Using proteomics in perinatal and neonatal sepsis: hopes and challenges for the future

Abstract

PURPOSE OF THE REVIEW: Particularities of the fetal immune response to infection cause a heightened inflammatory state that acts synergistically with microbial insult to induce damage. Proteomics offers the opportunity for detecting fetuses at risk of sepsis and neurological injury. RECENT FINDINGS: Molecular tools (16S-rRNA) demonstrate the diversity of microbial agents of intra-amniotic infection exceeds what is suspected clinically or is documented by cultures. The resulting inflammatory process has the potential to damage the fetus in utero. Stepwise algorithms [mass restricted (MR) score] have been developed to extract proteomic profiles characteristic of amniotic fluid (AF) inflammation. The MR score includes 4 proteomic biomarkers: defensin-2, defensin-1, S100A12 and S100A8 proteins. Other AF biomarkers relevant for preterm birth are S100A9 and insulin-like-growth-factor-binding protein 1 (IGFBP-1). S100A12, ligand for the receptor of advanced glycation end-products (RAGE), has the strongest association with histological chorioamnionitis and funisitis. Presence of S100A12 and S100A8 in AF is predictive of early-onset neonatal sepsis and poor neuro-developmental outcome. SUMMARY: Presence of AF proteomic biomarkers of inflammation is associated with increased inflammatory status of the fetus at birth. Future challenges are finding biomarkers that provide insight into molecular mechanisms of chronic fetal and neonatal cellular damage and identify candidates for early neuro-protection strategies.

“New” Bronchopulmonary Dysplasia

“…13 Given the promising data of using the noninvasive ventilation approach, further refinement of the nasal intermittent positive pressure ventilation technique, 16 perhaps with aerosolized surfactant, 72 has significant potential. Diagnostic approaches for early detection of sepsis, 73,74 and understanding the role of hyperoxia 75 with the hope of modifying the same to ameliorate lung injury, may help decrease the incidence of new BPD. In addition to the prevention of premature birth, identifying the specific components of genetic contribution holds the most promise to significantly impact on decreasing, or even curing, the new BPD.…”

Proteomics/diagnosis of chorioamnionitis and of relationships with the fetal exposome

“…52 One of the working models for infection-induced fetal damage is that some newborns have a genetic propensity to mount an increased state of inflammation in response to infection. Although infection-related preterm births have a disproportionately worse outcome than that attributed to prematurity alone, not all cases have a bad outcome.…”

“…54 This suggests that the decision to intervene is often taken too late in the pathophysiologic process to prevent end-organ damage. 52,54 Many studies have reported significant associations between histological chorioamnionitis/funisitis and early onset sepsis and IVH. 55–58 The major disadvantage of placental histological markers is that they are not available prior to birth or immediately after birth in the short time required to play a role in clinical decision-making.…”

Relationships among the concentrations of 25 inflammation-associated proteins during the first postnatal weeks in the blood of infants born before the 28th week of gestation

“…For example, IGFBP-1 is one of a small group of proteins whose aminiotic fluid concentrations are strongly associated with histological chorioamnionitis and funisitis in humans [41]. In addition, plasma concentrations of IGFBP-1 in animals, also increase during infection [42].…”