Coronavirus Infections in Children Including COVID-19
Identifieur interne : 001424 ( Pmc/Corpus ); précédent : 001423; suivant : 001425Coronavirus Infections in Children Including COVID-19
Auteurs : Petra Zimmermann ; Nigel CurtisSource :
- The Pediatric Infectious Disease Journal [ 0891-3668 ] ; 2020.
Abstract
Coronaviruses (CoVs) are a large family of enveloped, single-stranded, zoonotic RNA viruses. Four CoVs commonly circulate among humans: HCoV2-229E, -HKU1, -NL63 and -OC43. However, CoVs can rapidly mutate and recombine leading to novel CoVs that can spread from animals to humans. The novel CoVs severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. The 2019 novel coronavirus (SARS-CoV-2) is currently causing a severe outbreak of disease (termed COVID-19) in China and multiple other countries, threatening to cause a global pandemic. In humans, CoVs mostly cause respiratory and gastrointestinal symptoms. Clinical manifestations range from a common cold to more severe disease such as bronchitis, pneumonia, severe acute respiratory distress syndrome, multi-organ failure and even death. SARS-CoV, MERS-CoV and SARS-CoV-2 seem to less commonly affect children and to cause fewer symptoms and less severe disease in this age group compared with adults, and are associated with much lower case-fatality rates. Preliminary evidence suggests children are just as likely as adults to become infected with SARS-CoV-2 but are less likely to be symptomatic or develop severe symptoms. However, the importance of children in transmitting the virus remains uncertain. Children more often have gastrointestinal symptoms compared with adults. Most children with SARS-CoV present with fever, but this is not the case for the other novel CoVs. Many children affected by MERS-CoV are asymptomatic. The majority of children infected by novel CoVs have a documented household contact, often showing symptoms before them. In contrast, adults more often have a nosocomial exposure. In this review, we summarize epidemiologic, clinical and diagnostic findings, as well as treatment and prevention options for common circulating and novel CoVs infections in humans with a focus on infections in children.
Url:
DOI: 10.1097/INF.0000000000002660
PubMed: NONE
PubMed Central: 7158880
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PMC:7158880Le document en format XML
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<affiliation><nlm:aff id="aff2">Department of Paediatrics, The University of Melbourne</nlm:aff>
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<author><name sortKey="Curtis, Nigel" sort="Curtis, Nigel" uniqKey="Curtis N" first="Nigel" last="Curtis">Nigel Curtis</name>
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<front><div type="abstract" xml:lang="en"><p>Coronaviruses (CoVs) are a large family of enveloped, single-stranded, zoonotic RNA viruses. Four CoVs commonly circulate among humans: HCoV2-229E, -HKU1, -NL63 and -OC43. However, CoVs can rapidly mutate and recombine leading to novel CoVs that can spread from animals to humans. The novel CoVs severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. The 2019 novel coronavirus (SARS-CoV-2) is currently causing a severe outbreak of disease (termed COVID-19) in China and multiple other countries, threatening to cause a global pandemic. In humans, CoVs mostly cause respiratory and gastrointestinal symptoms. Clinical manifestations range from a common cold to more severe disease such as bronchitis, pneumonia, severe acute respiratory distress syndrome, multi-organ failure and even death. SARS-CoV, MERS-CoV and SARS-CoV-2 seem to less commonly affect children and to cause fewer symptoms and less severe disease in this age group compared with adults, and are associated with much lower case-fatality rates. Preliminary evidence suggests children are just as likely as adults to become infected with SARS-CoV-2 but are less likely to be symptomatic or develop severe symptoms. However, the importance of children in transmitting the virus remains uncertain. Children more often have gastrointestinal symptoms compared with adults. Most children with SARS-CoV present with fever, but this is not the case for the other novel CoVs. Many children affected by MERS-CoV are asymptomatic. The majority of children infected by novel CoVs have a documented household contact, often showing symptoms before them. In contrast, adults more often have a nosocomial exposure. In this review, we summarize epidemiologic, clinical and diagnostic findings, as well as treatment and prevention options for common circulating and novel CoVs infections in humans with a focus on infections in children.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Pediatr Infect Dis J</journal-id>
<journal-id journal-id-type="iso-abbrev">Pediatr. Infect. Dis. J</journal-id>
<journal-id journal-id-type="publisher-id">INF</journal-id>
<journal-title-group><journal-title>The Pediatric Infectious Disease Journal</journal-title>
</journal-title-group>
<issn pub-type="ppub">0891-3668</issn>
<issn pub-type="epub">1532-0987</issn>
<publisher><publisher-name>Williams & Wilkins</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmc">7158880</article-id>
<article-id pub-id-type="art-access-id">00001</article-id>
<article-id pub-id-type="doi">10.1097/INF.0000000000002660</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Special Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Coronavirus Infections in Children Including COVID-19</article-title>
<subtitle>An Overview of the Epidemiology, Clinical Features, Diagnosis, Treatment and Prevention Options in Children</subtitle>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Zimmermann</surname>
<given-names>Petra</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="aff1">*</xref>
<xref ref-type="aff" rid="aff2">†</xref>
<xref ref-type="aff" rid="aff3">‡</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Curtis</surname>
<given-names>Nigel</given-names>
</name>
<degrees>FRCPCH, PhD</degrees>
<xref ref-type="aff" rid="aff2">†</xref>
<xref ref-type="aff" rid="aff3">‡</xref>
<xref ref-type="aff" rid="aff4">§</xref>
</contrib>
<aff id="aff1">From the<label>*</label>
Department of Paediatrics, Fribourg Hospital HFR and Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland</aff>
<aff id="aff2"><label>†</label>
Department of Paediatrics, The University of Melbourne</aff>
<aff id="aff3"><label>‡</label>
Infectious Diseases Research Group, Murdoch Children’s Research Institute</aff>
<aff id="aff4"><label>§</label>
Infectious Diseases Unit, The Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia.</aff>
</contrib-group>
<author-notes><corresp id="c1">Address for correspondence: Petra Zimmermann, MD, PhD, Faculty of Science and Medicine, University of Fribourg, Route des Arsenaux 41, 1700 Fribourg, Switzerland. E-mail: <email xlink:href="petra.zimmermann@unifr.ch">petra.zimmermann@unifr.ch</email>
.</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>5</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="epub"><day>12</day>
<month>3</month>
<year>2020</year>
</pub-date>
<volume>39</volume>
<issue>5</issue>
<fpage>355</fpage>
<lpage>368</lpage>
<history><date date-type="accepted"><day>03</day>
<month>3</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.</copyright-statement>
<copyright-year>2020</copyright-year>
<license license-type="open-access"><license-p>This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.</license-p>
</license>
<license license-type="NIH OGC"><license-p>This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.</license-p>
</license>
</permissions>
<self-uri xlink:type="simple" xlink:href="inf-39-355.pdf"></self-uri>
