The Pediatric Infectious Disease Journal Covid 1

THE PEDIATRIC INFECTIOUS DISEASE JOURNAL
Wolters Kluwer Health
Pediatr Infect Dis J. 2020 May; 39(5): 355–368.

Published online 2020 Mar 12. doi: 10.1097/INF.0000000000002660
PMCID: PMC7158880
PMID: 32310621
Coronavirus Infections in Children Including COVID-

19
An Overview of the Epidemiology, Clinical Features, Diagnosis,
Treatment and Prevention Options in Children
Petra Zimmermann, MD, PhD *†‡
and Nigel Curtis, FRCPCH, PhD†‡§
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Abstract
Coronaviruses (CoVs) comprise a large family of enveloped, single-
stranded, zoonotic RNA viruses belonging to the family Coronaviridae,
order Nidovirales (Fig.(Fig.11).1 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.2,3 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.4–8 Human
coronaviruses (HCoVs) have also been associated with exacerbations of
chronic obstructive pulmonary disease,9 cystic fibrosis10 and asthma.11,12
FIGURE 1.
Summary of coronavirus diseases. COVID-19 indicates coronavirus disease 2019.
CoVs are classified
into Alphacoronaviruses and Betacoronaviruses (which are mainly found
in mammals such as bats, rodents, civets and humans)
and Gammacoronaviruses and Deltacoronaviruses (which are mainly
found in birds).8,13,14 Four CoVs commonly circulate among humans:
HCoV2-229E, -HKU1, -NL63 and -OC43.15,16 These viruses are believed
to have originally derived from bats (NL63, 229E),17,18 dromedary camels
(229E)19 and cattle (OC43).20 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.3,21,22 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.22–25 Another novel CoVs
emerged in Saudi Arabia in 2012, Middle East respiratory syndrome
coronavirus (MERS-CoV), which is transmitted from dromedary camels to
humans.26,27 The 2019 novel CoV (SARS-CoV-2), which originated in
China and is currently causing outbreaks globally, is a
novel Betacoronavirus belonging to the lineage B or subgenus
sarbecovirus, which includes SARS-CoV.28 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).28,29 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.28 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-2.30
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.
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EPIDEMIOLOGY
Common Circulating HCoVs
Common circulating HCoVs can be isolated from 4% to 6% of children
hospitalized for acute respiratory tract infections11,15,31 and from 8% of
children in an ambulatory setting (Table (Table11).15,32,33 Children under the
age of 3 years and children with heart disease are the most frequently
affected.4,15,35,36 Reinfections later in life are common32,115,116 despite the fact
that most individuals seroconvert to HCoVs during childhood.117–120 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.4,5,15,36
TABLE 1.
Characteristics of Human Coronaviruses
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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.5,15,16,31–33,36,79,81,121,122 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.31
Of the 4 common circulating HCoVs, NL63 and OC43 are the most
frequently isolated species.4,11,15,35,36 Cyclical patterns have been observed
for 229E and OC43, with outbreaks occurring every 2–4
years.4,15,32,35,82,116,119 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 NL63.4,5,11,15,32,123 HCoV-HKU1
has been reported to mainly occur in spring and summer in Hong
Kong,11,124 but in winter and spring in the United Kingdom and Brazil.4,15
SARS-CoV and MERS-CoV

