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Cough and environmental air pollution in China
Pulmonary Pharmacology & Therapeutics xxx (2015) 1e5
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Cough and environmental air pollution in China Qingling Zhang, Minzhi Qiu, Kefang Lai, Nanshan Zhong* Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases (Guangzhou Medical University) 151 Yanjiang Road, Guangzhou, Guangdong, 510120, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 October 2015 Accepted 7 October 2015 Available online xxx
With fast-paced urbanization and increased energy consumption in rapidly industrialized modern China, the level of outdoor and indoor air pollution resulting from industrial and motor vehicle emissions has been increasing at an accelerated rate. Thus, there is a significant increase in the prevalence of respiratory symptoms such as coughing, wheezing, and decreased pulmonary function. Experimental exposure research and epidemiological studies have indicated that exposure to particulate matter, ozone, nitrogen dioxide, and environmental tobacco smoke have a harmful influence on development of respiratory diseases and are significantly associated with cough and wheeze. This review mainly discusses the effect of air pollutants on respiratory health, particularly with respect to cough, the links between air pollutants and microorganisms, and air pollutant sources. Particular attention is paid to studies in urban areas of China where the levels of ambient and indoor air pollution are significantly higher than World Health Organization recommendations. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Cough Air pollutants Microorganism Particulate matter (PM) Environmental tobacco smoke (ETS)
1. Introduction With fast-paced urbanization and increased energy consumption in rapidly industrialized China, the level of outdoor and indoor air pollution resulting from industrial and motor vehicle emissions has quickly increased. According to People's Daily Online news, 25 provinces representing nearly half of the country were covered by heavy smog during 2013. There were 104 cities with high levels of pollution that resulted in smog that required military intervention. A recent study suggested that only 24 of 350 districts in China had an average annual concentration of particulate matter PM2.5 less than 10 m g/m3 whereas 166 districts had average annual PM2.5 concentrations greater than 35 m g/m3 (the World Health Organization (WHO) Interim Target 1) [1]. Air pollutants from factories and motor vehicle emissions have drawn special attention with respect to enhancing the prevalence of respiratory diseases and symptoms such as cough. As China's Ministry of Health has shown, there has been significantly increased morbidity and mortality among urban citizens over about the past 20 years [2]. In an animal study, exposure to the same PM2.5 concentrations often present in urban areasled to several adverse airway effects [3]. There are various airway inflammatory and immune responses that are
* Corresponding author. E-mail address: [email protected] (Q. Zhang).
dependent on the airway's response to the particulate chemical matter present in air pollution in urban areas. Evidence suggests that respiratory symptoms among children in northern China are positively associated with high concentrations of ambient air pollution and associations with environmental tobacco smoke (ETS) are greater than those with sulfur dioxide (SO2) and nitrogen dioxide (NO2) [4]. The aim of this review is to discuss the effect of air pollutants on respiratory health, especially cough, the association between air pollutants and microorganisms, and the sources of pollutants, with particular attention paid to studies in urban areas of China. 2. Cough and the effects of particulate matter Particulate matter (PM) differs in magnitude, form particle size, and chemical composition. PM comprises a mix of tiny solid fragments or liquid matter. PM of diameter less than 2.5 mm (PM2.5) makes up an important group of air pollutants that result in smog [5]. PM are divided according to their size, into PM10 (2.5e10 mm), PM2.5 (0.1e2.5 mm), and PM0.1 (<0.1 mm). The largest source of airborne PM is diesel-powered motor vehicle engines [6]. Other sources of PM include factories, power stations, wood and biomass fuel combustion, construction sites, and mining operations. Diesel powered car ownership has recently increased in China. Combustion of diesel fuel produces up to 100 times more particles than gasoline, indicating that diesel smoke may be a chief culprit in the
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increased morbidity owing to respiratory diseases [7]. In particular, PM2.5 and PM0.1 interact with alveolar epithelial cells and pulmonary alveolar macrophages and can directly reach the small airways and pulmonary alveoli. Additionally, nano-sized, ultrafine particles can directly infiltrate pulmonary alveoli and enter the bloodstream, which may produce a harmful effect on different body organs [8]. Controlled indoor exposure of normal subjects to diesel exhaust particles at levels of 200 mg/m3 led to neutrophilic inflammation and neutrophil release [9]. In a study of patients with asthma walking along a congested London street for 2 h, a decline in FEV1 and pulmonary neutrophilic inflammation indicated that these effects were associated with exposure to organic carbon and ultrafine particles [10]. Results from a study of 36 children with asthma who were exposed to air pollution showed a longitudinal association between PM2.5 from indoor and outdoor sources with cough and wheeze symptoms [11]. This study using a hybrid model linked daily signs of cough and wheeze with PM2.5 exposure; the odds ratios with an standard deviation increase in PM2.5 from indoor sources were 1.24 (cough) and 1.63 (wheeze), respectively. Ozone (O3) levels correlated with wheezing, and cough correlated with indoor PM2.5 from ambient sources. Evidence from a crosssectional study investigating the prevalence of irritative symptoms and chronic respiratory symptoms among 109 workers exposed to PM as a result of incense burning in a temple in Taiwan, and 118 unexposed workers in a control group, indicated that chronic cough was common in the exposure group [12]. That study also found that working in a temple increased the risk of acute irritative symptoms of the nose and throat. A study of 108 Swedish mild steel welders exposed to respirable dust (RD), manganese (Mn), and O3 showed that the welders frequently demonstrated job-related symptoms including nasal obstruction (33%), ocular symptoms (28%), and hacking cough (24%) [13]. According to that study, the geometric average exposures to RD and inhaled Mn were 1.3 mg/m3 and 0.08 mg/m3, respectively. Over 50% of Mn concentrations surpassed the occupational exposure limit in Sweden. In 7019 subjects in Switzerland tested at baseline in 1991 and followed up in 2002 and who were exposed to PM10 during the 12 months before each health evaluation, the mean of exposure to PM10 in 2002 was no higher than that in 1991 [14]. The results of that study indicated that symptoms caused by exposure to PM10 were as follows: fewer than 259 subjects had regular cough, fewer than 179 subjects had chronic cough or sputum, and fewer than 137 subjects had wheeze and shortness of breath. Therefore, a decline in particle concentration in Switzerland during the 11-year followup period was beneficial to improving respiratory symptoms among adults. However, in an experiment among children aged 24 months in New York City from 1998 to 2006, increased ambient nickel and vanadium levels were significantly related to wheeze, and increased elemental carbon levels were significantly related to cough during cold and flu season; however, total PM2.5 did not show an association with wheeze or cough [15]. 