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Association between Traffic Related Air Pollution and the Development of Asthma Phenotypes in Children: A Systematic Review.

1. Introduction

Childhood asthma is the most common chronic disease in children, with estimated prevalence of 14% in children worldwide [1, 2]. This high prevalence is also associated with significant economic burden. Asthma in school-aged children in the United States alone is estimated to cost nearly $6 billion annually in healthcare expenditures [3]. Given the high burden of disease as well as the complex and heterogeneous nature of childhood asthma, it is essential to investigate further beyond the incidence and outcomes associated with childhood asthma [4].

Among the first studies to investigate the differences between childhood asthma symptoms was the Tucson Children's Respiratory Study, which identified 4 separate wheezing phenotypes based on the longitudinal pattern of wheezing that was observed [5]. These phenotypic groups were based on the age of wheezing onset and the duration of wheezing and included the following groups: (1) no wheezing, (2) early transient wheezing (wheezing before age of 3 but not at age of 6 years), (3) persistent wheezing (wheezing both before age of 3 and at age of 6 years), and (4) late-onset wheezing (no wheezing before age of 3 but wheezing by age of 6 years) [5]. The existence of these phenotypes has been supported by further studies, using methods such as latent class analysis and group based trajectory modelling [4, 6-8]. Currently, childhood asthma consists of many different phenotypes, each associated with differing clinical and genetic markers, risk factors, outcomes, and responses to medication [9, 10]. Thus, understanding the different clinical phenotypes of childhood asthma and wheeze may lead to several benefits in diagnosis and treatment. These include knowledge of probable outcomes and prognosis, personalized treatments for patients, and understanding how environmental exposures can modify the risk of developing different childhood asthma or wheezing phenotypes [11].

Numerous studies have found traffic related air pollution (TRAP) to be associated with the onset of childhood asthma [12-16]. These results are further supported by a systematic review that showed strong associations between exposure to black carbon (BC), N[O.sub.2], [PM.sub.2.5] (atmospheric particulate matter less than 2.5 [micro]m in diameter), and [PM.sub.10] (atmospheric particulate matter less than 10.0 [micro]m in diameter) with the onset of childhood asthma [17]. The association between TRAP and different childhood asthma phenotypes is less understood. Earlier reviews have focused primarily on the association between TRAP and the onset of childhood asthma rather than the development of the asthma phenotype [17, 18]. Nevertheless, the effect of TRAP exposure on the development of different childhood asthma phenotypes may be significantly different. One study found no association between N[O.sub.2] exposure and either early transient wheeze or persistent wheeze phenotypes in children [14]. These findings conflict with another study that found an association between childhood N[O.sub.2] exposure and persistent wheeze in children [19]. These associations may also change with the pollutant being studied: although one study found no association between childhood N[O.sub.2] exposure and early transient wheezing, it found an association between childhood [PM.sub.2.5] exposure and early transient wheezing [14].

The purpose of this systematic review is to synthesize the results of observational epidemiological studies studying the association between TRAP exposure and the development of childhood asthma/wheezing phenotypes, namely, transient asthma/wheezing, late-onset asthma/wheezing, and persistent asthma/wheezing in children aged 0-18 years.

2. Methods

2.1. Selection Criteria. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement for reporting systematic reviews and meta-analyses [24]. The review included cross-sectional, case-control, and cohort studies which studied the association between TRAP exposure and the development of childhood asthma phenotypes, namely, early-transient asthma, late-onset asthma, and persistent asthma in children aged 0-18 years.

Studies were included if they

(1) were epidemiological or observational studies such as cross-sectional, cohort, or case-control studies;

(2) had some measure of TRAP (CO, [PM.sub.2.5], [PM.sub.10], and N[O.sub.2]) exposure [25] for children within the early life period between fetal stage and age of 12 (through either modelling or direct measurement);

(3) examined the association between TRAP exposure and development of asthma or wheeze outcomes when the child is aged 0-18 years;

(4) explicitly included at least one type of asthma/ wheezing phenotype (late-onset asthma/wheeze, persistent asthma/wheeze, and transient asthma/wheeze) in their outcomes.

Studies were excluded if they

(1) measured TRAP exposure only when children were aged > 12 years;

(2) were reviews, commentaries, experimental studies, letters to the editor, and so forth;

(3) were studies that only examine the association between TRAP exposure and asthma development without specifying the phenotype or look at exacerbation of asthma/wheeze, allergies, and so forth as the outcome;

(4) measured exclusively pollution exposure to non-TRAP pollutants, such as O3 or SO2;

(5) were non-English-language studies.

No studies were excluded on the basis of publication year.

