Respiratory syncytial virus prophylaxis for prevention of recurrent childhood wheeze and asthma: a protocol for a systematic review

Acute bronchiolitis is an extremely common acute lower respiratory tract infection in infants, with symptoms including coughing, shortness of breath, crackles, wheezing and poor nutrition [1]. The majority of young children will experience bronchiolitis, and approximately 3% will require hospital admission [1]. In many countries, bronchiolitis is the most common reason for hospitalisation of young children [1]. It has been shown that lower respiratory tract infections in early life, particularly in infancy, are associated with development of recurrent wheeze and asthma in later childhood [2]. Pre-term infants especially are at an increased risk of both severe bronchiolitis and recurrent wheeze or asthma development independently [3, 4].

The pathogenesis of asthma is multifactorial, but in simple terms, asthma causes hypersensitivity and inflammation of the airways, with common symptoms being wheeze and shortness of breath [5]. Recurrent wheeze in infancy has a significant effect on the quality of life of both the patients and their families [6]. An international study was carried out which surveyed random samples of the general population of infants. They found that 45.2% of infants in the study population had at least one wheezing episode, and 20.3% had recurrent wheeze, defined as three or more episodes of wheezing [7]. Asthma is the most prevalent chronic respiratory disease worldwide [8]. It has been estimated that the cost of asthma is approximately £1.1 billion in the UK, highlighting it as a key public health issue [9]. It creates a huge burden on both patients and health services in terms of quality of life and cost, with the most significant impact being amongst lower socioeconomic groups and ethnic minorities [10]. With the overall prevalence increasing globally, further research is needed into why this increase is happening, and whether or not there are any preventative measures that can be undertaken [10].

Acute bronchiolitis in early life is very strongly associated with an increased risk of asthma development [11]. It has been shown that infants hospitalised with acute bronchiolitis have a significantly increased risk of developing childhood wheeze and asthma, with one study from Finland finding the risk of recurrent wheeze or asthma development, after acute bronchiolitis at less than 6 months, to be twice that of the general population [12]. However, while this association is very well established, the mechanism by which this may occur is poorly understood; thus, this relationship is yet to be proven as being causal [13]. There is much debate over whether or not acute bronchiolitis is merely just the first manifestation of asthma, rather than being the cause of it. To assess causality, studies assessing the prevention of the proposed risk factor, i.e. bronchiolitis, on the outcome of asthma are needed [11].

The most common cause of acute bronchiolitis is respiratory syncytial virus (RSV), most often in infants up to 12 months. Rhinovirus is also a cause of acute bronchiolitis, generally occurring in slightly older infants [12]. RSV is an RNA virus which uses surface glycoproteins G and F to infect cells [14]. RSV-specific monoclonal antibodies are drugs which have shown efficacy in reducing RSV hospitalisations in high-risk infants, such as those born prematurely [15]. They work by binding to this F glycoprotein, preventing viral invasion of the host cells. This provides passive immunity by blocking the fusion of infected cells and reducing cell-to-cell transmission and viral activity [14, 16]. These monoclonal antibodies have a half-life of approximately 3 weeks hence the need for once-monthly injections during RSV season, to maintain a prophylactic level [17].

The main example of RSV-specific monoclonal antibodies is palivizumab. Palivizumab is a humanised monoclonal antibody which has been found to be effective in reducing hospitalisations due to RSV bronchiolitis in high-risk infants. It is injected once monthly from November to March as this is the typical RSV season [15]. Palivizumab has been repeatedly proven to be safe and well tolerated with very low rates of minor adverse events such as injection site reaction, fever, diarrhoea and irritability [18].

Motavizumab is derived from palivizumab, therefore making it a second-generation humanised monoclonal antibody. It was originally thought to display better efficacy and therefore had a lower dose requirement when compared to palivizumab [18, 19]. However, it is important to note that motavizumab was discontinued in 2010 due to questions due to its side effect profile, particularly in regard to serious skin reactions, and questions over whether or not it was actually more efficacious than palivizumab [18, 20, 21].

