Air pollution plays an important role in respiratory health for both children and adults. Inhalation of air pollutants, such as ozone (O3) and oxides of nitrogen (NOx) as well as particulate matter with aerodynamic diameter of <10 µm (PM10) and <2.5 µm (PM2.5), has been shown to induce inflammation, and long-term exposure has been associated with new onset of asthma in adults.1–3
Nitric oxide (NO) is a gaseous substance produced by epithelial cells in the respiratory tract in healthy subjects in small amounts, with substantially increased production during airway inflammation. The fraction of exhaled NO is a noninvasive biomarker of airway inflammation used to diagnose and monitor asthma. A substantial number of panel studies have reported that levels of the fraction of exhaled NO measured at an exhalation rate of 50 ml/s are increased in children with asthma after exposure to ambient O3 and PM2.5 as well as nitrogen dioxide (NO2), with averaging times ranging from hours to a few days.4–7 However, some studies found no association,8 and others have found varying directions of effects for various pollutants.9 A panel study of older adults showed associations between 6- and 24-hour exposure to PM2.5 and the fraction of exhaled NO at 50 ml/s,10 for both ambient and microenvironment air pollution exposure. Corresponding results have also been found for short-term exposure to elemental carbon in a panel study of adults with asthma11 and in a recent study among elderly persons with a history of coronary artery disease.12 In contrast, a recent experimental study on adults with mild asthma showed no effect on the fraction of exhaled NO at 50 ml/s when exposing the participants to particles in a road tunnel.13
Using geographical exposure measures representing long-term exposures, increased levels of the fraction of exhaled NO at 50 ml/s among asthmatic and nonasthmatic children living close to high traffic flow were observed in a cross-sectional study,14 whereas using a similar geographical exposure measure associations only in children with asthma were observed in a panel study.15 Most epidemiologic studies to date relating air pollution exposure to the fraction of exhaled NO have been conducted in children, and data on adults are sparse.
The standard method for measuring exhaled NO is a single-breath technique with an exhalation rate of 50 ml/s, which mainly represents the levels of the fraction of exhaled NO from the central airways and therefore cannot be used alone to determine whether the NO originates from the upper or the lower parts of the respiratory tract.16,17 Because different air pollutants are likely to affect different parts of the respiratory tract, measures separating effects in the central and distal parts of the airways are of particular interest. When measuring the fraction of exhaled NO at relatively high exhalation flow, a larger proportion of the exhaled NO is derived from the distal airways, that is, there is less time for air to become saturated with NO from the airway wall in central airways. This has been shown to be valid for subjects with alveolitis.18 Another approach is to mathematically model the concentrations of NO in distal airways (alveolar NO) as a function of flow.19–22 However, the best method for accurate modeling of NO from the distal airways is still uncertain, and validation of the various mathematical methods is lacking. The crude concentrations of the fraction of exhaled NO at different exhalation flow rates could, however, also be used to differentiate where inflammation is present along the airway tree. This has been elegantly demonstrated by Lehtimäki and colleagues18 who showed elevated levels of the fraction of exhaled NO at a flow rate of 300 ml/s but normal levels of the fraction of exhaled NO at 50 ml/s in subjects with alveolitis.18 In a cross-sectional study by Lehtonen et al,23 subjects with asbestosis had substantially higher levels of the fraction of exhaled NO at a flow rate of 300 ml/s than healthy controls (6.3 ppb [SE = 0.5] vs. 5.0 [0.5]), but similar fractions of exhaled NO at a flow rate of 50 and 100 ml/s. The approach to measure the fraction of exhaled NO with different flow rates has until now been used only in a few studies assessing effects of exposure, where differences in relative changes of concentrations of fraction of exposed NO after exposure at various flow rates could indicate where the main biological effect of the exposure takes place. We showed previously in an experimental study that woodsmoke particles affected the fraction of exhaled NO measured at a flow rate of 270 ml/s (representing the distal airways) but not at the more commonly used flow rate of 50 ml/s (representing more proximal airways).24
The aim of the present cross-sectional study was to investigate whether short-term exposure to O3, NOx, and PM10 within an adult population is associated with higher levels of exhaled NO using the fraction of exhaled NO measured with two different exhalation flows.