3. Cough and the effects of ETS and gases There is increasing evidence that exposure to environmental tobacco smoke (ETS) is associated with cough and wheezing among children as well as adults. Chen et al. conducted a survey of children 6e17 years of age with exposure to ETS owing to family members who smoked at home (>20 cigarettes per day) [16]. In children with no history of tonsillectomy or adenoidectomy (T/A), the prevalence of cough among those with 0, 1, and 2 þ family members who smoked was 8.9%, 12.2%, and 14.5%, respectively. In children with histories of T/A, relevant morbidity was 7.0%, 30.2%, and 36.8%, respectively. In comparison with children from nonsmoking families and no history of T/A, the adjusted odds ratio of children with
family members who smoked and a history of T/A was 7.19 (p < 0.001); the odds ratio was only 1.64 (p ¼ 0.11) in children with no T/A history. Therefore, children with family members who smoked were more likely to have a cough than those from nonsmoking families, and a history of tonsillectomy or adenoidectomy increased the apparent influence of ETS exposure on cough. A cross-sectional study, in which 55.8% of teenaged participants (279/500) were exposed to ETS, indicated that there is a strong association between respiratory symptoms and ETS exposure [17]. Nose irritation was seen in 84 of the 279 participants exposed to ETS (p ¼ 0.002). Asthma onset was observed in 38 of 279 exposed participants (p < 0.001). Cough was present in 168 of 279 exposed teens (p ¼ 0.037). Naupathia was seen in 41 of 279 exposed participants (p < 0.001). Lee et al. showed that exposure to ETS with a high concentration of nicotine evoked more intense and lasting airway irritation and cough in nonsmokers than smoke with a lower concentration of nicotine, suggesting that nicotine is the key cause of such respiratory symptoms [18]. An animal study, 43 dogs with chronic cough were classified into two groups (exposed and unexposed to ETS), and cotinine concentrations in peripheral blood were tested using a cutoff value of 0.21 ng/mL [19]. Indexes of airway obstruction in dogs exposed to ETS were far greater than among unexposed dogs. Increased cotinine concentrations in peripheral blood may lead to mild but persistent airflow limitation because nicotine stimulates parasympathetic responses and activates acetylcholine receptors. Therefore, persistent airflow limitation and exacerbation of cough are also suggestive of chemical and physical harm caused by ETS. However, in another study of 115 dogs with cough and 104 controls with symptoms other than cough, with both groups exposed to ETS for over 2 months, most dogs with cough were diagnosed with large airway disease (n ¼ 88; 77%), and 59 were diagnosed with tracheobronchomalacia (51%) [20]. No association was found between coughing and the month (p ¼ 0.239) or season (p ¼ 0.414), and ETS exposure was not a risk factor (p ¼ 0.243). Therefore, the findings of that study suggest that ETS exposure does not lead to exacerbation of cough. Air pollutant gases have a significant association with respiratory symptoms, including cough and wheeze. McLeod et al. demonstrated that exposure to SO2 activated the transient receptor potential vanilloid 1 (TRPV1) receptor in the nodose ganglia. This effect was equivalent to increased sensitivity and cough as a response to capsaicin [21]. Another study showed that there were lower cough thresholds with enhanced exposure to O3 [22]. Belanger et al. studied children with asthma exposed to indoor NO2 at concentrations below the United States Environmental Protection Agency (US EPA) outdoor standard of 53 ug/L [23]. Their results demonstrated increased wheezing, polypnea, and chest distress in study participants. In a cross-sectional study of 10-year-old children, elevated PM10 and carbon dioxide (CO2) levels present during normal daily activities were associated with a dry cough at night, wheezing, and rhinitis in 654 children and acoustic rhinitis in 193 children [24]. Schoolchildren who were exposed to CO2 (>1000 mg/ L) had a high risk of dry cough and rhinitis. A study of 352 infants showed at that in the first year of life, the morbidity of persistent cough, wheezing, and lower airway infection was 6.3%, 26.1% and 30.4%, respectively [25]. With a 10 mg/m3 increment in ambient NO2 concentration, the adjusted odds ratio of persistent cough was 1.40. These study results indicate that when infants are exposed to outdoor air pollution in the first year, the threat of persistent cough is enhanced. Belanger et al. [26] indicated that each 5ug/L increment (based on a threshold of 6 ug/L) in NO2 exposure was associated with a dose-dependent increment in asthma severity including night symptoms, rescue medication use, and wheezing. Children exposed to indoor NO2 at levels below the US EPA outdoor
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standard (53 ug/L) are at risk for enhanced asthma morbidity. 4. Microorganisms and air pollutants More and more evidence suggests that microorganisms are present together with air pollutants, which may exacerbate current respiratory diseases or lead to an increase in morbidity and mortality owing to respiratory or other diseases. Nevas et al. reported Clostridium botulinum type B was isolated from the gut contents of an infant aged 11 weeks who died suddenly, as well as from vacuum cleaner dust found in the infant's home [27]. Genetic similarity was found between the two isolates, demonstrating that dust may act as a carrier of C. botulinum spores, which can cause sudden death owing to infant botulism. In another study, bioaerosols were collected during a dust storm in North Africa and the dust analysed using bacterial 16S rRNA gene sequences [28]. Assessment using 16S rDNA clone libraries revealed the presence of various sporeforming bacteria over 3.3 mm in size and an even greater presence of Actinobacteria and Bacteroidetes than 3.3-mm-sized aerosol particles. A large fraction of the bacteria were found in respirable particles (<3.3 mm), which are associated with human pathogens related to several diseases. Thus, aerosolized bacteria in respirable particles may have significant impacts on human health. Sigaud et al. treated mice with interferon g (IFN-g) aerosol followed by exposure to concentrated ambient particles (CAPs) from urban air, then infected the mice with Streptococcus pneumoniae and evaluated pulmonary innate