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Severe COVID-19 Infection and Pediatric Comorbidities: A Systematic
Review and Meta-Analysis
Boyan K. Tsankov, Joannie M. Allaire, Michael A. Irvine, Alison A.
Lopez, Laura J. Sauv´
e, Bruce A. Vallance, Kevan Jacobson
PII: S1201-9712(20)32475-9
DOI: https://doi.org/10.1016/j.ijid.2020.11.163
Reference: IJID 4873
To appear in: International Journal of Infectious Diseases
Received Date: 20 August 2020
Revised Date: 9 November 2020
Accepted Date: 14 November 2020
Please cite this article as: {doi: https://doi.org/
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the addition of a cover page and metadata, and formatting for readability, but it is not yet the
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© 2020 Published by Elsevier.
1
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
Running title: COVID-19 and Children with Comorbidities
Affiliations : aDepartment of Pediatrics, BC, Children’s Hospital, Vancouver, BC; bDivision of
Gastroenterology, Hepatology and Nutrition, BC Children’s Hospital, Vancouver, BC; cDivision
of Infectious Diseases, BC Children’s Hospital, Vancouver, BC; dBC Children’s Hospital Research
Institute, University of British Columbia, Vancouver, BC; eDepartment of Immunology,
University of Toronto, Toronto, ON; fDepartment of Cellular and Physiological Sciences,
University of British Columbia, Vancouver, BC, Canada
Address correspondence to: Kevan Jacobson, Department of Pediatrics, Division of
Gastroenterology, Hepatology and Nutrition, BC Children’s Hospital,
4480 Oak Street, Vancouver, BC, Canada, V6H 3V4, [kjacobson@cw.bc.ca], (+1)-(604)-875-
2332 Ext 1
E-mail addresses: boyan.tsankov@mail.utoronto.ca (Tsankov, BK); jallaire@bcchr.ca (Allaire,
JA); Mike.Irvine@bcchr.ca (Irvine, MA); alison.lopez@cw.bc.ca (Lopez, AA);
bvallance@cw.bc.ca (Vallance, BA); kjacobson@cw.bc.ca (Jacobson, K)
Guarantor of the article: Kevan Jacobson
Financial Support: KJ has received research support from Janssen, AbbVie and 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.
Potential competing interest: none declared
Word Count: 3304
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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.
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ABSTRACT
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 1.27 – 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.
Keywords: Coronavirus, COVID-19, Pediatrics, Comorbidity, Meta-Analysis
Study Highlights:
What is known:
Adults with comorbidities are more likely to suffer from severe manifestations of COVID-
19
Children with COVID-19 have less severe disease manifestations than adults
Children may experience multisystem inflammatory syndrome due to COVID-19
What is new:
Children with comorbidities may be at an increased risk for PICU admission and/or severe
COVID-19
Children with comorbidities may be at an increased risk of mortality during COVID-19
infection
Childhood obesity likely contributes to more serious manifestations of COVID-19
INTRODUCTION
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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
from COVID-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 greater than 65 years (Wu et al., 2020;
Du et al., 2020), and underlying comorbidities such as diabetes, hypertension, and obesity (Caussy
et 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 et al., 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
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children (Szablewski, 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 specific oxygen concentrations less than 92%,
autoinflammatory 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 (Dufort et al. 2020; Riollano-Cruz et al. 2020;
Verdoni et al., 2020). Such reports indicate the potential (albeit uncommon) 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, Yan, and Guo, 2020; Hoang et al. 2020), these
reports did not evaluate the risk of severe SARS-CoV-2 infection specifically in children with pre-
existing conditions. Consequently, the objective 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
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Search Strategy and Selection Criteria
For this systematic review and meta-analysis PubMed, Medline, and Embase databases were
queried for articles published between 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 specifically 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 in accordance 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
comorbidities; adult only studies; articles where the pediatric comorbidity data was
indistinguishable from adult comorbidity data; pre-existing reviews, systematic-reviews, and
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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, NHLBI, NIH). 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; comorbidity 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 classified into representative broader categories
by BKT and KJ. Comorbidities such as trisomy 21, prematurity, and undefined 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 95th percentile
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
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admission 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, Carpenter, and Rücker 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 adjustment (IntHout, Ioannidis, and Borm 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, Breslow, and Greenland 1986). All analyses and data
visualization were conducted in R version 4.0.2 using the meta and tidyverse libraries (Team and
others 2020; Balduzzi, Rücker, and Schwarzer 2019; Wickham et al. 2019).