The study population consisted of subjects from the ADONIX (adult-onset asthma and exhaled NO) study, a general population–based study of men and women from 25 to 74 years of age living in Gothenburg, Sweden, or nearby areas. Initially, 14,554 participants were invited to the study, and the response rate to the baseline examination was approximately 46% (Figure). All participants received a postal questionnaire and an invitation for a clinical examination, as previously reported.25 At the clinical examination, participants also answered a general questionnaire that included questions on respiratory health, work and environmental exposures, and smoking. Asthma was defined as a positive answer to either of these questions: “Do you have or have you ever had asthma?” or “Have you had asthma diagnosed by a doctor?” Current cold was defined as having a cold or sore throat at the time of the clinical examination.
Blood serum samples were analyzed for eight main inhalation allergens using Phadiatop (Pharmacia, Uppsala, Sweden).26,27 Participants with a value of 0.35 kU/L or more of a specific immunoglobulin E were considered atopic.
Measurements of the Fraction of Exhaled NO
At the clinical examination, the fraction of exhaled NO was measured with an online NO monitoring system NIOX (Aerocrine AB, Stockholm, Sweden), at exhalation flow rates of 50 and 270 ml/s, after at least 4 hours of fasting, according to 2005 recommendations from the American Thoracic Society (ATS/ERS).16 NO levels were also measured daily on the research staff to assure that no shift in instrument response was seen. A ±10% deviation of the instant flow and ±5% of the mean flow during the plateau phase were acceptable. Exhalations were registered for each subject in triplicate within 10% deviation between June 2001 and January 2003 and in duplicate from February 2003 to December 2003, according to the subsequently published revised ATS/ERS recommendations16,28; we used the mean concentration.
Assessment of Air Pollution Exposure
The local environmental agency in Gothenburg provided hourly data on O3, NOx, and PM10 concentrations. These measurements were obtained at roof level from a monitoring station in the city center. O3 was measured using an ultraviolet absorption method, NOx was measured with a chemiluminescence monitor, and PM10 was measured using a tapered element oscillating microbalance monitor. Exposure was calculated for each subject as the 3-, 24-, and 120-hour average concentrations of air pollutants preceding measurement of the fraction of exhaled NO for each subject.
Linear regression was applied to estimate the association of the fraction of exhaled NO at flow rates of 50 and 270 ml/s with O3, NOx, and PM10, using both single- and multipollutant models with 95% confidence intervals. The variables of fraction of exhaled NO were log-transformed because of a skewed distribution. We adjusted for common predictors, including smoking, height, age, and atopy,29 and also for temperature and a current cold. In addition, we included year and month as factor variables in the model to account for time trends in the outcome variables. We studied potential effect modification by stratifying the analysis by atopy and by asthma. The results are presented as the mean percent change in the fraction of exhaled NO at 270 and 50 ml/s per one interquartile range (IQR) increase in the respective air pollutant. STATA 11.2 (StataCorp, College Station, TX; www.stata.com) statistical software package was used for all analyses.
Of the 5841 participants, 5,314 had information on all relevant covariates; of these, 5,261 had measured values of the fraction of exhaled NO at 50 ml/s, and 4,891 had values for the fraction of exhaled NO at 270 ml/s (Figure). Characteristics of the 5314 subjects are presented in Table 1. Levels of the fraction of exhaled NO at flow rates of 50 and 270 ml/s were higher in subjects with asthma or atopy (Table 2). The correlation between the fraction at flow rates of 50 and 270 ml/s was high (rSpearman = 0.85). Median, minimum, maximum, 25th and 75th percentile, and IQR of the O3, NOx, and PM10 exposure for subjects at the studied time lags are given in Table 3. There was a positive correlation between NOx and PM10, whereas the correlation between NOx and O3 was negative (eTable 1, http://links.lww.com/EDE/A726). The seasonal distribution of people with asthma and atopy, together with the median levels of NOx and O3, is presented in eTable 2 (http://links.lww.com/EDE/A726).
