Characteristics and Outcomes of Critically Ill Children With Multisystem Inflammatory Syndrome.

OBJECTIVES: To characterize the prevalence of pediatric critical illness from multisystem inflammatory syndrome in children (MIS-C) and to assess the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain on outcomes. DESIGN: Retrospective cohort study. SETTING: Database evaluation using the Virtual Pediatric Systems Database. PATIENTS: All children with MIS-C admitted to the PICU in 115 contributing hospitals between January 1, 2020, and June 30, 2021. MEASUREMENTS AND MAIN RESULTS: Of the 145,580 children admitted to the PICU during the study period, 1,338 children (0.9%) were admitted with MIS-C with the largest numbers of children admitted in quarter 1 (Q1) of 2021 ( n = 626). The original SARS-CoV-2 viral strain and the D614G Strain were the predominant strains through 2020, with Alpha B.1.1.7 predominating in Q1 and quarter 2 (Q2) of 2021. Overall, the median PICU length of stay (LOS) was 2.7 days (25-75% interquartile range [IQR], 1.6-4.7 d) with a median hospital LOS of 6.6 days (25-75% IQR, 4.7-9.3 d); 15.2% received mechanical ventilation with a median duration of mechanical ventilation of 3.1 days (25-75% IQR, 1.9-5.8 d), and there were 11 hospital deaths. During the study period, there was a significant decrease in the median PICU and hospital LOS and a decrease in the frequency of mechanical ventilation, with the most significant decrease occurring between quarter 3 and quarter 4 (Q4) of 2020. Children admitted to a PICU from the general care floor or from another ICU/step-down unit had longer PICU LOS than those admitted directly from an emergency department. CONCLUSIONS: Overall mortality from MIS-C was low, but the disease burden was high. There was a peak in MIS-C cases during Q1 of 2021, following a shift in viral strains in Q1 of 2021. However, an improvement in MIS-C outcomes starting in Q4 of 2020 suggests that viral strain was not the driving factor for outcomes in this population.

School Closures in the United States and Severe Respiratory Illnesses in Children: A Normalized Nationwide Sample.

OBJECTIVES: To determine the association between nationwide school closures and prevalence of common admission diagnoses in the pediatric critical care unit. DESIGN: Retrospective cohort study. SETTING: National database evaluation using the Virtual Pediatric Systems LLC database. PATIENTS: All patients admitted to the PICU in 81 contributing hospitals in the United States. MEASUREMENTS AND MAIN RESULTS: Diagnosis categories were determined for all 110,418 patients admitted during the 20-week study period in each year (2018, 2019, and 2020). Admission data were normalized relative to statewide school closure dates for each patient using geographic data. The "before school closure" epoch was defined as 8 weeks prior to school closure, and the "after school closure" epoch was defined as 12 weeks following school closure. For each diagnosis, admission ratios for each study day were calculated by dividing 2020 admissions by 2018-2019 admissions. The 10 most common diagnosis categories were examined. Significant changes in admission ratios were identified for bronchiolitis, pneumonia, and asthma. These changes occurred at 2, 8, and 35 days following school closure, respectively. PICU admissions decreased by 82% for bronchiolitis, 76% for pneumonia, and 76% for asthma. Nonrespiratory diseases such as diabetic ketoacidosis, status epilepticus, traumatic injury, and poisoning/ingestion did not show significant changes following school closure. CONCLUSIONS: School closures are associated with a dramatic reduction in the prevalence of severe respiratory disease requiring PICU admission. School closure may be an effective tool to mitigate future pandemics but should be balanced with potential academic, economic, mental health, and social consequences.

Age-Related Changes in the Nasopharyngeal Microbiome Are Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and Symptoms Among Children, Adolescents, and Young Adults.

