Fig. 2.1
Top 10 cause of death in the world in 2012 (World Health Organization reported COPD as top 3 cause of death in the world in 2012 http://www.who.int/mediacentre/factsheets/fs310/en/)
Fig. 2.2
Top 10 cause of death in Japan in 2013 (Japanese Ministry of Health, Labour and Welfare reported COPD as top 9 cause of death in Japan in 2013. http://www.mhlw.go.jp/toukei/saikin/hw/jinkou/kakutei13/dl/10_h6.pdf)
2.2 Risk Factors of COPD
2.2.1 Cigarette Smoking
It is known that pulmonary function in patients with COPD declines over time due to cigarette smoking [2]. In a recently conducted Framingham cohort study, decline over time in forced expiratory volume in one second (FEV1) was 38.2 mL/year [95 % confidence interval (CI), 33.9–42.6] in male smokers and 23.9 mL/year (95 % CI, 20.9–27.0) in female smokers, while it was 19.6 (95 % CI, 17.1–22.1) and 17.6 (95 % CI, 13.8–21.4) mL/year, respectively, in male and female nonsmokers [3]. In many clinical studies, FEV1 reduction over time was often 50–60 mL/year in untreated patients with COPD [4]. In short, it can be readily assumed that early identification of COPD and early achievement of smoking cessation are critical in individuals with high risk of COPD.
2.2.2 Other Risk Factors
A recent review article indicated that almost half of COPD cases had causes other than cigarette smoking [5]. In addition, an epidemiological study conducted in the USA, the UK, and Spain reported that the prevalence of COPD was about 23 % in nonsmokers [5]. In a regional epidemiological study conducted in Takahata in Yamagata Prefecture, airflow obstruction (FEV1/forced vital capacity (FVC) under 70 %) was found in 10 % overall, 16 % of male, and 6 % of female adults over 40 years old, while nonsmokers accounted for 6 % overall, 8 % of males, and 5 % of females [6]. Although a high percentage of nonsmokers was observed in especially women with airflow obstruction, in fact, almost half of men with airflow obstruction were also nonsmokers. Risk factors for COPD other than habitual cigarette smoking may include genetic predisposition, environmental factors, and social status.
2.2.2.1 Genetic Factors
As for genetically developing COPD, an α1-antitrypsin deficiency is a factor that is well known. However, it is less frequent in Japan, and so it is not sufficient to explain many cases of COPD development in nonsmokers. Recently, results of a genome-wide association study highlighted several disease candidate genes [7]. However, odds ratio having risk allele for developing COPD is not high enough, and a causal relation between disease candidate genes and the development of COPD is far from proven. Thus, disease candidate genes should be considered as one risk factor.
The association of advanced airway hypersensitivity to COPD is also known. In a cohort study conducted in the USA among 3099 subjects over 20 years, patients with asthma had 10 times higher likelihood of symptoms of chronic bronchiolitis and 17 times higher likelihood of progression to pulmonary emphysema [5].
Recently, the contribution of autoimmunity to COPD pathology was reported [8]. The Takahata study investigated the proportion of subjects testing positive for antinuclear antibodies in a regional population [9]. In males, a negative correlation between antinuclear antibodies and FEV1 was observed, and a positive rate of antinuclear antibodies was significantly higher in the severe airflow obstruction group than in the no/weak airflow obstruction group in male nonsmokers (Fig. 2.3). In other words, upregulated autoimmunity was suggested to be a risk factor for developing COPD.
Fig. 2.3
Percentage of positive for antinuclear antibody in male never-smokers: Takahata study (Antinuclear antibody levels were determined by MESACUP ANA EIA kit which can measure antibodies to several connective tissue disease antigens (ACTDA). An ACTDA index ≥20.0 was defined as positive [9]) (*P < 0.05 Chi-square test)
2.2.2.2 Environmental Factors
Occupational Airborne Particles
Occupational exposure to airborne particles can occur in various occupations. Some particles are considered to have a higher risk of developing COPD than cigarette smoking. In addition to tunnel excavation and mining-related inhalation of metallic substances, plastics, rubber, leather, and food may be the source of occupational airborne particles [10].
Air Pollution
Air pollution is roughly divided into indoor and outdoor air pollutants.
Indoor Air Pollutants
When biomass fuel is used, indoor air pollutant levels are much higher than that of the air outside. The indoor use of biomass fuel is less frequent in developed countries, while more than 90 % of individuals in rural areas use biomass fuel in developing countries; thus, half of the world population is burning biomass fuel [11]. The prevalence rate of COPD due to biomass fuel smoke in Turkish women is reported to be 23 % [5].
Wood, charcoal, and coal are used as biomass fuel, resulting in the production of hazardous substances including particulate matter (PM), carbon monoxide, nitrogen dioxide, sulfur dioxide, formaldehyde, polycyclic organic compounds, and acrolein [11]. In one meta-analysis, risk of COPD due to exposure to biomass fuel smoke was 2.44 times higher (95 % CI, 1.9–3.33) in the overall population, 4.30 times higher (95 % CI, 1.85–10.01) in males, 2.73 times higher (95 % CI, 2.28–3.28) in females, 2.31 times higher (95 % CI, 1.41–3.78) in Asian subjects, and 2.56 times higher (95 % CI, 1.71–3.83) in non-Asian subjects [12]. Smoking cigarettes further increases the risk more than 4 times [13]. The use of biomass fuel is associated with an increase in the number of individuals with respiratory symptoms, decrease of pulmonary function, and progression of COPD, and this effect is related to the magnitude of exposure to smoke and the duration of exposure [13].
