In 1969, Williams and McNicol [1] speculated that there was a spectrum of wheezing conditions in young children. At one end of the spectrum were children who had frequent regular episodes of wheeze from early life that continued into school age, and at the other end were children with ‘mild and evanescent’ wheeze, which was resolved by school age [1]. The hypothesis that preschool wheeze is not a single disease entity was confirmed in 1995 by the Tucson birth cohort study [2], which found that atopic sensitization is not a risk factor for preschool wheeze if wheeze resolves by school age, and that only a minority of children with preschool wheeze develop ‘atopic’ asthma during the school age years. To date, attempts to identify the minority of preschool ‘pre-asthmatics’ using the clinical pattern of wheeze (e.g. severe vs. mild, frequent vs. infrequent, episodic vs. continuous), or markers of atopy (e.g. low vs. high total IgE, specific IgE, and low vs. high blood eosinophils), have proved to be too inaccurate to be clinically useful [3,4]. Even the small proportion of young children with wheeze that is sufficiently severe to justify bronchial biopsy, do not have an airway wall eosinophilia that is characteristic of classical atopic asthma [5]. In reviewing this evidence, a 2008 European Respiratory Society (ERS) Task Force concluded that preschool children with wheeze should be divided into 2 groups: (i) ‘episodic (i.e. respiratory virus-triggered) wheeze’, and (ii) ‘multiple-trigger’ wheeze [6]. The term ‘persistent’ wheeze (i.e. wheeze both during and between colds) was dropped because it was also used by Martinez et al. [2] to describe a long-term outcome in the Tucson study. Although the ERS classification establishes a common framework for stratifying children in therapeutic trials, it begs the question whether the ‘multiple-trigger’ preschool wheeze phenotype is the same condition as school age asthma. Indeed, it remains entirely possible that, for the vast majority of wheezy preschool children, there is complete disassociation between atopic airway inflammation and wheeze – irrespective of ERS phenotype. How does this ongoing debate about preschool wheeze phenotypes affect research into the environmental influences on early atopic sensitization, and atopy-associated respiratory disease in young children? In this issue, Reimerink et al. [7] sought to assess the association between rotavirus and norovirus infection (determined by seropositivity) in the first year of life and both specific IgE to allergens and atopic symptoms. For respiratory outcomes, the authors divided children into: (i) recurrent wheeze in the first year of life, (ii) recurrent wheeze starting in the second year of life, and (iii) recurrent wheeze starting in the first year and continuing into the second year of life. Their finding that noravirus infection was associated with a lower risk of sensitization, but no reduction in the risk of recurrent wheeze, is entirely compatible with the hypothesis that most preschool wheeze is not atopic asthma. However, their finding of an association between rotavirus infection and recurrent preschool wheeze is more difficult to explain. Rotavirus is present in airway secretions from infants with diarrhoea [8], and it is possible that rotavirus infection enhances airway inflammation during subsequent colds – a putative interaction that merits assessment in animal and cell models. Because the environmental factors modulating the development of atopy remain elusive, well conducted studies with a clear testable hypothesis, such as that by Reimerink et al. [7], should be encouraged. It is very likely that further insights into preschool wheeze phenotypes will be provided by sophisticated mathematical techniques such as latent class analysis [9], and future studies of the development of atopic respiratory disease in young children will therefore require close collaboration between epidemiologists and academic respiratory paediatricians.
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Jun 1, 2010
Samatha Sonnappa 
Open Access