Systematic review of cardiac adverse effects in children and young people un-der 18 years of age after SARS-CoV-2 vaccination (preprint)

BackgroundReports of myocarditis and pericarditis following vaccination with mRNA vaccines for SARS-CoV-2 have occurred after countries began vaccinating adolescents. We undertook a systematic review of cardiac adverse effects associated with SARS-CoV-2 vaccine in children and young people (CYP)< 18 years. MethodsSystematic review with protocol prospectively registered with PROSPERO (CRD42021275380). Six electronic databases were searched from 1 December 2019 to 14 September 2021. Eligible studies were those reporting on CYP with reported or proven myocarditis, pericarditis and/or myopericarditis associated with vaccination against SARS-CoV-2. We summarized findings across all clinical cases reported in case report / case series studies. As a number of studies reported data from two publicly available vaccine surveillance systems, we updated estimates of reporting rates for cardiac adverse events up to 31 October for the US Vaccine Adverse Event Reporting System (VAERS) and 13 November for EudraVigilance covering European Union and European Economic Area (EUEA) countries. ResultsTwenty-one studies were included from 338 identified records. Seventeen were case reports/series describing a total of 127 CYP. Three studies described reporting rates from passive surveillance databases (VAERS, EudraVigilance, and the WHO VigiBase) and one described 22 cases from the US Vaccine Safety Datalink (VSD). Clinical series reported that 99.2% presented with chest pain, 100% had raised troponin and 73.8% had an abnormal ECG. Cardiovascular magnetic resonance (CMR) in 91 cases identified myocardial injury in 61.5%, with 90.1% showing late gadolinium enhancement. NSAIDs were the most common treatment (76.0%). One US dataset (VSD) estimated a significant excess of 29.6 events per million vaccine doses across both sexes and doses. There were 1129 reports of myocarditis and 358 reports of pericarditis from across the USA and EU/EEA. The VAERS reporting rate per million for myocarditis was 12.4 for boys and 1.4 for girls after the first dose, and 49.6 for boys and 6.1 for girls after the second dose. There was a marked trend for VAERS reporting to be highest soon after initiation of the vaccine schedule, suggesting reporting bias. ConclusionsCardiac adverse effects are very rare after mRNA vaccination for COVID-19 in CYP <18 years. The great majority of cases are mild and self-limiting without significant treatment. No data are yet available on children under 12 years. Larger detailed longitudinal studies are urgently needed from active surveillance sources.

Deaths in Children and Young People in England following SARS-CoV-2 infection during the first pandemic year: a national study using linked mandatory child death reporting data (preprint)

Background Deaths in children and young people (CYP) following SARS-CoV-2 infection are rare. Quantifying the risk of mortality is challenging because of high relative prevalence of asymptomatic and non-specific disease manifestations. Therefore, it is important to differentiate between CYP who have died of SARS-CoV-2 and those who have died of an alternative disease process but coincidentally tested positive. Methods During the pandemic, the mandatory National Child Mortality Database (NCMD) was linked to Public Health England (PHE) testing data to identify CYP (<18 years) who died with a positive SARS-CoV-2 test. A clinical review of all deaths from March 2020 to February 2021 was undertaken to differentiate between those who died of SARS-CoV-2 infection and those who died of an alternative cause but coincidentally tested positive. Then, using linkage to national hospital admission data, demographic and comorbidity details of CYP who died of SARS-CoV-2 were compared to all other deaths. Absolute risk of death was estimated where denominator data were available. Findings 3105 CYP died from all causes during the first pandemic year in England. 61 of these deaths occurred in CYP who tested positive for SARS-CoV-2. 25 CYP died of SARS-CoV-2 infection; 22 from acute infection and three from PIMS-TS. 99.995% of CYP with a positive SARS-CoV-2 test survived. The 25 CYP who died of SARS-CoV-2 equates to a mortality rate of 2/million for the 12,023,568 CYP living in England. CYP >10 years, of Asian and Black ethnic backgrounds, and with comorbidities were over-represented compared to other children. Interpretation SARS-CoV-2 is very rarely fatal in CYP, even among those with underlying comorbidities. These findings are important to guide families, clinicians and policy makers about future shielding and vaccination.

