Viral Detection by Reverse Transcriptase Polymerase Chain Reaction in Upper Respiratory Tract and Metagenomic RNA Sequencing in Lower Respiratory Tract in Critically Ill Children With Suspected Lower Respiratory Tract Infection.

OBJECTIVES: Viral lower respiratory tract infection (vLRTI) contributes to substantial morbidity and mortality in children. Diagnosis is typically confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal specimens in hospitalized patients; however, it is unknown whether nasopharyngeal detection accurately reflects presence of virus in the lower respiratory tract (LRT). This study evaluates agreement between viral detection from nasopharyngeal specimens by RT-PCR compared with metagenomic next-generation RNA sequencing (RNA-Seq) from tracheal aspirates (TAs). DESIGN: This is an analysis of of a seven-center prospective cohort study. SETTING: Seven PICUs within academic children's hospitals in the United States. PATIENTS: Critically ill children (from 1 mo to 18 yr) who required mechanical ventilation via endotracheal tube for greater than or equal to 72 hours. INTERVENTIONS: We evaluated agreement in viral detection between paired upper and LRT samples. Results of clinical nasopharyngeal RT-PCR were compared with TA RNA-Seq. Positive and negative predictive agreement and Cohen's Kappa were used to assess agreement. MEASUREMENTS AND MAIN RESULTS: Of 295 subjects with paired testing available, 200 (68%) and 210 (71%) had positive viral testing by RT-PCR from nasopharyngeal and RNA-Seq from TA samples, respectively; 184 (62%) were positive by both nasopharyngeal RT-PCR and TA RNA-Seq for a virus, and 69 (23%) were negative by both methods. Nasopharyngeal RT-PCR detected the most abundant virus identified by RNA-Seq in 92.4% of subjects. Among the most frequent viruses detected, respiratory syncytial virus demonstrated the highest degree of concordance (κ = 0.89; 95% CI, 0.83-0.94), whereas rhinovirus/enterovirus demonstrated lower concordance (κ = 0.55; 95% CI, 0.44-0.66). Nasopharyngeal PCR was more likely to detect multiple viruses than TA RNA-Seq (54 [18.3%] vs 24 [8.1%], p ≤ 0.001). CONCLUSIONS: Viral nucleic acid detection in the upper versus LRT reveals good overall agreement, but concordance depends on the virus. Further studies are indicated to determine the utility of LRT sampling or the use of RNA-Seq to determine LRTI etiology.

Tobacco smoke exposure, the lower airways microbiome and outcomes of ventilated children.

BACKGROUND: Tobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome. METHODS: Secondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g. RESULTS: Patients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality. CONCLUSION: Among critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities. IMPACT: Tobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children.

Temporal airway microbiome changes related to ventilator-associated pneumonia in children.

We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of Streptococcus, Lactobacillales and Prevotella were lower for VAP subjects versus non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23-0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included Prevotella species (19%), Pseudomonas aeruginosa (14%) and Streptococcus mitis/pneumoniae (10%). Mycoplasma and Ureaplasma were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.

Multisystem Inflammatory Syndrome in Children: Survey of Protocols for Early Hospital Evaluation and Management.

OBJECTIVE: To describe the similarities and differences in the evaluation and treatment of multisystem inflammatory syndrome in children (MIS-C) at hospitals in the US. STUDY DESIGN: We conducted a cross-sectional survey from June 16 to July 16, 2020, of US children's hospitals regarding protocols for management of patients with MIS-C. Elements included characteristics of the hospital, clinical definition of MIS-C, evaluation, treatment, and follow-up. We summarized key findings and compared results from centers in which >5 patients had been treated vs those in which ≤5 patients had been treated. RESULTS: In all, 40 centers of varying size and experience with MIS-C participated in this protocol survey. Overall, 21 of 40 centers required only 1 day of fever for MIS-C to be considered. In the evaluation of patients, there was often a tiered approach. Intravenous immunoglobulin was the most widely recommended medication to treat MIS-C (98% of centers). Corticosteroids were listed in 93% of protocols primarily for moderate or severe cases. Aspirin was commonly recommended for mild cases, whereas heparin or low molecular weight heparin were to be used primarily in severe cases. In severe cases, anakinra and vasopressors frequently were recommended; 39 of 40 centers recommended follow-up with cardiology. There were similar findings between centers in which >5 patients vs ≤5 patients had been managed. Supplemental materials containing hospital protocols are provided. CONCLUSIONS: There are many similarities yet key differences between hospital protocols for MIS-C. These findings can help healthcare providers learn from others regarding options for managing MIS-C.

Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The CAPITAL CHILL Randomized Clinical Trial.

Importance: Comatose survivors of out-of-hospital cardiac arrest experience high rates of death and severe neurologic injury. Current guidelines recommend targeted temperature management at 32 °C to 36 °C for 24 hours. However, small studies suggest a potential benefit of targeting lower body temperatures. Objective: To determine whether moderate hypothermia (31 °C), compared with mild hypothermia (34 °C), improves clinical outcomes in comatose survivors of out-of-hospital cardiac arrest. Design, Setting, and Participants: Single-center, double-blind, randomized, clinical superiority trial carried out in a tertiary cardiac care center in eastern Ontario, Canada. A total of 389 patients with out-of-hospital cardiac arrest were enrolled between August 4, 2013, and March 20, 2020, with final follow-up on October 15, 2020. Interventions: Patients were randomly assigned to temperature management with a target body temperature of 31 °C (n = 193) or 34 °C (n = 196) for a period of 24 hours. Main Outcomes and Measures: The primary outcome was all-cause mortality or poor neurologic outcome at 180 days. Neurologic outcome was assessed using the Disability Rating Scale, with poor neurologic outcome defined as a score greater than 5 (range, 0-29, with 29 being the worst outcome [vegetative state]). There were 19 secondary outcomes, including mortality at 180 days and length of stay in the intensive care unit. Results: Among 367 patients included in the primary analysis (mean age, 61 years; 69 women [19%]), 366 (99.7%) completed the trial. The primary outcome occurred in 89 of 184 patients (48.4%) in the 31 °C group and in 83 of 183 patients (45.4%) in the 34 °C group (risk difference, 3.0% [95% CI, 7.2%-13.2%]; relative risk, 1.07 [95% CI, 0.86-1.33]; P = .56). Of the 19 secondary outcomes, 18 were not statistically significant. Mortality at 180 days was 43.5% and 41.0% in patients treated with a target temperature of 31 °C and 34 °C, respectively (P = .63). The median length of stay in the intensive care unit was longer in the 31 °C group (10 vs 7 days; P = .004). Among adverse events in the 31 °C group vs the 34 °C group, deep vein thrombosis occurred in 11.4% vs 10.9% and thrombus in the inferior vena cava occurred in 3.8% and 7.7%, respectively. Conclusions and Relevance: In comatose survivors of out-of-hospital cardiac arrest, a target temperature of 31 °C did not significantly reduce the rate of death or poor neurologic outcome at 180 days compared with a target temperature of 34 °C. However, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02011568.

Foreign Body Esophageal Perforation Leading to Multifocal Brain Abscesses: A Case Report.

BACKGROUND: Among those aged 5 years or younger, foreign bodies are the fourth most common pediatric exposure reported to the American Association of Poison Control Centers. Although the majority of ingested foreign bodies pass through the gastrointestinal tract without complication, those that do not spontaneously pass can lead to a number of serious complications, such as gastrointestinal obstruction or perforation, which can be complicated by bleeding from aortoesophageal fistula, secondary mediastinitis, peritonitis, esophageal or gastrointestinal fistula formation, and abscesses. CASE REPORT: We present the case of a 10-month-old child who presented with new-onset focal seizure in the setting of multiple brain abscesses, ultimately found to be due to esophageal perforation from a retained, metallic esophageal foreign body. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Foreign bodies that are retained for longer than 24 h after ingestion have been associated with a higher risk of complications because they are less likely to pass spontaneously through the gastrointestinal tract. Early identification and removal of foreign bodies is necessary to prevent subsequent complications. In patients who have a subacute history of cough, gagging, vomiting, and decreased oral intake with an otherwise unknown cause, foreign-body ingestion or aspiration should be considered. In addition, central nervous system abscess and infection should be considered in patients with concerns about previous foreign body ingestion or aspiration and who are newly presenting with fever, focal neurologic changes, and irritability.

In-hospital outcomes of STEMI patients on warfarin undergoing primary PCI.

