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Abstract
Since the outbreak of coronavirus disease 2019 (COVID-19), in Wuhan, China, there were more than 1,773,000 confirmed infected
cases. This infection has spread to almost all countries around the world with reported high mortality and morbidity. Infections in
children and infants have been reported as well. The condition of the infected children was mostly mild. To date, there have been
two reported deaths in pediatrics testing positive for COVID-19 in China, and no deaths have been reported in the published evidence
from other countries. The therapy strategy for the children who suffer coronavirus disease (COVID-19) has been based on the adult
experience. The present review summarizes current knowledge of the etiology, epidemiology, clinical manifestations, transmission,
diagnosis, treatment, and prevention of COVID-19 infection in children and infants.
1. Context (at the age of 19 or less) (10). The reason for this is not
clear yet but it may be a combination of epidemiologic and
biologic factors or even due to non-reported pediatric in-
Patients who have dry cough, decreased to normal
fected cases. It must be remembered that during the out-
white blood cell counts, fever, initially identified as “fever
breaks of the Middle Eastern respiratory syndrome (MERS)
of unknown origin with pneumonia”, had been steadily in-
and severe acute respiratory syndrome (SARS), a limited
creasing in Wuhan, China, since December 2019 (1). The
number of cases with fewer hospitalizations, less mortal-
causative agent of this unexplained infected pneumonia,
ity, and milder symptoms were found in children and ado-
described as severe acute respiratory syndrome coron-
lescents in comparison to adults (11-14). Pediatric analysis
avirus 2 (SARS-CoV-2), is reported not only to cause severe
of available epidemiological data can provide situational
pneumonia but characterized by strong human-to-human
information about child health and provide a better un-
transmission (2, 3). The prevalence of coronavirus disease
derstanding of the prevalence and effects of COVID-19 in
2019 (COVID-19) is quickly increasing around the world,
these patients (15). Therefore, the present review is aimed
providing an important public health emergency with the
to summarize current knowledge on etiology, epidemiol-
possibility of an epidemic (4-7). By April 13, 2020, the
ogy, clinical manifestations, transmission, diagnosis, treat-
COVID-19 outbreak has affected over 1,773,084 people glob-
ment, and prevention of COVID-19 infection in children
ally with most of the cases being reported from China,
and infants in order to provide a better understanding of
United States of America, and Europe. The absolute num-
the disease in this population.
ber of deaths has surpassed 111,652 worldwide and is ex-
pected to increase further along with the rapid spread of
the disease (8, 9). 2. Etiology
The number of reported child and neonate cases is lim-
ited, leastways in the early stages of this prevalence. In a re- The first identification of coronaviruses occurred in
cent investigation, out of 44,672 COVID-19 cases approved late 1960s and they have been known to cause a widespread
in China, only 2.1% were observed in the pediatric patients colds and respiratory tract infections (16). The 2019-Novel
Copyright © 2020, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License
(http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly
cited.
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Deravi N et al.
Deravi N et al.
Deravi N et al.
In diagnosis, the coinfection of CoVID-19 with other bacte- patients consists of asymptomatic cases (56), patients with
ria and/or viruses must be anticipated (19). These discrim- upper respiratory infection (URI) and patients with mild
inant tests are important and molecular methods help in pneumonia (52).
accurate diagnosis.
Unlike in adults, a dependable pattern of laboratory 6.2. Moderate
derangements in children with COVID-19 is yet to be found.
Patients with moderate symptoms may represent res-
Clinicians are advised to monitor CRP and lymphocyte
piratory symptoms, radiographic features and fever (28).
count as signs of severe infection and to monitor PCT for
possible bacterial co-infection. IL-6 must be checked as a
possible prognostic predictor in severe COVID-19 (50). 6.3. Severe
Patients with severe symptoms may represent one of
the following criteria (28):
6. Clinical Manifestations
1) Dyspnea, RR > 30 times/min (In children: RR ≥
According to earlier studies, the incubation period of 70/min (in children with younger than 1 year), RR ≥
COVID-19 infections varies from 1 to 14 days, frequently in 50/min (in children older than 1 year) (52));
the range of 3 to 7 days (approximately 5.2 days) (19, 35, 2) Oxygen saturation < 93% in ambient air (< 90% in
49). Age of onset in children is estimated to range from 1.5 premature infants (52));
months to 17 years, with most cases having familial trans- 3) PaO2 /FiO2 < 300 mmHg.
