• airway inflammation;
  • asthma;
  • chronic obstructive pulmonary disease (COPD);
  • small airways;
  • treatment


  1. Top of page
  2. Abstract
  3. Methods to evaluate the distal lung: functional parameters, biomarkers and imaging
  4. The distal lung in asthma
  5. The distal lung in COPD
  6. Open questions on distal airway involvement in asthma and COPD and future directions
  7. Conclusions
  8. Acknowledgment
  9. Disclosure of funding
  10. Conflicts of interest
  11. References

To cite this article: Contoli M, Bousquet J, Fabbri LM, Magnussen H, Rabe KF, Siafakas NM, Hamid Q, Kraft M. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. Allergy 2010; 65: 141–151.


The involvement of small airways in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) has been debated for a long time. However, a proper definition of small airway disease is still lacking, and neither a widely accepted biomarker nor a functional parameter to assess small airway abnormalities and to explore the effect of tested compounds on small airways is available. Aiming towards increased knowledge and consensus on this topic, this perspective paper intends to (i) strengthen awareness among the scientific community on the role of small airways in asthma and COPD; (ii) examine the pros and cons of some biological, functional and imaging parameters in the assessment of small airway abnormalities; and (iii) discuss the evidence for distal airway pharmacological targeting in asthma and COPD.


beclomethasone dipropionate


computed tomography


chronic obstructive pulmonary disease


dry powder inhaler


exhaled nitric oxide


forced expiratory volume in 1 s


forced expiratory flow between 25% and 75% of the forced vital capacity


forced vital capacity




high-resolution computed tomography


inhaled corticosteroids


impulse oscillometry


long-acting β2-adrenoceptor agonists


eNO at multiple expiratory flows


residual volume

Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory diseases affecting the whole respiratory system, from central airways to lung parenchyma, with systemic effects (1, 2). The involvement of the distal lung, i.e., the peripheral membranous bronchioles < 2 mm in diameter (so-called small airways) and the lung parenchyma (3, 4), in the pathogenesis of asthma and COPD has been investigated and its significance debated. However, the relevance of the distal lung for the clinical presentation of the two diseases is still unclear, and a unanimously accepted approach to assess small airways in asthma and COPD is lacking.

Although several studies have addressed the pathophysiological events that occur in the small airways of patients with asthma and COPD, no biomarker or functional parameter has been widely accepted as the hallmark of small airway involvement. More importantly, although some parameters of small airways have been cross-sectionally associated with the presence of the disease (asthma or COPD vs healthy subjects) or with disease severity (severe vs mild patients) (5, 6), there are no available longitudinal data (7) to show that changes in or modulation of these biomarkers alter clinical outcomes of either condition. These limitations contribute to the under-recognition of the contribution of the distal lung in obstructive lung disease and result in limited awareness about the potential relevance of small airway abnormalities and their clinical impact.

New methods, including imaging and the indirect assessment of the lung periphery by optimizing markers (e.g., alveolar nitric oxide), have revived interest in the assessment of small airways. Moreover, the development of new compounds and of novel drug formulations that potentially target the peripheral lung, including new extrafine formulations of inhaled corticosteroids and β2-adrenoceptor agonists, brings the issue of the distal lung and its contribution to asthma and COPD pathobiology to the forefront once again. Based on this background, the aim of this review is to summarize the currently available knowledge on the role of the distal lung in asthma and COPD, and particularly to highlight the key unanswered questions. Reaching a consensus about the major issues regarding this topic would be the first step towards finding a way forward in understanding how to approach, evaluate and treat the small airways in asthma and COPD.

Methods to evaluate the distal lung: functional parameters, biomarkers and imaging

  1. Top of page
  2. Abstract
  3. Methods to evaluate the distal lung: functional parameters, biomarkers and imaging
  4. The distal lung in asthma
  5. The distal lung in COPD
  6. Open questions on distal airway involvement in asthma and COPD and future directions
  7. Conclusions
  8. Acknowledgment
  9. Disclosure of funding
  10. Conflicts of interest
  11. References

The distal lung compartment is a difficult anatomic area to study because of its relative inaccessibility. Several methods have been proposed and used to investigate this region of the lung, including complex and sometimes invasive techniques. Nonetheless, a universally accepted approach to assess small airways, and more generally the distal lung, in asthma and COPD is still lacking (Table 1).

Table 1.   Pros and cons of methods and of biological, functional and imaging parameters for the assessment of small airway abnormalities in asthma and chronic obstructive pulmonary disease
OutcomeMethodParametersProsConsOverall interest
  1. FEF25-75, forced expiratory flow between 25% and 75% of forced vital capacity; RV, residual volume; FVC, forced vital capacity; Scond, ventilation heterogeneity in the conductive airways; Sacin, ventilation heterogeneity in the acinar airways; HRCT, high-resolution computed tomography scan of the chest; MRI, magnetic resonance imaging; TBB, transbronchial biopsy; FeNO, exhaled nitric oxide; CalvNO, alveolar nitric oxide concentration.