OBJECTIVES: We sought to describe the safety and efficacy outcomes of patients on warfarin presenting with ST-elevation myocardial infarction (STEMI). BACKGROUND: Limited data exist on the outcomes and optimal management of STEMI patients on warfarin undergoing primary percutaneous coronary intervention (PCI). METHODS: Baseline characteristics and outcomes were prospectively collected for 2,390 consecutive STEMI patients referred for primary PCI. Patients were stratified based on warfarin use at baseline. The primary safety endpoint was the rate of in-hospital bleeding (a composite of major bleeding or minor bleeding) according to the thrombolysis in myocardial infarction (TIMI) classification. Efficacy endpoints included major adverse cardiovascular events (MACE), defined as death, myocardial infarction, or stroke, as well as intracranial bleeding, cardiogenic shock, and length of stay. Multiple logistic regression was used to determine if warfarin was independently associated with bleeding and MACE. RESULTS: Warfarin patients (n = 59 vs. n = 2,331) were significantly older (73.2 years vs. 61.7 years; P < 0.01), and more likely to present as Killip Class IV (13.6% vs. 2.7%; P < 0.01). TIMI major/minor bleeding occurred in 30.4% of the warfarin patients and 14.2% of the control patients (P < 0.01). After adjustment warfarin was independently associated with an increased risk of bleeding (OR 2.08; P = 0.04). Warfarin patients also had an increased frequency of MACE (20.3% vs. 5.9%; P < 0.01), though this was not significant after adjustment (OR 2.00; P = 0.10). CONCLUSIONS: STEMI patients on warfarin referred for primary PCI are more likely to experience bleeding. New strategies are needed to optimize the management and minimize bleeding in this high-risk population.

Identification of the Receptor-Binding Domain of the Spike Glycoprotein of Human Betacoronavirus HKU1.

UNLABELLED: Coronavirus spike (S) glycoproteins mediate receptor binding, membrane fusion, and virus entry and determine host range. Murine betacoronavirus (ß-CoV) in group A uses the N-terminal domain (NTD) of S protein to bind to its receptor, whereas the ß-CoVs severe acute respiratory syndrome CoV in group B and Middle East respiratory syndrome CoV in group C and several α-CoVs use the downstream C domain in their S proteins to recognize their receptor proteins. To identify the receptor-binding domain in the spike of human ß-CoV HKU1 in group A, we generated and mapped a panel of monoclonal antibodies (MAbs) to the ectodomain of HKU1 spike protein. They did not cross-react with S proteins of any other CoV tested. Most of the HKU1 spike MAbs recognized epitopes in the C domain between amino acids 535 and 673, indicating that this region is immunodominant. Two of the MAbs blocked HKU1 virus infection of primary human tracheal-bronchial epithelial (HTBE) cells. Preincubation of HTBE cells with a truncated HKU1 S protein that includes the C domain blocked infection with HKU1 virus, but preincubation of cells with truncated S protein containing only the NTD did not block infection. These data suggest that the receptor-binding domain (RBD) of HKU1 spike protein is located in the C domain, where the spike proteins of α-CoVs and ß-CoVs in groups B and C bind to their specific receptor proteins. Thus, two ß-CoVs in group A, HKU1 and murine CoV, have evolved to use different regions of their spike glycoproteins to recognize their respective receptor proteins. IMPORTANCE: Mouse hepatitis virus, a ß-CoV in group A, uses the galectin-like NTD in its spike protein to bind its receptor protein, while HCoV-OC43, another ß-CoV in group A, uses the NTD to bind to its sialic-acid containing receptor. In marked contrast, the NTD of the spike glycoprotein of human respiratory ß-CoV HKU1, which is also in group A, does not bind sugar. In this study, we showed that for the spike protein of HKU1, the purified C domain, downstream of the NTD, could block HKU1 virus infection of human respiratory epithelial cells, and that several monoclonal antibodies that mapped to the C domain neutralized virus infectivity. Thus, the receptor-binding domain of HKU1 spike glycoprotein is located in the C domain. Surprisingly, two ß-CoVs in group A, mouse hepatitis virus and HKU1, have evolved to use different regions of their spike glycoproteins to recognize their respective receptors.

Viral gastroenteritis in children in Colorado 2006-2009.