<abstract><p>Coronaviruses (CoVs) are a large family of enveloped, single-stranded, zoonotic RNA viruses. Four CoVs commonly circulate among humans: HCoV2-229E, -HKU1, -NL63 and -OC43. However, CoVs can rapidly mutate and recombine leading to novel CoVs that can spread from animals to humans. The novel CoVs severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. The 2019 novel coronavirus (SARS-CoV-2) is currently causing a severe outbreak of disease (termed COVID-19) in China and multiple other countries, threatening to cause a global pandemic. In humans, CoVs mostly cause respiratory and gastrointestinal symptoms. Clinical manifestations range from a common cold to more severe disease such as bronchitis, pneumonia, severe acute respiratory distress syndrome, multi-organ failure and even death. SARS-CoV, MERS-CoV and SARS-CoV-2 seem to less commonly affect children and to cause fewer symptoms and less severe disease in this age group compared with adults, and are associated with much lower case-fatality rates. Preliminary evidence suggests children are just as likely as adults to become infected with SARS-CoV-2 but are less likely to be symptomatic or develop severe symptoms. However, the importance of children in transmitting the virus remains uncertain. Children more often have gastrointestinal symptoms compared with adults. Most children with SARS-CoV present with fever, but this is not the case for the other novel CoVs. Many children affected by MERS-CoV are asymptomatic. The majority of children infected by novel CoVs have a documented household contact, often showing symptoms before them. In contrast, adults more often have a nosocomial exposure. In this review, we summarize epidemiologic, clinical and diagnostic findings, as well as treatment and prevention options for common circulating and novel CoVs infections in humans with a focus on infections in children.</p>
</abstract>
<kwd-group><kwd>severe acute respiratory syndrome coronavirus</kwd>
<kwd>Middle East respiratory syndrome coronavirus</kwd>
<kwd>severe acute respiratory syndrome coronavirus 2</kwd>
<kwd>epidemiology</kwd>
<kwd>symptoms</kwd>
<kwd>laboratory</kwd>
<kwd>imaging</kwd>
<kwd>treatment</kwd>
<kwd>vaccines</kwd>
<kwd>prevention</kwd>
<kwd>treatment</kwd>
<kwd>vaccines</kwd>
<kwd>prevention</kwd>
<kwd>SARS-CoV</kwd>
<kwd>MERS-CoV</kwd>
<kwd>SARS-CoV-2</kwd>
</kwd-group>
</article-meta>
</front>
<body><p>Coronaviruses (CoVs) comprise a large family of enveloped, single-stranded, zoonotic RNA viruses belonging to the family <italic>Coronaviridae</italic>
, order <italic>Nidovirales</italic>
(Fig.<xref ref-type="fig" rid="F1">1</xref>
).<sup><xref rid="R1" ref-type="bibr">1</xref>
</sup>
They can infect a variety of animals (including livestock, companion animals and birds), in which they can cause serious respiratory, enteric, cardiovascular and neurologic disease.<sup><xref rid="R2" ref-type="bibr">2</xref>
,<xref rid="R3" ref-type="bibr">3</xref>
</sup>
In humans, CoVs mostly cause respiratory and gastrointestinal symptoms ranging from the common cold to more severe disease such as bronchitis, pneumonia, severe acute respiratory distress syndrome (ARDS), coagulopathy, multi-organ failure and death.<sup><xref rid="R4" ref-type="bibr">4</xref>
–<xref rid="R8" ref-type="bibr">8</xref>
</sup>
Human coronaviruses (HCoVs) have also been associated with exacerbations of chronic obstructive pulmonary disease,<sup><xref rid="R9" ref-type="bibr">9</xref>
</sup>
cystic fibrosis<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
and asthma.<sup><xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R12" ref-type="bibr">12</xref>
</sup>
</p>
<fig id="F1" position="float"><label>FIGURE 1.</label>
<caption><p>Summary of coronavirus diseases. COVID-19 indicates coronavirus disease 2019.</p>
</caption>
<graphic xlink:href="inf-39-355-g001"></graphic>
</fig>
<p>CoVs are classified into <italic>Alphacoronaviruses</italic>
and <italic>Betacoronaviruses</italic>
(which are mainly found in mammals such as bats, rodents, civets and humans) and <italic>Gammacoronaviruses</italic>
and <italic>Deltacoronaviruses</italic>
(which are mainly found in birds).<sup><xref rid="R8" ref-type="bibr">8</xref>
,<xref rid="R13" ref-type="bibr">13</xref>
,<xref rid="R14" ref-type="bibr">14</xref>
</sup>
Four CoVs commonly circulate among humans: HCoV2-229E, -HKU1, -NL63 and -OC43.<sup><xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R16" ref-type="bibr">16</xref>
</sup>
These viruses are believed to have originally derived from bats (NL63, 229E),<sup><xref rid="R17" ref-type="bibr">17</xref>
,<xref rid="R18" ref-type="bibr">18</xref>
</sup>
dromedary camels (229E)<sup><xref rid="R19" ref-type="bibr">19</xref>
</sup>
and cattle (OC43).<sup><xref rid="R20" ref-type="bibr">20</xref>
</sup>
The origin of HCoV-HKU1 remains unknown. Several CoVs are known to circulate in animals (with bats acting as the main reservoir) but have not been associated with human infection.<sup><xref rid="R3" ref-type="bibr">3</xref>
,<xref rid="R21" ref-type="bibr">21</xref>
,<xref rid="R22" ref-type="bibr">22</xref>
</sup>
CoVs are capable of rapid mutation and recombination leading to novel CoVs that can spread from animals to humans. This occurred in China in 2002 when the novel CoV severe acute respiratory syndrome coronavirus (SARS-CoV) emerged, thought to have been transmitted from civet cats or bats to humans.<sup><xref rid="R22" ref-type="bibr">22</xref>
–<xref rid="R25" ref-type="bibr">25</xref>
</sup>
Another novel CoVs emerged in Saudi Arabia in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV), which is transmitted from dromedary camels to humans.<sup><xref rid="R26" ref-type="bibr">26</xref>
,<xref rid="R27" ref-type="bibr">27</xref>
</sup>
The 2019 novel CoV (SARS-CoV-2), which originated in China and is currently causing outbreaks globally, is a novel <italic>Betacoronavirus</italic>
belonging to the lineage B or subgenus sarbecovirus, which includes SARS-CoV.<sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
Sequencing shows that the genome is most closely related (87%–89% nucleotide identity) to the bat SARS-related CoV found in Chinese horseshoe bats (bat-SL-CoVZC45).<sup><xref rid="R28" ref-type="bibr">28</xref>
,<xref rid="R29" ref-type="bibr">29</xref>
</sup>
The outbreak of SARS-CoV-2 started in Wuhan city, Hubei province, China, where The Health Commission of Hubei province first announced a cluster of adults with pneumonia of unexplained etiology on December 31, 2019. A local seafood and animal market was identified as a potential source. However, the main driver of the outbreak is symptomatic and asymptomatic humans infected with SARS-CoV-2 from whom the virus can spread to others through respiratory droplets or direct contact.<sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
From Wuhan city SARS-CoV-2 has spread to other Chinese cities and internationally, threating to cause a global pandemic. The term COVID-19 is used for the clinical disease caused by SARS-CoV-2.<sup><xref rid="R30" ref-type="bibr">30</xref>
</sup>
</p>
<p>In this review, we summarize epidemiologic, clinical and diagnostic findings, as well as treatment and prevention options for common circulating and novel CoVs infections in humans with a focus on infections in children.</p>
<sec><title>EPIDEMIOLOGY</title>
<sec><title>Common Circulating HCoVs</title>
<p>Common circulating HCoVs can be isolated from 4% to 6% of children hospitalized for acute respiratory tract infections<sup><xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R31" ref-type="bibr">31</xref>
</sup>
and from 8% of children in an ambulatory setting (Table <xref rid="T1" ref-type="table">1</xref>
).<sup><xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R32" ref-type="bibr">32</xref>
,<xref rid="R33" ref-type="bibr">33</xref>
</sup>
Children under the age of 3 years and children with heart disease are the most frequently affected.<sup><xref rid="R4" ref-type="bibr">4</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R35" ref-type="bibr">35</xref>
,<xref rid="R36" ref-type="bibr">36</xref>
</sup>
Reinfections later in life are common<sup><xref rid="R32" ref-type="bibr">32</xref>
,<xref rid="R115" ref-type="bibr">115</xref>
,<xref rid="R116" ref-type="bibr">116</xref>
</sup>
despite the fact that most individuals seroconvert to HCoVs during childhood.<sup><xref rid="R117" ref-type="bibr">117</xref>
–<xref rid="R120" ref-type="bibr">120</xref>
</sup>
