Clinical features of COVID-19 in Pediatric Patients, long term effects (COPP2-study).

Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) is currently
responsible for a severe pandemic. It was first reported in Wuhan, Hubei
province in China in December 2019 (1). In the Netherlands, the first case was
reported on February 27th, 2020. (RIVM). Currently, the United States of
America, Spain, Italy and France are also major outbreak sites (date March
31st).
The infection leads to the disease known as Corona Virus Disease 2019
(COVID-19). Clinical features in adults range from mild non-specific
respiratory symptoms (e.g. sore throat, cough, fatigue, mucus, myalgia,
headache) to a more severe illness (e.g. fever, pneumonia, acute respiratory
stress syndrome, septic shock and multi-organ failure.). In adults, an
estimated 80% of infections follow a mild course, 13.8% of patients have severe
complaints and 6.1% of patient suffer from a very severe disease. In China, the
case fatality rate was estimated 2.3%, but the true case fatality rate may be
lower if there are more mildly symptomatic cases that are not detected. (2-4).
The current data suggest that SARS-CoV-2 infection is less severe in children.
The first data, summarized in a systematic review, show that children have
accounted for 1-5% of diagnosed COVID-19 cases as well as have milder symptoms,
where deaths are extremely rare. Clinical signs are similar to adults, but
appear to arise much less frequently. (7) In the largest study to date, over
90% of 2.143 children with laboratory verified SARS-CoV-2 were asymptomatic or
had mild to moderate disease, 5.2% had severe disease (dyspnoea, central
cyanosis, oxygen saturation < 92%), and 0.6% had critical disease, needing ICU
admittance, because of respiratory failure, ARDS, shock, or multi-organ
failure. Those with critical disease had underlying health conditions. Severe
disease was mostly seen in the children aged less than one year. (7-8)

In the US, 2572 children tested positive for SARS-CoV-2. Of these, signs and
symptoms were known in 291 children: 56% showed fever, 54% cough, 13% shortness
of breath, 23% myalgia, 7.2% a runny nose, 24% a sore throat, 28% headache, 11%
nausea/vomiting, 5.8% abdominal pain, 13% diarrhea. Among 345 cchildren with
information on underlying conditions 23% had at least one underlying condition,
(50% asthma, 31% cardiovascular disease, 13% immunosuppression). Six patients
were admitted to an ICU and, unfortunately, 3 children died. Review of these
cases is ongoing to confirm COVID-19 as the likely cause of death. 32%
occurred in children aged 15-17, 27% in children 10-14 years, 15% in children
aged 5-9 years, 11% in children aged 1-4 year and 15% in children < 1 year. (21)
In a subgroup of children, chest CT scans were performed. Imaging features were
normal, or showed mild abnormalities (up to 30% in PCR-confirmed COVID-19) (18,
and data derived from a submitted study). Follow-up CTs improved in 30%, while
25% remained normal and only 12% showed deterioration.

During the current pandemic novel scientific information about COVID-19 in
children emerges quickly. Although respiratory complaints remain the main
reason for admittance, we also see a large group of especially young children
with fever as main presenting symptom and a group of young teenagers with a
systemic mucocutaneous-enteric illness, or diagnosis of Multisystem
Inflammatory Syndrome in Children, (MIS-C C, frequently resulting in ICU
admittance (11,12).). A survey by the Dutch Pediatric Society showed 10
additional patients who were diagnosed with PIMS-TSMIS-C, in the early months
of the pandemic in 2020 (1412). However, by February 2021, we have already
treated around 110 patients with MIS-C in Dutch Hospitals, about 50% was
admitted to the paediatric intensive care unit, due to severe cardiogenic shock
(data NVK webinar, 16-2-2021 and website COPP study
https://www.covidkids.nl/scientific-dashboard/).

