Retrospective cohort of children and adolescents hospitalized by COVID-19 in Brazil from the beginning of the pandemic to August 1st, 2020

Nivreanes Tcherno Nulle Gomes Maria Isabella Claudino Haslett Ana Julia Silva e Alves Jadher Percio Magda Machado Saraiva Duarte Juliane Maria Alves Siqueira Malta Felipe Cotrim de Carvalho Walquiria Aparecida Ferreira de Almeida Caroline Gava Libia Roberta de Oliveira Souza Francieli Fontana Sutile Tardetti Fantinato Elizabeth David dos Santos About the authors

Abstract:

Objectives:

To characterize the study population, estimating the in-hospital lethality rate by state and analysing associated factors with COVID-19-related deaths.

Methods:

A retrospective cohort study was carried out of hospitalised children and adolescents diagnosed with COVID-19, confirmed by RT-PCR, whose outcome was death by COVID-19 or recovery, from 2020 March 1 to August 1. The data source was the Influenza Epidemiological Surveillance Information System (SIVEP-Gripe in Brazilian acronym), where patients with Severe Acute Respiratory Syndrome (SARS) are notified. Children were defined as those between the ages of 0 and 11, and adolescents those between 12 and 18. A bi and multivariate analysis were performed using Poisson Regression with robust variance, with adjusted Relative Risk as the final association measure.

Results:

A total of 4,930 cases were analysed; 2,553 (51.8%) were males, 2,335 (47.4%) were brown-skinned. The Federative Unit of Roraima presented the highest in-hospital case-fatality rate, with 68.8% (11/16). Multivariate analysis showed that belonging to the age group adolescent (RR = 1.59; 95%CI 1.12 - 2.25; p = 0.009), SARS-critical patient (RR = 4.56; 95%CI 2, 77 - 7.51; p < 0.001) and presenting immunological disorders (RR = 2.24; 95%CI 1.58 - 3.17; p < 0.001) as comorbidities were statistically associated factors with death by COVID-19.

Conclusion:

It was observed that adolescents, SARS-critical patients, and presence of immunological disorders were important factors associated with death. Active surveillance and differentiated care are recommended for patients with chronic diseases and special immunological conditions.

Keywords:
Child; Adolescent; Hospitalization; Coronavirus infections; Severe acute respiratory syndrome

INTRODUCTION

In December 2019, the world was put on alert, when a new type of coronavirus (later called SARS-CoV-2) was discovered to affect the respiratory tract of humans, causing from asymptomatic infections to the most severe manifestations, with acute respiratory syndromes that can cause death. The first cases, originated in Wuhan, China, spread rapidly across Chinese territory, reaching the entire Asian continent, and expanding to the European and American continents in less than three months11. Kamps BS, Hoffmann C. COVID Reference [Internet]. Hamburg: Steinhäuser Verlag; 2020 [acessado em 11 abr. 2020]. Disponível em: Disponível em: https://covidreference.com
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,22. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33.,33. Pan American Health Organization, World Health Organization. Brasil. Folha Informativa. COVID-19 (Doença Causada Pelo Novo Coronavírus) [Internet]. Pan American Health Organization, World Health Organization; 2020 [acessado em 11 abr. 2020]. Disponível em: Disponível em: https://www.paho.org/bra/index.php
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, until January 30, 2020, when the World Health Organization (WHO) stated that the spread of COVID-19 cases around the world constituted a Public Health Emergency of International Importance (PHEII)22. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33..

Virus transmission occurs through contact with respiratory droplets generated by infected people. The manifestations differ from organism to organism, depending on the immune system, the pre-existing conditions, the age, and the amount of virus with which one was exposed44. Saxena SK, editor. Coronavirus Disease 2019 (COVID-19): Epidemiology, Pathogenesis, Diagnosis, and Therapeutics. Springer Nature; 2020..

Children and adolescents seem to have been less affected by the COVID-19 pandemic since the infection occurs in a milder way in them55. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep 2020; 69(14): 422-6. https://doi.org/10.15585/mmwr.mm6914e4
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. More than a month after the start of cases, on January 20, 2020, China notified the first case in a child. Studies conducted in China, European countries, and the United States of America estimate that 1 to 5% of confirmed cases of COVID-19 occur in the population subgroup of children and adolescents55. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep 2020; 69(14): 422-6. https://doi.org/10.15585/mmwr.mm6914e4
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,66. Bellino S, Punzo O, Rota MC, Manso M, Urdiales AM, Andrianou X, et al. COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy. Pediatrics 2020; 146(4): e2020009399. https://doi.org/10.1542/peds.2020-009399
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. Still, the first major report from the Chinese Center for Disease Control and Prevention showed that of the 44,672 confirmed cases, only one death occurred among children and adolescents77. Safadi MA. The intriguing features of COVID-19 in children and its impact on the pandemic. J Pediatr (Rio J) 2020; 96(3): 265-8. https://doi.org/10.1016/j.jped.2020.04.001
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. In Brazil, the notification of the first case in this age group was on March 4, about a week after the notice of the arrival of the virus in the country88. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Coordenação-Geral do Programa Nacional de Imunizações. Grupo Técnico-Influenza. Dados do Sivep Gripe. Brasil: Ministério da Saúde; 2020..

