REspiratory Syncytial virus Consortium in EUrope (RESCEU) study: Defining the burden of disease of Respiratory Syncytial Virus in Europe.

The REspiratory Syncitial virus Consortium in EUrope (RESCEU) is an Innovative
Medicine Initiative (IMI) effort funded by the EU under the H2020 framework to
define and understand the burden of disease caused by human respiratory
syncytial virus (RSV) infection. RSV causes severe disease in young infants. It
was estimated that RSV was associated with 34 million cases of acute
respiratory tract infection (ARTI), 3.4 million ARTI hospitalizations and
55,000 to 199,000 deaths in children <5 years in 2005 worldwide. These
estimates were based on limited data and there is a substantial gap in
knowledge on morbidity and associated healthcare and social costs in Europe.
New vaccines and therapeutics against RSV are in development and will soon be
available on the European market. RESCEU will deliver knowledge of the
incidence and burden of disease RSV in young children and older adults in
Europe, which is essential for stakeholders (governments, etc) to take
decisions about prophylaxis and treatment.

Since January 2020 the novel coronavirus SARS-CoV-2 has spread through the
world with an unprecedented morbidity and mortality especially in older adults.
Children seems less affected by this virus. Data about burden of disease and
the role of children in transmission of the virus are currently lacking. This
information is important for decisionmakers regarding measures to control the
spread of SARS-CoV-2, e.g. is it necessary to close schools and daycare centers
or can they open again.

In addition various new variants of SARS-CoV-2 have emerged. It is not yet
clear what the role of these new variants is in transmission and disease burden
within families.
There is more and more evidence that SARS-CoV-2 causes long-term symptoms but
the incidence and severity of symptoms is not yet clear, especially in children.

As part of the efforts to control the spread of SARS-CoV-2, governments have
recommended a number of protective behaviours to prevent the spread of
SARS-CoV-2. This has also led to changes in epidemiology of other viruses like
RSV, with an absent winter peak last winter. The question is what the role is
of protective behaviour and how much it is influenced by perceived risks.

RSV infection is known to be associated with recurrent wheezing in the first
year of life. It is still unclear whether RSV infection at a young age is
associated with the development of asthma at school age and the mechanisms of
this possible association.

To determine the burden of disease due to RSV in young term born infants.

The active cohort study is expanded to other family members during the COVID-19
pandemic to gain insight in COVID-19 related burden to families. In addition we
would like to evaluate the role of new SARS-CoV-2 strains in spreading and
burden within families with young children.

By extending follow-up to school age (6 years), we expect to gain important
information on the association between RSV infection in the first year of life
and the subsequent development of asthma.

Prospective epidemiological, observational, multi-country, multicenter, cohort
study.

Because the total study population is split in two seperate birth cohorts with
specific study procedures, they are explained separate below:

Passive birth cohort (N=9000)
Parents will be asked to fill out a questionnaire at inclusion and at age one
year. In case of a hospitalization for respiratory infection within the first
year, data of this specific hospital admission will be collected
retrospectively after consent. If no hospitalization occurs within the first
year, follow-up ends at one year.
Only children who were admitted to the hospital for ARTI during the first year
of life will be followed up to the age of maximum 3 years by yearly
questionnaires.These questionnaires focus on long-term respiratory symptoms
following a RSV associated hospitalization.

During 2021 participants will be invited online to participate to the
protective behaviours sub-study. Parents who agree to participate will be asked
to complete two times the same online questionnaire 3-4 months apart. The
questionnaires seek information on parents perceived risk of COVID-19, RSV
infections, influenza infections and common cold for their child enrolled in
the RESCEU birth cohort study, as well as perceived efficacy and past and
current use of protective behaviours against respiratory infections.

Active birth cohort (N=1000)
Parents are asked to fill in a baseline questionnaire at inclusion and yearly
questionnaires until the age of 3 years. In addition, a blood sample, a
nasopharyngeal swab, nasal mucosal lining fluid , a buccal swab, and stool and
urine samples will be collected in the first week after birth. Taking a
nasopharyngeal swab, nasal mucosal lining fluid and a buccal swab can give a
brief moment of discomfort at the moment of sampling.
During the RSV season (October - May) within the first year of life parents
will be contacted weekly (by telephone or email and/or by (daily) telephone
app) to monitor respiratory symptoms of their child. Parents are asked to
contact the study team if the infant experiences an ARTI. The study team will
visit the infant within 72 hours at home and take 1 nasopharyngeal swab to
perform a point of care (POC) test for RSV and RT-PCR (and additional analyses
if RSV is positive). If RSV is positive, informed consent will be asked for
participation in the biomarker sub-study (n=480, maximum). If included in the
biomarker sub-study, the following additional sampling procedures will be
performed by the study team at the moment of infection and 6-8 weeks after
infection: A venous puncture (max 4 ml blood), stool and urine samples, a
buccal swab, a nasopharyngeal swab and nasal mucosal lining fluid will be
collected.

During the acute respiratory tract infection, parents are asked to complete a
daily diary on respiratory symptoms and quality of life (parental and their
child) for as long as the respiratory episode is present. After a respiratory
episode, parents are asked to complete a more extensive questionnaire on
respiratory symptoms, health care use and quality of life.

