Host-response biomarkers for diagnosis of late-onset septicemia and necrotizing enterocolitis in preterm infants

Abstract

Preterm infants are highly susceptible to life-threatening infections that are clinically difficult to detect, such as late-onset septicemia and necrotizing enterocolitis (NEC). Here, we used a proteomic approach to identify biomarkers for diagnosis of these devastating conditions. In a case-control study comprising 77 sepsis/NEC and 77 nonsepsis cases (10 in each group being monitored longitudinally), plasma samples collected at clinical presentation were assessed in the biomarker discovery and independent validation phases. We validated the discovered biomarkers in a prospective cohort study with 104 consecutively suspected sepsis/NEC episodes. Proapolipoprotein CII (Pro-apoC2) and a des-arginine variant of serum amyloid A (SAA) were identified as the most promising biomarkers. The ApoSAA score computed from plasma apoC2 and SAA concentrations was effective in identifying sepsis/NEC cases in the case-control and cohort studies. Stratification of infants into different risk categories by the ApoSAA score enabled neonatologists to withhold treatment in 45% and enact early stoppage of antibiotics in 16% of nonsepsis infants. The negative predictive value of this antibiotic policy was 100%. The ApoSAA score could potentially allow early and accurate diagnosis of sepsis/NEC. Upon confirmation by further multicenter trials, the score would facilitate rational prescription of antibiotics and target infants who require urgent treatment.

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

“…However, unbiased exploratory "omic" approaches such as genome-wide expression profiling have the potential to reveal proteins, genes and pathways that have diagnostic, treatment and prognostic implications that were previously unknown and or unsuspected (36,37). Expression measurement of the entire genome would not be required once a suitable set of predictive genes (<100) is identified.…”

Elevated levels of circulating cell-free DNA and neutrophil proteins are associated with neonatal sepsis and necrotizing enterocolitis in immature mice, pigs and infants

“…1,2 The incidence of LOS and NEC in very low birth weight infants (VLBW; < 1500 g) are approximately 21% and 7%, respectively, and the etiology and pathogenesis of these diseases are still incompletely understood. 3,4 Many diagnostic biomarkers for LOS and NEC have been suggested but most of them lack adequate sensitivity and precision.…”

“…2 Similarly, early NEC diagnosis is difficult (e.g. according to Bell scores) and advanced NEC conditions requiring surgery is associated with high mortality.…”

Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors

“…During endotoxemia, circulating SAA levels are significantly elevated (up to 1,000-fold) within 16-24 h as a result of de novo expression of early cytokine inducers and subse-quent synthesis and secretion of SAAs (12,13). Clinically, SAAs have been implicated as biomarkers in cardiovascular disorders (14), ulcerative colitis (15) and sepsis (16). Extracellular SAA signals via a family of receptors including the receptor for advanced glycation end products (RAGE) (17), TLR2 (18,19) and TLR4 (20) to activate NLRP3 inflammasome (21) and to induce various cytokines and chemokines (22)(23)(24)(25).…”