Until epidemiological week (EW) 31, which ended on August 1, 2020, 17,580,163 cases of the disease have been confirmed worldwide. At the time, Brazil already accumulated 2,707,877 cases99. Brasil. Boletim Epidemiológico COVID-19. 2020; (25)..

Among the issues that seek to explain the relatively small number of children and adolescents affected by COVID-19 is the fact that these people present the ongoing development of the cellular and humoral immune system, the possible protection from previous infections by the respiratory syncytial virus, and the immaturity of receptors called angiotensin 2 (ACE-2) converting enzymes in childhood1010. Nunes MDR, Pacheco STA, Costa CIA, Silva JA, Xavier WS, Victória JZ. Exames diagnósticos e manifestações clínicas da COVID-19 em crianças: revisão integrativa. Texto Contexto - Enferm 2020; 29: e20200156. https://doi.org/10.1590/1980-265x-tce-2020-0156
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. In addition, the control measures proposed by the governments, which include the closure of educational institutions and the consequent greater social isolation, stand out1111. Vilelas JMDS. O novo coronavírus e o risco para a saúde das crianças. Rev Latino-Am Enfermagem 2020; 28. https://doi.org/10.1590/1518-8345.0000.3320
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.

An aspect of interest relates to the role of children and adolescents as reservoirs of SARS-CoV-2 and in the dynamics of disease transmission1212. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 infection in children. N Engl J Med 2020; 382(17): 1663-5. https://doi.org/10.1056/nejmc2005073
https://doi.org/https://doi.org/10.1056/...
,1313. Qiu H, Wu J, Hong L, Luo Y, Song Q, Chen D. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect Dis 2020; 20(6): 689-96. http://dx.doi.org/10.1016/S1473-3099(20)30198-5
https://doi.org/http://dx.doi.org/10.101...
,1414. Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020; 382(12): 1177-9. https://doi.org/10.1056/nejmc2001737
https://doi.org/https://doi.org/10.1056/...
,1515. Kam K, Yung CF, Cui L, Pin Lin RT, Mak TM, Maiwald M, et al. A well infant with coronavirus disease 2019 (COVID-19) with high viral load. Clin Infect Dis 2020; 71(15): 847-9. http://dx.doi.org/10.1093/cid/ciaa201
https://doi.org/http://dx.doi.org/10.109...
,1616. Zhang T, Cui X, Zhao X, Wang J, Zheng J, Zheng G, et al. Detectable SARS-CoV-2 viral RNA in feces of three children during recovery period of COVID-19 Pneumonia. J Med Virol 2020; 92(7): 909-14. http://dx.doi.org/10.1002/jmv.25795
https://doi.org/http://dx.doi.org/10.100...
. The adoption of preventive measures such as respiratory etiquette, hand washing, social distancing, among others, is not well understood by this age group and, for children under two years old, pediatricians do not recommend mask use, since there is a risk of suffocation1717. Zomer TP, Erasmus V, van Beeck EF, Tjon-A-Tsien A, Richardus JH, Voeten HA. Hand hygiene compliance and environmental determinants in child day care centers: an observational study. Am J Infect Control 2013; 41(6): 497-502. https://doi.org/10.1016/j.ajic.2012.06.005
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,1818. Clark J, Henk JK, Crandall PG, Crandall MA, O’Bryan CA. An observational study of handwashing compliance in a child care facility. Am J Infect Control 2016; 44(12): 1469-74. https://doi.org/10.1016/j.ajic.2016.08.006
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.

At the end of April 2020, doctors in the United Kingdom issued an alert on the occurrence of clinical manifestations temporarily related to COVID-19 infection in children and adolescents, called Pediatric Multisystem Inflammatory Syndrome1919. Davies P, Evans C, Kanthimathinathan HK, Lillie J, Brierley J, Waters G, et al. Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study. Lancet Child Adolesc Health 2020; 4: 669-77. https://doi.org/10.1016/S2352-4642(20)30215-7
https://doi.org/https://doi.org/10.1016/...
.