Acute gastroenteritis accounts for a significant burden of medically attended illness in children under the age of five. For this study, four multiplex reverse transcription PCR assays were used to determine the incidence of adenovirus, astrovirus, coronavirus, norovirus GI and GII, rotavirus, and sapovirus in stool samples submitted for viral electron microscopy (EM) to the Children's Hospital Colorado. Of 1105 stool samples available, viral RNA/DNA was detected in 247 (26.2%) of 941 pediatric samples (median age = 2.97 years, 54% male) with 28 (3.0%) positive for more than one virus. Adenovirus, astrovirus, norovirus GI, norovirus GII, rotavirus, and sapovirus were detected in 95 (10.0%), 33 (3.5%), 8 (0.9%), 90 (9.6%), 49 (5.2%), and 2 (0.2%) of the pediatric samples, respectively. No coronaviruses were identified. Sequencing of norovirus positive samples indicated an outbreak of norovirus strain GII.4 in 2006 with evidence of numerous circulating strains. Multiple samples from the same immunocompromised patients demonstrated symptomatic shedding of norovirus for up to 32 weeks and astrovirus for 12 weeks. RT-PCR detected 99 of 111 (89%) adenovirus-positive samples versus 12 (11%) by EM, and 186 of 192 (97%) sapovirus/astrovirus/norovirus-positive samples versus 21 (11%) by EM. Noroviruses and adenoviruses are common causes of gastroenteritis in children. Immunocompromised patients can be infected with multiple viruses and shed viruses in their stools for prolonged periods. This data support the superiority of RT-PCR compared to EM for diagnosis of viral gastroenteritis.

The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients.

Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.

Outbreak of Invasive Group A Streptococcus in Children-Colorado, October 2022-April 2023.

BACKGROUND: In the fall of 2022, we observed a sharp rise in pediatric Invasive Group A Streptococcus (iGAS) hospitalizations in Colorado. We compared the epidemiology, clinical features, and patient outcomes in this outbreak to prior years. METHODS: Between October 2022 and April 2023, we prospectively identified and reviewed iGAS cases in hospitalized pediatric patients at Children's Hospital Colorado. Using laboratory specimen records, we also retrospectively compared the number of patients with sterile site GAS-positive cultures across three time periods: pre-COVID-19 (January 2015-March 2020), height of COVID-19 pandemic (April 2020-September 2022), and outbreak (October 2022-April 2023). RESULTS: Among 96 prospectively identified iGAS cases, median age was 5.7 years old; 66% were male, 70% previously healthy, 39% required critical care, and four patients died. Almost 60% had associated respiratory viral symptoms, 10% had toxic shock syndrome, and 4% had necrotizing fasciitis. Leukopenia, bandemia, and higher C-reactive protein values were laboratory findings associated with need for critical care. There were significantly more cases during the outbreak (9.9/month outbreak vs 3.9/month pre-pandemic vs 1.3/month pandemic), including more cases with pneumonia (28% outbreak vs 15% pre-pandemic vs 0% pandemic) and multifocal disease (17% outbreak vs 3% pre-pandemic vs 0% pandemic), P < .001 for all. CONCLUSIONS: Outbreak case numbers were almost triple the pre-pandemic baseline. The high percentage of cases with associated viral symptoms suggests a link to coinciding surges in respiratory viruses during this time. Invasive GAS can be severe and evolve rapidly; clinical and laboratory features may help in earlier identification of critically ill children.

The antibiotic resistance reservoir of the lung microbiome expands with age.

Antimicrobial resistant lower respiratory tract infections (LRTI) are an increasing public health threat, and an important cause of global mortality. The lung microbiome influences LRTI susceptibility and represents an important reservoir for exchange of antimicrobial resistance genes (ARGs). Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene (ARG) burden, however corollary studies in the lung microbiome remain absent, despite the respiratory tract representing one of the most clinically significant sites for drug resistant infections. We performed a prospective, multicenter observational study of 261 children and 88 adults with acute respiratory failure, ranging in age from 31 days to ≥ 89 years, admitted to intensive care units in the United States. We performed RNA sequencing on tracheal aspirates collected within 72 hours of intubation, and evaluated age-related differences in detectable ARG expression in the lung microbiome as a primary outcome. Secondary outcomes included number and classes of ARGs detected, proportion of patients with an ARG class, and composition of the lung microbiome. Multivariable logistic regression models (adults vs children) or continuous age (years) were adjusted for sex, race/ethnicity, LRTI status, and days from intubation to specimen collection. Detection of ARGs was significantly higher in adults compared with children after adjusting for sex, race/ethnicity, LRTI diagnosis, and days from intubation to specimen collection (adjusted odds ratio (aOR): 2.16, 95% confidence interval (CI): 1.10-4.22). A greater proportion of adults compared with children had beta-lactam ARGs (31% (CI: 21-41%) vs 13% (CI: 10-18%)), aminoglycoside ARGs (20% (CI: 13-30%) vs 2% (CI: 0.6-4%)), and tetracycline ARGs (14% (CI: 7-23%) vs 3% (CI: 1-5%)). Adults ≥70 years old had the highest proportion of these three ARG classes. The total bacterial abundance of the lung microbiome increased with age, and microbiome alpha diversity varied with age. Taxonomic composition of the lung microbiome, measured by Bray Curtis dissimilarity index, differed between adults and children (p = 0.003). The association between age and increased ARG detection remained significant after additionally including lung microbiome total bacterial abundance and alpha diversity in the multivariable logistic regression model (aOR: 2.38, (CI: 1.25-4.54)). Furthermore, this association remained robust when modeling age as a continuous variable (aOR: 1.02, (CI: 1.01-1.03) per year of age). Taken together, our results demonstrate that age is an independent risk factor for ARG detection in the lower respiratory tract microbiome. These data shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.

