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Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
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Original article
Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study Kento Satoa, Yoko Shibataa,b,n, Sumito Inouea, Akira Igarashia, Yoshikane Tokairina, Keiko Yamauchia, Tomomi Kimuraa, Takako Nemotoa, Masamichi Satoa, Hiroshi Nakanoa, Hiroyoshi Machidaa, Michiko Nishiwakia, Maki Kobayashia, Sujeong Yanga, Yukihiro Minegishia, Kodai Furuyamaa, Tomoka Yamamotoa, Tetsu Watanabea, Tsuneo Kontaa, Yoshiyuki Uenoc, Takeo Katoc, Takamasa Kayamac, Isao Kubotaa a Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan b Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, 1 Hikariga-Oka, Fukushima 960-1295, Japan c Global Center of Excellence Program Study Group, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan
art i cle i nfo
ab st rac t
Article history:
Background: Few studies are available regarding the annual decline of forced expiratory
Received 25 August 2017
volume in 1 s (FEV1) in chronic obstructive pulmonary disease patients with mild airflow obstruction. This study sought to clarify to what extent cigarette-smoking individuals with mild airflow obstruction lose pulmonary function annually.
Abbreviations: AFO, airflow obstruction; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; JRS, Japanese Respiratory Society; LAMA, long-acting muscarinic antagonist n Corresponding author at: Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, 1 Hikariga-Oka, Fukushima 960-1295, Japan. Fax: þ81 24 548 9366. E-mail addresses: [email protected] (K. Sato), [email protected] (Y. Shibata), [email protected] (S. Inoue), [email protected] (A. Igarashi), [email protected] (Y. Tokairin), [email protected] (K. Yamauchi), [email protected] (T. Kimura), [email protected] (T. Nemoto), [email protected] (M. Sato), [email protected] (H. Nakano), [email protected] (H. Machida), [email protected] (M. Nishiwaki), [email protected] (M. Kobayashi), [email protected] (S. Yang), [email protected] (Y. Minegishi), [email protected] (K. Furuyama), [email protected] (T. Yamamoto), [email protected] (T. Watanabe), [email protected] (T. Konta), [email protected] (Y. Ueno), [email protected] (T. Kato), [email protected] (T. Kayama), [email protected] (I. Kubota). https://doi.org/10.1016/j.resinv.2017.11.011 2212-5345/& 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Received in revised form
Methods: From 2004 to 2006, pulmonary function tests were performed on people 440
15 November 2017
years of age, during the annual health checkup held in Takahata, Yamagata, Japan (initial
Accepted 24 November 2017
study population, n ¼3253). In 2011, pulmonary function tests were performed again on participants who agreed to undergo reexamination (follow-up study population, n ¼838).
Keywords: Airflow obstruction Annual health check Chronic obstructive pulmonary disease (COPD) Smoking FEV1
Results: Smokers have decreased pulmonary function in terms of percent forced vital capacity (FVC), %FEV1, and FEV1/FVC; the stages of airflow obstruction were also more severe in smokers than never-smokers. The annual decline in FEV1 was significantly greater in smokers than in never-smokers. The median annual decline in FEV1 was most significant in individuals with mild airflow obstruction. The annual decline in FEV1 was greater in smokers with mild airflow obstruction than in smokers with moderate airflow obstruction. In analyzing the decline in %FEV1, the annual change in smokers with mild airflow obstruction was greater than that in smokers with normal spirometric values. Conclusion: The annual decline in FEV1 was most significant in smokers with mild airflow obstruction in a Japanese general population. This highlights the importance of early detection of chronic obstructive pulmonary disease patients among the general population in order to prevent disease progression in undiagnosed patients. & 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. The most important risk factor for COPD is inhalation of cigarette smoke. Epidemiological studies have demonstrated that a decline in pulmonary function such as forced expiratory volume in 1 s (FEV1) was more rapid in continuous smokers than in never-smokers or intermittent smokers, in the general population [1]. As COPD treatment by bronchodilator inhalation has improved, COPD outcomes have also improved [2,3]. Clinical trials of long-acting muscarinic antagonists (LAMAs) and LAMAs plus long-acting beta agonists in COPD have demonstrated reduction of symptoms such as dyspnea, exacerbation, and mortality in patients with COPD who have moderate to very severe airflow obstruction (AFO) [2,3]. Additionally, subgroup analysis in the Understanding Potential Long-Term Impacts on Function with Tiotropium study demonstrated that tiotropium significantly reduced the decline in FEV1 in COPD patients with moderate AFO, those without receiving other maintenance therapies, or those aged 50 years or less [4–6]. Since most clinical trials did not include COPD patients with mild AFO, there was no evidence regarding the clinical benefits of treating COPD patients with mild AFO. COPD patients with mild AFO have fewer symptoms and less frequent exacerbations than patients with moderate or severe AFO. Therefore, most of these patients remain undiagnosed and untreated, and keep smoking cigarettes [7]. Previously, Tantucci et al. reported that the most rapid decline in FEV1 was observed in COPD patients with moderate AFO, based on a summary of data from numerous clinical trials; however, observations of the decline in FEV1 in COPD patients with mild AFO are rarely reported [8]. Therefore, the impact of cigarette smoke inhalation on patients with early stage COPD has not yet been fully clarified. In Japan, the prevalence of COPD is estimated at about 8% in the population aged 40 years or older [9]. We also demonstrated that the prevalence of AFO was 10.6% in the general
population of Takahata, Yamagata, Japan [10]. Most subjects with abnormal spirometry findings have remained undiagnosed and untreated for respiratory disorders, and many of them smoke cigarettes. We hypothesized that the impact of cigarette smoke inhalation on subjects with mild AFO is greater than on those with moderate to severe AFO. This study aimed to test this hypothesis.
2.
Materials and methods
2.1.