Given these peculiarities related to these age groups, and the importance of understanding the impact of the new coronavirus in the community, there is a need to generate evidence on hospital admissions of children and adolescents by the COVID-19 Brazil, to contribute to the conduct of actions to protect and promote the health of the public, as well as to inform decision-making.

In this sense, this article aims to analyze children and adolescents hospitalized for COVID-19 in Brazil, with the specific objectives of:

  • characterize the study population in time, person and place;

  • estimate the in-hospital mortality rate per federal unit (FU);

  • analyze factors associated with COVID-19 deaths in this population subgroup.

METHODS

A retrospective cohort study of hospitalized children and adolescents was conducted, with a diagnosis of COVID-19 confirmed in the molecular biology test (reverse transcription followed by polymerase chain reaction - Real-Time PCR) and with detectable result for SARS-CoV-2, having death by COVID-19 or recovery as the outcome.

Secondary, non-nominal data were used from the epidemiological Influenza Surveillance Information System (SIVEP-Gripe in its Portuguese acronym), in the public domain, made available on the Ministry of Health’s (MS) website and accessed on September 14, 2020, including reported cases with a date of onset of signs and symptoms between March 1 and August 1, 2020 (EW 10 to 31).

The data analyzed comprised the 27 FU of the country, with an estimated population of 211.7 million people in 2020. Children under 19 represent 31.2%, with 66.1 million children and adolescents2020. Instituto Brasileiro de Geografia e Estatística. Estratificação da população estimada segundo faixas etárias [Internet]. Brasil: Instituto Brasileiro de Geografia e Estatística [acessado em 21 maio 2020]. Disponível em Disponível em https://observatoriocrianca.org.br/cenario-infancia/temas/populacao/1048-estratificacao-da-populacao-estimada-pelo-ibge-segundo-faixas-etarias?filters=1,1626;1,1627
https://observatoriocrianca.org.br/cenar...
.

The individual aged between 0 (zero) and 11 full years was considered as a child and the adolescent was considered as one belonging to the age group of 12 to 18 full years2121. Brasil. Presidência da República. Lei n⁰ 8.609 de 13 de julho de 1990 - Estatuto da Criança e do Adolescente [Internet]. 1990 [acessado em 1º out. 2020]. Disponível em: Disponível em: http://www.planalto.gov.br/ccivil_03/leis/l8069.htm
http://www.planalto.gov.br/ccivil_03/lei...
.

The following case definitions were used:

  • Severe Acute Respiratory Syndrome (SARS): case of COVID - 19 with the presence of at least one of the following signs and symptoms: dyspnea, respiratory distress, low O2 saturation (<95%) in ambient air and cyanosis2222. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Coordenação-Geral do Programa Nacional de Imunizações. Grupo Técnico-Influenza. Guia de Vigilância Epidemiológica. Vigilância de Síndromes Respiratórias Agudas. COVID-19. Brasil: Ministério da Saúde ; 2020..

  • Critical-SARS: case of SARS that required hospitalization in an intensive care unit (ICU) or required ventilatory support, invasive or non-invasive.

The definition of SARS was based on that described in the chapter on Surveillance of Severe Acute Respiratory Syndromes of the Epidemiological Surveillance Guide2222. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Coordenação-Geral do Programa Nacional de Imunizações. Grupo Técnico-Influenza. Guia de Vigilância Epidemiológica. Vigilância de Síndromes Respiratórias Agudas. COVID-19. Brasil: Ministério da Saúde ; 2020., and the definition of critical-SARS developed for this study was adapted from Chung’s et al. classifications 2323. Chung M, Bernheim A, Mei X, Zhang N, Huang M, Zeng X, et al. CT imaging features of 2019 novel coronavirus (2019-nCoV). Radiology 2020; 295(1): 202-7. https://doi.org/10.1148/radiol.2020200230
https://doi.org/https://doi.org/10.1148/...
in order to analyze the level of severity and the risk factor for death.

The variables of interest approached in this study were: epidemiologic week of the onset of symptoms, changes in (deaths, and recovered), date of development, and FU of residence, and hospital stay; sex (male, female, and unspecified); age in years; self-reported color-race (white, black, yellow, brown, and indigenous); signs and symptoms, comorbidity, chest X-Ray results (normal, interstitial infiltrates, consolidation, joint, and other), hospitalization in the ICU; ventilatory support (invasive and non-invasive); and the use of the antiviral medication. For the analysis of death-associated factors, secondary variables were created and added based on the main ones, namely: age in years/age group (child and adolescent); race/color (black/brown and white) 2424. Instituto Brasileiro de Geografia e Estatística. Diretoria de Pesquisas. Coordenação de Trabalho e Rendimento. Pesquisa Nacional por Amostra de Domicílio Contínua 2012/2019 [Internet]. Instituto Brasileiro de Geografia e Estatística [acessado em 22 maio 2020]. Disponível em Disponível em https://www.ibge.gov.br/estatisticas/sociais/trabalho/17270-pnad-continua.html?=&t=o-que-e
https://www.ibge.gov.br/estatisticas/soc...
,2525. Instituto Brasileiro de Geografia e Estatística. Diretoria de Pesquisas. Coordenação de População e Indicadores Sociais. Desigualdades sociais por cor ou raça no Brasil [Internet]. Rio de Janeiro: Instituto Brasileiro de Geografia e Estatística; 2019 [acessado em 22 maio 2020]. Disponível em: Disponível em: https://biblioteca.ibge.gov.br/index.php/biblioteca catalogo?view=detalhes&id=2101681
https://biblioteca.ibge.gov.br/index.php...
; SARS and critical-SARS.