In contrast to other respiratory tract viruses [eg, respiratory syncytial virus (RSV)], there is no decrease in the relative prevalence of HCoVs infections with increasing age.<sup><xref rid="R4" ref-type="bibr">4</xref>
,<xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R36" ref-type="bibr">36</xref>
</sup>
</p>
<table-wrap id="T1" position="float"><label>TABLE 1.</label>
<caption><p>Characteristics of Human Coronaviruses</p>
</caption>
<graphic xlink:href="inf-39-355-g002"></graphic>
</table-wrap>
<p>In 11%–46% of cases, common circulating HCoVs are found as coinfections with other respiratory viruses such as adeno-, boca-, rhino-, RSV, influenza or parainfluenza virus.<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R16" ref-type="bibr">16</xref>
,<xref rid="R31" ref-type="bibr">31</xref>
–<xref rid="R33" ref-type="bibr">33</xref>
,<xref rid="R36" ref-type="bibr">36</xref>
,<xref rid="R79" ref-type="bibr">79</xref>
,<xref rid="R81" ref-type="bibr">81</xref>
,<xref rid="R121" ref-type="bibr">121</xref>
,<xref rid="R122" ref-type="bibr">122</xref>
</sup>
Symptomatic children whose only detectable respiratory virus is a HCoV are reported to more likely suffer from an underlying chronic disease compared with children coinfected with other respiratory viruses.<sup><xref rid="R31" ref-type="bibr">31</xref>
</sup>
</p>
<p>Of the 4 common circulating HCoVs, NL63 and OC43 are the most frequently isolated species.<sup><xref rid="R4" ref-type="bibr">4</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R35" ref-type="bibr">35</xref>
,<xref rid="R36" ref-type="bibr">36</xref>
</sup>
Cyclical patterns have been observed for 229E and OC43, with outbreaks occurring every 2–4 years.<sup><xref rid="R4" ref-type="bibr">4</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R32" ref-type="bibr">32</xref>
,<xref rid="R35" ref-type="bibr">35</xref>
,<xref rid="R82" ref-type="bibr">82</xref>
,<xref rid="R116" ref-type="bibr">116</xref>
,<xref rid="R119" ref-type="bibr">119</xref>
</sup>
Seasonal patterns have also been observed: in the Northern Hemisphere, common circulating HCoVs mostly cause infections in humans between December and May, and in the Southern Hemisphere between March and November with peaks in late winter/early spring for 229E and OC43 and in autumn for NL63.<sup><xref rid="R4" ref-type="bibr">4</xref>
,<xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R32" ref-type="bibr">32</xref>
,<xref rid="R123" ref-type="bibr">123</xref>
</sup>
HCoV-HKU1 has been reported to mainly occur in spring and summer in Hong Kong,<sup><xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R124" ref-type="bibr">124</xref>
</sup>
but in winter and spring in the United Kingdom and Brazil.<sup><xref rid="R4" ref-type="bibr">4</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
</sup>
</p>
</sec>
<sec><title>SARS-CoV and MERS-CoV</title>
<p>SARS-CoV is a novel group 2b <italic>Betacoronavirus</italic>
which initially emerged in Guangdong province, south China in 2002,<sup><xref rid="R23" ref-type="bibr">23</xref>
–<xref rid="R25" ref-type="bibr">25</xref>
</sup>
then spread to Hong Kong and from there rapidly to many other countries.<sup><xref rid="R125" ref-type="bibr">125</xref>
</sup>
It caused severe lower respiratory tract infection with a severe morbidity and a high case-fatality rate (approaching 50% in individuals over 60 years of age, overall 10%).<sup><xref rid="R63" ref-type="bibr">63</xref>
,<xref rid="R106" ref-type="bibr">106</xref>
,<xref rid="R107" ref-type="bibr">107</xref>
,<xref rid="R126" ref-type="bibr">126</xref>
</sup>
Person-to-person transmission of SARS-CoV is well established.<sup><xref rid="R55" ref-type="bibr">55</xref>
</sup>
The virus has spread to 29 countries and has been estimated to have caused more than 8000 infections and 774 deaths worldwide (Table <xref rid="T1" ref-type="table">1</xref>
).<sup><xref rid="R52" ref-type="bibr">52</xref>
</sup>
</p>
<p>MERS-CoV is a novel group 2c <italic>Betacoronavirus</italic>
which first appeared in Saudi Arabia in 2012.<sup><xref rid="R26" ref-type="bibr">26</xref>
,<xref rid="R27" ref-type="bibr">27</xref>
,<xref rid="R127" ref-type="bibr">127</xref>
</sup>
It can spread from person-to-person<sup><xref rid="R128" ref-type="bibr">128</xref>
</sup>
and can cause severe lower respiratory tract infections with a case-fatality rate of 20% to 40%.<sup><xref rid="R67" ref-type="bibr">67</xref>
,<xref rid="R106" ref-type="bibr">106</xref>
,<xref rid="R108" ref-type="bibr">108</xref>
–<xref rid="R112" ref-type="bibr">112</xref>
</sup>
Apart from being endemic in the Middle East, there was a nosocomial outbreak of MERS-CoV in South Korea in 2014, involving 16 hospitals and 186 patients, caused by a medical doctor returning from the Middle East.<sup><xref rid="R49" ref-type="bibr">49</xref>
,<xref rid="R68" ref-type="bibr">68</xref>
</sup>
MERS-CoV spread to 27 countries causing an estimated 2494 infections and 858 deaths (Table <xref rid="T1" ref-type="table">1</xref>
).<sup><xref rid="R53" ref-type="bibr">53</xref>
</sup>
</p>
<p>The overall reproductive number (R0) for SARS-CoV was estimated to be 0.3–2.9<sup><xref rid="R37" ref-type="bibr">37</xref>
,<xref rid="R39" ref-type="bibr">39</xref>
,<xref rid="R40" ref-type="bibr">40</xref>
,<xref rid="R42" ref-type="bibr">42</xref>
,<xref rid="R43" ref-type="bibr">43</xref>
,<xref rid="R47" ref-type="bibr">47</xref>
</sup>
and for MERS-CoV to be 0.5–3.5 (Table <xref rid="T1" ref-type="table">1</xref>
).<sup><xref rid="R39" ref-type="bibr">39</xref>
,<xref rid="R46" ref-type="bibr">46</xref>
,<xref rid="R48" ref-type="bibr">48</xref>
</sup>
R0s largely depend on geographic location, stage of the outbreak and inclusion of only nosocomial versus general transmission. Both viruses have been associated with early super-spreading events with R0s of up to 22 for SARS-CoV<sup><xref rid="R39" ref-type="bibr">39</xref>
,<xref rid="R40" ref-type="bibr">40</xref>
,<xref rid="R43" ref-type="bibr">43</xref>
</sup>
and up to 30 for MERS-CoV.<sup><xref rid="R39" ref-type="bibr">39</xref>
,<xref rid="R49" ref-type="bibr">49</xref>
</sup>
These large numbers of secondary infections have been mostly associated with nosocomial outbreaks: 30% of all SARS-CoV cases (mostly health care workers) and 44%–100% of all MERS-CoV cases (mostly patients) occurred from nosocomial transmissions.<sup><xref rid="R39" ref-type="bibr">39</xref>
,<xref rid="R55" ref-type="bibr">55</xref>
,<xref rid="R56" ref-type="bibr">56</xref>
</sup>
These super-spreading events were followed by reduced spread in the following generations of viruses with a decrease in the R0s to 0.8 for SARS-CoV<sup><xref rid="R39" ref-type="bibr">39</xref>
</sup>
and to 0.7 for MERS-CoV (Table <xref rid="T1" ref-type="table">1</xref>
).<sup><xref rid="R128" ref-type="bibr">128</xref>
</sup>
Therefore, both SARS-CoV and MERS-CoV have low potential for long-term sustained community transmission. No human SARS-CoV infections have been detected since July 2003. However, SARS-CoV-like viruses can be found in bats, which are known to be able infect human cells without adaptation, making it possible for SARS-CoVs to reemerge<sup><xref rid="R84" ref-type="bibr">84</xref>
</sup>
(as has now happened with SARS-CoV-2). The zoonotic transmission of MERS-CoV to humans has continued, attributed to the role of dromedary camels as a reservoir and their close contact with humans (in contrast to human-bat-interactions).<sup><xref rid="R21" ref-type="bibr">21</xref>
</sup>
</p>
</sec>
<sec><title>SARS-CoV-2</title>
<p>Early in the SARS-CoV-2 outbreak, it was shown that person-to-person transmission was the main driver.<sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
The R0 for SARS-CoV-2 is currently estimated at 2.7.<sup><xref rid="R38" ref-type="bibr">38</xref>
</sup>
The incubation period is estimated at 5–6 days, which is similar to that for SARS-CoV and MERS-CoV.<sup><xref rid="R38" ref-type="bibr">38</xref>
,<xref rid="R63" ref-type="bibr">63</xref>
–<xref rid="R65" ref-type="bibr">65</xref>
,<xref rid="R67" ref-type="bibr">67</xref>
–<xref rid="R72" ref-type="bibr">72</xref>
