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1Irfan O, etal. Arch Dis Child 2021;0:1–9. doi:10.1136/archdischild-2020-321385
Global child health
Clinical characteristics, treatment and outcomes of
paediatric COVID-19: a systematic review and
meta- analysis
Omar Irfan,1 Fiona Muttalib,1 Kun Tang,1,2 Li Jiang,1 Zohra S Lassi,3
Zulfiqar Bhutta 1,4
To cite: IrfanO, MuttalibF,
TangK, etal. Arch Dis Child
Epub ahead of print: [please
include Day Month Year].
doi:10.1136/
archdischild-2020-321385
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1Centre for Global Child Health,
The Hospital for Sick Children,
Toronto, Ontario, Canada
2Vanke School of Public Health,
Tsinghua University, Beijing,
China
3Robinson Research Institute,
Adelaide Medical School, The
University of Adelaide, Adelaide,
South Australia, Australia
4Institute for Global Health
& Development, Aga Khan
University, Karachi, Pakistan
Correspondence to
Dr Zulfiqar Bhutta, Centre
for Global Child Health, The
Hospital for Sick Children,
Toronto, ON M5G 1X8, Canada;
zulfiqar. bhutta@ sickkids. ca
Received 11 December 2020
Revised 25 January 2021
Accepted 27 January 2021
© Author(s) (or their
employer(s)) 2021. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published
by BMJ.
ABSTRACT
Objective Compare paediatric COVID-19 disease
characteristics, management and outcomes according to
World Bank country income level and disease severity.
Design Systematic review and meta- analysis.
Setting Between 1 December 2019 and 8 January
2021, 3350 articles were identified. Two reviewers
conducted study screening, data abstraction and
quality assessment independently and in duplicate.
Observational studies describing laboratory- confirmed
paediatric (0–19 years old) COVID-19 were considered
for inclusion.
Main outcomes and measures The pooled
proportions of clinical findings, treatment and outcomes
were compared according to World Bank country income
level and reported disease severity.
Results 129 studies were included from 31 countries
comprising 10 251 children of which 57.4% were
hospitalised. Mean age was 7.0 years (SD 3.6), and
27.1% had a comorbidity. Fever (63.3%) and cough
(33.7%) were common. Of 3670 cases, 44.1% had
radiographic abnormalities. The majority of cases
recovered (88.9%); however, 96 hospitalised children
died. Compared with high- income countries, in low-
income and middle- income countries, a lower proportion
of cases were admitted to intensive care units (ICUs)
(9.9% vs 26.0%) yet pooled proportion of deaths among
hospitalised children was higher (relative risk 2.14,
95% CI 1.43 to 3.20). Children with severe disease
received antimicrobials, inotropes and anti- inflammatory
agents more frequently than those with non- severe
disease. Subgroup analyses showed that a higher
proportion of children with multisystem inflammatory
syndrome (MIS- C) were admitted to ICU (47.1% vs
22.9%) and a higher proportion of hospitalised children
with MIS- C died (4.8% vs 3.6%) compared with the
overall sample.
Conclusion Paediatric COVID-19 has a favourable
prognosis. Further severe disease characterisation in
children is needed globally.
INTRODUCTION
The coronavirus disease (COVID-19) pandemic
caused by severe acute respiratory syndrome coro-
navirus-2 has spread from a local outbreak in
China to a global pandemic within months. On 31
December 2019, a cluster of cases with pneumonia
of unknown cause emerged from Wuhan, China.
On 30 January 2020, the WHO declared the coro-
navirus outbreak a Public Health Emergency of
International Concern, and on 11 March 2020, a
pandemic. As of 21 January 2021, there have been
over 95.6 million confirmed COVID-19 cases and
over 2.0 million associated deaths from 216 coun-
tries, areas or territories.1 Children under-19 years
of age comprise a small proportion (1%–10%)
of the total reported cases2–5 with a lower risk of
developing critical illness from COVID-19 infection
compared with adults.6 Prior systematic reviews
of paediatric COVID-19 have described a mild
disease in children with good outcomes.4 7 8 Since
the publication of these reviews, the pandemic has
spread extensively around the globe. In addition to
pulmonary manifestations of COVID-19 in chil-
dren, reports from Europe, North America, Latin
America and Asia have emerged, describing a multi-
system inflammatory syndrome children (MIS- C)
related to COVID-19 infection.9–12 COVID-19
has also disrupted essential maternal and child
health interventions, including outpatient visits and
vaccinations for young children in most countries,
further worsening the existing burden on health-
care provision and delivery.13
The objective of this review, in addition to
providing a comprehensive update of the evolving
paediatric COVID-19 literature, is a unique
comparison of reported cases in low- income and
middle- income countries (LMICs) to high- income
countries (HICs) and of children with severe
versus non- severe disease. Furthermore, the review
provides a subgroup analysis of children presenting
with symptoms of MIS- C and neonatal cases.