Air trapping, ventilation heterogeneity measurementLung function testsFEF25-75Noninvasive, easy to performInfluenced by large airway obstruction and volume changes; not correlating with inflammation; low reproducibilityClinical trials Research Patient’s care
RV, FVCNoninvasive, easy to perform; correlating with small airways obstruction; high reproducibility and low variabilityFurther studies requiredClinical trials Research Patient’s care
Nitrogen washout testsSingle breathGood reproducibility and sensitivityNot widely available, to be performed by trained staffClinical trials Research Patient’s care
• Closing volume
• Closing capacity
• Phase III slope
Multiple breathGood reproducibility and sensitivityNot widely available, to be performed by trained staffClinical trials Research Patient’s care
• Scond
• Sacin
Forced oscillationsPeripheral resistanceSimplicity, reproducibilityNot widely availableClinical trials Research
ImagingHRCTPromising, information on airways patencyCostly, technically demanding, perceived as riskyClinical trials Research
• Lung attenuation
MRI with inhaled hyperpolarized gasesHigher resolutionCostly, technically demandingClinical trials Research
• Lung attenuation
Inflammation and remodelling measurementTBBInflammatory and remodelling markersHighly informativeInvasiveClinical trials Research
Sputum inductionInflammatory markersNoninvasiveIssues of reproducibility and standardizationClinical trials Research
Exhaled NOFeNO, CalvNONoninvasiveFurther studies needed, computational extrapolation requiredClinical trials Research

Functional parameters


Worldwide, the most widely employed pulmonary function test to assess and monitor obstructive pulmonary diseases is spirometry. However, it is widely recognized that forced expiratory volume in 1 s (FEV1) does not provide comprehensive evaluation of the whole bronchial tree. In particular, it does not properly reflect small airway abnormalities specifically, but does reflect the cross-sectional area of the lung (5, 8).

Other lung function parameters have been proposed and investigated as markers of small airway function. One of them is forced expiratory flow between 25% and 75% of forced vital capacity (FEF25–75), although the literature supporting its validity is not conclusive and conflicting data have been presented. Serial measures of FEF25–75 are highly variable, and FEF25–75 levels are influenced by large airway obstruction and volume changes. Additionally, this parameter did not correlate with small airway inflammation as determined by lung biopsies obtained through bronchoscopy (9).

Lung volume measures, including forced vital capacity (FVC), residual volume (RV), total lung capacity and functional residual capacity, which have been used to characterize air trapping and, hence, small airway function, may provide more reliable information. Among them, RV has shown a closer relationship with changes in peripheral resistance, indicating that it could correlate with small airway functions (10). Similarly, FVC improvements have been observed after treatment with extrafine formulations when compared with non-extrafine treatments; these improvements suggest that extrafine formulations lead to a greater reduction in air trapping, which reflects small airway obstruction (11). (Fig. 1)


Figure 1.  Assessment of air trapping as a result of small airways closure. Small airways abnormalities (e.g., inflammatory cells infiltrating the airway wall, increased mucus plugging and smooth muscle hypertrophy) (1) lead to small airways closure or near closure (2), thus causing peripheral air trapping (3). Air trapping can be assessed by means of the single-breath nitrogen washout test (increased phase III slope, closing capacity [CC] and closing volume [CV]), lung function tests (e.g., increased residual volume [RV] or decreased forced vital capacity [FVC]), and imaging techniques such as high-resolution computed tomography (HRCT) (lung inhomogeneity with hyperlucent areas on expiration indicated by red arrows). Nitrogen washout test image taken from “Pulmonary Physiology” by Michael Levitzky (2003), courtesy of The McGraw-Hill Companies, Inc. HRCT image courtesy of the Department of Radiology, University of Virginia.

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Other methods

Impulse oscillometry (IOS) and the nitrogen washout test are two promising techniques to assess small airway function in both asthma and COPD. IOS allows for the calculation of peripheral airway resistance (12–14), with preliminary studies suggesting that IOS measurements could be used to diagnose obstructive lung disease. In particular, it has been shown that this test is more sensitive than FEV1 for measuring the physiological effects of bronchodilators in asthma and COPD (15).

Nitrogen washout can distinguish between ventilation inhomogeneity originating in the peripheral conducting airways vs the more proximal conducting airways: analysis of the washout curve generated in the single-breath or multiple-breath tests can actually provide information regarding distal lung abnormalities. In the single-breath test in particular, increased closing volume (CV) or closing capacity (CC) and increase in the phase III slope of the washout curve reflect air trapping because of small airway closure or near closure (Fig. 1) (16, 17). Notably, alterations in parameters obtained through single-breath nitrogen washout can be correlated with poor control: a study by in ‘t Veen et al. showed that asthmatic individuals with recurrent exacerbations have increased CV and CC compared with controls with equally severe but stable asthma, implying that airway closure at relatively high lung volumes under clinically stable conditions might be a risk factor for severe exacerbations in asthmatic patients (17). Additionally, a longitudinal study proved that small airway narrowing detected through an increase in the phase III slope of the nitrogen washout curve contributed in predicting the development of COPD in patients who smoke (7).

Based on this ability, washout techniques could be regarded as valuable methods to assess small airway and/or distal lung function (6, 18).

Overall, tests such as IOS and nitrogen washout can be used not only to investigate functional abnormalities of small airways, but also possibly to longitudinally monitor the effects of tested compounds on small airways. However, further studies evaluating small airway abnormalities are needed to specifically validate these functional tests and to assess whether they can be used in a daily clinical setting.


The small airways represent a region of the airways not easily reached by bronchoscopy without fluoroscopic guidance. This means that, in order to study biomarkers of small airways directly, peripheral specimens derived from surgical resection and transbronchial biopsies are needed. Although in the past such invasive techniques have proven to be fundamental for assessing the pathology of small airways in asthma and COPD and are still performed in explorative studies, they obviously are not applicable in daily clinical practice.

