Bronchial Eosinophilia in Exacerbation of Bronchitis
An Allergic Profile of Inflammation?

Ulrich Costabel, M.D.

Department of Pneumology/Allergy, Ruhrlandklinik, Essen, Germany

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Cigarette smoking is associated with airway inflammation. Susceptible smokers may develop complex disease manifestations with various clinical phenotypes ranging from simple chronic bronchitis without airflow obstruction to chronic obstructive pulmonary disease (COPD) with mild to severe degrees of airway obstruction and emphysema. In addition, airway hyperreactivity may be present. Traditionally, based on simple sputum investigations, the airway inflammation of COPD was thought to be dominated by neutrophils, in contrast to asthma with eosinophils as pivotal effector cells. Does this still hold true?

When interpreting studies on airway inflammation, several issues need to be considered in order to understand possible differences in results. These include the different techniques applied (biopsy versus bronchoalveolar lavage [BAL] versus induced sputum), the different compartments investigated (central versus peripheral airways versus lung parenchyma), the different layers of the airway walls (subepithelial mucosa versus epithelium versus the intraluminal space), or different stages or phases of the disease (asymptomatic versus simple chronic bronchitis versus COPD versus emphysema; stable phase versus exacerbation). Nevertheless, the message which emerged from these investigations of the past 10 yr can briefly be summarized as follows: asymptomatic smokers show an accumulation of cells in the alveolar spaces, mainly of macrophages with the characteristic smokers' inclusions. Compared with asymptomatic smokers, those with symptoms and mild COPD have an increase in CD8⁺ T lymphocytes in central (1, 2) and peripheral airways (3). Finally, those with severe COPD develop a prominent neutrophilia in the subepithelium of the central airways as compared with asymptomatic smokers (4).

Are exacerbations of chronic bronchitis characterized by specific features? In this issue of the Journal, Zhu and colleagues provide further evidence that an exacerbation of chronic bronchitis is associated with tissue eosinophilia (pp. 109-116) (5). They performed immunohistology and in situ hybridization on bronchial biopsies and postulated that an "allergic profile" of inflammation including the CD4 T-helper type 2 (Th2) associated cytokines interleukin-4 (IL-4) and interleukin-5 (IL-5) (6) can also occur in chronic bronchitis, not only in asthma, and that a marked upregulation of the eosinophil chemoattractant RANTES (regulated upon activation, normal T-cell expressed and secreted) in the epithelium and subepithelium most likely accounted for the increased eosinophilia. Where is now the distinction between a patient with bronchitis and one with asthma? Is inflammation the same for both diseases? Before reaching such a strong conclusion, several issues should be taken into consideration.

First, there is the general limitation regarding data from a cross-sectional study. The investigators compared three groups of nonatopic subjects: healthy nonsmokers with normal lung function, nonasthmatic smokers with chronic bronchitis and mild airflow limitation in a stable phase of their disease (their mean FEV₁ was 75% predicted), and nonasthmatic smokers with chronic bronchitis who sought medical advice for an exacerbation (their mean FEV₁ was 61% predicted). Thus, it is not clear whether there was not a baseline difference in the group studied during exacerbation, regarding their profile of inflammatory cells and cytokines. Was this group characterized by an eosinophilic bronchitis already before the exacerbation occurred? Obviously, repeated bronchial biopsies aiming at a longitudinal investigation of individual changes are invasive procedures which may be applied only reluctantly. Such serial studies would be more feasible with induced sputum analysis, although the target cells are different (luminal cells in induced sputum versus epithelial and subepithelial location in biopsy). What could have been done in the present study, however, to strengthen the data and to allow comparison with previously published induced sputum data, is a parallel analysis of induced sputum. Second, biopsies obtained during bronchoscopy access the central airways (surely an important site for asthma), but not the peripheral small airways which play a crucial role in the development of smoking-related bronchial inflammation, at least in the initial stage. Finally, Zhu and colleagues do not provide data on possible airway hyperreactivity, in terms of the PC₂₀ response to methacholine challenge. Those patients with bronchitis and exacerbations may have had associated bronchial hyperreactivity, i.e., an "asthmatic component" of their diseases, which might have accounted, at least partially, for the observed tissue eosinophilia.

Is "allergic profile" of inflammation the correct term for the findings in this study? There are some arguments against this. First, the Th2 cytokines IL-4 and IL-5 were expressed in all individuals to the same degree, without significant difference between the groups, including the healthy nonsmokers. This may indicate that the cytokines are constitutively expressed, and that other stimuli are responsible for the eosinophilia. Second, an eosinophilia is not exclusively related or synonymous to an "allergic profile"; a good example is idiopathic pulmonary fibrosis with increase in eosinophils in BAL fluid, but without known allergic mechanism.

The most striking finding associated with an exacerbation was the upregulation of RANTES in both inflammatory and epithelial cells. The discussion of this finding is very sound, with strong emphasis on viral infections as the most likely cause of RANTES upregulation, and the synergistic function of CD8⁺ cytolytic cells to enhance the reaction of a FAS-ligand-dependent apoptosis of virally infected cells (7). By this mechanism relapsing exacerbations due to viral infections may pave the way for chronic bronchitis to permanent tissue damage and may accelerate the decline in lung function. CD8⁺ cells seem to be important already early in the pathogenesis of COPD. Saetta and associates showed that smokers with mild COPD had greater numbers of CD8⁺ cells in peripheral airways than asymptomatic smokers, whereas the other inflammatory cells, including neutrophils, were similar (3). In contrast, activated CD4⁺ cells are the predominant T-cell subsets in airways of asthmatics (8).

Do these findings apply to all exacerbations of COPD? Viruses are important triggers of COPD exacerbations, but some exacerbations may be triggered by bacterial infections. Other possible triggers may be inhaled allergens or chemical sensitizers, which would likely be also associated with eosinophilia. In exacerbations caused by bacterial infection, however, one would expect no tissue eosinophilia and no allergic profile, but instead an increase in neutrophils and upregulation of IL-8 as an important neutrophil chemoattractant. We have no information from Zhu and colleagues about the number of neutrophils and the expression of IL-8 in the bronchial mucosa of their patients. Further investigations of similar type in patients with COPD should analyze neutrophils and neutrophil-related mediators and cytokines as well, and also try to probe for the presence of viruses or bacteria.

Whether the subset of COPD patients with eosinophilic bronchitis and the so called "allergic profile" of inflammation during exacerbations should be the target for long-term treatment with inhaled corticosteroids remains to be determined. Patients with COPD who show a response to oral corticosteroids have increased BAL eosinophilia (9). In COPD associated with eosinophilic bronchitis, inhaled corticosteroids improved FEV₁ and reversed the eosinophilia, but did not change the neutrophils (10). In summary, further studies of the type presented by Zhu and colleagues in this Journal are definitely needed to improve our understanding of the underlying pathophysiology and to elucidate potential treatment modalities in the complex disease labeled COPD.

	References

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