Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants

Abstract

Background: The goal was to identify cytokines associated with necrotizing enterocolitis (NEC). Based on our earlier reports of decreased tissue expression of transforming growth factor (TGF)-β, we hypothesized that infants with NEC also have low blood TGF-β levels. We further hypothesized that because fetal inflammation increases the risk of NEC, infants who develop NEC have elevated blood cytokine levels in early neonatal period.

Methods: Data on 104 extremely-low-birth-weight infants with NEC and 893 without NEC from 17 centers were analyzed. Clinical information was correlated with blood cytokine levels on postnatal day 1 (D1), D3, D7, D14, and D21.

Results: Male gender, non-Caucasian/non-African American ethnicity, sepsis, lower blood TGF-β and interleukin (IL)-2 levels, and higher IL-8 levels were associated with NEC. The NEC group had lower TGF-β levels than controls since D1. The diagnosis of NEC was associated with elevated IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand-2, macrophage inflammatory protein-1β/CC-motif ligand-3, and C-reactive protein.

Conclusion: Clinical characteristics, such as gender and ethnicity, and low blood TGF-β levels are associated with higher risk of NEC. Infants who developed NEC did not start with high blood levels of inflammatory cytokines, but these rose mainly after the onset of NEC.

Figure 1

Differential expression of cytokines in blood spots from infants in the NEC (drawn before the onset of NEC; broken lines) and control groups (solid lines). Line diagrams depict median cytokine values on day 1 (D1), D3, D7, D14, and D21, not adjusted for other cytokines or clinical variables: (A) TGF-β₁, (B) IL-1β, (C) IL-2, (D) IL-4, (E) IL-5, (F) IL-6, (G) IL-10, (H) IL-12, (I) IL-17, (J) IL-18, (K) TNF, (L) LT-α, (M) IFN-γ, (N) GM-CSF, (O) MCP-1/CCL2, (P) MIP-1α/CCL3, (Q) MIP-1β/CCL4, (R) RANTES/CCL5, (S) IL-8/CXCL8, (T) NT-4, (U) MMP-9, (V) sIL-6R, (W) TREM-1, (X) BDNF, (Y) CRP. * indicates p<0.05

Figure 2

Receiver-operator characteristics (ROC) of TGF-β in blood spots from infants in the NEC (drawn before the onset of NEC) and control groups. Red markers on the curve indicate TGF-β concentrations. A cut-off TGF-β level of 1380 pg/mL (marked by broken lines in the figure) correctly classified 61.2% infants in the NEC group (true positives) but gave a false-positive result in 35.7% controls.