COVID-19 and multisystem inflammatory syndrome in hospitalized children

Abstract

Background: Direct comparisons of paediatric hospitalizations for acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) can inform health system planning. We describe the absolute and relative hospital burden of acute paediatric COVID-19 and MIS-C in Canada.

Methods: This national prospective study was conducted via the Canadian Paediatric Surveillance Program from March 2020–May 2021. Children younger than 18 years old and hospitalized for acute COVID-19 or MIS-C were included in the analysis. Outcomes included supplemental oxygen (low-flow oxygen or high-flow nasal cannula), ventilation (non-invasive or conventional mechanical), vasopressors, paediatric intensive care unit (PICU) admission, or death. Adjusted risk differences (aRD) and 95% confidence intervals (CI) were calculated to identify factors associated with each diagnosis.

Results: Overall, we identified 330 children hospitalized for acute COVID-19 (including five deaths) and 208 hospitalized for MIS-C (including zero deaths); PICU admission was required for 49.5% of MIS-C hospitalizations versus 18.2% of acute COVID-19 hospitalizations (aRD 20.3; 95% CI, 9.9–30.8). Resource use differed by age, with children younger than one year hospitalized more often for acute COVID-19 (aRD 43.4% versus MIS-C; 95% CI, 37.7–49.1) and more children 5–11 years hospitalized for MIS-C (aRD 38.9% vs. acute COVID-19; 95% CI, 31.0–46.9).

Conclusion: While there were more hospitalizations and deaths from acute paediatric COVID-19, MIS-C cases were more severe, requiring more intensive care and vasopressor support. Our findings suggest that both acute COVID-19 and MIS-C should be considered when assessing the overall burden of severe acute respiratory syndrome coronavirus 2 in hospitalized children.

Introduction

Along with hospitalization for acute coronavirus disease 2019 (COVID-19), multisystem inflammatory syndrome in children (MIS-C) has emerged as a serious yet infrequent complication of paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Though MIS-C was first described in the United Kingdom in April 2020, to date, few studies have directly compared characteristics and outcomes associated with these two diagnoses ^{Footnote 1 Footnote 2 Footnote 3 Footnote 4}. Case series describing MIS-C indicate higher proportions of severe disease relative to acute COVID-19, despite much lower incidence of MIS-C in the community, estimated at 316 cases per million SARS-CoV-2 infections among those younger than 21 years of age ^{Footnote 5 Footnote 6 Footnote 7}. Differences in the associated use of hospital resources (e.g. ventilation or hemodynamic support requiring intensive care) between these two disease entities are not well known and may have implications for future paediatric pandemic planning. We aimed to describe the absolute and relative hospital burden of acute paediatric COVID-19 infection and MIS-C during the first fifteen months of the pandemic in Canada, prior to the emergence of the Omicron variant and the approval of SARS-CoV-2 vaccines for use in children.

Methods

We conducted a national prospective study via the Canadian Paediatric Surveillance Program (CPSP) from March 2020–May 2021, during which time ancestral SARS-CoV-2 lineages and later the Alpha (B.1.1.7) variant of concern were dominant. The CPSP is a public health surveillance network that includes more than 2,800 paediatricians and paediatric subspecialists across Canada, who were surveyed weekly and asked to voluntarily report any incident cases to this study. In addition to the survey report, study co-investigators from 13 university health centres across Canada actively reported all cases from their institutions. Cases of children younger than 18 years of age and hospitalized with acute SARS-CoV-2 infection or paediatric inflammatory multisystem syndrome (PIMS) were eligible to be reported. While cases were reported based on a surveillance definition of PIMS, we applied a post-hoc case definition of MIS-C according to the World Health Organization ^{Footnote 8}. By definition, all patients with MIS-C had a documented linkage to SARS-CoV-2 (i.e. positive polymerase chain reaction, rapid antigen or serology test, or a close contact with microbiologically confirmed SARS-CoV-2). For all SARS-CoV-2 hospitalizations, the reporting physician indicated whether the hospitalization was due to acute COVID-19 or if incidental infection was identified upon routine screening; this was confirmed by dual case adjudication by the study team to ensure consistency. We therefore compared two mutually exclusive groups for this analysis: children hospitalized for acute COVID-19 versus children hospitalized for MIS-C. Further details regarding the study design are described elsewhere, and surveillance definitions are available ^{Footnote 9 Footnote 10 Footnote 11}.