</sup>
The serial interval is estimated to be 8 days, also similar to the other novel CoVs (Table <xref rid="T1" ref-type="table">1</xref>
).<sup><xref rid="R38" ref-type="bibr">38</xref>
,<xref rid="R45" ref-type="bibr">45</xref>
,<xref rid="R48" ref-type="bibr">48</xref>
,<xref rid="R70" ref-type="bibr">70</xref>
</sup>
By March 2020, the World Health Organization reported that SARS-CoV-2 had spread to over 100 countries and caused over 100,000 infections and over 3500 deaths.<sup><xref rid="R54" ref-type="bibr">54</xref>
</sup>
At that time the case-fatality rate was uncertain but estimated at 0.9%–3%,<sup><xref rid="R54" ref-type="bibr">54</xref>
,<xref rid="R113" ref-type="bibr">113</xref>
,<xref rid="R114" ref-type="bibr">114</xref>
</sup>
which is much lower than for SARS-CoV and MERS-CoV (6%–17% and 20%–40%, respectively).<sup><xref rid="R63" ref-type="bibr">63</xref>
,<xref rid="R67" ref-type="bibr">67</xref>
,<xref rid="R106" ref-type="bibr">106</xref>
–<xref rid="R112" ref-type="bibr">112</xref>
</sup>
</p>
</sec>
</sec>
<sec><title>SYMPTOMS</title>
<sec><title>Common HCoVs</title>
<p>In children, common circulating HCoVs can cause common cold symptoms such as fever,<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R32" ref-type="bibr">32</xref>
</sup>
rhinitis,<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
</sup>
otitis,<sup><xref rid="R5" ref-type="bibr">5</xref>
</sup>
pharyngitis,<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
</sup>
laryngitis<sup><xref rid="R5" ref-type="bibr">5</xref>
</sup>
and headache,<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R16" ref-type="bibr">16</xref>
,<xref rid="R81" ref-type="bibr">81</xref>
</sup>
but also bronchitis,<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
</sup>
bronchiolitis,<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
</sup>
wheezing,<sup><xref rid="R4" ref-type="bibr">4</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R32" ref-type="bibr">32</xref>
</sup>
pneumonia,<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R81" ref-type="bibr">81</xref>
,<xref rid="R82" ref-type="bibr">82</xref>
</sup>
and, in up to 57% of cases, gastrointestinal symptoms (which are more common in children than adults).<sup><xref rid="R5" ref-type="bibr">5</xref>
–<xref rid="R7" ref-type="bibr">7</xref>
</sup>
In a study including children and adults, fatigue, headache, myalgia and sore throat were more common in HCoV-infected patients compared with RSV-infected patients, while fever, cough and dyspnea were more frequent in the later.<sup><xref rid="R36" ref-type="bibr">36</xref>
</sup>
Fewer patients infected with HCoVs had fever compared with those infected with RSV or influenza.<sup><xref rid="R36" ref-type="bibr">36</xref>
</sup>
</p>
<p>In children, HCoV-NL63 has been associated with conjunctivitis,<sup><xref rid="R78" ref-type="bibr">78</xref>
</sup>
croup,<sup><xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R79" ref-type="bibr">79</xref>
,<xref rid="R80" ref-type="bibr">80</xref>
</sup>
asthma exacerbations,<sup><xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R12" ref-type="bibr">12</xref>
</sup>
febrile seizures<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
and HCoV-HKU1 with febrile seizures.<sup><xref rid="R7" ref-type="bibr">7</xref>
</sup>
Rare cases of neurologic diseases have also been described (eg, the detection of HCoV in cerebrospinal fluid in a child presenting with acute disseminated encephalomyelitis<sup><xref rid="R83" ref-type="bibr">83</xref>
</sup>
or in cerebrospinal fluid of adults with multiple sclerosis.)<sup><xref rid="R129" ref-type="bibr">129</xref>
,<xref rid="R130" ref-type="bibr">130</xref>
</sup>
A suspected association between HCoVs and Kawasaki disease could not be confirmed.<sup><xref rid="R131" ref-type="bibr">131</xref>
,<xref rid="R132" ref-type="bibr">132</xref>
</sup>
Common HCoVs can be isolated from asymptomatic individuals.<sup><xref rid="R16" ref-type="bibr">16</xref>
</sup>
During an infection, the viral load is high in the first 2 days and decreases thereafter.<sup><xref rid="R29" ref-type="bibr">29</xref>
</sup>
A correlation between viral load and severity of disease has not been observed<sup><xref rid="R29" ref-type="bibr">29</xref>
</sup>
This contrasts with SARS-CoV for which a higher initial viral load is independently associated with a worse prognosis, including a higher case-fatality rate.<sup><xref rid="R133" ref-type="bibr">133</xref>
,<xref rid="R134" ref-type="bibr">134</xref>
</sup>
Virus particles can be isolated from nasopharyngeal secretions up to 14 days after the onset of infection.<sup><xref rid="R135" ref-type="bibr">135</xref>
</sup>
</p>
</sec>
<sec><title>SARS-CoV</title>
<p>There are 3 case series that report a total of 41 children who were affected by SARS-CoV.<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
The virus was associated with milder disease in children compared with adults, and no deaths have been reported in children.<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
,<xref rid="R86" ref-type="bibr">86</xref>
</sup>
Symptomatic children with SARS-CoV infection were reported to have fever (91%–100%),<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
myalgia (10%–40%),<sup><xref rid="R57" ref-type="bibr">57</xref>
,<xref rid="R58" ref-type="bibr">58</xref>
</sup>
rhinitis (33%–60%),<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
sore throat (5%–30%),<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
cough (43%–80%),<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
dyspnea (10%–14%),<sup><xref rid="R38" ref-type="bibr">38</xref>
,<xref rid="R84" ref-type="bibr">84</xref>
</sup>
headache (14%–40%)<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
and, less commonly, vomiting (20%),<sup><xref rid="R57" ref-type="bibr">57</xref>
,<xref rid="R59" ref-type="bibr">59</xref>
</sup>
abdominal pain (10%),<sup><xref rid="R57" ref-type="bibr">57</xref>
</sup>
diarrhea (10%)<sup><xref rid="R58" ref-type="bibr">58</xref>
,<xref rid="R59" ref-type="bibr">59</xref>
</sup>
and febrile seizures (10%).<sup><xref rid="R57" ref-type="bibr">57</xref>
</sup>
In total, 50%–80% of children had other family members who were infected<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
and 30% had a nosocomial contact with SARS-CoV.<sup><xref rid="R57" ref-type="bibr">57</xref>
</sup>
Most children recover quickly from an infection with SARS-CoV.<sup><xref rid="R86" ref-type="bibr">86</xref>
</sup>
However, abnormalities on chest computed tomography (CT) can persist for several months (eg, air trapping and ground-glass opacifications).<sup><xref rid="R136" ref-type="bibr">136</xref>
</sup>
</p>
<p>There is no evidence that SARS-CoV can be vertically transmitted to the fetus.<sup><xref rid="R137" ref-type="bibr">137</xref>
</sup>
However, SARS-CoV infections during pregnancy have been associated with possible miscarriage, intrauterine growth retardation and preterm delivery.<sup><xref rid="R137" ref-type="bibr">137</xref>
,<xref rid="R138" ref-type="bibr">138</xref>
</sup>
</p>
</sec>
<sec><title>MERS-CoV</title>
<p>Most case series of patients infected with MERS-CoV report a low proportion (0.1%–4%) of children.<sup><xref rid="R34" ref-type="bibr">34</xref>
,<xref rid="R76" ref-type="bibr">76</xref>
,<xref rid="R109" ref-type="bibr">109</xref>
,<xref rid="R110" ref-type="bibr">110</xref>
,<xref rid="R139" ref-type="bibr">139</xref>
,<xref rid="R140" ref-type="bibr">140</xref>
</sup>
In a large case series of 2235 children with acute respiratory tract infection who presented to a tertiary hospital in Saudi Arabia during the MERS-CoV epidemic (2012–2013), none tested positive for MERS-CoV (Table <xref rid="T1" ref-type="table">1</xref>
).<sup><xref rid="R34" ref-type="bibr">34</xref>
</sup>
There are 2 small case series of children infected with MERS-CoV: one including 31 children with a mean age of 10 years<sup><xref rid="R60" ref-type="bibr">60</xref>
</sup>
and the other one only 7 children.<sup><xref rid="R76" ref-type="bibr">76</xref>
</sup>
