Document text
Severe COVID-19 Infection and Pediatric Comorbidities:
A Systematic Review and Meta-Analysis
Boyan K. Tsankova,b,d,e, Joannie M. Allairea,b,d, Michael A. Irvined, Alison A. Lopeza,c,d,
Laura J. Sauvéa,c,d, Bruce A. Vallancea,b,d, Kevan Jacobsona,b,d,f,*
aDepartment of Pediatrics, BC Children ’s Hospital, Vancouver, BC, Canada
bDivision of Gastroenterology, Hepatology and Nutrition, BC Children ’s Hospital, Vancouver, BC, Canada
cDivision of Infectious Diseases, BC Children ’s Hospital, Vancouver, BC, Canada
dBC Children ’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
eDepartment of Immunology, University of Toronto, Toronto, ON, Canada
fDepartment of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
A R T I C L E I N F O
Article history:
Received 20 August 2020
Received in revised form 9 November 2020
Accepted 14 November 2020
Keywords:
CoronavirusCOVID-19PediatricsComorbidityMeta-AnalysisA B S T R A C T
Objective: There is limited information on the severity of COVID-19 infection in children with
comorbidities. We investigated the effects of pediatric comorbidities on COVID-19 severity by means of a
systematic review and meta-analysis of published literature.
Methods: PubMed, Embase, and Medline databases were searched for publications on pediatric COVID-19
infections published January 1st to October 5th, 2020. Articles describing at least one child with and
without comorbidities, COVID-19 infection, and reported outcomes were included.
Results: 42 studies containing 275,661 children without comorbidities and 9,353 children with
comorbidities were included. Severe COVID-19 was present in 5.1% of children with comorbidities, and in
0.2% without comorbidities. Random-effects analysis revealed a higher risk of severe COVID-19 among
children with comorbidities than for healthy children; relative risk ratio 1.79 (95% CI 1.2 7 – 2.51; I2 = 94%).
Children with underlying conditions also had a higher risk of COVID-19-associated mortality; relative risk
ratio 2.81 (95% CI 1.31 – 6.02; I2 = 82%). Children with obesity had a relative risk ratio of 2.87 (95% CI 1.16 –
7.07; I2 = 36%).
Conclusions: Children with comorbidities have a higher risk of severe COVID-19 and associated mortality
than children without underlying disease. Additional studies are required to further evaluate this
relationship.
© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc- nd/4.0/).
Introduction
The severe acute respiratory syndrome coronavirus 2 (SARS
CoV 2) is the causative agent of the human coronavirus disease 2019
(COVID 19) pandemic that officially began on March 11, 2020
(Cucinotta and Vanelli, 2020). At the time of writing of this report
November 9th, 2020 there had been 50,539,082 confirmed cases
with an associated 1,258,321 deaths worldwide resulting fromCOVID 19 infection (COVID 19 Map, 2020). The virus primarily
affects the lower respiratory tract, and infected individuals primarily
present with fever, cough, and dyspnea, however gastrointestinal
(GI) manifestations can also occur (Huang et al., 2020; Shi et al.,
2020). Although the infection course is usually non fatal, severe
COVID 19 infection with life threatening presentations of acute
respiratory distress syndrome (ARDS) and multiple organ failure can
occur (Huang et al., 2020; Zhou et al., 2020). Risk factors for severe
manifestations of SARS CoV 2 illness and associated mortality
include age greaterthan65 years (Du et al., 2020; Wu andMcGoogan,
2020), and underlying comorbidities such as diabetes, hypertension,
and obesity (Caussyet al., 2020; Du et al., 2020; Guan et al., 2020; Wu
and McGoogan, 2020).
Multiple studies on COVID 19 infection in children have noted
differences in infection rates, symptoms, and mortality as
compared to adults (Dong et al., 2020; Wu and McGoogan,* Corresponding author at: Department of Pediatrics, Division of Gastroenterol-
ogy, Hepatology and Nutrition, BC Children’s Hospital, 4480 Oak Street, Vancouver,
BC, V6H 3V4, Canada.
E-mail addresses: [email protected] (B.K. Tsankov),
[email protected] (J.M. Allaire), [email protected] (M.A. Irvine),
[email protected] (A.A. Lopez), [email protected] (B.A. Vallance),
[email protected] (K. Jacobson).
https://doi.org/10.1016/j.ijid.2020.11.163
1201-9712/© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).International Journal of Infectious Diseases 103 (2021) 246–256
Contents lists available at ScienceDirect
International Journal of Infectious Diseases
jo urnal home page: www.elsevier.com/lo cat e/ ij id
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071458
2020). One of the most comprehensive early studies of pediatric
patients with SARS CoV 2 infection reported that children develop
a relatively mild disease course with 83% of confirmed cases
presenting with mild to moderate infection, with an additional 13%
being asymptomatic, and only 3% presenting with severe and
critical illness (Dong et al., 2020). However, such early case series
potentially suffer from decreased testing of mildly infected
individuals thereby leading to a potentially low rate of documented
asymptomatic infections. A recent outbreak in a children ’s
overnight camp in the United States reported an asymptomatic
infection rate of 26% among COVID 19 infected children (Sza
blewski, 2020). Nonetheless, the disease course in children can be
heterogenous in nature, with the most common clinical signs and
symptoms including fever, headaches, and sore throat (Szablewski,
2020). Critical illness in children and adults alike typically
manifests with severe pneumonia characterized by speci fic oxygen
concentrations less than 92%, autoin flammatory shock, and
respiratory distress (Sankar et al., 2020). Such cases frequently
require mechanical ventilation and treatment with antiviral and
immunomodulating regimens (Sankar et al., 2020; Zimmermann
and Curtis, 2020).
Even so, previous reports have indicated clusters of an
inflammatory syndrome, called “Multisystem Inflammatory
Syndrome associated with COVID 19 (MIS C) ” or “Paediatric
inflammatory multisystem syndrome (PIMS) ” Kawasaki like
disease, a potentially fatal vasculitis, occurring in children
following COVID 19 infection (Riollano Cruz et al., 2020 ; Verdoni
et al., 2020 ). Such reports indicate the potential (albeit uncom
mon) for severe and potentially fatal COVID 19 in pediatric
patients. Although previous studies have established pre existing
comorbidities as significant risk factors for severe SARS CoV 2
infection in adults (Du et al., 2020; Guan et al., 2020 ), questions
remain regarding childhood comorbidities and associated COVID
19 outcomes. While systematic reviews and meta analyses
examining COVID 19 in pediatric patients have been published
(Ding et al., 2020; Hoang et al. 2020 ), these reports did not
evaluate the risk of severe SARS CoV 2 infection speci fically in
children with pre existing conditions. Consequently, the objec
tive of this systematic review and meta analysis is to examine the
relative risk of severe COVID 19 infection and associated
mortality in children with comorbidities.
Methods
Search Strategy and Selection Criteria
For this systematic review and meta analysis PubMed, Medline,
and Embase databases were queried for articles published from
January 1st, 2020 until October 5th, 2020. The Medline and Embase
searches were conducted via the Ovid interface. The search terms
“COVID 19 ”, “SARS nCoV 2 ”, “SARS CoV 2 ”, “2019 nCoV ”, “novel
coronavirus ”, and “coronavirus ” were used to obtain articles
relating to the novel coronavirus pandemic occurring in 2020. To
obtain literature pertaining speci fically to SARS CoV 2 infection in
pediatric patients, the terms “child* ”, “pediatr* ”, “paediatr* ”,
“teenage ”, “adolescent ”, “infant” , and “newborn ” were queried
in conjunction with the coronavirus search. For the full search
queries, see Supplement S1. To capture articles potentially missed
by our systematic search, Google Scholar was queried for articles
pertaining to COVID 19 infection in pediatric patients. Further
articles were obtained by examining the references of highly
relevant systematically retrieved articles. Only articles in English
were considered for inclusion. References were managed with
Endnote (version X9.0) software which was also used for duplicate
removal. The systematic literature search was performed inaccordance with the Preferred Reporting Items for Systematic
Reviews and Meta Analyses (PRISMA) recommendations (Moher
et al., 2009).
