30-Day Outcomes of Children and Adolescents With COVID-19: An International Experience

and 2 across ABSTRACT Objectives: To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children/adolescents diagnosed or hospitalized with COVID-19, and to compare them in secondary analyses with patients diagnosed with previous seasonal influenza in 2017-2018. Methods: International network cohort using real-world data from European primary care records (France/Germany/Spain), South Korean claims and US claims and hospital databases. We included children/adolescents diagnosed and/or hospitalized with COVID-19 at age <18 between January and June 2020. We described baseline demographics, comorbidities, symptoms, 30-day in-hospital treatments and outcomes including hospitalization, pneumonia, acute respiratory distress syndrome (ARDS), multi-system inflammatory syndrome (MIS-C), and death. Results: A total of 242,158 children/adolescents diagnosed and 9,769 hospitalized with COVID-19, and 2,084,180 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were more common among hospitalized vs diagnosed with COVID-19. Dyspnea, bronchiolitis, anosmia and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital prevalent treatments for COVID-19 included repurposed medications (<10%), and adjunctive therapies: systemic corticosteroids (6.8%-7.6%), famotidine (9.0%-28.1%), and antithrombotics such as aspirin (2.0%-21.4%), heparin (2.2%-18.1%), and enoxaparin (2.8%-14.8%). Hospitalization was observed in 0.3% to 1.3% of the COVID-19 diagnosed cohort, with undetectable (N<5 per database) 30-day fatality. Thirty-day outcomes including pneumonia and hypoxemia were more frequent in COVID-19 than influenza. Conclusions: Despite negligible fatality, complications including hospitalization, hypoxemia and pneumonia were more frequent in children/adolescents with

use of VA data was reviewed by the Department of Veterans Affairs Central IRB, was determined to meet the criteria for exemption under Exemption Category 4 (3), and approved for Waiver of HIPAA Authorization. The IRB number for use of HIRA data was AJIB-MED-EXP20-065. The research was approved by the Columbia University Institutional Review Board as an OHDSI network study. The use of SIDIAP was approved by the Clinical Research Ethics Committee of the IDIAPJGol (project code: 20/070-PCV). The use of CPRD was approved by the Independent Scientific Advisory Committee (ISAC) (protocol number 20_059RA2). The use of IQVIA-OpenClaims, IQVIA-LPD-France, and IQVIA-DA-Germany were exempted from IRB approval.

INTRODUCTION
Since January 2020, a growing number of infections by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented pressure on healthcare systems worldwide. COVID-19 affects all age groups, with pediatric population representing 3.7% of reported cases. 1 Despite children/adolescents being more susceptible to certain infectious diseases due to their developing immune system, 2 clinical manifestations of COVID-19 are generally milder in the pediatric population, 3,4 with better outcomes and lower mortality rates than adults. 5 Nevertheless, there is evidence of children/adolescents with COVID-19 requiring hospitalization and intensive care unit (ICU)-level care. Reports from the United States (US) or China revealed that a low number of pediatric COVID-19 cases were hospitalized (5.7%) 6 or admitted to the ICU (1.8%) 7 , respectively. A study conducted in 25 European countries, on the other hand, found that in a sample of 582 children/adolescents, 63% were hospitalized. 8 Since the data included in this last study was limited to April 2020, the high admission rate reported could reflect temporal trends in testing availability as only the most ill children might have been tested during this period.
To date, most clinical guidelines recommend supportive care as the mainstay of therapy in children, [9][10][11] but there is little data to recommend or reject the use of specific immunomodulatory drugs or antivirals, particularly from clinical trials in the pediatric population. 12 It also remains to be elucidated whether children/adolescents show a different clinical presentation. 13 We conducted a literature review for articles published in PubMed and Medrxiv between December 2019 and June 2020 that reported on patients with a confirmed COVID-19 diagnosis. Of the 1320 studies that met the inclusion criteria, only 79 studies were on children/adolescents, most of which (63%) were local case reports or case series. This compellingly demonstrates a large by guest on May 30, 2021 www.aappublications.org/news Downloaded from remaining gap in existing efforts to define the characteristics of the pediatric population in a realworld setting at a large scale.
In this study, we aimed to describe the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes of children/adolescents diagnosed or hospitalized with COVID-19 in the US, Europe and Asia. In addition, we compared these cohorts with children/adolescents diagnosed with seasonal influenza in 2017-2018 as a benchmark in a secondary analysis.

Study design, setting and data sources
This study is part of the Characterizing Health Associated Risks, and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) study, a large-scale multinational cohort study using routinelycollected primary care and hospital EHRs, hospital billing data and insurance claims data from the US, Europe (the Netherlands, Spain, the UK, Germany and France) and Asia (South Korea and China).
From the nineteen databases contributing data to CHARYBDIS, only those with data on patients below the age of 18 years with a clinical diagnosis of COVID-19 or a SARS-CoV-2 positive test between January and June 2020 were included. A cohort of children/adolescents diagnosed with seasonal influenza in 2017-2018 was included for comparison.
To be included in the study, databases had to have a minimum of 140 children/adolescents). This cut-off was deemed necessary to estimate with sufficient precision (confidence interval width of ±5%) the prevalence of a previous condition or 30-day risk of an outcome affecting 10% of the by guest on May 30, 2021 www.aappublications.org/news Downloaded from study population. Data results for this paper were extracted from CHARYBDIS results on the 1 st of October 2020. Figure 1 represents the selection process of the databases for this study. Eleven databases fulfilled the inclusion criteria: STARR-OMOP (US), 14  HealthVerity, HIRA; and IQVIA-OpenClaims. A more detailed description of the included data sources is available in eTable 1.