Long-COVID is the lay term for long term complaints in the period of weeks to
months after COVID-19.In adults, many researchers have expressed their concern
about the high frequency of long-term complaints after the active phase of
COVID-19, resulting in persistent morbidity, reduced quality of life and
inability to participate in family and working life. Recent literature
describes a percentage of 10% of patients in the general population.
In the last couple of months multiple developments has led us to believe that
*long COVID* in children deserves more attention than it currently gets. In
scientific literature, case series of small cohorts of paediatric patients with
complaints of long COVID are emerging. Our own research group performed a
survey among Dutch paediatricians, revealing 89 cases of children, suspected of
long COVID, treated by Dutch paediatricians. All were not admitted in the
hospital in the acute phase of COVID-19, but were suffering from long term
complaints, like fatigue (87%), dyspnea (55%), concentration difficulties
(45%), headaches (38%), thoracic pain complaints (35%), stomach ache (33%). 36%
experienced severe limitations in daily functioning, like less or no school
attendance. We suspect that these children are only the tip of the iceberg
since some children with long-COVID may only be treated by the general
practitioner. Furthermore, long-COVID is still an unknown phenomenon to many
paediatricians, likely resulting in underdiagnosing.

The COPP and COPP-IMM study are two large multicenter, observational,
prospective cohort studies in hospital-setting in the Netherlands, on pediatric
COVID-19 and MIS-C.Currently, 53 of the 72 pediatric departments in the
Netherlands are participating in COPP and 13 out of 72 will participate in
COPP-IMM. From an international view this is an unique study in which national
collaboration of most pediatric departments provides an excellent overview of
the impact of COVID-19 in pediatric care. The COPP study and COPP-IMM study aim
to include all pediatric cases in hospitals in the Netherlands, and
collaborates closely with the Dutch Pediatric Society and researchers from all
seven University Medical Centers in the Netherlands.
For COPP2, we aim to include all children with COVID-19 who were diagnosed in
the outpatient department or were hospitalized, and who were included in the
COPP study or COPP-IMM study, in which their clinical features were described.
These study cohorts make it possible to give a scientific answer to our growing
concerns about long-COVID in children. Therefore, we sought collaboration with
different sections of the Dutch Pediatric Society. After consultation with
specialists we developed an algorithm for clinical follow-up procedures based
on symptoms or risk factors
In summary, next to follow-up of pulmonary sequela and quality of life, we will
also investigate neurocognitive and olfactory morbidity, and the long-term
immunological response in all patients. Depending on symptoms and risk factors
of these children, nephrological, cardiac or thrombotic sequelae will be
evaluated as standard care. We ask parents/caregivers and/or their children for
permission to retrieve the results of these investigations from their medical
file as part of our study.

primary objectives
- To asses sequelae of COVID-19, at 4 to 12-months following a COVID-19
diagnosis among pediatric patients receiving care in the hospital or outpatient
setting in the Netherlands.
- To determine risk factors for long-COVID among COVID-19 hospitalized and
outpatient pediatric patients in the Netherlands.
- To obtain a detailed immunological profile of children at 4-12 months of
follow-up after presenting to Dutch hospitals with COVID-19 or with SARS-CoV-2
related post-infectious inflammatory syndrome (MIS-C).


Secondary objectives
- To describe pulmonary function testing abnormalities in the follow-up of
children with COVID-19.
- To describe exhaled breath profiles (SpiroNose/GC-MS) in children with a
history of COVID-19.
- To describe CT abnormalities in patients with chronic respiratory complaints
and/or pulmonary function test abnormalities and a history of COVID-19.
- To assess the quality of life in all children with a history of COVID-19.
- To assess parental perception of cognitive functioning and executive
functioning in all children with a history of COVID-19
- To assess neurocognitive functioning in a consecutive sample of children with
a history of COVID-19 (aged 6 or older)
- To correlate the immunological profiles with detailed clinical parameters
- To evaluate if at 4 to 12 months follow-up there is robust cellular and
humoral immunity to SARS-CoV-2 in children who have presented to Dutch
hospitals with COVID-19 related disease.
- To determine if there is a difference in the long-term cellular and humoral
immunity to SARS-CoV-2 in children with COVID-19 COVID-19 related disease.
- To describe prevalence of olfactory dysfunction in children with a history
of COVID-19.
• To identify frequency and risk factors of increased fatigue (according to
PROMIS pediatric fatigue) in children with a history of COVID-19 or MIS-C.