Sputum induction after inhalation of hypertonic saline is a noninvasive method that has proven to be more applicable in clinical practice for exploring inflammatory cells in central airways. Modified protocols have been proposed to assess whether this technique can also evaluate inflammation in peripheral airways. In particular, it has been proposed that sequentially induced sputum, i.e., sequential inductions performed after short time intervals (20–30 min), might provide information on distal airway inflammation (19–24). However, this technique may be associated with issues surrounding reproducibility and standardization, and no studies have directly compared the inflammatory profile in sputum with small airway assessment by transbronchial biopsies.

Exhaled nitric oxide (eNO) is the most widely used marker in exhaled breath. Alveolar nitric oxide, derived by measurements of eNO at multiple expiratory flows (MEFeNO), has largely been investigated as a potential hallmark of distal lung inflammation (6, 25). It has been demonstrated that MEFeNO is increased in patients with asthma and COPD at different levels of severity (25). Moreover, recent studies suggest that MEFeNO measurements are reproducible, free of diurnal variation and can be applied in both asthma and COPD (25, 26). However, since alveolar nitric oxide measurement is derived from a computational extrapolation that follows eNO evaluation at different flow rates, rather than being directly quantified, the clinical significance of such a marker is not firmly established. Studies are needed to compare this biomarker with pathology to increase confidence that alveolar nitric oxide is truly a distal lung measurement.


Imaging is a novel area for the direct assessment of small airway involvement in asthma and COPD that deserves further investigation and improvement. High-resolution computed tomography (HRCT) is a noninvasive method that could provide anatomical details of the bronchial tree. HRCT can only estimate wall thickness of bronchi that are ≥ 2 mm in diameter (27, 28). Therefore, although this does not allow direct assessment of the signs of small airway abnormalities, such as bronchial wall thickening, indirect measures of small airway patency could be obtained (29, 30). In particular, air trapping and ventilation heterogeneity, which have been related to small airway closure, have been quantified using HRCT and correlated to functional parameters of small airway abnormalities (28, 29, 31, 32) (Fig. 1). Interestingly, some studies have also suggested that HRCT parameters that indicate air trapping could be selectively modulated by inhaled treatments (i.e., extrafine beclomethasone dipropionate [BDP]) (33) and by systemic treatments (34). However, despite the results obtained so far suggesting that this technique is promising, it is still costly, technically demanding and hampered by exposure of patients to radiation.

Additionally, there is increasing interest in magnetic resonance imaging following inhalation of hyperpolarized helium and xenon, as this could provide further insight into small airway involvement in asthma and COPD (35–38). Indeed, these gas-enhanced techniques allow higher resolution, and they could detect and quantify ventilation and perfusion heterogeneity, which is mainly because of regional and dynamic patterns of airway closure (39) but also because of distal lung abnormalities without radiation exposure (40). Hyperpolarized helium has been used to assess regional airflow obstruction and ventilation defects in asthma, as well as for the evaluation of COPD emphysema, by providing information at the alveolar and small airway level. However, at this time, these techniques are only available in a few centres, are technically demanding and are not established for clinical applications.

Research questions on methods evaluating small airways

Beyond debating which markers of small airways could be considered the most sensitive, specific and reproducible, a key point of discussion is whether a link between them can be established. In this regard, studies evaluating correlations between pathological alterations of small airways, documented by techniques that can directly sample small airways (e.g., transbronchial biopsies), and functional and/or imaging parameters, are the first step. Two such studies have been performed; however, one evaluated the relationship of distal airway inflammation with FEV1, the other the relationship of distal airway inflammation with total lung capacity and thoracic gas volumes (9, 41). If strong relationships exist between distal airway inflammation and noninvasive measures of distal lung function, the precise role of the distal lung in asthma could be more effectively defined. In addition, it could be determined whether interventions that target this lung compartment can significantly alter asthma outcomes. Finally, the role of these biomarkers in daily clinical practice could be determined.

The distal lung in asthma

  1. Top of page
  2. Abstract
  3. Methods to evaluate the distal lung: functional parameters, biomarkers and imaging
  4. The distal lung in asthma
  5. The distal lung in COPD
  6. Open questions on distal airway involvement in asthma and COPD and future directions
  7. Conclusions
  8. Acknowledgment
  9. Disclosure of funding
  10. Conflicts of interest
  11. References

Asthma is a chronic inflammatory disease of the lung and is physiologically characterized by airway obstruction and bronchial hyperresponsiveness (1). By using sophisticated techniques of endobronchial catheterization, it has been documented that the distal lung, including small airways, is not a ‘quiet zone’ but actively contributes to enhanced airway hyperresponsiveness. Therefore, the distal airways are a significant site of airflow obstruction in asthmatic patients (42).

Distal lung hyperreactivity

The distal lung is recognized as an important site of airway hyperreactivity. Experimental studies performed in smooth muscle isolated from animal and human bronchi showed an increased contractile response of small compared with large airways to both nonspecific (acetylcholine) (43) and specific (allergen-mediated) (44) stimuli. Intriguingly, increased hyperreactive responses of small airways are further enhanced when measured in vivo in asthmatic subjects relative to normal controls and are less responsive to bronchodilators (45). This shows that the distal lung contributes to airway dynamics and that the reactivity of small airways in asthmatic patients is increased compared with that in normal subjects.

Pathological findings

Most of the currently available data on pathological abnormalities of small airways in asthma are derived from postmortem or surgical samples and, more recently, from transbronchial biopsies (Fig. 2).


Figure 2.  Pathological findings in the small airways and distal lung compartment of asthmatic patients. Panel (A) Peripheral airway of a severe asthmatic patient showing: lumen occlusion (1); subepithelial fibrosis (2); increase in smooth muscle mass (3); and inflammatory infiltrate (4). Panel (B) Inflammatory infiltrate in the lung parenchyma (1) and vessels (2) of a severe asthmatic patient. Panel (C) Immunostaining of small airway with major basic protein (1 – in red) showing a large number of eosinophils around the small airway (2). Panel (D) Immunostaining on eotaxin in small airway of asthmatic subject using an immunofluorescence technique.

