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The Role of Air Pollution in Adult-Onset Asthma: A Review of the Current Evidence
Benedicte Jacquemin, M.D., Ph.D. 1, 2 Tamara Schikowski, M.D., Ph.D. 3, 4 Anne Elie Carsin 58 Anna Hansell, M.B., B.Chir., Ph.D. 9, 10 Ursula Krmer, Ph.D. 11 Jordi Sunyer, M.D., Ph.D. 58 Nicole Probst-Hensch, M.D., Ph.D. 3, 4 Francine Kauffmann, M.D. 1, 2 Nino Knzli, M.D., Ph.D. 3, 4
1 Centre for Research in Epidemiology and Population Health (CESP),

Semin Respir Crit Care Med 2012;33:606 619.

Abstract

Keywords

asthma incidence air pollution adults traf c ultrane particulate matter

The causes of adult-onset asthma are poorly established, and the asthmogenic role of air pollution has been investigated primarily in children. This review assesses the current evidence of the association between air pollution and asthma incidence among subjects free of asthma at least until late childhood. Seven publications from ve study populations fullled the inclusion criteria (one case-control and six cohort studies). All but one used markers of local traf c-related air pollution to characterize long-term exposure. Those studies reported similar associations with traf c-related air pollution. However, protocols, denitions of asthma, and exposure assignment were rather heterogeneous, and three publications relied on the same study; thus we abstain from meta-analytic summaries. Reported patterns of effect modication (e.g., by sex, atopy, or smoking) were inconsistent. Overall, the role of traf c-related air pollution in adult-onset asthma is less conclusive than in childhood asthma. Larger studies with more consistent denitions of phenotypes and exposure assessment for local traf crelated pollutants (e.g., ultrane particles) are needed. Pooling existing cohorts such as in the ongoing European ESCAPE and TRANSPHORM consortia are promising steps. There is, however, a need for large-scale megacohorts to investigate these effects in standardized ways and to identify the most susceptible populations.

Issue Theme Asthma; Guest Editors, J. Christian Virchow, M.D. and Peter J. Barnes, D.M., F.R.S.

Copyright 2012 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0032-1325191. ISSN 1069-3424.

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Villejuif, France 2 Universit Paris Sud, Villejuif, France 3 Swiss Tropical and Public Health Institute, Basel, Switzerland 4 University of Basel, Basel, Switzerland 5 Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain 6 Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain 7 Hospital del Mar Research Institute (IMIM), Barcelona, Spain 8 Universitat Pompeu Fabra, Barcelona, Spain 9 MRC-HPA Centre for Environment and Health, Imperial College London, London, United Kingdom 10 Imperial College Healthcare NHS Trust, St. Mary s Hospital, London, United Kingdom 11 Leibniz Research Institute for Environmental Medicine, Dsseldorf, Germany

Address for correspondence and reprint requests Nino Knzli, M.D., Ph.D., Swiss Tropical and Public Health Institute, P.O. Box 4002, Basel, Switzerland (e-mail: Nino.Kuenzli@unibas.ch).

The Role of Air Pollution in Adult-Onset Asthma

Asthma incidence has increased in the last decades, and although the epidemic may have reached a plateau in some Western countries, it remains a public health concern affecting between 5 and 10% of the general population.1 Although genetic factors certainly play a role in asthmagenesis,2,3 the secular trends indicate the high relevance of environmental factors. It is challenging to investigate the contribution of environmental exposures to the onset of asthma given the complexities of the exposome4 and the fact that a range of obstructive pathologies may be grouped under the clinical phenotype of asthma.5 Asthma often appears in childhood, may stay inactive for a long time, and then reappear or worsen later in life. However, the notion that asthma may always begin during childhood is not supported by more recent studies reporting new onset of asthma during adulthood.6 Indeed, in the ongoing debate about asthma possibly consisting of various phenotypes, adult-onset asthma may be seen as a distinct phenotype and under the novel concept of categorizing disease entities by underlying mechanismsor endotypesseparate consideration of adult-onset asthma in etiologic research is preferable.7 Genetic studies indicate as well differences between childhood asthma and adult-onset asthma.3 However, apart from occupational asthma, which might be responsible for some 10 to 25% of adult asthma,8 the causes of asthma onset in adults have not been extensively investigated, although the incidence rate of adult-onset asthma (i.e., onset after age 16) is also not negligible (between one and four per 1000 persons per year).9 A few studies have described other determinants such as female gender, lung function, atopy, obesity, and parental history of asthma.6,10 To investigate the possible causal role of ambient air pollution in the development of adult-onset asthma, it is important to distinguish acute effects of air pollution from the long-term contribution of pollutants to the development of the underlying pathology. Given that partly different mechanisms may be involved in triggering exacerbations among asthmatics versus promoting the development of hyperreactive airways, this distinction is important in planning and interpreting studies. Because it is well known that exposure to ambient air pollution is associated with asthma exacerbations1114 (e.g., measured as asthma attacks or exacerbations of symptoms or increases in medication, emergency visits, or hospitalization),1517 the investigation of associations between long-term cumulative exposure to air pollutants and asthma onset need to rely on other outcomes than these events. Candidates are the prevalence or preferably the incidence of doctor-diagnosed asthma or the course of chronic preclinical markers of the phenotype. The literature of the long-term effect of air pollution on asthma onset is dominated by studies of children.18,19 In children, proximity to traf c is associated with an increase in asthma prevalence and incidence,2022 with substantial evidence for a causal asthmogenic role of the pollutants occurring in high concentrations along busy roads.19,23,24 In contrast, in the 2010 Health Effects Institute report on traf c-related air pollution, the expert panel concluded that the evidence between exposure to traf c-related pollution

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and adult-onset asthma was inadequate and insuf cient because only one study was available.25 The biological mechanisms that could explain the association between air pollution and asthma incidence include chronic airway in ammation mediated by direct local irritation and by oxidative stress.26 Air pollution is also associated with lung function growth,27 levels,28,29 and decline.30 All these features are implicated in both asthma severity and etiology. This article reviews the current evidence of a correlation between adult-onset asthma and air pollution.

Methods
Through a PubMed search, we reviewed original articles in peer-reviewed journals published until June 2011. The terms searched were asthma and air pollution or traf c and incidence or onset, setting the limits to the articles in English and in adults. The search resulted in 576 papers, for which we screened the title, the abstract, and the full article when necessary to identify the papers according to the criteria that will be described here. In addition, we compared the list with recent reviews based on publications up to November 2009 on air pollution and respiratory health,18,19,23,24 con rming that our search did not miss any eligible paper. We included only longitudinal or case-control studies that investigate the determinants of adult-onset asthma among those free of asthma at least until late childhood. Underreporting of childhood asthma at baseline survey of adults may overestimate adult-onset asthma among those with recurrent asthma in the follow-up investigations. Thus information about age of onset is important to reliably de ne adult-onset asthma. Cross-sectional associations between air pollution and adult-onset asthma prevalence may be a proxy for the investigation of adult-onset incidence if age of onset is known, if relapse and remission were constant, and if there is no self-selection of residential location after asthma onset.18 Because these are rather unknown factors, we focus our review on incidence studies. However, we will discuss the use or limitations of prevalence in the discussion, providing a summary table of the three adult asthma prevalence publications (based on two studies) in Table S1. A Canadian study in press at the time this review was submitted is not included here either, although asthma incidence in young adults (N 395) who were free of asthma during childhood was considered as an outcome in the 2004 2006 follow-up of this cohort of >3000 children rst examined in 19761986.31 Assignment of air pollution exposure was not clearly described, and analyses were based on dichotomous air pollution exposure categories (high versus low). This limits the quantitative interpretation and comparison of both the statistically signi cant ndings seen for SO2 and the null ndings reported for particles in association with adult-onset asthma. Under the null hypothesis, incidence of adult-onset asthma should not be associated with the past long-term exposure to air pollutants. We thus included in this review all studies investigating the association between objectively measured markers of exposure to ambient air pollution and
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Table S1 Description of Studies Assessing the Association between Air Pollution Exposure and Asthma Prevalence in Adults Year of the Study Air Pollution Exposure Markers Self-reported exposure to traf c at home, traf c intensity at home address, NOx dispersion models (250 250 m) for 2001 Asthma triggered by allergic factors, urban vs periurban area Urban vs periurban area Interactions Tested Main Results Subjects Age and Characteristics Asthma Definition Number of Cases/ Study Population 686/9274

Reference

Design and Location of Study

Seminars in Respiratory and Critical Care Medicine

Lindgren et al, 200955

Cross-sectional, Malm, Sweden

2000

From 18 to 77 from general population

Positive answer to Have you been diagnosed by a doctor as having asthma? No information about age of onset 473/9319

Living close to traf c was associated with higher asthma prevalence No association was found with NOx

The Role of Air Pollution in Adult-Onset Asthma

Lindgren et al, 200956 Self-reported exposure to traf c at home, traf c intensity at home address, NOx dispersion models (250 250 m) for 2001

Cross-sectional, Malm, Sweden

2000

From 18 to 77 from general population

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Positive answer to Have you been diagnosed by a doctor as having asthma? and asthma symptoms in the last 12 months No information about age of onset Positive answer to Do you have asthma? No information about age of onset 2140/ 22693 for the crosssectional analysis and 705 cases/ 2856 controls for the case-control analysis NOx dispersion models (250 250 m) for 2001, traf c intensity at residential and workplace addresses, self-reported traf c exposure and self-reported time spent in traf c and commuting

Living close to traf c was associated with higher current allergic asthma prevalence No association was found with NOx

Jacquemin et al.

Lindgren et al, 201054

Cross-sectional and nested case-control, Scania, Sweden

2004 and 2005

From 18 to 65 from the general population for the cross-sectional analysis and asthma cases matched with three controls by sex

None

Living close to traf c was associated with higher asthma prevalence No association was found with NO No association was found either with exposure at workplace or with time spent in traf c

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Table 1 Description of Studies Assessing the Association between Air Pollution Exposure and Adult-Onset Asthma
Year of Study Recruited in 1977 and followed up in 1987 and 1992 From 27 to 87 years old at baseline, living in California since 1967 at least, nonsmoking Seventh-Day Adventists Subjects who said no to self-reported doctor told asthma but yes to the same question in 1982 or 1987 101/3091 Subjects Age and Characteristics Asthma Incidence Definition Number of Cases/ Study Population Air Pollution Exposure Markers PM10, SO4, NO2, SO2, O3, and O38 hour average assessed and averaged from 1973 to 1992 at home and work addresses, using the three closest xed monitoring stations Home outdoor NO2 measurements for 1 week, standardized and adjusted to represent annual average (for the year of the recruitment) Traf c intensity at home address in a 200 m buffer 116 asthma onset, 58 asthma incidence cases/3824 NO2 dispersion models (50 50 m) Distance to nearest major road < 50 m Both estimates at home addresses for the year 1990 Asthma onset: subjects who said no to asthma attacks and to asthma medication in the last 12 months at baseline, and said yes to ever asthma or asthma diagnosed by a doctor at follow-up. Asthma incidence: the same denition plus age of onset between both surveys Subjects who answered no to ever asthma at baseline but yes at follow-up. A sensitivity analysis was done in subjects who reported age of onset between both surveys

Reference

Study

Design and Location of Study

McDonnell et al, 199933

AHSMOG

Prospective cohort, in California, USA

Modig et al, 200625 From 20 to 60, asthmatic cases, controls from general population Suspected cases from the primary health care were reported, then each case was clinically examined

Lulea

Case-control, in Lulea, Sweden

19951999

203 cases and 203 sexand age-matched controls

Modig et al, 200937 Recruited in 1990 and followed up in 1999 From 18 to 45 at recruitment, from general population

RHINE

Prospective cohort, in three Swedish cities (RHINE)

The Role of Air Pollution in Adult-Onset Asthma

Seminars in Respiratory and Critical Care Medicine

Jacquemin et al, 200943

ECRHS

Prospective cohort, in 17 cities from seven European countries (ECRHS)

Recruited in 199094 and followed up in 19992001

From 20 to 44 at recruitment, from general population

186 (but only 79 reported age of onset between both surveys)/4185

NO2 dispersion models (1 1 km) for 2001 for all Europe: APMoSPHERE

(Continued)

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Table 1 (Continued)
Year of Study Recruited in 199094 and followed up in 19992001 From 20 to 44 at recruitment, from general population 387 with at least one symptom and 123 with at least two/4394 Subjects Age and Characteristics Asthma Incidence Definition Number of Cases/ Study Population Air Pollution Exposure Markers NO 2 dispersion models (1 1km) for 2001 for all Europe: APMoSPHERE

Reference

Study

Design and Location of Study

Seminars in Respiratory and Critical Care Medicine

Jacquemin et al, 200942

ECRHS

Prospective cohort, in 17 cities from 7 European countries (ECRHS)

The Role of Air Pollution in Adult-Onset Asthma

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Subjects who answered no to ever asthma, asthma medication or asthma symptoms at baseline but reported an asthma score (based on asthma symptoms in the last 12 months) >1 at follow-up (thus in subjects with a score of 0 plus no asthma at baseline and with a score of at least 1 at follow-up) Subjects who answered yes to asthma attacks or asthma medication in the last 12 months at follow-up among those who said no to the same questions at baseline Subjects who answered yes to ever asthma and was it conrmed by a doctor at follow-up among those without asthma (dened with the same questions) or COPD (dened with lung function measurements) at baseline and reported an age of onset between both surveys 120/2577

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Castro-Giner et al, 200941

ECRHS

Prospective cohort, in 13 cities from 6 European countries (ECRHS), Gene air pollution interactions

Recruited in 199094 and followed up in 19992001 From 20 to 44 at recruitment, from general population

NO 2 dispersion models (1 1 km) for 2001 for all Europe: APMoSPHERE

Jacquemin et al.

Knzli et al, 200947 From 18 to 60 at recruitment, neversmokers without asthma or COPD, from general population

SAPALDIA

Prospective cohort in eight Swiss areas

recruited in 199091 and followed up in 200002

41/2725

Traf c-related PM10 change, from 1990 and 2000 using dispersion model (200 200 m)

Incidence, by year of publication. AHSMOG, Adventist Health and Smog Study; APMoSPHERE, Air Pollution Modeling for Support to Policy on Health and Environmental Risk in Europe; COPD, chronic obstructive pulmonary disease; ECRHS, European Community Respiratory Health Survey; RHINE, Respiratory Health in Northern Europe; SAPALDIA, Swiss Study on Air Pollution and Lung and Heart Diseases in Adults.

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The Role of Air Pollution in Adult-Onset Asthma

adult-onset asthma. Studies and results based on reported exposure to traf c were disregarded.32 Studies dealing with childhood asthma are not included,19,23,24 nor are investigations on acute manifestations of adult asthma (such as wheezing, exacerbations, or chronic bronchitis symptoms) in association with air pollution. Also excluded are ecologic comparisons, studies dealing only with indoor air pollution and studies of other chronic obstructive respiratory diseases such as chronic obstructive pulmonary disease (COPD).

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Results
In total, seven publications from ve study populations ful lled the inclusion criteria. We present them in the order of publication date. The studies are summarized in Table 1 and the main results presented in Table 2. The earliest study identi ed to report an association between long-term exposure to air pollution (namely ozone) and asthma incidence was a cohort of nonsmoking California Seventh-Day Adventists assessing the long-term health effects of ambient air pollutants (AHSMOG [Adventist Health and Smog Study]).33 Subjects were recruited in 1977, aged between 25 and 87, and followed up in 1987 and 1992. All of them were current nonsmokers, and 36% of males and 14% of females were ex-smokers. Air pollution estimates were derived using monthly interpolations from the three nearest xed-site monitoring stations in California to the residential and working place zip code centroids. The monitoring network was not dense at these times; thus, whereas this re ects a personal assignment of ambient concentrations, it is a proxy of personal exposure to urban background pollution rather than a measure of local traf c-related exposure conditions. Monthly indices were averaged, cumulated, and then averaged for the last 20 years because study participants were required at baseline to have lived at least for the previous 10 years in the study area. This analysis33 included 2881 subjects with available estimates of air pollution exposure. Asthma incidence was de ned with a positive answer to the question Has a doctor ever told you have asthma? in any of the two follow-ups but not at baseline. At some point during follow-up more than 80% of the new cases of asthma reported symptoms compatible with a diagnosis of asthma. In males, reported doctor-diagnosed asthma was signi cantly associated with the 20 year mean 8 hour average ambient O3 concentration [risk ratio (RR) 2.1 (1.0 to 4.2) per 27 ppb increase] (Table 2). No associations were found in women, nor with other measures of urban background pollution (PM10, SO4, NO2, and SO2). Previously in the same population, an association was reported between total suspended sulfates and new cases of asthma.34 Also, long-term exposure to both O3 and total suspended particles (TSP) was found to be associated with several respiratory symptoms; however, these cannot be considered markers of incidence.35,36 The study by Modig and colleagues25 was the rst to investigate the contribution of traf c-related pollution to adult-onset asthma. In this study, traf c was characterized by measurements of outdoor NO2 and traf c ow at the subjects residences. There were 203 clinically examined

incident cases of asthma among the population of a Swedish town aged 20 to 60 years (71,000 inhabitants). The cases were age- and sex-matched with 203 control subjects without asthma selected from the Swedish population registry. The asthma diagnosis was based on a standardized clinical examination. The subjects with asthma had a tendency to have higher residential exposure to traf c ows and home outdoor concentrations of NO2 compared with the controls; however, the association did not reach statistical signi cance and was only borderline signi cant for the 67 cases with positive skin tests (OR 1.2 (1.01.3) per 1 g/m3) (Table 2). Models included adjustment for smoking in this population with some 25% of current smokers and 50% never-smokers. Modig et al37 conducted another study including 3824 participants from three Swedish cities included in the Respiratory Health in Northern Europe cohort (RHINE).38 Subjects were recruited in 1990, aged between 18 and 45 years old, and followed up in 1999. Exposure at each participants home was estimated with dispersion models using winter half-year concentrations of NO2. They also used the distance between the participants home address and the nearest major road. They de ned subjects with asthma onset as those who answered no to asthma symptoms in the last 12 months and to asthma medication in the last 12 months at baseline and yes to any of those question plus yes to ever asthma at follow-up. In a stricter de nition, age of asthma onset was required to be after the rst survey. There were 107 asthmaonset cases but only 55 incident cases based on the stricter de nition. There was a positive association between both asthma onset and more strictly de ned asthma incidence and the levels of NO2 [odds ratio (OR) 1.5 (1.1 to 2.0) and 1.5 (1.0 to 2.4)], respectively, per 10 g/m3 increase) as well as living within 50 meters of a major road (OR 2.9 (1.7 to 5.0) and 3.8 (1.9 to 7.8), respectively) (Table 2). Results were adjusted for smoking in this population, with close to 50% never-smokers. In the European Community Respiratory Health Survey (ECRHS)39,40 associations between NO2 and asthma incidence were investigated in three interrelated publications.4143 Subjects were recruited from 1990 to 1994, at age 20 to 44 years, and followed up 8 to 12 years later. In both analyses more than 4000 adults from 17 cities from seven countries were included [Sweden (Gteborg, Ume, and Uppsala), United Kingdom (Ipswich and Norwich), Germany (Erfurt), Belgium (Antwerp), France (Paris and Grenoble), Italy (Verona, Pavia, and Torino), and Spain (Albacete, Barcelona, Huelva, Galdakao, and Oviedo)]. Subjects home addresses were geocoded and linked to outdoor NO2 estimates, considered a marker of local traf c- related pollution. This information was obtained from the 1 km2 background NO2 surface modeled in APMoSPHERE (Air Pollution Modeling for Support to Policy on Health and Environmental Risk in Europe).44 In total, 183 incident cases were identi ed, with 95 con rming that the onset occurred between both surveys. Some 42 to 45% were never-smokers in these ECRHS-based analyses, and models adjusted for smoking status. In the rst paper, asthma incidence was de ned in the classic way,43 where cases were answering positively to the question Have you ever had asthma? in ECRHS II among
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Table 2 Main Results of Studies Described in Table 1

Association for All the Population Not applicable as only nonsmokers Risk ratio for an increase of 27 ppb of O38 hour average in males: 2.09 (1.034.16), in females: 0.86 (0.581.26) Not tested Not tested No Stratication by ever-smoking showed that the association was similar in ex-smokers than in never-smokers (estimates not shown) No No Association by Sex Association by Smoking Association by Atopy Other Interaction Tested Main Message O38 hour average is associated with adult asthma incidence in males No other pollutants (including NO2 or PM10) were associated with asthma incidence.

Reference

Study

Range and Mean of Exposure Metric

Seminars in Respiratory and Critical Care Medicine

McDonnell et al, 199933

AHSMOG

O3 8 hour average 0.074.9 ppb (46.5) O3 mean range 0.040.7 ppb (25.7) PM10 0.083.8 g.m-3 (50.3) SO2 0.010.5 ppb (6.8) NO2 0.060.1 (35.4) OR for an increase of 1 g.m3 of NO2: in subjects with positive SPT: 1.2 (1.01.3) with negative SPT:1.0 (0.91.1)

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Modig et al, 2006 25

Lulea

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NO2 (modeled winter average) 3.345.6 (17.9) g. m3

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In subjects who had lived at least 2 years at the present home OR for living close to high traf c ow (in a 200 m buffer): 2.4 (0.96.2) OR for an increase of 1 g.m3 of NO 2: 1.1 (0.91.2) For onset asthma: OR for NO2 per 10 g.m3: 1.46 (1.071.99) OR for distance to major road < 50 m: 2.92 (1.704.98) For asthma incidence: OR for NO2 per an increase of 10 g. m3: 1.54 (1.002.36) OR for distance to major road < 50 m: 3.88 (1.937.82) OR for NO2 per 10 g.m3: For onset asthma: in males:1.57 (0.972.52) in females: 1.30 (0.962.04) For asthma incidence: in males:1.32 (0.642.74) in females: 1.67 (0.982.74) Not tested OR for NO2 per 10 g.m3: For onset asthma: in subjects with hay fever at baseline: 1.31 (0.852.04) Without hay fever at baseline: 1.55 (1.032.35) For asthma incidence: in subjects with hay fever at baseline: 1.15 (0.592.24) without hay fever at baseline: 1.79 (1.043.05)

Living close to high traf c was nonsignicantly associated with asthma incidence. NO2 was associated with adult asthma incidence only in subjects with a positive SPT. OR for NO2 per 10 g.m3: For onset asthma: in subjects with wheeze at baseline: 1.62 (1.032.57) Without wheeze at baseline: 1.34 (0.902.00) For asthma incidence: in subjects with wheeze at baseline: 2.08 (1.123.87) Without wheeze at baseline: 1.19 (0.662.12) NO2 exposure and living close to a major road were associated with asthma onset and incidence in adults

Jacquemin et al.

Modig et al, 2009 37

RHINE

NO2 adjusted for temperature in cases: 2.529.9 (median 5.6) NO2 in controls 2.523.1 (median 6.0)

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Table 2 (Continued )
Association for All the Population OR for NO2 per 10 g.m3: 1.43 (1.022.01) When only considering those reporting age of asthma onset between the two surveys: 1.72 (0.993.00) Ratio of the mean score (RMS) per 10 g.m3 in subjects with a 0 score and no asthma at baseline: 1.27 (1.111.45) Ratio of the mean score (RMS) per 10 g.m3: in males: 1.32 (1.121.56) in females: 1.14 (0.971.34) Ratio of the mean score (RMS) per 10 g. m 3 : in never- and ex-smokers: 1.30 (1.111.52) in smokers: 1.07 (0.921.26) Not tested Association of NO2 per 10 g.m3 increase: in atopics: NQO1 rs291766 CC: 1.24 (0.841.91) in nonatopics: NQO1 rs291766 CC: 2.38 (1.135.68) Higher effect in atopics not signicant. No Ratio of the mean score (RMS) per 10 g.m3: in atopics at baseline: 1.37 (1.141.65) in nonatopics at baseline: 1.20 (1.021.41) Ratio of the mean score (RMS) per 10 g.m3: in subjects with BHR at baseline: 1.27 (0.941.72) without BHR at baseline: 1.18 (1.021.37) OR for NO 2 per 10 g.m3: in males: 1.31 (0.762.27) in females: 1.53 (0.992.38) Not tested OR for NO2 per 10 g.m3: in atopics: 1.31 (0.842.04) in nonatopics: 1.57 (0.922.67) No Association by Sex Association by Smoking Association by Atopy Other Interaction Tested Main Message NO2 was associated with asthma incidence in adults

Reference

Study

Range and Mean of Exposure Metric

Jacquemin et al, 2009 43

ECRHS

NO2 IQR 20.733.3 median 27.7 max 63

Jacquemin et al, 2009 42

ECRHS

See above

NO2 is associated with the asthma score, which is an alternative to assess asthma incidence in adults. Association was stronger in never-ex smokers A signicant interaction was found between NQO1 rs2917666 and NO2 for newonset of asthma.

Castro-Giner et al, 200941 Association of NO2 per 10 g.m3 increase in this gene air pollution interaction: NQO1 rs291766 CC: 2.02 (1.163.73) NQO1 rs291766 CG/GG: 1.26 (0.831.99) Association of NO2 per 10 g.m3 increase: in males NQO1 rs291766 CC: 1.39 (0.822.46) in females NQO1 rs291766 CC: 1.81 (1.133.09) Effect slightly higher in males (HR in gure and not tables, thus hard to extract) Only tested in never-smokers. HR for 1 g.m3 change in traf c PM10: 1.30 (1.051.61) Not applicable as only tested in never-smokers

ECRHS

See above

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Knzli et al, 200947

SAPALDIA

Traf c related PM10 change in g.m3 p25 (-0.80) p50 (-0.39) p75 (-0.21) and from Fig. I (not shown here; from original publication) extracted $9, max $7.4

Higher effects (none signicant) in subjects with parental asthma, parental allergies (p 0.088), BHR and age > 40.

Increase in traf c PM10 is associated with asthma incidence in adults nonsmokers. Residential proximity to busy roads was not associated to asthma

Seminars in Respiratory and Critical Care Medicine

Only the adjusted estimates are shown unless specied otherwise. AHSMOG, Adventist Health and Smog Study; BHR, bronchial hyperreactivity; ECRHS, European Community Respiratory Health Survey; HR, hazard rate; IQR, interquartile range; RHINE, Respiratory Health in Northern Europe; SAPALDIA, Swiss Study on Air Pollution and Lung and Heart Diseases in Adults; SPT, skin prick test.

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(particulate matter up to 10 m in diameter) was signi cantly associated with asthma incidence among 2725 neversmokers (hazard ratio 1.3 (1.0 to 1.6) per 1 g/m3 change in traf c-related PM10)47 (Table 2). The air pollution estimates at both surveys were predicted and interpolated to the homes addresses using dispersion models that took into account source-speci c emission and meteorological data. The population-based sample of adults (age 18 to 60) was recruited in 1991 and followed up in 2002. Asthma incidence was de ned as positive answers to both Have you ever had asthma? and was this con rmed by a doctor? at the followup in those without asthma or COPD at baseline. The reported age of onset had to be after the rst survey, resulting in 41 new cases of asthma.

those subjects who answered no to this question in ECRHS I. The association between asthma incidence and NO2 was stronger when restricting the analysis to those who reported an age of onset between both surveys (thus with a coherent age of onset), but it reached statistical signi cance only in the total sample [OR 1.4 (1.0 to 2.0) per 10 g/m3 increase] (Table 2). Associations in nonsmokers were stronger. In a further analysis, the asthma de nition was based on the asthma score previously proposed45,46 as an alternative way of de ning asthma.42 Although the score is based on symptomsotherwise not included in the reviewwe consider it because this de nition of asthma is based on a whole cluster of symptoms, used as a novel approach to de ne asthma phenotypes on a continuous scale rather than as a dichotomous entity.45,46 As shown, a high score is very speci c for doctors diagnosed asthma. The analyses of Jacquemin et al42 used the number of reported respiratory symptoms out of ve: wheeze and breathlessness, feeling of chest tightness, attack of shortness of breath at rest, attack of shortness of breath after exercise, and woken by attack of shortness of breath during the last 12 months.45,46 The score was derived in ECRHS II in subjects without asthma or asthma symptoms in ECRHS I. An incident case was one with a 0 score and no asthma ever at baseline but at least a score of 1 at follow-up. Based on the score, 387 subjects had at least one symptom and 123 had at least two at follow-up. A signi cant association between traf c-related air pollution and the asthma score in those with no asthma and no symptoms at baseline was observed [ratio of the mean score (RMS) 1.2 (1.0 to 1.5) per 10 g/m3 increase] (Table 2). Associations with traf c-related pollution were strongest for those moving from score 0 to a score ! 3 (RMS 2.57, 95% CI 1.31 to 5.04), thus reporting a group of symptoms shown to be strongly predictive of doctors diagnosed asthma.46 Signi cant interactions with smoking status were reported with stronger associations in nonsmokers. The third analyses of ECRHS data investigated the role of genetic polymorphisms potentially modifying the association between NO2 and asthma incidence and prevalence.41 Prevalence of current asthma was de ned as a positive response to either of two questions in ECRHS II: attack of asthma during the last 12 months or current use of asthma medication. Asthma incidence was de ned as reporting asthma (using the same de nition as already described) in ECRHS II excluding people who reported asthma or a history of asthma in ECRHS I. They evaluated polymorphisms in genes involved in oxidative stress pathways [glutathione S-transferases M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) and NAD(P)H (nicotinamid adenine dinucleotide phosphatase), quinine oxidoreductase (NQO1)], in ammatory response [tumor necrosis factor (TNFA)], immunological response [Toll-like receptor 4 (TLR4)], and airway reactivity [adrenergic receptor 2 (ADRB2)]. A signi cant interaction was found between NQO1 rs2917666 and NO2 for asthma prevalence and new-onset asthma (p 0.04) (Table 2). In the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) the association between the 11 year change in home outdoor traf c-related PM10
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Discussion
We found seven publications based on data from ve adult asthma studies (Table 1). The prospective studies showed rather consistent positive associations between metrics of long-term exposure to ambient air pollution and asthma incidence (Table 2). Six of them (from four studies) found associations with markers of traf c-related local air pollution, namely NO225,37,42,43 and modeled traf c-related particulate matter.47 One study compared traf c intensity measures and NO2, nding stronger associations for the former.37 Due to the heterogeneity in the de nitions of asthma, the differences in the exposure assessment (discussed later), and the lack of independence of estimates (with three analyses based on ECHRS), we abstain from a meta-analysis of the results summarized in Table 2. A very recent systematic review considering asthma incidence concluded that air pollution may play a causal role in the development of asthma19; however, several differences in our review need to be taken into account. The aim of our review was to focus only on adult-onset asthma, whereas Anderson et al19 summarized the literature across all ages. The pathophysiological mechanisms leading to the chronic phenotype of asthma are complex, and many remain unknown. Childhood and adult-onset asthma may be partly different phenotypes.3,48,49 Under this concept one may conjecture differences in the causal patterns and underlying mechanisms of the various disease entitiesor endotypeslabeled as asthma7; thus research may need to assess the causes of childhood and adult-onset asthma separately. The rather strong evidence for a causal role of air pollution in the development of childhood asthma19 may not be generalized to adults without studies conducted in this age group. Our review focuses strictly on studies where incidence was dened as a chronic condition (e.g., dened as reported doctors diagnosed asthma) or in one case based on new onset of a cluster of asthma symptoms among those with no asthma and no symptoms at baseline.42 We excluded studies (or results reported in the studies included in our review) where asthma was dened through the expression of exacerbations (e.g., period prevalence of single symptoms such as wheezing). As also emphasized by Anderson et al,19 there is strong evidence that exacerbations can be caused by acute peaks of air pollution

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exposureamong many factors. This evidence of acute effects of air pollution on asthma has implications for the approach and ability to investigate the long-term contribution of air pollution to the development of asthma. Assuming air pollution was only a trigger of exacerbations (e.g., triggering wheezing episodes), then the period prevalence of wheezing would be associated with the average (e.g., annual mean) concentrations of ambient air pollution because the annualor any long-termmean ultimately depends on the daily levels of pollution. In other words, asthmatics living at a more polluted residence will have a higher probability to report a wheezing history (e.g., during the last 12 months) than asthmatics living at a cleaner site even if air pollution had only acute effects on wheezing. It is for this reason that symptom frequencies or any other expressions of acute asthma-related problems such as attacks, increased use of inhalers, or hospitalizations can hardly be used to unambiguously investigate the role of air pollution in the development of asthma. Accordingly, we have also not included recent analyses of the large Danish Diet, Cancer, and Health (DCH) cohort.50 In that innovative analysis, long-term average concentrations of modeled home outdoor NO2 were associated with an increase in rst-ever asthma-related hospitalization in the elderly. Asthma incidence among the 53,143 adult participants (age 50 to 65 at baseline, in 199397), was de ned as a rst-ever hospitalization due to asthma occurring during the 10.2 years of median follow-up time (until 2006). There were 821 subjects (1.5%) experiencing such a rst hospitalization. Although the exposure assessment was rather unique, taking into account 35 years, those long-term mean NO2 values were highly correlated with the means across shorter periods, including the last year prior to hospital admission. As a consequence, models could not include both acute and long-term exposure terms to possibly disentangle the contributions of different time windows of exposure. It is thus impossible to clarify whether the observed associations re ect an estimate of the acute effects versus a long-term increase of the pool of asthmatics due to long-term exposure to pollution. An increase of this pool would likely result in increased asthma-related hospitalizations, irrespective of current pollution.51 Moreover, de ning asthma incidence by the occurrence of hospital admissions captures only the most severe subset of adult-onset asthma because not all asthmatics experience hospitalizations. We have also not included studies reporting higher symptom rates in population-based samples (thus including nonasthmatics and asthmatics) such as the SAPALDIA (Swiss Study on Air Pollution and Lung and Heart Diseases in Adults) analyses52,53 included in the review by Anderson et al.19 Although symptoms are a key feature leading to doctors diagnosed asthma, a symptom period alone is not suf cient to de ne asthma, and none of these symptoms are per se a good proxy for asthma prevalence or incidence. Moreover, the observed associations with pollution may again re ect increased period prevalence due to the sum of all acute effects of air pollution experienced during the past 12 months. We did instead include the ECRHS analysis based on the score. Although this is symptom based as well, it is not the

