Onset of structural airway changes in preschool wheezers: a window and target for secondary
asthma prevention?
Sejal Saglani1, Andrew Bush1
1 Leukocyte Biology and Respiratory Paediatrics, National Heart and Lung Institute, Imperial College
and Royal Brompton Hospital, London
Correspondence to:
Dr Sejal Saglani
Reader in Respiratory Paediatrics
368 Sir Alexander Fleming Building
Imperial College London
London SW7 2AZ
Tel: 0044 2075943167
Fax: 0044 2075943119
Email: s.saglani@imperial.ac.uk
Funders: SS is an NIHR Career Development Fellow, AB is an NIHR Senior Investigator
Running title: Preschool wheeze and remodelling
Data from birth cohort studies shows convincingly that lung function is reduced in the early
preschool years in children who develop asthma1-3. The loss in lung function is maximal by school
age and tracks to adulthood without recovery4, 5. We also have evidence from biopsy studies in very
young children that suggests although the pathological abnormalities of asthma (eosinophilic
inflammation and a specific feature of airway remodelling, increased reticular basement membrane
(RBM) thickness) were not present in infants with respiratory symptoms and reversible airflow
obstruction at a median age of 1 year6, they were present in preschool children with severe
recurrent wheeze aged 3 years7, 8. Interestingly, the increased RBM thickness was not yet maximal at
preschool age, but by school-age (median age 12 years) was equivalent to that seen in adults with
asthma9. Combined, the biopsy studies to date suggested a gradual development of airway
remodelling in symptomatic children with severe wheezing between infancy and school-age,
reflecting the lung function data from longitudinal birth cohorts. Acknowledging these data are from
several different studies, and the biopsy studies are only cross-sectional, it has been proposed that
the majority of structural airway changes in asthma develop early in life, in the first 5 years in
parallel with the abnormalities of lung function, and subsequently remain10. These changes may also
explain the irreversible loss of lung function that is sustained through adulthood.
In addition to RBM thickness, other features of airway remodelling that have been reported in
preschool wheezers include angiogenesis and epithelial shedding, both increased compared to agematched, non-wheezing controls8. Airway smooth muscle (ASM) has only been reported in one study
of preschool children with severe recurrent wheeze, and was not different in amount between
wheezers and controls (median age 3 years)11. The most interesting finding was that early airway
smooth muscle was the only predictor of future asthma development, not RBM thickness nor
eosinophilic inflammation.
It has become apparent that abnormal structural airway wall changes occur early in children with
wheeze, however, to date, studies have predominantly grouped together all children between 1 and
5 years old. Even this relatively small time period is likely to be too large to appreciate when
abnormal changes begin since the period of rapid airway growth in healthy children is in the first 2-3
years, and indeed it has been shown that normal development of the RBM is maximal in the first
year of life12. In this regard, the manuscript by Guillaume et al [add as reference] adds significantly to
our knowledge of the early development of structural airway wall changes in children with severe
wheeze. 49 preschool children were split into those aged ≤36 months (n=20) or 37-59 months
(n=29). RBM thickness was lower in the younger group, and although there was a lot of overlap
between groups, this confirms the previous findings that the abnormal thickening develops during
the preschool years.
Importantly, inflammation was not related to any marker of airway remodelling, thus suggesting
anti-inflammatory therapies are unlikely to modify structural changes. Moreover, markers of airway
remodelling were not different between multiple trigger and episodic viral wheezers, suggesting
clinical wheeze phenotypes cannot be used as a surrogate to determine the presence of airway
remodelling, and supports the proposition that prediction of disease outcome by school-age cannot
be based solely on clinical preschool wheeze phenotypes.
An intriguing novel finding included the presence of increased ASM in atopic compared to nonatopic preschool wheezers [Guillaume et al]. In contrast, other markers of remodelling including
RBM thickness, increased vessels and epithelial loss have previously found to be similar in atopic and
non-atopic preschool wheezers8. These data suggest a closer relationship between ASM muscle and
atopy than any of the other structural airway changes. However, in contrast to RBM thickness, the
amount of ASM was not different between younger and older preschool wheezers. Bearing in mind
ASM is the only structural cell that has been reported as a predictor of future asthma, these new
findings suggest functional characteristics of ASM in atopic children with severe recurrent wheeze
that are likely to develop asthma may be altered early. ASM remodelling is also the only change that
has been convincingly associated with alterations in lung function in paediatric asthma.13 The
relationship between increased ASM and atopy in preschool wheezers found here may therefore
explain the early abnormalities in lung function reported from birth cohorts in atopic children that
develop asthma. ASM mass was greater by school-age in children with established disease compared
to preschool wheezers, suggesting a window between preschool and school-age during which an
intervention targeted to prevent ASM dysfunction, specifically in atopic severe preschool wheezers
may allow disease modification.
The challenges of performing biopsy studies in very young children cannot be under estimated, and
for this reason, non-wheezing controls could not be included in this study. This does mean that the
findings need to be interpreted with caution, since they may simply reflect normal developmental
changes, especially since we do not know which, if any of the children included will develop asthma,
and assessments of lung function were not made. However, allowing for this limitation, when these
data are put into the context of findings from the relatively few other biopsy studies that have been
performed in preschool children with severe wheeze, we now have some really interesting direction
towards an optimal time period for intervention (early preschool age), and also the likely optimal
airway cell that perhaps should be targeted, in the context of atopy, to allow us to achieve the
ultimate goal of secondary prevention in asthma (Figure 1).
Legend for figure:
Figure 1. Relationships between lung function, structural airway changes and atopic sensitisation
in preschool wheeze. Preschool children with recurrent wheeze that develop asthma by school-age
have an early reduction in lung function that develops between birth and 6 years. Structural airway
changes develop in parallel between 1 and 6 years in preschool wheezers, and the changes in airway
smooth muscle are specifically increased in those that have evidence of early atopic sensitisation.
Combined, the pathophysiological data suggest a window between 1 and 3 years during which an
intervention may minimise reduction in lung function and allow disease modification.
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