METHODS
The protocol of the review is registered with
PROSPERO (CRD42020183134). This systematic
review is reported in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-
analysis (PRISMA).
SEARCH METHODS
The review includes a comprehensive search of
MEDLINE, Embase, WHO COVID-19 Data-
base, Chinese COVID-19 Databases (CNKI and
Wangfang), Latin- American and Caribbean Health
Sciences Literature (LILACS) from 1 December
2019 to 8 January 2021. Complementary searches
were conducted in Google Scholar, John Hopkins
Health Resource, WHO news and the Chinese and
US CDC Library. MedRxiv, BioRxiv and ChinaXiv
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2Irfan O, etal. Arch Dis Child 2021;0:1–9. doi:10.1136/archdischild-2020-321385
Global child health
were searched for preprints. No language restrictions were
applied.
A search strategy was formulated and administered as shown
in online supplemental table 1.
STUDY SELECTION
Observational studies reporting children (0–19 years old) with
laboratory‐confirmed COVID-19 (serology or RT- PCR) were
considered for inclusion. Studies with a subset of children 0–19
years were included if disaggregated data for children were
provided. Studies were screened for any overlap in paediatric
cases by reviewing institution details and the period reported.
Review articles, case reports, commentaries and letters not
presenting any original data were excluded. Case reports were
excluded to reduce risk of selection bias and over- representation
of extreme cases. Covidence Software (2016) was used for
screening by two reviewers independently and in duplicate. Key
reference lists were screened for additional studies.
DATA EXTRACTION
Two reviewers conducted data extraction using a prepiloted data
form. Data extracted included authors’ names, date of publi-
cation, study- design, city, country, number of cases, gender,
comorbidities, travel and contact history, diagnostic tests for
COVID-19, clinical details, laboratory tests, radiological find-
ings, management and outcomes. Disaggregated data by age
groups (0–5 years, 5–10 years and >10 years old) and reported
disease severity was extracted where available. Criteria for severe
disease were as defined within each individual study and included
admission to intensive care units (ICUs), use of mechanical venti-
lation, multiorgan failure and presence of hypoxia (oxygen satu-
ration <92%).
QUALITY ASSESSMENT
Individual study quality was evaluated independently by the
review authors using quality assessment tools developed by the
National Heart Lung and Brain Institute (NHLBI)14 (https://
www. nhlbi. nih. gov/ health- topics/ study- quality- assessment-
tools). Study quality was scored out of 8, based on clarity of
study objectives, case definition, consecutive inclusion of cases,
comparability of included patients, definition and measurement
of outcomes, length of follow- up, statistical methods and results.
Studies with score 6–8 were considered to be good quality, 4–5
considered fair quality and <4 considered poor quality.
DATA SYNTHESIS
Categorical data were summarised as counts and proportions.
The pooled proportions of reported findings were calculated
using Comprehensive Meta- Analysis 2.2.027 using random-
effects model. I2 was calculated to examine statistical hetero-
geneity (I2>50% considered high heterogeneity). The clinical
features and outcomes were compared according to (1) World
Bank country income level (HICs versus LMICs)15 and (2)
reported disease severity (severe versus non- severe) using pooled
proportions and their 95% CIs, supplemented by relative- risk
(RR). Subgroup analyses of children with MIS- C and neonatal
cases were conducted.
RESULTS
After removal of duplicates, 3350 citations were screened for
inclusion. Full texts of 198 studies were screened and 129
studies2 3 9–12 16–138 were included (online supplemental figure
1). Sixty- nine studies were excluded as they either presented
overlapping data, did not provide age- disaggregated data for
children or were commentaries, editorials or reviews. In terms
of study setting, 13 studies were population- based national
surveillance studies, 94 studies included only children admitted
to hospital and 22 studies reported patients presenting to outpa-
tient clinics or emergency departments (hospitalisation rate of
24.2%, 385/1590).
Sixty studies were from HICs (n=6528) and
69 studies from LMICs (n=3723). Almost one-
third of included studies were from China (36/129,
28.0%),2 16–33 35 37–43 45 52 53 55–57 71 74 138 one- fifth were from the USA
(24/129, 18.6%)3 9 10 47 58 60 64 68–70 79 81 82 85–87 93 98 109 110 115 120 133 136
together comprising almost half of the included sample size
(n=4758, 46.4.%). The country of origin of included studies
and study characteristics are summarised in online supplemental
figure 2, tables 2 and 3.
