Risk factors for COVID-19 mortality among children and adolescents in Rio de Janeiro state, 2020-2023

Risk factors for COVID-19 mortality among children and adolescents in Rio de Janeiro state, 2020-2023 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk factors for COVID-19 mortality among children and adolescents in Rio de Janeiro state, 2020-2023 Lívia Esteves, Carlos Eduardo Raymundo, Roberto Andrade Medronho This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6207262/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Children and adolescents with COVID-19 typically present milder symptoms of the infection, with fatal outcomes being rare. This study aimed to analyze the main risk factors for mortality in this population group. Methods A cross-sectional study was performed to analyze reported COVID-19 cases among individuals under 18 years old in Rio de Janeiro state, Brazil, from March 2021 to September 2023. Pearson's chi-square test was used for categorical variables, and the Wilcoxon test for numerical variables. The significance level was set at 5%. Logistic regression analysis was performed to identify factors associated with COVID-19 mortality in individuals under 18. Results Infants under 1 year old had a higher mortality risk (OR = 4.70; 95% CI: 2.45–9.60) compared to adolescents aged 15–17 years. Non-white individuals had a lower mortality risk compared to white individuals (OR = 0.64; 95% CI: 0.41–0.99). The presence of fever (OR = 1.83; 95% CI: 1.17–2.89), dyspnea (OR = 11.83; 95% CI: 7.50-18.74), and oxygen saturation below 95% (OR = 11.97; 95% CI: 3.78–33.19) was associated with a higher mortality risk. Patients with heart disease (OR = 7.74; 95% CI: 3.89–14.58) and immunodeficiency/immunosuppression (OR = 17.16; 95% CI: 8.58–32.14) had a higher mortality risk. Infection during the predominance of variants B1_wild (OR = 3.44; CI 1.75–6.81), Gamma (OR = 3.93; CI 2.13–7.44), and Delta (OR = 2.27; CI 1.02–4.84) was associated with a higher mortality risk compared to the Omicron variant. Conclusions The main risk factors for death were fever, dyspnea, oxygen saturation below 95% on room air, age under one year, cardiac disease comorbidity, immunodeficiency, and infection during the predominance of B1_wild, Gamma, and Delta variants. Understanding the epidemiological profile and risk factors for mortality in this population is essential to inform effective prevention and control measures and guide optimal clinical management. COVID-19 children and adolescents risk factors mortality Figures Figure 1 Background COVID-19 is an infectious disease caused by the SARS-CoV-2 virus that primarily affects the respiratory system in adults and children. Clinical manifestations of infection in children and adolescents are typically milder than in adults, who tend to develop more severe cases and have higher mortality rates [ 1 – 6 ]. Our understanding of how SARS-CoV-2 affects children and adolescents has evolved significantly as the pandemic has progressed. In this group, infection manifests heterogeneously, ranging from asymptomatic or mild cases (common cold symptoms) to lower respiratory tract infections, gastrointestinal involvement, and a wide range of other manifestations. Severe cases in children can manifest as severe acute respiratory syndrome and pediatric multisystem inflammatory syndrome (PIMS) [ 7 ]. Global adult mortality rates increased sharply during the COVID-19 pandemic in 2020 and 2021, reversing declining trends pre-pandemic. Meanwhile, infant mortality rates decreased, albeit slower than in previous years [ 8 ]. In Brazil, data from the Mortality Information System (Sistema de Informação sobre Mortalidade - SIM), from 2020 to 2021, analyzed by Fiocruz's Child Health Observatory revealed that COVID-19 caused the death of two children under 5 years daily, with the highest mortality rates concentrated among children aged 29 days to 1 year [ 9 ]. According to Kitano et al. [ 10 ], Brazil has the highest number of pediatric COVID-19 deaths (under 19 years) worldwide among 138 countries. According to Sousa et al. [ 11 ], Rio de Janeiro ranked 19th among Brazilian states for mortality rates in individuals under 20 years of age and second within the Southeast region. A U-shaped severity curve has been demonstrated in children diagnosed with COVID-19, with infants under 1 year of age and adolescents aged 10–14 years at higher risk of developing severe COVID-19 [ 7 ]. According to Oliveira et al. [ 12 ], COVID-19 mortality risk factors in Brazil included age (under 2 years and 12–19 years), Indigenous ethnicity, residence in the North and Northeast regions, and one or more comorbidities. In Brazil, a country with vast territory and significant socioeconomic diversity, the relationship between COVID-19 mortality and sociodemographic variables is evident, as demonstrated by Sousa et al. [ 11 ]. In this study, living in the Northern region (comprising the North and Northeast macroregions) triples the risk of COVID-19 mortality among individuals under 20 years of age compared to the Southern region (comprising the South, Southeast, and Central-West macroregions). Compared to White individuals, Brown, East-Asian, and Indigenous populations had a significantly higher mortality risk. Sousa et al. [ 11 ] assessed the relationship between non-communicable diseases and COVID-19 mortality risk in individuals under 20 years of age in Brazil. The mortality rate among those with chronic non-communicable diseases was 15.8%, compared to 5.6% in healthy children and adolescents. Except for asthma, all comorbidities increased mortality rates, particularly kidney disease (29.2%) and cardiovascular disease (26.3%). In record time in the history of medicine, the first COVID-19 vaccine doses began to be administered worldwide in December 2020. Initially, only individuals aged 18 and older received the doses, followed by the inclusion of pediatric age groups, with approval in Brazil for children 6 months and older. In Brazil, COVID-19 vaccination was made available to adolescents aged 12 and older starting in June 2021. In Rio de Janeiro state, vaccination coverage rates were as follows: 0.96% for the third dose in children aged 6 months to 2 years; 0.11% for the third dose in children aged 3–4 years; 49.50% for the second dose in children aged 5–11 years; and 80.10% for the second dose in adolescents aged 12–17 years [ 13 ]. According to the 2022 demographic census, Rio de Janeiro is Brazil's third most populous state, with its capital being the country's second-largest city. Despite its relatively small territorial area, the state has a high population density of 366.97 inhabitants/km². Although it represents the country's second-largest economy, significant income disparities exist between the state's capital city, suburban areas, and rural regions. The study period (2020–2023) encompassed the pre-vaccination phase and the predominance of all SARS-CoV-2 variants that circulated in the state (Alpha, Zeta, Gamma, Delta, and Omicron), enabling assessment of the disease's impact on this population. All COVID-19 cases and deaths were identified through the state of Rio de Janeiro's existing notification systems for cases, severe cases, and deaths. Most available studies have determined in-hospital case fatality rates, making it difficult to assess the true impact of COVID-19 in the community. Rio de Janeiro state represents an urbanized region in a developing country characterized by social inequality. This study analyzed risk factors for COVID-19 mortality among children and adolescents in Rio de Janeiro from 2020 to 2023. Methods The study aimed to characterize the epidemiological profile of the disease in children and adolescents under 18 years in Rio de Janeiro state from January 2020 to September 2023 and to identify risk factors for mortality in this age group, determining case fatality and mortality rates. A cross-sectional study was conducted to assess the association between individual predictors (age, sex, race/skin color), clinical variables (signs, symptoms, and comorbidities), and epidemiological factors (metropolitan region of residence, notification year, season, and dominant COVID-19 variant) with mortality among confirmed COVID-19 cases. COVID-19 cases in Brazil are mandatorily reported through two national notification systems: e-SUS Notifica (Ministry of Health Notification System) and SIVEP-Gripe (Influenza Epidemiological Surveillance Information System). e-SUS Notify is a nationwide system for recording suspected and confirmed cases of COVID-19 and influenza-like illness, implemented during the pandemic to serve both public and private healthcare facilities (primary care units, medical offices, clinics, healthcare centers, and emergency units). SIVEP-Gripe records all patients admitted to public or private hospitals with influenza-like illness, dyspnea/respiratory distress, persistent chest pressure, oxygen saturation below 95% on room air, or cyanosis. All patients included in this system have documented demographic data, clinical characteristics, and place of residence. This study included patients under 18 years with confirmed COVID-19 diagnosis who were reported in both e-SUS NOTIFICA and SIVEP-Gripe databases. Confirmed cases of COVID-19 influenza-like illness were obtained from the Brazilian Ministry of Health's e-SUS Notify system. Confirmed cases of severe acute respiratory syndrome (SARS) due to COVID-19 were obtained from the Ministry of Health's SIVEP-Gripe database. These two databases were linked using probabilistic record linkage. A consistency analysis was performed to remove duplicate entries from the resulting database. Within six months, duplicate records were defined as multiple notifications for the same case in the database. The National Mortality Information System (Sistema de Informações sobre Mortalidade - SIM) is a nationwide epidemiological surveillance system that regularly collects mortality data. The Death Certificate (DC) is Brazil's fundamental and essential document for mortality data collection. It is also Brazil's death assessment reference system. Subsequently, the database resulting from linking e-SUS NOTIFICA with SIVEP-Gripe was again linked through probabilistic record linkage to the Ministry of Health's SIM to identify COVID-19 deaths not recorded in either SIVEP-Gripe or e-SUS NOTIFICA. After this final linkage, 511 all-cause deaths were identified in the SIM between January 1, 2020, and September 6, 2023, among individuals under 18 years of age in Rio de Janeiro State who had been reported as COVID-19 cases in SIVEP-Gripe and e-SUS NOTIFICA surveillance systems. An individual analysis of these deaths was then conducted by examining the underlying cause, antecedent causes, and contributing causes documented in the Death Certificates. Deaths were classified as follows: a) COVID-19 deaths were those with ICD-10 codes B34.2 ("Coronavirus infection of the unspecified site") + U07.1 ("COVID-19, virus identified through laboratory testing") or B34.2 + U07.2 ("COVID-19, virus not identified, clinically-epidemiologically diagnosed, listed as the underlying cause of death. It is attributed to a clinical or epidemiological diagnosis of COVID-19 where laboratory confirmation is inconclusive or unavailable"); M303 ("mucocutaneous lymph node syndrome - Kawasaki") + U10.9 ("COVID-19-associated multisystem inflammatory syndrome, unspecified"); B34.2 + U92.1 ("confirmed COVID-19 reinfection") and B94.8 ("sequelae of other specified infectious and parasitic diseases") + U09.9 ("post-COVID-19 condition, unspecified"), according to the Ministry of Health [14]. The World Health Organization (WHO) codes U07.1 and U07.2 serve as pandemic markers in Brazil and must always follow code B34.2 on the same line. On the Death Certificate, when a sequence of events mentions Multisystem Inflammatory Syndrome (MIS-C), codes M30.3 + marker U10.9 must be entered on the same line. When COVID-19 reinfection is mentioned in the death certificate, codes B34.2 and marker U92.1 must be listed on the same line. Codes B94.8 and marker U09.9 must be listed on the same line of the medical certificate when documenting post-COVID-19 sequelae events. b) A suspected COVID-19 death was one where COVID-19-related codes were recorded in Part II of the Death Certificate as a significant contributing factor. In contrast, the underlying cause and antecedents were coded as unspecified respiratory or infectious diseases. c) A COVID-19-related death was one where the disease codes were recorded in Part II of the Death Certificate. However, a different underlying cause of death was specified, excluding unspecified respiratory or infectious diseases. d) COVID-19 was ruled out as the cause of death when COVID-19 codes were not recorded on the death certificate as the underlying cause, its antecedents (Part I), or as a significant contributing factor (Part II). Of the 511 deaths identified through linkage, 282 were excluded due to other causes; COVID-19 caused 213; COVID-19 likely caused six deaths; and 10 deaths occurred during active COVID-19 infection. This study considered COVID-19-confirmed deaths (n=213) as the outcome. Age was stratified