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Severe COVID-19 Infection and Pediatric Comorbidities: A Systematic Review and Meta-Analysis

Authors:
  • BC Children's Hospital Research Institute

Abstract and Figures

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.
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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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© 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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17
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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18
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
Journal Pre-proof
19
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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in Hubei province, China: a multicentre retrospective observational study. The Lancet
Rheumatology 2020;0. https://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;395:105462. https://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;39:355368.
https://doi.org/10.1097/INF.0000000000002660.
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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
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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32
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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33
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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... This anomaly is multifactorial and could be related to less access to high-quality medical care, socioeconomic status, or less testing of children with less severe diseases. In a meta-analysis of children with COVID-19, acute malnutrition, anemia, and obesity were associated with a higher risk of severe disease and mortality [2]. Furthermore, an analysis of global disease burden suggested a link between fatal COVID-19 and populations with a high burden of undernutrition [3]. ...
... In contrast, anemia was not associated with mild and moderate cases of COVID-19 [28,30]. A link between undernutrition and COVID-19 disease severity was identified across income stratification but did not ascertain the degree of malnutrition severity with COVID-19 disease severity [2,3,6]. A higher proportion of severely malnourished children could be linked with the poor outcomes identified in LMIC compared with HIC [3]. ...
Article
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Background: The objectives are to determine the incidence of malnutrition and anemia and evaluate the association between nutritional status and COVID-19-related clinical outcomes in children hospitalized for COVID-19. Methods: This multi-island inpatient survey presents data from nine hospitals in three Caribbean islands on children from birth to 17 years from September 2020 to July 2021. We explore statistical associations with inpatient characteristics and potential differences between malnourished and well-nourished children. Results: Among children hospitalized for COVID-19, 6.8 % were stunted, 6.6% were underweight, 13.6% were overweight/obese, and 30% had anemia. Anemia was associated with multi-system inflammatory syndrome (MIS-C) in children but not with malnutrition. The prevalence of underweight children exceeded the 4.4% prevalence in the general pediatric population in islands, and there was a greater-than-expected prevalence of overweight children hospitalized with COVID-19. Two deaths in children with severe malnutrition, COVID, and septicemia, were identified. Conclusion: Hospitalizations exceeded baseline population rates of under-nutrition and over nutrition. The deaths of two children may be a compound effect on immunity by nutrition severity and COVID-19 disease. Vulnerability to admissions due to the known effects of COVID-19 on nutrition is possible. The severity of malnutrition may determine clinical outcomes in children, and nutrition management should play an integral role in the management of susceptible children.
... Panorama que cambiaba en el 2021, los resultados de los estudios mostraban suficiente evidencia para determinar las diferencias en la respuesta inmunitaria y los factores que influyen en los patrones clínicos, epidemiológicos y fisiopatológicos de la enfermedad (Pousa et al., 2021). En tal sentido, la identificación temprana de la infección por SARS-COV-2 tiene efectos directos sobre el manejo y control de la transmisión de esta enfermedad (Alsohime et al., 2020) más aun, en aquellos que tienen comorbilidades, lo cual los hace propensos a un mal pronóstico (Tsankov et al., 2021). ...
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El Covid-19 es una enfermedad infecciosa que ha causado importantes tasas de morbi-mortalidad en la población mundial, como medidas para contener la infección por SARS-CoV-2, se recomendó el uso de mascarilla, la higienización de las manos, procesos de vacunación, además, los Estados, impusieron la cuarentena obligatoria; medidas que han provocado impactos en la actitud de los individuos para asumir las políticas de salubridad mencionadas. Con el objetivo de evaluar las actitudes hacia el Covid-19, se realizó un estudio observacional de tipo psicométrico con una muestra de 296 personas, se propuso un instrumento de 28 ítems dispuestos en tres dimensiones. Para el proceso de validación se realizó revisión por jueces expertos, evaluaron claridad, suficiencia y pertinencia de cada ítem con respecto a la variable y su dimensión. Luego se efectuó análisis factorial confirmatorio y se estimó la consistencia interna con índice de alpha de Cronbach (α). Como resultado, el instrumento tiene adecuadas propiedades psicométricas para evaluar la actitud hacia el Covid-19 (α=0,880), con tres dimensiones: emotiva-afectiva (α=0,738); cognitiva-creencias (α=0,788) y volitiva-comportamental (α=0,638), esta última se conserva ya que en su conjunto no afecta la confiabilidad general del instrumento. Se concluye que el CAPC-19 es una herramienta válida y confiable para evaluar las actitudes hacia la actual pandemia, el cual puede ser adaptado en diferentes grupos poblacionales y contextos. Se recomienda su uso en estudios de ámbito nacional, para estimar la predisposición de los individuos e identificar vulnerabilidad y, así diseñar estrategias que disminuyan la incertidumbre en beneficio de la salud poblacional.
... Other studies also showed patients with comorbidities were at greater risk of severe disease, which rose further when more than one chronic condition was present. 21,22 During the second period, we also observed lower rates of asymptomatic cases, probably related to changes in testing criteria during pandemia in Argentina. Other factors inherent to the new variants, such as higher transmission and virulence rates, increased reinfection potential, and development of mutations potentially dampening efficacy of natural or vaccine-induced neutralizing antibodies were described around the world. ...
Article
Background: Information on the impact of the different variants in children in Latin America is scarce. The objective of this study was to describe epidemiologic and clinical features of COVID-19 infection in children under 18 years of age in Argentina, comparing the periods before and after the circulation of new variants. Methods: Observational, cross-sectional, multicentric, analytical study. All patients under 18 years of age with confirmed SARS-CoV-2 infection admitted at 22 healthcare centers were included. Two study periods were established: Period 1 (EW10-2020 to EW12-2021) for the Wuhan strain; Period 2 (EW13 to EW35 2021) for Alpha, Gamma, Delta and Lambda variants. Findings: A total of 6330 confirmed cases were included. Period 1: 3575 (56.5%), period 2: 2755 (43.5%). During period 2, a lower number of asymptomatic cases was observed, while general, respiratory and neurologic signs and symptoms increased in all age groups. Oxygen therapy requirement was higher during the first period (36.7% vs 19.1%; P < 0.001). No significant differences were observed in the rates of severe or critical cases (6.3% vs 5,4%; P = 0.102), intensive care admission (2.1% vs 2%; P < 0.656) or case fatality (0.3% vs 0.5 %; P < 0.229). MIS-C cases occurred more frequently during the first period (1.9% vs 1.1%; P = 0.009). Interpretation: The clinical spectrum of COVID-19 in Argentina has evolved. With the emergence of new variants, although the number of asymptomatic cases declined, numbers of severe and critical cases, as well as case fatality rates in children, remained unchanged.
... According to many researchers, coronavirus infection in children is mild, even asymptomatic. However, a severe course of the disease is not excluded [6][7][8]. According to researchers, children are a potential source for the spread of COVID-19 infection, and the fact that the disease is asymptomatic and mild in them leads to the assessment of the epidemiological importance of the child population in the spread of the new coronavirus infection [9,10]. ...
Article
Full-text available
Predicting the Severity of COVID-19 Pneumonia in Children Huseynova I.Y., Hasanov A.Q., Gafarov I.A. Today, the relationship between cytokines in blood serum and the pathogenesis of the disease during COVID-19 in children has not yet been fully clarified. Research shows that the course of the disease in children is more satisfactory than in adults. However, the clinical profiles and pathophysiology of COVID-19 in children remain unclear. The aim of our study was to determine the level of cytokines in children with COVID-19 pneumonia and to study their role in predicting the severity of the disease. For this purpose, 75 children under the age of 18 were included. The patients included in the study were divided into 2 groups according to the degree of severity: 49 (65.3%) moderately severe patients with COVID-19 pneumonia were included in group I, and 26 (34.7%) patients with severe COVID-19 pneumonia were included in group II. Clinical, instrumental and laboratory examinations, determination of cytokines IL-1β, IL-6, IL-18, vitamin D, fibrinogen, ferritin and D-dimer levels were included in the examination methods of patients. Fever (66 cases (88.0%)) and cough (74 cases (98.7%)) were the most frequently reported cases. Laboratory examinations of blood in children with COVID-19 (PCR) showed a tendency to lymphocytosis and thrombocytopenia, an increase in ESR, CRP, ferritin, D-dimer, fibrinogen, and cytokines levels. In comparison between groups, the levels of IL-1β, IL-6, IL-18 increased in group II compared to group I. Determination of pro-inflammatory cytokines IL-1β, IL-6, IL-18 in children with COVID-19 (PCR), depending on the severity of the disease, is appropriate for early diagnosis and prediction of the course of the disease. Keywords: Children, COVID-19, Cytokine Profile, Prognosis
... In this context, the need for an integrated approach to promote physical activity, lifestyle counseling and psychological support seems to be crucial [83][84][85][86]. Moreover, obesity is a risk factor for COVID-19 infection and infected patients with obesity are more likely to experience a severe form of the disease [87][88][89][90][91]. Previous research has shown that a high body mass index (BMI) was correlated with an increased need for mechanical ventilation in adult patients with a BMI > 35 kg/m2 [92], and this correlation was independent of the presence of any other comorbidities, gender or age [93][94][95][96][97]. Therefore, it seems reasonable to recommend the COVID-19 vaccination to obese patients, especially those with a higher BMI [98]. ...
