Objective: Studying smokers with normal spirometry requires monitoring tools of the peripheral lung. A validated multiple breath washout technique was used to assess possible recovery of smoking-induced small airway malfunction in acinar and conductive lung zones.
Methods: Eighty-seven smokers with a smoking history of at least 10 pack-years but absence of spirometric airflow obstruction were invited for assessment of lung function and small airway function at baseline and after 1 wk, 3 mo, 6 mo, and 12 mo of smoking cessation. A control group of 16 persistent smokers was studied at the same time intervals.
Measurements and Main Results: Of the 87 smokers, 66, 32, 28, and 21% successfully ceased smoking for 1 wk, 3 mo, 6 mo, and 12 mo, respectively. Lung function parameters remained essentially unaffected by smoking cessation. Ventilation heterogeneity showed transient improvements after 1 wk in the acinar lung compartment with a return to baseline afterwards. By contrast, there were persistent improvements in the conductive airway compartment; for example, smokers who successfully quit smoking for 12 mo (n = 18) showed a 30 and 42% reduction of conductive airways abnormality after 1 wk and 1 yr, respectively.
Conclusions: Smokers with early signs of small airway malfunction who successfully quit smoking show sustained improvements of conductive airway malfunction. In contrast, acinar airway malfunction quickly returns to baseline after a transient improvement.
It has been shown that smoking cessation can slow disease progression, as evidenced by a decrease in the rate of decline in forced expiratory volume in 1 sec (FEV1) in the years following smoking cessation (1, 2). Most of these studies included smokers with a diagnosis of chronic obstructive pulmonary disease (COPD) and the degree of airway obstruction of the smokers under study was not always homogeneous. However, a recent report by Willemse and colleagues (3) has indicated that besides the higher inflammatory content in induced sputum obtained from smokers with COPD versus so-called asymptomatic smokers at baseline, both types of smokers show markedly different evolution patterns of inflammatory markers as a function of smoking cessation duration. For instance, interleukin-8 actually increased in patients with COPD after 12 mo of smoking cessation, whereas it decreased in the asymptomatic smokers. Also after 1 yr, the number and percentage of macrophages had decreased in asymptomatic smokers, contrasting with absence of change in the COPD group. In a group of smokers close to the cut-off for obstruction (average FEV1/FVC, 71 ± 13 [SD] %), Swan and colleagues (4) observed significantly decreased macrophage ratings after only 1 to 2 mo of smoking cessation.
One could argue about the definition of the asymptomatic smoker, considering that smokers entering a smoking cessation program may not be entirely asymptomatic; yet, from a functional viewpoint, we can identify the smoker without airway obstruction on the basis of FEV1/FVC. These smokers are difficult to monitor because smoking-induced lung disease mainly originates in the lung periphery, where spirometric measurement is insensitive to lung structural change. Alternative methods have been explored for an early detection of small airway malfunction in smokers (5–8) that include ventilation distribution tests such as the single breath washout that has also been used in a smoking cessation scenario (6, 7). The phase III slope of the single breath washout was shown to decrease with smoking cessation and this improvement continued for 6 to 8 mo, after which it remained stable (7). However, the single breath washout does not allow determination of the level of the bronchial tree at which the airway function improves. Recently, the multiple breath washout (MBW) test has been shown to detect abnormality in the small airways around the acinar entrance, both in the conductive and acinar lung zone compartments, from a smoking history of 10 pack-years onwards (8). Because one of the main objectives for early detection is early intervention, and the best intervention is smoking cessation, the same MBW tools can now be used to monitor potential reversal of early small airway dysfunction with smoking cessation. We set out to investigate which of the affected airways had a potential for recovery with different smoking cessation periods up to 1 yr. Although Swan and Denk (9) could not, over a 1-yr observation interval, identify a “safe point” at which former smokers are no longer at risk for relapse, 1 yr is an arbitrary evaluation interval often used in smoking cessation studies.