immune response to the treatments [29]. Their results indicated that the combination of IFN-g and CAPs exposure increased pulmonary inflammation by recruiting more polymorphonuclear granulocytes (PMN) to the lung and enhancing activation of pro-inflammatory cytokine mRNAs. Therefore, combined IFN-g and CAPs exposure lead to alveolar inflammation owing to oxidant stress, resulting in loss of antibacterial function in PMN recruitment and pulmonary alveolar macrophages. Rintala et al. concluded that the bacterial species typically found in indoor dust are complex and mainly Gram-positive [30]. Tiny bacterial particles find excellent refuge inside buildings. There were rate changes of the phyla and species with seasonal variation. Studies have shown that human exposure to bacterial particles is associated with human mortality. Polymenakou et al. concluded that tiny particles act as carriers of respirable bacteria [31]. Breathable bacteria from minute dust particles may pose a vital risk to human health. Whiteside et al. demonstrated significantly less endotoxin in paper bedding than other types of bedding, with the highest endotoxin levels found in corncob and hardwood beddings [32]. The ranges of endotoxin concentration were 1913e4504 endotoxin units per gram (EU/g) in corncob bedding, 3121e5401 EU/g in hardwood bedding, 1586e2416 EU/g in corncobepaper mixed bedding, and less than 5e105 EU/g in paper bedding. Coliform levels ranged from less than 10e7591 colony forming units (cfu)/g in corncob beddings, 90 to 4010 cfu/g in corncobepaper mixed beddings, from less than 10 to 137 cfu/g in hardwood beddings, and less than 10 cfu/g in paper beddings. Mean dust content was less than 0.15% in all bedding types. A survey by Maier et al. revealed that the dominant bacteria have a significant correlation with asthma, proving that the microorganisms typically present in households may play an important part in the development of childhood asthma [33]. Sordillo et al. conducted a study of microorganisms from bedding and household dust, which indicated that sweeping the house no less than once a week was associated with a drop in gram-negative and gram-positive bacteria as well as fungi [35]. The presence of dogs or cats in the home was associated with increased household bacteria or fungi. Leski et al. found latent human pathogenic bacteria from desert dust in Kuwait and Iraq, including Clostridium perfringens,
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Bacillus, Mycobacterium, Brucella, and Coxiella burnetii [34]. C. burnetii acts as a primary and infectious latent pathogen that infects humans primarily via airborne transmission. Hogerwerf et al. detected C. burnetii DNA in respirable PM10 dust from three goat farms, demonstrating that low levels of C. burnetii are carried by breathable particulates [36]. Davis et al. made a first report of cultivating MSSA (methicillinesusceptible Staphylococcus aureus) and MRSA (methicillin-resistant S. aureus) from dust in the homes of children with asthma. Of 19 samples, two from room surfaces and three from pillows contained MRSA. Of 19 samples from pillows, MSSA was found in four [37]. S. aureus was detected in seven of eight pillow samples from eight children's homes. Johanssonet et al. found highly concentrated streptomycetes in household dust, which has a significant association with a decline in exhaled nitric oxide levels among children with asthma (p < 0.001) but not among healthy children [38]. Veillette et al. highlighted that dust from vacuum cleaners acted as a vehicle of indoor moulds and bacteria associated with human diseases originating from bioaerosol exposure [39]. Adhikari et al. suggested an association between bacterial levels from household dust and short- and long-term indoor mould contamination. However, only mould that was present had a correlation with air bacterial levels. [40]. Cao et al. indicated that PM2.5 samples taken during periods of severe smog in Beijing consisted of archaeal, viral, eukaryotic, and bacterial reads (0.8%, 0.1%, 13.0% and 86.1%, respectively), whereas these percentages in PM10 samples were 0.8%, 0.1%,18.3% and 80.8%, respectively [41]. In sum, increasing evidence suggests that air pollutants acting as carriers for microorganisms in indoor and outdoor environments produce substantial impacts on human health. 5. Air pollution and human health in China With fast-paced urbanization and increased energy consumption in modern, industrialized China, levels of outdoor and indoor air pollution resulting from industrial and motor vehicle emissions are increasing rapidly, as is the proportion of urban population, increasing from 18% in 1978 to 52% in 2012. As a major air pollutant, concentrations of PM2.5 in urban areas of China are far larger than in rural areas. According to one study, only 24 of 350 districts in China had an annual PM2.5 concentration less than 10 m g/m3, whereas there were 166 districts with annual PM2.5 concentrations over the WHO Interim Target-1 of 35 m g/m3 [1]. Districts with high PM2.5 levels were in southeastern Sichuan, in a belt from Tianjin to southern Hebei, throughout northeastern Henan, eastern Shandong, northeastern Anhui, Jiangsu Province, and Shanghai. There were 223 of 350 districts with DPM2.5 (DPM2.5 ¼ urban PM2.5 e non-urban PM2.5) levels ranging between 0 and 10 m g/m3, whereas there only 41 districts with DPM2.5 below 0 g/m3, mainly in western China (except for Langfang), Jiaxing, and Zhuhai. There were 85 districts with DPM2.5 levels greater than 10 mg/m3, which were divided into two belts. One was from northern Hebei and Beijing, through Shanxi Province, northwestern Henan, and southern Shaanxi, eventually ending in southeastern Sichuan (the BeijingeSichuan belt). The second belt was from Shanghai, through Zhejiang Province, southern Anhui, Hunan and Jiangxi, ending in Guangxi and Guangdong provinces (the ShanghaieGuangdong belt). The DPM2.5 level of the BeijingeSichuan belt was far larger than that of the ShanghaieGuangdong belt. Another study in Beijing showed the average level of PM2.5 in 20 indoor public locations was 3346 ± 3863 mg/m3, ranging between 6 mg/m3 and 1956 mg/m3 (750.6 ± 521.6 mg/m3 in karaoke bars, 317.9 ± 235.3 mg/m3 in restaurants, 157.5 ± 98.5 mg/m3 in cyber cafes, and 116.9 ± 1001 mg/m3 in bath houses) [42]. The PM2.5 levels in restaurants and karaoke bars were far higher than those in the other two locations. In the
