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Rapid antibiotic administration is known to improve sepsis outcomes, however early diagnosis remains challenging due to complex presentation. Our objective was to develop a model using readily available electronic health record (EHR) data capable of recognizing infant sepsis at least 4 hours prior to clinical recognition. We performed a retrospective case control study of infants hospitalized ≥48 hours in the Neonatal Intensive Care Unit (NICU) at the Children's Hospital of Philadelphia between September 2014 and November 2017 who received at least one sepsis evaluation before 12 months of age. We considered two evaluation outcomes as cases: culture positive-positive blood culture for a known pathogen (110 evaluations); and clinically positive-negative cultures but antibiotics administered for ≥120 hours (265 evaluations). Case data was taken from the 44-hour window ending 4 hours prior to evaluation. We randomly sampled 1,100 44-hour windows of control data from all times ≥10 days removed from any evaluation. Model inputs consisted of up to 36 features derived from routine EHR data. Using 10-fold nested cross-validation, 8 machine learning models were trained to classify inputs as sepsis positive or negative. When tasked with discriminating culture positive cases from controls, 6 models achieved a mean area under the receiver operating characteristic (AUC) between 0.80-0.82 with no significant differences between them. Including both culture and clinically positive cases, the same 6 models achieved an AUC between 0.85-0.87, again with no significant differences. Machine learning models can identify infants with sepsis in the NICU hours prior to clinical recognition. Learning curves indicate model improvement may be achieved with additional training examples. Additional input features may also improve performance. Further research is warranted to assess potential performance improvements and clinical efficacy in a prospective trial.

ObjectiveTo determine how hypotension in the first 48 h of sepsis management impacts acute kidney injury (AKI) development and persistence.Study designRetrospective study of patients > 1 month to < 20 years old with sepsis in a pediatric ICU between November 2012 and January 2015 (n = 217). All systolic blood pressure (SBP) data documented within 48 h after sepsis recognition were collected and converted to percentiles for age, sex, and height. Time below SBP percentiles and below pediatric advanced life support (PALS) targets was calculated by summing elapsed time under SBP thresholds during the first 48 h. The primary outcome was new or persistent AKI, defined as stage 2 or 3 AKI present between sepsis day 3–7 using Kidney Disease: Improving Global Outcomes creatinine definitions. Secondary outcomes included AKI-free days (days alive and free of AKI) and time to kidney recovery.ResultsFifty of 217 sepsis patients (23%) had new or persistent AKI. Patients with AKI spent a median of 35 min under the first SBP percentile, versus 4 min in those without AKI. After adjustment for potential confounders, the odds of AKI increased by 9% with each doubling of minutes spent under this threshold (p = 0.03). Time under the first SBP percentile was also associated with fewer AKI-free days (p = 0.02). Time spent under PALS targets was not associated with AKI.ConclusionsThe duration of severe systolic hypotension in the first 48 h of pediatric sepsis management is associated with AKI incidence and duration when defined by age, sex, and height norms, but not by PALS definitions.

BackgroundThe Child Opportunity Index (COI) is a multidimensional measure of US neighbourhood-level conditions needed for healthy development. COI is associated with healthcare delivery and outcomes. Formal quality improvement (QI) may influence the relationship between COI, quality of care and outcomes in children.ObjectiveTo assess the association between COI and paediatric sepsis care delivery and outcomes and determine if baseline disparities in care change over time among hospitals in the Improving Pediatric Sepsis Outcomes (IPSO) collaborative.MethodsRetrospective cohort study of IPSO patients probabilistically linked to the Pediatric Health Information System database from 2017 to 2021. Primary exposure was COI. We estimated differences in the proportions of patients in each COI quintile identified via standardised sepsis recognition protocols (screening tool, huddle documentation and/or order set use) and who received a bundle of recommended care (standardised sepsis recognition, plus bolus <1 hour and antibiotic <3 hours). We further assessed the timeliness of each bundle component and mortality. We evaluated changes in standardised sepsis recognition over time using generalised linear models.Results31 260 sepsis cases from 24 hospitals were included. Cross-sectional analysis over the entire study period found patients in the Very High COI quintile were most likely to be identified via standardised recognition protocols and receive IPSO’s recommended care bundle (67.7% and 46%, respectively). Over time, standardised sepsis recognition improved for all; the greatest improvements were among inpatients in the Very Low COI quintile.ConclusionDisparities exist in paediatric sepsis care delivery by COI. Over the course of the IPSO collaborative, care improved most for children in the lowest COI quintile. QI collaboratives focused on standardisation and shared learning may reduce disparities.

In 2015, we founded Pedi Lyme Net, a pediatric Lyme disease research network comprising 8 emergency departments in the United States. Of 2,497 children evaluated at 1 of these sites for Lyme disease, 515 (20.6%) were infected. This network is a unique resource for evaluating new approaches for diagnosing Lyme disease in children.