DEMOGRAPHICS AND EPIDEMIOLOGY
A total of 9335 children from the 129 case series were included
in the meta- analysis. Of 8455 children for whom initial dispo-
sition was reported, 4851 were hospitalised (57.4%). Among
them, 55.5% were men. The patient’s ages ranged from 0 to 17
years with mean age of 7.0±3.6 years. Ninety- one of the 129
studies reported age- disaggregated data for infection incidence
as shown in online supplemental table 4. Nearly half of the cases
were >10 years of age. Contact exposure to COVID-19 was
reported in 64.0% of cases. Travel history to an epicentre was
reported in 13.0% cases. At- least one underlying comorbidity
was reported in 27.1% of cases. The most common reported
comorbidities were immunosuppression (15.8%) and lung
disease (12.5%).
CLINICAL MANIFESTATIONS
Table 1 summarises the clinical manifestations reported in the
studies. There were 13.1% asymptomatic cases (95% CI 10.4%
to 16.3%) who presented primarily through contact expo-
sure in family- clusters (parents, siblings and other relatives).
The most common presenting symptoms were fever (63.3%,
95% CI 58.6% to 68.4%) and cough (33.7%, 95% CI 29.6% to
38.1%) followed by nausea or vomiting (20.0%, 95% CI 16.5%
to 24.0%) and diarrhoea (19.6%, 95% CI 16.1% to 23.7%).
Other symptoms included dyspnoea, nasal- symptoms, rashes,
kawasaki- like symptoms, conjunctivitis, fatigue, abdominal
pain and neurological symptoms. Sixty- seven of the 129 studies
reported age disaggregated data for clinical features (online
supplemental table 5). Clinical features were similar in the three
age groups: ≤5 years, >5 to ≤10 years, >10 years with higher
prevalence of abdominal symptoms in children>5 years.
RADIOLOGICAL AND LABORATORY FINDINGS
One thousand five hundred and thirty cases out of 3670 (44.1%,
95% CI 39.5% to 48.9%) cases had radiological abnormali-
ties; ground glass opacities (27.4%) were the most commonly
reported abnormality.
Sixty- six studies provided details on laboratory- markers
(table 2). Pooled analysis revealed increased C- Reactive Protein
(CRP) (54.2%, 95% CI 41.5% to 66.3%), serum- ferritin (46.7%,
95% CI 32.3% to 61.7%), lactate dehydrogenase (LDH) (36.5%,
95% CI 26.5% to 47.8%) and d- dimers (35.2%, 95% CI 22.1%
to 51.0%) as the most common abnormalities. Other reported
abnormalities included elevated erythrocyte sedimentation rate
(ESR), lymphopaenia, procalcitonin and biomarkers for organ
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Global child health
injury including elevated levels of pro B- type natriuretic peptide,
troponin and creatine kinase- MB as shown in table 2.
MANAGEMENT
Details of clinical management are as shown in table 3. Commonly
used therapies among hospitalised children were antimicrobials
(32.2%, 95% CI 25.2% to 40.1%), intravenous immunoglobulin
(IVIG) (19.5%, 95% CI 13.5% to 27.2%) and systemic- steroids
(19.3, 95% CI 14.9% to 24.9%). Other treatment regimens
included aspirin, inotropic drugs, inhaled interferon-α (IFN‐α),
antimalarials and antivirals (ribavirin, oseltamivir, lopinavir,
ritonavir and litonavir). Mechanical ventilation was provided to
490 patients (12.2%, 95% CI 9.7% to 15.3%).
PROGNOSIS AND SEVERE CASES
One thousand three hundred and fifty- nine patients (22.9%,
95% CI 17.6% to 29.2%) were admitted to ICUs (table 3).