Which children and young people are at higher risk of severe disease and death after SARS-CoV-2 infection: a systematic review and individual patient meta-analysis (preprint)

BackgroundWe aimed to use individual patient data to describe pre-existing factors associated with severe disease, primarily admission to critical care, and death secondary to SARS-CoV-2 infection in children and young people (CYP) in hospital. MethodsWe searched Pubmed, European PMC, Medline and Embase for case series and cohort studies that included all CYP admitted to hospital with [≥]30 CYP with SARS-CoV-2 or [≥]5 CYP with PIMS-TS or MIS-C. Eligible studies contained 1) details of age, sex, ethnicity or co-morbidities, and 2) an outcome which included admission to critical care, mechanical invasive ventilation, cardiovascular support, or death. Studies reporting outcomes in more restricted grouping of co-morbidities were eligible for narrative review. Authors of eligible studies were approached for individual patient data (IPD). We used random effects meta-analyses for aggregate study-level data and multilevel mixed effect models for IPD data to examine risk factors (age, sex, comorbidities) associated with admission to critical care and death. Data shown are odds ratios and 95% confidence intervals (CI). Findings81 studies were included, 57 in the meta-analysis (of which 22 provided IPD) and 26 in the narrative synthesis. Most studies had an element of bias in their design or reporting. Sex was not associated with critical care or death. Compared with CYP aged 1-4 years, infants had increased odds of admission to critical care (OR 1.63 (95% CI 1.40-1.90)) and death (OR 2.08 (1.57-2.86)). Odds of death were increased amongst CYP over 10 years (10-14 years OR 2.15 (1.54-2.98); >14 years OR 2.15 (1.61-2.88)). Number of comorbid conditions was associated with increased odds of admission to critical care and death for COVID-19 in a dose-related fashion. For critical care admission odds ratios were: 1 comorbidity 1.49 (1.45-1.53); 2 comorbidities 2.58 (2.41-2.75); [≥]3 comorbidities 2.97 (2.04-4.32), and for death: 1 comorbidity 2.15 (1.98-2.34); 2 comorbidities 4.63 (4.54-4.74); [≥]3 co-morbidities 4.98 (3.78-6.65). Odds of admission to critical care were increased for all co-morbidities apart from asthma (0.92 (0.91-0.94)) and malignancy (0.85 (0.17-4.21)) with an increased odds of death in all co-morbidities considered apart from asthma. Neurological and cardiac comorbidities were associated with the greatest increase in odds of severe disease or death. Obesity increased the odds of severe disease and death independently of other comorbidities. InterpretationHospitalised CYP at greatest vulnerability of severe disease or death from SARS-CoV-2 infection are infants, teenagers, those with cardiac or neurological conditions, or 2 or more comorbid conditions, and those who are obese. These groups should be considered higher priority for vaccination and for protective shielding when appropriate. Whilst odds ratios were high, the absolute increase in risk for most comorbidities was small compared to children without underlying conditions. FundingRH is in receipt of a funded fellowship from Kidney Research UK. JW is in receipt of a Medical Research Council Fellowship. Putting Research Into ContextO_ST_ABSEvidence before this studyC_ST_ABSThe risk factors for severe disease following SARS-CoV-2 infection in adults has been extensively studied and reported, with good evidence that increasing age, non-white ethnicity, male gender and co-morbidities increase the risk. SARS-CoV-2 infection in children and young people (CYP) infrequently results in hospital admission and very rarely causes severe disease and death, making it difficult to discern the impact of a range of potential risk factors for severe disease in the many small to moderate sized published studies. More recent larger publications have aimed to address this question in specific populations but the global experience has not been described. We searched Pubmed, European PMC, Medline and Embase from the 1st January 2020 to 21st May 2021 for case series and cohort studies that included all CYP admitted to hospital with 30 children with reverse transcriptase-PCR confirmed SARS-CoV-2 or 5 CYP defined as having PIMS-TS or MIS-C. 57 studies met the eligibility criteria for meta-analysis. Added value of this studyTo our knowledge, this is the first meta-analysis to use individual patient data to compare the odds and risk of critical care admission and death in CYP with COVID-19 and PIMS-TS. We find that the odds of severe disease in hospitalised children is increased in those with multiple co-morbidities, cardiac and neurological co-morbidities and those who are obese. However, the additional risk compared to children without co-morbidity is small. Implications of all the available evidenceSevere COVID-19 and PIMS-TS, whilst rare, can occur in CYP. We have identified pre-existing risk factors for severe disease after SARS-CoV-2 and recommend that those with co-orbidities which place them in the highest risk groups are prioritised for vaccination.