into the following groups: under 1 year, 1-4 years, 5-9 years, 10-14 years, and 15-17 years. Sex was classified as female, male, or not reported. Race/ethnicity was categorized as White, Black, Brown, Asian, Indigenous, or not reported. The race/skin color variable was also dichotomized into white and non-white. Clinical variables were categorized as present, absent, or unreported, including fever, cough, sore throat, dyspnea, oxygen saturation below 95%, ageusia, anosmia, and diarrhea. The presence of comorbidity variable, which included respiratory disease, kidney disease, heart disease, diabetes mellitus, and immunodeficiency/immunosuppression, was classified as yes, no, or not reported. Comorbidity was analyzed as a dichotomous variable (present/absent) and a three-level categorical variable (none, one, or two or more pre-existing medical conditions). The region of residence was categorized into Rio de Janeiro municipality, Ilha Grande Bay, Coastal Lowlands, South-Central, Middle Paraíba Valley, Metropolitan I (excluding Rio de Janeiro municipality), Metropolitan II, Northwest, North, and Mountain regions. Rio de Janeiro municipality was separated from Metropolitan Region I due to being the most populous municipality in the area. The case notification year variable was categorized as 2020, 2021, 2022, or 2023. The season variable was categorized as summer, fall, winter, or spring. The predominant SARS-CoV-2 variant during the study period was classified as B.1 (wild type), Zeta, Gamma, Delta, and Omicron. Each dominant variant's start and end dates were determined according to the Rio de Janeiro State Health Department bulletin by state region, thus assuming that all cases occurring within each dominant variant's period were attributed to that variant [15]. Statistical analyses and database linkage were performed using R x64 4.0.0 through RStudio Desktop. Bivariate descriptive analysis was performed using bar charts, pie charts, and boxplots for the numerical predictor variable (age) and contingency tables for categorical predictor variables. Pearson's chi-square test was used for categorical predictor variables, while the Wilcoxon test was used for the numerical predictor variable. The significance level was set at 5%. Logistic regression analysis was performed to identify factors associated with COVID-19 mortality in individuals under 18 years. Furthermore, model goodness-of-fit was assessed using sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), Youden's index, Receiver Operating Characteristic (ROC) curve, and Matthews correlation coefficient (MCC). The mortality rate was calculated using population data by age group from the 2022 Brazilian Institute of Geography and Statistics (IBGE) demographic census. Results From January 2020 to September 2023, a total of 241,533 COVID-19 cases and 213 deaths were reported among children and adolescents under 18 years of age in Rio de Janeiro state. The case fatality rate was 0.09%, and the mortality rate was 5.81 per 100,000 children and adolescents under 18 years of age. The distribution of cases over the years showed that 29,380 (12.2%) cases were registered in 2020, 75,187 (31.1%) in 2021, 128,025 (53%) in 2022, and 8,941 (3.7%) cases through September 2023. The age distribution revealed COVID-19 cases as follows: 21,738 (9.0%) in infants under 1 year; 37,352 (15.5%) in children aged 1-4 years; 55,989 (23.2%) in those aged 5-9 years; 69,356 (28.7%) in those aged 10-14 years; and 57,098 (23.6%) in adolescents aged 15-18 years. The sex distribution revealed that 114,810 (47.5%) cases occurred in males and 126,722 (52.5%) in females. Regarding race/skin color, 66,532 (40.3%) cases occurred in White individuals, 11,143 (6.8%) in Black individuals, 2,967 (1.8%) in Asian individuals, 84,013 (51.0%) in Brown individuals, and 238 (0.1%) in Indigenous individuals, with 76,640 cases missing this information. The distribution by skin color showed that 66,532 (40.3%) of cases occurred among white children and adolescents, while 98,361 (59.7%) occurred among non-white individuals. Table 1 shows the distribution of cases according to clinical, epidemiological, and demographic variables. Cough was reported in 114.723 (47.6%) cases, followed by cough in104,294 (43.3%), sore throat in 61,555 (25.6%), dyspnea in 15,317 (6.4%), diarrhea in 6,598 (2.7%), anosmia in 790 (0.3%), ageusia in 288 (0.1%), and oxygen saturation below 95% in 104 (0.04%) cases. Regarding comorbidities, the respiratory disease was present in 5,094 (2.1%) cases, kidney disease in 117 (0.05%), heart disease in 1,112 (0.5%), diabetes mellitus in 627 (0.3%), and immunodeficiency/immunosuppression in 753 (0.3%) cases. A total of 234,182 (97.0%) children and adolescents had no comorbidities, while 7,017 (2.9%) had one comorbidity, and 334 (0.14%) had two or more comorbidities. The distribution by metropolitan region showed that 117,270 (48.6%) cases lived in Rio de Janeiro municipality, 3,595 (1.5%) in Ilha Grande Bay, 9,734 (4.0%) in the Coastal Lowlands, 7,794 (3.2%) in Center-South, 19,308 (8.0%) in Médio Paraíba, 20,805 (8.6%) in Metropolitan Region I (excluding Rio de Janeiro municipality), 21,096 (8.7%) in Metropolitan Region II, 9,369 (3.9%) in the Northwest region, 11,762 (4.9%) in the North region, and 20,800 (8.6%) in the Mountain region. The number of reported cases per year showed that 29,380 (12.2%) occurred in 2020, 75,187 (31.1%) in 2021, 128,025 (53%) in 2022, and 8,941 (3.7%) in 2023 (through September). The seasonal distribution of cases revealed that 101,217 (41.9%) occurred in summer, 50,679 (21.0%) in autumn, 54,751 (22.7%) in winter, and 34,866 (14.4%) in spring. The distribution of cases according to the predominant COVID-19 variant showed that 137,342 (56.9%) cases occurred during Omicron's predominance, 21,298 (8.8%) during B1_wild's predominance, 18,459 (7.6%) during Zeta's predominance, 33,694 (14.0%) during Gamma's predominance, and 30,740 (12.7%) during Delta's predominance. The annual distribution of COVID-19 deaths was 85 (40.0%) in 2020, 108 (50.7%) in 2021, 19 (8.9%) in 2022, and 1 (0.5%) in 2023 (January to September). Figure 1 shows the case fatality rate distribution by age group. The case fatality rate was 0.5% in infants under 1 year of age, 0.05% in children aged 1-4 years, 0.03% in those aged 5-9 years, 0.05% in those aged 10-14 years, and 0.06% in adolescents aged 15-17 years. Age-specific mortality rates were 69.89 per 100,000 infants under 1 year; 2.63 per 100,000 children aged 1-4 years; 1.87 per 100,000 children aged 5-9 years; 3.52 per 100,000 children and adolescents aged 10-14 years; and 4.07 per 100,000 adolescents aged 15-17 years. Table 2 shows the association between independent variables and death from COVID-19. Children under 1 year of age had a higher mortality risk compared to adolescents aged 15-17 years (OR = 8.63; 95% CI: 5.92-12.9). Black children and adolescents with COVID-19 had a higher mortality risk compared to White individuals (OR 1.68; 95% CI 1.08-2.54), while Brown individuals had a lower mortality risk compared to White individuals (OR 0.59; 95% CI 0.43-0.79). Oxygen saturation below 95% (OR=84.5; CI 35.2-171), dyspnea (OR=25.8; CI 18.7-35.8), and fever (OR=2.56; CI 1.87-3.53) was associated with higher mortality risk, while sore throat (OR=0.16; CI 0.07-0.32) and diarrhea (OR=0.17; CI 0.01-0.74) were associated with a lower mortality risk. Regarding comorbidities, kidney disease (OR=117; CI 40.7-266), immunodeficiency/immunosuppression (OR=82.3; CI 48.8-132), heart disease (OR=73.9; CI 46.4-114), diabetes mellitus (OR=47.3; CI 23.8-85.0), and respiratory disease (OR=3.86; CI 2.22-6.22) were associated with higher COVID-19 mortality. Having one comorbidity increases the mortality risk (OR=8.22; 95% CI: 5.68-11.6) while having two or more comorbidities substantially increases the mortality risk (OR=96.2; 95% CI: 57.9-152). The mortality risk was higher among children and adolescents living in the Northwest metropolitan region (OR=4.41; 95% CI 1.18-28.5) and metropolitan region I (excluding Rio de Janeiro municipality) (OR=7.69; 95% CI 2.37-47.2) compared to those living in the Center-South region. Having contracted COVID-19 in 2021 (OR=12.9; CI 2.88-226) and 2022 (OR=25.9; CI 5.78-457), compared to 2023 (through September), was associated with a higher mortality risk, as did infection during autumn (OR=4.97; CI 3.43-7.37), winter (OR=2.70; CI 1.78-4.13), and spring (OR=2.35; CI 1.44-3.80), compared to summer. Infection during the predominance of variants B1_wild (OR=23.6; CI 14.7-39.8), Zeta (OR=10.1; CI 5.66-18.2), Gamma (OR=11.6; CI 7.12-19.8), and Delta (OR=8.05; CI 4.71-14.2) was associated with a higher mortality risk compared to cases during Omicron predominance. Table 3 shows the logistic regression results for the association between independent variables and death from COVID-19. Children under 1 year of age had a higher mortality risk (OR=4.70; 95% CI: 2.45-9.60) compared to those aged 15-17 years. Non-white children and adolescents had a lower mortality risk compared to white children (OR=0.64; 95% CI: 0.41-0.99). Regarding symptoms, fever (OR=1.83; 95% CI: 1.17-2.89), dyspnea (OR=11.83; 95% CI: 7.50-18.74), and oxygen saturation below 95% (OR=11.97; 95% CI: 3.78-33.19) were associated with a higher mortality risk. Children and adolescents presenting with sore throat had a lower mortality risk (OR=0.06; 95% CI: 0.01-0.19). Children and adolescents with heart disease (OR=7.74; 95% CI: 3.89-14.58) and immunodeficiency/immunosuppression (OR=17.16; 95% CI: 8.58-32.14) had a higher mortality risk. Infection during the predominance of B1_wild (OR=3.44; CI 1.75-6.81), Gamma (OR=3.93; CI 2.13-7.44), and Delta (OR=2.27; CI 1.02-4.84) variants was associated with a higher mortality risk compared to the Omicron variant. Discussion COVID-19 case fatality rates among individuals under 18 years of age remain relatively low compared to adults, regardless of the predominant variant. Current evidence suggests that pediatric populations show lower infection rates and milder disease severity, accounting for approximately 5% of cases with an extremely low case fatality rate (0-0.69%) [ 16 ]. In the meta-analysis by Wang et al. [ 17 ] covering January to October 2020, a case fatality rate of 0.28% was found among children and adolescents. A study conducted in Brazil [ 18 ] found an in-hospital case fatality rate of 8.2% in 2020 and 6.9% in 2021 among patients under 19 years of age. Hillesheim et al. [ 19 ] found a 9.5% in-hospital case fatality rate among Brazilian children and adolescents through September 2020. A multicenter study conducted in April 2020 involving 82 healthcare institutions across 25 European countries reported a 0.69% case fatality rate among individuals under 18 years of age [ 6 ]. According to Bertran et al. [ 20 ], in England, the infection case fatality rate among children and adolescents under 20 years of age was 0.70 per 100,000 estimated SARS-CoV-2 infections between March 2020 and December 2021. According to UNICEF [ 21 ], of the 4.4 million COVID-19 deaths recorded worldwide through December 2023, only 0.4% occurred in children and adolescents under 20 years of age. According to Smith et al. [ 22 ], between March 2020 and February 2021, the COVID-19 mortality rate among individuals under 18 years of age in England was approximately two deaths per million inhabitants (mortality rate of 0.2 per 100,000 for COVID-19, compared to 25.5 per 100,000 for all other causes of death), demonstrating extremely low COVID-19 mortality among children and adolescents in the country. A cohort study conducted in Mexico from 2020 to 2022 by Solórzano-Santos et al. [ 23 ] in individuals under 18 years of age found a case fatality rate of 0.39%. This country remained among the ten countries worldwide with the highest adult case fatality rate. In Ecuador, a study conducted by Ortiz-Prado et al. [ 24 ] from 2020 to 2021 in individuals under 18 years of age revealed an overall incidence rate of 612 cases per 100,000 children and adolescents, a mortality rate of 3 per 100,000 inhabitants under 18 years, and a case fatality rate of 0.76% during the first 16 months of the pandemic. In Portugal, from 2020 to 2021, according to Elias et al. [ 25 ], case fatality and mortality rates were low, at 1.8 per 100,000 cases and 1.2 per 1,000,000 inhabitants under 18 years of age, respectively. A study conducted in Germany between 2020 and 2021 by Sorg et al. [ 26 ] reported a case fatality rate of 0.09 per 10,000 individuals under 18 years of age. A study by Evans-Gilbert et al. [ 27 ] across 15 Caribbean countries from 2020 to 2021 in individuals under 19 years revealed case fatality rates for ages 0–9 and 10–19 years were 2.80% and 0.70% in Haiti, 0.10% and 0.20% in Jamaica, and 0.00% and 0.14% in Trinidad, compared to global rates of 0.17% and 0.1%, respectively. A meta-analysis including 16,027 articles and 225 national reports from 216 countries conducted by Kitano et al. [ 10 ] revealed a significantly higher case fatality rate in low- and middle-income countries than in high-income countries (0.24% and 0.013%, respectively). In Rio de Janeiro state, we found a case fatality rate of 