Study design: This will be a multi-center, descriptive observational
prospective cohort study.

Duration: Following an initial baseline registration as part of the COPP study
or the COPP-IMM study, children and their caregivers will be requested to
return for a follow-up visit at 4 to 12 months after COVID-19 or MIS-C
diagnosis. We will enroll participants throughout a 1.5 year period.

Setting: Pediatric department. Children previously included at the COPP or the
COPP-IMM study who provided consent to be approached for a possible
participation in the COPP2 study. 53 hospitals are participating in the COPP
study, from April 2020 through March 2021 over 169 patients were included.
Seventeen COPP sites have currently expressed interest in participating in the
COPP-IMM study, which is currently under review at the METC-LDD
(NL76177.058.21). The exact number of children that will be included in both
COPP and COPP-IMM depends on the course of the pandemic, but we expect to
include at least 30 children in COPP-IMM, and at least 200 in COPP. Children
from both the COPP and COPP-IMM study will be asked to participate in the COPP2
study.

Description: Children aged 0-17 years who were diagnosed with COVID-19 will be
recruited from the COPP/COPP-IMM studies, if they gave permission to be
approached for follow-up studies.
Study measurements include: questionnaires and physical examination, growth
measurements and immunological profile for all children and exhaled breath
(SpiroNose/GC-MS), pulmonary function, exercise testing, odour identification
testing, urine testing, cardiac and nefrological markers, neurocognitive
evaluation and Chest CT scans in a subgroup of patients.

All participants will undergo:
- physical examination
- 5 questionnaires (1: pulmonary symptoms, 2: quality of life, 2:
neurocognitive functioning)
- blood withdrawal

A subgroup of patiënt will undergo:
- pulmonary function testing
- excercise testing
- exhaled breath analysis
- odour identification testing
- neurocognitive functioning testing

This study includes only minors. Since COVID-19 in children in less severe than
in adults, the long term effects cannot be deduced from future adult studies.
In the future, the results of this study may lead to a better understanding for
the need of follow-up of pediatric COVID-19 patients.
In the event that incidental findings are discovered, patients will be referred
to their general pediatrician or pediatric pulmonologist.


Physical examination takes approximately 5 minutes to perform.
The questionnaires take about approximately 55 minutes to fill in.
Pulmonary function testing takes 1 hour, patients, older than 4 years of age,
will be asked to breath in and out for several times. They will have a
moutpiece in their mouth and a clamp on their nose. Burden is low.
Body pleghysmography will be conducted in patients older than 8 years of age.
They will be asked to breath in and out for several times, with a mouthpiece in
their mouth and a clamp on their nose. Burden is low .
Excercise testing will take about 1 hour to perform. Children from 6 years of
age will be asked to excercise, also with a mouthpiece in their mouth.
Burden is low.
The analysis of exhaled breath is also simple. The child will be asked to
breath tidally through a mouthpiece into a breath sampling system, while
watching cartoons. It can be performed by children from 2 years old on and does
not cause any distress.
The Chest CT protocol consists of a CT without IV contrast, performed during
the inspiratory phase. When children can follow instructions, an expiratory
phase will be added (>6yr). Anesthesia is not needed to perform the CT scan;
young children will be held by a vacuum mattress, which holds them still, while
being comfortable. The scan takes about 1 minute to perform, with preparation
and explanation approximately 10 minutes in total time. a CT scan is only
performed in patiënt with persisting respiratory symptoms or pulmonary function
test abnormalities.
odour identification testing takes about 5 minutes and gives no burden.
bloodwithdrawal takes about 20 minutes and is a bit painful. We use positive
language and topical anaesthetic medication to reduce the burden.