2.2. Health Outcomes. The primary health outcomes assessed were childhood asthma/wheezing phenotypes. Articles with either wheezing phenotypes or asthma phenotypes as outcomes were included for analysis. Although wheezing is a nonspecific symptom that is not always associated with childhood asthma, wheezing phenotypes have long been used to characterize the corresponding childhood asthma phenotypes [18, 26, 27]. To account for the differing follow-up times between studies, asthma/wheezing phenotypes were divided into 3 groups with the following modified definitions based on the Tucson Children's Respiratory Study [5]:

(1) Transient asthma/wheezing: onset of asthma or wheezing before or at age of 3 and no asthma or wheezing after age 3

(2) Persistent asthma/wheezing: onset of asthma or wheezing before or at age of 3, with evidence of asthma or wheezing after age of 3

(3) Late-onset asthma/wheezing: onset of asthma or wheezing after age of 3

2.3. Search Strategy. Searches were performed in the PubMed, Embase, and Scopus databases for relevant articles. Search strings containing terms for "asthma," "vehicle emissions," and "children" were used. An example search string for PubMed is given below:

("Asthma"[Mesh] OR asthma OR wheeze) AND ("Motor Vehicles"[Mesh] OR "Vehicle Emissions"[Mesh] OR traffic OR car OR truck OR bus OR motorcycle OR automobile OR vehicle OR exhaust) AND ("Child"[Mesh] OR "Infant"[Mesh] OR childhood OR children OR infant OR baby OR paediatric OR pediatric OR paediatrics OR pediatrics)

The search was performed in May 2018 and included papers published until May 2018.

2.4. Quality Assessment. The Critical Appraisal Skills Programme (CASP) checklist for cohort studies was used to assess the quality of applicable studies [28]. CASP consists of 12 questions used to evaluate the quality of cohort studies. The CASP criteria were used to evaluate cohort studies for (1) selection bias in the cohorts used, (2) measurement, classification, or recall bias in exposures, (3) measurement or classification bias in outcomes, (4) adjustment for appropriate confounders, (5) length and completeness of follow-up, and (6) potential validity of results. Two reviewers (N.L. and A.N.) independently assessed each article using the CASP criteria.

2.5. Data Extraction. Relevant information was extracted independently by two reviewers (N.L. and A.N.). Information was extracted from supplementary materials when deemed necessary. Disagreements on what information to extract were resolved via consensus by both reviewers. Extracted information included authors, study location, year of publication, study design, study population, pollutant and exposure information, asthma and wheezing phenotype definitions, and outcome data.

3. Results

3.1. Search Results. A literature search was conducted in the PubMed, Embase, and Scopus databases, yielding 1706 unique articles. After initial screening, 233 articles were chosen for full-text review, using the selection criteria and 7 articles were deemed suitable for inclusion [4, 14, 19-23]. Figure 1 represents the PRISMA flow diagram for article selection in this study.

3.2. Study Characteristics. The 7 studies included were published from 2007 to 2018, with all being cohort studies [4, 14, 19-23]. Among the 7 studies, one birth cohort was utilized twice in separate studies [14,19]. 111 038 individuals across these 7 studies were included (duplicated cohorts were counted twice). The sample size in the included studies ranged from 2871 to 68 195 individuals. Studies were conducted in Canada, France, USA, Sweden, Netherlands, and Norway and were all English language studies. The length of follow-up varied among the 7 studies, with all studies starting from birth and the end of follow-up ranging from age 4-12. To estimate pollutant exposure, 3 studies utilized Land Use Regression (LUR) and 4 utilized dispersion modelling. CO, N[O.sub.2], N[O.sub.x], [PM.sub.2.5], and [PM.sub.10] were the traffic related air pollutants assessed. The number of studies measuring each individual pollutant is as follows:

(i) CO: 1 study

(ii) N[O.sub.2]: 4 studies

(iii) N[O.sub.x]: 3 studies

(iv) [PM.sub.2.5]: 4 studies

(v) [PM.sub.10]:1 study

Due to the differing follow-up times among the included studies, phenotypic definitions varied by study. 5 studies reported results in the form of odds ratios for asthma phenotype riskper unit of pollutant exposure ([micro]g/m3) [14,19-21, 23]. One study, that by Sbihi et al., divided the cohort into quartiles based on exposure quartiles to the lowest quartile of pollutant exposure [4]. The last study, that by Pennington et al., reported asthma phenotype risk in the form of absolute risk difference between different exposure groups [22]. Complete study characteristics, including phenotypic definitions, can be found in Table 1, while the individual results for each study can be found in Table 2. Due to the low number of included studies, we were unable to conduct a meta-analysis.

3.3. Quality Assessment of Studies. All included studies were considered to be of sufficient quality for inclusion. The most common limitations identified from the CASP checklist were the potential for recall bias in studies where outcomes were reported via questionnaire and not adjusting for potential confounders.

3.4. Effect of CO on Childhood Asthma Phenotype Development. The sole study which measured CO exposure measured only persistent childhood asthma by age of 5 as a phenotypic outcome [22]. Prenatal exposure to CO was associated with an absolute risk increase of 3.5% for persistent asthma at age of 5. Exposure to CO during the 1st year of life was associated with an absolute risk increase of 3.9% for persistent asthma at age of 5.

3.5. Effect of N[O.sub.2] on Childhood Asthma Phenotype Development. Of the four studies that measured the association between N[O.sub.2] and the development of childhood asthma phenotypes, two reported associations for transient, persistent, and late-onset asthma/wheeze, one reported associations for transient and persistent wheeze, and one study reported solely the association for late-onset asthma [4, 14, 19, 21]. Two studies reported results from an identical study cohort (PIAMA) [14,19].

