Editorial
The intriguing features of COVID-19 in children and its impact on the pandemic
As características intrigantes da COVID-19 em crianças e seu impacto na pandemia
Marco Aurélio Palazzi Safadi
Faculdade de Ciências Médicas da Santa Casa de São Paulo, Departamento de Pediatria, São Paulo, SP, Brazil
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"apellidos" => "Silveira" ] 2 => array:2 [ "nombre" => "Paolo" "apellidos" => "Manzoni" ] 3 => array:2 [ "nombre" => "Guilherme" "apellidos" => "Sant’Anna" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "pt" => array:9 [ "pii" => "S2255553620300410" "doi" => "10.1016/j.jpedp.2020.04.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2255553620300410?idApp=UINPBA000049" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755720301431?idApp=UINPBA000049" "url" => "/00217557/0000009600000003/v2_202006040749/S0021755720301431/v2_202006040749/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "The intriguing features of COVID-19 in children and its impact on the pandemic" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "265" "paginaFinal" => "268" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Marco Aurélio Palazzi Safadi" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Marco Aurélio Palazzi" "apellidos" => "Safadi" "email" => array:1 [ 0 => "masafadi@uol.com.br" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Faculdade de Ciências Médicas da Santa Casa de São Paulo, Departamento de Pediatria, São Paulo, SP, Brazil" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "As características intrigantes da COVID-19 em crianças e seu impacto na pandemia" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In December, 2019 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, emerged in China, associated with reported clusters of patients with pneumonia who were epidemiologically linked to a seafood and wet live animal market in the city of Wuhan, Hubei Province.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">1</span></a> COVID-19, the term used for the clinical disease caused by SARS-CoV-2, was declared a pandemic by the World Health Organization (WHO) on March 11 — the first ever caused by a coronavirus.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">2</span></a> As of April 2nd, the number of confirmed cases worldwide has almost reached one million, with 50,000 deaths, and with confirmed cases in almost all countries from all continents.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">3</span></a> The number of reported COVID-19 cases is certainly underestimating the true burden of disease, given the widespread unavailability of tests, and also the significant proportion of persons that, despite being infected, develop asymptomatic or mild unidentified forms of the disease.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">4</span></a> Therefore, we should be careful when calculating the case fatality rates (CFR) of COVID-19 (currently at global rates as high as 5%), acknowledging that these rates will likely be lower once the denominator is adjusted to reflect the true number of individuals who acquired the infection. Seroprevalence studies, once available, will provide information on the proportion of the population that was infected, making possible a more accurate estimation of the CFR associated with COVID-19 in the different age groups and populations.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Given the rapid spread (determined by its basic reproduction number – <span class="elsevierStyleItalic">R</span><span class="elsevierStyleInf">0</span>, estimated at the beginning of the epidemic as a value of 2.38 [95% CI: 2.04–2.77])<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">4</span></a> and the profound global impact of COVID-19, with increasing rates of hospitalizations and mortality among a population fully naïve to the virus, as well as the lack of available vaccines or specific efficacious antivirals against SARS-CoV-2, the COVID-19 pandemic represents the most serious public health threat associated with a respiratory viral infection since the 1918 influenza A H1N1 pandemic.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Preliminary data from China, confirmed in the most recent experience from Europe and US, shows that the elderly, particularly those with determined underlying health conditions, are disproportionally at higher risk for severe COVID-19-associated illness and death when compared with younger adults, adolescents, and children.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">6–10</span></a> In the first large report from the Chinese Center for Disease Control and Prevention, including 44,672 confirmed cases of COVID-19, only one death occurred in a person aged ≤19 years and approximately 80% of deaths occurred among adults aged ≥ 60 years.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">8</span></a> The first report from the US of outcomes among patients with COVID-19 has indicated that 80% of deaths occurred among adults aged ≥65 years, with the highest percentage of severe outcomes among persons aged ≥85 years, and no fatalities among persons aged ≤19 years.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">9</span></a> In Italy, only 1.1% of the initial deaths reported occurred among persons <50 years, and none of them were children.