American Journal of Respiratory and Critical Care Medicine

It has been shown that structural changes in small airways of smokers with average smoking histories greater than 35 pack-years could be reflected in the single-breath washout test. The more sophisticated multiple breath washout test (MBW) has the potential to anatomically locate the affected small airways in acinar and conductive lung zones through increased phase III slope indices Sacin and Scond, respectively. Pulmonary function, Sacin, and Scond were obtained in 63 normal never-smokers and in 169 smokers classified according to smoking history (< 10 pack-years; 10–20 pack-years; 20–30 pack-years; > 30 pack-years). Compared with never-smokers, significant changes in Sacin (p = 0.02), Scond (p < 0.001), and diffusing capacity (DLCO; p < 0.001) were detected from greater than 10 pack-years onwards. Spirometric abnormality was significant only from greater than 20 pack-years onwards. In smokers with greater than 30 pack-years and DLCO less than 60% predicted, the presence of emphysema resulted in disproportionally larger Sacin than Scond increases. We conclude that Scond and Sacin can noninvasively detect airway changes from as early as 10 pack-years onwards, locating the earliest manifestations of smoking-induced small airways alterations around the acinar entrance. In these early stages, the associated DLCO decrease may be a reflection of ventilation heterogeneity rather than true parenchymal destruction. In more advanced stages of smoking-induced lung disease, differential patterns of Sacin and Scond are characteristic of the presence of parenchymal destruction in addition to peripheral airways alterations.

The study of Cosio and colleagues (1) is a landmark in the demonstration of a relationship between structure of the peripheral lung and noninvasive measurements of pulmonary function. In particular, the 34 smokers in that study were classified in four groups (I to IV) according to a total pathology score of the small airways (< 2 mm internal diameter), including inflammatory cell infiltrate, squamous cell metaplasia of the airway epithelium, and airway wall fibrosis. Increasing total pathology severity scores were accompanied by increasing ventilation heterogeneity as measured from the N2 phase III slope of the VC single-breath washout test (SBWVC). Group I (normal pathology score and an average smoking history of 17 pack-years) had normal spirometry and normal N2 phase III slopes, whereas group II (abnormal pathology score and an average smoking history of approximately 40 pack-years) still had normal spirometry but abnormally high N2 phase III slopes; groups III and IV (with increasing pathology scores but comparable smoking history) had both abnormal spirometry and abnormal N2 phase III slopes. It was concluded that a test of unevenness of ventilation can detect structural change in the small airways of smokers long before spirometry can, and possibly at a time when structural changes are still potentially reversible.

Several decades of ventilation distribution studies have identified potential contributors to the N2 phase III slope of a SBWVC other than the small airways, such as gravity (2), or airway closure in the first portion of a SBWVC inspiration (3). Nevertheless, the Cosio study (1) continues to be misinterpreted to mean that any increase in the N2 phase III slope of the SBWVC is a demonstration of small airways alterations. In the context of smoking-induced lung disease, the early SBWVC studies had led to deceiving results in predicting decline in FEV1 (4, 5), and the SBWVC test has been largely abandoned as a tool to monitor the small airways, except for one 13-year follow-up study (6).

With our present understanding of washout tests, the N2 phase III slope analysis of the multiple-breath washout (MBW) (7, 8) has several major advantages with respect to the SBWVC: (1) it is hardly affected by gravity (9) and, therefore, better suited to represent intrinsic airway structure than the SBWVC; (2) it is not affected by airway closure below functional residual capacity (FRC), which is known to also affect the SBWVC phase III slope in a complex fashion (3); and (3) it can distinguish between proximal and peripheral origins of ventilation heterogeneity, which is impossible with a SBW unless tracer gases of different diffusivities are used (10). These advantages probably contribute to the ability of the MBW test to indeed identify early structural changes, as this study will show, even in smokers with a smoking history of as little as 10 pack-years. Finally, in the particular case of monitoring the smoker's lung, which potentially involves a huge number of small airways (i.e., all airways with diameters < 2 mm), the classification of airway deterioration in conductive and/or acinar lung compartments is a valuable distinction to make.

The purpose of the present work is to revive the interest of using noninvasive tests of ventilation distribution in the original context of the study of small airways in the smoker's lung by applying a state-of-the-art MBW ventilation distribution technique that can be used to identify conductive and acinar ventilation defects, as has been recently done in a number of specific clinical settings (1114).

