Document text
Pediatric Pulmonology. 2021;56:1342 1356. wileyonlinelibrary.com/journal/ppul 1342 |© 2021 Wiley Periodicals LLCReceived: 10 November 2020 |Revised: 9 January 2021 |Accepted: 19 February 2021
DOI: 10.1002/ppul.25344
REVIEW
COVID ‐19 in childhood: Transmission, clinical presentation,
complications and risk factors
Melissa K. Siebach RN, BSN1,2|Giovanni Piedimonte MD3|Sylvia H. Ley PhD, RD1
1Department of Epidemiology, Tulane
University School of Public Health and
Tropical Medicine, New Orleans,
Louisiana, USA
2Department of Tropical Medicine, Tulane
University School of Public Health and
Tropical Medicine, New Orleans,
Louisiana, USA
3Departments of Pediatrics, Biochemistry, and
Molecular Biology, Tulane University Schoolof Medicine, New Orleans, Louisiana, USA
Correspondence
Sylvia H. Ley, PhD, RD, Department of
Epidemiology, Tulane University School of
Public Health and Tropical Medicine, 1440
Canal St, M.B. 8318, New Orleans, LA 70112,
USA.
Email: [email protected]
Funding information
National Science Foundation,
Grant/Award Number: 2031761; Dean'sCOVID‐19 Rapid Response grant from Tulane
University School of Public Health and
Tropical Medicine; National Institute of
General Medical Sciences of the National
Institutes of Health, Grant/Award Number:P20GM109036; National Heart, Lung and
Blood Institutes of Health,
Grant/Award Number: RO1 HL ‐061007Abstract
Children less than 18 years of age account for an estimated 2% –5% of reported severe
acute respiratory syndrome coronavirus 2 (SARS CoV 2) cases globally. Lower pre-
valence of coronavirus disease 2019 (COVID 19) among children, in addition to higher
numbers of mild and asymptomatic cases, continues to provide challenges in de-
termining appropriate prevention and treatment courses. Here, we summarize the
current evidence on the transmission, clinical presentation, complications and risk
factors in regard to SARS CoV 2 in children, and highlight crucial gaps in knowledge
going forward. Based on current evidence, children are rarely the primary source of
secondary transmission in the household or in child care and school settings and are
more likely to contract the virus from an adult household member. Higher transmission
rates are observed in older children (10 –19 years old) compared with younger children
( <10 years old). While increasing incidence of COVID 19 in neonates raises the sus-
picion of vertical transmission, it is unlikely that breast milk is a vehicle for transmission
from mother to infant. The vast majority of clinical cases of COVID 19 in children are
mild, but there are rare cases that have developed complications such as multisystem
inflammatory syndrome in children, which often presents with severe cardiac symp-
toms requiring intensive care. Childhood obesity is associated with a higher risk of
infection and a more severe clinical presentation. Although immediate mortality rates
among children are low, long term respiratory, and developmental implications of the
disease remain unknown in this young and vulnerable population.
KEYWORDS
epidemiology, pulmonology (general), social dimensions of pulmonary medicine
1|INTRODUCTION
Children less than 18 years of age account for an estimated 1.7% of
severe acute respiratory syndrome coronavirus 2 (SARS ‐CoV‐2)
clinical infections in the United States,1with global estimates rangingfrom 2.02to 4.8%.3The low prevalence of pediatric cases has made it
difficult to draw conclusive statements about many aspects of the
virus in this population, but the reported case numbers are likely an
underestimation of the true pediatric case load, as many cases in
children are mild or asymptomatic.4Initial observations report that
Abbreviations: ACE 2, angiotensin converting enzyme 2; CDC, Center for Disease Control and Prevention; COVID 19, coronavirus disease 2019; CRP, C reactive protein; CXR, chest
radiography; ICU, intensive care unit; KD, Kawasaki disease; MERS CoV, Middle Eastern respiratory syndrome coronavirus; MIS C, multisystem inflammatory syndrome in children; NP,
nasopharyngeal; RNA, ribonucleic acid; RSV, respiratory syncytial virus; RT PCR, reverse transcription polymerase chain reaction; SAR, secondary attack rate; SARS CoV, severe acuterespiratory syndrome coronavirus 1; SARS CoV 2, severe acute respiratory syndrome coronavirus 2; TSS, toxic shock syndrome; UNICEF, United Nation Children's Fund; WHO, World HealthOrganization.
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the clinical course is generally milder and outcomes are better in
children.5Also, as the pandemic progresses, clinicians report an in-
creasing number of cases of multisystem inflammatory syndrome in
children (MIS ‐C), a severe inflammatory syndrome following
coronavirus disease 2019 (COVID ‐19) exposure or infection. Though
rare, this syndrome has the potential to cause devastating outcomesin children and as the pandemic continues cases of MIS‐C are likely
to increase. These findings have underscored the limitations of cur-rent knowledge regarding COVID ‐19 in children and have raised
questions about the implications for long ‐term respiratory and de-
velopmental prognosis. We seek to comprehensively examine what iscurrently known and what knowledge we still lack about transmis-sion, clinical presentation, complications, and risk factors as they
pertain to SARS ‐CoV‐2 infection in the pediatric population. In so
doing, we seek to link these four areas of concentration, providing
the reader with an overview of the risk of COVID ‐19 to children.
2|METHODS
A literature review was carried out to identify both published andnon‐ peer‐ reviewed pre‐ print original studies and review papers
from January to December 2020, relating to the transmission,
clinical presentation, complications, and risk factors of COVID ‐19
in the pediatric population. Searches were conducted in PubMed,
MedRxiv, and the Johns Hopkins “COVID ‐19, Maternal and Child
Health, Nutrition ”repository. Case studies and papers containing
duplicate analysis of data already included in our review were notselected.
2.1 |Transmission
According to the WHO,6SARS ‐CoV‐2 is transmitted directly and
indirectly through the respiratory secretions of those infected. Sev-eral studies have also looked at the prevalence and implications of
fecal viral shedding in the pediatric population and the implications
for transmission.