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same study, indoor and outdoor monitoring sites in Beijing indicated the mean level of indoor PM2.5 was 87.76 mg/m3, which was lower than that of outdoor PM2.5 (128.79 mg/m3). Indoor PM2.5 levels during smog periods were higher than mean levels of indoor PM2.5. Indoor PM2.5 during periods with fireworks was higher than that during Chinese New Year and mean indoor PM2.5 levels. High concentrations of PM2.5 are a major factor in the development of haze and also of respiratory diseases or other diseases. Evidence from Guangzhou suggests that there have been more deaths during haze periods, which have lasted an average of 278 days each year, than deaths during non-haze periods, owing especially to respiratory and cardiovascular illnesses [43]. Zhan et al. indicated that there was a vital, concentration-dependent correlation between daily mortality and PM10 in Taiyuan [44]. The threshold level of total mortality was 85 mg/m3, whereas that of cancer mortality 89.59 mg/m3. The threshold level of cardiovascular, cerebrovascular, and respiratory mortality was 122.54 mg/m3. Another study of mortality in Shenyang, China revealed that there was a 10 mg/m3 increase of mean annual PM10 levels, resulting in 55% increased risk of death caused by cardiovascular disease [45]. Adjusted hazard ratios for cardiovascular mortality with a 10 mg/ m3 increment of NO2 was 2.46, whereas this was 2.44 for cerebrovascular mortality. Another study indicated a strong association between PM10, CO, and NO2 and daily mortality owing to respiratory diseases in Beijing [46]. In a study among 6730 Chinese children aged 3e7 years from 50 kindergartens in seven northeastern cities of China, Liu et al. calculated 3-year levels of PM10, SO2, and NO2 [47]. These authors found the morbidity of respiratory symptoms was far greater among children who lived in these locations near a busy road, close to a factory or industrial chimney, and also in children who had a coal-burning device or recent renovations in their home, or who had family members who smoked at home. In that study, PM10 had an association with constant cough and sputum and onset of allergic rhinitis in girls. However, associations between respiratory symptoms and PM10, SO2, and NO2 were not significant in boys. In 2007, the average daily levels of NO2, PM10 and SO2 in Guangzhou, China were 61.04, 82.51, and 51.67 mg/m3, respectively, A positive correlation was found with premature births in the city, with a mean increase in infants born prematurely of 21.47 [48]. A survey across the 18 regions in Liaoning Province showed TSP levels ranging from 188 to 689 mg/m3, SO2 from 14 to 140 mg/m3, and NO2 levels from 29 to 94 mg/m3 [49]. Increases in the prevalence of constant cough (21e28%), constant sputum (21e30%), and asthma (39e56%) were found to be associated with increments in levels of those air pollutants (172 mg/m3 for TSP, 69 mg/m3 for SO2, and 30 mg/m3 for NO2). Thus, a concentrationrelated relationship was found between outdoor air pollutants in this northeastern Chinese province and respiratory symptoms among children, of which the relationship with TSP was more pronounced than that with SO2 and NO2. Wang et al. also suggested a long-term effect between ambient air pollutants and morbidity owing to respiratory symptoms among adults in Beijing [50]. A study in Shenyang indicated that indoor air pollution presented a high risk for asthma among children [51]. Limits to sources of air pollutants can improve indoor and ambient air quality and can also reduce mortality owing to respiratory or other diseases. Evidence suggests there is a drop in concentrations of indoor air pollutants when key measures are taken, which include restricting exposure to outdoor air pollutants, reducing indoor sources of air pollutants, and implementing policies to improve indoor and outdoor air quality [52]. During the 2008 Olympic Games, hourly and daily levels of CO, PM10, NO2, and O3 were in accord with the China National Ambient Air Quality Standards because traffic limits measures were taken to reduce traffic-associated air pollution in urban areas [53]. During the 16th
Asian Games, air quality in Guangzhou also improved significantly as a result of controls placed on vehicle exhaust, industrial emissions, and biomass combustion [54]. Carrying out such measures could result in significant decreases in the prevalence and mortality owing to respiratory or other diseases as well as significant reductions in the social costs of air pollution. 6. Conclusion There is increasing evidence to suggest that air pollutants including PM, ozone, nitrogen dioxide, and ETS have harmful effects on human respiratory health. Studies from China as well as other countries have demonstrated that high concentrations of both indoor and outdoor air pollutants lead to cough and other respiratory symptoms as well as an increase in mortality. Air pollutants as carriers of pathogenic microorganisms lead to exacerbation of respiratory diseases and increased morbidity. Recent studies have indicated that air pollutant concentrations, especially of PM2.5 in urban areas of China, are significantly higher than WHO standards, resulting in aggravation of respiratory symptoms and asthma and higher mortality. Limiting exposure to outdoor air pollutants, eliminating the sources of indoor air pollutants, and instating governmental policies to reduce overall air pollutant levels can lead to greater improvement in outdoor and indoor air quality. In addition, efficacious preventive measures and treatments must be found to adequately address the health effects of environmental air pollution in China. Conflict of interest The authors declare no conflict of interest. Acknowledgements We are grateful to Prof. Kian Fan Chung who is the honorary professor of Guangzhou Institute of Respiratory Diseases, Guangzhou Medical University, China for his helpful discussions and amending on this paper. Qingling Zhang is supported by a grant from State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, China. References [1] Lijian Han, Weiqi Zhou, Weifeng Li, b Li Li, Impact of urbanization level on urban air quality: a case of fine particles (PM 2.5 ) in Chinese cities, Environ. Pollut. 194 (2014), 163e170. [2] Yinping Zhang, Jinhan Mo, Charles J. Weschler, Reducing health risks from indoor exposures in rapidly developing urban China, Environ. Health Perspect. 121 (2013) 751e755. [3] P. Zhang, G. Dong, B. Sun, L. Zhang, X. Chen, et al., Long-term exposure to ambient air pollution and mortality due to cardiovascular disease and cerebrovascular disease in Shenyang, China, PLoS One 6 (6) (2011) e20827. [4] Guowei Pan, Shujuan Zhang, Yiping Feng, Ken Takahashi, et al., Air pollution and children's respiratory symptoms in six cities of Northern China, Respir. Med. 104 (2010) 1903e1911. [5] J.G. Watson, Visibility: science and regulation, J. Air Waste Manag. Assoc. 52 (2002) 628e713. n, C. Janson, B. Jarvholm, B. Forsberg, Vehicle exhaust outside [6] L. Modig, K. Tore the home and onset of asthma among adults, Eur. Respir. J. 33 (2009) 1261e1267. [7] Suh-Young Lee, Yoon-Seok Chang, Sang-Heon Cho, Allergic diseases and air pollution, Asia Pac. Allergy 3 (2013) 145e154. [8] A. Nemmar, P.H. Hoet, B. Vanquickenborne, et al., Passage of inhaled particles into the blood circulation in humans, Circulation 105 (2002) 411e414. [9] J.A. Nightingale, R. Maggs, P. Cullinan, et al., Airway inflammation after controlled exposure to diesel exhaust particulates, Am. J. Respir. Crit. Care Med. 162 (2000) 161e166. [10] J. McCreanor, P. Cullinan, M.J. Nieuwenhuijsen, et al., Respiratory effects of exposure to diesel traffic in persons with asthma, N. Engl. J. Med. 357 (2007) 2348e2358. [11] R. Habre, E. Moshier, W. Castro, A. Nath, A. Grunin, A. Rohr, J. Godbold,