For the descriptive analysis, measures of absolute and relative frequency, central tendency and dispersion were calculated. The in-hospital mortality rate was calculated considering the total number of hospital deaths divided by the total number of hospitalized cases, multiplied by 100. For the bivariate analysis, Fisher’s Exact Test was applied, as an association measure the gross Relative Risk (RR) with confidence interval (CI) 95% and p < 0.05, and in the comparison between medians, the Mann-Whitney U test was used.

In order to remove possible confounding factors, multivariate statistical analysis was performed using Poisson regression with robust variance, considering the number of independent variables obtained by bivariate analysis (p < 0.20). Thus, the option was a regression of the type backward stepwise. The association measure adopted was the adjusted relative risk (adjusted RR), respecting the absence of multicollinearity (correlation between two or more independent variables) in the model. The likelihood-ratio test was considered for choosing the best model.

For data processing and analysis, the following programs were used: Epi InfoTM 7.2, Stata/SE 13.1, QGIS 2.18 “Las Palmas” and Microsoft Excel 2016.

RESULTS

In the period between March 1 and August 1, 2020, corresponding to EW 10 to 31, 302,066 hospitalized cases for COVID-19 were reported, of which 295,867 (97.9%) were adults and elderly and 6,199 (2.1%) were children and adolescents. Of these, 365 (5.9%) were diagnosed according to clinical and epidemiological criteria and 904 (14.6%) had no record of the outcome. As shown in Figure 1, in the study period, 4,930 (79.5%) cases with outcome (death or recovery) constituted the study population, of which 500 (10.1%) evolved to death and 4,430 (89.9%) were classified as recovered. Among the deaths, 323 (64.6%) were children (zero to 11 full years).

Figure 1.
Distribution flowchart of hospitalized cases for COVID-19, from March 1 to August 1, Brazil, 2020.

Regarding the distribution of cases over the period, it was observed that 1,554 (31.5%) of hospitalizations occurred between EW 10 to 20 (March 1 to May 16, 2020), with an average of three deaths/day, and 3,376 (68.5%) between EW 21 to 31 (May 17 to August 1, 2020), with an average of four deaths/day (data not presented in table).

Considering the distribution of cases according to the FU of residence, São Paulo had the highest frequency of hospitalized patients, with 1,320 (26.8%), of which 1,247 (94.5%) recovered and 73 (4.5%) evolved to death. Subsequently the Amazon with 517 (10,5%) hospitalized patients, of which 491 (95,0%) recovered and 26 (5%) died (Figures 2A and 2B and Supplementary Material).

Figure 2.
(A) Recovered cases of children and adolescents hospitalized by COVID-19 second federative unit of residence, March 1 to August 1, Brazil, 2020; (B) Deaths of children and adolescents hospitalized by COVID-19 second Federative unit of residence, March 1 to August 1, Brazil, 2020; (C) Intra-hospital mortality rates per federative unit of hospitalization, March 1 to August 1, Brazil, 2020.

Regarding the highest in-hospital mortality rates per FU of hospitalization, Roraima presented 68.8% (n = 11/16), Acre 35.7% (n = 5/14) and Alagoas 24.6% (n = 17/69) (Figure 2C).

Of the total of 4,930 cases, 3,610 were children (73.2%) and 1,320 (26.8%) adolescents. Males represented 2,553 (51.8%).

The mean age of children and adolescents was 6.2 years (SD = 6.4). The mean of those who progressed to death was 6.8 years (SD = 7.1) and for those recovered, it was 6.1 years (SD = 6.4) (Table 1).

Table 1.
Characterization of hospitalized cases of COVID-19 in children and adolescents, according to sex, age group, ethnicity/skin color, and evolution (n = 4,930) from March 1 to August 1, Brazil, 2020

The highest fatality rates occurred in the age groups of 15 to 18 years, with 13.6%, from 12 to 14 years, with 13.1%, and of children under one year old, with 12.6% (Table 1).