mission (51). Accordingly 93.5% of infected children were In another article, some other criteria have been at-
reported in family clusters (39). At the onset of the dis- tributed to this stage of disease (52), such as:
ease, the most common symptoms are fever, fatigue, dry 1) Intercostal, subcostal and suprasternal retractions,
cough and diarrhea (28, 49, 52). Most of the pediatric nasal flaring, apnea, cyanosis and etc.
cases represent low to moderate fever, and in some cases 2) Blood gases: PaCO2 > 50 mmHg, PaO2 < 60 mmHg.
no fever (52). Other symptoms include headache, sputum 3) Consciousness impairment: lethargy, restlessness,
production, dyspnea, lymphopenia, and hemoptysis (48, convulsion, coma, etc.
53-55). Chest CT scans reveal clinical features presented 4) Nourishment problems: Poor appetite, poor feed-
as pneumonia, and in more severe cases, abnormal fea- ing, and even dehydration.
tures such as acute respiratory distress syndrome (ARDS) 5) Myocardial damage: Increased level of myocardial
(54). As the infection progresses, after about 1 week, dys- enzyme, cardiomegaly, electrocardiogram ST-T changes
pnea, cyanosis and other related symptoms can appear, and even cardiac insufficiency in severe cases.
and they can be accompanied by systemic toxic symptoms 6) Other manifestations: coagulation disorders (pro-
such as restlessness (malaise), loss of appetite and reduced longed prothrombin time (PT) and elevated level of d-
activity (52). The disease progression in some children dimer), gastrointestinal dysfunction, rhabdomyolysis and
might be rapid and result in respiratory failure. In these raised levels of liver enzymes.
severe cases, even, irreversible bleeding (and coagulation
dysfunction), metabolic acidosis and septic shock are pos- 6.4. Critical
sible (52). Muscle ache, headache, confusion, rhinorrhea,
Critical patients may exhibit one or more of the follow-
sore throat, sputum production, nausea (and vomiting)
ing conditions (28):
and chest pain have been reported as symptoms of COVID-
1) Respiratory failure (patients represent acute respira-
19 infection (28, 40, 54).
tory distress syndrome (ARDS) and refractory hypoxemia,
According to guidelines for diagnosis and treatments
which is irresponsible to conventional oxygen therapy,
for COVID-19 published by the National Health Commis-
such as oxygen mask or nasal catheter (52));
sion of China, based on the severity of symptoms, COVID-19
2) Septic shock;
is classified to 4 levels (28):
3) Multiple organ failure;
There have been a few reports about COVID-19 infec-
6.1. Mild
tion in newborns as well. According to Shen et al. (19)
Most of the pediatric cases show mild clinical manifes- no newborns delivered from infected mothers have been
tations (19). They only have mild symptoms without any shown to be COVID-19 positive (19). There were no infec-
radiographic features (28). Most of these patients recover tions among newborns until the publication of their work
in about 1 - 2 weeks after onset of the disease. Few may in until January 29th 2020. However, by March 1st, 2020,
progress to lower respiratory infections (19). This group of Lu et al. (2) reported three newborns with COVID-19 mainly
Deravi N et al.
as part of family cluster cases. A 17 days old newborn diag- Medical personnel must wear caps, surgical mask, medi-
nosed with COVID-19 showed cough, fever and milk vom- cal overalls and goggles or face shield for daily medical du-
iting. His mother was infected as well (57). The second ties. Goggles or face shields must necessarily been worn
(birth to 1 month) presented with fever on 5th day after when collecting respiratory samples; latex gloves must be
birth. In this case the mother was infected as well (48). The worn on activities that involve coming in contact with
third case whose mother was infected, was silent and di- body fluid, secreta or excreta and blood. Face shield or
agnosed 30 hours after birth by the viral nucleic acid test goggles, surgical mask, latex gloves, respiratory hood and
(56). From these, we understand that milk vomiting, short- medical protective clothing must be worn when necessary,
ness of breath, fever and cough are symptoms of COVID-19 to prevent splash or aerosol during bronchoscopy, opera-
infection in neonates (birth to 1 month). The vital signs of tions of endotracheal intubation, sputum suction and air-
these neonates were found to be stable. There have also not way nursing. Patients and their family must wear surgical
been any severe emergency cases (51, 57-59). On the other masks (18).
