Until recently, asthma was considered predominantly a disease of the central airways. Two factors contributed to this misconception:
Recently, the use of sophisticated imaging, immunohistochemical techniques and transbronchial biopsies have confirmed the presence of similar, even more severe, inflammatory processes in the smaller peripheral airways.1, 2
Defined as airways found beyond the seventh or eighth branch and as having a diameter of less than 2 mm, the inflammation that occurs in the peripheral branches has both differences and similarities to that observed in the larger airways.1 For example, in the larger airways, activated lymphocytes are distributed equally between the inner and outer part of the airway wall, while there are more eosinophils in the inner part.
In contrast, in small airways, activated lymphocytes and eosinophils are found mainly in the outer wall.1, 3 Also, greater numbers of activated eosinophils appear in the periphery than in the central airways, suggesting greater inflammatory activity in
the periphery.4 In addition, evidence of remodeling similar to that in the larger airways has been reported.4
Symptomatic asthma is characterized by premature airway closure. Nocturnal asthma has been related to an ‘uncoupling’ of the airway walls from the surrounding parenchyma through attachments via elastic fibers.5 Uncoupling reduces recoil in the surrounding tissue, and may be induced by chronic small-airway inflammation, or vice versa.5
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Significant increases in inflammation and peripheral resistance have even been demonstrated in asymptomatic patients.6, 7 In one study, asymptomatic patients with mild asthma had FEV1 values in the normal range, yet the mean forced expiratory flow rate at 25% to 75% of forced vital capacity (FEF25–75%) was significantly below that of healthy control subjects.6 This value is suggested as a surrogate measure of peripheral airway function.
In patients with mild asthma, high-resolution computed tomography used before and after methacholine challenge showed a decrease in pulmonary function that correlated with a decrease in the area of the smallest visible airways. Such a decrease was not seen in medium or large visible airways. Mean predicted FEV1 decreased by 24% after methacholine challenge and a 95% decrease in the area of small airways was detected.8
Such findings in the peripheral airways of asymptomatic patients with mild asthma suggest that the impact of the disease may be more significant than previously recognized,7 and causes two major areas of concern:
Therefore, chronic inflammation of the peripheral airways may account for sudden, severe exacerbations even in asymptomtic patients with mild asthma.
When two groups of patients with similarly severe asthma (one group with recurrent exacerbations and one without exacerbations) were compared during a clinically stable period (i.e. they were well controlled), those with frequent exacerbations showed evidence of increased airway closure, a finding that suggests small-airway involvement.9 Similar findings, although not significant, have been found in patients with mild asthma.10 Therefore, despite the fact that they may have otherwise stable asthma, patients of all severities may be prone to serious, unexpected bouts of bronchoconstriction, which highlights the importance of treatment with ICS to reduce excessive airway narrowing.11
Inflammation in the small airways at the periphery demands treatment with the ability to reach into these airways. Ideally, if an agent has the ability to reach into the peripheral airways, it should be able to provide efficacy at lower doses and with fewer systemic effects than comparable compounds that remain in the larger airways.
The ability of an inhaled agent to be deposited in the peripheral airways depends largely on its physicochemical characteristics. Smaller, less dense particles are more likely to reach the peripheral airways.7, 12 HFA–MDI corticosteroid solutions provide extra-fine aerosols that have been shown to penetrate more effectively into the peripheral regions of the lung than HFA or chlorofluorocarbon (CFC) suspension formulations13. Alvesco® has been shown to reach the peripheral airways sing two and three-dimensional imaging.14
References:
1. Hamid Q, Song Y, Kotsimbos TC, Minshall E, Bai TR, Hegele RG, et al. Inflammation of small airways in asthma. J Allergy Clin Immunol 1997;100:44–51.
2. Sutherland ER, Martin RJ. Distal lung inflammation in asthma. Ann Allergy Asthma Immunol 2002;89:119–124;quiz 24-5, 211.
3. Haley KJ, Sunday ME, Wiggs BR, Kozakewich HP, Reilly JJ, Mentzer SJ, et al. Inflammatory cell distribution within and along asthmatic airways. Am J Respir Crit Care Med 1998;158:565–572.
4. Carroll N, Elliot J, Morton A, James A. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405–410.
5. Irvin CG, Pak J, Martin RJ. Airway-parenchyma uncoupling in nocturnal asthma. Am J Respir Crit Care Med 2000;161:50–56.
6. Wagner EM, Liu MC, Weinmann GG, Permutt S, Bleecker ER. Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990;141:584–588.
7. Martin RJ. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol 2002;109:S447–S460.
8. Goldin JG, McNitt-Gray MF, Sorenson SM, Johnson TD, Dauphinee B, Kleerup EC, et al. Airway hyperreactivity: assessment with helical thin-section CT. Radiology 1998;208:321–329.
9. In ‘t Veen JC, Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000;161:1902–1906.
10. King GG, Eberl S, Salome CM, Young IH, Woolcock AJ. Differences in airway closure between normal and asthmatic subjects measured with single-photon emission computed tomography and technegas. Am J Respir Crit Care Med 1998;158:1900–1906.
11. Engelstätter R, Escher A, Haefner D. Low incidence of oropharyngeal adverse events in asthma patients treated with ciclesonide. Eur Respir J 2005;26(Suppl 49):255s.
12. Derendorf H, Nave R, Drollmann A, Cerasoli F, Wurst W. Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur Respir J 2006;28:1042–1050.
13. Zeidler M, Corren J. Hydrofluoroalkane formulations of inhaled corticosteroids for the treatment of asthma. Treat Respir Med 2004;3:35–44.
14. Leach CL, Bethke TD, Boudreau RJ, Hasselquist BE, Drollmann A, Davidson P, et al. Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers.J Aerosol Med 2006;19:117–126.