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Background: Hospitalization rates for childhood pneumonia vary widely. Risk-based clinical decision support (CDS) interventions may reduce unwarranted variation., Methods: We conducted a pragmatic randomized trial in two US pediatric emergency departments (EDs) comparing electronic health record (EHR)-integrated prognostic CDS versus usual care for promoting appropriate ED disposition in children (<18 years) with pneumonia. Encounters were randomized 1:1 to usual care versus custom CDS featuring a validated pneumonia severity score predicting risk for severe in-hospital outcomes. Clinicians retained full decision-making authority. The primary outcome was inappropriate ED disposition, defined as early transition to lower- or higher-level care. Safety and implementation outcomes were also evaluated., Results: The study enrolled 536 encounters (269 usual care and 267 CDS). Baseline characteristics were similar across arms. Inappropriate disposition occurred in 3% of usual care encounters and 2% of CDS encounters (adjusted odds ratio: 0.99, 95% confidence interval: [0.32, 2.95]). Length of stay was also similar and adverse safety outcomes were uncommon in both arms. The tool's custom user interface and content were viewed as strengths by surveyed clinicians (>70% satisfied). Implementation barriers include intrinsic (e.g., reaching the right person at the right time) and extrinsic factors (i.e., global pandemic)., Conclusions: EHR-based prognostic CDS did not improve ED disposition decisions for children with pneumonia. Although the intervention's content was favorably received, low subject accrual and workflow integration problems likely limited effectiveness. Clinical Trials Registration: NCT06033079., (© 2024 Society of Hospital Medicine.)

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., (© 2024. The Author(s).)

Introduction: Most providers have routinely performed universal lumbar puncture (LP) on well-appearing, febrile infants 22 to 28 days old. In 2021, the American Academy of Pediatrics recommended clinicians should perform an LP in this age group if inflammatory markers are abnormal. This quality improvement project aimed to decrease LP rates in febrile infants 22 to 28 days old in the emergency department (ED) within 1 year, regardless of race/ethnicity, from a baseline of 87%., Methods: We used our institution's quality improvement framework to perform multiple Plan-Do-Study-Act cycles. A multidisciplinary team reviewed the febrile infant literature, local epidemiology, and identified key drivers. We provided departmental education, updated our clinical pathway, and used clinical decision support. We analyzed baseline (January 2017-March 2022) and intervention data (April 2022-March 2024) and tracked data using statistical process control charts. Our primary outcome measure was rates of LP in the ED for this cohort. Process measures included rates of infants with procalcitonin results. ED length of stay, rates of first LP attempt after hospitalization, and missed bacterial meningitis were balancing measures., Results: The baseline LP rate of 87% decreased to 44% during the intervention period, resulting in a downward centerline shift. There were no significant differences when LP rates were analyzed by race/ethnicity. There was an upward centerline shift in the process measure of infants with procalcitonin results. There was no observed special cause variation in our balancing measures., Conclusion: Quality improvement efforts, including education, clinical pathway updates, and clinical decision support, safely reduced rates of LPs in febrile infants 22 to 28 days old., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Our goal was to identify predictors of invasive bacterial infection (ie, bacteremia and bacterial meningitis) in febrile infants aged 2-6 months. In our multicenter retrospective cohort, older age and lower temperature identified infants at low risk for invasive bacterial infection who could safely avoid routine testing., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this multicenter, cross-sectional, secondary analysis of 4042 low-risk febrile infants, nearly 10% had a contaminated culture obtained during their evaluation (4.9% of blood cultures, 5.0% of urine cultures, and 1.8% of cerebrospinal fluid cultures). Our findings have important implications for improving sterile technique and reducing unnecessary cultures., Competing Interests: Declaration of Competing Interest Colleen K. Gutman was supported by NIH/NCATS grant number KL2TR001429. Paul L. Aronson is supported by NIH/NICHD grant number R03 HD110741. The NIH had no role in the design and conduct of the study. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: To assist clinicians with identifying children at risk of severe outcomes, we assessed the association between laboratory findings and severe outcomes among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children and determined if SARS-CoV-2 test result status modified the associations., Methods: We conducted a cross-sectional analysis of participants tested for SARS-CoV-2 infection in 41 pediatric emergency departments in 10 countries. Participants were hospitalized, had laboratory testing performed, and completed 14-day follow-up. The primary objective was to assess the associations between laboratory findings and severe outcomes. The secondary objective was to determine if the SARS-CoV-2 test result modified the associations., Results: We included 1817 participants; 522 (28.7%) SARS-CoV-2 test-positive and 1295 (71.3%) test-negative. Seventy-five (14.4%) test-positive and 174 (13.4%) test-negative children experienced severe outcomes. In regression analysis, we found that among SARS-CoV-2-positive children, procalcitonin ≥0.5 ng/mL (adjusted odds ratio [aOR], 9.14; 95% CI, 2.90-28.80), ferritin >500 ng/mL (aOR, 7.95; 95% CI, 1.89-33.44), D-dimer ≥1500 ng/mL (aOR, 4.57; 95% CI, 1.12-18.68), serum glucose ≥120 mg/dL (aOR, 2.01; 95% CI, 1.06-3.81), lymphocyte count <1.0 × 10 9 /L (aOR, 3.21; 95% CI, 1.34-7.69), and platelet count <150 × 10 9 /L (aOR, 2.82; 95% CI, 1.31-6.07) were associated with severe outcomes. Evaluation of the interaction term revealed that a positive SARS-CoV-2 result increased the associations with severe outcomes for elevated procalcitonin, C-reactive protein (CRP), D-dimer, and for reduced lymphocyte and platelet counts., Conclusions: Specific laboratory parameters are associated with severe outcomes in SARS-CoV-2-infected children, and elevated serum procalcitonin, CRP, and D-dimer and low absolute lymphocyte and platelet counts were more strongly associated with severe outcomes in children testing positive compared with those testing negative., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Unwarranted variation in disposition decisions exist among children with pneumonia. We validated three prognostic models for predicting pneumonia severity among children in the emergency department (ED) and hospital., Methods: We performed a two-center, prospective study of children 6 months to <18 years presenting to the ED with pneumonia from January 2014 to May 2019. We evaluated three previously developed disease-specific prognostic models which use demographic, clinical, and diagnostic predictor variables, with each model estimating risk for Very Severe (mechanical ventilation or shock), Severe (ICU without very severe features), and Moderate/Mild (Hospitalization without severe features or ED discharge) pneumonia. Predictive accuracy was measured using discrimination (concordance or c-statistic) and re-calibration., Results: There were 1088 children included in one or more of the three models. Median age was 3.6 years and the majority of children were male (53.7%) and identified as non-Hispanic White (63.7%). The distribution for the ordinal severity outcome was mild or moderate (79.1%), severe (15.9%), and very severe (4.9%). The three models each demonstrated excellent discrimination (C-statistic range across models [0.786-0.803]) with no appreciable degradation in predictive accuracy from the derivation cohort., Conclusions: All three prognostic models accurately identified risk for three clinically meaningful levels of pneumonia severity and demonstrated very good predictive performance. Physiologic variables contributed the most to model prediction. Application of these objective tools may help standardize and improve disposition and other management decisions for children with pneumonia., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Electronic health record-based clinical decision support (CDS) is a promising antibiotic stewardship strategy. Few studies have evaluated the effectiveness of antibiotic CDS in the pediatric emergency department (ED)., Objective: To compare the effectiveness of antibiotic CDS vs. usual care for promoting guideline-concordant antibiotic prescribing for pneumonia in the pediatric ED., Design: Pragmatic randomized clinical trial., Setting and Participants: Encounters for children (6 months-18 years) with pneumonia presenting to two tertiary care children s hospital EDs in the United States., Intervention: CDS or usual care was randomly assigned during 4-week periods within each site. The CDS intervention provided antibiotic recommendations tailored to each encounter and in accordance with national guidelines., Main Outcome and Measures: The primary outcome was exclusive guideline-concordant antibiotic prescribing within the first 24 h of care. Safety outcomes included time to first antibiotic order, encounter length of stay, delayed intensive care, and 3- and 7-day revisits., Results: 1027 encounters were included, encompassing 478 randomized to usual care and 549 to CDS. Exclusive guideline-concordant prescribing did not differ at 24 h (CDS, 51.7% vs. usual care, 53.3%; odds ratio [OR] 0.94 [95% confidence interval [CI]: 0.73, 1.20]). In pre-specified stratified analyses, CDS was associated with guideline-concordant prescribing among encounters discharged from the ED (74.9% vs. 66.0%; OR 1.53 [95% CI: 1.01, 2.33]), but not among hospitalized encounters. Mean time to first antibiotic was shorter in the CDS group (3.0 vs 3.4 h; p = .024). There were no differences in safety outcomes., Conclusions: Effectiveness of ED-based antibiotic CDS was greatest among those discharged from the ED. Longitudinal interventions designed to target both ED and inpatient clinicians and to address common implementation challenges may enhance the effectiveness of CDS as a stewardship tool., (© 2023 Society of Hospital Medicine.)

