Research Article: Is European Medicines Agency (EMA) sepsis criteria accurate for neonatal sepsis diagnosis or do we need new criteria?

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Funda Tuzun, Hasan Ozkan, Merih Cetinkaya, Ebru Yucesoy, Ozge Kurum, Burcu Cebeci, Ertan Cakmak, Aydan Ozkutuk, Pembe Keskinoglu, Bora Baysal, Abdullah Kumral, Nuray Duman, Girish Chandra Bhatt.


Currently, there is a lack of clear definition for neonatal sepsis. The Pediatric Committee of the European Medicines Agency (EMA) developed consensus criteria to ensure a standardization for neonatal sepsis definition. However, there is no evidence supporting the accuracy of the EMA sepsis criteria in neonatal sepsis diagnosis. The main objective of this study was to evaluate the diagnostic accuracy of EMA sepsis criteria for proven neonatal sepsis.

A multicenter prospective cohort study was conducted from October 2015 to November 2018. Infants with a gestational age over 34th weeks, diagnosed with clinical sepsis and received antibiotics according to the EMA criteria or experienced neonatologists’ opinion were included. Blood culture or multiplex real time-PCR or 16S-rRNA positive infants were accepted as “proven sepsis”. The predictive performance of EMA criteria for proven sepsis was evaluated by sensitivity, specificity, accuracy, and area under the curve measures of receiver operator characteristic curves. Data-mining methods were used for further analysis.

Among the 245 included infants, the EMA criteria were positive in 97 infants (39.6%), while proven sepsis was diagnosed in 113 infants (46.1%). The sensitivity, specificity, and accuracy of the EMA criteria for proven sepsis were 44.2% (95%CI: 34.9–53.9), 64.4% (95%CI: 55.6–72.5), 55.1% (95%CI: 46.6–59.4) respectively. None of the clinical and laboratory parameters had sufficient performance individually in terms of sensitivity, specificity and accuracy measures. The diagnostic performance was similar when different clinical findings were added to the EMA sepsis criteria or assessment of the score was interpreted in different ways.

Results highlighted that clinician opinion and standard laboratory tests are limited in the neonatal sepsis diagnosis. The EMA criteria also did not efficiently meet the diagnostic accuracy measures for neonatal sepsis. A predictive sepsis definition and rapid bedside point-of care tests are urgently needed.

Partial Text

Neonatal sepsis remains a leading cause of mortality and morbidity although considerable advances have been made in the area of neonatology. Early diagnosis of sepsis is challenging because of the absence of specific symptoms and suboptimal diagnostic value of laboratory tests, which leads to a very low clinical suspicion index and high rates of empiric antimicrobial treatment [1, 2]. An accepted definition of sepsis in neonates is lacking, and a consensus definition for neonatal sepsis is urgently needed. In 2005, the International Pediatric Sepsis Consensus Conference defined sepsis as SIRS in presence of suspicious or definite infection in infants aged above 37 weeks. However, the diagnostic accuracy of certain parameters included in the criteria of SIRS such as white blood cell count and body temperature are insufficient in neonates [3].

During the three years study period, a total of 245 babies fully met the study criteria (Fig 1). The basic demographic and clinical data of the study group are shown in Table 1.

Results of the present study revealed that EMA sepsis criteria did not efficiently meet the diagnostic accuracy measures for proven neonatal sepsis. The diagnostic performance was far below the ideal levels, when different clinical findings were added to the EMA sepsis criteria or assessment of the score was interpreted in different ways. These data emphasize the restricted accuracy of initial clinician opinion and standard laboratory tests to detect bacterial infection, especially for EONS. Results highly support the invitation of Wynn and Polin for an urgent consensus for the diagnosis and definition of neonatal sepsis [14, 15].

Neonatal sepsis is a dynamic, complex and heterogeneous physio-pathological process. The clinical findings are ambiguous and diagnostic performance of current inflammatory biomarkers show inconsistency depending on the process. Therefore, critical problems arise in the prompt and accurate diagnosis of neonatal sepsis with use of static definitions and assessments. Hopefully in the near future, an integration of clinical signs, laboratory and sophisticated molecular tests including multi-omics technologies and microarray chips will enable for timely and accurate diagnosis of neonatal sepsis.