Study population
The Yamagata–Takahata study formed part of the Molecular Epidemiological Study of the Regional Characteristics of the 21st Century Centers of Excellence Program and the Global Centers of Excellence Program in Japan [10–19]. The Ethics Committee of Yamagata University School of Medicine approved this study (approval date, December 21, 2009; approval number, H21-131), and written informed consent was provided by all participants. The study used data from an annual community health checkup in which all residents of Takahata (a town in Japan) aged 40 years or older were invited to participate. From 2004 to 2006, 3520 subjects were enrolled in the study and received initial spirometric examinations. Altogether, 264 subjects and 3 subjects were excluded from the analysis because their spirometry data did not meet the specified criteria and because of refusal of the follow-up examination, respectively (initial study population, n ¼3253). In 2011, 873 subjects among the initial study population agreed to undergo spirometry again [15]. One subject was excluded due to an error in spirometry measurements. Since forced vital capacity (FVC) o80% indicated the presence of restrictive ventilation disorders, such as interstitial pneumonias, we also excluded 34 subjects with FVC o 80% and FEV1/FVCZ0.7. Finally, data from 838 subjects were used for the analysis (follow-up study population) [15]. The subjects’ medical histories, smoking
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Table 1 – Characteristics of the initial study population and follow-up study population during 2004–2006.
Age, years Male sex, % Body mass index, kg/m2 Ever-smoker, % Brinkman index, cigarette years %FVC %FEV1 FEV1/FVC, % Airflow obstruction, % Non/mild/moderate/severe History of respiratory diseases, % Respiratory medication, %
Initial population (n ¼ 3253)
Follow-up population (n ¼ 838)
P
62.3710.4 46.1 23.573.2 35.6 0 (0–200) 98.7714.6 97.8716.5 78.677.8 10.4 89.6/4.2/5.0/1.1 2.5 0.7
60.378.8 46.4 23.472.9 32.7 0 (0–50) 101.0712.0 100.2714.2 78.976.9 8.9 91.1/4.3/4.2/0.5 2.3 0.4
o0.0001 0.87 0.595 0.116 0.102 o 0.0001 o 0.0001 0.314 0.217 0.274 0.71 0.33
Table 2 – Subjects’ characteristics relative to smoking status during 2004–2006.
Age, years Male sex, % Body mass index, kg/m2 Brinkman index, cigarette years %FVC %FEV1 FEV1/FVC, % Airflow obstruction, % Non/mild/moderate/severe History of respiratory diseases, % Respiratory medication, %
Never smokers (n ¼ 564)
Smokers (n ¼ 274)
P
60.078.8 25.50 23.473.1 0 101.8711.8 102.1713.6 80.276.0 5.3 96.7/2.7/2.4/0.18 1.2 0.3
61.178.9 89.4 23.472.7 600 (400–900) 99.5712.4 96.3714.7 76.277.9 16.4 83.6/7.7/7.7/1.1 4.4 0.4
0.085 o 0.0001 0.941 o 0.0001 0.008 o 0.0001 o 0.0001 o 0.0001 o 0.0001 0.004 0.981
habits, current use of medications, and clinical symptoms were documented using a self-reported questionnaire. However, details regarding diagnosis of respiratory diseases (such as COPD and asthma) and respiratory medications (such as bronchodilators or inhaled corticosteroids) were not available. The lifetime consumption of cigarettes was expressed according to the Brinkman index (number of cigarettes per day years of smoking) [19]. Asthma-like features could not be evaluated due to the lack of information on blood eosinophil count, serum immunoglobulin E levels, and fractional exhaled nitric oxide [20].
2.2.
Measurements
Spirometric parameters (FVC and FEV1) were measured using standard techniques, with subjects performing FVC maneuvers on a CHESTAC-25 part II EX instrument (Chest Corp., Tokyo, Japan) according to the guidelines of the Japanese Respiratory Society (JRS) [21]. A bronchodilator was not administered prior to spirometry. The highest value of at least 3 FVC maneuvers by each subject was used for the analysis. The results were assessed by 2 pulmonary physicians who visually inspected the flow-volume curves and excluded subjects with inadequate data as defined by the JRS criteria [21]. The presence of AFO was determined by prebronchodilator FEV1/FVC o 0.7. Subsequently, the severity of AFO was assessed as the percentage of the predicted value of FEV1 as follows: mild, FEV1% predicted Z80; moderate,
50rFEV1% predicted o 80; severe, FEV1% predicted o 50. The annual changes in %FEV1 (%/year) were calculated as ([value of 2011 spirometry – value of initial spirometry] / value of initial spirometry) 100 / time between observations (years) [14–16].
2.3.
Statistical analyses
For continuous variables, data are presented as the mean 7 standard deviation or median (interquartile range). Chisquare tests were performed to evaluate differences in proportion. Student's t-test and Wilcoxon's rank-sum test were performed for parametric and nonparametric comparisons of two groups, respectively. One-way analysis of variance and SteelDwass tests were performed for parametric and nonparametric multiple comparisons, respectively. Statistical significance was inferred for two-sided P-values o 0.05. All statistical analyses were performed using JMP version 11 software (SAS Institute Inc., Cary, NC, USA).
3.
Results
The characteristics of the subjects in the initial and follow-up studies are shown in Table 1. The follow-up population was younger and had better pulmonary function than the initial population. Therefore, subjects who were older and had poorer pulmonary functions in the initial population appeared to
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Fig. 1 – Annual change in forced expiratory volume in 1 s (FEV1) and FEV1 percent predicted (%FEV1) relative to smoking status. Spirometry was first performed from 2004 to 2006 in a Japanese general population. In 2011, spirometry was performed again in this study population. The annual changes in FEV1 (A) and %FEV1 (B) are shown relative to smoking status.
Table 3 – Subjects’ characteristics relative to the severity of airflow obstruction (AFO) during 2004–2006.
Age, years Male sex, % Body mass index, kg/m2 Brinkman index, cigarette years Never-smokers, % History of respiratory diseases, % Respiratory medication, %
Normal (n ¼ 763)
Mild AFO (n ¼ 36)
Moderate AFO (n ¼ 35)
Severe AFO (n ¼ 4)
P
59.978.7 43.90 23.573.0 0 (0–0) 70.0 1.7 0.3
62.279.4 63.9 22.372.5 50 (0–700)* 41.7 5.6 0.0
66.677.5 80 23.072.7 500 (0–855)* 40.0 11.4 2.9
69.577.1 75 23.775.4 525 (0–1050) 25.0 0.0 0.0
o 0.0001 o 0.0001 o 0.0001 o 0.0001 o 0.0001 0.001 0.090
*Po0.001 versus normal.
