FormalPara Key Summary Points

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infection and hospitalisation for respiratory illness in children under 5 years of age worldwide.

Seasonal RSV infection and its consequences (such as bronchiolitis) place considerable burden on healthcare systems, including in France, emphasising the importance of strategies to reduce RSV transmission, such as efficient epidemiology tracking to anticipate and plan healthcare resources.

Non-pharmaceutical interventions have been shown to reduce transmission and associated hospitalisations and intensive care admissions.

Pharmaceutical approaches to prevent RSV infection include passive immunisation via maternal vaccination or administration of long-acting monoclonal antibodies at birth (or soon after), and active immunisation of infants.

The implementation of national RSV surveillance programs combined with parent education regarding the importance of reducing RSV transmission, and a routine RSV primary prevention program (incorporating immunisation strategies) will assist in reducing the impact of RSV infection on the French healthcare system.

Introduction

Respiratory syncytial virus (RSV) is a highly contagious single-stranded, negative-sense RNA virus that infects most children at least once by the age of 2 years [1, 2]. RSV is the most common cause of acute lower respiratory tract infection (LRTI) and hospitalisation for respiratory illness in children under 5 years of age worldwide [3, 4]. Infections usually follow a seasonal pattern, the timing of which varies by year and geographical location [5]. In temperate Northern Hemisphere countries, including France, increased RSV burden generally coincides with colder temperatures in the period from October/November to March/April, with peak infection rates in France in November/December [5, 6]. This causes additional strain on hospitals already facing overlapping seasonal epidemics of other respiratory viruses such as influenza [7].

Infection with RSV does not provide durable immunity and, therefore, reinfections frequently occur, although these are generally milder than primary infections [2, 8]. Primary and recurrent RSV generally starts as an upper respiratory tract infection that tends to be more severe and prolonged than a common cold [2]. Most children have a self-limiting course of disease that responds to supportive home care [2, 9]. However, during the first year of life, otherwise healthy infants with a primary RSV infection are at increased risk of progressing to severe LRTI, with the highest risk during the first 3 months of life [10]. Although the risk of severe disease and hospitalisation is highest in children with known risk factors (prematurity or comorbidities) [11], up to 90% of children hospitalised with RSV-related LRTI are born at term and have no underlying medical conditions [10, 12, 13].

Bronchiolitis is an inflammation of the small airways of the lungs that typically presents in children in the first 2 years of life and is commonly associated with RSV infection [9, 14,15,16]. Acute viral bronchiolitis may vary from mild respiratory symptoms, such as cough, tachypnoea, and increased respiratory effort [2, 9, 16], to severe respiratory insufficiency, requiring ventilator support and necessitating or prolonging stays in high dependency units, such as paediatric intensive care units (PICUs) [16, 17].

In most cases, treatment of RSV LRTI is limited to supportive care, including hydration, supplemental oxygen, and respiratory support (mechanical ventilation or more cost-effective continuous positive airway pressure and high-flow nasal cannula) in severe cases of respiratory distress [17,18,19]. No medications have been validated as safe and effective for the treatment of severe RSV disease and, thus, primary prevention strategies should play an essential role in reducing the burden of RSV illness in young children [20, 21].

In 2020/2021, an increased incidence of late-season RSV LRTIs was observed in France after the relaxation of stringent non-pharmaceutical COVID-19 public health measures while a curfew, social distancing, and respiratory hygiene practices (masks) in adults were maintained (Fig. 1). When the COVID-19-associated public health measures were further relaxed, the subsequent RSV season (2021/2022) started earlier than usual but was of a similar size to that of previous seasons; however, the 2022/2023 season has also started early and has been associated with a particularly large number of infections and hospitalisations [22, 23]. This suggests that asymptomatic or mildly symptomatic adults play a major role in the chain of RSV transmission [24,25,26]. The impact on RSV of these non-pharmaceutical COVID-19 health measures, and its resurgence after their relaxation [26,27,28,29,30,31,32], emphasises both the importance of such measures in preventing RSV infection and illness in children, and the fact that these measures were insufficient to suppress a low, nearly undetectable, circulation and transmission of RSV. Thus, there is a need to evaluate public health measures targeting RSV transmission in the general population [26].