Integrated host/microbe metagenomics enables accurate lower respiratory tract infection diagnosis in critically ill children.

BACKGROUNDLower respiratory tract infection (LRTI) is a leading cause of death in children worldwide. LRTI diagnosis is challenging because noninfectious respiratory illnesses appear clinically similar and because existing microbiologic tests are often falsely negative or detect incidentally carried microbes, resulting in antimicrobial overuse and adverse outcomes. Lower airway metagenomics has the potential to detect host and microbial signatures of LRTI. Whether it can be applied at scale and in a pediatric population to enable improved diagnosis and treatment remains unclear.METHODSWe used tracheal aspirate RNA-Seq to profile host gene expression and respiratory microbiota in 261 children with acute respiratory failure. We developed a gene expression classifier for LRTI by training on patients with an established diagnosis of LRTI (n = 117) or of noninfectious respiratory failure (n = 50). We then developed a classifier that integrates the host LRTI probability, abundance of respiratory viruses, and dominance in the lung microbiome of bacteria/fungi considered pathogenic by a rules-based algorithm.RESULTSThe host classifier achieved a median AUC of 0.967 by cross-validation, driven by activation markers of T cells, alveolar macrophages, and the interferon response. The integrated classifier achieved a median AUC of 0.986 and increased the confidence of patient classifications. When applied to patients with an uncertain diagnosis (n = 94), the integrated classifier indicated LRTI in 52% of cases and nominated likely causal pathogens in 98% of those.CONCLUSIONLower airway metagenomics enables accurate LRTI diagnosis and pathogen identification in a heterogeneous cohort of critically ill children through integration of host, pathogen, and microbiome features.FUNDINGSupport for this study was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (UG1HD083171, 1R01HL124103, UG1HD049983, UG01HD049934, UG1HD083170, UG1HD050096, UG1HD63108, UG1HD083116, UG1HD083166, UG1HD049981, K23HL138461, and 5R01HL155418) as well as by the Chan Zuckerberg Biohub.

White Tongue Because of Uremic Stomatitis as a Sign of Advanced Kidney Disease.

We present a case of a previously healthy adolescent male who initially presented to his primary care physician with the chief complaint of a "large and white tongue," who subsequently was diagnosed with end-stage kidney disease (ESKD) and associated uremic stomatitis. This patient required admission to a PICU for acute renal replacement therapy with intermittent hemodialysis, and his hospital course was complicated by generalized tonic-clonic seizures. ESKD is difficult to diagnose in the pediatric population because these patients are often asymptomatic in the early stages given the insidiousness of underlying disorders. Renal disease should be considered in the differential diagnosis of a child with a white tongue not being the result of oral candidiasis.

Lower respiratory tract infections in children requiring mechanical ventilation: a multicentre prospective surveillance study incorporating airway metagenomics.