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Cough and environmental air pollution in China Qingling Zhang, Minzhi Qiu, Kefang Lai, Nanshan Zhong* Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases (Guangzhou Medical University) 151 Yanjiang Road, Guangzhou, Guangdong, 510120, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 October 2015 Accepted 7 October 2015 Available online xxx
With fast-paced urbanization and increased energy consumption in rapidly industrialized modern China, the level of outdoor and indoor air pollution resulting from industrial and motor vehicle emissions has been increasing at an accelerated rate. Thus, there is a significant increase in the prevalence of respiratory symptoms such as coughing, wheezing, and decreased pulmonary function. Experimental exposure research and epidemiological studies have indicated that exposure to particulate matter, ozone, nitrogen dioxide, and environmental tobacco smoke have a harmful influence on development of respiratory diseases and are significantly associated with cough and wheeze. This review mainly discusses the effect of air pollutants on respiratory health, particularly with respect to cough, the links between air pollutants and microorganisms, and air pollutant sources. Particular attention is paid to studies in urban areas of China where the levels of ambient and indoor air pollution are significantly higher than World Health Organization recommendations. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Cough Air pollutants Microorganism Particulate matter (PM) Environmental tobacco smoke (ETS)
1. Introduction With fast-paced urbanization and increased energy consumption in rapidly industrialized China, the level of outdoor and indoor air pollution resulting from industrial and motor vehicle emissions has quickly increased. According to People's Daily Online news, 25 provinces representing nearly half of the country were covered by heavy smog during 2013. There were 104 cities with high levels of pollution that resulted in smog that required military intervention. A recent study suggested that only 24 of 350 districts in China had an average annual concentration of particulate matter PM2.5 less than 10 m g/m3 whereas 166 districts had average annual PM2.5 concentrations greater than 35 m g/m3 (the World Health Organization (WHO) Interim Target 1) [1]. Air pollutants from factories and motor vehicle emissions have drawn special attention with respect to enhancing the prevalence of respiratory diseases and symptoms such as cough. As China's Ministry of Health has shown, there has been significantly increased morbidity and mortality among urban citizens over about the past 20 years [2]. In an animal study, exposure to the same PM2.5 concentrations often present in urban areasled to several adverse airway effects [3]. There are various airway inflammatory and immune responses that are
* Corresponding author. E-mail address: [email protected] (Q. Zhang).
dependent on the airway's response to the particulate chemical matter present in air pollution in urban areas. Evidence suggests that respiratory symptoms among children in northern China are positively associated with high concentrations of ambient air pollution and associations with environmental tobacco smoke (ETS) are greater than those with sulfur dioxide (SO2) and nitrogen dioxide (NO2) [4]. The aim of this review is to discuss the effect of air pollutants on respiratory health, especially cough, the association between air pollutants and microorganisms, and the sources of pollutants, with particular attention paid to studies in urban areas of China. 2. Cough and the effects of particulate matter Particulate matter (PM) differs in magnitude, form particle size, and chemical composition. PM comprises a mix of tiny solid fragments or liquid matter. PM of diameter less than 2.5 mm (PM2.5) makes up an important group of air pollutants that result in smog [5]. PM are divided according to their size, into PM10 (2.5e10 mm), PM2.5 (0.1e2.5 mm), and PM0.1 (<0.1 mm). The largest source of airborne PM is diesel-powered motor vehicle engines [6]. Other sources of PM include factories, power stations, wood and biomass fuel combustion, construction sites, and mining operations. Diesel powered car ownership has recently increased in China. Combustion of diesel fuel produces up to 100 times more particles than gasoline, indicating that diesel smoke may be a chief culprit in the
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increased morbidity owing to respiratory diseases [7]. In particular, PM2.5 and PM0.1 interact with alveolar epithelial cells and pulmonary alveolar macrophages and can directly reach the small airways and pulmonary alveoli. Additionally, nano-sized, ultrafine particles can directly infiltrate pulmonary alveoli and enter the bloodstream, which may produce a harmful effect on different body organs [8]. Controlled indoor exposure of normal subjects to diesel exhaust particles at levels of 200 mg/m3 led to neutrophilic inflammation and neutrophil release [9]. In a study of patients with asthma walking along a congested London street for 2 h, a decline in FEV1 and pulmonary neutrophilic inflammation indicated that these effects were associated with exposure to organic carbon and ultrafine particles [10]. Results from a study of 36 children with asthma who were exposed to air pollution showed a longitudinal association between PM2.5 from indoor and outdoor sources with cough and wheeze symptoms [11]. This study using a hybrid model linked daily signs of cough and wheeze with PM2.5 exposure; the odds ratios with an standard deviation increase in PM2.5 from indoor sources were 1.24 (cough) and 1.63 (wheeze), respectively. Ozone (O3) levels correlated with wheezing, and cough correlated with indoor PM2.5 from ambient sources. Evidence from a crosssectional study investigating the prevalence of irritative symptoms and chronic respiratory symptoms among 109 workers exposed to PM as a result of incense burning in a temple in Taiwan, and 118 unexposed workers in a control group, indicated that chronic cough was common in the exposure group [12]. That study also found that working in a temple increased the risk of acute irritative symptoms of the nose and throat. A study of 108 Swedish mild steel welders exposed to respirable dust (RD), manganese (Mn), and O3 showed that the welders frequently demonstrated job-related symptoms including nasal obstruction (33%), ocular symptoms (28%), and hacking cough (24%) [13]. According to that study, the geometric average exposures to RD and inhaled Mn were 1.3 mg/m3 and 0.08 mg/m3, respectively. Over 50% of Mn concentrations surpassed the occupational exposure limit in Sweden. In 7019 subjects in Switzerland tested at baseline in 1991 and followed up in 2002 and who were exposed to PM10 during the 12 months before each health evaluation, the mean of exposure to PM10 in 2002 was no higher than that in 1991 [14]. The results of that study indicated that symptoms caused by exposure to PM10 were as follows: fewer than 259 subjects had regular cough, fewer than 179 subjects had chronic cough or sputum, and fewer than 137 subjects had wheeze and shortness of breath. Therefore, a decline in particle concentration in Switzerland during the 11-year followup period was beneficial to improving respiratory symptoms among adults. However, in an experiment among children aged 24 months in New York City from 1998 to 2006, increased ambient nickel and vanadium levels were significantly related to wheeze, and increased elemental carbon levels were significantly related to cough during cold and flu season; however, total PM2.5 did not show an association with wheeze or cough [15]. 3. Cough and the effects of ETS and gases There is increasing evidence that exposure to environmental tobacco smoke (ETS) is associated with cough and wheezing among children as well as adults. Chen et al. conducted a survey of children 6e17 years of age with exposure to ETS owing to family members who smoked at home (>20 cigarettes per day) [16]. In children with no history of tonsillectomy or adenoidectomy (T/A), the prevalence of cough among those with 0, 1, and 2 þ family members who smoked was 8.9%, 12.2%, and 14.5%, respectively. In children with histories of T/A, relevant morbidity was 7.0%, 30.2%, and 36.8%, respectively. In comparison with children from nonsmoking families and no history of T/A, the adjusted odds ratio of children with
family members who smoked and a history of T/A was 7.19 (p < 0.001); the odds ratio was only 1.64 (p ¼ 0.11) in children with no T/A history. Therefore, children with family members who smoked were more likely to have a cough than those from nonsmoking families, and a history of tonsillectomy or adenoidectomy increased the apparent influence of ETS exposure on cough. A cross-sectional study, in which 55.8% of teenaged participants (279/500) were exposed to ETS, indicated that there is a strong association between respiratory symptoms and ETS exposure [17]. Nose irritation was seen in 84 of the 279 participants exposed to ETS (p ¼ 0.002). Asthma onset was observed in 38 of 279 exposed participants (p < 0.001). Cough was present in 168 of 279 exposed teens (p ¼ 0.037). Naupathia was seen in 41 of 279 exposed participants (p < 0.001). Lee et al. showed that exposure to ETS with a high concentration of nicotine evoked more intense and lasting airway irritation and cough in nonsmokers than smoke with a lower concentration of nicotine, suggesting that nicotine is the key cause of such respiratory symptoms [18]. An animal study, 43 dogs with chronic cough were classified into two groups (exposed and unexposed to ETS), and cotinine concentrations in peripheral blood were tested using a cutoff value of 0.21 ng/mL [19]. Indexes of airway obstruction in dogs exposed to ETS were far greater than among unexposed dogs. Increased cotinine concentrations in peripheral blood may lead to mild but persistent airflow limitation because nicotine stimulates parasympathetic responses and activates acetylcholine receptors. Therefore, persistent airflow limitation and exacerbation of cough are also suggestive of chemical and physical harm caused by ETS. However, in another study of 115 dogs with cough and 104 controls with symptoms other than cough, with both groups exposed to ETS for over 2 months, most dogs with cough were diagnosed with large airway disease (n ¼ 88; 77%), and 59 were diagnosed with tracheobronchomalacia (51%) [20]. No association was found between coughing and the month (p ¼ 0.239) or season (p ¼ 0.414), and ETS exposure was not a risk factor (p ¼ 0.243). Therefore, the findings of that study suggest that ETS exposure does not lead to exacerbation of cough. Air pollutant gases have a significant association with respiratory symptoms, including cough and wheeze. McLeod et al. demonstrated that exposure to SO2 activated the transient receptor potential vanilloid 1 (TRPV1) receptor in the nodose ganglia. This effect was equivalent to increased sensitivity and cough as a response to capsaicin [21]. Another study showed that there were lower cough thresholds with enhanced exposure to O3 [22]. Belanger et al. studied children with asthma exposed to indoor NO2 at concentrations below the United States Environmental Protection Agency (US EPA) outdoor standard of 53 ug/L [23]. Their results demonstrated increased wheezing, polypnea, and chest distress in study participants. In a cross-sectional study of 10-year-old children, elevated PM10 and carbon dioxide (CO2) levels present during normal daily activities were associated with a dry cough at night, wheezing, and rhinitis in 654 children and acoustic rhinitis in 193 children [24]. Schoolchildren who were exposed to CO2 (>1000 mg/ L) had a high risk of dry cough and rhinitis. A study of 352 infants showed at that in the first year of life, the morbidity of persistent cough, wheezing, and lower airway infection was 6.3%, 26.1% and 30.4%, respectively [25]. With a 10 mg/m3 increment in ambient NO2 concentration, the adjusted odds ratio of persistent cough was 1.40. These study results indicate that when infants are exposed to outdoor air pollution in the first year, the threat of persistent cough is enhanced. Belanger et al. [26] indicated that each 5ug/L increment (based on a threshold of 6 ug/L) in NO2 exposure was associated with a dose-dependent increment in asthma severity including night symptoms, rescue medication use, and wheezing. Children exposed to indoor NO2 at levels below the US EPA outdoor
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standard (53 ug/L) are at risk for enhanced asthma morbidity. 4. Microorganisms and air pollutants More and more evidence suggests that microorganisms are present together with air pollutants, which may exacerbate current respiratory diseases or lead to an increase in morbidity and mortality owing to respiratory or other diseases. Nevas et al. reported Clostridium botulinum type B was isolated from the gut contents of an infant aged 11 weeks who died suddenly, as well as from vacuum cleaner dust found in the infant's home [27]. Genetic similarity was found between the two isolates, demonstrating that dust may act as a carrier of C. botulinum spores, which can cause sudden death owing to infant botulism. In another study, bioaerosols were collected during a dust storm in North Africa and the dust analysed using bacterial 16S rRNA gene sequences [28]. Assessment using 16S rDNA clone libraries revealed the presence of various sporeforming bacteria over 3.3 mm in size and an even greater presence of Actinobacteria and Bacteroidetes than 3.3-mm-sized aerosol particles. A large fraction of the bacteria were found in respirable particles (<3.3 mm), which are associated with human pathogens related to several diseases. Thus, aerosolized bacteria in respirable particles may have significant impacts on human health. Sigaud et al. treated mice with interferon g (IFN-g) aerosol followed by exposure to concentrated ambient particles (CAPs) from urban air, then infected the mice with Streptococcus pneumoniae and evaluated pulmonary innate immune response to the treatments [29]. Their results indicated that the combination of IFN-g and CAPs exposure increased pulmonary inflammation by recruiting more polymorphonuclear granulocytes (PMN) to