hand, maternal hypoxemia as a result of severe infection As with SARS-CoV and MERS-CoV, there is no specific
could cause premature delivery, intrauterine asphyxia and drug treatment for COVID-19. The general treatments in-
other further risks. Neonates, specifically preterm new- clude resting, symptomatic and supportive treatments;
borns, may represent non-specific symptoms, which re- including preservation of water acid-base balance and
quires careful observation (52). electrolyte and the supply of oxygen. Extracorporeal
We see that most pediatric cases show mild symptoms, membrane lung (ECMO), high-dose pulmonary surfac-
without any sign of pneumonia or fever. They mostly have tant (PS), high-frequency oscillatory ventilation (HFOV)
good prognosis and, within 1 - 2 weeks after disease on- and inhaled nitric oxide (iNO) may be useful for new-
set, they recover fully. Only a few cases have presented in- borns with severe acute respiratory distress syndrome.
fections in their lower respiratory tract (19). According to Moreover, three drug combinations (mercaptopurine plus
Shen et al. (19) despite the generally mild cases in children, melatonin, toremifene plus emodin and sirolimus plus
the probable risk of death in pediatric population must dactinomycin) are candidate repurpose drugs. In addi-
not be ignored. During epidemics of Middle East respi- tion, convalescent sera from COVID-19 recovered cases may
ratory syndrome (MERS) and severe acute respiratory syn- be helpful for COVID-19 infection, because of a significant
drome (SARS), ARDS and death happened among pediatric decrease in the death rate following this treatment (2, 18).
patients as well (12, 60-62). It is also important to know that Shen et al. (19) reported that IFN-α atomization is an alter-
the data from these studies have been conducted based on native of treatment for COVID-19 pneumonia. The safety
a limited number of patients, and therefore, continuous and the efficacy of interferon in the treatment of COVID-
observation of further cases is recommended. (Table 1). 19 children must be confirmed (19). Lopinavir/ritonavir
(LPVr) is mostly used to treat HIV. LPVr is recommended
7. Infection Control and Treatment for treating COVID-19, centered on the clinical experience
in MERS and SARS treatment. Chloroquine diphosphate
Lu et al. (2) reported that early identification and isola- (CD) is an optimized medication based on the composi-
tion are necessary for control of COVID-19. With reference tion of an antimalarial medicine named quinine that is
to MERS management, COVID-19 neonates must be placed mostly used for parenteral amoebiasis, malaria, etc. CD
in rooms with negative pressure or in rooms in which the has demonstrated clear effectiveness in adult clinical tri-
room exhaust is filtered through high-efficiency particu- als for COVID-19 treatment. Until now, no CD dosage is rec-
late air (HEPA) filters. Visiting must not be allowed for ommended for children with COVID-19 (64). Ribavirin is
COVID-19 neonates (2). Even if there are no clinical man- an antiviral drug with a wide spectrum and inhibitory ef-
ifestation, children who are from families with clustered fects on DNA viruses and RNA viruses. In China and other
infections must be screened for COVID-19 to exclude poten- nations, various age limits and dosage forms of ribavirin
tial sources of infection. To protect children with underly- are being administered. For children with COVID-19, intra-
ing diseases, early isolation must be performed. Enhanc- venous ribavirin has been recommended 2 - 3 times daily at
ing protection during delivery and isolating the newborns a dosage of 10 mg/kg per time (maximum 500 mg per time)
immediately after delivery is imperative (63). According to (65). Arbidol (umifenovir) is an antiviral compound with a
the standard prevention protocol, good personal protec- wide spectrum, and has been recommended for influenza
tion, environmental ventilation, ward management, hand treatment and prophylaxis in China and Russia. Arbidol
hygiene, medical waste management, object surface disin- shows activities against various RNA and DNA viruses (66).
fection and cleaning and other hospital infection control Arbidol was seen to be efficient in vitro to SARS-CoV-2 (67).
work, are necessary to reduce nosocomial infection (18). Until now, no dosage of arbidol has been recommended for
Deravi N et al.