Thirty- eight studies provided disaggregated data for severe cases
(table 4). A higher proportion of children with severe disease had
symptoms consistent with MIS- C and received antimicrobials,
inotropes and anti- inflammatory agents compared with those
with non- severe disease. There were no deaths among children
Table 1 Clinical symptoms among reported paediatric COVID-19 cases
Characteristics Events/total patients Mean proportion % (95% CI) Heterogeneity I2 (%)
Comorbidity 1590/6086
27.1 (23.1 to 31.5) 37.6
Fever 3576/6296 63.3 (58.6 to 68.4) 34.9
Cough 1807/5261 33.7 (29.6 to 38.1) 34.4
Nausea/vomiting 880/4243 20.0 (16.5 to 24.0) 25.7
Diarrhoea 796/4884 19.6 (16.1 to 23.7) 13.4
Dyspnoea 879/5332 17.5 (14.4 to 21.1) 23.7
Nasal symptoms 1080/5406 16.6 (13.9 to 19.7) 10.6
Rashes 744/4387 15.5 (11.9 to 19.9) 25.9
Fatigue 709/4474 15.5 (12.6 to 19.3) 26.3
Abdominal pain 626/4135 15.3 (11.9 to 19.4) 26.5
Kawasaki shock/sign 821/4365 13.3 (9.8 to 17.9) 30.6
Asymptomatic 1114/6084 13.1 (10.4 to 16.3) 15.4
Neurological symptoms 693/5475 12.1 (10.1 to 14.6) 17.6
Conjunctivitis 529/4998 10.5 (7.8 to 14.0) 21.0
Pharyngeal erythema 428/3638 9.0 (6.7 to 12.0) 0.0
Table 2 Laboratory and radiological features among reported paediatric COVID-19 cases
Characteristics Events/total patients Mean proportion % (95% CI) Heterogeneity I2 (%)
Inflammatory marker
CRP ↑556/1165
54.2 (41.5 to 66.3) 21.4
Ferritin ↑247/525 46.7 (32.3 to 61.7) 46.5
LDH ↑356/922 36.5 (26.5 to 47.8) 35.6
Procalcitonin ↑137/879 21.3 (12.2 to 34.5) 24.9
Leukocytes ↑138/953 19.9 (13.3 to 28.8) 21.4
Lymphocytes ↓359/1347 19.0 (12.8 to 27.1) 0.0
ESR ↑248/838 18.9 (11.8 to 28.9) 0.0
IL-6 ↑41/341 13.1 (5.5 to 28.2) 7.1
Leucopaenia (+) 77/1037 10.7 (7.7 to 14.6) 0.0
Lymphocytes ↑66/1264 8.2 (4.9 to 13.5) 0.0
Neutrophils ↑22/574 7.8 (4.8 to 12.4) 0.0
Biomarkers for organ injury
proBNP ↑211/441 45.5 (28.5 to 63.5) 49.5
Troponin ↑239/703 39.7 (24.7 to 57.0) 30.5
LFTs ↑287/816 29.8 (20.3 to 41.6) 10.8
CKMB ↑82/293 25.5 (13.4 to 43.0) 31.1
RFTs ↑86/344 17.6 (7.6 to 35.6) 23.6
Coagulopathy markers
D- dimers ↑272/711 35.2 (22.1 to 51.0) 19.1
Fibrinogen ↑168/438 17.5 (7.6 to 35.4) 0.0
Radiological test
Abnormal CXR/CT 1530/3670 44.1 (39.5 to 48.9) 35.0
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Table 3 Clinical management and outcomes among reported paediatric COVID-19 cases
Characteristics Events/total patients Mean proportion % (95% CI) Heterogeneity I2 (%)
Clinical management
Antibiotics 1345/3610
32.2 (25.2 to 40.1) 41.9
IVIG 698/3522 19.5 (13.5 to 27.2) 18.4
Systemic steroids 801/4229 19.3 (14.9 to 24.9) 23.7
Antiviral 527/4019 15.3 (11.1 to 20.7) 4.5
Mechanical ventilation 490/5406 12.2 (9.7 to 15.3) 15.5
Inotropes 354/3856 11.8 (8.3 to 16.4) 11.5
Antimalarial 336/3299 9.9 (6.9 to 14.0) 0.0
Aspirin 238/2588 9.0 (5.9 to 13.6) 78.1
Interferon 138/2598 7.7 (4.9 to 11.8) 0.0
Traditional medicine 22/4229 4.0 (2.8 to 5.6) 38.7
Clinical outcomes
Recovered 8704/9335 88.9 (86.0 to 91.2) 36.3
ICU admission 1359/9335 22.9 (17.6 to 29.2) 37.2
Deaths 96/6902 3.6 (2.8 to 4.5) 24.3
ICU, intensive care unit; IVIG, intravenous immunoglobulin.