avoid undergoing reexamination (Table 1). In the follow-up study, smokers were more likely to be male and to have poorer pulmonary functions than never-smokers, while age and body mass index were not different between smokers and neversmokers (Table 2). The percentage of subjects who had a history of respiratory diseases was significantly greater among smokers than among never-smokers, while the percentage of the subjects who had received respiratory medications was not different between never-smokers and smokers in this study (Table 2). The annual decline in FEV1 of smokers was larger than that of never-smokers, although the annual decline in %FEV1 of smokers tended to be larger than that of never-smokers; however, the difference did not reach statistical significance (Fig. 1). Subjects were older, were more likely to be male, were thinner, were more exposed to cigarette smoke, and fewer were never-smokers according to the severity of AFO (Table 3). In addition, the percentage of subjects who had received respiratory medication was very low, even among those with mild and severe AFO (Table 3). As shown in Table 3, the number of subjects with severe AFO was not sufficient for meaningful analysis (n ¼ 4), and these subjects were excluded from subsequent analyses. Fig. 2 shows the annual declines in FEV1 and %FEV1 relative to the severity of AFO (Fig. 2A and C). The annual declines in FEV1 and %FEV1
among never-smokers were not significantly different according to the severity of AFO (Fig. 2B and D, left). However, annual declines in FEV1 and %FEV1 in smokers were significantly different among groups (Fig. 2B and D, right). Post hoc analyses revealed that the annual declines in FEV1 and % FEV1 of smokers with mild AFO were greater than those of smokers with moderate AFO and smokers without AFO, respectively. Although the amount of cigarette smoke exposure was greater in smokers with moderate AFO than in smokers without AFO, the amount of cigarette smoke exposure in smokers with mild AFO was not greater than that in other smokers (Table 4). Declines in FEV1 and %FEV1 of smokers were significantly greater than those of never-smokers among subjects with no AFO or mild AFO (Fig. 3). In contrast, the declines in FEV1 and %FEV1 among subjects with moderate AFO did not differ significantly between smokers and never-smokers. Among subjects without AFO in the initial study, 5.4% of neversmokers and 20.5% of ever-smokers had AFO in the 2011 follow-up study (Fig. 4). Among subjects with airflow obstruction in the initial study, most of the ever-smokers had AFO in 2011, but 43.3% of never-smokers did not (Fig. 4). As some subjects with AFO in the initial study, but not in the follow-up study, might have had asthma, we also compared the annual change in FEV1 among subjects, excluding
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Fig. 2 – Annual changes in forced expiratory volume in 1 s (FEV1) and FEV1 percent predicted (%FEV1) relative to the severity of airflow obstruction (AFO) in the cohort overall, never-smoking, or smoking subjects. Box-and-whisker plots show annual changes in FEV1 (A) and %FEV1 (C) relative to the severity of AFO. In addition, these changes in FEV1 (B) and %FEV1 (D) are separately demonstrated for never-smokers (B, left and D, left) and smokers (B, right and D, right). Boxes show interquartile ranges of the values; lines in the boxes show the median values. Whiskers show the range of nonoutliers. Plots show the outliers. P values for the Wilcoxon test are shown in the figures. *P o 0.05 in post hoc analysis using the SteelDwass test. Table 4 – Amount of cigarette consumption relative to the severity of airflow obstruction (AFO) in smokers during 2004– 2006.
Brinkman index, cigarette years
Normal, smoker (n ¼ 158)
Mild AFO, smoker (n ¼ 16)
Moderate AFO, smoker (n ¼ 18)
P
600 (393.8–860)
700 (400–930)
820 (693.8–1207.5)*
0.01
*Po0.001 versus normal. Brinkman index could not be calculated due to lack of precise information in 81 subjects.
these individuals. Even with these subjects excluded, the annual declines in FEV1 and %FEV1 among never-smokers were not significantly different according to the severity of AFO (Table 5A); however, similar to the results presented in Fig. 2, the annual declines in FEV1 and %FEV1 among smokers with mild AFO were greater than those of smokers with moderate AFO and smokers without AFO, respectively (Table 5B).
4.
Discussion
In this study, the annual decline in FEV1 relative to AFO was evaluated in a Japanese general population. In accordance with our hypothesis, the annual declines in FEV1 and %FEV1 were most rapid among smokers with mild AFO. This suggests that the milder the AFO, the greater the impact of smoking on the respiratory function deterioration in smokers. To date, insufficient evidence has been accumulated regarding the annual deterioration of respiratory function among COPD patients with mild AFO. We considered that annual deterioration in respiratory function might be the largest among COPD patients with mild AFO. Although all individuals with AFO in this study may not have been COPD patients, the results of this study call for a review of conventional dogma.
Tantucci et al. reported that the annual decline in FEV1 was 40 mL/year in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 COPD, 47–79 mL/year in GOLD2, 56–59 mL/year in GOLD3, and o 35 mL/year in GOLD4 [8]. In the present study, the median FEV1 change was 34.3 mL/ year in the normal respiratory function group, -42.1 mL/year in those with mild AFO, 30.0 mL/year in those with moderate AFO, and -15.0 mL/year in those with severe AFO. Thus, in the present study, the decline in FEV1 was greatest in subjects with mild AFO. In particular, these changes in subjects with mild AFO were significantly greater in smokers than in never-smokers (Fig. 3). Since Japanese individuals are smaller in size and have smaller lung capacities than Westerners, it is difficult to compare these data directly with the data of Tantucci et al. [8]. At the very least, the annual decline in FEV1 among Japanese subjects seems to be greatest among smoking individuals with mild AFO. In this study, we measured deterioration in pulmonary function not only by changes in the absolute FEV1 value, but also by changes in %FEV. In many previous papers, annual deterioration of pulmonary function in patients with COPD was evaluated based on the absolute value of FEV1 [2,8,22]. However, the biological damage associated with a certain absolute amount of deterioration of FEV1 would differ depending on an individual's physical size and lung capacity.
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Fig. 3 – Annual changes in forced expiratory volume in 1 s (FEV1) and FEV1 percent predicted (%FEV1) relative to smoking habit according to the severity of airflow obstruction (AFO). Box-and-whisker plots show annual changes of FEV1 (A) and % FEV1 (B) relative to the habit of cigarette smoking in normal (left), mild AFO (center), and moderate AFO (right). Boxes show interquartile ranges of the values’ lines within the boxes show the median values. Whiskers show the range of nonoutliers. Plots show the outliers. *P o 0.05 in the Wilcoxon test.
Fig. 4 – Changes in the presence of airflow obstruction (AFO) in subjects in the initial study (2004–2006) through the follow-up study (2011) relative to smoking status. Among subjects without AFO in the initial study, 5.4% of neversmokers and 20.5% of ever-smokers had AFO in the 2011 follow-up study. Among subjects with AFO in the initial study, most ever-smokers had airflow obstruction in 2011, but 43.3% of never-smokers did not.
