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Summary
Lancet Child Adolesc Background After the acute phase of SARS-CoV-2 infection, children can develop long COVID symptoms. We aimed
Health
to investigate the prevalence of long-lasting symptoms, the duration and intensity of symptoms, quality of life,
2022; 6: 614–23
number of sick days and absences from daycare or school, and psychological and social outcomes in children aged 0–
Published Online
June 22, 2022 14 years who had been infected with SARS-CoV-2 relative to controls with no history of SARS-CoV-2 infection.
https://doi.org/10.1016/
S2352-4642(22)00154-7 Methods A nationwide cross-sectional study was conducted including children with a confirmed SARS-CoV-2-positive
See Comment page 595 PCR test (cases) and matched controls from Danish national registers. A survey was sent to mothers (proxy reporting)
Department of Cardiology of children aged 0–14 years who had had a positive SARS-CoV-2 test between Jan 1, 2020, and July 12, 2021, and a
(Prof S Kikkenborg Berg PhD, control group matched (1:4) by age and sex. The survey included the Pediatric Quality of Life Inventory (PedsQL) and
P Palm PhD,
the Children’s Somatic Symptoms Inventory-24 (CSSI-24) to capture current overall health and wellbeing, and
Prof H Bundgaard DMSc,
A Vinggaard Christensen PhD), ancillary questions about the 23 most common long COVID symptoms. Descriptive statistics and logistic regression
Department of Paediatrics and analysis were used. Clinically relevant differences were defined as those with a Hedges’ g score greater than 0·2. This
Adolescents Medicine study is registered at ClinicalTrials.gov (NCT04786353).
(U Nygaard PhD),
and Department of
Infectious Findings Responses to the survey were received from 10 997 (28·8%) of 38 152 cases and 33 016 (22·4%) of 147 212
Disease controls between July 20, 2021, and Sept 15, 2021. Median age was 10·2 years (IQR 6·6–12·8) in cases and 10·6 years
(Prof S Dam Nielsen DMSc), (6·9–12·9) in controls. 5267 (48·2%) cases and 15 777 (48·3%) controls were female, and 5658 (51·8%) cases and 16 870
Rigshospitalet, Copenhagen
(51·7%) controls were male. Cases had higher odds of reporting at least one symptom lasting more than 2 months than
University Hospital,
Copenhagen, Denmark; Faculty did controls in the 0–3 years age group (478 [40·0%] of 1194 vs 1049 [27·2%] of 3855; OR 1·78 [95% CI 1·55–2·04],
of Health and Medical p<0·0001), 4–11 years age group (1912 [38·1%] of 5023 vs 6189 [33·7%] of 18 372; 1·23 [1·15–1·31], p<0·0001),
Sciences, University of and 12–14 years age group (1313 [46·0%] of 2857 vs 4454 [41·3%] of 10 789; 1·21 [1·11–1·32], p<0·0001). Differences
Copenhagen,
Copenhagen, Denmark
in CSSI-24 symptom scores between cases and controls were statistically significant but not clinically relevant. Small
(Prof S Kikkenborg Berg, clinically relevant differences in PedsQL quality-of-life scores related to emotional functioning were found in favour
U Nygaard, Prof H Bundgaard, of cases in the children aged 4–11 years (median score 80·0 [IQR 65·0–95·0]) in cases vs 75·0 [60·0–85·0] in
Prof S Dam Nielsen); The controls; p<0·0001) and 12–14 years (90·0 [70·0–100·0] vs (85·0 [65·0–95·0], p<0·0001). PedsQL social
National Institute of Public
Health, University of Southern
functioning scores were also higher in cases (100·0 [90·0–100·0] than controls (95·0 [80·0–100·0]) in the 12–14
Denmark, Copenhagen, years age group (p<0·0001; Hedges g>0·2).
Denmark (M N S Petersen MSc,
S Rosenkilde MSc, Interpretation Compared with controls, children aged 0–14 years who had a SARS-CoV-2 infection had more prevalent long-
A B Thorsted MSc,
Prof A K Ersbøll
lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social
PhD, functioning in cases than in controls in older children. The burden of symptoms among children in the control group
Prof L C Thygesen PhD) requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be
Correspondence to: beneficial.
Prof Selina Kikkenborg Berg,
Department of Cardiology,
Rigshospitalet, Copenhagen
Funding A P Møller and Chastine Mc-Kinney Møller Foundation.