BACKGROUND: Lower respiratory tract infections (LRTI) are a leading cause of critical illness and mortality in mechanically ventilated children; however, the pathogenic microbes frequently remain unknown. We combined traditional diagnostics with metagenomic next generation sequencing (mNGS) to evaluate the cause of LRTI in critically ill children. METHODS: We conducted a prospective, multicentre cohort study of critically ill children aged 31 days to 17 years with respiratory failure requiring mechanical ventilation (>72 h) in the USA. By combining bacterial culture and upper respiratory viral PCR testing with mNGS of tracheal aspirate collected from all patients within 24 h of intubation, we determined the prevalence, age distribution, and seasonal variation of viral and bacterial respiratory pathogens detected by either method in children with or without LRTI. FINDINGS: Between Feb 26, 2015, and Dec 31, 2017, of the 514 enrolled patients, 397 were eligible and included in the study (276 children with LRTI and 121 with no evidence of LRTI). A presumptive microbiological cause was identified in 255 (92%) children with LRTI, with respiratory syncytial virus (127 [46%]), Haemophilus influenzae (70 [25%]), and Moraxella catarrhalis (65 [24%]) being most prevalent. mNGS identified uncommon pathogens including Ureaplasma parvum and Bocavirus. Co-detection of viral and bacterial pathogens occurred in 144 (52%) patients. Incidental carriage of potentially pathogenic microbes occurred in 82 (68%) children without LRTI, with rhinovirus (30 [25%]) being most prevalent. Respiratory syncytial virus (p<0·0001), H influenzae (p=0·0006), and M catarrhalis (p=0·0002) were most common in children younger than 5 years. Viral and bacterial LRTI occurred predominantly during winter months. INTERPRETATION: These findings demonstrate that respiratory syncytial virus, H influenzae, and M catarrhalis contribute disproportionately to severe paediatric LRTI, co-infections are common, and incidental carriage of potentially pathogenic microbes occurs frequently. Further, we provide a framework for future epidemiological and emerging pathogen surveillance studies, highlighting the potential for metagenomics to enhance clinical diagnosis. FUNDING: US National Institutes of Health and CZ Biohub.

Investigating Health Disparities Associated With Multisystem Inflammatory Syndrome in Children After SARS-CoV-2 Infection.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complication that has disproportionately affected racial/ethnic minority children. We conducted a pilot study to investigate risk factors for MIS-C aiming to understand MIS-C disparities. METHODS: This case-control study included MIS-C cases and SARS-CoV-2-positive outpatient controls less than 18 years old frequency-matched 4:1 to cases by age group and site. Patients hospitalized with MIS-C were admitted between March 16 and October 2, 2020, across 17 pediatric hospitals. We evaluated race, ethnicity, social vulnerability index (SVI), insurance status, weight-for-age and underlying medical conditions as risk factors using mixed effects multivariable logistic regression. RESULTS: We compared 241 MIS-C cases with 817 outpatient SARS-CoV-2-positive at-risk controls. Cases and controls had similar sex, age and U.S. census region distribution. MIS-C patients were more frequently previously healthy, non-Hispanic Black, residing in higher SVI areas, and in the 95th percentile or higher for weight-for-age. In the multivariable analysis, the likelihood of MIS-C was higher among non-Hispanic Black children [adjusted odds ratio (aOR): 2.07; 95% CI: 1.23-3.48]. Additionally, SVI in the 2nd and 3rd tertiles (aOR: 1.88; 95% CI: 1.18-2.97 and aOR: 2.03; 95% CI: 1.19-3.47, respectively) were independent factors along with being previously healthy (aOR: 1.64; 95% CI: 1.18-2.28). CONCLUSIONS: In this study, non-Hispanic Black children were more likely to develop MIS-C after adjustment for sociodemographic factors, underlying medical conditions, and weight-for-age. Investigation of the potential contribution of immunologic, environmental, and other factors is warranted.

IVIG Compared With IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children.

OBJECTIVES: To compare initial treatment with intravenous immunoglobulin (IVIG) versus IVIG plus infliximab in multisystem inflammatory syndrome in children (MIS-C). METHODS: Single-center retrospective cohort study of patients with MIS-C who met Centers for Disease Control and Prevention criteria and received treatment from April 2020 to February 2021. Patients were included and compared on the basis of initial therapy of either IVIG alone or IVIG plus infliximab. The primary outcome was need for additional therapy 24 hours or more after treatment initiation. RESULTS: Seventy-two children with MIS-C met inclusion criteria. Additional therapy was needed in 13 of 20 (65%) who received IVIG alone and 16 of 52 (31%) who received IVIG plus infliximab (P = .01). The median (interquartile range) ICU lengths of stay were 3.3 (2.2 to 3.8) and 1.8 (1.1 to 2.1) days, respectively (P = .001). New or worsened left ventricular dysfunction developed in 4 of 20 (20%) and 2 of 52 (4%) (P = .05), and new vasoactive medication requirement developed in 3 of 20 (15%) and 2 of 52 (4%), respectively (P = .13). The median percentage changes in the C-reactive protein level at 24 hours posttreatment compared with pretreatment were 0% (-29% to 66%) and -46% (-62% to -15%) (P < .001); and at 48 hours posttreatment, -5% (-41% to 57%) and -70% (-79% to -49%) respectively (P < .001). There was no significant difference in hospital length of stay, time to fever resolution, vasoactive medication duration, or need for diuretics. CONCLUSIONS: Patients with MIS-C initially treated with IVIG plus infliximab compared with those treated with IVIG alone were less likely to require additional therapy and had decreased ICU length of stay, decreased development of left ventricular dysfunction, and more rapid decline in C-reactive protein levels.