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">One of the most striking and consistent findings from COVID-19 reports globally is that, in contrast with infected adults, children rarely experience severe forms of the disease. The spectrum of manifestations described in 171 children (1 day–15 years) infected with SARS-CoV-2 and treated at the Wuhan Children's Hospital showed that the most common signs and symptoms included cough (present in 48.5% of the cases), pharyngeal erythema (46.2%), and fever (41.5%). Other less common signs and symptoms found in less than 10% of the children were diarrhea, fatigue, rhinorrhea, and nasal congestion. Tachypnea on admission was found in 28.7% of the children and hypoxemia (oxygen saturation <92% during the period of hospitalization) in only 2.3% of the children. The most common radiologic finding was bilateral ground glass opacity, observed in 1/3 of the cases.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">11</span></a> Strikingly, and similar to what has been observed in adults with COVID-19 pneumonia,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a> imaging abnormalities were found in chest computed tomography (CT) from asymptomatic children, highlighting the concept that evaluation of imaging features with clinical and laboratory findings may facilitate early diagnosis of COVID-19 pneumonia.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In the largest case series of pediatric patients reported to date, 2143 children with suspected or confirmed COVID-19 were included. Among the 731 children with virologically-confirmed disease, 94 (12.9%), 315 (43.1%), and 300 (41%) were classified as asymptomatic, mild, or moderate cases, respectively, together accounting for 97% of the confirmed cases. The proportions of children classified as severe and critical cases, respectively 2.5% and 0.6%, were substantially lower than those observed in adults with COVID-19. Interestingly, infants and pre-school children were more likely to have severe clinical manifestations than older children, which is in line with previous data of children with non-SARS-CoV-2 coronavirus infections.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">13</span></a> In another study that investigated the clinical features of a cohort of 36 children with COVID-19 in China, the authors found that approximately half of the cases were either asymptomatic or had only mild acute upper respiratory symptoms, and the other half had moderate disease with pneumonia. Clinical manifestations of COVID-19 in children are much milder than in adults.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">14</span></a> Compared with pediatric patients with influenza infection, children with COVID-19 had a larger proportion of asymptomatic cases, although pneumonia was more prevalent. Based on the experience from the first cases treated in our hospital in Sao Paulo (unpublished data), pediatricians should be alert for the possibility of co-infections with other respiratory viruses when treating infants and young children with COVID-19.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Available data on COVID-19 severity in children with comorbidities are scarce, limiting the possibility to identify conditions at increased risk of complications and mortality. Clinical and laboratorial markers of disease severity and poorer outcomes are being investigated. Preliminary results, most of them from adult patients, showed that respiratory distress on admission and lymphopenia, increased cytokine levels (particularly IL-6, IL-10, and TNFα) and a rise in <span class="elsevierStyleSmallCaps">d</span>-dimer over time, and decreased IFNγ expression in CD4+ T cells are associated with severe COVID-19.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">11,15</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The reasons for the overwhelmingly lower risk of severe forms of COVID-19 in children (consistent with what was also previously observed for SARS and Middle East respiratory syndrome [MERS] coronavirus outbreaks), when compared to older age groups, remain elusive and several hypotheses have been raised to explain this phenomenon,<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">16,17</span></a> including different patterns of immunological responses across ages, with adults being more likely, once infected with SARS-CoV-2, to develop unbalanced immune responses, leading to a cytokine storm often associated with lung damage and poorer prognosis for patients, as opposed to infants and children, in whom differences in the innate immunity and a more efficient T cell response to clear the virus would be expected.<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">17,18</span></a> Cross protection acquired from prior exposure to human coronaviruses (HuCoV), frequently associated with mild infections in children, has also been raised as a theoretical explanation for the lower severity in children, which does not appear to be a reasonable hypothesis given the lack of severe cases reported in very young infants, an age group unlikely to have been previously exposed to these HuCoV infections. In my understanding, the most attractive hypothesis for the lower severity of COVID-19 may be related to the expression of angiotensin-converting enzyme 2 (ACE2) on type I and II alveolar epithelial cells. ACE2 was found to be the receptor for SARS-CoV-2, necessary for host cell entry and subsequent viral replication.