Late-Onset Neonatal Sepsis: A Case-Control Study (Sepsis)

Evaluation of Traditional Biomarkers and Novel Inflammatory Indices in the Diagnosis of Late-Onset Neonatal Sepsis: A Case-Control Study

The diagnosis of late-onset sepsis in term neonates has been studied less than that of early-onset sepsis. Procalcitonin (PCT) and C-reactive protein (CRP) are commonly used biomarkers in the diagnosis of sepsis. However, their diagnostic advantage for late-onset sepsis (GNS) is debatable. Rapid and accurate diagnosis of late-onset infection in newborn infants remains a significant goal in clinical practice worldwide. Therefore, the accuracy of diagnostic tests needs to be improved. This study aimed to evaluate the effectiveness of serum biomarkers in the diagnosis and treatment monitoring of late neonatal sepsis (LOS) in term neonates.

Study Overview

• Status: Completed
• Conditions: Late Onset Neonatal Sepsis; Inflammation Indices
• Intervention / Treatment: Diagnostic test: serum biomarker

Detailed Description

Early diagnosis and detection of LOS are challenging due to its often nonspecific symptoms and the limited diagnostic efficacy of commonly used biomarkers. Therefore, a combined evaluation of clinical and laboratory findings is necessary. While initial assessment often includes nonspecific tests such as complete blood count and inflammatory markers, the most important test is a blood culture of at least 1 mL of blood before antibiotic administration.Although acute phase reactants such as C-reactive protein (CRP), procalcitonin (PCT), and various interleukins are used to support the diagnosis of sepsis in newborns, they are also elevated by other non-infectious inflammatory causes (fetal hypoxia, birth stress, RDS, MAS, IVH, surgery, and pneumothorax). Serum CRP could be a useful biomarker for LOS in newborn infants if it can be demonstrated to have acceptable levels of accuracy. Currently, the role of serum CRP in diagnostic algorithms for late-onset infection is largely varied in the absence of robust evidence to inform the development of guidelines or protocols. Further studies have shown that the immature/total neutrophil ratio and absolute neutrophil values are poor predictors of LOS. Due to age-specific, gestational age-dependent, and neonatal physiological changes in the early postpartum period, there is no consensus on the threshold value of serum PCT levels in bacterial infection.Common laboratory markers of infection, such as white blood cell count (WBC), immature neutrophil/total neutrophil ratio (IT ratio), hematological tests (thrombocytopenia), and acute phase reactants (CRP, PCT), do not have sufficient specificity and sensitivity to detect all infected newborns.Literature analysis has shown that, despite extensive research, the diagnosis and antibiotic treatment of neonatal sepsis cannot currently be determined based on a single biomarker. However, instead of searching for new biomarkers, testing combinations of two or more of the currently available biomarkers seems easier and more productive. The literature has focused primarily on the diagnosis of LOS in preterm neonates. Our current study differs from previous studies in that it evaluates the systemic inflammation aggregate index (SIAI) and systemic inflammation index (SII) values serially, in addition to classical biomarkers. Our aim is to identify a practical combination of commonly used laboratory tests that can evaluate the diagnosis and monitoring of term LOS when suspected.

• Study Type: Observational
• Enrollment (Actual): 128

Contacts and Locations

Study Locations

• Turkey (Türkiye)
  • Mersin, Turkey (Türkiye), 33310
    • Mersin University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

The study was conducted with two groups: term patients (38-42 weeks' gestation) and controls. The control group was selected to match the sepsis group as closely as possible (at a 1:1 ratio) in terms of demographic characteristics, and taking gestational age into account

Description

Inclusion Criteria:

• Term newborn
• Late-onset neonatal sepsis

Exclusion Criteria:

• Preterm newborn
• Major congenital anomaly
• Congenital metabolic disease
• Hemolytic anemia
• Hematological diseases
• Congenital leukemia
• Dyserythropoietic anemia
• Early-onset neonatal sepsis

Control group

• Neonatal jaundice (indirect hyperbilirubinemia)
• Transient neonatal tachypnea
• Early neonatal sepsis