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Pathological findings from autopsies, surgical specimens and transbronchial biopsies have clearly shown that CD3+ T lymphocytic and eosinophilic inflammation is not just a feature of central airways, but also involves the small airways and lung parenchyma of asthmatic patients (46–48). Intriguingly, a higher number of activated eosinophils has been found in the peripheral airways compared with the central airways (49), indicating that a similar but more severe inflammation could be present in the small airways of some asthmatic patients (Fig. 2). Moreover, it has been observed that the number of inflammatory cells was significantly higher in the distal airways of patients with nocturnal asthma compared with non-nocturnal asthma and was correlated with lung function impairment at night, suggesting that peripheral airway inflammation plays a significant role in the pathogenesis of nocturnal asthma (50).

Remodelling is also a well-known characteristic of the central airways of asthmatic patients (51). However, features of remodelling, such as increases in the thickness of adventitial, submucosal and muscle layers and of the reticular basal membrane, have also been demonstrated in peripheral airways of asthmatic patients (52, 53) (Fig. 2).

Evidence of small airways pharmacological targeting in asthma

Anti-inflammatory treatment with inhaled corticosteroids (ICS), with or without long-acting β2-adrenoceptor agonists (LABA), is the cornerstone of asthma management (1). Nevertheless, a considerable subset of asthmatic patients neither benefit from ICS nor gain optimal asthma control (1) even with ICS/LABA combinations (54). Whether specifically targeting distal lung abnormalities can lead to further clinical benefit is still an open question. In this context, interest has been raised by hydrofluoroalkane (HFA) pressurized metered-dose inhalers, which can deliver compounds with a mass median aerodynamic diameter that is significantly smaller than other available devices. Thus, these devices are able to increase peripheral airways drug deposition (55–58). Interestingly, in asthmatic patients, the dose of non-extrafine BDP required to achieve an improvement in lung function is 2.5 times higher than the dose of HFA extrafine formulation required to produce the same increase in FEV1 (59). The efficacy:potency ratio of extrafine BDP is even higher when a functional parameter likely related to small airways (forced expiratory flow rates at middle to low volumes) is considered (59). Thus, these data lead to the speculation that targeting the distal lung in asthmatic patients is a relevant issue, because comparable clinical effects can be obtained with a lower amount of delivered compound and with fewer unwanted effects.

Although it might be expected that increased distal lung deposition is associated with increased systemic effects, such as suppression of cortisol production, data from clinical trials did not document any increased risk of systemic effects with either a single inhaled ICS extrafine formulation (60) or a combination of ICS (BDP)/LABA extrafine therapy (11, 61) compared with non-extrafine therapy. In particular, treatment with an extrafine ICS/LABA combination resulted in a reduced suppression of the hypothalamic–pituitary–adrenal axis, as indicated by a significant increase in cortisol levels in those patients treated with extrafine combination compared with those treated with equipotent dose of non-extrafine BDP plus LABA (65). Taken together, these data suggest that targeting the distal lung is safe in asthmatic patients and it may also result in a reduced impact on the hypothalamic–pituitary–adrenal axis.

In terms of efficacy, preliminary studies have investigated whether an extrafine ICS formulation vs a non-extrafine ICS treatment has a greater impact on distal lung abnormalities in asthma (24, 33, 62, 63). Although these studies are considered to be exploratory, they still offer some hints for future research. For instance, by using late phase–induced sputum and computed tomography scanning, studies suggest that an extrafine approach can further decrease distal lung inflammation and reduce peripheral airway air trapping compared with conventional non-extrafine delivery of ICS. Additionally, in a study by Huchon et al., a new extrafine fixed combination BDP/formoterol delivered by an HFA pressurized metered-dose inhaler has recently demonstrated superiority over the non-extrafine single components, administered as free combination, in improving asthma control (64) (Fig. 3). In the fixed combination, the dose of BDP was 2.5 times lower than the comparator product, indicating that the new extrafine formulation is able to achieve greater efficacy per μg of delivered steroid when compared with conventional BDP. However, whether the clinical superiority in terms of control can be related to increased impact on distal lung abnormalities has not been investigated in studies properly designed to address this question.


Figure 3.  Effect of an extrafine inhaled corticosteroid/long-acting β2-adrenoceptor agonist combination on asthma control. In terms of percentage of days with asthma control, the extrafine fixed combination beclomethasone dipropionate (BDP)/formoterol is significantly superior to the non-extrafine free combination beclomethasone dipropionate plus formoterol and non-extrafine beclomethasone dipropionate monotherapy groups. Asthma control was defined as no nocturnal awakenings, no symptoms and no use of salbutamol. Adapted from Huchon et al. Respir Med 2009 (64).

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Another study has evaluated different parameters and techniques in asthmatic patients already receiving non-extrafine ICS (dry powder inhaler [DPI]-budesonide and/or DPI-fluticasone) who were then switched to an extrafine formulation (HFA-BDP) (65). Although different formulations of different compounds were compared, the data suggested that extrafine formulations could modulate functional and inflammatory abnormalities of the distal lung that are not adequately controlled by non-extrafine formulations in asthmatic patients. Further studies in this direction are needed.