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association of pollution with the period prevalence of a single symptom but indeed with the change from a state without asthma or symptoms into a state characterized by a cluster of symptoms shown to have a very high positive predictive value for doctors diagnosed asthma.45 This is not the case for any single symptom, and the fact that the strongest associations were observed for the change from score 0 to ! 3 symptoms supports the interpretation as asthma incidence. Exposure assessment methods were heterogeneous across studies (Table 1). Accurate and relevant exposure assessment is fundamental to assessing relationships of asthma onset with air pollution. As seen in the literature on childhood asthma, studies that did not describe local trafc-related pollution with its known substantial within-community gradients consistently fail to see any association instead with urban background pollutants.18 The evidence of a causal role of air pollution in the development of childhood asthma is based entirely on studies assigning some markers of local trafc-related pollution.19,23,24 Those pollutants (e.g., ultrane particles, CO, or NO) show substantial spatial gradients over short distances, within communities with a steep drop-off in pollutants to background levels within 200 to 250 m distance from a road.23 All the adult studies but AHSMOG33 attempted to characterize the local home outdoor exposure conditions and specify local traf c-related pollution, using markers known to be related to those types of pollutants with high spatial gradients within communities such as locally modeled NO2 (or NOx),25,37,42,43 traf c-related particulate matter estimated from emission-based dispersion models47 or distance to busy roads.25,37 Although all seven publications estimated air pollution concentrations at the individual level (i.e., at least the residential addresses), McDonnell et al33 did so through interpolation to the closest monitors, which at that time were rather sparse. Thus the study did not capture local traf crelated pollution, and, if the latter matters it is not surprising that the study nds no association with any marker of combustion-related particulate pollution. In ECRHS4143 the investigators used NO2 estimates derived from dispersion models on a quite large 1 1 km grid. Although the local contrasts in exposure are not well captured on a 1 1 km grid either, local contrasts remained rather large, possibly due to the ECRHS restriction to include only cities with at least 200,000 inhabitants rather than smaller towns. As shown in Anderson et al19 in studies of children, associations between pollution and asthma were positive only in studies using markers of the local traf c-related pollution whereas urban background pollution was not associated with asthma onset nor prevalence. This discrepancy is particularly interesting in light of the fact that, for other respiratory (and cardiovascular) effects of ambient air pollution, such clear differences between associations based on urban background versus local traf c-related pollutants did not emerge. For example, in the SAPALDIA study, symptoms correlated both with the urban background level of pollution53 and the more sophisticated locally assigned metrics.52 This may indicate that the speci c toxicological properties of these pollutants relate to partly different mechanisms relevant in asthma development.
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Thus, in contrast to the incidence studies, Lindgren et als5456 three publications on prevalence provide con icting results with suggestive associations seen for proximity to busy roads but null ndings for local estimates of NO2. Disease-based moving patterns and environmental preferences in the selection of residential location may affect prevalence studies more strongly than prospective studies, but the ndings are inconsistent and not easily explained.

Of interest is the distinction of prevalence and incidence studies. As conceptualized by Anderson et al,18 asthma prevalence studies may, in theory, lead to the same conclusion as incidence studies if remission and relapse do not occur or are constant; thus prevalence studies could support the assessment of evidence. Unfortunately, in studies of children, the vast majority of prevalence studies lack any information of traf c-related local air pollution; thus the null ndings for the prevalence studies18 cannot be considered inconsistent with the positive ndings on incidence studies, which were mostly based on traf c-related pollution. However, in case of adult studies, the situation is different. There are no adultonset asthma prevalence studies published except the three recent prevalence-based publications conducted in Sweden by Lindgren et al based on two different populations.5456 In a study including 9319 adults from 18 to 77 years old from Malm and surrounding areas, Lindgren at al55 evaluated the association between traf c related air pollution and asthma prevalence (among other respiratory diseases, such as COPD or asthma symptoms). A positive answer to Have you been diagnosed by a doctor as having asthma? de ned asthma prevalence. The authors did not have information on age of asthma onset. Objective markers of air pollution exposure were traf c intensity within 100 m of the residence and NOx individually assigned from dispersion models on a grid of 250 m2. The study reported that living within 100 m of a road with heavy traf c (>10 cars/min) was associated with a higher prevalence of asthma diagnosis [OR 1.4 (1.0 to 1.9)]. In a second publication in the same study, Lindgren et al56 showed that living close to traf c was associated with current allergic asthma (i.e., asthma triggered by allergic factors such as pollen or furred animals), [(OR 1.3 (1.1 to 1.7)] but not with nonallergic asthma. No association was found with home outdoor modeled NOx in any of the two analyses. Indeed, the analyses provided numerous estimates on various subgroups and measures of exposure with rather inconsistent patterns, and in the subgroup of suburban dwellers, NOx was inversely related to asthma prevalence. In another population, in a two-step case-control study, Lindgren at al54 assessed the association between traf c exposure and asthma prevalence. In the rst step, 24,819 adults (age 18 to 65) from Scania, for whom they had home addresses, were included. In a second phase they conducted a nested case-control study of adults including 2856 participants who were asked for their work address and time spent in traf c. Complete weighted traf c exposure information was available for 1488 subjects. Exposure estimates were derived from NOx dispersion models, both at home and at work addresses. They also linked the addresses to the national road database to integrate exposure to traf c during commute in a model of total NOx exposure, re ecting the timeweighted average for home, work, and commute-related concentrations. Asthma prevalence was de ned as a positive answer to Do you have asthma? They also found that living within 50 m of a road with high traf c was associated with higher asthma prevalence [OR 1.8 (1.1 to 2.8)]. However, no association was found with any of the NO2-based analyses (home, total, work or commute).
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Mechanisms
To elucidate the speculation that local traf c-related air pollutants (e.g., ultra ne particles) affect asthma development differently than larger particles, one would need to understand the web of mechanisms causing asthma in general and the mediating pathways of air pollution. The most accepted mechanisms of lung damage caused by particulate matter are in ammation (mainly due to oxidative and nitrosative stress) and reduction of the defense capacity increasing susceptibility to infections.57 In studies of children, it has been suggested that the mechanisms linked to asthma incidence include allergic sensitization. In particular diesel exhaust may act as an adjuvant affecting the immune response to environmental allergens. Nel emphasized the distinct properties and contributions of the ultra ne fraction of particles (i.e., those with high spatial differences within communities) and the larger PM fractions.58 The immunologic effects of particles may depend on the alveolar translocation, which in turn heavily depends on particle size. However, allergy is far less important in adult-onset asthma; thus the relevance of these immunologic pathways is less clear in adults,59 and interactions between pollution and markers of allergies were inconsistent across the studies reviewed. Several studies used NO2 as the marker of air pollution. This raises the question as to whether NO2 per se could be causally implied. The toxic effect of NO2 on the human respiratory tract at ambient concentrations is less important than for other gases (e.g., ozone) or particles. At an experimental level, as a free radical, NO2 has the capacity of depleting the antioxidants of the lung tissue, causing subsequent injury and in ammation.60 Using animal or in vitro models, NO2 produces eosinophilic in ammation, enhances epithelial damage, reduces mucin expression and increases baseline smooth muscle tone.6063 Repeated exposure to high doses of NO2 is associated with increased breath frequency and decreased lung distensibility and gas exchange.64 It has also been explained that NO2 decreases bactericidal activity and alveolar macrophage activity.63,65,66 Whether these experimental ndings can be extrapolated to human environmental exposure conditions is not known.