7Based on a systematic review of contact tracing
programs and population studies, the susceptibility of children to
COVID ‐19 was lower than adults, although the role that they played
in transmission was not conclusive.8
The prominence of mild and asymptomatic illness in pediatric
patients has created concern that the true prevalence of disease in
this age group has been underreported.4,5Population ‐based
seroprevalence studies have had conflicting results.9–11The
seroprevalence of antibodies in children was consistent with that of
adults in the same area in the UK,9implying that children and adults
are equally susceptible to the virus, however, in Italy seroprevalence
increased with age.11Similar to reports in the adult population, ra-
cial, and socioeconomic disparities have also been noted among pe-diatric populations with studies noting higher rates of transmissionamong racial and/or ethnic minority groups
12with more severe
health outcomes.132.1.1 |Household transmission
Table 1 presents transmission sources as reported in several pedia-
tric studies. Available data indicate that SARS ‐CoV‐2 ‐positive adults
living in the household are the primary source of infection for chil-
dren. It should be noted that shelter ‐in‐place orders decreased
outdoor activities in most countries and likely led to the increase ofviral spread within households.
14In an investigation of 110 cases
stemming from 11 infection clusters in Japan, close contact in anindoor setting contributed to all 11 clusters.
15In South Korea,
household cases were the primary source of infection until mid‐March, 2020, when imported cases became the most prevalent.
4In
the UK, a population‐based seroprevalence study of children re-
ported that neither age nor gender had any association with positive
results, but contact with a household member with confirmedCOVID ‐19 was a significant predictor for seropositivity.
9
Although children are usually infected by SARS ‐CoV‐2 ‐positive
adults living in the household, several studies have shown that theoverall risk of contagion to children is lower than that of other adults
residing in the same household.
14,23In a meta‐analysis looking at
secondary attack rates (SAR) in the household setting ( n54 stu-
dies),14the overall estimated SAR for household contacts was 16.6%,
while that of close contacts was just 4.8%. Spouses of infected in-dividuals were at greater risk than other household members (37.8%
vs. 17.8%), whereas the rate of secondary household transmission tochildren was significantly lower than adults (16.8% vs. 28.3%).
14
A child's age may also affect the risk of transmission. In South
Korea, analysis of data for 59,000 contacts of 5700 index casesfound that a total of 11.8% of household contacts tested positive for
COVID ‐19.
24When further stratified by age, the infection rate was
18.6% for index cases aged 10 19 years, and 5.3% for ages
0 9 years.24Consistently, in a study of Swiss students, the ser-
oprevalence of SARS ‐CoV‐2 antibodies decreased with age.10
2.1.2 |Maternal –fetal and perinatal transmission
Vertical transmission was demonstrated with SARS ‐CoV ‐1, and the
same risk theoretically exists for SARS ‐CoV ‐2, as the viral receptor
(angiotensin ‐converting enzyme 2 [ACE ‐2]) is widely expressed in the
placenta.25Although a systematic review of 18 studies ( n157 mo-
thers and 160 neonates) found no evidence of vertical transmission,26
the growing number of confirmed neonatal cases of COVID ‐19 infec-
tion has reinforced the suspicion that SARS ‐CoV ‐2 is similarly capable
of crossing the placenta to infect fetal lungs. A recent study identifiedthree neonates delivered from COVID ‐positive mothers with pneu-
monia on chest radiography (CXR) obtained at birth and nasophar-yngeal (NP) swabs positive for SARS ‐CoV ‐2 on Days 2 and 4 of life and
negative on Day 6 7.
27One of these patients was born at 31 weeks of
gestation via cesarean delivery due to fetal distress and required re-suscitation. Although vertical transmission was not found in severalother neonates born to COVID ‐19 infected mothers, it is critical to note
that most of such data have been limited by extremely small sample sizeSIEBACH ET AL.
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(frequently n1), a lack of cord blood or amniotic fluid evidence (the
gold standard to prove vertical transmission), and provide little or no
information on the outcome of the infants. A more recent systematic
review ( n2 0 5 i n f a n t s o f C O V I D ‐positive mothers) found that while
vertical transmission of COVID ‐19 is unlikely, antibodies against
SARS ‐CoV ‐2 were found in 10/11 (90%) infants who were tested.28As
pregnant women are more susceptible than the general population to
respiratory pathogens including COVID ‐19, maternal infection and in-
flammation in response to the virus could affect the developing fetusand even postnatal life. With the continuing pandemic of COVID ‐19,
there is general consensus further studies are warranted to investigatepregnant women with COVID ‐19, follow ‐up the pregnancy outcomes,
and monitor postnatal development of the fetus.
2.1.3 |Breastfeeding
Based on the earliest 13 case studies/series ( n4 8 m i l ks a m p l e s f r o m
32 women combined), only one sample contained virus, while SARS ‐
CoV ‐2 antibodies were found in two other samples.29However, the
sample collection and analytical methods were not provided in detail inthese case reports, raising questions on methodological quality andpotential for contamination. In a longitudinal study of two COVID ‐19
positive mothers following delivery (Day 0), the first mother's sampleswere all negative for SARS ‐CoV ‐2 RNA, but milk samples from days 10,
12, and 13 postdelivery were positive for the second mother.
30The
positive milk samples coincided with mild symptoms in the secondmother and her infant tested positive for COVID ‐19 on Day 11. The
first infant also tested positive for COVID ‐19, although viral RNA was
absent in the first mother's samples.
30In another study (n 6 4
breastmilk samples from 18 COVID ‐19 positive mothers) viral RNA was
isolated in one sample, but no replication ‐competent virus was de-
tected.31Both breastmilk samples ( n37 milk samples) and breast
swabs ( n70 swabs collected before and after cleaning the breast with
soap and water before feeding) were analyzed from 18 COVID ‐19‐
positive women.32SARS ‐CoV ‐2 RNA was not present in the milk
samples, but was present on one of the pre ‐cleaning swabs. Further-
more, SARS ‐CoV ‐2 antibodies were detected in all 37 milk samples.32In
addition, a systematic review of 37 studies (n 77 infants of COVID ‐
positive mothers) found no evidence of SARS ‐CoV ‐2 transmission.33As
SARS ‐CoV ‐2 transmission through breastmilk is unlikely, both the
World Health Organization (WHO) and UNICEF currently recommend
mothers with suspected or confirmed COVID ‐19 initiate or continue
breastfeeding while following guidance on hygiene and mask use.34,35
For situations requiring donor milk, p asteurization of human milk by the
Holder method (62.5°C for 30 min) inactivates SARS ‐CoV ‐2.36
2.2 |Child Care
As of July 31, 52 (33 confirmed) SARS ‐CoV‐2 cases had occurred in
29/666 (4.3%) child care facilities in Rhode Island.37Twenty of these
facilities only reported a single case, with no evidence of secondaryTABLE 1 SARS ‐CoV‐2 transmission in chi dren
StudyParticipants
nMedianAgePositive SARS ‐
CoV ‐2
n(%)SARS ‐CoV ‐2 confirmed
adu t househo d contactn(%)Symptomatic adu thouseho d contactn(%)Sib ingn(%)Community/unknownn(%)Internationatrave (imported)n(%)
Garazzino et a .