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">19</span></a> Therefore, a limited expression of ACE2 in childhood, a period where lungs are still in development, could protect children from severe forms of disease. Interestingly, men have higher levels of ACE2 in their alveolar cells comparing to women, which could also explain the higher rates of worse outcomes in the male sex,<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">7–10</span></a> a trend also observed in studies in children, when comparing rates of hospitalization between boys and girls.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">11,13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Data from China looking at the risk of <span class="elsevierStyleItalic">in utero</span> transmission did not show any evidence of congenital infection with SARS-CoV-2 from mothers with COVID-19 pneumonia.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">20,21</span></a> However, two recent studies reported intriguing results: the first one<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">22</span></a> demonstrated the presence of IgM and IgG antibodies in blood sera collected at birth from two infants born to mothers with COVID-19 pneumonia, and the second one<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">23</span></a> described three infants with early-onset SARS-CoV-2 infection. Although provocative, it is important to note that none of the infants described in these two studies had virological evidence of SARS-CoV-2 infection, emphasizing the need for more data before establishing that SARS-CoV-2 infection can be acquired <span class="elsevierStyleItalic">in utero.</span></p><p id="par0045" class="elsevierStylePara elsevierViewall">Although at this time we do not know whether mothers with COVID-19 can transmit the SARS-CoV-2 <span class="elsevierStyleItalic">via</span> breast milk, the WHO, as well as the Brazilian Society of Pediatrics, made clear recommendations supporting mothers to breastfeed their infants.<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">24,25</span></a> Therefore, precautions to avoid transmission of the virus to the infant should be followed, including hand washing before holding the infant and wearing a face mask when in close contact.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A crucial point for investigation – yet to be determined – is the role of children in transmission. Several studies conducted in different populations and age groups demonstrated that a significant proportion of COVID-19 cases were diagnosed without presenting symptoms or with very mild presentations,<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">11,14,26–28</span></a> likely to be missed with the current case-definition ascertainment criteria. Despite being asymptomatic or oligosymptomatic, infected infants and children may have high viral loads in their nasopharynx, as well as fecal shedding of SARS-CoV-2 for longer periods.<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">29–31</span></a> Moreover, a study performed in Shenzen compared cases identified through symptomatic surveillance and contact tracing, showing that children were at similar risk of being infected as adults.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">32</span></a> Together, all this evidence shows that children are susceptible to SARS-CoV-2 infection, frequently presenting asymptomatic or mild forms of disease, representing a substantial source of infection in the community, which anticipates that they may play an important role in viral transmission. Robust epidemiologic studies, able to shed light on the uncertainties behind the exact role that children play on the transmission of SARS-CoV-2, are urgently needed.</p><p id="par0055" class="elsevierStylePara elsevierViewall">This information will be of paramount importance to help guide and modulate non-pharmaceutical interventions, implemented to reduce the magnitude of the epidemic peak of COVID-19 and lead to a smaller number of overall cases, hospitalizations, and deaths from this devastating disease. These interventions, which include not only home isolation of suspected cases and quarantine of household contacts, but also population-wide social distancing, as well as school and university closures, face several challenges to being implemented in a timely manner and effectively sustained for longer periods.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">5</span></a> In places like Brazil we must acknowledge that these challenges are even greater, considering the proportion of the population that lives in extreme poverty, in large, densely populated cities.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Understanding how SARS-CoV-2 emerged and jumped animal species, from a bat reservoir, and probably with Malayan pangolins acting as intermediate hosts before zoonotic transfer,<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">33</span></a> is also crucial. Among the important lessons learned from this coronavirus pandemic one is that urgent measures should be taken to extinguish these wet markets of live wild animals in Asia. These markets are a potential source for the periodic emergence of zoonotic respiratory viruses that can adapt to humans, representing a continued threat to the world, unless serious measures are taken to change this scenario.</p><p id="par0065" class="elsevierStylePara elsevierViewall">At the time of writing, no specific anti-viral is currently available to treat COVID-19. Treatment in children includes fluid and nutritional intake, together with oxygen supplementation and ventilatory support.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">34</span></a> Due to the rare number of severe cases in children, there is no data on the safety and efficacy of the different therapeutic interventions that are being tested in adults.