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ƐƏѶѶ | Acta Paediatrica. 2020;109:1088–1095. wileyonlinelibrary.com/journal/apaƐ|$! &$
In December 2019, there was an outbreak of a new infectious dis-
ease in Wuhan in the Hubei Province of China.1 Coronavirus dis-
e a s e 2 0 1 9 ( C O V I D - 1 9 ) i s c a u s e d b y t h e s e v e r e a c u t e r e s p i r a t o r y syndrome coronavirus 2 (SARS-CoV-2), which was also previously known as 2019-nCoV. It is the seventh coronavirus.
On March 11, 2020, the World Health Organization (WHO) classi-
fied the outbreak as a pandemic. An interactive web-based real-time COVID-19 reporting system, known as a dashboard, has been set up
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I: 10.1111/apa.15270
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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, di stribution and reproduction
in any medium, provided the original work is properly cited and is not used for commercial purposes.
© 2020 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.00u;b-|bomvĹ COVID-19, coronavirus disease 2019; SARS, severe acute respiratory syndrome; SARS-CoV-2, severe acute respiratory syndrome cor onavirus 2.1Department of Medical Epidemiology
and Biostatistics, Karolinska Institutet, Stockholm, Sweden
2Department of Paediatrics, Orebro
University Hospital, Orebro, Sweden
3Division of Epidemiology and Public
Health, School of Medicine, University of Nottingham, UK
4Department of Medicine, Columbia
University College of Physicians and Surgeons, New York, NY, USA
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Jonas F Ludvigsson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.Email: [email protected]0v|u-1|
blĹ The coronavirus disease 2019 (COVID-19) pandemic has affected hundreds of
thousands of people. Data on symptoms and prognosis in children are rare.
;|_o7vĹ A systematic literature review was carried out to identify papers on
COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using the MEDLINE and Embase databases between January 1 and March 18, 2020.!;vѴ|vĹ The search identified 45 relevant scientific papers and letters. The review
showed that children have so far accounted for 1%-5% of diagnosed COVID-19 cases, they often have milder disease than adults and deaths have been extremely rare. Diagnostic findings have been similar to adults, with fever and respiratory symp-toms being prevalent, but fewer children seem to have developed severe pneumonia. Elevated inflammatory markers were less common in children, and lymphocytopenia seemed rare. Newborn infants have developed symptomatic COVID-19, but evidence of vertical intrauterine transmission was scarce. Suggested treatment included pro-viding oxygen, inhalations, nutritional support and maintaining fluids and electrolyte balances.om1ѴvbomvĹ The coronavirus disease 2019 has occurred in children, but they seemed
to have a milder disease course and better prognosis than adults. Deaths were ex-tremely rare.
+)! "
2019-nCoV, children, coronavirus, COVID-19, newborn, SARS-CoV2
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by the Center for Systems Science and Engineering at Johns Hopkins
University, Baltimore, Maryland, USA.2 By March 18, 2020, there
had been more than 2 00 000 confirmed cases and more than 8000 deaths due to COVID-19. This corresponds to a 4.0% case fatality rate.
A number of studies have reviewed symptoms and characteris-
tics of adults with COVID-19. Although some of these studies have also included a smaller number of children,
34 the aggregated data on
children with COVID-19 are rare. This paper summarises the find-ings of a systematic literature review on the current knowledge of COVID-19 in children.
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The review was carried out at the Karolinska Institutet, Stockholm, Sweden, and the Medline (used by PubMed) and Embase data-bases were searched for relevant terms related to COVID-19 and SARS-CoV2 in children. This search was carried out by two highly experienced librarians at the Institutet, and the search algorithm is presented in Appendix S1. There were 89 papers published in Medline between January 1 and March 18, 2020 and eight pub-l i c a t i o n s i n E m b a s e d u r i n g t h e s a m e p e r i o d . O f t h o s e , 44 w e r e deemed relevant to this review.
5-48 Also on March 18, but later
during the day, the New England Journal of Medicine published a
Letter to the Editor describing 1391 children assessed for SARS-CoV-2
49 (171 confirmed cases). That letter was also included in this
review. The initial search was complemented by a further Medline search on March 19, 2020 by the author. This focused on 2019-nCoV, but this did not yield any additional studies (Appendix S1). This means that the current review was based on 45 scientific pa-pers and letters. Most of the studies originated from China and it was notable that there were very few reports on children from Italy, Iran or South Korea, despite the large number of patients with diagnosed COVID-19 in those countries. There was no pre-specified protocol prior to the current review.
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The review with the largest number of positive COVID- 1 9 cases was a Chinese paper by the Chinese Novel Coronavirus Pneumonia
Emergency Response Epidemiology Team w i t h 7 2 , 3 1 4 s u b j e c t s ,
and this found that about 2% of the 44 672 confirmed cases of COVID- 19 were children aged 0- 19 years.
