Introduction
In population studies, one in three children under the age of 3 years have at least one episode of wheezing prior to their third birthday, and 50% by the age of 6 years [
6,
20,
21,
24]. Most preschool children with wheeze only do so during viral upper respiratory tract infections (episodic viral wheeze, EVW) [
7]. Some young children also wheeze in response to other triggers such as cigarette smoke, fog or allergens (multiple trigger wheeze, MTW) [
7]. In the majority of these wheezy preschool children, symptoms disappear between the ages of 3 and 6 years [
24,
36]. Disappearance of wheeze over time is more likely in preschool children with a low level of lung function in infancy [
24,
36], with maternal smoking [
1,
24] and in children with EVW [
9,
16].
The common perception that EVW has a high likelihood of spontaneous resolution over time is based on general population studies which examined the outcome of wheeze in children who had at least one episode of (usually mild) wheezing [
7]. Preschool children with more frequent or more severe episodes of wheezing are more likely to develop asthma than children with mild or isolated episodes of wheeze in early life [
4,
9,
10,
23]. Clinical studies on the outcome of more severe wheeze in early childhood are rare, however. Only a few studies have investigated the long-term prognosis of preschool children hospitalised for a severe episode of wheezing [
17,
37]. To our knowledge, no follow-up studies of clinical cohorts of preschool children with EVW have been performed to date.
We hypothesised that preschool children with EVW, referred to a hospital setting for management of their wheezing disorder, would have more severe symptoms and would therefore be at higher risk of wheeze persisting beyond the preschool years than children with viral associated wheeze in population studies.
Discussion
In contrast to population studies, in which the large majority of preschool children with EVW become symptom free between the ages of 3 and 6 years [
9,
24,
36], we found that two thirds of preschool children with severe EVW referred to a hospital-based paediatric asthma clinic had current asthma at the age of 5–10 years (Fig.
2). Children with current asthma at age 5–10 years had elevated FeNO levels (Table
2). The only risk factor significantly associated to current asthma at the age of 5–10 years in these preschool children with EVW was a positive family history of asthma (Table
3), independent of age, gender and duration of follow-up. Our results suggest that EVW, when severe enough to warrant referral to secondary care, is not an innocuous disease which may be expected to disappear once children reach primary school age but carries a high likelihood of developing into bronchial asthma.
To our knowledge, ours is the first study to follow up a hospital-based cohort of preschool children with EVW to the age when the presence of asthma can be reliably assessed. Until now, all data on the risk of persistence of wheeze in preschool children has come from population studies. Although such studies may be useful and informative to unravel the different clinical phenotypes of preschool wheezing and their outcome at population level, these data cannot be used to predict the outcome of children with more severe recurrent wheeze managed and followed up in secondary or tertiary care. Our results are in line with results from two Scandinavian cohorts of young children (<2 years of age) admitted to hospital for severe wheezing, where 40–49% of patients had asthma at the age of 5–7 years [
17,
37]. Further follow-up showed that the high risk of asthma persisted into adulthood [
15]. Taken together, these data may be used in paediatric hospitals and departments to counsel parents of preschool children with EVW on the expected outcome of wheeze in these patients.
The factors associated with current asthma in our study (positive family history of asthma and elevated FeNO levels at age 5–10 years) are in accordance with results from population studies on the outcome of preschool wheeze [
1,
9,
11,
24]. Although there was a clear trend for atopic sensitization at preschool age to be more common in children with current asthma at follow-up, the low number of patients tested for atopic sensitization in our study reduced the power to demonstrate the statistical significance of this difference (Table
3). Children seen in a hospital setting with severe EVW and a positive family history of asthma or evidence of atopy may therefore be considered at high risk of asthma at 5–10 years of age.
Almost half of the preschool children with EVW whose symptoms persisted to or recurred before the age of 5–10 years not only had symptoms during viral colds at school age but also responded to other triggers (Fig.