the lung and enhancing activation of pro-inflammatory cytokine mRNAs. Therefore, combined IFN-g and CAPs exposure lead to alveolar inflammation owing to oxidant stress, resulting in loss of antibacterial function in PMN recruitment and pulmonary alveolar macrophages. Rintala et al. concluded that the bacterial species typically found in indoor dust are complex and mainly Gram-positive [30]. Tiny bacterial particles find excellent refuge inside buildings. There were rate changes of the phyla and species with seasonal variation. Studies have shown that human exposure to bacterial particles is associated with human mortality. Polymenakou et al. concluded that tiny particles act as carriers of respirable bacteria [31]. Breathable bacteria from minute dust particles may pose a vital risk to human health. Whiteside et al. demonstrated significantly less endotoxin in paper bedding than other types of bedding, with the highest endotoxin levels found in corncob and hardwood beddings [32]. The ranges of endotoxin concentration were 1913e4504 endotoxin units per gram (EU/g) in corncob bedding, 3121e5401 EU/g in hardwood bedding, 1586e2416 EU/g in corncobepaper mixed bedding, and less than 5e105 EU/g in paper bedding. Coliform levels ranged from less than 10e7591 colony forming units (cfu)/g in corncob beddings, 90 to 4010 cfu/g in corncobepaper mixed beddings, from less than 10 to 137 cfu/g in hardwood beddings, and less than 10 cfu/g in paper beddings. Mean dust content was less than 0.15% in all bedding types. A survey by Maier et al. revealed that the dominant bacteria have a significant correlation with asthma, proving that the microorganisms typically present in households may play an important part in the development of childhood asthma [33]. Sordillo et al. conducted a study of microorganisms from bedding and household dust, which indicated that sweeping the house no less than once a week was associated with a drop in gram-negative and gram-positive bacteria as well as fungi [35]. The presence of dogs or cats in the home was associated with increased household bacteria or fungi. Leski et al. found latent human pathogenic bacteria from desert dust in Kuwait and Iraq, including Clostridium perfringens,
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Bacillus, Mycobacterium, Brucella, and Coxiella burnetii [34]. C. burnetii acts as a primary and infectious latent pathogen that infects humans primarily via airborne transmission. Hogerwerf et al. detected C. burnetii DNA in respirable PM10 dust from three goat farms, demonstrating that low levels of C. burnetii are carried by breathable particulates [36]. Davis et al. made a first report of cultivating MSSA (methicillinesusceptible Staphylococcus aureus) and MRSA (methicillin-resistant S. aureus) from dust in the homes of children with asthma. Of 19 samples, two from room surfaces and three from pillows contained MRSA. Of 19 samples from pillows, MSSA was found in four [37]. S. aureus was detected in seven of eight pillow samples from eight children's homes. Johanssonet et al. found highly concentrated streptomycetes in household dust, which has a significant association with a decline in exhaled nitric oxide levels among children with asthma (p < 0.001) but not among healthy children [38]. Veillette et al. highlighted that dust from vacuum cleaners acted as a vehicle of indoor moulds and bacteria associated with human diseases originating from bioaerosol exposure [39]. Adhikari et al. suggested an association between bacterial levels from household dust and short- and long-term indoor mould contamination. However, only mould that was present had a correlation with air bacterial levels. [40]. Cao et al. indicated that PM2.5 samples taken during periods of severe smog in Beijing consisted of archaeal, viral, eukaryotic, and bacterial reads (0.8%, 0.1%, 13.0% and 86.1%, respectively), whereas these percentages in PM10 samples were 0.8%, 0.1%,18.3% and 80.8%, respectively [41]. In sum, increasing evidence suggests that air pollutants acting as carriers for microorganisms in indoor and outdoor environments produce substantial impacts on human health. 5. Air pollution and human health in China With fast-paced urbanization and increased energy consumption in modern, industrialized China, levels of outdoor and indoor air pollution resulting from industrial and motor vehicle emissions are increasing rapidly, as is the proportion of urban population, increasing from 18% in 1978 to 52% in 2012. As a major air pollutant, concentrations of PM2.5 in urban areas of China are far larger than in rural areas. According to one study, only 24 of 350 districts in China had an annual PM2.5 concentration less than 10 m g/m3, whereas there were 166 districts with annual PM2.5 concentrations over the WHO Interim Target-1 of 35 m g/m3 [1]. Districts with high PM2.5 levels were in southeastern Sichuan, in a belt from Tianjin to southern Hebei, throughout northeastern Henan, eastern Shandong, northeastern Anhui, Jiangsu Province, and Shanghai. There were 223 of 350 districts with DPM2.5 (DPM2.5 ¼ urban PM2.5 e non-urban PM2.5) levels ranging between 0 and 10 m g/m3, whereas there only 41 districts with DPM2.5 below 0 g/m3, mainly in western China (except for Langfang), Jiaxing, and Zhuhai. There were 85 districts with DPM2.5 levels greater than 10 mg/m3, which were divided into two belts. One was from northern Hebei and Beijing, through Shanxi Province, northwestern Henan, and southern Shaanxi, eventually ending in southeastern Sichuan (the BeijingeSichuan belt). The second belt was from Shanghai, through Zhejiang Province, southern Anhui, Hunan and Jiangxi, ending in Guangxi and Guangdong provinces (the ShanghaieGuangdong belt). The DPM2.5 level of the BeijingeSichuan belt was far larger than that of the ShanghaieGuangdong belt. Another study in Beijing showed the average level of PM2.5 in 20 indoor public locations was 3346 ± 3863 mg/m3, ranging between 6 mg/m3 and 1956 mg/m3 (750.6 ± 521.6 mg/m3 in karaoke bars, 317.9 ± 235.3 mg/m3 in restaurants, 157.5 ± 98.5 mg/m3 in cyber cafes, and 116.9 ± 1001 mg/m3 in bath houses) [42]. The PM2.5 levels in restaurants and karaoke bars were far higher than those in the other two locations. In the
