Non-eosinophilic asthma and the innate immune response.

T he concept that there may be heterogeneity of the underlying pathology of asthma has a long pedigree: 80 years ago, Rackemann suggested that a subgroup of patients with intrinsic asthma had disease driven by bacterial infection of the upper and lower respiratory tract and the authors of an early postmortem study were struck by the heterogeneity of lower airway inflammatory response in fatal asthma. However, since then the prevailing view, largely driven by bronchial biopsy studies of limited numbers of patients with relatively mild disease, has been that there are more similarities than differences in the pathology of subtypes of asthma. Thus, asthma is currently viewed as a condition characterised by TH2 cytokinemediated eosinophilic airway mucosal inflammation. 4 The development of simple methods to assess airway inflammation non-invasively using induced sputum which are applicable to a wide variety of patients has renewed interest in investigation of the pathological heterogeneity of asthma. Using this technique, Turner et al unexpectedly found that just under half of 34 patients studied during a minor asthma exacerbation had no sputum eosinophilia. Fahy et al made a similar observation in patients studied during a more significant exacerbation; many patients had sputum evidence of neutrophilic airway inflammation. Subsequently non-eosinophilic asthma has been shown to be present in 25% of patients presenting to an adult respiratory clinic with symptomatic asthma, 9 in patients with occupational asthma and in up to 50% of patients with asthma treated with high doses of inhaled corticosteroids. The concept that non-eosinophilic asthma represents a pathologically distinct form of the disease is supported by work by Wenzel et al showing that a subgroup of patients with refractory asthma had distinctive, noneosinophilic pathology and normal basement membrane thickness on bronchial biopsy. Similar bronchial biopsy findings have been reported in patients with noneosinophilic asthma treated with inhaled b2 agonists only. 13 In a longitudinal study of patients with severe asthma the absence of sputum eosinophils was a stable feature over 12 months in a number of patients; other studies indicate that non-eosinophilic pathology can be found in corticosteroid naive patients with symptoms as well as those receiving inhaled corticosteroid therapy. 6 These observations suggest that, in some patients at least, non-eosinophilic asthma is a stable phenotype. Moreover, the distinctive sputum features cannot be solely due to the effects of corticosteroid therapy. Non-eosinophilic asthma is of particular interest for several reasons. First, several uncontrolled studies have suggested that it is associated with a poor short-term response to inhaled corticosteroid therapy. 6 15 16 This has been confirmed in a recent double blind placebo controlled study. There is also evidence that the long-term therapeutic effects of corticosteroid therapy are disappointing: a longitudinal study has shown that patients with persistently non-eosinophilic sputum were able to substantially reduce corticosteroid therapy without any obvious increase in the frequency of asthma exacerbations over 12 months. A lot more work needs to be done before we can conclude that noneosinophilic asthma is a stable asthma phenotype that does not respond to corticosteroid therapy. However, there does seem to be sufficient data to raise this as a strong possibility and to suggest that noneosinophilic asthma is a clinically important entity worthy of further research. A second point of interest is the possibility that an entirely different kind of inflammation to the TH2 driven eosinophilic airway mucosal inflammation normally associated with asthma can be associated with airway hyper-responsiveness and variable air flow obstruction. Many investigators have highlighted the presence of increased sputum markers of neutrophilic inflammation in patients with non-eosinophilic asthma. 17 Neutrophilic lower airway inflammatory responses occur in response to a wide variety of stimuli including: viral and bacterial infection; chronic inflammation of structures embryologically linked to the airways ; and inhaled stimuli such as hypertonic saline, endotoxin, 22 ozone, cigarette smoke, other pollutants and occupational irritants. 26 A common feature of these immune responses is the involvement of innate immunity, and Douwes et al have suggested that the interaction between elements of this primitive immune response and the airway might be important in the development of the airway hyper-responsiveness and variable air flow obstruction seen in non-eosinophilic asthma. Tumour necrosis factor (TNF) a might be particularly important in this regard as treatment with the TNFa antagonist etanercept has been shown to be associated with a significant improvement in airway responsiveness and air flow obstruction in patients with severe asthma. The concept that activation of the innate immune response in the airway occurs in non-eosinophilic asthma has been investigated in a study reported by Simpson et al (see p 211) in this issue of Thorax. The investigators measured expression of innate immune response receptors and cytokines, the concentration of the proinflammatory cytokine IL8 and the levels of lipopolysaccharide and endotoxin in induced sputum in patients with asthma, bronchiectasis and controls. The group with asthma were subcategorised into inflammatory phenotypes based on the induced sputum differential inflammatory cell count; all were nonsmokers. The authors found increased expression of mRNA for several innate immune response receptors and cytokines, increased IL8 and a trend to increased endotoxin concentration in induced sputum in patients who were classified as having neutrophilic asthma. Potentially pathogenic bacteria were identified in 43% of the patients with neutrophilic asthma, a finding that is in keeping with Rackemann’s identification of a subgroup with bacterial asthma. Overall, the inflammatory profile seen in neutrophilic asthma was similar to that seen in patients with bronchiectasis, although the sputum endotoxin concentration tended to be higher and the proportion with bacterial colonisation lower in patients with neutrophilic asthma. These findings strongly support the hypothesis that activation of the innate immune response occurs in noneosinophilic asthma. The observations are cross-sectional, and it is important to investigate the effect of interventions such as bacterial eradication or removal of sources of inhaled endotoxin on the clinical and inflammatory expression of the disease before we can conclude that EDITORIALS 193