Possible benefit:
There is no clear direct clinical benefit for the subjects participating in
this proposed study. However, the results of this study aim to support the
understanding of the burden of RSV disease which is important for the
implication of future preventive and therapeutic interventions. None of the
study procedures is associated with any risk for serious complications. If
possible, sample collection will be performed in addition to standard care
(e.g. in case of hospitalization with planned blood draws) to prevent an extra
moment of discomfort.
There is a risk of minor complications due to study procedures such as a nose
bleed after a nose swab or bruise after a blood draw. These complications are
generally infrequent and of minor severity.

COVID-19 related part
Information regarding the burden of disease of SARS-CoV-2 and the role of
children in transmission is currently lacking. Given the extent and severity of
the current pandemic, the burden and risks of participating outweights the
knowledge this research could add.

Families who participate in the active birth cohort who gave consent to be
informed about new studies will be invited to participate.

The COVID-19 related part consists of 2 parts:
1. Standard household follow-up
Parents are instructed to take a combined oro-and nasopharyngeal swab (viral
detection) and a saliva sample (antibodies) every 4-6 weeks from each member of
the household during 23 weeks (in total 4 times) and to fill out a short
questionnaire. This sample will be tested for SARS-CoV-2 within 72 hours.
Taking a combined oro-and nasopharyngeal swab can give a brief moment of
discomfort at the moment of sampling. In addition parents are contacted weekly
by means of a study app and will be instructed to contact the study team if any
member of the household developed respiratory symptoms (cough, sore throat,
runny or congested nose, dyspnea) and/or fever and/or loss of taste and smell.

2. Household outbreak study
When any member of the household has symptoms or a household member has a
positive SARS-CoV-2 test with the 4-6 weekly screening, all members will take a
combined oro-and nasopharyngeal swab, a saliva sample and a blood sample by
means of a finger prick. A finger prick can give a brief moment of discomfort
at the moment of sampling. Parents will get precise instructions how to do this
by themselves and their children. If parents/caretakers are reluctant to take
blood samples from a child, a study or home visit will be planned for this
procedure. Parents are asked to fill out a short diary (app) about symptom
severity for all family members during 21 days. If any other member of the
household will develop symptoms, another combined oro-and nasopharyngeal swab
and saliva sample will be taken from that household member and the symptom
diary will be prolonged for all household members until 21 days after the last
member started to develop symptoms. If any of the household members has a
positive SARS-CoV-2 test, all household members are asked to collect a stool
(SARS-CoV-2 PCR) and saliva sample (SARS-CoV-2 PCR and antibodies) weekly
during the period they fill out the diary. The finger prick will be repeated 10
days after the diaries have been finished.
Household members will participate maximum 2 times in the outbreak study.

There is no clear clinical benefit for the subjects participating in the
COVID-related part of the study. However, with the results of this study we aim
to obtain more information about the burden of SARS-CoV-19 infection in
children and their role in transmission which is important for the implication
of future preventive interventions (e.g. school closure).

3. CoKids Follow-up Study:
During the extended period from end of the original CoKids study up to the 1st
of July 2021, when a household member with ARI symptoms is identified (an index
case), the whole household will undergo testing through a combined oro- and
nasopharyngeal swab and oral sponges. Only the oro- and nasopharyngeal swab of
the index case will be tested initially. When a SARS-CoV-2 infection is
established, the rest of the household oro- and nasopharyngeal swabs will be
tested for SARS-CoV-2 as well. In addition, the type of SARS-CoV-2 strain will
be analyzed for all positive swabs. Serological testing using a finger prick
will only be done in case a SARS-CoV-2 infection of the index case is
established. All other routine procedures in the case of a SARS-CoV-2 infection
will remain the same as mentioned above in the household outbreak study.
When no SARS-CoV-2 infection is detected, no further PCR testing of other
household oro- and nasopharyngeal swabs will take place and the Corona outbreak
study will not be started.
In the event of new ARI complaints (suspected case) in another household
member, the whole household will be asked to collect an oro- and nasopharyngeal
swab and salivary sponges. Again only the oro- and nasopharyngeal of the
household member with new ARI complaints will be tested for SARS-CoV-2 in the
first instance, and when a SARS-CoV-2 infection is established, additional
testing of the remaining household swabs will be performed. A household will be
tested a maximum of two times during one episode, which is defined as: the
onset of complaints within another household member within 5 days after the
initial index case.

Additionally, a household that tested positive for SARS-CoV-2 will be matched
with a corresponding household who participated in the household outbreak
study. These households will be asked to fill out questionnaires to study
long-term sequelae of a SARS-CoV-2 infection, such as effects on general
well-being/functioning, cognition, fatigue, anxiety & depression and long term
symptoms (to study the possible presence of the so called *long-COVID*
syndrome). Matching a SARS-CoV-2 positive household with a household from the
outbreak study (SARS-CoV-2 negative) gives us the opportunity to evaluate the
different clinical symptoms and get a better understanding of the core symptoms
of a SARS-CoV-2 infection. These questionnaires will be asked to all family
members to fill out 6 and 12 months after infection.
Children aged 0-18 years will receive an additional questionnaire 4 weeks and
12 weeks after their SARS-CoV-2 test.

4. Extension until 6 year of age
Parent of participating children will complete a questionnaire after 4, 5 and 6
years. If there has been a hospital admission due to respiratory complaints in
the last year, data from this specific admission will be collected after
permission from the parents. There are no direct benefits to participating. The
results of the study may contribute to better knowledge about the disease
burden of RSV, which is important for future treatment or implementation of
prevention strategies.