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
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There were 13310 studies identified from our systematic search across the three databases (Figure
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. 98 articles
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; Blumfield et al., 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 manifestations 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).
Study Patient Characteristics
From the 42 articles, a total of 285,004 pediatric patients with laboratory-confirmed SARS-CoV-
2 infection were identified. 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
to extrapolate age-category data in 362 children. Of these, 138 (38%) were under 1 year of age, 82
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(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; 𝜒2 = 602.31 (P < 0.001); I2 = 94%) (Figure 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; Blumfield et al., 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 (Figure 2). Furthermore, studies such as the
CDC Mortality and Morbidity Weekly Report (Leeb et al., 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 (Figure 3).
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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 (Figure 4). Across the 19 articles, of the 274,647 pediatric patients
without comorbidities and COVID-19 infection, 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 et al., 2020; Oualha et al.,
2020; Riollano-Cruz et al., 2020; Yayla et al., 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; Blumfield and Levin, 2020; Chao et al., 2020, de
Farias et al., 2020; Derespina et al., 2020; Diorio et al., 2020; Eghbali et al., 2020; Götzinger et
al., 2020; Kainth et al., 2020; Leeb et al., 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; 𝜒2 = 97.85 (P < 0.001); I2 =
82%) (Figure 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 et al., 2020) did children with comorbidities have a lower risk
of mortality during the course of COVID-19 (Figure 4). Notably, subsequent sensitivity analysis
confirmed that no one article significantly affected the relative risk ratio of mortality among
children with pre-existing conditions (Figure 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 (Figures 2 and 4). We
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next sought to examine the potential impact of specific comorbidities on the risks of severe SARS-
CoV-2 manifestations. For details on the underlying conditions represented among all 9, 353
children with comorbidities regardless of COVID-19 severity, see Supplement 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; de Farias et al., 2020; DeBiasi et al.,
2020; Derespina et al., 2020; Giacomet et al., 2020; Gonzalez-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; Gonzalez-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 et al., 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 et
al., 2020; Giacomet et al., 2020; Gonzalez-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; Kainth et
al., 2020; Oualha et al., 2020; Giacomet et al., 2020; Gonzalez-Dambrauskas et al., 2020;
Götzinger et al., 2020; Shekerdemian et al., 2020; Zachariah et al., 2020), 26 had immune disorders
(Belhadjer et al., 2020; Chao et al., 2020; Kainth et al., 2020; Mannheim et al., 2020; Shekerdemian
et al., 2020; Swann et al., 2020; Zachariah et al., 2020), 19 had 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
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(Eghbali et al., 2020; Garcia-Salido et al., 2020; Kaushik et al., 2020; Oualha et al., 2020;
Shekerdemian et al., 2020; Yayla et al., 2020; Zachariah et al., 2020), and 11 had cancer (Chao et
al., 2020; Diorio et al., 2020; Kainth et al., 2020; Du et al., 2020; Gonzalez-Dambrauskas et al.,
2020; Götzinger 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; Gonzalez-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 hepatobiliary disease (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;
de Farias et al., 2020; DeBiasi et al., 2020; Derespina et al., 2020; Giacomet et al., 2020; Gonzalez-
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 and SARS-CoV-2 infection, we obtained a relative risk ratio of 2.87 (95%
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CI 1.16 – 7.07; 𝜒2 = 7.81 (P = 0.17); I2 = 36%) (Figure 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-defined 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-19 severity in children remain unclear. Although
a previous correspondence 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, hypertension, malignancies, chronic respiratory disease and
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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 mild
and asymptomatic COVID-19 infection rates, 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 specific comorbidities are a vulnerable population at high 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 that note that patients who had a BMI greater
than or equal to 35kg/m2 required invasive mechanical ventilation due to SARS-CoV-2 infection
more frequently than their leaner counterparts (Caussy et al., 2020; Simmonet 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 baseline increases in 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 baseline 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.
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Unfortunately, we were unable to determine whether other comorbidities such as childhood cancer
increases risk of severe COVID-19. This is in part due to the paucity of case-controlled literature
examining the outcomes of children with COVID-19 who have well-defined comorbid conditions.
