Epidemiology and role of SARS-CoV-2 Linkage in Paediatric Inflammatory Multisystem Syndrome (PIMS): A Canadian Paediatric Surveillance Program National Prospective Study (preprint)

Background: Paediatric inflammatory multisystem syndrome (PIMS) is a rare but serious condition temporally associated with SARS CoV2 infection. Using the Canadian Paediatric Surveillance Program (CPSP), a national surveillance system, we aimed to 1) study the impact of SARS CoV2 linkage on clinical and laboratory characteristics, and outcomes in hospitalized children with PIMS across Canada 2) identify risk factors for ICU admission, and 3) establish the minimum national incidence of hospitalizations due to PIMS and compare it to acute COVID 19. Methods: Weekly online case reporting was distributed to the CPSP network of more than 2800 pediatricians, from March 2020 to May 2021. Comparisons were made between cases with respect to SARS CoV2 linkage. Multivariable modified Poisson regression was used to identify risk factors for ICU admission and Minimum incidence proportions were calculated. Findings: In total, 406 PIMS cases were analyzed, of whom 202 (49.8%) had a positive SARS CoV2 linkage, 106 (26.1%) had a negative linkage, and 98 (24.1%) had an unknown linkage. The median age was 5.4 years (IQR 2.5 to 9.8), 60% were male, and 83% had no identified comorbidities. Compared to cases with a negative SARS CoV2 linkage, children with a positive SARS CoV2 linkage were older (8.1 years [IQR 4.2 to 11.9] vs 4.1 years [IQR 1.7 to 7.7]; p<0.001), had more cardiac involvement (58.8% vs 37.4%; p<0.001), gastrointestinal symptoms (88.6% vs 63.2%; p<0.001), and shock (60.9% vs 16.0%; p<0.001). At risk groups for ICU admission include children >=6 years and those with a positive SARS CoV2 linkage. No deaths were reported. The minimum incidence of PIMS hospitalizations during the study period was 5.6 hospitalizations per 100,000 population <18 years. Interpretation: While PIMS is rare, almost 1 in 3 hospitalized children required ICU admission and respiratory/hemodynamic support, particularly those >=6 years and with a positive SARS CoV2 linkage. Funding: Financial support for the CPSP was received from the Public Health Agency of Canada.

Risk factors for severe COVID-19 in hospitalized children in Canada: A national prospective study from March 2020--May 2021 (preprint)

Background: Children living with chronic comorbid conditions are at increased risk for severe COVID-19, though there is limited evidence regarding the risks associated with specific conditions and which children may benefit from targeted COVID-19 therapies. The objective of this study was to identify factors associated with severe disease among hospitalized children with COVID-19 in Canada. Methods: We conducted a national prospective study on hospitalized children with microbiologically confirmed SARS-CoV-2 infection via the Canadian Paediatric Surveillance Program from April 2020--May 2021. Cases were reported voluntarily by a network of >2800 paediatricians. Hospitalizations were classified as COVID-19-related, incidental infection, or infection control/social admissions. Severe disease (among COVID-19-related hospitalizations only) was defined as disease requiring intensive care, ventilatory or hemodynamic support, select organ system complications, or death. Risk factors for severe disease were identified using multivariable Poisson regression, adjusting for age, sex, concomitant infections, and timing of hospitalization. Findings: We identified 544 children hospitalized with SARS-CoV-2 infection, including 60{middle dot}7% with COVID-19-related disease and 39{middle dot}3% with incidental infection or infection control/social admissions. Among COVID-19-related hospitalizations (n=330), the median age was 1{middle dot}9 years (IQR 0{middle dot}1--13{middle dot}3) and 43{middle dot}0% had chronic comorbid conditions. Severe disease occurred in 29{middle dot}7% of COVID-19-related hospitalizations (n=98/330), most frequently among children aged 2-4 years (48{middle dot}7%) and 12-17 years (41{middle dot}3%). Comorbid conditions associated with severe disease included technology dependence (adjusted risk ratio [aRR] 2{middle dot}01, 95% confidence interval [CI] 1{middle dot}37-2{middle dot}95), neurologic conditions (e.g. epilepsy and select chromosomal/genetic conditions) (aRR 1{middle dot}84, 95% CI 1{middle dot}32-2{middle dot}57), and pulmonary conditions (e.g. bronchopulmonary dysplasia and uncontrolled asthma) (aRR 1{middle dot}63, 95% CI 1{middle dot}12-2{middle dot}39). Interpretation: While severe outcomes were detected at all ages and among patients with and without comorbidities, neurologic and pulmonary conditions as well as technology dependence were associated with increased risk of severe COVID-19. These findings may help guide vaccination programs and prioritize targeted COVID-19 therapies for children. Funding: Financial support for the CPSP was received from the Public Health Agency of Canada.