University Hospital,
2100 Copenhagen, Denmark Copyright © 2022 Elsevier Ltd. All rights reserved.
selina@rh.dk
Research in context
Evidence before this study duration of each symptom and the intensity of the
symptom, Before designing this study, we searched PubMed in as well as including findings on psychological wellbeing,
social Jan 4, 2021, to identify studies investigating long COVID in wellbeing, and daycare and school absence during the
children. The search terms used were “child” OR “children” AND pandemic. The present study supports the findings from the
“COVID-19” AND “symptoms” OR “long COVID”. We found one literature, and contributes a large data set including a
control paper from Sweden, including a case description of five group.
children. We searched Google Scholar and found one preprint
Implications of all the available evidence
study from Italy that included 75 post-COVID-19 children with
Results from this LongCOVIDKidsDK study—combined with
no control group and a website (longcovidkids.org) reporting a
survey of child long COVID symptoms. Furthermore, we findings from other studies that included a control group—
have shown persistent symptoms to be more prevalent in
searched ClinicalTrials.gov for ongoing studies in the COVID-19
children after SARS-CoV-2 infection; however, the clinical
database. The first papers reporting on long COVID in children
differences on a population level seem to be small.
found high prevalence of long-lasting symptoms but were
Knowledge of long COVID in children is important to guide
clinical
small, did not include the youngest children, and lacked
recognition and management of COVID-19. Furthermore,
laboratory-confirmed SARS-CoV-2 test results and a control
group. Few recent studies including controls have reported the findings on the symptom burden among children in the
control group require attention, as pandemic symptoms
symptoms to also be highly prevalent among controls. As of
due to lockdown and social distancing have been suggested.
October,
COVID to2021, a new case
be symptoms definition
lasting 8 weeksfrom
or WHO defines
longer, whichlong
is Looking atand
recognised the multi-professional
available evidence, long
long COVID
COVIDmust be for
clinics
seldom reported in earlier studies, in which 4 weeks was often
children might be beneficial. Long school closures and social
used as a cutoff.
distancing might compromise children’s wellbeing and
Added value of this study quality of life during a pandemic.
We investigated long COVID according to the WHO case
definition in children aged 0–14 years. We reported on the
conducted by parent proxy report and was sent to mood swings, nausea, fever, loss of appetite, trouble
mothers, or to a father or legal guardian if no mother breathing, dark circles under the eyes, palpitations,
existed,17 of all children who tested positive for SARS- trouble remembering or concentrating, cold hands or
CoV-2 in Denmark and of matched controls. From feet, cough, chapped lips, dizziness when standing, light
15 years of age, adolescents can legally receive mail sensitivity, discoloured fingers or toes, and extreme
from public institutions; therefore, adolescents aged paleness. The following symptoms were not asked
15–18 years responded to the survey themselves, and are about in the 0–2 years age group: chest pain, headache,
reported in a separate publication.14 Questionnaires, sore throat, dizziness, trouble remembering or
including an invitation and two reminders, were sent concentrating, dizziness when standing, and light
by mail via e-Boks (a secure digital post-box) and sensitivity.
answered in REDCap (a web application for online The CSSI-24 is a 24-item generic questionnaire
surveys) between July 20 and Sept 15, 2021.18 identifying the presence of various somatic symptoms
All Danish children and adolescents aged 0–14 years in children. The items are scored on a five-point Likert
with a positive SARS-CoV-2 test registered between scale from zero (not at all) to four (a whole lot) in
Jan 1, 2020, and July 12, 2021, were included and sent the past 2 weeks. A higher sum score indicates more
invitations. Participants were identified from the Danish somatic distress.19 The CSSI-24 was not included in the
COVID-19 database, which covers all Danes with a positive survey for the 0–2 years age group as the symptoms
SARS-CoV-2 test. As of July 12, the database included would be too difficult to assess for that age group.
4·2% of Danes aged 0–14 years. At the same time, The 23-item generic questionnaire PedsQL consists of
controls who had never had a positive SARS-CoV-2 test four dimensions of health-related quality of life in
were identified from the Danish Civil Registration children aged 0–14 years. The questionnaire is available
System and included using exposure density matching in different versions with items appropriate for
by sex and age in a 1:4 ratio at the time of the cases’ different age groups. The dimensions include physical,
positive tests. All participants were alive at inclusion. emotional, social, and daycare or school functioning
Notably, open public testing free of charge was available over the previous month.20 The scores range from 0–
for all by August, 2020, whereas testing was only 100, with higher scores indicating better health.
