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ORIGINAL ARTICLE

Relationship between Habit of Cigarette Smoking

and Airflow Limitation in Healthy Japanese

Individuals: The Takahata Study

Daisuke Osaka 1, Yoko Shibata 1, Shuichi Abe 1, Sumito Inoue 1, Yoshikane Tokairin 1,

Akira Igarashi 1, Keiko Yamauchi 1, Tomomi Kimura 1, Michiko Sato 1, Hiroyuki Kishi 1,

Noriaki Takabatake 1, Makoto Sata 1, Tetsu Watanabe 1, Tsuneo Konta 1, Sumio Kawata 2,

Takeo Kato 3 and Isao Kubota 1

Abstract

Background Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation.

The prevalence of airflow limitation in Japan is 10.9% (16.4% of males and 5.0% of females). Cigarette

smoking is well known as a major cause of COPD. However, few epidemiological studies have evaluated the

effects of cigarette smoking on pulmonary function in healthy subjects.

Methods Subjects aged 40 years or older (n=2,917), who had participated in a community-based annual

health check in Takahata, Japan, from 2004 through 2005, were enrolled in the study. The smoking histories

of these subjects were investigated using a self-reported questionnaire. Forced vital capacity (FVC), forced

expiratory volume in 1 second (FEV1), and forced expiratory flow at 25-75% of FVC (FEF25-75) were mea-

sured by standard procedures using spirometric machines.

Results There were 554 current smokers (18.6%) and 403 former smokers (13.8%). The prevalence of air-

flow limitation defined by FEV1/FVC


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Inter Med 49: 1489-1499, 2010 DOI: 10.2169/internalmedicine.49.3364

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countries, air pollution resulting from the burning of wood

and other biomass fuels has been identified as an additional

risk factor for COPD (2, 3).

Spirometry is a useful tool to diagnose and evaluate the

severity of respiratory disease. A forced vital capacity (FVC)

maneuver can be used to evaluate the condition of the air-

ways. Vital capacity (VC) and forced expiratory volume in 1second (FEV1) are clinical markers for respiratory disease. A

percent predicted VC (%VC) value of less than 80% indi-

cates restrictive disease of the lung, while a FEV1/FVC ratio

of less than 70% is indicative of airflow limitation (4). Also,

forced expiratory flow at 25-75% of FVC (FEF25-75) is

known to be a parameter which correlates well with the total

amount of inhaled cigarette smoke in patients with

COPD (5, 6). In these patients, age and the initial value of

FEV1 were the most reliable predictors of death (7). There-

fore, it is necessary to perform pulmonary function tests in

order to diagnose and treat COPD. However, pulmonary

function testing is not widely performed even for current

heavy smokers, and many COPD patients remain undiag-

nosed (8-13).

The prevalence of airflow limitation in Japanese people

aged 40 years or older is reported to be 10.9% (16.4% of

males and 5.0% of females) (14). Cigarette smoking is well

known to be a major cause of COPD. However, there are

only a few reports of cohort studies that have evaluated the

impact of cigarette smoking on airflow limitation (15-17). In

this study, we evaluated the pulmonary function tests of

Japanese individuals who participated in a community-based

annual health check in Takahata, Yamagata. Predictive equa-tions for FVC, FEV1 and FEF25-75 were derived from never

smoking subjects in this study. Age-related changes in %

FVC, percent predicted FEV1 (%FEV1) and percent pre-

dicted FEF25-75 (%FEF25-75) were cross-sectionally compared

between non-smokers and smokers, in order to perform an

epidemiological assessment of the effect of cigarette smok-

ing on pulmonary function.

Methods

Study populationThis study formed part of the Molecular Epidemiological

Study utilizing the Regional Characteristics of 21st Century

Centers of Excellence (COE) Program and the Global COE

Program in Japan. Details of the study methodology have

been described elsewhere (18). The study was approved by

the institutional ethics committee and all participants gave

written informed consent.

This study utilized a community-based annual health

check, in which all inhabitants of Takahata town (total

population 26,026) in northern Japan, who were aged 40

years or older, were invited to participate. This region has aresident population of 15,222 adults aged 40 years or older

(7,109 males and 8,113 females). From June 2004 through

November 2005, 1,380 males and 1,735 females (total

3,165) participated in the program and agreed to enroll in

the study. However, due to incomplete data 248 subjects

were excluded from the analysis. Data for a total of 2,917

subjects (1,325 males, 1,592 females) was entered into the

final statistical analysis.

Subjects used a self-reported questionnaire to document

their medical histories, current medications and clinicalsymptoms. Current, former or never smokers were catego-

rized according to the responses on the self-reported ques-

tionnaire. Subjects who categorized themselves as never

smokers despite indicating the number of cigarettes smoked

per day or the number of years of smoking were categorized

as former smokers.

