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Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.
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COVID-19/inmunología , COVID-19/patología , SARS-CoV-2/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Adolescente , Alarminas/inmunología , Autoanticuerpos/inmunología , Linfocitos T CD8-positivos/inmunología , Niño , Preescolar , Citotoxicidad Inmunológica/genética , Endotelio/inmunología , Endotelio/patología , Humanos , Células Asesinas Naturales/inmunología , Células Mieloides/inmunología , Células Plasmáticas/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Terminal extubation (TE) and terminal weaning (TW) during withdrawal of life-sustaining therapies (WLSTs) have been described and defined in adults. The recent Death One Hour After Terminal Extubation study aimed to validate a model developed to predict whether a child would die within 1 hour after discontinuation of mechanical ventilation for WLST. Although TW has not been described in children, pre-extubation weaning has been known to occur before WLST, though to what extent is unknown. In this preplanned secondary analysis, we aim to describe/define TE and pre-extubation weaning (PW) in children and compare characteristics of patients who had ventilatory support decreased before WLST with those who did not. DESIGN: Secondary analysis of multicenter retrospective cohort study. SETTING: Ten PICUs in the United States between 2009 and 2021. PATIENTS: Nine hundred thirteen patients 0-21 years old who died after WLST. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 71.4% ( n = 652) had TE without decrease in ventilatory support in the 6 hours prior. TE without decrease in ventilatory support in the 6 hours prior = 71.4% ( n = 652) of our sample. Clinically relevant decrease in ventilatory support before WLST = 11% ( n = 100), and 17.6% ( n = 161) had likely incidental decrease in ventilatory support before WLST. Relevant ventilator parameters decreased were F io2 and/or ventilator set rates. There were no significant differences in any of the other evaluated patient characteristics between groups (weight, body mass index, unit type, primary diagnostic category, presence of coma, time to death after WLST, analgosedative requirements, postextubation respiratory support modality). CONCLUSIONS: Decreasing ventilatory support before WLST with extubation in children does occur. This practice was not associated with significant differences in palliative analgosedation doses or time to death after extubation.
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Extubación Traqueal , Desconexión del Ventilador , Niño , Adulto , Humanos , Recién Nacido , Lactante , Preescolar , Adolescente , Adulto Joven , Estudios Retrospectivos , Respiración Artificial , Privación de TratamientoRESUMEN
OBJECTIVES: To describe the doses of opioids and benzodiazepines administered around the time of terminal extubation (TE) to children who died within 1 hour of TE and to identify their association with the time to death (TTD). DESIGN: Secondary analysis of data collected for the Death One Hour After Terminal Extubation study. SETTING: Nine U.S. hospitals. PATIENTS: Six hundred eighty patients between 0 and 21 years who died within 1 hour after TE (2010-2021). MEASUREMENTS AND MAIN RESULTS: Medications included total doses of opioids and benzodiazepines 24 hours before and 1 hour after TE. Correlations between drug doses and TTD in minutes were calculated, and multivariable linear regression performed to determine their association with TTD after adjusting for age, sex, last recorded oxygen saturation/F io2 ratio and Glasgow Coma Scale score, inotrope requirement in the last 24 hours, and use of muscle relaxants within 1 hour of TE. Median age of the study population was 2.1 years (interquartile range [IQR], 0.4-11.0 yr). The median TTD was 15 minutes (IQR, 8-23 min). Forty percent patients (278/680) received either opioids or benzodiazepines within 1 hour after TE, with the largest proportion receiving opioids only (23%, 159/680). Among patients who received medications, the median IV morphine equivalent within 1 hour after TE was 0.75 mg/kg/hr (IQR, 0.3-1.8 mg/kg/hr) ( n = 263), and median lorazepam equivalent was 0.22 mg/kg/hr (IQR, 0.11-0.44 mg/kg/hr) ( n = 118). The median morphine equivalent and lorazepam equivalent rates after TE were 7.5-fold and 22-fold greater than the median pre-extubation rates, respectively. No significant direct correlation was observed between either opioid or benzodiazepine doses before or after TE and TTD. After adjusting for confounding variables, regression analysis also failed to show any association between drug dose and TTD. CONCLUSIONS: Children after TE are often prescribed opioids and benzodiazepines. For patients dying within 1 hour of TE, TTD is not associated with the dose of medication administered as part of comfort care.