available for symptomatic cases before that date. Thus, Questions were included about sick leave and
the control group might include children who had had absence from daycare or school within the past year
COVID-19 and who were initially asymptomatic and and height and weight. The WHO classification of
therefore not tested. weight status in children and adolescents was used.22
In the survey, controls were asked whether they Parents of children with a SARS-CoV-2 positive test
suspected that they had been infected with SARS-CoV-2 were asked subjectively to assess the perceived acute
even though they did not have a positive test. Controls symptom burden within the first 4 weeks following the
who reported suspicion of having been infected by positive test as either no symptoms, mild symptoms, or
SARS-CoV-2 but who had not been tested were severe symptoms. These categories were not further
excluded from the analyses. Controls who were defined.
infected in the time between register extraction of the
population (July 12, 2021) and invitation to survey were Data sources and management
instructed not to reply. Cases were asked questions about the 23 common long
The study was permitted by the data protection COVID symptoms for the period since the SARS-CoV-2
agency (P-2021-195) and registered at ClinicalTrials.gov infection was diagnosed, including questions about
(NCT04786353). Register data access was granted by The symptom intensity (never, almost never, sometimes,
Danish Health Data Authority (FSEID 00005625 and often, or almost always) and duration (eg, 1 week, 1
00005757). Ethics committee approval is not required for month, 2 months), up to a duration of 12 months or
surveys in Denmark. longer. The control group was asked about the same
symptoms and was divided into four random groups of
Variables equal size with 3, 6, 9, or 12 months recall times to
Survey data were collected using ancillary questions match the varying recall times in the case group.
regarding long-lasting COVID-19-related symptoms We defined long-lasting symptoms as those lasting
See Online for
appendix
(appendix p 28), as well as the validated questionnaires 2 months or longer, in line with the WHO definition of
Children’s Somatic Symptoms Inventory (CSSI-24)19 and long COVID.5 In these analyses, participants were only
Pediatric Quality of Life Inventory (PedsQL), which included if they had a recall period long enough to have
captured current overall health and wellbeing. 20 Ancillary potentially had a symptom for 2 months. Participants
questions about long COVID symptoms included the with a recall period less than 2 months were excluded. We
23 most common symptoms identified from the Long also did a sensitivity analysis in which we defined long
COVID Kids Rapid Survey January 2021.21 The COVID as symptoms lasting for more than 12 weeks,
symptoms were stomach ache, chest pain, headache, because other guidelines define the presence of
fatigue, pain in muscles or joints, sore throat, symptoms lasting for 3 months or longer as long
dizziness, rashes, COVID.6
A Age 0–3 years Children with symptoms, n/N (%) OR (95% CI) p value
Cases Controls
Stomach aches
Fatigue 40/1194 (3·4%) 53/3855 (1·4%) 2·48 (1·63–3·77) <0·0001
Pain in muscles or joints 41/1194 (3·4%) 36/3855 (0·9%) 3·50 (2·21–5·55) <0·0001
