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To validate a computational phenotype that identifies acute brain dysfunction (ABD) based on clinician concern for neurologic or behavioral changes in pediatric sepsis.Retrospective observational study.Single academic children's hospital.Four thousand two hundred eighty-nine index sepsis episodes.None.An existing computational phenotype of ABD was optimized to include routinely collected variables indicative of clinician concern for acute neurologic or behavioral change (completion of CT or MRI, electroencephalogram, or new antipsychotic administration). First, the computational phenotype was compared with an ABD reference standard established from chart review of 527 random sepsis episodes to determine criterion validity. Next, the computational phenotype was compared with a separate validation cohort of 3,762 index sepsis episodes to determine content and construct validity. Criterion validity for the final phenotype had sensitivity 83% (95% CI, 76-89%), specificity 93% (90-95%), positive predictive value 84% (77-89%), and negative predictive value 93% (90-96%). In the validation cohort, the computational phenotype identified ABD in 35% (95% CI 33-36%). Content validity was demonstrated as those with the ABD computational phenotype were more likely to have characteristics of neurologic dysfunction and severe illness than those without the ABD phenotype, including nonreactive pupils (15% vs 1%; p0.001), Glasgow Coma Scale less than 5 (44% vs 12%; p0.001), greater than or equal to two nonneurologic organ dysfunctions (50% vs 25%; p0.001), and need for intensive care (81% vs 65%; p0.001). Construct validity was demonstrated by higher odds for mortality (odds ratio [OR], 6.9; 95% CI, 5.3-9.1) and discharge to rehabilitation (OR, 11.4; 95% CI 7.4-17.5) in patients with, versus without, the ABD computational phenotype.A computational phenotype of ABD indicative of clinician concern for new neurologic or behavioral change offers a valid retrospective measure to identify episodes of sepsis that involved ABD. This computational phenotype provides a feasible and efficient way to study risk factors for and outcomes from ABD using routinely collected clinical data.

IMPORTANCE: Pediatric sepsis definitions have evolved, and some have proposed using the measure used in adults to quantify organ dysfunction, a Sequential Organ Failure Assessment (SOFA) score of 2 or more in the setting of suspected infection. A pediatric adaptation of SOFA (pSOFA) showed excellent discrimination for mortality in critically ill children but has not been evaluated in an emergency department (ED) population. OBJECTIVE: To delineate test characteristics of the pSOFA score for predicting in-hospital mortality among (1) all patients and (2) patients with suspected infection treated in pediatric EDs. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study took place from January 1, 2012, to January 31, 2020 in 9 US children’s hospitals included in the Pediatric Emergency Care Applied Research Network (PECARN) Registry. The data was analyzed from February 1, 2020, to April 18, 2022. All ED visits for patients younger than 18 years were included. EXPOSURES: ED pSOFA score was assigned by summing maximum pSOFA organ dysfunction components during ED stay (each 0-4 points). In the subset with suspected infection, visit meeting criteria for sepsis (suspected infection with a pSOFA score of 2 or more) and septic shock (suspected infection with vasoactive infusion and serum lactate level >18.0 mg/dL) were identified. MAIN OUTCOMES AND MEASURES: Test characteristics of pSOFA scores of 2 or more during the ED stay for hospital mortality. RESULTS: A total of 3 999 528 (female, 47.3%) ED visits were included. pSOFA scores ranged from 0 to 16, with 126 250 visits (3.2%) having a pSOFA score of 2 or more. pSOFA scores of 2 or more had sensitivity of 0.65 (95% CI, 0.62-0.67) and specificity of 0.97 (95% CI, 0.97-0.97), with negative predictive value of 1.0 (95% CI, 1.00-1.00) in predicting hospital mortality. Of 642 868 patients with suspected infection (16.1%), 42 992 (6.7%) met criteria for sepsis, and 374 (0.1%) met criteria for septic shock. Hospital mortality rates for suspected infection (599 502), sepsis (42 992), and septic shock (374) were 0.0%, 0.9%, and 8.0%, respectively. The pSOFA score had similar discrimination for hospital mortality in all ED visits (area under receiver operating characteristic curve, 0.81; 95% CI, 0.79-0.82) and the subset with suspected infection (area under receiver operating characteristic curve, 0.82; 95% CI, 0.80-0.84). CONCLUSIONS AND RELEVANCE: In a large, multicenter study of pediatric ED visits, a pSOFA score of 2 or more was uncommon and associated with increased hospital mortality yet had poor sensitivity as a screening tool for hospital mortality. Conversely, children with a pSOFA score of 2 or less were at very low risk of death, with high specificity and negative predictive value. Among patients with suspected infection, patients with pSOFA-defined septic shock demonstrated the highest mortality.

Multisystem inflammatory syndrome in children (MIS-C) is a syndrome of abnormal immune response after severe acute respiratory syndrome coronavirus 2 infection that can result in organ dysfunction including severe cardiovascular compromise in children. Increased evidence supports a clinical and laboratory profile in MIS-C distinct from Kawasaki disease, with MIS-C typically occurring in older children and with more prominent gastrointestinal and neurologic symptoms, as well as increased inflammation, lymphopenia, and cardiac injury on laboratory testing. However, high-level evidence regarding best practices for treatment and long-term outcomes in MIS-C is limited.

