Testing for Neonatal Sepsis: The Next Generation of Biomarkers

newbornNeonatal sepsis is a systemic infection prevalent in preterm and very low birth weight infants and causes high morbidity. Most cases of neonatal sepsis are caused by pathogenic bacteria that invade the bloodstream, triggering an abrupt and overwhelming infection in the target organs accompanied by a systemic inflammatory response. Testing for neonatal sepsis is challenging because it does not affect a specific organ and presents multiple symptoms that are often confused with other related conditions (1). Current diagnostic tests for sepsis include those that identify markers of the host response to infection (e.g., procalcitonin, C reactive protein, cytokines, etc.) and those that detect bacterial infection in blood (bacteremia) (2). The lack of specific diagnostic biomarkers for early and accurate detection of neonatal sepsis has spurred the quest for next-generation biomarkers using powerful mass screening technologies such as proteomics.

Proteomic profiling technologies have aided in the discovery of novel biomarkers of neonatal sepsis. Buhimschi et al. (3), have used SELDI-TOF (Surface Enhanced Laser Desorption/Ionization-Time of Flight) mass spectrometry to identify a proteomic fingerprint specific to intra-amniotic inflammation in pregnant women, which is a combination of four biomarkers: neutrophil defensin 1, neutrophil defensin 2, S100A12 and S100A8. A cohort of 104 pregnant women underwent testing of the amniotic fluid and were assigned a “mass restricted score” ranging from 0 to 4 based on the number of markers detected over the background. Neonates of mothers with higher scores (3 or greater) had increased incidence of early-onset neonatal sepsis as compared to those with lower scores (less than 3). Further, the presence of S100A8 in the amniotic fluid proteome had the strongest association with the development of neonatal sepsis.

In another study, Ng et al. (4), employed MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization-Time of Flight)-based proteomics to identify two promising biomarkers for the early diagnosis of neonatal sepsis, namely, proapolipoprotein CII (Pro-apoC2) and the des-arginine variant of serum amyloid A (SAA). A combination of the two markers (“ApoSAA score”) was independently validated for its utility in deciding to limit or completely stop antibiotic treatment in true-negative sepsis cases with a negative predictive value of 100%.

Although blood culture has remained the gold standard for detecting sepsis in neonates, false negatives are a common occurrence in instances where the bacterial density is below the detection limit or the patient may have received antibiotic treatment prior to the blood culture. Recent studies have employed mass spectrometry techniques to identify bacteria in blood cultures with a positive identification value >99%.5 By reducing the amount of time required to identify the pathogenic species, mass spectrometry-based testing can facilitate timely and specific administration of antibiotic therapy.

The advent of new molecular tests and sophisticated technology have improved the chances of newborn survival by providing early and accurate diagnosis of sepsis, tailored therapeutics and shorter hospitalization. Continued efforts in the discovery and validation of biomarkers and refinement of proteomic technologies hold a promise for the early diagnosis and treatment of neonatal sepsis in the near future.

References

  1. Mussap, M. (2012) Laboratory medicine in neonatal sepsis and inflammation. J. of Matern. Fetal Neonatal Med. 25,32–34.
  2. Srinivasan, L. and Harris M.C. (2012) New technologies for the rapid diagnosis of neonatal sepsis. Curr. Opin. in Pediatr. 24, 165–171.
  3. Buhimschi, C.S. et al. (2007) Proteomic profiling of the amniotic fluid to detect inflammation, infection and neonatal sepsis. PLoS Med. 4, e18.
  4. Ng, P.C. et al. (2010) Host-response biomarkers for diagnosis of late-onset septicemia and necrotizing enterocolitis in preterm infants. J. Clin. Invest. 120, 2989-3000)
  5. La Scola, B. and Raoult, D. (2009) Direct identification of bacteria in positive blood culture bottles by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. PLOS One 4, e8041)
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Radhika Ganeshan

Technical Services Scientist at Promega Corporation

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