Following deduplication, the reference titles were reviewed by
BKT. Titles that did not imply a subject matter relevant to COVID 19
in pediatric patients were excluded. Following title review, the full
text content of the remaining literature was thoroughly analyzed
by the author BKT. The following exclusion criteria were applied to
the full text articles: articles not mentioning pediatric comorbid
ities; adult only studies; articles where the pediatric comorbidity
data was indistinguishable from adult comorbidity data; pre
existing reviews, systematic reviews, and meta analyses; articles
with patients without confirmed COVID 19 infections; basic
science studies; clinical discussions, recommendations, and
guidelines; articles without reported patient outcomes; and
studies of other coronaviruses. Articles containing at least one
paediatric patient with comorbidities, and one paediatric patient
without comorbidities were included. Furthermore, we included
articles for which the severity and outcomes of SARS CoV 2
infection in the paediatric patients was clearly defined. Following
full text review, BKT and KJ graded the remaining studies using the
National Institutes of Health (NIH) Quality Assessment Tool for
Case Series and Studies (Study Quality Assessment Tools, 2020).
Any disagreements in rating were handled via discussion by the
two reviewers until a consensus was reached. For the literature
grading see Supplement S2.
Data Extraction and Case Definitions
The study authors; design; country of origin; aims; pediatric
sample size; COVID 19 infection counts; disease severity; comor
bidity counts; pediatric intensive care unit (PICU) admittance
counts; and mortality counts were extracted from the included
literature. The extracted comorbidities were either defined by the
studies or classi fied into representative broader categories by BKT
and KJ. Comorbidities such as trisomy 21, prematurity, and
unde fined genetic abnormalities were deemed as “other ” pre
existing conditions. Obesity was defined by the studies where
available, or by the authors as a body mass index (BMI) at or greater
than the 95thpercentile for children of the same age and sex
according to CDC definitions (Defining Childhood Obesity, 2019).
To operationalize severe COVID 19 infection across the different
studies, severe infection was deemed as any SARS CoV 2 infection
requiring supplemental help to normal breathing and/or admis
sion to a PICU unless otherwise explicitly stated in the literature.
Finally, paediatric patients were defined as participants suffering
from COVID 19 who were below 21 years of age.
Statistical Analyses
PICU admission and mortality outcomes were assessed using a
random effects meta analysis (Schwarzer et al., 2015). A random
effects model was chosen due to the potential variation in sampled
study populations leading to differences in outcomes by co
morbidities. Estimation of random effects variance was conducted
using the Sidik Jonkman estimator with Hartung Knapp adjust
ment (IntHout et al., 2014). For individual trials with no events in
one or both groups, a continuity correction of the opposite
treatment arm size was added to each cell for each effect measure
(Sweeting et al., 2004). Binary estimators including risk ratios, and
risk difference were estimated using the Mantel Haenszel method
(Mantel and Haenszel 1959; Robins et al., 1986). All analyses and
data visualization were conducted in R version 4.0.2 using the meta
and tidyverse libraries (Balduzzi et al., 2019; Team, R Core, and
others, 2020; Wickham et al., 2019).B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
247
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071459
Role of the Funding Source
This study did not receive any funding. The study design, data
analysis, and writing of the manuscript was conceptualized only by
the authors.
Results
There were 13310 studies identi fied from our systematic search
across the three databases (Fig. 1). Following de duplication, 8206
records were reviewed based on a title screen, of which 7398 were
deemed irrelevant to the subject matter of this study. The full texts of
the remaining 808 articles were reviewed for the presence of pediatric
study participants who had: 1) pre existing comorbidities; and 2)
COVID 19 infection, for which clear outcomes were reported. 98articles then underwent literature grading, with 86 studies deemed
fair for further analysis. Among these 86 articles, only 42 had pediatric
case control participants without comorbidities with either severe
COVID 19 and/or COVID 19 associated mortality. Five studies (Bellino
et al., 2020 ; Bixler et al., 2020 ; Blum field and Levin, 2020 ; Moraleda
et al., 2020 ; Otto et al., 2020 ) only examined children who died from
COVID 19 and were therefore only included in the mortality analysis.
These 42 studies were therefore the basis for our analysis examining
the effects of comorbidities on severe and potentially fatal manifes
tations of pediatric SARS CoV 2 infection. Among the 42 articles, 18
studies were from the USA (43%), and 4 studies were from China (10%),
Italy (10%), and Spain (10%) respectively. Of the remaining studies, 3
were from France (7%), 2 were from the United Kingdom (5%), and Iran
(5%), and 1 was from Austria (2%), Brazil (2%), India (2%), Turkey (2%),
and Uruguay (2%) (Table 1).
Fig. 1. PRISMA flow diagram for the identi fication of studies pertaining to COVID-19 and children with comorbidities published between January 1 st, 2020 and October 5th,
2020.B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
248
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071460
Table 1
Summary and characteristics of the 42 studies included in this systematic review and meta-analysis.
STUDY Study type Country Study Aim COVID-19
Infection(N = 285,004)Withcomorbiditiesand COVID-19
(n = 9353)COmorbiditiesand Severe
COVID-19A
(n = 481)Comorbiditiesand mortality
(N = 135)
(Abdel-Mannan
et al., 2020)Retrospective U.K Report neurological manifestations of children with
COVID-194 1 1 0
(Anand et al.,
2020)Retrospective India Describe the clinical profile of neonates born to
mothers with COVID-197 3 0 0
(Bellino et al.,
2020)Retrospective Italy Describe characteristics of COVID-19 in pediatric
patients3836 206 4
(Belhadjer et al.,
2020)Retrospective France Report cases of acute heart failure associated with
COVID-19 in children31 4 4 0
(Bhumbra et al.,
2020)Retrospective USA Describe the infection course of children
hospitalized with COVID-1924 8 3
(Biko et al.,
2020)Retrospective USA Describe imaging features, comorbidities, and
outcomes of children with COVID-19313 41 17 0
(Bixler et al.,
2020)Retrospective USA Report the SARS-CoV-2-associated deaths in
children residing in the USA121 91 91
(Blum field and
Levin, 2020)Retrospective USA Report the outcomes of critically-ill children with
COVID-1918 12 2
(Cai et al., 2020) Case-series China Report the outcomes and clinical characteristics of
pediatric patients with COVID-19 that did not have
respiratory symptoms as the first manifestation of
infection5 3 2 0
(Chao et al.,
2020)Retrospective USA Report the risk factors associated with severe
COVID-19 in pediatric patients46 31 12 1
(de Farias et al.,
2020)Prospective Brazil Describe the characteristics of COVID-19-associated
PIMS in 11 children11 5 5 2
(DeBiasi et al.,
2020)Retrospective USA Examine the epidemiology of pediatric COVID-19
infection in Washington, DC165 69 5 0
(Derespina
et al., 2020)Retrospective USA Describe outcomes of COVID-19 in children in New
York City70 52 52 2
(Diorio et al.,
2020)Prospective USA Report the hematological differences between MIS-
C and COVID-19 in children14 13 9 2
(Du et al., 2020) Retrospective China Report the outcomes of and laboratory
characteristics of COVID-19 among hospitalized
pediatric patients with a focus on allergic patients182 59 2 0