Lung function and MBW testing were performed in a standard fashion (see online supplement). Lung function indices included FEV1, PEF, FVC, mean forced mid-expiratory flow (FEF25–75), forced expiratory flow after exhalation of 75% FVC (FEF75), single-breath carbon monoxide transfer factor (DlCO), plethysmographic measurement of lung volume at functional residual capacity (FRCpl), and specific airway conductance (sGaw). From MBW testing, we obtained indices of conductive (Scond) and acinar (Sacin) ventilation heterogeneity, and ventilated FRC (FRCMBW).

The theory of the MBW phase III slope analysis leading to indices Scond and Sacin has been previously described (8), and the computation of Scond and Sacin is reiterated in the online supplement. It implies that ventilation heterogeneity can be attributed to different lung depths, and that Scond and Sacin are intrinsically independent (11). Because Scond and Sacin are derived from phase III slopes, their value increases when ventilation heterogeneity increases. In particular, Sacin will increase in value if ventilation heterogeneity is increased in the acinar lung zone, due to an alteration of the intraacinar asymmetry, irrespective of flow asynchrony. On the other hand, Scond will increase if the conductive airways and their subtended units undergo an increase in flow asynchrony (such that the best ventilated units empty preferentially early in expiration) and/or an increased difference of their specific ventilation.


The study protocol was approved by the hospital's ethics committee. One hundred seventy two smokers (77 males/95 females) with a wide range of smoking histories participated in this prospective study covering a 2-year period. A detailed smoking history was obtained and expressed as number of pack-years (1 pack-year = 20 cigarettes/day/year). All smokers had been instructed to abstain from smoking for at least 4 hours before testing. Most smokers (125 out of 172) were recruited either from hospital personnel smoking rooms or from outpatients on their first visit to the smoking cessation clinic; they had never visited a pulmonary function laboratory before, and had no medical history of respiratory disease. These volunteers were classified according to smoking history (< 10 pack-years; 10 ⩽ pack-years < 20; 20 ⩽ pack-years < 30; pack-years ⩾ 30). In addition to the volunteers, another 47 patients with documented overt chronic obstructive pulmonary disease (COPD) and a smoking history of greater than 30 pack-years were recruited from the Respiratory Division's Out-Patient Clinic. These patients with COPD were contacted before their scheduled control visit to the Out-Patient Clinic. They were stable at the time of testing (no change in treatment, no exacerbations for greater than 3 months).

Control values were obtained for lung function and MBW indices in normal never-smokers. To avoid the confounding effects from possible bronchial hyperresponsiveness (8), all control subjects had to test negative on a histamine bronchoprovocation test with a cumulative dose up to 2 mg histamine, to be included in the control group (n = 63).

Statistical Analysis

Using Statistica 5.1 (StatSoft, Tulsa, OK), one-way analysis of variance was performed to detect differences in all MBW and pulmonary function variables between the different smoker subgroups. Bonferroni adjustment was used to test for post hoc differences with a significance level set at p = 0.05. Pearson correlation analyses were also performed.

The lung function and MBW data obtained from the never-smokers and from the smokers with a smoking history of less than 30 pack-years are summarized in Table 1

TABLE 1. Lung function and multiple-breath washout results obtained in smokers with less than 30 pack-years smoking history and never-smokers

 (n = 63)

Smokers (pack-years < 10)
 (n = 27)

Smokers (10 ⩽ pack-years < 20)
 (n = 35)

Smokers (20 ⩽ pack-years < 30)
 (n = 29)

Age, yr311  30238*1  43*1
Smoking history, pack-years00   5.7*0.516.6*0.5  25.6*0.6
Lung function
 FEV1, % predicted1121 11321142 108 4
 FEV1/FVC, % 841  831 821  79*1
 FEF25–75, % predicted1032  983 983  86*5
 FEF75, % predicted 953  914 834  71*5
 DLCO, % predicted 992  92385*3  81*3
 sGaw, 1/cm H2O · s0.1590.006   0.1560.010   0.1760.010   0.1490.008
 Sacin, L−10.0720.003   0.0790.005 0.100*0.009   0.124*0.014
 Scond, L−10.0280.001   0.0330.003 0.040*0.002   0.049*0.003
 FRCMBW, ml3309120290414330561423259 166

*Significantly different from never-smokers (one-way analysis of variance; post-hoc Bonferroni p < 0.05).

