This systematic review aimed to evaluate evidence around whether RSV prophylaxis, using monoclonal antibodies, reduced the risk of preterm infants developing recurrent wheeze or asthma in childhood. According to our primary analysis, including all studies regardless of quality, and infants of all gestational ages, we did not identify a statistically significant benefit for this outcome. However, our two pre-defined subgroup analyses, in which we excluded studies of very low quality, and focussed on infants born after 32 weeks gestation, did find statistically significant benefits on monoclonal antibody therapy on the risk of recurrent wheeze and asthma.
We noted three studies whose relative risk results showed a different effect to the overall result. O’Brien et al. showed a relative risk of 1.10 for the primary outcome with monoclonal antibody prophylaxis using motavizumab.  They concluded that prophylaxis with motavizumab had no effect on subsequent recurrent wheeze. However, the reported confidence intervals are extremely wide, meaning that the true effect could lie anywhere between 0.61 and 1.97. When assessing quality of this evidence using the GRADE approach, it was concluded as being a high quality study. It was a RCT with a low risk of recall or sponsorship bias. However it is important to note it was performed in a population of Native American infants only, who have been shown to be at an increased risk of serious RSV bronchiolitis, with the RSV-associated hospital admission rate being almost 2.5 times that of infants in the general US population of the same age.   Another important factor to consider is that this study was the only study investigating motavizumab as the monoclonal antibody prophylaxis. While motavizumab has been proven to be efficacious in terms of reducing RSV-hospitalisations in various studies,  this study was the first to assess its efficacy in reducing recurrent wheeze.  Thus, results for this study may not be as generalizable to use of other monoclonal antibodies in a non-native American population.
Carroll et al. report a cohort study which also appeared to show the opposite effect to the overall pooled effect.  When using the GRADE approach to assess the quality of each study, this study was found to have a considerable risk of confounding. The authors report measuring adherence to palivizumab as 0% adherence, <70% adherence and >70% adherence, however due to the specificities of the research question in this systematic review, the <70% adherence group and the >70% adherence group were combined. Accordingly, many included patients in the treatment group may not have received the intervention. Furthermore, more infants in the >70% adherence group had chronic lung disease, lower median birth weight, longer median birth hospital stay and also were generally smaller for gestational age than in the other groups.  These are all known risk factors for increased severity of RSV infection and subsequent childhood wheeze,    Accordingly, this may have skewed results and may account for the observation in this study that palivizumab use was significantly associated with increased risk of recurrent wheeze.
The cross-sectional study carried out by Simoes et al (2019) also demonstrated a seemingly opposite result to the overall pooled result.  When assessing quality of evidence this paper was also deemed to be very low quality due to confounding in relation to gestational age. There was a significant difference in gestational age between the palivizumab treated group and the untreated group, 28 weeks and 34 weeks respectively. As a result of this, this study also appears to show that palivizumab use is associated with an increased risk of recurrent wheeze. 
The remaining studies each showed a significant reduction in relative risk for the primary outcome with use of monoclonal antibody prophylaxis. However, it is important to highlight that the quality of this evidence varied widely and was mostly graded as low quality evidence, with only one high quality RCT – the MAKI Trial. 
Recurrent wheeze represents a huge public and global health problem. It has been estimated that the cost of asthma is approximately £1.1 billion in the UK.  On the level of the individual child affected, recurrent childhood wheeze can significantly impact quality of life. It can lead to inability to partake in physical exercise and play, and as affect the child’s education and development.  There is also substantial burden on the family in terms of working days lost for parents/carers. A recent epidemiological study using electronic health care records to estimate the prevalence of recurrent wheeze found that parent-reported wheezing prevalence was 12.9%.  Thus any intervention to reduce recurrent wheeze prevalence would have the potential to significantly improve the lives of many children and families as well as having considerable financial benefits.
