Air pollution constitutes a significant stimulus of asthma exacerbations; however, the impacts of exposure to major air pollutants on asthma-related hospital admissions and emergency room visits (ERVs) have not been fully determined.
We sought to quantify the associations between short-term exposure to air pollutants [ozone (O3), carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter ≤10μm (PM10) and PM2.5] and the asthma-related emergency room visits (ERV) and hospitalizations.
Systematic computerized searches without language limitation were performed. Pooled relative risks (RRs) and 95% confidence intervals (95%CIs) were estimated using the random-effect models. Sensitivity analyses and subgroup analyses were also performed.
After screening of 246 studies, 87 were included in our analyses. Air pollutants were associated with significantly increased risks of asthma ERVs and hospitalizations [O3: RR(95%CI), 1.009 (1.006, 1.011); I2 = 87.8%, population-attributable fraction (PAF) (95%CI): 0.8 (0.6, 1.1); CO: RR(95%CI), 1.045 (1.029, 1.061); I2 = 85.7%, PAF (95%CI): 4.3 (2.8, 5.7); NO2: RR(95%CI), 1.018 (1.014, 1.022); I2 = 87.6%, PAF (95%CI): 1.8 (1.4, 2.2); SO2: RR(95%CI), 1.011 (1.007, 1.015); I2 = 77.1%, PAF (95%CI): 1.1 (0.7, 1.5); PM10: RR(95%CI), 1.010 (1.008, 1.013); I2 = 69.1%, PAF (95%CI): 1.1 (0.8, 1.3); PM2.5: RR(95%CI), 1.023 (1.015, 1.031); I2 = 82.8%, PAF (95%CI): 2.3 (1.5, 3.1)]. Sensitivity analyses yielded compatible findings as compared with the overall analyses without publication bias. Stronger associations were found in hospitalized males, children and elderly patients in warm seasons with lag of 2 days or greater.
Citation: Zheng X-y, Ding H, Jiang L-n, Chen S-w, Zheng J-p, Qiu M, et al. (2015) Association between Air Pollutants and Asthma Emergency Room Visits and Hospital Admissions in Time Series Studies: A Systematic Review and Meta-Analysis. PLoS ONE 10(9): e0138146. https://doi.org/10.1371/journal.pone.0138146
Editor: Tim S. Nawrot, Hasselt University, BELGIUM
Received: March 21, 2015; Accepted: August 25, 2015; Published: September 18, 2015
Copyright: © 2015 Zheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are included within the paper and its Supporting Information.
Funding: This study was supported by a grant from School of Public Health and Tropical Medicine of Southern Medical University, China (Grant No. GW201322). This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
Competing interests: The authors have declared that no competing interests exist.
Asthma is characterized by airway hyperresponsiveness and inflammation, the pivotal components leading to the cascades of pro-inflammatory mediator release and airflow limitation  that are associated with allergen exposures, air pollution, cigarette smoking and noxious particle insults .
The relationship between air pollution and asthma has been well-established [3–89], particularly in the countries with rapid urbanization and industrialization. Three multi-center studies conducted in Europe [14,51] and Australia  reported an overall insignificant association between major air pollutants and the asthma-related emergency room visits (ERVs), except for nitrogen dioxide (NO2) [14,53] and particulate matter with a diameter of 10 μm or less (PM10) ; whereas other multi-city studies conducted in Korea and Europe demonstrated different magnitudes of the associations between asthma exacerbation and ozone (O3)  and sulfur dioxide (SO2) [5,76] pollution. Moreover, exposure to environmental NO2 and PM10 has recently been associated with worsening of symptoms and lung function decline during asthma exacerbations [90–92].
Whilst the adverse impacts of air pollution on asthma exacerbations have been confirmed, the effect sizes and the extent to which any single pollutant acts as a surrogate of other pollutants are less clear. As epidemiologic evidence regarding the effects of air pollution on asthma accumulates, it is crucial to consider different concentration-response functions (CRFs, defined as the percentage change in any health outcome per unit change in concentration, to different air pollutants ), based on the concurrent evidence. Determination of the effect modification across studies may also be challenging because of the underlying geographic diversity, heterogeneous primary outcome indices, the differences in statistical algorithms, the complexity of multiple pollutants and other confounders .
Consequently, meticulous risk assessments exploring the influences of multiple air pollutants, calculated as the CRFs , are warranted. In view that the quantification between air pollution and asthma-related ERVs or hospitalizations has been well-established and that the majority of population is exposed to air pollution, the relative risks (RRs) and population attributable fractions (PAFs) of individual pollutants on asthma-related ERVs or hospitalizations should be taken into account. Furthermore, investigations of the effect modification may provide further insights into these associations . For instance, there have been the literature reports delineating stronger pollution effects during the warm seasons, despite the culmination of pediatric asthma attacks during cold seasons [1,4,5,17,18,24,52,54,85]. Sex [5,7,37,40,50,68] and age [16,24,30,38,57] differences might also confound the asthma outcomes to air pollutant exposure.
In this study, we sought to conduct a systematic review and meta-analysis on the association between short-term exposure to air pollutants and asthma-related ERVs and hospital admissions based on time-series and case-crossover studies, thus offering rationales to improve public health and environmental protection. We further assessed the impacts of age, sex, season, hospital variance and long lag patterns (lag >2days) on these associations.
Eligibility criteria and literature searches
Systematic searches were conducted to identify studies focusing on short-term exposures, defined as the duration of up to 7 days to one of the air pollutants associated with asthma exacerbation. These studies involved all age intervals without language limitation. We excluded: (1) animal studies, ex vivo and toxicological studies, summaries, commentaries and editorials, case reports and case series; (2) duplicate publications; (3) studies evaluating long-term exposure only; (4) non-peer reviewed articles (a potential source of bias); (5) study duration of less than one year; (6) no original data. Authors were contacted by e-mail in case data were incomplete. Studies were excluded if no reply was obtained despite repeated contacts with corresponding authors.
