Look Who’s Talking: Host and Pathogen Drivers of Staphylococcus epidermidis Virulence in Neonatal Sepsis

Preterm infants are at increased risk for invasive neonatal bacterial infections. S. epidermidis, a ubiquitous skin commensal, is a major cause of late-onset neonatal sepsis, particularly in high-resource settings. The vulnerability of preterm infants to serious bacterial infections is commonly attributed to their distinct and developing immune system. While developmentally immature immune defences play a large role in facilitating bacterial invasion, this fails to explain why only a subset of infants develop infections with low-virulence organisms when exposed to similar risk factors in the neonatal ICU. Experimental research has explored potential virulence mechanisms contributing to the pathogenic shift of commensal S. epidermidis strains. Furthermore, comparative genomics studies have yielded insights into the emergence and spread of nosocomial S. epidermidis strains, and their genetic and functional characteristics implicated in invasive disease in neonates. These studies have highlighted the multifactorial nature of S. epidermidis traits relating to pathogenicity and commensalism. In this review, we discuss the known host and pathogen drivers of S. epidermidis virulence in neonatal sepsis and provide future perspectives to close the gap in our understanding of S. epidermidis as a cause of neonatal morbidity and mortality.

The Multi-Component Causes of Late Neonatal Sepsis—Can We Regulate Them?

Elucidating the mechanisms of bacterial translocation is crucial for the prevention and treatment of neonatal sepsis. In the present study, we aimed to evaluate the potential of lactoferrin to inhibit the development of late-onset blood infection in neonates. Our investigation evaluates the role of key stress factors leading to the translocation of intestinal bacteria into the bloodstream and, consequently, the development of life-threatening sepsis. Three stress factors, namely weaning, intraperitoneal administration of Gram-positive cocci and oral intake of Gram-negative rods, were found to act synergistically. We developed a novel model of rat pups sepsis induced by bacterial translocation and observed the inhibition of this process by supplementation of various forms of lactoferrin: iron-depleted (apolactoferrin), iron-saturated (hololactoferrin) and manganese-saturated lactoferrin. Additionally, lactoferrin saturated with manganese significantly increases the Lactobacillus bacterial population, which contributes to the fortification of the intestinal barrier and inhibits the translocation phenomenon. The acquired knowledge can be used to limit the development of sepsis in newborns in hospital neonatal intensive care units.

Neonatal sepsis: a systematic review of core outcomes from randomised clinical trials

Background The lack of a consensus definition of neonatal sepsis and a core outcome set (COS) proves a substantial impediment to research that influences policy and practice relevant to key stakeholders, patients and parents. Methods A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the included studies, the described outcomes were extracted in accordance with the provisions of the Core Outcome Measures in Effectiveness Trials (COMET) handbook and registered. Results Among 884 abstracts identified, 90 randomised controlled trials (RCTs) were included in this review. Only 30 manuscripts explicitly stated the primary and/or secondary outcomes. A total of 88 distinct outcomes were recorded across all 90 studies included. These were then assigned to seven different domains in line with the taxonomy for classification proposed by the COMET initiative. The most frequently reported outcome was survival with 74% (n = 67) of the studies reporting an outcome within this domain. Conclusions This systematic review constitutes one of the initial phases in the protocol for developing a COS in neonatal sepsis. The paucity of standardised outcome reporting in neonatal sepsis hinders comparison and synthesis of data. The final phase will involve a Delphi Survey to generate a COS in neonatal sepsis by consensus recommendation. Impact This systematic review identified a wide variation of outcomes reported among published RCTs on the management of neonatal sepsis. The paucity of standardised outcome reporting hinders comparison and synthesis of data and future meta-analyses with conclusive recommendations on the management of neonatal sepsis are unlikely. The final phase will involve a Delphi Survey to determine a COS by consensus recommendation with input from all relevant stakeholders.