Among those under one year old, 171 (4.7%) had symptoms on the same day of birth, of which 33 (19.3%) developed to death. Among the latter, 18 (54.5%) were hospitalized in the ICU, with a median of zero day (Q1-Q3: 0 - 0) between the date of onset of signs and symptoms and hospitalization. The median between the date of onset of signs and symptoms and the date of diagnosis by RT-PCR was six days (Q1-Q3: 3 - 9) (data not shown in Table).

Of the 4,930 cases, 2,335 (47.4%) self-reported race-color as Brown, of which 250 (10.7%) died. The race/color white comes next, with 1,237 (25.1%) cases, of which 98 (7.9%) were death (Table 1).

A total of 1,219 (24.7%) cases were admitted to the ICU. Of these, 300 (24.6%) progressed to death and 919 (75.4%) recovered. As for the imaging tests of the cases admitted to the ICU, 667 (54.7%) had chest X-ray records, resulting in interstitial infiltrate present in 68 (22.7%) deaths and 187 (20.3%) recovered. Regarding ventilatory support during ICU hospitalization, of 822 cases (67.4%) that received this resource, 442 (53.8%) needed the invasive type, of which 220 (49.8%) developed to death and 222 (50.2%) recovered (data not presented in Table).

Of the 4,930 cases, 3,180 (64.5%) met the definition of SARS, of which 1,857 (37.7%) met the definition of critical-SARS.

The most frequent signs and symptoms among the 500 cases of SARS that evolved into death were dyspnea with 350 (70%), respiratory distress with 346 (69.2%), fever with 339 (67.8%) and low oxygen saturation with 300 (60%) (Figure 3A). Among the 207 deaths with comorbidities, the most frequent were immunopathology with 56 (27.1%), heart disease with 53 (25.6%) and neuropathy with 50 (24.2%) (Figure 3B).

Figure 3.
(A) Signs and symptoms of cases hospitalized by COVID-19 in children and adolescents according to evolution, March 1 to August 1, Brazil, 2020 (n = 4,930); (B) Comorbidities of cases hospitalized by COVID-19 in children and adolescents according to evolution, March 1 to August 1, Brazil, 2020 (n = 1,214).

The median time between onset of symptoms and hospitalization was three days for both deaths and recoveries (Q1-Q3: from 0 to 6, and from 1 to 6, respectively; p = 0.006); The median period of time between the check-in and for the change, for those who have died, it was six days (Q1-Q3: 2 - 14), and the recovered five days (Q1-Q3: 3 - 11) with p = 0.971; and, in between, the hospital stay in the ICU, and the evolution to death was five days (Q1-Q3: 2 - 14, 2 - 11, respectively; p = 0.591).

In the bivariate analysis, it was found that they had a higher risk of progressing to death in all the cases that were presented to the following factors: being in the age group of adolescents (RR = OR 1.49; 95% CI 1.26 - 1,78; p < 0.001); - be of the race/color, self-reported black/mixed-brown race (RR = 1.34; 95%CI 1.08 - cop $ 1.68; p < 0.008); it has been ranked as critical-SARS (RR = 4.13; 95%CI 3.43 - 3.96; p < 0.001); have heart disease (RR = WITH 2.07; 95%CI 1.58 - 2.72; p < 0.001), immunopathology (RR = 1.74; 95%CI 1.32 - 2.30; p < 0.001), diabetes (RR= 1.57; 95%CI 1.08 - 2.30; p = 0.032), and neuropathy (RR = 1.47; 95%CI 1.09 - to 1.97; p = 0.013). Asthma was configured as a risk reduction factor for death (RR = 0.25; 95%CI 0.10 - 0.62; p = 0.003 (Table 2).

Table 2.
Bivariate and multivariate analysis of factors associated with the risk of developing to death from COVID-19 in children and adolescents, March 1 to August 1, Brazil, 2020 (R2 = 0.1381).

The other variables that are related to the signs and symptoms of respiratory disease were tested in a bivariate analysis, that is, low oxygen saturation (RR = 4.12; 95%CI 3,33 - 5,09; p < 0.001), respiratory distress (RR = 3.23; 95%CI 2.57 - 4.06; p < 0.001), dyspnea (RR = 3; 95%CI 2.39 - 3.78; p < 0.001), and cyanosis (RR = 2.89; 95%CI 1.66 - 5.05; p = 0.003) (data not shown in table). These variables were grouped in the set of the critical-SARS variable to compose the best regression model.