Baseline characteristics and severity outcomes were ascertained for both case definitions using a standardized case report form. Severity outcomes included requirements for supplemental oxygen (either low-flow oxygen or high-flow nasal cannula), ventilation (either non-invasive, conventional mechanical or high-frequency oscillatory ventilation), vasopressors, paediatric intensive care unit (PICU) admissions or death. Characteristics were summarized using medians, interquartile ranges (IQR), frequencies and percentages. Frequencies between one and four were reported as "fewer than five" while some larger frequencies were presented as ranges to prevent back calculation, in accordance with CPSP privacy policy. Adjusted risk differences (aRD) were calculated to identify factors associated with each diagnosis, adjusting for age, sex, presence of one or more comorbid conditions, and the timing of hospitalization (classified in five three-month periods from March 2020–May 2021). Differences in continuous variables (i.e. age and PICU length of stay) were assessed using Wilcoxon rank-sum tests. The temporal lag (in weeks) between all Canadian SARS-CoV-2 case counts (ascertained from the Public Health Agency of Canada) ^{Footnote 12} and hospitalizations reported to CPSP were assessed using Spearman's rank correlation coefficient. The p-values <0.05 were considered statistically significant. Analyses were conducted in Stata v17.0 ^{Footnote 13}.

Results

Overall, 330 children hospitalized for acute COVID-19 and 208 hospitalized for MIS-C were reported during the surveillance period (Figure 1, Table 1). The median age among acute COVID-19 patients (1.9 years; IQR 0.1–13.3) was significantly younger than those with MIS-C (8.1 years; IQR 4.2–11.6; p<0.001). More children younger than one year of age were hospitalized for acute COVID-19 than with MIS-C (aRD 43.4%; 95% CI, 37.7–49.1), while more children aged 5–11 years were hospitalized for MIS-C than acute COVID-19 (aRD 38.9%; 95% CI, 31.0–46.9). Chronic comorbid conditions were more common amongst acute COVID-19 patients (43.0% vs. 15.9% with MIS-C; aRD 38.0%; 95% CI, 31.0–45.1).

Figure 1 - Text description

The flowchart describes the flow of case reports submitted to the Canadian Paediatric Surveillance Program (CPSP) COVID-19 study, and how they were processed to reach the final analysis sample size. Overall, the CPSP COVID-19 study received 1,240 case reports of hospitalized children which were eligible to be analyzed in this study. Among these case reports, 192 (15.4%) duplicates and 17 (1.4%) incomplete reports were removed. Therefore, 1,031 unique hospitalizations with complete reports were reported and included 544 eligible hospitalizations of SARS-CoV-2 hospitalizations and 487 eligible hospitalizations of paediatric inflammatory multisystem syndrome (PIMS). From these subtotals, 214/544 (39.3%) SARS-CoV-2 hospitalizations were excluded because they were admitted with incidental infection only, while 279/487 (57.3%) PIMS hospitalizations were excluded because they did not meet the post hoc case definition of multisystem inflammatory syndrome in children (MIS-C). Therefore, the analysis included 330 COVID-19 hospitalizations and 208 MIS-C hospitalizations.

Table 1: Characteristics of children hospitalized for acute COVID-19 and multisystem inflammatory syndrome in children