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Analgesia , Lorazepam , Niño , Humanos , Preescolar , Extubación Traqueal , Dolor/tratamiento farmacológico , Analgésicos Opioides/uso terapéutico , Morfina/uso terapéutico , BenzodiazepinasRESUMEN
BACKGROUND: Human infection with group C Streptococcus is extremely rare and a select number of cases have been reported to cause acute pharyngitis, acute glomerulonephritis, skin and soft tissue infections, septic arthritis, osteomyelitis, pneumonitis, and bacteremia. In pediatrics, this bacteria is known to cause epidemic food-borne pharyngitis, pneumonia, endocarditis, and meningitis, and has reportedly been isolated in the blood, meninges, sinuses, fingernail, peritonsillar abscess, and thyroglossal duct cyst, among others. CASE REPORT: Our patient was a 7-year-old previously healthy female who presented with abnormal movements of her upper body and grimaces of her face that progressively worsened over time. Initial laboratory resulted revealed 3+ protein on urinalysis and elevated antistreptolysin-O and anti-DNAse antibody levels, and echocardiogram showed mild-to-moderate mitral regurgitation. We describe a rare case of group C Streptococcus resulting in rheumatic heart disease in a child, with a detailed review of the literature pertaining to the diagnosis and management of this infection. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Early recognition of rheumatic heart disease is crucial in the overall outcome of the condition and therefore knowledge of the symptoms associated with condition is also imperative. Group C Streptococcus is rarely associated with rheumatic heart disease and most children exhibiting acute onset of common symptoms, such as chorea, fever, carditis, and rash (erythema marginatum) will present to the emergency department first. Increased awareness and prompt recognition, as done with this child, will result in proper follow-up and adequate management of this condition in all patients.
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Cardiopatía Reumática/microbiología , Infecciones Estreptocócicas/complicaciones , Niño , Corea/microbiología , Femenino , Humanos , Miocarditis/microbiología , Infecciones Estreptocócicas/microbiología , StreptococcusRESUMEN
Introduction: Status asthmaticus (SA) is a cause of many pediatric hospitalizations. This study sought to evaluate how a standardized asthma care pathway (ACP) in the electronic medical record impacted the length of stay (LOS). Methods: An interdisciplinary team internally validated a standardized respiratory score for patients admitted with SA to a 25-bed pediatric intensive care unit (PICU) at a tertiary children's hospital. The respiratory score determined weaning schedules for albuterol and steroid therapies. In addition, pharmacy and information technology staff developed an electronic ACP within our electronic medical record system using best practice alerts. These best practice alerts informed staff to initiate the pathway, wean/escalate treatment, transition to oral steroids, transfer level of care, and complete discharge education. The PICU, stepdown ICU (SD ICU), and acute care units implemented the clinical pathway. Pre- and postintervention metrics were assessed using process control charts and compared using Welch's t tests with a significance level of 0.05. Results: Nine hundred two consecutive patients were analyzed (598 preintervention, 304 postintervention). Order set utilization significantly increased from 68% to 97% (P < 0.001), PICU LOS decreased from 38.4 to 31.1 hours (P = 0.013), and stepdown ICU LOS decreased from 25.7 to 20.9 hours (P = 0.01). Hospital LOS decreased from 59.5 to 50.7 hours (P = 0.003), with cost savings of $1,215,088 for the patient cohort. Conclusions: Implementing a standardized respiratory therapist-driven ACP for children with SA led to significantly increased order set utilization and decreased ICU and hospital LOS. Leveraging information technology and standardized pathways may improve care quality, outcomes, and costs for other common diagnoses.
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The novel coronavirus (severe acute respiratory syndrome coronavirus-2) has led to a global pandemic. In the adult population, coronavirus disease 2019 (COVID-19) has been found to cause multiorgan system damage with predicted long-term sequelae. We present a case of a 10-year-old boy with a history of ROHHAD (rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation) who presented with hypoxia, emesis, and abdominal pain. Imaging found bilateral ground glass opacities in the lungs and a pericardial effusion. Laboratory evaluation was concerning for elevated inflammatory markers. Remdesivir, hydroxychloroquine, and anticoagulation (heparin and enoxaparin) were utilized. The patient's severe respiratory failure was managed with conventional mechanical ventilation, inhaled nitric oxide, and airway pressure release ventilation. We hope that this report provides insight into the course and management of the severe acute pediatric COVID-19 patient, specifically with underlying comorbidities such as ROHHAD. Clinical trial registration is none.
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Foreign body aspiration (FBA) is a common cause of unintentional-injury mortality. Modern bronchoscopy techniques have reduced mortality in children with FBA. In this article, we described a case of a 16-month-old child with refractory hypoxia where flexible bronchoscopy performed by the intensivist led to prompt etiology recognition and proper treatment. Patients presenting with respiratory distress with persistent hypoxia should be evaluated for FBA, considering initial chest X-ray can be normal in at least 30% of the cases. Intensivists trained in flexible bronchoscopy techniques possess a valuable tool to obtain diagnostic information avoiding delays in diagnosis and initiation of unnecessary therapies, such as extracorporeal membrane oxygenation.