Lung function measurements

FVC, FEV1 and FEF25-75 were measured using standard

spirometric techniques, with subjects performing FVC ma-

neuvers on a CHESTAC-25 part II EX instrument (Chest

Corp., Tokyo, Japan) under guideline of the Japanese Respi-

ratory Society (JRS) (19). Bronchodilator was not adminis-

tered prior to measurements. The highest value from at least

three FVC maneuvers by each subject was used for the

analysis. Two pulmonary physicians assessed the results of

flow-volume curves by visual inspection, and they excluded

subjects with poor studied data according to JRS crite-

ria (19).

Subjects with an FEV1/FVC ratio


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Table 1.Comparison of the Baseline Characteristics between Men

and Women

All subjects Men Women

Number 2917 1325 1592

Age (years) 62.8 10.2 63.3 10.3 62.5 10.1

Height (cm) 156.8 9.0 163.5 6.9 151.2 6.2 **

Weight (kg) 57.9 10.3 62.8 10.0 53.9 8.6 **

BMI (kg/m2) 23.5 3.2 23.5 3.0 23.6 3.4

Never smoker, n (%) 1970 (67.5%) 513 (38.7%) 1457 (91.5%) **

Current smoker, n (%) 544 (18.6%) 452 (34.1%) 92 (5.8%) **

Former smoker, n (%) 403 (13.8%) 360 (27.2%) 43 (2.7%) **

Positive for the history of

pulmonary diseases, n (%)

64 (2.2%) 46 (3.5%) 18 (1.1%) **

BMI: body mass index, **: p < 0.001 v.s. Men

Results

Baseline characteristics of the participants

The baseline characteristics of the 2,917 subjects whose

data was entered into final analysis are shown in Table 1.

The mean age was 62.8 years, and there were 554 current

smokers (18.6%) and 403 former smokers (13.8%). The pro-

portion of smokers was higher among males than females.

2.2% subjects had medical history of pulmonary diseases

(male: 3.5%, female: 1.1%). However, the rate of prior diag-

nosed bronchial asthma or COPD patients in this populationwas unknown, because the self-reported questionnaire did

not ask the detail of pulmonary diseases.

Age, gender, smoking history and pulmonary func-

tion

The relationships between age and the absolute values of

FVC, FEV1 and FEF25-75 are demonstrated in Fig. 1. Absolute

values of FVC, FEV1 and FEF25-75 declined with age in both

never-smokers and former/current-smokers. However, the

rates of decline of FEV1 and FEF25-75 in males, and FVC,

FEV1 and FEF25-75 in females were significantly greater in

the former/current-smoker group than in the never-smoker

group. In contrast, the difference in the rates of decline in

FVC between smoking and non-smoking male subjects did

not reach statistical significance.

Because absolute values of FVC, FEV1 and FEF25-75 were

not adjusted for age or body size of the subjects, we at-

tempted to compare the age-related changes in FVC, FEV1

and FEF25-75 using standardized values for these parameters.

Predictive equations for reference values of FVC, FEV1 and

FEF25-75 based on the age, height (HT) and body weight

(BW) of the subject were derived from never-smoking sub-

jects by backward stepwise, multiple linear regression analy-sis (Table 2). The equations for the spirometric parameters

derived from this study are indicated in Table 2. The equa-

tions for FVC and FEV1 were correlated with those of

JRS (24): FVC (male), R = 0.992, SEE = 0.070; FVC (fe-

male), R = 0.999, SEE = 0.013; FEV1 (male), R = 0.996,

SEE = 0.040; FEV1 (female), R = 0.998, SEE = 0.024.

Predictive equations for FVC, FEV1 and FEF25-75 were also

derived for male smoking subjects, using backward step-

wise, multiple linear regression analysis. However, it was

not possible to derive equations for female smokers due to

the small number of these subjects. The equations for male

smokers were: FVC (male smoker) = - 1.4425 - (0.0329

age) + (0.043 HT), R2 = 0.543, SEE = 0.520; FEV1 (male

smoker) = 0.6852 - (0.0371 age) + (0.0245 HT) +

(0.0052 BW), R2 = 0.555, SEE = 0.477; and FEF25-75

(male smoker) = 5.26 - (0.0613 age) + (0.0168 BW), R

2

= 0.355, SEE = 0.982.