49 Of these, 0.9% were
under the age of 10 years at diagnosis.49 Italian data, published on
March 18, 2020, reported that only 1.2% of 22 512 Italian cases with COVID-19 were children,
50 with no deaths. In fact, no deaths
had been recorded below the age of 30 years in Italy.50 Of 4226
COVID-19 cases detected in the United States until March 16, 2020, 5% were children.51 Children constituted less than 1% of all
US hospitalisations.51
In the early stages of the epidemic, many children with
C O V I D - 1 9 w e r e p a r t o f f a m i l y c l u s t e r s w i t h t h e d i s e a s e .18,45 A
large number of the cases described in this review originated from the Chinese city of Wuhan, whic h has nine million inhabitants.
Wuhan is situated 1150 km south of Beijing and 840 km west of Shanghai and is the capital of the Hubei Province, which has 58 million inhabitants.
The incubation period in children is usually about two days with
a range of 2-10 days.
7
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The COVID- 19 symptoms seem to be less severe in children than in adults.
14 One study by Dong et al examined 2143 children who were
identified through laboratory tests by a combination of clinical mani-festations and exposure history. Of these, 34.1% had laboratory-con-firmed disease, while the remainder had clinically suspected disease.
14
Their symptoms were typical of acute respiratory infections and in-cluded fever, cough, a sore throat, sneezing, myalgia and fatigue. A number of children were wheezing. Another study from the Wuhan Children's hospital,
52 which probably overlapped with the Dong
et al study,14 reviewed 171 children with confirmed disease and pre-
sented more detailed symptoms. The most common symptoms were cough (48.5%), pharyngeal erythema (46.2%) and a fever of at least 37.5°C (41.5%).
52 The authors reported that 32.1% of the children had
fever above 38°C and that most of these had 38.1°C-39.0°C.52 Other
studies have suggested that fever in children is usually below 39°C.7
Other symptoms52 were diarrhoea (8.8%), fatigue (7.6%), rhinor-
rhoea (7.6%) and vomiting (6.4%). Four out of 171 children (2.3%) had low oxygen saturations of less than 92%. It should be noted that s o m e C O V I D - 1 9 p u b l i c a t i o n s h a v e d e f i n e d l o w o xy g e n s a t u r a t i o n as below 93% or 94%. A substantial proportion of children demon-strated tachypnoea (28.7%) and tachycardia (42.1%) on hospital ad-mission.
52 In a smaller case series of 10 Chinese children diagnosed
outside Wuhan, eight had fever and six had a cough.7 In a study that
has only been published in Chinese so far, but was referenced by Yang et al,
45 76.1% of 134 children with COVID-19 had fever.;mo|;v
• The coronavirus disease 2019 (COVID-19) pandemic has
affected hundreds of thousands of people worldwide, but data on how it affects children are rare.
• A systematic literature review identified 45 papers and let-
ters published up to 18 March, and this showed that chil-dren have so far accounted for 1%-5% of diagnosed cases.
• Children often have milder disease than adults, and
deaths have been extremely rare.
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ƐƏƖƏ | LUDVIGSSON
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In the largest child case series so far,14 more than 90% of the 2,143
children diagnosed with laborator y-verified or clinically diagnosed
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remainder, 5.2% had severe disease and 0.6% had critical disease.14
According to the disease severity classification used by several Chinese publications, severe disease was defined as dyspnoea, cen-tral cyanosis and an oxygen saturation of less than 92%.
14 Critical
disease required respiratory failure, sometimes with acute respira-tory distress syndrome, shock and signs of multi-organ failure, such as encephalopathy, heart failure, abnormal coagulation and acute renal failure.
The prevalence of severe and critical disease was 10.6% in
children aged <1 at diagnosis, 1-5 years (7.3%), 6-10 years (4.2%), 11-15 years (4.1%) and 16-17 years (3.0%).
14 Half of the children with
critical COVID-19 in this study were less than one year of age,14 and
a high prevalence of severe disease was seen in very young children also in another study.
13 Of 171 children treated at Wuhan Children's
Hospital, three (1.8%) required intensive care and all of those had un-derlying diseases. There was one case of hydronephrosis, one child was undergoing chemotherapy for leukaemia and another had intus-susception. Yang et al have noted that the child with hydronephrosis
in question had bilateral hydronephrosis with renal calculus.
