Late-onset Sepsis In Preterm Infants Research Articles

Recommendations for antibiotic use in hospitalized preterm infants with late-onset sepsis in the neonatal intensive care unit

Late-onset sepsis (LOS) is commonly seen in neonates who are hospitalized for extended periods, particularly in very low birth weight infants (VLBWI) and extremely low birth weight infants (ELBWI). Currently, the management of LOS in preterm infants faces dual challenges of delayed diagnosis and treatment, as well as antibiotic overtreatment. To address these issues, the Hunan Neonatal Medical Quality Control Center and the Neonatology Group of Perinatal Medical Committee of Hunan Medical Association organized a group of neonatal experts from Hunan Province to formulate recommendations based on published literature and statistical data from the Hunan Neonatal Medical Quality Control Center, as well as real-world practices in most neonatal intensive care units in Hunan Province. The group of neonatal experts proposed 15 recommendations for the diagnosis and antibiotic treatment of LOS in hospitalized preterm infants in the neonatal intensive care unit.

The Potential of Fecal Volatile Organic Compound Analysis for the Early Diagnosis of Late-Onset Sepsis in Preterm Infants: A Narrative Review.

Early diagnosis and treatment of late-onset sepsis (LOS) is crucial for survival, but challenging. Intestinal microbiota and metabolome alterations precede the clinical onset of LOS, and the preterm gut is considered an important source of bacterial pathogens. Fecal volatile organic compounds (VOCs), formed by physiologic and pathophysiologic metabolic processes in the preterm gut, reflect a complex interplay between the human host, the environment, and microbiota. Disease-associated fecal VOCs can be detected with an array of devices with various potential for the development of a point-of-care test (POCT) for preclinical LOS detection. While characteristic VOCs for common LOS pathogens have been described, their VOC profiles often overlap with other pathogens due to similarities in metabolic pathways, hampering the construction of species-specific profiles. Clinical studies have, however, successfully discriminated LOS patients from healthy individuals using fecal VOC analysis with the highest predictive value for Gram-negative pathogens. This review discusses the current advancements in the development of a non-invasive fecal VOC-based POCT for early diagnosis of LOS, which may potentially provide opportunities for early intervention and targeted treatment and could improve clinical neonatal outcomes. Identification of confounding variables impacting VOC synthesis, selection of an optimal detection device, and development of standardized sampling protocols will allow for the development of a novel POCT in the near future.

Intestinal metabolomics in premature infants with late-onset sepsis

We aimed to investigate the characteristics of intestinal metabolomics and non-invasive biomarkers for early diagnosis of late-onset sepsis (LOS) by analyzing gut metabolites in preterm infants with LOS. We collected stool samples from septic and healthy preterm infants for analysis by liquid chromatography–mass spectrometry. 123 different metabolites were identified and 13 pathways were mainly involved. Glycine, serine, and threonine metabolism; glyoxylate and dicarboxylic acid metabolism; glutathione metabolism; primary bile acid biosynthesis; steroid synthesis; pentose and glucuronic acid interconversion may be involved in the pathogenesis of LOS in preterm infants. The significant changes of N-Methyldopamine, cellulose, glycine, gamma-Glutamyltryptophan, N-Ribosylnicotinamide and 1alpha, 25-dihydroxycholecalciferol showed specific diagnostic values and as non-invasive biomarkers for LOS.

Carboxyhemoglobin as biomarker of late-onset sepsis in preterm infants

Carboxyhemoglobin (COHb) is considered a biomarker of oxidative stress and previous studies reported an increase in COHb levels in preterm infants who develop late-onset sepsis (LOS). Our aim was to assess the correlation between COHb levels and the risk for LOS development. We retrospectively studied 100 preterm infants, 50 in the LOS and 50 in the no LOS group. COHb levels were measured on the day of diagnosis of the first episode of LOS, 3, 2, and 1 days before and 1 and 4 days after the onset of LOS. Logistic regression analysis showed that a higher level of COHb 2 days before the diagnosis of LOS increases the risk for LOS development (OR 12.150, 95% Cl 1.311–12.605; P = 0.028). A COHb level of 1.55% measured 2 days before the diagnosis of LOS is the best predictive threshold for LOS with a sensitivity of 70% and a specificity of 70%. Conclusion: Increased levels of COHb may predict the diagnosis of LOS in very preterm infants with a good accuracy. If further studies confirm our findings, this easy-to-measure biomarker could provide neonatologists with another tool for monitoring and early diagnosis of sepsis in high-risk patients.What is Known:• Carboxyhemoglobin (COHb) is a biomarker of oxidative stress.• Previous studies reported an increase in COHb levels in preterm infants who develop late-onset sepsis (LOS).What is New:• COHb levels increased two days before the diagnosis of LOS and this increase was associated with the risk for developing LOS.• ROC curve analysis for COHb measured two days before the diagnosis of LOS showed that 1.55% is the best predictive threshold for LOS with a sensitivity of 70% and a specificity of 70%.

Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants: A Nationwide Case-Control Study.

Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks' gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography-ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p-value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker.

DeepLOS: Deep learning for late-onset sepsis prediction in preterm infants using heart rate variability

Late onset sepsis (LOS) is one of the main causes of death in preterm infants in a neonatal intensive care unit (NICU). LOS can be better treated with early detection, reducing its morbidity and mortality. In this study, an end-to-end deep learning model called DeepLOS was developed to predict LOS in preterm infants in a NICU. The model is based on a residual convolutional neural network (ResNet) with feature map (or channel) attention and uses RR intervals (i.e., interbeat intervals) as input. The model was trained and tested on a dataset composed of 128 preterm infants (60 blood-culture-proven LOS patients and 68 control patients). To minimize the possible age effect on modeling, we also considered an age-matched dataset including 32 LOS and 32 control patients from the full dataset. Prediction was done with a one-hour (non-overlapping) sliding window from 24 h before LOS to onset of LOS. We used 5-fold patient-independent cross validation and F-score to evaluate the model performance. The DeepLOS achieves an F-score of 0.72 for the full dataset and 0.73 for the matched dataset in LOS prediction for all one-hour segments, outperforming the baseline ResNet model without channel attention. F-score is generally higher (>0.75) when coming closer to the onset of LOS. Our study demonstrates the feasibility of deep learning for end-to-end LOS prediction in preterm infants. Furthermore, the model uses readily available RR intervals as input only; and is therefore vendor-processing independent and has the potential to be easily deployed in different NICUs.

Prediction for late-onset sepsis in preterm infants based on data from East China.

AimTo construct a prediction model based on the data of premature infants and to apply the data in our study as external validation to the prediction model proposed by Yuejun Huang et al. to evaluate the predictive ability of both models.MethodsIn total, 397 premature infants were randomly divided into the training set (n = 278) and the testing set (n = 119). Univariate and multivariate logistic analyses were applied to identify potential predictors, and the prediction model was constructed based on the predictors. The area under the curve (AUC) value, the receiver operator characteristic (ROC) curves, and the calibration curves were used to evaluate the predictive performances of prediction models. The data in our study were used in the prediction model proposed by Yuejun Huang et al. as external validation.ResultsIn the current study, endotracheal intubation [odds ratio (OR) = 10.553, 95% confidence interval (CI): 4.959–22.458], mechanical ventilation (OR = 10.243, 95% CI: 4.811–21.806), asphyxia (OR = 2.614, 95% CI: 1.536–4.447), and antibiotics use (OR = 3.362, 95% CI: 1.454–7.775) were risk factors for late-onset sepsis in preterm infants. The higher birth weight of infants (OR = 0.312, 95% CI: 0.165–0.588) and gestational age were protective factors for late-onset sepsis in preterm infants. The training set was applied for the construction of the models, and the testing set was used to test the diagnostic efficiency of the model. The AUC values of the prediction model were 0.760 in the training set and 0.796 in the testing set.ConclusionThe prediction model showed a good predictive ability for late-onset sepsis in preterm infants.

Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: a multicenter cohort study

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics’ effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19–0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35–0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85–0.97]; p = 0.003).Conclusion: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored.What is Known:• Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis.• The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated.What is New:• Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged.• A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.