(Eghbali et al.,
2020)Case-series Iran Describe 4 cases of pediatric COVID-19 in Iran 4 2 2 1
(Garazzino
et al., 2020)Retrospective Italy Report outcomes and disease characteristics of
COVID-19 among multiple pediatric care centres in
Italy168 33 2 0
(García-Salido
et al., 2020)Prospective Spain Describe series of children admitted to a Spanish
PICU due to COVID-197 1 1 0
(Giacomet et al.,
2020)Retrospective Italy Describe the characteristics of severe vs non-severe
COVID-19 in children127 20 6 0
(González-
Dambrauskaset al., 2020)Retrospective Uruguay Examine the characteristics and
outcomes of pediatric patients in PICUs due to
COVID-19 infection17 12 12 1
(Götzinger
et al., 2020)Cross-sectional Austria Examine the characteristics and outcomes of
children with COVID-19 across Europe582 145 25 2
(Kainth et al.,
2020)Retrospective USA Describe the presentation, course, and severity of
pediatric COVID-1965 30 10 1
(Kaushik et al.,
2020)Retrospective USA Assess the outcomes of COVID-19-associated MIS-C 33 16 16
(Leeb, 2020) Retrospective USA Examine the epidemiology of COVID-19 among US
children277,285 7738 109 14
(Lovinsky-Desir
et al., 2020)Retrospective USA Examine the impact of asthma on COVID-19
severity55 24 24
(Mannheim
et al., 2020)Case-series USA Report the clinical characteristics of pediatric
COVID-19 in Chicago64 13 4
(Meslin et al.,
2020)Case-series France Present outcomes of 6 children with COVID-19 in
France6 2 0 0
(Moraleda et al.,
2020)Case-series Spain Describe clinical features of MIS-C in Spain 31 10 2
(Moreno-
Galarraga
et al., 2020)Retrospective Spain Describe the presentations of COVID-19 in Spain 11 4 0 0
(Otto et al.,
2020)Retrospective USA Describe the outcomes and features of COVID-19 in
children424 242 2
(Oualha et al.,
2020)Retrospective France Describe severe presentations of COVID-19 in
children27 19 19 2
(Parri et al.,
2020)Retrospective Italy Examine the diagnostic, clinical presentation,
interventions and outcomes of pediatric patients
with confirmed COVID-19 in Italy.170 38 6 0
(Riollano-Cruz
et al., 2020)Retrospective USA Describe the first COVID-19 MIS-C associated cases
in New York City15 5 4 0B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
249
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071461
Study Patient Characteristics
From the 42 articles, a total of 285,004 pediatric patients with
laboratory con firmed SARS CoV 2 infection were identi fied.Among this cohort, 9,353 (3.3%) had at least one underlying
comorbidity (Table 1). Gender demographic data was available for
280,999 COVID 19 infected children, of which 142,411 (50.7%)
were female and 138,588 (49.3%) were male. We were able toTable 1 (Continued )
STUDY Study type Country Study Aim COVID-19
Infection(N = 285,004)Withcomorbiditiesand COVID-19
(n = 9353)COmorbiditiesand Severe
COVID-19A
(n = 481)Comorbiditiesand mortality
(N = 135)
(Schwartz et al.,
2020)Case-series Iran Describe the characteristics and outcomes of
COVID-19 in neonates in Iran19 15 10 0
(Shekerdemian
et al., 2020)Cross-sectional USA Characterize COVID-19 infection in North American
PICUs48 40 40
(Sun et al.,
2020)Retrospective China Examine the clinical characteristics of pediatric
COVID-198 1 1 0
(Swann et al.,
2020)Prospective UK Explore the clinical characteristics of pediatric
COVID-19 and MIS-C in the UK651 276 63 6
(Tagarro et al.,
2020)Retrospective Spain Describe the epidemiology and treatment of
COVID-19 in Madrid41 11 1 0
(Waltuch et al.,
2020)Case series USA Describe the characteristics and outcomes of 4
pediatric cases of COVID-194 2 2 0
(Yayla, 2020) Retrospective Turkey Examine characteristics of COVID-19 in children in
Turkey220 21 2 0
(Zachariah
et al., 2020)Retrospective USA Compare the features of pediatric COVID-19 disease
between severe and mild infection50 33 8
(Zheng et al.,
2020)Retrospective China Describe the clinical characteristics of pediatric
COVID-1925 2 2 0
Abbreviations: COVID-19 - coronavirus disease 2019; PICU - pediatric intensive care unit.
ADefined by the studies, or PICU admission, or need for supplemental breathing aid during the course of infection.
Fig. 2. Pooled estimate of the relative risk of severe COVID-19 among pediatric patients with comorbidities.B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
250
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071462
extrapolate age category data in 362 children. Of these, 138 (38%)
were under 1 year of age, 82 (21%) 1 to 5 years of age, 31 (8%) 6 to
10, 22 (6%) 10 14, and 89 (23%) were older than 14 years of age. To
the best of our ability, we have excluded any study participants that
were over 21 years, such as those present in the study by DeBiasi
and colleagues.
Relative Risk of Pediatric Comorbidities on Severe COVID 19 Infection
Among the 9,353 pediatric patients with SARS CoV 2
infection and underlying comorbidities, 481 (5.1%) had severe
COVID 19 and/or were admitted to a PICU (Table 1). In contrast,
only 579 of the 275,661 (0.21%) pooled pediatric patients
without comorbidities had a severe manifestation of COVID 19.
Employing a random effects model to examine the relative risk
of severe COVID 19 and/or PICU admission among children with
comorbidities, we obtained a total relative risk ratio of 1.79 (95%
CI 1.27 2.51; x2= 602.31 (P < 0.001); I2= 94%) (Fig. 2). It is
important to note that only 37 studies were included in this
analysis as 5 studies only examined COVID 19 associated deaths
(Bellino et al., 2020; Bixler et al., 2020; Blum field and Levin, 2020;
Moraleda et al., 2020; Otto et al., 2020). Nonetheless, 7 studies
(Anand et al., 2020; Kainth et al., 2020; Meslin et al., 2020;
Moreno Galarraga et al., 2020; Riollano Cruz et al., 2020; Schwartz
et al., 2020; Tagarro et al., 2020) had a higher risk ratio of severe
COVID 19 among pediatric patients without comorbidities than
those with underlying conditions (Fig. 2). Furthermore, studies
such as the CDC Mortality and Morbidity Weekly Report (Leeb,
2020) had noticeably larger participant cohort populations than
other reports. To examine the potential preferential bias of these
studies towards the overall relative risk ratio of our analysis, we
individually excluded each of the 37 studies to determine the
overall effect of each singular study on the net relative risk ratio.
Notably, no article significantly influenced the risk ratio in either
direction (Fig. 3).Relative Risk of Pediatric Comorbidities on Mortality Associated with
COVID 19 Infection
Nineteen of the 42 articles included in this meta analysis
reported children who died while being infected with SARS CoV 2
(Fig. 4). Across the 19 articles, of the 274,647 pediatric patients
with COVID 19 infection without comorbidities, only 77 (0.03%)
died across 8 studies (Bixler et al., 2020; Cai et al., 2020; Du et al.,
2020; Götzinger et al., 2020; Leeb, 2020; Oualha et al., 2020;
Riollano Cruz et al., 2020; Yayla, 2020). In contrast, 134 (1.5%) of
the 8960 children with pre existing conditions died during the
course of their SARS CoV 2 infection across 15 studies (Bellino
et al., 2020; Bixler et al., 2020; Blum field and Levin, 2020; Chao
et al., 2020; Derespina et al., 2020; Diorio et al., 2020; Eghbali et al.,
2020; de Farias et al., 2020; Götzinger et al., 2020; Kainth et al.,
2020; Leeb, 2020; Moraleda et al., 2020; Otto et al., 2020; Oualha
et al., 2020; Swann et al., 2020) (Table 1). The random effects
model used to determine the risk of mortality among children with
comorbidities and COVID 19 relative to pediatric patients without
comorbidities revealed a total risk ratio of 2.81 (95% CI 1.31 6.02;
x2= 97.85 (P < 0.001); I2= 82%) (Fig. 4). In only five of the studies
(Cai et al., 2020; Du et al., 2020; Oualha et al., 2020; Riollano Cruz
et al., 2020; Yayla, 2020) did children with comorbidities have a
lower risk of mortality during the course of COVID 19 (Fig. 4).