Table 4 Comparison of clinical symptoms, management and outcomes among reported paediatric COVID-19 non- severe (n=2402 cases, 64
studies) and severe (n=796 cases, 38 studies) cases
Characteristics
Non- severe cases Severe cases
RR severe vs non-
severe (95% CI)
Events/total
patients
Mean proportion %
(95% CI)
Events/total
patients
Mean proportion %
(95% CI)
Clinical symptoms
Fever 1394/2404 51.4 (45.7 to 57.0)
608/756 80.2 (73.6 to 85.5)
1.39 (1.32 to 1.46)
Pharyngeal erythema 541/1149 8.6 (5.1 to 14.0) 41/585 8.8 (5.1 to 14.8) 0.15 (0.11 to 0.20)
Cough 587/1521 35.1 (29.2 to 41.5) 225/618 34.0 (24.6 to 44.9) 0.94 (0.84 to 1.07)
Comorbidity 541/2283 19.8 (14.5 to 26.4) 351/764 44.1 (34.9 to 53.8) 1.94 (1.74 to 2.16)
Nausea/vomiting 206/1291 12.1 (8.7 to 16.6) 224/632 41.0 (36.7 to 45.5) 2.27 (1.93 to 2.67)
Dyspnoea 260/1646 12.7 (9.5 to 16.8) 237/701 36.4 (26.5 to 47.5) 2.14 (1.84 to 2.49)
Nasal symptoms 402/1659 14.1 (9.9 to 19.7) 91/652 15.8 (10.6 to 23.0) 0.58 (0.47 to 0.71)
Fatigue 192/1319 13.8 (10.4 to 18.0) 151/505 20.3 (15.3 to 33.4) 2.05 (1.70 to 2.48)
Kawasaki shock/sign 135/1243 8.5 (5.6 to 12.6) 242/695 30.7 (19.3 to 45.0) 3.21 (2.65 to 3.87)
Rashes 168/1587 10.3 (7.6 to 13.7) 180/660 32.3 (22.3 to 44.2) 2.58 (2.13 to 3.11)
Abdominal pain 95/1193 8.1 (5.8 to 11.3) 184/621 28.4 (18.8 to 40.4) 3.72 (2.96 to 4.67)
Diarrhoea 144/1326 13.5 (10.6 to 17.1) 217/632 35.3 (26.3 to 45.4) 3.16 (2.62 to 3.82)
Conjunctivitis 111/1621 7.5 (5.1 to 10.8) 116/657 22.6 (15.1 to 32.4) 2.58 (2.02 to 3.29)
Neurological symptoms 200/2230 11.0 (9.0 to 13.4) 118/703 17.4 (11.9 to 24.6) 1.87 (1.52 to 2.31)
Clinical management
Mechanical ventilation – – 322/735 43.8 (33.8 to 54.3) –
Antiviral 217/715 26.5 (17.5 to 38.1) 136/567 24.1 (16.2 to 34.3) 0.79 (0.66 to 0.95)
Interferon 127/685 20.2 (11.6 to 32.3) 4/445 6.8 (3.6 to 12.3) 0.05 (0.02 to 0.13)
Antibiotics 180/363 21.6 (14.2 to 31.3) 365/566 59.6 (44.3 to 73.3) 1.30 (1.15 to 1.47)
Antimalarial 73/717 10.1 (6.4 to 16.4) 123/537 22.9 (14.3 to 34.6) 2.25 (1.72 to 2.94)
IVIG 54/721 11.8 (7.2 to 18.8) 202/498 41.1 (27.0 to 56.8) 5.42 (4.10 to 7.15)
Systemic steroids 46/721 8.9 (5.4 to 14.4) 265/575 46.8 (35.7 to 58.2) 7.22 (5.39 to 9.69)
Inotropes 24/718 6.8 (4.1 to 11.7) 171/498 33.6 (21.2 to 48.9) 10.27 (6.81 to 15.50)
Traditional medicine 18/723 7.4 (4.8 to 11.3) 4/575 6.3 (3.8 to 10.3) 0.28 (0.10 to 0.82)
Aspirin 11/683 6.7 (4.3 to 10.4) 83/445 14.9 (7.9 to 26.4) 11.58 (6.25 to 21.47)
Clinical outcomes
ICU – – 793/796 95.0 (92.1 to 96.8) –
Recovered 1700/1925 85.4 (76.5 to 91.2) 532/796 77.6 (67.5 to 85.3) 0.76 (0.72 to 0.80)
Deaths 0/1925 44/796 8.0 (5.2 to 12.1)
ICU, intensive care unit; IVIG, intravenous immunoglobulin.
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categorised as non- severe and 44 deaths among severe cases,
where disaggregated data were provided. Hospital outcomes
were reported for 9335 children; 8704 cases (88.9%, 95% CI
86.0% to 91.2%) were definitively discharged, 96 died and
remaining children either remained hospitalised at the time of
reporting or were readmitted.
COMPARISON OF OUTCOMES ACCORDING TO WORLD BANK
COUNTRY CLASSIFICATION
Of the included studies that reported clinical characteristics
and outcomes, 60 studies were from HICs (n=6528) and 69
studies from LMICs (n=3723) as show in table 5. Studies in
LMICs included a higher proportion of hospitalised children
(1981/3723, 53.2%) compared with HIC studies (2897/6528,
44.4%). Abdominal symptoms and symptoms consistent with
MIS- C were more frequently reported in HICs. A lower propor-
tion of children in LMICs were admitted to the ICU (RR 0.56,
95% CI 0.50 to 0.63, p<0.05), mechanically ventilated (RR
0.32, 95% CI 0.26 to 0.39, p<0.05) and treated with different
therapies; inotropes, antimicrobials, steroids, aspirin and IVIG.