Time-series studies (including case-crossover studies) were searched comprehensively in EMBASE, PubMed, Cochrane Central Register of Controlled Trials and EBM Reviews–Cochrane Database of Systematic Reviews, Web of Science, Ovid and Highwire up to March 2015 (no start date specified). References were checked for additional data. When the same population was used in several publications, only the largest and the most complete study (i.e. multi-cities study) was included. In addition, single-city study with different time periods from multi-cities study was also accepted. We used a combination of keywords related to the types of exposure (air pollution, CO, PM10, PM2.5, SO2, NO2 and O3) and the outcomes of asthma exacerbations (hospital admission and ER visit). (See Search Strategies in the online supplements for further details)
Quality score assessment
This study complies with the preferred reporting items of PRISMA . Since no validated scales of time-series and case-crossover studies were recommended by New Castle Ottawa and Cochrane risk of bias tool, we evaluated the validity based on Mustafic’s study . Three components were assessed, including asthma diagnosis (0 to 1 point), air pollutant measures (0 to 1) and adjustment for confounders (0 to 3). We confirmed asthma exacerbation if coded by International Classification of Diseases, American Thoracic Society, National Asthma Education or Prevention Program or International Classification of Primary Care 2 (0 for no valid criteria). The frequency of measurement and missing data were considered (1 point for measurements performed daily with <25% missing data, otherwise 0 point was assigned). Regarding the potential confounders, 1 point was scored if long-term trends, seasonality and temperature were all adjusted, otherwise 0 point was assigned. Any additional adjustment for the humidity or day-of-week was added for 1 point. Any adjustment made for influenza epidemics and holidays was added for 1 point. Studies fulfilling 5 points were analyzed in sensitivity analyses.
Study selection and data extraction
Two independent reviewers (S.C. and H.D.) screened the abstracts and titles. Full texts were reviewed to determine eligibility for inclusion. Disagreement was resolved by discussion. If consensus was not reached, another reviewer (X.Z.) was consulted to vote for final decisions.
A standardized form was used for data extraction including the main characteristics (author, year of publication, location and period, type of study, age and sex of populations, title and journal), outcome measures (general practitioner’s house calls, primary care visits, asthma-related hospitalization and ERV), the quality of measurement methods and adjustments (long-term trend, seasonality, temperature, humidity, days of the week, holidays and influenza epidemics). Data extraction was done by two independent reviewers (W.G. and L.J.) for comparisons. Disagreements were resolved by consultation with the third reviewer (X.Z.).
As current evidence suggests a linear association between air pollutants and asthma-related ERVs and hospital admissions, the standardized effect estimates were expressed as the risk ratios (RRs) and 95% confidence intervals (95%CIs), derived from single-pollutant models reporting RRs (95%CIs) or percentage change (95%CIs), and further recalculated to reflect a 10 μg/m3 increase in the pollutants by assuming a linear relationship of all pollutants, except for CO (1 mg/m3 increase) . There was a time lag (measured in days) between short-term air pollution and asthma exacerbations; however, each of the included study varied in lag selection patterns. Some authors recommended the use of the most significant estimate, irrespective of the direction. Given the lack of standardized methods of reporting, we adopted a priori lag selection scheme proposed by Atkinson et al . If only one lag estimate for a given pollutant/outcome pair was demonstrated (either the only one was analyzed or reported), it would be included for analyses. If multiple lag estimates were reported, the selection algorithms were: 1) the most frequently used lag in all selected studies; 2) single lags, but not cumulative/distributed lags, were selected as a priority.
Random-effect model is the most conservative tool incorporating within- and between-study heterogeneity in 95%CI, and has been adopted for studies investigating different populations with anticipated significant heterogeneity which is calculated using the I2 test. The I2 values of 0 to 30, 30 to 50, and greater than 50 denoted low, moderate and high heterogeneity, respectively . This algorithm is currently recommended by Cochrane collaboration (http://www.cochrane.org) despite concerns of underpowered statistics.
The prevalence of exposure to air pollution in the population was estimated to be 100%, which is imputed from the epidemiological studies reporting effect estimates . Population attributable fractions (PAFs) were calculated from RRs (95%CI) in overall analyses, calculated as PAF = (RR−1)/RR.
To explore the heterogeneity in our pooled analysis, sensitivity analyses of the lag patterns and study quality were applied, based on the studies with the same and most commonly used lag pattern or the studies with 5 scores.
Subgroup analyses of the study characteristics were conducted to combine the effects for evaluating the differences between strata-specific estimates (age, sex, seasons, hospitalization or ERVs). Additional subgroup analyses were performed for short- (≤2 days) and long-lag (>2 days) patterns. The default for short-lag patterns was the most frequently used for individual pollutants; otherwise, lag1 or lag0 or lag 0–1 served as surrogates. For long-lag patterns, single lag was a priority selection compared with the cumulative lag.
Potential publication bias was assessed by using the asymmetric plot and confirmed by the Egger’s test .
Statistical analyses were conducted using STATA 11.2 (Stata, College Station, TX, USA). All tests were two-sided and statistical significance was defined as P<0.05, except for the heterogeneity assessment (P<0.10).
The PRISMA checklist for this meta-analysis could be found in S1 File in the supporting information.
We initially identified 1099 literature reports. After screening for the titles and abstracts, 246 full-text articles were assessed for eligibility, of which 87 were included (86 in English and 1 in Spanish, Fig 1).
Main characteristics of 87 eligible studies, consisting of 62 time-series and 25 case cross-over studies, are displayed in S1 Table. Databases were extracted from 46 ERVs, 37 hospital admissions and 4 ERVs/hospital admissions. The study cohort consisted of the general population. Lag exposures varied from a specific day (single-lag) to 7 days or less before the onset of asthma exacerbations.
Of the 87 included studies, 50 focused on children, 21 on adults, 13 on elderly population, and 44 on general population. Only 12 studies have conducted sex modification analyses, with 12 male and 11 female sub-datasets. 31 studies were performed in warm seasons and 25 in cold seasons.
Mean 24-hr or 8-hr maximum concentrations of six pollutants are demonstrated in S1 Table.
Associations between the six major air pollutants and asthma-related ERVs/hospitalizations were statistically significant [O3: 71 studies; RR (95%CI), 1.009 (1.006, 1.011); I2 = 87.8%, PAF (95%CI): 0.8 (0.6, 1.1); CO: 42 studies; RR (95%CI), 1.045 (1.029, 1.061); I2 = 85.7%, PAF (95%CI): 4.3 (2.8, 5.7); NO2: 66 studies; RR (95%CI), 1.018 (1.014, 1.022); I2 = 87.6%, PAF (95%CI): 1.8 (1.4, 2.2); SO2: 65 studies; RR (95%CI), 1.011 (1.007, 1.015); I2 = 77.1%, PAF (95%CI): 1.1 (0.7, 1.5); PM10: 51 studies; RR (95%CI), 1.010 (1.008, 1.013); I2 = 69.1%, PAF (95%CI): 1.1 (0.8, 1.3); PM2.5: 37 studies; RR (95%CI), 1.023 (1.015, 1.031); I2 = 82.8%, PAF (95%CI): 2.3 (1.5, 3.1)]. (Table 1, Figs 2–7).
