Neonatal sepsis remains an important cause of morbidity and mortality in neonates. In this prospective, multisite observational study, proteomics and extracellular particle analysis were performed on platelet-poor plasma from neonates at the point of clinical suspicion for sepsis ( n = 110). Neonates were then classified by their clinical teams into three groups: culture-proven sepsis, culture-negative sepsis, or non-sepsis. Neonates with culture-proven sepsis demonstrated statistically significant differences in their analyzed proteome compared to neonates deemed to have non-sepsis, while those with culture-negative sepsis did not. Extracellular particle concentration and type, as determined by flow cytometry, did not differ between the three groups. This study provides further evidence that culture-proven sepsis and culture-negative sepsis are not equivalent diagnoses in the neonatal population without a consensus definition for sepsis. The proteins identified in the culture-positive group may be of utility in determining neonatal sepsis endotypes, but this would require further validation.
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