Which children and young people are at higher risk of severe disease and death after SARS-CoV-2 infection: a systematic review and individual patient meta-analysis (preprint)

Background We aimed to use individual patient data to describe pre-existing factors associated with severe disease, primarily admission to critical care, and death secondary to SARS-CoV-2 infection in children and young people (CYP) in hospital.Methods We searched Pubmed, European PMC, Medline and Embase for case series and cohort studies that included all CYP admitted to hospital with 30 CYP with SARS-CoV-2 or 5 CYP with PIMS-TS or MIS-C. Eligible studies contained 1) details of age, sex, ethnicity or co-morbidities, and 2) an outcome which included admission to critical care, mechanical invasive ventilation, cardiovascular support, or death. Studies reporting outcomes in more restricted grouping of co-morbidities were eligible for narrative review. Authors of eligible studies were approached for individual patient data (IPD). We used random effects meta-analyses for aggregate study-level data and multilevel mixed effect models for IPD data to examine risk factors (age, sex, comorbidities) associated with admission to critical care and death. Data shown are odds ratios and 95% confidence intervals (CI).Findings 81 studies were included, 57 in the meta-analysis (of which 22 provided IPD) and 26 in the narrative synthesis. Most studies had an element of bias in their design or reporting. Sex was not associated with critical care or death. Compared with CYP aged 1-4 years, infants had increased odds of admission to critical care (OR 1.63 (95% CI 1.40-1.90)) and death (OR 2.08 (1.57-2.86)). Odds of death were increased amongst CYP over 10 years (10-14 years OR 2.15 (1.54-2.98); >14 years OR 2.15 (1.61-2.88)). Number of comorbid conditions was associated with increased odds of admission to critical care and death for COVID-19 in a dose-related fashion. For critical care admission odds ratios were: 1 comorbidity 1.49 (1.45-1.53); 2 comorbidities 2.58 (2.41-2.75); ≥3 comorbidities 2.97 (2.04-4.32), and for death: 1 comorbidity 2.15 (1.98-2.34); 2 comorbidities 4.63 (4.54-4.74); ≥3 co-morbidities 4.98 (3.78-6.65). Odds of admission to critical care were increased for all co-morbidities apart from asthma (0.92 (0.91-0.94)) and malignancy (0.85 (0.17-4.21)) with an increased odds of death in all co-morbidities considered apart from asthma. Neurological and cardiac comorbidities were associated with the greatest increase in odds of severe disease or death. Obesity increased the odds of severe disease and death independently of other comorbidities.Interpretation Hospitalised CYP at greatest vulnerability of severe disease or death from SARS-CoV-2 infection are infants, teenagers, those with cardiac or neurological conditions, or 2 or more comorbid conditions, and those who are obese. These groups should be considered higher priority for vaccination and for protective shielding when appropriate. Whilst odds ratios were high, the absolute increase in risk for most comorbidities was small compared to children without underlying conditions.

Deaths in Children and Young People in England following SARS-CoV-2 infection during the first pandemic year: a national study using linked mandatory child death reporting data (preprint)