Fig. 1
figure 1

Weekly number of respiratory syncytial virus (RSV) reported cases in France during the epidemiologic seasons 2016/17 to 2020/21*. Figure from van Summeren et al. 2020 [29], licensed under CC BY 4.0/portion shown with arrow label modified to indicate season date. *Data source: European Influenza Surveillance Network. C, COVID-19 restrictions re-implemented 2021; H, winter school holidays

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In this review, we explore the importance of reinforcing the working partnership between parents, healthcare professionals, and public health authorities for the implementation of appropriate RSV prevention strategies in France, beginning with an overview of the epidemiology of paediatric RSV and associated costs.

Search Strategy and Selection Criteria

Using the general search terms “respiratory syncytial virus”, “bronchiolitis”, “Europe”, and “France”, we searched PubMed for recently published articles (January 2018 onwards) potentially relevant to this review. Articles that focused on the epidemiology, healthcare resource use, costs, and public health management of RSV in France and other European countries were selected for inclusion.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Epidemiology and the Impact of Non-pharmaceutical Interventions

Although most RSV-associated deaths occur in resource-limited countries, RSV is associated with substantial morbidity and healthcare resource utilisation worldwide, including in high-income European countries [3, 4, 13, 14, 33, 34]. A retrospective analysis (funded by Sanofi Pasteur and AstraZeneca) of data on RSV-associated hospitalisations in France covering an 8-year period from 2010 to 2018 found that the number of such hospitalisations in children aged under 5 years ranged from 43,715 to 54,616 per season (Table 1) [13]. Of these hospitalisations, 3% overall (N = 12,496 stays) required PICU admission. Most of the burden was observed in children younger than 1 year, in whom RSV was a leading cause of hospitalisation, responsible for up to 28% of all-cause hospitalisations versus 6% of all-cause hospitalisations in older children during the RSV season. Children younger than 1 year of age represented 69% of RSV-associated hospitalisations and approximately 95% of PICU stays. Among infants younger than 3 months old who were hospitalised as a result of RSV, 7% were admitted to a PICU versus 4% of all children under 1 year of age and 0.5% of children aged 1 year or older. The total number of RSV-associated hospitalisations over the 8-year period was similar for children born outside the RSV season (April to September) and for those born during each RSV season. In total, 87% of children hospitalised for RSV were otherwise healthy, and of the children whose gestational age was known (N = 270,048), 89% were born at term, as were more than half of those admitted to a PICU [13].

Table 1 Number of RSV hospital stays and total hospitalisation cost by age group during RSV seasons from 2010 through 2018 in children aged under 5 years in France
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After the introduction of strict non-pharmaceutical public health measures in France during the first COVID-19 pandemic wave in February to March 2020, widespread circulation of RSV ceased and PICU admissions for bronchiolitis decreased significantly [26,27,28,29,30,31,32]. One study found an 85.3% reduction in PICU admissions for bronchiolitis between September and December 2020 versus predicted admissions [32], while another study found a 36% decrease in admissions for respiratory viral infections from March to May 2020 compared with admissions in March to May 2019 [31]. However, a delayed RSV epidemic, relatively small and short, occurred in France in early 2021 after the relaxation of the measures (Fig. 1) [28, 29]. This delayed 2020/21 RSV season had some atypical features, including an increased proportion of hospitalisations in infants older than 3 months [24, 26,27,28,29, 35]. It is unclear whether children with a first RSV infection at an older age are less prone to severe infection [29], but the older median age of children with RSV-associated LRTI in 2020/21 may have been responsible for the shorter median length of hospital stay and less frequent admission to PICUs during this season [26]. As a result of the lack of RSV in the environment during 2020/2021, the corresponding birth cohorts are immunologically naïve to RSV. This explains the subsequent observation that very severe RSV-associated LRTI (RSV infection leading to hospitalisation, SpO2 < 90%, and inability to feed) developed in children of an older age when RSV reappeared [27]. The 2021/2022 RSV season started earlier than usual and was of a similar size to pre-COVID seasons, despite some residual hygiene measures being in place (particularly mask wearing among commuters and during indoor meetings) [27, 28]. In contrast, the 2022/2023 season has been characterised by an early start and a high number of emergency room visits and hospitalisations for bronchiolitis among children under 2 years [22, 23].

It should be noted that even stringent non-pharmaceutical interventions (NPI) do not completely prevent RSV from circulating, especially in households and semi-closed communities such as daycare centres. NPI cannot reasonably be applied throughout childhood and throughout the period of intense RSV circulation; however, behavioural changes among household contacts of newborns and young infants (i.e. increased hand washing, covering the mouth when coughing, and avoidance of large gatherings and close contact with sick people) are likely to assist in decreasing the incidence of infection in infants aged 3 months or younger [25, 27] and, therefore, ongoing promotion of these measures is recommended [25, 36].

Healthcare Resource Utilisation and Distribution

The morbidity associated with near-universal RSV infection in young children is the source of substantial healthcare and economic burden, including visits to general practitioners (GPs), paediatricians, and emergency departments, as well as inpatient, PICU, and prescription drug costs [12, 33, 37,38,39]. Direct nonmedical costs (i.e. transportation and food) and indirect costs (i.e. productivity loss) incurred by caregivers and families of children with RSV infection further add to the financial and societal burden of RSV illness [33]. Studies in both high- and low-income countries have demonstrated the impact on families of having a child hospitalised as a result of RSV, in terms of time burden associated with hospital visits, and out-of-pocket expenses (such as travel, parking, meals in the hospital, and added costs of childcare for siblings) that can lead to financial hardship [40, 41]. Also, given the prolonged morbidity associated with RSV LRTI sequelae, long-term costs are likely to be substantial when monitored beyond the acute period [33].

From 2010 to 2018 in France, children born at term generated 66% of the total cost of RSV-associated hospitalisation (89% when considering term and unknown gestational age children). Irrespective of the season, risk factors, and gestational age, children under the age of 1 year represented almost 80% of the cost of hospitalisation, of which half was generated by infants younger than 3 months, likely the result of a higher rate of PICU admission in this youngest age group. The median length of hospital stay was three nights for children under 1 year of age and two nights for children aged 1 year or older [13]. The costs of RSV-associated hospitalisations in all children younger than 5 years old ranged from €93.2 million to €144.2 million per season (Table 1) [13]. During this period, the mean total cost of RSV hospitalisation was €116.4 million, with a mean cost per stay of €2289. The estimated mean cost of RSV-associated hospitalisation of a child with at least one risk factor (congenital heart defects or bronchopulmonary dysplasia, Down syndrome, or cystic fibrosis with pulmonary manifestations) was higher than that for a child without risk factors (€2947 vs €2208, respectively) [13]. The mean estimated cost per hospitalisation in children younger than 1 year old was €2607. As observed in others counties, ICU use and cost has increased substantially in recent years in France [42]. Data from the University Hospital of Lyon show that the cost of hospitalisation per child over four successive RSV seasons (2014–2016) was higher in children younger than 1 month (€4892 for a 5.0-day median stay) than in those aged 1–3 months (€3958 for a 4.0-day median stay) and in those aged 3 months to 1 year (€3234 for a 4.0-day median stay) [43]. When considering these reported RSV-associated hospitalisation cost and burden estimates, one should note that these may be under-estimates, as the virus involved in hospitalisations is not always determined or accurately recorded [13]. Further, the immediate and longer-term (post-discharge) economic and humanistic impact of RSV-associated hospitalisations were not determined in these studies [13, 43]. These burdens may be particularly important for families considered to be living with precariousness (a multifaceted concept that describes a set of undesirable circumstances related to employment [including low wages], economic insecurity, inadequate housing, health problems, and a lack of social networks) [44].

The high annual cost of RSV-associated hospitalisations in young children in France in the pre-COVID-19 pandemic era reflected the considerable pressure placed on the French hospital system and health resources every winter by RSV infection in infants born inside or outside their first RSV season, as well as the impact on hospital resources and healthcare workers, including potential saturation of PICUs, particularly at the peak of the season. The associated severe disruption to patient flow and the impact on bed capacity resulted in delays for the treatment of non-RSV diseases (e.g. elective surgeries or other specialist-led hospitalisations) and frequent reprioritisation/reallocation of resources was needed [13]. Now that most COVID-19 pandemic-related public health measures have been relaxed in France, significant paediatric hospital resources could be freed up and allocated elsewhere if a successful RSV primary prevention program could be implemented in all young children [13, 33].