The distal lung in COPD

  1. Top of page
  2. Abstract
  3. Methods to evaluate the distal lung: functional parameters, biomarkers and imaging
  4. The distal lung in asthma
  5. The distal lung in COPD
  6. Open questions on distal airway involvement in asthma and COPD and future directions
  7. Conclusions
  8. Acknowledgment
  9. Disclosure of funding
  10. Conflicts of interest
  11. References

Pathological findings

COPD is the most common chronic inflammatory disease of the airways. It is characterized by persistent and mainly progressive airflow limitation, and by co-morbid extra-pulmonary conditions that significantly contribute to the increased severity and mortality of the disease (2). A chronic inflammatory infiltrate is present in both the central and peripheral airways of patients with COPD. CD8+ T cells are not only present in the central and peripheral airways and in lung parenchyma, but the number of CD8+ T cells in the distal airways negatively correlates with airflow obstruction in patients with COPD (66), suggesting that they play a key role in the pathogenesis of COPD (70).

From a pathological point of view, COPD is characterized by two distinct and frequently coexisting aspects: small airway abnormalities and parenchymal destruction (emphysema) (67) (Fig. 4). These lesions, leading to bronchial lumen occlusion (small airway abnormalities) and/or causing decreased elastic recoil (parenchymal destruction), are not only associated with airflow limitation in COPD, but are also considered major contributors to lung function decline. Indeed, there is growing recognition that increased resistance in the small airways plays a greater role in airflow limitation in COPD than decreased elastic recoil as a result of emphysema (68). Additionally, there are strong correlations between lung function, airway wall area, the degree of luminal occlusion and the inflammatory infiltrate in the small airways of patients with COPD (4). Notably, a positive correlation between the severity of COPD and the number of lymphoid follicles in the small airways has also been observed (4) (Fig. 4). This suggests that an abnormal adaptive immune response, possibly because of pathogenic or non-self antigenic exposure, occurs in the small airways of patients with COPD, and that this event has pathogenetic implications (69).


Figure 4.  Pathological findings in the small airways of COPD patients. Panel (A) Lumen occlusion with inflammatory exudate (1); and thick airway wall with increase in smooth muscle mass (2). Panel (B) Lymphoid follicle in small airways of COPD patients (1).

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Evidence of distal airways pharmacological targeting in COPD

Treatment of distal airways abnormalities in COPD is a poorly investigated area. There have been very few properly designed clinical trials evaluating the function or the structure of the distal airways before and after therapeutic intervention and the possible clinical effects. The mainstay of therapy in COPD is currently represented by the use of bronchodilators, particularly the long-acting bronchodilators (2), which might decrease air trapping with a subsequent beneficial effect on both symptoms and exercise capacity.

From observations in human airway preparations, it has emerged that small airways are at least as sensitive to relevant bronchoconstricting mediators as the corresponding large airways (70). In tissue preparations obtained from resected lungs, β2-adrenoceptor agonists reversed the carbachol-induced contraction in a concentration-dependent manner (71). In particular, indacaterol and formoterol displayed the highest intrinsic efficacy. Whether this effect could be translated to clinical benefit in patients remains to be established.

COPD is considered by some to be a ‘steroid-resistant’ disease. However, in a 12-week study, extrafine BDP reduced residual volume by ∼ 13% of the predicted volume, whereas no effect on FEV1 was observed (72). This reduction indicates that the small-particle inhaled steroid may improve pulmonary function by the reduction of hyperinflation. Reaching the distal part of the lung, where inflammation is present, may provide new opportunities in the treatment of COPD. Therefore, studies testing the effect of steroids or, even more interestingly, fixed ICS/LABA combinations on small airway abnormalities in patients with COPD could provide some answers in this instance.

Open questions on distal airway involvement in asthma and COPD and future directions

  1. Top of page
  2. Abstract
  3. Methods to evaluate the distal lung: functional parameters, biomarkers and imaging
  4. The distal lung in asthma
  5. The distal lung in COPD
  6. Open questions on distal airway involvement in asthma and COPD and future directions
  7. Conclusions
  8. Acknowledgment
  9. Disclosure of funding
  10. Conflicts of interest
  11. References

Despite the mounting body of physiological and pathological evidence documenting the role of small airways in the pathogenesis of asthma and COPD, a standardized definition of small airways, and more precisely of small airway disease, is lacking.

Furthermore, what still has to be defined is the link between physiological abnormalities of small airways and clinical presentation; the longitudinal evaluation of small airways, and more generally of distal lung involvement, in the natural history of asthma and COPD to understand whether this involvement starts inception of disease or occurs with progression; and the possibility of reversing small airway and distal lung abnormalities by pharmacological intervention (Table 2).

Table 2.   Open questions on small airway involvement in asthma and COPD
How could the ‘small airway disease’ be defined?
What is the link between small airway abnormalities and clinical presentation in asthma and COPD?
When does small airway involvement become relevant in the natural history of the disease?
Is it possible to reverse small airway abnormalities with pharmacological treatment?

The observation that the distal lung is a site of inflammation and lung function abnormality both in asthma and COPD represents a rationale for targeting this lung compartment with pharmacological treatment. Indeed, it could be speculated that additional clinical benefits might be achieved by treating both large and small airways through a uniform distribution of a drug throughout the respiratory tract. However, data that could convincingly support this concept are limited. Available evidence has mostly been obtained from small pilot studies. Nonetheless, such trials could be a starting point to assess further the impact of treatments on the distal lung. A properly designed study, powered to show that a treatment is able to modify significantly a selected parameter/marker of small airways and that by doing so could significantly impact clinical outcomes, is therefore urgently needed.