Notably, subsequent sensitivity analysis confirmed that no one
article significantly affected the relative risk ratio of mortality
among children with pre existing conditions (Fig. 5).
Relative Risks of Various Pediatric Comorbidities on Severe COVID 19
Manifestations
Our previously presented analyses hinted at a higher risk of
severe COVID 19 infection and associated mortality among pediatric
patients with underlying comorbidities (Figs. 2 and 4). We next
sought to examine the potential impact of speci fic comorbidities on
Fig. 3. Sensitivity analysis of the influence of each included study on the overall relative risk of severe COVID-19 among children with comorbidities.B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
251
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071463
the risks of severe SARS CoV 2 manifestations. For details on the
underlying conditions represented among all 9,353 children with
comorbiditiesregardlessof COVID 19 severity, seeSupplement S3. In
the 42 studies included in this meta analysis, we found that among
children with severe COVID 19, 64 children were obese (Abdel
Mannan et al., 2020; Chao et al., 2020; DeBiasi et al., 2020; Derespina
et al., 2020; de Farias et al., 2020; Giacomet et al., 2020; González
Dambrauskas et al., 2020; Kaushik et al., 2020; Lovinsky Desir et al.,
2020; Shekerdemian et al., 2020; Swann et al., 2020; Waltuch et al.,
2020; Zachariah et al., 2020), 58 had chronic respiratory disease
(Belhadjer et al., 2020; Chao et al., 2020; DeBiasi et al., 2020; Diorio
et al., 2020; González Dambrauskas et al., 2020; Götzinger et al.,
2020; Kaushik et al., 2020; Lovinsky Desir et al., 2020; Mannheim
et al., 2020; Riollano Cruz et al., 2020; Shekerdemian et al., 2020;Swann et al., 2020; Waltuch et al., 2020; Yayla, 2020; Zachariah et al.,
2020), 45 had cardiovascular disease (Chao et al., 2020; DeBiasi et al.,
2020; Derespina et al., 2020; Diorio et al., 2020; Eghbali et al., 2020;
Garazzino etal., 2020; Giacometetal., 2020; González Dambrauskas
et al., 2020; Götzinger et al., 2020; Kainth et al., 2020; Kaushik et al.,
2020; Mannheim et al., 2020; Schwartz et al., 2020; Shekerdemian
et al., 2020; Swann et al., 2020; Zachariah et al., 2020; Zheng et al.,
2020), 33 had neurologic disorders (Cai et al., 2020; Chao et al., 2020;
DeBiasi et al., 2020; Diorio et al., 2020; Giacomet et al., 2020;
González Dambrauskas et al., 2020; Götzinger et al., 2020; Kainth
et al., 2020; Oualha et al., 2020; Shekerdemian et al., 2020; Zachariah
et al., 2020), 26 had immune disorders (Belhadjer et al., 2020; Chao
etal., 2020; Kainthetal.,2020; Mannheim etal., 2020; Shekerdemian
et al., 2020; Swann et al., 2020; Zachariah et al., 2020), and 19 had
Fig. 4. Pooled estimate of the relative risk of COVID-19-associated mortality among pediatric patients with comorbidities.
Fig. 5. Sensitivity analysis of the relative contributions of each study toward the relative risk of mortality during COVID-19 infection in pediatric patients with comorbidities.B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
252
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071464
metabolic disease (DeBiasi et al., 2020; Derespina et al., 2020;
Riollano Cruz et al., 2020; Shekerdemian et al., 2020; Waltuch et al.,
2020; Zachariah et al., 2020; Zheng et al., 2020). Additionally,12 had
hematologic disorders (Eghbali et al., 2020; García Salido et al.,
2020; Kaushik et al., 2020; Oualha et al., 2020; Shekerdemian et al.,
2020; Yayla, 2020; Zachariah et al., 2020), and 11 had cancer (Chao
et al., 2020; Diorio et al., 2020; Du et al., 2020; González
Dambrauskas et al., 2020; Götzinger et al., 2020; Kainth et al.,
2020; Sun et al., 2020). Five children had renal disease (Cai et al.,
2020; Götzinger et al., 2020; Oualha et al., 2020), and 2 had GI
comorbidities (Giacomet et al., 2020) respectively. Seventy one
children had other conditions (Diorio et al., 2020; Garazzino et al.,
2020; González Dambrauskas et al., 2020; Götzinger et al., 2020;
Kainth et al., 2020; Kaushik et al., 2020; Mannheim et al., 2020;
Schwartz et al., 2020; Shekerdemian et al., 2020; Swann et al., 2020;
Zachariah et al., 2020) including prematurity, trisomy 21, or other
genetic abnormalities. Finally, only 1 child presented with allergies
(Du et al.,2020) and hepatobiliarydisease(Riollano Cruz et al., 2020)
respectively.
We next analyzed the relative contribution of childhood obesity
to pediatric COVID 19 severity. We chose to focus primarily on
obesity as it has an easily definable metric (i.e. BMI) that can be
compared across multiple studies. Although 64 pediatric patients
with underlying obesity presented with severe COVID 19 across 13
studies (Abdel Mannan et al., 2020; Chao et al., 2020; DeBiasi et al.,
2020; Derespina et al., 2020; de Farias et al., 2020; Giacomet et al.,
2020; González Dambrauskas et al., 2020; Kaushik et al., 2020;
Lovinsky Desir et al., 2020; Shekerdemian et al., 2020; Swann et al.,
2020; Waltuch et al., 2020; Zachariah et al., 2020), we chose to
perform a meta analysis only on the studies that included case
control participants (Abdel Mannan et al., 2020; Chao et al., 2020;
Giacomet et al., 2020; Moreno Galarraga et al., 2020; Swann et al.,
2020; Zachariah et al., 2020). Examining the risk of obesity on
COVID 19 severity in relation to children without comorbidities,
we obtained a relative risk ratio of 2.87 (95% CI 1.16 7.07; x2= 7.81
(P = 0.17); I2= 36%) (Fig. 6). We also examined the relative risk of
childhood cancer on severe COVID 19 (Supplement S4), from
which we were not able to draw any conclusions due to the
confidence interval of the relative risk ratio spanning a value of 1.0.
Taken together, these results indicate that childhood obesity likely
increases risk of severe COVID 19. However, more case controlled,
well de fined studies are needed to examine the effects that other
childhood comorbidities such as cancer have on risk of severe
manifestations of SARS CoV 2.
Discussion
Current meta analyses of publications involving children with
COVID 19 infection primarily examine the overall characteristics,
symptoms, and outcomes of SARS CoV 2 infection regardless of
comorbidity status (Ding et al., 2020; Hoang et al., 2020;
Ludvigsson, 2020). Studies suggest that children typically have a
milder infection course than adults, with an overall good
prognosis. However, the effects of comorbidities on COVID 19severity in children remain unclear. Although a previous corre
spondence suggested a worse SARS CoV 2 infection course in
children with comorbidities (Harman et al., 2020), the small
sample size precludes definitive conclusions. In this systematic
review and meta analysis of 42 articles, we report that children
with comorbidities are at higher risk for severe manifestations of
COVID 19 and associated mortality relative to previously healthy
children. Furthermore, we also note that childhood obesity
probably leads to a worse COVID 19 prognosis. To our knowledge,
we are the first to report these findings.