Prevalence of airflow limitation

The data for the prevalence of airflow limitation defined

by FEV1/FVC


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Figure 1.Age-related changes in spirometric parameters in the Takahata population. Graphs

show the relationships between age and FVC (A, males; B, females), FEV1(C, males; D, females)

and FEF25-75(E, males; F, females). Open circles indicate never smokers and closed circles,former/current smokers. Dashed line indicates the regression for never smokers and solid line, the

regression for former/current smokers. The difference in the slopes of the regression lines between

never-smokers and former/current-smokers was compared by analysis of covariance (ANCOVA),

as indicated in the inset. Spirometric parameters declined significantly with age in smokers com-

pared with never-smokers, except for FVC in males.

ANCOVA p=0.1146 ANCOVA p=0.0283

never smoker

former /current smoker

age age

FE

F25-7

5

ANCOVA p


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Table 2.Backward Stepwise, Multiple Linear Regression Analysis

of Spirometric Parameters

Coefficient Standard

error

t p r

age -0.0288 0.0025 -11.57


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Figure 2.Prevalence and severity of airflow limitation in the Takahata population. Graphs show

relationships between FEV1/FVC and %FEV1in males (A) and females (B). The symbols in the

area of less than 70% for FEV1/FVC indicate individuals with airflow limitation. Among these indi

viduals, the severity of airflow limitation was stratified according to the GOLD criteria: mild:%FEV1 80%, moderate: 50% %FEV1


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Table 3.Comparison of the Degree of Airflow Limitation between

Never Smoker and Former/Current Smoker

male female

airflow

limitationnever smoker

former/current

smokernever smoker

former/current

smoker

no 460 (89.7%) 650 (80.1%) 1374 (94.3%) 125 (92.6%)

mild 27 (5.3%) 61 (7.5%) 38 (2.6%) 4 (3.0%)

moderate 19 (3.7%) 80 (9.9%) 39 (2.7%) 5 (3.7%)

severe 6 (1.2%) 19 (2.3%) 6 (0.4%) 1 (0.7%)

very severe 1 (0.2%) 2 (0.3%) 0 (0%) 0 (0%)

In male subjects, the proportion of air flow limitation was significantly different

between never smoker and former/current smoker (chi-square test, p


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Table 5.Comparison of the Prevalence of Airflow Limitation Defined by Lower Limit of Normal

Value between Never Smoker and Former/Current Smoker in Each Generation

(A)Male

age (year)

male 40-49 50-59 60-69 70-

NS SM NS SM NS SM NS SM

FEV1% aLLN 38 (97.4) 104 (98.1) 107 (98.2) 198 (94.7) 178 (95.7) 232 (89.9) 166 (92.7) 196 (82.0)

FEV1% bLLN 1 (2.6) 2 (1.9) 2 (1.8) 11 (5.3) 8 (4.3) 26 (10.1) 13 (7.3) 43 (18.0)

P value vs NS 0.7994 0.1428 0.024 0.0014

(B) female

age (year)

female 40-49 50-59 60-69 70-

NS SM NS SM NS SM NS SM

FEV1% aLLN 142 (98.6) 39 (92.9) 356 (95.4) 52 (96.3) 473 (95.0) 25 (86.2) 417 (94.3) 7 (70.0)

FEV1% bLLN 2 (1.4) 3 (7.1) 17 (4.6) 2 (3.7) 25 (5.0) 4 (13.8) 25 (5.7) 3 (30.0)

P value vs NS 0.0425 0.7761 0.0440 0.0016

Predicted equations of FEV1/FVC (FEV1%) obtained from never smokers in this study are indicated below;

Predicted FEV1% (male) = 85.76 0.112 age, standard error of estimate (SEE) = 7.94, Predicted FEV1%

(female) = 88.77 0.143 age, SEE = 6.38. NS: never smoker, SM: former/current smoker, aLLN: above

lower limit of normal, bLLN: below lower limit of normal, Statistical analysis: chi-square test

Table 6.Relative Risk of Airflow Limitation(A)airflow limitation defined by FEV1/FVC < 0.7

Subject

characteristic (n)Relative risk 95% C.I. p value

Age, years

40 - 49 (331) 1 (reference) - -

50 - 59 (745) 2.28 1.08 4.80 0.025

60 - 69 (971) 4.52 2.26 9.17 < 0.0001

70 - (870) 7.28 3.62 14.65 < 0.0001

Gender

Female (1592) 1 (reference) -

Male (1325) 2.78 2.20 3.50 < 0.0001

Smoking status

Never (1970) 1 (reference) - -

Current (544) 2.74 2.16 3.48 < 0.0001

Former (403) 2.48 1.89 3.25 < 0.0001

Pack-years *

0 (1970) 1 (reference) - -

> 0,


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Figure 3.Age-related changes in standardized spirometric parameters in the Takahata

population. Graphs show the relationships between age and %FVC (A: males, B: females), %FEV1

(C: males, D: females) and %FEF25-75(E: males, F: females), following standardization of the spiro-

metric measurements using predicted values. Open circles indicate never smokers and closed cir-

cles, former/current smokers. Dashed line indicates the regression for never smokers and solid line

the regression for former/current smokers. The difference in the slopes of the regression lines be-

tween never-smokers and former/current-smokers were compared by analysis of covariance (AN-

COVA), as indicated in the inset. Standardized spirometric parameters declined significantly with

age, in smokers compared with never-smokers, except for FVC in males.