  1. Top of page
  2. Abstract
  3. Methods to evaluate the distal lung: functional parameters, biomarkers and imaging
  4. The distal lung in asthma
  5. The distal lung in COPD
  6. Open questions on distal airway involvement in asthma and COPD and future directions
  7. Conclusions
  8. Acknowledgment
  9. Disclosure of funding
  10. Conflicts of interest
  11. References

Several years have passed since it was first suggested that the distal lung could play a role in obstructive lung disease. Despite the large number of studies performed to describe their pathophysiology in asthma and COPD and specifically to assess their abnormalities, important open questions are still not answered.

The issue of defining a suitable approach for studying small airways has emerged. Many attempts have been made to validate a standardized method to selectively measure small airway impairment. This method has to be reproducible and reliable, should be applicable in clinical practice, and should correlate with pathology and with clinical outcomes. All these requirements certainly make searching for this new ‘gold standard’ a difficult task.

It is likely that a combination of techniques, including lung function tests such as evaluation of lung volumes through spirometry and/or the single-breath nitrogen washout, possibly associated with imaging, could be the most suitable approach. Once defined and accepted, these techniques would have to be used in a properly designed clinical study aimed at assessing the impact of treatments targeting the distal lung and possibly at establishing a correlation between the modification of distal lung parameters and improvement in the clinical status of the patient.

Ultimately, it will be fundamental to elucidate whether by targeting the distal lung in asthmatic and COPD patients the pathophysiological events that occur in this anatomic area could be modulated, and whether a pharmacological approach that includes medication distributed throughout the distal lung could achieve any further clinical benefit in the management of the two diseases. This would hopefully lead to a more comprehensive and complete approach to the treatment of asthma and COPD.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Methods to evaluate the distal lung: functional parameters, biomarkers and imaging
  4. The distal lung in asthma
  5. The distal lung in COPD
  6. Open questions on distal airway involvement in asthma and COPD and future directions
  7. Conclusions
  8. Acknowledgment
  9. Disclosure of funding
  10. Conflicts of interest
  11. References

Marco Contoli has received sponsorship from Chiesi Farmaceutici, Boehringer Ingelheim and AstraZeneca. Jean Bousquet has received sponsorship from Chiesi Farmaceutici, GlaxoSmithKline, Novartis, Astra Zeneca, UCB, Schering-Plough and Nycomed. Leonardo Fabbri has received sponsorship from Chiesi Farmaceutici, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp and Dohme, Novartis, Nycomed, Roche, Pfizer, Sigma-Tau, Menarini, Schering-Plough, Union Chimique Belge, Italian Ministry of Health, and Italian Ministry for University and Research. Helgo Magnussen has received sponsorship from Chiesi Farmaceutici, Almirall, AstraZeneca, Boehringer Ingelheim, Nycomed, Novartis and Schering-Plough. Klaus Rabe has received sponsorship from Chiesi Farmaceutici, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Nycomed, Merck Sharp and Dohme, GlaxoSmithKline, Roche and AltanaPharma. Nikolaos Siafakas has received funding from Chiesi Farmaceutici, GlaxoSmithKline, Boehringer Ingelheim, Nycomed, AstraZeneca and Abbott. Qutayba Hamid has received sponsorship from Chiesi Farmaceutici, Genentech and GlaxoSmithKline. Monica Kraft has received sponsorship from Chiesi Farmaceutici and GlaxoSmithKline.