In both studies, 42% of children were asymptomatic.<sup><xref rid="R60" ref-type="bibr">60</xref>
,<xref rid="R76" ref-type="bibr">76</xref>
</sup>
In the case series of 7 children, 57% suffered from fever, 28% from vomiting and diarrhea and 14% from cough and shortness of breath.<sup><xref rid="R76" ref-type="bibr">76</xref>
</sup>
Two children required oxygen supplementation and one mechanical ventilation.<sup><xref rid="R76" ref-type="bibr">76</xref>
</sup>
In the other case series, 2 died (6%).<sup><xref rid="R60" ref-type="bibr">60</xref>
</sup>
The main sources of MERS-CoV infection in children were household (32%) and other contacts (23%), followed by nosocomial transmission (19%).<sup><xref rid="R60" ref-type="bibr">60</xref>
</sup>
</p>
<p>Eight cases of MERS-CoV maternal infections during pregnancy have been reported (occurring between 20 and 28 weeks of pregnancy), three of the affected infants died.<sup><xref rid="R141" ref-type="bibr">141</xref>
–<xref rid="R144" ref-type="bibr">144</xref>
</sup>
</p>
</sec>
<sec><title>SARS-CoV-2</title>
<p>Different case definitions for COVID-19 cases in adults and children from authoritive sources as of March 2020 are detailed in Table <xref rid="T2" ref-type="table">2</xref>
. Children are less commonly affected by SARS-CoV-2, the Chinese Centers for Disease Control and Prevention reports that of the 72,314 cases reported as of February 11, 2020, only 2% were in individuals of less than 19 years of age.<sup><xref rid="R114" ref-type="bibr">114</xref>
</sup>
There are 3 case series of children who have been infected with SARS-CoV-2.<sup><xref rid="R61" ref-type="bibr">61</xref>
,<xref rid="R72" ref-type="bibr">72</xref>
,<xref rid="R77" ref-type="bibr">77</xref>
</sup>
The first included 20 children up to January 31, 2020, in the Province of Zhejiang,<sup><xref rid="R72" ref-type="bibr">72</xref>
</sup>
the second 34 children between January 19, 2020, and February 7, 2020, in the Province of Shenzhen,<sup><xref rid="R61" ref-type="bibr">61</xref>
</sup>
and the third 9 infants from different provinces in China.<sup><xref rid="R77" ref-type="bibr">77</xref>
</sup>
The case series with 34 children provides the most clinical details: none of the children had an underlying disease, 65% had common respiratory symptoms, 26% had mild disease and 9% were asymptomatic.<sup><xref rid="R61" ref-type="bibr">61</xref>
</sup>
The most common symptoms were fever (50%) and cough (38%).<sup><xref rid="R61" ref-type="bibr">61</xref>
</sup>
In the case series of 20 children, presentation was with low to moderate or no fever, rhinitis, cough, fatigue, headache, diarrhea and, in more severe cases, with dyspnea, cyanosis and poor feeding, but the numbers were not specified.<sup><xref rid="R72" ref-type="bibr">72</xref>
</sup>
In the series of 9 infants, only 4 were reported to have fever. One infant was asymptomatic.<sup><xref rid="R77" ref-type="bibr">77</xref>
</sup>
Additional asymptomatic children infected with SARS-CoV-2 outside these case series have also been described (eg, a 10-year-old asymptomatic child with radiologic ground-glass lung opacities on chest CT).<sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
Most infected children recover 1–2 weeks after the onset of symptoms and no deaths from SARS-CoV-2 had been reported by February 2020.<sup><xref rid="R72" ref-type="bibr">72</xref>
</sup>
</p>
<table-wrap id="T2" position="float"><label>TABLE 2.</label>
<caption><p>Case Definitions for SARS-CoV-2 Infections in Adults and Children (as of February 2020)</p>
</caption>
<graphic xlink:href="inf-39-355-g003"></graphic>
</table-wrap>
<p>From these series, it appears that children have milder clinical symptoms than adults<sup><xref rid="R61" ref-type="bibr">61</xref>
,<xref rid="R72" ref-type="bibr">72</xref>
</sup>
(as has been reported for SARS-CoV and MERS-CoV infections),<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R60" ref-type="bibr">60</xref>
,<xref rid="R76" ref-type="bibr">76</xref>
,86</sup>
which could mean children might not be tested for SARS-CoV-2 as frequently as adults. It has therefore been suggested that asymptomatic or mildly symptomatic children might transmit the disease.<sup><xref rid="R147" ref-type="bibr">147</xref>
</sup>
However, the majority of children infected with SARS-CoV-2 thus far have been part of a family cluster outbreak [100% in the infants series, in which other family member had symptoms before the infants in all cases; 82% in the case series of 34 children;<sup><xref rid="R61" ref-type="bibr">61</xref>
</sup>
and the majority in the one with 20 children (exact number not specified)].<sup><xref rid="R72" ref-type="bibr">72</xref>
</sup>
This is similar to SARS-CoV, in which 50%–80%<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
of children were reported to have an affected household contact<sup><xref rid="R60" ref-type="bibr">60</xref>
</sup>
and to MERS-CoV in which it was 32%.<sup><xref rid="R60" ref-type="bibr">60</xref>
</sup>
</p>
<p>A study prepublished in early March 2020 suggests that children are just as likely as adults to become infected with SARS-CoV-2 but are less likely to be symptomatic or develop severe symptoms.<sup><xref rid="R246" ref-type="bibr">246</xref>
</sup>
However, the importance of children in transmitting the virus remains uncertain.</p>
<p>From a small case series of 9 mothers who were infected with SARS-CoV-2, there is, to date, no evidence that SARS-CoV-2 can be vertically transmitted to the infant.<sup><xref rid="R148" ref-type="bibr">148</xref>
</sup>
</p>
</sec>
</sec>
<sec><title>LABORATORY FINDINGS</title>
<p>Laboratory findings from children are similar with infections caused by different novel CoVs (Table <xref rid="T1" ref-type="table">1</xref>
). The white blood cell count is typically normal or reduced with decreased neutrophil<sup><xref rid="R85" ref-type="bibr">85</xref>
</sup>
and/or lymphocyte counts.<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
,<xref rid="R72" ref-type="bibr">72</xref>
,86</sup>
Thrombocytopenia may occur.<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
,<xref rid="R76" ref-type="bibr">76</xref>
,86</sup>
C-reactive protein and procalcitonin levels are often normal.<sup><xref rid="R72" ref-type="bibr">72</xref>
</sup>
In severe cases, elevated liver enzymes,<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
,<xref rid="R72" ref-type="bibr">72</xref>
,86</sup>
lactate dehydrogenase levels,<sup><xref rid="R57" ref-type="bibr">57</xref>
</sup>
as well as a abnormal coagulation and elevated <sc>d</sc>
-dimers have been reported.<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
,<xref rid="R72" ref-type="bibr">72</xref>
,86</sup>
</p>
<sec><title>SARS-CoV-2</title>
<p>The same laboratory findings has above have been observed for children infected with SARS-CoV-2.<sup><xref rid="R61" ref-type="bibr">61</xref>
</sup>
In the case series of 34 children, the white blood cell count was normal in 83%, neutropenia and lymphopenia were each found in 1 case (3%). The lactate dehydrogenase level was elevated in 30% of cases.<sup><xref rid="R61" ref-type="bibr">61</xref>
</sup>
C-reactive protein and procalcitonin levels were each elevated in 1 case only (3%).</p>
</sec>
</sec>
<sec><title>RADIOLOGIC FINDINGS</title>
<p>Similar to the laboratory findings, radiologic findings from children are also similar across infections with different novel CoVs (Table <xref rid="T1" ref-type="table">1</xref>
). On chest radiography, children mostly show bilateral patchy airspace consolidations often at the periphery of the lungs, peribronchial thickening and ground-glass opacities.<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
,<xref rid="R76" ref-type="bibr">76</xref>
,86,87</sup>
Chest CT mostly shows airspace consolidations and ground-glass opacities.<sup><xref rid="R89" ref-type="bibr">89</xref>
</sup>
</p>
<sec><title>SARS-CoV-2</title>
<p>CT changes observed in children infected with SARS-CoV-2 include bilateral multiple patchy, nodular ground-glass opacities, speckled ground-glass opacities and/or infiltrating shadows in the middle and outer zone of the lung or under the pleura.<sup><xref rid="R61" ref-type="bibr">61</xref>
