Early life exposure to traffic-related air pollution and lung function in adolescence assessed with impulse oscillometry
Authors: Erica S. Schultz, Jenny Hallberg, Per M. Gustafsson, Matteo Bottai, Tom Bellander, Anna Bergström, Inger Kull, Olena Gruzieva, Per Thunqvist, Göran Pershagen, Erik Melén
Journal: Journal of Allergy and Clinical Immunology (2016)

Most studies linking air pollution exposure and lung function have focused on spirometry measurements, a method that mostly reflects total airway resistance and large airway function, rather than peripheral airway obstruction.1Quanjer P.H. Weiner D.J. Pretto J.J. Brazzale D.J. Boros P.W. Measurement of FEF25-75% and FEF75% does not contribute to clinical decision making.Eur Respir J. 2014; 43: 1051-1058Crossref PubMed Scopus (134) Google Scholar It has been reported in animal studies that small aerosol particles in the size range typical of traffic-related air pollution are deposited in the peripheral airways.2Kuehl P.J. Anderson T.L. Candelaria G. Gershman B. Harlin K. Hesterman J.Y. et al.Regional particle size dependent deposition of inhaled aerosols in rats and mice.Inhal Toxicol. 2012; 24: 27-35Crossref PubMed Scopus (69) Google Scholar Indices related to peripheral airway function correlate with health status and asthma symptoms in children and adults.3van der Wiel E. ten Hacken N.H. Postma D.S. van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review.J Allergy Clin Immunol. 2013; 131: 646-657Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 4Lipworth B. Manoharan A. Anderson W. Unlocking the quiet zone: the small airway asthma phenotype.Lancet Respir Med. 2014; 2: 497-506Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar However, it is unknown whether exposure to traffic-related air pollution affects peripheral airway function. We have previously reported associations between exposure to traffic-related air pollution during the first year of life and lung function decrements measured by spirometry in children and adolescents.5Schultz E.S. Hallberg J. Bellander T. Bergstrom A. Bottai M. Chiesa F. et al.Early-life exposure to traffic-related air pollution and lung function in adolescence.Am J Respir Crit Care Med. 2016; 193: 171-177Crossref PubMed Scopus (92) Google Scholar Here, we assessed peripheral airway function in adolescence using impulse oscillometry (IOS).6Hallberg J. Thunqvist P. Schultz E.S. Kull I. Bottai M. Merritt A.S. et al.Asthma phenotypes and lung function up to 16 years of age—the BAMSE cohort.Allergy. 2015; 20: 12598Google Scholar IOS is a noninvasive, effort-independent technique to assess airway resistance and reactance, allowing for discrimination between peripheral and central airway dysfunction. Our aim was to test whether long-term traffic-related air pollution during infancy is associated with IOS indices related to peripheral obstruction in adolescence. We used data from BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey), a longitudinal prospective birth cohort of 4089 children recruited between 1994 and 1996 in Stockholm, Sweden. Information on background characteristics, respiratory health, and exposure factors was obtained from repeated questionnaires up to age 16 years.6Hallberg J. Thunqvist P. Schultz E.S. Kull I. Bottai M. Merritt A.S. et al.Asthma phenotypes and lung function up to 16 years of age—the BAMSE cohort.Allergy. 