Therefore, it is reasonable to use %FEV1 when comparing deterioration of FEV1 over time, adjusting for the influence of factors such as age, sex, and physique. Additionally, in the comparison using %FEV1, the annual decline in pulmonary function was most significant among smokers with mild AFO. Previous reports have shown that the decline in pulmonary function is accelerated by smoking [1]. In this study, it was also shown that the change in pulmonary function of individuals with normal pulmonary function and mild AFO was significantly accelerated by smoking. This result indicates that impairment of the respiratory system caused by
smoking is more pronounced in the earlier stages, and it is more likely that development of the disease can be prevented by intervention at an early stage. The pulmonary function of COPD patients has been shown to improve with smoking cessation [23]. In addition, tiotropium inhalation has been shown to inhibit declining FEV1 over time among COPD patients under 50 years of age, as well as GOLD2 COPD patients [4–6]. Recently, the impact of exacerbation on declining FEV1 has been shown to be greatest in COPD patients with mild AFO [24], and tiotropium inhalation has been demonstrated to inhibit declining postbronchodilator FEV1, reduce the risk of exacerbation, and be more effective than placebo in terms of the modified Medical Research Council score and COPD assessment test score in early stage COPD patients [25]. We assume that the prognosis will be further improved by identifying COPD patients at an earlier stage and by performing earlier treatment intervention using bronchodilators such as tiotropium. Unfortunately, in many countries, COPD is left undiagnosed and untreated [26]. Pulmonary function testing at the time of medical checkup can be expected to lead to the earliest identification of patients with COPD. However, pulmonary function testing on all subjects at the time of medical checkup would require a large budget, which may be difficult to achieve. Therefore, effective screening tests using COPD questionnaires should be conducted, and spirometry should be performed in the clinic on those who give a positive response on the questionnaires [27]. In addition, it is necessary to encourage
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Table 5 – Annual changes in forced expiratory volume in 1 s (FEV1) and FEV1 percent predicted (%FEV1) relative to the severity of airflow obstruction (AFO) in the cohort of never-smoking (A) and smoking subjects (B), excluding those who had AFO in the initial examination (2004–2006), but not in the follow-up examination (2011). A. Never-smokers
Annual change in FEV1, mL/year Annual change in %FEV1, %/year
Normal (n ¼534)
Mild AFO (n ¼8)
Moderate AFO (n ¼8)
30.7 ( 50.0 to 15.7) 0.34 ( 1.06 to 0.38)
26.4 ( 81.3 to 1.07) 0.42 ( 3.31 to 0.89)
36.4 ( 48.1 to 28.2) 0.86 ( 1.66 to 0.32)
B. Smokers
Annual change in FEV1, mL/year Annual change in %FEV1, %/year
Normal (n¼ 229)
Mild AFO (n ¼ 20)
Moderate AFO (n ¼19)
41.6 ( 60.0 to 24.3)a 0.46 ( 1.15 to 0.09)n
56.4 ( 85.7 to 37.1) 1.21 ( 2.36 to 0.41)
30.0 ( 65.7 to 8.6)n 0.58 ( 2.32 to 0.77)
Thirteen never-smokers and three smokers who had AFO in the initial study, but not in the follow-up study, were excluded from this analysis because those subjects might have had asthma. n Po0.05 versus mild AFO. a P¼ 0.09 versus mild AFO.
individuals to understand the deterioration of personal health and the social burden of diseases related to COPD. Lange and colleagues demonstrated that low FEV1 in early life stages is associated with the development of COPD, and that an accelerated decline in FEV1 is not always observed in patients with COPD [28]. In the Childhood Asthma Management Program trial, bronchial asthma in adolescents was shown to be a risk factor for developing COPD in the future [29]. Therefore, impairment of pulmonary development is thought to be an important factor in the pathogenesis of COPD. As shown in Figs. 2 and 3 of the present study, some smokers with AFO may exhibit an annual decline in FEV1 similar to subjects with normal pulmonary functions. In addition, among 75 subjects with AFO in the initial study, 30 were never-smokers, and 13 subjects did not have AFO in 2011 (Fig. 4). Some of these subjects may have had asthma. Although our study period was not as long as that of the study by Lange et al., asthma may be an important pathogenic factor for AFO in never-smokers. There are limitations to the present study. First, the decline in FEV1 was calculated from the difference between pulmonary function test measurements at two time points. This study was based on the annual health check, and pulmonary function testing is not a routine examination in the Japanese annual health checkup system; thus, pulmonary function tests could not be performed frequently due to a limited research budget. Second, although 838 subjects were enrolled in this analysis, the number of subjects with AFO was small. However, this study is valuable, as the subjects were recruited from a general Japanese population. Third, the results of the present study may not be applicable to nonJapanese individuals due to ethnic differences. Fourth, information on the history of cigarette smoking may not be precise in some subjects. In annual health checkups based on a self-reported questionnaire, it was difficult to acquire precise information on the history of cigarette smoking. Some ever-smoking subjects did not completely answer questions
on their daily consumption of cigarettes and the age at beginning or quitting smoking. In particular, some quitters wrongly declared themselves as never-smokers, because they had not been smoking at that time. Finally, precise information regarding medication was not available in this study. Few subjects were treated with bronchodilators in 2004 2006, but significantly more number of subjects with moderate AFO may have received this treatment in 2011, since tiotropium became available in 2004. In addition, many symptomatic subjects with moderate AFO may have quit smoking during the study period, since the percentage of smokers in Japan significantly decreased between 2004 and 2011 [30].
5.
Conclusion
In this study, the annual decline in FEV1 may be most significant in smokers with mild AFO in a Japanese general population. This result may emphasize the importance of early identification of COPD patients among the general population in order to prevent disease progression in undiagnosed patients.
Acknowledgements We thank Taiko Aita and Emiko Nakamura (Yamagata University) for their contributions and excellent assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Funding Global Centers of Excellence Program of the Japan Society for the Promotion of Science (15K09240).
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Conflict of interests Yoko Shibata: Lecture fees, Boehringer Ingelheim Japan,
[16]
AstraZeneca Japan; research funding, Novartis Pharma. Other authors declare no competing interests.
