RESCEU CLINICAL STUDIES

RESCEU is developing a number of clinical studies across Europe. Although numerous studies on the subject of RSV infection have been performed in the past decades, there is still a lack of knowledge about how much burden this virus causes in certain populations. We know about high risk groups for severe RSV infection, such as children who are born prematurely and children with congenital heart or lung disease. However, RSV also causes severe disease in other groups such as term born children and older adults. Because these groups have not been identified as the classic high-risk groups, less research has been addressed to target these populations. RESCEU intends to address the knowledge gaps on RSV such as medical and economic burden in healthy term infants, elderly, and those with other illnesses.

In order to better understand the burden and impact of severe RSV disease in the above-mentioned populations, RESCEU has designed 4 Clinical Studies:

Birth cohort study
Infant case-control study
Older adults study
Chronic Obstructive Pulmonary Disease (COPD) study

The following clinical centres are participating:

University Medical Center Utrecht: birth cohort, infant case-control and older adults studies.
University of Oxford: birth cohort, infant case-control and older adults studies.
Servicio Galego de Saúde: birth cohort and infant case-control study.
Turku University Hospital: birth cohort study.
University of Antwerp: older adults study.
University of Edinburgh: birth cohort study.
Imperial College of London: Infant case-control and COPD studies.
University of Groningen: COPD study.

CLINICAL STUDY No. 1 – BIRTH COHORT [1]

Objective

RESCEU aims to understand the impact of severe RSV infection in healthy term babies. Much research has been performed on the occurrence of RSV infection in prematurely born children and children with underlying cardiac or pulmonary disease. However, the majority of new-borns are healthy and term born (being born after 37 weeks of pregnancy). We perform this study to get a better understanding of the frequency of RSV infection in these healthy children, to see which children develop more severe disease and how RSV impacts the quality of life in these children and their families.

Study Design

This clinical study is establishing a birth cohort of 10,000 healthy term born infants from large delivery centres across Europe. This study takes place in the United Kingdom, the Netherlands, Spain and Finland. Each centre recruits 2000 infants by approaching pregnant women shortly before or after giving birth.

Children start participating right after birth before any respiratory infection has taken place. The study is subdivided in two study groups (arms): an active surveillance arm and a passive surveillance arm. Both arms of the study focus on the disease burden of RSV but the active surveillance study entails collection of blood, nasal mucus, urine and stool as well as information collected from questionnaires, whereas the passive arm uses only information obtained via questionnaires. Sampling (collection of bodily fluids such as blood) takes place shortly after birth and during home visits in case the child has an actual respiratory infection. The samples which are collected in this study are used for biomarker analysis. Biomarkers are indicators of health which can indicate whether someone is more or less at risk of developing a certain illness. Biomarkers can be measured in blood, nasal mucus or other bodily fluids. We want to know if certain markers can tell us more about the risk of severe infection or whether symptoms can persist after the infection has gone. The two study arms are explained below.

Active surveillance cohort (1,000 participants)

Inclusion of participants starts in the first week after birth. If consent is given for participation in the active cohort, parents are asked to complete a questionnaire and samples (blood, nasal mucus, urine, stool) are taken in the first week of life.

During the first year of life we monitor the baby on any signs of respiratory infection by weekly contact with parents during RSV-season. If symptoms of respiratory illness are reported, a home visit is planned were we collect a bit of nasal mucus (snot) from which we can test whether the infection is caused by the RS-virus.This test can tell us within half an hour whether the infection is caused by RSV.

If RSV is present, permission is obtained from the parents to collect additional samples for biomarker analysis, consisting of a blood sample, a stool and a urine sample. The same samples will be repeated after 6-8 weeks, when the child is healthy again.

After the first year and at the end of year two and three, parents fill out a questionnaire. This questionnaire includes questions about respiratory symptoms such as wheezing (a whistling sound made by the child while breathing out), the use of respiratory medication, doctor’s visits for respiratory symptoms and questions about their quality of life. If a child is hospitalized during the study with a respiratory infection, we collect data from that hospital visit record to see what virus caused the infection on to see how the child was treated.

The study procedures of the active group are graphically displayed in the scheme below:

ARTI = acute respiratory tract infection. The RSV season is defined as 1^st of October until the 1^st of May.

[1] In research and statistics, a cohort is a group of individuals who share a characteristic at some specific time and who are then followed forward in time, with data being collected at one or more suitable intervals. The most common use of the term is to describe a birth cohort, in which all the group members are born in a specified time period (source: https://medical-dictionary.thefreedictionary.com/cohort).

Passive cohort (9,000 participants)

Parents that have decided/agreed to participate in the passive cohort are asked to complete a baseline questionnaire in the first week(s) after birth. After one year they will complete another questionnaire which includes a question to see if their child has been hospitalized due to an acute respiratory tract infection (ARTI). If so the study team will examine the hospital records to check if RSV has been documented. Should this be the case, information about the hospitalization will be obtained from medical data and parents will be asked to complete another questionnaire when their child turns 2 and 3 years, about persisting symptoms such as wheezing while breathing or repeated respiratory infections. If the child is not hospitalized in the first year of life, the study participation stops after the first year.