Cognitive dysfunction after out-of-hospital cardiac arrest: Rate of impairment and clinical predictors.

BACKGROUND: The purpose of this study was to evaluate the rate and domains of cognitive impairment in out-of-hospital cardiac arrest (OHCA) survivors, as compared to patients who experienced a myocardial infarction (MI), and to explore mechanisms and predictors of this impairment. METHODS AND RESULTS: OHCA survivors with "good" neurological recovery (i.e., Cerebral Performance Categories Scale ≤ 2) (n = 79), as well as a control group of MI patients (n = 69), underwent a comprehensive neuropsychological assessment. Forty-three percent of OHCA survivors were cognitively impaired (in the lowest decile on a global measure of cognitive functioning). Rates of impairment were approximately six times higher in the OHCA group than the MI group. Attention, memory, language and executive function were affected. Downtime was a significant predictor of cognitive impairment; the interaction between downtime and immediate intervention was significant such that, at short downtimes, receiving cardiopulmonary resuscitation (CPR) or defibrillation within 1 min of collapse predicted less cognitive impairment. CONCLUSIONS: OHCA survivors - even those with seemingly good neurological recovery - are at risk for cognitive impairment. Cognitive rehabilitation may be an important consideration post-OHCA.

Ending student mistreatment: early successes and continuing challenges.

Problem: Student mistreatment represents an ongoing challenge for US medical schools. Students experiencing mistreatment may become marginalized and cynical, and they have higher rates of burnout, depression and substance use disorders. Although numerous attempts to eliminate mistreatment have been proposed, best practices remain elusive. We formed a unique student-faculty collaboration (the Ending Mistreatment Task Force) that allowed all voices to be heard and enabled identification of five interventions to reduce mistreatment.Intervention: The EMTF developed and implemented five key interventions: 1) a shared mistreatment definition; 2) measures to increase faculty accountability, including adding professionalism expectations to faculty members' contracts and performance reviews; 3) a Professionalism Office to respond promptly to students' reports of mistreatment and provide feedback to faculty; 4) tools to help teachers provide authentic learning environments for students, while addressing generational misunderstandings; and 5) student-produced videos, helping faculty understand the impact of mistreatment as seen through students' eyes.Context: These interventions occurred at one medical school where mistreatment reports were consistently above national averages.Impact: Over 6 years, the interventions helped reduce the rate of student-reported mistreatment by 36% compared with a 4% decline across all US medical schools.Lessons: The collaborations between students and faculty helped each party identify unexpected misunderstandings and challenges. We learned that students want hard questions, although faculty are often afraid to challenge students for fear of offending them or being reported. We clarified differences between mistreatment and sub-optimal learning environments and openly discussed the pervasive opinion that 'some' mistreatment is important for learning. We also identified ongoing challenges, including the need to solicit residents' perspectives regarding mistreatment and develop proper responses to disrespectful comments directed at patients, family and colleagues. The collaboration reinforced students' and faculty members' shared commitment to upholding a respectful learning and clinical care environment and ending mistreatment.

Severe SARS-CoV-2 Infection in a Pediatric Patient Requiring Extracorporeal Membrane Oxygenation.

The overwhelming majority of pediatric cases of SARS-CoV-2 infection are mild or asymptomatic with only a handful of pediatric deaths reported. We present a case of severe COVID-19 infection in a pediatric patient with signs of hyperinflammation and consumptive coagulopathy requiring intubation and extracorporeal membrane oxygenation (ECMO) and eventual death due to ECMO complications.