Spirometry was obtained by means of standardized equipment (Vmax 20C; SensorMedics, Bilthoven, The Netherlands). From the forced expiratory curve, we used FEV1, FVC, and forced expiratory flow after exhalation of 75% FVC (FEF75); predicted values for FEV1 and FEF75 were based on those provided by the European Community for Steel and Coal. We also measured single breath carbon monoxide transfer factor (dlCO) and specific airway conductance (sGaw; Models 2200 and 6200; SensorMedics). A Micro Smokerlyzer (Bedfont Scientific, Rochester, UK) was used to monitor exhaled CO for a double-check of self-reported smoking cessation.
The N2 MBW test—that is, 20 to 25 inspirations of 1 L pure O2, starting from functional residual capacity with continuous monitoring of N2 concentration and volume—was performed according to standardized methods extensively reported elsewhere (8, 10, 11). For the theory of MBW N2 phase III slope analysis leading to indices of conductive (Scond) and acinar (Sacin) ventilation heterogeneity, see the online supplement. It implies that Scond and Sacin are intrinsically independent and not comparable (11). Because Scond and Sacin are derived from phase III slopes, their value increases when ventilation heterogeneity increases. In particular, Sacin will increase if an alteration of the intraacinar asymmetry occurs—for example, by differential airway wall thickening of any two daughter branches. Scond will increase if the conductive airways and their subtended units show an increase in heterogeneity of specific ventilation or flow asynchrony (such that the best-ventilated units empty preferentially early in expiration).
The study protocol was approved by the local ethics committee. Spanning a 3-yr period, 87 smokers (41 male, 46 female) began the smoking cessation protocol, with visits to the lung function laboratory projected at baseline (day of smoking cessation, > 4 h after the last cigarette), and after 1 wk, 3 mo, 6 mo, and 12 mo. Because the informed consent stipulated that subjects could withdraw from the study at any time, it was expected that smokers who could not sustain smoking cessation for the entire study period would not appear for the projected visit following their smoking resumption. Exclusion criteria at study entry were spirometric diagnosis of airway obstruction (FEV1/FVC < 70% at baseline) and smoking history of less than 10 pack-years, because the earliest signs of small airway malfunction have been seen to appear from 10 pack-years onwards (8). Of the 87 subjects included, 75 used either nicotine replacement therapy (n = 24) or bupropion therapy (n = 51), depending on individual preferences or medical contraindications. In parallel, 20 persistent smokers without airway obstruction (i.e., with baseline FEV1/FVC > 70%) were recruited to be studied at the same time intervals. For all study subjects, each study visit included lung function and ventilation distribution testing after bronchodilatation with 200 μg salbutamol delivered via an antistatic coated spacer (12).
Using Statistica 5.1 (StatSoft, Tulsa, OK), we used one-way analysis of variance to detect baseline differences between study subgroups and one-way repeated-measures analysis of variance to detect longitudinal changes within each subgroup. Bonferroni adjustment was used to test for post hoc differences. A χ2 test was used to test for differences in the proportion of smokers using different smoking cessation pharmacotherapies in different subgroups.
Data reported here are lung function and ventilation heterogeneity parameters obtained after dilation on each visit in four successively smaller subgroups of subjects who remained abstinent from smoking for at least 1 wk (1-wk subgroup, n = 57), 3 mo (3-mo subgroup, n = 28), 6 mo (6-mo subgroup, n = 24), and 12 mo (12-mo subgroup, n = 18). The proportion of subjects receiving nicotine replacement therapy or bupropion was not significantly different among the four subgroups (p > 0.1). The characteristics of all subject subgroups are provided in Table 1, showing no statistical differences in any of the displayed parameters; note the substantial intersubject variability in most of these parameters. Although intersubject variability does not matter for this longitudinal study, we did include a control group of persistent smokers to double-check the absence of longitudinal intrasubject variability for these measurements in this particular type of study population. The 16 persistent smokers (6 male, 10 female) who participated in all visits (4 of 20 did not return for the 12-mo visit) were generally younger (32 ± 9 [SD] yr) and had a shorter smoking history (13 ± 8 [SD] pack-years) than the smoking cessation participants.