  1. Top of page
  2. Abstract
  3. Methods to evaluate the distal lung: functional parameters, biomarkers and imaging
  4. The distal lung in asthma
  5. The distal lung in COPD
  6. Open questions on distal airway involvement in asthma and COPD and future directions
  7. Conclusions
  8. Acknowledgment
  9. Disclosure of funding
  10. Conflicts of interest
  11. References
  • 1
    Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention: NHLBI/WHO workshop report. 2002. NIH Publication report: Bethesda: National Institutes of Health, National Heart, Lung and Blood Institute, 2002:1116.Publication No. 02-3659. Last Update 2008. Available on-line at
  • 2
    Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO workshop report. Bethesda: National Institutes of Health, National Heart, Lung and Blood Institute, 2001. Publication No 2701: 1–108. Last Update 2008. Available on-line at
  • 3
    Baraldo S, Saetta M, Cosio MG. Pathophysiology of the small airways. Semin Respir Crit Care Med 2003;24:465472.
  • 4
    Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:26452653.
  • 5
    Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J et al. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med 1978;298:12771281.
  • 6
    Van Veen IH, Sterk PJ, Schot R, Gauw SA, Rabe KF, Bel EH. Alveolar nitric oxide versus measures of peripheral airway dysfunction in severe asthma. Eur Respir J 2006;27:951956.
  • 7
    Stanescu D, Sanna A, Veriter C, Robert A. Identification of smokers susceptible to development of chronic airflow limitation: a 13-year follow-up. Chest 1998;114:416425.
  • 8
    Kraft M, Cairns CB, Ellison MC, Pak J, Irvin C, Wenzel S. Improvements in distal lung function correlate with asthma symptoms after treatment with oral Montelukast. Chest 2006;130:17261732.
  • 9
    Sutherland ER, Martin RJ, Bowler RP, Zhang Y, Rex MD, Kraft M. Physiologic correlates of distal lung inflammation in asthma. J Allergy Clin Immunol 2004;113:10461050.
  • 10
    Kraft M, Pak J, Martin RJ, Kaminsky D, Irvin CG. Distal lung dysfunction at night in nocturnal asthma. Am J Respir Crit Care Med 2001;163:15511556.
  • 11
    Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy 2007;62:11821188.
  • 12
    Kaminsky DA, Irvin CG, Lundblad L, Moriya HT, Lang S, Allen J et al. Oscillation mechanics of the human lung periphery in asthma. J Appl Physiol 2004;97:18491858.
  • 13
    Kolsum U, Borrill Z, Roy K, Starkey C, Vestbo J, Houghton C et al. Impulse oscillometry in COPD: identification of measurements related to airway obstruction, airway conductance and lung volumes. Respir Med 2009;103:136143.
  • 14
    Goldman MD. Clinical application of forced oscillation. Pulm Pharmacol Ther 2001;14:341350.
  • 15
    Borrill ZL, Houghton CM, Tal-Singer R, Vessey SR, Faiferman I, Langley SJ et al. The use of plethysmography and oscillometry to compare long-acting bronchodilators in patients with COPD. Br J Clin Pharmacol 2008;65:244252.
  • 16
    Bourdin A, Paganin F, Prefaut C, Kieseler D, Godard P, Chanez P. Nitrogen washout slope in poorly controlled asthma. Allergy 2006;61:8589.
  • 17
    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;161:19021906.
  • 18
    Brundler JP, Lewis CM, De Kock MA. Functional classification of chronic airflow limitation based on flow-volume and single-breath nitrogen washout criteria. Respiration 1983;44:19.
  • 19
    Gershman NH, Liu H, Wong HH, Liu JT, Fahy JV. Fractional analysis of sequential induced sputum samples during sputum induction: evidence that different lung compartments are sampled at different time points. J Allergy Clin Immunol 1999;104:322328.
  • 20
    Holz O, Jörres RA, Koschyk S, Speckin P, Welker L, Magnussen H. Changes in sputum composition during sputum induction in healthy and asthmatic subjects. Clin Exp Allergy 1998;28:284292.
  • 21
    Magnussen H, Holz O. Monitoring airway inflammation in asthma by induced sputum. Eur Respir J 1999;13:57.
  • 22
    Richter K, Holz O, Jorres RA, Mucke M, Magnussen H. Sequentially induced sputum in patients with asthma or chronic obstructive pulmonary disease. Eur Respir J 1999;14:697701.
  • 23
    Tsoumakidou M, Tzanakis N, Siafakas NM. Induced sputum in the investigation of airway inflammation of COPD. Respir Med 2003;97:863871.
  • 24
    Hauber HP, Taha R, Bergeron C, Migounov V, Hamid Q, Ron Olivenstein R. Effects of hydrofluoroalkane and dry powder-formulated corticosteroids on sputum inflammatory markers in asthmatic patients. Can Respir J 2006;13:7378.
  • 25
    Brindicci C, Ito K, Resta O, Pride NB, Barnes PJ, Kharitonov SA. Exhaled nitric oxide from lung periphery is increased in COPD. Eur Respir J 2005;26:5259.
  • 26
    Brindicci C, Ito K, Barnes PJ, Kharitonov SA. Differential flow analysis of exhaled nitric oxide in patients with asthma of differing severity. Chest 2007;131:13531362.
  • 27
    De Jong PA, Muller NL, Pare PD, Coxson HO. Computed tomographic imaging of the airways: relationship to structure and function. Eur Respir J 2005;26:140152.
  • 28
    Mikos M, Grzanka P, Sladek K, Pulka G, Bochenek G, Soja J et al. High-resolution computed tomography evaluation of peripheral airways in asthma patients: comparison of focal and diffuse air trapping. Respiration 2009;77:381388.
  • 29
    Ueda T, Niimi A, Matsumoto H, Takemura M, Hirai T, Yamaguchi M et al. Role of small airways in asthma: investigation using high-resolution computed tomography. J Allergy Clin Immunol 2006;118:10191025.
  • 30
    Cohen J, Douma WR, Ten Hacken NHT, Vonk JM, Oudkerk M, Postma DS. Ciclesonide improves measures of small airway involvement in asthma. Eur Respir J 2008;31:12131220.
  • 31
    Omori H, Fujimoto K, Katoh T. Computed-tomography findings of emphysema: correlation with spirometric values. Curr Opin Pulm Med 2008;14:110114.
  • 32
    Jain N, Covar RA, Gleason MC, Newell JD Jr, Gelfand EW, Spahn JD. Quantitative computed tomography detects peripheral airway disease in asthmatic children. Pediatr Pulmonol 2005;40:211218.
  • 33
    Goldin JG, Tashkin DP, Kleerup EC, Greaser LE, Haywood UM, Sayre JW et al. Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography. J Allergy Clin Immunol 1999;104:S258S267.
  • 34