In addition to hospital admissions for acute RSV infection, long-term consequences of RSV LRTI (recurrent wheezing, reduced lung function, and asthma), ongoing GP and outpatient visits, and subsequent hospitalisations should also be considered when evaluating the societal and financial burden of RSV infection, and the cost-effectiveness of primary prevention programs [2, 14, 15]. A considerable proportion of children are re-hospitalised following an initial hospitalisation for RSV. In France, from 2010 to 2018, 21% of children were hospitalised for any cause in the 3 months following an initial RSV-associated hospitalisation, of whom almost two-thirds (64%) were less than 1 year of age [13]. However, the rates of re-hospitalisation due to other diseases following initial admission were not known. Another hospitalisation due to RSV occurred during this time frame in 12% of children, with a higher incidence in preterm (21.6%) than term (11.2%) children [13]. Although it is not known whether the association of RSV with recurrent wheeze/asthma is causal, avoidance of chronic respiratory morbidity and associated resource use is a potential secondary advantage of successful strategies to prevent RSV infection in all young children [2, 14, 15, 45, 46]. Additionally, prevention of chronic respiratory morbidity limits the negative impact on a child’s quality of life (e.g. family disorganisation, traumatic stress, impact on daily activities, and emotional burden in the child, parents, and siblings).

Management Options for Prevention: A Public Health Perspective

During the first 2 years of the COVID-19 pandemic, the benefits of non-pharmaceutical measures on RSV infection in infants have been obvious, although temporary, since the benefits were suspended when the restrictions were lifted [25]. Now, the impetus should be to prevent the onset of pandemic restriction “fatigue” and encourage people to maintain certain long-term non-pharmaceutical hygiene measures. In particular, appropriate use of masks, physical distancing, avoiding close contact with sick people, covering the mouth when coughing, and hand and surface hygiene measures should remain a major public health priority to prevent RSV infection and illness. These measures should be actively promoted in the families of all children up to 1 year of age (but particularly in those who have children younger than 3 months) in France, and other countries, for the foreseeable future, at least during the classical period of RSV seasonal epidemics [25, 27, 47]. Healthcare systems need to be prepared for future annual outbreaks of RSV infections as public health interventions and international travel restrictions are inevitably relaxed [29, 48,49,50].

The development of effective surveillance systems that collect information about RSV epidemics, including seasonality, strain characteristics, disease burden/severity, and risk groups, is key to inform decision-making around treatment and prevention strategies for RSV. Such systems could be used to assess the effectiveness and impact of diverse immunisation strategies. Sentinel surveillance systems are those created with surveillance as the primary goal and consist of high-quality networks that systematically sample patients; France has two such systems specifically for RSV surveillance, which are GP- and hospital-based, respectively [51]. Non-sentinel systems, of which France has one, are passive and collect notifications of cases or laboratory results [51]. While sentinel surveillance systems may be considered the preferred option, they have the disadvantage of covering only a small proportion of the population and, therefore, they may not capture information from paediatric populations, unless specifically focused on infants [51]. Genomic surveillance should be used to establish the strains of RSV that are circulating, the severity of disease caused by each strain, and any genetic evolution of the virus. This will provide important information on the impact of immunisation on disease caused by different virus subtypes, and conversely the impact of viral changes on vaccine/antiviral efficacy and antigen detection. All RSV-positive samples received in central laboratories in France are typed [51]. The development of cohesive, region-wide RSV surveillance in the European Union (EU) has been suggested, in which national systems conform to specific recommendations [52]. The aim is to ensure consistency of data collection across member states, which will allow harmonisation of data reporting and comparison at the European level [52].

