Downloaded from http://journals.lww.com/pidj by BhDMf5ePHKbH4TTImqenVPWx2hcEpdL/D6N0g932qMGpKFzZDAnLb0xNs03xkC8p on 07/25/2020 Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 39, Number 8, August 2020 www.pidj.com | 749 Accepted for publication March 15, 2020. From the *Neonatal Unit, First Department of Pediatrics, School of Medicine, National & Kapodistrian University of Athens and †Department of Clinical Biochemistry, “Agia Sofia” Children’s Hospital, Athens, Greece. Funding was received from National and Kapodistrian University of Athens, Greece. The funding organization played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report or in the decision to submit the report for publication. The authors have no conflicts of interest to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Address for correspondence: Tania Siahanidou, MD, PhD, Neonatal Unit, First Department of Pediatrics, School of Medicine, National & Kapodistrian Uni- versity of Athens, “Agia Sofia” Children’s Hospital, Athens 11527, Greece. E-mail: siahan@med.uoa.gr. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. MATERNAL-NEONATAL REPORTS Background: To evaluate the performance of serum amyloid-A (SAA), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo- A1) levels in the identification and monitoring of neonatal sepsis. Methods: This prospective study included 113 full-term septic neonates (postnatal age 4–28 days) admitted to the Special Care Neonatal Unit of a University Hospital from January 1, 2016, to April 30, 2019, and 68 healthy neonates (controls). Blood samples were drawn serially in septic neonates at enrollment and on days 1, 3 and 7, and once in controls, for SAA, HDL-C and Apo-A1 determination. Results: At enrollment, SAA levels were significantly higher in septic neo- nates in comparison with controls (median 50.7 vs. 3.5 mg/L; P < 0.0001); HDL-C and Apo-A1 levels were significantly lower in patients than in con- trols (P < 0.001 and P < 0.006, respectively). SAA levels were higher in culture-positive compared with culture-negative sepsis (median 202.0 vs. 14.2 mg/L; P < 0.0001). HDL-C and Apo-A1 levels did not differ signifi- cantly between culture-positive and culture-negative sepsis. Receiver oper- ating characteristic curve analysis of SAA levels at enrollment resulted in significant areas under the curve (AUC) for detecting sepsis {AUC = 0.929 [95% confidence interval: 0.885–0.973]; P < 0.0001} and also for discrimi- nating between culture-positive and culture-negative sepsis [AUC = 0.933 (95% confidence interval: 0.882–0.984); P < 0.0001]. The combination of HDL-C and Apo-A1 with SAA increased its diagnostic performance. Fur- thermore, serial SAA levels following enrollment could indicate clinical response in septic neonates. Conclusions: SAA seems to be a useful biomarker for identification and monitoring of neonatal sepsis, and also for discriminating between culture- positive and culture-negative sepsis. HDL-C and Apo-A1 could be used as complementary markers. Key Words: neonatal sepsis, biomarkers, lipids, SAA, neonates (Pediatr Infect Dis J 2020;39:749–755) S epsis is a major cause of morbidity and mortality in neonates 1 and may also have severe long-term consequences, 2 including adverse neurodevelopmental outcomes 2,3 and possibly increased risk for the later development of asthma and allergy. 4 Interestingly, in experimental animals, even a single episode of neonatal infection possesses a programming effect on later neuroimmune function. 5 Early diagnosis of neonatal sepsis is of great importance; however, it may be challenging as blood culture is time-consuming and of questionable accuracy, whereas no ideal diagnostic laboratory bio- marker exists yet. 6 Identification of new or complementary bio- markers, as early, sensitive and specific diagnostic tools, would be valuable to guide prompt initiation of antibiotics, but also to avoid unnecessary treatment of noninfectious cases. 7,8 Serum amyloid-A protein (SAA), a phylogenetically highly conserved protein synthesized predominantly by the liver in response to proinflammatory cytokines, has been proven as an acute phase reactant with its blood concentrations increasing up to 1000-fold, or more, following appropriate stimuli. 9,10 In the circulation, SAA asso- ciates with high-density lipoprotein cholesterol (HDL-C) during the acute phase response and becomes its main apolipoprotein (Apo) by displacing Apo-A1. 11–13 Circulating HDL-C particles containing SAA have a greatly reduced half-life as SAA on HDL-C is cleared more rapidly than other HDL-C Apos. 10,11,14 In septic adults, SAA has been recognized as a specific and accurate biomarker, 15–17 whereas promi- nent decreases in serum HDL-C and Apo-A1 levels at the acute phase of sepsis have also been reported. 14,18–21 The role of SAA protein as a diagnostic or follow-up marker of neonatal sepsis has not been clarified yet, as relevant studies have shown contradictory results. 22–24 In a published meta-analysis, SAA showed moderate accuracy, which was better than that of C-reactive protein (CRP), in the diagnosis of neonatal sepsis. 25 However, the number of studies included in the meta-analysis was rather small and there was also significant heterogeneity among studies. Thus, it was proposed that further investigation of the diagnostic accuracy of SAA in neonatal sepsis and correlation with other biomarkers is required. 25,26 As regards, the properties of HDL-C and Apo-A1 as biomarkers in neonatal sepsis, there is limited knowledge as only 1 small study has been published so far. 27 To the best of our knowl- edge, no previous study has compared the diagnostic accuracy of SAA with that of HDL-C or Apo-A1 in septic neonates. The aim of this study was to evaluate the value of SAA pro- tein, as well as that of HDL-C and Apo-A1 serum levels, in the diagnosis and monitoring of neonatal sepsis. MATERIALS AND METHODS Subjects and Study Protocol This prospective study was carried out in the Special Care (Level II) Neonatal Unit of the First Department of Pediatrics of National and Kapodistrian University of Athens; the enrollment period was continuous and lasted from January 2016 to April 2019. The study population comprised 181 term neonates. Of them, 113 neonates [mean ± standard deviation (SD) gestational age 38.8 ± 1.4 weeks; birthweight 3219.1 ± 463.5 g; male/female 80/33] were enrolled at 17.0 ± 6.6 days of life due to clinical signs and symptoms of sep- sis. 28 Sepsis was defined according to the criteria established by the ISSN: 0891-3668/20/3908-0749 DOI: 10.1097/INF.0000000000002682 Clinical Value of Serum Amyloid-A Protein, High-density Lipoprotein Cholesterol and Apolipoprotein-A1 in the Diagnosis and Follow-up of Neonatal Sepsis Vasiliki Bourika, MSc, MD,* Eugenia Hantzi, MSc,† Athanasios Michos, PhD, MD,* Alexandra Margeli, PhD,† Ioannis Papassotiriou, PhD,† and Tania Siahanidou, PhD, MD*