OBJECTIVE: Heterogeneity has hampered sepsis trials, and sub-phenotyping may assist with enrichment strategies. However, biomarker-based strategies are difficult to operationalize. Four sub-phenotypes defined by distinct temperature trajectories in the first 72 hours have been reported in adult sepsis. Given the distinct epidemiology of pediatric sepsis, the existence and relevance of temperature trajectory-defined sub-phenotypes in children is unknown. We aimed to classify septic children into de novo sub-phenotypes derived from temperature trajectories in the first 72 hours, and compare cytokine, immune function, and immunometabolic markers across subgroups. METHODS: This was a secondary analysis of a prospective cohort of 191 critically ill septic children recruited from a single academic pediatric intensive care unit. We performed group-based trajectory modeling using temperatures over the first 72 hours of sepsis to identify latent profiles. We then used mixed effects regression to determine if temperature trajectory-defined sub-phenotypes were associated with cytokine levels, immune function, and mitochondrial respiration. RESULTS: We identified four temperature trajectory-defined sub-phenotypes: hypothermic, normothermic, hyperthermic fast-resolvers, and hyperthermic slow-resolvers. Hypothermic patients were less often previously healthy and exhibited lower levels of pro- and anti-inflammatory cytokines and chemokines. Hospital mortality did not differ between hypothermic children (17%) and other sub-phenotypes (3 to 11%; p = 0.26). CONCLUSIONS: Critically ill septic children can be categorized into temperature trajectory-defined sub-phenotypes that parallel adult sepsis. Hypothermic children exhibit a blunted cytokine and chemokine profile. Group-based trajectory modeling has utility for identifying subtypes of clinical syndromes by incorporating readily available longitudinal data, rather than relying on inputs from a single timepoint.

Objective:To describe the cumulative seroprevalence of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) antibodies during the coronavirus disease 2019 (COVID-19) pandemic among employees of a large pediatric healthcare system.Design, setting, and participants:Prospective observational cohort study open to adult employees at the Children’s Hospital of Philadelphia, conducted April 20–December 17, 2020.Methods:Employees were recruited starting with high-risk exposure groups, utilizing e-mails, flyers, and announcements at virtual town hall meetings. At baseline, 1 month, 2 months, and 6 months, participants reported occupational and community exposures and gave a blood sample for SARS-CoV-2 antibody measurement by enzyme-linked immunosorbent assays (ELISAs). A post hoc Cox proportional hazards regression model was performed to identify factors associated with increased risk for seropositivity.Results:In total, 1,740 employees were enrolled. At 6 months, the cumulative seroprevalence was 5.3%, which was below estimated community point seroprevalence. Seroprevalence was 5.8% among employees who provided direct care and was 3.4% among employees who did not perform direct patient care. Most participants who were seropositive at baseline remained positive at follow-up assessments. In a post hoc analysis, direct patient care (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.03–3.68), Black race (HR, 2.70; 95% CI, 1.24–5.87), and exposure to a confirmed case in a nonhealthcare setting (HR, 4.32; 95% CI, 2.71–6.88) were associated with statistically significant increased risk for seropositivity.Conclusions:Employee SARS-CoV-2 seroprevalence rates remained below the point-prevalence rates of the surrounding community. Provision of direct patient care, Black race, and exposure to a confirmed case in a nonhealthcare setting conferred increased risk. These data can inform occupational protection measures to maximize protection of employees within the workplace during future COVID-19 waves or other epidemics.

Background/aims Despite evidence that preferential use of balanced/buffered fluids may improve outcomes compared with chloride-rich 0.9% saline, saline remains the most commonly used fluid for children with septic shock. We aim to determine if resuscitation with balanced/buffered fluids as part of usual care will improve outcomes, in part through reduced kidney injury and without an increase in adverse effects, compared to 0.9% saline for children with septic shock. Methods The Pragmatic Pediatric Trial of Balanced versus Normal Saline Fluid in Sepsis (PRoMPT BOLUS) study is an international, open-label pragmatic interventional trial being conducted at > 40 sites in the USA, Canada, and Australia/New Zealand starting on August 25, 2020, and continuing for 5 years. Children > 6 months to Discussion PRoMPT BOLUS will provide high-quality evidence for the comparative effectiveness of buffered/balanced crystalloids versus 0.9% saline for the initial fluid management of children with suspected septic shock in emergency settings. Trial registration PRoMPT BOLUS was first registered at ClinicalTrials.gov (NCT04102371) on September 25, 2019. Enrollment started on August 25, 2020.

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. Impact This 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.

Black children with Lyme disease compared with children of other races were less likely to have an erythema migrans lesion diagnosed (adjusted odds ratio, 0.34; 95% confidence interval, .14-.79) but more likely to have a swollen joint (adjusted odds ratio, 3.68; 95% confidence interval, 2.13-6.36) after adjustment for age and local Lyme incidence.

Background Bacterial meningitis in low-risk febrile young infants (FYIs) aged >28 days has become increasingly rare. Routine performance of lumbar puncture (LP) in these infants is associated with adverse consequences and may be unnecessary. We modified our clinical practice guideline (CPG) to reduce the number of FYIs 29 to 56 days old who receive LP. Methods This quality improvement project sought to modify a preexisting CPG to diagnose and manage FYIs 0 to 56 days old that eliminated routine performance of LP in children 29 to 56 days old who were considered low-risk for serious bacterial infection. The change was implemented by making adjustments to the online CPG. A statistical process control chart was used to assess the affect of the initiative on our primary outcome of LP rate in this population of FYIs. Results Postimplementation of the CPG initiative, 71% of FYIs 29 to 56 days old did not receive LP, compared with 42% preimplementation. This practice change was also associated with fewer hospitalizations, lower median emergency department (ED) length of stay, and fewer 72-hour ED revisits. Over 3 years of sustained practice, 1/713 (0.1%; 95% confidence interval, 0%-0.8%) low-risk FYI returned within 72 hours and was subsequently treated for probable bacterial meningitis, although cerebrospinal fluid culture was negative for bacterial growth. Conclusions A change in CPG reduced the number of LPs performed in febrile infants 29 to 56 days old. This change resulted in fewer LPs, hospitalizations, ED revisits, and a lower ED length of stay for FYIs 29 to 56 days old.