Rashes 5/1194 (0·4%) 7/3855 (0·2%) 1·84 (0·54–6·30) 0·33
Mood swings 53/1194 (4·4%) 104/3855 (2·7%) 1·57 (1·11–2·22) 0·010
Nausea 73/1194 (6·1%) 146/3855 (3·8%) 1·63 (1·22–2·19) 0·0011
Fever 5/1194 (0·4%) 1–4/3855 8·30 (1·61–42·91) 0·011
Loss of appetite 22/1194 (1·8%) 13/3855 (0·3%) 5·89 (2·95–11·77) <0·0001
Trouble breathing 49/1194 (4·1%) 42/3855 (1·1%) 3·72 (2·44–5·67) <0·0001
Dark circles under eyes 18/1194 (1·5%) 12/3855 (0·3%) 4·40 (2·13–9·11) <0·0001
Palpitations* 17/1194 (1·4%) 9/3855 (0·2%) 6·15 (2·60–14·55) <0·0001
Cold hands or feet ·· ·· ·· ··
Cough 14/1194 (1·2%) 12/3855 (0·3%) 3·94 (1·81–8·56) 0·0005
Chapped lips* 77/1194 (6·4%) 55/3855 (1·4%) 4·65 (3·27–6·64) <0·0001
Discoloured fingers or toes* ·· ·· ·· ··
Extreme paleness ·· ·· ·· ··
6/1194 (0·5%) 5/3855 (0·1%) 3·25 (0·94–11·24) 0·063
Stomach aches
Chest pain 60/2857 (2·1%) 244/10 789 (2·3%) 0·91 (0·68–1·22) 0·54
Headache 23/2857 (0·8%) 25/10 789 (0·2%) 3·53 (2·00–6·24) <0·0001
Fatigue 142/2857 (5·0%) 346/10 789 (3·2%) 1·55 (1·27–1·90) <0·0001
Pain in muscles or joints 285/2857 (10·0%) 807/10 789 (7·5%) 1·39 (1·21–1·60) <0·0001
Sore throat 82/2857 (2·9%) 218/10 789 (2·0%) 1·47 (1·13–1·90) 0·0036
Dizziness 30/2857 (1·1%) 20/10 789 (0·2%) 5·32 (2·99–9·46) <0·0001
Rashes 50/2857 (1·8%) 83/10 789 (0·8%) 2·32 (1·63–3·31) <0·0001
Mood swings 81/2857 (2·8%) 293/10 789 (2·7%) 1·03 (0·81–1·33) 0·79
Nausea 230/2857 (8·1%) 1113/10 789 (10·3%) 0·75 (0·65–0·88) 0·0002
Fever 38/2857 (1·3%) 118/10 789 (1·1%) 1·25 (0·86–1·81) 0·24
Loss of appetite 1–4/2857 5/10 789 (0·1%) 2·98 (0·80–11·10) 0·10
Trouble breathing 93/2857 (3·3%) 288/10 789 (2·7%) 1·22 (0·96–1·54) 0·11
Dark circles under eyes 37/2857 (1·3%) 48/10 789 (0·4%) 2·94 (1·91–4·53) <0·0001
Palpitations 63/2857 (2·2%) 195/10 789 (1·8%) 1·24 (0·93–1·65) 0·15
Trouble remembering and concentrating 19/2857 (0·7%) 41/10 789 (0·4%) 1·66 (0·95–2·90) 0·073
Cold hands or feet 170/2857 (6·0%) 697/10 789 (6·5%) 0·91 (0·76–1·08) 0·29
Cough 79/2857 (2·8%) 272/10 789 (2·5%) 1·12 (0·87–1·44) 0·40
Chapped lips 22/2857 (0·8%) 33/10 789 (0·3%) 2·39 (1·38–4·15) 0·0018
Dizziness when standing 59/2857 (2·1%) 178/10 789 (1·6%) 1·26 (0·94–1·70) 0·12
Light sensitivity 50/2857 (1·8%) 94/10 789 (0·9%) 2·10 (1·48–2·97) <0·0001
Discoloured fingers or toes 29/2857 (1·0%) 146/10 789 (1·4%) 0·74 (0·49–1·11) 0·14
Extreme paleness 1–4/2857 10/10 789 (0·1%) 1·51 (0·47–4·81) 0·45
17/2857 (0·6%) 78/10 789 (0·7%) 0·82 (0·48–1·38) 0·45
0·25 0·50 1·00 2·00 4·00 8·00 16·00
Figure 2: Forest plot of symptoms lasting at least 2 months in cases and controls
OR=odds ratio. *For the 0–3-years age group, estimates are not shown for palpitations, chapped lips, and discoloured fingers or toes because the groups were too small.
1–12 months 13–24 months 2–3 years* 4–11 years 12–14 years
Cases Controls Cases Controls Cases Controls Cases Controls Cases Controls
(n=105) (n=348) (n=427) (n=1062) (n=917) (n=2445) (n=6032) (n=18 372) (n=3516) (n=10 789)
CSSI-24
Mean (SD) NA NA NA NA 2·5 (4·8) 2·5 (4·2) 3·0 (5·1)† 3·4 (4·8)† 4·3 (7·0)† 4·7 (6·2)†
Median (IQR) NA NA NA NA 1·0 (0·0–3·0) 1·0 (0·0–3·0) 1·0 (0·0–4·0) 2· 0 (0·0–5·0) 1·0 (0·0–5·0) 3·0 (1·0–5·0)
PedsQL
Physical functioning
Mean (SD) 93·7 (11·2)† 87·8 (12·2)† 94·2 (9·1)† 87·3 (12·0)† 94·8 (10·2) 94·8 (8·2) 94·7 (11·4)† 92·9 (11·8)† 93·0 (13·0)† 91·2 (13·3)†
Median (IQR) 100·0 91·7 100·0 88·9 100·0 100·0 100·0 96·9 100·0 96·9