As for other indoor air-polluting substances, secondary cigarette smoke, nitrogen dioxide, and mold are also reported to be associated with COPD. An increase in passive smoke exposure is associated with increased risk of COPD [14]. In a recent report from Sweden, the prevalence of COPD in nonsmokers was 4.2 % in subjects without passive cigarette smoke exposure, 8.0 % in subjects breathing passive cigarette smoke at home, 8.3 % in subjects with cigarette smoke exposure at their previous workplace, and 14.7 % in subjects with cigarette smoke exposure at home and at both previous and current workplaces [15].
Outdoor Air Pollution
Air-polluting substances are produced with the use of biomass fuel at home, industrial gases, and the exhaust from motor vehicles. Nitrogen dioxide, ozone, and PM are typical substances [16]. Recently, fine PM (PM2.5) blowing in from China has drawn attention as an environmental issue, and its harmful effect on the health of Japanese citizens is concerning. Causality between air pollution and COPD has not been fully elucidated; thus, air pollution is considered to be one of the risk factors for developing COPD. In a cohort study conducted among individuals without diagnosed COPD in Vancouver, Canada, elevation in black carbon concentrations in ambient air was associated with an increase in COPD hospitalizations and COPD mortality during the follow-up period, and exposure to higher levels of wood smoke pollution was associated with an increase in COPD hospitalizations [17]. Moreover, it was reported that in women living less than 100 m from a busy road, COPD was 1.79 times more likely than for women living farther away, as epidemiological data suggesting an association between air pollutants from motor vehicles and COPD [16].
2.2.2.3 Low Socioeconomic Status
Prevalence of COPD patients caused by extreme malnutrition, low intake of antioxidant-rich food, and poor living environment are currently not fully assessed in Japan. It is hard to evaluate this, because groups that have a lower socioeconomic status are less likely to visit medical institutions, and they are more frequently exposed to cigarette smoke.
2.3 Decline in FEV1 in Patients with COPD
A large-scale clinical study reported a greater decline in pulmonary function in patients with COPD in the early stages of airflow obstruction [18]. In addition, a greater decline in pulmonary function was indicated in subjects with milder airflow obstruction in a recent clinical study conducted in subjects with an average age of about 60 years [19]. On the other hand, a clinical study conducted in subjects with an average age of about 50 years revealed a greater decline in pulmonary function in subjects with severe airflow obstruction [20]. This may be because, in natural history of COPD development, a rapid decline in pulmonary function occurs in earlier stage of the disease, and then this decline is slowed once a certain age has been reached partly due to cessation of smoking or reduction of cigarette inhalation per day.
Nishimura et al. reported a decline in pulmonary function in patients with COPD in a Hokkaido COPD cohort study (Japan) [21]. This study indicated that patients with COPD consisted of “pulmonary function sustainers” whose pulmonary function was less likely to deteriorate over time and “pulmonary function decliners” whose pulmonary function did deteriorate over time. In other words, deterioration over time of pulmonary function in patients with COPD may not be uniform. A recent report from Lange et al. also indicated that not all COPD developed because of a rapid decline in FEV1, but individuals whose pulmonary function declined originally in their youth developed COPD through a slow decline in FEV1 due to persistent smoking [22].
2.4 Incidence of COPD
Although the investigative method varies widely among studies, the prevalence rate of COPD is reported to be between 2.8 and 15.7 (1000 person-years) [23]. A report from Japan identified that the prevalence rate per 1000 person-years was 8.1 (95 % CI, 7.3–8.9) in males and 3.1 (95 % CI, 2.4–3.8) in females despite there being few epidemiological studies investigating COPD prevalence rates in Japan [24].
2.5 Prevalence of COPD
The COPD prevalence rate is high globally. The PLATINO study and the BOLD study are studies representative of COPD. In the former study, a positive rate of airflow obstruction after inhalation of a bronchodilator was investigated in several cities in Latin American countries, and positive rates were reported as 7.8–19.4 % [25]. The latter study examined the prevalence rate of stage II or higher COPD in the criteria of Global Initiative for Chronic Obstructive Lung Disease (GOLD) in subjects 40 years or older in Western countries and reported that the prevalence rate was 16.4 %, 8.5 %, and 10.4 % in men, women, and the overall population [26].
In Japan, a positive rate of airflow obstruction in subjects 40 years or older was investigated in the NICE study between September and December 2000 without inhaling bronchodilator. In this study, randomly selected general citizens were enrolled to conform to the population rate by age structure in Japan, and spirometry was performed in 2343 subjects in 35 medical facilities in 18 prefectures. As a result, airflow obstruction was indicated in 16.4 %, 5.0 %, and 10.9 % of males, females, and the overall population [27]. When excluding airflow obstruction due to asthma, the COPD prevalence rate was 8.6–10.9 %.
There are only a few studies reporting prevalence rate of airflow obstruction in regional general populations in Japan. Osaka et al. reported that spirometry (without the use of a bronchodilator) was performed in a regional annual health check in Takahata (hereafter referred to as the Takahata study) from 2004 to 2006 [6]. The Takahata study indicated that the FEV1 percentage predicted decreased with age in cigarette smokers in both males and females (Fig. 2.4). Airflow obstruction was observed in 16.4 % in males, 5.8 % in females, and 10.6 % in overall subjects 40 years or older participating in the regional annual health check [6]. As shown in Fig. 2.5, the prevalence of airflow obstruction increased with age. Airflow obstruction was observed especially in approximately 25 % of males 70 years or older [6]. The prevalence of airflow obstruction in males 70 years or older increased to approximately 35 % when they were former/current smokers [6]. Moreover, the number of patients with moderate to severe airflow obstruction rapidly increased in subjects 50 years or older [6].
