Comorbidities, clinical characteristics and outcomes of COVID-19 in pediatric patients in a tertiary medical center in the Netherlands

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World Journal of Pediatrics
https://doi.org/10.1007/s12519-022-00564-y
RESEARCH LETTER
Comorbidities, clinical characteristics andoutcomes ofCOVID‑19
inpediatric patients inatertiary medical center intheNetherlands
AmritaBiharie1 · Maya W.Keuning1· Katja C.Wolthers2· DasjaPajkrt1
Received: 29 December 2021 / Accepted: 27 April 2022
© Children's Hospital, Zhejiang University School of Medicine 2022
* Amrita Biharie
a-biharie@hotmail.com
1 Department ofPediatric Infectious Diseases, Rheumatology
andImmunology, Amsterdam University Medical
Centers Location Academic Medical Center, University
ofAmsterdam, Meibergdreef 9, 1105AZAmsterdam,
Netherlands
2 Department ofMedical Microbiology, Amsterdam University
Medical Centers Location Academic Medical Center,
University ofAmsterdam, Amsterdam, Netherlands
Having pre-existing comorbidities is described as a risk
factor for more severe disease in adult corona virus disease
2019 (COVID-19) and in infections with SARS-CoV-1 and
MERS-CoV [1]. In adult SARS-CoV-2 infections, patients
with pre-existing underlying comorbidities, such as chronic
obstructive pulmonary disease, cardiovascular disease, dia-
betes and obesity, are more likely to have severe disease
compared to healthy adults [2]. An inconsistency is seen in
current findings on the association with comorbidities and
pediatric COVID-19 severity. An important limitation in cur-
rently available studies is limited data: severe disease is rare
in children compared to adults, and most studies describe
COVID-19 severity merely by reporting intensive care unit
(ICU) admission or mortality rates instead of detailed data
on clinical presentation and outcomes.
A severe manifestation of SARS-CoV-2 infection is multi
inflammatory syndrome in children (MIS-C), which usually
follows weeks after SARS-CoV-2 infection and is charac-
terized by gastrointestinal symptoms, muco-cutaneous signs
and cardiovascular involvement. Several studies describe the
association between comorbidities and incidence or mortal-
ity of MIS-C [3, 4]. To our knowledge, there are no data on
the association between pre-existing comorbidities and the
severity of MIS-C.
Thus, the primary aim of this retrospective study was
to describe in detail the pre-existing comorbidities and the
severity of SARS-CoV-2 infections in pediatric patients in a
tertiary medical center in the Netherlands. Second, we aimed
to assess the association between comorbidities and disease
severity of both acute COVID-19 and MIS-C in pediatric
patients. These data will help to determine which groups
of children are more vulnerable to severe acute COVID-19
and severe MIS-C, which could aid development of clinical
SARS-CoV-2 infection care and management strategies.
This retrospective, observational cohort study was car-
ried out at the tertiary medical center, Amsterdam UMC,
the Netherlands. Inclusion criteria were in- and outpatients
younger than or equal to 18years with a positive polymer-
ase chain reaction (PCR) test or serum antibodies (total Ig)
against SARS-CoV-2 between March 2020 and April 2021.
Patients were excluded when no data on clinical characteris-
tics of the SARS-CoV-2 infection were available.
Data describing pre-existing comorbidities, COVID-19
severity and clinical outcomes were retrieved from medi-
cal records. Comorbidities were assessed by extracting data
on pre-existing disorders based on ICD-10 codes and body
mass index (BMI). A pre-existing disorder was found to be
relevant when the disorder could potentially interact with
the immune system or other bodily functions which could
influence disease severity. The pre-existing comorbidities
were classified into comorbidity groups based on the affected
organ system. We used the definition of childhood obesity
using BMI corrected for age and sex in 2000 by Cole etal.,
to assess the prevalence of obesity for patients aged 2 years
or older [5].
Disease severity of pediatric acute COVID-19 was classi-
fied by Dong etal. into five categories: asymptomatic, mild,
moderate, severe and critical [6]. For statistical analyses,
asymptomatic, mild and moderate cases were combined
as non-severe disease, and severe and critical cases were
combined as severe disease. Based on the WHO criteria for
MIS-C and parallel to the classification mentioned above,
the severity of MIS-C was described as moderate, severe or
critical [6, 7]. Moderate cases were classified as non-severe,
and severe and critical disease were combined as severe dis-
ease for the statistical analysis. Clinical outcome described
hospitalization, ICU admission and mortality rates in both

World Journal of Pediatrics
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acute COVID-19 and MIS-C. Long-term symptoms after
acute COVID-19, known as post-COVID-19 syndrome, were
reported based on the clinical definition of post-COVID-19
syndrome according to the NICE guidelines [8]; symptoms
that developed during or after acute COVID-19 continuing
for more than 12weeks.