Study participants and follow-up
Two non-mutually exclusive cohorts were included: 1) children/adolescents with COVID-19 diagnosis or a SARS-CoV-2 positive test (index date was the first of the two events), 2) Symptoms recorded at index date included fever, cough, dyspnea, malaise or fatigue, myalgia, anosmia or hyposmia or dysgeusia, gastrointestinal tract symptoms, diarrhea, vomits and nausea.
All drugs prescribed/dispensed during the 30-days follow-up after the index date were ascertained. Individual medications were categorized using Anatomical Therapeutic Chemical (ATC) groupings. For the study of medications potentially used for COVID-19, we assessed all medications included in at least two randomized controlled trials. 16 The list was further enriched with suggestions from key stakeholders including regulatory agencies, key opinion leaders, and pharma industry. Medicines of interest were grouped into: 1) repurposed medications-those with alternative indications but believed to be efficacious as antivirals, 2) adjuvant therapiesused allegedly for the treatment or prevention of COVID-19 complications. 17  The 30-day outcomes described in the diagnosed cohorts included hospitalization, death, pneumonia, and multi-system inflammatory syndrome in children (MIS-C, Kawasaki disease, or toxic shock syndrome). In the hospitalized cohorts, we additionally report sepsis, total cardiovascular disease events, acute respiratory disease syndrome (ARDS), cardiac arrhythmia, and bleeding. The definition of each outcome is provided in eTable 2.
We used the OHDSI Cohort Diagnostics to assess the fitness of use of each comorbidity per database. This tool represents the codes used for the definition of each condition and the prevalence of these conditions by sex, age groups and calendar year for each database. Results from cohort diagnostics of the definitions of COVID-19, seasonal influenza, and comorbidities are publicly available at: https://data.ohdsi.org/Covid19CharacterizationCharybdisDiagCovid/; https://data.ohdsi.org/Covid19CharacterizationCharybdisDiagInfluenza/; https://data.ohdsi.org/Covid19CharacterizationCharybdisDiagFeature/; and https://data.ohdsi.org/Covid19CharacterizationCharybdisDiagStrata/.

Statistical analyses
All data were standardized to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). 18  Demographics, history of comorbidities, symptoms and outcomes were summarized as proportions, calculated by dividing the number of people within a given category by the total number of people in each specific cohort. The proportion of users of each medication was determined for the hospitalized children/adolescents as the percentage of subjects who had >=1 day during the time window overlapping with a drug use period for each medication or drug class of interest. Utilization of repurposed and adjuvant drugs up to 30 days after admission was described.
The distribution of conditions a year prior to index, symptoms at index, outcomes and medications up to 30 days post-index date in COVID-19 diagnosed cohort were compared to the hospitalized COVID-19 or the diagnosed influenza cohorts. Standardized mean differences (SMD) were calculated when comparing the characteristics of study cohorts.
We performed a sensitivity analysis describing characteristics of cases with no prior observation time in order to understand the impact of lack of prior observation time in the results.
We used R version 3.6 (R Foundation for Statistical Computing, Vienna, Austria) for data visualization. All the data partners obtained Institutional Review Board (IRB) approval or exemption to conduct this study, as required.
All the data partners received Institutional Review Board (IRB) approval or exemption.

