractant for eosinophils), T reg cells (T regulatory cells), PAF (platelet activating factor), LPS (lipopolysacharide – bacterial metabolite that activates TLR4, pRBC (packed red blood cells).

Figure 3

Schematic of NEC subset ontogeny. Five NEC subsets are shown. At the top of the chart, clinical risk factors and pathways of ontogeny are described. Within the intestinal epithelial cell layers, most common time windows of presentation and mucosal health are characterized. In the bottom portion of the schematic, characteristic findings at presentation on the CBC and the intrinsic vascular tone within the lamina propria of the villi are characterized. Each subset has a novel ontogeny in comparison to the others. NEC after delayed feeds may ultimately be found to be a subcomponent of the other subsets (particularly transfusion and lymphocytosis associated NEC subsets), since rigorous investigation of potential triggers at the time of presentation have not been reported. Term NEC can also rightly be called “ischemia-triggered NEC” and can rarely occur in preterm / late preterm infants when the described precedent conditions are fulfilled. EGP = eosinophil granule protein.