Asthma: alternative anti-inflammatory agents needed for patient subgroup
Summary
Five million adult asthmatics may have predominantly neutrophilic inflammation. Whilst this phenotype is usually associated with severe asthma, it may be more prevalent across the range of disease severities than originally thought. The emergence of this phenotype in asthma raises important implications for treatment practice.Severe asthma is a term that encompasses patients with a steroid-resistant, irreversible, refractory, brittle, near fatal and difficult-to-control or poorly controlled condition. Both genetic and environmental elements are likely to play an important role in the development of severe disease, although it is unclear what is the most important factor in its development.
Although many asthmatics have been severely affected for most of their lives, there appears to be a group of mainly female, non-atopic adults that develop severe disease in adulthood. The European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA) found that, in patients aged 17-65 years of age, severe asthma was 2.8 times more common in females than males.
ENFUMOSA study found increased neutrophils in severe asthmatics
An important finding from the ENFUMOSA study was the presence of increased neutrophils in the circulation and in the sputum, which were the only cell type significantly higher in severe asthmatics than mild-moderate asthmatics. As a result, the group has suggested that severe asthma is a different disease to mild-moderate asthma. Moreover, there is evidence that patients with milder forms of asthma also have evidence of neutrophilic inflammation.
A vital outcome of this study was that it demonstrated for the first time that patients who are steroid-naive can also present with predominantly neutrophilic airway inflammation. Inhaled corticosteroids are thought to prolong neutrophil survival by inhibition of apoptosis, hence the presence of neutrophils in severe asthma may reflect treatment with high doses of corticosteroids (although the extent to which they genuinely potentiate neutrophil activity is far from clear). The fact that steroid-naive patients also demonstrate neutrophilic inflammation may provide a mechanism by which subjects evolve into more severe cases.
Thus, although the role of eosinophils, mast cells, and T cells in asthma has long been recognized, there appears to be a large subgroup of mainly non-atopic adult patients whose predominant inflammatory cells are neutrophils. Neutrophilic airway inflammation can be induced by several non-allergenic exposures such as bacterial endotoxins, viral infections, particulate air pollution, and ozone. The neutrophil has the capability of causing tissue destruction and until recently, neutrophilia has been regarded more as a feature of chronic obstructive pulmonary disease than asthma.
Five million adult patients have neutrophilic airway inflammation
It is estimated that five million adult patients have predominately neutrophilic airway inflammation in the , and five major markets in the EU, including the , , , , , and . The presence of neutrophilic airway inflammation in a large proportion of adult asthmatics raises important implications for treatment practice.
Firstly, if these asthmatics have a diminished or suboptimal sensitivity to corticosteroids, alternative anti-inflammatory agents would be required. Inhibition of targets such as IL-8 may normalize the exaggerated accumulation of activated neutrophils in the airways and are thus potential targets for therapeutic intervention in severe asthma.
Secondly, the findings suggest the need for greater use of tools to identify noneosinophilic asthma so that the most appropriate therapy can be employed. Currently, the diagnosis of asthma includes a history taking, physical examination, assessment of atopy and measurement of lung function. Newer alternatives for asthma diagnosis includes the measurement of induced sputum cell counts as an indicator of airway inflammation, which is increasingly being considered as a noninvasive means of evaluating airway inflammation. However, whilst a safe and relatively simple procedure, it is not without hazard and can make patients feel wheezy and/or nauseous. As such, there is an urgent need to develop less invasive means by which to measure airway inflammation.
Analyses of different markers of atopy in the ENFUMOSA study also showed that total serum IgE was lower in the severe asthmatics than in those with controlled disease, which may influence the effectiveness of therapeutic strategies based on the concept of a predominance of IgE mediated mechanisms, such as Novartis's Xolair (omalizumab). However, the mechanism by which anti-IgE therapy reduces asthma exacerbations is uncertain, and it remains to be determined whether anti-IgE therapy might be beneficial to patients with severe nonallergic asthma, including those with predominately neutrophilic airway inflammation. There is evidence for local IgE production, possibly directed at bacterial or viral antigens, and that an IgE-dependent mechanism might promote elastase release by neutrophils at allergic sites.
Research continues on role of the neutrophil in the pathogenesis of asthma
Whilst research is ongoing to elucidate the role of the neutrophil in the pathogenesis of asthma, there is strong evidence to suggest that a distinct phenotype of asthma exists with active neutrophilic inflammation, which may be present either alone or in conjunction with eosinophilic inflammation. Whilst this phenotype is most usually associated with severe asthma, it may be more common than currently appreciated across the range of disease severities.
Further studies are required to define the prevalence of this asthma phenotype, especially in steroid naive asthmatic patients, and in children. Furthermore, debate continues on whether severe asthma is a different disease to mild-moderate asthma or is an extension of mild asthma with an inadequate response to corticosteroids.
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