2015; 20: 12598Google Scholar The current study population includes 2415 adolescents with information on air pollution exposure, confounder variables, and IOS data. In the present analyses, modeled levels of nitrogen oxides (NOx) and particulate matter with an aerodynamic diameter of less than 10 μm (PM10) from road traffic were used in the exposure assessment. PM10 mainly consists of coarse particles resulting from road surface erosion, while nitrogen oxides (and ultrafine particles) are directly emitted in motor vehicle exhaust. The methodology for calculating individual long-term exposure to local traffic-related PM10 and NOx has been described elsewhere.5Schultz E.S. Hallberg J. Bellander T. Bergstrom A. Bottai M. Chiesa F. et al.Early-life exposure to traffic-related air pollution and lung function in adolescence.Am J Respir Crit Care Med. 2016; 193: 171-177Crossref PubMed Scopus (92) Google Scholar In brief, outdoor levels of air pollution at individual residential and school addresses were calculated using emission inventories and a mathematical model combining data on road traffic, meteorological conditions, and topography. The calculations are based on assumptions of the atmospheric dispersion of the pollutants. The time-weighted (duration at each address) average outdoor levels of air pollution concentrations during the first year of life and 1 year before the 16-year follow-up were entered as continuous variables in the models. IOS at the age of 16 years was performed using the Jaeger MasterScreen-IOS system (Carefusion Technologies, San Diego, Calif) described in detail elsewhere.6Hallberg J. Thunqvist P. Schultz E.S. Kull I. Bottai M. Merritt A.S. et al.Asthma phenotypes and lung function up to 16 years of age—the BAMSE cohort.Allergy. 2015; 20: 12598Google Scholar, 7Goldman M.D. Saadeh C. Ross D. Clinical applications of forced oscillation to assess peripheral airway function.Respir Physiol Neurobiol. 2005; 148: 179-194Crossref PubMed Scopus (187) Google Scholar Briefly, pressure oscillation with frequencies varying between 5 and 35 Hz were superimposed on tidal breathing, producing recordable waveforms. Advanced signal processing was then used to extract the respiratory mechanic components from the recorded waveforms. The primary outcomes resistance (R) and reactance (X) were plotted against frequency. Resistance is defined as the ratio of the pressure drop (in Pascal, Pa) over an airway segment and the flow (L·s−1) through that segment. Reactance is simplistically described as the amount of recoil generated against the pressure wave. We used the following IOS variables as our outcomes: (1) resistance at 5 and 20 Hz (R5 and R20), as indices of total and proximal airway resistance; (2) the fall in resistance between R5 and R20 (R5-R20), reflecting peripheral airway resistance; and (3) the square root of the integrated area of low frequency reactance (AX0.5), assumed to reflect the reactance of the peripheral airways, and serving as a confirmatory index to R5-R20.7Goldman M.D. Saadeh C. Ross D. Clinical applications of forced oscillation to assess peripheral airway function.Respir Physiol Neurobiol. 2005; 148: 179-194Crossref PubMed Scopus (187) Google Scholar Associations between exposure and IOS data were assessed by median regression, due to right skewed distribution. Results are presented for R5-R20 with the unit Pa·L−1·s, and for AX0.5 with the unit (Pa·L−1)0.5 per 10 μg/m3 for NOx and per 5 μg/m3 for PM10. Quantile regression was performed to estimate the 95th percentiles of each IOS index specific to age, height, and weight in males and females separately (for details, see the Methods section in this article's Online Repository at www.jacionline.org). Logistic regression between air pollution exposure during the first year of life and lung function was performed with the outcome dichotomized as above versus below the estimated 95th percentiles for R5-R20 and AX0.5. Analyses were performed with Stata 11 (StataCorp LP, College Station, Tex). A 10 μg/m3 increase in exposure to traffic-NOx in the first year of life was associated with a significant increase of 2.0 Pa·L−1·s in R5-R20 (95% CI, 0.3-3.6, P = .02) and