SARS-CoV is a novel group 2b Betacoronavirus which initially emerged
in Guangdong province, south China in 2002,23–25 then spread to Hong
Kong and from there rapidly to many other countries.125 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%).63,106,107,126 Person-to-person transmission of SARS-CoV is well
established.55 The virus has spread to 29 countries and has been estimated
to have caused more than 8000 infections and 774 deaths worldwide
(Table (Table11).52
MERS-CoV is a novel group 2c Betacoronavirus which first appeared in
Saudi Arabia in 2012.26,27,127 It can spread from person-to-person128 and can
cause severe lower respiratory tract infections with a case-fatality rate of
20% to 40%.67,106,108–112 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.49,68 MERS-CoV spread to 27 countries
causing an estimated 2494 infections and 858 deaths (Table (Table11).53
The overall reproductive number (R0) for SARS-CoV was estimated to be
0.3–2.937,39,40,42,43,47 and for MERS-CoV to be 0.5–3.5 (Table
(Table11).39,46,48 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-CoV39,40,43 and up to 30 for MERS-
CoV.39,49 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.39,55,56 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-
CoV39 and to 0.7 for MERS-CoV (Table (Table11).128 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 reemerge84 (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).21
SARS-CoV-2
Early in the SARS-CoV-2 outbreak, it was shown that person-to-person
transmission was the main driver.28 The R0 for SARS-CoV-2 is currently
estimated at 2.7.38 The incubation period is estimated at 5–6 days, which is
similar to that for SARS-CoV and MERS-CoV.38,63–65,67–72 The serial interval
is estimated to be 8 days, also similar to the other novel CoVs (Table
(Table11).38,45,48,70 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.54 At that time the case-fatality
rate was uncertain but estimated at 0.9%–3%,54,113,114 which is much lower
than for SARS-CoV and MERS-CoV (6%–17% and 20%–40%,
respectively).63,67,106–112
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SYMPTOMS
Common HCoVs
In children, common circulating HCoVs can cause common cold
symptoms such as
fever,5,11,32 rhinitis,5,11 otitis,5 pharyngitis,5,11 laryngitis5 and headache,5,16,81 but
also bronchitis,5,11 bronchiolitis,5,11 wheezing,4,11,32 pneumonia,5,81,82 and, in up
to 57% of cases, gastrointestinal symptoms (which are more common in
children than adults).5–7 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.36 Fewer patients infected with
HCoVs had fever compared with those infected with RSV or influenza.36
In children, HCoV-NL63 has been associated with
conjunctivitis,78 croup,11,79,80 asthma exacerbations,11,12 febrile seizures11 and
HCoV-HKU1 with febrile seizures.7 Rare cases of neurologic diseases
have also been described (eg, the detection of HCoV in cerebrospinal fluid
in a child presenting with acute disseminated encephalomyelitis83 or in
cerebrospinal fluid of adults with multiple sclerosis.)129,130 A suspected
association between HCoVs and Kawasaki disease could not be
confirmed.131,132 Common HCoVs can be isolated from asymptomatic
individuals.16 During an infection, the viral load is high in the first 2 days
and decreases thereafter.29 A correlation between viral load and severity of
disease has not been observed29 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.133,134 Virus particles can be
isolated from nasopharyngeal secretions up to 14 days after the onset of
infection.135
SARS-CoV
There are 3 case series that report a total of 41 children who were affected
by SARS-CoV.57–59 The virus was associated with milder disease in
children compared with adults, and no deaths have been reported in
children.57–59,86 Symptomatic children with SARS-CoV infection were
reported to have fever (91%–100%),57–59 myalgia (10%–40%),57,58 rhinitis
(33%–60%),57–59 sore throat (5%–30%),57–59 cough (43%–80%),57–59 dyspnea
(10%–14%),38,84 headache (14%–40%)57–59 and, less commonly, vomiting
(20%),57,59 abdominal pain (10%),57 diarrhea (10%)58,59 and febrile seizures
(10%).57 In total, 50%–80% of children had other family members who
were infected57–59 and 30% had a nosocomial contact with SARS-
CoV.57 Most children recover quickly from an infection with SARS-
CoV.86 However, abnormalities on chest computed tomography (CT) can
persist for several months (eg, air trapping and ground-glass
opacifications).136
There is no evidence that SARS-CoV can be vertically transmitted to the
fetus.137 However, SARS-CoV infections during pregnancy have been
associated with possible miscarriage, intrauterine growth retardation and
preterm delivery.137,138
MERS-CoV
Most case series of patients infected with MERS-CoV report a low
proportion (0.1%–4%) of children.34,76,109,110,139,140 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 (Table11).34 There are 2
small case series of children infected with MERS-CoV: one including 31
children with a mean age of 10 years60 and the other one only 7
children.76 In both studies, 42% of children were asymptomatic.60,76 In the
case series of 7 children, 57% suffered from fever, 28% from vomiting and
diarrhea and 14% from cough and shortness of breath.76 Two children
required oxygen supplementation and one mechanical ventilation.76 In the
other case series, 2 died (6%).60 The main sources of MERS-CoV infection
in children were household (32%) and other contacts (23%), followed by
nosocomial transmission (19%).60
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.141–144
SARS-CoV-2
Different case definitions for COVID-19 cases in adults and children from
authoritive sources as of March 2020 are detailed in Table Table2.2.
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.114 There are 3 case series of children who have been
infected with SARS-CoV-2.61,72,77 The first included 20 children up to