Definition of abbreviations: DLCO = carbon monoxide diffusing capacity; FEF25–75 = forced expiratory flow between 25 and 75% FVC; FEF75 = forced expiratory flow after expiration of 75% FVC; FRCMBW = FRC measured by MBW; FRCpl = FRC measured by plethysmography; FRCpl−FRCMBW = FRCpl minus FRCMBW; MBW = multiple-breath washout test; Sacin = index of acinar conductive ventilation (see text); Scond = index of acinar ventilation heterogeneity (see text); sGaw = specific airway conductance.

; all smokers were current smokers. The average smoking history of the three smoker subgroups amounted to 5.7 pack-years, 16.6 pack-years, and 25.6 pack-years, respectively. In the smokers with a smoking history of 10 or more pack-years, DlCO (p < 0.001), Sacin (p = 0.02), and Scond (p < 0.001) were significantly different from the never-smokers, whereas the corresponding spirometric indices, FEV1/FVC (p > 0.1), FEF25–75 (p > 0.1), and FEF75 (p = 0.07), were not significantly different. In the smokers with a smoking history of 20 or more pack-years, significant reductions were observed for FEV1/FVC (p < 0.001), FEF25–75 (p = 0.002), and FEF75 (p < 0.001). Other lung function measurements, such as FEV1, sGaw, and FRCMBW, were similar between the four subgroups of Table 1, and trapped volume (i.e., FRCpl minus FRCMBW) was not significantly different from zero in any of these subgroups.

We also considered individual abnormality on the small airways indices (Scond, Sacin, FEF75, and DlCO) by considering the number of subjects with values below a mean of −1.96 *SD (for “abnormal” FEF75 and DlCO) or values over a mean of +1.96 *SD (for “abnormal” Scond and Sacin); respective mean and SD values were established on the basis of the 63 normal subjects. Of the 91 smokers with less than 30 pack-years, the number of “abnormal” subjects were: n = 10 (FEF75), n = 19 (DlCO); n = 24 (FEF75 or DlCO), n = 28 (Scond), n = 23 (Sacin), and n = 39 (Scond or Sacin). Of the 24 subjects with an abnormal FEF75 or abnormal DlCO, 14 also had an abnormal Scond or Sacin. Conversely, the remaining 25 of 39 subjects with abnormal Scond or Sacin showed no abnormality in terms of FEF75 or DlCO whatsoever.

Considering only the 91 smokers of Table 1, correlations between Sacin and number of pack-years (r = 0.38) and between Scond and number of pack-years (r = 0.39) were highly significant (p < 0.001 for both). As expected, the smoker subgroups with the longer smoking history were somewhat older than the smokers with a smoking history of less than 10 pack-years and the never-smokers. We, therefore, needed to validate that the observed Sacin and Scond changes were true reflections of early airway impairment rather than artifacts related to age. Among the 63 never-smokers whose ages ranged between 20 and 55 years, no significant correlations were found between Sacin or Scond and age (p > 0.1 for both).

The smoker group with a smoking history of 30 or more pack-years (n = 81; 34 volunteers and 47 patients with COPD) was subdivided into three subgroups according to the presence of airway obstruction and/or the presence of emphysema. Smokers with an FEV1/FVC ⩾ 70% were labeled as non-COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (15). Smokers with an FEV1/FVC of less than 70%, a DlCO of less than 60% predicted, and emphysema confirmed by high resolution computed tomography scan were labeled as COPD/E to designate a typical COPD group with definite presence of emphysema. Finally, smokers with an FEV1/FVC of less than 70% and a DlCO of 70% predicted or greater were labeled as COPD/− to indicate a typical COPD group with a low probability of major emphysematous lesions. We deliberately adopted a 10% margin on the DlCO above the 60% predicted cutoff (below which a high-resolution computed tomography scan request is clinically indicated) to avoid a gray zone of patients with COPD with possible emphysema without high-resolution computed tomography scan confirmation. Out of the 34 undocumented (volunteer) smokers with a smoking history of 30 or more pack-years, none had a DlCO below 60% predicted, and three subjects were discarded because their DlCO was in the gray zone between 60 and 70% predicted. For all smokers with a smoking history of 30 or more pack-years, we adopted these stringent classification criteria to obtain subgroups with distinct pathologic features for a systematic comparison of lung function and MBW indices in more advanced smoking-induced lung disease. Note also that in the COPD groups, not all smokers were current smokers (with smoke cessation times, as indicated by the patients, ranging from 6 months to 20 years); in the COPD/− group 18 out of 26 were current smokers, and in the COPD/E group 11 out of 27 were current smokers.