,<xref rid="R88" ref-type="bibr">88</xref>
</sup>
These findings are unspecific and milder compared with those in adults.<sup><xref rid="R88" ref-type="bibr">88</xref>
</sup>
</p>
</sec>
</sec>
<sec><title>DIAGNOSIS</title>
<p>The main basis for diagnosis of infections with HCoVs is real-time polymerase chain reaction (RT-PCR) on upper or lower respiratory secretions.<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
,<xref rid="R90" ref-type="bibr">90</xref>
–<xref rid="R96" ref-type="bibr">96</xref>
</sup>
For SARS-CoV, MERS-CoV and SARS-CoV-2, higher viral loads have been detected in samples from the lower respiratory tract compared with the upper respiratory tract.<sup><xref rid="R28" ref-type="bibr">28</xref>
,<xref rid="R149" ref-type="bibr">149</xref>
</sup>
Therefore, in clinically suspected cases with an initially negative result on nasopharyngeal or throat swab, repeat testing of upper respiratory tract samples or (preferably) testing of lower respiratory tract samples should be done. RT-PCRs on stool samples can be positive for HCoVs but is not used for routine diagnosis.<sup><xref rid="R91" ref-type="bibr">91</xref>
,<xref rid="R98" ref-type="bibr">98</xref>
,<xref rid="R99" ref-type="bibr">99</xref>
</sup>
For SARS-CoV and SARS-CoV-2, rare cases with positive PCRs in blood have been reported.<sup><xref rid="R28" ref-type="bibr">28</xref>
,<xref rid="R150" ref-type="bibr">150</xref>
</sup>
Serology has been used to diagnose infections with SARS-CoV and MERS-CoV, but is not useful in the acute phase of the infection.<sup><xref rid="R100" ref-type="bibr">100</xref>
–<xref rid="R103" ref-type="bibr">103</xref>
</sup>
Cross-reactivities between antibodies against SARS-CoV and common CoVs have been observed.<sup><xref rid="R151" ref-type="bibr">151</xref>
</sup>
</p>
<sec><title>SARS-CoV-2</title>
<p>Whole genome sequencing allowed the rapid development of molecular diagnostic tests for SARS-CoV-2.<sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
RT-PCR for genes encoding the internal RNA-dependent RNA polymerase and surface spike glycoprotein are commonly used.<sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
</p>
</sec>
</sec>
<sec><title>TREATMENT</title>
<p>Supportive treatment including sufficient fluid and calorie intake, and additional oxygen supplementation should be used in the treatment of children infected with HCoVs. The aim is to prevent ARDS, organ failure and secondary nosocomial infections. If bacterial infection is suspected broad-spectrum antibiotics such as second or third generation cephalosporins may be used.</p>
<sec><title>SARS-CoV</title>
<p>In the absence of specific antiviral drugs for CoVs, broad-spectrum antiviral drugs, such as interferon alpha and beta or ribavirin were used for the treatment of SARS-CoV, including in children.<sup><xref rid="R57" ref-type="bibr">57</xref>
–<xref rid="R59" ref-type="bibr">59</xref>
</sup>
Ribavirin was subsequently shown to be ineffective or even harmful because it can cause hemolytic anemia or liver dysfunction.<sup><xref rid="R152" ref-type="bibr">152</xref>
</sup>
In adults, interferon-alpha alone or together with ribavirin also did not consistently improve outcomes.<sup><xref rid="R152" ref-type="bibr">152</xref>
,<xref rid="R153" ref-type="bibr">153</xref>
</sup>
There is some evidence that intravenous corticosteroids led to clinical and radiologic improvement in SARS-CoV-infected individuals.<sup><xref rid="R58" ref-type="bibr">58</xref>
</sup>
However, a systematic review showed that the evidence for this is inconclusive and corticosteroids might also be harmful (delayed viral clearance, avascular necrosis, osteoporosis, new onset of diabetes).<sup><xref rid="R152" ref-type="bibr">152</xref>
</sup>
There is some evidence from adult studies that lopinavir/ritonavir (Kaletra) started early during infection is associated with improved clinical outcomes (decreased intubation, ARDS and death rates).<sup><xref rid="R154" ref-type="bibr">154</xref>
,<xref rid="R155" ref-type="bibr">155</xref>
</sup>
However, a systematic review found inconclusive results for the use of lopinavir/ritonavir because of a possible selection bias in many of the studies.<sup><xref rid="R152" ref-type="bibr">152</xref>
</sup>
Inconclusive results were also found for intravenous immunoglobulins because studies did not account for comorbidities, stage of illness and effect of other treatments.<sup><xref rid="R152" ref-type="bibr">152</xref>
</sup>
There is no evidence for the use of monoclonal antibodies against tumor necrosis factor alpha.<sup><xref rid="R156" ref-type="bibr">156</xref>
</sup>
</p>
</sec>
<sec><title>MERS-CoV</title>
<p>There are no studies on treatment outcomes for MERS-CoV in children. In adults, as for SARS-CoV, interferon or ribavirin alone or in combination have not been shown to have a clear benefit.<sup><xref rid="R157" ref-type="bibr">157</xref>
–<xref rid="R159" ref-type="bibr">159</xref>
</sup>
Mycophenolate mofetil, which inhibits guanine (and therefore RNA) synthesis, was identified as a potential anti-MERS-CoV drug in vitro.<sup><xref rid="R160" ref-type="bibr">160</xref>
</sup>
However, animal studies showed that the drug leads to worse outcomes with higher viral loads in lung and extrapulmonary tissues.<sup><xref rid="R161" ref-type="bibr">161</xref>
</sup>
Consistent with this, renal transplant patients on mycophenolate mofetil have been reported to develop severe and sometimes fatal MERS-CoV infections.<sup><xref rid="R162" ref-type="bibr">162</xref>
</sup>
</p>
</sec>
<sec><title>SARS-CoV-2</title>
<p>Until the results of on-going clinical trials become available, there is no definitive evidence on which to base treatment of patients infected with SARS-CoV-2. The only treatment recommendation for children, published by the Zhejiang University School of Medicine, suggests the use of nebulized interferon alpha-2b and oral lopinavir/ritonavir together with corticosteroids for complications (ARDS, encephalitis, hemophagocytic syndrome or septic shock) and intravenous immunoglobulin for severe cases.<sup><xref rid="R72" ref-type="bibr">72</xref>
</sup>
</p>
<p>However, as none of these therapies have shown a clear benefit in the treatment of other novel CoVs, it is questionable whether they will be beneficial in the treatment of SARS-CoV-2. Neither the World Health Organization nor the US Centers for Disease Control and Prevention recommends any specific treatment in children or adults.<sup><xref rid="R97" ref-type="bibr">97</xref>
,<xref rid="R163" ref-type="bibr">163</xref>
</sup>
Despite this, in the previously mentioned case series of the 34 children infected with SARS-CoV-2, 59% were treated with lopinavir/ritonavir.<sup><xref rid="R61" ref-type="bibr">61</xref>
</sup>
None of the children received glucocorticoids or immunoglobulins.<sup><xref rid="R61" ref-type="bibr">61</xref>
</sup>
</p>
</sec>
<sec><title>Other Therapeutic Options</title>
<sec><title>Monoclonal Antibodies</title>
<p>Despite their diversity, CoVs share many proteins among different species, which is helpful for the design of new drugs. One of them is the surface structural spike glycoprotein S, which is responsible for virus-cell interaction.<sup><xref rid="R164" ref-type="bibr">164</xref>
</sup>
Monoclonal antibodies (from convalescent human plasma, animal plasma or manufactured) against the spike glycoprotein S have been shown to inhibit fusion of CoVs with human cells and to decrease mortality rate in SARS-CoV-infected patients.<sup><xref rid="R165" ref-type="bibr">165</xref>
–<xref rid="R171" ref-type="bibr">171</xref>
</sup>
A protein, which also inhibits the spike glycoprotein S, although it is not a monoclonal antibody, has been isolated from a red alga called Griffithsia.<sup><xref rid="R172" ref-type="bibr">172</xref>
</sup>
However, to date, it has only been tested in animal studies.<sup><xref rid="R172" ref-type="bibr">172</xref>
</sup>
</p>