Other RSV-specific monoclonal antibody biosimilars to palivizumab do exist. Suptavumab was developed recently; however, it failed to meet its primary endpoint in clinical trials and was withdrawn in 2017 [22]. Even more recently developed is nirsevimab, which has a longer half-life than palivizumab thus offers protection against RSV through one single intramuscular injection [23]. Lunamab is another RSV-specific monoclonal antibody which was developed as a cheaper biosimilar to palivizumab aimed at low-income countries [24]. However, given that these are only recently developed, it is unlikely we will come across any longer term follow-up studies with regard to recurrent wheeze.

Monoclonal antibodies are expensive drugs. It is estimated that the cost of palivizumab is around £3000–£5000 per child [25]. Despite its proven efficacy and the high prevalence of RSV infection in infancy, most children will not experience a severe illness; therefore, it is not cost-effective to give to all infants [13, 25]. A systematic review analysing the cost-effectiveness of RSV prophylaxis based on the outcome of bronchiolitis found that it is cost-effective within certain subgroups of infants who are considered to be at high risk. These subgroups include very early pre-term infants (< 32 weeks), children with congenital heart disease and aboriginal children [26]. It also found that in infants of 33–35 weeks gestational age, RSV prophylaxis could be cost-effective against bronchiolitis if also based on the presence of certain risk factors which include chronological age, number of siblings, history of atopy, absence of breast-feeding, cigarette smoke exposure and day care attendance [27].

While these cost-effectiveness analyses have concluded that passive immunoprophylaxis is not financially viable for all infants born late pre-term (33–35 weeks), they have mainly been based on the outcome of RSV bronchiolitis itself, and not recurrent wheeze [28]. Given that the lungs of infants born late pre-term are not as immunologically developed as those born over 35 weeks, and also given the fact that the RSV hospitalisation rate amongst these late pre-term infants ranges between 3.75 and 9.8%, it is clear that this is a population which cannot be ignored [29]. A sub-group analysis in this gestational age group of infants will highlight their relative risk of recurrent wheeze after receiving RSV-specific monoclonal antibody prophylaxis and potentially re-open the discussion on the cost-effectiveness of monoclonal antibodies in this sub-group of pre-term infants.

The aim of this systematic review is to determine whether or not giving monoclonal antibody RSV prophylaxis in infancy reduces the risk of recurrent wheeze or asthma development in later childhood. This will then potentially provide some answers to the question of causality in the association of RSV infection and subsequent asthma.

This systematic review and meta-analysis will be investigating if intervention with RSV prophylaxis compared with no prophylaxis has any effect on the outcome of recurrent wheeze or asthma in a population of infants born early pre-term to term. A literature search will be carried out across a number of databases, including Medline, Embase, Web of Science and PubMed, using a comprehensive search strategy. We will also contact the manufacturers of the monoclonal antibodies for any unpublished data. Studies will then be screened according to title and abstract, and then text body using clear inclusion and exclusion criteria. This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) recommendations, and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) standards will be adhered to in reporting the findings (Additional file 1: Appendix 1).

Asthma is the most prevalent chronic respiratory disease worldwide creating a huge burden on patients and services [7]. If this review demonstrates that RSV prophylaxis reduces asthma risk, this supports the hypothesis of a causal relationship between RSV infection and asthma development. This could have potentially huge clinical implications if there is the possibility of reducing rates of recurrent childhood wheeze with the use of RSV-specific monoclonal antibodies. This result and the subsequent sub-group analysis could also have significant implications in terms of which infants qualify as being ‘at-risk’ enough to receive the monoclonal antibodies and could thereafter open the discussion and allow for future studies on cost-effectiveness analysis of monoclonal antibodies with regard to reduction of recurrent wheeze. Also, if the review supports the hypothesis of a causal relationship between RSV bronchiolitis and subsequent recurrent wheeze, this will prompt further studies on the biological mechanism by which this may occur. On the contrary, if RSV prophylaxis is shown to have no effect on rates of asthma development, this will then open the debate further into whether the association between RSV infection in infancy and subsequent asthma development is actually causal or not.