Early analyses in adults with COVID 19 indicated that older age
(Zhou et al., 2020) and comorbidities such as diabetes, hyperten
sion, malignancies, chronic respiratory disease and obesity are
significant risk factors for severe infection (Caussy et al., 2020;
Guan et al., 2020; Yang et al., 2020). As such, the early lockdown
measures implemented across the world in the spring of 2020
were aimed at protecting vulnerable populations (i.e., the elderly,
and people with comorbid conditions) from COVID 19 infection, as
well as preventing the overburdening of hospitals. In contrast,
early epidemiological studies of pediatric populations (Dong et al.,
2020) cited high rates of mild and asymptomatic COVID 19
infection, with certain publications advocating for their return to
school (Munro and Faust, 2020; van Bruwaene et al., 2020). The
results from our study suggest that children with speci fic
comorbidities are a vulnerable population at risk for potentially
life threatening consequences of COVID 19 infection.
We report that childhood obesity is likely associated with a
worsened prognosis of COVID 19 infection. This is in keeping with
several adult studies noting that patients who had a BMI greater
than or equal to 35 kg/m2required invasive mechanical ventilation
due to SARS CoV 2 infection more frequently than their leaner
counterparts (Caussy et al., 2020; Simonnet et al., 2020). The
effects of childhood obesity in potentiating severe COVID 19 are
unsurprising. The high visceral adiposity present in obese
individuals is known to induce higher levels of local and systemic
inflammatory cytokines such as Interleukin 6 (IL 6), and C reactive
protein (CRP) (Fontana et al., 2007). The increased baseline of these
cytokines in obesity are also likely the result of increased pro
inflammatory macrophage populations that have been observed in
this population (Russo and Lumeng, 2018). These cytokines have
been positively correlated with COVID 19 severity (Zeng et al.,
2020) and their higher levels in obese individuals may contribute
to their increased susceptibility to severe infection. However,
childhood obesity likely contributes to severe COVID 19 infection
in additional ways.
Unfortunately, we were unable to determine whether other
comorbidities increase risk of severe COVID 19. This is in part due
to the paucity of case controlled literature examining the out
comes of children with COVID 19 who have well de fined comorbid
conditions. Towards this aim, various international Surveillance
Epidemiology of Coronavirus (COVID 19) Under Research Exclu
sion (SECURE) databases and registries are set up to prospectively
collect data, and will be particularly helpful in defining risk of
COVID 19 infection and severity in patients with comorbidities.
However, to date the available data remain quite limited. Apart
from a recent article (Brenner et al., 2020a ) and the SECURE IBD
database (Brenner et al., 2020b), a multi national database
examining the outcomes of patients with IBD and COVID 19,
limited literature examining the effects of GI diseases on COVID 19
outcomes in children has been published. Furthermore, although
recent approaches have begun examining the effects of COVID 19
infection on diseases such as sickle cell disease (SSD) (McCloskey
et al., 2020; Hussain et al., 2020), limited data exist for other
systemic diseases. For example, for rheumatic diseases, apart from
a retrospective report (Zhong et al., 2020), only a speculative
review on the topic has been published (Licciardi et al., 2020). With
Fig. 6. Relative risk of childhood obesity on severe manifestations of COVID-19B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
253
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071465
reports of MIS C occurring in cohorts of children with COVID 19
infection (Riphagen et al., 2020; Verdoni et al., 2020) the dynamics
and underlying characteristics of severe infection in the context of
autoin flammatory comorbidities in children require further study.
Study Strengths
Our study has several important strengths. To our knowledge,
this is the first systematic review and meta analysis that examines
the relative risk of severe COVID 19 and associated mortality
among children with comorbidities. Furthermore, our study is the
first to show that childhood obesity likely increases the risk of
severe COVID 19 infection course. Lastly, our study has a relatively
large sample size of 9,353 children with comorbidities among 42
articles. This relatively large sample size and study number allows
for high statistical power, enabling accurate conclusions to be
drawn from the study results.
Study Limitations
Our systematic review and meta analysis have several potential
limitations. Most importantly, there likely exists variations in PICU
admission criteria across the studies, particularly regarding
children with comorbidities and COVID 19 infection. We cannot
ascertain whether admission to the PICU was primarily due to
problems with underlying comorbidities in some children, with
COVID 19 infection being subsequently discovered. Therefore, the
increased risk of severe COVID 19 infection among children with
comorbidities addressed in this meta analysis could be the result
of a selection bias of PICU admission in favor of children with
underlying conditions. Furthermore, our study is subject to a high
degree of study heterogeneity due to the small sample size in some
of the included studies. In addition, based on the large body of
rapidly published literature surrounding COVID 19 infection,
some studies may have used similar participants. Therefore, we
cannot be certain that patients were not duplicated in our study.
Our meta analysis was also not able to capture the relative risk that
comorbidities other than obesity contribute to severe SARS CoV 2
viral infection. This is due to the sub population heterogeneity of
comorbidities that limits the ability to draw accurate comparisons
between studies. Lastly, our meta analysis ampli fies the ascer
tainment bias of the primary literature. Asymptomatic COVID 19
infections among children with comorbidities do occur (Poli et al.,
2020), however in most jurisdictions at this time, testing of
asymptomatic or pauci symptomatic children is very limited
outside of outbreak settings. Consequently, such mild cases among
children with comorbidities are likely less represented in the
primary literature and therefore in our analysis. We therefore call
for further availability of data on pediatric patients with
comorbidities and COVID 19 outcomes, regardless of illness
severity. Such broader representation within the literature would
increase the accuracy of relative risk computation within this
population by future meta analyses.
Conclusions
To our knowledge, this is the first systematic review and meta
analysis examining the severity of COVID 19 infection among
pediatric patients with comorbidities. We report that children with
pre existing conditions are at a greater risk of severe COVID 19 and
associated mortality. In particular, childhood obesity is likely
positively correlated with COVID 19 severity. However, further
cross sectional, case controlled studies examining the effects of
speci fic well de fined comorbidities are required to examine the
effects that pediatric underlying conditions play in COVID 19
severity.Author Contributions
BKT: study concept and design; literature review, acquisition of
data; literature grading; analysis and interpretation of data;
statistical analysis; drafting of the manuscript; approval of final
manuscript.
JMA: study concept and design; critical revision of the
manuscript for important intellectual content; approval of final
manuscript.
MAI: statistical analysis, analysis and interpretation of data;
critical revision of the manuscript for important intellectual
content; approval of final manuscript.
AAL: literature review; critical revision of the manuscript for
important intellectual content; approval of final manuscript.
LJS: critical revision of the manuscript for important intellectual
content; approval of final manuscript.
BAV: study concept and design; critical revision of the
manuscript for important intellectual content; approval of final
manuscript.
KJ: study concept and design; literature grading; review and
interpretation of data; drafting of the manuscript, critical revision
of the manuscript for important intellectual content; approval of
final manuscript.
Ethics Approval
No ethics approval was required for this publication.
Potential competing interest
None declared.
Financial Support
KJ has received research support from Janssen, AbbVie and
adMare Bioinnovations (formerly the Center for Drug Research and
development CDRD). KJ has served on the advisory boards of
Janssen, AbbVie, and Merck and participates in the speaker ’s
bureau for AbbVie and Janssen.
The remaining authors disclose no conflicts of interest.
Acknowledgements
K.J. is a Senior Clinician Scientist supported by the Children with
Intestinal and Liver Disorders (CHILD) Foundation and the BC
Children ’s Hospital Research Institute Clinician Scientists Award
Program, University of British Columbia. B.A.V. holds the CHILD
Foundation Chair in Pediatric Gastroenterology. B.K.T. was
supported by a Natural Sciences and Engineering Research Council
of Canada Undergraduate Student Research Award (NSERC USRA).