0.09% between January 2020 and September 2023. While most studies above report in-hospital case fatality rates, this study analyzed community case fatality rates. The case fatality rate in this study is considerably higher than those reported in Portuguese and German studies but comparable to rates observed in low- and middle-income countries. The COVID-19 mortality rate among children and adolescents under 19 years of age in the United States from August 2021 to July 2022 was 1.0 per 100,000 children and adolescents. By age group, mortality rates were 4.3 deaths per 100,000 children under 1 year of age, 0.6 per 100,000 children aged 1–4 years, 0.4 per 100,000 children aged 5–9 years; 0.5 per 100,000 children aged 10–14 years; and 1.8 per 100,000 adolescents aged 15–19 years. Deaths in individuals under 19 years of age accounted for 2% of all-cause mortality in this age group, ranking as the eighth leading cause of death overall, the fifth among disease-related deaths (excluding unintentional injuries, assault, and suicide), and the first among deaths caused by infectious or respiratory diseases compared to 2019 [ 28 ]. In Brazil, Szwarcwald et al. [ 29 ] reported mortality rates per age group: 0.3 per 10,000 children aged 0–9 years, 0.2 per 10,000 children and adolescents aged 10–19 years, and 10.0 per 10,000 adults aged 40–49 years. The mortality rate found in Rio de Janeiro state was 5.81 per 100,000 children and adolescents under 18 years of age, higher than the rates reported in the studies above. COVID-19 case fatality rate in infants under one year of age exceeds that of other pediatric age groups, as demonstrated by previous studies [ 1 , 19 , 23 , 24 , 28 , 30 , 31 ]. According to Kitano et al.'s meta-analysis [ 10 ], the highest mortality rates per million children and case fatality rates were observed in infants under one year of age: 10.03 and 0.58% globally; 5.39 and 0.07% in high-income countries and 10.98 and 1.30% in low- and middle-income countries. In Rio de Janeiro state, from 2020 to 2021, case fatality rates were the highest among infants under one year of age (0.5%) compared to other age groups. The U-shaped case fatality rate curve, with higher rates among infants under 1 year and individuals over 15 years of age, has been demonstrated in studies by Oliveira et al. [ 12 ], Mccormick et al. [ 32 ], Flaxman et al. [ 28 ], and Harwood et al. [ 31 ], was not observed in deaths among children and adolescents in Rio de Janeiro state. This study followed a J-shaped case fatality curve, with the highest peak among infants under one year of age, consistent with mortality patterns reported in the literature. The higher mortality risk among Black and Indigenous children and adolescents reported by Mccormick et al. [ 32 ] and Oliveira et al. [ 12 ] was identified in the univariate analysis of deaths in Rio de Janeiro state. However, multivariate analysis showed no statistical significance. Data from Kim et al. [ 33 ] demonstrate that across 14 U.S. states from March to August 2020, the cumulative COVID-19-associated hospitalization rate among children (8.0 per 100,000 population) remained low compared to adults (164.5 per 100,000 population), one in three hospitalized children required intensive care unit admission. There were racial and ethnic disparities in hospitalizations: Black and Hispanic children and adolescents experiencing higher hospitalization rates than non-Hispanic White children. The annual distribution of deaths in Rio de Janeiro state from 2020 to 2023 revealed that 90.6% occurred during the first two years of the pandemic, with a marked reduction in subsequent years. During 2020 and 2021, the B1_wild, Gamma, and Delta variants predominated, leading to higher mortality rates. According to Wiedenmann et al.'s systematic review [ 34 ], although most COVID-19 infections resulted in mild illness among individuals under 18 years of age, more severe cases were reported in association with Delta and Gamma variants, while Omicron infections proved less severe than Delta infections. According to Marks et al. [ 35 ], concurrent with increased Omicron variant circulation, COVID-19-associated hospitalization rates among children and adolescents aged 0–17 years rose sharply in late December 2021 in the United States, particularly among children aged 0–4 years who were not yet eligible for vaccination. During Delta and Omicron predominance periods, hospitalization rates remained lower among fully vaccinated adolescents aged 12–17 years than their unvaccinated peers. According to a U.S. study on COVID-19 severity in individuals under 18 years from 2020 to December 2021, while 1 in 16 children infected with SARS-CoV-2 experienced moderate or severe illness, the risk of severe disease remained unchanged with the emergence of the Delta variant, despite its high transmissibility. A transient increase in severity was observed during the Alpha variant phase (March-June 2021), followed by declines during the Delta variant phase (July-December 2021) [ 36 ]. The Martin et al. [ 37 ] cohort study in the United States showed that hospitalization rates remained stable when comparing children during the Delta and pre-Delta eras with a lower risk of severe illness. A study by Zhu et al. [ 38 ] conducted across nine countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, the United Kingdom, and the United States) over three distinct periods demonstrated a consistent decline in ICU admissions across all age groups over the SARS-CoV-2 waves among individuals under 18 years of age. The results were consistent when the data was restricted to unvaccinated children. A study by Hani et al. [ 39 ] in England demonstrated that the infection case fatality rate following Omicron was 2 per million infections, representing a sevenfold reduction compared to the initial pandemic wave. In Rio de Janeiro state, the highest number of cases was recorded in 2022 (53%) during the Omicron predominance, with a reduction in mortality rates. Although children and adolescents are less susceptible to COVID-19, pre-existing comorbidities may predispose them to severe illness. The presence of immunodeficiency/immunosuppression and cardiac disease comorbidities was strongly associated with the mortality risk (OR 21.8 and 4.73, respectively) among children and adolescents in Rio de Janeiro state. A meta-analysis by Tsankov et al. [ 40 ] summarized the relationship between COVID-19 infection and pediatric comorbidities across 42 studies encompassing 275,661 children. The results showed that children with comorbidities had a hazard ratio of 1.79 for severe COVID-19 infection and 2.81 for COVID-19 mortality rate. A UK cohort study of 26,322 patients under 18 years of age with COVID-19 found that comorbidities associated with hospital admission included diabetes mellitus, congenital heart disease, cerebral palsy, epilepsy, and sickle cell disease [ 41 ]. As an increasingly prevalent condition among children, obesity has been identified as one of the most significant risk factors for mechanical ventilation in children aged 2 years and older with COVID-19 [ 42 ]. Results from other studies also support the notion that obesity and type 2 diabetes are risk factors for severe pediatric COVID-19 [ 41 , 43 ]. Furthermore, other specific comorbidities, such as cardiovascular diseases, neoplasms, and immunosuppression, have been associated with COVID-19 severity [ 43 – 45 ]. According to Flores-Cisneros et al. [ 46 ], comorbidities such as kidney disease or immunosuppression increased the mortality risk across all age groups. Harwood et al. [ 31 ] identified that among hospitalized patients with SARS-CoV-2 infection, those under 1 year of age, over 10 years old, and individuals with cardiac conditions, neurological disorders, obesity, or two or more comorbidities had the highest mortality risk. However, odds ratios were high, and the absolute risk increase for most comorbidities was slight compared to children without underlying conditions. Data from a European study showed that the most common comorbidities associated with ICU admission were chronic lung disease, congenital heart disease, neurological disorders, and malignancies [ 6 ]. A study by Woodruff et al. [ 47 ], analyzing 3,106 hospitalized children with confirmed COVID-19 infection across 14 U.S. states, demonstrated an increased risk of severe disease among hospitalized children under 2 years of age with chronic lung disease, neurological disorders, cardiovascular disease, prematurity, and airway anomalies. Among hospitalized children aged 2–17 years, risk factors included feeding tube dependency, diabetes mellitus, and obesity. Severe COVID-19 occurred at a rate of 12.0 per 100,000 children overall and was highest among infants, Hispanic children, and non-Hispanic Black children. According to Souza et al. [ 11 ], having two or more comorbidities (excluding asthma) increased the risk of COVID-19 mortality nearly tenfold among individuals under 19 years of age in Brazil. According to Aparício et al.'s meta-analysis [ 48 ], although the absolute risk of severe COVID-19 in children and adolescents without comorbidities is relatively low, one or more underlying conditions were associated with a markedly increased risk. Clinical signs and symptoms of oxygen saturation below 95% and dyspnea were strongly associated with the mortality risk (OR 4.20 and 3.55, respectively). At the same time, fever was also associated with a higher mortality risk (OR 1.96) among children and adolescents in Rio de Janeiro state. Shi et al. [ 49 ] showed that dyspnea was associated with poor prognosis in children and adolescents with COVID-19. The presence of lower respiratory tract infection signs or symptoms (dyspnea and/or decreased oxygen saturation) at COVID-19 presentation was associated with ICU admission according to Götzinger et al.'s multicenter study [ 6 ]; in this study, fever was the most common presenting sign, observed in 65% of individuals. A study conducted by Ng et al. [ 50 ] found that a history of fever, fever upon admission, and dyspnea were predictors of moderate and severe disease among children hospitalized with COVID-19. The sore throat was identified as a protective factor against COVID-19 mortality in children and adolescents (OR 0.06) in Rio de Janeiro state. This finding has not been previously reported. A sore throat is a prevalent symptom in upper respiratory viral infections, which relies on the patient's subjective report. Only those capable of verbal expression can reliably report this symptom among children and adolescents. Furthermore, since it is a common symptom in various viral infections, this finding may be due to misclassification of viral etiology, as confirmatory tests for SARS-CoV-2 infection were not performed in most cases. For mortality analysis in this study, we included only deaths directly attributable to COVID-19, excluding cases where COVID-19 was either a probable cause or was present but not the primary cause of death. Due to the small fatalities among probable cases and COVID-19 deaths, no significant differences were observed in the modeling tests performed. Therefore, the results of this study are strengthened by their high specificity. The temporal aspect was not a limitation in this study, given that SARS-CoV-2 infection manifests as an acute disease, and its potential outcome (death) occurs shortly after disease onset. Although this was a cross-sectional study, data on symptom onset and death dates were available, albeit collected at a single time point. Selection bias is a potential study limitation, as sample representativeness may have been compromised by not including all COVID-19 cases among individuals under 18 years in Rio de Janeiro state. The underreporting of cases in children and adolescents was due to the asymptomatic or oligosymptomatic nature of the disease, as well as limited testing availability, particularly in the early stages of the pandemic. Testing requires nasal or nasopharyngeal swab insertion, which leads to many families refusing to authorize the examination in children. Furthermore, in the beginning, people were advised to stay home and only seek medical care if severe symptoms developed. Additionally, hospitalized patients may have died without being tested and, consequently, without a COVID-19 diagnosis. COVID-19 cases may have been misdiagnosed as other diseases, and correctly diagnosed cases may have gone unreported to health surveillance services. PIMS was a novel condition discovered during the pandemic that was difficult to diagnose clinically. Information bias was a limitation due to potential errors in data collection or completion of notification forms. Data collection regarding children and adolescents typically relies on information a responsible caregiver provides. Race/skin color data were self-reported, possibly introducing bias into the study results. Information on symptoms and comorbidities (risk factors included in SIVEP-GRIPE) was self-reported (provided by patients or their family members). Therefore, patient awareness of their clinical condition may have influenced the analysis. Additionally, some variables may be incorrectly coded in electronic