45
The percentage of 123 US children with COVID-19 in need of hos-
pital admission was 1.6%-2.5% with no child needing intensive care.51
ƒĺƓ | ;-|_v
In a study of 44 672 confirmed COVID-19 cases up to February 11, 2020 (both adults and children), there were 965 deaths (2.2%). One child died in the 10-19 year age group,
49 and no children aged
0-9 years died. No more information was given about the child who died and whether the test for COVID-19 was performed before or after death. The authors mentioned that some testing was carried out retrospectively, but they were not any more specific. The dead child was probably the 14-year-old boy described in the paper by Dong et al
14 The two research groups seem to have used the same
data source, from China's Infectious Disease Information System49
and the Chinese Center for Disease Control and Prevention,14 and
they seemed to cover much of the same time period.1449 Lu et al also
reported the death of a 10-month-old child with intussusception and multi-organ failure.
52 None of the 123 US children with COVID-19
have died so far.51 This means that this review was able to identify
two deaths in children with COVID-19 up to March 18, 2020.
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One study reported that of 171 children diagnosed and admitted to hospital between January and 26 February, and 149 (87.1%) had been discharged by March 8, 2020.
52 In addition, a study by Cao et al of 398 paediatric cases outside the Hubei Province claimed that
most of the children recovered within 1-2 weeks.8
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Early studies in adult populations found increased liver enzymes, anaemia and increased inflammatory markers, such as erythrocyte sedimentation rate, C-reactive protein, procalcitonin and sometimes hyperglycaemia.
53 Data on laboratory markers in children with COVID-
19 were rare, according to this review. The exception was a study by Henry et al t h a t s u m m a r i s e d t h e f i n d i n g s f r o m 1 2 d i f f e r e n t s t u d i e s
on 66 children.
17 The authors found that 69.2% of the children had
normal leucocyte counts and that neutrophilia (4.6%) and neutropenia (6.0%) were rare. Only two children (3.0%) experienced lymphocyto-penia.
17 C-reactive protein and procalcitonin were increased in 13.6%
and 10.6% of cases, respectively.17 In a separate study that was not
reviewed by Henry et al, lymphocytopenia was seen in 3.5% children.52
The clinical spectrum of children with COVID-19 has often been
similar to that of influenza. This was demonstrated by a Chinese study of 366 children up to the age of 16 years, who were hospital-ised with respiratory symptoms in the early phase of the epidemic.
25
Many of these children did not have COVID-19 but were instead di-agnosed with the influenza A or B virus.
25
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Lu et al reported that ground-glass opacity was seen in a third of 171
diagnosed children.52 Local or bilateral patchy shadowing was seen
in 18.7% and 12.3%, respectively. Overall, 15.8% of children did not h a v e s y m p t o m s o f i n f e c t i o n s o r r a d i o l o g i c a l f e a t u r e s o f p n e u m o -nia.
52 A clinical diagnosis of pneumonia was made in 64.9% of the
children.52
A second study reviewed five children23 and reported that three
h ad modest p a t c h y g r o u nd - g l a s s o p ac i ti es o n c o m pu t ed c h est t o -mography. This was consistent with data reported by Liu et al
24
Finally, Xia et al e x a m i n e d 2 0 c h i l d r e n w i t h c o m p u t e d t o m o g r a -
phy and found that 16 (80%) had some abnormalities, including halo signs, with ground-glass opacities seen in 12 patients (60%).
42
Another Chinese report, cited in Yang et al,45 found viral pneumo-
nia-like changes in 70.4% of 134 children undergoing chest imaging. It was unclear whether this was carried out using X-rays or com-puted tomography.
ƒĺѶ |];
In the largest Chinese paediatric case series to date, of 2143 subjects, the median age at paediatric diagnosis was seven years.
14 The median
was 6.7 years (range 1 day to 15 years) in 171 patients from the Wuhan Children's Hospital, who were better characterised.
52 Children of all
ages can be infected, including newborn infants and young children.41
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According to data from the Nation al Health Commission of China,
cited by Cai et al ,8 three neonatal cases were reported up to 20
February. At the same time, the total number of adult and paediatric
cases in China was close to 80 000. The first neonate had fever and a cough for three days, and the second had a runny nose and vomiting for one week. The youngest child, who was diagnosed at 30 hours of age, after being born to an infected mother, had respiratory distress, but no fever.
Schwartz reviewed five publications from China and was able to
identify 38 pregnant women with 39 offspring
30: nine of the offspring
were described in detail by Chen et al10 and another 10 by Zhu et al.48
Of the 39 offspring, 30 were tested for COVID-19 and all of them were negative. Schwartz noted that none of the pregnant women had developed severe pneumonia or died. The relatively mild disease course in the 38 pregnant women was consistent with the conclusion of a World Health Organization joint mission that investigated 149 pregnant women and found that pregnancy did not seem to be a risk factor for severe COVID-19 disease.