Objective In Lyme disease endemic areas, Lyme and septic arthritis often present similarly. A published septic knee arthritis clinical prediction rule includes 2 high-risk predictors: absolute neutrophil count of 10,000 cells/mm or greater and erythrocyte sedimentation rate of 40 mm/h or greater. The objective of the study was to externally validate this prediction rule in a multicenter prospective cohort. Methods We enrolled a prospective cohort of children with knee monoarthritis undergoing evaluation for Lyme disease at 1 of 8 Pedi Lyme Net emergency departments located in endemic areas. We defined a case of septic arthritis with a positive synovial fluid culture or a synovial fluid white blood cell count of 50,000 or greater per high powered field with a positive blood culture and Lyme arthritis with a positive or equivocal C6 EIA, followed by a positive supplemental immunoblot. Other children were classified as having inflammatory arthritis. We report the performance of the septic arthritis clinical prediction rule in our study population. Results Of the 543 eligible children, 13 had septic arthritis (2.4%), 234 Lyme arthritis (43.1%), and 296 inflammatory arthritis (54.5%). Of the 457 children (84.2%) with available laboratory predictors, all children with septic arthritis were classified as high risk (sensitivity, 100%; 95% confidence interval [CI], 62.8%-100%; specificity, 68.1%; 95% CI, 63.6-73.3; negative predictive value, 278/278 [100%]; 95% CI, 98.6%-100%). Of the 303 low-risk children, 52 (17.2%) underwent diagnostic arthrocentesis. Conclusions The septic knee arthritis clinical prediction rule accurately distinguished between septic and Lyme arthritis in an endemic area. Clinical application may reduce unnecessary invasive diagnostic procedures.

BACKGROUND The Rule of 7's classifies children as low-risk for Lyme meningitis with the absence of the following: ≥7 days of headache, any cranial neuritis or ≥70% cerebrospinal fluid mononuclear cells. We sought to broadly validate this clinical prediction rule in children with meningitis undergoing evaluation for Lyme disease. METHODS We performed a patient-level data meta-analysis of 2 prospective and 2 retrospective cohorts of children ≤21 years of age with cerebrospinal fluid pleocytosis who underwent evaluation for Lyme disease. We defined a case of Lyme meningitis with a positive 2-tier serology result (positive or equivocal first-tier enzyme immunoassay followed by a positive supplemental immunoblot). We applied the Rule of 7's and report the accuracy for the identification of Lyme meningitis. RESULTS Of 721 included children with meningitis, 178 had Lyme meningitis (24.7%) and 543 had aseptic meningitis (75.3%). The pooled data from the 4 studies showed the Rule of 7's has a sensitivity of 98% [95% confidence interval (CI): 89%-100%, I2 = 71%], specificity 40% (95% CI: 30%-50%, I2 = 75%), and a negative predictive value of 100% (95% CI: 95%-100%, I2 = 55%). CONCLUSIONS The Rule of 7's accurately identified children with meningitis at low-risk for Lyme meningitis for whom clinicians should consider outpatient management while awaiting Lyme disease test results.

It is unknown whether febrile infants 29 to 60 days old with positive urinalysis results require routine lumbar punctures for evaluation of bacterial meningitis.To determine the prevalence of bacteremia and/or bacterial meningitis in febrile infants ≤60 days of age with positive urinalysis (UA) results.Secondary analysis of a prospective observational study of noncritical febrile infants ≤60 days between 2011 and 2019 conducted in the Pediatric Emergency Care Applied Research Network emergency departments. Participants had temperatures ≥38°C and were evaluated with blood cultures and had UAs available for analysis. We report the prevalence of bacteremia and bacterial meningitis in those with and without positive UA results.Among 7180 infants, 1090 (15.2%) had positive UA results. The risk of bacteremia was higher in those with positive versus negative UA results (63/1090 [5.8%] vs 69/6090 [1.1%], difference 4.7% [3.3% to 6.1%]). There was no difference in the prevalence of bacterial meningitis in infants ≤28 days of age with positive versus negative UA results (∼1% in both groups). However, among 697 infants aged 29 to 60 days with positive UA results, there were no cases of bacterial meningitis in comparison to 9 of 4153 with negative UA results (0.2%, difference -0.2% [-0.4% to -0.1%]). In addition, there were no cases of bacteremia and/or bacterial meningitis in the 148 infants ≤60 days of age with positive UA results who had the Pediatric Emergency Care Applied Research Network low-risk blood thresholds of absolute neutrophil count4 × 103 cells/mm3 and procalcitonin0.5 ng/mL.Among noncritical febrile infants ≤60 days of age with positive UA results, there were no cases of bacterial meningitis in those aged 29 to 60 days and no cases of bacteremia and/or bacterial meningitis in any low-risk infants based on low-risk blood thresholds in both months of life. These findings can guide lumbar puncture use and other clinical decision making.