In single-pollutant models, the 120-hour average concentration of O3 was positively associated with the fraction of exhaled NO at 270 ml/s (4.0% [95% confidence interval = 1.0 to 7.1] per IQR) and at 50 ml/s (4.4% [1.0 to 7.9] per IQR; Table 4). No clear associations were seen for NOx or PM10.
In the multipollutant models, which included O3, NOx, and PM10 simultaneously with the same averaging time, the O3 effect was strengthened; an increase of one IQR in the 3-, 24-, and 120-hour average levels of O3 was associated with higher fractions of exhaled NO at 270 ml/s (Table 4). A small effect was also seen for the association of 24-hour NOx level with the fraction of exhaled NO at 270 ml/s. Exposure to PM10 did not elevate the fraction of exhaled NO at 270 ml/s at any of the three time lags; instead, there was a suggested weak opposite direction of effect. The association of O3 with the fraction of exhaled NO at 50 ml/s was less pronounced than that of exhaled NO at 270 ml/s, while the association with the other pollutants was weak or negative. Restricting the analysis of the 120-hour lag pollution levels on the fraction of exhaled NO at 270 ml/s to nonsmokers and ex-smokers reduced the number of participants to 4,022. Although the magnitude of some estimates changed slightly, the main patterns of effect estimates remained (data not shown).
Effect modification was studied for the associations of O3 and NOx with the fraction of exhaled NO at 50 and 270 ml/s; the models showed effects with asthma and atopy in the main analysis. The results of the fraction of exhaled NO at 270 ml/s are presented in Table 5, for a single- and multipollutant model and separately for each stratum. Interaction was seen in the single-pollutant models for effect modification of both O3 and NOx on the fraction of exhaled NO, with more negative effects for O3 and more positive effect for NOx among persons with asthma. In the adjusted multipollutant models (where the inverse correlation between the two pollutants is better addressed), the effect of O3 among people with asthma remained mostly negative. These were weakly positive for the 120-hour concentrations, but with negative coefficients for 3- and 24-hour concentrations although with wide confidence intervals. In the multipollutant model, persons with asthma tended to have higher concentrations of the fraction of exhaled NO at 270 ml/s with increasing NOx levels. No clear differences in effects were seen between participants with and without atopy. The associations of the fraction of exhaled NO at 50 ml/s showed a similar pattern as the fraction of exhaled NO at 270 ml/s but less pronounced (results not shown).
As a sensitivity analysis, we reconsidered the main multipollutant analysis of the fraction of exhaled NO at 270 ml/s and 120-hour lag excluding three winter months (December, January, and February) to better account for potential bias from lower respiratory infections on the effects of the pollutants on people with asthma. The analysis showed similar patterns of effects as with the full data set.
Of the initial 5841 participants available in the cohort, 527 were excluded from the analysis due to missing covariates (Figure). Comparing this group with the remaining 5,314 showed no important differences in age, asthma, atopy, or the levels of O3 or NOx, although those excluded were on average shorter and more often smokers.
In a community-based population recruited from a community-wide random sample, this study is one of the first to report an association of ambient air pollution with the fraction of exhaled NO at 270 ml/s. In the adjusted multipollutant models, the level of FENO270 was elevated after exposure to O3, while the effects of NOx were small and the trend with PM10 mostly negative. A similar but less clear association was seen for the 120-hour average exposure to O3 in relation to the fraction of exhaled NO at 50 ml/s.