54 H o w e v e r , h a v i n g C O V I D- 1 9
during pregnancy may still have an impact on foetal outcome, namely foetal distress, potential preterm birth and respiratory distress.
48
ƒĺƐƏ |";
Dong et al14 reported that 56.6% of the 2143 patients in their study
were boys.
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A number of case reports have described comorbidities in children with COVID-19, but this review was unable to identify any study that quantified the prevalence of comorbidities in children. The section on disease severity in this paper notes that one study of 171 patients found that the three who required intensive care all had an underly-ing disease.
52
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COVID-19 has mostly been diagnosed using nasal or pharyngeal swabs or blood specimens that were positive for 2019-nCoV nucleic acid using real-time, reverse transcriptase-polymerase chain reac-tion assays. Alternative diagnostics have included genetic sequenc-ing of specimens from the respiratory tract or blood consistent with SARS-CoV2.
Clinical diagnosis has been used for some cases, at least in
China.
14 Diagnoses have been based on the presence of at least two
symptoms (fever, respiratory symptoms, gastrointestinal symptoms or fatigue), combined with laboratory tests (normal or low white blood cell count, and increased C-reactive protein) and an abnormal chest X-ray. Dong et al reported that other infectious diseases, such
as influenza, were excluded before the patients were diagnosed with COVID-19, but no details were given.
14 This means that some of the
cases reported in the Chinese papers did not have laboratory-veri-fied diagnoses.
ƒĺƐƒ |-m-];l;m|-m7|u;-|l;m|
This review was not able to identify any drug trials or testing that was specifically aimed at children. Most publications that commented on treatment mentioned supportive treatment, including oxygen ther-apy
7 and antibiotics for ba cterial superinfections.7 Some,40,32 but not
all researchers,7 recommended antiviral treatment. Antiviral treat-
men t was clearly used in se v ere cases, but da ta on its e fficacy in children with COVID-19 are missing.
Chinese physicians have recommended that children diagnosed
with COVID-19 undergo a chest X-ray examination, preferably com-puted tomography.
32 A detailed epidemiological history should be
taken. An extensive clinical examination should be performed and laboratory tests taken. Differential diagnoses include influenza virus, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, human metapneumovirus and other known viral infec-tions. They also include mycoplasma pneumoniae and chlamydia
pneumonia and bacterial pneumonia.
32 Recommended treatment is
outlined in Table 1.
One Chinese consensus group recommended discharge from
h o s p i t a l w h e n t h r e e c r i t e r i a w e r e s a t i s f i e d . T h e s e w e r e t h a t t h e child's body temperature had been normal for three days, the re-spiratory symptoms had improved and the SARS-CoV2 tests were negative. This group also stressed the importance of blocking trans-mission routes.
32 The importance of potential faecal transmission
remains unclear.35
The secondary consequences of schools being closed and chil-
d r e n b e i n g c o n f i n e d t o t h e i r h o m e w e r e r e v i e w e d b y W a n g et al .
The authors suggested that these measures may have negative ef-fects on the children's physical and mental health. Such adverse ef-fects included longer screen time, irregular sleep, less healthy diets that resulted in weight gain and loss of cardiorespiratory fitness.
37
In a study that was not related to the COVID-19 pandemic, Sprang et al reported that when children were quarantined and isolated
after health-related disasters this could greatly increase the risk of post-traumatic stress disorder (data based on survey, focus groups and interviews from 398 parents).
55
Zhang and Liu reviewed the potential interventions for COVID-
19, but these were primarily aimed at adult patients.46 In addition to
nutritional support, the authors mention treatment with interferons, intravenous gamma globulin, thymosin alpha-1, thymopentin, levami-sole, cyclosporine A and traditional Chinese medicine.
46 Of note, one
in three patients treated with intravenous gamma globulin during the SARS 2003 epidemic developed venous thromboembolism.
46
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Ɠ| "&""
This systematic review aimed to define the current evidence on
COVID-19 in children. It identified 45 relevant publications, but I cannot rule out that there were other reports that my search al-gorithm may have missed. The literature search was carried out in English, but some identified papers presented results in Chinese but with English abstracts or summaries.
C O V I D - 1 9 i s e i t h e r r a r e i n c h i l d r e n o r i t h a s n o t b e e n d i a g -
nosed that often because this age group remain asymptomatic. One study suggested that 86% of all early COVID-19 infections in China remained undiagnosed.
56 While undiagnosed (undocu-
mented) cases may have a lower transmission rate, their greater number suggests that they may have been the source of 79% of all early cases.
56 This may have implications if children with few
symptoms are cared for by elderly people who constitute a risk group for COVID-19.