Background and Objectives: Written discharge instructions help to bridge hospital-to-home transitions for patients and families, though substantial variation in discharge instruction quality exists. We aimed to assess the association between participation in an Institute for Healthcare Improvement Virtual Breakthrough Series collaborative and the quality of pediatric written discharge instructions across 8 US hospitals., Methods: We conducted a multicenter, interrupted time-series analysis of a medical records-based quality measure focused on written discharge instruction content (0-100 scale, higher scores reflect better quality). Data were from random samples of pediatric patients (N = 5739) discharged from participating hospitals between September 2015 and August 2016, and between December 2017 and January 2020. These periods consisted of 3 phases: 1. a 14-month precollaborative phase; 2. a 12-month quality improvement collaborative phase when hospitals implemented multiple rapid cycle tests of change and shared improvement strategies; and 3. a 12-month postcollaborative phase. Interrupted time-series models assessed the association between study phase and measure performance over time, stratified by baseline hospital performance, adjusting for seasonality and hospital fixed effects., Results: Among hospitals with high baseline performance, measure scores increased during the quality improvement collaborative phase beyond the expected precollaborative trend (+0.7 points/month; 95% confidence interval, 0.4-1.0; P < .001). Among hospitals with low baseline performance, measure scores increased but at a lower rate than the expected precollaborative trend (-0.5 points/month; 95% confidence interval, -0.8 to -0.2; P < .01)., Conclusions: Participation in this 8-hospital Institute for Healthcare Improvement Virtual Breakthrough Series collaborative was associated with improvement in the quality of written discharge instructions beyond precollaborative trends only for hospitals with high baseline performance., (Copyright © 2023 by the American Academy of Pediatrics.)

Study Objective: Validated prediction rules identify febrile neonates at low risk for invasive bacterial infection. The optimal approach for older febrile infants, however, remains uncertain., Methods: We performed a retrospective cohort and nested case-control study of infants 2 to 6 months of age presenting with fever (≥38.0 °C) to 1 of 5 emergency departments. The study period was from 2011 to 2019. The primary outcome was invasive bacterial infection, defined by the growth of pathogenic bacteria from either blood or cerebrospinal fluid culture. Secondary outcomes included obtaining bacterial cultures (blood, cerebrospinal fluid, or urine), administering antibiotics, and hospitalization. For the nested case-control study, we age-matched infants with invasive bacterial infection to 3 infants without invasive bacterial infection, sampled from the overall cohort., Results: There were 21,150 eligible patient encounters over 9-years, and 101 infants had a documented invasive bacterial infection (0.48%; 95% confidence interval [CI], 0.39% to 0.58%). Invasive bacterial infection prevalence ranged from 0.2% to 0.6% among the 5 sites. The frequency of bacterial cultures ranged from 14.5% to 53.5% for blood, 1.6% to 12.9% for cerebrospinal fluid, and 31.8% to 63.2% for urine. Antibiotic administration varied from 19.2% to 46.7% and hospitalization from 16.6% to 28.3%. From the case-control study, the estimated invasive bacterial infection prevalence for previously healthy, not pretreated, and well-appearing febrile infants was 0.32% (95% CI, 0.24% to 0.41%)., Conclusion: Although invasive bacterial infections were uncommon among febrile infants 2 to 6 months in the emergency department, the approach to diagnosis and management varied widely between sites. Therefore, evidence-based guidelines are needed to reduce low-value testing and treatment while avoiding missing infants with invasive bacterial infections., (Copyright © 2022 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Underlying comorbidities are common in children with pneumonia., Objective: To determine associations between comorbidity-related functional limitations and risk for severe pneumonia outcomes., Design, Setting, and Participants: We prospectively enrolled children <18 years with and without comorbidities presenting to the emergency department with clinical and radiographic pneumonia at two institutions. Comorbidities included chronic conditions requiring daily medications, frequent healthcare visits, or which limited age-appropriate activities. Among children with comorbidities, functional limitations were defined as none or mild, moderate, and severe., Main Outcomes and Measures: Outcomes included an ordinal severity outcome, categorized as very severe (mechanical ventilation, shock, or death), severe (intensive care without very severe features), moderate (hospitalization without severe features), or mild (discharged home), and length of stay (LOS). Multivariable ordinal logistic regression was used to examine associations between comorbidity-related functional limitations and outcomes, while accounting for relevant covariates., Results: A cohort of 1116 children, including 452 (40.5%) with comorbidities; 200 (44.2%) had none or mild functional limitations, 93 (20.6%) moderate, and 159 (35.2%) had severe limitations. In multivariable analysis, comorbidity-related functional limitations were associated with the ordinal severity outcome and LOS (p < .001 for both). Children with severe functional limitations had tripling of the odds of a more severe ordinal (adjusted odds ratio [aOR]: 3.01, 95% confidence interval [2.05, 4.43]) and quadrupling of the odds for longer LOS (aOR: 4.72 [3.33, 6.70]) as compared to children without comorbidities., Conclusion: Comorbidity-related functional limitations are important predictors of disease outcomes in children with pneumonia. Consideration of functional limitations, rather than the presence of comorbidity alone, is critical when assessing risk of severe outcomes., (© 2022 Society of Hospital Medicine.)