January 31, 2020, in the Province of Zhejiang,72 the second 34 children
between January 19, 2020, and February 7, 2020, in the Province of
Shenzhen,61 and the third 9 infants from different provinces in China.77 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.61 The most
common symptoms were fever (50%) and cough (38%).61 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.72 In the series of 9 infants, only 4 were reported to have fever.
One infant was asymptomatic.77 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).28 Most infected children recover 1–2 weeks after
the onset of symptoms and no deaths from SARS-CoV-2 had been
reported by February 2020.72
TABLE 2.
Case Definitions for SARS-CoV-2 Infections in Adults and Children (as of
February 2020)
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From these series, it appears that children have milder clinical symptoms
than adults61,72 (as has been reported for SARS-CoV and MERS-CoV
infections),57–60,76,86 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.147 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;61 and the majority in the
one with 20 children (exact number not specified)].72 This is similar to
SARS-CoV, in which 50%–80%57–59 of children were reported to have an
affected household contact60 and to MERS-CoV in which it was 32%.60
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.246 However, the
importance of children in transmitting the virus remains uncertain.
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.148
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LABORATORY FINDINGS
Laboratory findings from children are similar with infections caused by
different novel CoVs (Table (Table1).1). The white blood cell count is
typically normal or reduced with decreased neutrophil85 and/or lymphocyte
counts.57–59,72,86 Thrombocytopenia may occur.57–59,76,86 C-reactive protein and
procalcitonin levels are often normal.72 In severe cases, elevated liver
enzymes,57–59,72,86 lactate dehydrogenase levels,57 as well as a abnormal
coagulation and elevated D-dimers have been reported.57–59,72,86
SARS-CoV-2
The same laboratory findings has above have been observed for children
infected with SARS-CoV-2.61 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.61 C-reactive protein and procalcitonin levels were each
elevated in 1 case only (3%).
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RADIOLOGIC FINDINGS
Similar to the laboratory findings, radiologic findings from children are
also similar across infections with different novel CoVs (Table
(Table1).1). On chest radiography, children mostly show bilateral patchy
airspace consolidations often at the periphery of the lungs, peribronchial
thickening and ground-glass opacities.57–59,76,86,87 Chest CT mostly shows
airspace consolidations and ground-glass opacities.89
SARS-CoV-2
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.61,88 These findings are unspecific and milder
compared with those in adults.88
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DIAGNOSIS
The main basis for diagnosis of infections with HCoVs is real-time
polymerase chain reaction (RT-PCR) on upper or lower respiratory
secretions.5,15,90–96 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.28,149 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.91,98,99 For SARS-CoV and SARS-CoV-2, rare cases with
positive PCRs in blood have been reported.28,150 Serology has been used to
diagnose infections with SARS-CoV and MERS-CoV, but is not useful in
the acute phase of the infection.100–103 Cross-reactivities between antibodies
against SARS-CoV and common CoVs have been observed.151
SARS-CoV-2
Whole genome sequencing allowed the rapid development of molecular
diagnostic tests for SARS-CoV-2.28 RT-PCR for genes encoding the
internal RNA-dependent RNA polymerase and surface spike glycoprotein
are commonly used.28
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TREATMENT
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.
SARS-CoV
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.57–59 Ribavirin was
subsequently shown to be ineffective or even harmful because it can cause
hemolytic anemia or liver dysfunction.152 In adults, interferon-alpha alone
or together with ribavirin also did not consistently improve
outcomes.152,153 There is some evidence that intravenous corticosteroids led
to clinical and radiologic improvement in SARS-CoV-infected
individuals.58 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).152 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).154,155 However, a systematic review found inconclusive results for the
use of lopinavir/ritonavir because of a possible selection bias in many of
the studies.152 Inconclusive results were also found for intravenous
immunoglobulins because studies did not account for comorbidities, stage
of illness and effect of other treatments.152 There is no evidence for the use
of monoclonal antibodies against tumor necrosis factor alpha.156
MERS-CoV
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.157–159 Mycophenolate mofetil,
which inhibits guanine (and therefore RNA) synthesis, was identified as a
potential anti-MERS-CoV drug in vitro.160 However, animal studies
showed that the drug leads to worse outcomes with higher viral loads in
lung and extrapulmonary tissues.161 Consistent with this, renal transplant
patients on mycophenolate mofetil have been reported to develop severe
and sometimes fatal MERS-CoV infections.162
SARS-CoV-2
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.72
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.97,163 Despite this,
in the previously mentioned case series of the 34 children infected with
SARS-CoV-2, 59% were treated with lopinavir/ritonavir.61 None of the
children received glucocorticoids or immunoglobulins.61
Other Therapeutic Options