BACKGROUND: Children are less susceptible to SARS-CoV-2 infection and typically have milder illness courses than adults, but the factors underlying these age-associated differences are not well understood. The upper respiratory microbiome undergoes substantial shifts during childhood and is increasingly recognized to influence host defense against respiratory pathogens. Thus, we sought to identify upper respiratory microbiome features associated with SARS-CoV-2 infection susceptibility and illness severity. METHODS: We collected clinical data and nasopharyngeal swabs from 285 children, adolescents, and young adults (<21 years) with documented SARS-CoV-2 exposure. We used 16S ribosomal RNA gene sequencing to characterize the nasopharyngeal microbiome and evaluated for age-adjusted associations between microbiome characteristics and SARS-CoV-2 infection status and respiratory symptoms. RESULTS: Nasopharyngeal microbiome composition varied with age (PERMANOVA, P < .001; R2 = 0.06) and between SARS-CoV-2-infected individuals with and without respiratory symptoms (PERMANOVA, P  = .002; R2 = 0.009). SARS-CoV-2-infected participants with Corynebacterium/Dolosigranulum-dominant microbiome profiles were less likely to have respiratory symptoms than infected participants with other nasopharyngeal microbiome profiles (OR: .38; 95% CI: .18-.81). Using generalized joint attributed modeling, we identified 9 bacterial taxa associated with SARS-CoV-2 infection and 6 taxa differentially abundant among SARS-CoV-2-infected participants with respiratory symptoms; the magnitude of these associations was strongly influenced by age. CONCLUSIONS: We identified interactive relationships between age and specific nasopharyngeal microbiome features that are associated with SARS-CoV-2 infection susceptibility and symptoms in children, adolescents, and young adults. Our data suggest that the upper respiratory microbiome may be a mechanism by which age influences SARS-CoV-2 susceptibility and illness severity.

The Temporal Relationship Between Local School Closure and Increased Incidence of Pediatric Diabetic Ketoacidosis.

Importance: The incidence of pediatric diabetic ketoacidosis (DKA) increased early in the COVID-19 pandemic, but the relative contribution of behavioral changes and viral-related pathophysiology are unknown. Objective: To evaluate the relationship between school closure date and onset of increased DKA to help clarify the etiology of the increased incidence. Design: A multi-center, quality-controlled Pediatric Intensive Care Unit (PICU) database was used to identify the number of admissions to a participating PICU with DKA on each calendar day from 60 days before local school closure to 90 days after, and compared to baseline data from the same periods in 2018-2019. Interrupted time series and multiple linear regression analyses were used to identify admission rates that differed significantly between 2020 and baseline. Setting: Eighty-one PICUs in the United StatesParticipants: Children ages 29 days to 17 years admitted to a PICU with DKAExposures: Statewide school closureMain outcome/measure: Rate of admission to the PICU for DKA. Results: There were 1936 admissions for children with DKA in 2020 and 1795 admissions/year to those same PICUs in 2018-2019. Demographics and clinical outcomes did not differ before school closure, but pandemic-era patients were less often white and had longer hospital length of stay in the post-school closure period. The difference between 2020 admissions and 2018-2019 admissions was not different than zero before school closure, and significantly higher than zero after school closure, but was significantly increased in 2020 at >30 days after school closure (p = 0.039). Conclusions/Relevance: An increase in pediatric DKA admissions began one month after school closures. Given that behavioral changes started near school closure dates and viral activity peaked weeks after, this suggests that behavioral factors may not be the primary etiology and it is possible that SARS-CoV-2 infection may have direct effects on pediatric DKA.

Severe Acute Respiratory Syndrome Coronavirus 2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.

BACKGROUND: Child with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of SARS-CoV-2-related illnesses that the viruses causes in children. METHODS: We conducted a prospective cohort study of children and adolescents (aged <21 years) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time polymerase chain reaction assay. RESULTS: Of 382 children, 293 (77%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (P < .0001), less likely to have asthma (P = .005), and more likely to have an infected sibling contact (P = .001) than uninfected children. Children aged 6-13 years were frequently asymptomatic (39%) and had respiratory symptoms less often than younger children (29% vs 48%; P = .01) or adolescents (29% vs 60%; P < .001). Compared with children aged 6-13 years, adolescents more frequently reported influenza-like (61% vs 39%; P < .001) , and gastrointestinal (27% vs 9%; P = .002), and sensory symptoms (42% vs 9%; P < .0001) and had more prolonged illnesses (median [interquartile range] duration: 7 [4-12] vs 4 [3-8] days; P = 0.01). Despite the age-related variability in symptoms, wWe found no difference in nasopharyngeal viral load by age or between symptomatic and asymptomatic children. CONCLUSIONS: Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while asthma is associated with decreased risk. Age-related differences in clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for coronavirus disease 2019 and in developing screening strategies for schools and childcare settings.

Asymptomatic or mild symptomatic SARS-CoV-2 infection elicits durable neutralizing antibody responses in children and adolescents.