OBJECTIVES: To describe the characteristics and outcomes of afebrile infants ≤60 days old with invasive bacterial infection (IBI). METHODS: We conducted a secondary analysis of a cross-sectional study of infants ≤60 days old with IBI presenting to the emergency departments (EDs) of 11 children’s hospitals from 2011 to 2016. We classified infants as afebrile if there was absence of a temperature ≥38°C at home, at the referring clinic, or in the ED. Bacteremia and bacterial meningitis were defined as pathogenic bacterial growth from a blood and/or cerebrospinal fluid culture. RESULTS: Of 440 infants with IBI, 78 (18%) were afebrile. Among afebrile infants, 62 (79%) had bacteremia without meningitis and 16 (20%) had bacterial meningitis (10 with concomitant bacteremia). Five infants (6%) died, all with bacteremia. The most common pathogens were Streptococcus agalactiae (35%), Escherichia coli (16%), and Staphylococcus aureus (16%). Sixty infants (77%) had an abnormal triage vital sign (temperature 15 000 cells per μL, absolute band count >1500 cells per μl, or positive urinalysis. Presence of an abnormal vital sign, examination finding, or laboratory test result had a sensitivity of 91% (95% confidence interval 82%–96%) for IBI. CONCLUSIONS: Most afebrile young infants with an IBI had vital sign, examination, or laboratory abnormalities. Future studies should evaluate the predictive ability of these criteria in afebrile infants undergoing evaluation for IBI.

Key Points sC5b9 plasma levels are elevated in children with SARS-CoV-2 infection, even if they have minimal symptoms of COVID-19. A high proportion of children with SARS-CoV-2 infection met clinical criteria for TMA., Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C., Visual Abstract

Objectives To describe the Children's Hospital Association's Improving Pediatric Sepsis Outcomes sepsis definitions and the identified patients; evaluate the definition using a published framework for evaluating sepsis definitions. Design Observational cohort. Setting Multicenter quality improvement collaborative of 46 hospitals from January 2017 to December 2018, excluding neonatal ICUs. Patients Improving Pediatric Sepsis Outcomes Sepsis was defined by electronic health record evidence of suspected infection and sepsis treatment or organ dysfunction. A more severely ill subgroup, Improving Pediatric Sepsis Outcomes Critical Sepsis, was defined, approximating septic shock. Interventions Participating hospitals identified patients, extracted data, and transferred de-identified data to a central data warehouse. The definitions were evaluated across domains of reliability, content validity, construct validity, criterion validity, measurement burden, and timeliness. Measurements and main results Forty hospitals met data quality criteria across four electronic health record platforms. There were 23,976 cases of Improving Pediatric Sepsis Outcomes Sepsis, including 8,565 with Improving Pediatric Sepsis Outcomes Critical Sepsis. The median age was 5.9 years. There were 10,316 (43.0%) immunosuppressed or immunocompromised patients, 4,135 (20.3%) with central lines, and 2,352 (11.6%) chronically ventilated. Among Improving Pediatric Sepsis Outcomes Sepsis patients, 60.8% were admitted to intensive care, 26.4% had new positive-pressure ventilation, and 19.7% received vasopressors. Median hospital length of stay was 6.0 days (3.0-13.0 d). All-cause 30-day in-hospital mortality was 958 (4.0%) in Improving Pediatric Sepsis Outcomes Sepsis; 541 (6.3%) in Improving Pediatric Sepsis Outcomes Critical Sepsis. The Improving Pediatric Sepsis Outcomes Sepsis definitions demonstrated strengths in content validity, convergent construct validity, and criterion validity; weakness in reliability. Improving Pediatric Sepsis Outcomes Sepsis definitions had significant initial measurement burden (median time from case completion to submission: 15 mo [interquartile range, 13-18 mo]); timeliness improved once data capture was established (median, 26 d; interquartile range, 23-56 d). Conclusions The Improving Pediatric Sepsis Outcomes Sepsis definitions demonstrated feasibility for large-scale data abstraction. The patients identified provide important information about children treated for sepsis. When operationalized, these definitions enabled multicenter identification and data aggregation, indicating practical utility for quality improvement.

Objective To characterize the cohort of missed sepsis patients since implementation of an electronic sepsis alert in a pediatric emergency department (ED). Methods Retrospective cohort study in a tertiary care children's hospital ED from July 1, 2014, to June 30, 2017. Missed patients met international consensus criteria for severe sepsis requiring intensive care unit admission within 24 hours of ED stay but were not treated with the sepsis pathway/order set in the ED. We evaluated characteristics of missed patients compared with sepsis pathway patients including alert positivity, prior intensive care unit admission, and laboratory testing via medical record review. Outcomes included timeliness of antibiotic therapy and need for vasoactive medications. Results There were 919 sepsis pathway patients and 53 (5%) missed patients during the study period. Of the missed patients, 41 (77%) had vital signs that flagged the sepsis alert. Of these 41 patients, 13 (32%) had a documented sepsis huddle where the team determined that the sepsis pathway was not indicated and 28 (68%) had no sepsis alert-related documentation. Missed patients were less likely to receive timely antibiotics (relative risk, 0.4; 95% confidence interval, 0.3-0.7) and more likely to require vasoactive medications (relative risk, 4.3; 95% confidence interval, 2.9-6.5) compared with sepsis patients. Conclusions In an ED with an electronic sepsis alert, missed patients often had positive sepsis alerts but were not treated for sepsis. Missed patients were more likely than sepsis pathway patients to require escalation of care after admission and less likely to receive timely antibiotics.

