key: cord-0718938-dz6xulee
authors: Farrar, D. S.; Drouin, O.; Moore Hepburn, C.; Baerg, K.; Chan, K.; Cyr, C.; Donner, E. J.; Embree, J. E.; Farrell, C.; Forgie, S.; Giroux, R.; Kang, K. T.; King, M.; Laffin Thibodeau, M.; Orkin, J.; Ouldali, N.; Papenburg, J.; Pound, C. M.; Price, V. E.; Proulx-Gauthier, J.-P.; Purewal, R.; Ricci, C.; Sadarangani, M.; Salvadori, M. I.; Thibeault, R.; Top, K. A.; Viel Theriault, I.; Kakkar, F.; Morris, S. K.
title: Risk factors for severe COVID-19 in hospitalized children in Canada: A national prospective study from March 2020--May 2021
date: 2022-04-07
journal: nan
DOI: 10.1101/2022.04.06.22273409
sha: f6ab5f53d66c6da3ad534aba5efbcbc2e905455a
doc_id: 718938
cord_uid: dz6xulee

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.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is typically mild 2 or asymptomatic in children as compared to adults, however, severe outcomes including 3 hospitalization and death due to coronavirus disease 2019 (COVID-19) have been reported. 1,2 4 Chronic comorbid conditions are an important prognostic factor for disease progression, outcomes was restricted to patients hospitalized with COVID-19-related disease. Multivariable Poisson regression with robust standard errors was used to identify risk factors for severe 1 1 1 COVID-19, reported using adjusted risk ratios (aRR). The primary adjusted model, defined a 1 1 2 priori, included age, sex, concomitant infections, timing of hospitalization, and chronic conditions (categorized as none, non-complex, or complex). Child age was entered as a 1 1 4 continuous variable using a restricted cubic spline with four knots at evenly-spaced percentiles. 1 1 5 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ;  To assess the role of specific conditions, the chronic comorbid condition variable was substituted 1 1 6 with each individual condition or subcategory and analyzed as described above. A separate 1 1 7 model was conducted among children <1 year only to assess very young age (i.e. <1 month 1 1 8 versus 1-11 months) and premature births (vs. term births), adjusting only for those variables due 1 1 9 to a smaller available sample size. Minimum population-based incidence proportions were by 2020 midyear population denominators from Statistics Canada. 21 Confidence intervals (CI) 1 2 2 were computed by assuming a Poisson distribution. Data analysis was conducted in Stata version 1 2 3 17·0, using a statistical significance threshold of α =0·05. 22 Ethical approval 1 2 6 The CPSP operates under the authority derived from Section 4 of the Department of Health Act 1 2 7 and Section 3 of the PHAC act. Approval was obtained from Research Ethics Boards at Health 1 2 8 Canada-PHAC (REB #2020-002P), the Hospital for Sick Children (REB #1000070001), the 1 2 9 Centre Hospitalier Universitaire Sainte-Justine (IRB #MP-21-2021-2901), and at individual sites 1 3 0 as required by local policies. Role of the funding source 1 3 3 The CPSP is governed by an independent Scientific Steering Committee (SSC) comprised of 1 3 4 individuals from both CPS and PHAC (the funder). Members of the SSC reviewed and approved 1 3 5 the study design. Individuals from PHAC, CPS, and the SSC participated in interpretation of the 1 3 6 data. The final report was provided to PHAC for review, however the study team maintained 1 3 7 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 7, 2022. ;  scientific independence and the authors were under no obligation to accept or incorporate 1 3 8 changes to the manuscript. 

