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Progress has been made in the reduction of morbidity and mortality from neonatal sepsis. However, diagnosis continues to rely primarily on conventional microbiologic techniques, which can be inaccurate. The objective of this review is to provide the clinician with an overview of the current information available on diagnosing this condition. We review currently available diagnostic approaches for documenting neonatal sepsis and also describe novel approaches for diagnosing infection in neonates who are under development and investigation. Substantial progress has been made with molecular approaches and further development of non-culture-based methods offer promise. The potential ability to incorporate antimicrobial resistance gene testing in addition to pathogen identification may provide a venue to incorporate a predominantly molecular platform into a larger program of neonatal care.

Sepsis has a huge impact on global mortality and has been declared as a priority by the World Health organisation the WHO.1 Children have a high incidence of sepsis especially in the neonatal with an estimated 3 million babies affected worldwide and mortality ranges from 11 to 19%.2 In addition, long-term neurodevelopmental outcomes are affected but this is largely unquantified. However, challenges remain in the early recognition, diagnosis and standardised management of sepsis. This series on Sepsis and inflammation in children reviews the conundrums of diagnostic criteria, biomarkers, management and future strategies to improve outcomes.

Background Bloodstream infections remain a challenge for neonatologists, as traditional culture-based methods are time-consuming and rely on adequate blood volume. Next-generation sequencing (NGS) offers an alternative, as it can identify microbial cell-free DNA (mcfDNA) in a small blood sample, providing rapid pathogen detection. This study aimed to assess the diagnostic performance of DISQVER®-NGS compared to blood cultures in neonatal patients with suspected sepsis. Methods In neonates with suspected sepsis, blood cultures and samples for NGS were prospectively collected. Patients were divided into four categories: 1) sepsis, blood culture positive, 2) clinical sepsis, culture negative, 3) suspected sepsis, 4) validation cohort. Results NGS detected bacterial, viral or fungal mcfDNA in 24 of 82 samples. Blood cultures were collected in 46 of 84 patients (15/46 positive). DISQVER® correctly identified pathogens in 9/15 patients with a positive blood culture, two with intrinsic resistance to their antibiotic regimen. In seven samples NGS reported the mcfDNA of bacteria that could have theoretically grown in culture but did not. Conclusions NGS may enhance sensitivity in sepsis diagnostics by detecting mcfDNA in neonates with suspected sepsis. Interpreting NGS results requires correlation with clinical data, laboratory values, and routine microbiological tests for a comprehensive understanding of the patient’s condition. Impact Conventional blood culture methods have limitations in accuracy and turnaround time. The study aimed to investigate the diagnostic performance of the Next-Generation Sequencing method DISQVER® compared to traditional blood cultures in neonatal patients with suspected sepsis. Our findings suggest that NGS has the potential to augment the precision of conventional diagnostic techniques, can lead to improved detection of pathogens and targeted treatment approaches in neonatal sepsis. It is emphasized that further validation and integration with clinical and microbiological data are required to ensure optimal clinical utility.

Procalcitonin (PCT) and C-reactive protein (CRP) are commonly used biomarkers, but their diagnostic advantage for neonatal early-onset (EOS) or late-onset (LOS) sepsis is controversial. In a comprehensive literature review we found significant heterogeneity between studies in sample timing, cut-off values, consideration of blood culture results for sepsis classification, and definition of EOS versus LOS. We identified 39 studies directly comparing PCT with CRP, but only four in very low birth weight (VLBW) neonates. The mean sensitivity for EOS, LOS, and EOS + LOS was 73.6%, 88.9%, and 76.5% for PCT, compared to 65.6%, 77.4%, and 66.4% for CRP, respectively. Mean specificity of PCT and CRP was 82.8% versus 82.7% for EOS, 75.6% versus 81.7% for LOS, and 80.4% versus 91.3% for EOS + LOS. More studies directly comparing both biomarkers for EOS and LOS, especially in extremely and very-low-birth-weight infants, are needed to determine their clinical value for guidance of antibiotic therapy in neonatal sepsis.

Neonatal sepsis, a leading cause of newborn mortality, arises from systemic infections due to an immature immune system. Its subtle early symptoms complicate timely diagnosis. Hematological parameters act as an indicator for early detection, crucial for prompt treatment, improving prognosis, and are not a challenging or cumbersome process. The primary objective was to evaluate the significance of hematological parameters including red blood cell (RBC), WBC, and platelet counts in the context of neonatal sepsis. This hospital-based cohort study examined 73 neonates admitted to the neonatal intensive care unit (NICU) of Saveetha Medical College and Hospital, Chennai, India during the period of January 2023 to March 2024. All the new born patients were presented with blood culture-confirmed septicemia. The investigation identified Klebsiella pneumoniae as the most prevalent etiological agent (26.02%), followed by Coagulase-Negative Staphylococci (CONS) and Acinetobacter baumannii (both 8.2%). Alterations in total leukocyte count and hematocrit were observed in 57% and 68.1% of cases, respectively, providing a prompt indication of infection status. Subsequent analyses revealed prominent leukocytosis, hematocrit irregularities, and thrombocytopenia, frequently manifesting in septic cases and demonstrating potential as early markers for neonatal sepsis. The study highlights the diagnostic value of hematological alterations, such as leukocytosis and hematocrit distortion, in the prompt identification of septicemia among neonates. Based on the findings, it is recommended that routine hematological screening to be integrated as a standard component of neonatal sepsis diagnosis for rapid investigation of neonatal sepsis.