Data analysis was performed with Statistical Package for
the Social Sciences (SPSS) using Fisher’s or Fisher–Free-
man–Halton exact tests. A P value < 0.05 was considered
statistically significant. Odds ratios were calculated to
describe strengths of associations. In case of contingency
tables containing a value of zero, Firth’s penalized logistic
regression was used to calculate a corresponding odds ratio
for the Fisher’s exact test to mitigate sparse data bias [9].
A total of 83 patients were included in this study, among
which 46 patients had pre-existing comorbidities. In Table1,
data on demographics and patient characteristics are summa-
rized. Most common pre-existing comorbidities were obe-
sity (n = 10, 21.7%), respiratory disorders (n = 9, 19.6%) and
neurological disorders (n = 8, 17.4%). For a detailed descrip-
tion of pre-existing comorbidities in each comorbidity group
(Supplementary table).
From the 58 patients with acute COVID-19, 38 (65.5%)
had a pre-existing comorbidity. Most patients had mild
COVID-19 disease, in the patient group without comor-
bidities (n = 16, 80.0%) as well as in the patient group with
comorbidities (n = 24, 63.2%). All the eight patients with
severe or critical disease (13.8%), had pre-existing comor-
bidities. One of these patients died due to the consequences
of COVID-19. Table2 summarizes data on severity and hos-
pital admission per group (comorbidities versus no comor-
bidities). More severe acute COVID-19 was seen in patients
Table 1 Patient characteristics and key demographics
a Patients with negative or unknown PCR results were included only when (IgM and/or IgG) antibodies against SARS-CoV-2 in serum were pre-
sent. IQR interquartile range.
Patient characteristics No comorbidities
(n = 37)
Comorbidities
(n = 46)
Sex, n (%)
Male 23(62.2) 23 (50.0)
Female 14 (37.8) 23 (50.0)
Age, year, median (IQR) 11.0 (4.5–14.5) 11.5 (4.8–16.0)
Weight, kg, median (IQR) 44.3 (26.6–57.3) 45.7 (19.5–64.0)
Height, cm, median (IQR) 154.0 (122.5–168.0) 145.0 (110.0–168.0)
BMI, median (IQR) 18.6 (16.6–20.7) 18.9 (16.0–23.8)
Pre-existing comorbidities, n (%)
Obesity 10 (21.7)
Respiratory disorder 9 (19.6)
Systemic auto immune disorder 3 (6.5)
Neurological disorder 8 (17.4)
Cardiovascular disorder 5 (10.9)
Endocrine system disorder 4 (8.7)
Hematological disorder 2 (4.3)
Gastrointestinal disorder 3 (6.5)
Urogenital system disorder 6 (13.0)
Genetic/chromosomal abnormalities 6 (13.0)
Cancer 2 (4.3)
Other comorbidities 4 (8.7)
Pharmacological treatment, n (%) 27 (58.7)
Immunosuppressant medication 7 (15.2)
PCR confirmed SARS-CoV-2 infection, n (%) 22 (59.5) 37 (80.4)
PCR result negative or unknown, n (%)a15 (40.5) 9 (19.6)
Reason for testing, n (%)
Unknown 5 (13.5) 4 (8.7)
Clinical suspicion of SARS-CoV-2 infection 31 (83.8) 39 (84.8)
Symptoms suspicious for COVID-19 31 (83.8) 33 (71.7)
Contact with COVID-19 case 10 (27.0) 15 (32.6)
Routinely (before procedure) 1 (2.7) 2 (4.3)

World Journal of Pediatrics
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with pre-existing comorbidities compared to those without
comorbidities (P = 0.041, OR 11.42, 95% CI 1.29–1507.49).
Patients with a pre-existing comorbidity also had a higher
risk of being admitted to the ICU (P = 0.032, OR = 11.72,
95% CI 1.31–1547.79) than those without comorbidities.