(91·7–100·0) (79·2–100·0) (91·7–100·0) (80·6–97·2) (93·8–100·0) (90·6–100·0) (93·8–100·0) (90·6–100·0) (90·6–100·0) (87·5–100·0)
Physical symptoms
Mean (SD) 84·4 (13·0) 85·1 84·9 (12·9)†‡ 89·1 (9·7)†‡ NA NA NA NA NA NA
(80·0–92·5)
Median (IQR) 85·0 (75·0– 87·5 87·5 (77·5– 90·0 (82·5– NA NA NA NA NA NA
95·0) (80·0–92·5) 95·0) 97·5)
Emotional functioning
Mean (SD) 75·5 (16·9) 75·8 (13·7) 73·6 (16·2)†‡ 77·0 (12·8)†‡ 75·5 (18·1) 73·5 (15·4) 78·2 (19·1)†‡ 73·3 (18·0)†‡ 83·2 (19·5)†‡ 79·2 (19·2)†‡
Median (IQR) 75·0 79·2 75·0 77·1 75·0 75·0 80·0 75·0 90·0 85·0
(64·6–89·6) (68·8–85·4) (62·0–85·4) (68·8–87·5) (65·0–90·0) (65·0–85·0) (65·0–95·0) (60·0–85·0) (70·0–100·0) (65·0–95·0)
Social functioning
Mean (SD) 94·7 (9·3) 93·0 (11·4) 93·3 (11·0) 93·0 (9·9) 93·8 (10·8)† 93·0 (10·8)† 92·3 (13·3)† 89·6 (15·0)† 91·4 (15·4)†‡ 87·9 (17·5)†‡
Median (IQR) 100·0 100·0 100·0 95·0 100·0 100·0 100·0 95·0 100·0 95·0
(93·8–100·0) (87·5–100·0) (90·0–100·0) (90·0–100·0) (90·0–100·0) (90·0–100·0) (90·0–100·0) (85·0–100·0) (90·0–100·0) (80·0–100·0)
School functioning
Mean (SD) NA NA NA NA 92·9 (12·1) 93·0 (11·3) 86·8 (15·3)† 84·2 (15·4)† 83·7 (18·0)† 80·9 (17·8)†
Median (IQR) NA NA NA NA 100·0 100·0 90·0 90·0 90·0 85·0
(90·0–100·0) (91·7–100·0) (80·0–100·0) (75·0–95·0) (75·0–100·0) (70·0–95·0)
Cognitive functioning
Mean (SD) 87·7 (17·4) 88·6 (16·0) 87·3 (16·5)† 84·7 (16·3)† NA NA NA NA NA NA
Median (IQR) 100·0 100·0 (75·0– 94·4 (77·8– 88·9 (75·0– NA NA NA NA NA NA
(75·0–100·0) 100·0) 100·0) 100·0)
among those aged 12–14 years, fatigue, mood swings, (table 2).
and trouble remembering or concentrating were most
common. The prevalence of symptoms lasting at least 2,
3, 6, 9, and 12 months are presented in the appendix
(pp 3–13). With increasing duration of symptoms, the
proportion of children with those symptoms tended to
decrease.
In cases
CSSI-24=Children’s Somatic Symptoms agedPedsQL=Pediatric
Inventory. 12–14 years,Quality
moreofgirls than boys
Life Inventory. had at
*Missing school functioning scores: 27 cases, 77 controls. †Statistically significant (p<0·0009), based o
Table 2: Symptom burden and health-related quality of life in COVID-19 cases and controls
least one symptom lasting more than 2 months (732
[52·7%] of 1390 vs 573 [39·6%] of 1448; OR 1·70 [95% CI
1·47–1·97],
p<0·0001), and a similar pattern was seen in the control
group (2388 [46·1%] of 5176 vs 2010 [36·8%] of 5465;
1·47
[1·36–1·59], p<0·0001). In the younger age groups,
sex differences were only found for controls aged 4–11
years (3054 [34·6%] of 8818 vs 3079 [32·8%] of
9383; 1·15
[1·08–1·23], p<0·0001; appendix p 14).
For CSSI-24 symptom scores, we found differences
between cases and controls that were statistically
significant but not clinically relevant (Hedges’ g≤0·2)
www.thelancet.com/child-adolescent Vol 6 September 6
Articl
Discussion
In this study of Danish children with a history of SARS-
CoV-2 infection and age-sex-matched controls with no
history of SARS-CoV-2 infection, we found that cases in
all age groups had higher odds of having long-lasting
symptoms, but cases in the oldest age groups (4–11
and 12–14 years) had better quality-of-life scores than
did controls. Additionally, cases had more sick days
and more daycare or school absences than did controls
www.thelancet.com/child-adolescent Vol 6 September 6
Articl