IntroductionSepsis affects 25.2 million children per year globally and causes 3.4 million deaths, with an annual cost of hospitalisation in the USA of US$7.3 billion. Despite being common, severe and expensive, therapies and outcomes from sepsis have not substantially changed in decades. Variable case definitions, lack of a reference standard for diagnosis and broad spectrum of disease hamper efforts to evaluate therapies that may improve sepsis outcomes. This landscape analysis of community-acquired childhood sepsis in Australia and New Zealand will characterise the burden of disease, including incidence, severity, outcomes and cost. Sepsis diagnostic criteria and risk stratification tools will be prospectively evaluated. Sepsis therapies, quality of care, parental awareness and understanding of sepsis and parent-reported outcome measures will be described. Understanding these aspects of sepsis care is fundamental for the design and conduct of interventional trials to improve childhood sepsis outcomes.Methods and analysisThis prospective observational study will include children up to 18 years of age presenting to 12 emergency departments with suspected sepsis within the Paediatric Research in Emergency Departments International Collaborative network in Australia and New Zealand. Presenting characteristics, management and outcomes will be collected. These will include vital signs, serum biomarkers, clinician assessment of severity of disease, intravenous fluid administration for the first 24 hours of hospitalisation, organ support therapies delivered, antimicrobial use, microbiological diagnoses, hospital and intensive care unit length-of-stay, mortality censored at hospital discharge or 30 days from enrolment (whichever comes first) and parent-reported outcomes 90 days from enrolment. We will use these data to determine sepsis epidemiology based on existing and novel diagnostic criteria. We will also validate existing and novel sepsis risk stratification criteria, characterise antimicrobial stewardship, guideline adherence, cost and report parental awareness and understanding of sepsis and parent-reported outcome measures.Ethics and disseminationEthics approval was received from the Royal Children’s Hospital of Melbourne, Australia Human Research Ethics Committee (HREC/69948/RCHM-2021). This included incorporated informed consent for follow-up. The findings will be disseminated in a peer-reviewed journal and at academic conferences.Trial registration numberACTRN12621000920897; Pre-results.

Sepsis is a major cause of morbidity and mortality in children. While adverse outcomes can be reduced through prompt initiation of sepsis protocols including fluid resuscitation and antibiotics, provision of these therapies relies on clinician recognition of sepsis. Recognition is challenging in children because early signs of shock such as tachycardia and tachypnea have low specificity while hypotension often does not occur until late in the clinical course. This narrative review highlights the important context that has led to the rapid growth of pediatric sepsis screening in the United States. In this review, we (1) describe different screening tools used in US emergency department, inpatient, and intensive care unit settings; (2) highlight details of the design, implementation, and evaluation of specific tools; (3) review the available data on the process of integrating sepsis screening into an overall sepsis quality improvement program and on the effect of these screening tools on patient outcomes; (4) discuss potential harms of sepsis screening including alarm fatigue; and (5) highlight several future directions in sepsis screening, such as novel tools that incorporate artificial intelligence and machine learning methods to augment sepsis identification with the ultimate goal of precision-based approaches to sepsis recognition and treatment.ImpactThis narrative review highlights the context that has led to the rapid growth of pediatric sepsis screening nationally.Screening tools used in US emergency department, inpatient, and intensive care unit settings are described in terms of their design, implementation, and clinical performance.Limitations and potential harms of these tools are highlighted, as well as future directions that may lead to a more precision-based approach to sepsis recognition and treatment.

Due to the life cycle of its vector, Lyme disease has known seasonal variation. However, investigations focused on children have been limited. Our objective was to evaluate the seasonality of pediatric Lyme disease in three endemic regions in the United States. We enrolled children presenting to one of eight Pedi Lyme Net participating emergency departments. Cases were classified based on presenting symptoms: early (single erythema migrans (EM) lesion), early-disseminated (multiple EM lesions, headache, cranial neuropathy, or carditis), or late (arthritis). We defined a case of Lyme disease by the presence of an EM lesion or a positive two-tier Lyme disease serology. To measure seasonal variability, we estimated Fourier regression models to capture cyclical patterns in Lyme disease incidence. While most children with early or early-disseminated Lyme disease presented during the summer months, children with Lyme arthritis presented throughout the year. Clinicians should consider Lyme disease when evaluating children with acute arthritis throughout the year.

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

Objective Mitochondrial dysfunction, linked to sepsis-related organ failure, is unknown in febrile illness. Methods Prospective study of children in an Emergency Department (ED) with febrile illness or without infection (ED controls); secondary analysis of ICU patients with sepsis or without infection (ICU controls). Mitochondrial oxygen consumption measured in peripheral blood mononuclear cells using respirometry, with primary outcome of spare respiratory capacity (SRC). Mitochondrial content measured as citrate synthase (CS: febrile illness and ED controls) and mitochondrial to nuclear DNA ratio (mtDNA:nDNA: all groups). Results SRC was lower in febrile illness (6.7 ± 3.0 pmol/sec/10 6 cells) and sepsis (5.7 ± 4.7) than ED/PICU controls (8.5 ± 3.7; both p  < 0.05), but not different between febrile illness and sepsis ( p  = 0.26). Low SRC was driven by increased basal respiration in febrile illness and decreased maximal uncoupled respiration in sepsis. Differences were no longer significant after adjustment for patient demographics. Febrile illness demonstrated lower CS activity than ED controls ( p  = 0.07) and lower mtDNA:nDNA than both ED/PICU controls and sepsis (both p  < 0.05). Conclusion Mitochondrial SRC was reduced in both febrile illness and sepsis, but due to distinct mitochondrial profiles and impacted by demographics. Further work is needed to determine if mitochondrial profiles could differentiate febrile illness from early sepsis. Impact statement Mitochondrial dysfunction has been linked to organ failure in sepsis, but whether mitochondrial alterations are evident in febrile illness without sepsis is unknown. In our study, while mitochondrial spare respiratory capacity (SRC), an index of cellular bioenergetic reserve under stress, was reduced in children with both febrile illness and sepsis compared to children without infections, low SRC was driven by increased basal respiration in febrile illness compared with decreased maximal uncoupled respiration in sepsis. Additional research is needed to understand if distinct mitochondrial profiles could be used to differentiate febrile illness from early sepsis in children.