Two of the studies that listed transient asthma/wheezing as an outcome found a significant association between N[O.sub.2] exposure and transient wheezing [4,19], with the third study reporting no significant association [14]. However, a significant association was reported by Sbihi et al. only when the second and fourth exposure quartiles were compared to the lowest quartile. No association was observed between N[O.sub.2] exposure and transient wheezing when the third exposure quartile was compared to the lowest quartile [4].

Of the three studies that reported persistent asthma/ wheezing, two studies reported no association between N[O.sub.2] and persistent wheezing [14, 19]. The third study reported significant associations for the second and third exposure quartiles compared to the reference quartile; but the highest exposure quartile was not associated with persistent asthma [4].

Two of three studies found no association between N[O.sub.2] and late-onset asthma/wheezing [14, 21]. Significant associations for the second and third exposure quartiles with late-onset asthma were reported by the third study, but the highest exposure quartile was not associated with late-onset asthma [4].

3.6. Effect of N[O.sub.x] on Childhood Asthma Phenotype Development. Among the three studies that measured the association between N[O.sub.x] exposure and the development of childhood asthma phenotypes, two studies studied transient wheezing, persistent wheezing, and late-onset wheezing as outcomes [20,23]. One study studied solely persistent asthma [22].

Pennington et al. found that prenatal exposure to N[O.sub.x] was associated with an absolute risk increase of 3.8% for persistent asthma at age of 5, while exposure to N[O.sub.x] during the 1st year of life was associated with an absolute risk-increase of 4.0% for persistent asthma [22].

Both studies which reported odds ratios for phenotypic outcomes found a significant association between N[O.sub.x] exposure and persistent wheezing, with no association found with N[O.sub.x] and either transient or late-onset wheezing [20, 23].

3.7. Effect of [PM.sub.2.5] on Childhood Asthma Phenotype Development. Among the four studies which measured the association between [PM.sub.2.5] exposure and the development of childhood asthma phenotypes, two studies studied transient wheezing, persistent wheezing, and late-onset asthma or wheezing as outcomes [4, 14]. One study reported associations for transient and persistent wheeze [19]. The final study contained solely persistent asthma as a phenotypic outcome [22]. Two studies, those by Brauer et al. and Gehring et al., reported results from an identical study cohort (PIAMA) [14,19].

Pennington et al. found that prenatal exposure to [PM.sub.2.5] was associated with an absolute risk increase of 4.4% for persistent asthma at age of 5 [22]. Exposure to [PM.sub.2.5] during the 1st year of life was associated with an absolute risk increase of 4.5% for persistent asthma at age of 5.

Among the three studies which reported associations between [PM.sub.2.5] and transient asthma or wheezing, two reported a significant association [14, 19]. The third one by Sbihi et al. reported a significant association between transient asthma and the second and third exposure quartiles [4]. However, the highest exposure quartile was not associated with transient asthma.

Two of three studies found no association between [PM.sub.2.5] exposure and persistent wheezing or asthma phenotype [14, 19]. Sbihi et al. found that the second exposure quartile of [PM.sub.2.5] was associated with persistent asthma, but there was no association between [PM.sub.2.5] and the third and fourth quartiles [4].

Gehring et al. reported an association between [PM.sub.2.5] and late-onset wheezing [14]. Sbihi et al. also reported that the second and third exposure quartiles were associated with late-onset asthma, although there was no association with the highest exposure quartile [4].

3.8. Effect of [PM.sub.10] on Childhood Asthma Phenotype Development. Nordling et al. reported the association between [PM.sub.2.5] exposure and the development of transient wheezing, persistent wheezing, and late-onset wheezing as outcomes [20]. No significant association was found between [PM.sub.10] and any of the three wheezing phenotypes.

4. Discussion

Although previous studies have looked at TRAP and the onset of childhood asthma, to our knowledge this is the first attempt to systematically evaluate the available literature on the effect of TRAP exposure with the development of childhood asthma or wheezing phenotypes. 7 studies were included for final analysis. The results suggest that TRAP is associated with the development of childhood transient and persistent asthma/wheezing phenotypes but may not be associated with late-onset asthma/wheezing. Nevertheless, the significance of these associations is inconsistent among the included studies and any interpretation of the results should be drawn cautiously. Stratifying studies by pollutant reduced the number of eligible studies per pollutant and made a meta-analysis unfeasible.

Early childhood exposure to TRAP has significant impacts on lung development [16]. Starting from the early postnatal period till about 1.5 years of age, bulk alveolar formation in the lungs leads to substantial structural remodeling of the lung parenchyma [26, 29]. Microvascular maturation in the lungs also occurs starting from the early postnatal period till about 2-3 years of age. Damage to the lungs during the developmental periods has been associated with the development of long-term sequelae [27, 30, 31]. Additionally, compared to adults, children are more likely to be outdoors and active, have a higher ventilation rate, and are more likely to inhale pollutants into the distal lung, with accordingly higher exposure to TRAP [32].