130

100

70

40

130

100

70

40

160

130

100

70

40

%

FEV1

%

FVC

never smoker former /current smoker

%

FVC

%

FEV1

%F

EF25-7

5

%F

EF25-7

5

h i

j k

l m

130

100

70

40

300

200

100

300

200

100

0

ANCOVA p=0.2338

age40 50 60 70 80

ANCOVA p=0.0055

ANCOVA p=0.0001 ANCOVA p=0.0004

ANCOVA p


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Figure 4.The effect of cigarette smoking on standardized spirometric parameters in subjects in

the Takahata population. Graphs show the relationships between standardized spirometric pa-

rameters and pack-years of smoking. %FVC (A: males and B: females) and %FEV1(C: males and

D: females) were significantly correlated with pack-years. %FEF25-75was significantly correlated

with pack-years in male subjects (E), but not in female subjects (F).

r=-0.11423p=0.0082

r=-0.16068p=0.0002

r=-0.15623p=0.0003

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exposed to cigarette smoke compared with populations liv-

ing in other areas of Japan. Takahata town has an aging

population, and therefore the age-distribution in the present

study also differed from that of the NICE study (Table 3).

Since the prevalence of airflow limitation is higher in older

persons, this is a possible explanation for the differences in

the severity of airflow limitation between subjects in the

NICE study and those in the present study. This explanation

is partly supported by the report by Omori et al (11). They

demonstrated the prevalence of AFL0.7 on hospital-based

medical check-up in Japanese subjects aged 40-69, and dem-

onstrated the severity of airflow limitation between smokersand nonsmokers according to the age decade of the subjects,

whereas NICE study lacked this analysis. The proportion of

moderate airflow limitation in smokers increased with in-

creasing decades of subjects in their paper, although the pro-

portion of mild airflow limitation in smokers was still the

highest in the subjects aged 60-69 (11).

The annual rate of decline in FEV1 in the Japanese popu-

lation can be estimated from the equation for FEV1 derived

in the present study. In never-smokers, the estimated annual

rate of decline in FEV1 was 28 mL for males and 20 mL for

females, while in male former/current smokers it was 37

mL. Fletcher and Peto investigated the effect of cigarette

smoking on the decline in FEV1 in male workers in Lon-

don (15). Recently, analysis of data from the Framingham

Offspring Cohort also demonstrated that the decline in FEV1was more rapid in smokers than in never-smokers (16). To

date, no epidemiological analysis has been performed on the

impact of cigarette smoking on pulmonary function in the


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Japanese population. This is the first study to demonstrate

the decline in pulmonary function (FEV1, as well as FVC

and FEF25-75) in Japanese subjects, by statistical analysis of

data from spirometric measurements performed as part of a

community-based annual health check.

There are a couple of limitations to this study. Self-

reported questionnaires may not always provide accuratedata, due to misunderstanding of the questionnaire or failure

to accurately recall smoking histories. The questionnaire

asked the existence of history of pulmonary diseases and

current therapy for pulmonary disease, but did not ask the

details. Thus, the prevalence of bronchial asthma or medica-

tion for the disease was not revealed in this questionnaire.

In addition, because the cigarette smoking rate in Japanese

females was low, the number of female subjects enrolled in

this study was only 135 (Table 1). However, despite these

limitations, the study clearly demonstrated the impact of

cigarette smoking on pulmonary function in a Japanese

population.

In conclusion, cigarette smoking enhances the prevalence

of airflow limitation. Cigarette smoking was also shown to

be a factor that correlated with the decline in %FEV1 in

both males and females. The present study clearly demon-

strated that long-term cigarette smoking increases the risk of

airflow limitation in healthy individuals. The findings from

this epidemiological study have demonstrated that early ces-sation of smoking is necessary in order to prevent the devel-

opment of COPD among smokers.

Acknowledgement

We thank Taiko Aita, and Eiji Tsuchida for their excellent

technical assistance.

Funding: This study was supported by a grant-in-aid from the

Global COE program of the Japan Society for the Promotion of

Science and grants-in-aid for Scientific Research from the Minis-

try of Education, Culture, Sports, Science and Technology, Japan

(18590835, 18790530, 19590880, and 20590892).

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