Only children in LMICs received inhaled IFN‐α. Among the
hospitalised cases, 40 deaths were reported in HICs compared
with 56 in LMICs (pooled proportion 2.9% vs 5.2%). Risk-
adjusted mortality according to severity of illness could not be
calculated due to lack of data (table 5).
SUBGROUP ANALYSES OF CHILDREN PRESENTING WITH
MIS-C, AND COVID-19 IN NEONATES
Thirty- one studies (n=1208) with 22 from HIC (n=602),
reported series of children presenting with MIS- C. Fever,
abdominal pain and diarrhoea were the most common symp-
toms. Nearly half of children (638/1208) who met criteria for
MIS- C were admitted to ICU (449/638, 70.3% of which were
from HIC) compared with 22.9% in the overall analysis (online
supplemental tables 6 and 7).
Disaggregated data were available on 184 neonates with fever;
inability to feed/lethargy and dyspnoea were the most commonly
Table 5 Comparison of clinical symptoms, management and outcomes among reported paediatric COVID-19 cases in HICs (n=5641 cases, 60
studies) and LMICs (n=3694, 69 studies)
Characteristics
HICs LMICs RR
LMICs vs HICs,
(95% CI)Events/total patients
Mean proportion %
(95% CI)
Events/total
patients
Mean proportion %
(95% CI)
Clinical symptoms
Fever 2276/3332 72.0 (66.3 to 77.0)
1300/2964 50.0 (47.4 to 52.6)
0.64 (0.61 to 0.67)
Cough 995/2730 33.2 (27.5 to 39.5) 812/2531 39.2 (36.2 to 42.3) 0.88 (0.82 to 0.95)
Comorbidity 1069/3357 33.7 (27.4 to 38.5) 521/2729 20.8 (18.3 to 23.4) 0.60 (0.55 to 0.66)
Rashes 491/2109 24.9 (17.9 to 33.5) 253/2278 20.2 (17.5 to 23.2) 0.48 (0.41 to 0.55)
Nausea/vomiting 668/2374 30.3 (24.3 to 37.0) 212/1869 15.3 (12.6 to 18.3) 0.40 (0.35 to 0.46)
Conjunctivitis 309/2732 13.1 (8.4 to 20.1) 220/2266 19.5 (16.9 to 22.5) 0.86 (0.73 to 1.01)
Dyspnoea 543/2454 23.6 (18.5 to 29.6) 336/2878 20.6 (18.1 to 23.4) 0.53 (0.47 to 0.60)
Kawasaki shock/sign 583/2087 21.9 (14.1 to 32.5) 238/2278 21.4 (18.5 to 24.6) 0.37 (0.33 to 0.43)
Fatigue 394/1943 16.8 (12.2 to 22.6) 315/2531 15.6 (13.3 to 18.3) 0.61 (0.54 to 0.70)
Abdominal pain 457/2266 22.7 (16.4 to 30.5) 169/1869 16.6 (12.9 to 21.1) 0.45 (0.38 to 0.53)
Nasal symptoms 425/2549 17.8 (14.4 to 21.8) 269/2519 15.4 (13.2 to 17.8) 0.64 (0.56 to 0.74)
Diarrhoea 527/2365 27.5 (21.5 to 34.6) 125/1105 14.7 (12.4 to 17.3) 0.51 (0.42 to 0.61)
Neurological symptoms 493/3197 15.0 (11.6 to 19.0) 200/2278 10.4 (8.8 to 12.3) 0.57 (0.49 to 0.67)
Asymptomatic 263/2428 6.4 (4.2 to 9.7) 851/3656 20.2 (18.4 to 22.1) 2.15 (1.89 to 2.44)
Pharyngeal erythema 73/1494 6.7 (4.3 to 10.1) 519/2531 40.7 (37.4 to 44.0) 4.20 (3.31 to 5.32)
Clinical management
Antibiotics 908/1875 36.4 (25.6 to 48.7) 437/1735 27.0 (22.9 to 31.5) 0.52 (0.47 to 0.57)
IVIG 504/1867 31.6 (20.3 to 45.5) 194/1655 14.7 (12.1 to 17.7) 0.43 (0.37 to 0.51)
Aspirin 187/985 16.0 (9.1 to 26.8) 51/1603 10.4 (7.2 to 14.7) 0.17 (0.12 to 0.23)
Systemic steroids 566/2523 27.2 (19.0 to 37.3) 235/1706 18.0 (15.2 to 21.2) 0.61 (0.53 to 0.71)
Inotropes 309/2309 19.1 (12.3 to 28.5) 45/1547 11.9 (8.5 to 16.5) 0.22 (0.16 to 0.30)
Antimalarial 241/1696 13.6 (8.7 to 20.8) 95/1603 13.5 (10.5 to 17.3) 0.42 (0.33 to 0.52)
Mechanical ventilation 387/2930 17.2 (13.1 to 22.3) 103/2476 10.8 (8.6 to 13.4) 0.32 (0.26 to 0.39)
Antiviral 230/2372 11.4 (7.7 to 16.6) 297/1647 25.2 (21.1 to 29.9) 1.86 (1.58 to 2.18)
Interferon 0/995 – 138/1603 30.5 (24.1 to 37.7) –
Traditional medicine 0/2523 – 22/1706 11.3 (8.0 to 15.7) –
Clinical outcomes
Recovered 5269/5641 91.0 (87.7 to 93.4) 3435/3694 83.9 (81.2 to 86.2) 0.99 (0.98 to 1.01)
ICU admission 993/5641 26.0 (24.0 to 28.0) 366/3694 9.9 (8.5 to 11.6) 0.56 (0.50 to 0.63)
Deaths 40/4710 2.9 (2.1 to 4.1) 56/2192 5.2 (4.1 to 6.7) 2.14 (1.43 to 3.20)
HICs, high- income countries; ICU, intensive care unit; IVIG, intravenous immunoglobulin; LMICs, low- income and middle- income countries; RR, relative risk.