Background A "champagne tap" is a lumbar puncture with no cerebrospinal fluid (CSF) red blood cells (RBCs). Clinicians disagree whether the absence of CSF white blood cells (WBCs) is also required. Aims As supervising providers frequently reward trainees after a champagne tap, we investigated how varying the definition impacted the frequency of trainee accolades. Materials & methods We performed a secondary analysis of a retrospective cross-sectional study of infants ≤60 days of age who had a CSF culture performed in the emergency department (ED) at one of 20 centers participating in a Pediatric Emergency Medicine Collaborative Research Committee (PEM CRC) endorsed study. Our primary outcomes were a champagne tap defined by either a CSF RBC count of 0 cells/mm3 regardless of CSF WBC count or both CSF RBC and WBC counts of 0 cells/mm3 . Results Of the 23,618 eligible encounters, 20,358 (86.2%) had both a CSF RBC and WBC count obtained. Overall, 3,147 (13.3%) had a CSF RBC count of 0 cells/mm3 and 377 (1.6%) had both CSF WBC and RBC counts of 0 cells/mm3 (relative rate 8.35, 95% confidence interval 7.51 to 9.27). Conclusions In infants, a lumbar puncture with a CSF RBC count of 0 cells/mm3 regardless of the CSF WBC count occurred eight-times more frequently than one with both CSF WBC and RBC counts of 0 cells/mm3 . A broader champagne tap definition would allow more frequent recognition of procedural success, with the potential to foster a supportive community during medical training, potentially protecting against burnout.

OBJECTIVE: To derive and validate a model of risk of septic shock among children with suspected sepsis, using data known in the electronic health record at hospital arrival. STUDY DESIGN: This observational cohort study at 6 pediatric emergency department and urgent care sites used a training dataset (5 sites, April 1, 2013, to December 31, 2016), a temporal test set (5 sites, January 1, 2017 to June 30, 2018), and a geographic test set (a sixth site, April 1, 2013, to December 31, 2018). Patients 60 days to 18 years of age in whom clinicians suspected sepsis were included; patients with septic shock on arrival were excluded. The outcome, septic shock, was systolic hypotension with vasoactive medication or ≥30 mL/kg of isotonic crystalloid within 24 hours of arrival. Elastic net regularization, a penalized regression technique, was used to develop a model in the training set. RESULTS: Of 2464 included visits, septic shock occurred in 282 (11.4%). The model had an area under the curve of 0.79 (0.76–0.83) in the training set, 0.75 (0.69–0.81) in the temporal test set, and 0.87 (0.73–1.00) in the geographic test set. With a threshold set to 90% sensitivity in the training set, the model yielded 82% (72%−90%) sensitivity and 48% (44%−52%) specificity in the temporal test set, and 90% (55%−100%) sensitivity and 32% (21%−46%) specificity in the geographic test set. CONCLUSIONS: This model estimated the risk of septic shock in children at hospital arrival earlier than existing models. It leveraged the predictive value of routine electronic health record data through a modern predictive algorithm and has the potential to enhance clinical risk stratification in the critical moments before deterioration.

OBJECTIVES A method to identify pediatric sepsis episodes that is not affected by changing diagnosis and claims-based coding practices does not exist. We derived and validated a surveillance algorithm to identify pediatric sepsis using routine clinical data and applied the algorithm to study longitudinal trends in sepsis epidemiology. DESIGN Retrospective observational study. SETTING Single academic children's hospital. PATIENTS All emergency and hospital encounters from January 2011 to January 2019, excluding neonatal ICU and cardiac center. EXPOSURE Sepsis episodes identified by a surveillance algorithm using clinical data to identify infection and concurrent organ dysfunction. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A surveillance algorithm was derived and validated in separate cohorts with suspected sepsis after clinician-adjudication of final sepsis diagnosis. We then applied the surveillance algorithm to determine longitudinal trends in incidence and mortality of pediatric sepsis over 8 years. Among 93,987 hospital encounters and 1,065 episodes of suspected sepsis in the derivation period, the surveillance algorithm yielded sensitivity 78% (95% CI, 72-84%), specificity 76% (95% CI, 74-79%), positive predictive value 41% (95% CI, 36-46%), and negative predictive value 94% (95% CI, 92-96%). In the validation period, the surveillance algorithm yielded sensitivity 84% (95% CI, 77-92%), specificity of 65% (95% CI, 59-70%), positive predictive value 43% (95% CI, 35-50%), and negative predictive value 93% (95% CI, 90-97%). Notably, most "false-positives" were deemed clinically relevant sepsis cases after manual review. The hospital-wide incidence of sepsis was 0.69% (95% CI, 0.67-0.71%), and the inpatient incidence was 2.8% (95% CI, 2.7-2.9%). Risk-adjusted sepsis incidence, without bias from changing diagnosis or coding practices, increased over time (adjusted incidence rate ratio per year 1.07; 95% CI, 1.06-1.08; p < 0.001). Mortality was 6.7% and did not change over time (adjusted odds ratio per year 0.98; 95% CI, 0.93-1.03; p = 0.38). CONCLUSIONS An algorithm using routine clinical data provided an objective, efficient, and reliable method for pediatric sepsis surveillance. An increased sepsis incidence and stable mortality, free from influence of changes in diagnosis or billing practices, were evident.

