Persistent Wheezing in Very Young Preschool Children Reflects Lower Respiratory Inflammation

Hans Bisgaard

Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Persistent wheezing is the most common chronic disease in young preschool children, a considerable burden to the child and the community, and a challenge to pediatricians. This is an area in which there is minimal investigation, evidence of efficacy, and hence few data with which to make treatment decisions.

Inhaled corticosteroids (ICS) improve symptoms and reduce the number of exacerbations, even in toddlers with persistent wheezing, which strongly suggests the inflammatory nature of the disease. However, ICS generally do not provide full control in this age group (1, 2). It is not known whether this is due to insufficient patient adherence, too low a dose of steroids, pharmacogenetic heterogeneity, or a distinct pathology in early asthma or in subgroups of wheezy young children.

Subgrouping may be attempted from the clinical picture, epidemiological evidence, or evidence from immunopathology. The clinical picture suggests a subgroup of patients prone to wheezing closely associated with viral infections but with no clinical symptoms outside of such infections. ICS provide only modest beneficial effects in such children (3). However, the clinical separation of this subgroup is not well defined. Most asthma symptoms are virally driven, even in atopic asthma. Viral-induced wheeze may be a different disorder or may represent a mild and transient form within the spectrum of asthma immunopathology. Epidemiological evidence suggests subgroups based on persistence or self-limiting, transient symptoms, as supported by differences in risk factors (4). However, any subgrouping needs to be based on differences in pathology. There is as yet no such evidence. In actual fact there is very little evidence of the nature of the pathology of persistent wheezing in young preschool children.

Biopsy studies in pediatric asthma have mainly been limited to school children with asthma, with reports of classical features of asthma pathology (5). Eosinophilic infiltration was rare in a recent report, but this may have been confounded by ICS used up to 4 weeks before the biopsy (6). Bronchial biopsies from 27 steroid-naive children who had been bronchoscoped at the median age of 9 because of recurrent or chronic respiratory symptoms were reevaluated in a retrospective study (7). In the 16 children who had bronchial asthma at follow-up, eosinophils in the bronchial mucosa were significantly increased compared with those children whose respiratory symptoms did not progress to asthma. There was no apparent relation between symptom duration and eosinophilia, suggesting eosinophils to be present from onset of asthma. Apparently, allergy is not driving such eosinophilia (8).

There are few reports on the inflammatory nature of persistent wheezing in young preschool children. Indirect measurements have attested to its inflammatory nature. Exhaled nitric oxide was significantly increased in young preschool children with asthma. It increased further subsequent to dose reduction of ICS (9).

Direct evidence of inflammation has been provided by studies of lavage, either through a suction catheter or bronchoscope. These methods need further standardization and viral or bacterial infection may confound the results. The lavage studies have indicated increased total cell counts in groups of young preschool children with "virally induced wheeze" as well as groups of atopic asthma. Proportions of neutrophils were increased in the children with viral-induced wheeze contrasting increased proportions of eosinophils in children with atopic asthma (11, 12). However, these children were not age matched, and it is therefore not clear whether the reported differences in cell proportions can be ascribed to different clinical subgroups, concurrent infection, or reflect the early events of asthma pathology versus more progressed events of asthma pathology.

Krawiec and coworkers in this issue of the American Journal of Respiratory and Critical Care Medicine report data on bronchoalveolar lavage (BAL) in very young preschool children (mean age 15 mo) with persistent wheeze compared with age-matched controls without any lung symptoms (pp. 1338- 1343) (10). Subjects with evidence for current viral or bacterial infections were excluded. The children had a history of persistent wheeze, relief of symptoms from bronchodilator treatment, and relapse following withdrawal of medication as well as repeated severe attacks requiring prednisolone. This suggests a pragmatic diagnosis of asthma, and the children represent the more severe end of the spectrum.

The BAL in these children shows a 3-fold increase of total cell numbers in the children with asthma, but no significantly changed distribution between the inflammatory cell phenotypes. The total numbers of lymphocytes and epithelial cells were increased as reported in adult asthmatics, but in contrast to adult data macrophages and neutrophils were also upregulated, while eosinophils and mast-cell were less predominant. Eicosanoid levels were generally up-regulated in the children with asthma as compared with normal control subjects, with large increases in mediators potentially derived from the epithelium. These findings support a nonspecific inflammatory response. However, the numbers of children studied were small, and subgroups could therefore be difficult to discern. It is noteworthy that the use of ICS was not associated with significant effects on cell differentials nor on the concentration of eicosanoids (10, 12), which may reflect incomplete control by ICS on this type of inflammation.

In conclusion, the available evidence suggests that asthma, when defined pragmatically from symptoms and treatment response, reflects a chronic airway inflammatory condition from a very early age. Interestingly, the data suggest a nonspecific inflammation, implying that the eosinophils may not be as predominant an inflammatory cell in very early asthma while macrophages and neutrophiles are more dominant compared with the asthma immunopathology in older asthmatics. Possible interpretations may consider that the pathology of the early events at the onset of asthma may differ from established asthma. Or it may be considered that the pathology reported is reminiscent of infectious pathology. Could it even reflect the initiating or causative events of asthma from microbial colonization? Alternatively, the findings reflect different subgroups of persistent wheezers. The latter may seem the more likely interpretation. However, there is as yet no consistent evidence with respect to airway pathology within age-matched children to support the separation into different subgroups of symptoms of asthma. Research into direct and indirect measurements of airway inflammation in young preschool children with wheezing is urgently needed to clarify these questions and to provide information on inflammatory phenotypes and their possible correlation with clinically defined subgroups. We clearly need such evidence to be able to tailor strategies for effective treatment and early intervention.

	References

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