Characteristic	Diagnosis		aRDFootnote a, %	95% CI	p-value
	COVID-19	MIS-C
Total hospitalizations, NFootnote b	330	208	-	-	-
Age (years), median (IQR)Footnote c	1.9 (0.1–13.3)	8.1 (4.2–11.6)	-	-	<0.001
Age (years), n (%)
Younger than 1	140 (42.4)	9 (4.3)	43.4	37.7–49.1	<0.001
1–4	68 (20.6)	52 (25.0)	−2.9	−10.4–4.6	0.45
5–11	30 (9.1)	98 (47.1)	−38.9	−46.9–−31.0	<0.001
12–17	92 (27.9)	49 (23.6)	−1.6	−9.6–6.4	0.69
Sex, n (%)
Female	145 (43.9)	76 (36.5)	6.2	−4.9–17.3	0.27
Male	185 (56.1)	132 (63.5)	−6.2	−17.3–4.9	0.27
Comorbid conditions, n (%)Footnote d
None/unknown	188 (57.0)	175 (84.1)	−38.0	−45.1–−31.0	<0.001
1 or more	142 (43.0)	33 (15.9)	38.0	31.0–45.1	<0.001
Population group, n (%)
White	75 (22.7)	63 (30.3)	−12.4	−22.8–−2.0	0.02
South Asian	40 (12.1)	25 (12.0)	1.4	−6.0–8.7	0.71
Arab/West Asian	39 (11.8)	16 (7.7)	4.4	−2.3–11.1	0.20
Black	39 (11.8)	29 (13.9)	−2.2	−9.5–5.1	0.56
Indigenous	28 (8.5)	9 (4.3)	4.8	−0.6–10.3	0.08
East/Southeast Asian	18 (5.5)	12 (5.8)	3.0	−2.2–8.1	0.26
Latin American	5 (1.5)	18 (8.7)	−7.5	−13.3–−1.7	0.01
Unknown	92 (27.9)	49 (23.6)	-	-	-
Table 1 abbreviations Abbreviations: aRD, adjusted risk difference; CI, confidence interval; COVID-19, coronavirus disease 2019; IQR, interquartile range; MIS-C, multisystem inflammatory syndrome in children; -, not applicable Table 1 Footnote a All comparisons adjusted for age category, sex, comorbid conditions, and timing of hospitalization. Positive risk differences indicate a characteristic was more common for acute COVID-19 while negative risk differences indicate a characteristic was more common for MIS-C Table 1 Return to footnote a referrer Table 1 Footnote b Overall, 544 hospitalized children with severe acute respiratory syndrome coronavirus 2 infection were reported to the Canadian Paediatric Surveillance Program, among whom 330 children were admitted due to acute COVID-19; 493 hospitalized children were reported with suspected paediatric inflammatory multisystem syndrome, among whom 208 children met the World Health Organization definition of MIS-C Table 1 Return to footnote b referrer Table 1 Footnote c Continuous age was missing for four patients with acute COVID-19, though categorical age could still be determined Table 1 Return to footnote c referrer Table 1 Footnote d Comorbidities were reported as any of the following conditions: congenital heart disease, diabetes, gastrointestinal/liver disease, genetic/metabolic conditions, hematologic disorders, immunodeficiencies, malignancies, neurologic or neurodevelopmental conditions, obesity, pulmonary disease (i.e. asthma or other chronic lung disease), renal disease, rheumatologic/autoimmune disorders, tracheostomy, transplants or other conditions Table 1 Return to footnote d referrer

The PICU admission was required for 49.5% of MIS-C hospitalizations versus 18.2% of acute COVID-19 hospitalizations (aRD 20.3; 95% CI 9.9–30.8), though the proportion of children younger than five years of age admitted to PICU was similar (19.7% vs. 15.4%; Table 2). The median length of PICU stay was one day greater for acute COVID-19 (four days; IQR 2–7) than MIS-C (three days; IQR 2–4; p=0.04). Vasopressor use was more common for MIS-C than acute COVID-19 at all ages (35.6% vs. 2.4%; aRD 23.1%; 95% CI, 15.8–30.4). The proportion of all patients requiring supplemental oxygen and mechanical ventilation were similar (24.6% and 10.9% for acute COVID-19 vs. 30.3% and 9.6% for MIS-C, respectively). Five deaths due to acute COVID-19 were reported versus zero due to MIS-C.