cfDNA and DNases: New Biomarkers of Sepsis in Preterm Neonates—A Pilot Study

Introduction: An early and accurate diagnosis of early onset neonatal sepsis (EONS) and late onset neonatal sepsis (LONS) is essential to improve the outcome of this devastating conditions. Especially, preterm infants are at risk. Reliable biomarkers are rare, clinical decision-making depends on clinical appearance and multiple laboratory findings. Markers of NET formation and NET turnover might improve diagnostic precision. Aim of this study was to evaluate the diagnostic value of NETs in sepsis diagnosis in neonatal preterm infants. Methods: Plasma samples of neonatal preterm infants with suspected sepsis were collected. Blood samples were assayed for markers of NET formation and NET turnover: cfDNA, DNase1, nucleosome, NE, and H3Cit. All clinical findings, values of laboratory markers, and epidemiological characteristics were collected retrospectively. Two subpopulations were created to divide EONS from LONS. EMA sepsis criteria for neonatal sepsis were used to generate a sepsis group (EMA positive) and a control group (EMA negative). Results: A total of 31 preterm neonates with suspected sepsis were included. Out of these, nine patients met the criteria for sepsis according to EMA. Regarding early onset neonatal sepsis (3 EONS vs. 10 controls), cfDNA, DNase I, nucleosome, and CRP were elevated significantly. H3Cit and NE did not show any significant elevations. In the late onset sepsis collective (6 LONS vs. 12 controls), cfDNA, DNase I, and CRP differed significantly compared to control group.

Serum miR-34a-5p and miR-199a-3p as new biomarkers of neonatal sepsis

Background Neonatal sepsis is a serious condition. Recent clinical studies have indicated that microRNAs (miRNAs) are key players in the pathogenesis of sepsis, which could be used as biomarkers for this condition. Patients and methods A total of 90 neonates with sepsis and 90 healthy neonates were enrolled in this study. qRT-PCR was performed to measure the expression levels of serum miR-34a-5p and miR-199a-3p. Results miR-34a-5p and miR-199a-3p serum levels were significantly reduced in neonates with sepsis compared with those in healthy neonates (P = 0.006 and P = 0.001, respectively). Significant correlations of miR-34a-5p and miR-199a-3p with each of TLC, RDW, RBS, and C-reactive protein (CRP) as well as SNAPII were observed, indicating their associations with the severity of neonatal sepsis. Conclusion miR-34a-5p and miR-199a-3p may be useful as novel biomarkers in neonatal sepsis and may provide a new direction for its treatment.

Detection of pathogens associated with early-onset neonatal sepsis in cord blood at birth using quantitative PCR

Background: Early onset neonatal sepsis (EONS) typically begins prior to, during or soon after birth and may be rapidly fatal. There is paucity of data on the aetiology of EONS in sub-Saharan Africa due to limited diagnostic capacity in this region, despite the associated significant mortality and long-term neurological impairment. Methods: We compared pathogens detected in cord blood samples between neonates admitted to hospital with possible serious bacterial infection (pSBI) in the first 48 hours of life (cases) and neonates remaining well (controls). Cord blood was systematically collected at Kilifi County Hospital (KCH) from 2011-2016, and later tested for 21 bacterial, viral and protozoal targets using multiplex PCR via TaqMan Array Cards (TAC). Results: Among 603 cases (101 [17%] of whom died), 179 (30%) tested positive for ≥1 target and 37 (6.1%) tested positive for multiple targets. Klebsiella oxytoca, Escherichia coli/Shigella spp., Pseudomonas aeruginosa, and Streptococcus pyogenes were commonest. Among 300 controls, 79 (26%) tested positive for ≥1 target, 11 (3.7%) were positive for multiple targets, and K. oxytoca and P. aeruginosa were most common. Cumulative odds ratios across controls: cases (survived): cases (died) were E. coli/Shigella spp. 2.6 (95%CI 1.6-4.4); E. faecalis 4.0 (95%CI 1.1-15); S. agalactiae 4.5 (95%CI 1.6-13); Ureaplasma spp. 2.9 (95%CI 1.3-6.4); Enterovirus 9.1 (95%CI 2.3-37); and Plasmodium spp. 2.9 (95%CI 1.4-6.2). Excluding K. oxytoca and P. aeruginosa as likely contaminants, aetiology was attributed in 9.4% (95%CI 5.1-13) cases using TAC. Leading pathogen attributions by TAC were E. coli/Shigella spp. (3.5% (95%CI 1.7-5.3)) and Ureaplasma spp. (1.7% (95%CI 0.5-3.0)). Conclusions: Cord blood sample may be useful in describing EONS pathogens at birth, but more specific tests are needed for individual diagnosis. Careful sampling of cord blood using aseptic techniques is crucial to minimize contamination. In addition to culturable bacteria, Ureaplasma and Enterovirus were causes of EONS.