16( ta y) 168 2.3 168 (100) 113 (67) ‐‐ ‐ 0 (0)
Zachariah et a .17(New York) 50 9 50 (100) 26 (52) 9 (18) ‐‐ ‐
Götzinger et a .18(Europe) 582 5 582 (100) 324 (56) ‐ 24 (4) 234 (40) ‐
Han et a .4(South Korea) 91 11 91 (100) 57 (63)a‐‐ 15 (16)/4 (4) 15 (17)
Cura Yay a et a .19(Turkey) 220 10 220 (100) 217 (99)b‐‐ ‐ /3 (1) ‐
Lu et a .20(Wuhan) 171 6.7 171 (100) 131 (77) 23 (14) ‐ 2 (1)/15 (9) ‐
Yonker et a .21(MA, USA) 49 12.7 49 (100) 33 (67) ‐ 9 (18) 9 (18)/ ‐‐
Antunez ‐Montes et a .22(Latin
America)409 3 409 (100) 165 (40) ‐ 5 (1) 62 (15)/177 (43) ‐
Abbreviation: SARS ‐CoV ‐2, severe acute respiratory syndrome coronavirus 2.
aA househo d members inc uded, author did not specify whether adu t or sib ing was the source.
bBoth househo d and c ose contacts inc uded in this data point.1344 |
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transmission, while possible secondary transmission occurred in four
centers, accounting for 17 cases. Contact tracing and testing data forchild care facilities in Salt Lake City, Utah, in April July, 2020,
reported 31 confirmed cases of COVID ‐19 between three facilities,
42% (13/31) of which occurred in children.
38Asymptomatic trans-
mission from children to adult contacts was confirmed in two cases.Index cases for all three facilities were determined to be adult staff
members.
38
2.2.1 |School opening and transmission
Table 2 provides data from studies analyzing secondary transmission
of SARS ‐CoV‐2 in the school setting. In South Korea, children were
not the primary source of transmission within schools, as secondary
cases were all a result of contact with an infected staff member.39In
England, staff had higher incidence rates than students andaccounted for most cases linked to outbreaks.
40In Ireland, no
secondary transmission of COVID ‐19 was reported in a follow ‐up of
1025 exposed school contacts.41These exposures included activities
such as music lessons and choir practice, both of which are assumedto be high ‐risk activities for transmission.41Of 18 cases of secondary
transmission in Australia, five cases occurred in three schools andthe other 13 occurred in a single early childhood education center
where the cluster outbreak was traced to a single adult staff mem-
ber.
42The overall child ‐to‐child SAR was 0.3% (2/649) and the child
to staff SAR was 1.0% (1/103), while the staff ‐to‐staff SAR was
4.4% (7/160) and the staff ‐to‐child SAR was 1.5% (8/536).42In
Switzerland, researchers randomly analyzed seroprevalence among2585 students (6 16 years old) in 55 schools and found that at least
one seropositive case was reported in 36/55 schools with no
evidence of clustered outbreaks or secondary transmission.
10
In Hong Kong, only 5 of 20 cases in children (5 17 years old) were
associated with two clustered school outbreaks.43In Germany, 137
COVID ‐19 ‐positive students attended school for at least one day
while infectious.44Only six of these cases contributed to the trans-
mission of SARS ‐CoV‐2 to an additional 11 students. No additional
secondary transmission was reported despite extensive screeningand monitoring of more than 2300 close school contacts.
44Authors
of both papers acknowledged the contribution of infection ‐control
measures, such as social distancing and masking, to the low trans-mission rates.
43,44Child ‐to‐child transmission within the school
TABLE 2 SARS ‐CoV‐2 secondary transmission in the school setting
Study School typesSARS ‐CoV ‐2 index
cases (age)Contacts tested
n(%) Secondary infections SAR
Yoon et al.39
(South Korea)5 kindergartens 5 students 670 0 0
15 elementary schools 19 students 2453 1 0.04%
8 middle schools 8 students 1962 0 0
12 high schools 13 students 4747 0 0
Yung et al.45
(Singapore)Preschool A 1 student (5) 34 0 0
Preschool B 1 adult staff 77 (73) 16 staff 0 students 0
Secondary school 1 student (12) 8 0 0
Danis et al.46
(French Alps)3 schools 1 student (9)
(visited all 3 schools
while symptomatic)55 (64) 0 0
Heavey et al.41
(Rep. of Ireland)1 primary school 2
seconday schoolsa3 children 3 adult staff ‐b1 (staff to staff) 0
Macartney et al.42
(Australia)10 ECECsc
15 schools12 students 15 adult
staff633 (44) 8 staff 10 students 1.2%
Ehrhardt et al.44
(Germany)childcare facilities
primary schoolssecondary schoolsvocational schools137 students (only 6
cases led tosecondary infection)>2300 11 students (an additional 4
students were infectedfrom 2 staff members)‐
Stein ‐Zamir et al.
47
(Israel)1 high school
(grades 7 12)2 students 1161 (99) students
151 (99) staff153 students
25 staffStudents: 13.2%Staff: 16.6%
Abbreviations: ECEC, early childhood education and care centers; SAR, secondary attack rate; SARS ‐CoV ‐2, severe acute respiratory syndrome
coronavirus 2.
aAuthor did not specify the type of schools at which the adult staff members worked. Also, no clarification was made about whether more than one of the
six cases was present in a single school.
b1025 contacts were monitored, symptomatic individuals were referred for testing, but exact numbers are unknown ± ECEC: early childhood education
and care centers. Account for daycare, preschool and after ‐school care programs.SIEBACH ET AL.
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setting was uncommon and not the primary source of SARS ‐CoV‐2
infection in children.44
Ten days after schools reopened in Jerusalem in May, 2020, two
separate cases of COVID ‐19 in the same high ‐school led to the
infection of almost 260 people.47Within the school community, 153
students and 25 staff members were infected. Overly crowded
classrooms without appropriate social distancing and the suspension
of mask ‐wearing for several days in response to a heat wave likely
contributed to the outbreak.47
School infections peaked in Victoria, Australia, when community
transmission was high, but transmission among children was notschool driven.
