Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Respective role of non-pharmaceutical interventions on bronchiolitis outbreaks, an interrupted time series analysis based on a multinational surveillance system.

BACKGROUND: Bronchiolitis is a major source of morbimortality among young children worldwide. Non-pharmaceutical interventions (NPIs) implemented to reduce the spread of SARS-CoV-2 may have had an important impact on bronchiolitis outbreaks, as well as major societal consequences. Discriminating between their respective impacts would help define optimal public health strategies against bronchiolitis. We aimed to assess the respective impact of each NPI on bronchiolitis outbreaks in 14 European countries. METHODS: We conducted a quasi-experimental interrupted time-series analysis based on a multicentre international study. All children diagnosed with bronchiolitis presenting to the paediatric emergency department of one of the 27 centres from January 2018 to March 2021 were included. We assessed the association between each NPI and change in the bronchiolitis trend over time by seasonally adjusted multivariable quasi-Poisson regression modelling. RESULTS: In total, 42 916 children were included. We observed an overall cumulative 78% reduction (95%CI [-100;-54], p<0.0001) in bronchiolitis cases following NPI implementation. The decrease varied between countries from -97% (95%CI [-100;-47], p=0.0005) to -36% (95%CI [-79;+07], p=0.105). Full lockdown (IRR 0.21, 95%CI [0.14;0.30], p<0.001), secondary-school closure (IRR 0.33, 95%CI [0.20;0.52], p<0.0001), wearing a mask indoors (IRR 0.49, 95%CI [0.25;0.94], p=0.034), and teleworking (IRR 0.55, 95%CI [0.31;0.97], p=0.038) were independently associated with reducing bronchiolitis. CONCLUSION: Several NPIs were associated with a reduction of bronchiolitis outbreaks, including full lockdown, school closure, teleworking and facial masking. Some of these public health interventions may be considered to further reduce the global burden of bronchiolitis.

Influence of epidemics and pandemics on paediatric ED use: a systematic review.

OBJECTIVE: To assess the impact of epidemics and pandemics on the utilisation of paediatric emergency care services to provide health policy advice. SETTING: Systematic review. DESIGN: Searches were conducted of Medline, EMBASE, CINAHL, Scopus, Web of Science and the Cochrane Library for studies that reported on changes in paediatric emergency care utilisation during epidemics (as defined by the WHO). PATIENTS: Children under 18 years. INTERVENTIONS: National Institutes of Health quality assessment tool for observational cohort and cross-sectional studies was used. MAIN OUTCOME MEASURES: Changes in paediatric emergency care utilisation. RESULTS: 131 articles were included within this review, 80% of which assessed the impact of COVID-19. Studies analysing COVID-19, SARS, Middle East respiratory syndrome (MERS) and Ebola found a reduction in paediatric emergency department (PED) visits, whereas studies reporting on H1N1, chikungunya virus and Escherichia coli outbreaks found an increase in PED visits. For COVID-19, there was a reduction of 63.86% (95% CI 60.40% to 67.31%) with a range of -16.5% to -89.4%. Synthesis of results suggests that the fear of the epidemic disease, from either contracting it or its potential adverse clinical outcomes, resulted in reductions and increases in PED utilisation, respectively. CONCLUSIONS: The scale and direction of effect of PED use depend on both the epidemic disease, the public health measures enforced and how these influence decision-making. Policy makers must be aware how fear of virus among the general public may influence their response to public health advice. There is large inequity in reporting of epidemic impact on PED use which needs to be addressed. TRIAL REGISTRATION NUMBER: CRD42021242808.

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health.

Presentations of children to emergency departments across Europe and the COVID-19 pandemic: A multinational observational study.

BACKGROUND: During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. METHODS AND FINDINGS: Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRRs), using predicted counts for each site as offset to adjust for case-mix differences, were used to compare age groups, diagnoses, and outcomes. Reductions in pediatric ED attendances, hospital admissions, and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (IRR 2.26, 95% CI 1.90 to 2.70, p < 0.001) and in children aged <12 months (12 to <24 months IRR 0.86, 95% CI 0.84 to 0.89; 2 to <5 years IRR 0.80, 95% CI 0.78 to 0.82; 5 to <12 years IRR 0.68, 95% CI 0.67 to 0.70; 12 to 18 years IRR 0.72, 95% CI 0.70 to 0.74; versus age <12 months as reference group, p < 0.001). The lowering of pediatric intensive care admissions was not as great as that of general admissions (IRR 1.30, 95% CI 1.16 to 1.45, p < 0.001). Lower triage urgencies were reduced more than higher triage urgencies (urgent triage IRR 1.10, 95% CI 1.08 to 1.12; emergent and very urgent triage IRR 1.53, 95% CI 1.49 to 1.57; versus nonurgent triage category, p < 0.001). Reductions were highest and sustained throughout the study period for children with communicable infectious diseases. The main limitation was the retrospective nature of the study, using routine clinical data from a wide range of European hospitals and health systems. CONCLUSIONS: Reductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell. TRIAL REGISTRATION: ISRCTN91495258 https://www.isrctn.com/ISRCTN91495258.

Utilisation of children’s emergency care services during epidemics and pandemics: a systematic review

663 Figure 1[Figure omitted. See PDF] 663 Figure 2[Figure omitted. See PDF]ConclusionThis systematic review demonstrates that pandemics have significantly different impacts on paediatric emergency service utilisation depending on the epidemic/pandemic. Evidence from 80 papers that across the world demonstrates children’s attendances to Emergency Departments significantly fell during the COVID19 pandemic. The reasons for this are not entirely clear but are likely related to the public health response and parent/carer concern about the severity of the disease process.As public health messaging can impact on public behaviours, public health departments and related healthcare organisations must be aware how fear of viruses amongst the general public may influence their response to public health advice. There is inequality between low-middle and high income countries in reporting the impact of emergency service utilisation for children.

Responses of paediatric emergency departments to the first wave of the COVID-19 pandemic in Europe: a cross-sectional survey study.

OBJECTIVE: Understanding how paediatric emergency departments (PEDs) across Europe adapted their healthcare pathways in response to COVID-19 will help guide responses to ongoing waves of COVID-19 and potential future pandemics. This study aimed to evaluate service reconfiguration across European PEDs during the initial COVID-19 wave. DESIGN: This cross-sectional survey included 39 PEDs in 17 countries. The online questionnaire captured (1) study site characteristics, (2) departmental changes and (3) pathways for children with acute illness pre and during the first wave of COVID-19 pandemic (January-May 2020). Number of changes to health services, as a percentage of total possible changes encompassed by the survey, was compared with peak national SARS-CoV-2 incidence rates, and for both mixed and standalone paediatric centres. RESULTS: Overall, 97% (n=38) of centres remained open as usual during the pandemic. The capacity of 18 out of 28 (68%) short-stay units decreased; in contrast, 2 units (7%) increased their capacity. In 12 (31%) PEDs, they reported acting as receiving centres for diverted children during the pandemic.There was minimal change to the availability of paediatric consultant telephone advice services, consultant supervision of juniors or presence of responsible specialists within the PEDs.There was no relationship between percentage of possible change at each site and the peak national SARS-CoV-2 incidence rate. Mixed paediatric and adult hospitals made 8% of possible changes and standalone paediatric centres made 6% of possible changes (p=0.086). CONCLUSION: Overall, there was limited change to the organisation or delivery of services across surveyed PEDs during the first wave of the COVID-19 pandemic.

Treatment of Multisystem Inflammatory Syndrome in Children.

BACKGROUND: Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. METHODS: We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation. RESULTS: Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups. CONCLUSIONS: We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).