N[O.sub.2], [PM.sub.2.5], and [PM.sub.10] have been reported to be the primary constituents of TRAP [33], and long-term exposure to these pollutants in mice has been shown to lead to elevated levels of interleukin-6, a proinflammatory cytokine associated with inflammation and pulmonary diseases such as asthma [33-36]. TRAP exposure has also been associated with elevated expression of the Clca3 gene [33]. In animal models, expression of Clca3 has led to mucous cell metaplasia and airway hyperreactivity, leading to the development of episodic recurrent airway obstruction [37-40]. As the mucous cell metaplasia developed, it was observed that Muc5ac was the primary airway mucin expressed, which is also characteristic of human asthma [36,37]. Consequently, it has been suggested that the association of TRAP with asthma onset maybe due to the expression of Clca3 [33].

Genetic factors may also in part explain the heterogeneity in asthma and wheezing phenotype results presented in this review. Among children exposed to N[O.sub.2], those with either a GSTP1 rs1138272 or rs1695 single nucleotide polymorphism (SNP) were found to be at an increased risk for asthma in a study combining multiple birth cohorts [41]. Additionally, high exposure to diesel exhaust particles (DEP) in children with the GST-P1 Val105 polymorphism was associated with a high risk of persistent wheezing [42]. Thus, differing genotypes among those exposed to TRAP may lead to differences in asthma or wheezing phenotypic outcomes.

Childhood asthma is a complex disease that involves many genetic and environmental factors, as well as interplay between these factors. Male children are at higher risk of childhood asthma than females, although this is reversed after puberty [43-46]. Male sex has also been shown to modify the association between prenatal [PM.sub.2.5] exposure and childhood asthma onset [47]. It is uncertain whether similar interactions between sex and other forms of TRAP exist for childhood asthma onset. Exposure to other allergens such as mites is also associated with childhood asthma and can modify the risk of childhood asthma associated with TRAP [48]. Other environmental exposures such as prenatal smoke exposure, home dampness, and prenatal acetaminophen use can modify the association of genetic risk factors with childhood asthma onset [49-51].

Several limitations of this systematic review must be acknowledged. Firstly, the low number of eligible studies makes it difficult to draw any firm conclusions. Given that we assessed each pollutant separately, the number of studies per pollutant was reduced even further. Secondly, the heterogeneity in phenotype definitions and in study follow-up length may be a source of bias. The original phenotypic definitions from the Tucson Children's Respiratory Study measured outcomes at ages of 3 and 6 to define wheezing phenotype [5]. Given the differing follow-up length across the available studies, a child's phenotypic classification may differ between studies based on the definition used. A child with wheezing at ages of 3 and 4 but not at age of 6 would be classified as transient wheeze by Gehring et al. but would be persistent wheeze under Nordling et al., as follow-up ends at age of 4. It is therefore important to account for these differences in phenotype definition between studies. Finally, all but two studies used parental reporting of wheezing or asthma symptoms via questionnaire response to report asthma or wheezing in children. Although standard, this may lead to recall bias in the results. These limitations suggest that further studies studying TRAP exposure and the onset of childhood asthma and wheezing phenotypes are warranted.

5. Conclusion

Based on the results of this systematic review, there is evidence to suggest an association between TRAP exposure and transient as well as persistent childhood asthma/wheezing phenotypes. Conversely, TRAP may not be associated with late-onset asthma/wheezing phenotype. However, results remain inconsistent among different studies. The low number of studies per pollutant, as well as the heterogeneity in study methods such as follow-up length and in the phenotypic definitions of asthma and wheezing used, indicates the need for further studies on this topic.

https://doi.org/10.1155/2018/4047386

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors would like to thank Alison Farrell who assisted with creating and performing the literature search. This work was funded by the Janeway Children's Hospital Foundation and Faculty of Medicine, Memorial University of Newfoundland.

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[48] I. J. Wang, T. H. Tung, C. S. Tang, and Z. H. Zhao, "Allergens, air pollutants, and childhood allergic diseases," International journal of hygiene and environmental health, vol. 219, no. 1, pp. 66-71, 2016.

[49] A. Sadeghnejad, W. Karmaus, S. H. Arshad, R. Kurukulaaratchy, M. Huebner, and S. Ewart, "IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study," Respiratory Research, vol. 9, 2008.

[50] S. O. Shaheen, R. B. Newson, S. M. Ring, M. J. Rose-Zerilli, J. W. Holloway, and A. J. Henderson, "Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma," The Journal of Allergy and Clinical Immunology, vol. 126, no. 6, pp. 1141.e7-1148.e7, 2010.

[51] C. H. Tsai, K. Y. Tung, C. H. Chen, and Y. L. Lee, "Tumour necrosis factor G-308A polymorphism modifies the effect of home dampness on childhood asthma," in Occupational and Environmental Medicine, 2011.

Nelson Lau [ID], (1) Alex Norman, (1) Mary Jane Smith, (2) Atanu Sarkar, (3) and Zhiwei Gao [ID] (1)

(1) Department of Clinical Epidemiology, Faculty of Medicine, Memorial University of Newfoundland, Newfoundland and Labrador, Canada

(2) Discipline of Pediatrics, Faculty of Medicine, Memorial University of Newfoundland, Newfoundland and Labrador, Canada

(3) Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, Newfoundland and Labrador, Canada

Correspondence should be addressed to Zhiwei Gao; zgao@mun.ca

Received 19 July 2018; Accepted 15 November 2018; Published 2 December 2018

Academic Editor: Katarzyna Zorena

Caption: Figure 1: Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for article selection.
Table 1: Characteristics of included studies.

Study Reference           Study design      Age group
and setting

(Brauer et al., 2006),    Birth cohort      Birth-4 years
Utrecht, Netherlands      (PIAMA)
[19]

(Gehring et al., 2010),   Birth cohort      Birth-8 years
Utrecht, Netherlands      (PIAMA)
[14]

(Nordling et al.,         Birth cohort      Birth-4 years
2007), Stockholm,         (BAMSE)
Sweden [20]

(Oftedal et al.,          Birth cohort      Birth-10 years
2009), Oslo, Norway       (Oslo)
[21]

(Pennington et al.,       Birth cohort      Birth-6 years
2018), Atlanta,           (KAPPA)
Georgia, USA [22]

(Ranciere et al,          Birth cohort      Birth-4 years
2017), Paris, France      (PARIS)
[23]

(Sbihi et al.,            Birth cohort      Birth-10 years
2017), Vancouver,
British Columbia,
Canada [4]

Study Reference        Participants      Exposure
and setting            included          assessment

(BraueretaL, 2006),    4146              LUR model
Utrecht, Netherlands
[19]

(GehringetaL, 2010),   3863              LUR model
Utrecht, Netherlands
[14]

(Nordlingetal.,        3515              Dispersion
2007), Stockholm,                        model
Sweden [20]

(Oftedaletal.,         2871              Dispersion
2009), Oslo, Norway                      model (EPISODE)
[21]

(Pennington et al.,    24 608            Dispersion
2018), Atlanta,                          model (RUNE)
Georgia, USA [22]

(Ranciere et al,       3840              Dispersion
2017), Paris, France                     model (Extra
[23]                                     Index)

(Sbihi et al.,         68195             LUR model
2017), Vancouver,
British Columbia,
Canada [4]

Study Reference           Traffic related     Traffic related
and setting               pollutants          pollutants measured

(Brauer et al., 2006),    [PM.sub.2.5],       [PM.sub.2.5] mean:
Utrecht, Netherlands      N[O.sub.2]          16.9, range:
[19]                                          [13.5,25.2]
                                              [micro]g/[m.sup.3];
                                              N[O.sub.2] mean:
                                              25.4, range:
                                              [12.6,58.4]
                                              [micro]g/[m.sup.3]

(Gehring et al., 2010),   [PM.sub.2.5],       [PM.sub.2.5] mean:
Utrecht, Netherlands      N[O.sub.2]          16.9, range: [13.5,
[14]                                          25.2] [micro]/
                                              [m.sup.3];
                                              N[O.sub.2] mean:
                                              25.4, range:
                                              [12.6,58.4]
                                              [micro]g/[m.sup.3]

(Nordling et al.,         [PM.sub.10],        [PM.sub.10] mean:
2007), Stockholm,         N[O.sub.x]          3.9, 5th/95th
Sweden [20]                                   percentile: [0.94,
                                              6.8] [micro[g/
                                              [m.sup.3];
                                              N[O.sub.x] mean:
                                              23.1, 5th/95th
                                              percentile:
                                              [4.7,48.7] [micro]g/
                                              [m.sup.3]

(Oftedal et al.,          N[O.sub.2]          N[O.sub.2] range:
2009), Oslo, Norway                           (1.4, 65.1), mean:
[21]                                          25.3 [micro]g/
                                              [m.sup.3];

(Pennington et al.,       CO, [PM.sub.2.5],   CO median: 0.59 ppm;
2018), Atlanta,           N[O.sub.x]          N[O.sub.x] median:
Georgia, USA [22]                             55.5 ppb
                                              [PM.sub.2.5] range:
                                              (0.06,13.8), median
                                              1.55 [micro]g/
                                              [m.sup.3]

(Ranciere et al,          N[O.sub.x]          N[O.sub.2] range:
2017), Paris, France                          (39.0, 257.0),
[23]                                          median: 75 [micro]g/
                                              [m.sup.3]

(Sbihi et al.,            N[O.sub.2],         N[O.sub.2] range:
2017), Vancouver,         [PM.sub.2.5]        (15.0, 53.7),
British Columbia,                             median: 33.3
Canada [4]                                    [PM.sub.2.5] range:
                                              (3.2, 7.6), median:
                                              5.4 [micro]g/
                                              [m.sup.3]

Study Reference           Asthma assessment     Transient asthma/
and setting                                     wheezing definition

(Brauer et al., 2006),    Parental reporting    Report of wheezing
Utrecht, Netherlands      of asthma/wheeze      at age of 3 but not
[19]                                            at age of 4

(Gehring et al., 2010),   Parental report of    Report of wheezing
Utrecht, Netherlands      wheezing              before age of 3 but
[14]                                            no wheezing after
                                                age of 6

(Nordling et al.,         Parental report of    At least 3 episodes
2007), Stockholm,         wheezing              of wheezing before
Sweden [20]                                     age of 2 but no
                                                episodes between
                                                ages of 3 and 4

(Oftedal et al.,          Parental reporting    None
2009), Oslo, Norway       of doctor/diagnosed
[21]                      asthma/wheeze

