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RSV ComNet I: disease burden of RSV infections in young children (<5 years) in primary care. Results of the pilot study in Italy & the Netherlands winter of 2019/20.

Summeren, J. van, Kwakkelstein, S., Hooiveld, M., Hendriksen, J., Caini, S., Korevaar, J., Dückers, M., Paget, J., Rizzo, C., Pandolfi, E., Gesualdo, F., Piccioni, L., Concato, C., Chironna, M., Loconsole, D., Meijer, A., Demont, C., Bangert, M. RSV ComNet I: disease burden of RSV infections in young children (5 years) in primary care. Results of the pilot study in Italy & the Netherlands winter of 2019/20. Utrecht: Nivel, 2020. 46 p.
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Introduction
Respiratory diseases are one of the leading causes of morbidity and mortality among young children, and respiratory syncytial virus (RSV) is the most common pathogen causing these respiratory diseases. RSV burden of disease studies have mostly been focused on the morbidity and mortality rates of RSV infections. With the development of respiratory syncytial virus (RSV) vaccine candidates and monoclonal antibodies, there is a need to better understand the burden of RSV infections among young children, especially in primary care.

Aim
The aim of this RSV ComNet pilot study is to develop and evaluate the feasibility of a disease burden study protocol to measure the clinical burden, health care utilisation and societal impact of RSV infections in children (<5 years) in primary care. The disease burden study protocol is piloted in two European countries, Italy and the Netherlands, in the winter season 2019/20. In addition, we have described the disease burden in Italy and the Netherlands.

Methods
In this prospective cohort study, children aged <5 years who visited their general practitioner (Netherlands) or paediatrician (Italy) (in the following primary care physician, PCP), met the WHO acute respiratory infection (ARI) case definition for RSV infection and had a positive lab-confirmed test result for RSV were eligible for the study.
At consultation (day 1), the PCP collected a nasopharyngeal swab (in the Netherlands also an oropharyngeal swab) and completed a short swabbing questionnaire (patient demographics and clinical symptoms). Parents completed two subsequent questionnaires, after 14 days (health care utilisation, days of illness, socio-economic impact and current health status) and after 30 days (quality of life, QoL, PedsQL questionnaire).
In Italy, the disease burden study protocol was implemented in a network of paediatricians more often involved in scientific studies and in the Netherlands in an existing routine influenza surveillance system. Another important difference between countries was the method of data collection: in Italy telephone interviews were used compared to digital questionnaires in the Netherlands.

Main findings
In Italy 293 children were swabbed, among which 119 (41%) were RSV positive and 116 were included in the RSV ComNet study. In the Netherlands, 152 were swabbed, among which 32 (21%) were RSV positive and 12 were included in the study. Parents completed the questionnaires in a short amount of time, in Italy the average time was 7 minutes on the Day_14 questionnaire and 10 minutes on the Day_30 questionnaire, in the Netherlands the average time was 4 minutes for both questionnaires. Although most children did return to their normal daily activities fourteen days after swabbing (92% in Italy and 83% in the Netherlands), a significant number of children did have persistent symptoms (34% and 67%, respectively).
The most important lessons learnt from this pilot study were that: 1) the size of the network of PCPs needs to be adequate to capture sufficient RSV positive cases, 2) regular communication between researchers, reference laboratories and PCPs is important for successful patient recruitment, 3) a personal approach to invite children (and parents) to participate in the study leads to a higher response rate, 4) the PedsQL QoL questionnaire is not appropriate in children under the age of five.
The results showed that 6% of the children in Italy (7/116) and 17% of the children (2/12) in the Netherlands were hospitalised. More specific details regarding the clinical burden, health care utilisation and societal impact are reported in the report.
Some small adjustments to the disease burden study protocol for future ComNet studies are suggested in the report. Most importantly we recommend to measure fever in the Day_1
RSV ComNet Country Reports final August 2020 5
questionnaire, measure the socio-economic impact of the RSV disease on both parents, measure the health care utilisation and socio-economic impact also over the period between the Day_14 and Day_30 questionnaire, and measure the complications related to the RSV disease in the Day_30 questionnaire. In addition, we advise against the use of the PedsQL questionnaire. Currently, we are exploring other opportunities to get insight into the QoL of the children, for example by measuring the impact of the child’s illness on the family.

Conclusions
This study showed that it is feasible to implement the RSV ComNet disease burden study protocol in a routine influenza surveillance system, as well as in a network of PCPs more often involved in scientific research. In addition, an RSV infection seems to cause a significant burden in young children (<5 years) in primary care, however, more research with larger sample sizes is needed in the future. For future studies it will be important to estimate the burden of RSV not only on an individual patient level but also on a population level.