2). This confirms earlier observations that EVW may develop over time into MTW and vice versa [
30]. Although there was a trend for family history of asthma to be associated with MTW, our study was underpowered to identify risk factors for MTW. In the other half of EVW preschool children, the pattern of wheezing only during viral colds persisted into school age. This is in agreement with earlier studies showing that EVW is not confined to the preschool age range but may also be observed in school-aged children and adults [
13,
25].
The relationship of lung function and FeNO at school age to wheezing disorders in preschool children is unclear. In the Tucson study, both reduced lung function during infancy and EVW were associated with wheeze resolving before the sixth birthday [
9,
24]. Because lung function tends to track throughout childhood [
31], children with EVW may therefore be expected to have reduced lung function at school age. However, no clear relationship between lung function and preschool wheezing phenotypes were observed in other birth cohort studies [
19,
21]. Similarly, EVW in preschool children has been associated with elevated, normal and reduced FeNO levels in different studies [
8,
11,
12,
28]. This suggests that EVW may not be a well-defined clinical entity and may comprise different inflammatory and functional phenotypes [
29]. The normal level of lung function in the children with current asthma in our study is in accordance with a range of previous studies [
3,
27,
33]. The elevated FeNO levels in the patients with current asthma supports the notion that these children did indeed have atopic asthma and were not overdiagnosed or incorrectly treated as such because of nonspecific respiratory symptoms.
We acknowledge the following limitations of our study. First, our study sample was relatively small, limiting our ability to identify risk factors for asthma at the age of 5–10 years. We deliberately chose to be very strict in including only children with exclusive EVW and to exclude patients in whom the hospital chart records either suggested MTW or were insufficient to confirm that wheeze only occurred during viral colds. Sadly, many hospital chart records contained missing data on the pattern of wheeze in early childhood (Fig.
1). Our study population was representative of the root population of 134 children positively identified as having EVW (Table
1) and of the original population seen in our hospital in terms of age and gender. Other studies in larger prospective hospital-based cohorts of EVW patients are needed to confirm our results.
A second disadvantage is that we had no data to confirm the presence of respiratory viruses in the airways during episodes of wheezing in early childhood. Studies that did look at respiratory viruses in preschool wheeze have suggested that rhinovirus and respiratory syncytial virus may be of particular importance in increasing the likelihood of persistent asthma [
14,
16,
18,
22,
32]. Most clinicians, however, refrain from testing for respiratory viruses in wheezy preschool children, and viral testing is not recommended in clinical guidelines for preschool wheeze [
7]. Thus, our results reflect current clinical practice in which the pattern of wheeze in early childhood (EVW versus MTW) is only assessed through parental history.
Thirdly, the duration of follow-up was variable in our study, ranging from 3.7 to 8.8 years. Given the favourable natural history of EVW in population studies [
9,
24], we considered the possibility that children with a longer time period between initial symptoms at preschool age and follow-up at the age of 5–10 years would be more likely to have outgrown their symptoms. This, however, was not the case (Table
3), and the relationship of positive family history of asthma to current asthma at the age of 5–10 years remained significant after adjustment for the duration of follow-up.
A final limitation is that our study was performed in a single centre, which may limit the generalizability of our findings. Because our paediatric asthma clinic is situated in the only district general hospital in a catchment area of 400,000 inhabitants, we believe that our study sample is representative of the preschool children with EVW in secondary care.
In conclusion, our study shows that preschool children with EVW, who have been referred to a hospital-based paediatric asthma clinic because of severe symptoms, have a high risk of persistent asthma at the age of 5–10 years. This is in agreement with earlier follow-up studies of preschool children admitted to hospital for severe virus-associated wheeze. Episodic viral wheeze in preschool children should therefore not be regarded as a transient and innocuous disease, in particular when symptoms are severe enough to warrant referral to secondary care. We recommend to evaluate, manage and follow up preschool children with severe EVW as seriously as one would in school-aged children with asthma.