J.A. is supported by a Canadian Institute for Health Research
(CIHR)/Canadian Association of Gastroenterology and Michael
Smith Foundation for Health Research (MSFHR) research fellow
ships.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in
the online version, at doi:https://doi.org/10.1016/j.ijid.2020.11.163.
References
Abdel-Mannan O, Eyre M, Löbel U, Bamford A, Eltze C, Hameed B, et al. Neurologic
and Radiographic Findings Associated With COVID-19 Infection in Children.
JAMA Neurol 2020;, doi:http://dx.doi.org/10.1001/jamaneurol.2020.2687.
Anand P, Yadav A, Debata P, Bachani S, Gupta N, Gera R. Clinical profile, viral load,
management and outcome of neonates born to COVID 19 positive mothers: aB.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
254
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071466
tertiary care centre experience from India. Eur J Pediatr 2020;1 –13, doi:http://
dx.doi.org/10.1007/s00431-020-03800-7.
Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a
practical tutorial. Evidence-Based Mental Health 2019;22:153 –60, doi:http://
dx.doi.org/10.1136/ebmental-2019-300117.
Belhadjer Zahra, Mathilde Méot, Fanny Bajolle, Diala Khraiche, Antoine Legendre,
Samya Abakka, et al. Acute Heart Failure in Multisystem Inflammatory
Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic.
Circulation 2020;142:429 –36, doi:http://dx.doi.org/10.1161/CIRCULATIO-
NAHA.120.048360.
Bellino S, Punzo O, Rota MC, Del Manso M, Urdiales AM, Andrianou X, et al. COVID-
19 Disease Severity Risk Factors for Pediatric Patients in Italy. Pediatrics
2020;146:, doi:http://dx.doi.org/10.1542/peds.2020-009399 e2020009399.
Bhumbra S, Malin S, Kirkpatrick L, Khaitan A, John CC, Rowan CM, et al. Clinical
Features of Critical Coronavirus Disease 2019 in Children. Pediatric Critical Care
Medicine. , doi:http://dx.doi.org/10.1097/PCC.000 0000000002511 Publish
Ahead of Print.
Biko DM, Ramirez-Suarez KI, Barrera CA, Banerjee A, Matsubara D, Kaplan SL, et al.
Imaging of children with COVID-19: experience from a tertiary children ’s
hospital in the United States. Pediatr Radiol 2020;, doi:http://dx.doi.org/
10.1007/s00247-020-04830-x.
Bixler D, Miller AD, Mattison CP, Taylor B, Komatsu K, Peterson Pompa X, et al. SARS-
CoV-2-Associated Deaths Among Persons Aged <21 Years - United States,
February 12-July 31, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1324 –9, doi:
http://dx.doi.org/10.15585/mmwr.mm6937e4.
Blum field E, Levin TL. COVID-19 in pediatric patients: a case series from the Bronx.
NY. Pediatr Radiol 2020;50:1369 –74, doi:http://dx.doi.org/10.1007/s00247-
020-04782-2.
Brenner EJ, Ungaro RC, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, et al.
Corticosteroids, But Not TNF Antagonists, Are Associated With Adverse COVID-
19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an
International Registry. Gastroenterology 2020[163 TD$DIFF]a;
S0016508520306557, doi:http://dx.doi.org/10.1053/j.gastro.2020.05.032.
Brenner EJ, Ungaro RC, Colombel JF, Kappelman MD. SECURE-IBD Database Public
Data Update. 2020 covidibd.org. Accessed on November 9, 2020.
Cai X, Ma Y, Li S, Chen Y, Rong Z, Li W. Clinical Characteristics of 5 COVID-19 Cases
With Non-respiratory Symptoms as the First Manifestation in Children. Front
Pediatr 2020;8:258, doi:http://dx.doi.org/10.3389/fped.2020.00258.
Caussy C, Wallet F, Laville M, Disse E. Obesity is Associated with Severe Forms of
COVID-19. Obesity 2020;28:1175, doi:http://dx.doi.org/10.1002/oby.22842.
Chao JY, Derespina KR, Herold BC, Goldman DL, Aldrich M, Weingarten J, et al.
Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children
and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical
Center in New York City. The Journal of Pediatrics 2020;223:, doi:http://dx.doi.
org/10.1016/j.jpeds.2020.05.006 14-19.e2.
COVID-19 Map. Johns Hopkins Coronavirus Resource Center n.d. https://coronavi-
rus.jhu.edu/map.html (accessed August 17, 2020). 2020.
Cucinotta D, Vanelli M. WHO Declares COVID-19 a Pandemic. Acta Bio Medica
Atenei Parmensis 2020;91:157 –60, doi:http://dx.doi.org/10.23750/abm.
v91i1.9397.
de Farias ECF, Pedro Piva J, de Mello MLFMF, do Nascimento LMPP, Costa CC,
Machado MMM, et al. Multisystem Inflammatory Syndrome Associated With
Coronavirus Disease in Children: A Multi-centered Study in Belém, Pará, Brazil.
Pediatr Infect Dis J 2020;39:e374 –86, doi:http://dx.doi.org/10.1097/
INF.0000000000002865.
DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, et al. Severe Coronavirus
Disease-2019 in Children and Young Adults in the Washington, DC, Metropoli-
tan Region. The Journal of Pediatrics 2020;223:, doi:http://dx.doi.org/10.1016/j.
jpeds.2020.05.007 199-203.e1.
Defining Childhood Obesity. Overweight & Obesity | CDC. 2019. . (accessed August
19, 2020) https://www.cdc.gov/obesity/childhood/de fining.html.
Derespina KR, Kaushik S, Plichta A, Conway EE, Bercow A, Choi J, et al. Clinical
Manifestations and Outcomes of Critically Ill Children and Adolescents with
Coronavirus Disease 2019 in New York City. The Journal of Pediatrics 2020;226:,
doi:http://dx.doi.org/10.1016/j.jpeds.2020.07.039 55-63.e2.
Ding Y, Yan H, Guo W. Clinical Characteristics of Children With COVID-19: A Meta-
Analysis. Front Pediatr 2020;8, doi:http://dx.doi.org/10.3389/fped.2020.00431.
Diorio C, Henrickson SE, Vella LA, McNerney KO, Chase J, Burudpakdee C, et al.
Multisystem inflammatory syndrome in children and COVID-19 are distinct
presentations of SARS –CoV-2. J Clin Invest 2020;130, doi:http://dx.doi.org/
10.1172/JCI140970.
Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of COVID-19 Among
Children in China. Pediatrics 2020;145, doi:http://dx.doi.org/10.1542/
peds.2020-0702.
Du H, Dong X, Zhang J, Cao Y, Akdis M, Huang P, et al. Clinical characteristics of 182
pediatric COVID-19 patients with different severities and allergic status. Allergy
2020; all.14452. https://doi.org/10.1111/all.14452.
Eghbali A, Shokrollahi S, Mahdavi NS, Mahdavi NSA, Dabbagh A. COVID-19 in
pediatric patients: A case series. 1 2020;5:3 –5, doi:http://dx.doi.org/10.22037/
jcma.v5i1.29690.
Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral Fat Adipokine Secretion
Is Associated With Systemic Inflammation in Obese Humans. Diabetes
2007;56:1010 –3. https://doi.org/10.2337/db06-1656.
Garazzino S, Montagnani C, Donà D, Meini A, Felici E, Vergine G, et al. Multicentre
Italian study of SARS-CoV-2 infection in children and adolescents, preliminarydata as at 10 April 2020. Eurosurveillance 2020;25:2000600, doi:http://dx.doi.
org/10.2807/1560-7917.ES.2020.25.18.2000600.
García-Salido A, Leoz-Gordillo I, Martínez de Azagra-Garde A, Nieto-Moro M,
Iglesias-Bouzas MI, García-Teresa MÁ, et al. Children in Critical Care Due to
Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Experience in a
Spanish Hospital. Pediatric Critical Care Medicine 2020;, doi:http://dx.doi.org/
10.1097/PCC.0000000000002475 Publish Ahead of Print.