48Controlling community incidence is likely an effec-
tive means of controlling transmission within the educational set-
ting.40In Sweden and Finland, the cumulative incidence rates of
COVID ‐19 among school ‐age children were similar across both
countries despite Sweden's decision not to close childcare facilitiesor primary schools. Health officials in Sweden concluded that school
closures did not significantly impact the overall prevalence ofCOVID ‐19 among 1 19 year ‐olds.
49Daycare, primary, or secondary
school teachers were not at increased risk for SARS ‐CoV‐2
infection.49
Children do not appear to be the primary drivers of SARS ‐CoV‐2
transmission in the home or school settings and often present with
mild or asymptomatic cases when infected.
3|CLINICAL PRESENTATION IN
CHILDREN
Table 3 summarizes 12 studies reporting clinical data of children
with diagnosed or suspected COVID ‐19.5The heterogeneity in study
participant selection criteria must be noted among these studies,which may have affected both clinical presentation and severity of
the cases reported.
In a systematic review of literature regarding the clinical pre-
sentation of COVID ‐19 in children, the most commonly reported
symptoms were fever and cough.
54In a cohort study involving 651
pediatric cases in the UK, fever and a runny nose were more common
in younger children, while vomiting, abdominal pain, headache and a
sore throat showed an increasing trend with age.50Older children
were more likely to present with respiratory distress than infants
(44% vs. 7%).17Less common symptoms include seizures16,50,53and
loss of taste and smell.4,17
A study of 2143 (731 laboratory ‐confirmed) pediatric cases re-
ported to the Chinese Center for Disease Control and Preventionfound that 94.1% of cases could be classified as asymptomatic, mild,
or moderate.
5The mild category (50.9%) included symptoms such as
fever, fatigue, myalgia, cough, sore throat, runny nose, and sneezing.5
In Turkey, of 220 positive pediatric cases, 145 (70.5%) were classi-fied as asymptomatic (25.5%) or mild (45%).
19In South Korea, 22%
of COVID ‐19 ‐positive study participants remained asymptomatic
throughout a 3 ‐week monitoring period.4A systematic review of
studies ( n4300 confirmed pediatric cases) reported that 18.9% ofchildren were asymptomatic.55The majority of studies reported a
mortality rate of less than 2% (Table 3).
There is a significant difference in the median age between
studies, with the lowest being 2.3 years old16and the highest 13
years.51Infants (aged < 1 year) account for between 30% and 40% of
participants in half of the studies (Table 3). The high proportion ofinfants could be influenced by a tendency for parents to seek medical
attention for this age group and an increased likelihood that physi-cians will admit them to hospitals.
16A multivariate analysis reported
an association between neonatal period ( <1 month of age) and ICU
admission (odd ratio 5.06).18,50
Several studies noted that COVID ‐19 positive patients had ele-
vated blood markers indicative of inflammation.17,19,50,51,53One
study reported that 38.8% (47/121) of participants had high con-
centrations of the inflammatory marker C ‐reactive protein (CRP).16
Moreover, children with more serious symptoms were found to have
significantly higher CRP levels than those with a milder presenta-
tion.17In Turkey, lymphopenia was the most common abnormal lab
value found amongst participants (13.5%; 85/220).19
While COVID ‐19 in children can present with a variety of
symptoms, pediatric cases are most often mild or asymptomatic. Inrare cases, children can develop severe complications followinginfection.
4|COMPLICATIONS IN CHILDREN
4.1 |Multisystem inflammatory syndrome in
children (MIS‐ C)
Starting in late April 2020, a hyperinflammatory syndrome likelyrelated to COVID ‐19 has been reported in growing numbers of
children.
56,57This syndrome has been named multisystem in-
flammatory syndrome in children (MIS ‐C) and its clinical pre-
sentation has many similarities to Kawasaki Disease (KD)58and
Toxic Shock Syndrome (TSS), particularly the elevation of multiple
inflammatory markers with severe cardiac involvement.50,56,59 –62
In the UK, MIS ‐C is referred to as pediatric inflammatory multi-
system syndrome temporarily associated with SARS ‐CoV ‐2
(PIMS ‐TS).63
Table 4summarizes 14 studies looking at patients with po-
tential or diagnosed cases of MIS ‐C. The information is presented in
table format for ease of viewing, but not necessarily for comparison
among studies as they vary greatly in size and scope. Patientselection also varies among studies, with earlier studies respondingto an unusual increase in KD cases in the pediatric population and
selecting study cases from those with a definitive KD diagnosis.
Later, as the medical and scientific community became aware ofMIS ‐C as a distinct condition, more formal diagnostic character-
istics were sought.
64Since then, the WHO,65the Centers for
Disease Control (CDC)66in the United States, and the Royal
College of Paediatrics and Child Health63in the UK have all
provided separate case definitions.1346 |
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TABLE 3 Demography, clinical characteristics and outcomes of SARS ‐CoV‐2 in children
Study Patients nMedian
AgeInfants
(0‐1 yrs)
n(%)Male
n(%)PositiveSARS ‐
CoV ‐2
RT‐PCR
n(%)Underlyingmedical
conditions
n(%)No
symptoms
n(%Fevern(%)Respiratory
(cough/SOB)
n(%)Pneumonian(%)GI(vomiting/
diarrhea)
n(%)Hospitalizedn(%)ICU care/mechanical
ventilation
n(%)Mortalityn(%)
Zachariah
et al.
17
(New York)50 11 14 (34) 27 (54) 50 (100) 33 (67) 0 (0) 40 (80) 23 (46)/
17 (34)‐ 7 (14) 50 (100) ‐/9 (18) 1 (2)
Götzinger
et al.18
(Europe)582 5 230
(40)d311
(53)582 (100) 145 (25) 92 (16) 379
(65)313 (54)/ ‐ 93/198 (47) 128 (22) 363 (62) 48 (8)/25 (4) 4 (1)
Garazzino
et al.16(Italy)168 2.3 66 (39) 94 (56) 168 (100) 33 (20) 4 (3) 138
(32)82 (49)/
16 (10)75 (45) 9 (5)/
22 (13)110 (65) 2 (1)/2 (1) 0 (0)
Swann
et al.50(UK)651 4.6 225 (35) 367
(56)651 (100) 276 (42) 0 (0) 431/
617(70)233/599
(39)/173/570 (30)‐ 179/
564(32)651 (100) 116/632
(18)/58/620 (9)6/627 (1)
Dong et al.