OBJECTIVES The pediatric emergency department (ED)–based Pediatric Septic Shock Collaborative (PSSC) aimed to improve mortality and key care processes among children with presumed septic shock. METHODS This was a multicenter learning and improvement collaborative of 19 pediatric EDs from November 2013 to May 2016 with shared screening and patient identification recommendations, bundles of care, and educational materials. Process metrics included minutes to initial vital sign assessment and to first and third fluid bolus and antibiotic administration. Outcomes included 3- and 30-day all-cause in-hospital mortality, hospital and ICU lengths of stay, hours on increased ventilation (including new and increases from chronic baseline in invasive and noninvasive ventilation), and hours on vasoactive agent support. Analysis used statistical process control charts and included both the overall sample and an ICU subgroup. RESULTS Process improvements were noted in timely vital sign assessment and receipt of antibiotics in the overall group. Timely first bolus and antibiotics improved in the ICU subgroup. There was a decrease in 30-day all-cause in-hospital mortality in the overall sample. CONCLUSIONS A multicenter pediatric ED improvement collaborative showed improvement in key processes for early sepsis management and demonstrated that a bundled quality improvement–focused approach to sepsis management can be effective in improving care.

To determine whether the receipt of more than or equal to 30 mL/kg of intravenous fluid in the first hour after emergency department (ED) arrival is associated with sepsis-attributable mortality among children with hypotensive septic shock.This is a retrospective cohort study set in 57 EDs in the Improving Pediatric Sepsis Outcomes quality improvement collaborative. Patients less than 18 years of age with hypotensive septic shock who received their first intravenous fluid bolus within 1 hour of arrival at the ED were propensity-score matched for probability of receiving more than or equal to 30 mL/kg in the first hour. Sepsis-attributable mortality was compared. We secondarily evaluated the association between the first-hour fluid volume and sepsis-attributable mortality in all children with suspected sepsis in the first hour after arrival at the ED, regardless of blood pressure.Of the 1,982 subjects who had hypotensive septic shock and received a first fluid bolus within 1 hour of arrival at the ED, 1,204 subjects were propensity matched. In the matched patients receiving more than or equal to 30 mL/kg of fluid, 26 (4.3%) of 602 subjects had 30-day sepsis-attributable mortality compared with 25 (4.2%) of 602 receiving less than 30 mL/kg (odds ratio 1.04, 95% confidence interval 0.59 to 1.83). Among the patients with suspected sepsis regardless of blood pressure, 30-day sepsis-attributable mortality was 3.0% in those receiving more than or equal to 30 mL/kg versus 2.0% in those receiving less than 30 ml/kg (odds ratio 1.52, 95% confidence interval 0.95 to 2.44.) CONCLUSION: In children with hypotensive septic shock receiving a timely first fluid bolus within the first hour of ED care, receiving more than or equal to 30 mL/kg of bolus intravenous fluids in the first hour after arrival at the ED was not associated with mortality compared with receiving less than 30 mL/kg.

Children with a bacterial musculoskeletal infection (MSKI) require prompt identification and treatment. In Lyme disease endemic areas, children with an MSKI can present similarly to those with Lyme arthritis. Our goal was to derive a clinical prediction rule to accurately identify children at a low risk for an MSKI.We enrolled children with monoarthritis presenting to 1 of 6 Pedi Lyme Net centers and performed a procalcitonin (PCT) and a first-tier Lyme C6 enzyme immunoassay (EIA) test. Our primary outcome was an MSKI (septic arthritis, osteomyelitis, or pyomyositis). Using recursive partitioning with k-fold cross validation, we derived a clinical prediction rule to identify children at a low risk of an MSKI. We calculated the accuracy of our novel rule in a derivation cohort.Of the 735 children in the derivation cohort with an available research biosample, 39 (5%) had an MSKI (18 had septic arthritis, 20 had osteomyelitis, and 1 had pyomyositis), 260 (37%) had Lyme arthritis, and 436 (53%) had other inflammatory arthritis. Children with a PCT level of more than or equal to 0.50 ng/mL and those with a C-reactive protein (CRP) level of more than or equal to 0.6 mg/dL with a negative Lyme C6 EIA were classified as not low risk for an MSKI. Of the 451 (61%) children categorized as low risk, none had an MSKI (sensitivity 100%, 95% confidence interval 91.0% to 100%; specificity 74.2%, 95% confidence interval 70.5% to 77.6%).A novel clinical decision rule that includes PCT, CRP, and a first-tier Lyme EIA was highly sensitive for MSKIs. Although broader external validation is required, the application of this rule may safely reduce invasive testing, procedures, and treatment for low risk children.

Background: A history of Lyme disease can complicate the interpretation of Lyme disease serology in acutely symptomatic patients. Materials and Methods: We prospectively enrolled children undergoing evaluation for Lyme disease in the emergency department of one of eight participating Pedi Lyme Net centers. We selected symptomatic children with a Lyme disease history (definite, probable, or none) as well as an available research biosample. We defined a Lyme disease case with either an erythema migrans (EM) lesion or positive two-tier serology with compatible symptoms. Using a generalized estimating equation, we examined the relationship between time from previous Lyme disease diagnosis and current Lyme disease after adjustment for patient demographics and symptoms as well as clustering by center. Results: Of 2501 prospectively enrolled study patients, 126 (5.0%) reported a history of definite or probable Lyme disease. Of these children with previous Lyme disease, 47 met diagnostic criteria for Lyme disease at the time of enrollment (37.3%; 95% confidence interval [CI] 29.1-45.7%); 2 had an EM lesion, and 45 had positive two-tier Lyme disease serology. Over time from the previous Lyme disease diagnosis, the less likely the patient met diagnostic criteria for Lyme disease (adjusted odds ratio 0.62 per time period; 95% CI 0.46-0.84). Conclusions: For children with a history of Lyme disease before enrollment, one-third met the diagnostic criteria for acute Lyme disease with a declining rate over time from previous Lyme disease diagnosis. Novel Lyme disease diagnostics are needed to help distinguish acute from previous Lyme disease.