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Full-text available
SARS-CoV-2 was the first pathogen implied in a worldwide health emergency in the last decade. Containment measures have been adopted by various countries to try to stop infection spread. Children and adolescents have been less clinically involved by COVID-19, but the pandemic and consequent containment measures have had an important influence on the developmental ages. The COVID-19 pandemic and the subsequent lockdown periods have influenced the nutrition and lifestyles of children and adolescents, playing an epigenetic role in the development of nutrition and metabolic diseases in this delicate age group. The aim of our review is to investigate the effects of the COVID-19 pandemic on nutrition and metabolic diseases in the developmental ages. Moreover, we have analyzed the effect of different containment measures in children and adolescents. An increase in being overweight, obesity and type 2 diabetes mellitus has been detected. Concerning type 1 diabetes mellitus, although a validated mechanism possibly linking COVID-19 with new onset type 1 diabetes mellitus has not been yet demonstrated, barriers to the accessibility to healthcare services led to delayed diagnosis and more severe presentation of this disease. Further studies are needed to better investigate these relationships and to establish strategies to contain the nutritional and metabolic impact of new pandemics in the developmental ages.
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Endothelial dysfunction underlies many of the major complications following hematopoietic cell transplantation (HCT), including transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and engraftment syndrome (ES). Emerging evidence similarly implicates endothelitis and microangiopathy in severe COVID-19-related multi-system organ dysfunction. Given the overlap in these two illness states, we hypothesize that prior COVID-19 infection may increase risk for HCT-related endotheliopathies. This retrospective, multicenter study included patients aged 0-25 years who underwent autologous or allogeneic HCT for any indication between January 1, 2020 and September 21, 2021, with close attention to those infected with COVID-19 in either the six months prior to transplant or twelve months following transplant. Incidences of TA-TMA, VOD/SOS, and ES were compared among patients with COVID-19 infection pre-HCT and post-HCT, as well as with historical controls who were never infected with SARS-CoV-2. Those who underwent HCT following COVID-19 infection displayed significantly increased rates of TA-TMA compared to those who were never infected. Additionally, our data suggests a similar trend for increased VOD/SOS and ES rates, although this did not reach statistical significance. Therefore, a history of COVID-19 infection prior to undergoing HCT may be a nonmodifiable risk factor for endothelial-related complications following HCT. Further studies are warranted to better clarify this relationship among larger cohorts and in the era of the Omicron SARS-CoV-2 variants.
Chapter
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection leads to milder disease in children compared with adults. Nonetheless, severe cases of pediatric coronavirus disease 2019 (COVID‐19), as well as COVID‐19‐associated multisystem inflammatory syndrome in children, have been reported across the globe. Therefore, an understanding of SARS‐CoV‐2 pathogenesis, transmission, and clinical manifestations in children is critical in the prevention and management of such cases. This chapter provides a comprehensive description of the epidemiology, transmission, clinical manifestations, diagnosis, and management of SARS‐CoV‐2 infection in the pediatric population, from neonates to adolescents. SARS‐CoV‐2‐related syndromes, such as multisystem inflammatory syndrome in children and pediatric postacute sequelae of COVID‐19, are also discussed.