The study procedures of the passive group are graphically displayed in the scheme below:

CLINICAL STUDY No.2 – INFANT CASE-CONTROL

Objective

All children get infected by RSV during childhood. However, some children only get a runny nose while others suffer from severe breathing problems that require hospital admission. We do not know exactly why certain children experience more severe disease than others. Can we predict severe disease using biomarkers seen in the blood of children or based on a clinical profile? The aim of the study is to compare why certain children experience more severe symptoms while others have milder symptoms.

Study Design

This study involves children who are born at term and experience an infection caused by RSV. In contrast to the birth cohort study where participants are included before they get sick, participants in the case-control study are included at the time they experience a RSV infection. The main aim of the study is to look at biomarkers to see why certain children get sicker than others. Biomarkers are indicators of health which can indicate whether someone is more or less at risk of developing a certain illness. Biomarkers can be measured in blood, nasal mucus or other bodily fluids. We want to know if certain markers can tell us more about the risk of severe infection or whether symptoms can persist after the infection has gone. Also, we evaluate the impact of RSV infection on the quality of life using parental questionnaires. This study is called a case-control study because we want to compare groups of children; those cases of children who are admitted to hospital with an RSV infection, while the controls are children who have a RSV infection but do not need to be hospitalized. In total 500 previously healthy infants, 50 children with underlying disease and 80 healthy infants without RSV infection at all are studied. Table 1. Shows the different groups of children included in the study. There are multiple groups in this study because we want to compare biomarkers in children with different backgrounds (healthy or with underlying disease), and with various levels of severity of infection.

Samples are collected at the time of illness and 6-8 weeks after infection to look into biomarkers which can tell us more about why certain children experience more severe and prolonged disease than others.

Table 1. Number of participants per group in the Case-Control study
	Cases (hospitalized with RSV infection)	Controls (RSV infection but no hospitalization)	Healthy children (No RSV infection)
Healthy children	250	250	80
Underlying disease	25	25	–

The study procedures of the Case-Control study are graphically displayed in the scheme below:

CLINICAL STUDY No.3 – OLDER ADULTS>60 YEARS

Objective

Evidence from studies performed in the United States indicate that disease caused by RSV is not only limited to children but also affects older adults. Since no long-lasting immunity is obtained after an RSV infection, reinfection occurs. In older adults RSV can cause flu-like symptoms such as a runny nose, cough and fever but is also known to cause pneumonia which can require hospitalization. The RESCEU study in adults is designed to look at RSV in the older adults in order to better understand how often RSV occurs in this population, who gets sick and who develops more serious disease. Furthermore, we look at the impact of RSV infections on frailty and the quality of life in these participants.

Study Design

This study will take place during two consecutive winter seasons in which 500 participants are included each winter giving a total of 1,000 participants.

Older adults, aged 60 years and above, are recruited before the start of the winter season in August and September. During the winter season respiratory symptoms are monitored through weekly contact with the participant (either online or by telephone). In case of a respiratory infection a home visit is performed where a nasal mucus sample is collected to test whether the participant has an acute respiratory tract infection caused by RSV. In case RSV is present, additional collection of samples (blood, nasal mucus) is performed during the visit and again 6-8 weeks after the infection. During respiratory infections, participants complete a diary in which they score symptom severity, health care utilization and quality of life.

At the end of the season, all participants are visited once more for an end-of study visit to complete a questionnaire on respiratory symptoms, doctor’s visits and chances that have occurred during the study. These changes can be in presence of disease, use of medication and other influences that disease could have on their living.

The study procedure is summarised by the graph below:

CLINICAL STUDY No.4 – CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Objective

We know that people with pulmonary or cardiac disease are at increased risk of a severe infection caused by RSV. This has been studied in children but we are interested to see the incidence of RSV in adults with lung disease. More specifically, we look at adults with Chronic Obstructive Pulmonary Disease, also known as COPD. The purpose of this study is to determine the incidence rate of RSV infection, theburden of disease and impact on the quality of life.

Study Design

In total, 500 adults with a diagnosis of COPD will participate in this study. Participants are followed-up for 3 years to see how often they experience a respiratory infection or exacerbation of their COPD. All participants visit the clinic at the start of the study and then every 6 months for the next 3 years. During these visits, a questionnaire is filled out and lung function is measured. In addition, samples are taken for biomarker analysis. Biomarkers can be measured in blood, nasal mucus or other bodily fluids. We want to know if certain markers can tell us more about the risk of severe infection or whether symptoms can persist after the infection has gone.

During the whole study period participants keep track of/record symptoms of respiratory infections in a diary. If they experience an exacerbation they are instructed to come to the clinic for an exacerbation visit in combination with treatment. During this visit blood and respiratory samples are collected, a questionnaire is filled out and lung function is evaluated.

Study procedure is summarised in the chart below: