Therapeutic significance of distal airway inflammation in asthma,☆☆,

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Abstract

Inflammation in asthma is not merely confined to the large central airways but also extends to the small peripheral airways. Distal lung inflammation can be observed even in patients with asthma with mild disease and normal spirometric readings. Subjects with asymptomatic asthma can exhibit significant increases in peripheral airway resistance, likely the result of distal lung inflammation. As determined from measurements of eosinophilic and other cellular infiltrates, the inflammatory response in the distal lung can exceed that in the large airways. Nocturnal asthma, a natural model of cyclic asthma worsening, is associated with an increase in nighttime distal lung inflammation, as evidenced by the accumulation of alveolar tissue eosinophils. Distal lung disease appears to increase the risk of recurrent asthma exacerbation, whereas disease-related anatomic changes in the small airways of the distal lung are prominent in fatal asthma. The clinical significance of distal lung disease makes this region an important therapeutic target. Chlorofluorocarbon (CFC)-based preparations of inhaled corticosteroids used to treat airway inflammation produce aerosols of relatively large particle size (~4 μm); such aerosols have poor access to the distal lung. New formulations of inhaled corticosteroids that use hydrofluoroalkane (HFA) propellants can have smaller particle sizes (~1 μm). Extrafine HFA aerosols have better access to the distal lung, with less oropharyngeal deposition. Imaging studies suggest that anti-inflammatory medication delivered as an extrafine aerosol produces beneficial changes in distal lung function. In one study, an HFA formulation of an inhaled corticosteroid reduced air trapping to a greater degree than a CFC formulation of the same corticosteroid. By extending the delivery of anti-inflammatory medication to the distal lung, the new HFA-based corticosteroids have the potential to treat asthma more effectively and at reduced steroid doses. (J Allergy Clin Immunol 2002;109:S447-60.)

Introduction

Asthma is characterized by airway obstruction and hyperresponsiveness to constricting stimuli. This condition typically assumes a course of periodic or sporadic exacerbation that often occurs against a background of chronically impaired pulmonary function. In the past, before emphasis was placed on the inflammatory component of asthma, its clinical manifestations were viewed as the sole targets of pharmacologic intervention; treatment, primarily with bronchodilating agents, was aimed at alleviating acute attacks. The therapeutic approach to asthma underwent a fundamental change when it was treated as a disease of airway inflammation. Pulmonary obstruction and bronchial reactivity occurred secondary to an ongoing inflammatory process, one that was active even during quiescent periods when symptoms abated. Recognition of the underlying nature of the disease led to the introduction of antiinflammatory steroids as a controlling therapy in the maintenance and treatment of asthma. Inhaled corticosteroids rapidly gained acceptance as the mainstay of therapy in the treatment of persistent asthma.1 This review examines (1) histologic evidence, (2) physiologic correlates, (3) imaging of mid-zone airways, and (4) targeted therapeutic sites relating to inhaled corticosteroid therapy of distal airway inflammation in asthma.

Although their success in ameliorating the symptoms of asthma and in preventing exacerbations is not disputed, inhaled corticosteroids do not appear to be a panacea. After more than 20 years' experience with their widespread use, it is apparent that a substantial number of patients with asthma receiving such therapy are steroid insensitive and continue to experience frequent exacerbations.2 Furthermore, the natural age-related decline in pulmonary function, which occurs at a faster pace in patients with asthma, is not completely normalized with long-term corticosteroid therapy.3, 4 These observations suggest that lingering regions of inflammation may remain beyond the reach of current inhaled steroid formulations.

Although questions continue to be raised concerning the adequacy of antiinflammatory therapy in asthma, our understanding of the extent of its inflammatory disease process continues to advance. Until recently, asthma was considered a disease primarily of the central airways, whereas the contribution of distal lung inflammation to its development and persistence had gone largely unexamined. The distal airways (also referred to as the peripheral or small airways ) have been ignored primarily for 2 reasons: (1) they are, by nature, less available for observation than the larger proximal airways, and (2) commonly used physiologic measures of pulmonary function are weighted toward measuring the caliber of the large airways. In turn, histopathologic evidence of inflammatory disease in the central airways is more easily correlated with gross measures of lung performance.5 Therefore, characterization of asthma as a disease of the central airways has been motivated more by convenience than by scientific evidence.

With the introduction of sophisticated imaging6 and immunohistochemical7 techniques, it has become increasingly evident that small distal airways are indeed significant sites of inflammation in asthma. It has been proposed that distal airway inflammation contributes to a host of clinically significant processes in asthma. Distal inflammation may play a role in airway hyperresponsiveness, nocturnal asthma, spontaneous exacerbations of symptoms, asthma complicated by smoking and/or viral respiratory tract inflections, and severe steroiddependent asthma. The importance of distal inflammation in asthma has called attention to the fact that inhaled corticosteroids—the first line of therapy for asthma prophylaxis—are not efficiently delivered to the distal lung by conventional formulations. This has led to suggestions that the effectiveness of inhaled antiinflammatory medications could improve if more drug is deposited in the small and large airways.8

This review presents evidence that distal lung inflammation plays a significant role in asthma and that in-flammation at distal sites is currently undertreated. Recent improvements in the design and formulation of inhaled corticosteroids increase delivery of these drugs to the distal lung, which may address some of their current therapeutic limitations. The potential therapeutic and safety benefits of disseminated pulmonary antiinflammatory therapy are discussed.

Section snippets

Histologic evidence of distal lung inflammation

Convincing evidence that distal airways and lung parenchyma are significant sites of inflammation in asthma comes from studies identifying cellular infiltrates in these areas. Fiberoptic bronchoscopic sampling and cellular staining techniques used to identify inflammatory infiltrates were first applied in studies of large airway inflammation.9 Such studies identified not only the composition of the cellular infiltrates but also their activation status. For example, using histochemical staining

Physiologic correlates of distal airway inflammation

For beneficial results to be derived from asthma treatment, some attempt at measuring the contribution of distal airway inflammation to diminished pulmonary function must be made. There is a possibility that even with ample histologic evidence of distal airway inflammation, the actual effect on lung function might be negligible compared with the effect on larger proximal airways. Numerous studies have attempted to correlate clinical measures of standard lung function with the presence and

Imaging of the mid-zone airways

The entire branching network of distal airways cannot easily be visualized directly with current radiographic techniques. Thin-section computed tomography (CT) can reveal anatomic details of the lung only as small as 200 to 300 μm, corresponding to wall thickness in airways 2 mm in diameter or larger.33 This CT is at the uppermost limit of small airway dimensions, making the method inadequate for visualizing smaller airways. Highresolution CT (HRCT) studies have attempted to view anatomic

Distal lung targeting of inhaled corticosteroids

At present, inhaled corticosteroids remain the mainstay of therapy for the long-term control of asthma.1 Although their efficacy and safety are established, the therapeutic actions of inhaled corticosteroids at sites of small airway inflammation are still the subject of ongoing research. These studies are particularly challenging because of the relative anatomic inaccessibility of the distal lung and the difficulty of separating the distal lung and large airways physiologically.

Conclusions

Although the distal airways are significant and persistent sites of inflammation in asthma, inflammation in this lung compartment appears to be undertreated with most current inhaled medications. The weight of evidence from clinical and preclinical studies of inhaled bronchodilators and corticosteroids strongly supports the role of aerosol particle size, as well as corticosteroid potency, as important considerations for achieving optimum efficacy in patients with asthma. The fact that smaller

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    Supported by Forest Laboratories, Inc., New York, NY.

    ☆☆

    Dr Martin has no significant financial relationship or interest in Forest Laboratories, Inc. He has prepared this report to present factual, unbiased information and attests that no commercial association has influenced this report, nor does this publication constitute a commercial or personal conflict of interest.

    Reprint requests: Richard J. Martin, MD, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206.

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