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Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Original article
Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study Kento Satoa, Yoko Shibataa,b,n, Sumito Inouea, Akira Igarashia, Yoshikane Tokairina, Keiko Yamauchia, Tomomi Kimuraa, Takako Nemotoa, Masamichi Satoa, Hiroshi Nakanoa, Hiroyoshi Machidaa, Michiko Nishiwakia, Maki Kobayashia, Sujeong Yanga, Yukihiro Minegishia, Kodai Furuyamaa, Tomoka Yamamotoa, Tetsu Watanabea, Tsuneo Kontaa, Yoshiyuki Uenoc, Takeo Katoc, Takamasa Kayamac, Isao Kubotaa a Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan b Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, 1 Hikariga-Oka, Fukushima 960-1295, Japan c Global Center of Excellence Program Study Group, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan
art i cle i nfo
ab st rac t
Article history:
Background: Few studies are available regarding the annual decline of forced expiratory
Received 25 August 2017
volume in 1 s (FEV1) in chronic obstructive pulmonary disease patients with mild airflow obstruction. This study sought to clarify to what extent cigarette-smoking individuals with mild airflow obstruction lose pulmonary function annually.
Abbreviations: AFO, airflow obstruction; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; JRS, Japanese Respiratory Society; LAMA, long-acting muscarinic antagonist n Corresponding author at: Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, 1 Hikariga-Oka, Fukushima 960-1295, Japan. Fax: þ81 24 548 9366. E-mail addresses: [email protected] (K. Sato), [email protected] (Y. Shibata), [email protected] (S. Inoue), [email protected] (A. Igarashi), [email protected] (Y. Tokairin), [email protected] (K. Yamauchi), [email protected] (T. Kimura), [email protected] (T. Nemoto), [email protected] (M. Sato), [email protected] (H. Nakano), [email protected] (H. Machida), [email protected] (M. Nishiwaki), [email protected] (M. Kobayashi), [email protected] (S. Yang), [email protected] (Y. Minegishi), [email protected] (K. Furuyama), [email protected] (T. Yamamoto), [email protected] (T. Watanabe), [email protected] (T. Konta), [email protected] (Y. Ueno), [email protected] (T. Kato), [email protected] (T. Kayama), [email protected] (I. Kubota). https://doi.org/10.1016/j.resinv.2017.11.011 2212-5345/& 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Received in revised form
Methods: From 2004 to 2006, pulmonary function tests were performed on people 440
15 November 2017
years of age, during the annual health checkup held in Takahata, Yamagata, Japan (initial
Accepted 24 November 2017
study population, n ¼3253). In 2011, pulmonary function tests were performed again on participants who agreed to undergo reexamination (follow-up study population, n ¼838).
Keywords: Airflow obstruction Annual health check Chronic obstructive pulmonary disease (COPD) Smoking FEV1
Results: Smokers have decreased pulmonary function in terms of percent forced vital capacity (FVC), %FEV1, and FEV1/FVC; the stages of airflow obstruction were also more severe in smokers than never-smokers. The annual decline in FEV1 was significantly greater in smokers than in never-smokers. The median annual decline in FEV1 was most significant in individuals with mild airflow obstruction. The annual decline in FEV1 was greater in smokers with mild airflow obstruction than in smokers with moderate airflow obstruction. In analyzing the decline in %FEV1, the annual change in smokers with mild airflow obstruction was greater than that in smokers with normal spirometric values. Conclusion: The annual decline in FEV1 was most significant in smokers with mild airflow obstruction in a Japanese general population. This highlights the importance of early detection of chronic obstructive pulmonary disease patients among the general population in order to prevent disease progression in undiagnosed patients. & 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. The most important risk factor for COPD is inhalation of cigarette smoke. Epidemiological studies have demonstrated that a decline in pulmonary function such as forced expiratory volume in 1 s (FEV1) was more rapid in continuous smokers than in never-smokers or intermittent smokers, in the general population [1]. As COPD treatment by bronchodilator inhalation has improved, COPD outcomes have also improved [2,3]. Clinical trials of long-acting muscarinic antagonists (LAMAs) and LAMAs plus long-acting beta agonists in COPD have demonstrated reduction of symptoms such as dyspnea, exacerbation, and mortality in patients with COPD who have moderate to very severe airflow obstruction (AFO) [2,3]. Additionally, subgroup analysis in the Understanding Potential Long-Term Impacts on Function with Tiotropium study demonstrated that tiotropium significantly reduced the decline in FEV1 in COPD patients with moderate AFO, those without receiving other maintenance therapies, or those aged 50 years or less [4–6]. Since most clinical trials did not include COPD patients with mild AFO, there was no evidence regarding the clinical benefits of treating COPD patients with mild AFO. COPD patients with mild AFO have fewer symptoms and less frequent exacerbations than patients with moderate or severe AFO. Therefore, most of these patients remain undiagnosed and untreated, and keep smoking cigarettes [7]. Previously, Tantucci et al. reported that the most rapid decline in FEV1 was observed in COPD patients with moderate AFO, based on a summary of data from numerous clinical trials; however, observations of the decline in FEV1 in COPD patients with mild AFO are rarely reported [8]. Therefore, the impact of cigarette smoke inhalation on patients with early stage COPD has not yet been fully clarified. In Japan, the prevalence of COPD is estimated at about 8% in the population aged 40 years or older [9]. We also demonstrated that the prevalence of AFO was 10.6% in the general
population of Takahata, Yamagata, Japan [10]. Most subjects with abnormal spirometry findings have remained undiagnosed and untreated for respiratory disorders, and many of them smoke cigarettes. We hypothesized that the impact of cigarette smoke inhalation on subjects with mild AFO is greater than on those with moderate to severe AFO. This study aimed to test this hypothesis.
2.
Materials and methods
2.1.
Study population
The Yamagata–Takahata study formed part of the Molecular Epidemiological Study of the Regional Characteristics of the 21st Century Centers of Excellence Program and the Global Centers of Excellence Program in Japan [10–19]. The Ethics Committee of Yamagata University School of Medicine approved this study (approval date, December 21, 2009; approval number, H21-131), and written informed consent was provided by all participants. The study used data from an annual community health checkup in which all residents of Takahata (a town in Japan) aged 40 years or older were invited to participate. From 2004 to 2006, 3520 subjects were enrolled in the study and received initial spirometric examinations. Altogether, 264 subjects and 3 subjects were excluded from the analysis because their spirometry data did not meet the specified criteria and because of refusal of the follow-up examination, respectively (initial study population, n ¼3253). In 2011, 873 subjects among the initial study population agreed to undergo spirometry again [15]. One subject was excluded due to an error in spirometry measurements. Since forced vital capacity (FVC) o80% indicated the presence of restrictive ventilation disorders, such as interstitial pneumonias, we also excluded 34 subjects with FVC o 80% and FEV1/FVCZ0.7. Finally, data from 838 subjects were used for the analysis (follow-up study population) [15]. The subjects’ medical histories, smoking
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Table 1 – Characteristics of the initial study population and follow-up study population during 2004–2006.