of 0.17 (Pa·L−1)0.5 in AX0.5 (95% CI, 0.01-0.34; P = .04) (Table I). Adjustment for subsequent exposure time windows, short-term exposures, or moving anytime during follow-up did not change the results (see Table E1 in this article's Online Repository at www.jacionline.org). No associations were seen for either R5 or R20 on their own, or from exposure during year 15 to 16 (see Table E2 in this article's Online Repository at www.jacionline.org). Further analyses of first year of life exposure to traffic-NOx suggested stronger associations in boys and in subjects with asthma at 16 years, but not in those with allergic sensitization at 16 years (Table I). The effect modification in R5-R20 analyses was significant for asthma (P = .04 for interaction), but not for sex (P = .56). The results for PM10 were in line with those of NOx, but not statistically significant. To determine whether exposure to air pollution was associated with a more severe peripheral airway obstruction, we analyzed NOx and PM10 exposure in relation to the odds of having R5-R20 and AX0.5 above versus below the estimated 95th percentile. Associations were indicated between exposure to traffic-NOx and traffic-PM10 during the first year of life and above the 95th percentile of R5-R20 and AX0.5 (Fig 1). In these analyses, PM10 exposure was most prominently associated with the IOS indices. Exposure characteristics as well as lung function and anthropometry data for the present study population are presented in Tables E3 and E4, respectively (see this article's Online Repository at www.jacionline.org).Table IStratified analyses of NOx and PM10 exposure during the first year of life and IOS measurements at age 16 yearsNOx (per 10 μg/m3)R5-R20 (Pa·L−1·s)AX0.5 (Pa·L−1)0.5Nβ∗Beta defined as change in R5-R20 or AX0.5 per 10 μg/m3 of NOx or per 5 μg/m3 of PM10. Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.95% CIP valueβ∗Beta defined as change in R5-R20 or AX0.5 per 10 μg/m3 of NOx or per 5 μg/m3 of PM10. Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.95% CIP valueAll2.00.33.6.020.170.010.34.042415Females0.3−2.22.7.820.16−0.120.44.261239Males3.21.25.2<.010.23−0.010.46.061176Asthma at 16 y†Defined as at least 4 episodes of wheeze in the last 12 months or at least 1 episode in combination with prescription of inhaled corticosteroids. Yes6.70.113.3.051.220.481.97<.01160 No1.6−0.23.5.070.16−0.000.33.062199Sensitized at 16 y‡Defined as IgE values for Phadiatop (airborne allergens) and/or food-mix/Fx5 (food allergens) ≥0.35 kU/L (Thermo Fischer Scientific, Uppsala, Sweden). Yes2.4−0.85.6.140.20−0.010.41.071094 No1.2−1.33.7.350.16−0.030.35.101267PM10 (per 5 μg/m3)R5-R20 (Pa·L−1·s)AX0.5 (Pa·L−1)0.5Nβ∗Beta defined as change in R5-R20 or AX0.5 per 10 μg/m3 of NOx or per 5 μg/m3 of PM10. Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.95% CIP valueβ∗Beta defined as change in R5-R20 or AX0.5 per 10 μg/m3 of NOx or per 5 μg/m3 of PM10. Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.95% CIP valueAll3.0−2.18.0.250.40−0.080.89.102415Females−1.8−9.15.5.630.24−0.621.11.581239Males4.9−0.410.2.070.43−0.191.05.171176Asthma at 16 y†Defined as at least 4 episodes of wheeze in the last 12 months or at least 1 episode in combination with prescription of inhaled corticosteroids. Yes24.2−0.649.0.063.861.406.31<.01160 No3.4−1.68.3.180.36−0.120.83.142199Sensitized at 16 y‡Defined as IgE values for Phadiatop (airborne allergens) and/or food-mix/Fx5 (food allergens) ≥0.35 kU/L (Thermo Fischer Scientific, Uppsala, Sweden). Yes4.7−4.213.6.300.32−0.280.91.291094 No1.8−5.08.6.600.50−0.111.10.111267∗ Beta defined as change in R5-R20 or AX0.5 per 10 μg/m3 of NOx or per 5 μg/m3 of PM10. Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.