Importance: Little is known about the risk factors for, and the risk of, developing post-COVID-19 conditions (PCCs) among children., Objectives: To estimate the proportion of SARS-CoV-2-positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2-negative children, and to assess factors associated with PCCs., Design, Setting, and Participants: This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2-positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2-negative controls., Exposure: SARS-CoV-2 detected via nucleic acid testing., Main Outcomes and Measures: Post-COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey., Results: Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2-positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2-positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2-positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00])., Conclusions and Relevance: In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.

Introduction: Peripheral blood mononuclear cells (PBMCs) are commonly used to compare mitochondrial function in patients with versus without sepsis, but how these measurements in this mixed cell population vary by composition of immune cell subtypes is not known, especially in children. We determined the effect of changing immune cell composition on PBMC mitochondrial respiration and content in children with and without sepsis., Methods: PBMC mitochondrial respiration and citrate synthase (CS) activity, a marker of mitochondrial content, were measured in 167 children with sepsis at three timepoints (day 1-2, 3-5, and 8-14) and once in 19 nonseptic controls. The proportion of lymphocytes and monocytes and T, B, and NK cells was measured using flow cytometry. More specific CD4+ and CD8+ T cell subsets were measured from 13 sepsis patients and 6 controls. Spearman's correlation and simple and mixed effects linear regression were used to determine the association of PBMC mitochondrial measures with proportion of immune cell subtypes., Results: PBMC mitochondrial respiration and CS activity were correlated with proportion of monocytes, lymphocytes, T B, and NK cells in controls, but not in sepsis patients. PBMC mitochondrial respiration was correlated with CD4+ and CD8+ T cell subsets in both groups. After controlling for differences in immune cell composition between groups using linear regression models, PBMC respiration and CS activity remained lower in sepsis patients than controls., Conclusions: Mitochondrial measurements from PBMCs varied with changes in immune cell composition in children with and without sepsis. However, differences in PBMC mitochondrial measurements between sepsis patients and controls were at least partially attributable to the effects of sepsis rather than solely an epiphenomena of variable immune cell composition., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Objective: To determine whether empirical antibiotic initiation and selection for children with pneumonia was associated with procalcitonin (PCT) levels when results were blinded to clinicians., Methods: We enrolled children <18 years with radiographically confirmed pneumonia at 2 children's hospitals from 2014 to 2019. Blood for PCT was collected at enrollment (blinded to clinicians). We modeled associations between PCT and (1) antibiotic initiation and (2) antibiotic selection (narrow versus broad-spectrum) using multivariable logistic regression models. To quantify potential stewardship opportunities, we calculated proportions of noncritically ill children receiving antibiotics who also had a low likelihood of bacterial etiology (PCT <0.25 ng/mL) and those receiving broad-spectrum therapy, regardless of PCT level., Results: We enrolled 488 children (median PCT, 0.37 ng/mL; interquartile range [IQR], 0.11-2.38); 85 (17%) received no antibiotics (median PCT, 0.32; IQR, 0.09-1.33). Among the 403 children receiving antibiotics, 95 (24%) received narrow-spectrum therapy (median PCT, 0.24; IQR, 0.08-2.52) and 308 (76%) received broad-spectrum (median PCT, 0.46; IQR, 0.12-2.83). In adjusted analyses, PCT values were not associated with antibiotic initiation (odds ratio [OR], 1.02, 95% confidence interval [CI], 0.97%-1.06%) or empirical antibiotic selection (OR 1.07; 95% CI, 0.97%-1.17%). Of those with noncritical illness, 246 (69%) were identified as potential targets for antibiotic stewardship interventions., Conclusion: Neither antibiotic initiation nor empirical antibiotic selection were associated with PCT values. Whereas other factors may inform antibiotic treatment decisions, the observed discordance between objective likelihood of bacterial etiology and antibiotic use suggests important opportunities for stewardship., (Copyright © 2022 by the American Academy of Pediatrics.)