records due to data entry errors. Missing or incorrect data in the database may have distorted the results. The entry in the "case progression" field may have introduced information bias, given that 46 cases recorded as deaths in SIVEP-Gripe were not found in the SIM, even after exhaustive searching. The quality of records, accuracy of information, and data consistency may vary, potentially affecting the results' reliability. The clinical symptom of sore throat may have conferred protection against COVID-19 mortality since it relies on the patient's subjective report, which occurs only when speech capability is present. Since the case fatality rate was higher among children under 1 year of age, older children and adolescents who survived were more likely to report this symptom. Furthermore, since not all reported cases were tested, the sore throat symptoms may have been misclassified as COVID-19 when other, less lethal infections caused them. Since this study relies on secondary databases not initially designed for research purposes, potential confounding factors such as income and education levels were unavailable in the datasets. Known confounding factors were controlled for using logistic regression. Although cross-sectional studies based on databases may have limited generalizability, this study covered the entire state of Rio de Janeiro, providing robust representation for the Southeast region and potentially for Brazil. Although the cross-sectional design cannot detect temporal changes, this limitation was minimized by capturing data according to notification year, death year, and dominant variant. In this study, we did not control for pandemic mitigation policies such as lockdown and vaccination. Secondary databases lack detailed information regarding exposure intensity, duration, and context, such as contact time, number of household contacts, viral load through RT-PCR, and comorbidity severity. Cases that began during the study period may have resulted in deaths after the study endpoint and could not be included in this analysis; however, the dominant Omicron variant has a low mortality rate, and consequently, the likelihood of death was low for this variant. Conclusions COVID-19 in children and adolescents in Rio de Janeiro state from 2020 to September 2023 emerged as a significant infection in this population group. Although mortality rates were low, they were more substantial among children under one year of age and higher than in other countries or regions. The main risk factors for death were fever, dyspnea, oxygen saturation below 95% on room air, age under one year, cardiac disease as a comorbidity, immunodeficiency, and infection during the predominance of B1_wild, Gamma, and Delta variants. Understanding the epidemiological profile and risk factors for mortality in this population is essential to inform effective prevention and control measures and guide optimal clinical management. The impact of COVID-19 on child and adolescent mortality was most significant during the pandemic's first two years, and continued assessment of the disease's impact is necessary, particularly regarding immunization effects and specific characteristics of future variants. Declarations Ethics approval and consent to participate This study complies with Resolution 466/2012, the Declaration of Helsinki and all its amendments, and Good Clinical Practice (Document of the Americas). The study was submitted to the Research Ethics Committee (Comitê de Ética e Pesquisa - CEP) of the Institute of Collective Health Studies at the Federal University of Rio de Janeiro (Certificate of Submission for Ethical Evaluation (Certificado de Apresentação de Apreciação Ética - CAAE: 66422623.5.0000.5286). The study was approved by the CEP (approval number 5,883,512). Clinical Trial Number: Not Applicable Availability of data and materials All data analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author. Competing interests The authors declare no competing interests. Funding This work was supported by FAPERJ (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro) Authors' contributions Esteves, L. designed the study. Esteves, L. Raymundo, CE. Medronho, RA. collected and analyzed the data. Esteves, L. Raymundo, CE. Medronho, RA. interpreted the results. Esteves, L. wrote the manuscript. Medronho RA. contributed to the refinement of the manuscript. The final manuscript has been read and approved by the authors. References Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020;145(6):e20200702. Ludvigsson JF. 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Ng DC, Liew CH, Tan KK, Chin L, Ting GS, Fadzilah NF, et al. Risk factors for disease severity among children with Covid-19: a clinical prediction model. BMC Infect Dis. 2023;23(1):398. Tables Tables 1 to 3 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 18 Mar, 2025 Editor assigned by journal 16 Mar, 2025 Submission checks completed at journal 16 Mar, 2025 First submitted to journal 11 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6207262","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":429580471,"identity":"f6d6106a-627f-44cb-8990-db35b2373a7e","order_by":0,"name":"Lívia Esteves","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYBACPmYGhgNw3gcgZmMnoIUNqkUCxGGcARXBrwVKg7Uw84BJQlrYeQwP/Kioq+OXSD782ebXNnmgUxk/fMzB5zAeg4M9Zw5LSM5IS5PO7btt2MbMwCw5cxs+LWwJB3jbDkgYnDljxpzbc5sRqIWNmZeAloN//9VJ2J85//mzZc9teyK0MB84zNvALGHA3sMgzfDjdiJxWmSOHZaccbzNTLK34XZyGzNjM16/8PMfbP74pqaOn7+Z+fGHH39u285vbz744SMeLaiAsQ1MNhCrHgT+kKJ4FIyCUTAKRgoAABypSohuQvt0AAAAAElFTkSuQmCC","orcid":"","institution":"Federal University of Rio de Janeiro","correspondingAuthor":true,"prefix":"","firstName":"Lívia","middleName":"","lastName":"Esteves","suffix":""},{"id":429580472,"identity":"ce16a033-a157-423d-8234-b6f90f6e38a8","order_by":1,"name":"Carlos Eduardo Raymundo","email":"","orcid":"","institution":"Rio de Janeiro State University","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"Eduardo","lastName":"Raymundo","suffix":""},{"id":429580473,"identity":"97f4610b-de96-49a7-84aa-026b1696e09a","order_by":2,"name":"Roberto Andrade Medronho","email":"","orcid":"","institution":"Federal University of Rio de Janeiro","correspondingAuthor":false,"prefix":"","firstName":"Roberto","middleName":"Andrade","lastName":"Medronho","suffix":""}],"badges":[],"createdAt":"2025-03-11 23:38:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6207262/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6207262/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78736473,"identity":"04e3141e-a41c-471c-b662-c22defd2f3b7","added_by":"auto","created_at":"2025-03-18 08:23:15","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":106444,"visible":true,"origin":"","legend":"\u003cp\u003eshows the case fatality rate distribution by age group.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6207262/v1/2678549772f8339af4c4e088.jpg"},{"id":78736723,"identity":"42f7f43e-698c-4f98-806e-88f153a52780","added_by":"auto","created_at":"2025-03-18 08:23:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":617286,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6207262/v1/4217a74c-1a85-427b-a1e7-f8c3f6c9590b.pdf"},{"id":78735014,"identity":"beae2129-f7ac-4573-bd41-45a7b68750e7","added_by":"auto","created_at":"2025-03-18 08:07:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25537,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6207262/v1/8db75c5e4d72668d3b91ad57.docx"},{"id":78735011,"identity":"5b27f25a-42b9-49b1-b0a3-071e27e91afd","added_by":"auto","created_at":"2025-03-18 08:07:15","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23436,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6207262/v1/fa8aa4e90198975e68cea20c.docx"},{"id":78736121,"identity":"5f23fffe-8477-4886-b355-be245b8d4647","added_by":"auto","created_at":"2025-03-18 08:15:15","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":18588,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6207262/v1/0a11e0f917a2f054dac860c3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk factors for COVID-19 mortality among children and adolescents in Rio de Janeiro state, 2020-2023","fulltext":[{"header":"Background","content":"\u003cp\u003eCOVID-19 is an infectious disease caused by the SARS-CoV-2 virus that primarily affects the respiratory system in adults and children. Clinical manifestations of infection in children and adolescents are typically milder than in adults, who tend to develop more severe cases and have higher mortality rates [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur understanding of how SARS-CoV-2 affects children and adolescents has evolved significantly as the pandemic has progressed. In this group, infection manifests heterogeneously, ranging from asymptomatic or mild cases (common cold symptoms) to lower respiratory tract infections, gastrointestinal involvement, and a wide range of other manifestations. Severe cases in children can manifest as severe acute respiratory syndrome and pediatric multisystem inflammatory syndrome (PIMS) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGlobal adult mortality rates increased sharply during the COVID-19 pandemic in 2020 and 2021, reversing declining trends pre-pandemic. Meanwhile, infant mortality rates decreased, albeit slower than in previous years [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn Brazil, data from the Mortality Information System (Sistema de Informa\u0026ccedil;\u0026atilde;o sobre Mortalidade - SIM), from 2020 to 2021, analyzed by Fiocruz's Child Health Observatory revealed that COVID-19 caused the death of two children under 5 years daily, with the highest mortality rates concentrated among children aged 29 days to 1 year [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to Kitano et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], Brazil has the highest number of pediatric COVID-19 deaths (under 19 years) worldwide among 138 countries. According to Sousa et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], Rio de Janeiro ranked 19th among Brazilian states for mortality rates in individuals under 20 years of age and second within the Southeast region.\u003c/p\u003e \u003cp\u003eA U-shaped severity curve has been demonstrated in children diagnosed with COVID-19, with infants under 1 year of age and adolescents aged 10\u0026ndash;14 years at higher risk of developing severe COVID-19 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to Oliveira et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], COVID-19 mortality risk factors in Brazil included age (under 2 years and 12\u0026ndash;19 years), Indigenous ethnicity, residence in the North and Northeast regions, and one or more comorbidities.\u003c/p\u003e \u003cp\u003eIn Brazil, a country with vast territory and significant socioeconomic diversity, the relationship between COVID-19 mortality and sociodemographic variables is evident, as demonstrated by Sousa et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In this study, living in the Northern region (comprising the North and Northeast macroregions) triples the risk of COVID-19 mortality among individuals under 20 years of age compared to the Southern region (comprising the South, Southeast, and Central-West macroregions). Compared to White individuals, Brown, East-Asian, and Indigenous populations had a significantly higher mortality risk. Sousa et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] assessed the relationship between non-communicable diseases and COVID-19 mortality risk in individuals under 20 years of age in Brazil. The mortality rate among those with chronic non-communicable diseases was 15.8%, compared to 5.6% in healthy children and adolescents. Except for asthma, all comorbidities increased mortality rates, particularly kidney disease (29.2%) and cardiovascular disease (26.3%).\u003c/p\u003e \u003cp\u003eIn record time in the history of medicine, the first COVID-19 vaccine doses began to be administered worldwide in December 2020. Initially, only individuals aged 18 and older received the doses, followed by the inclusion of pediatric age groups, with approval in Brazil for children 6 months and older. In Brazil, COVID-19 vaccination was made available to adolescents aged 12 and older starting in June 2021. In Rio de Janeiro state, vaccination coverage rates were as follows: 0.96% for the third dose in children aged 6 months to 2 years; 0.11% for the third dose in children aged 3\u0026ndash;4 years; 49.50% for the second dose in children aged 5\u0026ndash;11 years; and 80.10% for the second dose in adolescents aged 12\u0026ndash;17 years [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to the 2022 demographic census, Rio de Janeiro is Brazil's third most populous state, with its capital being the country's second-largest city. Despite its relatively small territorial area, the state has a high population density of 366.97 inhabitants/km\u0026sup2;. Although it represents the country's second-largest economy, significant income disparities exist between the state's capital city, suburban areas, and rural regions.