Table 2: Outcomes of acute COVID-19 and multisystem inflammatory syndrome in children hospitalizations, overall and by age category

OutcomeFootnote a	Diagnosis		aRDFootnote b, %	95% CI	p-value
	COVID-19	MIS-C
All hospitalizations
Supplemental oxygen	81/330 (24.6)	63/208 (30.3)	−5.6	−15.2–3.9	0.25
Ventilation	36/330 (10.9)	20/208 (9.6)	1.7	−4.9–8.2	0.62
Vasopressors	8/330 (2.4)	74/208 (35.6)	−23.1	−30.4–−15.8	<0.001
PICU admission	60/330 (18.2)	103/208 (49.5)	−20.3	−30.8–−9.9	<0.001
PICU length of stay (days)	4 (2–7 days)	3 (2–4 days)	-	-	0.04
ECMO	0/330 (0.0)	0/208 (0.0)	-	-	-
Death	5/330 (1.5)	0/208 (0.0)	-	-	-
Age younger than 5 years
Supplemental oxygen	36/208 (17.3)	10/61 (16.4)	−0.1	−13.0–12.6	0.98
Ventilation	18–21/208 (8.7–10.1)Footnote c	Fewer than 5/61 (fewer than 8.2)	12.8	7.0–18.5	<0.001
Vasopressors	5–7/208 (2.4–3.4)Footnote c	8/61 (13.1)	−4.7	−12.1–2.6	0.21
PICU admission	32/208 (15.4)	12/61 (19.7)	2.5	−8.8–13.8	0.66
PICU length of stay (days)	4 (2–6 days)	3 (1–3 days)	-	-	0.02
Age 5–11 years
Supplemental oxygen	8/30 (26.7)	37/98 (37.8)	−12.9	−35.0–9.3	0.25
Ventilation	Fewer than 5/30 (fewer than 16.7)	7–10/98 (7.1–10.2)Footnote c	−9.8	−18.5–−1.1	0.03
Vasopressors	0/30 (0.0)	42/98 (42.9)	-	-	-
PICU admission	7/30 (23.3)	61/98 (62.2)	−34.5	−57.7–−11.3	0.004
PICU length of stay (days)	2 (1–9 days)	3 (2–4 days)	-	-	0.68
Age 12–17 years
Supplemental oxygen	37/92 (40.2)	16/49 (32.7)	−9.2	−27.2–8.9	0.32
Ventilation	11–14/92 (12.0–15.2)Footnote c	6–9/49 (12.2–18.4)Footnote c	−6.9	−25.1–11.3	0.46
Vasopressors	Fewer than 5/92 (fewer than 5.4)	24/49 (49.0)	−43.5	−63.3–−23.8	<0.001
PICU admission	21/92 (22.8)	30/49 (61.2)	−38.1	−57.2–−19.0	<0.001
PICU length of stay (days)	6 (3–8 days)	4 (2–5 days)	-	-	0.11
Table 2 abbreviations Abbreviations: aRD, adjusted risk difference; CI, confidence interval; COVID-19, coronavirus disease 2019; ECMO, extracorporeal membrane oxygenation; MIS-C, multisystem inflammatory syndrome in children; PICU, paediatric intensive care unit; -, not applicable Table 2 Footnote a Descriptive statistics are presented as frequency and proportions, or medians and interquartile ranges Table 2 Return to footnote a referrer Table 2 Footnote b All comparisons adjusted for sex, comorbid conditions, and timing of hospitalization. Comparisons for all hospitalizations also adjust for age category. Positive risk differences indicate an outcome was more common for acute COVID-19 while negative risk differences indicate an outcome was more common for MIS-C Table 2 Return to footnote b referrer Table 2 Footnote c Frequencies and percentages are reported using ranges to prevent back calculation of frequencies fewer than five Table 2 Return to footnote c referrer

Acute paediatric COVID-19 hospitalization trends lagged behind all Canadian SARS-CoV-2 infection waves by one week (Spearman's ρ=0.89), versus a lag of six weeks for MIS-C hospitalizations (Spearman's ρ=0.82; Figure 2).