OBJECTIVES To identify independent predictors of and derive a risk score for invasive herpes simplex virus (HSV) infection. METHODS In this 23-center nested case-control study, we matched 149 infants with HSV to 1340 controls; all were ≤60 days old and had cerebrospinal fluid obtained within 24 hours of presentation or had HSV detected. The primary and secondary outcomes were invasive (disseminated or central nervous system) or any HSV infection, respectively. RESULTS Of all infants included, 90 (60.4%) had invasive and 59 (39.6%) had skin, eyes, and mouth disease. Predictors independently associated with invasive HSV included younger age (adjusted odds ratio [aOR]: 9.1 [95% confidence interval (CI): 3.4–24.5] 28 days), prematurity (aOR: 2.3, 95% CI: 1.1 to 5.1), seizure at home (aOR: 6.1, 95% CI: 2.3 to 16.4), ill appearance (aOR: 4.2, 95% CI: 2.0 to 8.4), abnormal triage temperature (aOR: 2.9, 95% CI: 1.6 to 5.3), vesicular rash (aOR: 54.8, (95% CI: 16.6 to 180.9), thrombocytopenia (aOR: 4.4, 95% CI: 1.6 to 12.4), and cerebrospinal fluid pleocytosis (aOR: 3.5, 95% CI: 1.2 to 10.0). These variables were transformed to derive the HSV risk score (point range 0–17). Infants with invasive HSV had a higher median score (6, interquartile range: 4–8) than those without invasive HSV (3, interquartile range: 1.5–4), with an area under the curve for invasive HSV disease of 0.85 (95% CI: 0.80–0.91). When using a cut-point of ≥3, the HSV risk score had a sensitivity of 95.6% (95% CI: 84.9% to 99.5%), specificity of 40.1% (95% CI: 36.8% to 43.6%), and positive likelihood ratio 1.60 (95% CI: 1.5 to 1.7) and negative likelihood ratio 0.11 (95% CI: 0.03 to 0.43). CONCLUSIONS A novel HSV risk score identified infants at extremely low risk for invasive HSV who may not require routine testing or empirical treatment.

Objectives To compare timeliness of sepsis recognition and initial treatment in patients with and without high-risk comorbid conditions. Methods This was a retrospective cohort study of patients presenting to a pediatric emergency department (ED) who triggered a vital sign-based electronic sepsis alert resulting in bedside "huddle" assessment per institutional practice. A positive sepsis alert was defined as age-specific tachycardia or hypotension, concern for infection, and at least 1 of the following: abnormal capillary refill, abnormal mental status, or a high-risk condition. High-risk conditions were derived from the American Academy of Pediatrics sepsis alert tool. Patients with a positive alert underwent bedside huddle resulting in a decision regarding initiation of sepsis protocol. Placement on the protocol and time to initiation of protocol and individual therapies were compared for patients with and without high-risk conditions. Results During the 1-year study period, there were 1107 sepsis huddle alerts out of 96,427 ED visits. Of these, 713 (65%) had identified high-risk conditions, and 394 (35%) did not. Among patients with sepsis huddles, there was no difference in sepsis protocol initiation for patients with high-risk conditions compared with those without (24.8% vs 22.0%, P = 0.305). Between patients with high-risk conditions and those without, there were no differences in median time from triage to sepsis protocol activation, triage to initial intravenous antibiotic, triage to initial intravenous fluid therapy, or ED length of stay. Conclusions Timeliness of care initiation was no different in high-risk patients with sepsis when using an electronic sepsis alert and protocolized sepsis care.

BACKGROUND: Resuscitation with crystalloid fluid is a cornerstone of pediatric septic shock treatment. However, the optimal type of crystalloid fluid is unknown. We aimed to determine the feasibility of conducting a pragmatic randomized trial to compare balanced (lactated Ringer’s [LR]) with 0.9% normal saline (NS) fluid resuscitation in children with suspected septic shock. METHODS: Open-label pragmatic randomized controlled trial at a single academic children’s hospital from January to August 2018. Eligible patients were >6 months to

Background Variability in 2-tier Lyme disease test results according to the specific first-tier enzyme immunoassay (EIA) in children has not been examined rigorously. In this study, we compared paired results of clinical 2-tier Lyme disease tests to those of the C6 peptide EIA followed by supplemental immunoblotting (C6 2-tier test). Methods We performed a prospective cohort study of children aged ≥1 to ≤21 years who were undergoing evaluation for Lyme disease in the emergency department at 1 of 6 centers located in regions in which Lyme disease is endemic. The clinical first-tier test and a C6 EIA were performed on the same serum sample with supplemental immunoblotting if the first-tier test result was either positive or equivocal. We compared the results of the paired clinical and C6 2-tier Lyme disease test results using the McNemar test. Results Of the 1714 children enrolled, we collected a research serum sample from 1584 (92.4%). The clinical 2-tier EIA result was positive in 316 (19.9%) children, and the C6 2-tier test result was positive or equivocal in 295 (18.6%) children. The clinical and C6 2-tier test results disagreed more often than they would have by chance alone (P = .002). Of the 39 children with either a positive clinical or C6 2-tier test result alone, 2 children had an erythema migrans (EM) lesion, and 29 had symptoms compatible with early disseminated Lyme disease. Conclusions Two-tier Lyme disease test results differed for a substantial number of children on the basis of the specific first-tier test used. In children for whom there is a high clinical suspicion for Lyme disease and who have an initially negative test result, clinicians should consider retesting for Lyme disease.