Age, years Male sex, % Body mass index, kg/m2 Ever-smoker, % Brinkman index, cigarette years %FVC %FEV1 FEV1/FVC, % Airflow obstruction, % Non/mild/moderate/severe History of respiratory diseases, % Respiratory medication, %
Initial population (n ¼ 3253)
Follow-up population (n ¼ 838)
P
62.3710.4 46.1 23.573.2 35.6 0 (0–200) 98.7714.6 97.8716.5 78.677.8 10.4 89.6/4.2/5.0/1.1 2.5 0.7
60.378.8 46.4 23.472.9 32.7 0 (0–50) 101.0712.0 100.2714.2 78.976.9 8.9 91.1/4.3/4.2/0.5 2.3 0.4
o0.0001 0.87 0.595 0.116 0.102 o 0.0001 o 0.0001 0.314 0.217 0.274 0.71 0.33
Table 2 – Subjects’ characteristics relative to smoking status during 2004–2006.
Age, years Male sex, % Body mass index, kg/m2 Brinkman index, cigarette years %FVC %FEV1 FEV1/FVC, % Airflow obstruction, % Non/mild/moderate/severe History of respiratory diseases, % Respiratory medication, %
Never smokers (n ¼ 564)
Smokers (n ¼ 274)
P
60.078.8 25.50 23.473.1 0 101.8711.8 102.1713.6 80.276.0 5.3 96.7/2.7/2.4/0.18 1.2 0.3
61.178.9 89.4 23.472.7 600 (400–900) 99.5712.4 96.3714.7 76.277.9 16.4 83.6/7.7/7.7/1.1 4.4 0.4
0.085 o 0.0001 0.941 o 0.0001 0.008 o 0.0001 o 0.0001 o 0.0001 o 0.0001 0.004 0.981
habits, current use of medications, and clinical symptoms were documented using a self-reported questionnaire. However, details regarding diagnosis of respiratory diseases (such as COPD and asthma) and respiratory medications (such as bronchodilators or inhaled corticosteroids) were not available. The lifetime consumption of cigarettes was expressed according to the Brinkman index (number of cigarettes per day years of smoking) [19]. Asthma-like features could not be evaluated due to the lack of information on blood eosinophil count, serum immunoglobulin E levels, and fractional exhaled nitric oxide [20].
2.2.
Measurements
Spirometric parameters (FVC and FEV1) were measured using standard techniques, with subjects performing FVC maneuvers on a CHESTAC-25 part II EX instrument (Chest Corp., Tokyo, Japan) according to the guidelines of the Japanese Respiratory Society (JRS) [21]. A bronchodilator was not administered prior to spirometry. The highest value of at least 3 FVC maneuvers by each subject was used for the analysis. The results were assessed by 2 pulmonary physicians who visually inspected the flow-volume curves and excluded subjects with inadequate data as defined by the JRS criteria [21]. The presence of AFO was determined by prebronchodilator FEV1/FVC o 0.7. Subsequently, the severity of AFO was assessed as the percentage of the predicted value of FEV1 as follows: mild, FEV1% predicted Z80; moderate,
50rFEV1% predicted o 80; severe, FEV1% predicted o 50. The annual changes in %FEV1 (%/year) were calculated as ([value of 2011 spirometry – value of initial spirometry] / value of initial spirometry) 100 / time between observations (years) [14–16].
2.3.
Statistical analyses
For continuous variables, data are presented as the mean 7 standard deviation or median (interquartile range). Chisquare tests were performed to evaluate differences in proportion. Student's t-test and Wilcoxon's rank-sum test were performed for parametric and nonparametric comparisons of two groups, respectively. One-way analysis of variance and SteelDwass tests were performed for parametric and nonparametric multiple comparisons, respectively. Statistical significance was inferred for two-sided P-values o 0.05. All statistical analyses were performed using JMP version 11 software (SAS Institute Inc., Cary, NC, USA).
3.
Results
The characteristics of the subjects in the initial and follow-up studies are shown in Table 1. The follow-up population was younger and had better pulmonary function than the initial population. Therefore, subjects who were older and had poorer pulmonary functions in the initial population appeared to
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Fig. 1 – Annual change in forced expiratory volume in 1 s (FEV1) and FEV1 percent predicted (%FEV1) relative to smoking status. Spirometry was first performed from 2004 to 2006 in a Japanese general population. In 2011, spirometry was performed again in this study population. The annual changes in FEV1 (A) and %FEV1 (B) are shown relative to smoking status.
Table 3 – Subjects’ characteristics relative to the severity of airflow obstruction (AFO) during 2004–2006.
Age, years Male sex, % Body mass index, kg/m2 Brinkman index, cigarette years Never-smokers, % History of respiratory diseases, % Respiratory medication, %
Normal (n ¼ 763)
Mild AFO (n ¼ 36)
Moderate AFO (n ¼ 35)
Severe AFO (n ¼ 4)
P
59.978.7 43.90 23.573.0 0 (0–0) 70.0 1.7 0.3
62.279.4 63.9 22.372.5 50 (0–700)* 41.7 5.6 0.0
66.677.5 80 23.072.7 500 (0–855)* 40.0 11.4 2.9
69.577.1 75 23.775.4 525 (0–1050) 25.0 0.0 0.0
o 0.0001 o 0.0001 o 0.0001 o 0.0001 o 0.0001 0.001 0.090
*Po0.001 versus normal.