Children have represented some 2% of diagnosed cases in
China,
49 1.2% of cases in Italy50 and 5% of COVID-19-positive cases
in the United States.51 These low figures were consistent with data
from the SARS epidemic in 2003, when 6.9% of the positive cases were children, but none died. These data, from the e-SARS database in Hong Kong, were cited by Caselli et al.
9
Earlier reports regarding adults with COVID-19 indicated a high
prevalence of comorbidities.57 For example, comorbidities were re-
ported in 26.0% of 44 672 confirmed cases recorded by the Chinese
Novel Coronavirus Pneumonia Emergency Response Epidemiology Team .
49 In adults, the most common comorbidities were hyperten-
sion, diabetes, cardiovascular di sease and chronic respiratory dis-
ease. The report did not contain any information on the prevalence of these diseases in members of the general population who were a similar age. However, 67.2% of those who died from COVID-19 had a comorbidity and this higher prevalence
49 suggests that comorbidity
is a risk factor for poor prognosis. This review only identifies case reports of children with COVID-19 and comorbidities. In adults, can-cer does not seem to be a risk factor for severe disease. One of the 171 hospitalised children in the Lu et al study
44 had leukaemia and
was receiving ongoing chemotherap y when being diagnosed with
COVID-19. Recommendations for the management of sick children who are diagnosed with COVID-19 are appearing quickly.
44 While
death is extremely rare in children with COVID-19, it can occur in patients who are already very sick.
Coronavirus disease 2019 seems to have a milder course in chil-
dren than in adults, and the obvious question is why? Several sugges-tions have been put forward. Children, especially smaller children, tend to have many viral infections. It is possible that repeated viral exposure supports the immune system when it responds to SARS-CoV-2. There have also been suggestions that the SARS-CoV-2 S protein binds to the angiotensin-converting enzyme (ACE) 2
58 and
that children may be protected against SARS-CoV-2 because this en-zyme is less mature at a younger age. The immune system undergoes substantial changes from birth to adulthood.
59
The proportion of children with COVID-19 with elevated inflam-
matory markers has reportedly been low.17 Severe cases of COVID-
1 9 h a v e b e e n l i n k e d t o i n c r e a s e d l e v e l s o f p r o c a l c i t o n i n . H e n r y et al cited a Chinese paper that described how a young, very sick in-
fant developed high interleukin-6 levels
17 and trials of interleukin-6
inhibitors are on their way. Other trials underway are examining the efficacy of the drugs remdesivir and chloroquine.
It is worth noting that studies focusing on adults have reported
very high rates of lymphocytopenia. For example, Guan et al studied
1099 subjects and found that the rate was 83.2% in adults. However, only nine of the subjects were children.
3 These adult data contrasted
with data from a study of 171 children, where only 3.5% had lym-phocytopenia,
52 and the 3.0% in the case series published by Henry
et al17 Future studies on the severity of COVID-19 should focus on
the role of lymphocytes and their interaction with SARS-COV2. In the 2003 SARS epidemic, a study cited by Henry et al
17 reported that $ Ɛ Recommended treatment, after Shen et al32
u;-|_bm]-m7-bu- |_;uvrrou| m=;1|bov7bv;-v; r;ubl;m|-Ѵ|u;-|l;m|a
Ox
ygen supply Caloric intake (for a review of nutritional
interventions see Zhang and Liu46)Antibiotics when there are
bacterial superinfectionsInterferon-alphab
Inhalations W
ater and electrolyte supply/balance Lopinavir/litonavirb
Ke
eping respiratory tract
unobstructedAnti-pyretics if high fever Interleukin-6 inhibitorsb
Re
gular re-examination of
airways Arbidol, oseltamivir, ribavirin
and other anti-influenza drugsb
Non-
invasive/invasive
respiratory support/mechanical
ventilation including ECMO Glucocorticoids
Fluid resuscitation, vasoactive
drugs Immunoglobulin
Traditional Chinese medicine
aNot yet supported by the literature.
bSuggested dosages and pharmacological aspects of antiviral treatment of COVID-19 in children have been reviewed by Wang and Zhu .40
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|ƐƏƖƒ LUDVIGSSON
lymphocytopenia was seen in 46% of children and that neutropenia
was seen in 52%.
Lack of smoking in children is unlikely to explain the lower prev-
a l e n c e o f s e v e r e C O V I D - 1 9 i n p a e d i a t r i c p a t i e n t s . S m o k i n g d o e s not seem to be a major feature in the pathogenesis of COVID-19 in adults.
3
It is important to note that a large share of the scientific ev-
i d e n c e s o f a r h a s o r i g i n a t e d f r o m C h i n a , a n d i t i s p o s s i b l e t h a t country-specific factors there differ from children in some other countries. These include differences in day care and nutritional status and to what extent children come into contact with sick individuals.