Giacomet V, Barcellini L, Stracuzzi M, Longoni E, Folgori L, Leone A, et al.
Gastrointestinal Symptoms in Severe COVID-19 Children. The Pediatric
Infectious Disease Journal 2020;39:e317, doi:http://dx.doi.org/10.1097/
INF.0000000000002843.
González-Dambrauskas S, Vásquez-Hoyos P, Camporesi A, Díaz-Rubio F, Piñeres-
Olave BE, Fernández-Sarmiento J, et al. Pediatric Critical Care and COVID-19.
Pediatrics 2020;146, doi:http://dx.doi.org/10.1542/peds.2020-1766.
Götzinger F, Santiago-García B, Noguera-Julián A, Lanaspa M, Lancella L, Calò
Carducci FI, et al. COVID-19 in children and adolescents in Europe: a
multinational, multicentre cohort study. The Lancet Child & Adolescent Health
2020;4:653 –61, doi:http://dx.doi.org/10.1016/S2352-4642(20)30177-2.
Guan W, Liang W, Zhao Y, Liang H, Zi-sheng Chen, Li Y, et al. Comorbidity and its
impact on 1590 patients with COVID-19 in China: a nationwide analysis.
European Respiratory Journal 2020;55:, doi:http://dx.doi.org/10.1183/
13993003.00547-2020.
Harman K, Verma A, Cook J, Radia T, Zuckerman M, Deep A, et al. Ethnicity and
COVID-19 in children with comorbidities. The Lancet Child & Adolescent Health
2020;4:e24 –5, doi:http://dx.doi.org/10.1016/S2352-4642(20)30167-X.
Hoang A, Chorath K, Axel Moreira, Evans M, Burmeister-Morton F, Burmeister F,
et al. COVID-19 in 7780 pediatric patients: A systematic review. EClinicalMe-
dicine 2020;24, doi:http://dx.doi.org/10.1016/j.eclinm.2020.100433.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected
with 2019 novel coronavirus in Wuhan. China. The Lancet 2020;395:497 –506,
doi:http://dx.doi.org/10.1016/S0140-6736(20)30183-5.
Hussain FA, Njoku FU, Saraf SL, Molokie RE, Gordeuk VR, Han J. COVID-19 infection
in patients with sickle cell disease. Br J Haematol 2020;189:851 –2, doi:http://
dx.doi.org/10.1111/bjh.16734.
IntHout J, Ioannidis JP, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for
random effects meta-analysis is straightforward and considerably outperforms
the standard DerSimonian-Laird method. BMC Medical Research Methodology
2014;14:25. https://doi.org/10.1186/1471-2288-14-25.
Kainth MK, Goenka PK, Williamson KA, Fishbein JS, Subramony A, Barone S, et al.
Early Experience of COVID-19 in a US Children ’s Hospital. Pediatrics 2020;146:,
doi:http://dx.doi.org/10.1542/peds.2020-003186 e2020003186.
Kaushik S, Aydin SI, Derespina KR, Bansal PB, Kowalsky S, Trachtman R, et al.
Multisystem Inflammatory Syndrome in Children Associated with Severe Acute
Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional
Study from New York City. The Journal of Pediatrics 2020;224:24 –9, doi:http://
dx.doi.org/10.1016/j.jpeds.2020.06.045.
Leeb RT. COVID-19 Trends Among School-Aged Children — United States, March 1–
September 19, 2020. MMWR Morb Mortal Wkly Rep 2020;69, doi:http://dx.doi.
org/10.15585/mmwr.mm6939e2.
Licciardi F, Giani T, Baldini L, Favalli EG, Caporali R, Cimaz R. COVID-19 and what
pediatric rheumatologists should know: a review from a highly affected
country. Pediatric Rheumatology 2020;18:35, doi:http://dx.doi.org/10.1186/
s12969-020-00422-z.
Lovinsky-Desir S, Deshpande DR, De A, Murray L, Stingone JA, Chan A, et al. Asthma
among hospitalized patients with COVID-19 and related outcomes. Journal of
Allergy and Clinical Immunology 2020;, doi:http://dx.doi.org/10.1016/j.
jaci.2020.07.026 S0091674920311003.
Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a
better prognosis than adults. Acta Paediatr 2020;, doi:http://dx.doi.org/10.1111/
apa.15270.
Mannheim J, Gretsch S, Layden JE, Fricchione MJ. Characteristics of Hospitalized
Pediatric Coronavirus Disease 2019 Cases in Chicago, Illinois, March –April 2020.
Journal of the Pediatric Infectious Diseases Society 2020;, doi:http://dx.doi.org/
10.1093/jpids/piaa070 piaa070.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective
studies of disease. J Natl Cancer Inst 1959;22:719 –48.
McCloskey KA, Meenan J, Hall R, Tsitsikas DA. COVID-19 infection and sickle cell
disease: a UK centre experience. Br J Haematol 2020;190:e57 –8, doi:http://dx.
doi.org/10.1111/bjh.16779.
Meslin P, Guiomard C, Chouakria M, Porcher J, Duquesne F, Tiprez C, et al.
Coronavirus Disease 2019 in Newborns and Very Young Infants: a Series of Six
Patients in France. The Pediatric Infectious Disease Journal 2020;39:e145, doi:
http://dx.doi.org/10.1097/INF.00 00000000002743 .
Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP. Preferred Reporting Items for
Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLOS
Medicine 2009;6:e1000097, doi:http://dx.doi.org/10.1371/journal.pmed.
1000097 .
Moraleda C, Serna-Pascual M, Soriano-Arandes A, Simó S, Epalza C, Santos M, et al.
Multi-in flammatory Syndrome in Children Related to Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) in Spain. Clinical Infectious Diseases
2020;, doi:http://dx.doi.org/10.1093/cid/ciaa1042 ciaa1042.
Moreno-Galarraga L, Urretavizcaya-Martínez M, Alegría Echauri J, García Howard M,
Ruperez García E, Aguilera-Albesa S, et al. SARS-CoV-2 infection in children
requiring hospitalization: the experience of Navarra, Spain. World J Pediatr
2020;16:614 –22, doi:http://dx.doi.org/10.1007/s12519-020-00393-x.B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
255
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071467
Munro APS, Faust SN. Children are not COVID-19 super spreaders: time to go back to
school. Archives of Disease in Childhood 2020;105:618 –9, doi:http://dx.doi.org/
10.1136/archdischild-2020-319474.
Otto WR, Geoghegan S, Posch LC, Bell LM, Coffin SE, Sammons JS, et al. The
Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in a
Pediatric Healthcare Network in the United States. Journal of the Pediatric
Infectious Diseases Society 2020;, doi:http://dx.doi.org/10.1093/jpids/piaa074
piaa074.
Oualha M, Bendavid M, Berteloot L, Corsia A, Lesage F, Vedrenne M, et al. Severe and
fatal forms of COVID-19 in children. Archives de Pédiatrie 2020;27:235 –8, doi:
http://dx.doi.org/10.1016/j.arcped.2020.05.010.
Parri N, Lenge M, Cantoni B, Arrighini A, Romanengo M, Urbino A, et al. COVID-19 in
17 Italian Pediatric Emergency Departments. Pediatrics 2020;e20201235, doi:
http://dx.doi.org/10.1542/peds.2020-1235.
Poli P, Timpano S, Goffredo M, Padoan R, Badolato R. Asymptomatic case of Covid-19
in an infant with cystic fibrosis. Journal of Cystic Fibrosis 2020;19:e18, doi:
http://dx.doi.org/10.1016/j.jcf.2020.03.017.
Riollano-Cruz M, Akkoyun E, Briceno-Brito E, Kowalsky S, Reed J, Posada R, et al.