Multivariate analysis showed that these associated factors with COVID-19 death remained: belonging to the adolescent age group (RR = 1.59; 95%CI 1.12 - 2.25; p = 0.009), having been classified as SARS-critical (RR = 4.56; 95%CI 2.77 - 7.51; p < 0.001) and having immunopathology (RR = 2.24; 95%CI 1.58 - 3.17; p < 0.001). Asthma remained a factor associated with reduced risk of death (RR = 2.24; 95%CI 1.58 - 3.17; p < 0.001) (Table 2).

DISCUSSION

The present study characterized the cases of COVID-19 that occurred in children and adolescents in Brazil who were hospitalized and reported in Sivep-Gripe. More than two-thirds of the cases were recorded in children under five years old and more than half of the cases occurred in male children and adolescents.

Although the population most susceptible to the new coronavirus is mainly composed of elderly people with low immunity2626. Li W, Cui H, Li K, Fang Y, Li S. Chest computed tomography in children with COVID-19 respiratory infection. Pediatr Radiol [Internet] 2020 [acessado em 14 abr. 2020]; 50(6): 796-9. Disponível em: https://dx.doi.org/10.1007/s00247-020-04656-7
https://doi.org/https://dx.doi.org/10.10...
, it should be noted that respiratory viruses are a common cause of respiratory tract infection in children, being considered an important reason for hospitalizations2727. Lin C-Y, Hwang D, Chiu N-C, Weng L-C, Liu H-F, Mu J-J, et al. Increased detection of viruses in children with respiratory tract infection using PCR. Int J Environ Res Public Health [Internet]. 2020 [acessado em 11 abr. 2020]; 17(2): 564. Disponível em: https://dx.doi.org/10.3390/ijerph17020564
https://doi.org/https://dx.doi.org/10.33...
.

At the beginning of the pandemic, the discussion began on the role of children and adolescents as reservoirs of SARS-CoV-2 and in the dynamics of disease transmission1212. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 infection in children. N Engl J Med 2020; 382(17): 1663-5. https://doi.org/10.1056/nejmc2005073
https://doi.org/https://doi.org/10.1056/...
,1313. Qiu H, Wu J, Hong L, Luo Y, Song Q, Chen D. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect Dis 2020; 20(6): 689-96. http://dx.doi.org/10.1016/S1473-3099(20)30198-5
https://doi.org/http://dx.doi.org/10.101...
,1414. Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020; 382(12): 1177-9. https://doi.org/10.1056/nejmc2001737
https://doi.org/https://doi.org/10.1056/...
,1515. Kam K, Yung CF, Cui L, Pin Lin RT, Mak TM, Maiwald M, et al. A well infant with coronavirus disease 2019 (COVID-19) with high viral load. Clin Infect Dis 2020; 71(15): 847-9. http://dx.doi.org/10.1093/cid/ciaa201
https://doi.org/http://dx.doi.org/10.109...
,1616. Zhang T, Cui X, Zhao X, Wang J, Zheng J, Zheng G, et al. Detectable SARS-CoV-2 viral RNA in feces of three children during recovery period of COVID-19 Pneumonia. J Med Virol 2020; 92(7): 909-14. http://dx.doi.org/10.1002/jmv.25795
https://doi.org/http://dx.doi.org/10.100...
. It is important to emphasize that these scenarios have changed with the new clinical presentations of the disease in children. This is because some of them evolved into Pediatric Multisystem Inflammatory Syndrome, with severe clinical manifestations and similar picture to those observed in children and adolescents with Kawasaki disease, incomplete Kawasaki disease, and/or toxic shock syndrome2828. Mahase E. Covid-19: concerns grow over inflammatory syndrome emerging in children. BMJ [Internet] 2020 [acessado em 13 jun. 2020]; 369: m1710. Disponível em: https://dx.doi.org/10.1136/bmj.m1710
https://doi.org/https://dx.doi.org/10.11...
, which were not objects of this study.

A considerable number of children was found presenting signs and symptoms less than 24 hours after birth, and almost a fifth of these children evolved to death, most having been admitted to the ICU on the same day they were born - although there is still missing information on the serological condition of their mothers during pregnancy. Even so, the suspicion of vertical transmission is raised, corroborating Alzamora et al., who reported cases of infection in newborns with RT - PCR positive between 16 and 30 hours after birth, pointing to this possibility2929. Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, Rosa M. COVID-19 grave durante a gravidez e possível transmissão vertical. Am J Perinatol 2020; 37(8): 861-5. https://doi.org/10.1055/s-0040-1710050
https://doi.org/https://doi.org/10.1055/...
.