To date, the only pharmaceutical agent available to prevent severe RSV infection in children is the RSV-specific monoclonal antibody palivizumab [20, 53,54,55]. Compared with placebo or no intervention, palivizumab has been shown to reduce RSV hospitalisation in high-risk infants in randomised trials, with a review of five trials reporting a risk ratio (RR) of 0.44 (95% confidence interval [CI] 0.30–0.64) for such hospitalisations at 2-years’ follow up, although with little to no impact on mortality (RR 0.69, 95% CI 0.42–1.15) [56, 57]. However, palivizumab has not been studied in healthy children and it may be cost-effective only for some subgroups of high-risk children [53]. Passive immunisation with palivizumab is therefore only reimbursed by the French public welfare system for the following subgroups of high-risk infants, as outlined by French Transparency Committee guidelines: birth at no more than 32 weeks’ gestation with respiratory disease attested by O2 requirement at 28 days and (1) age less than 6 months at RSV epidemic onset or (2) age less than 24 months at RSV epidemic onset and moderate or severe bronchopulmonary dysplasia requiring treatment in the previous 6 months; and (3) age less than 24 months at RSV epidemic onset and haemodynamically significant congenital heart disease [53, 58].

Otherwise healthy infants born at term account for up to 90% of RSV-associated hospitalisations in France [13]. Therefore, unless palivizumab is used off-label and not in accordance with Transparency Committee guidance, only a small, very high-risk proportion of the French infant population stands to benefit from RSV immunoprophylaxis [53, 58, 59]. In one study, off-label use of palivizumab was observed in relatively high proportions of the overall (term + preterm) infant population (40% of infants aged less than 6 months and 59% of infants aged less than 24 months) [58]. However, widespread use of palivizumab is restricted by its high acquisition cost, its short half-life (requiring up to five monthly intramuscular injections during the RSV season [20, 60]), and poor compliance (which often leads to incomplete prophylaxis) [53]. There is a clear need for a long-acting, cost-effective alternative to palivizumab to protect all infants, regardless of gestational age at birth or comorbidities, throughout their first RSV season [20, 21, 61].

Potential future universal approaches to RSV prevention combine different passive and active immunisation strategies and include (1) maternal vaccination during pregnancy, (2) infant vaccination, and (3) administration of long-acting monoclonal antibodies to infants at birth/soon thereafter, possibly followed by infant vaccination to protect them during their second RSV season (Fig. 2) [62].

Fig. 2
figure 2

Potential future options for prevention of respiratory syncytial virus in the first year of life. Figure from Azzari et al. 2021 [14], licensed under a Creative Commons Attribution 4.0 International License, and Janet et al. [62]: Respiratory syncytial virus seasonality and its implications on prevention strategies. Human Vaccines and Immunotherapeutics 2018, 14(1):234–44, reprinted by permission from Taylor & Francis Ltd. http://www.tandfonline.com

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Maternal vaccination would result in the passive immunisation of infants before delivery by transfer of protective antibodies. As a result of waning acquired antibodies over time, protection from maternal vaccination would likely range from 2 to 4 months, so this would be a valid option to bridge the gap between birth and active vaccination only for children whose birth is expected to occur during or just before the RSV season [14, 62, 63]. If, for example, RSV vaccination of mothers provided infants with 4 months’ protection, then only those born in France between September and February would receive protection throughout the peak of their first RSV season, with the greatest reduction of disease occurring in those born in October or November. Although efficient transfer of maternal RSV antibodies to infants has been shown to occur after maternal RSV vaccination [64], this approach failed to confer protection from medically significant RSV-associated LRTI in infants during up to 90 days of life (the primary outcome) in the only completed phase 3 clinical trial of maternal RSV vaccination to date [63]. However, there was evidence of vaccine efficacy against the secondary endpoints of RSV-associated LRTI with severe hypoxaemia and RSV LRTI hospitalisation, suggesting potential benefits of a maternal RSV vaccination strategy [63, 65, 66]. Nevertheless, it should be noted that effective vaccination during pregnancy relies on the transport of antibodies across the placenta. This is an active process, which is saturable and competitive, and may therefore be negatively affected by maternal levels of various factors including immunoglobulins [67] (as has been shown for the transfer of specific antibodies against measles and tetanus from mother to newborn [67, 68]) and antibodies induced by other vaccines administered during pregnancy, such as those for influenza and pertussis. Further, the best time-window for vaccination to induce the most antibody transfer has yet to be defined.