\u003c/p\u003e \u003cp\u003eThe study period (2020\u0026ndash;2023) encompassed the pre-vaccination phase and the predominance of all SARS-CoV-2 variants that circulated in the state (Alpha, Zeta, Gamma, Delta, and Omicron), enabling assessment of the disease's impact on this population.\u003c/p\u003e \u003cp\u003eAll COVID-19 cases and deaths were identified through the state of Rio de Janeiro's existing notification systems for cases, severe cases, and deaths. Most available studies have determined in-hospital case fatality rates, making it difficult to assess the true impact of COVID-19 in the community. Rio de Janeiro state represents an urbanized region in a developing country characterized by social inequality.\u003c/p\u003e \u003cp\u003eThis study analyzed risk factors for COVID-19 mortality among children and adolescents in Rio de Janeiro from 2020 to 2023.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe study aimed to characterize the epidemiological profile of the disease in children and adolescents under 18 years in Rio de Janeiro state from January 2020 to September 2023 and to identify risk factors for mortality in this age group, determining case fatality and mortality rates. A cross-sectional study was conducted to assess the association between individual predictors (age, sex, race/skin color), clinical variables (signs, symptoms, and comorbidities), and epidemiological factors (metropolitan region of residence, notification year, season, and dominant COVID-19 variant) with mortality among confirmed COVID-19 cases.\u003c/p\u003e\n\u003cp\u003eCOVID-19 cases in Brazil are mandatorily reported through two national notification systems: e-SUS Notifica (Ministry of Health Notification System) and SIVEP-Gripe (Influenza Epidemiological Surveillance Information System). e-SUS Notify is a nationwide system for recording suspected and confirmed cases of COVID-19 and influenza-like illness, implemented during the pandemic to serve both public and private healthcare facilities (primary care units, medical offices, clinics, healthcare centers, and emergency units). SIVEP-Gripe records all patients admitted to public or private hospitals with influenza-like illness, dyspnea/respiratory distress, persistent chest pressure, oxygen saturation below 95% on room air, or cyanosis. All patients included in this system have documented demographic data, clinical characteristics, and place of residence. This study included patients under 18 years with confirmed COVID-19 diagnosis who were reported in both e-SUS NOTIFICA and SIVEP-Gripe databases.\u003c/p\u003e\n\u003cp\u003eConfirmed cases of COVID-19 influenza-like illness were obtained from the Brazilian Ministry of Health's e-SUS Notify system. Confirmed cases of severe acute respiratory syndrome (SARS) due to COVID-19 were obtained from the Ministry of Health's SIVEP-Gripe database. These two databases were linked using probabilistic record linkage. A consistency analysis was performed to remove duplicate entries from the resulting database. Within six months, duplicate records were defined as multiple notifications for the same case in the database.\u003c/p\u003e\n\u003cp\u003eThe National Mortality Information System (Sistema de Informações sobre Mortalidade - SIM) is a nationwide epidemiological surveillance system that regularly collects mortality data. The Death Certificate (DC) is Brazil's fundamental and essential document for mortality data collection. It is also Brazil's death assessment reference system.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubsequently, the database resulting from linking e-SUS NOTIFICA with SIVEP-Gripe was again linked through probabilistic record linkage to the Ministry of Health's SIM to identify COVID-19 deaths not recorded in either SIVEP-Gripe or e-SUS NOTIFICA.\u003c/p\u003e\n\u003cp\u003eAfter this final linkage, 511 all-cause deaths were identified in the SIM between January 1, 2020, and September 6, 2023, among individuals under 18 years of age in Rio de Janeiro State who had been reported as COVID-19 cases in SIVEP-Gripe and e-SUS NOTIFICA surveillance systems. An individual analysis of these deaths was then conducted by examining the underlying cause, antecedent causes, and contributing causes documented in the Death Certificates.\u003c/p\u003e\n\u003cp\u003eDeaths were classified as follows:\u003c/p\u003e\n\u003cp\u003ea) \u003cstrong\u003eCOVID-19 deaths\u0026nbsp;\u003c/strong\u003ewere those with ICD-10 codes B34.2 (\"Coronavirus infection of the unspecified site\") + U07.1 (\"COVID-19, virus identified through laboratory testing\") or B34.2 + U07.2 (\"COVID-19, virus not identified, clinically-epidemiologically diagnosed, listed as the underlying cause of death. It is attributed to a clinical or epidemiological diagnosis of COVID-19 where laboratory confirmation is inconclusive or unavailable\"); M303 (\"mucocutaneous lymph node syndrome - Kawasaki\") + U10.9 (\"COVID-19-associated multisystem inflammatory syndrome, unspecified\"); B34.2 + U92.1 (\"confirmed COVID-19 reinfection\") and B94.8 (\"sequelae of other specified infectious and parasitic diseases\") + U09.9 (\"post-COVID-19 condition, unspecified\"), according to the Ministry of Health [14].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe World Health Organization (WHO) codes U07.1 and U07.2 serve as pandemic markers in Brazil and must always follow code B34.2 on the same line. On the Death Certificate, when a sequence of events mentions Multisystem Inflammatory Syndrome (MIS-C), codes M30.3 + marker U10.9 must be entered on the same line. When COVID-19 reinfection is mentioned in the death certificate, codes B34.2 and marker U92.1 must be listed on the same line. Codes B94.8 and marker U09.9 must be listed on the same line of the medical certificate when documenting post-COVID-19 sequelae events.\u003c/p\u003e\n\u003cp\u003eb) \u003cstrong\u003eA suspected COVID-19 death\u0026nbsp;\u003c/strong\u003ewas one where COVID-19-related codes were recorded in Part II of the Death Certificate as a significant contributing factor. In contrast, the underlying cause and antecedents were coded as unspecified respiratory or infectious diseases.\u003c/p\u003e\n\u003cp\u003ec) \u003cstrong\u003eA COVID-19-related death\u0026nbsp;\u003c/strong\u003ewas one where the disease codes were recorded in Part II of the Death Certificate. However, a different underlying cause of death was specified, excluding unspecified respiratory or infectious diseases.\u003c/p\u003e\n\u003cp\u003ed) \u003cstrong\u003eCOVID-19 was ruled out\u0026nbsp;\u003c/strong\u003eas the cause of death when COVID-19 codes were not recorded on the death certificate as the underlying cause, its antecedents (Part I), or as a significant contributing factor (Part II).\u003c/p\u003e\n\u003cp\u003eOf the 511 deaths identified through linkage, 282 were excluded due to other causes; COVID-19 caused 213; COVID-19 likely caused six deaths; and 10 deaths occurred during active COVID-19 infection. This study considered COVID-19-confirmed deaths (n=213) as the outcome.\u003c/p\u003e\n\u003cp\u003eAge was stratified into the following groups: under 1 year, 1-4 years, 5-9 years, 10-14 years, and 15-17 years. Sex was classified as female, male, or not reported. Race/ethnicity was categorized as White, Black, Brown, Asian, Indigenous, or not reported. The race/skin color variable was also dichotomized into white and non-white.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinical variables were categorized as present, absent, or unreported, including fever, cough, sore throat, dyspnea, oxygen saturation below 95%, ageusia, anosmia, and diarrhea. The presence of comorbidity variable, which included respiratory disease, kidney disease, heart disease, diabetes mellitus, and immunodeficiency/immunosuppression, was classified as yes, no, or not reported. Comorbidity was analyzed as a dichotomous variable (present/absent) and a three-level categorical variable (none, one, or two or more pre-existing medical conditions).\u003c/p\u003e\n\u003cp\u003eThe region of residence was categorized into Rio de Janeiro municipality, Ilha Grande Bay, Coastal Lowlands, South-Central, Middle Paraíba Valley, Metropolitan I (excluding Rio de Janeiro municipality), Metropolitan II, Northwest, North, and Mountain regions. Rio de Janeiro municipality was separated from Metropolitan Region I due to being the most populous municipality in the area. The case notification year variable was categorized as 2020, 2021, 2022, or 2023. The season variable was categorized as summer, fall, winter, or spring. The predominant SARS-CoV-2 variant during the study period was classified as B.1 (wild type), Zeta, Gamma, Delta, and Omicron. Each dominant variant's start and end dates were determined according to the Rio de Janeiro State Health Department bulletin by state region, thus assuming that all cases occurring within each dominant variant's period were attributed to that variant [15].\u003c/p\u003e\n\u003cp\u003eStatistical analyses and database linkage were performed using R x64 4.0.0 through RStudio Desktop.\u003c/p\u003e\n\u003cp\u003eBivariate descriptive analysis was performed using bar charts, pie charts, and boxplots for the numerical predictor variable (age) and contingency tables for categorical predictor variables. Pearson's chi-square test was used for categorical predictor variables, while the Wilcoxon test was used for the numerical predictor variable. The significance level was set at 5%.\u003c/p\u003e\n\u003cp\u003eLogistic regression analysis was performed to identify factors associated with COVID-19 mortality in individuals under 18 years. Furthermore, model goodness-of-fit was assessed using sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), Youden's index, Receiver Operating Characteristic (ROC) curve, and Matthews correlation coefficient (MCC).\u003c/p\u003e\n\u003cp\u003eThe mortality rate was calculated using population data by age group from the 2022 Brazilian Institute of Geography and Statistics (IBGE) demographic census.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom January 2020 to September 2023, a total of 241,533 COVID-19 cases and 213 deaths were reported among children and adolescents under 18 years of age in Rio de Janeiro state. The case fatality rate was 0.09%, and the mortality rate was 5.81 per 100,000 children and adolescents under 18 years of age.\u003c/p\u003e\n\u003cp\u003eThe distribution of cases over the years showed that 29,380 (12.2%) cases were registered in 2020, 75,187 (31.1%) in 2021, 128,025 (53%) in 2022, and 8,941 (3.7%) cases through September 2023.\u003c/p\u003e\n\u003cp\u003eThe age distribution revealed COVID-19 cases as follows: 21,738 (9.0%) in infants under 1 year; 37,352 (15.5%) in children aged 1-4 years; 55,989 (23.2%) in those aged 5-9 years; 69,356 (28.7%) in those aged 10-14 years; and 57,098 (23.6%) in adolescents aged 15-18 years.\u003c/p\u003e\n\u003cp\u003eThe sex distribution revealed that 114,810 (47.5%) cases occurred in males and 126,722 (52.5%) in females. Regarding race/skin color, 66,532 (40.3%) cases occurred in White individuals, 11,143 (6.8%) in Black individuals, 2,967 (1.8%) in Asian individuals, 84,013 (51.0%) in Brown individuals, and 238 (0.1%) in Indigenous individuals, with 76,640 cases missing this information. The distribution by skin color showed that 66,532 (40.3%) of cases occurred among white children and adolescents, while 98,361 (59.7%) occurred among non-white individuals.\u003c/p\u003e\n\u003cp\u003eTable 1 shows the distribution of cases according to clinical, epidemiological, and demographic variables.\u003c/p\u003e\n\u003cp\u003eCough was reported in 114.723 (47.6%) cases, followed by cough in104,294 (43.3%), sore throat in 61,555 (25.6%), dyspnea in 15,317 (6.4%), diarrhea in 6,598 (2.7%), anosmia in 790 (0.3%), ageusia in 288 (0.1%), and oxygen saturation below 95% in 104 (0.04%) cases.\u003c/p\u003e\n\u003cp\u003eRegarding comorbidities, the respiratory disease was present in 5,094 (2.1%) cases, kidney disease in 117 (0.05%), heart disease in 1,112 (0.5%), diabetes mellitus in 627 (0.3%), and immunodeficiency/immunosuppression in 753 (0.3%) cases. A total of 234,182 (97.0%) children and adolescents had no comorbidities, while 7,017 (2.9%) had one comorbidity, and 334 (0.14%) had two or more comorbidities.\u003c/p\u003e\n\u003cp\u003eThe distribution by metropolitan region showed that 117,270 (48.6%) cases lived in Rio de Janeiro municipality, 3,595 (1.5%) in Ilha Grande Bay, 9,734 (4.0%) in the Coastal Lowlands, 7,794 (3.2%) in Center-South, 19,308 (8.0%) in Médio Paraíba, 20,805 (8.6%) in Metropolitan Region I (excluding Rio de Janeiro municipality), 21,096 (8.7%) in Metropolitan Region II, 9,369 (3.9%) in the Northwest region, 11,762 (4.9%) in the North region, and 20,800 (8.6%) in the Mountain region.\u003c/p\u003e\n\u003cp\u003eThe number of reported cases per year showed that 29,380 (12.2%) occurred in 2020, 75,187 (31.1%) in 2021, 128,025 (53%) in 2022, and 8,941 (3.7%) in 2023 (through September). The seasonal distribution of cases revealed that 101,217 (41.9%) occurred in summer, 50,679 (21.0%) in autumn, 54,751 (22.7%) in winter, and 34,866 (14.4%) in spring.\u003c/p\u003e\n\u003cp\u003eThe distribution of cases according to the predominant COVID-19 variant showed that 137,342 (56.9%) cases occurred during Omicron's predominance, 21,298 (8.8%) during B1_wild's predominance, 18,459 (7.6%) during Zeta's predominance, 33,694 (14.0%) during Gamma's predominance, and 30,740 (12.7%) during Delta's predominance.\u003c/p\u003e\n\u003cp\u003eThe annual distribution of COVID-19 deaths was 85 (40.0%) in 2020, 108 (50.7%) in 2021, 19 (8.9%) in 2022, and 1 (0.5%) in 2023 (January to September).\u003c/p\u003e\n\u003cp\u003eFigure 1\u0026nbsp;shows the case fatality rate distribution by age group.\u003c/p\u003e\n\u003cp\u003eThe case fatality rate was 0.5% in infants under 1 year of age, 0.05% in children aged 1-4 years, 0.03% in those aged 5-9 years, 0.05% in those aged 10-14 years, and 0.06% in adolescents aged 15-17 years.\u003c/p\u003e\n\u003cp\u003eAge-specific mortality rates were 69.89 per 100,000 infants under 1 year; 2.63 per 100,000 children aged 1-4 years; 1.87 per 100,000 children aged 5-9 years; 3.52 per 100,000 children and adolescents aged 10-14 years; and 4.07 per 100,000 adolescents aged 15-17 years.\u003c/p\u003e\n\u003cp\u003eTable 2\u0026nbsp;shows the association between independent variables and death from COVID-19. Children under 1 year of age had a higher mortality risk compared to adolescents aged 15-17 years (OR = 8.63; 95% CI: 5.92-12.9). Black children and adolescents with COVID-19 had a higher mortality risk compared to White individuals (OR 1.68; 95% CI 1.08-2.54), while Brown individuals had a lower mortality risk compared to White individuals (OR 0.59; 95% CI 0.43-0.79). Oxygen saturation below 95% (OR=84.5; CI 35.2-171), dyspnea (OR=25.8; CI 18.7-35.8), and fever (OR=2.56; CI 1.87-3.53) was associated with higher mortality risk, while sore throat (OR=0.16; CI 0.07-0.32) and diarrhea (OR=0.17; CI 0.01-0.74) were associated with a lower mortality risk. Regarding comorbidities, kidney disease (OR=117; CI 40.7-266), immunodeficiency/immunosuppression (OR=82.3; CI 48.8-132), heart disease (OR=73.9; CI 46.4-114), diabetes mellitus (OR=47.3; CI 23.8-85.0), and respiratory disease (OR=3.86; CI 2.22-6.22) were associated with higher COVID-19 mortality. Having one comorbidity increases the mortality risk (OR=8.22; 95% CI: 5.68-11.6) while having two or more comorbidities substantially increases the mortality risk (OR=96.2; 95% CI: 57.9-152). The mortality risk was higher among children and adolescents living in the Northwest metropolitan region (OR=4.41; 95% CI 1.18-28.5) and metropolitan region I (excluding Rio de Janeiro municipality) (OR=7.69; 95% CI 2.37-47.2) compared to those living in the Center-South region.\u003c/p\u003e\n\u003cp\u003eHaving contracted COVID-19 in 2021 (OR=12.9; CI 2.88-226) and 2022 (OR=25.9; CI 5.78-457), compared to 2023 (through September), was associated with a higher mortality risk, as did infection during autumn (OR=4.97; CI 3.43-7.37), winter (OR=2.70; CI 1.78-4.13), and spring (OR=2.35; CI 1.44-3.80), compared to summer. Infection during the predominance of variants B1_wild (OR=23.6; CI 14.7-39.8), Zeta (OR=10.1; CI 5.66-18.2), Gamma (OR=11.6; CI 7.12-19.8), and Delta (OR=8.05; CI 4.71-14.2) was associated with a higher mortality risk compared to cases during Omicron predominance.\u003c/p\u003e\n\u003cp\u003eTable 3\u0026nbsp;shows the logistic regression results for the association between independent variables and death from COVID-19. Children under 1 year of age had a higher mortality risk (OR=4.70; 95% CI: 2.45-9.60) compared to those aged 15-17 years. Non-white children and adolescents had a lower mortality risk compared to white children (OR=0.64; 95% CI: 0.41-0.99). Regarding symptoms, fever (OR=1.83; 95% CI: 1.17-2.89), dyspnea (OR=11.83; 95% CI: 7.50-18.74), and oxygen saturation below 95% (OR=11.97; 95% CI: 3.78-33.19) were associated with a higher mortality risk. Children and adolescents presenting with sore throat had a lower mortality risk (OR=0.06; 95% CI: 0.01-0.19). Children and adolescents with heart disease (OR=7.74; 95% CI: 3.89-14.58) and immunodeficiency/immunosuppression (OR=17.16; 95% CI: 8.58-32.14) had a higher mortality risk. Infection during the predominance of B1_wild (OR=3.44; CI 1.75-6.81), Gamma (OR=3.93; CI 2.13-7.44), and Delta (OR=2.27; CI 1.02-4.84) variants was associated with a higher mortality risk compared to the Omicron variant.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCOVID-19 case fatality rates among individuals under 18 years of age remain relatively low compared to adults, regardless of the predominant variant. Current evidence suggests that pediatric populations show lower infection rates and milder disease severity, accounting for approximately 5% of cases with an extremely low case fatality rate (0-0.69%) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the meta-analysis by Wang et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] covering January to October 2020, a case fatality rate of 0.28% was found among children and adolescents. A study conducted in Brazil [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] found an in-hospital case fatality rate of 8.2% in 2020 and 6.9% in 2021 among patients under 19 years of age. Hillesheim et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] found a 9.5% in-hospital case fatality rate among Brazilian children and adolescents through September 2020. A multicenter study conducted in April 2020 involving 82 healthcare institutions across 25 European countries reported a 0.69% case fatality rate among individuals under 18 years of age [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. According to Bertran et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], in England, the infection case fatality rate among children and adolescents under 20 years of age was 0.70 per 100,000 estimated SARS-CoV-2 infections between March 2020 and December 2021. According to UNICEF [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], of the 4.4\u0026nbsp;million COVID-19 deaths recorded worldwide through December 2023, only 0.4% occurred in children and adolescents under 20 years of age. According to Smith et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], between March 2020 and February 2021, the COVID-19 mortality rate among individuals under 18 years of age in England was approximately two deaths per million inhabitants (mortality rate of 0.2 per 100,000 for COVID-19, compared to 25.5 per 100,000 for all other causes of death), demonstrating extremely low COVID-19 mortality among children and adolescents in the country. A cohort study conducted in Mexico from 2020 to 2022 by Sol\u0026oacute;rzano-Santos et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] in individuals under 18 years of age found a case fatality rate of 0.39%. This country remained among the ten countries worldwide with the highest adult case fatality rate. In Ecuador, a study conducted by Ortiz-Prado et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] from 2020 to 2021 in individuals under 18 years of age revealed an overall incidence rate of 612 cases per 100,000 children and adolescents, a mortality rate of 3 per 100,000 inhabitants under 18 years, and a case fatality rate of 0.76% during the first 16 months of the pandemic. In Portugal, from 2020 to 2021, according to Elias et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], case fatality and mortality rates were low, at 1.8 per 100,000 cases and 1.2 per 1,000,000 inhabitants under 18 years of age, respectively. A study conducted in Germany between 2020 and 2021 by Sorg et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] reported a case fatality rate of 0.09 per 10,000 individuals under 18 years of age. A study by Evans-Gilbert et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] across 15 Caribbean countries from 2020 to 2021 in individuals under 19 years revealed case fatality rates for ages 0\u0026ndash;9 and 10\u0026ndash;19 years were 2.80% and 0.70% in Haiti, 0.10% and 0.20% in Jamaica, and 0.00% and 0.14% in Trinidad, compared to global rates of 0.17% and 0.1%, respectively. A meta-analysis including 16,027 articles and 225 national reports from 216 countries conducted by Kitano et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] revealed a significantly higher case fatality rate in low- and middle-income countries than in high-income countries (0.24% and 0.013%, respectively). In Rio de Janeiro state, we found a case fatality rate of 0.09% between January 2020 and September 2023. While most studies above report in-hospital case fatality rates, this study analyzed community case fatality rates. The case fatality rate in this study is considerably higher than those reported in Portuguese and German studies but comparable to rates observed in low- and middle-income countries.\u003c/p\u003e \u003cp\u003eThe COVID-19 mortality rate among children and adolescents under 19 years of age in the United States from August 2021 to July 2022 was 1.0 per 100,000 children and adolescents. By age group, mortality rates were 4.3 deaths per 100,000 children under 1 year of age, 0.6 per 100,000 children aged 1\u0026ndash;4 years, 0.4 per 100,000 children aged 5\u0026ndash;9 years; 0.5 per 100,000 children aged 10\u0026ndash;14 years; and 1.8 per 100,000 adolescents aged 15\u0026ndash;19 years. Deaths in individuals under 19 years of age accounted for 2% of all-cause mortality in this age group, ranking as the eighth leading cause of death overall, the fifth among disease-related deaths (excluding unintentional injuries, assault, and suicide), and the first among deaths caused by infectious or respiratory diseases compared to 2019 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In Brazil, Szwarcwald et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] reported mortality rates per age group: 0.3 per 10,000 children aged 0\u0026ndash;9 years, 0.2 per 10,000 children and adolescents aged 10\u0026ndash;19 years, and 10.0 per 10,000 adults aged 40\u0026ndash;49 years. The mortality rate found in Rio de Janeiro state was 5.81 per 100,000 children and adolescents under 18 years of age, higher than the rates reported in the studies above.\u003c/p\u003e \u003cp\u003eCOVID-19 case fatality rate in infants under one year of age exceeds that of other pediatric age groups, as demonstrated by previous studies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. According to Kitano et al.'s meta-analysis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], the highest mortality rates per million children and case fatality rates were observed in infants under one year of age: 10.03 and 0.58% globally; 5.39 and 0.07% in high-income countries and 10.98 and 1.30% in low- and middle-income countries. In Rio de Janeiro state, from 2020 to 2021, case fatality rates were the highest among infants under one year of age (0.5%) compared to other age groups.\u003c/p\u003e \u003cp\u003eThe U-shaped case fatality rate curve, with higher rates among infants under 1 year and individuals over 15 years of age, has been demonstrated in studies by Oliveira et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], Mccormick et al. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], Flaxman et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], and Harwood et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], was not observed in deaths among children and adolescents in Rio de Janeiro state. This study followed a J-shaped case fatality curve, with the highest peak among infants under one year of age, consistent with mortality patterns reported in the literature.\u003c/p\u003e \u003cp\u003eThe higher mortality risk among Black and Indigenous children and adolescents reported by Mccormick et al. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and Oliveira et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] was identified in the univariate analysis of deaths in Rio de Janeiro state. However, multivariate analysis showed no statistical significance. Data from Kim et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] demonstrate that across 14 U.S. states from March to August 2020, the cumulative COVID-19-associated hospitalization rate among children (8.0 per 100,000 population) remained low compared to adults (164.5 per 100,000 population), one in three hospitalized children required intensive care unit admission. There were racial and ethnic disparities in hospitalizations: Black and Hispanic children and adolescents experiencing higher hospitalization rates than non-Hispanic White children.\u003c/p\u003e \u003cp\u003eThe annual distribution of deaths in Rio de Janeiro state from 2020 to 2023 revealed that 90.6% occurred during the first two years of the pandemic, with a marked reduction in subsequent years. During 2020 and 2021, the B1_wild, Gamma, and Delta variants predominated, leading to higher mortality rates. According to Wiedenmann et al.'s systematic review [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], although most COVID-19 infections resulted in mild illness among individuals under 18 years of age, more severe cases were reported in association with Delta and Gamma variants, while Omicron infections proved less severe than Delta infections. According to Marks et al. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], concurrent with increased Omicron variant circulation, COVID-19-associated hospitalization rates among children and adolescents aged 0\u0026ndash;17 years rose sharply in late December 2021 in the United States, particularly among children aged 0\u0026ndash;4 years who were not yet eligible for vaccination. During Delta and Omicron predominance periods, hospitalization rates remained lower among fully vaccinated adolescents aged 12\u0026ndash;17 years than their unvaccinated peers. According to a U.S. study on COVID-19 severity in individuals under 18 years from 2020 to December 2021, while 1 in 16 children infected with SARS-CoV-2 experienced moderate or severe illness, the risk of severe disease remained unchanged with the emergence of the Delta variant, despite its high transmissibility. A transient increase in severity was observed during the Alpha variant phase (March-June 2021), followed by declines during the Delta variant phase (July-December 2021) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The Martin et al. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] cohort study in the United States showed that hospitalization rates remained stable when comparing children during the Delta and pre-Delta eras with a lower risk of severe illness. A study by Zhu et al. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] conducted across nine countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, the United Kingdom, and the United States) over three distinct periods demonstrated a consistent decline in ICU admissions across all age groups over the SARS-CoV-2 waves among individuals under 18 years of age. The results were consistent when the data was restricted to unvaccinated children. A study by Hani et al. [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] in England demonstrated that the infection case fatality rate following Omicron was 2 per million infections, representing a sevenfold reduction compared to the initial pandemic wave. In Rio de Janeiro state, the highest number of cases was recorded in 2022 (53%) during the Omicron predominance, with a reduction in mortality rates.\u003c/p\u003e \u003cp\u003eAlthough children and adolescents are less susceptible to COVID-19, pre-existing comorbidities may predispose them to severe illness. The presence of immunodeficiency/immunosuppression and cardiac disease comorbidities was strongly associated with the mortality risk (OR 21.8 and 4.73, respectively) among children and adolescents in Rio de Janeiro state. A meta-analysis by Tsankov et al. [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] summarized the relationship between COVID-19 infection and pediatric comorbidities across 42 studies encompassing 275,661 children. The results showed that children with comorbidities had a hazard ratio of 1.79 for severe COVID-19 infection and 2.81 for COVID-19 mortality rate. A UK cohort study of 26,322 patients under 18 years of age with COVID-19 found that comorbidities associated with hospital admission included diabetes mellitus, congenital heart disease, cerebral palsy, epilepsy, and sickle cell disease [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. As an increasingly prevalent condition among children, obesity has been identified as one of the most significant risk factors for mechanical ventilation in children aged 2 years and older with COVID-19 [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Results from other studies also support the notion that obesity and type 2 diabetes are risk factors for severe pediatric COVID-19 [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, other specific comorbidities, such as cardiovascular diseases, neoplasms, and immunosuppression, have been associated with COVID-19 severity [\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. According to Flores-Cisneros et al. [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], comorbidities such as kidney disease or immunosuppression increased the mortality risk across all age groups. Harwood et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] identified that among hospitalized patients with SARS-CoV-2 infection, those under 1 year of age, over 10 years old, and individuals with cardiac conditions, neurological disorders, obesity, or two or more comorbidities had the highest mortality risk. However, odds ratios were high, and the absolute risk increase for most comorbidities was slight compared to children without underlying conditions. Data from a European study showed that the most common comorbidities associated with ICU admission were chronic lung disease, congenital heart disease, neurological disorders, and malignancies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A study by Woodruff et al. [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], analyzing 3,106 hospitalized children with confirmed COVID-19 infection across 14 U.S. states, demonstrated an increased risk of severe disease among hospitalized children under 2 years of age with chronic lung disease, neurological disorders, cardiovascular disease, prematurity, and airway anomalies. Among hospitalized children aged 2\u0026ndash;17 years, risk factors included feeding tube dependency, diabetes mellitus, and obesity. Severe COVID-19 occurred at a rate of 12.0 per 100,000 children overall and was highest among infants, Hispanic children, and non-Hispanic Black children. According to Souza et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], having two or more comorbidities (excluding asthma) increased the risk of COVID-19 mortality nearly tenfold among individuals under 19 years of age in Brazil. According to Apar\u0026iacute;cio et al.'s meta-analysis [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], although the absolute risk of severe COVID-19 in children and adolescents without comorbidities is relatively low, one or more underlying conditions were associated with a markedly increased risk.\u003c/p\u003e \u003cp\u003eClinical signs and symptoms of oxygen saturation below 95% and dyspnea were strongly associated with the mortality risk (OR 4.20 and 3.55, respectively). At the same time, fever was also associated with a higher mortality risk (OR 1.96) among children and adolescents in Rio de Janeiro state. Shi et al. [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] showed that dyspnea was associated with poor prognosis in children and adolescents with COVID-19. The presence of lower respiratory tract infection signs or symptoms (dyspnea and/or decreased oxygen saturation) at COVID-19 presentation was associated with ICU admission according to G\u0026ouml;tzinger et al.'s multicenter study [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]; in this study, fever was the most common presenting sign, observed in 65% of individuals. A study conducted by Ng et al. [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] found that a history of fever, fever upon admission, and dyspnea were predictors of moderate and severe disease among children hospitalized with COVID-19.\u003c/p\u003e \u003cp\u003eThe sore throat was identified as a protective factor against COVID-19 mortality in children and adolescents (OR 0.06) in Rio de Janeiro state. This finding has not been previously reported. A sore throat is a prevalent symptom in upper respiratory viral infections, which relies on the patient's subjective report. Only those capable of verbal expression can reliably report this symptom among children and adolescents. Furthermore, since it is a common symptom in various viral infections, this finding may be due to misclassification of viral etiology, as confirmatory tests for SARS-CoV-2 infection were not performed in most cases.\u003c/p\u003e \u003cp\u003eFor mortality analysis in this study, we included only deaths directly attributable to COVID-19, excluding cases where COVID-19 was either a probable cause or was present but not the primary cause of death. Due to the small fatalities among probable cases and COVID-19 deaths, no significant differences were observed in the modeling tests performed. Therefore, the results of this study are strengthened by their high specificity.\u003c/p\u003e \u003cp\u003eThe temporal aspect was not a limitation in this study, given that SARS-CoV-2 infection manifests as an acute disease, and its potential outcome (death) occurs shortly after disease onset. Although this was a cross-sectional study, data on symptom onset and death dates were available, albeit collected at a single time point.\u003c/p\u003e \u003cp\u003eSelection bias is a potential study limitation, as sample representativeness may have been compromised by not including all COVID-19 cases among individuals under 18 years in Rio de Janeiro state. The underreporting of cases in children and adolescents was due to the asymptomatic or oligosymptomatic nature of the disease, as well as limited testing availability, particularly in the early stages of the pandemic. Testing requires nasal or nasopharyngeal swab insertion, which leads to many families refusing to authorize the examination in children. Furthermore, in the beginning, people were advised to stay home and only seek medical care if severe symptoms developed. Additionally, hospitalized patients may have died without being tested and, consequently, without a COVID-19 diagnosis. COVID-19 cases may have been misdiagnosed as other diseases, and correctly diagnosed cases may have gone unreported to health surveillance services. PIMS was a novel condition discovered during the pandemic that was difficult to diagnose clinically.\u003c/p\u003e \u003cp\u003eInformation bias was a limitation due to potential errors in data collection or completion of notification forms. Data collection regarding children and adolescents typically relies on information a responsible caregiver provides. Race/skin color data were self-reported, possibly introducing bias into the study results. Information on symptoms and comorbidities (risk factors included in SIVEP-GRIPE) was self-reported (provided by patients or their family members). Therefore, patient awareness of their clinical condition may have influenced the analysis.\u003c/p\u003e \u003cp\u003eAdditionally, some variables may be incorrectly coded in electronic records due to data entry errors. Missing or incorrect data in the database may have distorted the results. The entry in the \"case progression\" field may have introduced information bias, given that 46 cases recorded as deaths in SIVEP-Gripe were not found in the SIM, even after exhaustive searching. The quality of records, accuracy of information, and data consistency may vary, potentially affecting the results' reliability. The clinical symptom of sore throat may have conferred protection against COVID-19 mortality since it relies on the patient's subjective report, which occurs only when speech capability is present. Since the case fatality rate was higher among children under 1 year of age, older children and adolescents who survived were more likely to report this symptom. Furthermore, since not all reported cases were tested, the sore throat symptoms may have been misclassified as COVID-19 when other, less lethal infections caused them.\u003c/p\u003e \u003cp\u003eSince this study relies on secondary databases not initially designed for research purposes, potential confounding factors such as income and education levels were unavailable in the datasets. Known confounding factors were controlled for using logistic regression.\u003c/p\u003e \u003cp\u003eAlthough cross-sectional studies based on databases may have limited generalizability, this study covered the entire state of Rio de Janeiro, providing robust representation for the Southeast region and potentially for Brazil. Although the cross-sectional design cannot detect temporal changes, this limitation was minimized by capturing data according to notification year, death year, and dominant variant. In this study, we did not control for pandemic mitigation policies such as lockdown and vaccination.\u003c/p\u003e \u003cp\u003eSecondary databases lack detailed information regarding exposure intensity, duration, and context, such as contact time, number of household contacts, viral load through RT-PCR, and comorbidity severity.\u003c/p\u003e \u003cp\u003eCases that began during the study period may have resulted in deaths after the study endpoint and could not be included in this analysis; however, the dominant Omicron variant has a low mortality rate, and consequently, the likelihood of death was low for this variant.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eCOVID-19 in children and adolescents in Rio de Janeiro state from 2020 to September 2023 emerged as a significant infection in this population group. Although mortality rates were low, they were more substantial among children under one year of age and higher than in other countries or regions.\u003c/p\u003e \u003cp\u003eThe main risk factors for death were fever, dyspnea, oxygen saturation below 95% on room air, age under one year, cardiac disease as a comorbidity, immunodeficiency, and infection during the predominance of B1_wild, Gamma, and Delta variants.