5
(China)2143 7 379 (18) 1213
(57)731 (34) ‐ 94 (4) ‐‐ ‐ ‐ ‐ ‐ ‐
Han et al.4
(SouthKorea)91 11 6 (7) 53 (58) 91 (100) 6 (7) 20 (22) 62 (68) 54 (60) ‐ 16 (18) 91 (100)
a0 (0)/0 (0) 0 (0)
Shekerdemian
et al.51
(USA/Canada)48 13 8 (17) 25 (52) 48 (100) 40 (83) 1 (2) ‐ 35 (73) ‐ 1 (2) 48 (100) 48 (100)/
18 (38)2 (4)
Cura Yayla
et al.
19
(Turkey)220 10 ‐ 105
(48)220
(100)b22 (10) 55 (26) 89 (41) 79 (36)/9 (4) 74 (34) 9 (4)/17 (8) 220 (100) 3 (1) 2 (1)
Lu et al.20
(Wuhan)171 6.7 31 (18) 104
(61)171 (100) ‐ 27 (16) 71 (42) 83 (49)/
49 (29)111 (65) 11 (6)/
15 (9)‐ 3 (2)/3 (2) 1 (1)
Parri et al.52
(Italy)100 3.3 40 (40) 57 (57) 100 (100) 27 (27) 21 (21) 28/
54(52)44 (44)/
11 (11)20 (20) 10 (10) 67 (67) ‐/1 (1) 0 (0)
Yonker et al.
21
(MA, USA)49 12.7 2 (4) 23 (47) 49 (100) ‐ 0 (0) 25 (51) 23 (47)/8 (16) ‐ 3 (6)/3 (6) ‐‐ ‐
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4.2 |Clinical presentation of MIS‐ C
Fever, gastrointestinal complaints, rash, and conjunctivitis have been
reported as the most prevalent symptoms MIS‐C (Table 4), although
a combination of these symptoms must be present in order forpatients to meet the case definition for MIS‐C or PIMS ‐TS.
64Due to
the overlapping clinical features of MIS‐C and KD, RT ‐PCR and
antibody testing are needed to confirm MIS‐C.58,60,67
4.3 |MIS‐C and SARS ‐CoV ‐2 testing results
Although the causality of MIS ‐C is currently inconclusive, several
studies have noted an increase in cases 4 6 weeks following a spike in
COVID ‐19 cases within a population.50,62,69,72,73In several studies,
patients found to be negative for SARS ‐CoV ‐2b yR T ‐PCR were
positive for SARS ‐CoV ‐2 antibodies.56,59SARS ‐CoV ‐2R T ‐PCR was
positive in 52% of cases, while SARS ‐CoV ‐2 antibodies were found in
almost 71% of cases across all available studies (Table 4). Riphagen
et al.67reported that all eight cases in their study tested negative for
SARS ‐CoV ‐2b yR T ‐PCR, but no mention of antibody testing was
noted.67Serum samples from 29 pediatric patients, showed that cases
classified as MIS ‐C had higher IgG antibody titers than their non ‐MIS ‐
Cc o u n t e r p a r t s ,74which is consistent with the delayed onset of MIS ‐C
cases following COVID ‐19 exposure and/or infection.74UK patients
with MIS ‐C who were antibody ‐positive were younger (median age
10.0 years vs. 12.4 years) and more likely to be of non ‐White ethnicity
than those who were positive by RT ‐PCR,50suggesting that more
testing is needed in younger and minority children. Conjunctivitis
(71% vs. 16%) and abdominal pain (95% vs. 44%) were more common
in patients positive for SARS ‐CoV ‐2 antibodies, whereas those who
were diagnosed by RT ‐PCR testing were more likely to present with
shortness of breath (52% vs. 14%).50
4.4 |MIS‐C and patient characteristics
Due to the severity of the clinical presentation, children withMIS ‐Co f t e nr e q u i r eI C U ‐level care, especially to manage cardiac
complications. In one study, children with MIS ‐C were five times
m o r el i k e l yt ob ea d m i t t e dt ot h eI C U ,
50while another study
reported that 14 of 15 MIS ‐C patients were admitted to the ICU
within 24 h of hospital admission.59In Latin America, lower
socioeconomic status was found to have a significant associationwith MIS ‐C diagnosis and the need for mechanical ventilation.
22
Different from adults, there are conflicting data regarding
comorbidities that place children at higher risk for COVID ‐19
complications, and several studies reported that the majority of
their pediatric subjects did not have any significant past medical
history.22,56,59,62,67A possible exception to these findings was
reported where five of six patients diagnosed with MIS‐ C
had a pre ‐existing medical condition, four of whom were
immunocompromised.70TABLE 3 (Continued)
Study Patients nMedian
AgeInfants(0‐1 yrs)
n(%)Ma en(%)PositiveSARS ‐
CoV ‐2
RT‐PCR
n(%)Under ying
medica
conditionsn(%)Nosymptomsn(%Fevern(%)Respiratory(cough/SOB)n(%)Pneumonian(%)GI
(vomiting/
diarrhea)n(%)Hospita izedn(%)ICU care/
mechanica
venti ationn(%)Morta ityn(%)
Chiara ‐Chi et
et a .
53(Perú)91 6 28 (31)d58 (64) 46 (51) 49 (54) 0 (0) 18 (40) 20 (18)/
13 (14)26 (37)c11 (13)/ ‐ 91 (100) 22 (24)/ ‐ 9 (10)
Antunez ‐Montes
et a .22(Latin
America)409 3 36 (9) 222
(54)409 (100) 83 (20) 49 (12) 238
(58)244 (60) 170 (42) 101 (25) 409 (100) 32 (10)/29 (7) 17 (4)
Note : G symptoms inc ude abdomina pain, vomiting, and diarrhea.