Abstract: 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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Severe outcomes among youths with SARS-CoV-2 infections are poorly characterized., Objective: To estimate the proportion of children with severe outcomes within 14 days of testing positive for SARS-CoV-2 in an emergency department (ED)., Design, Setting, and Participants: This prospective cohort study with 14-day follow-up enrolled participants between March 2020 and June 2021. Participants were youths aged younger than 18 years who were tested for SARS-CoV-2 infection at one of 41 EDs across 10 countries including Argentina, Australia, Canada, Costa Rica, Italy, New Zealand, Paraguay, Singapore, Spain, and the United States. Statistical analysis was performed from September to October 2021., Exposures: Acute SARS-CoV-2 infection was determined by nucleic acid (eg, polymerase chain reaction) testing., Main Outcomes and Measures: Severe outcomes, a composite measure defined as intensive interventions during hospitalization (eg, inotropic support, positive pressure ventilation), diagnoses indicating severe organ impairment, or death., Results: Among 3222 enrolled youths who tested positive for SARS-CoV-2 infection, 3221 (>99.9%) had index visit outcome data available, 2007 (62.3%) were from the United States, 1694 (52.6%) were male, and 484 (15.0%) had a self-reported chronic illness; the median (IQR) age was 3 (0-10) years. After 14 days of follow-up, 735 children (22.8% [95% CI, 21.4%-24.3%]) were hospitalized, 107 (3.3% [95% CI, 2.7%-4.0%]) had severe outcomes, and 4 children (0.12% [95% CI, 0.03%-0.32%]) died. Characteristics associated with severe outcomes included being aged 5 to 18 years (age 5 to <10 years vs <1 year: odds ratio [OR], 1.60 [95% CI, 1.09-2.34]; age 10 to <18 years vs <1 year: OR, 2.39 [95% CI 1.38-4.14]), having a self-reported chronic illness (OR, 2.34 [95% CI, 1.59-3.44]), prior episode of pneumonia (OR, 3.15 [95% CI, 1.83-5.42]), symptoms starting 4 to 7 days prior to seeking ED care (vs starting 0-3 days before seeking care: OR, 2.22 [95% CI, 1.29-3.82]), and country (eg, Canada vs US: OR, 0.11 [95% CI, 0.05-0.23]; Costa Rica vs US: OR, 1.76 [95% CI, 1.05-2.96]; Spain vs US: OR, 0.51 [95% CI, 0.27-0.98]). Among a subgroup of 2510 participants discharged home from the ED after initial testing and who had complete follow-up, 50 (2.0%; 95% CI, 1.5%-2.6%) were eventually hospitalized and 12 (0.5%; 95% CI, 0.3%-0.8%) had severe outcomes. Compared with hospitalized SARS-CoV-2-negative youths, the risk of severe outcomes was higher among hospitalized SARS-CoV-2-positive youths (risk difference, 3.9%; 95% CI, 1.1%-6.9%)., Conclusions and Relevance: In this study, approximately 3% of SARS-CoV-2-positive youths tested in EDs experienced severe outcomes within 2 weeks of their ED visit. Among children discharged home from the ED, the risk was much lower. Risk factors such as age, underlying chronic illness, and symptom duration may be useful to consider when making clinical care decisions.

Objective: We aimed to evaluate the association of height of fever with invasive bacterial infection (IBI) among febrile infants <=60 days of age., Methods: In a secondary analysis of a multicentre case-control study of non-ill-appearing febrile infants <=60 days of age, we compared the maximum temperature (at home or in the emergency department) for infants with and without IBI. We then computed interval likelihood ratios (iLRs) for the diagnosis of IBI at each half-degree Celsius interval., Results: The median temperature was higher for infants with IBI (38.8°C; IQR 38.4-39.2) compared with those without IBI (38.4°C; IQR 38.2-38.9) (p<0.001). Temperatures 39°C-39.4°C and 39.5°C-39.9°C were associated with a higher likelihood of IBI (iLR 2.49 and 3.40, respectively), although 30.4% of febrile infants with IBI had maximum temperatures <38.5°C., Conclusions: Although IBI is more likely with higher temperatures, height of fever alone should not be used for risk stratification of febrile infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine if serum procalcitonin, an indicator of bacterial etiology in pneumonia in all ages and a predictor of severe pneumonia in adults, is associated with disease severity in children with community-acquired pneumonia., Methods: We prospectively enrolled children 2 months to <18 years with clinical and radiographic pneumonia at 2 children's hospitals (2014-2019). Procalcitonin samples were obtained at presentation. An ordinal outcome scale of pneumonia severity was defined: very severe (intubation, shock, or death), severe (intensive care admission without very severe features and/or high-flow nasal cannula), moderate (hospitalization without severe or very severe features), and mild (discharge). Hospital length of stay (LOS) was also examined. Ordinal logistic regression was used to model associations between procalcitonin and outcomes. We estimated adjusted odds ratios (aORs) for a variety of cut