avoid undergoing reexamination (Table 1). In the follow-up study, smokers were more likely to be male and to have poorer pulmonary functions than never-smokers, while age and body mass index were not different between smokers and neversmokers (Table 2). The percentage of subjects who had a history of respiratory diseases was significantly greater among smokers than among never-smokers, while the percentage of the subjects who had received respiratory medications was not different between never-smokers and smokers in this study (Table 2). The annual decline in FEV1 of smokers was larger than that of never-smokers, although the annual decline in %FEV1 of smokers tended to be larger than that of never-smokers; however, the difference did not reach statistical significance (Fig. 1). Subjects were older, were more likely to be male, were thinner, were more exposed to cigarette smoke, and fewer were never-smokers according to the severity of AFO (Table 3). In addition, the percentage of subjects who had received respiratory medication was very low, even among those with mild and severe AFO (Table 3). As shown in Table 3, the number of subjects with severe AFO was not sufficient for meaningful analysis (n ¼ 4), and these subjects were excluded from subsequent analyses. Fig. 2 shows the annual declines in FEV1 and %FEV1 relative to the severity of AFO (Fig. 2A and C). The annual declines in FEV1 and %FEV1
among never-smokers were not significantly different according to the severity of AFO (Fig. 2B and D, left). However, annual declines in FEV1 and %FEV1 in smokers were significantly different among groups (Fig. 2B and D, right). Post hoc analyses revealed that the annual declines in FEV1 and % FEV1 of smokers with mild AFO were greater than those of smokers with moderate AFO and smokers without AFO, respectively. Although the amount of cigarette smoke exposure was greater in smokers with moderate AFO than in smokers without AFO, the amount of cigarette smoke exposure in smokers with mild AFO was not greater than that in other smokers (Table 4). Declines in FEV1 and %FEV1 of smokers were significantly greater than those of never-smokers among subjects with no AFO or mild AFO (Fig. 3). In contrast, the declines in FEV1 and %FEV1 among subjects with moderate AFO did not differ significantly between smokers and never-smokers. Among subjects without AFO in the initial study, 5.4% of neversmokers and 20.5% of ever-smokers had AFO in the 2011 follow-up study (Fig. 4). Among subjects with airflow obstruction in the initial study, most of the ever-smokers had AFO in 2011, but 43.3% of never-smokers did not (Fig. 4). As some subjects with AFO in the initial study, but not in the follow-up study, might have had asthma, we also compared the annual change in FEV1 among subjects, excluding
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Fig. 2 – Annual changes in forced expiratory volume in 1 s (FEV1) and FEV1 percent predicted (%FEV1) relative to the severity of airflow obstruction (AFO) in the cohort overall, never-smoking, or smoking subjects. Box-and-whisker plots show annual changes in FEV1 (A) and %FEV1 (C) relative to the severity of AFO. In addition, these changes in FEV1 (B) and %FEV1 (D) are separately demonstrated for never-smokers (B, left and D, left) and smokers (B, right and D, right). Boxes show interquartile ranges of the values; lines in the boxes show the median values. Whiskers show the range of nonoutliers. Plots show the outliers. P values for the Wilcoxon test are shown in the figures. *P o 0.05 in post hoc analysis using the SteelDwass test. Table 4 – Amount of cigarette consumption relative to the severity of airflow obstruction (AFO) in smokers during 2004– 2006.
Brinkman index, cigarette years
Normal, smoker (n ¼ 158)
Mild AFO, smoker (n ¼ 16)
Moderate AFO, smoker (n ¼ 18)
P
600 (393.8–860)
700 (400–930)
820 (693.8–1207.5)*
0.01
*Po0.001 versus normal. Brinkman index could not be calculated due to lack of precise information in 81 subjects.
these individuals. Even with these subjects excluded, the annual declines in FEV1 and %FEV1 among never-smokers were not significantly different according to the severity of AFO (Table 5A); however, similar to the results presented in Fig. 2, the annual declines in FEV1 and %FEV1 among smokers with mild AFO were greater than those of smokers with moderate AFO and smokers without AFO, respectively (Table 5B).
4.
Discussion
In this study, the annual decline in FEV1 relative to AFO was evaluated in a Japanese general population. In accordance with our hypothesis, the annual declines in FEV1 and %FEV1 were most rapid among smokers with mild AFO. This suggests that the milder the AFO, the greater the impact of smoking on the respiratory function deterioration in smokers. To date, insufficient evidence has been accumulated regarding the annual deterioration of respiratory function among COPD patients with mild AFO. We considered that annual deterioration in respiratory function might be the largest among COPD patients with mild AFO. Although all individuals with AFO in this study may not have been COPD patients, the results of this study call for a review of conventional dogma.
Tantucci et al. reported that the annual decline in FEV1 was 40 mL/year in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 COPD, 47–79 mL/year in GOLD2, 56–59 mL/year in GOLD3, and o 35 mL/year in GOLD4 [8]. In the present study, the median FEV1 change was 34.3 mL/ year in the normal respiratory function group, -42.1 mL/year in those with mild AFO, 30.0 mL/year in those with moderate AFO, and -15.0 mL/year in those with severe AFO. Thus, in the present study, the decline in FEV1 was greatest in subjects with mild AFO. In particular, these changes in subjects with mild AFO were significantly greater in smokers than in never-smokers (Fig. 3). Since Japanese individuals are smaller in size and have smaller lung capacities than Westerners, it is difficult to compare these data directly with the data of Tantucci et al. [8]. At the very least, the annual decline in FEV1 among Japanese subjects seems to be greatest among smoking individuals with mild AFO. In this study, we measured deterioration in pulmonary function not only by changes in the absolute FEV1 value, but also by changes in %FEV. In many previous papers, annual deterioration of pulmonary function in patients with COPD was evaluated based on the absolute value of FEV1 [2,8,22]. However, the biological damage associated with a certain absolute amount of deterioration of FEV1 would differ depending on an individual's physical size and lung capacity.
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Fig. 3 – Annual changes in forced expiratory volume in 1 s (FEV1) and FEV1 percent predicted (%FEV1) relative to smoking habit according to the severity of airflow obstruction (AFO). Box-and-whisker plots show annual changes of FEV1 (A) and % FEV1 (B) relative to the habit of cigarette smoking in normal (left), mild AFO (center), and moderate AFO (right). Boxes show interquartile ranges of the values’ lines within the boxes show the median values. Whiskers show the range of nonoutliers. Plots show the outliers. *P o 0.05 in the Wilcoxon test.
Fig. 4 – Changes in the presence of airflow obstruction (AFO) in subjects in the initial study (2004–2006) through the follow-up study (2011) relative to smoking status. Among subjects without AFO in the initial study, 5.4% of neversmokers and 20.5% of ever-smokers had AFO in the 2011 follow-up study. Among subjects with AFO in the initial study, most ever-smokers had airflow obstruction in 2011, but 43.3% of never-smokers did not.