In particular, the presence of a neurological disorder
was found to be associated with acute COVID-19 severity
(P = 0.004, OR 16.11, 95% CI 2.51–103.55). In the group
of neurological disorders, 63% had epilepsy or frequent sei-
zures, 50% had cerebral palsy, and other disorders included
hydrocephalus and myasthenia gravis. Other main groups of
disorders, such as obesity or respiratory disorders, did not
show a significant association with disease severity. Table3
contains the difference in acute COVID-19 severity (non-
severe vs severe) between all comorbidity groups.
Twenty-eight patients were diagnosed with MIS-C as a
manifestation of SARS-CoV-2 infection. Twenty-five per-
cent of MIS-C patients (n = 7) had a pre-existing comor-
bidity. Twelve patients (42.9%) met the criteria for critical
disease (Table2). The majority of MIS-C patients did not
have comorbidities, and no significant associations between
comorbidities and severity of MIS-C were found. The key
findings of this study indicate that, although most pediatric
patients have non-severe disease, children with pre-existing
comorbidities are more likely to have more severe acute
COVID-19 than children without comorbidities. In particu-
lar, pediatric neurological disorders were associated with
more severe COVID-19.
Considerable inconsistency is seen in current evidence on
the association between comorbidities and pediatric COVID-
19 severity. A meta-analysis by Tsankov etal. combined
the findings of several heterogeneous articles, concluding
an association between comorbidities and acute COVID-
19 severity [10]. However, most of the included studies
had a small sample size and only described the association
between comorbidities and ICU admission or mortality rate
instead of severity as a detailed description of clinical char-
acteristics. This could create selection bias because children
with comorbidities could be admitted to the ICU as a preven-
tative measure instead of due to clinical deterioration [10].
Our study methods included a detailed clinical evaluation to
describe COVID-19 disease severity following a classifica-
tion system in addition to ICU admission.
Corroborating our findings, two studies, performed in
other countries and using a similar classification system,
found that children with comorbidities have a higher risk
for more severe COVID-19, including a larger cohort of
3837 pediatric patients [11, 12]. The other study also found
an association between more severe COVID-19 and neuro-
logical disorders, which included mostly epilepsy or severe
neuro-disability similar to the patients in our study [11].
Another multicenter observational study in the UK also
found that among comorbidities in patients who needed criti-
cal care due to COVID-19, neurological disorders (such as
neurodisability) were one of the most common [13]. Neuro-
logical disabilities, such as cerebral palsy, which influence
motor functions, could lead to difficulties in spontaneous
breathing and clearing respiratory secretions, which could
worsen respiratory infections and thus explain this associa-
tion with more severe acute COVID-19. Moreover, SARS-
CoV-2 can affect the nervous system through damage to
neuronal cells, muscle tissues and vascular cells, which are
likely to be more vulnerable in children with comorbidities
[14].
In contrast, three of the studies that used a similar
classification of severity, all with relatively small sample
sizes, found that having comorbidities was not associated
with disease severity in pediatric patients [15–17]. This
inconsistency is possibly due to the missing consensus
on definitions of relevant pre-existing comorbidities and
to a missing universal classification of disease severity
of acute COVID-19. In our results, we particularly did
not find an association between obesity and severity of
acute COVID-19, which has been seen in some other stud-
ies [10, 11]. It is thought that higher visceral adiposity is
associated with higher inflammatory cytokine levels cor-
related with COVID-19 severity, which might explain why
more severe acute COVID-19 can be seen in obese patients
[10]. We also do not report an association between res-
piratory disorders, such as asthma, and acute COVID-19
severity, which is in accordance with findings related to
SARS-CoV-1 and MERS-CoV infections [18]. It is sug-
gested that human coronaviruses may not have the capac-
ity to enhance asthmatic inflammation, unlike the human
rhinovirus or respiratory syncytial virus [18].
Our findings imply that having comorbidities is not a
risk factor for having more severe MIS-C compared to
having no comorbidities. This is in accordance with previ-
ous findings that pre-existing comorbidities among MIS-C
patients are rare [3]. Healthcare professionals should be
aware of the association between pre-existing comorbidi-
ties and severity of COVID-19 to determine adequate man-
agement strategies for this specific group. Furthermore,
the implications made in this study should be taken into
consideration in the debate on SARS-CoV-2 vaccination
in children. It is worth noting that the absolute numbers
of severe disease due to acute pediatric COVID-19 are
low and that the size of the effect comorbidities has on
disease severity remains uncertain. However, effects of
the COVID-19 pandemic on children in particular, such as
social isolation and interruption in education, also should
be considered in future management or prevention strate-
gies [19]. This study substantiates the need for large-scale
studies with well-defined evaluation and classification

World Journal of Pediatrics
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of disease severity to determine the true strength of the
association.
