key: cord-0270079-locpvslm authors: Schober, T.; Caya, C.; Barton, M.; Bayliss, A.; Bitnun, A.; Bowes, J.; Brenes-Chacon, H.; Bullard, J.; Cooke, S.; Dewan, T.; Dwilow, R.; El Tal, T.; Foo, C.; Gill, P.; Haghighi Aski, B.; Kakkar, F.; Lautermilch, J.; Laxer, R. M.; Lefebvre, M.-A.; Leifso, K.; Le Saux, N.; Lopez, A.; Manafi, A.; Morris, S. K.; Nateghian, A.; Panetta, L.; Petel, D.; Piche, D.; Purewal, R.; Restivo, L.; Roberts, A.; Sadarangani, M.; Scuccimarri, R.; Soriano-Fallas, A.; Tehseen, S.; Top, K. A.; Ulloa-Gutierrez, R.; Viel-Theriaul, I.; Wong, J. K.; Yea, C.; Yeh, A.; Yock-Corrales, A.; Robinson, J.; Papenburg, J. title: Risk factors for severe PCR-positive SARS-CoV-2 infection in hospitalized children: a multicenter cohort study date: 2021-10-29 journal: nan DOI: 10.1101/2021.10.28.21265616 sha: 9cefcb3b2363914c43c9c8a537a8a7a11e69bdb2 doc_id: 270079 cord_uid: locpvslm 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. The clinical presentation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is generally milder in children than in adults. However, children can also experience morbidity and mortality due to coronavirus disease 2019 (COVID-19). 1 It is important to identify risk factors for severe disease. This would allow for identification of patient groups that require closer monitoring or early treatment, and could also help guide targeted vaccination campaigns. While many countries started a vaccination program against SARS-CoV-2 for all adolescents older than 11 years of age in June/July 2021, others had limited access to vaccines or decided to focus on high-risk groups following WHO recommendations. 2, 3 Considering the usually benign clinical course of SARS-CoV-2 infection in children, the potential direct and societal benefits of universal versus targeted vaccination in the pediatric population need to be considered carefully. It is therefore of great practical value to know which children are at high risk of severe disease. Previous studies have attempted to identify risk factors for severe disease in pediatric patients for severe SARS-CoV-2 infection. [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Some risk factors such as presence of comorbidities, obesity, and increased inflammatory markers have been implicated, 5, 8, [10] [11] [12] [13] 15 but many studies were small and there is substantial heterogeneity. 16 Importantly, most major studies were from high-income countries and data from low and middle-income countries are scarce. Multisystem inflammatory syndrome in children (MIS-C) is a serious post-infectious complication of SARS-CoV-2 infection in children. Despite differences in the pathophysiology and clinical presentation, 17, 18 there is significant overlap between acute SARS-CoV-2 infection and PCR-positive MIS-C; it is frequently impossible to distinguish them and both contribute to the potentially preventable burden of SARS-CoV-2 in children. 7 The aim of this study was the identification of risk factors for severe disease in children hospitalized for symptomatic PCR-confirmed SARS-CoV-2 infection including PCR-positive MIS-C in a multicenter cohort study from Canada, Costa Rica, and Iran. Thirteen pediatric hospitals from the Canadian Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) group and two international collaborators (one each in Tehran, Iran, and San José, Costa Rica) entered all consecutive children <18 years of age admitted from February 1, 2020 through May 31, 2021 with PCR confirmed SARS-CoV-2 infection or MIS-C. Cases were identified through the microbiology laboratory, infection prevention and control and/or COVID-19 unit databases. The present study was restricted to symptomatic cases with detection of SARS-CoV-2 by molecular testing from a respiratory specimen during the current admission. Patients who were admitted for reasons other than their SARS-CoV-2 infection (i.e. incidental infections), as per each local investigator's adjudication, were excluded. Ethics approval was obtained from each participating institution's ethics research board, with waiver for informed consent for health records research (Supplementary methods). The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines were followed. 19 . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint Data on primary indication for admission, demographics, comorbidities, clinical presentation and course, coinfections, treatments, and complications were abstracted by the investigators from the patient's medical charts and managed using REDCap electronic data capture tools. The primary outcome, severe PCR-positive SARS-CoV-2 infection, was defined as a WHO clinical progression scale 20 of ≥6, i.e. oxygen by non-invasive ventilation or high flow or mechanical ventilation or vasopressors or death. For a secondary analysis, severe SARS-CoV-2 infection was defined as a WHO clinical progression scale 20 of ≥6 and/or admission to an intensive care unit (ICU). Baseline exposure variables included age, sex