The lung function and MBW data obtained on the three smoker subgroups with a smoking history of 30 pack-years or more are summarized in Table 2

TABLE 2. Lung function and multiple-breath washout results obtained in smokers with 30 pack-years smoking history or more

Non-COPD (n = 25)

COPD/− (n = 26)

COPD/E (n = 27)

Age, yr 48160*268*, 2
Smoking history, pack-years 43460 752 3
Lung function
 FEV1, % predicted101468*351*, 3
 FEV1/FVC, % 77157*245*, 2
 FEF25–75, % predicted 84628*217*1
 FEF75, % predicted 64522*217*1
 DLCO, % predicted 84282 247*, 2
 sGaw, 1/cm H2O · s0.1530.0130.060*0.0040.050*0.004
Multiple-breath washout
 Sacin, L−10.1490.0160.295*0.0260.444*, 0.037
 Scond, L−10.0430.0030.064*0.0040.068*0.006
 FRCMBW, ml32841433474 1493684139

*Significantly different from non-COPD group (one-way analysis of variance; post-hoc Bonferroni p < 0.05).

Significant difference between COPD/− and COPD/E groups (one-way analysis of variance; post-hoc Bonferroni p < 0.05).

Definition of abbreviations: COPD/− = COPD subjects with FEV1/FVC less than 70% and DLCO 70% predicted or greater; COPD/E = COPD subjects with FEV1/FVC less than 70%, DLCO less than 60% predicted and high-resolution computed topography–confirmed emphysema; DLCO = carbon monoxide diffusing capacity; FEF25–75 = forced expiratory flow between 25 and 75% FVC; FEF75 = forced expiratory flow after expiration of 75% FVC; FRCMBW = FRC measured by MBW; FRCpl = FRC measured by plethysmography; MBW = multiple-breath washout test; Sacin = index of acinar conductive ventilation (see text); Scond = index of acinar ventilation heterogeneity (see text); sGaw = specific airway conductance.

. There was no significant difference in smoking history between these three smoker subgroups (one-way analysis of variance; p = 0.07). Considering only the 78 smokers of Table 2, correlations between either Sacin or Scond and number of pack-years were not significant (p > 0.1 for both). Of all parameters listed in Table 2, only DlCO and FRCMBW did not differ between the COPD/− group and the non-COPD group. Despite the absence of FRCMBW change, FRCpl in the COPD/− group had increased to such an extent that the trapped volume assessed by the difference between both FRC measurements amounted to 675 ml, corresponding to approximately 20% of ventilated FRC. Between the COPD/− and COPD/E groups, significant differences were found in DlCO (by design), in FEV1, FEV1/FVC, and in Sacin, but not in FEF25–75, FEF75, or in Scond. Trapped volume was almost double in COPD/E versus COPD/− groups for a similar ventilated FRCMBW.

Figure 1

summarizes small airways behavior, as can be inferred from the combination of MBW analysis and spirometry, in the smoker's lung ranging from its earliest stages up to that in the patient with overt COPD. Given the pathophysiologic differences between the early and advanced disease process, and the overall age difference between the groups with less than 30 pack-years and 30 or more pack-years, a direct quantitative comparison between groups across either side of the 30 pack-year line may not be meaningful here. Figure 1 is merely meant to illustrate the differential Sacin and Scond response depending on the stage in the disease process. For instance, in smokers with a smoking history up to 30 pack-years, the progressive increase in airflow limitation in terms of FEV1/FVC (but not in FEV1; see Table 1) is paralleled by a progressive impairment in both Sacin and Scond. In the case of advanced smoking-induced alterations (⩾ 30 pack-years), Scond, and Sacin clearly show a differential pattern depending on whether or not additional obstruction in terms of FEV1/FVC (and also FEV1; see Table 2) originates from parenchymal loss as indicated by DlCO (and affecting only Sacin).

Direct comparisons between indices of lung function (reflecting global malfunction at a given lung depth) and indices of ventilation distribution (reflecting heterogeneous malfunction at a given lung depth) should be regarded with caution due to their intinsic differences. Nevertheless, we provide some scatterplots of selected lung function indexes (FEV1, FEF75, sGaw, and DlCO) against Sacin and Scond across all smokers in the online data supplement (Figures E1 to E3 in the online supplement). As expected, these plots show a picture of increasing Sacin and Scond, with decreasing FEV1, FEF75, Sgaw, or DLCO.