    Zeidler MR, Kleerup EC, Goldin JG, Kim HJ, Truong DA, Simmons MD et al. Montelukast improves regional air-trapping due to small airways obstruction in asthma. Eur Respir J 2006;27:307315.
  • 35
    Samee S, Altes T, Powers P, De Lange EE, Knight-Scott J, Rakes G et al. Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge. J Allergy Clin Immunol 2003;111:12051211.
  • 36
    Evans A, McCormack DG, Santyr G, Parraga G. Mapping and quantifying hyperpolarized 3He magnetic resonance imaging apparent diffusion coefficient gradients. J Appl Physiol 2008;105:693699.
  • 37
    Kauczor HU, Chen XJ, Van Beek EJ, Schreiber WG. Pulmonary ventilation imaged by magnetic resonance: at the doorstep of clinical application. Eur Respir J 2001;17:10081023.
  • 38
    Fain SB, Korosec FR, Holmes JH, O’Halloran R, Sorkness RL, Grist TM. Functional lung imaging using hyperpolarized gas MRI. J Magn Reson Imaging 2007;25:910923.
  • 39
    De Lange EE, Altes TA, Patrie JT, Gaare JD, Knake JJ, Mugler JP III et al. Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry. Chest 2006;130:10551062.
  • 40
    Yablonskiy DA, Sukstanskii AL, Leawoods JC, Gierada DS, Bretthorst GL, Lefrak SS et al. Quantitative in vivo assessment of lung microstructure at the alveolar level with hyperpolarized 3He diffusion MRI. Proc Natl Acad Sci USA 2002;99:31113116.
  • 41
    Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996;154:15051510.
  • 42
    Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J Appl Physiol 1992;72:10161023.
  • 43
    Mitchell HW, Cvetkovski R, Sparrow MP, Gray PR, McFawn PK. Concurrent measurement of smooth muscle shortening, lumen narrowing and flow to acetylcholine in large and small porcine bronchi. Eur Respir J 1998;12:10531061.
  • 44
    Ellis JL, Hubbard WC, Meeker S, Undem BJ. Ragweed antigen E and anti-IgE in human central versus peripheral isolated bronchi. Am J Respir Crit Care Med 1994;150:717723.
  • 45
    Wagner EM, Bleecker ER, Permutt S, Liu MC. Direct assessment of small airways reactivity in human subjects. Am J Respir Crit Care Med 1998;157:447452.
  • 46
    Corren J. Small airways disease in asthma. Curr Allergy Asthma Rep 2008;8:533539.
  • 47
    Tulic MK, Christodoulopoulos P, Hamid Q. Small airway inflammation in asthma. Respir Res 2001;2:333339.
  • 48
    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;100:4451.
  • 49
    Hamid QA. Peripheral inflammation is more important than central inflammation. Respir Med 1997;91(Suppl A):1112.
  • 50
    Kraft M, Martin RJ, Wilson S, Djukanovic R, Holgate ST. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med 1999;159:228234.
  • 51
    Jeffery PK. Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2004;1:176183.
  • 52
    Ebina M, Takahashi T, Chiba T, Motomiya M. Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. Am Rev Respir Dis 1993;148:720726.
  • 53
    Kuwano K, Bosken CH, Pare PD, Bai TR, Wiggs BR, Hogg JC. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;148:12201225.
  • 54
    Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836844.
  • 55
    Haussermann S, Acerbi D, Brand P, Herpich C, Poli G, Sommerer K et al. Lung deposition of formoterol HFA (Atimos/Forair) in healthy volunteers, asthmatic and COPD patients. J Aerosol Med 2007;20:331341.
  • 56
    Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in healthy volunteers. Chest 2002;122:510516.
  • 57
    Hampel F, Lisberg E, Guerin JC. Effectiveness of low doses (50 and 100 microg b.i.d) of beclomethasone dipropionate delivered as a CFC-free extrafine aerosol in adults with mild to moderate asthma. Study Group. J Asthma 2000;37:389398.
  • 58
    Holz O, Zuhlke I, Einhaus M, Welker L, Kanniess F, Branscheid D et al. Direct measurement of BDP and 17-BMP in bronchial and peripheral lung tissue after inhalation of HFA- vs CFC-driven aerosols. Pulm Pharmacol Ther 2004;17:233238.
  • 59
    Busse WW, Brazinsky S, Jacobson K, Stricker W, Schmitt K, Vanden Burgt J et al. Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol 1999;104:12151222.
  • 60
    Van Schayck CP, Donnell D. The efficacy and safety of QVAR (hydrofluoroalkane-beclometasone diproprionate extrafine aerosol) in asthma (part 1): an update of clinical experience in adults. Int J Clin Pract 2004;58:678688.
  • 61
    Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J 2007;29:682689.
  • 62
    Marshall BG, Wangoo A, Harrison LI, Young DB, Shaw RJ. Tumour necrosis factor-alpha production in human alveolar macrophages: modulation by inhaled corticosteroid. Eur Respir J 2000;15:764770.
  • 63
    Ohbayashi H, Adachi M. Hydrofluoroalkane-Beclomethasone dipropionate effectively improves airway eosinophilic inflammation including the distal airways of patients with mild to moderate persistent asthma as compared with fluticasone propionate in a randomized open double-cross study. Allergology International 2008;57:19.
  • 64
    Huchon G, Magnussen H, Chuchalin A, Dymek L, Gonod FB, Bousquet J. Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med 2009;103:4149.
  • 65
    Ohbayashi H. One-year evaluation of the preventative effect of hydrofluoroalkane-beclomethasone dipropionate on eosinophilic inflammation of asthmatic peripheral airways. Respiration 2007;74:146153.
  • 66
    Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:822826.
  • 67
    Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004;364:709721.
  • 68
    Sturton G, Persson C, Barnes PJ. Small airways: an important but neglected target in the treatment of obstructive airway diseases. Trends Pharmacol Sci 2008;29:340345.
  • 69
    Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 2009;360:24452454.
  • 70
    Persson CG. Small airway relaxation--a forgotten medical need. Pulm Pharmacol Ther 2008;21:13.
  • 71
    Sturton RG, Trifilieff A, Nicholson AG, Barnes PJ. Pharmacological characterization of indacaterol, a novel once daily inhaled β2 adrenoceptor agonist, on small airways in human and rat precision-cut lung slices. J Pharmacol Exp Ther 2008;324:270275.
  • 72
    John M, Bosse S, Oltmanns U, Schumacher A, Witt C. Effects of inhaled HFA beclomethasone on pulmonary function and symptoms in patients with chronic obstructive pulmonary disease. Respir Med 2005;99:14181424.