Monoclonal Antibodies
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.164 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.165–171 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.172 However, to date, it
has only been tested in animal studies.172
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.173–176 However, rapid mutation of CoVs poses a potential
problem, which might be diminished by using several monoclonal
antibodies targeting different epitopes.166
Protease Inhibitors
Endosomal and nonendosomal virus entry into cells can be reduced by
inhibiting responsible proteases.177–179 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.180,181 Moreover, PLpro
enzymes differ between CoVs species, making PLpro inhibitors narrow-
spectrum antiviral drugs against CoVs.182
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.154,161 However, as previously mentioned, these results are
considered inconclusive because of potential selection bias.152
Chloroquine
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.183 It also
interferes with glycosylation of cellular receptors of SARS-CoV.184 In
addition, in vitro studies show that chloroquine inhibits entry and postentry
stages of SARS-CoV-2 into cells.185 Moreover, chloroquine possesses
immune-modulating activity, which might enhance its antiviral effect in
vivo.185
RNA Synthesis Inhibitors
As previously mentioned, ribavirin, a guanosine analog has been shown to

be ineffective or even harmful against SARS-CoV152 and MERS-CoV.157–
159
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,186 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.187 RNA synthesis
inhibitors, which reduce the formation of double-membrane vesicles, a
hallmark of CoV2 replication, have been identified as potential antiviral
drugs.188,189 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.190
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VACCINES
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).191 However, the
propensity of CoVs to rapidly mutate and recombine poses a potential
problem for vaccine development.192–194 Furthermore, the enhanced disease
after viral challenges postvaccination has been observed in animal models
after several different vaccines.195–197
Live-attenuated Vaccines
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.198–200 In contrast, deletion of
open reading frames had little or no effect on viral loads in vitro and in
vivo.201 Other strategies under development for live-attenuated vaccines
against CoVs are genome rearrangement or gene knockouts.202–204 These
have the advantage that the vaccine virus cannot recombine with wild
viruses.
Inactivated Vaccines
In mouse models, inactivated vaccines successfully induce cellular and
humoral immunity (with many different neutralization antibodies) against
SARS-CoV191,205–207 and humoral immunity against MERS-CoV.208,209 In a
human phase 1 trial, inactivated vaccines against SARS-CoV were well
tolerated and elicited neutralizing antibodies.210 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.211 Moreover, concerns have been raised
that inactivated vaccines against SARS-CoV and MERS-CoV may lead to
harmful immune and/or inflammatory responses postchallenge.195,209
Subunit and Recombinant Vaccines

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.212–216 Some
studies show that subunit vaccines given intranasally might induce
stronger immune responses and mucosal immunity.217 Several subunit
vaccines have shown to be successful in animal challenging studies.218–220
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.218 In mice, similar results were achieved using recombinant
RBD protein vaccines from SARS-CoV.221
Viral Vectors Vaccines