points of procalcitonin ranging from 0.25 to 3.5 ng/mL., Results: The study included 488 children with pneumonia; 30 (6%) were classified as very severe, 106 (22%) as severe, 327 (67%) as moderate, and 25 (5%) as mild. Median procalcitonin in the very severe group was 5.06 (interquartile range [IQR] 0.90-16.83), 0.38 (IQR 0.11-2.11) in the severe group, 0.29 (IQR 0.09-1.90) in the moderate group, and 0.21 (IQR 0.12-1.2) in the mild group. Increasing procalcitonin was associated with increasing severity (range of aORs: 1.03-1.25) and increased LOS (range of aORs: 1.04-1.36). All comparisons were statistically significant., Conclusions: Higher procalcitonin was associated with increased severity and LOS. Procalcitonin may be useful in helping clinicians evaluate pneumonia severity., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

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 <36°C, heart rate ≥181 beats per minute, or respiratory rate ≥66 breaths per minute) or a physical examination abnormality (ill appearance, full or depressed fontanelle, increased work of breathing, or signs of focal infection). Forty-three infants (55%) had ≥1 of the following laboratory abnormalities: white blood cell count <5000 or >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., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Objectives: We aimed to describe the clinical and laboratory characteristics of febrile infants ≤60 days old with positive urinalysis results and invasive bacterial infections (IBI)., Methods: We performed a planned secondary analysis of a retrospective cohort study of febrile infants ≤60 days old with IBI who presented to 11 emergency departments from July 1, 2011, to June 30, 2016. For this subanalysis, we included infants with IBI and positive urinalysis results. We analyzed the sensitivity of high-risk past medical history (PMH) (prematurity, chronic medical condition, or recent antimicrobial receipt), ill appearance, and/or abnormal white blood cell (WBC) count (<5000 or >15 000 cells/μL) for identification of IBI., Results: Of 148 febrile infants with positive urinalysis results and IBI, 134 (90.5%) had bacteremia without meningitis and 14 (9.5%) had bacterial meningitis (11 with concomitant bacteremia). Thirty-five infants (23.6%) with positive urinalysis results and IBI did not have urinary tract infections. The presence of high-risk PMH, ill appearance, and/or abnormal WBC count had a sensitivity of 53.4% (95% confidence interval: 45.0-61.6) for identification of IBI. Of the 14 infants with positive urinalysis results and concomitant bacterial meningitis, 7 were 29 to 60 days old. Six of these 7 infants were ill-appearing or had an abnormal WBC count. The other infant had bacteremia with cerebrospinal fluid pleocytosis after antimicrobial pretreatment and was treated for meningitis., Conclusions: The sensitivity of high-risk PMH, ill appearance, and/or abnormal WBC count is suboptimal for identifying febrile infants with positive urinalysis results at low risk for IBI. Most infants with positive urinalysis results and bacterial meningitis are ≤28 days old, ill-appearing, or have an abnormal WBC count., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Objective: The aim of the study was to compare presenting clinical and laboratory features among children meeting the surveillance definition for multisystem inflammatory syndrome in children (MIS-C) across a range of illness severities., Methods: This is a retrospective single-center study of patients younger than 21 years presenting between March 1 and May 15, 2020. Included patients met the Centers for Disease Control and Prevention criteria for MIS-C (inflammation, fever, involvement of 2 organ systems, lack of alternative diagnoses). We defined 3 subgroups by clinical outcomes: (1) critical illness requiring intensive care interventions; (2) patients meeting Kawasaki disease (KD) criteria but not requiring critical care; and (3) mild illness not meeting either criteria. A comparator cohort included patients with KD at our institution during the same time frame in 2019., Results: Thirty-three patients were included (5, critical; 8, 2020 KD; 20, mild). The median age for the critical group was 10.9 years (2.7 for 2020 KD; 6.0 for mild, P = 0.033). The critical group had lower median absolute lymphocyte count (850 vs 3005 vs 2940/uL, P = 0.005), platelets (150 vs 361 vs 252 k/uL, P = 0.005), and sodium (129 vs 136 vs 136 mmol/L, P = 0.002), and higher creatinine (0.7 vs 0.2 vs 0.3 mg/dL, P = 0.002). In the critical group, 60% required vasoactive medications, and 40% required mechanical ventilation. Clinical and laboratories features were similar between the 2020 and 2019 KD groups., Conclusions: We describe 3 groups with inflammatory syndromes during the SARS-CoV-2 pandemic. The initial profile of lymphopenia, thrombocytopenia, hyponatremia, and abnormal creatinine may help distinguish critically ill MIS-C patients from classic/atypical KD or more benign acute inflammation.