† Defined as at least 4 episodes of wheeze in the last 12 months or at least 1 episode in combination with prescription of inhaled corticosteroids.‡ Defined as IgE values for Phadiatop (airborne allergens) and/or food-mix/Fx5 (food allergens) ≥0.35 kU/L (Thermo Fischer Scientific, Uppsala, Sweden). Open table in a new tab Our results indicate that exposure to air pollutants from local traffic during infancy is associated with peripheral airway indices in adolescence, particularly in those with asthma. This extends our previous findings from the spirometry analyses, where we found a negative association on FEV1 from exposure during infancy.5Schultz E.S. Hallberg J. Bellander T. Bergstrom A. Bottai M. Chiesa F. et al.Early-life exposure to traffic-related air pollution and lung function in adolescence.Am J Respir Crit Care Med. 2016; 193: 171-177Crossref PubMed Scopus (92) Google Scholar Notably, this was observed primarily in individuals without asthma. The observed effects are small in absolute terms and may have little impact on a healthy individual living in areas with low pollution levels, but are likely to be relevant in areas with high pollution levels and for susceptible groups such as individuals with respiratory diseases. Dose and location of depositions in the airway tree depends on the density, shape, size, and hygroscopy of particles as well as breathing pattern, anatomy, and reactivity of the airways.8Jaques P.A. Kim C.S. Measurement of total lung deposition of inhaled ultrafine particles in healthy men and women.Inhal Toxicol. 2000; 12: 715-731Crossref PubMed Scopus (238) Google Scholar In experimental settings, it has been observed that deposition of inhaled ultrafine particles (which is closely linked to modeled NOx) is increased in those with asthma, relative to healthy subjects.9Chalupa D.C. Morrow P.E. Oberdorster G. Utell M.J. Frampton M.W. Ultrafine particle deposition in subjects with asthma.Environ Health Perspect. 2004; 112: 879-882Crossref PubMed Scopus (283) Google Scholar This could be a potential mechanism underlying the stronger association between air pollution and peripheral airway function observed in individuals with asthma, compared with previous results on FEV1, where the association was strongest in individuals without asthma.5Schultz E.S. Hallberg J. Bellander T. Bergstrom A. Bottai M. Chiesa F. et al.Early-life exposure to traffic-related air pollution and lung function in adolescence.Am J Respir Crit Care Med. 2016; 193: 171-177Crossref PubMed Scopus (92) Google Scholar We analyzed both NOx and PM10 as markers of traffic air pollutants and it should be recognized that these pollutants are highly correlated and that this study cannot elucidate in detail which component or mixture of traffic-related air pollution negatively influences the airways. In conclusion, our study contributes new knowledge about the negative effects of exposure to traffic-related air pollutants during infancy on airway resistance and reactance in adolescence. In particular, our results suggest that the peripheral conducting airways are affected by traffic-related air pollutants. Quantile regression was performed to estimate the 95th percentiles of each IOS index specific to age, height, and weight in males and females separately.E1Bottai M. Pistelli F. Di Pede F. Baldacci S. Simoni M. Maio S. et al.Percentiles of inspiratory capacity in healthy nonsmokers: a pilot study.Respiration. 