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6Irfan O, etal. Arch Dis Child 2021;0:1–9. doi:10.1136/archdischild-2020-321385
Global child health
reported symptoms. Twenty- one neonates (16.6%, 95% CI
11.2% to 23.9%) were asymptomatic at the time of diagnosis.
QUALITY ASSESSMENT OF INCLUDED STUDIES
One hundred and twenty- one studies were determined to be
of good quality while eight were of fair quality (online supple-
mental table 8). Studies were primarily downgraded for incom-
plete case definition,29 31 44 46 48–50 130 135 138 incomplete case
follow- up,10 23 24 26 29 32 35 44 51 53 77 82 85 90 94 99 106 112–114 120 130
135–137 missing data2 3 19–21 29 35 42–44 52 57 74 89 92–94 117 128 and non-
consecutive patient enrolment,9 11 12 16 18–26 28 30–35 37–39 50 57 61–73
80 82 87 89–91 93 95 102 109 110 112 114 123 125 126 129 134–136 which raises
concern that the included sample could be biased towards more
severe presentations.
DISCUSSION
Global knowledge of COVID-19 epidemiology, clinical charac-
teristics and management has continued to evolve since the onset
of the pandemic. Children have been noted to have relatively
lower rates of severe illness and low mortality; however, they
have been impacted by MIS- C.4 139
The findings of our review, the largest in terms of published
systematic reviews on paediatric COVID-19, are consistent with
previous reviews that identified predominance of infection in
school- age children, slight male predisposition, prevalence of
comorbidities among children with COVID-19 and low hospi-
talisation and mortality rates.2 4 140 The clinical presentation in
children is heterogeneous, including a wide spectrum of clinical
features. Fever and cough were the most commonly reported
presenting symptoms, in line with the previously published
systematic reviews.4 141A U- shaped curve of severity has been
demonstrated in children diagnosed with COVID-19 with
infants under 1 year of age and adolescents 10–14 years of age
at higher risk of developing severe COVID-19.3 47 75 Due to lack
of age- disaggregated data, we could not reliably compare the
frequency of severe cases by age group in this review. Reported
risk factors for severe disease among children include age, viral
load142 and presence of comorbidities.3 There is a possibility that
children with comorbidities may have been hospitalised related
to their underlying chronic condition and incidentally deter-
mined to have COVID-19 infection or investigated more exten-
sively. Some of the common comorbidities reported in children
with COVID-19 infection include asthma, immunosuppression,
congenital heart disease, kidney disease and obesity.3 4 47
Regional differences were identified in the comparison of
clinical features, treatment and outcomes between HICs and
LMICs. Pooled estimates of hospital mortality were higher in
LMICs compared with HICs. Given that it was not possible
to calculate risk- adjusted mortality rates for COVID-19, it is
unclear whether observed differences in mortality are related to
selection bias (eg, differences in severity of illness of included
patients or differences in case definitions and inclusion criteria)
or differences in available hospital resources. Nevertheless, there
is ongoing concern that, in LMICs with high burden of illness
and health system limitations, children with severe disease and
MIS- C may be at greater risk for adverse outcomes and death
than perceived to date. The differences in frequency of observed
clinical features may be related to increasing recognition of
MIS- C over the course of the pandemic and their inclusion in
more recent COVID-19 case series, but is likely similar between
HICs and LMICs.
Comparisons of clinical features and outcomes according
to severity of illness were limited by heterogeneous reporting
across the included case series. A higher proportion of children
with severe disease demonstrated symptoms consistent with
MIS- C (fever, abdominal symptoms, rash, neurological symp-
toms, conjunctivitis) and received IVIG, steroids and inotropes.