The self-declared ethnicity/skin color parda represents half of those who evolved to death, being the predominant ethnicity/skin color in the Brazilian population of low income, right next to the black2525. Instituto Brasileiro de Geografia e Estatística. Diretoria de Pesquisas. Coordenação de População e Indicadores Sociais. Desigualdades sociais por cor ou raça no Brasil [Internet]. Rio de Janeiro: Instituto Brasileiro de Geografia e Estatística; 2019 [acessado em 22 maio 2020]. Disponível em: Disponível em: https://biblioteca.ibge.gov.br/index.php/biblioteca catalogo?view=detalhes&id=2101681
https://biblioteca.ibge.gov.br/index.php...
, which indicates the importance of social inequalities in the evolution of the disease. The study by Silva Filho et al. suggests that the lack of home infrastructure leads to a higher risk of contagion and spread of respiratory infections3030. Silva Filho EBS, Silva AL, Santos AO, Dall’Acqua DSV, Souza LFB. Infecções Respiratórias de Importância Clínica: uma Revisão Sistemática. Rev FIMCA 2017; 4(1): 716. https://doi.org/10.37157/fimca.v4i1.5
https://doi.org/https://doi.org/10.37157...
. Souza also showed that mortality from respiratory diseases increased worryingly in all Brazilian regions3131. Souza IDTD. Mortalidade por doenças respiratórias no Brasil e suas regiões: série histórica 2000-2013 [trabalho de conclusão de curso]. Natal: Universidade Federal do Rio Grande do Norte; 2016.. Given the considered levels of social inequality in the country, a disproportionate effect of COVID-19 among the most vulnerable is likely.

As to the signs and symptoms presented, most of those who died presented dyspnea, respiratory distress, fever, low oxygen saturation, and cough. As for comorbidities, there was a predominance of immunopathologies, followed by unspecified heart diseases and neuropathies.

A study conducted in Iran with 30 children hospitalized with COVID-19 found similar results regarding clinical manifestations and comorbidities. There were reports of leukemia among the comorbidities present in some children who evolved to death, with fever, dyspnea, and cough being the most frequently presented signs and symptoms3232. Soltani J, Sedighi I, Shalchi Z, Sami G, Moradveisi B, Nahidi S. Pediatric coronavirus disease 2019 (COVID-19): An insight from west of Iran. North Clin Istanb [Internet] 2020 [acessado em 11 jun. 2020]; 7(3): 284-91. Disponível em: https://dx.doi.org/10.14744%2Fnci.2020.90277
https://doi.org/https://dx.doi.org/10.14...
.

Almost a third of those hospitalized needed ICU care. However, more than a third of those who needed ventilatory support received it invasively. Among the changes observed on the chest X-ray of these patients, more than two-thirds of those who presented interstitial infiltrate died.

The Roraima FU showed the highest in-hospital mortality rate in the analyzed period. This rate may be overestimated, since this FU and Acre State together have the lowest hospitalization records, which may suggest underreporting of hospitalized cases. It should be recalled that, for this study, only cases with outcome (death or recovery) were considered.

Multivariate analysis of factors associated with COVID-19 death showed that adolescents had a higher risk of developing death compared to children. Some hypotheses may explain this peculiarity, including that children have lower expression of ACE-2, and immature ACE-2 receptors in childhood may hinder cell invasion. The other would be the existence of some protection due to previous infections by the respiratory syncytial virus1010. Nunes MDR, Pacheco STA, Costa CIA, Silva JA, Xavier WS, Victória JZ. Exames diagnósticos e manifestações clínicas da COVID-19 em crianças: revisão integrativa. Texto Contexto - Enferm 2020; 29: e20200156. https://doi.org/10.1590/1980-265x-tce-2020-0156
https://doi.org/https://doi.org/10.1590/...
,3333. Sociedade Brasileira de Pediatria. Departamento Científico de Pneumologia. Nota de Alerta. COVID-19 em crianças: envolvimento respiratório [Internet]. Sociedade Brasileira de Pediatria; 2020 [acessado em 13 jun. 2020]. Disponível em: Disponível em: https://www.sbp.com.br/imprensa/detalhe/nid/covid-19-em-criancas-envolvimento-respiratorio/
https://www.sbp.com.br/imprensa/detalhe/...
. Those who progressed to the critical stage of the disease (SARS-critical) presented almost five times more risk of evolving to death. Cough and headache were not directly associated factors, but were determinants for increased risk when present, independently adjusting the regression model analyzed with other variables.

Among the comorbidities, immunopathology was an important factor associated with COVID-19 death in hospitalized children and adolescents. In this study, although most of those who evolved to death had heart disease and/or neuropathy as a underlying disease, these comorbidities did not remain as factors directly associated to death, but were important for increased risk, independently adjusting the regression model analyzed with other variables.