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Background: Work of breathing (WOB) and non-comorbidities factors in the respiratory system are the two probable findings in pediatric COVID-19 patients. However, the association of those factors with level of care was not well reported. Purpose: This study aimed to identify the relation between potential predictors including comorbidity, low nutritional fulfillment, infectious disease, shock, cough, O2 saturation reduction, abnormal blood gas analysis and sore throat with the level of care among pediatric COVID-19 patients. We also analyzed the synergistic correlation of non-comorbidities factors in the respiratory system and work of breathing to predict level of care in pediatric COVID-19 patients. Methods: A cross-sectional study was conducted in the six referral hospitals from July to September 2020 in four provinces in Indonesia. An observation checklist was used to collect data from the medical records of pediatric patients with COVID-19, including medical diagnosis, demographic, and clinical manifestation. This study included 423 participants aged from 0 to 18. The multivariate logistic regression was performed to test the adjusted odds ratios (AORs) with the 95% confidence intervals (CIs) of the association between WOB, non-comorbid respiratory, and level of care. Moreover, dummy variables (2x2) were made to analyze synergistic correlation of non-comorbid respiratory disease and WOB. The AOR with the 95% CIs was applied in the association between the complication of non-comorbid respiratory diseases and high work of breathing with level of care among pediatric patients with COVID-19. Results: Results showed that age, presence of comorbidity, nutritional fulfillment, infectious disease, shock, work of breathing, O2 saturation reduction, abnormal blood gas analysis, sore throat, and convulsive meningeal consciousness were significantly associated with the level of care (p
Article
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Objective The majority of pediatric severe acute respiratory syndrome coronavirus 2 (COVID-19) cases demonstrate asymptomatic, mild or moderate disease. The main symptoms in children with COVID-19 are respiratory symptoms but some patients develop gastrointestinal symptoms and liver injury. We aim to review gastrointestinal symptoms and liver injury in children with confirmed COVID-19 infection. Method This is a retrospective case note review of children with positive COVID-19 nasal Polymerase Chain Reaction aged 0–18 years admitted to a tertiary pediatric hospital from March 1st till June 1st 2020. Results 180 children were identified. Mean age was 5 years (Range: 0.01–17), the majority of patients were school aged (30%). Patients were mainly from East Asia 81 (45%) and Arabs 67 (37%). Gastrointestinal symptoms were encountered in 48 (27%) patients and 8 (4%) patients had only Gastrointestinal symptoms with no associated fever or respiratory symptoms. Liver injury was seen in 57 (32%) patients. Patients with fever and cough were more likely to have gastrointestinal symptoms ( P = <0.001 and 0.004 respectively). Fever was more likely to be associated with liver injury ( P = 0.021). Children with abdominal pain were more likely to have elevated C-Reactive Protein ( P = 0.037). Patients with diarrhea and vomiting were more likely to have elevated procalcitonin ( P = 0.034 and 0.002 respectively). Children with Gastrointestinal symptoms were not more likely to be admitted to Pediatric Intensive Care Unit ( P = 0.57). Conclusion COVID-19 infection in children can display gastrointestinal symptoms at initial presentation. Additionally, gastrointestinal symptoms can be the only symptoms patients display. We demonstrated that children with gastrointestinal symptoms and liver injury can develop more severe COVID-19 disease and are more likely to have fever, cough, and raised inflammatory markers. Identifying children with gastrointestinal manifestations needs to be part of the initial screening assessment of children. What is known? • Pediatric COVID-19 cases mostly demonstrate asymptomatic, mild or moderate disease. • The symptoms in children are mainly respiratory but some display gastrointestinal symptoms. • Children with COVID-19 display increased gastrointestinal symptoms when compared to adults. What is new? • Children with COVID-19 displaying gastrointestinal symptoms are more likely to have fever, cough and elevated inflammatory markers. • Children with liver injury are more likely to develop fever. • Children with gastrointestinal involvement in COVID-19 are more likely to demonstrate more severe disease but are not more likely to be admitted to PICU.
Article
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Background: Variability in presentation of children with coronavirus disease 2019 (COVID-19) is a challenge in emergency departments (EDs) in terms of early recognition, which has an effect on disease control and prevention. We describe a cohort of 170 children with COVID-19 and differences with the published cohorts. Methods: Retrospective chart reviews on children (0-18 years) evaluated in 17 Italian pediatric EDs. Results: In our cohort (median age of 45 months; interquartile range of 4 months-10.7 years), we found a high number of patients <1 year with COVID-19 disease. The exposure happened mainly (59%) outside family clusters; 22% had comorbidities. Children were more frequently asymptomatic (17%) or with mild diseases (63%). Common symptoms were cough (43%) and difficulty feeding (35%). Chest computed tomography, chest radiograph, and point-of-care lung ultrasound were used in 2%, 36%, and 8% of cases, respectively. Forty-three percent of patients were admitted because of their clinical conditions. The minimal use of computed tomography and chest radiograph may have led to a reduced identification of moderate cases, which may have been clinically classified as mild cases. Conclusions: Italian children evaluated in the ED infrequently have notable disease symptoms. For pediatrics, COVID-19 may have rare but serious and life-threatening presentations but, in the majority of cases, represents an organizational burden for the ED. These data should not lower the attention to and preparedness for COVID-19 disease because children may represent a source of viral transmission. A clinically driven classification, instead of a radiologic, could be more valuable in predicting patient needs and better allocating resources.
Article
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Background: Imaging of novel coronavirus disease 2019 (COVID-19) has been described in adults, but children have milder forms of disease. Pediatric imaging descriptions are of asymptomatic children, raising the question of whether imaging is needed in this patient group. Objective: To describe the utilization and imaging findings in children with COVID-19 along with the comorbidities, treatment and short-term outcomes. Materials and methods: We retrospectively reviewed pediatric patients who had a confirmed positive test for COVID-19 during a 2-month period. We noted symptoms and presence of imaging at presentation. Comorbidities were recorded for children with imaging. Children were categorized as having multisystem inflammatory syndrome in children (MIS-C) if they met criteria for the disorder. For children who were admitted to the hospital, we documented length of hospital stay, need for intensive care unit care/ventilator support, and treatment regimen. We evaluated all imaging for acute/chronic abnormalities including chest radiographs for interstitial or alveolar opacities, distribution/symmetry of disease, zonal predominance, and pleural abnormalities. We performed descriptive statistics and compared children with MIS-C with the cohort using a Fisher exact test. Results: During the study period, 5,969 children were tested for COVID-19, with 313 (5%) testing positive. Of these, 92/313 (29%) were asymptomatic and 55/313 (18%) had imaging and were admitted to the hospital for treatment. Forty-one of 55 patients (75%) with imaging had comorbidities. Chest radiographs were the most common examination (51/55 patients, or 93%) with most demonstrating no abnormality (34/51, or 67%). Children with MIS-C were more likely to have interstitial opacities and pleural effusions. US, CT or MRI was performed in 23/55 (42%) children, 9 of whom had MIS-C. Only one chest CT was performed. Conclusion: In our study, most pediatric patients with COVID-19 did not require hospital admission or imaging. Most children with imaging had comorbidities but children with MIS-C were more likely to have no comorbidities. Children with imaging mostly had normal chest radiography. Advanced imaging (US, CT, MRI) was less common for the care of these children, particularly CT examination of the chest and for children without MIS-C.
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Since February 12, 2020, approximately 6.5 million cases of SARS-CoV-2 infection, the cause of coronavirus disease 2019 (COVID-19), and 190,000 SARS-CoV-2-associated deaths have been reported in the United States (1,2). Symptoms associated with SARS-CoV-2 infection are milder in children compared with adults (3). Persons aged <21 years constitute 26% of the U.S. population (4), and this report describes characteristics of U.S. persons in that population who died in association with SARS-CoV-2 infection, as reported by public health jurisdictions. Among 121 SARS-CoV-2-associated deaths reported to CDC among persons aged <21 years in the United States during February 12-July 31, 2020, 63% occurred in males, 10% of decedents were aged <1 year, 20% were aged 1-9 years, 70% were aged 10-20 years, 45% were Hispanic persons, 29% were non-Hispanic Black (Black) persons, and 4% were non-Hispanic American Indian or Alaska Native (AI/AN) persons. Among these 121 decedents, 91 (75%) had an underlying medical condition,* 79 (65%) died after admission to a hospital, and 39 (32%) died at home or in the emergency department (ED).† These data show that nearly three quarters of SARS-CoV-2-associated deaths among infants, children, adolescents, and young adults have occurred in persons aged 10-20 years, with a disproportionate percentage among young adults aged 18-20 years and among Hispanics, Blacks, AI/ANs, and persons with underlying medical conditions. Careful monitoring of SARS-CoV-2 infections, deaths, and other severe outcomes among persons aged <21 years remains particularly important as schools reopen in the United States. Ongoing evaluation of effectiveness of prevention and control strategies will also be important to inform public health guidance for schools and parents and other caregivers.