The Use of Probiotics in Preterm Infants

Probiotics are live microorganisms that positively affect host health by altering the composition of the host microbiota. Gastrointestinal dysbiosis refers to adverse alterations of the intestinal flora and is associated with several diseases, including necrotizing enterocolitis, late-onset sepsis in preterm infants as well as atopic disease, colic, diabetes, and diarrhea in term infants. The risk factors for gastrointestinal dysbiosis are preterm birth, cesarean section delivery, and formula feeding, in contrast to term birth infants, vaginal delivery and breast milk feeding. Probiotics have been used to restore synbiosis in infants with gastrointestinal dysbiosis. Probiotics inhibit colonization of pathogenic bacteria in the gastrointestinal tract, thereby improving the barrier function of the gastrointestinal tract, and the immune function. In preterm infants, probiotics reduce mortality as well as rates of necrotizing enterocolitis and late-onset sepsis. The combined use of probiotics such as &lt;i&gt;Lactobacillus&lt;/i&gt; and &lt;i&gt;Bifidobacterium&lt;/i&gt; and the combination of probiotics with prebiotics yield better outcomes in the prevention of necrotizing enterocolitis than those achieved with a single pro- or prebiotic strain. However, the routine use of probiotics has been hindered by the lack of pharmaceutical-quality products, and a definite effect has yet to be demonstrated in preterm infants with a birth weight &lt;1,000 g. Therefore, to reduce the risk of necrotizing enterocolitis in preterm infants, probiotics should be provided along with breast milk and other strategies aimed at preventing gastrointestinal dysbiosis.

Mean Platelet Volume and Mean Platelet Volume/Platelet Count Ratio Are Predictors of Late-Onset Sepsis in Preterm Infants: A Case-Control Study

Objective: Our aim was to assess mean platelet volume (MPV) and mean platelet volume to platelet count ratio (MPR) in the setting of late-onset sepsis (LOS) and their association with the type of bacteria causing LOS. Study design: The MPV and MPR levels were obtained at the onset of LOS and then assessed in intra/inter group analyses in preterm infants. Results: Overall, 136 preterm infants were enrolled. The MPV and MPR levels were higher during a LOS event (P < 0.001). A MPV cutoff of >9.2 was related with a sensitivity of 63% and a specificity of 73% for predicting LOS (P < 0.001). A MPR cutoff of >0.15 was related with a sensitivity of 88% and a specificity of 63% for predicting gram negative LOS (P < 0.001). Conclusion: Elevated MPV values and MPR ratios may be helpful in assessing LOS.

Evaluation of Red Blood Cell Distribution Width-Platelet Ratio as an Early Predictor of Late-Onset Sepsis in Preterm Infants

Evaluation of Red Blood Cell Distribution Width-Platelet Ratio as an Early Predictor of Late-Onset Sepsis in Preterm Infants

Validity of serum and urinary hepcidin as biomarkers for late-onset sepsis in premature infants.

Background:Sepsis remains one of the leading causes of neonatal morbidity and mortality, particularly among premature infants. Blood culture is the ‘gold standard’ for the diagnosis of neonatal sepsis but is associated with several pitfalls.Aim of the work:We aim to evaluate the validity of measuring serum (S.Hep) and urinary hepcidin (U.Hep) concentrations as diagnostic biomarkers for late-onset sepsis (LOS) in preterm infants.Patients and Methods:The current case-control study included 73 cases of clinically and laboratory confirmed late-onset sepsis as the ‘case group’ and 50 nonseptic premature infants of comparable age and sex as the ‘control group’. S.Hep and U.Hep concentrations were evaluated at enrollment (acute sample) and after 1 week of treatment (convalescent sample).Results:Patients had a statistically significant higher concentration of both S.Hep and U.Hep as compared with nonseptic controls (p = 0.0001). Similarly, a significant reduction of both S.Hep and U.Hep was detected after 1 week of treatment (p = 0.001). A cut-off value of ⩾ 94.8 ng/ml of S.Hep and ⩾ 264 ng/mg of U.Hep/urinary creatinine showed high sensitivity, specificity, and positive predictive value in the diagnosis of neonatal LOS.Conclusions:Both S.Hep and U.Hep can function as promising accurate and rapid surrogate tests for the diagnosis of LOS. U.Hep measurement has the advantage of being noninvasive, with no hazards of phlebotomy, and is less variable throughout the day.

Probiotics (Bacillus clausii) for Prevention of Late-onset Sepsis in Preterm Infants (&lt;34 weeks): A Randomised Controlled Trial

Introduction: Late-onset Sepsis (LOS) causes significant morbidity and mortality in preterm infants. Probiotics have been suggested to improve the integrity of mucosal barrier by modifying the enteric microflora and suppress the overgrowth and translocation of pathogens in the gut, thus preventing life- threatening infections. Although probiotics have a definite role in prevention of Necrotising Enterocolitis (NEC) in preterm neonates, their effect on prevention of LOS in preterm neonates is still uncertain. Aim: To evaluate the role of probiotics in reducing incidence of LOS in preterm neonates (&lt;34 weeks). Materials and Methods: A double blinded randomised control trial was conducted in a tertiary care Neonatal Intensive Care Unit (NICU) in Karnataka, India between 1st January 2019 to 31st December 2019. Seventy haemodynamically stable preterm neonates, &lt;34 weeks of Gestational Age (GA), were randomised into ‘Probiotic’ and ‘Placebo’ groups. The probiotic group (n=36) was prophylactically administered Bacillus clausii suspension at a dose of 2.5 mL per-oral (0.4×109 spores in 1 mL) BD with breast milk, from initiation of enteral feeds till seven days, discharge/ death/LOS, whichever was earlier. The placebo group (n=34) received breast milk with sterile water 2.5 mL per- oral BD. All the neonates were investigated and managed as per standard hospital protocol. Primary outcome of the study was to find the incidence of LOS. Student’s t-test, Mann-Whitney U test, Chi-square test and Fisher’s exact test were used for statistical analysis. Results: There was no significant difference between the probiotic vs placebo group, with respect to incidence of LOS (11.11% vs 17.64%; (p&gt;0.05)) and duration of hospital stay (10.86±3.19 vs 11.23±2.98 days; (p&gt;0.05)). However, incidence of feed intolerance in the probiotic group (11.11%) was significantly less than that the other (26%) (p&lt;0.05). Conclusion: Probiotics, prophylactically fed enterally, did not reduce the incidence of LOS but provide a promising strategy to prevent feed intolerance in premature neonates.

Optimized Detection of Central Apneas Preceding Late-Onset Sepsis in Premature Infants.

In neonatal intensive care units, respiratory traces of premature infants developing late onset sepsis (LOS) may also show episodes of apneas. However, since clinical patient monitors often underdetect apneas, clinical experts are required to investigate patients' traces looking for these events. In this work we present a method to optimize an existing algorithm for central apnea (CA) detection and how we used it together with human annotations to investigate the occurrence of CAs preceding LOS.The algorithm was optimized by using a previously-annotated dataset consisting of 90 hours, extracted from 10 premature infants. This allowed to double precision (19.7% vs 9.3%, median values per patient) without affecting recall (90.5% vs 94.5%) compared to the original algorithm. This choice caused the missed identification of just 1 additional CA (4 vs 3) in the whole dataset. The optimized algorithm was then used to annotate a second dataset consisting of 480 hours, extracted from 10 premature infants diagnosed with LOS. Annotations were corrected by two clinical experts.A significantly higher number of CA annotations was found in the 6 hours prior to sepsis onset (p-value < 0.05). The use of the optimized algorithm followed by human annotations proved to be a suitable, time-efficient method to annotate CAs before sepsis in premature infants, enabling future use in large datasets.

Prospects for clinical applications of butyrate-producing bacteria.

As the major source of energy for colonic mucosal cells and as an important regulator of gene expression, inflammation, differentiation, and apoptosis in host cells, microbiota-derived butyrate can enhance the intestinal mucosal immune barrier, modulate systemic immune response, and prevent infections. Maintaining a certain level of butyrate production in the gut can help balance intestinal microbiota, regulate host immune response, and promote the development and maintenance of the intestinal mucosal barrier. Butyrate-producing bacteria act as probiotics and play important roles in a variety of normal biological functions. Bacteriotherapeutic supplementation by using fecal microbiota transplantation to restore butyrate-producing commensal bacteria in the gut has been very successful in the treatment of recurrent and refractory Clostridium difficile (C. difficile) infection or C. difficile-negative nosocomial diarrhea. Administration of probiotics that include butyrate-producing bacteria may have a role in the treatment of inflammatory bowel diseases and in the prevention of necrotizing enterocolitis and late-onset sepsis in premature infants. Furthermore, modulating gut microbiota with dietary approaches may improve intestinal dysbiosis commonly seen in patients with obesity-associated metabolic disorders. Supplementation with a butyrate-producing bacterial stain might be used to increase energy expenditure, improve insulin sensitivity, and to help control obesity and metabolic syndrome.

Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age\u2009\u2264\u200932\u2009weeks: a pilot single-center randomized controlled trial

BackgroundOropharyngeal administration of colostrum (OAC) may provide immunoprotective and anti-inflammatory effects that potentially reduce the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis and improve short-term outcomes. Our objective was to evaluate the role of OAC in the early prevention of NEC and late-onset sepsis in preterm infants with gestational age (GA) ≤ 32 weeks.MethodsA pilot, single-center, 1:1 parallel randomized controlled trial was conducted in a 40-bed tertiary neonatal intensive care unit (NICU) in China from 1 January 2019 to 30 September 2020. Preterm infants were randomly divided into two groups with GA ≤ 32 weeks. The OAC group included preterm infants who received 0.4 ml of maternal colostrum via the oropharyngeal route every 3 h for 10 days beginning within the first 48 h after birth, and the control group included preterm infants who received normal saline instead. Data from the two groups were collected and compared.ResultsA total of 127 infants in the OAC group and 125 infants in the control group were enrolled. The incidence of NEC (Bell stage 2 or 3) and late-onset sepsis were lower in the OAC group [2.36% vs. 10.40%, relative risk (RR) 0.23 (95% confidence interval (CI) 0.07, 0.78), adjusted RR 0.23 (95% CI 0.06, 0.84); 4.72% vs. 13.60%, RR 0.35 (95% CI 0.14, 0.85), adjusted RR 0.36 (95% CI 0.14, 0.95)]. In addition, the incidence of proven sepsis and intraventricular hemorrhage (IVH) (stage 3 or 4) were lower in the OAC group [2.36% vs. 8.80%, RR 0.27 (95% CI 0.08, 0.94); 1.57% vs. 7.20%, RR 0.22 (95% CI 0.05, 0.99)], and the time to achieve full enteral feeding was shorter (23.13 ± 9.45 days vs. 28.50 ± 14.80 days). No adverse reactions were observed in either group.ConclusionsOropharyngeal administration of colostrum is a safe and simple NICU procedure that may yield a potential effect in decreasing the incidences of NEC, late-onset sepsis, and severe IVH and shorten the time to achieve full enteral feeding in preterm infants with GA ≤ 32 weeks.Trial registrationChinese Clinical Trial Registry, ChiCTR1900023697, Registered 8 June 2019, retrospectively registered.

Exposure to intrauterine inflammation and late-onset sepsis in very preterm infants.

Late-onset sepsis is an important cause of mortality and morbidity in preterm infants. As these infants rely mostly on their innate immune system to fight off infection, enhancing this immune system by appropriate stimuli may prevent late-onset sepsis. However, it remains unclear which stimuli can enhance the neonatal immune system. This study aims to investigate the influence of intrauterine inflammation on late-onset sepsis. This is a retrospective cohort study in a Neonatal Intensive Care Unit in the Netherlands. Between 2005 and 2016, 1014 infants with ≤32 weeks gestational age and/or with a birth weight ≤1500 g were included. Intrauterine inflammation was subdivided into histological chorioamnionitis, fetal inflammatory response, and funisitis. Logistic and Cox regression analyses were performed to investigate the influence of intrauterine inflammation on late-onset sepsis. Thirty-six percent of the included infants developed late-onset sepsis; 24% of placentas showed intrauterine inflammation. Late-onset sepsis incidence did not differ between infants with or without exposure to intrauterine inflammation after adjustment for gestational age (histological chorioamnionitis aHR 0.928 [CI: 0.727-1.185], p = 0.551; fetal inflammatory response aHR 1.011 [CI: 0.793-1.288], p = 0.930); funisitis aHR 0.965 [CI: 0.738-1.263], p = 0.797). Late-onset sepsis in very preterm infants seems not to be associated with intrauterine inflammation. Intrauterine inflammation is not protective of developing late-onset sepsis in premature infants. A large cohort study on the effect of intrauterine inflammation on neonatal outcome. This study adds to existing knowledge on finding appropriate stimuli to enhance the immune system of premature infants to improve neonatal outcome.

Prediction of Late-Onset Sepsis in Preterm Infants Using Monitoring Signals and Machine Learning.