Considering that COVID-19 predominantly affects the respiratory tract and that respiratory virus infections are frequent causes of complication of asthma, there is concern that COVID-19 has a more severe presentation in asthmatic patients. Thus, several institutions linked to health considered asthma patients as a likely risk group for COVID-193434. Portugal. Direção-Geral de Saúde. COVID-19: Fase de mitigação abordagem do doente com suspeita ou infeção por SARS-CoV-2. Norma Orientação Clínica 004/2020 [Internet]. 2020 [acessado em 30 jul. 2020]. Disponível em: Disponível em: https://covid19.min-saude.pt/normas
https://covid19.min-saude.pt/normas...
,3535. Center of Disease Control COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 [Internet]. MMWR Morb Mortal Wkly Rep 2020 [acessado em 30 jul. 2020]; 69(13): 382-6. Disponível em: Disponível em: https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6913e2-H.pdf
https://www.cdc.gov/mmwr/volumes/69/wr/p...
. In this study, asthma was observed as a risk reduction factor for COVID-19 death in bivariate and multivariate analysis. Those who have this underlying disease could possibly be controlled at the time they were infected with SARS-CoV-2 or received differentiated care during hospitalization. It may also be that they were under corticosteroid treatment before becoming infected with SARS-CoV-2, which may positively influence the evolution of COVID-193636. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19. JAMA 2020; 324(13): 1330-41. http://doi.org/10.1001/jama.2020.17023
https://doi.org/http://doi.org/10.1001/j...
.

The results herein represent the population of children and adolescents hospitalized for COVID-19 and notified in the Sivep-Gripe throughout the national territory. Among the limitations, it was not possible to analyze the variables chest-in drawing and vacillation of nasal wing, which are important signs of severity in children, because they are variables that do not exist in the database, and these data were optionally recorded as other signs. Even though, many signs and symptoms may be underestimated due to the high occurrence of incompleteness, resulting from the lack of updating of the database, according to the patient’s evolution.

Children and adolescents, in addition to being seen as an age group with an important role in the dynamics of transmission1212. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 infection in children. N Engl J Med 2020; 382(17): 1663-5. https://doi.org/10.1056/nejmc2005073
https://doi.org/https://doi.org/10.1056/...
,1313. Qiu H, Wu J, Hong L, Luo Y, Song Q, Chen D. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect Dis 2020; 20(6): 689-96. http://dx.doi.org/10.1016/S1473-3099(20)30198-5
https://doi.org/http://dx.doi.org/10.101...
,1414. Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020; 382(12): 1177-9. https://doi.org/10.1056/nejmc2001737
https://doi.org/https://doi.org/10.1056/...
,1515. Kam K, Yung CF, Cui L, Pin Lin RT, Mak TM, Maiwald M, et al. A well infant with coronavirus disease 2019 (COVID-19) with high viral load. Clin Infect Dis 2020; 71(15): 847-9. http://dx.doi.org/10.1093/cid/ciaa201
https://doi.org/http://dx.doi.org/10.109...
,1616. Zhang T, Cui X, Zhao X, Wang J, Zheng J, Zheng G, et al. Detectable SARS-CoV-2 viral RNA in feces of three children during recovery period of COVID-19 Pneumonia. J Med Virol 2020; 92(7): 909-14. http://dx.doi.org/10.1002/jmv.25795
https://doi.org/http://dx.doi.org/10.100...
, also present vulnerability factors for aggravation. Therefore, there is still much to be discovered about SARS-CoV-2 infection in children and adolescents. However, the findings of this study bring attention to reflect on the most vulnerable subgroups and immunological conditions related to severity and death.

Children and adolescents vulnerable to the severity and death from COVID-19 must be included in public health policies as a risk group. In addition, it is necessary, during the on-going pandemic, to maintain active surveillance for children and adolescents, especially those with chronic diseases, particularly immunopathologies, cardiopathies, and neuropathies, which are part of a group of great importance and of greater risk for the severity and death from COVID-19. In addition, detailed investigation of children diagnosed with COVID-19 who have started signs and symptoms less than 24 hours after birth must be carried out to show a possible vertical transmission.

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  • Financial support: Training Program of Epidemiology Applied to the Services of the Brazilian Unified Health System (SUS), of the Health Surveillance Secretariat of the Ministry of Health, and Regional Project for Strengthening Disease Surveillance Systems in West Africa (REDISSE).

Publication Dates

  • Publication in this collection
    09 Aug 2021
  • Date of issue
    2021

History

  • Received
    01 Mar 2021
  • Reviewed
    14 Apr 2021
  • Accepted
    14 Apr 2021
  • Preprint
    16 Apr 2021
Associação Brasileira de Pós -Graduação em Saúde Coletiva São Paulo - SP - Brazil
E-mail: revbrepi@usp.br