(Pennington et al.,       At least one doctor   None
2018), Atlanta,           diagnosis of asthma
Georgia, USA [22]         and one asthma-
                          related medication
                          dispensing after the
                          first year of life
                          from medical records

(Ranciere et al,          Parental reporting     Wheezing occurring
2017), Paris, France      of doctor-diagnosed    between 0 and 2
[23]                      asthma or wheezing     years of age and not
                          in the past 12         till age of 4
                          months at ages of 1,
                          2, 3, and 4

(Sbihi et al.,            At least two primary   Asthma definition is
2017), Vancouver,         care physician         met by age of 1 with
British Columbia,         diagnoses within a     asthma prevalence
Canada [4]                12-month period or a   peaking among the
                          minimum of one         group by age of 2
                          hospital admission     and no asthma
                          was identified as      activity after age
                          asthma cases each      of 6b
                          year

Study Reference           Persistent asthma/     Late/onset asthma/
and setting               wheezing definition    wheezing definition

(Brauer et al., 2006),    Report of wheezing     No report of
Utrecht, Netherlands      at age of 3 as well    wheezing at age of 3
[19]                      as at age of 4         but wheezing
                                                 reported at age of
                                                 4a

(Gehring et al., 2010),   Report of wheezing     No report of
Utrecht, Netherlands      before age of 3 as     wheezing before age
[14]                      well as after age of   of 3 but wheezing at
                          6                      age of 6 or later

(Nordling et al.,         At least 1 wheezing    No episode of
2007), Stockholm,         episode before age     wheezing before age
Sweden [20]               of 2 and at least 1    of 2 but at least 1
                          wheezing episode       episode of wheezing
                          between ages of 3      between ages of 3
                          and 4                  and 4

(Oftedal et al.,          None                   Onset of doctor-
2009), Oslo, Norway                              diagnosed asthma
[21]                                             after age of 4 years

(Pennington et al.,       Evidence of incident   None
2018), Atlanta,           asthma who also had
Georgia, USA [22]         evidence of asthma
                          in the past year at
                          each follow-up age
                          up to age of 5 years

(Ranciere et al,          Wheezing occurring     Wheezing occurring
2017), Paris, France      between 0 and 2        between 2 and 4
[23]                      years of age and       years of age
                          persisting till age
                          of 4

(Sbihi et al.,            Asthma develops by     Asthma develops by
2017), Vancouver,         age of 3 with asthma   age of 3 with asthma
British Columbia,         prevalence peaking     prevalence peaking
Canada [4]                among the group by     among the group by
                          age of 4 that is       age of 6 and is
                          sustained until the    sustained until the
                          end of follow-upb      end of follow-upb

Study Reference           Adjustment variables   CASP comments
and setting

(Brauer et al., 2006),    Sex, study arm,        Pollutant levels
Utrecht, Netherlands      allergic mother/       only measured for
[19]                      father, mother/        four 2-week periods
                          fathers education,     in a single year,
                          maternal smoking       risk of recall bias,
                          during pregnancy,      no adjustment for
                          breastfeeding at 3     familial history of
                          months, gas stove,     asthma, race, or
                          unvented gas water     socioeconomic status
                          heater, siblings at    (outside of
                          birth, smoking at      education)
                          home, dampness in
                          living room/childs
                          bedroom, pets,
                          daycare attendance,
                          Dutch nationality,
                          moving houses before
                          age of 8

(Gehring et al., 2010),   Sex, study arm,        Pollutant levels
Utrecht, Netherlands      allergic mother/       only measured for
[14]                      father, mother/        four 2-week periods
                          fathers education,     in a single year,
                          maternal smoking       risk of recall bias,
                          during pregnancy,      no adjustment for
                          breastfeeding at 3     familial history of
                          months, gas stove,     asthma, race, or
                          unvented gas water     socioeconomic status
                          heater, siblings at    (outside of
                          birth, smoking at      education)
                          home, dampness in
                          living room/childs
                          bedroom, pets,
                          daycare attendance,
                          Dutch nationality,
                          moving houses before
                          age of 8

(Nordling et al.,         Municipality,          Risk of recall bias,
2007), Stockholm,         socioeconomic          no adjustment for
Sweden [20]               status, heredity,      race, endpoint is
                          mothers smoking        early for persistent
                          during pregnancy and   asthma diagnosis
                          infancy, year that
                          house was built,
                          damp or mold in the
                          home at birth, and
                          sex of the child

(Oftedal et al.,          Sex, parental atopy,   Risk of recall bias,
2009), Oslo, Norway       maternal smoking in    no adjustment for
[21]                      pregnancy, paternal    race nor
                          education, and         socioeconomic status
                          maternal marital       (except education
                          status at the          and marital status)
                          child's birth.
                          Parental atopy was
                          defined as a history
                          of maternal or
                          paternal asthma, hay
                          fever, or eczema

(Pennington et al.,       Sex, race,             Results presented as
2018), Atlanta,           ethnicity, maternal    absolute risk
Georgia, USA [22]         asthma, maternal       difference,
                          age, parental          difficult to
                          education, maternal    interpret
                          marital status,
                          neighborhood
                          socioeconomic status
                          (SES), birth year,
                          and city region