|Cessation rate, %||66||32||28||21|
|Age, yr||44 (8)||43 (8)||44 (7)||45 (7)||45 (6)|
|Pack-years||32 (20)||30 (16)||30 (17)||29 (16)||27 (9)|
|FEV1, %pred||107 (15)||109 (15)||112 (17)||113 (18)||113 (16)|
|FEF75, %pred||80 (27)||80 (29)||81 (32)||83 (33)||85 (33)|
|DlCO, %pred||80 (16)||83 (16)||84 (16)||85 (17)||88 (13)|
|sGaw, 1/cm H2O · s||0.155 (0.056)||0.157 (0.053)||0.162 (0.062)||0.160 (0.060)||0.164 (0.065)|
|Scond, L−1||0.047 (0.016)||0.046 (0.012)||0.047 (0.012)||0.046 (0.012)||0.045 (0.013)|
|Sacin, L−1||0.126 (0.090)||0.123 (0.101)||0.134 (0.101)||0.128 (0.091)||0.130 (0.088)|
Table 2 shows all lung function and ventilation heterogeneity parameters that have been shown to be meaningful for the characterization of smokers (8). The persistent smoker group (n = 16) did not show significant changes in any of the parameters in Table 2. For smoking cessation participants in the 1-wk subgroup (n = 57), significant but marginal improvements were observed in FEV1 (+1% predicted) and dlCO (+2% predicted) after 1 wk. A marked decrease (i.e., improvement) in Sacin was also seen after 1 wk, but this improvement no longer reached statistical significance in the 3-mo, 6-mo, or 12-mo subgroups. On the other hand, Scond showed a marked decrease (i.e., improvement) after only 1 wk, and this improvement persisted across all subgroups, that is, for sustained smoking cessation up to 1 yr of study.
|Smoking cessation||57||109 ± 15||110 ± 15*|
|28||112 ± 17||112 ± 17||109 ± 19|
|24||113 ± 18||112 ± 18||109 ± 20*||111 ± 16|
|18||113 ± 16||112 ± 18||109 ± 18†||110 ± 15||111 ± 16|
|Current smoking||16||117 ± 16||116 ± 16||117 ± 15||117 ± 14||116 ± 14|
|Smoking cessation||57||80 ± 29||84 ± 31|
|28||81 ± 32||85 ± 33||86 ± 40|
|24||83 ± 33||86 ± 35||86 ± 42||83 ± 33|
|18||85 ± 38||87 ± 34||85 ± 38||84 ± 31||79 ± 30|
|Current smoking||16||103 ± 33||105 ± 33||108 ± 25||113 ± 31||109 ± 33|
|DlCO % pred|
|Smoking cessation||57||83 ± 16||85 ± 15*|
|28||84 ± 16||86 ± 17||87 ± 14|
|24||85 ± 17||85 ± 18||88 ± 14||87 ± 16|
|18||88 ± 13||88 ± 17||89 ± 14||90 ± 13||91 ± 14|
|Current smoking||16||88 ± 17||89 ± 15||86 ± 15||82 ± 13||88 ± 17|
|sGaw, 1/cm H2O · s|
|Smoking cessation||57||0.157 ± 0.053||0.151 ± 0.042|
|28||0.162 ± 0.062||0.150 ± 0.043||0.158 ± 0.052|
|24||0.160 ± 0.060||0.149 ± 0.042||0.160 ± 0.053||0.140 ± 0.057|
|18||0.164 ± 0.065||0.151 ± 0.045||0.163 ± 0.057||0.148 ± 0.062||0.134 ± 0.056|
|Current smoking||16||0.142 ± 0.051||0.136 ± 0.039||0.153 ± 0.072||0.0137 ± 0.044||0.128 ± 0.039|
|Smoking cessation||57||0.046 ± 0.012||0.040 ± 0.011†|
|28||0.047 ± 0.012||0.041 ± 0.011†||0.039 ± 0.012†|
|24||0.046 ± 0.012||0.041 ± 0.011*||0.039 ± 0.012†||0.036 ± 0.012†|
|18||0.045 ± 0.013||0.040 ± 0.013||0.038 ± 0.012*||0.034 ± 0.013†||0.038 ± 0.010*|
|Current smoking||16||0.041 ± 0.012||0.039 ± 0.010||0.040 ± 0.010||0.038 ± 0.009||0.042 ± 0.015|
|Smoking cessation||57||0.123 ± 0.101||0.103 ± 0.060*|
|28||0.134 ± 0.101||0.115 ± 0.059||0.119 ± 0.065|
|24||0.128 ± 0.091||0.118 ± 0.059||0.120 ± 0.063||0.126 ± 0.074|
|18||0.130 ± 0.088||0.122 ± 0.059||0.130 ± 0.065||0.132 ± 0.078||0.127 ± 0.085|
| Current smoking||16||0.078 ± 0.044||0.071 ± 0.038||0.080 ± 0.054||0.072 ± 0.045||0.080 ± 0.040|