The most important findings of the present work can best be separated into observations related to early detection (smokers with a smoking history of less than 30 pack-years) and to more advanced smoking-induced lung injury (in smokers with a smoking history of 30 or more pack-years).

In the smokers with a smoking history less than 30 pack-years: (1) increased Scond and Sacin in smokers with as little as 10 pack-years smoking history, but normal spirometry and normal Sgaw, indicate early changes of small airways in both the conductive and acinar lung zone compartments, probably reflecting inflamed airways located around the acinar entrance; (2) decreased spirometric mid- and end-expiratory flows (FEF25–75, FEF75) in smokers with a smoking history of 20 or more pack-years reflect a more advanced deterioration in the small airways of which the anatomical location remains uncertain, but it is unlikely that even FEF75 would reflect small airways beyond the conductive lung zone compartment (16); (3) the decrease in DlCO in smokers with as little as a 10 pack-years smoking history is probably, at least in part, the result of a measurement artifact due to the underlying ventilation heterogeneity (as indicated by increased Scond and Sacin) (17), rather than the reflection of actual parenchymal damage in these very early stages of smoking-induced airways injury. Finally, we speculate that the progessive small airways dysfunction with increased smoking history observed here could be the noninvasive and functional equivalent of the correlation observed between increased expression of inflammatory mediators in epithelium harvested from small airways and smoking history of asymptomatic smokers (18). The fact that the transitory zone around the acinar entrance is so vulnerable to accumulation of particulate matter and associated airway wall thickening as opposed to the larger conducting airways (19), explains why indices reflecting small airways around the acinar entrance are so apt to identify the smoking-induced lung structure changes.

In the smokers with a smoking history of 30 pack-years or more, two striking analogies can be observed (Figure 1): (1) between FEF75 and Scond, the similar FEF75 in both COPD groups and the FEF75 difference between the non-COPD group and the two COPD groups is mimicked by Scond; and (2) between DlCO and Sacin, the marked DlCO difference between COPD/− and COPD/E groups is mimicked by Sacin. The fact that in the two COPD groups, both Scond and Sacin are increased with respect to the non-COPD group, and that Scond is increased to the same extent in both COPD groups, indicates a similar deterioration of the small airways around the acinar entrance in the patients with COPD with similar smoking histories, irrespective of the presence of emphysema. This can be brought in agreement with observations by Saetta and coworkers (20) of increased CD8+ T-lymphocytes and remodeling of peripheral airways in patients with COPD with respect to the asymptomatic smoker. The additional Sacin increase without further Scond increase in the COPD/E group then reflects an additional destruction of the alveolated air spaces.

Taken together across all smokers, Sacin and Scond patterns indicate that these noninvasive indices are not only very sensitive in picking up early changes, but maintain the ability to actually link ventilation distribution changes to anatomical structures in the more advanced stages of smoking-induced lung disease. The advantage of the combined use of Scond and Sacin (derived from the same MBW test) over the combined use of FEF75 and DlCO (derived from two different test maneuvers) can be best appreciated from the comparison between non-COPD and COPD/− groups (Figure 1). On the one hand, DlCO is similar between both groups, and FEF75 follows Scond behavior to represent deteriorated small conductive airways in the COPD/− group versus the non-COPD group. However, the deterioration of small acinar airways peripheral to the conductive compartment (as evidenced by a twofold Sacin increase between non-COPD and COPD/−) is information that cannot be gained from DlCO or FEF75, unless one speculates that the above-mentioned FEF75 decrease between COPD/− and non-COPD not only reflects conductive but also acinar small airways, which seems very unlikely (16). Also, in the early detection stages, the DlCO abnormality observed after 10 pack-years (when FEF75 is still unaffected) is very likely due to a ventilation heterogeneity–related artifact. We contend that direct measures of ventilation heterogeneity, such as Sacin and Scond, present a more attractive alternative to an index, such as DlCO, that is indirectly affected by ventilation heterogeneity.