A number of RSV vaccines for delivery to infants are in late-stage clinical development, but it will likely be several years until any vaccine is approved for routine clinical use [20, 69, 70]. Moreover, these vaccines will not be administered at birth, so not all children would be protected for the entirety of their first RSV season if prevention were to rely on vaccination alone [14, 62]. For example, a child born in France in October and immunised in a 2-, 3-, 4-month infant schedule (i.e. December, January, February) would remain susceptible during a large part of their first RSV season.

Nirsevimab, acting as a passive immunisation, is a unique long-acting monoclonal antibody that may lead to almost immediate protection of infants for an entire RSV season after a single intramuscular injection and has demonstrated promising clinical trial results in healthy term and preterm infants [20, 21, 63, 71,72,73]. Modelling studies have shown that a significantly extended half-life monoclonal antibody, such as nirsevimab, could have high public health benefits, reducing the burden of RSV-related medically attended LRTI by at least 50% through to 6–12 months of age [74, 75], with the estimated annual number needed to be passively immunised to prevent RSV comparing favourably with other childhood vaccines [76]. Depending on cost-effectiveness, administration could routinely take place pre-discharge from maternity units or during the first post-discharge paediatric follow-up visit in all neonates (routinely post-natal administration done 2 weeks after birth, between days 6 and 10; additional follow-up visits may occur between days 11 and 28 of life depending on the initial assessment), or during one of the recommended and reimbursed regular health visits closest to the pre-winter onset of the RSV season [77]. Either possibility could eventually be followed by infant vaccination to achieve more durable protection and eventually limit RSV circulation [14, 62]. The timing of the administration of nirsevimab could also be based on the infant’s month of birth relative to the RSV season, i.e. a child born between March and May could receive the monoclonal antibody using a pre-winter administration strategy, while a child born between October and February could receive it at birth. It should be kept in mind that the former strategy may require precise characterisation of the RSV season and evidence-based planning to succeed [61, 78], while a routine post-natal administration strategy would be relatively easy for physicians and parents to understand and adhere to. Healthcare professionals and medical societies will therefore need to work closely with public health authorities to ensure that appropriate, easily administrable strategies are in place to accommodate the routine use of new technologies, such as long-acting monoclonal antibodies, to prevent severe RSV infection in all infants [78].

Conclusions

National hospitalisation and cost data underline the importance of RSV epidemics in paediatric hospital capacity planning, as well as the urgent need for effective measures to prevent RSV disease in France. Epidemiological data on RSV in France is in line with international evidence, with most of the burden observed in children under 1 year of age born at term. Ongoing national surveillance of RSV (and possible incorporation of this into an EU-wide system) to allow the collection of data on seasonality, strain characteristics, community incidence, disease severity (including associated hospitalisation rates), and the onset of wheezing and asthma after RSV infection is important for informing prevention policies, and in monitoring their success in reducing the burden of RSV illness.

Reduction of the burden of RSV-associated LRTI will rely on education of parents about the importance of reducing exposure to and transmission of RSV. As part of this educational approach, non-pharmaceutical preventive practices, such as regular hand-washing and social distancing/avoiding close contact with sick people, should be strongly promoted to new parents to reduce RSV burden in RSV-naïve infants. Palivizumab should also continue to be used to reduce RSV disease burden in high-risk infants. Resource and cost savings could be realised and allocated to other healthcare services by an effective, routine RSV primary prevention program encompassing all infants when active and passive immunisation programs become available. Data on RSV vaccines and cost-effective, long-acting RSV monoclonal antibodies should inform policy for future public health decisions. In close collaboration with stakeholders responsible for prescribing and administering the new agents (i.e. obstetricians, paediatricians, GPs, nurses, pharmacists, and midwives), public health authorities should design prevention strategies and establish logistical pathways to ensure that all children are protected throughout their first RSV season, regardless of gestational age at birth or comorbidities. Reinforcement of an ongoing partnership and collaboration between the parents of newborn infants, public health authorities, and frontline primary healthcare professionals will be required for the smooth rollout of new RSV pharmaceutical preventive strategies to reduce the pressure that RSV places on healthcare systems each year.