Publication bias was detected in all analyses evaluating all pollutants except for PM2.5 (P = 0.06). See S1 Fig in the online supplement for the funnel plots of the relative risks of emergency/hospital admissions for asthma in relation to six air pollutants in the overall analyses. The Excel form of our database (S2 File) is also available in the supporting information.
There were significant associations between air pollutants and asthma-related ERVs/hospitalizations in the sensitivity analyses, based on 29 studies fulfilling the quality score of 5 points without significant publication bias [O3: 12 studies; RR (95%CI), 1.005 (1.002, 1.008); I2 = 55.7%; Egger’s test, P = 0.15; CO: 7 studies; RR (95%CI), 1.013 (1.000, 1.028); I2 = 13.6%; Egger’s test, P = 0.16; NO2: 11 studies; RR (95%CI), 1.009 (1.004, 1.015); I2 = 55.7%; Egger’s test, P = 0.16; SO2: 13 studies; RR (95%CI), 1.009 (1.003, 1.015); I2 = 57.9%; Egger’s test, P = 0.28; PM10: 7 studies; RR (95%CI), 1.006 (1.003, 1.009); I2 = 0.0%; Egger’s test, P = 0.53; PM2.5: 3 studies; RR (95%CI), 1.004 (1.000, 1.009); I2 = 0.0%; Egger’s test, P = 0.71] (Table 1, and S1 Fig in the online supplement for the funnel plots of the relative risks of emergency/hospital admissions for asthma in relation to six air pollutants regarding studies with a score of 5.)
Lag exposure was 0 day for O3, NO2 and SO2, and 1 day for CO, PM10 and PM2.5. Likewise, associations between the six air pollutants and asthma-related ERVs/hospitalizations were statistically significant [O3: 9 studies; RR (95%CI), 1.010 (1.005, 1.014); I2 = 22.4%; Egger’s test, P = 0.99; CO: 14 studies; RR (95%CI), 1.033 (1.001, 1.025); I2 = 0.0%; Egger’s test, P = 0.37; NO2: 11 studies; RR (95%CI), 1.010 (1.002, 1.018); I2 = 65.9%; Egger’s test, P = 0.93; SO2: 12 studies; RR (95%CI), 1.004 (1.000, 1.008); I2 = 41.8%; Egger’s test, P = 0.96; PM10: 12 studies; RR (95%CI), 1.005 (1.003, 1.008); I2 = 0.0%; Egger’s test, P = 0.42; PM2.5: 13 studies; RR (95%CI), 1.008 (1.003, 1.013); I2 = 6.6%; Egger’s test, P = 0.49]. No publication bias was detected. (Table 1, Fig 8)
Effect modification of O3, CO, NO2, PM10 and PM2.5 on asthma-related hospital admission and ERVs (stronger association for hospital admissions) was found.
In subgroup analysis of sex, more pronounced associations were demonstrated in males [CO: 1.080 (1.047, 1.113), NO2:1.028 (1.008, 1.038); PM10: 1.025 (1.011, 1.039); PM2.5: 1.013 (1.000, 1.018)]. No significant association was found in females, except for exposure to O3 [1.023 (1.006, 1.040)].
There was a tendency towards stronger associations between ERVs/hospital admissions and the six air pollutants in children [CO: 1.018 (1.013, 1.023); NO2: 1.018 (1.013, 1.023); SO2: 1.016 (1.011, 1.022); PM10: 1.013 (1.008, 1.018); PM2.5: 1.025 (1.013, 1.037)] and the elderly [CO: 1.094 (1.002, 1.185); NO2: 1.019 (1.013, 1.024); SO2: 1.024 (1.005, 1.044)] as compared with the adults.
Stronger associations can also be observed in warm seasons [CO: 1.166 (1.099, 1.232), NO2: 1.029 (1.018, 1.040); SO2: 1.018 (1.010, 1.026); PM10: 1.021 (1.007, 1.023); PM2.5: 1.028 (1.011, 1.044)], except for ozone exposure.
Additional subgroup analyses demonstrated that long-lag patterns that were associated with significant heterogeneity yielded a stronger association than short-lag patterns (Table 2).
We have systematically evaluated and confirmed the associations between short-term exposure to six air pollutants which are closely regulated by the environmental protection agencies and asthma-related ERV/hospitalizations, based on all available time-series and case-crossover studies. Low heterogeneity and no publication bias was observed in the sensitivity analyses. Our findings remained robust, despite potential publication bias resulting from the relatively small sample sizes in sensitivity analyses.
Mechanisms of air pollutants on eliciting asthma exacerbations
The observed effects of the six major air pollutants on asthma ERVs/hospitalization are biologically plausible. The major mechanisms of individual air pollutants responsible for triggering asthma exacerbations are as follows:
** NO2 and ozone have been implicated in eliciting lipid peroxidation of the cell membranes and the generation of various free radicals which collectively impair the structure and function of the asthmatic airways . Furthermore, exposure to ozone and (or) NO2 can also promote the release of inflammatory mediators (i.e. interleukin-8, granulocyte macrophage-colony stimulating factor ,
** SO2, a well-known inorganic chemical irritant, has been demonstrated to promote airway inflammation (increased levels of tumor growth factor-β in bronchoalveolar fluids) and eosinophilia, induce bronchospasm and airway fibrosis (a factor potentially leading to increased airway responsiveness) in asthma .
** Particulate matters harbor a more complex impact on asthmatic airways, since their deposition in the airways directly elicited airway inflammation, mucosal edema and cytotoxicity . The convergence of regulatory signals generated by particulate matter-induced oxidative stress in dendritic cells and their interactions may also be responsible for asthma exacerbations . Furthermore, the defective airway macrophage phagocytosis, resulting from increased prostaglandin E2 levels, could have augmented the adverse effects of inhaled carbonaceous particulate matters on eliciting exacerbations .
** The direct association between CO and asthma is unfortunately less clearer [29,107]. It is plausible that CO might act as a surrogate of other noxious gases which are derived from incompletely combusted products. Moreover, CO seemed to confer greater adverse impacts on asthmatic children because of their immature lung development.
Most studies were limited at all age intervals, which constituted an important effect modifier . In keeping with literature reports [16,24,30,38,57], we further confirmed that children and elderly people were more susceptible to asthma exacerbations. A plausible interpretation could be that children harbor immature lung growth and host-defense capacity and that, in elderly individuals, air pollution amplifies inflammatory responses of remodeled airways.
To date, effect modification by sex has not been well established [5,7,37–38,40,50,68]. The higher rate of asthma-related hospitalizations and ERVs in males could not justify the sex-related susceptibility, since the exposures (outdoor occupations, social activities) and biologic characteristics (i.e. hormonal levels, lung size and growth and airway inflammation) are different. Furthermore, greater effects of ozone on females were consistent with those in a previous report .