Prediction of late-onset sepsis (onset beyond day 3 of life) in preterm infants, based on multiple patient monitoring signals 24 hours before onset. Continuous high-resolution electrocardiogram and respiration (chest impedance) data from the monitoring signals were extracted and used to create time-interval features representing heart rate variability, respiration, and body motion. For each infant with a blood culture-proven late-onset sepsis, a Cultures, Resuscitation, and Antibiotics Started Here moment was defined. The Cultures, Resuscitation, and Antibiotics Started Here moment served as an anchor point for the prediction analysis. In the group with controls (C), an "equivalent crash moment" was calculated as anchor point, based on comparable gestational and postnatal age. Three common machine learning approaches (logistic regressor, naive Bayes, and nearest mean classifier) were used to binary classify samples of late-onset sepsis from C. For training and evaluation of the three classifiers, a leave-k-subjects-out cross-validation was used. Level III neonatal ICU. The patient population consisted of 32 premature infants with sepsis and 32 age-matched control patients. No interventions were performed. For the interval features representing heart rate variability, respiration, and body motion, differences between late-onset sepsis and C were visible up to 5 hours preceding the Cultures, Resuscitation, and Antibiotics Started Here moment. Using a combination of all features, classification of late-onset sepsis and C showed a mean accuracy of 0.79 ± 0.12 and mean precision rate of 0.82 ± 0.18 3 hours before the onset of sepsis. Information from routine patient monitoring can be used to predict sepsis. Specifically, this study shows that a combination of electrocardiogram-based, respiration-based, and motion-based features enables the prediction of late-onset sepsis hours before the clinical crash moment.

Plasma cytokine profiles in very preterm infants with late-onset sepsis.

Deficiencies in innate immune responses may contribute to the increased susceptibility to infection in preterm infants. In vivo cytokine profiles in response to sepsis in very preterm infants are not fully understood. To characterise plasma pro- and anti-inflammatory cytokine concentrations and pre-defined ratios in very preterm infants with late-onset sepsis (LOS). In this observational study, peripheral blood samples were collected at the time of evaluation for suspected LOS from 31 preterm infants (<30 weeks gestational age). Plasma cytokine concentrations were determined by 12-plex immunoassay. IL-10, IFN-γ, IL-12p70, IP-10, IL-6 and CCL2 were elevated in the majority infants with LOS (n = 12) compared to those without LOS (n = 19). There was no difference in TNF-α, IL-1β, IL-17AF, IL-8 and IL-15 concentrations between groups. IL-10/TNF-α ratios were increased, while CCL2/IL-10 and IL-12p70/IL-10 ratios were decreased in infants with LOS compared to those without. Very preterm infants have a marked innate inflammatory response at the time of LOS. The increase in IL-10/TNF-α ratio may indicate early immune hypo-responsiveness. Longitudinal studies with a larger number of participants are required to understand immune responses and clinical outcomes following LOS in preterm infants.

Preclinical Detection of Non-catheter Related Late-onset Sepsis in Preterm Infants by Fecal Volatile Compounds Analysis: A Prospective, Multi-center Cohort Study.

Late onset sepsis (LOS) in preterm infants is preceded by fecal volatile organic compound (VOC) alterations, suggesting an etiologic role of gut microbiota in LOS rather than being primarily caused by central venous catheters (CVC). To increase our knowledge about the involvement of the gut microbiota in LOS, we analyzed fecal samples from septic infants without a CVC. In this prospective multicenter study, fecal samples were collected daily from all infants born at ≤30 weeks gestation. Fecal VOC profiles up to 3 days prior to sepsis onset from infants with non-catheter-related LOS were compared with profiles from non-septic controls by means of High-Field Asymmetric Waveform Ion Mobility Spectrometry. In total, 104 fecal samples were analyzed. Fecal VOC profiles allowed for discrimination between non-catheter-related LOS cases (n = 24) and matched controls (n = 25). Discriminative accuracy increased after focusing on center of origin (area under the curve, sensitivity, specificity; 0.95, 100%, 83%) and after focusing on LOS cases caused by Staphylococcus epidermidis (0.95, 100%, 78%), the most cultured pathogen (n = 11). Fecal VOC profiles of preterm LOS infants without a CVC differed from matched controls underlining the increasing notion that aberrations in gut microbiota composition and activity may play a role in LOS etiology.