Neonatal sepsis significantly contributes to infant mortality rates. The absence of predictive markers has hindered timely clinical intervention, leading to elevated mortality. This study aimed to assess the prognostic relevance of the lactate dehydrogenase (LDH)-to-albumin ratio (LAR) in neonatal sepsis. A retrospective examination was conducted on a cohort of 130 neonates diagnosed with sepsis. Admission laboratory data were gathered. The optimal threshold for LAR was established using receiver operating characteristic curve analysis. Both univariate and multivariate analyses were performed to gauge the predictive efficacy of LAR. A statistical disparity in LAR was noted between survivors and non-survivors ( p  < 0.001). Multivariate analysis confirmed that LAR serves as an independent risk determinant for neonatal sepsis (Hazard ratio [HR] 11.236, 95% Confidence interval [CI] 3.311–38.462, p  < 0.001). ROC analysis indicated that the area under the curve for LAR was 0.806 across the entire cohort, 0.842 for early-onset sepsis, and 0.737 for late-onset sepsis. Moreover, with a cutoff value set at 23.72, LAR exhibited a prediction specificity of 88.2% and sensitivity of 70.0%. Our research indicates that elevated admission LAR is a negative prognostic indicator in neonatal sepsis, suggesting its potential as a valuable biomarker in clinical settings.

C-reactive protein (CRP) is a well-established marker of inflammation in neonates. Recent studies have shown the potential of CRP velocity as an early indicator of infection disorders in children and adults. However, data on CRP dynamics in the neonatal population remain limited. Our objective was to assess the dynamics of CRP levels and determine their clinical relevance in newborns admitted to the nursery. This is a retrospective review of medical records of neonates ≥ 35 weeks of gestation with a birth weight of ≥ 2000 g, who underwent partial sepsis work-up with at least 2 consecutive CRP measurements within the first 48-h of life, between January and December 2020. CRP dynamics were analyzed using CRP velocity (CRPv, mg/L/h), calculated by dividing the interval between the first two consecutive CRP measurements by the corresponding interval time. A total of 212 neonates were included in the study. Neonates admitted to the neonatal intensive care unit (NICU) presented with higher levels of CRPv (p = 0.047), and were more likely to experience hypoglycemia (p = 0.023) and respiratory distress (p = 0.023). Lower CRPv levels were associated with elective cesarean surgery (p = 0.043). Among neonates with CRPv ≥ 2 mg/L/h, female infants exhibited even higher CRPv values (p = 0.018). Only two cases of blood culture-confirmed neonatal sepsis were identified, with CRPv values of 3.22 and 0.02 mg/L/h., Neither case required NICU admission. Regression analyses revealed that higher gestational age was significantly associated with elevated CRPv levels (p = 0.004) whereas hypothermia was linked to lower CRPv values (p = 0.031). In neonates, CRP dynamics generally corresponded to their overall clinical condition but were also influenced by various non-infectious factors, including GA, mode of delivery and gender. Additionally, neonatologists should consider the recent finding that neonatal hypothermia was associated with decreased CRP levels when assessing ill-appearing newborns with low CRP measurements.

This study aimed to investigate serum zinc levels in term neonates with sepsis, evaluate its correlation with immune parameters, and assess zinc’s diagnostic efficacy in identifying neonatal sepsis. A prospective cohort study was conducted, involving two groups: 52 neonates diagnosed with sepsis who were admitted to the neonatal intensive care unit (NICU) of our hospital between January 2022 and June 2023, and 50 healthy controls matched for gestational age and birth weight. Serum zinc levels, cytokine profiles, and C-reactive protein (CRP) were measured in both cohorts. No statistically significant differences were observed in baseline characteristics between the sepsis group ( n  = 52) and the healthy controls group ( n  = 50). Neonates with sepsis exhibited significantly lower serum zinc levels compared to controls (52.6 ± 17.4 µg/dL vs. 83.2 ± 21.4 µg/dL, P  < 0.05), alongside markedly elevated pro-inflammatory cytokine levels (interleukin-6 [IL-6], interleukin-8 [IL-8], interleukin-10 [IL-10], and interleukin-12 [IL-12]). Spearman correlation analysis revealed significant associations: serum zinc levels showed a strong negative correlation with IL-6 ( r  = -0.510, P  < 0.05) and IL-8 ( r  = -0.625, P  < 0.05), while a positive correlation was observed with IL-12 ( r  = 0.627, P  < 0.05). Receiver Operating Characteristic (ROC) curve analysis demonstrated serum zinc’s moderate diagnostic utility for neonatal sepsis (area under the curve [AUC] = 0.812, P  < 0.0001), with a sensitivity of 78% and a specificity of 76.9%, respectively. These findings highlight zinc’s potential role in sepsis pathophysiology and diagnostic utility, despite its inferior performance compared to CRP (AUC = 0.865, P  < 0.0001). Our findings demonstrate an inverse correlation between serum zinc levels and inflammatory response intensity in neonatal sepsis. Zinc deficiency may serve as a diagnostic biomarker, given its significant negative association with pro-inflammatory cytokine profiles (IL-6, IL-8, and IL-12) and its moderate predictive accuracy for disease detection.