If the additive effects of air pollution were season-independent, then the PAFs and RRs would be higher during warm seasons because of fewer competing pollutants. However, unlike other pollutants, the association of ozone (a component of “photochemical cocktail” which is typically a warm-season pollutant [24,27,31–32,52,54,76,78,82,87]) and asthma exacerbations was similar between the warm and cold seasons. Unfortunately, the variability of temperature adjustment approaches and the lack of information regarding solar radiation and brightness have constrained our analyses in determining the seasonal modifications. Furthermore, limiting the analysis to the above-mentioned confounders might have minimized the number of eligible studies, possibly resulting in inaccurate conclusions.
Despite the weak associations between air pollution and asthma exacerbations, the effects of air pollution were globally considerable because the RRs and percentage increase were derived from large cohorts in time-series studies, reflecting significant healthcare utilization, immense social and economical burden. Despite that the high PAFs for outdoor air pollution was essentially imputed from the prevalence of exposure of 100%, this assumption may still be reasonable, since epidemiological studies generally assigned outdoor average level to all individuals. Furthermore, we quantified asthma risk according to the changes in air pollution, since asthma-related ERVs/hospitalizations and the changes in air pollutant concentrations would assume a linear correlation, and hence, no positive threshold  could be established.
First, the differences between ERVs and hospitalizations did have certain impacts on their utility for quantifying the observed associations with air pollution in subgroup analysis. However, a high degree of heterogeneity could be observed in analyses of all strata, including hospital admissions and ERVs. This might be linked to the various study design quality, inclusion criteria, analytic strategies and lag patterns. Heterogeneities were reduced dramatically among studies with a common analytic strategy (most commonly used lag patterns) or standardized protocol (study quality >5), highlighting the importance of standardized study protocol with the most appropriate lag.
Second, we did not analyze the association between air pollutants and other systemic diseases, therefore the multi-faceted adverse effects of air pollution could have been markedly diluted. Lower levels of air pollutants reportedly led to attenuated asthma symptoms [110–111], airway inflammation , lung function improvement  and less healthcare utilization and access to medications , confirming the roles of air pollution on eliciting asthma exacerbations.
Third, the coefficients from “single-pollutant” model were utilized despite potential interactions among different air pollutants. Regarding that the lack of crystal-clear exposure-asthma relationships hampered selection of additive or multiplicative model, and that a large number of complex parameters rendered the ideal ‘multivariate’ meta-analysis computationally impractical , we therefore independently analyzed the effects of individual pollutants [15, 17–18, 115].
Finally, the methodologies of lag selection remain controversial. Any particular lag selection would have excluded a considerable number of studies. In this study, we chose the most frequently used short lags (lag0, lag1 or lag0-1), since longer lags have been less consistently reported in previous literature and harbored a significant heterogeneity in our pooled analysis.
Our findings has called for the implementation of more stringent regulations on the traffic and industry, including the utilization of environmental-friendly fuels (i.e. liquid natural gas, diesel derived from biomass fuels, hydrogen gas), engines or techniques (such as hybrid vehicles, purely electric motors), and the utilization of filters or absorbers of noxious gases before release into the atmosphere, and the upgrading of traditional industrial facilities (i.e. cement production). The development of fine particle separating facial masks or intranasal gel might be useful for the patients who have difficulty in avoiding direct exposure to exposure, particularly at the workplace. The levels of air pollutants should also be incorporated into weather forecasts so as to issue alerts to population at risk, thus facilitating administration of preventative medications.
Short-term exposure to air pollutants confers an increased risk of asthma-related ERVs and hospital admissions. Our findings call for greater awareness of environmental protection and the implementation of effective measures to improve the quality of air, which may reduce the risks of adverse effects on the population’s health. However, the effects need to be interpreted cautiously since longer lags are essential in time-series studies to better determine the effects of outdoor air pollution on asthma outcomes.
S1 Fig. Funnel plots of the relative risks of ERVs/hospital admissions for asthma in relation to six air pollutants in the overall analyses and sensitivity analyses (studies with a score of 5).
Fig A. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to CO in the overall analyses; Fig B. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to NO2 in the overall analyses; Fig C. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to ozone in the overall analyses; Fig D. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to PM2.5 in the overall analyses; Fig E. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to PM10 in the overall analyses; Fig F. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to SO2 in the overall analyses; Fig G. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to CO in the sensitivity analyses regarding studies with a score of 5; Fig H. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to NO2 in the sensitivity analyses regarding studies with a score of 5; Fig I. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to ozone in the sensitivity analyses regarding studies with a score of 5; Fig J. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to PM2.5 in the sensitivity analyses regarding studies with a score of 5; Fig K. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to PM10 in the sensitivity analyses regarding studies with a score of 5; Fig L. Funnel plot of the relative risks of ERVs/hospital admissions for asthma in relation to SO2 in the sensitivity analyses regarding studies with a score of 5.
S2 File. The database of the association between six air pollutants and ERVs/hospital admissions for asthma in overall analyses (in Excel form).
Conceived and designed the experiments: XYZ WJG JPZ QC. Performed the experiments: XYZ HD LNJ SWC. Analyzed the data: XYZ MQ YXZ. Wrote the paper: XYZ WJG. Provided critical review of the manuscript and approved the final submission: WJG QC.
- 1. Busse WW, Lemanske RF. Asthma. N Engl J Med 2001; 344: 350–62 pmid:11172168
- 2. Koenig JQ. Air pollution and asthma. J Allergy Clin Immunol 1999; 104: 717–22 pmid:10518814
- 3. Thompson AJ, Shields MD. Acute asthma exacerbations and air pollutants in children living in Belfast, Northern Ireland. Arch Eviron Heal 2001; 56: 234–41
- 4. Strickland MJ, Darrow LA, Klein M, Flanders D, Sarnat JA, Waller LA, et al. Short-term associations between ambient air pollutants and pediatric asthma emergency department visits. Am J Respir Crit Care 2010; 182:307–16
- 5. Son JY, Lee JT, Park YH, Bell ML. Short-term effects of air pollution on hospital admissions in Korea. Epidemiology 2013; 24: 545–54 pmid:23676269
- 6. Mehta AJ, Schindler C, Perez L, Probst-Hensch N, Schwartz J, Brändli O, et al. Acute respiratory health effects of urban air pollutants in adults with different patterns of underlying respiratory disease. Swiss Med Wkly. 2012; 142: w13681. pmid:23076649
- 7. Samoli E, Nastos PT, Paliatsos AG, Katsouyanni K, Priftis KN. Acute effects of air pollution on pediatric asthma exacerbation: Evidence of association and effect modification. Environ Res 2011; 111: 418–24 pmid:21296347
- 8. Andersen ZJ, Wahlin P, Raaschou-Nielsen O, Ketzel M, Scheike T, Loft S. Size distribution and total number concentration of ultrafine and accumulation mode particles and hospital admissions in children and the elderly in Copenhagen, Denmark. Occup Environ Med 2008; 65: 458–66 pmid:17989204
- 9. Walters S, Griffiths RK, Ayres JG. Temporal association between hospital admissions for asthma in Birmingham and ambient levels of sulphur dioxide and smoke. Thorax 1994; 49: 133–40 pmid:8128402
- 10. Kim SY, Peel JL, Hannigan MP, Dutton SJ, Sheppard L, Clark ML, et al. The temporal lag structure of short-term associations of fine particulate matter chemical constituents and cardiovascular and respiratory hospitalizations. Environ Health Perspect 2012; 120: 1094–9 pmid:22609899
- 11. Paulu C, Smith AE. Tracking associations between ambient ozone and asthma-related emergency department visits using case-crossover analysis. J Public Health Management Practice 2008; 14, 581–91
- 12. Lee JT, Lee H, Song H, Hong YC, Cho YS, Shin SY, et al. Air Pollution and Asthma Among Children in Seoul, Korea. Epidemiology 2002; 13: 481–4 pmid:12094105
- 13. Delfino RJ, Becklake MR, Hanley JA. The relationship of urgent hospital admission for respiratory illnesses to photo chemical air pollution levels. Environ Res 1994; 67: 1–19 pmid:7925191
- 14. Sunyer J, Spix C, Quenel P, Ponce-de-Leon A, Ponka A, Barumandzadeh T, et al. Urban air pollution and emergency admissions for asthma in four European cities: the APHEA Project. Thorax 1997; 52: 760–5 pmid:9371204
- 15. Chardon B, Lefranc A, Granados D, Gre´my I. Air pollution and doctors’ house calls for respiratory diseases in the Greater Paris area (2000–3). Occup Environ Med 2007; 64: 320–4 pmid:17182644
- 16. Halonen JI, Lanki T, Yli-Tuomi T, Kulmala M, Tiittanen P, Pekkanen . Urban air pollution, and asthma and COPD hospital emergency room visits. Thorax 2008; 63: 635–41 pmid:18267984
- 17. Yang CY, Chen CC, Chen CY, Kuo HW. Air Pollution and Hospital Admissions for Asthma in a Subtropical City: Taipei, Taiwan. J Toxicol Env Heal A 2007; 70: 111–7
- 18. Tsai SS, Cheng MH, Chiu HF, Wu TN, Yang CY. Air Pollution and Hospital Admissions for Asthma in a Tropical City: Kaohsiung, Taiwan. Inhalation Toxicology 2006; 18: 549–54 pmid:16717026
- 19. Wong TW, Lau TS, Yu TS, Neller A, Wong SL, Tam W, et al. Air pollution and hospital admissions for respiratory and cardiovascular diseases in Hong Kong. Occup Environ Med 1999; 56: 679–83 pmid:10658547
- 20. Fusco D, Forastiere F, Michelozzi P, Spadea T, Ostro B, Arca M, et al. Air pollution and hospital admissions for respiratory conditions in Rome, Italy. Eur Respir J 2001; 17: 1143–50 pmid:11491157
- 21. Morgan G, Corbett S, Wlodarczyk J. Air pollution and hospital admissions in Sydney, Australia 1990 to 1994. Am J Public Health 1998; 88: 1761–6 pmid:9842371
- 22. Malig BJ, Green S, Basu R, Broadwin R. Coarse Particles and Respiratory Emergency Department Visits in California. Am J Epidemiol. 2013; 178(1): 58–69 pmid:23729683
- 23. Laurent O, Pedrono G, Segala C, Filleul L, Havard S, Deguen S, et al. Air pollution, asthma attacks, and socioeconomic deprivation: a small-area case-crossover Study. Am J Epidemiol 2008; 168: 58–65 pmid:18467319
- 24. Anderson HR, Leon APD, Bland JM, Bower JS, Emberlin J, Strachan DP. Air pollution, pollens, and daily admissions for asthma in London 1987–92. Thorax 1998; 53: 842–8 pmid:10193370
- 25. Ye F, Piver WT, Ando M, Portier CJ. Effects of temperature and air pollutants on cardiovascular and respiratory diseases for males and females older than 65 Years of age in Tokyo, July and August 1980–1995. Environ Health Perspect 2001; 109: 355–9 pmid:11335183
- 26. Smargiassi A, Kosatsky T, Hicks J, Plante C, Armstrong B, Villeneuve PJ, et al. Risk of asthmatic episodes in children exposed to sulfur dioxide stack emissions from a refinery point source in Montreal, Canada. Environ Health Perspect 2009; 117: 653–9 pmid:19440507
- 27. Szyszkowicz M. Ambient air pollution and daily emergency department visits for asthma in Edmonton, Canada. Int J Occup Med Env 2008; 21: 25–30
- 28. Lee SL, Wong WHS, Lau YL. Association between air pollution and asthma admission among children in Hong Kong. Clin Exp Allergy 2006; 36: 1138–46 pmid:16961713
- 29. Norris G, YoungPong SN, Koenig JQ, Larson TV, Sheppard L, Stout JW. An association between fine particles and asthma emergency department visits for children in Seattle. Environ Health Perspect 1999; 107: 489–93
- 30. Hajat S, Haines A, Goubet SA, Atkinson RW, Anderson HR. Association of air pollution with daily GP consultations for asthma and other lower respiratory conditions in London. Thorax 1999; 54: 597–605 pmid:10377204