Abbreviations: Pna, pneumonia; RT ‐PCR, reverse transcription po ymerase chain reaction; SARS ‐CoV ‐2, severe acute respiratory syndrome coronavirus 2; SOB, shortness of breath.
aA chi dren in study were p aced in iso ation, a but two of which were iso ated in a hospita setting regard ess of symptom status. Two chi dren were p aced in a nonhospita iso ation unit (Han et a ., 2020).
b9 (4) of tota were confirmed via serum antibody testing.
cAbnorma chest radiography ± remaining 45 (49%) participants confirmed via Ab testing.
dnc udes chi dren <2 years of age.1348 |
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TABLE 4 Demography, clinical characteristics and outcomes of multisystem inflammatory syndrome in children (MIS ‐C)
Study Patients nMedian
agen(%) MaleRace/ethnicitya
n(%)Positive
SARS ‐CoV ‐2
RT‐PCR
n(%)PositiveSARS ‐CoV ‐
2A b n(%)Underlyingmedical
conditions n(%)Primary (3)symptoms n(%)Cardiac
symptoms
n(%)Diagnosis ofshock n(%)ICU care/
mechanical
ventilation n(%)Mortalityn(%)
Riollano ‐Cruz
et al.
59
(New York)15 12 11 (73) 10 (66)
Hispanic/
Latino9 (60) 15 (100) 4 (27%) Fever: 15 (100); GI:
13 (87); Resp:3 (20)13 (87) 13 (87) 14 (93)/3 (20) 1 (7)
Riphagen
et al.
67(UK)8 8 5 (63) 6 (75) Afro ‐
Caribbean2 (25) ‐ 2 (25) Fever: 8 (100); GI: 8
(100);Conjunctivitis:5 (63)7 (88) 8 (100) 8 (100)/7 (88) 1 (13)
Whittaker
et al.
64
(England)58 9 38 (66) 22 (38) Black/
18 (31)Asian15 (26) 40/46 (87) 7 (12) Fever: 58 (100) GI:
31 (58); Rash:30 (52)8 (14) 29 (50) 23 (40)/25 (43) 1 (2)
Feldstein
et al.
56
(USA)186 8.3 115 (62) 29 (40)
Hispanic/Latino131 (70)
c‐ 51 (27) Fever: 186 (100); GI:
171 (92); Rash:110 (59)149 (80) 90 (48) 148 (80)/37(20) 4 (2)
Verdoni et al.
60
(Italy)10 7.5 7 (70) 8 (80) White 2 (20) 8 (80) ‐ Diarrhea: 6 (60);
Pna: 5 (50)6 (60) 5 (50) ‐ 0 (0)
Toubiana
et al.62
(France)21 7.9 9 (43) 12 (57) African
Ancestry8 (38) 19 (90) 0 (0) GI: 21 (100);
Conjunctivitis: 17
(81); Rash:
16 (76)16 (76) 17 (81) 17 (81)/11 (52) 0 (0)
Grimaud
et al.57
(France)20 10 10 (50) ‐ 10 (50) 15 (75) ‐ Fever: 20 (100); GI:
20 (100); Rash:
20 (100)20 (100) 20 (100) 20 (100)/8 (40) 0 (0)
Sadiq et al.68
(Pakistan)8 9.5 7 (88) ‐ 3 (38) 8 (100) 0 (0) Fever: 8 (100);
Conjunctivitis: 7(88); GI: 6 (75)5 (63) 2 (25) 2 (25)/1 (13) 1 (13)
Godfred ‐Cato
et al.
69
(USA)570 8 316 (55) 187 (41)
Hispanic/
153 (33)
Black, non ‐
Hispanic302 (53) 418 (73) 194 (34) GI: 518 (91); Resp:
359 (63);
Conjunctivitis:
276 (48)493 (87) 202 (35) 364 (64)/69 (13) 10 (2)
Pereira et al.70
(Brazil)6 8 5 (83) ‐ 4 (67) ‐ 5 (83) Fever: 6 (100); Resp:
5 (83); GI: 4 (67)6 (100) 5 (83) 5 (83)/5 (83) 4 (67)
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TABLE 4 (Continued)
Study Patients nMedian
agen(%) MaleRace/ethnicitya
n(%)PositiveSARS ‐CoV ‐2
RT‐PCR
n(%)Positive
SARS ‐CoV ‐
2A b n(%)Underlyingmedical
conditions n(%)Primary (3)symptoms n(%)Cardiac
symptoms
n(%)Diagnosis ofshock n(%)ICU care/
mechanical
ventilation n(%)Mortalityn(%)
Jain et al.
71
(India)23 7.2 11 (48) ‐ 9 (39) 7 (30) ‐ Fever: 23 (100); GI:
15 (70); Rash:14 (65)15 (65) 15 (65) ‐/9 (40) 1 (4)
Torres et al.
72
(Chile)27 6 14 (52) (85)b14 (52) 10 (37) 7 (26) Fever: 27 (100); GI:
17 (63); Rash:14 (52)12 (46) 12 (44) 16 (59)/12 (44) 0 (0)
Swann
et al.
50(UK)52 10.7 31 (60) 330 (51) White 28/50 (56) 22/50 (44) 15 (29) Fever; Rash;
Conjunctivitis21/37 (57) 25 (48) 38 (73)/14 (27) 0 (0)
Mamishi
et al.61
(Iran)45 7 24 (53) ‐ 10 (22) 35 (78) 6 (13) Fever: (91); GI: (58);
rash: (53)25 (56) 5 (11) ‐ 5 (11)
Yonker et al.21
(MA, USA)18 7.7 14 (78) 9 (50) White 18 (100) ‐ 2 (11) Fever: 18 (100);
Rash: 5 (28);
Vomiting: 5 (28)‐‐ ‐ ‐
Antunez ‐
Montes
et al.22
(LatinAmerica)95 7 52 (55) ‐ 23 (24) 72/88 (82) 11 (12) URI: 47 (50); GI: 43
(45); LRI: 23 (24)11 (12) 14 (15) 20 (21)/9 (10) 2 (2)
Note : Cardiac symptoms ex. abnormal EKG, elevated serum troponin and/or BNP, coronary artery abnormalities, arrythmias, ventricular dysfunction, myocarditis; features of Kawasaki Disease: includes
symptoms such as erythema and cracking of lips, strawberry tongue, rash, conjunctivitis, swollen hands and feet, myocarditis, lymphadenopathy (McCrindle et al.
58); and features of shock: hypotension,
tachycardia.