Heterogeneities and Susceptible Subgroups

Asthma de nitions, and therefore possibly phenotypes, differed across studies, although several used the same core questionnaires, namely ECRHS,42,43 SAPALDIA,47 and RHINE.37 All the studies de ned asthma onset, excluding

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subjects with self-reported asthma and/or asthma-like symptoms and/or doctor-diagnosed asthma at baseline, and designated as cases subjects reporting asthma at follow-up. All but one,25 which used clinical examinations, used the answers from a questionnaire. However, studies differed in the strict de nition of a new case; not all required age of onset to be prior to the baseline survey, meaning that these studies may include cases re ecting remissions of childhood asthma rather than truly new cases of asthma and are thus not appropriate for the investigation of causes of adult-onset asthma. As reported in ECRHS,42,43 SAPALDIA,47 and RHINE,37 at least some 50% of all new cases may be such remissions of previously unreported childhood asthma. Another issue to consider is the heterogeneity between the populations from the ve studies included in this review. In ECRHS42,43 and RHINE37 participants were younger than in the other studies. In SAPALDIA47 the association between asthma incidence and air pollution was observed only in never-smokers and in the AHSMOG33 only in nonsmokers, whereas all other studies adjusted for smoking status. The rst study was a case-control study, whereas all the others were population based.33,37,4143,47 Susceptibility factors, in particular related to sex (hormonal factors), atopy, physical activity, or diet (as modiers of oxidant response), comorbiditiesin particular COPDor lifestyles such as smoking were not consistently addressed. CastroGiner et al41 is the only study so far addressing geneair pollution interactions. The ndings strongly support the need to take biological susceptibilities into account. Three studies presented in this review addressed susceptibilities; the effect of air pollution on asthma seemed stronger in atopics in two studies37,47 and in nonatopics in the third,43 but none has enough power to show a signicant interaction. Results concerning gender differences were also inconsistent across the studies, even if the majority seemed to nd a higher association in males. In the AHSMOG study33 associations were only seen in males. In RHINE37 and SAPALDIA47 the association was slightly higher in males, whereas in ECRHS it was the same in both genders when the asthma score was used42 but was slightly higher in females when the classical denition was used.43 However, statistical power was insufcient to evaluate these differences. In SAPALDIA,47 air pollution was more strongly associated with young atopic asthma in males. In SAPALDIA, positive ndings were only observed in nonsmokers, and in ECHRS analyses, signals were also larger in nonsmokers, whereas the other studies give no clear information about interactions of pollution with smoking status. We agree with Anderson et al19 that none of the studies can clearly answer the question as to whether removal of air pollution exposure would result in fewer asthma cases or just postponement of asthma onset. This limitation is indeed true for most if not all established risk factors of chronic diseases. For example, smokers developing COPD might also have done so had they never smoked, but possibly at a later stage in life or in a less severe form. What is relevant from a public health perspective is that science-based preventive action (e.g., through stringent implementation of clean air policies) may at least prolong the disease-free state.

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Conclusion and Future Research Needs

The currently available studies on adult-onset asthma are not suf cient to allow rm conclusions about the causal role of ambient air pollution. Based on the prospective studies, results would be much in line with a causal role of traf crelated air pollution in the development of adult-onset asthma consistent with that seen for asthma in children. However, the inconsistency in the two prevalence studies between the signi cant results for traf c density (proximity) but null ndings for locally modeled NO2 cannot be dismissed. Those NO2 models may re ect similar traf c-related pollutants as those used in the adult incidence studies. It is worth noting that the three con icting publications are all based on the same geographic area in southern Sweden. However, if one gives stronger weight to the prospective incidence studies less prone to self-selection biasevidence for a causal role of traf c-related pollutants is stronger. Many questions remain unanswered and should be tackled in future studies in adults. There is in particular a need to characterize more rigorously and consistently the exposure to local traf c-related pollution, including traf c-related exposure during commute and at work. Lindgren et al54 made innovative attempts to do so for NO2. Given the null ndings it is dif cult to interpret the lack of any difference among homebased versus home-, work-, and commute-based results.54 Better characterization of the ultra ne fraction of vehicle exhaust emissions is needed to better understand exposures to different particle types. This includes the need to tackle ultra ne particle exposure during time spent in traf c or outdoors because this may contribute substantially to total exposure to traf c-related toxicants and be relatively more important than those exposures experienced at home.67 More rigorous and consistent de nitions of the adultonset asthma phenotype should be part of further investigations because the role of traf c-related air pollution may differ across phenotypes. This includes the need for a coherent distinction between adult-onset asthma and remission of childhood asthma later in life. As discussed, adults may forget the reporting of childhood asthma until the disease again becomes active. Consistent consideration of possible susceptibility factors such as gender or atopy is also needed to understand those at highest risk, which is of both clinical and public health relevance. A major challenge to address all the open questions relates to the need for having suf ciently large prospective cohort studies. None of the published studies has the power to investigate interactions because the number of new cases of asthma was rather low. In the future, megacohorts will provide opportunities to address these questions. Meanwhile a promising approach lays in the collaborative research combining comparable existing cohort studies. A promising initiative in this direction comes from the European ESCAPE and the related extension of the TRANSPHORM projects (www.escapeproject.org). The role of traf c-related air pollution in the development of chronic respiratory diseases in adults will be investigated across six existing cohort studies, including SAPALDIA,47 ECRHS,43 SALIA,68 EGEA,69,70 E3N,71
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17 Chen CH, Xirasagar S, Lin HC. Seasonality in adult asthma admis-

and the UK National Survey of Health and Development (1946 birth cohort).72

18

Acknowledgments The research leading to this paper has received funding from the European Communitys Seventh Framework Programs ESCAPE: FP7-ENV-20072011, under grant agreement number 211 250, and TRANSPHORM: FP7ENV-20092011, under grant agreement number 243 406.

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