As SARS-CoV-2 continues to spread globally, questions have emerged regarding the strength and durability of immune responses in specific populations. In this study, we evaluated humoral immune responses in 69 children and adolescents with asymptomatic or mild symptomatic SARS-CoV-2 infection. We detected robust IgM, IgG, and IgA antibody responses to a broad array of SARS-CoV-2 antigens at the time of acute infection and 2 and 4 months after acute infection in all participants. Notably, these antibody responses were associated with virus-neutralizing activity that was still detectable 4 months after acute infection in 94% of children. Moreover, antibody responses and neutralizing activity in sera from children and adolescents were comparable or superior to those observed in sera from 24 adults with mild symptomatic infection. Taken together, these findings indicate that children and adolescents with mild or asymptomatic SARS-CoV-2 infection generate robust and durable humoral immune responses that can likely contribute to protection from reinfection.

Changes in Pediatric ICU Utilization and Clinical Trends During the Coronavirus Pandemic.

BACKGROUND: Children have been less affected by the COVID-19 pandemic, but its repercussions on pediatric illnesses may have been significant. This study examines the indirect impact of the pandemic on a population of critically ill children in the United States. RESEARCH QUESTION: Were there significantly fewer critically ill children admitted to PICUs during the second quarter of 2020, and were there significant changes in the types of diseases admitted? STUDY DESIGN AND METHODS: This retrospective observational cohort study used the Virtual Pediatric Systems database. Participants were 160,295 children admitted to the PICU at 77 sites in the United States during quarters 1 (Q1) and 2 (Q2) of 2017 to 2019 (pre-COVID-19) and 2020 (COVID-19). RESULTS: The average number of admissions was similar between pre-COVID-19 Q1 and COVID-19 Q1 but decreased by 32% from pre-COVID-19 Q2 to COVID-19 Q2 (20,157 to 13,627 admissions per quarter). The largest decreases were in respiratory conditions, including asthma (1,327 subjects in pre-COVID-19 Q2 (6.6% of patients) vs 241 subjects in COVID-19 Q2 (1.8%; P < .001) and bronchiolitis (1,299 [6.5%] vs 121 [0.9%]; P < .001). The percentage of trauma admissions increased, although the raw number of trauma admissions decreased. Admissions for diabetes mellitus and poisoning/ingestion also increased. In the multivariable model, illness severity-adjusted odds of ICU mortality for PICU patients during COVID-19 Q2 increased compared with pre-COVID-19 Q2 (OR, 1.165; 95% CI, 1.00-1.357; P = .049). INTERPRETATION: Pediatric critical illness admissions decreased substantially during the second quarter of 2020, with significant changes in the types of diseases seen in PICUs in the United States. There was an increase in mortality in children admitted to the PICU during this period.

Severe Acute Respiratory Syndrome-Associated Coronavirus 2 Infection and Organ Dysfunction in the ICU: Opportunities for Translational Research.

OBJECTIVES: Since the beginning of the coronavirus disease 2019 pandemic, hundreds of thousands of patients have been treated in ICUs across the globe. The severe acute respiratory syndrome-associated coronavirus 2 virus enters cells via the angiotensin-converting enzyme 2 receptor and activates several distinct inflammatory pathways, resulting in hematologic abnormalities and dysfunction in respiratory, cardiac, gastrointestinal renal, endocrine, dermatologic, and neurologic systems. This review summarizes the current state of research in coronavirus disease 2019 pathophysiology within the context of potential organ-based disease mechanisms and opportunities for translational research. DATA SOURCES: Investigators from the Research Section of the Society of Critical Care Medicine were selected based on expertise in specific organ systems and research focus. Data were obtained from searches conducted in Medline via the PubMed portal, Directory of Open Access Journals, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, and Web of Science from an initial search from December 2019 to October 15, 2020, with a revised search to February 3, 2021. The medRxiv, Research Square, and clinical trial registries preprint servers also were searched to limit publication bias. STUDY SELECTION: Content experts selected studies that included mechanism-based relevance to the severe acute respiratory syndrome-associated coronavirus 2 virus or coronavirus disease 2019 disease. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: Not applicable. CONCLUSIONS: Efforts to improve the care of critically ill coronavirus disease 2019 patients should be centered on understanding how severe acute respiratory syndrome-associated coronavirus 2 infection affects organ function. This review articulates specific targets for further research.