Health outcomes
Outcomes in the 30-day period following the diagnosis of COVID-19 and hospitalization with COVID-19 are summarized in Table 1 and Figure 5. Hospitalization was observed in a low proportion (0.3% in HealthVerity-US, 1.4% in SIDIAP-Spain) in the ambulatory/claims databases with testing and testing results data available; in 3.5% in IQVIA-OpenClaims-US; and more frequent (7.6% in OPTUM-EHR-US to 33.2% in CUIMC-US) in hospital EHR databases. Other less common outcomes are reported in Table 1 has reported that children/adolescents (<19 year) accounted for 4% of confirmed COVID-19 cases in Australia. 22 Asthma and obesity were the most common baseline comorbidities in children/adolescents with COVID-19; this is in keeping with disease prevalence among a general pediatric population. 23 More strikingly, we observed a high prevalence of conditions that are relatively rare in children/adolescents, including congenital malformation/s, neurodevelopmental disorders, heart disease, type 1 diabetes mellitus, cancer, and chromosomal disorder/s. These conditions were more frequent amongst hospitalized children/adolescents with COVID-19 than those diagnosed with COVID-19. This is in line with previous studies suggesting that children with comorbidity history have higher risk of critical care admission. 21,24 The frequency of reported symptoms in our study is generally lower than what has been previously reported in the pediatric literature, 8,21,24 suggesting an underestimation in the register of symptoms in the form of structured data in busy actual care settings. An important finding is that COVID-19 diagnosed children/adolescents presented with higher rates of dyspnea, anosmia, and gastrointestinal symptoms than children with seasonal influenza. This information is clinically relevant for differential diagnosis between COVID-19 and influenza among children/adolescents. We observed great heterogeneity across countries in the use of in-hospital treatments among children/adolescents with COVID-19, which is in line with previous studies in adults. 25 Our analysis suggests little use of antiviral therapies overall, with about 5% of children/adolescents hospitalized with COVID-19 using lopinavir/ritonavir in South Korea (but none in the US); a variable proportion of use of oseltamivir (1% to 5%) in the US (but none in South Korea); a 4-6% of use of azithromycin, and limited use of hydroxychloroquine, ranging from 1% to around by guest on May 30, 2021 www.aappublications.org/news Downloaded from 4% in both countries. These values are lower than what we previously reported in adults (e.g. use of hydroxychloroquine was 57.9% in the overall population vs. 1% in children/adolescents in PREMIER-US), 25 but in line with recent European cohort studies in hospitalized children/adolescents with COVID-19. A study in the UK reported that 6% (38/591) of hospitalized children/adolescents with COVID-19 received antiviral drugs (30 received acyclovir, 7 received remdesivir, and 3 received chloroquine or hydroxychloroquine), 21 while a study in 25 European countries including 582 children/adolescents found that 7% were treated with hydroxychloroquine, 3% with remdesivir, 1% with lopinavir-ritonavir, 1% with oseltamivir. 8 In contrast, we observed substantial use of different adjunctive therapies; corticosteroids were used in 25-35% in the US but 7% in South Korea. Famotidine (2 to 20%), aspirin (10 to 30%) and vitamin D (2 to 15%) were used in the US but not in South Korea.
Antibiotics were also commonly used, with ceftriaxone and amoxicillin amongst the most commonly prescribed. This is consistent with the previous study in in UK where antibiotics were given to 69% (415/601) of hospitalized children with COVID-19. 21 It is reassuring that occurrence of severe outcomes during the 30 days after diagnosis of COVID-19 was rare in our study, which is in line with previous studies. 8,20,21,24 MIS-C was relatively uncommon, affecting 0.5%-3.1% of all diagnosed cases, but up to 0.9%-7.6% of those hospitalized with COVID-19. These results are in line with previous studies from Europe and the US which have suggested that COVID-19 may be associated with MIS-C in children. [26][27][28] A separate cohort study found recently that 11% of children with COVID-19 admitted to hospitals in the UK developed MIS-C. 21 These findings are of special relevance given the severity of this condition. Overall, all outcomes were more frequent in children/adolescents with COVID-19 diagnosis than those with a diagnosis of seasonal influenza in 2017-2018, suggesting more by guest on May 30, 2021 www.aappublications.org/news Downloaded from severe disease prognosis in children with COVID-19 than influenza. Future research is needed to characterize and determine the long-term outcomes of children/adolescents affected with COVID-19.

Strengths and limitations
This study has some limitations. First, this study is descriptive in nature. The observed differences between groups should therefore not be interpreted as causal effects. Second, our results are based on secondary data from electronic records collected for administrative and clinical management purposes and re-used for research which may affect the completeness of data recorded (e.g. lack of information on degree of prematurity or mortality) and may have erroneous entries, leading to potential misclassification. Such incompleteness could be differential in some instances (e.g. hospital vs primary care settings) and risk information bias for the proposed comparisons. The under-reporting of symptoms observed in these data is a key finding of this study, and should be taken into consideration in previous and future similar reports from 'real-world' cohorts. This could be due to the high workload in healthcare systems caused by the pandemic, coding practices, or difficulty of ascertainment of symptoms among preverbal children. Another limitation of this study is the inability to differentiate between children/adolescents tested for SARS-CoV-2 due to the presentation of symptoms versus those tested as part of surveillance campaigns. Finally, the currently available data is restricted to the first six months of 2020 coinciding with the peak of the COVID-19 pandemic in the studied countries, and therefore, we were not able to evaluate the possible changes in treatment and prognosis over time. This study is unique as our approach to characterizing children with an international scope allows for a wide range of variation in healthcare systems and policies against the COVID-19 pandemic. This enables a more complete understanding of the implications of the pandemic for different countries and regions in scope of an international comparison. It also poses a layer of heterogeneity that needs to be considered in the interpretation of our findings, opening a window for new research questions that need to be addressed; particularly around the public health approach for controlling the pandemic spread and severity in children/adolescents and overall.
This study represents, to our knowledge, the largest cohort study on pediatric COVID-19 to date,     *Proportions presented among diagnosed or hospitalized patients by database (column percentage), please note that hospitalized children/adolescents could also be included in the diagnosed cohorts; -data not available or below the minimum cell count required (5 individuals