Objectives: We aimed to describe the cerebrospinal fluid (CSF) profiles of infants ≤60 days old with bacterial meningitis and the characteristics of infants with bacterial meningitis who did not have CSF abnormalities., Methods: We included infants ≤60 days old with culture-positive bacterial meningitis who were evaluated in the emergency departments of 11 children's hospitals between July 1, 2011, and June 30, 2016. From medical records, we abstracted clinical and laboratory data. For infants with traumatic lumbar punctures (CSF red blood cell count of ≥10 000 cells per mm 3 ), we used a red blood cell count/white blood cell (WBC) count correction factor of 1000:1 to determine the corrected CSF WBC count. We calculated the sensitivity for bacterial meningitis of a CSF Gram-stain and corrected CSF pleocytosis (≥16 WBCs per mm 3 for infants ≤28 days old and ≥10 WBCs per mm 3 for infants 29-60 days old)., Results: Among 66 infants with bacterial meningitis, the sensitivity of a CSF Gram-stain was 71.9% (95% confidence interval [CI]: 59.2-82.4), and the sensitivity of corrected CSF pleocytosis was 80.3% (95% CI: 68.7-89.1). The sensitivity of combining positive Gram-stain results with corrected CSF pleocytosis was 86.4% (95% CI: 75.7-93.6). Of 9 infants with meningitis who had a negative Gram-stain result and no corrected CSF pleocytosis, 8 (88.9%) had either an abnormal peripheral WBC count (>15 000 or <5000 cells per μL) or bandemia >10%., Conclusions: Most infants ≤60 days old with bacterial meningitis have CSF pleocytosis or a positive Gram-stain result. Infants with no CSF pleocytosis and a negative Gram-stain result are unlikely to have bacterial meningitis in the absence of other laboratory abnormalities., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Introduction: Agreement between available procalcitonin (PCT) assays is unclear. We sought to compare concordance between Roche and bioMérieux PCT assays using pediatric samples., Methods: We evaluated 213 plasma samples from 208 children. We tested each sample on both the Roche and bioMérieux PCT platforms., Results: At ranges < 2 μg/L, the Roche platform had a mean negative bias of 0.13 μg/L versus the bioMérieux platform. This bias resulted in PCT levels that crossed accepted cut points in 12.7% of patients., Conclusions: PCT levels measured on either platform are similar, especially at PCT ranges used for antibiotic decision-making algorithms., Funding: This work was supported by an investigator-initiated research agreement through bioMérieux and by the National Institute of Allergy and Infectious Diseases Childhood Infection Research Program (ChIRP), National Institute of Health and the National Center for Advancing Translational Sciences of the National Institute of Health.

Objectives: To derive and internally validate a prediction model for the identification of febrile infants ≤60 days old at low probability of invasive bacterial infection (IBI)., Methods: We conducted a case-control study of febrile infants ≤60 days old who presented to the emergency departments of 11 hospitals between July 1, 2011 and June 30, 2016. Infants with IBI, defined by growth of a pathogen in blood (bacteremia) and/or cerebrospinal fluid (bacterial meningitis), were matched by hospital and date of visit to 2 control patients without IBI. Ill-appearing infants and those with complex chronic conditions were excluded. Predictors of IBI were identified with multiple logistic regression and internally validated with 10-fold cross-validation, and an IBI score was calculated., Results: We included 181 infants with IBI (155 [85.6%] with bacteremia without meningitis and 26 [14.4%] with bacterial meningitis) and 362 control patients. Twenty-three infants with IBI (12.7%) and 138 control patients (38.1%) had fever by history only. Four predictors of IBI were identified (area under the curve 0.83 [95% confidence interval (CI): 0.79-0.86]) and incorporated into an IBI score: age <21 days (1 point), highest temperature recorded in the emergency department 38.0-38.4°C (2 points) or ≥38.5°C (4 points), absolute neutrophil count ≥5185 cells per μL (2 points), and abnormal urinalysis results (3 points). The sensitivity and specificity of a score ≥2 were 98.8% (95% CI: 95.7%-99.9%) and 31.3% (95% CI: 26.3%-36.6%), respectively. All 26 infants with meningitis had scores ≥2., Conclusions: Infants ≤60 days old with fever by history only, a normal urinalysis result, and an absolute neutrophil count <5185 cells per μL have a low probability of IBI., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Drs Shapiro and Neuman have served as expert witnesses in malpractice cases involving the evaluation of infants with infections; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