In our prospective cohort of children undergoing evaluation for non-cutaneous Lyme disease, 02 (13.9% of those with Lyme disease) were not initially treated with an appropriate antibiotics and 356 (13.3% without Lyme disease) received potentially unnecessary antibiotics. Rapid and accurate diagnostics are needed to further improve initial antibiotic treatment decisions.

Bacterial meningitis in low-risk febrile young infants (FYIs) aged28 days has become increasingly rare. Routine performance of lumbar puncture (LP) in these infants is associated with adverse consequences and may be unnecessary. We modified our clinical practice guideline (CPG) to reduce the number of FYIs 29 to 56 days old who receive LP.This quality improvement project sought to modify a preexisting CPG to diagnose and manage FYIs 0 to 56 days old that eliminated routine performance of LP in children 29 to 56 days old who were considered low-risk for serious bacterial infection. The change was implemented by making adjustments to the online CPG. A statistical process control chart was used to assess the affect of the initiative on our primary outcome of LP rate in this population of FYIs.Postimplementation of the CPG initiative, 71% of FYIs 29 to 56 days old did not receive LP, compared with 42% preimplementation. This practice change was also associated with fewer hospitalizations, lower median emergency department (ED) length of stay, and fewer 72-hour ED revisits. Over 3 years of sustained practice, 1/713 (0.1%; 95% confidence interval, 0%-0.8%) low-risk FYI returned within 72 hours and was subsequently treated for probable bacterial meningitis, although cerebrospinal fluid culture was negative for bacterial growth.A change in CPG reduced the number of LPs performed in febrile infants 29 to 56 days old. This change resulted in fewer LPs, hospitalizations, ED revisits, and a lower ED length of stay for FYIs 29 to 56 days old.

In Lyme disease endemic areas, Lyme and septic arthritis often present similarly. A published septic knee arthritis clinical prediction rule includes 2 high-risk predictors: absolute neutrophil count of 10,000 cells/mm3 or greater and erythrocyte sedimentation rate of 40 mm/h or greater. The objective of the study was to externally validate this prediction rule in a multicenter prospective cohort.We enrolled a prospective cohort of children with knee monoarthritis undergoing evaluation for Lyme disease at 1 of 8 Pedi Lyme Net emergency departments located in endemic areas. We defined a case of septic arthritis with a positive synovial fluid culture or a synovial fluid white blood cell count of 50,000 or greater per high powered field with a positive blood culture and Lyme arthritis with a positive or equivocal C6 EIA, followed by a positive supplemental immunoblot. Other children were classified as having inflammatory arthritis. We report the performance of the septic arthritis clinical prediction rule in our study population.Of the 543 eligible children, 13 had septic arthritis (2.4%), 234 Lyme arthritis (43.1%), and 296 inflammatory arthritis (54.5%). Of the 457 children (84.2%) with available laboratory predictors, all children with septic arthritis were classified as high risk (sensitivity, 100%; 95% confidence interval [CI], 77.2%-100%; specificity, 68.1%; 95% CI, 63.6-73.3; negative predictive value, 278/278 [100%]; 95% CI, 98.6%-100%). Of the 303 low-risk children, 52 (17.2%) underwent diagnostic arthrocentesis.The septic knee arthritis clinical prediction rule accurately distinguished between septic and Lyme arthritis in an endemic area. Clinical application may reduce unnecessary invasive diagnostic procedures.

BACKGROUND: A 56 US hospital collaborative, Improving Pediatric Sepsis Outcomes, has developed variables, metrics and a data analysis plan to track quality improvement (QI)–based patient outcomes over time. Improving Pediatric Sepsis Outcomes expands on previous pediatric sepsis QI efforts by improving electronic data capture and uniformity across sites. METHODS: An expert panel developed metrics and corresponding variables to assess improvements across the care delivery spectrum, including the emergency department, acute care units, hematology and oncology, and the ICU. Outcome, process, and balancing measures were represented. Variables and statistical process control charts were mapped to each metric, elucidating progress over time and informing plan-do-study-act cycles. Electronic health record (EHR) abstraction feasibility was prioritized. Time 0 was defined as time of earliest sepsis recognition (determined electronically), or as a clinically derived time 0 (manually abstracted), identifying earliest physiologic onset of sepsis. RESULTS: Twenty-four evidence-based metrics reflected timely and appropriate interventions for a uniformly defined sepsis cohort. Metrics mapped to statistical process control charts with 44 final variables; 40 could be abstracted automatically from multiple EHRs. Variables, including high-risk conditions and bedside huddle time, were challenging to abstract (reported in CONCLUSIONS: A comprehensive data dictionary was developed for the largest pediatric sepsis QI collaborative, optimizing automation and ensuring sustainable reporting. These approaches can be used in other large-scale sepsis QI projects in which researchers seek to leverage EHR data abstraction.

Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. We performed a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesized that the proteome would reflect heterogeneity in hyperinflammation and vascular injury, and further identify pathogenic mediators of disease. Protein signatures demonstrated overlap between MIS-C, and the inflammatory syndromes macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). We demonstrate that PLA2G2A is a key marker of MIS-C that associates with TMA. We found that IFNγ responses are dysregulated in MIS-C patients, and that IFNγ levels delineate clinical heterogeneity.

Background: Urinary tract infections (UTIs) are the most common serious bacterial infection in young febrile infants, and the urinalysis (UA) is an accurate screening test for emergency department (ED) evaluation. Precise estimates of risk of concomitant bacteremia and/or bacterial meningitis (invasive bacterial infections; IBI) in febrile infants ≤ 60 days have been based on presence of UTIs rather than positive UAs, and lack large prospective study. Objective: We sought to determine the prevalence of IBIs in febrile infants 0-28 …