An expert consensus statement published by the World Journal of
Pediatrics
32 in late January 2020 included a number of recommenda-
tions (Table 1). However, these were clearly based on findings from adults. More recent studies on children with COVID-19 are likely to have an impact on future recommendations. For instance, the cur-rent paediatric recommendations in China do not reflect the milder disease course and the different laboratory findings seen in chil-dren.
17,32 It can therefore be questioned whether children with mild
COVID-19, normal inflammatory markers and normal oxygen levels should really undergo computed tomography or chest X-ray.
Although the data are scarce, there seems to be little, if any, ver-
tical intrauterine transmission fr om pregnant mothers to newborn
infants.
10 Cord blood and placental tissue in COVID-19-positive
mothers have been negative for SARS-COV2,16 and in a small se-
ries of 30 offspring none of the subjects developed COVID-19.30
Ho w ev er , it is w orth no ting that man y o f these children w ere de-livered by Caesarean section. To what extent maternal hypoxaemia in delivering mothers can lead to intrauterine asphyxia and preterm birth in the offspring seems to be unknown.
There have been reports of newborn infants who have tested
positive to COVID-19 after being born mothers who have also tested positive.
16 Chinese neonatologists and obstetricians have re-
cently proposed how to prevent and control COVID-19 infections in newborn infants.
22,38,60 Until now, there have been no reports of
COVID-19 transmission within neonatal intensive care units, but al-though children seem to have less symptoms than adult patients also newborn infants can suffer from respiratory distress and are likely to transmit the disease if sick.
8
The main strength of this study was that it used well-established
databases and wide-ranging search terms to pick up as many studies as possible up to March 18, 2020. The main limitation was that we were unable to read the full text of some of the identified Chinese studies but had to rely on English language summaries or publica-tions that referenced papers published in Chinese.
Ɣ|&"
In conclusion, this review identified 45 relevant studies on COVID-19 in children and the majority of the data were from China. Many of these studies seemed to overlap, with regard to the data they presented, and some of the children who were diagnosed with COVID-19 did not have their diagnoses verified by laboratory tests. This has implications for prognosis. For example, Dong et al found that children with suspected COVID- 1 9 had more se-
vere disease than those with laboratory-confirmed disease. This suggests that a number of suspected COVID-19 cases may have been caused by other pathogens,
14 and it may still be too early to
conclude that young children have a more severe COVID-19 than older children.
Our key findings were that the disease course in paediatric
COVID-19 was milder than in adults, children had a better prognosis and deaths were extremely rare.
) $"
We are grateful to the two librarians at the Karolinska Institutet University Library in Stockholm, Sweden, who performed the litera-ture search.
$"
$ ! "$
The author is co-ordinating an unrelated study on behalf of the Swedish Inflammatory Bowel Disease Quality Register that has re-ceived funding from the Janssen Corporation.
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1. Zhu NA, Zhang D, Wang W, et al. A Novel Coronavirus from Patients
with Pneumonia in China, 2019. N Engl J Med . 2020;382(8):727-733.
2. Dong E, Du H, Gardner L. An interactive web-based dashboard to
track COVID-19 in real time. Lancet Infect Dis . 2020. https://doi.
org/10.1016/S1473-3099(20)30120-1
3. Guan W-J, Ni Z-Y, Hu YU, et al. Clinical characteristics of coronavi-
rus disease 2019 in China. N Engl J Med . 2019;2020.
4. Li Q, Guan X, Wu P , et al. Early transmission dynamics in Wuhan,
China, of novel coronavirus-infected pneumonia. N Engl J Med .
2020;382:1199-1207.
5. Anonymous. COVID-19 in children: initial characterization of the
pediatric disease. Pediatrics. 2020;16:16.
6. Bajema KL, Oster AM, McGovern OL, et al. Persons evaluated for
2019 novel coronavirus - United States, January 2020. MMWR
Morb Mortal Wkly Rep . 2020;69:166-170.
7. Cai J, Xu J, Lin D, et al. A Case Series of children with 2019 novel
coronavirus infection: clinical and epidemiological features. Clin
Infect Dis . 2020;28:28.
8. Cao Q, Chen Y-C, Chen C-L, et al. SARS-CoV-2 infection in children:
Transmission dynamics and clinical characteristics. J Formos Med
Assoc. 2020;119:670-673.
9. Caselli D, Arico M. 2019-nCoV: polite with children! Pediatric rep .
2020;12:8495.
10. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauter-
ine vertical transmission potential of COVID-19 infection in nine
pregnant women: a retrospective review of medical records. Lancet .
2020;395:809-815.
11. Chen ZM, Fu JF, Shu Q. New coronavirus: new challenges for pedi-
atricians. World J Pediatr . 2020;10:10.