Figure 2 - Text description

The graph shows the number of COVID-19 and MIS-C hospitalizations among children younger than 18 years old by calendar week, as included in this study. These data are presented as three-week moving averages of the number of weekly hospitalizations. These data are then overlayed with the number of SARS-CoV-2 infections across Canada, separately amongst all ages and then amongst ages younger than 20 years, as publicly reported by the Public Health Agency of Canada. The x-axis ranges from January 8, 2020 to May 31, 2021, using calendar week units. The number of hospitalizations and infections in January and February 2020 all begin at or near zero, and thereafter increase gradually, reaching a first peak in spring 2020. Specifically, SARS-CoV-2 infections peaked at 12,609 weekly infections during the week of April 6, COVID-19 hospitalizations peaked at 4.3 average weekly hospitalizations during the week of April 27, and MIS-C hospitalizations peaked at 3.0 average weekly hospitalizations during the week of May 18. The number of infections and hospitalizations again begin to increase in fall 2020 and increase to a peak of 54,608 SARS-CoV-2 infections the week of December 21, a peak of 13.3 average COVID-19 hospitalizations the week of December 28, and a peak of 12.0 average MIS-C hospitalizations the week of January 18, 2021. After a steep decline in infections and hospitalizations in early 2021, SARS-CoV-2 infections and COVID-19 hospitalizations increase again. Specifically, SARS-CoV-2 infections peaked at 63,517 weekly infections during the week of March 29 and COVID-19 hospitalizations peaked at 13.7 average weekly hospitalizations during the week of April 26. MIS-C hospitalizations do not increase as quickly during this wave of the pandemic. Trends in SARS-CoV-2 infections among people younger than 20 years follow the same temporal pattern as all SARS-CoV-2 infections.

Discussion

Understanding the severity and associated in-hospital resource use required to manage acute paediatric COVID-19 and MIS-C is necessary to anticipate acute health system needs, and to make informed decisions regarding preventative measures including SARS-CoV-2 vaccination. Based on national surveillance data from March 2020 to May 2021, acute COVID-19 was found to have resulted in more paediatric hospitalizations and deaths and longer PICU stays, while MIS-C resulted in more PICU admissions and more frequent need for hemodynamic support. In this study, half of hospitalized MIS-C patients required intensive care, consistent with prior studies from the United Kingdom (44%) and the United States (64%) during the first year of the pandemic ^{Footnote 14 Footnote 15}. While PICU admissions among MIS-C patients were often initiated due to shock, these patients were likely stabilized rapidly with immune modulation and vasopressor support. This may explain the shorter PICU stays relative to patients with acute COVID-19, who typically require PICU admission due to respiratory distress and/or exacerbation of chronic comorbid conditions (e.g. neurologic or respiratory disease). The higher vasopressor and intensive care requirements for MIS-C, with similar rates of respiratory support requirements, are consistent with multiple United States studies ^{Footnote 2 Footnote 16}. A small number of acute COVID-19-related deaths were reported versus no MIS-C-related deaths, in part due to complications from chronic comorbid conditions among children with severe COVID-19 ^{Footnote 17}.

Despite comparable absolute rates of overall in-hospital resource use, there were important age differences in disease severity and the ensuing strategies used to support these patients. Infants (i.e. younger than one year old) rarely required hospitalization for MIS-C, presenting with lower rates of shock, coagulopathy and myocarditis relative to older children ^{Footnote 11 Footnote 18}. Conversely, infants were the most commonly hospitalized age group for acute COVID-19, in part due to the routine practice of admitting febrile infants for investigations and empiric treatment ^{Footnote 19}. Meanwhile, the requirement for hemodynamic support among children five years of age and older with MIS-C (43–49%) likely led to the high proportion of PICU admission among this age group relative to acute COVID-19, in keeping with other published literature ^{Footnote 3}.

While our study period ended prior to dominance of the Delta and Omicron lineages, these and future SARS-CoV-2 lineages may affect the relative in-hospital burden of acute COVID-19 infection and MIS-C. Studies from Denmark and Israel have found the incidence of MIS-C during Omicron waves fell to one tenth that of prior waves, after accounting for vaccination status ^{Footnote 20 Footnote 21}. Declines in the proportion of MIS-C patients admitted to PICU have also been observed (e.g. 61% during pre-Delta waves to 52% during the Delta wave in the United States ^{Footnote 22}; 49% during Delta waves to 21% during Omicron waves in Israel ^{Footnote 21}), though this may also reflect increased physician knowledge of MIS-C and refinement of supportive and treatment strategies. Uptake of paediatric and adolescent SARS-CoV-2 vaccines may also alter the relative in-hospital burden of disease, having shown effectiveness against both severe COVID-19 and MIS-C ^{Footnote 23 Footnote 24}.