Figures 1A and 1B graphically represent the time evolution (in log scale) of the indices of small airway ventilation heterogeneity in the conductive and acinar lung zone. Using the mean values for Scond and Sacin recently obtained from a group of 63 normal never-smokers without bronchial hyperresponsiveness to histamine (Scond = 0.028 ± 0.007 [SD] · L−1; Sacin = 0.072 ± 0.025 [SD] · L−1) (8), the cut-offs for abnormality (i.e., means plus 1.96 times SD) were established at Scond = 0.042 · L−1 and Sacin = 0.12 · L−1 (shaded areas in Figures 1A and 1B). As can be appreciated from Figure 1, the smokers from the 12-mo subgroup (n = 18; closed circles) showed a similar evolution pattern of ventilation heterogeneity with smoking cessation time compared with the larger subgroups that had resumed smoking before the end of the study (open circles). For instance, the change in Scond seen after only 1 wk in the 1-wk subgroup (n = 57) is nearly indistinguishable from that observed in the 3-mo, 6-mo, and 12-mo subgroups (n = 28, 24, and 18, respectively).
Figure 1A shows that the average Scond was above the line of Scond abnormality and fell below it after smoking cessation. Considering that normal Scond is 0.028 · L−1, the Scond decrease from an average of 0.046 · L−1 (baseline) to 0.040 · L−1 (1-wk cessation) in the 1-wk subgroup (n = 57) represents a 33% reduction (= [0.046 – 0.040]/[0.046 – 0.028]) of baseline conductive airway abnormality. The corresponding changes in the 12-mo subgroup (n = 18) were 30 and 42% reduction in Scond abnormality after 1 wk and 12 mo, respectively. Considering a normal Sacin of 0.072 · L−1 (Figure 1B), similar computation yielded a 40% reduction in the acinar airway abnormality in the 1-wk subgroup after only 1 wk (n = 57), but this improvement was less consistent across all subgroups, and did not persist for longer smoking cessation periods (Table 2).
Conductive airway malfunction is one of the earliest signs of smoking-induced small airway abnormality, typically observed in smokers with smoking histories greater than 10 pack-years and preceding the appearance of spirometric airflow obstruction (8). The present study shows that conductive airway abnormality could be improved by approximately one-third after only 1 wk of smoking cessation. In addition, this improvement was sustained, and after 1 yr, a 42% reduction of conductive airway abnormality was obtained in the smokers under study. Given that neither FEV1 nor FEF75 showed any change, we conclude that the sustained Scond decreases seen here reflect a functional recovery of the smallest airways that are still positioned in the conductive lung zone. Of all parameters in Table 2, Scond, Sacin, and dlCO were the ones that had been previously shown to pick up early signs of smoking-induced airway changes from 10 pack-years onwards (8). Nevertheless, the two indices related to the alveolar compartment, dlCO and Sacin, either showed a minor recovery (dlCO) or a transient one (Sacin) with smoking cessation up to 1 yr. This indicates a more obstinate smoking-induced damage of small airways in the acinar lung zone.