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INTRODUCTION: Paging is a vital part of patient care that allows quick contact between physicians and other hospital personnel. There was no structured way to send a page to physicians at our institution. We hypothesized that by standardizing paging format, scheduling laboratory draw times, and using order clean-up sheets, through a bundle of interventions called Better Etiquette for Effective Paging, we would decrease the number of pages received on the pediatric intensive care unit (PICU) resident pager by 15%. METHODS: This project was a quality improvement initiative in a 25-bed multidisciplinary PICU in a tertiary children's hospital. Baseline data collection was performed in December 2015, categorized by time of day received and type of page. Interventions were paging standards to include relevant information, scheduling laboratory draw times, and order clean-up sheets. We collected postintervention data over 3 years to monitor for sustained change. RESULTS: The average number of pages decreased from a baseline of 4.71 pages/patient/d in 2015 to 3.70 in 2016 (21% decrease), 3.32 in 2017 (30% decrease), and 2.74 in 2018 (42% decrease). The average PRISM 3 score remained similar in all sets (2.52, 2.50, 2.10, and 2.35). The standardized mortality ratio was not adversely affected by the decrease in pages (0.58, 1.07, 1.19, and 0). CONCLUSION: Standardizing the format of pages and using scheduled laboratory times with order clean-up sheets has decreased the number of pages/patient/d in the PICU by 42% without adversely affecting patient care. We can continue to improve communication among the patient care team by emphasizing efficient, standardized communication using Better Etiquette for Effective Paging.
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Critically ill patients who are intubated undergo multiple chest X-rays (CXRs) to determine endotracheal tube position; however, other modalities can save time, medical expenses, and radiation exposure. In this article, we evaluated the validity and interrater reliability of ultrasound to confirm endotracheal tube (ETT) position in patients. A prospective study was performed on intubated patients with cuffed ETTs. The accuracy of ultrasound to confirm correct ETT placement in 92 patients was 97.8%. Sensitivity, positive predictive value, and agreement of 97.7, 93.3, and 91.3% were found on comparing ultrasound to CXR findings. Ultrasound is feasible, reliable, and has good interrater reliability in assessing correct ETT position in children.
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Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.
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Autoinmunidad , COVID-19/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Inmunidad Adaptativa , Adolescente , Biomarcadores/metabolismo , COVID-19/genética , COVID-19/inmunología , COVID-19/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Síndrome de Liberación de Citoquinas/inmunología , Femenino , Humanos , Lactante , Inflamación/inmunología , Masculino , Síndrome Mucocutáneo Linfonodular/genética , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/metabolismo , Activación Neutrófila , Proteómica , RNA-Seq , Receptores de Antígenos de Linfocitos B/genética , Índice de Severidad de la Enfermedad , Síndrome de Respuesta Inflamatoria Sistémica/genética , Síndrome de Respuesta Inflamatoria Sistémica/metabolismoRESUMEN
Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vß chains results in Vß skewing, whereby T cells with specific Vß chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRß variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vß chain encoded by TRBV11-2 (Vß21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.
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COVID-19/inmunología , Regiones Determinantes de Complementariedad/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Linfocitos T/inmunología , COVID-19/genética , Niño , Regiones Determinantes de Complementariedad/genética , Femenino , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Masculino , Receptores de Antígenos de Linfocitos T alfa-beta/genética , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , Síndrome de Respuesta Inflamatoria Sistémica/genéticaRESUMEN
Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS-C patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 are expanded. Consistently, we detect elevated binding of serum IgG from severe MIS-C patients to activated human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology features of MIS-C with implications for predicting and managing this SARS-CoV2-induced critical illness in children.
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Multisystem Inflammatory Syndrome in Children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares many clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. The superantigen specificity for binding different Vß-chains results in Vß-skewing, whereby T cells with specific Vß-chains and diverse antigen specificity are overrepresented in the TCR repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR Βeta Variable gene (TRBV)11-2. Furthermore, TRBV11-2 skewing was remarkably correlated with MIS-C severity and serum cytokine levels. Further analysis of TRBJ gene usage and CDR3 length distribution of MIS-C expanding TRBV11-2 clones revealed extensive junctional diversity, indicating a superantigen-mediated selection process for TRBV expansion. In silico modelling indicates that polyacidic residues in TCR Vß11-2 engage in strong interactions with the superantigen-like motif of SARS-CoV-2 spike glycoprotein. Overall, our data indicate that the immune response in MIS-C is consistent with superantigenic activation.
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Pediatric pneumomediastinum and pneumopericardium (PPC) are rare complications, which can arise from various etiologies. We report a case of pediatric PPC secondary to an asthma exacerbation and discuss relevant diagnostic and management principles. Physicians must be aware of PPC and its implications due to the high mortality rate. PPC patients require close observation with continuous cardiorespiratory and telemetry monitoring, and providers experienced in the management of cardiac tamponade at a center capable of providing cardiothoracic surgical intervention. Time to resolution is multifactorial, but can be achieved promptly with supportive care and treatment of underlying condition.