12. Chen Z-M, Fu J-F, Shu Q, et al. Diagnosis and treatment recommen-
dations for pediatric respiratory infection caused by the 2019 novel coronavirus. World J Pediatr . 2020;05:05.
13. Cui Y, Tian M, Huang D, et al. A 55-Day-Old Female Infant infected
with COVID 19: presenting with pneumonia, liver injury, and heart damage. J Infect Dis . 2020;17:17.
090177e1981d7d9f\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071344
ƐƏƖƓ | LUDVIGSSON
14. Dong Y, Mo XI, Hu Y, et al. Epidemiological characteristics of
2143 pediatric patients with 2019 coronavirus disease in China.
Pediatrics. 2020;16:16.
15. Hageman JR. The coronavirus disease 2019 (COVID-19). Pediatr
Ann. 2020;49:e99-e100.
16. Han Y, Yang H. The transmission and diagnosis of 2019 novel coro-
navirus infection disease (COVID-19): a Chinese perspective. J Med
Virol . 2020;06:06.
17. Henry BM, Lippi G, Plebani M. Laboratory abnormalities in chil-
dren with novel coronavirus disease 2019. Clin Chem Lab Med .
2020;16:16.
18. Ji L-N, Chao S, Wang Y-J, et al. Clinical features of pediatric patients
with COVID-19: a report of two family cluster cases. World J Pediatr .
2020;16:16.
19. Kam KQ, Yung CF, Cui L, et al. A well infant with coronavirus disease
2019 (COVID-19) with high viral load. Clin Infect Dis . 2020;28:28.
20. Lai C-C, Liu YH, Wang C-Y, et al. Asymptomatic carrier state, acute
respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): facts and myths. J Microbiol
Immunol Infect . 2020;04:04.
21. Lee P-I, Hu Y-L, Chen P-Y, et al. Are children less susceptible to
COVID-19? J Microbiol Immunol Infect. 2020;25:25.
22. Li F, Feng ZC, Shi Y. Proposal for prevention and control of the 2019
novel coronavirus disease in newborn infants. Arch Dis Child Fetal
Neonatal Ed . 2020;04:04.
23. Li W, Cui H, Li K, et al. Chest computed tomography in children with
COVID-19 respiratory infection. Pediatr Radiol . 2020;11:11.
24. Liu H, Liu F, Li J, et al. Clinical and CT imaging features of the
COVID-19 pneumonia: focus on pregnant women and children. J
Infect . 2020;11:11.
25. Liu W, Zhang QI, Chen J, et al. Detection of COVID-19 in children in
early January 2020 in Wuhan, China. N Engl J Med . 2020;12:12.
26. Lu Q, Shi Y. Coronavirus disease (COVID-19) and neonate: what
neonatologist need to know. J Med Virol . 2020;01:01.
27 . Ma X -L, Chen Z, Zhu J- J, et al. Management strategies of neona-
tal jaundice during the coronavirus disease 2019 outbreak. World J
Pediatr . 2020;28:28.
28. Rasmussen SA, Smulian JC, Lednicky JA, et al. Coronavirus disease
2019 (COVID-19) and pregnancy: what obstetricians need to know. Am J Obstet Gynecol . 2020;24:24.
29. Rothan HA, Byrareddy SN. The epidemiology and pathogene-
sis of coronavirus disease (COVID-19) outbreak. J Autoimmun .
2020;102433.
30. Schwartz DA. An analysis of 38 pregnant women with COVID-19,
their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes. Arch Pathol Lab Med . 2020;17:17.
31. Schwartz DA, Graham AL. Potential maternal and infant outcomes
from (Wuhan) coronavirus 2019-nCoV infecting pregnant women: lessons from SARS, MERS, and other human coronavirus infections. Viruses . 2020;12:10.
32. Shen K, Yang Y, Wang T, et al. Diagnosis, treatment, and prevention
of 2019 novel coronavirus infection in children: experts' consensus statement. World J Pediatr . 2020;07:07.
33. Shen KL, Yang YH. Diagnosis and treatment of 2019 novel coro-
navirus infection in children: a pressing issue. World J Pediatr .
2020;05:05.
34. Sun K, Chen J, Viboud C. Early epidemiological analysis of the coro-
navirus disease outbreak based on crowdsourced data: a popula-tion-level observational study. Lancet Dig Health . 2020;2:e201-e208.
35. Tang AN, Tong Z-D, Wang H-L, et al. Detection of novel coronavi-
rus by RT -PCR in stool specimen from asymptomatic child, China. Emerg Infect Dis . 2020;26:17. 36. Team C-NIRS. COVID-19, Australia: epidemiology report 6
(Reporting week ending 19: 00 AEDT 7 March 2020). Commun Dis
Intell . 2018;2020:11.