Until now, it has been difficult to discriminate between effects on the central airways and effects on the distal airways, using a noninvasive method. The possibility of such discrimination would be an important step forward because it is likely that different air pollutants reach and affect different regions of the lung. For the distal regions, various mathematical models to calculate alveolar NO have been described, but to date no consensus on a useful best model has been achieved, and to our knowledge, all models are associated with some bias. In the current study, we chose to present the measured NO concentrations using two flow rates, that is, 50 and 270 ml/s (the maximum flow rate with our equipment), to represent the more proximal and distal parts of the airways. We observed indication of stronger associations on the higher flow rate, while the effects using the fraction of exhaled NO at 50 ml/s were less clear. This is in line with our previous experimental study on the effects of woodsmoke exposure.24 Although the correlation between the fraction of exhaled NO at 50 and 270 ml/s was high (rSpearman = 0.85), the median levels and magnitude of variation of the fraction of exhaled NO at 50 ml/s are higher (Table 2). This difference is likely explained by a larger contribution of NO from the central airways and supports the fraction of exhaled NO at 270 ml/s as a more specific measure of NO related to the parts of the airways most likely to be affected by air pollution.
The concept of induction of inflammation in the distal airways by O3 is in accordance with previous findings. An early study by Castleman et al,30 in 1980, exposed rhesus monkeys to O3 and showed a distinct effect in the bronchioli. A later study that examined the site of O3 absorption along the airway tree found that absorption is strongly associated with the cross-sectional area of the peripheral lung but not with the size of the central airways.31 The effect of O3 on the fraction of exhaled NO at 270 ml/s in our sample of adults was relatively small, with increases of around 5% for each IQR increase in O3.
Although there are previous experimental and panel studies showing no association between O3 and the fraction of exhaled NO,32–34 there are also studies in both children and adults reporting an elevation of the fraction of exhaled NO after ambient exposure to O3.5,7,12,35 Nickmilder et al7 examined the effect of ambient O3 levels on the fraction of exhaled NO in healthy children at six summer camps in Belgium. The results showed that children exposed to high levels of O3 had increasing levels of the fraction of exhaled NO at 50 ml/s throughout the day, whereas the levels decreased among children who were less exposed. Delfino and colleagues12 recently showed that the 5-day cumulative average of O3 was associated with higher levels of exhaled NO within a panel of elderly subjects with previous heart conditions.
In the main multipollutant models, no clear associations for the 5-day average NOx levels were seen in relation to exhaled NO, while an association could be seen for O3. This is consistent with results from a recent study on senior adults living in retirement communities.12 Nevertheless, NOx was included to represent local traffic emissions, and recent epidemiologic studies11,36 have shown effects of short-term exposure to ultrafine particles and black smoke (which often correlate well with NOx) on the fraction of exhaled NO at 50 ml/s. We saw a small association between the 24-hour NOx levels and the fraction of exhaled NO at 270 ml/s in the multipollutant model, indicating a corresponding short-term effect. However, in contrast to these studies, we used exposure data measured at an urban background station, and so exposure misclassification (the difference between ambient measurements and actual personal exposure) is an obvious issue. It is likely that this misclassification is independent of the measured values of fraction of exhaled NO (nondifferential), and thus, on average, the estimated association between exposure and outcome would be biased toward the null. This bias may also be larger for NOx than for O3 because of the potentially higher spatial variability of NOx in urban areas.
Our findings did not suggest a positive association between PM10 and the levels of the fraction of exhaled NO but rather the opposite. A previous study on asthma in adults showed associations of levels of PM10, PM2.5, and BS outside the participant’s home with the fraction of exhaled NO at 50 ml/s.37 Studies in children also suggest similar associations between PM2.5 and the fraction of exhaled NO at 50 ml/s.5,14 The elemental composition of PM10 in outdoor air is known to vary substantially both regionally and nationally,38 which might modulate the effect of the exposure, depending on the location of the measurements and the dominant emission sources. In this area, PM10 measured in urban background consists of a large fraction of long-distance transported particles together with a smaller fraction of locally produced particles. The fact that PM10 consists of two fractions with different origins and spatial variations could be one reason for the unexpected results because each of the fractions correlate differently with O3 and NOx. To further clarify this and to more firmly separate the effects of specific pollutants, additional studies are needed on the effects of different fractions of particles on the fraction of exhaled NO.