Background: Early diagnosis and treatment of neonatal sepsis are crucial to cut off its major medical consequences: lifelong morbidities, neurodevelopmental disabilities, and a high number of neonatal mortalities. Aim of the Work: This study is aimed at determining the diagnostic and prognostic performance of CD11b as a sepsis biomarker for detecting neonatal sepsis at early stages compared to nCD64 and the other conventional sepsis parameters. Methods: Two hundred eleven neonates were enrolled from three Egyptian neonatal ICUs (NICUs), and they were classified into two main groups: the control group ( n = 101) and the sepsis group ( n = 110). Enrolled neonates were subjected to full sepsis screening, including complete blood count (CBC), C‐reactive protein (CRP), blood cultures, and flow cytometry analysis for both CD64 and CD11b on the neutrophil surface (results represented as a percentage (percent) and mean fluorescent intensity (MFI) units for either biomarker). Results: nCD64% (median = 44.15 % ) was significantly enhanced in the sepsis group compared to the controls (median = 25 % ), achieving 90.8% specificity, 92.8% sensitivity, and AUC = 0.894, respectively. CD64 MFI and CD11b MFI could differentiate between sepsis and control groups but with low undesirable diagnostic performance (sensitivity: 72.5% and 59.1%; specificity: 54.4% and 69.4%; AUC: 0.634 and 0.144, respectively). CD11b% could not discriminate between sepsis and control neonates (sensitivity and specificity of 31.8% and 73.6%, respectively) with an AUC of 0.405. hs‐CRP had moderate diagnostic performance, achieving sensitivity and specificity of 69% and 78.15%, respectively, and AUC = 0.586. ROC analysis showed that combined hs‐CRP and CD64% results had the highest sensitivity and specificity in the current study, being 93.9% and 97.2%, with AUC = 0.938, respectively. Conclusion: CD64%, CD64 MFI, CD11b MFI, and hs‐CRP are increased in neonates with sepsis comparable to the controls. CD64% has a superior diagnostic performance comparable to nCD11b and hs‐CRP. Combined nCD64 with hs‐CRP measurement can provide rapid and accurate diagnostic modality for sepsis diagnosis in correlation with the patient’s clinical condition and context with the results of other hematological indices; neutrophil CD64 can be routinely applicable in NICUs for better sepsis management. It is statistically evident that nCD11b is less ideal compared to nCD64 as a diagnostic, prognostic, or monitoring sepsis marker.

Neonates with pneumonia (NWP) may experience unidentified life-threatening sepsis, yet distinguishing NWP from neonates with sepsis (NWS) based solely on clinical presentation remains challenging. This study aimed to evaluate the diagnostic utility of the C-reactive protein to platelet ratio (CPR) in distinguishing neonatal late-onset sepsis (LOS) among NWPs. From February 2016 to March 2022, a total of 1385 NWPs aged over 3 days were included. Of these, 174 neonates with confirmed positive blood cultures were categorized into the sepsis cohort, while the remainder formed the pneumonia cohort. All clinical data were retrospectively extracted from electronic medical records. CPR was calculated as the ratio of C-reactive protein levels to platelet count. Independent risk factors (IRFs) for neonatal LOS were identified through multivariate logistic regression. The diagnostic performance of CPR in identifying LOS among NWPs was analyzed using receiver operating characteristic (ROC) curve metrics. Statistical analyses were conducted using SPSS version 24.0 and MedCalc version 15.2.2. Neonates with NWS demonstrated significantly higher CPR compared to those with NWP alone. Further analysis revealed a notably increased incidence of sepsis among neonates exhibiting elevated CPR levels relative to those with lower values. Correlation analysis identified a direct association between CPR and elevated procalcitonin, creatinine, and urea nitrogen levels, as well as prolonged hospitalization. Multiple logistic regression analysis identified CPR as an IRF for late-onset NWS. ROC curve analysis demonstrated that CPR outperformed CRP and platelet count individually in diagnosing NWS, with a diagnostic sensitivity of 54% and specificity of 85%. CPR serves as an effective initial diagnostic marker with superior accuracy in distinguishing delayed NWS from NWP compared to CRP and platelet count alone.