The strengths of this study include the detailed informa-
tion on clinical characteristics and outcomes to carefully
assess the severity of COVID-19 infection and the asso-
ciation between the severity of MIS-C and pre-existing
comorbidities.
Our study has a few limitations. First, the retrospec-
tive observational study design may cause residual con-
founding. Second, because severe COVID-19 and hospital
admission is rare in children, our study consisted of a small
sample size. Selection bias may have affected the results,
because asymptomatic or mild children are not always
PCR-confirmed and, therefore, are under-represented.
Owing to the small sample, there was sparsity in numbers
included for statistical analyses, which contributes to the
broad confidence intervals. Various international databases
have been set up to prospectively study COVID-19 sever-
ity in patients with comorbidities, a promising develop-
ment [10]. Third, the study was carried out at a tertiary
center where mostly severely ill children or children with
complex comorbidities are treated, which can cause selec-
tion bias.
In conclusion, our findings show that pediatric acute
COVID-19 is mostly non-severe, but children with pre-
existing comorbidities are at risk for developing more severe
acute COVID-19 compared to patients without comorbidi-
ties. MIS-C is generally more severe than acute COVID-19.
However, no association was found between comorbidities
and severity of MIS-C. More prospective large-scale data
on the susceptibility of children with comorbidities for
severe acute COVID-19 are needed, as well as more data on
Table 2 Severity of disease and outcomes
Outcomes No comorbidities Comorbidities
Acute COVID-19 (n = 58) n = 20 n = 38
Severity, n (%)
Asymptomatic 0 (0) 2 (5.3)
Mild 16 (80.0) 24 (63.2)
Moderate 4 (20.0) 25 (10.5)
Severe 0 (0) 4 (13.2)
Critical 0 (0) 3 (7.9)
Hospital admission, n (%) 7 (35.0) 12 (31.6)
ICU admission, n (%) 0 (0) 6 (15.8)
Hospitalization duration, d, median (IQR)
Hospital admission 3.0 (0.0–6.0) 4.0 (2.0–11.0)
ICU admission 0 (0) 2.5 (1.8–10.3)
Mortality, n (%) 0 (0) 1 (2.6)
Post COVID syndrome, n (%) 6 (30.0) 2 (5.3)
Fatigue 4 (20.0) 2 (5.3)
Dyspnea 2 (10.0)
Concentration problems 2 (10.0)
Dizzines 1
MIS-C, n = 28 n = 21 n = 7
Severity, n (%)
Moderate 7 (33.3) 1 (14.3)
Severe 6 (28.6) 2 (28.6)
Critical 8 (38.1) 4 (57.1)
Hospital admission, n (%) 21 (100.0) 7 (100.0)
ICU admission, n (%) 11 (52.4) 5 (71.4)
Hospitalization duration, d, median (IQR)
Hospital admission 7.0 (5.0–8.0) 7 (7.0–10.0)
ICU admission 5.0 (3.0–6.0) 3.0 (2.5–6.5)
Mortality, n (%) 0 (0) 1 (0)
Long term complaints, n (%) 3 (14.3) 1 (14.3)

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risk factors for developing severe MIS-C to establish man-
agement strategies for SARS-CoV-2 infections in specific
groups of pediatric patients.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s12519- 022- 00564-y.
Author contributions AB: conceptualization, data curation, formal
analysis, investigation, methodology, project administration, visualiza-
tion, writing—original draft, and writing—review and editing; MWK:
conceptualization, project administration, visualization, writing—origi-
nal draft, and writing—review and editing; KCW: data curation and
resources; DP: conceptualization, project administration, resources,
software, supervision, and validation.
Funding None.
Data availability The data sets generated during and/or analyzed dur-
ing the current study are available from the corresponding author on
reasonable request.
Declarations
Ethical approval Approval and a waiver for the Medical Research
Involving Human Subjects Act was provided by the local medical
ethics review committee of Amsterdam UMC (Reference number
W21_273#21.300).
Conflict of interest No financial or non-financial benefits have been re-
ceived or will be received from any party related directly or indirectly
to the subject of this article.
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