Results from the multipollutant analysis stratified by asthma indicated that the effects of O3 and NOx on the fraction of exhaled NO at 270 ml/s may be different between people with and without asthma. Among people with asthma, there was a tendency for a negative association with O3, whereas a stronger positive association was suggested with NOx. Similar associations with O3 have previously been shown in studies among children with asthma.8,9 Scheduling of clinical investigations of the participants was not related to either asthma status (which was unknown) or expected levels of air pollution in the days preceding a visit. eTable 2 (http://links.lww.com/EDE/A726) shows the distribution of participants with asthma and atopy, and the median levels of NOx and O3 stratified by season. The proportions of people with asthma and atopy are similar in all seasons, except for a slightly higher proportion of persons with asthma during autumn. The highest levels of NOx were not during autumn but rather during winter. As a sensitivity analysis, we also excluded the three winter months from the stratified analysis of asthma, to better account for lower respiratory infections (which are not fully accounted for by adjusting for a current cold). Although some of the effect estimates changed slightly, the results showed similar patterns of effects. Hence, we believe that the slight differences in effects seen between subjects with and without asthma are not because of bias.
We chose a prespecified approach regarding the exposure time lags because we did not know what to expect. We included short (3-hour), intermediate (24-hour), and relatively long (5-day) time lags, keeping in mind that we consider this a study of short-term effects. The knowledge that different pollutants represent different compositions of substances also motivates consideration of more than one lag, as supported in our results that indicated the longer lag is more relevant for O3 while the intermediate seems more relevant for NOx.
We have chosen to focus on results from the multipollutant models because the consumption of O3 oxidizing oxidizes nitrogen monoxide to dioxide, creating a pronounced negative correlation between O3 and NOx. If we had not taken this relationship into account, we might have not only underestimated the size of the effect estimates but also assigned the wrong direction of the effects. This is the main reason for choosing to emphasize the results from the multipollutant models. The impact of the negative correlation between O3 and NOx is obvious in Table 4, where all effect estimates for NOx increase when adjusted for O3 and in some of the analyses also change from a protective to an adverse effect. This aspect is also relevant for the interpretation of the interaction analysis stratified by asthma.
Of the invited participants in the ADONIX study, the response rate was only 46%. Recently, a nonparticipation analysis based on registry data made within the INTERGENE study (the study from which the ADONIX participants originates) showed that nonresponders were more likely to be young, male, less educated, lower income, and of non-Nordic origin.39 Socioeconomic status has previously been shown to be related to long-term air pollution exposure in Sweden,40 but it is unlikely to be related to short-term variation in air pollution, which is the focus of this study. To our knowledge, there are no published data on the relationship between the fraction of exhaled NO and socioeconomic factors, although one might speculate that nutrition status and other lifestyle issues could in some way be related to the fraction of exhaled NO. The participants excluded as a result of missing covariates (Figure) were no different than those included regarding age or the prevalence of asthma and atopy. Nevertheless, those excluded were on average shorter and more often smokers, as reflected in lower fractions of exhaled NO at 50 ml/s values. This difference can be interesting from a clinical point of view, but it is unlikely to be a problem in the analysis relating air pollution to the fraction of exhaled NO.
The likelihood of socioeconomic factors being confounders of the relationship between exposure and outcome is consequently small, but effect modification by socioeconomic factors cannot be ruled out and should be considered in future studies. Restricting the analysis to only nonsmokers and ex-smokers did not affect our conclusions.
The cross-sectional design has disadvantages for studying short-term effects of air pollution on a biomarker, with possible confounding by both individual- and group-level factors. A panel with repeated measurements, together with higher spatial resolution on the exposure data, might have been a stronger design for internal validity, especially when looking at effect modification by small groups. However, the large study population, and the fact that the participants were randomly recruited over a period of several years and covering all seasons, strengthens the study and the results by reducing the risk of such confounding and also has advantages in terms of extrapolating to a larger population.
In conclusion, this population-based study suggests that in adults, ambient O3 produces a small increase in the fraction of exhaled NO at 270 ml/s, a measure of inflammation in the distal airways.
We are grateful to Swedish Heart and Lung Foundation, The Swedish Research Council Formas, The Swedish Society for Medical Research, and the Swedish Environmental Protection Agency for financial support of this study.
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