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Objective To characterise the clinical features of children and young people admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to coronavirus disease 2019 (covid-19) (MIS-C). Design Prospective observational cohort study with rapid data gathering and near real time analysis. Setting 260 hospitals in England, Wales, and Scotland between 17 January and 3 July 2020, with a minimum follow-up time of two weeks (to 17 July 2020). Participants 651 children and young people aged less than 19 years admitted to 138 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory confirmed SARS-CoV-2. Main outcome measures Admission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C. Results Median age was 4.6 (interquartile range 0.3-13.7) years, 35% (225/651) were under 12 months old, and 56% (367/650) were male. 57% (330/576) were white, 12% (67/576) South Asian, and 10% (56/576) black. 42% (276/651) had at least one recorded comorbidity. A systemic mucocutaneous-enteric cluster of symptoms was identified, which encompassed the symptoms for the WHO MIS-C criteria. 18% (116/632) of children were admitted to critical care. On multivariable analysis, this was associated with age under 1 month (odds ratio 3.21, 95% confidence interval 1.36 to 7.66; P=0.008), age 10-14 years (3.23, 1.55 to 6.99; P=0.002), and black ethnicity (2.82, 1.41 to 5.57; P=0.003). Six (1%) of 627 patients died in hospital, all of whom had profound comorbidity. 11% (52/456) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Children meeting MIS-C criteria were older (median age 10.7 (8.3-14.1) v 1.6 (0.2-12.9) years; P<0.001) and more likely to be of non-white ethnicity (64% (29/45) v 42% (148/355); P=0.004). Children with MIS-C were five times more likely to be admitted to critical care (73% (38/52) v 15% (62/404); P<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with fatigue (51% (24/47) v 28% (86/302); P=0.004), headache (34% (16/47) v 10% (26/263); P<0.001), myalgia (34% (15/44) v 8% (21/270); P<0.001), sore throat (30% (14/47) v (12% (34/284); P=0.003), and lymphadenopathy (20% (9/46) v 3% (10/318); P<0.001) and to have a platelet count of less than 150 × 10 ⁹ /L (32% (16/50) v 11% (38/348); P<0.001) than children who did not have MIS-C. No deaths occurred in the MIS-C group. Conclusions Children and young people have less severe acute covid-19 than adults. A systemic mucocutaneous-enteric symptom cluster was also identified in acute cases that shares features with MIS-C. This study provides additional evidence for refining the WHO MIS-C preliminary case definition. Children meeting the MIS-C criteria have different demographic and clinical features depending on whether they have acute SARS-CoV-2 infection (polymerase chain reaction positive) or are post-acute (antibody positive). Study registration ISRCTN66726260.
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Approximately 56 million school-aged children (aged 5-17 years) resumed education in the United States in fall 2020.* Analysis of demographic characteristics, underlying conditions, clinical outcomes, and trends in weekly coronavirus disease 2019 (COVID-19) incidence during March 1-September 19, 2020 among 277,285 laboratory-confirmed cases in school-aged children in the United States might inform decisions about in-person learning and the timing and scaling of community mitigation measures. During May-September 2020, average weekly incidence (cases per 100,000 children) among adolescents aged 12-17 years (37.4) was approximately twice that of children aged 5-11 years (19.0). In addition, among school-aged children, COVID-19 indicators peaked during July 2020: weekly percentage of positive SARS-CoV-2 test results increased from 10% on May 31 to 14% on July 5; SARS-CoV-2 test volume increased from 100,081 tests on May 31 to 322,227 on July 12, and COVID-19 incidence increased from 13.8 per 100,000 on May 31 to 37.9 on July 19. During July and August, test volume and incidence decreased then plateaued; incidence decreased further during early September and might be increasing. Percentage of positive test results decreased during August and plateaued during September. Underlying conditions were more common among school-aged children with severe outcomes related to COVID-19: among school-aged children who were hospitalized, admitted to an intensive care unit (ICU), or who died, 16%, 27%, and 28%, respectively, had at least one underlying medical condition. Schools and communities can implement multiple, concurrent mitigation strategies and tailor communications to promote mitigation strategies to prevent COVID-19 spread. These results can provide a baseline for monitoring trends and evaluating mitigation strategies.
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