2011; 82: 254-262Crossref PubMed Scopus (11) Google Scholar The estimates were obtained from a selected group of "healthy" subjects, which consisted of nonsmokers, not exposed to maternal smoking in utero or at baseline, born in gestational week 37 or later, with birth weight above 1500 g, never had a asthma diagnosis (at 1, 2, 4, 8, 12, or 16 years), and did not require respiratory support at birth. In addition, subjects were excluded if they had a disease that potentially might influence their lung function. Before estimating 95th percentiles, we visually inspected the scatterplots of IOS indexes against the predictors (age, height, and weight). Very few subjects were older than 18 years and/or more than 100 kg in weight. These outlying values were removed from the final group, which comprised 642 females and 577 males.Table E1Exposure to traffic-NOx during the first year of life and R5-R20 measurements at age 16 years, adjusted for subsequent exposure time windows, short-term exposure (1-7 d), or moved anytime during follow-up periodModelChange in Pa·L−1·s (95% CI) per 10 μg/m3 of traffic-NOxAllMalesFemalesMain model∗Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.2.0 (0.3 to 3.6)3.2 (1.2 to 5.2)0.3 (−2.2 to 2.7)Main model + adjustment for: NOx 1-8 y + 8-16 y3.1 (1.2 to 5.1)4.4 (1.5 to 7.2)1.5 (−1.7 to 4.6) Rh + Temp (1-7 d)†Short-term exposures: 1-week lag preceding lung function measurement, using hourly mean values from roof top monitoring stations (NOx, Rh, and Temp) and a rural station (ozon).E32.1 (0.5 to 3.8)3.1 (1.1 to 5.2)0.4 (−2.1 to 2.9) Rh + Temp + Ozon (1-7 d)†Short-term exposures: 1-week lag preceding lung function measurement, using hourly mean values from roof top monitoring stations (NOx, Rh, and Temp) and a rural station (ozon).E31.9 (0.0 to 3.8)3.1 (0.7 to 5.5)−0.3 (−3.0 to 2.5) Rh + Temp + NOx (1-7 d)†Short-term exposures: 1-week lag preceding lung function measurement, using hourly mean values from roof top monitoring stations (NOx, Rh, and Temp) and a rural station (ozon).E31.8 (−0.2 to 3.9)3.1 (0.9 to 5.4)0.7 (−2.6 to 3.9) Moved anytime 0-16 y1.8 (0.1 to 3.6)3.6 (1.6 to 5.5)−0.1 (−3.1 to 2.9)Rh, Relative humidity; Temp, temperature.∗ Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.† Short-term exposures: 1-week lag preceding lung function measurement, using hourly mean values from roof top monitoring stations (NOx, Rh, and Temp) and a rural station (ozon).E3Schultz E.S. Gruzieva O. Bellander T. Bottai M. Hallberg J. Kull I. et al.Traffic-related air pollution and lung function in children at 8 years of age: a birth cohort study.Am J Respir Crit Care Med. 2012; 186: 1286-1291Crossref PubMed Scopus (128) Google Scholar Open table in a new tab Table E2Associations of NOx and PM10 exposure during the first year of life and year 15-16 and IOS measurements at age 16 yearsExposure year 0-1Exposure year 15-16nβ∗Change in respective IOS measurement per 10 μg/m3 of NOx or per 5 μg/m3 of PM10. Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.95% CInβ∗Change in respective IOS measurement per 10 μg/m3 of NOx or per 5 μg/m3 of PM10. Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth.95% CINOx (per 10 μg/m3) R5 (Pa·L−1·s)24150.2−3.2 to 3.62297−0.4−8.4 to 7.5 R20 (Pa·L−1·s)2415−0.5−3.3 to 2.322971.6−5.7 to 9.0 R5-R20 (Pa·L−1·s)24152.00.3 to 3.62297−0.4−4.4 to 3.7 AX0.5 (Pa·L−1)0.524150.170.01 to 0.3422970.12−0.30 to 0.53PM10 (per 5 μg/m3) R5 (Pa·L−1·s)24154.3−5.9 to 14.522974.1−3.3 to 11 R20 (Pa·L−1·s)24156.3−2.2 to 14.822974.9−2.0 to 11.8 R5-R20 (Pa·L−1·s)24153.0−2.1 to 8.02297−1.5−5.5 to 2.5 AX0.5 (Pa·L−1)0.524150.40−0.08 to 0.8922970.04−0.35 to 0.43∗ Change in respective IOS measurement per 10 μg/m3 of NOx or per 5 μg/m3 of PM10. Calculated by median regression, adjusted for sex, age, height, weight at 16 years as well as municipality at birth. Open table in a new tab Table E3Distribution of selected exposure characteristics among all children in the cohort (N = 4089) and the children included in the present study on air pollution exposure and lung function at 16 years (n = 2415)Covariates∗Covariates relate to the first year of child's life if not otherwise stated.Full cohort(N = 4089)Study population at 16 y(n = 2415†Data include subjects with data on IOS at 16 years, municipality at birth, sex, age, weight, height at 16-years examination, as well as exposure information for the first year of life.)n%n%95% CISex: male206550.5117648.747.4-50.0Socioeconomic status of parents White collar worker332382.7201384.583.5-85.4Heredity Parents with allergy and/or asthma119129.574831.430.2-32.6Ethnicity Any parents born outside of Scandinavia54316.037216.115.3-17.0Mother smoking during pregnancy or at 2 mo of child56313.829412.211.4-13.0Environmental tobacco smoke exposure at 16 y413‡Data include subjects answering questionnaire or taking IgE measurement at 16 years, corresponding to 3034, 3108, 3115, and 2547 for environmental tobacco smoke, own smoking, asthma, and sensitization, respectively.13.628712.611.9-13.2Adolescence smoking at 16 y373‡Data include subjects answering questionnaire or taking IgE measurement at 16 years, corresponding to 3034, 3108, 3115, and 2547 for environmental tobacco smoke, own smoking, asthma, and sensitization, respectively.12.029812.411.8-13.1Asthma at 0-2 y33410.920810.09.3-10.7Asthma at 16 y199‡Data include subjects answering questionnaire or taking IgE measurement at 16 years, corresponding to 3034, 3108, 3115, and 2547 for environmental tobacco smoke, own smoking, asthma, and sensitization, respectively.6.41606.86.3-7.3Sensitized at 16 y1170‡Data include subjects answering questionnaire or taking IgE measurement at 16 years, corresponding to 3034, 3108, 3115, and 2547 for environmental tobacco smoke, own smoking, asthma, and sensitization, respectively.45.9109446.345.8-46.9Mean ± SDMean ± SD95% CIBirth weight (g)3530 ± 5583525 ± 5563510-3539Birth length (cm)50.2 ± 2.650.2 ± 2.550.2-50.2Gestational age (wk)39.5 ± 1.839.5 ± 1.839.4-39.6Exposure concentration during year 0-1 NOx (μg/m3)20.9 ± 16.521.6 ± 17.021.2-22.0 PM10 (μg/m3)5.8 ± 3.35.9 ± 3.35.8-6.0CIs constructed by applying finite population correction factor.∗ Covariates relate to the first year of child's life if not otherwise stated.† Data include subjects with data on IOS at 16 years, municipality at birth, sex, age, weight, height at 16-years examination, as well as exposure information for the first year of life.‡ Data include subjects answering questionnaire or taking IgE measurement at 16 years, corresponding to 3034, 3108, 3115, and 2547 for environmental tobacco smoke, own smoking, asthma, and sensitization, respectively. Open table in a new tab Table E4Lung function and anthropometry data from the 16-year examination in the BAMSE cohort and in the subgroup of subjects with asthma at age 16 yearsVariableFull study populationIndividuals with asthma∗Asthma at age 16 years was defined as at least 4 episodes of wheeze in the last 12 months or at least 1 episode in combination with prescription of inhaled corticosteroids.E2No.Mean ± SDNo.Mean ± SDAge (y)241516.7 ± 0.416016.7 ± 0.3Length (m)2415173.4 ± 9.0160172.3 ± 8.1Weight (kg)241565.5 ± 11.516067.1 ± 12.9IOSNo.MedianIQR%No.MedianIQR%R5 (Pa·L−1·s)2415360110160400123R20 (Pa·L−1·s)24153409016036593R5-R20 (Pa·L−1·s)241515501603373AX0.5 (Pa·L−1)0.52415156160198>P95: R5-R201737.22314.4>P95: AX0.51676.92918.1IQR, Interquartile range.∗ Asthma at age 16 years was defined as at least 4 episodes of wheeze in the last 12 months or at least 1 episode in combination with prescription of inhaled corticosteroids.E2Thacher J.D. Gruzieva O. Pershagen G. Neuman A. Wickman M. Kull I. et al.Pre- and postnatal exposure to parental smoking and allergic disease through adolescence.Pediatrics. 2014; 134: 428-434Crossref PubMed Scopus (91) Google Scholar Open table in a new tab Rh, Relative humidity; Temp, temperature. CIs constructed by applying finite population correction factor. IQR, Interquartile range.