BackgroundDeaths in children and young people (CYP) following SARS-CoV-2 infection are rare. Quantifying the risk of mortality is challenging because of high relative prevalence of asymptomatic and non-specific disease manifestations. Therefore, it is important to differentiate between CYP who have died of SARS-CoV-2 and those who have died of an alternative disease process but coincidentally tested positive.MethodsDuring the pandemic, the mandatory National Child Mortality Database (NCMD) was linked to Public Health England (PHE) testing data to identify CYP (<18 years) who died with a positive SARS-CoV-2 test. A clinical review of all deaths from March 2020 to February 2021 was undertaken to differentiate between those who died of SARS-CoV-2 infection and those who died of an alternative cause but coincidentally tested positive. Then, using linkage to national hospital admission data, demographic and comorbidity details of CYP who died of SARS-CoV-2 were compared to all other deaths. Absolute risk of death was estimated where denominator data were available. Findings3105 CYP died from all causes during the first pandemic year in England. 61 of these deaths occurred in CYP who tested positive for SARS-CoV-2. 25 CYP died of SARS-CoV-2 infection; 22 from acute infection and three from PIMS-TS. 99·995% of CYP with a positive SARS-CoV-2 test survived. The 25 CYP who died of SARS-CoV-2 equates to a mortality rate of 2/million for the 12,023,568 CYP living in England. CYP >10 years, of Asian and Black ethnic backgrounds, and with comorbidities were over-represented compared to other children.InterpretationSARS-CoV-2 is very rarely fatal in CYP, even among those with underlying comorbidities. These findings are important to guide families, clinicians and policy makers about future shielding and vaccination.

Risk factors for intensive care admission and death amongst children and young people admitted to hospital with COVID-19 and PIMS-TS in England during the first pandemic year (preprint)

Identifying which children and young people (CYP) are vulnerable to severe disease following SARS-CoV-2 is important to guide shielding and vaccination policy. Methods We used data for all inpatient hospital admissions in England in CYP aged 0-17 between March 1st 2015 to Feb 28th 2021, linked to paediatric intensive care unit (PICU) admission, and SARS-CoV-2 PCR testing, and deaths. We calculated odds ratios and predicted probability of PICU admission using generalized estimation equations, and compared these between COVID-19, PIMS-TS, other admissions in 2020/21, all admissions in 2019/20, and admissions due to influenza in 20219/20. Findings There were 6,338 COVID-19 hospitalisations, 259 PICU admissions and 8 deaths as well as 712 PIMS-TS hospitalisations, 312 PICU admissions and <5 deaths. Odds of PICU admission were increased amongst neonates and decreased amongst 15-17 compared with 1-4 year olds with COVID-19, increased in older CYP and females with PIMS-TS, and increased for Black compared with White ethnicity for both conditions. Odds of PICU admission with COVID-19 were increased for CYP with any comorbidity and were highest for CYP with multiple medical problems. Comorbidities associated with PICU admission among COVID-19 patients were similar to overall PICU admissions in 2019/20 and to influenza PICU admissions in 2019/20, but with higher odds. Interpreting associations with comorbidities within PIMS-TS was complex due to the multisystem nature of the disease. Interpretation CYP were at very low risk of severe disease and death from COVID-19 or PIMS-TS. Patterns of vulnerability for severe COVID-19 appear to magnify background risk factors for serious illness in CYP.

A national consensus management pathway for Paediatric Inflammatory Multisystem Syndrome - Temporally associated with SARS-CoV-2 (PIMS-TS): The results of a national Delphi process (preprint)

ObjectiveTo develop a consensus management pathway for children with Paediatric Inflammatory Multisystem Syndrome - Temporally associated with SARS-CoV-2 (PIMS-TS). DesignA three-phase online Delphi process and virtual consensus meeting sought consensus over the investigation, management and research priorities from 98 multidisciplinary participants caring for children with PIMS-TS. 46 participants (47%) completed all three phases. Participants were grouped into three panels and scored each statement from 1 (disagree) to 9 (strongly agree). In phase two participants were shown their panels scores, and in phase three all panels scores. Consensus agreement was defined as [≥]70% of participants in each panel scoring the statement 7-9, and <15% scoring 1-3, and consensus disagreement was the opposite of this. Statements which achieved consensus in 2/3 panels were discussed at the consensus meeting, and when [≥]70% participants agreed with the statement it achieved consensus. Results255 statements were assessed, with consensus agreement achieved for 111 (44%), consensus disagreement for 29 (11%), and no consensus for 115 (45%). The 140 consensus statements were used to derive the consensus management pathway. ConclusionsA national consensus pathway has been developed for children suspected of having the novel syndrome PIMS-TS in a timely, cost-efficient manner, in the midst of a global pandemic. Use of a rapid online Delphi process has made this consensus process possible. Future evidence will inform updates to this guidance, which in the interim provides a solid framework to support clinicians caring for children with PIMS-TS.