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Translating Basic Research Into Clinical Practice |

Small Airway Disease in Asthma and COPD: Clinical Implications FREE TO VIEW

Maarten van den Berge, MD; Nick H. T. ten Hacken, MD; Judith Cohen, MD; W. Rob Douma, MD; Dirkje S. Postma, MD
Author and Funding Information

From the Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Correspondence to: Dirkje S. Postma, MD, PhD, Department of Pulmonary, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands; e-mail: d.s.postma@long.umcg.nl


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(2):412-423. doi:10.1378/chest.10-1210
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Asthma and COPD have a high personal, societal, and economic impact. Both diseases are characterized by airway obstruction and an inflammatory process. The inflammatory process affects the whole respiratory tract, from central to peripheral airways that are <2 mm in internal diameter, the so-called small airways. There is an increased interest in small airway disease, and some new insights have been gained about the contribution of these small airways to the clinical expression of asthma and COPD, as reviewed in this article. Newly developed devices enable drugs to target the small airways, and this may have implications for treatment of patients with asthma, particularly those not responding to large-particle inhaled corticosteroids or those with uncontrollable asthma. The first studies in COPD are promising, and results from new studies are eagerly awaited.

Figures in this Article

Asthma and COPD are prevalent diseases with a high personal, societal, and economic impact. Both diseases are characterized by airway obstruction. An inflammatory process affects the whole respiratory tract, from central to peripheral airways that are <2 mm in internal diameter, the so-called small airways. In the past years there has been renewed interest in small airway disease and some new insights have been gained about the contribution of these small airways to the clinical expression of these two diseases. Furthermore, new inhalation devices have been developed allowing drugs to target the small airways and this may have implications for treatment of asthma and COPD now and in the near future.

The assessment and monitoring of small airway involvement in asthma and COPD is a challenging matter because the region is relatively inaccessible for functional measurements. Until now there has been no test with accepted cutoff values to measure the presence and severity of small airway involvement.

Pulmonary small airway function tests have been developed with respect to the physiology of small airways.1 Although the cross-sectional area increases toward the periphery of the lung, gas velocity decreases and airflow changes from turbulent to laminar. Obstruction of the small airways affects the distribution of ventilation and may lead to small airway closure accompanied by air trapping. Pulmonary function tests that are used to assess small airway pathology can be subdivided in tests measuring flow, airway resistance, inhomogeneity of ventilation distri­bution, airway closure, or air trapping.

Flow measures commonly used in small airway studies are forced expiratory flow rates at 50% of vital capacity (FEF50%) and at 25% to 75% of vital capacity (FEF25%-75%).2 Airway resistance can be measured with impulse oscillometry (IOS).3 Small airway obstruction is associated with an increase in resistance predominantly at lower frequencies (frequency-dependence resistance).4 Inhomogeneity of ventilation distribution can be assessed by the multiple-breath nitrogen washout test and by the single breath nitrogen washout (SBNW) test after inhalation of 100% oxygen.5-7

Air trapping and airway closure can be assessed with both dynamic flow-volume measurements and static lung volume measurements. A decrease in FVC may reflect air trapping. ΔFVC at the provocative concentration causing a 20% fall in FEV1 (PC20) methacholine has been described as a useful marker of air trapping as well.8,9 Additionally, the difference between slow inspiratory vital capacity (SVC) and FVC and the FVC to SVC ratio may be surrogate markers of the collapsibility of small airways.10-12 Common measures of static lung volumes related to air trapping and hyperinflation are functional residual capacity, resid­ual volume (RV), total lung capacity (TLC) and the RV/TLC ratio. Closing capacity and closing volume, the expiratory capacity and volume at which small airways collapse, can be obtained with the SBNW test.6,13,14

Peripheral airway inflammation can be examined by measuring nitric oxide (NO) concentrations in single breath exhaled air during different flow rates.15 Using a mathematical model, it is possible to discriminate between the bronchial and alveolar contribution. Alveolar NO measurements have shown good reproducibility and responsiveness to small particle inhaled corticosteroids (ICS) (Tables 1, 2).16-39

Table Graphic Jump Location
Table 1 —Overview of Lung Function Tests for SA Obstruction

BOS = bronchiolitis obliterans syndrome; ΔFVC = change in FVC at the provocative concentration causing a 20% fall in FEV1; FEF50% = forced expiratory flow rates at 50% of vital capacity; FEF25%-75% = forced expiratory flow rates at 25% to 75% of vital capacity; MCh = methacholine; NO = nitric oxide; PC20 = provocative concentration causing a 20% fall in FEV1; RV = residual volume; SA = small airway; SBNW = single breath nitrogen washout; SVC = slow inspiratory vital capacity; TLC = total lung capacity.

Table Graphic Jump Location
Table 2 —Summary of Studies With Small Particle Aerosols in Asthma Specifically Investigating Measures of SA Function

%pred = percent predicted; BDP = beclomethasone; BUD = budesonide; CFC = chlorofluorocarbon; CIC = ciclesonide; DPI = dry-powder inhaler; FORM = formoterol; FP = fluticasone propionate; HFA = hydrofluoroalkane; HRCT = high-resolution CT; ICS = inhaled corticosteroid; IOS = impulse oscillometry; MBNW = multiple breath nitrogen washout; PLAC = placebo; SALM = salmeterol. See Table 1 for expansion of other abbreviations.

Imaging techniques, such as high-resolution CT (HRCT) scanning and MRI with inhaled hyperpolarized gases, can be used to evaluate indirect signs of small airway obstruction, such as inhomogeneity of ventilation and air trapping, which are associated with remodeling.40-45 All above-mentioned parameters have been used in research and contributed to the progress made to understand involvement of small airways in asthma and COPD. Each test has its own features making it more or less useful in detecting and monitoring small airway disease, as summarized in Table 1. Unfortunately, no test is yet available that has all the requested features to diagnose, weigh, and monitor small airway disease in clinical practice. It appears that alveolar exhaled NO and air trapping measured with CT scanning are very solid and sensitive tests of small airway function/inflammation; however, these techniques are not available to every clinic. Furthermore, the benefit of CT scanning must be balanced against the burden on the patient. Tests that are easily accessible to virtually all respiratory clinics and are moderately sensitive to detect small airway involvement in asthma and COPD are RV/TLC via body plethysmography and FEF25%-75% via spirometry. The necessity of assessment of small airway function in patients with asthma or COPD has not been fully elucidated. In general, when regular first-choice treatment, which currently is large-sized particle ICS, is insufficient in achieving optimal control of disease, investigation of involvement of small airways is indicated.

Despite interest in small airway disease in asthma, the number of articles about the underlying pathology is surprisingly small, probably due to the relative inaccessibility of the small airways. Several studies collected tissue by using lung material from autopsied patients with fatal asthma, or from patients with asthma needing lung resection because of malignancy. More recent studies in subjects with nocturnal asthma used transbronchial biopsies, an invasive technique that limits its use for research purposes or routine practice. Because induced sputum or BAL also collect materials from central airways, they will not be discussed. Using a PubMed search we identified 13 resection studies and six transbronchial biopsy studies (Table 3).46-63 To assess the role of small airways in asthma, we investigated six questions in these studies.

Table Graphic Jump Location
Table 3 —Histologic Studies on the SAs in Asthma

BD = bronchodilator; CF = cystic fibrosis; CS = corticosteroids; EBBX = endobronchial biopsies; EG2 = eosinophil granulocyte-2; GRβ = glucocorticoid receptor β; IW = inner wall; LD = long duration; MBP = major basic protein; MCP4 = monocyte chemotactic protein-4; NA = nocturnal asthma, NNA = nonnocturnal asthma; OW = outer wall; PY = pack-years; SD = short duration; TBBX = transbronchial biopsies. See Tables 1 and 2 for expansion of other abbreviations.

(1) Do Small Airways in Patients With Asthma Differ From Those in Healthy Control Subjects?

Small airways are thickened in asthma by chronic inflammation in the epithelium, submucosa and muscle area.46-48 The outer wall is also more thickened, with higher numbers of lymphocytes, eosinophils, and neutrophils, accompanied by higher mRNA expression of IL-4, IL-5, and eotaxin.45,47,49,50-53,59

(2) Do Small Airways Differ Between Subpopulations of Asthma?

Patients with fatal asthma have more thickened small airways and higher numbers of eosinophils than those with nonfatal asthma.49.50 Patients with a short duration of fatal asthma have more goblet cells and neutrophils than those with a long duration.52 Patients with severe asthma have more neutrophils in lung parenchyma than patients with moderate asthma, and subjects with nocturnal asthma, as compared with non-nocturnal asthma, had more CD4+ lymphocytes and eosinophils, particularly at night.59-61 Finally, more severe asthma is associated with more severe air trapping (as measured with quantitative CT scanning), indicating small airway disease.64

(3) Is There Differential Inflammation in Proximal and More Distal Airways and Lung?

Some studies suggest that the cellular infiltrate increases toward the periphery, but others show similar or decreased infiltration.49,53-55,57,61,62 These contradictory findings are true for all studied cell types, which may reflect the heterogeneity of asthma as well as the different methods used in the studies (Table 3). The amount of collagen is lower in the small airways, but the smooth muscle presence is similar.31,52 Together this may contribute to an increased collapsibility and increased hyperresponsiveness of the small airways. However, these findings may be criticized because small and large airways are difficult to compare because of their completely different size and architecture.

(4) Are the Outer and Inner Walls Different in Small Airways?

There are indications that the outer wall is more inflamed than the inner wall, and that peribronchiolar regions are also involved in the inflammatory process.51,57,58,62 The latter may contribute to an uncoupling of the small airways and the surrounding lung parenchyma and thus increase collapsibility of small airways.

(5) Are Small Airways Changing Over Time, Spontaneously, or After Pharmacologic Intervention?

Subjects with nocturnal asthma show significant increases of eosinophils at night in the alveoli collected by transbronchial biopsies, together with CD4+ lymphocytes.60,61 Flunisolide reduces inflammation in the small airways together with smooth muscle actin in asthma.31,63

(6) Do Small Airway Changes Correlate With Lung Function?

One study in nocturnal asthma demonstrated that higher numbers of eosinophils in the alveoli correlate with increased airway obstruction at night.61 Also, flunisolide-induced reduction in smooth muscle area in the small airway walls correlates with improved midexpiratory flow rates.63 Together, these studies suggest that, at least in more severe asthma, the underlying inflammatory process is also present in the small airways. It may even be more intense and involve the complete airway wall and peribronchiolar region. Small airway disease appears also to be present in milder asthma, because several studies showed a higher degree of air trapping on HRCT scan even in mild disease.43,65 Definitive conclusions are hard to draw because asthma is a heterogeneous disease and different asthma populations have been investigated, the number of studies is small, and different techniques have been applied to characterize aspects of inflammation and remodeling.

COPD is defined as an abnormal inflammatory response of the lung to noxious particles and gases, mainly cigarette smoke.66 The smaller airways (<2 mm in internal diameter) offer little resistance in normal lungs but are the major site of obstruction in COPD. To assess the role of small airways in COPD, we raised the following questions:

(1) Is Small Airway Injury a Cause or Consequence of COPD?

It is generally accepted that inflammation exists in the small airways in COPD. Milic-Emili14 has proposed that the presence of airway closure during tidal breathing enhances peripheral airway inflammation from smoking per se due to mechanical injury. Thus, airway closure may constitute an important phenomenon for COPD development and not just be the consequence of COPD. This needs further study.

(2) Does Small Airway Inflammation or Remodeling Contribute to COPD?

The main pathologic features of COPD are found in these small airways and lung parenchyma (Fig 1).67 These features include tissue remodeling in the small airways (fibrosis and smooth muscle hypertrophy) and tissue destruction in the lung leading to emphysema.68 Hogg and coworkers69 investigated small airways in COPD extensively in relation to its severity and concluded that inflammation is an important feature of small airway disease. Particularly, lymphocytes may play a key role in enhancing and maintaining the inflammatory response, and a higher number of CD8+ cells and B cells has been detected in the wall of small airways of smokers with than without COPD.70-72 Furthermore, a more extensive bronchiolar infiltration of these cells correlates with a lower FEV1.69 Additionally, a higher number of CD8+ cells in the peripheral airways is associated with a more severe airway obstruction in COPD, suggesting that they play a key role in the pathogenesis of COPD.70 Quantification of dendritic cells in the small airways by immunohistochemistry revealed a higher number of langerin-positive dendritic cells in current smokers without COPD and in patients with COPD compared with never smokers and ex-smokers without COPD.73 Thus, dendritic cells may also play a role in the inflammatory orchestra in COPD. Interestingly, Hogg and colleagues69 showed that remodeling of the small airways, rather than inflammation, was the most important independent predictor of COPD progression in a multivariate regression analysis. Thus far, the exact mechanisms underlying small airway remodeling in COPD remain poorly understood. Several possible mechanisms have been put forward. First, it has been suggested that ongoing inflammation in the small airways is responsible for an increased production of transforming growth factor (TGF)-β leading to fibrosis and thickening of the airway wall. Second, aberrant repair processes in COPD may play a role. The latter is in agreement with the findings of Zandvoort and colleagues,74 who showed an abnormal response of lung fibroblasts derived from patients with COPD after exposure to cigarette smoke extract. Third, Churg and colleagues75 have suggested that cigarette smoke itself may directly induce the release of growth factors. They exposed mice to a single dose of cigarette smoke and measured growth factor gene expression levels in laser-capture microdissected small airways 2 and 24 h later. After 2 h, a time frame too short to induce a significant inflammatory response, increased levels of gene expression for TGF-β, platelet-derived growth factor, procollagen, and connective tissue growth factor were observed. Remarkably, the levels of TGF-β, platelet-derived growth factor, procollagen, and connective tissue growth factor decreased between 2 and 24 h, a time frame during which the inflammatory response develops. Taken together, these results may suggest that growth factor release and subsequent small airway remodeling can be the direct result of smoke exposure rather than being secondary to smoke-induced inflammatory responses.

Figure Jump LinkFigure 1. A, Normal small airway. B, Abnormal small airway with airway remodeling in COPD. The airway is narrowed by deposition in the interstitial space. (Reprinted with permission from Hogg et al.67)Grahic Jump Location
(3) Are Small Airway Disease and Tissue Destruction Driven By Similar Mechanisms in COPD?

Although it is now clear that both small airway remodeling and emphysema are important, the question remains whether the same mechanisms underlie these two different components of COPD. In this context, the findings of Gosselink and colleagues76 in lung tissue derived from 63 patients with COPD are of special interest. They examined the level of gene expression for 54 known tissue repair genes in paired samples of small airways and surrounding lung tissue separated by laser-capture microdissection. In the small airways, 2/54 repair genes increased and 8/54 genes decreased in association with FEV1. In contrast, 8/54 repair genes increased and 4/54 decreased in association with FEV1 in the surrounding lung tissue. Only two of the 54 repair genes examined were significantly associated with severity of FEV1 in both small airways and surrounding lung tissue. Taken together, the findings of this elegant study indicate that substantially different mechanisms underlie the process of small airway remodeling on the one hand and development of emphysema on the other hand.76 Finally, Hogg and colleagues77 have examined small airways and lung parenchyma in four lungs removed from patients with very severe COPD and four unused donor lungs by using micro-CT scanning. They found that the number of small airways and their minimal cross-sectional lumen area decreases significantly in COPD, both in areas with and without emphysematous destruction. These findings might suggest that the small airways become narrowed and are removed, at least in a subset of patients with COPD, by a process that begins prior to the onset of emphysema. This again signifies their importance as targets for disease prevention and intervention.

Asthma

With the introduction of the solution hydrofluo­roalkane (HFA) technology, pressurized metered dose inhalers (pMDIs) have become available, generating small particles with an average size of approximately 1 μm. Examples of currently available small-particle pMDIs are HFA-beclomethasone, HFA-beclomethasone/formoterol, HFA-flunisolide, and ciclesonide. The most important advantage of small-particle pMDIs is their higher lung deposition than conventional inhalers (50% to 60% vs 10% to 20%) and lower oropharyngeal deposition (30% to 40% vs >80%) (Fig 2).11 A disadvantage of the use of pMDIs vs dry-powder inhalers is that a better coordination is needed. In addition, pMDIs have to be conserved at a low temperature. Initially, there has been concern that the better peripheral deposition of small-particle pMDIs could be accompanied with more systemic side effects. However, this does not appear to be the case. No decrease in either 24-h urinary free cortisol or serum cortisol has been found with 800 μg HFA-beclomethasone compared with the same dose of chlorofluorocarbon (CFC)-beclomethasone.78,79 Several studies have shown that HFA-beclomethasone is as effective in improving FEV1 as two to three times the dose of CFC-beclomethasone.80,81

Figure Jump LinkFigure 2. A, γ-scintigraphic lung image produced after inhalation of chlorofluorocarbon-beclomethasone metered-dose inhaler (MDI). B, γ-scintigraphic lung image produced after inhalation of hydrofluoroalkane-beclomethasone MDI. (Reprinted with permission from Leach et al.11)Grahic Jump Location

It has been suggested that the use of small-particle aerosols may have additional clinical benefits. A limited number of studies have addressed this issue specifically, investigating measures of small airway function in patients with asthma (Table 2). Hauber and colleagues31 performed transbronchial biopsies before and after treatment with HFA-flunisolide. They found lower eosinophil numbers in the small airways after 6-week treatment with HFA flunisolide when compared with baseline. In addition, Cohen and colleagues32 observed improvements in alveolar NO and methacholine-induced air trapping on HRCT scan after treatment with ciclesonide compared with placebo. These findings show that small-particle ICS improve small airway inflammation and function in asthma. This is in agreement with findings of Goldin and colleagues,33 who directly compared HFA-beclomethasone 100 μg bid and CFC-beclomethasone 100 μg bid. Both treatments were equally effective in improving symptoms and FEV1, but HFA-beclomethasone reduced the amount of air trapping assessed with HRCT to a greater extent than CFC-beclomethasone. In contrast, reduction of air trapping was found to be similar in another study comparing HFA-beclomethasone 400 μg daily with an equipotent dose of fluticasone 500 μg daily.34 A better effect of a small-particle ICS on small airway function was confirmed in two further studies using IOS.4,37 Here, HFA-beclomethasone and ciclesonide improved airway resistance (R5-20) and reactance at 5 Hz as assessed by IOS more effectively than CFC-beclomethasone or fluticasone, respectively, whereas similar improvements in FEV1 and FEV1/FVC were found.4,37 Several studies investigated the effects of small-particle pMDIs on ventilation heterogene­ity as assessed with SBNW closing volume and closing capacity. Thongngarm and colleagues35 showed an improvement in SBNW closing volume with HFA-beclomethasone (320 μg daily) when compared with CFC-beclomethasone (320 μg daily). Finally, a recent study observed that small-particle combination treatment with HFA-beclomethasone/formoterol tended to improve SBNW closing capacity to a larger extent than fluticasone/salmeterol.38

Antiinflammatory treatment with ICS is the cornerstone of asthma management. Nevertheless, a considerable subset does not benefit from ICS nor can it reach asthma control.82 There is now a considerable amount of evidence that small-particle aerosols improve small airway function and inflammation to a higher extent than larger-particle aerosols. This could be clinically relevant, especially in those patients whose asthma is difficult to control. Recent findings of Verbanck and colleagues39 showed improvements in ventilation heterogeneity in 30 patients with asthma after treatment with HFA-beclomethasone compared with the same dose of budesonide. Importantly, a subgroup of 16 patients with more small airway disease at baseline (ie, more abnormal ventilation heterogeneity) benefitted most from treatment with HFA-beclomethasone, with additional improvements in FEV1, FEF25%-75%, and residual volume.

COPD

Inhaled corticosteroids are less effective in COPD than in asthma. Although ICS reduce the number of exacerbations and improve quality of life, the accelerated lung function loss that is present in COPD cannot be reduced,83,84 or can only be reduced in a subset of patients.85,86 One of the reasons ICS have not been shown to be as effective as wished for in COPD might be that large-particle ICS are deposited only in the central airways, whereas inflammation is also present in the small airways and lung tissue. Thus far, only a few studies have investigated the effects of a small-particle ICS in COPD. Tatsis and colleagues87 demonstrated a slightly better improvement in FEV1 and symptoms with HFA-beclomethasone compared with budesonide or fluticasone. However, their results are difficult to interpret, since a mixed population of patients with asthma and COPD was studied. van Beurden and colleagues88 compared effects of HFA-beclomethasone and fluticasone on the concentration of hydrogen peroxide in exhaled breath condensate of patients with COPD. Both treatments decreased the concentration of hydrogen peroxide to a similar extent. Finally, John et al89 investigated effects of a small-particle aerosol in COPD and observed a significant reduction in hyperinflation as reflected by RV/TLC % predicted after treatment with HFA-beclomethasone, whereas no effect on FEV1 was observed. This was a small study in 11 patients with COPD and no direct comparison with a larger-particle ICS was made.

Further, several alternative antiinflammatory therapies have been developed based on the available knowledge of small airway disease,90 such as SB505124, an inhibitor of TGF-β73, and AZ11557272, a dual inhibitor of matrix metalloproteinase-9 and matrix metalloproteinase-12. The latter has been shown to protect against the development of smoke-induced airway wall thickening and emphysema in the guinea pig.91

There is now a considerable amount of evidence that small-airway inflammation contributes importantly to the clinical expression of asthma and COPD. This is important, since new devices have become available that allow drugs to better target the small airways. Several studies in asthma have shown a larger improvement in small airway function and inflammation with small-particle aerosols than with larger-particle aerosols. This may be clinically relevant, especially for patients with uncontrollable asthma not responding to large-particle aerosols. Future studies are now needed to investigate whether this is indeed the case. Reaching the distal part of the lung, where the pathology of COPD is dominant, may open new avenues for improved management of COPD too. The first studies in COPD are promising and results from new studies are now eagerly awaited.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr van den Berge has received a research grant from GlaxoSmithKline. Dr Postma has received grants from AstraZeneca, GlaxoSmithKline, and Nycomed for research, and has been consultant to AstraZeneca, GlaxoSmithKline, Nycomed, and TEVA. Drs ten Hacken, Cohen, and Douma have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

CFC

chlorofluorocarbon

FEF50%

forced expiratory flow rates at 50% of vital capacity

FEF25%-75%

forced expiratory flow rates at 25% to 75% of vital capacity

HFA

hydrofluoroalkane

HRCT

high-resolution CT

ICS

inhaled corticosteroid

IOS

impulse oscillometry

NO

nitric oxide

PC20

provocative concentration causing a 20% fall in FEV1

pMDI

pressurized metered dose inhaler

RV

residual volume

SBNW

single breath nitrogen washout

SVC

slow inspiratory vital capacity

TGF

transforming growth factor

TLC

total lung capacity

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Figures

Figure Jump LinkFigure 1. A, Normal small airway. B, Abnormal small airway with airway remodeling in COPD. The airway is narrowed by deposition in the interstitial space. (Reprinted with permission from Hogg et al.67)Grahic Jump Location
Figure Jump LinkFigure 2. A, γ-scintigraphic lung image produced after inhalation of chlorofluorocarbon-beclomethasone metered-dose inhaler (MDI). B, γ-scintigraphic lung image produced after inhalation of hydrofluoroalkane-beclomethasone MDI. (Reprinted with permission from Leach et al.11)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Overview of Lung Function Tests for SA Obstruction

BOS = bronchiolitis obliterans syndrome; ΔFVC = change in FVC at the provocative concentration causing a 20% fall in FEV1; FEF50% = forced expiratory flow rates at 50% of vital capacity; FEF25%-75% = forced expiratory flow rates at 25% to 75% of vital capacity; MCh = methacholine; NO = nitric oxide; PC20 = provocative concentration causing a 20% fall in FEV1; RV = residual volume; SA = small airway; SBNW = single breath nitrogen washout; SVC = slow inspiratory vital capacity; TLC = total lung capacity.

Table Graphic Jump Location
Table 2 —Summary of Studies With Small Particle Aerosols in Asthma Specifically Investigating Measures of SA Function

%pred = percent predicted; BDP = beclomethasone; BUD = budesonide; CFC = chlorofluorocarbon; CIC = ciclesonide; DPI = dry-powder inhaler; FORM = formoterol; FP = fluticasone propionate; HFA = hydrofluoroalkane; HRCT = high-resolution CT; ICS = inhaled corticosteroid; IOS = impulse oscillometry; MBNW = multiple breath nitrogen washout; PLAC = placebo; SALM = salmeterol. See Table 1 for expansion of other abbreviations.

Table Graphic Jump Location
Table 3 —Histologic Studies on the SAs in Asthma

BD = bronchodilator; CF = cystic fibrosis; CS = corticosteroids; EBBX = endobronchial biopsies; EG2 = eosinophil granulocyte-2; GRβ = glucocorticoid receptor β; IW = inner wall; LD = long duration; MBP = major basic protein; MCP4 = monocyte chemotactic protein-4; NA = nocturnal asthma, NNA = nonnocturnal asthma; OW = outer wall; PY = pack-years; SD = short duration; TBBX = transbronchial biopsies. See Tables 1 and 2 for expansion of other abbreviations.

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