\u003c/p\u003e \u003cp\u003eUnderstanding the epidemiological profile and risk factors for mortality in this population is essential to inform effective prevention and control measures and guide optimal clinical management.\u003c/p\u003e \u003cp\u003eThe impact of COVID-19 on child and adolescent mortality was most significant during the pandemic's first two years, and continued assessment of the disease's impact is necessary, particularly regarding immunization effects and specific characteristics of future variants.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study complies with Resolution 466/2012, the Declaration of Helsinki and all its amendments, and Good Clinical Practice (Document of the Americas). The study was submitted to the Research Ethics Committee (Comitê de Ética e Pesquisa - CEP) of the Institute of Collective Health Studies at the Federal University of Rio de Janeiro (Certificate of Submission for Ethical Evaluation (Certificado de Apresentação de Apreciação Ética - CAAE: 66422623.5.0000.5286). The study was approved by the CEP (approval number 5,883,512).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number: Not Applicable\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by FAPERJ (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEsteves, L. designed the study. Esteves, L. Raymundo, CE. Medronho, RA. collected and analyzed the data. Esteves, L. Raymundo, CE. Medronho, RA. interpreted the results. Esteves, L. wrote the manuscript. Medronho RA. contributed to the refinement of the manuscript. The final manuscript has been read and approved by the authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020;145(6):e20200702.\u003c/li\u003e\n\u003cli\u003eLudvigsson JF. Systematic review of COVID‐19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(6):1088\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eMantovani A, Rinaldi E, Zusi C, Beatrice G, Saccomani MD, Dalbeni A. Coronavirus disease 2019 (COVID-19) in children and/or adolescents: a meta-analysis. Pediatr Res. 2020;89(4):733\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eVerity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. 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S\u0026iacute;ndrome respirat\u0026oacute;ria aguda grave por COVID-19 em crian\u0026ccedil;as e adolescentes no Brasil: perfil dos \u0026oacute;bitos e letalidade hospitalar at\u0026eacute; a 38a Semana Epidemiol\u0026oacute;gica de 2020 [Severe Acute Respiratory Syndrome due to COVID-19 among children and adolescents in Brazil: profile of deaths and hospital lethality as at Epidemiological Week 38, 2020]. Epidemiol Serv Sa\u0026uacute;de. 2020;29:e2020644.\u003c/li\u003e\n\u003cli\u003eBertran M, Amin-Chowdhury Z, Davies HG, Allen H, Clare T, Davison C, et al. COVID-19 deaths in children and young people in England, March 2020 to December 2021: An active prospective national surveillance study. PLoS Med. 2022;19(11):e1004118.\u003c/li\u003e\n\u003cli\u003eUNICEF (United Nations International Children\u0026apos;s Emergency Fund). Child mortality and COVID-19. UNICEF DATA. Available at: \u0026lt;https://data.unicef.org/topic/child-survival/covid-19/\u0026gt;. 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COVID-19 in Portugal: a retrospective review of paediatric cases, hospital and PICU admissions in the first pandemic year. BMJ Paediatr Open. 2022;6(1):e001499.\u003c/li\u003e\n\u003cli\u003eSorg AL, Hufnagel M, Doenhardt M, Diffloth N, Schroten H, Von Kries R, et al. Risk for severe outcomes of COVID-19 and PIMS-TS in children with SARS-CoV-2 infection in Germany. Eur J Pediatr. 2022;181(10):3635\u0026ndash;43.\u003c/li\u003e\n\u003cli\u003eEvans-Gilbert T, Lashley PM, Lerebours E, Sin Quee C, Singh-Minott I, Fernandes M, et al. Children and the coronavirus disease 2019 pandemic: a Caribbean perspective. Rev Panam Salud Publica. 2022;46:e135.\u003c/li\u003e\n\u003cli\u003eFlaxman S, Whittaker C, Semenova E, Rashid T, Parks RM, Blenkinsop A, et al. Assessment of COVID-19 as the Underlying Cause of Death Among Children and Young People Aged 0 to 19 Years in the US. JAMA Netw Open. 2023;6(1):e2253590.\u003c/li\u003e\n\u003cli\u003eSzwarcwald CL, Boccolini CS, da Silva de Almeida W, Soares Filho AM, Malta DC. COVID-19 mortality in Brazil, 2020-21: consequences of the pandemic inadequate management. Arch Pub Health. 2022;80(1):255.\u003c/li\u003e\n\u003cli\u003eCDC COVID-19 Response Team, Bialek S, Gierke R, Hughes M, McNamara LA, Pilishvili T, et al. Coronavirus Disease 2019 in Children \u0026mdash; United States, February 12\u0026ndash;April 2, 2020. MMWR. Morb Mortal Wkly Rep. 2020;69(14):422\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eHarwood R, Yan H, Da Camara NT, Smith C, Ward J, Tudur-Smith C, et al. Which children and young people are at higher risk of severe disease and death after hospitalisation with SARS-CoV-2 infection in children and young people: A systematic review and individual patient meta-analysis. eClinicalMedicine. 2022;44:101287.\u003c/li\u003e\n\u003cli\u003eMcCormick DW, Richardson LC, Young PR, Viens LJ, Gould CV, Kimball A, et al. Deaths in Children and Adolescents Associated With COVID-19 and MIS-C in the United States. Pediatrics. 2021;148(5):e2021052273.\u003c/li\u003e\n\u003cli\u003eKim, L. et al. Hospitalization Rates and Characteristics of Children Aged 18 Years Hospitalized with Laboratory-Confirmed COVID-19 \u0026mdash; COVID-NET, 14 States, March 1\u0026ndash; July 25, 2020. MMWR. Morb Mortal Wkly Rep. 2020;69(32):1081\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eWiedenmann, M. et al. SARS-CoV-2 variants of concern in children and adolescents with COVID-19: a systematic review. BMJ Open, v. 13, n. 10, p. e072280, out. 2023. \u003c/li\u003e\n\u003cli\u003eMarks KJ. Hospitalizations of children and adolescents with laboratory-confirmed COVID-19\u0026mdash;COVID-NET, 14 states, July 2021\u0026ndash;January 2022. MMWR. Morb Mortal Wkly Rep. 2022;71(7):271\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eForrest CB, Burrows EK, Mejias A, Razzaghi H, Christakis D, Jhaveri R, et al. . Severity of Acute COVID-19 in Children \u0026lt;18 Years Old March 2020 to December 2021. Pediatrics. 2022;149(4):e2021055765.\u003c/li\u003e\n\u003cli\u003eMartin B, DeWitt PE, Russell S, Anand A, Bradwell KR, Bremer C, et al. Characteristics, Outcomes, and Severity Risk Factors Associated With SARS-CoV-2 Infection Among Children in the US National COVID Cohort Collaborative. JAMA Netw Open. 2022;5(2):e2143151.\u003c/li\u003e\n\u003cli\u003eZhu Y, Almeida FJ, Baillie JK, Bowen AC, Britton PN, Brizuela ME, et al. International Pediatric COVID-19 Severity Over the Course of the Pandemic. JAMA Pediatrics. 2023;177(10):1073.\u003c/li\u003e\n\u003cli\u003eHani E, Bertran M, Powell A, Williams H, Birrell P, DeAngelis D, et al. Significantly lower infection fatality rates associated with SARS-CoV-2 Omicron (B.1.1.529) infection in children and young people: Active, prospective national surveillance, January-March 2022, England. J Infect. 2023;86(4):397\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eTsankov BK, Allaire JM, Irvine MA, Lopez AA, Sauv\u0026eacute; LJ, Vallance BA, et al. Severe COVID-19 Infection and Pediatric Comorbidities: A Systematic Review and Meta-Analysis. Int J Infect Dis. 2021;103:246\u0026ndash;56.\u003c/li\u003e\n\u003cli\u003eSaattci, D. et al. Association Between Race and COVID-19 Outcomes Among 2.6 Million Children in England. JAMA Pediatrics, v. 175, n. 9, p. 928, 1 set. 2021. \u003c/li\u003e\n\u003cli\u003eZachariah P, Johnson CL, Halabi KC, Ahn D, Sen AI, Fischer A, et al. Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children\u0026rsquo;s Hospital in New York City, New York. JAMA Pediatrics. 2020;174(10):e202430.\u003c/li\u003e\n\u003cli\u003eAntoon JW, Grijalva CG, Thurm C, Richardson T, Spaulding AB, II RJ, et al. Factors Associated With COVID‐19 Disease Severity in US Children and Adolescents. J Hosp Med. 2021;16(10):603\u0026ndash;10.\u003c/li\u003e\n\u003cli\u003eZheng F, Liao C, Fan QH, Chen HB, Zhao XG, Xie ZG, et al. Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China. Curr Med Sci. 2020;40(2):275\u0026ndash;80.\u003c/li\u003e\n\u003cli\u003eTagarro A, Epalza C, Santos M, Sanz-Santaeufemia FJ, Otheo E, Moraleda C, et al. Screening and Severity of Coronavirus Disease 2019 (COVID-19) in Children in Madrid, Spain. JAMA Pediatrics. 2021;175(3):316.\u003c/li\u003e\n\u003cli\u003eFlores-Cisneros L, Guti\u0026eacute;rrez-Vargas R, Escondrillas-Maya C, Zaragoza-Jim\u0026eacute;nez C, Garc\u0026iacute;a-Rodr\u0026iacute;guez G, L\u0026oacute;pez-Gatell H, et al. Risk factors for severe disease and mortality in children with COVID-19. Heliyon. 2024;10(1):e23629.\u003c/li\u003e\n\u003cli\u003eWoodruff RC, Campbell AP, Taylor CA, Chai SJ, Kawasaki B, Meek J, et al. Risk Factors for Severe COVID-19 in Children. Pediatrics. 2021;149(1):e2021053418.\u003c/li\u003e\n\u003cli\u003eAparicio C, Willis ZI, Nakamura MM, Wolf J, Little C, Maron GM, et al. Risk Factors for Pediatric Critical COVID-19: A Systematic Review and Meta-Analysis. J Pediatric Infect Dis Soc. 2024;13(7):352\u0026ndash;62.\u003c/li\u003e\n\u003cli\u003eShi Q, Wang Z, Liu J, Wang X, Zhou Q, Li Q, et al. Risk factors for poor prognosis in children and adolescents with COVID-19: A systematic review and meta-analysis. eClinicalMedicine. 2021;41:101155.\u003c/li\u003e\n\u003cli\u003eNg DC, Liew CH, Tan KK, Chin L, Ting GS, Fadzilah NF, et al. Risk factors for disease severity among children with Covid-19: a clinical prediction model. BMC Infect Dis. 2023;23(1):398.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, children and adolescents, risk factors, mortality","lastPublishedDoi":"10.21203/rs.3.rs-6207262/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6207262/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eChildren and adolescents with COVID-19 typically present milder symptoms of the infection, with fatal outcomes being rare. This study aimed to analyze the main risk factors for mortality in this population group.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA cross-sectional study was performed to analyze reported COVID-19 cases among individuals under 18 years old in Rio de Janeiro state, Brazil, from March 2021 to September 2023. Pearson's chi-square test was used for categorical variables, and the Wilcoxon test for numerical variables. The significance level was set at 5%. Logistic regression analysis was performed to identify factors associated with COVID-19 mortality in individuals under 18.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eInfants under 1 year old had a higher mortality risk (OR\u0026thinsp;=\u0026thinsp;4.70; 95% CI: 2.45\u0026ndash;9.60) compared to adolescents aged 15\u0026ndash;17 years. Non-white individuals had a lower mortality risk compared to white individuals (OR\u0026thinsp;=\u0026thinsp;0.64; 95% CI: 0.41\u0026ndash;0.99). The presence of fever (OR\u0026thinsp;=\u0026thinsp;1.83; 95% CI: 1.17\u0026ndash;2.89), dyspnea (OR\u0026thinsp;=\u0026thinsp;11.83; 95% CI: 7.50-18.74), and oxygen saturation below 95% (OR\u0026thinsp;=\u0026thinsp;11.97; 95% CI: 3.78\u0026ndash;33.19) was associated with a higher mortality risk. Patients with heart disease (OR\u0026thinsp;=\u0026thinsp;7.74; 95% CI: 3.89\u0026ndash;14.58) and immunodeficiency/immunosuppression (OR\u0026thinsp;=\u0026thinsp;17.16; 95% CI: 8.58\u0026ndash;32.14) had a higher mortality risk. Infection during the predominance of variants B1_wild (OR\u0026thinsp;=\u0026thinsp;3.44; CI 1.75\u0026ndash;6.81), Gamma (OR\u0026thinsp;=\u0026thinsp;3.93; CI 2.13\u0026ndash;7.44), and Delta (OR\u0026thinsp;=\u0026thinsp;2.27; CI 1.02\u0026ndash;4.84) was associated with a higher mortality risk compared to the Omicron variant.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe main risk factors for death were fever, dyspnea, oxygen saturation below 95% on room air, age under one year, cardiac disease comorbidity, immunodeficiency, and infection during the predominance of B1_wild, Gamma, and Delta variants. Understanding the epidemiological profile and risk factors for mortality in this population is essential to inform effective prevention and control measures and guide optimal clinical management.\u003c/p\u003e","manuscriptTitle":"Risk factors for COVID-19 mortality among children and adolescents in Rio de Janeiro state, 2020-2023","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-18 08:07:11","doi":"10.21203/rs.3.rs-6207262/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-18T10:55:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-17T02:26:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-17T02:25:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-03-11T23:24:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c208c143-baf8-4eb7-b7a4-5f1c9610129f","owner":[],"postedDate":"March 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-31T23:53:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-18 08:07:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6207262","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6207262","identity":"rs-6207262","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}