Safety of COVID-19 vaccines in pregnancy: a Canadian National Vaccine Safety (CANVAS) Network study (preprint)

BackgroundPregnant individuals have been receiving COVID-19 vaccines following pre-authorization clinical trials in non-pregnant people. This study aimed to determine significant health events amongst pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals. MethodsStudy participants were pregnant and non-pregnant females aged 15-49 years who had received any COVID-19 vaccine, and pregnant unvaccinated controls. Participants reported significant health events occurring within seven days of vaccination. We employed multivariable logistic regression to examine significant health events associated with mRNA vaccines. FindingsOverall 226/5,597(4.0%) vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227/3,108(7.3%) after dose two, compared with 11/339(3.2%) pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event after dose two of mRNA-1273 (aOR 4.4,95%CI 2.4-8.3) compared to pregnant unvaccinated controls, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant females had decreased odds of a significant health event compared to non-pregnant females after both dose one (aOR 0.63,95%CI 0.55-0.72) and dose two (aOR 0.62,95%CI 0.54-0.71) of mRNA vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention. InterpretationCOVID-19 mRNA vaccines have a good safety profile in pregnancy. Rates of significant health events were higher after dose two of mRNA-1273 compared with unvaccinated controls, with no difference when considering events leading to medical consultation. Rates of significant health events were lower in pregnant females than similarly aged non-pregnant individuals. FundingThis work was supported by the COVID-19 Vaccine Readiness funding from the Canadian Institutes of Health Research and the Public Health Agency of Canada CANVAS grant number CVV-450980 and by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Reference Group and the COVID-19 Immunity Task Force.

Risk factors for severe PCR-positive SARS-CoV-2 infection in hospitalized children: a multicenter cohort study (preprint)

Importance: Children are less likely than adults to have severe outcomes from SARS-CoV-2 infection and the corresponding risk factors are not well established. Objective: To identify risk factors for severe disease in symptomatic children hospitalized for PCR-positive SARS-CoV-2 infection. Design: Cohort study, enrollment from February 1, 2020 until May 31, 2021 Setting 15 children's hospitals in Canada, Iran, and Costa Rica Participants: Patients <18 years of age hospitalized with symptomatic SARS-CoV-2 infection, including PCR-positive multisystem inflammatory syndrome in children (MIS-C) Exposures: Variables assessed for their association with disease severity included patient demographics, presence of comorbidities, clinical manifestations, laboratory parameters and chest imaging findings. Main Outcomes and Measures: The primary outcome was severe disease defined as a WHO COVID-19 clinical progression scale of [≥]6, i.e., requirement of non-invasive ventilation, high flow nasal cannula, mechanical ventilation, vasopressors, or death. Multivariable logistic regression was used to evaluate factors associated with severe disease. Results: We identified 403 hospitalizations. Median age was 3.78 years (IQR 0.53-10.77). At least one comorbidity was present in 46.4% (187/403) and multiple comorbidities in 18.6% (75/403). Severe disease occurred in 33.8% (102/403). In multivariable analyses, presence of multiple comorbidities (adjusted odds ratio 2.24, 95% confidence interval 1.04-4.81), obesity (2.87, 1.19-6.93), neurological disorder (3.22, 1.37-7.56), anemia, and/or hemoglobinopathy (5.88, 1.30-26.46), shortness of breath (4.37, 2.08-9.16), bacterial and/or viral coinfections (2.26, 1.08-4.73), chest imaging compatible with COVID-19 (2.99, 1.51-5.92), neutrophilia (2.60, 1.35-5.02), and MIS-C diagnosis (3.86, 1.56-9.51) were independent risk factors for severity. Comorbidities, especially obesity (40.9% vs 3.9%, p<0.001), were more frequently present in adolescents [≥]12 years of age. Neurological disorder (3.16, 1.19-8.43) in children <12 years of age and obesity (3.21, 1.15-8.93) in adolescents were the specific comorbidities associated with disease severity in age-stratified adjusted analyses. Sensitivity analyses excluding the 81 cases with MIS-C did not substantially change the identified risk factors. Conclusions and Relevance: Pediatric risk factors for severe SARS-CoV-2 infection vary according to age and can potentially guide vaccination programs and treatment approaches in children.