- 31. Tenias JM, Ballester F, Rivera ML. Association between hospital emergency visits for asthma and air pollution in Valencia, Spain. Occup Environ Med 1998; 55: 541–7 pmid:9849541
- 32. Stieb DM, Burnett RT, Beveridge RC, Brook J. Association between ozone and asthma emergency department visits in Saint John, New Brunswick, Canada. Environ Health Perspect 1996; 104: 1354–9 pmid:9118879
- 33. Chew FT, Goh DYT, Ooi BC, Saharom R, Hui JKS, Lee BW. Association of ambient air pollution levels with acute asthma exacerbation among children in Singapore. Allergy 1999; 54: 320–9 pmid:10371090
- 34. Petroeschevsky A, Simpsom RW, Thalib L, Rutherford S. Associations between outdoor air pollution and hospital admissions in Brisbane, Australia. Arch Environ Health 2001; 56: 37–52 pmid:11256855
- 35. Magas OK, Gunter JM, Regens JL. Ambient air pollution and daily pediatric hospitalizations for asthma. Env Sci Pollut Res 2007; 14: 19–23
- 36. Lee JT, Son JY, Kim H, Kim SY. Effect of air pollution on asthma-related hospital admissions for children by socioeconomic status associated with area of residence. Arch Environ Occup Health 2006; 61: 123–30 pmid:17672354
- 37. Lin M, Chen Y, Burnett RT, Villeneuve PJ, Krewski D. Effect of short-term exposure to gaseous pollution on asthma hospitalization in children: a bi-directional case-crossover analysis. J Epidemiol Community Health 2003; 57: 50–5 pmid:12490649
- 38. Ko FWS, Tam W, Wong TW, Lai CKW, Wong GWK, Leung TF, et al. Effects of air pollution on asthma hospitalization rates in different age groups in Hong Kong. Clin Exp Allergy 2007; 37: 1312–9. pmid:17845411
- 39. Krmpotic D, Luzar-Stiffler V, Rakusic N, Stipic Markovic A, Hrga I, Pavlovic M. Effects of traffic air pollution and hornbeam pollen on adult asthma hospitalizations in Zagreb. Int Arch Allergy Immunol 2011; 156: 62–8 pmid:21447960
- 40. Lin M, Chen Y, Villeneuve PY, Burnett RT, Lemyre L, Hertzman C, et al. Gaseous air pollutants and asthma hospitalization of children with low household income in Vancouver, British Columbia, Canada. Am J Epidemiol 2004; 159: 294–303 pmid:14742290
- 41. Galan I, Tobı´as A, Banegas JR, Ara´nguez E. Short-term effects of air pollution on daily asthma emergency room admissions. Eur Respir J 2003; 22: 802–8 pmid:14621088
- 42. Jazbec A, Simic D, Hrsak J, Perosgolubicic T, Kujundzic D, Sega K, et al. Short-term effects of ambient nitrogen oxides on the number of emergency asthma cases in Zagreb, Croatia. Arh hig rada toksikol, 1999 50: 171–82 pmid:10566194
- 43. Mohr LB, Luo S, Mathias E, Tobing R, Homan S, Sterling D. Influence of season and temperature on the relationship of elemental carbon air pollution to pediatric asthma emergency room visits. J Asthma 2008; 45: 936–43 pmid:19085586
- 44. Lin M, Chen Y, Burnett RT, Villeneuve PJ, Krewski D. The Influence of ambient coarse particulate matter on asthma hospitalization in children: case-crossover and time-series analyses. Environ Health Persp 2002; 110: 575–81
- 45. Schouten JP, Vonk JM, Graaf AD. Short term effects of air pollution on emergency hospital admissions for respiratory disease: results of the APHEA project in two major cities in The Netherlands, 1977–89. J Epidemiol Commun H 1996; 50: 22–9
- 46. Castellsague J, Sunyer J, Saez M, Anto JM. Short-term association between air pollution and emergency room visits for asthma in Barcelona. Thorax 1995; 50: 1051–6 pmid:7491552
- 47. Chakraborty P, Chakraborty A, Ghosh D, Mandal J, Biswas S, Mukhopadhyay UK, et al. Effect of airborneAlternariaconidia, ozone exposure, PM10 and weather on emergency visits for asthma in school-age children in Kolkata city, India. Aerobiologia 2014; 30:137–148
- 48. Abe T, Tokuda Y, Ohde S, Ishimatsu S, Nakamura T, Birrer RB. The relationship of short-term air pollution and weather to ED visits for asthma in Japan. Am J Emerg Med 2007; 27: 153–9
- 49. Boutin-Forzano S, Adel N, Gratecos L, Jullian H, Garnier JM, Ramadour M, et al. Visits to the emergency room for asthma attacks and short-term variations in air pollution: a case-crossover study. Respiration 2004; 71: 134–7 pmid:15031567
- 50. Pereira G, Cook A, Vos AJBD, Holman CDAJ. A case-crossover analysis of traffic-related air pollution and emergency department presentations for asthma in Perth, Western Australia. Med J Australia 2010; 193: 511–4 pmid:21034384
- 51. Atkinson RW, Anderson HR, Sunyer J, Ayres J, Baccini M, Vonk JM, et al. Acute effects of particulate air pollution on respiratory admissions: results from APHEA 2 project. Am J Respir Crit Care Med 2001; 164: 1860–6 pmid:11734437
- 52. Silverman RA, Ito K. Age-related association of fine particles and ozone with severe acute asthma in New York City. J Allergy Clin Immunol 2010; 125: 367–73 pmid:20159246
- 53. Barnett AG, Williams GM, Schwartz J, Neller AH, Best TL, Petroeschevsky , et al. Air pollution and child respiratory health: A case-crossover study in Australia and New Zealand. Am J Respir Crit Care Med 2005; 171:1272–8 pmid:15764722
- 54. Jalaludin BB, Khalaj B, Sheppeard V, Morgan G. Air pollution and ED visits for asthma in Australian children: a case-crossover analysis. Int Arch Occup Environ Health 2008; 81: 967–974 pmid:18094989
- 55. Medina S, Tertre AL, Quenel P, Moullec YL, Lameloise P. Air pollution and doctors’ house calls: results from the ERPURS system for monitoring the effects of air pollution on public health in Greater Paris, France, 1991–1995. Environ Res 1997; 75: 73–84 pmid:9356196
- 56. Jaffe DH, Singer ME, Rimm AA. Air pollution and emergency department visits for asthma among Ohio Medicaid recipients, 1991–1996. Environ Res 2003; 91:21–28 pmid:12550084
- 57. Lavigne E, Villeneuve PJ, Cakmak S. Air pollution and emergency department visits for asthma in Windsor, Canada. Can J Public Heal 2012; 103:4–8
- 58. Stieb DM, Szyszkowicz M, Rowe BH, Leech JA. Air pollution and emergency department visits for cardiac and respiratory conditions: a multi-city time-series analysis. Environ Heal 2009; 8: 25
