We describe 12 patients with symptomatic asthma who had a distinct sputum and bronchial biopsy pattern characterised by the absence of eosinophilic airway inflammation and a normal subepithelial layer thickness. In common with previous reports, patients tended to be non‐atopic middle aged women. Some had sputum evidence of neutrophilic airway inflammation, although increased neutrophil numbers were not evident in bronchoscopy samples. Importantly, 8 weeks of treatment with inhaled mometasone had no significant effect on airway responsiveness and asthma quality of life compared with placebo. This was in contrast to findings in patients with asthma and eosinophilic airway inflammation where inhaled steroids were associated with a marked improvement in these measures.
Our patients were sufficiently symptomatic to warrant an increase in treatment based on their Juniper asthma control score and all had clear objective evidence of asthma, so the absence of eosinophilic airway inflammation seen in our patients does not reflect remission of underlying disease. Indeed, they had more symptoms than the patients with eosinophilic asthma who participated in the double‐blind placebo‐controlled study. The absence of sputum eosinophils was evident before entry into the study and was a consistent feature during the study. No patients with non‐eosinophilic asthma had evidence of eosinophilic airway inflammation on bronchoscopy or in the six sputum tests done throughout the study, five of which were done off inhaled corticosteroids. These observations support the hypothesis that non‐eosinophilic asthma represents a stable clinical phenotype which is not solely explained by the effects of treatment.11
Our finding of a normal subepithelial layer thickness in our patients with non‐eosinophilic asthma is consistent with the finding by Wenzel and colleagues in severe asthma.7
The fact that thickening of the subepithelial layer is found in patients with rhinitis and in patients with eosinophilic bronchitis without asthma and not in those with non‐eosinophilic asthma suggests that this finding may be related to eosinophilic airway inflammation rather than asthma per se. Longitudinal studies have suggested that increased subepithelial layer thickness is a longer term marker of eosinophilic airway inflammation than cell counts,22
so the observation that subepithelial layer thickness is normal in non‐eosinophilic asthma increases our confidence that the absence of eosinophilic airway inflammation is a stable feature.
We acknowledge that our biopsy study observations were made on a small number of patients and that we did not adjust for multiple comparisons. Our findings should therefore be regarded as hypothesis‐generating rather than definitive. However, biopsies were examined blind to patient status and the magnitude and consistency of the effect makes a chance finding unlikely.
The cause of airway inflammation was not specifically investigated in our study. None of the patients had CT evidence of bronchiectasis, symptoms to suggest recent respiratory tract infection or a significant smoking history, and atopy was unusual. The association with female gender and onset of symptoms in middle age is similar to observations made in chronic cough,23
and it is possible that there are some similarities between these conditions. Other studies have reported increased sputum neutrophil counts and IL‐8 concentrations6
and have speculated that the inflammatory response is due to stimuli such as environmental endotoxin, viral infection or ozone leading to activation of the innate immune system and consequent release of proinflammatory cytokines.24
Our finding of a reduced IL‐8 concentration in the sputum supernatants of patients with non‐eosinophilic asthma was unexpected and in contrast to previously reported findings;24
one possible explanation is that there are different types on non‐eosinophilic asthma with varying degrees of neutrophilic inflammation.25
Perhaps the main point of interest in non‐eosinophilic asthma is the suggestion that it represents a corticosteroid resistant form of the disease. Our study is the first double‐blind randomised controlled trial to specifically compare the response to inhaled corticosteroids in eosinophilic and non‐eosinophilic asthma. The observations were made on a small number of patients and there was a difference in baseline severity of symptoms and airway responsiveness between and within the group which could have compromised our results. In addition, the small sample size means that we had limited power to detect carry‐over effects. However, there were clear differences in primary outcome measures that were above the level that the study was powered to detect, suggesting that they were real differences. The significantly reduced response to inhaled mometasone in patients with non‐eosinophilic asthma compared with eosinophilic asthma is consistent with the findings of previous uncontrolled studies.5,8,9
In contrast to these findings, Godon et al26
found a similar response to inhaled corticosteroids in patients who were classified as eosinophilic or non‐eosinophilic on the basis of a single sputum sample. However, these observations were based on an uncontrolled study in patients with symptomatic asthma who were recruited during a period of poor asthma control and it is possible that the improvement seen in patients with non‐eosinophilic asthma reflected regression to the mean. In addition, patients were younger and more likely to be atopic than the patients with non‐eosinophilic asthma identified by us, so it is possible that the populations were different.
Although our study showed a difference in response to inhaled corticosteroids in eosinophilic compared with non‐eosinophilic asthma, we cannot conclude from our sample size that there is no significant response to inhaled mometasone in patients with non‐eosinophilic asthma. Similarly, our study does not allow us to draw any conclusions about the long‐term benefits of inhaled corticosteroids. However, an earlier 12 month study has suggested no increase in exacerbation frequency in non‐eosinophilic asthma despite substantial reductions in the dose of oral and inhaled corticosteroids.11
Further appropriately powered studies should address this important question in more detail.
Our findings suggest that eosinophilic and non‐eosinophilic asthma represent distinct clinical and pathological phenotypes. They provide further evidence against a causal relationship between eosinophilic airway inflammation and variable airflow obstruction and airway hyperresponsiveness, but provide support for the concept that airway hyperresponsiveness and variable airflow obstruction are causally related to the presence of tryptase positive mast cells in the airway smooth muscle. We have shown that patients with non‐eosinophilic asthma have a significantly reduced short‐term response to inhaled cortico‐steroids than those with eosinophilic asthma. Longer larger studies are required to determine whether inhaled corticosteroids can be safely withdrawn in patients with this asthma phenotype.