Mini-Symposium: Asthma Phenotypes
Inflammatory Phenotypes in Stable and Acute Childhood Asthma

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Summary

Asthma is a complex disease with a significant inflammatory component characterized by repeated episodes of exacerbation and inflammatory changes in both large and peripheral airways. The clinical course of childhood asthma varies substantially among individuals. The reasons why the clinical course of asthma displays persistence and even progression in some children but is intermittent in others remains unclear. Children with asthma are different from adults with asthma. Inflammatory involvement in children with asthma appears to be localised more in peripheral than central airways, and the inflammatory phenotype displays differences from adults. Children with acute asthma display a dominant eosinophilic inflammatory phenotype instead of the neutrophilic phenotype that is seen in adults with acute asthma. Corticosteroids do not alter the natural history of the disease and may not prevent progressive decline of lung function in the subset of severe asthma. The underlying inflammatory mechanisms involved in the decline of lung function remains to be elucidated. Non-invasive biomarkers for monitoring lung function and inflammation are needed in children to track and monitor pathological changes in the distal airways, as is the development of therapeutic strategies that effective to peripheral airway in this vulnerable population. This review summarises our present understanding of airway inflammatory phenotypes in children with asthma and factors determining disease severity in exacerbations of asthma, and focuses on studies evaluating relationships between clinical features and the dominant inflammatory phenotypes in disease prognosis in a variety of asthma populations. This presents the crucial steps for describing the strategies associated with improvements for paediatric asthma care.

Introduction

Asthma is a heterogeneous syndrome comprising different phenotypes that manifest with cough, wheeze, shortness of breath, and chest tightness. It is the most common chronic disease in childhood and the prevalence has been increasing in industrialised countries over decades. Although both childhood and adulthood asthma share similar features, there are epidemiological and clinical characteristics suggesting a difference in the nature, disease history and magnitude of airway inflammation1, 2. In children with asthma, the patterns of inflammation and remodelling vary among individuals. We cannot yet differentiate with certainty whether the future course of a child with wheezing will be persistent asthma or transient wheeze3, 4. The reasons for the variability in the clinical course of asthma that leads to persistence and even progression in some children but is intermittent in others remain unknown. The temporal course and causes of chronic airway inflammation and remodelling, as well as the interplay between these key histopathologic changes in asthma, are also poorly clarified5.

Childhood asthma frequently persists to adulthood and the available evidence suggests that the severity of childhood asthma predicts the severity of asthma in adulthood1, 2. Children with severe asthma experience persistent symptoms despite maximal conventional treatment. Fraction of exhaled nitric oxide (FEno) and sputum eosinophils can be used as markers of airway inflammation to guide treatment with corticosteroids, but very few data are available on their utility in children6. Currently there is no standard definition for what constitutes disease persistence as opposed to disease progression in asthma or criteria on how and when progression should be measured or evaluated. Despite the availability of evidence based guidelines for the management of paediatric asthma, a significant gap remains between accepted best practices for paediatric asthma care and actual care delivered to asthmatic patients. Current therapies are targeting both airway inflammation and airway hyperreactivity, which often effectively relieve and prevent symptoms in the majority of patients. However, some patients experience persistent symptoms and a progressive decline in lung function, described as irreversible or refractory asthma. There are many unanswered questions about different inflammatory phenotypes in relation with airway remodelling; the contribution of distinct airway resident cells to development of irreversible asthma; the role of biomarkers in predicting persistent asthma; and effectiveness of current therapies on childhood asthma and disease progression.

Section snippets

Features of childhood asthma

Normally the lower airway is sterile. Nonetheless, defects in the local immune system can lead to infection in the lower airways7, 8. Both clinical and experimental evidence suggest an important role for respiratory infections as triggers of asthma attacks in adults and in children. Viral respiratory infections are considered the most common precipitating factors of acute asthma and have been shown to be associated with more than 80% of asthma exacerbations in children9, 10. Atypical bacteria,

Inflammatory phenotypes in stable childhood asthma

The airway inflammatory patterns in asthma are heterogeneous and current guidelines describe asthma as a disorder where many cells and cellular elements play a role in disease pathogenesis20. Asthma can be defined as eosinophilic or non-eosinophilic based on the presence of eosinophils in sputum. Further studies demonstrated that inflammatory process in asthma is more heterogeneous in terms of response to treatment5. Atopy and eosinophilic bronchitis are important in asthma, and about 50% of

Inflammatory phenotypes in acute childhood asthma

Acute asthma is one of the most common problems confronting the emergency department. The least understood phenotype in human asthma is the severe form of the disease exemplified by acute severe exacerbations requiring hospitalisation. One of the underlying trigger mechanisms is the consistent observation at the time of hospitalisation that most affected children also have respiratory viral infections. This suggests that inflammation arising from host antiviral defence may interact with

Comparison of inflammatory phenotypes between adults and children

A cross-sectional study investigated each of the four different inflammatory phenotypes in adults and children with stable and acute asthma. The different patterns of inflammatory phenotypes are summarised in Figure 1 26.

The distribution of phenotypes was similar between adult stable asthma and children with stable asthma. However, there were differences in the relative frequency of the phenotypes between acute adult asthma and children with acute asthma (Figure 1), as well as between acute

Potential biomarkers on monitoring distal airway inflammation

Endobrochial biopsy and bronchoalveolar lavage (BAL) have been traditionally been used for assessment of airway inflammation. A number of research groups have demonstrated an association between FeNO and airway eosinophils, measured either using BAL or endobronchial biopsy in children with asthma6, 39. However, bronchoscopy is not particularly practical for most children or most centres. Even in specialised centres, bronchoscopic assessment of airway inflammation cannot be performed on multiple

Conclusions and future directions

This review has given an outline of airway inflammatory phenotypes in various forms of asthma in children with a developmental perspective on similarities and differences to adults with asthma. Asthma still remains a challenge because the number of emergency visits and hospitalizations for asthmatic children. There are many factors underlying the exacerbation-prone phenotypes and these have recently been reviewed43. Most of these factors are probably common to children and adults, but there are

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