- 59. Romero-Placeres M, Mas-bermejo P, Lacasana-Navarro M, Tellez Rojo-Solis, Aguilar-Valdes J, Romieu I. Air pollution, bronchial asthma, and acute respiratory infections in minors, Habana City. Salud Publica Mex 2004; 46: 222–33 pmid:15368865
- 60. Wilson AM, Wake CP, Kelly T, Salloway JC. Air pollution, weather, and respiratory emergency room visits in two northern New England cities: an ecological time-series study. Environ Res 2005; 97: 312–21 pmid:15589240
- 61. Chimonas MAR, Gessner BD. Airborne particulate matter from primarily geologic, non-industrial sources at levels below National Ambient Air Quality Standards is associated with outpatient visits for asthma and quick-relief medication prescriptions among children less than 20 years old enrolled in Medicaid in Anchorage, Alaska. Environ Res 2007; 103: 397–404 pmid:17049511
- 62. Sluaghter JC, Kim E, Sheppard L, Sullivan JH, Larson TV, Claiborn C. Association between particulate matter and emergency room visits, hospital admissions and mortality in Spokane, Washington. J Expo Anal Env Epid 2005; 15: 153–9
- 63. Li S, Batterman S, Wasilevich E, Wahl R, Wirth J, Su FC, et al. Association of daily asthma emergency department visits and hospital admissions with ambient air pollutants among the pediatric Medicaid population in Detroit: Time-series and time-stratified case-crossover analyses with threshold effects. Environ Res 2011; 111: 1137–47 pmid:21764049
- 64. Mar T, Koenig JQ, Primomo J. Associations between asthma emergency visits and particulate matter sources, including diesel emissions from stationary generators in Tacoma, Washington. Inhal Toxicol 2010; 22: 445–8 pmid:20384437
- 65. Amancio CT, Nascimento LFC. Asthma and air pollutants: a time series study. Rev Assoc Med Bras 2012; 58: 302–7 pmid:22735221
- 66. Cirera L, Garcia-Marcos L, Gimenez J, Moreno-Grau S, Tobias A, Perez-Fernandez V, et al. Daily effects of air pollutants and pollen types on asthma and COPD hospital emergency visits in the industrial and Mediterranean Spanish city of Cartagena. Allergol Immunopathol (Madr) 2012; 40: 231–7
- 67. Cassino C, Ito K, Bader I, Ciotoli C, Thurston G, Reibman J. Cigarette smoking and ozone-associated emergency department use for asthma by adults in New York city. Am J Respir Crit Care Med 1999; 159: 1773–9 pmid:10351917
- 68. Iskandar A, Andersen ZJ, Bonnelykke K, Ellermann T, Andersen KK, Bisgaard H. Coarse and fine particles but not ultrafine particles in urban air trigger hospital admission for asthma in children. Thorax 2012; 67: 252–7 pmid:22156960
- 69. Evans KA, Halterman JS, Hopke PK, Fagnano M, Rich DQ. Increased ultrafine particles and carbon monoxide concentrations are associated with asthma exacerbation among urban children. Environ Res 2014, 129: 11–19 pmid:24528997
- 70. Sheppard L, Levy D, Norris G, Larson TV, Koenig JQ. Effects of ambient air pollution on nonelderly asthma hospital admissions in Seattle, Washington, 1987–1994. Epidemiology 1999; 10: 23–30 pmid:9888276
- 71. Morgan G, Sheppeard V, Khalaj B, Ayyar A, Lincoln D, Jalaudin B, et al. Effects of bushfire smoke on daily mortality and hospital admissions in Sydney, Australia. Epidemiology 2010; 21: 47–55 pmid:19907335
- 72. Yamazaki S, Shima M, Yoda Y, Oka K, Kurosaka F, Shimizu S, et al. Association of ambient air pollution and meteorological factors with primary care visits at night due to asthma attack. Environ Health Prev Med 2013; 18: 401–6 pmid:23640199
- 73. Neidell M, Kinney PL. Estimates of the association between ozone and asthma hospitalizations that account for behavioral responses to air quality information. Environ Science Policy 2010; 13: 97–103
- 74. Santus P, Russo A, Madonini E, Allegra L, Blasi F, Centanni S, et al. How air pollution influences clinical management of respiratory diseases. A case-crossover study in Milan. Respir Res 2012; 13: 95 pmid:23078274
- 75. Sunyer J, Atkinson R, Ballester F, Tertre AL, Ayres JG, Forastiere F, et al. Respiratory effects of sulphur dioxide: a hierarchical multicity analysis in the APHEA 2 study. Occup Environ Med 2003; 60: e2 pmid:12883029
- 76. Babin S, Burkom H, Holtry R, Tabernero N, Davies-Cole J, Stokes L, et al. Medicaid patient asthma-related acute care visits and their associations with ozone and particulates in Washington, DC, from 1994–2005. Inter J Env Res Pub Heal 2008; 18: 209–21
- 77. Yamazaki S, Shima M, Ando M, Nitta H, et al. Modifying Effect of age on the association between ambient ozone and nighttime primary care visits due to asthma attack. J Epidemiol 2009; 19: 143–51 pmid:19398846
- 78. Mar TF, Koenig JQ. Relationship between visits to emergency departments for asthma and ozone exposure in greater Seattle, Washington. Ann Allergy Asthma Immunol 2009; 103: 474–9 pmid:20084840
- 79. Hernandez-Cadena L, Téllez-Rojo MM, Sanín-Aguirre LH, Lacasaña-Navarro M, Campos A, Romieu I. Relationship between emergency room visits for respiratory disease and atmospheric pollution in Ciudad Juárez, Chihuahua. Salud Publica Mex 2000; 42: 288–97 pmid:11026070
- 80. Fletcher T, Gouveia N. Respiratory diseases in children and outdoor air pollution in San Paulo, Brazil: a time series analysis. Occup Environ Med 2000; 57: 477–83 pmid:10854501
- 81. Fung KY, Luginaah I, Goerey KM, Webster G. Air pollution and daily hospitalization rates for cardiovascular and respiratory diseases in London, Ontario. Int J Environ Stud. 2005; 62: 677–85 pmid:20703387
- 82. Ito K, Thurston GD, Silverman RA. Characterization of PM2.5, gaseous pollutants, and meteorological interactions in the context of time-series health effects models. J Expo Sci Environ Epidemiol 2007;17: S45–S60 pmid:18079764
- 83. Hua J, Yin Y, Peng L, Du L, Geng F, Zhu LP. Acute effects of black carbon and PM2.5 on children asthma admissions: A time-series study in a Chinese city. Sci Tot Envir 2014; 481:433–438
- 84. Cadelis G, Tourres R, Molinie J. Short-term effects of the particulate pollutants contained in saharan dust on the visits of children to the emergency department due to asthmatic conditions in Guadeloupe (French Archipelago of the Caribbean). PLoS One 2014; 9: e91136 pmid:24603899