(Ranciere et al,          Sex, birth weight,     Potential for recall
2017), Paris, France      family socioeconomic   bias, no adjustment
[23]                      status, maternal       for race, endpoint
                          education level,       is early for
                          maternal history of    persistent wheezing
                          asthma, allergic       diagnosis
                          rhinitis, or eczema,
                          paternal history of
                          asthma, allergic
                          rhinitis, or eczema,
                          maternal smoking
                          during pregnancy,
                          exposure to
                          environmental
                          tobacco smoke at
                          home during the
                          first year,
                          exclusive
                          breastfeeding during
                          the first 3 months,
                          type of child care
                          during the first 6
                          months, stressful
                          family events during
                          the first 2 years,
                          body mass index >
                          85th percentile for
                          age and sex at 2-3
                          years, use of gas
                          for cooking or
                          heating in the home,
                          and visible mold in
                          the home

(Sbihi et al.,            Sex, parity,           Did not adjust for
2017), Vancouver,         breastfeeding          familial history of
British Columbia,         initiation, birth      asthma, race,
Canada [4]                weight, delivery       ethnicity Odds
                          mode, maternal         ratios reported only
                          smoking and            to 1 decimal place,
                          educational            only study to find
                          attainment, and        an association
                          household income       between TRAP and
                                                 late-onset asthma

(a) No result on the association between pollutant exposure and
late-onset asthma phenotype was reported.

(b) Asthma phenotypes were defined based on group based trajectory
modelling.

Table 2: Effect of TRAP and childhood asthma phenotypes in included
studies.

Study reference and    Traffic related        Transient asthma/
setting                pollutant              wheezinga

Braueret al., 2006     [PM.sub.2.5]           OR: 1.16,95% (Cl:
(Total n = 4146;                              1.00 /1.34 per 4.4
                                              [micro]g/[m.sup.3]
                                              increase of PM25

Pollutant Exposure     N[O.sub.2]             OR: 1.13 (95% Cl:
2588) [19]                                    1.00 /1.28) per 10.6
                                              /[micro]g/[m.sup.3]
                                              increase of
                                              N[O.sub.2]

Gehring et al., 2010   [PM.sub.2.5]           OR: 1.29 (95% Cl:
(n = 3863;                                    1.04 /1.62) per 3.2
N[O.sub.2] n = 96681                          [micro][micro]g/
ri4l                                          [m.sup.3] increase
                                              of PM25

                       N[O.sub.2]             OR: 1.17 (95% Cl:
                                              0.97 /1.41) per 10.4
                                              /[micro]g/[m.sup.3]
                                              increase of
                                              N[O.sub.2]

Nordling et al.,       [PM.sub.10]            OR: 0.90 (95% Cl:
2007 (n = 3515) [20]                          0.45 /1.81) per 6/
                                              [micro]g/[m.sup.3]
                                              increase of
                                              [PM.sub.2.5]

                       N[O.sub.x]             OR: 0.82 (95% Cl:
                                              0.48 /1.40) per 44
                                              [micro][micro]g/
                                              [m.sup.3] increase
                                              of N[O.sub.x]

Oftedal et al., 2009   N[O.sub.2]             None
(n= 2871, N[O.sub.2]
n = 2329) [21]

Pennington et al.,     CO                     None
2018 (Total n = 24
608; prenatal
exposure n = 6795;
1st year of life n =
7755) [22]

                       [PM.sub.2.5]           None

                       N[O.sub.x]             None

Ranciere et al.,       N[O.sub.x]             OR: 1.03, 95% Cl:
2017 (n = 3840,                               0.91 /1.17 per 26 /
N[O.sub.x] n = 698)                           [micro]g/[m.sup.3]
[23]                                          increase of
                                              N[O.sub.2]
                                              equivalent

Sbihi et al., 2017     N[O.sub.2]             1 vs 0 OR: 1.10 (95%
(n = 68 195,                                  Cl: 1.0 -1.3)
N[O.sub.2] n = 68                             2 vs 0 OR: 1.04
                                              (95% Cl: 0.9 -1.2)
024) [4]b                                     (3 vs 0 OR: 1.10
                                              (95% Cl: 1.0 -1.3)

                       [PM.sub.2.5]           1 vs 0 OR: 1.15 (95%
                                              Cl: 1.0 -1.3) 2 vs 0
                                              OR: 1.21 (95% Cl:
                                              1.1 -1.4) 3 vs 0 OR:
                                              1.05 (95% Cl: 0.9 -
                                              1.2)

Study reference and    Persistent asthma/     Late/onset asthma/
setting                wheezing (a)           wheezing (a)

Brauer et al., 2006    OR: 1.19 (95% Cl:      None
(Total n = 4146;       0.96 /1.48) per 3.3
                       /[micro]g/[m.sup.3]
                       increase of
                       [PM.sub.2.5]

Pollutant Exposure     OR: 1.13 (95% Cl:      None
2588) [19]             0.99 /1.29) per 10.4
                       /[micro]g/[m.sup.3]
                       increase of
                       N[O.sub.2]