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.222,223 Adenovirus-based
vaccines carrying parts MERS-CoV have been shown to reduce morbidity
and mortality (undetectable or reduced pulmonary viral loads) in mouse
models.196,224 Initially, pulmonary hemorrhages were observed postviral
challenge.196 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.196 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.225 A adenovirus-based MERS-CoV
vaccine has moved into a phase I clinical trial.226
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.227 Adenovirus-based vaccines administered
intranasally led to immunoglobulin A antibody production which has been
associated with superior protection from virus replication in lungs.227 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.
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.228 However, a similar vaccine used in ferrets led
to increased liver damage after SARS-CoV challenge.197
Further vector vaccines for SARS-CoV that have been tested in animals
are based on recombinant parainfluenza virus,229,230 live-attenuated
recombinant measles virus,231 attenuated rabies virus232 and
attenuated Salmonella.233
DNA Vaccines
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.234,235 Three DNA
vaccines against MERS-CoV have advanced into clinical trials.236–238
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OTHER STRATEGIES FOR CONTROLLING EMERGING

CORONAVIRUSES
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.239 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
history240 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.241 Protective gear
should include water-resistant gowns, disposable gloves, N95 masks and
goggles or face shields.240 Only suction catheters and mechanical
respirators with a closed-circuit system and viral filters should be
used.240 In contrasts, nebulizers, oxygen masks or nasal continuous positive
airway pressure systems should not be used on an open ward.240,241 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.242–244 The persistence depends on
temperature (shorter duration at 30–40°C) and humidity (longer at higher
humidity).245 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.72,244
Go to:
SUMMARY
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.246 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.
Go to:
Footnotes
P.Z. is supported by a Fellowship from the European Society for Paediatric
Infectious Diseases.
The authors have no conflicts of interest to disclose.

P.Z. drafted the initial article. N.C. critically revised the article and both authors
approved the final article as submitted.
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Wolters Kluwer Public Health Emergency Collection. 2020 May; 39(5)355
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Pediatr Infect Dis J. 2020 May; 39(5): 355–368.

Coronavirus Infections in Children Including COVID-

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

SARS-CoV and MERS-CoV

Other Therapeutic Options

Chloroquine, which is commonly used against malaria and autoimmune

As previously mentioned, ribavirin, a guanosine analog has been shown to

Subunit and Recombinant Vaccines

Viral Vectors Vaccines

OTHER STRATEGIES FOR CONTROLLING EMERGING

The authors have no conflicts of interest to disclose.

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Elsevier Public Health Emergency Collection. ; ()

 Coronavirus Infections in Children Including COVID-19

Coronavirus Infections in Children Including COVID-19

Wolters Kluwer Public Health Emergency Collection. 2020 May; 39(5)355

 Characterization and complete genome sequence of a novel coronavirus, coronavirus

See more ...

 Human coronavirus NL63 infection and other coronavirus infections in children

See more ...

 An outbreak of coronavirus OC43 respiratory infection in Normandy, France.[Clin Infect

See more ...

 Epidemiological and clinical features of human coronavirus infections among different

See more ...

 Identification of a novel coronavirus in patients with severe acute respiratory syndrome.

See more ...

See more ...

 Comparing nonpharmaceutical interventions for containing emerging epidemics.[Proc

See more ...

See more ...

 An outbreak of coronavirus OC43 respiratory infection in Normandy, France.[Clin Infect

See more ...

See more ...

 Clinical presentations and outcome of severe acute respiratory syndrome in children.

See more ...

 Infants born to mothers with severe acute respiratory syndrome.[Pediatrics. 2003]

See more ...

 Acute viral respiratory infections among children in MERS-endemic Riyadh, Saudi

See more ...

See links ...

 [Retracted: Clinical and epidemiological characteristics of 34 children with 2019 novel

See more ...

 Clinical characteristics and intrauterine vertical transmission potential of COVID-19

 A case-control study of SARS versus community acquired pneumonia.[Arch Dis Child.

See more ...

 [Retracted: Clinical and epidemiological characteristics of 34 children with 2019 novel

 Clinical presentations and outcome of severe acute respiratory syndrome in children.

See more ...

 [Retracted: Clinical and epidemiological characteristics of 34 children with 2019 novel

See more ...

 Clinical presentations and outcome of severe acute respiratory syndrome in children.

See more ...

 Review Diagnosis and treatment recommendations for pediatric respiratory infection

 Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.

See more ...