Compared with previous reviews, several at an earlier stage
of the pandemic,4 7 8 140 143 this review has several strengths.
Using a broad search strategy implemented in English, Chinese
and Spanish databases, we summarise evidence from 129
studies from 31 different countries, the largest sample to- date.
We excluded case reports to minimise selective reporting of
extreme and atypical cases. We also attempted to reduce possible
overlap in cases to prevent duplications. We identified differ-
ences in features from studies in HICs compared with LMICs,
and between severe and non- severe cases, although with limited
available data. Finally, we report subgroup analyses for neonates,
and children presenting with MIS- C.
The review is limited primarily by the small sample sizes of
individual studies, limitations in study reporting, and study
quality limitations due to non- consecutive patient enrolment,
unclear case definition and incomplete follow- up to hospital
discharge. Our approach of pooling proportions is subject to bias
and wide confidence- intervals due to small study sample size.
We could not undertake multivariate analysis to identify risk
factors for severe infection or adverse outcome in children due
to lack of individual- patient- data. The inclusion of asymptom-
atic cases could have contributed to underestimation of the prev-
alence of clinical characteristics and optimism in the reporting
of outcomes. Finally, it should be noted that a large number
(36/129, 28.0%) of the included studies were from China.
While the Chinese healthcare system is well- resourced in certain
regions, many of the Chinese studies included were conducted
in the city of Wuhan or in Hubei Province (n=9, 32.1%), where
the gross domestic product per capita is less than half of that of
Beijing and Shanghai.144 Therefore, the findings of studies from
China may be generalisable to the socioeconomic and health
development status of other middle- income countries.
This review contributes to the global understanding of paedi-
atric COVID-19 disease and supports priority setting in research
for current pandemic and future outbreaks. This body of litera-
ture would be improved by complete reporting of larger series
with consecutive recruitment of patients, specific case definitions
and complete long- term follow- up to determine global epidemi-
ological trends, age‐specific burden of disease and illness trajec-
tory following COVID-19 infection. Improved characterisation
of disease severity and increased reports from low- income coun-
tries are needed to better understand differences in clinical mani-
festations, resource utilisation and outcome by region, which
can be integrated in future updated analyses. The concern for
selection bias remains as it is possible that in LMICs, the popu-
lation of hospitalised children was sicker and at higher baseline
risk of death, independent of resources. Individual- patient- data
meta- analysis would be of benefit to characterise risk factors
for severe disease, clinical features in different age groups and
account for observed differences in outcome. With respect to
clinical management, none of the therapies instituted in the
treatment of children with severe COVID-19 disease have been
demonstrated to improve outcome in randomised trials; there-
fore, a recommendation regarding their use is challenging. Given
that children appear less likely to develop severe respiratory
disease, but are at risk of multiorgan dysfunction due to MIS- C,
further studies are needed to characterise the clinical trajectory
of this novel syndrome and determine the optimal treatment for
it. Finally, there remains paucity of studies reporting long- term
prognosis of COVID-19 in children.145
on February 17, 2021 by guest. Protected by copyright.http://adc.bmj.com/Arch Dis Child: first published as 10.1136/archdischild-2020-321385 on 16 February 2021. Downloaded from
7
Irfan O, etal. Arch Dis Child 2021;0:1–9. doi:10.1136/archdischild-2020-321385
Global child health
CONCLUSION
Our review suggests that children predominantly contracted mild
form of infection but could be at risk of more severe outcomes. It
is crucial to take into consideration risk factors including contact-
exposure, underlying comorbidities, young age and male sex which
may increase the risk of severe disease. While we have identified
several elements that highlight the disease spectrum and higher risk
of adverse outcomes in certain settings, such as LMICs, there is the
need for much closer scrutiny of this illness globally with individual
patient data analysis.
Contributors ZB conceptualised the study and secured funding. ZSL and OI drafted
the study protocol, conducted the literature search, study screening, selection and
data extraction and drafted the manuscript. LJ and KT designed the data collection
instruments, collected data, carried out data analyses and reviewed and revised
the manuscript. FM drafted the initial manuscript and reviewed and revised the
manuscript. All authors critically reviewed the manuscript for important intellectual
content and approved the final manuscript as submitted. ZB is the guarantor.
Funding This review was funded in part by a grant from UNICEF (Headquarters) in
partnership with the International Pediatric Association and with core support from
the Centre for Global Child Health (Toronto) and the Center of Excellence in Women
& Child Health, The Aga Khan University, Karachi, Pakistan
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
Data availability statement Data are available upon request
Supplemental material This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non- commercial. See:http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
ORCID iD
ZulfiqarBhutta http:// orcid. org/ 0000- 0003- 0637- 599X
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