Gehring et al., 2010   OR: 1.37, 95% Cl:      OR: 1.18,95% Cl:
(n = 3863;             0.99 /1.91 per 3.2 /   1.01 /1.37 per 3.2 /
N[O.sub.2] n = 96681   [micro]g/[m.sup.3]     [micro]g/[m.sup.3]
ri4l                   increase of            increase of
                       [PM.sub.2.5]           [PM.sub.2.5]

                       OR: 1.30 95% (Cl:      OR: 1.13 95% (Cl:
                       0.99 /1.72) per 10.4   0.99/1.35) per 10.4
                       /[micro]g/[m.sup.3]    /[micro]g/[m.sup.3]
                       increase of            increase of
                       N[O.sub.2]             N[O.sub.2]

Nordling et al.,       OR: 1.64 (95% Cl:      OR: 0.94 (95% Cl:
2007 (n = 3515) [20]   0.90/3.00) per 3 /     0.42/2.11) per 6 /
                       [micro]g/[m.sup.3]     [micro]g/[m.sup.3]
                       increase of            increase of
                       [NO.sub.x]             [PM.sub.2.5]

                       OR: 1.60,95% (Cl:      OR: 0.87, 95% (Cl:
                       1.09/2.36) per 44 /    0.47 /1.60) per 44 /
                       [micro]g/[m.sup.3]     [micro]g/[m.sup.3]
                       increase of            increase of
                       [NO.sub.x]             [NO.sub.x]

Oftedal et al., 2009   None                   OR: 1.05 (95% Cl:
(n= 2871, N[O.sub.2]                          0.64 /1.72) per 27.3
n = 2329) [21]                                /[micro]g/[m.sup.3]
                                              increase of
                                              N[O.sub.2]

Pennington et al.,     Prenatal exposure      None
2018 (Total n = 24     absolute risk
608; prenatal          increase: 3.5% (95%
exposure n = 6795;     Cl: 1.5%, 6.2%) per
1st year of life n =   2.7-fold increase CO
7755) [22]

                       Age 1 exposure         None
                       absolute risk
                       increase: 3.9% (95%
                       Cl: 1.5%, 6.2%) per
                       2.7-fold increase CO
                       Prenatal exposure
                       absolute risk
                       increase: 4.4% (95%
                       Cl: 2.3%, 6.4%) per
                       2.7-fold increase
                       [PM.sub.2.5] Age 1
                       exposure absolute
                       risk increase: 4.5%
                       (95% Cl: 2.3%, 6.6%)
                       per 2.7-fold
                       increase CO

                       Prenatal exposure      None
                       absolute risk
                       increase: 3.8% (95%
                       Cl: 1.7%, 5.9%) per
                       2.7-fold increase
                       N[O.sub.x] Age 1
                       exposure absolute
                       risk increase: 4.0%
                       (95% Cl: 1.8%, 6.1%)
                       per 2.7-fold
                       increase N[O.sub.x]

Ranciere et al.,       OR: 1.27,95% Cl:       OR: 1.19, (95% Cl:
2017 (n = 3840,        (1.09 /1.47) per 26    0.89/1.33) per 26 /
N[O.sub.x] n = 698)    /[micro]g/[m.sup.3]    [micro]g/[m.sup.3]
[23]                   increase of            increase of
                       N[O.sub.2]             N[O.sub.2]
                       equivalent             equivalent

Sbihi et al., 2017     1 vs 0 OR: 1.42 (95%   1 vs 0 OR: 1.18 (95%
(n = 68 195,           Cl: 1.1 -1.8) 2 vs 0   Cl: 1.0 -1.4) 2 vs 0
N[O.sub.2] n = 68      OR: 1.20 (95% Cl:      OR: 1.29 (95% Cl:
                       1.0 -1.5) 3 vs 0 OR:   1.1 -1.5). 3 vs 0
024) [4]b              1.05 (95% Cl: 0.9 -    OR: 1.00 (95% Cl:
                       1.2)                   0.8 -1.2).

                       1 vs 0 OR: 1.17 (95%   1 vs 0 OR: 1.13, 95%
                       Cl: 1.0 -1.4) 2 vs 0   Cl: 1.0 -1.3 2 vs 0
                       OR: 1.0 (95% Cl: 0.8   OR: 1.25,95% Cl: 1.1
                       -1.2) 3 vs 0 OR:       -1.5 3 vs 0 OR:
                       0.86 (95% Cl: 0.7 -    0.97, 95% Cl: 0.8 -
                       1.1)                   1.1)

(a) Results in boldface indicate significant results at the 95%
confidence level.

(b) Reported ORs compared higher exposure quartiles [micro]groups
1, 2, and 3) to the lowest exposure quartile (reference group = 0).
N[O.sub.2] exposure ranged from 15 to 53.7 [micro]g/[m.sup.3];
[PM.sub.2.5] exposure ranged from 3.2 to 7.6
[micro]g/[m.sup.3].
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Title Annotation:Review Article
Author:Lau, Nelson; Norman, Alex; Smith, Mary Jane; Sarkar, Atanu; Gao, Zhiwei
Publication:International Journal of Chronic Diseases
Geographic Code:1CANA
Date:Jan 1, 2018
Words:7989
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