Monoclonal antibodies are expensive, and analyses based on RSV bronchiolitis outcomes suggest their use is only cost-effective for certain high risk groups, such as early pre-term infants (<32 weeks). However later preterm infants aged between 32 and 26 weeks gestation also have high RSV hospitalisation rates (3.75% and 9.8%) and immunological differences in lung development.  Our pre-specified sub-group analysis of 3 studies focusing on infants with gestational age ranging from 32 weeks to 36 weeks showed a statistically significant relative risk of 0.35, suggesting that some infants in this cohort may benefit from RSV prophylaxis to reduce their risk of subsequent recurrent wheeze. Cost-effectiveness analysis of RSV prophylaxis, based on the composite outcome of RSV bronchiolitis and recurrent wheeze in this specific gestational category, is necessary to draw more robust conclusions about this issue.
While there is an established association between RSV infection and subsequent recurrent wheeze, the question of whether or not this can be called asthma remains. The MAKI trial (Scheltema et al.) was initially published in 2013 as a one year follow up study, however in this systematic review we included the 6 year follow up data. The original one-year study found a statistically significant reduction in the proportion of infants with recurrent wheeze in the palivizumab treated group.  In the 6 year follow up study, while a significant difference between treatment and control groups in parent reported asthma at age 6 years was noted, no significant difference in lung function tests or physician diagnosed asthma was evident.  Prais et al. reported in 2016 the results of a study on the short and long term effects of palivizumab use in premature infants and reported a significant reduction in rates of recurrent wheeze during the first 2 years of life in those who received palivizumab (27% compared to 70% in the untreated group).  However, by school age there was no significant difference in recurrent wheeze or pulmonary function tests. This suggests that monoclonal antibody prophylaxis may have a protective effect on the airway short term but not long term. Data from this study were not included in this meta-analysis due to the fact that the majority of infants included were diagnosed with bronchopulmonary dysplasia. 
RSV infection itself causes direct damage to the lungs, particularly in premature infants, for example ciliary destruction, necrosis of epithelial cells, inflammation of the submucosa and bronchiolar plugging from mucous secretions.  Considering this and the fact that studies have shown no significant effect of RSV prophylaxis on lung function at school age, it could be hypothesised that post-RSV recurrent wheeze may not represent atopic asthma but rather results from direct damage of the RSV infection to the lungs which gradually improves with time and age. This is supported by previous work by Martinez et al. who investigated factors affecting wheezing before the age of 3 years and at 6 years and concluded most infants who wheeze do not have an increased risk of asthma or allergy later in life.  Using the same study population as Simoes et al 2007, the same research team explored the protective effect of palivizumab prophylaxis on recurrent wheeze in atopic vs non-atopic children. They found that immunoprophylaxis reduced the relative risk by 80% in non-atopic children, but had no effect in those with a family history of atopy.  Taking all this into consideration, it may be that RSV prophylaxis with monoclonal antibody reduces the risk of RSV infection in certain groups by preventing the airway from direct damage by RSV and reducing subsequent risk of recurrent wheeze. However, if the mechanism by which RSV causes recurrent wheeze is independent of atopy, in children with an atopic predisposition, RSV prophylaxis would not reduce the risk of subsequent or asthma.
Firm conclusions from this systematic review are hindered the lack of good quality evidence. Only eight studies were eligible to be included in the review and of these 8, only 2 were considered to be of high quality. The significant statistical heterogeneity between the studies and publication bias found is likely to affect the overall pooled results of this meta-analysis, introducing significant risk of bias. Ideally, more RCTs are needed to investigate the role of monoclonal antibody prophylaxis on the outcome of recurrent wheeze. However, such RCTs in at-risk populations would be difficult given the proven benefit of palivizumab in prevention of severe RSV bronchiolitis in pre-term infants. A further major limitation is the lack of long-term follow up in the studies included. This meant that our outcome used was recurrent wheezing rather than true asthma. Further studies with longer follow up are required to address the question of RSV prevention and asthma causation.
The main strength of this systematic review and meta-analysis is the thorough literature search, careful study selection with strict inclusion criteria, and comprehensive assessment of bias using the established GRADE approach. Furthermore, the findings of this study are in support of existing evidence for the association between RSV bronchiolitis and recurrent wheeze / asthma.