Towards this aim, various international Surveillance Epidemiology of Coronavirus (COVID-19)
Under Research Exclusion (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., 2020) and the SECURE-IBD database (SECURE-IBD Database), 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 exists 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 reports of MIS-C occurring in cohorts of children with
COVID-19 infection (Davies and Evans, 2020; Riphagen et al., 2020; Verdoni et al., 2020) the
dynamics and underlying characteristics of severe infection in the context of autoinflammatory
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
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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 which allows for accurate
conclusions to be drawn based on 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 of 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 the studies. Lastly, our
meta-analysis amplifies the ascertainment bias of the primary literature. Asymptomatic COVID-
19 infections among children with comorbidities do occur (Poli et al., 2020), however in most
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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 specific well-defined
comorbidities are required to examine the effects that pediatric underlying conditions play in
COVID-19 severity.
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
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Association of Gastroenterology and Michael Smith Foundation for Health Research (MSFHR)
research fellowships.
Ethics Approval: No ethics approval was required for this publication.
Figure 1. PRISMA flow diagram for the identification of studies pertaining to COVID-19 and
children with comorbidities published between January 1st, 2020 and October 5th, 2020.
Figure 2. Pooled estimate of the relative risk of severe COVID-19 among pediatric patients with
comorbidities.
Figure 3. Sensitivity analysis of the influence of each included study on the overall relative risk
of severe COVID-19 among children with comorbidities.
Figure 4. Pooled estimate of the relative risk of COVID-19-associated mortality among pediatric
patients with comorbidities.
Figure 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.
Figure 6. Relative risk of obesity on severe manifestations of COVID-19 in pediatric patients.
Table 1. Summary and characteristics of the 42 studies included in this systematic review and
meta-analysis.
Supplement S1. Search queries used for the PubMed, Embase (Ovid), and Medline (Ovid),
Supplement S2. Literature grading of 98 studies after full-text review
Supplement S3. Comorbidity characteristics of 9,353 pediatric patients with comorbidities and
COVID-19 infection for whom data is available across the 42 studies.
Supplement S4. Relative risk of cancer on severe manifestations of COVID-19 in pediatric
patients.
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Figure 1. PRISMA flow diagram for the identification of studies pertaining to COVID-19 and
children with comorbidities published between January 1st, 2020 and October 5th, 2020.
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Figure 2. Pooled estimate of the relative risk of severe COVID-19 among pediatric patients with
comorbidities.
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Figure 3. Sensitivity analysis of the influence of each included study on the overall relative risk
of severe COVID-19 among children with comorbidities.
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Figure 4. Pooled estimate of the relative risk of COVID-19-associated mortality among pediatric
patients with comorbidities.
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Figure 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.
Figure 6: Relative risk of childhood obesity on severe manifestations of COVID-19
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STUDY
STUDY TYPE
COUNTRY
STUDY AIM
COVID-19
INFECTION
(N = 285,004)
WITH
COMORBIDITIES
AND COVID-19
(N = 9353)
COMORBIDITIES
AND SEVERE
COVID-19A
(N = 481)
COMORBIDITIES
AND MORTALITY
(N = 135)
Abdel-
Mannan et al.
Retrospective
U.K
Report neurological manifestations of
children with COVID-19
4
1
1
0
Anand et al.
Retrospective
India
Describe the clinical profile of neonates
born to mothers with COVID-19
7
3
0
0
Bellino et al.
Retrospective
Italy
Describe characteristics of COVID-19 in
pediatric patients
3836
206
4
Belhadjer et
al.
Retrospective
France
Report cases of acute heart failure
associated with COVID-19 in children
31
4
4
0
Bhumbra et al.
Retrospective
USA
Describe the infection course of children
hospitalized with COVID-19
24
8
3
Biko et al.
Retrospective
USA
Describe imaging features, comorbidities,
and outcomes of children with COVID-19
313
41
17
0
Bixler et al.
Retrospective
USA
Report the SARS-CoV-2-associated deaths
in children residing in the USA
121
91
91
Blumfield et
al.
Retrospective
USA
Report the outcomes of critically-ill
children with COVID-19
18
12
2
Cai et al.
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
infection
5
3
2
0
Chao et al.
Retrospective
USA
Report the risk factors associated with
severe COVID-19 in pediatric patients
46
31
12
1
De Farias et
al.
Prospective
Brazil
Describe the characteristics of COVID-19-
associated PIMS in 11 children
11
5
5
2
DeBiasi et al.
Retrospective
USA
Examine the epidemiology of pediatric
COVID-19 infection in Washington, DC
165
69
5
0
Derespina et
al.