Few published reports exist about the fate of small airway function or inflammation after smoking cessation in smokers without airway obstruction. Even in smokers with FEV1/FVC around the 70% cut-off for obstruction, FEV1/FVC was not necessarily related to inflammatory markers (4). Nevertheless, Swan and colleagues (4) showed that macrophages recovered from induced sputum markedly decreased after only 1 mo and the decrease was maintained after 12 mo of smoking cessation. These authors pointed out that this prompt cellular response contrasted with the slow changes in conventional lung function parameters in their study. The quick response of small airway ventilation heterogeneity seen in the present study may well be the functional equivalent of inflammatory changes Swan and colleagues observed after smoking cessation. Three decades ago, Buist and colleagues (7) had already shown the potential of ventilation heterogeneity to monitor the smoker's lung, observing marked decreases in the single breath phase III slope after 1 mo of smoking cessation. However, from these phase III slopes, it is impossible to derive in which lung zones these improvements in ventilation heterogeneity take place.
The respective patterns of change in the conductive and acinar compartments observed here with Scond and Sacin parallel those found in the airways and alveolar NO production derived from exhaled NO measurements reported by Hogman and colleagues (13). In that study, 4 wk of smoking cessation in smokers with FEV1 and dlCO values comparable to ours resulted in an increase of the abnormally low airway NO to normal values and no change in the alveolar NO. Regardless of the exact reason for the abnormally low NO in the airway compartment of the smokers versus never-smokers, it is the airway and not the alveolar space that appears to most consistently respond to smoking cessation. On the border between conductive and acinar lung compartments, respiratory bronchiolitis has been observed in all current smokers (ranging from 6 to 200 pack-years) and in approximately 50% of ex-smokers (ranging from 5 to 180 pack-years) without any correlation between occurrence of respiratory bronchiolitis and number of pack-years (14). Although obtained in a cross-sectional study with a very wide range of smoking histories, these pathology data indicate that there is a potential for repair but they also point to an irreversible component in the damage of these small airways situated around the entrance to the gas-exchanging lung zone.
In the acinar space, inflammatory processes with different time constants and functionalities appear to be at work (15, 16). For instance, Skold and colleagues (15) found that cells recovered from bronchoalveolar lavage fluid of smokers (with ∼ 23 pack-years smoking history) decreased consistently after 1 mo of smoking cessation, but that considerable fluorescent tobacco material trapped inside alveolar macrophages persisted in the alveolar space for up to 15 mo. In another study, Skold and colleagues (16) showed transient changes in accumulated extracellular matrix compounds such as albumin and hyaluronan in bronchoalveolar lavage fluid within the first few months of smoking cessation, with a return to baseline for longer smoking cessation periods up to 15 mo. A direct relationship between any of these separate inflammatory processes and a cumulative parameter of acinar airway function such as Sacin is unlikely. Rather, the transient pattern of Sacin recovery after 1 wk and subsequent return to baseline abnormality may reflect the presence of different underlying inflammatory damage and repair processes with different time constants.
We conclude that small airway function as measured by MBW-derived parameters is abnormal in smokers without spirometric evidence of airway obstruction, and that these abnormalities in small airway ventilation heterogeneity can be partly reversed after smoking cessation. This recovery already occurs after 1 wk and persists in the conductive lung zone, more specifically in the airways peripheral to the small airways sampled by spirometric endexpiratory flows. Such findings of small airway improvement could be used in the encouragement of the so-called asymptomatic smoker to start or maintain smoking cessation. A recent Cochrane database systematic review (17) judged existing studies of insufficient quality to be conclusive about the effectiveness of biomedical risk assessment such as genetic susceptibility to positively influence smoking cessation. Although measurement of abnormal small airway function at baseline could provide another index of biomedical risk, its improvement as smoking cessation follow-up proceeds could provide a positive stimulus to maintain adherence to smoking cessation, as was shown when ex-smokers were confronted with their improving inflammatory markers during smoking cessation follow-up (4). Finally, the noninvasive measures of peripheral lung function presented here provide clues as to how deep in the lungs and in what time frames, other, possibly more invasive techniques, could monitor in situ pathology during smoking cessation protocols.
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