: media-1vid110.1542/5840460609001PEDS-VA&#95;2018-1879 Video Abstract OBJECTIVES: To evaluate the Rochester and modified Philadelphia criteria for the risk stratification of febrile infants with invasive bacterial infection (IBI) who do not appear ill without routine cerebrospinal fluid (CSF) testing., Methods: We performed a case-control study of febrile infants ≤60 days old presenting to 1 of 9 emergency departments from 2011 to 2016. For each infant with IBI (defined as a blood [bacteremia] and/or CSF [bacterial meningitis] culture with growth of a pathogen), controls without IBI were matched by site and date of visit. Infants were excluded if they appeared ill or had a complex chronic condition or if data for any component of the Rochester or modified Philadelphia criteria were missing., Results: Overall, 135 infants with IBI (118 [87.4%] with bacteremia without meningitis and 17 [12.6%] with bacterial meningitis) and 249 controls were included. The sensitivity of the modified Philadelphia criteria was higher than that of the Rochester criteria (91.9% vs 81.5%; P = .01), but the specificity was lower (34.5% vs 59.8%; P < .001). Among 67 infants >28 days old with IBI, the sensitivity of both criteria was 83.6%; none of the 11 low-risk infants had bacterial meningitis. Of 68 infants ≤28 days old with IBI, 14 (20.6%) were low risk per the Rochester criteria, and 2 had meningitis., Conclusions: The modified Philadelphia criteria had high sensitivity for IBI without routine CSF testing, and all infants >28 days old with bacterial meningitis were classified as high risk. Because some infants with bacteremia were classified as low risk, infants discharged from the emergency department without CSF testing require close follow-up., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Shapiro has served as an expert witness in malpractice cases involving the evaluation of febrile children; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Major galaxy mergers are thought to play an important part in fuelling the growth of supermassive black holes 1 . However, observational support for this hypothesis is mixed, with some studies showing a correlation between merging galaxies and luminous quasars 2,3 and others showing no such association 4,5 . Recent observations have shown that a black hole is likely to become heavily obscured behind merger-driven gas and dust, even in the early stages of the merger, when the galaxies are well separated 6-8 (5 to 40 kiloparsecs). Merger simulations further suggest that such obscuration and black-hole accretion peaks in the final merger stage, when the two galactic nuclei are closely separated 9 (less than 3 kiloparsecs). Resolving this final stage requires a combination of high-spatial-resolution infrared imaging and high-sensitivity hard-X-ray observations to detect highly obscured sources. However, large numbers of obscured luminous accreting supermassive black holes have been recently detected nearby (distances below 250 megaparsecs) in X-ray observations 10 . Here we report high-resolution infrared observations of hard-X-ray-selected black holes and the discovery of obscured nuclear mergers, the parent populations of supermassive-black-hole mergers. We find that obscured luminous black holes (bolometric luminosity higher than 2 × 10 44 ergs per second) show a significant (P < 0.001) excess of late-stage nuclear mergers (17.6 per cent) compared to a sample of inactive galaxies with matching stellar masses and star formation rates (1.1 per cent), in agreement with theoretical predictions. Using hydrodynamic simulations, we confirm that the excess of nuclear mergers is indeed strongest for gas-rich major-merger hosts of obscured luminous black holes in this final stage.

Objectives: To help guide empiric treatment of infants ≤60 days old with suspected invasive bacterial infection by describing pathogens and their antimicrobial susceptibilities., Study Design: Cross-sectional study of infants ≤60 days old with invasive bacterial infection (bacteremia and/or bacterial meningitis) evaluated in the emergency departments of 11 children's hospitals between July 1, 2011 and June 30, 2016. Each site's microbiology laboratory database or electronic medical record system was queried to identify infants from whom a bacterial pathogen was isolated from either blood or cerebrospinal fluid. Medical records of these infants were reviewed to confirm the presence of a pathogen and to obtain demographic, clinical, and laboratory data., Results: Of the 442 infants with invasive bacterial infection, 353 (79.9%) had bacteremia without meningitis, 64 (14.5%) had bacterial meningitis with bacteremia, and 25 (5.7%) had bacterial meningitis without bacteremia. The peak number of cases of invasive bacterial infection occurred in the second week of life; 364 (82.4%) infants were febrile. Group B streptococcus was the most common pathogen identified (36.7%), followed by Escherichia coli (30.8%), Staphylococcus aureus (9.7%), and Enterococcus spp (6.6%). Overall, 96.8% of pathogens were susceptible to ampicillin plus a third-generation cephalosporin, 96.0% to ampicillin plus gentamicin, and 89.2% to third-generation cephalosporins alone., Conclusions: For most infants ≤60 days old evaluated in a pediatric emergency department for suspected invasive bacterial infection, the combination of ampicillin plus either gentamicin or a third-generation cephalosporin is an appropriate empiric antimicrobial treatment regimen. Of the pathogens isolated from infants with invasive bacterial infection, 11% were resistant to third-generation cephalosporins alone., (Copyright © 2018 Elsevier Inc. All rights reserved.)