During the fifteen-month study period, 544 children hospitalized with SARS-CoV-2 infection 1 4 1 met this study's inclusion criteria ( Figure S1 ). Among these cases, 330 (60·7%) were 1 4 2 hospitalized with COVID-19-related disease, while the remainder were incidental cases admitted 1 4 3 for unrelated care (n=201, 36·9%) or admitted for infection control or social purposes (n=13, 1 4 4 2·4%). Overall, 15·3% of cases were hospitalized during the first pandemic wave (peaking in 1 4 5 April 2020), 50·0% during the second wave (peaking in January 2021), and 34·7% during the 1 4 6 third wave (peaking in April 2021; Figure S2 ). Hospitalizations were reported from all regions 1 4 7 across Canada, most commonly from the most populous provinces of Ontario (n=229; 42·1%) 1 4 8 and Quebec (n=194; 35·7%). Of the 330 COVID-19-related hospitalizations, 70·3% (n=232) met criteria for non-severe disease while 29·7% (n=98) met criteria for severe disease ( Table 1 ). The median age at 1 5 2 admission was 1·9 years (IQR 0·1-13·3) and was lower among patients with non-severe COVID- 19 (0·8 years, IQR 0·1-9·7) than those with severe COVID-19 (6·5 years, IQR 1·5-14·8; 1 5 4 p<0·001). Accounting for underlying population size, study period incidence proportions for 1 5 5 COVID-19 hospitalization and severe COVID-19 were highest among children <1 year of age 1 5 6 (37·9 hospitalizations and 5·4 severe cases per 100,000 population) and lowest among children 5- 11 years of age (1·0 hospitalizations and 0·4 severe cases per 100,000 population; Table 2 ). Concomitant infections were reported among 8·2% of cases (n=27), including most commonly 1 5 9 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 7, 2022. ;  urinary tract infections (n=10). Among 140 patients <1 year old, 12·9% (n=18) were born at <37 1 6 0 weeks gestation. (n=142), including 23·9% (n=79) classified as non-complex conditions and 19.1% (n=63) 1 6 4 classified as complex conditions (Table 1 ). Neurologic and neurodevelopmental disorders were 1 6 5 most common (n=46, 13·9%) and included epilepsy (n=20), chronic encephalopathies (n=19 Table 3 ). Forty-four patients (13·3%) were obese, all aged ≥ 5 years, with a median Pulmonary conditions were reported in 34 patients (10·3%), including asthma most commonly congenital heart disease (n=14, 4·2%), gastrointestinal/liver disease (n=10, 3·0%), diabetes (n=8 1 7 4 including 7 who were insulin dependent), and malignancies (n=8, 2·4%; including 6 with 1 7 5 leukemia). Finally, 16 patients (4·8%) had pre-existing technology dependence requirements 1 7 6 including 12 requiring parenteral nutrition and seven with either tracheostomy or home oxygen 1 7 7 requirements. Compared to patients hospitalized for other reasons, children hospitalized for 1 7 8 COVID-19 were more likely to be obese (13·3% vs. 3·7%, p<0·001) and have pulmonary conditions (10·3% vs. 3·3%, p=0·002) but less likely to have psychiatric disorders (<1·5% vs. Table S1 ). CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 7, 2022. ;

Among COVID-19-related hospitalizations, 60 (18·2%) children were admitted to the ICU for a 1 8 3 median duration of four days (IQR 2-7, Table 4 ). Including patients admitted to the ward and 1 8 4 ICU, nearly one-third (n=108) required respiratory or hemodynamic support, including 19·1% 1 8 5 (n=63) who required support greater than low-flow oxygen. Mechanical ventilation was required 1 8 6 for 7·6% of children (n=25), while few (n=8, 2·4%) required vasopressors and none required children died due to complications of acute COVID-19, at a mean age of 8·1 years (standard disease (48·7%, n=19/39), followed by those aged 12-17 years (41·3%, n=38/92), 5-11 years 1 9 2 (36·7%, n=11/30), 6-23 months (28·3%, n=13/46), and finally <6 months (13·8%, n=17/123). Children aged 2-4 years were more often admitted to ICU (33·3%, n=13/39) while children aged 12-17 years more often required any respiratory or hemodynamic support (51·1%, n=47/92). The proportion of children with chronic comorbid conditions by age group is described in Table S2 , 1 9 6 while severity and treatment outcomes by pandemic wave is described in Table S3 . There was a significant nonlinear relationship between age and severe COVID-19 ( Figure 1 ), 1 9 9 whereby children <1 year had significantly lower risk of severe disease while risk was highest . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ; https://doi.org/10.1101/2022.04.06.22273409 doi: medRxiv preprint requirements (vs. none, aRR 2·01, 95% CI 1·37-2·95; Figure 2 ). Bronchopulmonary dysplasia severe disease (aRR 0·33, 95% CI 0·05-2·20) while those with uncontrolled asthma were (aRR Figure S3 ). Among children with obesity, only those with known BMIZ >3 had higher risk of severe disease (aRR 1·90, 95% CI 1·10-3·28). Immunosuppression (aRR 0·43, 95% CI 0·16- 1·16) and malignancies (aRR 0·65, 95% CI 0·22-1·90) were not associated with higher risk of by 3·47 times that of term-born children (95% CI 1·69-7·09). Notably, when analyzed as a single variable, non-complex conditions (aRR 1·10, 95% CI 0·71-1·69) and complex conditions (aRR compared to children with no known comorbid conditions. In this national prospective surveillance study, we described risk factors for disease severity and across Canada prior to emergence of the Omicron variant and the approval of paediatric COVID- 19 vaccines. Overall, the CPSP voluntary reporting system captured 58% of children <18 years (unpublished data; source: case information received by PHAC from provinces and territories). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ; https://doi.org/10.1101/2022.04.06.22273409 doi: medRxiv preprint While severe outcomes were rare in absolute terms, among COVID-19-related hospitalizations, 2 2 9 one in three patients required respiratory or hemodynamic support (including one in five 2 3 0 requiring greater than low-flow oxygen) while one in five required ICU admission, and five 2 3 1 patients reported to the study died from their infection. Severe outcomes were identified across 2 3 2 all age groups and among patients both with and without comorbid conditions. We estimated a 2 3 3 lower proportion of severe COVID-19 than interim CPSP analyses (29·7% here vs. 50·0% in our 2 3 4 prior report 16 ). This was in part due to a change in definition from initial criteria adapted from subjective reports of organ involvement such as non-specific respiratory distress, coagulopathy, 2 3 7 and minimal supplemental oxygen requirements (Table S4) . Our results are similar to a US study 2 3 8 of hospitalized patients with a primary diagnosis of COVID-19 (20·7% with severe disease), but the proportion with severe disease remained higher than most studies which included incidental 2 4 0 cases in their study denominators (e.g. 4·1-15·4%). [24] [25] [26] These differences may also be Child age was an important predictor of severe disease. After multivariable adjustment, 2 4 4 hospitalized infants (i.e. children <1 year of age) had significantly lower risk of severe disease 2 4 5 compared to older children, yet population-based incidence proportions of severe COVID-19 for 2 4 6 this age group were between 3-18 times higher than older age groups. Lower in-hospital risk of 2 4 7 severe disease is likely a result of lower thresholds for admission for febrile infants, in particular the highest risk of severe disease, including 33% admitted to ICU and 26% requiring ventilation. Chronic comorbid conditions associated with the neurologic or pulmonary systems had increased 2 5 4 risk of severe disease roughly 1·5-2·5 times that of all other children. Epilepsy is now a well- of seizures during infection as well as associated respiratory complications such as aspiration, 2 5 7 and warrants dedicated study of specific epileptic subgroups. 5, 28 Technology dependence, most 2 5 8 notably patients requiring home oxygen, tracheostomy, or gastrostomy tubes were at particularly infections such as influenza and respiratory syncytial virus. 29, 30 Notably, complex conditions as a focus should be paid on specific conditions rather than broad categories as is often the case in Previous studies have shown mixed evidence of asthma as a risk factor for severe COVID- 19. 5, 7, 10, 24 In this study, we demonstrate that controller medications may act as an effect modifier, 2 6 7 whereby a lack of daily controller medications significantly increased the risk of severe disease. This finding suggests that asthma controllers may be protective against respiratory 2 6 9 complications, and children lacking these medications may experience reduced access to care or be less likely to be actively followed in a clinical setting. This is supported by a recent population-based study that showed a marked increase in risk of SARS-CoV-2 hospitalization among school-aged children with poorly-controlled asthma. 33 2 7 3 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ;  analysis of risk factors was conducted within hospitalized patients only, and therefore may differ 2 9 7 from risk factors of severe disease among all children with COVID-19. Analyses of risk factors 2 9 8 could not be conducted within age strata and for example, effects of obesity may not be 2 9 9 generalizable to children <5 years of age. 37 Finally, population group of the child was reported In this national prospective surveillance study, severe COVID-19 was detected across all age conditions, as well as technology dependence requirements were associated with higher risk of severe COVID-19. These findings may be used to inform vaccination and booster campaigns, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ; We searched Medline and PubMed for published materials and medRxiv for pre-print 3 1 4 publications between January 1, 2020 and February 28, 2022. Search terms used included the 3 1 5 following combination of words and did not include language limitations: "COVID-19" OR "SARS-CoV-2" OR "coronavirus"; "children" OR "pediatric" OR "adolescent" OR "youth"; 3 1 7 "hospitalized" or "admitted"; "severe" OR "critical" OR "intensive care" OR "complications" 3 1 8 OR "mortality" OR "death" OR "risk factors". We identified numerous descriptive studies were commonly associated with severe outcomes, including diabetes, neurologic conditions, and conflicting results particularly regarding younger children (i.e. <1 year). The Canadian Paediatric Surveillance Program collected detailed data on clinical presentations 3 2 9 and chronic comorbid conditions among nearly 60% of all paediatric SARS-CoV-2 comorbid conditions. We confirm neurologic and pulmonary conditions as risk factors for severe 3 3 3 disease, including specifically epilepsy, bronchopulmonary dysplasia, and uncontrolled asthma. We also identify greater risk among children with technology dependence requirements, as well Children at all ages and both with and without comorbid conditions may experience severe Children <5 years remain a key unvaccinated group both in Canada and globally. These findings . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ;  AUTHOR CONTRIBUTIONS 3 4 7 The study was conceived by DSF, OD, CMH, FK, and SKM. DSF conducted statistical analysis 3 4 8 and wrote the first draft of the manuscript. All authors had access to the data, and DSF, CMH, 3 4 9 MLT, MK, and SKM have accessed and verified the data underlying the study. All authors 3 5 0 contributed to data collection, reviewed the study results and manuscript, and approved of the The authors wish to thank the paediatricians, paediatric subspecialists, and health professionals 3 5 5 who voluntarily respond to CPSP surveys. The authors are also grateful to the staff and managers 3 5 6 of the CPSP for their commitment to this study, as well as members of the CPSP Scientific Steering Committee who serve as stewards of the program. They also thank the members and 3 6 2 Krista Baerg has received royalties from Brush Education, and provided contracted services to 3 6 3 the College of Medicine, University of Saskatchewan and Saskatchewan Health Authority - 3 6 4 Saskatoon. She also served on the Board of Directors of the Saskatchewan Pain Society Inc., and is Chair of the Acute Care Committee of the Canadian Paediatric Society, and served on the billing/finance committee of the Pediatric Section of the Ontario Medical Association. Catherine 3 6 8 Farrell is Chair of the Scientific Steering Committee for the Canadian Paediatric Surveillance . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ;  Program and member of the Board of Directors of the Canadian Critical Care Society. She has 3 7 0 received funding from Health Canada and the Canadian Institutes of Health Research, as well as 3 7 1 an honorarium for a presentation at a continuing education conference from the Université de 3 7 2 Sherbrooke. Sarah Forgie is the President of the Association of Medical Microbiology and 3 7 3 Infectious Disease Canada, and received an honorarium for participation in the Senior Medical 3 7 4 Advisory Committee at Ryerson Medical School. Fatima Kakkar has received salary support for 3 7 5 protected time from the FRQS Chercheur Boursieurs Program, and received honoraria for 3 7 6 presentations given to the Association des Pédiatres du Québec. She has also served on the 3 7 7 Quebec COVID-19 maternal-child health advisory committee, and received grants from FRQS Director of Children's Mental Health of Ontario, and the Director of medical affairs for the fees from Merck, honouraria from Astra-Zeneca and Seegene, and is a voting member of the 3 8 4 National Advisory Committee on Immunization. He is also site principal investigator for 3 8 5 industry trials by MedImmune, Merck, Astra-Zeneca, and Sanofi, and is Medical Lead of the 3 8 6 Study Steering Committee for AbbVie. Rupeena Purewal is a consultant for Verity . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ; Age was analyzed using Poisson regression with robust standard errors, where age was entered into the model as a restricted cubic spline with four knots. Predicted probabilities of severe disease were then exponentiated to visualize continuous risk ratios. The analysis adjusted for sex, comorbid conditions (categorized as none, non-complex, or complex), concomitant infections (any vs. none), and timing of hospitalization (first, second, or third wave).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. Adjusted risk ratios (aRR) were calculated using Poisson regression with robust standard errors. The x-axis depicts risk ratios by factors of two (i.e. 2-4-6-8 and 1/2-1/4-1/6-1/8-1/10). The primary model included continuous age (as analyzed in Figure 1 ), sex, concomitant infections, timing of hospitalization, and chronic condition category (i.e. none/unknown, non-complex, complex). Separate models were then run for each specific chronic condition, by substituting the overall chronic condition category with only the condition of interest. Finally, age <1 month and prematurity status were assessed in a separate model containing only children <1 year old (n=140, including 20 severe cases), and did not adjust for additional variables due to a smaller available sample size. e.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. ; .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 7, 2022. ; Table 3 . Chronic comorbid conditions among COVID-19-related hospitalizations.

All COVID-19 related cases 1 Multiple specific conditions could be reported (e.g. two or more neurologic conditions) and therefore may not sum to category total. 2 Obesity was physician-reported and could not be confirmed for children missing height and weight data (n=22). 3 Defined as immunocompromising medications, primary or secondary immunodeficiency otherwise specified, or chronic rheumatologic or autoimmune disorder. 4 Defined as parenteral nutrition, respiratory technology requirements (i.e. home oxygen or tracheostomy), or dialysis.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 7, 2022. ;

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Page 31 of 31 1 Multiple supports could be reported and therefore specific supports do not sum to any supports.