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">35</span></a> If we mirror what was found in other respiratory infections, like influenza, one key finding was that the earlier it is possible to start the antivirals, after onset of symptoms, the better the outcomes will be. Assuming that most of these studies were performed in critical patients, usually during the late stage of the disease, we should be cautious when interpreting the results and try to design trials that have the power to answer these uncertainties on the efficacy as well as the potential side effects in the different age groups and clinical presentations of COVID-19.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The development of a vaccine against SARS-CoV-2 is a clear priority. Several platforms are being investigated, including RNA- and DNA-based vaccines, subunit-recombinant vaccines, live-attenuated vaccines, and viral vector vaccines, among others. Previous experience with candidate vaccines against SARS-CoV and MERS-CoV paved the way and will facilitate the development of vaccines for SARS-CoV-2. There is concern regarding several aspects, including the possibility of inducing antibody-dependent enhancement (ADE), increasing the risk of severe disease among vaccinated subjects, the lack of specific correlates of protection for SARS-CoV-2, the capacity for large scale production, and the need for adjuvants (to optimize immune responses as well as for dose sparing).<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Until a vaccine becomes available, which is not expected for another 12–18 months from now if everything works well, we should implement timely and effective non-pharmaceutical interventions to reduce the burden of disease and to protect the most vulnerable population, minimizing the tremendous societal cost we are already facing, expand the health-care capacity, provide sufficient protective equipment for health-care workers, stimulate frequent hand washing – and when feasible, the use of masks – and increase, as much as possible, the capacity for testing suspected cases. The time has come to, at last, learn lessons from pandemics that can be transmitted to future generations.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0080" class="elsevierStylePara elsevierViewall">The author declares no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Safadi MA. The intriguing features of COVID-19 in children and its impact on the pandemic. J Pediatr (Rio J). 2020;96:265–8.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:36 [ 0 => array:3 [ "identificador" => "bib0185" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel coronavirus from patients with pneumonia in China, 2019" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Zhu" 1 => "D. Zhang" 2 => "W. Wang" 3 => "X. Li" 4 => "B. Yang" 5 => "J. 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Halton" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMp2005630" "Revista" => array:3 [ "tituloSerie" => "N Engl J Med" "fecha" => "2020" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32222134" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/00217557/0000009600000003/v2_202006040749/S0021755720301418/v2_202006040749/en/main.assets" "Apartado" => array:4 [ "identificador" => "10177" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Editorials" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/00217557/0000009600000003/v2_202006040749/S0021755720301418/v2_202006040749/en/main.pdf?idApp=UINPBA000049&text.app=https://jped.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755720301418?idApp=UINPBA000049" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 4 | 8 |
| 2024 October | 23 | 31 | 54 |
| 2024 September | 35 | 57 | 92 |
| 2024 August | 51 | 38 | 89 |
| 2024 July | 45 | 46 | 91 |
| 2024 June | 37 | 36 | 73 |
| 2024 May | 30 | 12 | 42 |
| 2024 April | 35 | 26 | 61 |
| 2024 March | 30 | 24 | 54 |
| 2024 February | 39 | 24 | 63 |
| 2024 January | 30 | 29 | 59 |
| 2023 December | 23 | 28 | 51 |
| 2023 November | 38 | 35 | 73 |
| 2023 October | 39 | 42 | 81 |
| 2023 September | 35 | 47 | 82 |
| 2023 August | 30 | 23 | 53 |
| 2023 July | 32 | 16 | 48 |
| 2023 June | 23 | 10 | 33 |
| 2023 May | 33 | 26 | 59 |
| 2023 April | 29 | 15 | 44 |
| 2023 March | 65 | 29 | 94 |
| 2023 February | 41 | 26 | 67 |
| 2023 January | 40 | 18 | 58 |
| 2022 December | 79 | 45 | 124 |
| 2022 November | 51 | 28 | 79 |
| 2022 October | 85 | 41 | 126 |
| 2022 September | 62 | 41 | 103 |
| 2022 August | 65 | 38 | 103 |
| 2022 July | 73 | 56 | 129 |
| 2022 June | 51 | 33 | 84 |
| 2022 May | 55 | 34 | 89 |
| 2022 April | 131 | 45 | 176 |
| 2022 March | 85 | 57 | 142 |
| 2022 February | 54 | 26 | 80 |
| 2022 January | 60 | 32 | 92 |
| 2021 December | 37 | 23 | 60 |
| 2021 November | 31 | 15 | 46 |
| 2021 October | 27 | 33 | 60 |
| 2021 September | 45 | 20 | 65 |
| 2021 August | 33 | 15 | 48 |
| 2021 July | 26 | 14 | 40 |
| 2021 June | 48 | 12 | 60 |
| 2021 May | 63 | 18 | 81 |
| 2021 April | 316 | 45 | 361 |
| 2021 March | 341 | 23 | 364 |
| 2021 February | 75 | 7 | 82 |
| 2021 January | 95 | 13 | 108 |
| 2020 December | 51 | 19 | 70 |
| 2020 November | 49 | 28 | 77 |
| 2020 October | 35 | 18 | 53 |
| 2020 September | 90 | 19 | 109 |
| 2020 August | 133 | 40 | 173 |
| 2020 July | 133 | 34 | 167 |
| 2020 June | 130 | 43 | 173 |
| 2020 May | 79 | 32 | 111 |
| 2020 April | 40 | 18 | 58 |
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