© 2004 American Thoracic Society
Eosinophils in Asthma and Airway HyperresponsivenessTo the Editor:We congratulate Flood-Page and colleagues (1) on successfully undertaking an important study of the effects of anti–interleukin-5 (IL-5) therapy on eosinophilic inflammation in subjects with asthma. This study supports the observation by Leckie and coworkers (2) that anti–IL-5 treatment causes a decrease in the number of airway eosinophils without influencing airway hyperresponsiveness. In our view this provides further evidence that eosinophilic airway inflammation and airway hyperresponsiveness are not causally associated. Flood-Page and colleagues take a contrary view, largely on the basis of their earlier study, which they claim showed a more complete amelioration of submucosal eosinophils after treatment with prednisolone. However, the decrease in submucosal eosinophil numbers after treatment with prednisolone was not significantly different from placebo, although prednisolone caused an improvement in airway hyperresponsiveness (3). In addition, we question the specificity of major basic protein (MBP) as an eosinophil marker. Nakajima and colleagues (4) have shown that lung mast cells contain MBP. Thus, some of the MBP-positive cells that remain in the bronchial submucosa after treatment may be mast cells. In contrast to MBP, eosinophilic cationic protein is not expressed by mast cells; thus, it would be helpful to know whether using this more specific marker decreased the number of eosinophils more markedly in response to anti–IL-5 treatment. Our view that disordered airway physiology is disassociated from eosinophilic inflammation finds support from the demonstration that a sputum and bronchial submucosal eosinophilia occurs in eosinophilic bronchitis, a condition that presents with chronic cough without airway hyperresponsiveness. The only immunopathologic feature present in asthma but not eosinophilic bronchitis was increased numbers of mast cells within the airway smooth muscle bundles (5), suggesting that microlocalization of mast cells with airway smooth muscle cells and the consequent cell interactions leads to airway hyperresponsiveness. This is not to say that the eosinophil has no role in the pathophysiology of asthma. There is evidence that the eosinophil is important in cough, airway remodeling, and asthma exacerbations (6). The role in exacerbations may be particularly important because an asthma management strategy directed at normalizing the sputum eosinophil count reduced the number of severe exacerbations compared with standard management (7). The potential of anti–IL-5 as a therapy for asthma and the role of the eosinophil in asthma could be better realized by studying the effect of this treatment on these other outcomes rather than clinging to the concept that eosinophilic airway inflammation and airway hyperresponsiveness are causally associated.
Institute for Lung Health University Hospitals of Leicester Leicester, United Kingdom REFERENCES
From the Authors: It is important to emphasize that the aim of our study was not to address the effect of anti–interleukin-5 (IL-5) treatment on airway hyperresponsiveness (AHR), but rather to determine whether anti–IL-5 actually depleted bronchial mucosal eosinophils (1). Thus, we differ from Brightling and Pavord in the interpretation of our data because mepolizumab treatment reduced, but did not deplete, eosinophils, indicating that the role of this cell in AHR remains unanswered. Although the observations on eosinophilic bronchitis (2) are of considerable interest, they do not necessarily rule out a role for eosinophils in AHR. It is arguable that eosinophils are necessary, but not sufficient, for AHR and that smooth muscle mast cell infiltration may be an additional essential factor. Such questions will not be fully resolved until it is possible to deplete both cell types from the airways. We do not believe that we mistook mast cells for eosinophils because similar results to MBP were obtained with EG2 and Congo Red staining. The comments on eosinophils in asthma exacerbations and remodeling are not contentious because we have data showing that anti–IL-5 treatment reduces extracellular matrix protein deposition in the bronchial subepithelial basement (3), indicating that the cell may have important downstream effects as a result of chronic inflammation. Furthermore, it is difficult to discard completely much of the previous circumstantial data linking eosinophils with asthma severity (4), and in this respect it is a cause of concern that larger clinical studies of anti–IL-5 from two companies remain unreported well over a year after completion. In a previous study, we showed that corticosteroid treatment was associated with a significant decrease in the number of bronchial mucosal eosinophils (5). However, cell numbers cannot be equated with function because, for example, IL-5 transgenic mice have massive eosinophilia without lung damage. Conversely, airway CD3+ and CD4+ T cells are not usually increased in mild to moderate asthma despite clear evidence that the cytokines they produce are of a Th2 profile not observed in control subjects (6). Although it is possible to dissociate AHR from both eosinophils and IgE in animal models, this has not yet been demonstrated in humans, and, as our study showed, such hypotheses cannot be effectively tested until we have effective means of depleting eosinophils in vivo in human asthma.
National Heart and Lung Institute Imperial College London, United Kingdom REFERENCES
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