Cardiac and Inflammatory Necrotizing Enterocolitis in Newborns Are Not the Same Entity

Abstract

Background: Necrotizing enterocolitis (NEC) is an often-fatal neonatal disease involving intestinal hyperinflammation leading to necrosis. Despite ongoing research, (1) conflicting results and (2) comorbidities of NEC patients make early NEC detection challenging and may complicate therapy development. Most research suggests that NEC pathogenesis is multifactorial, involving a combination of (1) gut prematurity; (2) abnormal bacterial colonization; and (3) ischemia-reperfusion (I/R) injury. As neutrophil extracellular traps (NETs) partially mediate I/R injury and drive inflammation in NEC, we hypothesized that NETs contribute to NEC development; particularly in cardiac patients.Methods: A retrospective analysis of baseline characteristics, clinical signs, laboratory parameters, and imaging was conducted for surgically verified NEC cases over 10 years. Patients were stratified into two groups: (1) prior medically or surgically treated cardiac disease (cardiac NEC) and (2) no cardiac comorbidities (inflammatory NEC). Additionally, histology was reassessed for neutrophil activation and NETs formation.Results: A total of 110 patients (cNEC 43/110 vs. iNEC 67/110) were included in the study, with cNEC neonates being significantly older than iNEC neonates (p = 0.005). While no significant differences were found regarding clinical signs and imaging, laboratory parameters revealed that cNEC patients have significantly increased leucocyte (p = 0.024) and neutrophil (p < 0.001) counts. Both groups also differed in pH value (p = 0.011). Regarding histology: a non-significant increase in staining of myeloperoxidase within the cNEC group could be found in comparison to iNEC samples. Neutrophil elastase (p = 0.012) and citrullinated histone H3 stained (p = 0.041) slides showed a significant markup for neonates diagnosed with cNEC in comparison to neonates with iNEC.Conclusion: The study shows that many standardized methods for diagnosing NEC are rather unspecific. However, differing leucocyte and neutrophil concentrations for iNEC and cNEC may indicate a different pathogenesis and may aid in diagnosis. As we propose that iNEC is grounded rather in sepsis and neutropenia, while cNEC primarily involves I/R injuries, which involves neutrophilia and NETs formation, it is plausible that I/R injury due to interventions for cardiac comorbidities results in pronounced neutrophil activation followed by a hyperinflammation reaction and NEC. However, prospective studies are necessary to validate these findings and to determine the accuracy of the potential diagnostic parameters.

Clinical Characteristics and Potential Pathogenesis of Cardiac Necrotizing Enterocolitis in Neonates with Congenital Heart Disease: A Narrative Review

“…Cardiac NEC most frequently involves the colon and distal ileum due to the susceptibility to superior and inferior MA blood supply interruptions in these regions [ 36 ], often referred to as ‘watershed zones’ [ 35 ]. Mechanistically, mesenteric hypoperfusion initiates endothelial inflammation and increases vascular permeability and neutrophil, leukocyte, and platelet accumulation and activation due to endothelial production of adhesion molecules [ 37 ]. Cytokine release by endothelial cells exacerbates the inflammatory response, which spreads throughout the submucosa to the mucosa, increasing intestinal epithelial permeability [ 38 ].…”

The emerging role of neutrophilic extracellular traps in intestinal disease

“…IBD is a chronic intestinal inflammatory disease that involves innate and acquired immune responses, mainly ulcerative colitis (UC) and Crohn's disease (CD), with a multifactorial pathogenesis involving genetic susceptibility, epithelial barrier defects, dysregulated immune response, and environmental factors [ 107 , 108 ]. As a potential disease mechanism, NETs play an important role in a variety of immune-mediated diseases, including IBD, systemic lupus erythematosus, rheumatoid arthritis and so on [ 109 – 111 ].…”

Stem cell therapy as a promising strategy in necrotizing enterocolitis

“…AF-MSCs secrete growth factors, which activate COX-2 either directly or indirectly by promoting the activation of epidermal growth factor receptors, thereby suppressing gut oxidation, facilitating villus cells proliferation, and reducing apoptosis (Zani et al 2014a ). Moreover, AF-MSC-mediated activation of COX-2 results in the secretion of tumor necrosis factor-induced protein 6, which can migrate to injured ileum tissue and attenuate intestinal ischemia/reperfusion injury, thereby blocking the onset of NEC (Koike et al 2020 ; Klinke et al 2020 ).…”