<p>Angiotensin-converting enzyme 2, dipeptidyl peptidase 4, aminopeptidase N, O-acetylated sialic acid are further host receptors for HCoVs and monoclonal antibodies against these proteins might be useful in treatment of infections.<sup><xref rid="R173" ref-type="bibr">173</xref>
–<xref rid="R176" ref-type="bibr">176</xref>
</sup>
However, rapid mutation of CoVs poses a potential problem, which might be diminished by using several monoclonal antibodies targeting different epitopes.<sup><xref rid="R166" ref-type="bibr">166</xref>
</sup>
</p>
</sec>
<sec><title>Protease Inhibitors</title>
<p>Endosomal and nonendosomal virus entry into cells can be reduced by inhibiting responsible proteases.<sup><xref rid="R177" ref-type="bibr">177</xref>
–<xref rid="R179" ref-type="bibr">179</xref>
</sup>
Papain-like proteases (PLpro) are involved in viral replication in CoVs and are further potential targets for treatment. Numerous PLpro inhibitors have been identified. However, none of them has been validated in in vivo studies.<sup><xref rid="R180" ref-type="bibr">180</xref>
,<xref rid="R181" ref-type="bibr">181</xref>
</sup>
Moreover, PLpro enzymes differ between CoVs species, making PLpro inhibitors narrow-spectrum antiviral drugs against CoVs.<sup><xref rid="R182" ref-type="bibr">182</xref>
</sup>
</p>
<p>A further protein involved in viral replication is CoV main proteinase, which is inhibited by lopinavir. However, as previously mentioned, lopinavir (plus ritonavir) has been shown to be effective against CoVs in animal and nonrandomized studies of SARS-CoV-infected humans.<sup><xref rid="R154" ref-type="bibr">154</xref>
,<xref rid="R161" ref-type="bibr">161</xref>
</sup>
However, as previously mentioned, these results are considered inconclusive because of potential selection bias.<sup><xref rid="R152" ref-type="bibr">152</xref>
</sup>
</p>
<sec><title>Chloroquine</title>
<p>Chloroquine, which is commonly used against malaria and autoimmune diseases, increases the endosomal pH thereby inhibiting virus-cell fusion, and is therefore a potential broad-spectrum antiviral drug.<sup><xref rid="R183" ref-type="bibr">183</xref>
</sup>
It also interferes with glycosylation of cellular receptors of SARS-CoV.<sup><xref rid="R184" ref-type="bibr">184</xref>
</sup>
In addition, in vitro studies show that chloroquine inhibits entry and postentry stages of SARS-CoV-2 into cells.<sup><xref rid="R185" ref-type="bibr">185</xref>
</sup>
Moreover, chloroquine possesses immune-modulating activity, which might enhance its antiviral effect in vivo.<sup><xref rid="R185" ref-type="bibr">185</xref>
</sup>
</p>
</sec>
</sec>
<sec><title>RNA Synthesis Inhibitors</title>
<p>As previously mentioned, ribavirin, a guanosine analog has been shown to be ineffective or even harmful against SARS-CoV<sup><xref rid="R152" ref-type="bibr">152</xref>
</sup>
and MERS-CoV.<sup><xref rid="R157" ref-type="bibr">157</xref>
–<xref rid="R159" ref-type="bibr">159</xref>
</sup>
Immucillin-A, a new adenosine analog that has recently been developed, inhibits the viral RNA polymerase of a wide range of RNA viruses, including SARS-CoV and MERS-CoV,<sup><xref rid="R186" ref-type="bibr">186</xref>
</sup>
and might be useful in the treatment of other HCoVs. Furthermore, inhibitors of helicase (which are proteins unwinding double-stranded RNA into single strands during replication) might be useful in treatment of CoVs.<sup><xref rid="R187" ref-type="bibr">187</xref>
</sup>
RNA synthesis inhibitors, which reduce the formation of double-membrane vesicles, a hallmark of CoV2 replication, have been identified as potential antiviral drugs.<sup><xref rid="R188" ref-type="bibr">188</xref>
,<xref rid="R189" ref-type="bibr">189</xref>
</sup>
A double-stranded RNA activated caspase oligomerizer (DRACO) that targets long viral double-stranded RNA and induces apoptosis of infected cells, but spares healthy cells, might also be useful in the treatment of CoVs.<sup><xref rid="R190" ref-type="bibr">190</xref>
</sup>
</p>
</sec>
</sec>
</sec>
<sec><title>VACCINES</title>
<p>Several vaccines against HCoVs are in development with the aim of preventing infection, reducing disease severity and viral shedding. The main antigens for vaccine development are the structural spike glycoprotein S or its receptor-binding domain (RBD).<sup><xref rid="R191" ref-type="bibr">191</xref>
</sup>
However, the propensity of CoVs to rapidly mutate and recombine poses a potential problem for vaccine development.<sup><xref rid="R192" ref-type="bibr">192</xref>
–<xref rid="R194" ref-type="bibr">194</xref>
</sup>
Furthermore, the enhanced disease after viral challenges postvaccination has been observed in animal models after several different vaccines.<sup><xref rid="R195" ref-type="bibr">195</xref>
–<xref rid="R197" ref-type="bibr">197</xref>
</sup>
</p>
<sec><title>Live-attenuated Vaccines</title>
<p>The advantage of live-attenuated vaccines is that they usually induce a robust and long-lasting immune response, including cellular and humoral immunity to many different antigens. In SARS-CoV animal studies, attenuated mutants with deletion of the structural E gene have been shown to induce neutralizing antibodies, reduce viral loads and protect from clinical symptoms of SARS-CoV infection.<sup><xref rid="R198" ref-type="bibr">198</xref>
–<xref rid="R200" ref-type="bibr">200</xref>
</sup>
In contrast, deletion of open reading frames had little or no effect on viral loads in vitro and in vivo.<sup><xref rid="R201" ref-type="bibr">201</xref>
</sup>
Other strategies under development for live-attenuated vaccines against CoVs are genome rearrangement or gene knockouts.<sup><xref rid="R202" ref-type="bibr">202</xref>
–<xref rid="R204" ref-type="bibr">204</xref>
</sup>
These have the advantage that the vaccine virus cannot recombine with wild viruses.</p>
</sec>
<sec><title>Inactivated Vaccines</title>
<p>In mouse models, inactivated vaccines successfully induce cellular and humoral immunity (with many different neutralization antibodies) against SARS-CoV<sup><xref rid="R191" ref-type="bibr">191</xref>
,<xref rid="R205" ref-type="bibr">205</xref>
–<xref rid="R207" ref-type="bibr">207</xref>
</sup>
and humoral immunity against MERS-CoV.<sup><xref rid="R208" ref-type="bibr">208</xref>
,<xref rid="R209" ref-type="bibr">209</xref>
</sup>
In a human phase 1 trial, inactivated vaccines against SARS-CoV were well tolerated and elicited neutralizing antibodies.<sup><xref rid="R210" ref-type="bibr">210</xref>
</sup>
However, no challenge studies have been done in humans, and in monkey challenge studies, no clear evidence of protection was shown despite the induction of strong cellular and humoral responses.<sup><xref rid="R211" ref-type="bibr">211</xref>
</sup>
Moreover, concerns have been raised that inactivated vaccines against SARS-CoV and MERS-CoV may lead to harmful immune and/or inflammatory responses postchallenge.<sup><xref rid="R195" ref-type="bibr">195</xref>
,<xref rid="R209" ref-type="bibr">209</xref>
</sup>
</p>
</sec>
<sec><title>Subunit and Recombinant Vaccines</title>
<p>Subunit vaccines are purified antigens, usually combined with adjuvants and are the most popular method in the development of vaccines against novel CoVs. For SARS-CoV and MERS-CoV, these are mostly developed from spike glycoprotein S, RBD or nucleocapsid protein.<sup><xref rid="R212" ref-type="bibr">212</xref>
–<xref rid="R216" ref-type="bibr">216</xref>
</sup>
Some studies show that subunit vaccines given intranasally might induce stronger immune responses and mucosal immunity.<sup><xref rid="R217" ref-type="bibr">217</xref>
</sup>
Several subunit vaccines have shown to be successful in animal challenging studies.<sup><xref rid="R218" ref-type="bibr">218</xref>
–<xref rid="R220" ref-type="bibr">220</xref>
</sup>
</p>
<p>In a study in monkeys, recombinant RBD protein was used to successfully reduce viral loads in lungs and oropharynx and to prevent MERS-CoV pneumonia.<sup><xref rid="R218" ref-type="bibr">218</xref>
</sup>
In mice, similar results were achieved using recombinant RBD protein vaccines from SARS-CoV.<sup><xref rid="R221" ref-type="bibr">221</xref>
</sup>
</p>
</sec>