Retrospective
USA
Describe outcomes of COVID-19 in
children in New York City
70
52
52
2
Diorio et al.
Prospective
USA
Report the hematological differences
between MIS-C and COVID-19 in
children
14
13
9
2
Du et al.
Retrospective
China
Report the outcomes of and laboratory
characteristics of COVID-19 among
182
59
2
0
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hospitalized pediatric patients with a
focus on allergic patients
Eghbali et al.
Case-series
Iran
Describe 4 cases of pediatric COVID-19 in
Iran
4
2
2
1
Garazzino et
al.
Retrospective
Italy
Report outcomes and disease
characteristics of COVID-19 among
multiple pediatric care centres in Italy
168
33
2
0
Garcia-Salido
et al.
Prospective
Spain
Describe series of children admitted to a
Spanish PICU due to COVID-19
7
1
1
0
Giacomet et
al.
Retrospective
Italy
Describe the characteristics of severe vs
non-severe COVID-19 in children
127
20
6
0
Gonzalez-
Dambrauskas
et al.
Retrospective
Uruguay
Examine the characteristics and
outcomes of pediatric patients in PICUs
due to COVID-19 infection
17
12
12
1
Gotzinger et
al.
Cross-sectional
Austria
Examine the characteristics and outcomes
of children with COVID-19 across Europe
582
145
25
2
Kainth et al.
Retrospective
USA
Describe the presentation, course, and
severity of pediatric COVID-19
65
30
10
1
Kaushik et al.
Retrospective
USA
Assess the outcomes of COVID-19-
associated MIS-C
33
16
16
Leeb et al.
Retrospective
USA
Examine the epidemiology of COVID-19
among US children
277,285
7738
109
14
Lovinsky-
Desir et al.
Retrospective
USA
Examine the impact of asthma on COVID-
19 severity
55
24
24
Mannheim et
al.
Case-series
USA
Report the clinical characteristics of
pediatric COVID-19 in Chicago
64
13
4
Meslin et al.
Case-series
France
Present outcomes of 6 children with
COVID-19 in France
6
2
0
0
Moraleda et
al.
Case-series
Spain
Describe clinical features of MIS-C in
Spain
31
10
2
Moreno-
Galarraga et
al.
Retrospective
Spain
Describe the presentations of COVID-19
in Spain
11
4
0
0
Otto et al.
Retrospective
USA
Describe the outcomes and features of
COVID-19 in children
424
242
2
Oualha et al.
Retrospective
France
Describe severe presentations of COVID-
19 in children
27
19
19
2
Parri et al.
Retrospective
Italy
Examine the diagnostic, clinical
presentation, interventions and outcomes
170
38
6
0
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of pediatric patients with confirmed
COVID-19 in Italy.
Riollano-Cruz
et al.
Retrospective
USA
Describe the first COVID-19 MIS-C
associated cases in New York City
15
5
4
0
Schwartz et al.
Case-series
Iran
Describe the characteristics and outcomes
of COVID-19 in neonates in Iran
19
15
10
0
Shekerdemian
et al.
Cross-sectional
USA
Characterize COVID-19 infection in
North American PICUs
48
40
40
Sun et al.
Retrospective
China
Examine the clinical characteristics of
pediatric COVID-19
8
1
1
0
Swann et al.
Prospective
UK
Explore the clinical characteristics of
pediatric COVID-19 and MIS-C in the UK
651
276
63
6
Tagarro et al.
Retrospective
Spain
Describe the epidemiology and treatment
of COVID-19 in Madrid
41
11
1
0
Waltuch et al.
Case series
USA
Describe the characteristics and outcomes
of 4 pediatric cases of COVID-19
4
2
2
0
Yayla et al.
Retrospective
Turkey
Examine characteristics of COVID-19 in
children in Turkey
220
21
2
0
Zachariah et
al.
Retrospective
USA
Compare the features of pediatric COVID-
19 disease between severe and mild
infection
50
33
8
Zheng et al.
Retrospective
China
Describe the clinical characteristics of
pediatric COVID-19
25
2
2
0
Table 1. Summary and characteristics of the 42 studies included in this systematic review and meta-analysis.
Abbreviations: COVID-19, coronavirus disease 2019; PICU, pediatric intensive care unit
A Defined by the studies, or PICU admission, or need for supplemental breathing aid during the course of infection
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