country of admission, admission period (arbitrarily divided into prior to July 1, 2020; July 1 until Dec 31 2020; Jan 1 until May 31, 2021), and comorbidities. These chronic health conditions were classified using the Canadian National Advisory Committee on Immunization risk group classification for influenza 21 and adapted according to putative risk factors for severe COVID-19 in children (Supplementary methods). Other potential predictor variables (measured at any point during the hospitalization) were: clinical manifestations, viral co-infection (defined as laboratory detection of any other virus; testing at the discretion of the clinical team), bacterial co-infection (defined as laboratory detection of ≥1 bacteria treated with antibiotics; testing and treatment at the discretion of the clinical team), chest imaging abnormalities (chest x-ray or CT compatibility with COVID-19 based on the reporting physician's assessment), laboratory parameters (age-defined leukocytosis, leukopenia, neutrophilia, neutropenia, thrombocytosis or thrombocytopenia 22 ; C-reactive Protein [CRP] >50mg/L; Ferritin >5000 mcg/L; albumin <29g/L), diagnosis of MIS-C (as defined by WHO criteria 23 ). . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint Data were analyzed using R version 3.5.2 (R Core Team, Vienna, Austria). Statistical significance was assessed by using 2-tailed tests, with an α of 0.05. Baseline and demographic characteristics were summarized using descriptive statistics. Categorical data were compared using chi-square or Fisher's exact test as appropriate and continuous data compared using Wilcoxon rank sum test. Statistical testing was limited to hypothesis-driven and biologically plausible comparisons; accordingly, correction for multiple hypothesis testing was not done. Logistic regression analyses were performed to determine crude and adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CIs) for factors associated with se1vere disease. For the multivariable models, we considered variables with p-value ≤0.2 on univariable analyses and, a priori, variables which were potential confounders based on literature or clinical experience. Model selection was guided by Akaike Information Criteria, using backward and forward selection. Pre-specified sensitivity (excluding MIS-C cases) and age-stratified analyses (children under 12 years old and adolescents ≥ 12 years old) were also performed. . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint From February 1, 2020 through May 31, 2021, 982 children younger than 18 years of age hospitalized for SARS-CoV-2-related illness and/or PCR-positive MIS-C were reported from the 15 study hospitals. We excluded 579 cases in whom SARS-CoV-2 was not confirmed by molecular testing from respiratory specimens or because the patient was admitted for non-SARS-CoV-2-related reasons. We included the remaining 403 hospitalizations (Figure 1 ). . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint The primary outcome of severe disease (WHO COVID-19 clinical progression scale ≥6) occurred in 102 (25%) of 403 children ( Among individual comorbidities, obesity, non-asthma pulmonary disease, hypertension, neurological and chromosomal disorders were also risk factors, but not immunosuppression ( diagnosis were independent predictors of severe disease (Figure 2) . In a separate model adjusting for the same covariates, we examined the effect of the number of comorbidities instead of each comorbidity individually. The presence of multiple comorbidities (OR 2.24, 95% CI 1.04-4.81), but not of a single comorbidity (OR 1.71, 95% CI 0.86-3.43) was a statistically significant risk factor ( Figure 2 ). Limiting . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint the multivariable analysis to baseline characteristics identified the same risk factors as the aforementioned models which included clinical, laboratory, and outcome parameters (eTable 1). We further analyzed the data using the secondary outcome of ICU admission and/or a WHO COVID-19 clinical progression scale of ≥6. There were 128 severe cases (31.8%) using this definition. ICU admission as a sole criterion excluded 10 patients with high flow nasal cannula and/or non-invasive ventilation who were managed outside of an ICU. Of 118 patients admitted to ICU, 26 (22%) did not meet our primary severity definition. Contrary to our primary unadjusted analyses, single comorbidity, chromosomal disorders, and hypertension were not significantly associated with severe disease (eTable 2). In unadjusted stratified analyses by age, risk factors for severity in children <12 years were nearly identical to the overall study population (eTable 3-4). However, in multivariable models, the only individual comorbidity to remain significantly associated with severity was neurologic disorders (eTable 6). Among adolescents ≥ 12 years of age, the only comorbidity associated with severity was obesity (eTable 6). Of note, risk factors were not equally distributed between the two age groups. More adolescents had any (66.7% vs. 40.2%, p<0.001) or multiple (25.8% vs. 16.5%, p=0.049) comorbidities than younger children; obesity was markedly more common in adolescents (40.9% vs 3.9%, p<0.001). In a sensitivity analysis, we excluded the 81 cases who met WHO MIS-C criteria. Results were very similar to the overall patient population, except that anemia and/or hemoglobinopathy and neutrophilia lost significance in the multivariable analysis (eTables 7-8). . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint In this multicenter cohort study from three countries, we identified risk factors for severe disease among children admitted to hospital for PCR-positive symptomatic SARS-CoV-2 infection. Previous studies have been either limited to administrative data, 4, 8, 12 were smaller, [5] [6] [7] 10, 11, 13, 14 or had a different scope. 18 We confirmed several previously described risk factors for severity on multivariable analyses: presence of multiple comorbidities, 4,6,9,12-15 obesity, 5, 8, 11, 14 neurological disorders, 8, 14 anemia and/or hemoglobinopathy, 24 shortness of breath, 6 bacterial and/or viral coinfections, 6,15 chest imaging compatible with COVID-19 5,13 , neutrophilia, 13 and MIS-C diagnosis. 5, 18 Additionally, older age, 4,10-12 hypertension, 8 and chromosomal disorders, 25 increased CRP, 10, 11, 13, 15, 24 and low albumin were associated with higher odds of a severe course in unadjusted analyses only, but not in multivariable models, indicating that other factors may have been confounding this association or that our study was underpowered to assess less frequent comorbidities. We also found evidence that age modifies the effect of individual comorbidities, with neurological disorders strongly associated with severe disease in children under 12 years old, whereas only obesity predicted severe disease in adolescents. Less than 5% of severe cases in our cohort were immunocompromised and impaired immunity was not associated with severity, in keeping with past pediatric studies. 5, 13, 14 A recent study on children with cancer showed a higher rate of complications following SARS-CoV-2 infection among the severely immunocompromised. 26 However, the study lacked a control group and immunocompromised children are extremely heterogeneous with multiple comorbidities complicating the interpretation. Accordingly, our data support the concept that a dysregulated rather than an insufficient immune response is a greater contributor to severe SARS-CoV-2 infection in the majority of children and adults requiring hospitalization. 17 . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint Previous studies have described a bimodal age pattern regarding severe disease, with a first peak in the very young and a second increase in adolescence mimicking global non-SARS-CoV-2-related childhood mortality. 4, 5, 7, 12 Infants in our study population were over-represented compared to the general pediatric population. For Canadian children, the proportion of infants was 4.3 times higher than its share of the population, 27 suggesting a higher risk of hospitalization. It is likely that some young infants with mild symptoms were admitted for observation, especially early during the pandemic, or to rule-out serious bacterial infection. 28 We did not see a higher rate of severe courses according to age, in line with other studies which restricted their analysis to hospitalized children. 10, 14, 15 Infants typically have a significantly higher baseline all-cause morbidity and mortality than older children. 29 Analyses which include all SARS-CoV-2 positive patients independent of their symptoms may mimic the baseline risk and not necessarily the infection-related complications. Similar to other studies, we saw a higher rate of severe disease in adolescents in our univariable analysis (Table 3) , 4,10-12 but this was not confirmed in the multivariable models ( Figure 2 ). This age group had a different risk profile than younger children, with obesity as the only comorbidity significantly associated with illness severity. Guzman et al. also observed that obesity was an independent risk factor for critical illness in adolescents but not younger children. 30 This association more closely resembles adults, in whom metabolic risk factors are among the most important. 31 The observed higher proportion of severe cases among adolescents in crude analyses could be mainly due to the markedly higher prevalence of obesity (40.9% in adolescents vs 3.9% in younger children in our study) and other comorbidities. Our primary outcome differed from many previous studies which defined severity as ICU admission. [5] [6] [7] [8] 15 ,24 ICU admissions are simple to measure, but can be problematic as a severity outcome because of heterogeneity across study sites due to dependence on local health care delivery structures and practice. . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint In addition, patients with some comorbidities or within certain age categories may be admitted to ICU mainly for monitoring or for treatment of a condition independent of the severity of the current illness, e.g. patients with tracheostomy or type-1 diabetes mellitus. 32 Therefore, we used the more objective WHO COVID-19 clinical progression scale which is based on the need for mechanical or medical support of vital functions, 20 similar to the definition used by Ouldali et al. 10 Our comparative analysis of two different severity criteria shows that the effect of several important risk factors would have been obscured using ICU admission alone to define severity. We decided to include all hospitalized symptomatic patients with positive SARS-CoV-2 PCR, independent of the diagnosis of MIS-C. Although the pathophysiology is different, 17 Our study has limitations. First, reporting may not have been uniform across centers despite the use of a study protocol and a standardized data capture tool. This includes but is not limited to the interpretation of chest radiographs, definition of obesity, and the severity of comorbidities. Also, the respective comorbidities can represent a heterogeneous group of diseases with different etiologies. Second, despite being one of the largest pediatric cohort studies with more than 100 severe cases, the numbers of some individual comorbidities are small. This might overestimate or underestimate the impact of infrequent . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint comorbidities such as anemia and/or hemoglobinopathy, chromosomal, or cardiac disorders. Third, laboratory investigations were not systematically performed. Complete blood counts, CRP, and albumin values were missing in 4.2%, 15%, and 67%, respectively. We therefore could not assess the latter in multivariable models. Moreover, laboratory investigations were done at the clinicians' discretion, not at set time points during the illness. Other parameters previously described as risk factors could not be evaluated. This includes ethnicity 4, 7, 9, 12 which was not readily accessible from hospital records. In addition, viral sequencing data was not available, accordingly we cannot evaluate the impact of different SARS-CoV-2 variants. Fourth, indications for testing for SARS-CoV-2 likely varied by center and over time, which might have affected the clinical spectrum of included patients. However, since we analyzed symptomatic hospitalized patients admitted for SARS-CoV-2 infection or PCR-positive MIS-C in centers with availability of SARS-CoV-2 PCR tests, we do not expect this to bias our results. Fifth, our study was not population-based. Most participating hospitals are referral centers so milder hospitalized cases might have been missed and this might overestimate the rate of severe courses. In addition, there were only two hospitals from Costa Rica and Iran, representing one-third of the total sample size; they may not be representative of middle-income countries in general. A major strength of our study includes its multicenter, multi-national design covering the first 15 months of the COVID-19 pandemic. The patient population of symptomatic children hospitalized for PCRconfirmed SARS-CoV-2 is well-defined and reduces potential biases from including incidental detections of SARS-CoV-2. Finally, this study represents one of the largest yet comprehensive datasets with over 100 severe cases, thereby allowing us to identify differences in risk factor profiles across age groups. In conclusion, we identified several independent risk factors for severe disease in children hospitalized for symptomatic PCR-positive SARS-CoV-2 infection, namely the presence of multiple comorbidities, obesity, anemia and/or hemoglobinopathy, neurological disorder, shortness of breath, bacterial and/or . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint viral coinfections, chest imaging compatible with COVID-19, neutrophilia, and MIS-C diagnosis. Based on our analysis, age was not an independent risk factor, but the apparent increased risk in adolescents is mainly secondary to the presence of age-specific comorbidities. Furthermore, age appears to modify the effect of specific comorbidities such as obesity. Improved understanding of pediatric risk factors for severe SARS-CoV-2 infection among children requiring hospitalization can guide management and refine risk-benefit analyses of pediatric vaccination programs against SARS-CoV-2. . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint We thank Dr. Joanna Merckx for her thoughtful review of an earlier version of this manuscript. The study was conceived and supervised by Joan Robinson and Jesse Papenburg. Analysis was conducted by Chelsea Caya and Tilmann Schober. Tilmann Schober wrote the first draft of the manuscript. All authors contributed to data collection and interpretation, reviewed the manuscript critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work. The corresponding authors will consider data sharing requests that are accompanied by a study protocol and approval by an independent research ethics board. None . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint Manish Sadarangani has been an investigator on projects funded by GlaxoSmithKline, Merck, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. Jesse Papenburg reports grants to his institution from MedImmune, Sanofi Pasteur and AbbVie, and personal fees from AbbVie, all outside of the submitted work. Shaun K Morris has received honoraria for lectures from GlaxoSmithKline and was a member of an ad hoc advisory board for Pfizer Canada, both outside of the submitted work. . 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 October 29, 2021. . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint 18 (6.8%) 5 (4.7%) 2 (6.7%) 25 (6.2%) IQR interquartile range; MIS-C multisystem inflammatory syndrome in children . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint . 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) Mean length of hospitalization in days (SD) 12 5.9 (6.0) 6.5 (8.1) 9.3 (6.6) 6.3 (6.7) Median length of hospitalization in days (IQR BiPAP bilevel positive airway pressure; CPAP continuous positive airway pressure; CT computed tomography; CRP Creactive protein; CXR chest x-ray; ICU intensive care unit; IQR interquartile range; MIS-C multisystem inflammatory syndrome in children; MV mechanical ventilation; SD standard deviation 1 A total of 35 children were missing data on fever prior to or during admission (17 from Canada, 16 from Costa Rica and 2 from Iran) resulting in a total N of 368. 2 Children with one of the following are included: blood culture thought to be truly positive and/or positive endotracheal tube cultures treated with antibiotics for presumptive bacterial pneumonia and/or positive bacterial culture from another site treated with antibiotics. 3 Children are listed more than once if they had more than one chest imaging result (e.g., chest x-ray and or chest CT). 5 A total of 17 children were missing leukocyte values (14 from Canada and 3 from Costa Rica) resulting in a total N of 386. 6 A total of 21 children were missing neutrophil values (18 from Canada and 3 from Costa Rica) resulting in a total N of 382. Cut-off values for neutrophilia are age dependent. 7 A total of 18 children were missing platelet values (15 from Canada and 3 from Costa Rica) resulting in a total N of 385. 8 A total of 60 children were missing a CRP value (41 from Canada and 19 from Costa Rica) resulting in a total N of 343. 9 The variable assessing highest ferritin value used and a total of 220 children were missing a value (135 from Canada, 75 from Costa Rica and 10 from Iran) resulting in a total N of 183. 10 A total of 271 children were missing albumin values (192 from Canada, 61 from Costa Rica and 18 from Iran) resulting in a total N of 132. . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint 11 Supplemental oxygen but no ICU admission includes those on oxygen, high flow nasal cannula, CPAP/BiPAP on regular or COVID-19 wards. 12 A total of 4 children are missing date of discharge from hospital (2 from Canada and 2 from Iran). . 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) . 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) . 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 October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265616 doi: medRxiv preprint Among Children and Adolescents -COVID-NET, 14 States JCVI issues updated advice on COVID-19 vaccination of children aged 12 to 15 COVID-19 Vaccines Advice SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years -United States Severe Acute Respiratory Syndrome Coronavirus 2 Clinical Syndromes and Predictors of Disease Severity in Hospitalized Children and Youth COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study Risk Factors for Severe COVID-19 in Children Underlying Medical Conditions Associated With Severe COVID-19 Illness Among Children Demographic predictors of hospitalization and mortality in US children with COVID-19 Factors Associated With Severe SARS-CoV-2 Infection Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children's Hospital in Clinical characteristics and risk factors for death among hospitalised children and adolescents with COVID-19 in Brazil: an analysis of a nationwide database Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study Characteristics of children admitted to hospital with acute SARS-CoV-2 infection in Canada in 2020 Clinical Features and Prognostic Factors of Pediatric SARS-CoV-2 Infection: Results From an Italian Multicenter Study Risk factors associated with severe outcomes of COVID-19: An updated rapid review to inform national guidance on vaccine prioritization in Canada. medRxiv Immune determinants of COVID-19 disease presentation and severity Additional information is available for 14/22 patients: obstructive sleep apnea (n=5) pulmonary hypertension (n=2); cystic fibrosis (n=1); chronic aspiration pneumonia (n=1) Pierre-Robin anomaly (n=1)