Table 1. Current Available Data About the Clinical Manifestation of COVID-19 in Children
Chen et al. Henry et al. Cai Jiehao et al. Wei Xia et al.
children with COVID-19. coronavirus-NL63 (HCoV-NL63), and SARS-CoV-2 all use the
It has been reported that it is not advisable to com- same angiotensin-converting enzyme-2 (ACE2) as their cell
bine three or more antiviral drugs at the same time (64). receptor in humans (20, 71, 72). An experimental mouse
Cai et al. (68) have reported that no antivirals are neces- model study has shown that ACE2 is involved in protective
sary for non-severe self-limiting COVID. In consideration mechanisms in the lungs and additionally protect against
of the seasonal overlap between COVID and influenza, in- severe lung injuries that result from respiratory virus in-
fluenza virus screening is required to eliminate the pos- fections. Furthermore, its expression in rat lung has been
sible coinfection of these agents (68). Appropriate antibi- found to dramatically decrease with age (73). ACE2 is also
otics should be applied timely if there is sign of secondary known to protect against severe acute lung injuries, which
bacterial infection (18). Yang et al. (63) stated that sec- could be triggered by acid aspiration, sepsis, lethal avian
ondary infection may be caused by the premature use and influenza A H5N1, and SARS virus infection (74, 75). These
extreme use of antibiotics and corticosteroids. Consider- findings may not be necessarily related with a lower sus-
ing that symptoms of children with viral respiratory infec- ceptibility of children to 2019-nCoV, but can be regarded as
tion are mild and can be self-healed, antiviral agents must a possible reason, which needs to be further investigated.
not be used, except for critical cases (63). During the treat-
ment, children’s vital signs, SpO2 , etc. must be monitored.
9. Home Confinement Impacts on Children During
Critical cases must be identified as soon as possible (18).
the 2019-nCoV Outbreak
8. Are Children Less Susceptible to 2019-nCoV? Following the widespread COVID-19 outbreak, many
schools around the world have been closed by the or-
In a recent study, Henry et al. (15) reported that the der of governments to stop the spread of the virus. This
reason behind the reduced susceptibility among pediatric has caused millions of children and adolescents to stay at
patients is still unknown. The fewer pediatric cases may home. Although education has largely continued through
be a result of underreporting of children and infant cases media, such as television and the Internet, long-term
as well as a combination of epidemiologic and biologic school closures could have negative physical and psy-
factors. Another study by Lee et al. (69) reported that chological effects on children (76). Post-traumatic stress
fewer outdoor activities by children and less international scores in children who had been quarantined have been
travel, which translates to less contact with infected peo- shown to be four times higher than inchildren who hadn’t
ple could be possible reasons. Accordingly, the number of been quarantined (77). Government, families, schools,
pediatric patients may increase in future; thus fewer pedi- and other elements of society must be aware of the ad-
atric cases at the beginning of such a pandemic does not verse physical and psychological consequences of long-
necessarily mean that children and infants are less suscep- term stay at home and provide children and adolescents
tible to COVID-19 infection. Furthermore, since children with appropriate training and education to help them
have not normally been exposed to as much air pollution maintain a healthy lifestyle, nutritious diet, regular sleep,
and cigarette smoke as adults, they have fewer underly- and adequate physical activity (76). Parents’ committees
ing disorders. Therefore more active innate immune re- should work together to fulfil the needs of many students
sponse and healthier respiratory tracts are generally ob- with the school requirements as well as to support chil-
served in children, which make them less susceptible to dren’s rights for a healthy lifestyle. Accordingly, psychol-
coronavirus disease (70). Moreover, the SARS virus, human ogists must provide online services to cope with anxiety
Deravi N et al.
from becoming infected, mental health disorders that usu- Ahsan did critical revision of the manuscript for impor-
ally result from domestic conflicts and probable tension tant intellectual content and drafting of the manuscript.
with parents (78), COVID-19 is now a pandemic and all coun- Melika Mokhtari did drafting of the manuscript, analysis,
tries involved in this disease should consider the effects of and interpretation of data. Maryam Vaezjalali did critical
quarantine on children and adolescents to prevent long- revision of the manuscript for important intellectual
term harm to them (76). Since children do not have much content-Study supervision.
power to express their basic needs, parents and govern- Conflict of Interests: The authors confirm that they have
ments must ensure that all mental and physical impacts of no conflicts of interest.
the 2019-nCoV pandemic on children are kept minimal.
Funding/Support: No funding.
10. Conclusions
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