37. Wang G, Zhang Y, Zhao J, et al. Mitigate the effects of home con-
f i n e m e n t o n c h i l d r e n d u r i n g t h e C O V I D - 1 9 o u t b r e a k . Lancet .
2020;04:04.
38. W
ang L, Shi Y, Xiao T, et al. Chinese expert consensus on the peri-
natal and neonatal management for the prevention and control of the 2019 novel coronavirus infection (First edition). Ann Trans Med .
2020;8:47.
39. Wang S, Guo L, Chen L, et al. A case report of neonatal COVID-19
infection in China. Clin Infect Dis . 2020;12:12.
40. Wang Y, Zhu LQ. Pharmaceutical care recommendations for anti-
viral treatments in children with coronavirus disease 2019. World J
Pediatr . 2020;12:12.
41. Wei M, Yuan J, Liu YU, et al. Novel coronavirus infection in hospital-
ized infants under 1 year of age in China. JAMA . 2020;14:14.
42. Xia W, Shao J, Guo YU, et al. Clinical and CT features in pediat-
ric patients with COVID-19 infection: different points from adults. Pediatr Pulmonol . 2020;05:05.
43. Xu X-W, Wu X-X, Jiang X-G, et al. Clinical findings in a group
of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ.
2020;368:m606.
44. Yang C, Li C, Wang S, et al. Clinical strategies for treating pediatric
cancer during the outbreak of 2019 novel coronavirus infection. Pediatr Blood Cancer . 2019;2020:e28248.
45. Yang PU, Liu P, Li D, et al. Corona Virus Disease 2019, a growing
threat to children? J Infect . 2020;03:03. https://doi.org/10.1016/j.
jinf.2020.02.024.
46. Zhang L, Liu Y. Potential interventions for novel coronavirus in
China: a systematic review. J Med Virol . 2020;92:479-490.
47 . Zhao S, Ling K, Yan H, et al. Anesthetic management of patients
with suspected or confirmed 2019 novel coronavirus infec-tion during emergency procedures. J Cardiothorac Vasc Anesth .
2020;28:28.
48. Zhu H, Wang L, Fang C, et al. Clinical analysis of 10 neonates born
to mothers with 2019-nCoV pneumonia. Transl . 2020;9:51-60.
49. Zhang Y. TheEpidemiological Characteristics of an Outbreak of
2019 Novel Coronavirus Diseases (COVID-19) — China, 2020. Chinese Journal of Epidemiology (by The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team). 2020.
5 0 . L i v i n g st o n E, B u c h e r K. C o r o n a v i r u s d i s e a s e 2 0 1 9 ( C O V I D- 1 9 ) i n
Italy. JAMA . 2020.
51. Bialek S, Boundy E, Bowen V, et al. Severe outcomes among pa-
tients with coronavirus disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep .
2020;69:343-346.
52. Lu X, Zhang L, Du H, et al. SARS-CoV-2 infection in children. N Engl
J Med . 2020.
53. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical char-
acteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet . 2020;395:507-513.
54. WHO. Report of the WHO-China Joint Mission on Coronavirus
Disease 2019 (COVID-19). (https://www.who.int/docs/defau lt-
sourc e/coron aviru se/who-china-joint-missi on-on-covid-19-final-
report.pdf; accessed: March 19, 2020), 2020.
55. Sprang G, Silman M. Posttraumatic stress disorder in parents and
youth after health-related disasters. Disaster Med Public Health Prep .
2013;7:105-110.
56. Li R, Pei S, Chen B, et al. Substantial undocumented infection facil-
itates the rapid dissemination of novel coronavirus (SARS-CoV2). Science . 2020.
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|ƐƏƖƔ LUDVIGSSON
57. Huang C, Wang Y, Li X, et al. Clinical features of patients in-
fected with 2019 novel coronavirus in Wuhan. China. Lancet .
2020;395:497-506
58. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of
the 2019-nCoV spike in the prefusion conformation. Science .
2020;367:1260-1263.
59. Simon AK, Hollander GA, McMichael A. Evolution of the im-
m u n e s y s t e m i n h u m a n s f r o m i n f a n c y t o o l d a g e . Proc Biol Sci .
1821;2015:20143085.
60. Liang H, Acharya G. Novel corona virus disease (COVID-19) in
pregnancy: What clinical recommendations to follow? Acta Obstet
Gynecol Scand . 2020;99:439-442."& !$
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Additional supporting information may be found online in the Supporting Information section.
o|o1b|;|_bv-u|b1Ѵ;Ĺ Ludvigsson JF. Systematic review of
COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr . 2020;109:1088–1095.
https://doi.org/10.1111/apa.15270
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