Abbreviations: Ab, antibodies; GI, gastrointestinal complaints ex. diarrhea, vomiting, abdominal pain; KD, Kawasaki Disease; LRI, lower respiratory tract infection ex. pneumonia, bronchitis; Pna, pneumonia;
Resp, respiratory complaints ex. cough, shortness of breath; RT ‐PCR, reverse transcription polymerase chain reaction; SARS ‐CoV ‐2, severe acute respiratory syndrome coronavirus 2; URI, upper respiratory
tract infection ex. rhinitis, pharyngitis, tonsillitis, otitis.
aLargest racial or ethnic group(s) reported in each study. Language used is that of the authors. Swann et al.50reported that children of black ethnicity were over represented in their study population
compared to the general population (10% vs. 4.7%). No other authors offered context for racial/ethnic data. It is also assumed that neither race nor ethnicity are mutually exclusive.
b85% of participant's parents reported being of Chilean descent.
cValue includes participants who tested positive for SARS ‐CoV ‐2 antibodies.1350
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Though pediatric mortality rates are low, even among those di-
agnosed with MIS ‐C, there continues to be significant concern re-
garding which, if any, comorbidities place children at increased risk
for COVID ‐19 infection.
5|COMORBIDITIES AND SEVERITY
Obesity, chronic respiratory diseases (particularly asthma), and a
compromised or suppressed immune system are the most common
underlying medical conditions that have been cited. Table 5 sum-
marizes 12 studies that have included comorbidity data.
5.1 |Obesity
Obesity was the most common comorbidity among hospitalizedCOVID ‐positive children, with a significant association between
obesity and severe cases requiring mechanical ventilation in children
2 years and older.
17A retrospective study from Wuhan, China re-
ported that an elevated body mass index (BMI) was correlated with
an increased mortality risk in COVID ‐19 patients aged 14 45
years.79In another study, 30% (14/46) of admitted pediatric patients
testing positive for COVID ‐19 were obese, but no correlation was
noted between obesity and ICU admissions.75Finally, an analysis of
nationwide data from pediatric cases in Mexico reported that obese
children were 39% more likely to have a SARS ‐CoV‐2 infection.77
The effect of the COVID ‐19 lockdown policies on weight gain in
children is also of concern. A cross ‐sectional survey of 584 house-
holds in the United States reported that families are buying more
nonperishable and highly processed foods, and a third of families alsoreported an increase in their consumption of snack foods and des-serts.
80In a longitudinal study of 41 obese youth in Italy, the intake
of food items linked to obesity, such as potato chips, red meat, andsugary drinks had increased significantly while time spent in sportsactivities had decreased during the first 3 weeks of the national
lockdown.
81The wide disruption in the diet and activities of children
due to lockdown policies has the potential to worsen the ongoing
obesity epidemic, which in turn places children at greater risk for
COVID ‐19 infection.82
5.2 |Chronic respiratory disease
As COVID ‐19 is primarily a respiratory illness, asthma and other
respiratory conditions were initially thought to place children athigher risk for more severe symptoms. However, there are conflict-
ing data about the risk of COVID ‐19 in children with chronic re-
spiratory illnesses. A study looking exclusively at COVID ‐19 patients
receiving ICU care
51did not show a significantly higher proportion of
asthmatics than studies looking at all hospitalized children.69Un-
derlying respiratory conditions were present in only 4.3% (21/491)
of those requiring general care, while 10.4% (12/115) of thoserequiring ICU care reported the same.50Not one of 67 studies in-
cluded in a systemic review reported asthma as a comorbidity or risk
factor for children and COVID ‐19.83In a study of COVID ‐19 pe-
diatric cases in Mexico, asthma was reported in 3.8% (806) of allcases, but was not associated with increased severity of infection;those reporting asthma were not more likely to develop pneumonia,
nor were they at higher risk for hospitalization.
77
Surprisingly, an Italian study reported a much lower prevalence
of asthma in their pediatric COVID ‐19 cohort than in the general
population (2% vs. 11%).78Researchers postulated the potential for
asthma to act as a protectant due to adaptation in the immune re-
sponse of pediatric asthmatics.78Behavioral factors may also have
contributed to the lower prevalence of pediatric asthmatics among
COVID cohorts. Several studies reporting a significant decrease in
pediatric asthma ‐related visits to emergency departments and an
increased utilization of telehealth raise the possibility that parents
with vulnerable children are being proactive in protecting them
against unnecessary exposure to COVID ‐19.84,85
5.3 |Immune system compromise
Comorbidities involving immunocompromise include organ trans-
plants, malignancies, and aplastic anemia (Table 5). Notably, some
studies used immunocompromised and immunodeficient inter-
changeably.18Individuals using immunosuppressants and those
receiving chemotherapy and/or radiation are considered to beimmunosuppressed.
Available data concerning the risk of COVID ‐19 in patients with
immunodeficiencies and/or immunosuppression are contradictory. Ina study of 91 pediatric cases in South Korea, none reported an ex-isting immunodeficiency.
4These 91 cases account for 76.5% of all
pediatric cases in the country, excluding a cluster outbreak within a
religious community.4In Spain, 8/51 (15%) of the total pediatric
COVID ‐19 cases for a single month were immunocompromised.86
Only 8.1% (53/599) of pediatric cases in the UK reported use ofimmunosuppressants before being hospitalized for COVID‐19.
50
There was no association between immunosuppressant use and cri-
tical care admission.50In Mexico, immunodeficiencies were reported
in 3.8% (808) of all cases and were associated with a four ‐fold in-
crease of COVID ‐19 pneumonia and eight ‐fold increase in the risk of
hospital admission.77
5.4 |Viral co ‐infections
In a retrospective study from China, researchers reported that 47.1%(16/34) of COVID ‐19 ‐positive pediatric patients were infected with
additional respiratory pathogens, including Mycoplasma pneumoniae ,
influenza type A and B, and respiratory syncytial virus (RSV).
87In
another study from China, 10 pediatric patients were extensivelyevaluated and all were negative for both common viruses (RSV, in-
fluenza, etc.), SARS ‐CoV, and MERS ‐CoV.
7In Italy, 5.9% (10/168) ofSIEBACH ET AL.