Therefore, it is reasonable to use %FEV1 when comparing deterioration of FEV1 over time, adjusting for the influence of factors such as age, sex, and physique. Additionally, in the comparison using %FEV1, the annual decline in pulmonary function was most significant among smokers with mild AFO. Previous reports have shown that the decline in pulmonary function is accelerated by smoking [1]. In this study, it was also shown that the change in pulmonary function of individuals with normal pulmonary function and mild AFO was significantly accelerated by smoking. This result indicates that impairment of the respiratory system caused by
smoking is more pronounced in the earlier stages, and it is more likely that development of the disease can be prevented by intervention at an early stage. The pulmonary function of COPD patients has been shown to improve with smoking cessation [23]. In addition, tiotropium inhalation has been shown to inhibit declining FEV1 over time among COPD patients under 50 years of age, as well as GOLD2 COPD patients [4–6]. Recently, the impact of exacerbation on declining FEV1 has been shown to be greatest in COPD patients with mild AFO [24], and tiotropium inhalation has been demonstrated to inhibit declining postbronchodilator FEV1, reduce the risk of exacerbation, and be more effective than placebo in terms of the modified Medical Research Council score and COPD assessment test score in early stage COPD patients [25]. We assume that the prognosis will be further improved by identifying COPD patients at an earlier stage and by performing earlier treatment intervention using bronchodilators such as tiotropium. Unfortunately, in many countries, COPD is left undiagnosed and untreated [26]. Pulmonary function testing at the time of medical checkup can be expected to lead to the earliest identification of patients with COPD. However, pulmonary function testing on all subjects at the time of medical checkup would require a large budget, which may be difficult to achieve. Therefore, effective screening tests using COPD questionnaires should be conducted, and spirometry should be performed in the clinic on those who give a positive response on the questionnaires [27]. In addition, it is necessary to encourage
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Table 5 – Annual changes in forced expiratory volume in 1 s (FEV1) and FEV1 percent predicted (%FEV1) relative to the severity of airflow obstruction (AFO) in the cohort of never-smoking (A) and smoking subjects (B), excluding those who had AFO in the initial examination (2004–2006), but not in the follow-up examination (2011). A. Never-smokers
Annual change in FEV1, mL/year Annual change in %FEV1, %/year
Normal (n ¼534)
Mild AFO (n ¼8)
Moderate AFO (n ¼8)
30.7 ( 50.0 to 15.7) 0.34 ( 1.06 to 0.38)
26.4 ( 81.3 to 1.07) 0.42 ( 3.31 to 0.89)
36.4 ( 48.1 to 28.2) 0.86 ( 1.66 to 0.32)
B. Smokers
Annual change in FEV1, mL/year Annual change in %FEV1, %/year
Normal (n¼ 229)
Mild AFO (n ¼ 20)
Moderate AFO (n ¼19)
41.6 ( 60.0 to 24.3)a 0.46 ( 1.15 to 0.09)n
56.4 ( 85.7 to 37.1) 1.21 ( 2.36 to 0.41)
30.0 ( 65.7 to 8.6)n 0.58 ( 2.32 to 0.77)
Thirteen never-smokers and three smokers who had AFO in the initial study, but not in the follow-up study, were excluded from this analysis because those subjects might have had asthma. n Po0.05 versus mild AFO. a P¼ 0.09 versus mild AFO.
individuals to understand the deterioration of personal health and the social burden of diseases related to COPD. Lange and colleagues demonstrated that low FEV1 in early life stages is associated with the development of COPD, and that an accelerated decline in FEV1 is not always observed in patients with COPD [28]. In the Childhood Asthma Management Program trial, bronchial asthma in adolescents was shown to be a risk factor for developing COPD in the future [29]. Therefore, impairment of pulmonary development is thought to be an important factor in the pathogenesis of COPD. As shown in Figs. 2 and 3 of the present study, some smokers with AFO may exhibit an annual decline in FEV1 similar to subjects with normal pulmonary functions. In addition, among 75 subjects with AFO in the initial study, 30 were never-smokers, and 13 subjects did not have AFO in 2011 (Fig. 4). Some of these subjects may have had asthma. Although our study period was not as long as that of the study by Lange et al., asthma may be an important pathogenic factor for AFO in never-smokers. There are limitations to the present study. First, the decline in FEV1 was calculated from the difference between pulmonary function test measurements at two time points. This study was based on the annual health check, and pulmonary function testing is not a routine examination in the Japanese annual health checkup system; thus, pulmonary function tests could not be performed frequently due to a limited research budget. Second, although 838 subjects were enrolled in this analysis, the number of subjects with AFO was small. However, this study is valuable, as the subjects were recruited from a general Japanese population. Third, the results of the present study may not be applicable to nonJapanese individuals due to ethnic differences. Fourth, information on the history of cigarette smoking may not be precise in some subjects. In annual health checkups based on a self-reported questionnaire, it was difficult to acquire precise information on the history of cigarette smoking. Some ever-smoking subjects did not completely answer questions
on their daily consumption of cigarettes and the age at beginning or quitting smoking. In particular, some quitters wrongly declared themselves as never-smokers, because they had not been smoking at that time. Finally, precise information regarding medication was not available in this study. Few subjects were treated with bronchodilators in 2004 2006, but significantly more number of subjects with moderate AFO may have received this treatment in 2011, since tiotropium became available in 2004. In addition, many symptomatic subjects with moderate AFO may have quit smoking during the study period, since the percentage of smokers in Japan significantly decreased between 2004 and 2011 [30].
5.
Conclusion
In this study, the annual decline in FEV1 may be most significant in smokers with mild AFO in a Japanese general population. This result may emphasize the importance of early identification of COPD patients among the general population in order to prevent disease progression in undiagnosed patients.
Acknowledgements We thank Taiko Aita and Emiko Nakamura (Yamagata University) for their contributions and excellent assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Funding Global Centers of Excellence Program of the Japan Society for the Promotion of Science (15K09240).
Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011
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Conflict of interests Yoko Shibata: Lecture fees, Boehringer Ingelheim Japan,
[16]
AstraZeneca Japan; research funding, Novartis Pharma. Other authors declare no competing interests.
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Please cite this article as: Sato K, et al. Impact of cigarette smoking on decline in forced expiratory volume in 1 s relative to severity of airflow obstruction in a Japanese general population: The Yamagata–Takahata study. Respiratory Investigation (2017), https://doi.org/10.1016/j.resinv.2017.11.011