Finally, it is interesting to note that trapped volume at FRC, assessed as the difference between FRCpl and FRCMBW, is only apparent in the patient with overt COPD (Table 2). Another hallmark of the patient with COPD is the decreased sGaw, also an index derived from plethysmography but which is less subject to mouth versus alveolar pressure artifacts when measured in obstructed patients than FRCpl (21). The normal sGaw values in all non-COPD smokers and the sudden drop in sGaw in the patient with COPD, clearly shows that large airway obstruction is involved only in the patient with overt COPD, irrespective of the presence of emphysema. This highlights the importance of being able to noninvasively assess small airways dysfunction in the screening of smokers before they develop overt COPD. The large airway obstruction can be brought in agreement with immunopathology data by Lams and colleagues (22) showing increased numbers of CD8+ cells infiltrating the large airway epithelium of patients with COPD with respect to asymptomatic smokers. We must point out, however, that any suggested associations between lung functional data (from spirometry or ventilation distribution) and biological markers of a lung disease process need to be interpreted with caution. Indeed, the way in which different markers of airway wall inflammation result in a functional change by affecting either static airway caliber or the dynamics of airway expansion is not trivial.

In the advanced stages of smoking-induced lung disease, small airways changes can be identified by histologic inspection or immunohistochemical assessment of lung resections (1, 19, 23). By attributing pathology scores, as in the study of Cosio and colleagues (1), small airway histomorphometry can then be correlated with indices of ventilation distribution, such as the VC SBW N2 phase III slope (note that in the Cosio study, the group with a normal pathology score had an average smoking history of 17 pack-years). Although this study demonstrated that a morphologic change in the small airways did affect the SBW, other contributors to the VC nitrogen SBW test have now been identified (2, 3), precluding its usage today as an unequivocal reflection of small airways. When a modified SBW with He and SF6 tracer gases was used to accentuate the small airways content in the phase III slope to study smokers' lungs, Van Muylem and coworkers (23) found significant correlations with scores of fibrosis and inflammation of the respiratory bronchioles. Besides the practical aspects of performing He and SF6 SBW tests (mass spectrometer) as an alternative to measuring MBW derived Scond and Sacin (N2 analyzer), there is another critical issue. The individual He and SF6 SBW phase III slopes, reflecting structural changes in the proximal and peripheral acinus, respectively (24), are bound to be contaminated by the conductive airways contribution to the SBW phase III slope (which is isolated by means of Scond in the MBW test). The SF6-He phase III slope difference and any change thereof can be unequivocally attributed to a change within the acinar lung zone. However, some degree of acinar structure change could be missed by the SF6-He SBW phase III slope difference: if structure changes in the proximal and peripheral acinar lung zone are such that they affect respective He and SF6 slopes to a similar extent, no net effect on the SF6-He slope difference will be observed (such structure changes should be detected by Sacin in the MBW test).

In the early stages of smoking-induced lung disease, a gold standard of peripheral lung damage to validate noninvasive indices of small airways dysfunction is as yet impossible to obtain in human subjects. However, animal studies have provided some validation of MBW related indices. Tsang and coworkers (25) demonstrated a differential response of proximal and peripheral MBW indices to oleic acid–induced pulmonary edema in mongrel dogs where indeed only the peripheral MBW index was affected. In rats with different types of induced emphysema (26) and smoking-induced lesions of the nonalveolated small airways (27), significant correlations could be obtained between ventilation distribution tests and histomorphometry. The cutoff between the proximal and peripheral MBW index in each species is dictated by the location of the O2–N2 diffusion front and can be computed on the basis of a realistic lung morphometry. In human adult lungs, the diffusion front is situated at the level of the acinar entrance (24), hence, proximal and peripheral indices of ventilation heterogeneity are referred to as conductive and acinar ventilation heterogeneity and quantified by Scond and Sacin, respectively.

We conclude that the use of MBW to noninvasively probe early smoking-induced lung alterations has addressed the expectations put forward by the Cosio group study (1) that tests of unevenness of ventilation, could offer the possibility to show abnormalities at a time when pathologic changes are still potentially reversible. To the best of our knowledge no other studies have since emerged that were able to noninvasively detect smoking-induced ventilation heterogeneities originating in the small airways, from as early as 10 pack-years smoking history onwards. This makes the MBW test an eligible screening tool in the management of smoking-induced lung disease, and responds to the need for improved noninvasive mechanical tests of lung function expressed in recent recommendations for future research in COPD (28).

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Correspondence and requests for reprints should be addressed to Sylvia Verbanck, AZ-VUB, Consultatie Pneumologie, Laarbeeklaan 101, 1090 Brussels, Belgium. E-mail:


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