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same study, indoor and outdoor monitoring sites in Beijing indicated the mean level of indoor PM2.5 was 87.76 mg/m3, which was lower than that of outdoor PM2.5 (128.79 mg/m3). Indoor PM2.5 levels during smog periods were higher than mean levels of indoor PM2.5. Indoor PM2.5 during periods with fireworks was higher than that during Chinese New Year and mean indoor PM2.5 levels. High concentrations of PM2.5 are a major factor in the development of haze and also of respiratory diseases or other diseases. Evidence from Guangzhou suggests that there have been more deaths during haze periods, which have lasted an average of 278 days each year, than deaths during non-haze periods, owing especially to respiratory and cardiovascular illnesses [43]. Zhan et al. indicated that there was a vital, concentration-dependent correlation between daily mortality and PM10 in Taiyuan [44]. The threshold level of total mortality was 85 mg/m3, whereas that of cancer mortality 89.59 mg/m3. The threshold level of cardiovascular, cerebrovascular, and respiratory mortality was 122.54 mg/m3. Another study of mortality in Shenyang, China revealed that there was a 10 mg/m3 increase of mean annual PM10 levels, resulting in 55% increased risk of death caused by cardiovascular disease [45]. Adjusted hazard ratios for cardiovascular mortality with a 10 mg/ m3 increment of NO2 was 2.46, whereas this was 2.44 for cerebrovascular mortality. Another study indicated a strong association between PM10, CO, and NO2 and daily mortality owing to respiratory diseases in Beijing [46]. In a study among 6730 Chinese children aged 3e7 years from 50 kindergartens in seven northeastern cities of China, Liu et al. calculated 3-year levels of PM10, SO2, and NO2 [47]. These authors found the morbidity of respiratory symptoms was far greater among children who lived in these locations near a busy road, close to a factory or industrial chimney, and also in children who had a coal-burning device or recent renovations in their home, or who had family members who smoked at home. In that study, PM10 had an association with constant cough and sputum and onset of allergic rhinitis in girls. However, associations between respiratory symptoms and PM10, SO2, and NO2 were not significant in boys. In 2007, the average daily levels of NO2, PM10 and SO2 in Guangzhou, China were 61.04, 82.51, and 51.67 mg/m3, respectively, A positive correlation was found with premature births in the city, with a mean increase in infants born prematurely of 21.47 [48]. A survey across the 18 regions in Liaoning Province showed TSP levels ranging from 188 to 689 mg/m3, SO2 from 14 to 140 mg/m3, and NO2 levels from 29 to 94 mg/m3 [49]. Increases in the prevalence of constant cough (21e28%), constant sputum (21e30%), and asthma (39e56%) were found to be associated with increments in levels of those air pollutants (172 mg/m3 for TSP, 69 mg/m3 for SO2, and 30 mg/m3 for NO2). Thus, a concentrationrelated relationship was found between outdoor air pollutants in this northeastern Chinese province and respiratory symptoms among children, of which the relationship with TSP was more pronounced than that with SO2 and NO2. Wang et al. also suggested a long-term effect between ambient air pollutants and morbidity owing to respiratory symptoms among adults in Beijing [50]. A study in Shenyang indicated that indoor air pollution presented a high risk for asthma among children [51]. Limits to sources of air pollutants can improve indoor and ambient air quality and can also reduce mortality owing to respiratory or other diseases. Evidence suggests there is a drop in concentrations of indoor air pollutants when key measures are taken, which include restricting exposure to outdoor air pollutants, reducing indoor sources of air pollutants, and implementing policies to improve indoor and outdoor air quality [52]. During the 2008 Olympic Games, hourly and daily levels of CO, PM10, NO2, and O3 were in accord with the China National Ambient Air Quality Standards because traffic limits measures were taken to reduce traffic-associated air pollution in urban areas [53]. During the 16th
Asian Games, air quality in Guangzhou also improved significantly as a result of controls placed on vehicle exhaust, industrial emissions, and biomass combustion [54]. Carrying out such measures could result in significant decreases in the prevalence and mortality owing to respiratory or other diseases as well as significant reductions in the social costs of air pollution. 6. Conclusion There is increasing evidence to suggest that air pollutants including PM, ozone, nitrogen dioxide, and ETS have harmful effects on human respiratory health. Studies from China as well as other countries have demonstrated that high concentrations of both indoor and outdoor air pollutants lead to cough and other respiratory symptoms as well as an increase in mortality. Air pollutants as carriers of pathogenic microorganisms lead to exacerbation of respiratory diseases and increased morbidity. Recent studies have indicated that air pollutant concentrations, especially of PM2.5 in urban areas of China, are significantly higher than WHO standards, resulting in aggravation of respiratory symptoms and asthma and higher mortality. Limiting exposure to outdoor air pollutants, eliminating the sources of indoor air pollutants, and instating governmental policies to reduce overall air pollutant levels can lead to greater improvement in outdoor and indoor air quality. In addition, efficacious preventive measures and treatments must be found to adequately address the health effects of environmental air pollution in China. Conflict of interest The authors declare no conflict of interest. Acknowledgements We are grateful to Prof. Kian Fan Chung who is the honorary professor of Guangzhou Institute of Respiratory Diseases, Guangzhou Medical University, China for his helpful discussions and amending on this paper. Qingling Zhang is supported by a grant from State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, China. References [1] Lijian Han, Weiqi Zhou, Weifeng Li, b Li Li, Impact of urbanization level on urban air quality: a case of fine particles (PM 2.5 ) in Chinese cities, Environ. Pollut. 194 (2014), 163e170. [2] Yinping Zhang, Jinhan Mo, Charles J. Weschler, Reducing health risks from indoor exposures in rapidly developing urban China, Environ. Health Perspect. 121 (2013) 751e755. [3] P. Zhang, G. Dong, B. Sun, L. Zhang, X. Chen, et al., Long-term exposure to ambient air pollution and mortality due to cardiovascular disease and cerebrovascular disease in Shenyang, China, PLoS One 6 (6) (2011) e20827. [4] Guowei Pan, Shujuan Zhang, Yiping Feng, Ken Takahashi, et al., Air pollution and children's respiratory symptoms in six cities of Northern China, Respir. Med. 104 (2010) 1903e1911. [5] J.G. Watson, Visibility: science and regulation, J. Air Waste Manag. Assoc. 52 (2002) 628e713. n, C. Janson, B. Jarvholm, B. Forsberg, Vehicle exhaust outside [6] L. Modig, K. Tore the home and onset of asthma among adults, Eur. Respir. J. 33 (2009) 1261e1267. [7] Suh-Young Lee, Yoon-Seok Chang, Sang-Heon Cho, Allergic diseases and air pollution, Asia Pac. Allergy 3 (2013) 145e154. [8] A. Nemmar, P.H. Hoet, B. Vanquickenborne, et al., Passage of inhaled particles into the blood circulation in humans, Circulation 105 (2002) 411e414. [9] J.A. Nightingale, R. Maggs, P. Cullinan, et al., Airway inflammation after controlled exposure to diesel exhaust particulates, Am. J. Respir. Crit. Care Med. 162 (2000) 161e166. [10] J. McCreanor, P. Cullinan, M.J. Nieuwenhuijsen, et al., Respiratory effects of exposure to diesel traffic in persons with asthma, N. Engl. J. Med. 357 (2007) 2348e2358. [11] R. Habre, E. Moshier, W. Castro, A. Nath, A. Grunin, A. Rohr, J. Godbold,
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Please cite this article in press as: Q. Zhang, et al., Cough and environmental air pollution in China, Pulmonary Pharmacology & Therapeutics (2015), http://dx.doi.org/10.1016/j.pupt.2015.10.003