Multisystem inflammatory syndrome in children related to COVID-19: A New
York City experience. J Med Virol 2020;26224, doi:http://dx.doi.org/10.1002/
jmv.26224.
Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyper-
inflammatory shock in children during COVID-19 pandemic. The Lancet
2020;395:1607 –8, doi:http://dx.doi.org/10.1016/S0140-6736(20)31094-1.
Robins J, Breslow N, Greenland S. Estimators of the Mantel-Haenszel Variance
Consistent in Both Sparse Data and Large-Strata Limiting Models. Biometrics
1986;42:311, doi:http://dx.doi.org/10.2307/2531052.
Russo L, Lumeng CN. Properties and functions of adipose tissue macrophages in
obesity.Immunology2018;155:407 –17, doi:http://dx.doi.org/10.1111/imm.13002.
Sankar J, Dhochak N, Kabra SK, Lodha R. COVID-19 in Children: Clinical Approach
and Management. Indian J Pediatr 2020;87:433 –42, doi:http://dx.doi.org/
10.1007/s12098-020-03292-1.
Schwartz DA, Mohagheghi P, Beigi B, Zafaranloo N, Moshfegh F, Yazdani A. Spectrum
of neonatal COVID-19 in Iran: 19 infants with SARS-CoV-2 perinatal infections
with varying test results, clinical findings and outcomes. The Journal of
Maternal-Fetal & Neonatal Medicine 2020;1 –10, doi:http://dx.doi.org/10.1080/
14767058.2020.1797672.
Schwarzer G, Carpenter JR, Rücker G. Meta-Analysis with R. Springer International
Publishing; 2015, doi:http://dx.doi.org/10.1007/978-3-319-21416-0.
Shekerdemian LS, Mahmood NR, Wolfe KK, Riggs BJ, Ross CE, McKiernan CA, et al.
Characteristics and Outcomes of Children With Coronavirus Disease 2019
(COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care
Units. JAMA Pediatr 2020;174:868 –73, doi:http://dx.doi.org/10.1001/jamapedi-
atrics.2020.1948.
Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81
patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. The
Lancet Infectious Diseases 2020;20:425 –34, doi:http://dx.doi.org/10.1016/
S1473-3099(20)30086-4.
Simonnet A, Chetboun M, Poissy J, Raverdy V, Noulette J, Duhamel A, et al. High
Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus-2
(SARS-CoV-2) Requiring Invasive Mechanical Ventilation. Obesity
2020;28:1195 –9, doi:http://dx.doi.org/10.1002/oby.22831.
Study Quality Assessment Tools. NHLBI, NIH. n.d. 2020. . (accessed July 26, 2020)
https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools.
Sun D, Li H, Lu X-X, Xiao H, Ren J, Zhang F-R, et al. Clinical features of severe pediatric
patients with coronavirus disease 2019 in Wuhan: a single center ’s
observational study. World J Pediatr 2020;16:251 –9, doi:http://dx.doi.org/
10.1007/s12519-020-00354-4.
Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM, et al. Clinical
characteristics of children and young people admitted to hospital with covid-19
in United Kingdom: prospective multicentre observational cohort study. BMJ
2020;m3249, doi:http://dx.doi.org/10.1136/bmj.m3249.Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of
continuity corrections in meta-analysis of sparse data. Stat Med 2004;23:1351 –
75, doi:http://dx.doi.org/10.1002/sim.1761.
Szablewski CM. SARS-CoV-2 Transmission and Infection Among Attendees of an
Overnight Camp — Georgia, June 2020. MMWR Morb Mortal Wkly Rep 2020;69,
doi:http://dx.doi.org/10.15585/mmwr.mm6931e1.
Tagarro A, Epalza C, Santos M, Sanz-Santaeufemia FJ, Otheo E, Moraleda C, et al.
Screening and Severity of Coronavirus Disease 2019 (COVID-19) in Children in
Madrid, Spain. JAMA Pediatr 2020;, doi:http://dx.doi.org/10.1001/jamapedi-
atrics.2020.1346.
Team, R Core, and others. “R: A Language and Environment for Statistical
Computing. ” Vienna, Austria. 2020.
van Bruwaene L, Mustafa F, Cloete J, Goga A, Green RJ. What are we doing to the
children of South Africa under the guise of COVID-19 lockdown?. SAMJ: South
African Medical Journal 2020;110:1 –2, doi:http://dx.doi.org/10.7196/
SAMJ.2020.v110i7.14932.
Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An
outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-
CoV-2 epidemic: an observational cohort study. The Lancet 2020;395:1771 –8,
doi:http://dx.doi.org/10.1016/S0140-6736(20)31103-X.
Waltuch T, Gill P, Zinns LE, Whitney R, Tokarski J, Tsung JW, et al. Features of COVID-
19 post-infectious cytokine release syndrome in children presenting to the
emergency department. The American Journal of Emergency Medicine 2020;,
doi:http://dx.doi.org/10.1016/j.ajem.2020.05.058 S0735675720304034.
Wickham H, Averick M, Bryan J, Chang W, McGowan LD, François R, et al. Welcome
to the Tidyverse. Journal of Open Source Software 2019;4:1686, doi:http://dx.
doi.org/10.21105/joss.01686.
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus
Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314
Cases From the Chinese. 2020.
Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its
effects in patients infected with SARS-CoV-2: a systematic review and meta-
analysis. International Journal of Infectious Diseases 2020;94:91 –5, doi:http://
dx.doi.org/10.1016/j.ijid.2020.03.017.
Yayla BCC. Characteristics and Management of Children with COVID-19 in Turkey.
Balkan Med J n.d.;37. , doi:http://dx.doi.org/10.4274/balkanmedj.galenos.2020.
2020.7.52.
Zachariah P, Johnson CL, Halabi KC, Ahn D, Sen AI, Fischer A, et al. Epidemiology,
Clinical Features, and Disease Severity in Patients With Coronavirus Disease
2019 (COVID-19) in a Children ’s Hospital in New York City, New York. JAMA
Pediatr 2020;174:e202430, doi:http://dx.doi.org/10.1001/jamapediatrics.
2020.2430.
Zeng F, Huang Y, Guo Y, Yin M, Chen X, Xiao L, et al. Association of inflammatory
markers with the severity of COVID-19: A meta-analysis. International Journal
of Infectious Diseases 2020;96:467 –74, doi:http://dx.doi.org/10.1016/j.
ijid.2020.05.055.
Zheng F, Liao C, Fan Q, Chen H, Zhao X, Xie Z, et al. Clinical Characteristics of Children
with Coronavirus Disease 2019 in Hubei, China. CURR MED SCI 2020;40:275 –80,
doi:http://dx.doi.org/10.1007/s11596-020-2172-6.
Zhong J, Shen G, Yang H, Huang A, Chen X, Li Dong, et al. COVID-19 in patients with
rheumatic disease in Hubei province, China: a multicentre retrospective
observational study. The Lancet Rheumatology 2020;, doi:http://dx.doi.org/
10.1016/S2665-9913(20)30227-7.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective
cohort study. The Lancet 2020;395:1054– 62, doi:http://dx.doi.org/10.1016/
S0140-6736(20)30566-3.
Zimmermann P, Curtis N. Coronavirus Infections in Children Including COVID-
19: An Overview of the Epidemiology, Clinical Features, Diagnosis,
Treatment and Prevention Options in Children. The Pediatric Infectious
Disease Journal 2020;39:355 –68, doi:http://dx.doi.org/10.1097/INF. 000000
000000 2660 .B.K. Tsankov, J.M. Allaire, M.A. Irvine et al. / International Journal of Infectious Diseases 103 (2021) 246 –256
256
090177e1981d83c6\Final\Final On: 20-Sep-2021 20:00 (GMT)
FDA-CBER-2022-5812-0071468