<sec><title>Viral Vectors Vaccines</title>
<p>Adenovirus-based vectors encoding SARS proteins (eg, nucleocapsid protein, spike glycoprotein S and other membrane proteins) have been shown to be immunogenic in mice and rhesus macaques in whom they induced humoral and cellular vaccine responses.<sup><xref rid="R222" ref-type="bibr">222</xref>
,<xref rid="R223" ref-type="bibr">223</xref>
</sup>
Adenovirus-based vaccines carrying parts MERS-CoV have been shown to reduce morbidity and mortality (undetectable or reduced pulmonary viral loads) in mouse models.<sup><xref rid="R196" ref-type="bibr">196</xref>
,<xref rid="R224" ref-type="bibr">224</xref>
</sup>
Initially, pulmonary hemorrhages were observed postviral challenge.<sup><xref rid="R196" ref-type="bibr">196</xref>
</sup>
However, adding a CD40 ligand to the vaccine enhanced immunogenicity and efficacy, and also prevented inadvertent pulmonary pathology, which makes this vaccine a promising strategy.<sup><xref rid="R196" ref-type="bibr">196</xref>
</sup>
Nonetheless, preexisting immunity against adenovirus might reduce efficacy. This might be addressed by giving a viral-based vaccine followed by a recombinant vaccine as a booster.<sup><xref rid="R225" ref-type="bibr">225</xref>
</sup>
A adenovirus-based MERS-CoV vaccine has moved into a phase I clinical trial.<sup><xref rid="R226" ref-type="bibr">226</xref>
</sup>
</p>
<p>One study, comparing an inactivated SARS-CoV vaccine with an adenovirus-based vaccine against SARS-CoV, found that the first led to higher humoral responses.<sup><xref rid="R227" ref-type="bibr">227</xref>
</sup>
Adenovirus-based vaccines administered intranasally led to immunoglobulin A antibody production which has been associated with superior protection from virus replication in lungs.<sup><xref rid="R227" ref-type="bibr">227</xref>
</sup>
This indicates that measuring serum neutralizing antibodies might not be a sufficient way of assessing vaccine efficacy for HCoV as mucosal immunity might be more important.</p>
<p>For SARS-CoV, a poxvirus has also been used as a vector for an intranasally and intramuscularly administered vaccine. This vaccine-induced neutralizing antibodies and reduced viral loads in the respiratory tract of challenged mice.<sup><xref rid="R228" ref-type="bibr">228</xref>
</sup>
However, a similar vaccine used in ferrets led to increased liver damage after SARS-CoV challenge.<sup><xref rid="R197" ref-type="bibr">197</xref>
</sup>
</p>
<p>Further vector vaccines for SARS-CoV that have been tested in animals are based on recombinant parainfluenza virus,<sup><xref rid="R229" ref-type="bibr">229</xref>
,<xref rid="R230" ref-type="bibr">230</xref>
</sup>
live-attenuated recombinant measles virus,<sup><xref rid="R231" ref-type="bibr">231</xref>
</sup>
attenuated rabies virus<sup><xref rid="R232" ref-type="bibr">232</xref>
</sup>
and attenuated <italic>Salmonella</italic>
.<sup><xref rid="R233" ref-type="bibr">233</xref>
</sup>
</p>
</sec>
<sec><title>DNA Vaccines</title>
<p>Vaccines containing DNA encoding the spike glycoprotein seem to induce a more robust response of neutralizing antibodies against MERS-CoV than vaccines only containing the RBD protein. They have been shown to protect rhesus macaques from MERS-CoV pneumonia.<sup><xref rid="R234" ref-type="bibr">234</xref>
,<xref rid="R235" ref-type="bibr">235</xref>
</sup>
Three DNA vaccines against MERS-CoV have advanced into clinical trials.<sup><xref rid="R236" ref-type="bibr">236</xref>
–<xref rid="R238" ref-type="bibr">238</xref>
</sup>
</p>
</sec>
</sec>
<sec><title>OTHER STRATEGIES FOR CONTROLLING EMERGING CORONAVIRUSES</title>
<p>After quickly spreading across the globe, SARS-CoV was contained in 2003 after a highly effective global public health response. This highlights the urgent need for rapid and effectful strategies of infection control. One of the main challenges with novel CoVs is the high potential for nosocomial transmission.<sup><xref rid="R239" ref-type="bibr">239</xref>
</sup>
Health care settings seem to increase the risk of viral transmission due to aerosol-generating procedures such as intubation and bronchoscopy. Appropriate hospital hygiene practices are therefore crucial to limit nosocomial outbreaks. The main aims are to effectively triage patients with fever, respiratory symptoms and a contact history<sup><xref rid="R240" ref-type="bibr">240</xref>
</sup>
and to apply stringent infection control measures such as isolating patients and quarantine contacts as early as possible. Ideally, each patient is placed in a single negative pressure room. If this is not possible, patients and health care workers should be cohorted.<sup><xref rid="R241" ref-type="bibr">241</xref>
</sup>
Protective gear should include water-resistant gowns, disposable gloves, N95 masks and goggles or face shields.<sup><xref rid="R240" ref-type="bibr">240</xref>
</sup>
Only suction catheters and mechanical respirators with a closed-circuit system and viral filters should be used.<sup><xref rid="R240" ref-type="bibr">240</xref>
</sup>
In contrasts, nebulizers, oxygen masks or nasal continuous positive airway pressure systems should not be used on an open ward.<sup><xref rid="R240" ref-type="bibr">240</xref>
,<xref rid="R241" ref-type="bibr">241</xref>
</sup>
Needless to say, strict hand hygiene needs to be applied and visitors should be avoided or limited to an absolute minimum. HCoVs have been shown to persist on dry surfaces for up to 9 days.<sup><xref rid="R242" ref-type="bibr">242</xref>
–<xref rid="R244" ref-type="bibr">244</xref>
</sup>
The persistence depends on temperature (shorter duration at 30–40°C) and humidity (longer at higher humidity).<sup><xref rid="R245" ref-type="bibr">245</xref>
</sup>
HCoVs, including novel CoVs, can be inactivated by heating to 56°C for 30 minutes or by using lipid solvents such as ethanol (>75%), isopropanol (>70%), formaldehyde (>0.7%), povidone-iodine (>0.23%), sodium hypochlorite (>0.21%), hydrogen peroxide (>0.5%), but not chlorhexidine.<sup><xref rid="R72" ref-type="bibr">72</xref>
,<xref rid="R244" ref-type="bibr">244</xref>
</sup>
</p>
</sec>
<sec><title>SUMMARY</title>
<p>SARS-CoV, MERS-CoV and SARS-CoV-2 infections seem to affect children less commonly and less severely as compared with adults. This might be because children are less frequently exposed to the main sources of transmission (which until now has been disproportionally nosocomial) or because they are less exposed to animals. However, it could also be that children are less frequently symptomatic or have less severe symptoms and are therefore less often tested, leading to an underestimate of the true numbers infected. In relation to SARS-CoV-2, a study prepublished in early March 2020 suggests that children are just as likely as adults to become infected with this virus but are less likely to be symptomatic or develop severe symptoms.<sup><xref rid="R246" ref-type="bibr">246</xref>
</sup>
However, the importance of children in transmitting the virus remains uncertain. The majority of children infected by a novel CoVs reported thus far have a documented household contact, often showing symptoms before them, suggesting the possibility that children are not an important reservoir for novel CoVs. The clinical, laboratory and radiologic features in children are similar for all novel CoVs, except more children infected with SARS-CoV presented with fever compared with SARS-CoV-2 or MERS-CoV. To date, no deaths in children have been reported for SARS-CoV or SARS-CoV-2, except (in the case of the former) for infants of mothers who were infected during pregnancy.</p>
</sec>
</body>
<back><fn-group><fn fn-type="financial-disclosure"><p>P.Z. is supported by a Fellowship from the European Society for Paediatric Infectious Diseases.</p>
</fn>
<fn fn-type="COI-statement"><p>The authors have no conflicts of interest to disclose.</p>
</fn>
<fn fn-type="equal"><p>P.Z. drafted the initial article. N.C. critically revised the article and both authors approved the final article as submitted.</p>
</fn>
</fn-group>
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