- 85. Cheng MH, Cheng CC, Chiu HF, Yang CY. Fine Particulate Air Pollution and Hospital Admission For Asthma: A Case-crossover Study in TAipei. Journal of Toxicology and Environmental Health, Part A, 2014; 77:1071–1083
- 86. Cai J, Zhao A, Zhao J, Chen R, Wang W, Ha S, et al. Acute effects of air pollution on asthma hospitalization in Shanghai, China. Environ Pollution 2014; 191:139–44
- 87. Gleason JA, Bielory L, Fagliano JA. Associations between ozone, PM2.5, and four pollen types on emergency department pediatric asthma events during the warm season in New Jersey: A case-crossover study. Environ Res 2014; 132: 421–9 pmid:24858282
- 88. Sacks JD, Rappold AG, Davis JA, Richardson DB, Waller AE, Luben TJ. Influence of Urbanicity and County Characteristics on the Association between Ozone and Asthma Emergency Department Visits in North Carolina. Environ Health Perspect 2014; 122:506–12 pmid:24569869
- 89. Raun LH, Ensor KB, Persse D. Using community level strategies to reduce asthma attacks triggered by outdoor air pollution: a case crossover analysis. Environ Heal 2014; 13:58
- 90. Ward DJ, Ayres JG. 2004. Particulate air pollution and panel studies in children: a systematic review. Occup Environ Med 61: e13 pmid:15031404
- 91. Weinmayr G, Romeo E, Sario MD, Weiland SK, Forastiere F. Short-term effects of PM10 and NO2 on respiratory health among children with asthma or asthma-like symptoms: A systematic review and meta-analysis. Environ Health Perspect 2010; 118: 449–57 pmid:20064785
- 92. Goodman JE, Chandalia JK, Thakali S, Seeley M. Meta-analysis of nitrogen dioxide exposure and airway hyper-responsiveness in asthmatics. Crit Rev Toxicol 2009; 39:719–42 pmid:19852559
- 93. Levy JI, Diez D, Dou YP, Barr CD, Dominici F. A meta-analysis and multisite time-series analysis of the differential toxicity of major fine particulate matter constituents. Am J Epidemiol 2012; 175:1091–9 pmid:22510275
- 94. Mauderly JL, Samet JM. Is there evidence for synergy among air pollutants in causing health effects? Environ Health Perspect 2009; 117:1–6 pmid:19165380
- 95. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339:b2535 pmid:19622551
- 96. Mustafic H, Jabre P, Caussin C, Murad MH, Escolano S, Tafflet M, et al. Main Air Pollutants and Myocardial Infarction: A Systematic Review and Meta-analysis. JAMA 2012; 307:713–21 pmid:22337682
- 97. Atkinson RW, Kang S, Anderson HR, Mills IC, Walton HA. Epidemiological time series studies of PM2.5 and daily mortality and hospital admissions: a systematic review and meta-analysis. Thorax. 2014;69:660–5. pmid:24706041
- 98. Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327:557–60 pmid:12958120
- 99. Nawrot TS, Perez L, Künzli N, Munters E, Nemery B. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet 2011; 377:732–40 pmid:21353301
- 100. Egger M, Smith DG, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315:629–34 pmid:9310563
- 101. Hoek G., Beelen R., de Hoogh K., Vienneau D., Gulliver J., Fischer P., Briggs D.,2008. A review of land-use regression models to assess spatial variation of outdoor air pollution. Atmos. Environ. 42, 7561e7578
- 102. Bayram H, Sapsford RJ, Abdelaziz MM, Khair OA. Effect of ozone and nitrogen dioxide on the release of proinflammatory mediators from bronchial epithelial cells of nonatopic nonasthmatic subjects and atopic asthmatic patients in vitro. J Allergy Clin Immunol 2001;107(2):287–94. pmid:11174195
- 103. Cai C, Xu J, Zhang M, Chen XD, Li L, Wu J, Lai HW, Zhong NS. Prior SO2 exposure promotes airway inflammation and subepithelial fibrosis following repeated ovalbumin challenge. Clin Exp Allergy. 2008;38: 1680–7 pmid:18631350
- 104. Henderson RF, Benson JM, Hahn FF, Hobbs CH, Jones RK, Mauderly JL, McClellan RO, Pickrell JA. New approaches for the evaluation of pulmonary toxicity: bronchoalveolar lavage fluid analysis. Fundam Appi Toxicol 1985; 5:451–458
- 105. Li N, Buglak N. Convergence of air pollutant-induced redox-sensitive signals in the dendritic cells contributes to asthma pathogenesis. Toxicol Lett 2015;237(1):55–60. pmid:26026960
- 106. Brugha RE, Mushtaq N, Round T, Gadhvi DH, Dundas I, Gaillard E, et al. Carbon in airway macrophages from children with asthma. Thorax 2014; 69:654–659 pmid:24567296
- 107. American Thoracic Society. Health effects of outdoor air pollution. Committee of the Environmental and Occupational Health Assembly of the American Thoracic Society. Am J Respir Crit Care Med 1999;153: 3–50.
- 108. Mikerov AN, Phelps DS, Gan X, et al. Effects of ozone exposure and infection on bronchoalveolar lavage: Sex differences in response patterns. Toxicol Lett 2014: 230:333–44 pmid:24769259
- 109. Pope CA III, Dockery DW. Health effects of fine particulate air pollution: lines that connect. J Air Waste Manag Assoc 2006; 56:706–42
- 110. Pilotto LS, Nitschke M, Smith BJ, Pisaniello J, Ruffin RE, McElroy HJ, et al. Randomized controlled trial of unflued gas heater replacement on respiratory health of asthmatic school children. Int J Epidemiol 2003; 33:208–14
- 111. Howden-Chapman P, Pierse N, Nicholls S, Gillespie-BennetT J, Viggers H, Cunningham M, Phipps R, et al. Effects of improved home heating on asthma in community dwelling children: randomised controlled trial. BMJ 2008; 337:a141
- 112. Renzetti G, Silvestre G, D’Amario C, Bottini E, Gloria-Bottini F, Bottini N, et al. Less air pollution leads to rapid reduction of airway inflammation and improved airway function in asthmatic children. Pediatrics 2009; 123:1051–8 pmid:19255039
- 113. Li Y, Wang W, Kan H, Xu X, Chen B. Air quality and outpatient visits for asthma in adults during the 2008 Summer Olympic Games in Beijing. Sci Total Environ 2010; 408:1226–1227 pmid:19959207
- 114. Gasparrini A, Armstrong B. Reducing and meta-analysing estimates from distributed lag non-linear models. BMC Med Res Meth 2013; 13:1
- 115. Hastie T, Tibshirani R. Generalized Additive Models. London, Chapman and Hall, 1990