Limitations

There are several limitations to this study. First, the voluntary nature of CPSP reporting means that not all paediatric hospitalizations in Canada were identified. The number of hospitalizations reported in this study may therefore differ from provincial reports, which use administrative data. Moreover, the limited availability of molecular and serologic testing during the early pandemic likely resulted in some cases failing to meet the case definition of MIS-C. Data were also collected prior to emergence of the Delta and Omicron variants, and before implementation of paediatric and adolescent SARS-CoV-2 vaccine programs. The PICU admission criteria may have differed by age, centre and diagnosis. Nevertheless, this study provided a unique opportunity to compare children hospitalized for acute COVID-19 infection and MIS-C using data ascertained with the same surveillance methods, timeframe and patient population, with physician case review to ensure all reported cases met the case definitions.

Conclusion

Our findings suggest that both acute COVID-19 and MIS-C need to be considered when assessing the overall burden of SARS-CoV-2 in hospitalized children, and have implications for future pandemic planning with respect to hospital resource use. Given the high proportion of children requiring PICU support for MIS-C, in tandem with the limited number of specialized hospital beds, it is clear these resources need to be anticipated for future pandemic waves. Moreover, given the low overall rates of vaccination among children younger than 12 years of age ^{Footnote 25}, awareness of disease severity from both acute COVID-19 and MIS-C may inform parents and policymakers in their decision-making regarding paediatric vaccines.

Authors' statement

DSF — Conceptualization, methodology, validation, formal analysis, investigation, data curation, writing (original draft)

CMH — Conceptualization, methodology, validation, investigation, writing (review & editing), supervision, funding acquisition

OD — Investigation, writing (review & editing)

TET — Investigation, writing (review & editing)

MPM — Investigation, writing (review & editing)

RAB — Investigation, writing (review & editing)

MK — Validation, investigation, data curation, writing (review & editing)

MLT — Methodology, validation, investigation, data curation, writing (review & editing), project administration

KB — Investigation, writing (review & editing)

GBB — Investigation, writing (review & editing)

CB — Investigation, writing (review & editing)

TLB — Investigation, writing (review & editing)

SMB — Investigation, writing (review & editing)

KC — Investigation, writing (review & editing)

CC — Investigation, writing (review & editing)

ND — Investigation, writing (review & editing)

EJD — Investigation, writing (review & editing)

JEE — Investigation, writing (review & editing)

CF — Investigation, writing (review & editing)

AF — Investigation, writing (review & editing)

SF — Investigation, writing (review & editing)

RG — Investigation, writing (review & editing)

KTK — Investigation, writing (review & editing)

BL — Investigation, writing (review & editing)

RML — Investigation, writing (review & editing)

BWM — Investigation, writing (review & editing)

JO — Investigation, writing (review & editing)

JP — Investigation, writing (review & editing)

CMP — Investigation, writing (review & editing)

VEP — Investigation, writing (review & editing)

JPPG — Investigation, writing (review & editing)

RP — Investigation, writing (review & editing)

MS — Investigation, writing (review & editing)

MIS — Investigation, writing (review & editing)

RP — Investigation, writing (review & editing)

KAT — Investigation, writing (review & editing)

IVT — Investigation, writing (review & editing)

EH — Conceptualization, investigation, writing (review & editing), supervision

RS — Conceptualization, investigation, writing (review & editing), supervision

RSMY — Conceptualization, investigation, writing (review & editing), supervision

FK — Conceptualization, methodology, investigation, writing (review & editing), supervision

SKM — Conceptualization, methodology, investigation, writing (review & editing), supervision

CPSP COVID-19 Study Team — Investigation, writing (review & editing)

F Kakkar and S Morris were co-senior authors.