Prediction modelling in the early detection of neonatal sepsis

Background Prediction modelling can greatly assist the health-care professionals in the management of diseases, thus sparking interest in neonatal sepsis diagnosis. The main objective of the study was to provide a complete picture of performance of prediction models for early detection of neonatal sepsis. Methods PubMed, Scopus, CINAHL databases were searched and articles which used various prediction modelling measures for the early detection of neonatal sepsis were comprehended. Data extraction was carried out based on Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies checklist. Extricate data consisted of objective, study design, patient characteristics, type of statistical model, predictors, outcome, sample size and location. Prediction model Risk of Bias Assessment Tool was applied to gauge the risk of bias of the articles. Results An aggregate of ten studies were included in the review among which eight studies had applied logistic regression to build a prediction model, while the remaining two had applied artificial intelligence. Potential predictors like neonatal fever, birth weight, foetal morbidity and gender, cervicovaginitis and maternal age were identified for the early detection of neonatal sepsis. Moreover, birth weight, endotracheal intubation, thyroid hypofunction and umbilical venous catheter were promising factors for predicting late-onset sepsis; while gestational age, intrapartum temperature and antibiotics treatment were utilised as budding prognosticators for early-onset sepsis detection. Conclusion Prediction modelling approaches were able to recognise promising maternal, neonatal and laboratory predictors in the rapid detection of early and late neonatal sepsis and thus, can be considered as a novel way for clinician decision-making towards the disease diagnosis if not used alone, in the years to come.

Prevalence of Anti-leptospiral IgM and Detection of Pathogenic Leptospira Species DNA in Neonates Presenting With Clinical Sepsis in Southwestern Uganda

BackgroundLeptospirosis is an emerging neglected zoonotic disease that presents with nonspecific signs/symptoms and it can be mistaken for other diseases. Due to limited diagnostic capacity and unawareness, data on human leptospirosis particularly in neonates is scarce in many sub-Saharan countries. It has been underreported hindering preventive and control measures in place. The study aimed at determining prevalence of leptospirosis as a cause of febrile illness in neonates using a commercially available IgM ELISA and a quantitative real-time PCR (qPCR). MethodsThis was a descriptive cross-sectional study that included 103 neonatal sepsis cases whose parents/legal guardians gave informed consent. Data on demographic and clinical characteristics was collected using structured data collection form. EDTA whole blood sample was collected from the neonates by trained study nurses. From the samples, IgM ELISA was done using automated analyzers, DNA extracted and qPCR was performed using primers for LipL32, specific for the pathogenic leptospires. ResultsThe prevalence of anti-leptospiral IgM among the neonates as determined by ELISA was 4.3%, where all of them presented with lethargy and poor feeding. No pathogenic Leptospira species DNA was amplified by qPCR.ConclusionsEvidence of leptospirosis was demonstrated in neonatal sepsis cases in this study. The findings suggest considerations of leptospirosis in the differential diagnosis of neonates with sepsis. More data is needed on the real epidemiology, clinical features and burden of leptospirosis in neonates. There is need to include intermediate pathogenic species of Leptospira in the diagnostic qPCR assays.

Predictors of mortality among neonates hospitalized with neonatal sepsis: a case control study from southern Ethiopia

Background Neonatal sepsis, which resulted from bacterial, viral, and fungal invasions of the bloodstream, is the major cause of neonatal mortality and neurodevelopmental impairment among neonates. It is responsible for more than one-third of neonatal deaths in Ethiopia. Frequently neonates referred to health facilities are at high risk of death. Hence, assessing and preventing the predictors of mortality in neonatal sepsis helps to reduce the burden of neonatal mortality. Objectives To determine predictors of mortality among neonates admitted with sepsis at Durame general hospital, southern Ethiopia, 2020. Methods Institution-based unmatched case-control study was carried out from March 8 to 30, 2020, among 219 neonates in Durame general hospital in southern Ethiopia. Neonates admitted with sepsis and died were considered as cases and neonates admitted with sepsis and survived (discharged alive) as controls. Cases were selected by taking the deaths of neonates consecutively among those neonates admitted with the diagnosis of neonatal sepsis. The next immediate three corresponding controls were selected by lottery method from the Neonatal Intensive Care Unit (NICU) case registration book. Data was collected by using structured pretested checklists from neonates’ records and then entered into Epi data version 3.1 and exported to SPSS version 20. Logistic regression was used to identify the predictors of mortality. Statistical significance was declared at P < 0.05. Results A total of 55 cases and 164 controls were included in this study. More than three quarters (81.8%) of cases had early onset sepsis. The multivariable logistic regression analysis showed that predictors of mortality in this study were; poor feeding [AOR = 4.15; 95% CI (1.64, 10.49)], respiratory distress [AOR = 2.72; 95% CI (1.31, 5.61)], estimated gestational age less than 37 weeks [AOR = 4.64; 95% CI (2.17, 9.91)], and convulsion [AOR = 3.13; 95% CI (1.12, 8.76)]. Conclusion This study showed that prematurity, convulsion, poor feeding, and respiratory distress were the predictors of sepsis-related neonatal mortality. It is important to pay attention to septicemic babies with any of the identified predictors to reduce sepsis-related mortality.