Exclusion criteria Perinatal asphyxia, Meconium aspiration syndrome Polycythemia İntraventricular hemoragy Pneumothorax Hemolytic Anemia

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patient group 1 control group 2; The control group was selected to match the sepsis group as closely as possible (at a 1:1 ratio) in terms of demographic characteristics and taking gestational age into account	Diagnostic test: serum biomarker; that of diagnosis of sepsis, and on the third and seventh days after the commencement of antibiotic therapy. SII was calculated using the formula (neutrophils×platelets)/lymphocytes, and SIAI using neutrophils×monocytes×platelets / lymphocytes
control group and patient group; Neonates born before the 38th week of pregnancy, with major congenital anomaly or congenital metabolic disease, babies born to substance-dependent mothers, with hemolytic anemia or other hematological diseases (such as congenital leukemia, dyserythropoetic anemia, or severe hemolytic diseases), and babies diagnosed with immunodeficiency, with early-onset sepsis, with histories of surgery, or with deficient laboratory data were excluded. All babies diagnosed with LOS and meeting none of the exclusion criteria were enrolled and constituted the LOS cohort. In case of more than one LOS episode, only the first was included in the analysis. Babies with neonatal jaundice (indirect hyperbillurubinemia) of non-hemolytic causes that resolved with phototherapy alone, with transient neonatal tachypnea resolving within the first 24 hours and with no sepsis attack, and infants with non-infectious causes admitted to the NICU were included in the control group. Exclusion criteria for the control gr	Diagnostic test: serum biomarker; that of diagnosis of sepsis, and on the third and seventh days after the commencement of antibiotic therapy. SII was calculated using the formula (neutrophils×platelets)/lymphocytes, and SIAI using neutrophils×monocytes×platelets / lymphocytes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary outcome measure	Immature granulocyte (IG) percentage, the neutrophil/lymphocyte ratio (NLR), CRP, PCT, SIAI, and SII values were recorded from retrospective file data on the first day, that of diagnosis of sepsis, and on the third and seventh days after the commencement of antibiotic therapy. SII was calculated using the formula (neutrophils×platelets)/lymphocytes, and SIAI using neutrophils×monocytes×platelets / lymphocytes. Diagnostic performance was assessed using receiver operating characteristic (ROC) curve analysis. This study aimed to evaluate the diagnostic performance of commonly used and novel inflammatory biomarkers, both individually and in combination, focusing on their temporal dynamics. The performance of diagnostic biomarkers (CRP, PCT, IG, SII, and SIAI) was evaluated using receiver operating characteristic (ROC) curve analysis. For each biomarker, the area under the curve (AUC), sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were planned to be c	From July 2020 to July 2024
practical and effective biomarker combination consisting of widely available laboratory tests capable of being used in the diagnosis and monitoring of LOS in term neonates.	Term late onset sepsis diagnosis	From July 2020 to July 2024
Diagnostic efficacy of biomarkers in late neonatal sepsis	LOS was defined as onset of sepsis symptoms after the 72nd hour (third day). LOS resulted in respiratory symptoms (apnea, tachypnea, desaturation, and increasing mechanical ventilator support requirements), hemodynamic symptoms (bradycardia, skin color changes, decreased peripheral perfusion, hypotension and cardiovascular impairment, and inotropic therapy requirements), metabolic abnormalities (hypoglycemia, hyperglycemia, or metabolic acidosis abnormalities), body temperature irregularities (hypo or hyperthermia), feeding intolerance, and neurological symptoms (hypotonia, poor sucking, and low neurological activity) . Sepsis was evaluated using complete blood count, CRP, PCT, and blood culture. In line with our routine clinical protocol, specimens were collected from neonates with sepsis before the initiation of antibiotic therapy.	Baseline and 3, 7-day serum biomarker

Collaborators and Investigators

• Sponsor: Mersin University

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2020
• Primary Completion (Actual): July 1, 2024
• Study Completion (Actual): July 1, 2025

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: June 4, 2026
• First Posted (Actual): June 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: biomarkers; late onset sepsis; CRP; PCT; term newborn; inflammation indices
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Neonatal Sepsis
• Other Study ID Numbers: Mersin University Neonatology

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Special sensitive population

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No