Competing interests

CMH is the Director of Children's Mental Health of Ontario, and the Director of Medical Affairs for the Canadian Paediatric Society and Canadian Paediatric Surveillance Program. MPM has received consulting fees from Sobin and Abbvie and payment for expert testimony from the Canadian Medical Protective Association. RAB has received honoraria and participated in advisory boards with SOBI, Roche, Amgen, and AbbVie. KB served as Past President of the Community Paediatrics Section of the Canadian Paediatric Society and has received royalties from Brush Education. TLB is an employee of the Public Health Agency of Canada (PHAC). KC is Chair of the Acute Care Committee of the Canadian Paediatric Society and is past-president of the Emergency Medicine Section of the Canadian Paediatric Society. EJD is Chair of the Scientific Research Committee and a director of Epilepsy Canada. She is also a member of Partners Against Mortality in Epilepsy and the advisory boards of Cardiol, Pendopharm and Stoke Therapeutics. CF is Chair of the Scientific Steering Committee for the Canadian Paediatric Surveillance Program, former Chair of the Specialty Committee in Paediatrics of the Royal College of Physicians and Surgeons of Canada, former president of the Canadian Paediatric Society, and member of the Executive as Secretary of the Canadian Critical Care Society. She has received reimbursement for travel expenses from Canadian Paediatric Society and the Royal College of Physicians and Surgeons of Canada. She has also received an honorarium for a presentation at a continuing education conference from the Université de Sherbrooke. SF is the President of the Association of Medical Microbiology and Infectious Disease Canada and has received consulting fees from Toronto Metropolitan University. RML has received honoraria for serving as a consultant to Sobi, Novartis, Sanofi, and Eli Lilly, as chair for data monitoring committees for Eli Lilly and Novartis, and from the Canadian Rheumatology Association. JP has received consultant fees from AbbVie, honoraria from AbbVie, AstraZeneca and Seegene, and he received respiratory virus testing materials from Seegene for his institution. He has participated in ad hoc advisory board meetings for AbbVie and Merck and is a voting member of the National Advisory Committee on Immunization. RP is a consultant for Verity Pharmaceuticals. MS is supported via salary awards from the BC Children's Hospital Foundation and the Michael Smith Foundation for Health Research and has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. MIS is an employee of the Public Health Agency of Canada. EH has participated in advisory board meetings of CSL-Behring and Takeda, data safety monitoring boards of Rocket Pharmaceutical and Jasper Therapeutics, and has patent applications with Immugenia and Immune Biosolutions. RS has received honoraria and served on an advisory board and as a consultant with Novartis, honoraria from Canadian Rheumatology Association, is a board member for Rheumatology for All, and her institution receives funding from Bristol Myers Squibb for a patient registry for which she is Principal Investigator. RSMY has received grant funding from CFI, CIHR, Genome Canada, PHAC and the COVID-19 Immunity Task Force, and The Arthritis Society; is a member of the Science and Industry Advisory Committee at Genome Canada and Medical Advisory Board at Kawasaki Disease Canada; and a member of a data safety monitoring board for a study on IL-1 inhibitors for Kawasaki Disease. FK has received honoraria for presentations given to the Association des Pédiatres du Québec and receives CMV testing kits from Altona Diagnostics. SKM has received honoraria for lectures from GlaxoSmithKline, was a member of ad hoc advisory boards for Pfizer Canada and Sanofi Pasteur, and is an investigator on an investigator led grant from Pfizer. DSF, OD, TET, MK, and MLT have no conflicts of interest to report.

Funding

Financial support for the Canadian Paediatric Surveillance Program (CPSP) was received from the Public Health Agency of Canada (PHAC). The CPSP is governed by an independent Scientific Steering Committee (SSC) comprised of individuals from both the Canadian Paediatric Society and PHAC. Members of the SSC reviewed and approved the study design. Individuals from PHAC, CPS, and the SSC participated in interpretation of the data. The final report was provided to PHAC for review, though the study team maintained scientific independence and authors were under no obligation to accept or incorporate changes to the manuscript.