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TABLE 5 Demography and comorbidities of SARS ‐CoV‐2 positive children
Study Participants nMedian AgeMale
n(%) Comorbidities n(%) Obesitya+n(%)Chronic Respiratory Illnessn(%) Asthma n(%)Immuno ‐compromised/
suppressed
bn(%)
Zachariah et al.17(New York) 50 11 27 (54) 33 (67) 11 (22) 2 (4) 6 (12) 8 (16)
Shekerdemianet al.51(USA/Canada) 48 13 25 (52) 40 (83) 7 (15) 2 (4) ‐ 11 (23)
Chao et al.75(New York) 46 13 31 (67) ‐ 14 (30) ‐ 11 (24) 3 (7)
Godfred ‐Cato et al.69(U.S.) 570 8 316 (55) ‐ 146 (26) 48 (8) ‐‐
Kim et al.76(USA) 576 8 292 (51) 94/222 (42) 42/111 (38) 40/222 (18) 30/222 (14) 12/222 (5)
Leon ‐Abarco77(Mexico) 21,161 ‐‐ ‐ 655 (3) ‐ 806 (4) 808 (4)
Ciprandi et al.78(Italy) 52 6.2 24 (46) ‐‐ ‐ 1 (2) ‐
Garazzino et al.16(Italy) 168 2.3 94 (56) 33 (20) ‐ 7 (4) ‐ 3 (2)/4 (2)
Götzinger et al.18(Europe) 582 5 311 (53) 145 (25) ‐ 29 (5)c16 (3) 3 (1)/29 (5)
Han et al.4(South Korea) 91 11 53 (58) 6 (7) ‐ 0 (0) 3 (3) 0 (0)
Swann et al.50(UK) 651 4.6 367 (56) 276 (42) ‐‐ 45/615 (7) 48/615 (8)/53/599 (9)
Yonker et al.21(MA, USA) 49 12.7 23 (47) ‐ 13 (27) ‐ 6 (12) 0 (0)
Antunez ‐Montes et al.22
(Latin America)409 3 222 (54) 83 (20) ‐‐ ‐ 18 (4)/12 (3)
Abbreviations: BMI, body mass index; SARS ‐CoV ‐2, severe acute respiratory syndrome coronavirus 2.
aObesity is defined as BMI (or sex and weight for length percentiles for patients younger than 2) at or above the 95th percentile for age.
bSolid organ transplant, hematologic malignancies, solid tumors, hematopoietic stem cell transplant recipient, aplastic anemia.
cStudy explicitly states or demonstrates the inclusion of asthma in data point for chronic respiratory illness.1352
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study participants had co ‐infections,16while in Perú, M. pneumoniae
was found in 10% (9/91) of participants.53In Latin America, 3.4%
(14/409) of participants tested positive for a viral co ‐infection,
although no significant association was found between co ‐infections
and ICU admission or mechanical respiratory support.22In contrast,
in Europe, 5% (29/582) of participants tested positive for a viral co ‐
infection and patients with one or more viral co ‐infections were
more likely to have signs or symptoms of upper or lower respiratory
tract infection at presentation.18Individuals with viral co ‐infection
were also significantly more likely to require ICU admission,
respiratory support, and vasoactive medications.18
Overall, there is limited data regarding the presence of viral
coinfections within the COVID ‐19 ‐positive pediatric population.
There is also limited evidence regarding the influence of these co-
infections in either increasing a patient's susceptibility to COVID ‐19
or in contributing to a more severe course of disease. With expected
peaks of additional respiratory pathogens like influenza and re-
spiratory syncytial virus during the winter season, we will likely ex-perience the true impact of multiviral respiratory infections in terms
of both incidence and clinical severity.
6|SUMMARY
Preliminary findings are generally optimistic respecting incidence
and severity of SARS ‐CoV‐2 infection in the pediatric population.
Children do not appear to be the primary source of transmissionwithin either the household or school environments, and are mostlikely to contract the virus from an adult household member. As
SARS ‐CoV‐2 transmission through breastmilk is unlikely, the current
recommendation for mothers with suspected or confirmed
COVID ‐19 is to initiate or continue breastfeeding while following
guidance on hygiene and mask use. Findings on perinatal transmis-
sion are inconclusive, and further studies of pregnancy outcomes and
post ‐natal fetal development of infants of COVID ‐positive women
are warranted.
The large proportion of cases studied thus far have shown that
children often have a mild or asymptomatic presentation. While rare,there are hundreds of children in the United States that have met
case definition for MIS‐C.
69Despite the potential for catastrophic
outcomes, the WHO, the CDC, and the Royal College of Paediatrics
and Child Health have all provided formal diagnostic criteria for
MIS‐C,63,65,66allowing for faster treatment and an overall positive
prognosis for those children who are diagnosed.69In addition,
mortality rates remain low.50,56,64,69Findings on chronic respiratory
illnesses, compromised immunity, and viral co ‐infections as risk
factors for COVID ‐19 in children are inconclusive, but comorbidities
such as obesity are associated with a higher risk of infection and a
more severe clinical course of disease.17,75,77,79
The lower incidence and severity of SARS ‐CoV‐2 infections in
children should not allow our focus to shift away from a highly vul-nerable population with potential developmental implications. The
novelty of COVID ‐19 has presented many challenges, but there arealso unique opportunities to study longitudinally children that have
been affected from infancy through childhood and into adulthood.Continued testing and longer‐term investigations are warranted to
provide data on risk factors for infection and MIS‐C, long‐term re-
spiratory and developmental outcomes, as well as behavioral andlifestyle influences. Indeed, such knowledge may assist in framing
public policy responses that would protect children and mitigate
future epidemics.
ACKNOWLEDGMENTS
This study was supported by the National Science Foundation grant
(2031761) and Dean's COVID ‐19 Rapid Response grant from Tulane
University School of Public Health and Tropical Medicine; GP was
supported by grant RO1 HL ‐061007 from the National Heart, Lung
and Blood Institutes of Health; SHL was supported by grant
P20GM109036 from the National Institute of General Medical
Sciences of the National Institutes of Health. The funder/sponsor did
not participate in the work.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
AUTHOR CONTRIBUTIONS
Melissa K Siebach: conceptualization (supporting); methodology
(equal); writing original draft (lead); writing review & editing (equal).Giovanni Piedimonte : writing original draft (supporting); writing
review & editing (equal). Sylvia H Ley : conceptualization (lead);
funding acquisition (lead); methodology (equal); supervision (lead);writing original draft (supporting); writing review & editing (equal).
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no data sets weregenerated or analyzed during the current study.
ORCID
Giovanni Piedimonte
https://orcid.org/0000-0003-1640-1928
Sylvia H. Ley https://orcid.org/0000-0003-0084-2630
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How to cite this article: Siebach MK, Piedimonte G, Ley SH.
COVID ‐19 in childhood: Transmission, clinical presentation,
complications and risk factors. Pediatric Pulmonology . 2021;
56:1342 1356. https://doi.org/10.1002/ppul.253441356 |
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