Although studies have been conducted to evaluate the extent to which the use of asthma medication modifies the health effects of air pollution, the results have not been clear. The findings from previous studies are contradictory, and the magnitudes of reported effects have been questioned. For example, Hiltermann et al24
reported that stratification by steroid use did not affect the magnitude of the observed associations between the shortness of breath with NO2
. Contrary to this observation, Peters et al25
reported that medication use was not a confounder but attenuated the assocations between particle pollution and peak expiratory flow and symptoms in asthmatics. Using improved exposure data, recent studies on eNO and air pollution have supported the findings reported by Peters et al that the use of ICS modified the assocation between eNO and particle pollution.12–13,15
However, the reported direction of modification was different. Delfino et al12
reported that the associations beween (a) eNO and ambient particle matter with a diameter of less than or equal to 2.5 microns (PM2.5
) and (b) personal and abmeint organic carbon were only significant in participants taking ICS alone. Koenig's group found no assocations between eNO and PM2.5
in the children on ICS therapy.13–15
Our study demonstrates that ambient air pollution is associated with eNO among patients with persistent asthma on well-defined asthma medication regimens. The significant associations were observed in all three asthma medication regimens. These results appear to show that the typical asthma medication could not counteract airway inflammation effects of air pollution among patients with persistent asthma. Specifically, the patients on triamcinolone decreased the sensitivity to PM10
but increased the sensitivity to NO2
. We further observed that the patients on salmeterol appeared to be more vulnerable to NO2
, compared with the placebo group.
While exposure metrics and study populations were different, the differences between our findings and previous ones may be due to the major difficulties involved in the study of the interaction between the exposure and asthma medication, such as the difficulty of collecting precise information about various asthma medication regimens as well as about homogeneity of asthma status. These difficulties stem largely from the study of people who are living in uncontrolled environments. By using asthma clinical trial data, we could make full use of more specific and more precise infomration on asthma medication regimens, extensive and high quality health outcome measures, and on documentation of homogeneous asthma status at the baseline. In addition, the 119 study participants provided 480 person-days of observations. This sample size is larger than those in the previous similar studies.12–13
Therefore, we were able specifically to assess health effects of air pollution among asthmatics on the 3 asthma medications.
Previous studies have shown that long-acting beta-adrenergic agonists are effective as bronchodilators.26
However, overuse of the agonists, or their use as monotherapy, may contribute to a worsening of asthma control.27
Mclvor et al27
showed that patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control. They further proposed that treatment with salmeterol may mask worsening airway inflammation and delay awareness of worsening asthma. In addition, Lazarus et al18
showed that salmeterol was not more effective than a placebo at suppressing airway inflammation. Under conditions of air pollution, it is plausible that asthma patients treated with β2
-agonists may experience more inhalation exposure to pollutants because the bronchodilation may result in greater pollutant deposition in the lower airways. This may be particularly true for the respiratory effect of the coarse particles. In the inhaled corticosteroid group, PM10
was not significantly associated with eNO. Overall, we found less significant associations in the inhaled corticosteroid group, with the exception of the effects of NO2
. These results may indicate that inhaled corticosteroid could effectively counteract airway inflammation by PM10
We observed consistent effects of NO2
on airway inflammation in the present study. Although the effects of NO2
have been proven to be plausible in experimental studies, only mild airway inflammation has been demonstrated in human experimental studies of exposure to a concentration of NO2
(2000 ppb) that is nearly 2 orders of magnitude higher than the estimated mean ambient exposure of the participants in this study.28–29
Furthermore, neutrophilic airway inflammation has not been consistently shown to be associated with increased eNO.28–30
can be a marker of motor vehicle emissions. The observed NO2
effects may be attributed to traffic-related air pollution in the 6 study cities in which local traffic was much heavier than that in a suburban area. This speculation is supported by recent panel studies. Steerenberg et al30
reported a statistically significant association between ambient NO2
and eNO and concluded that children living in areas with moderate levels of traffic-related air pollution had increased levels of eNO. Adamkiewicz et al11
also reported that exposure to ambient NO2
among an elderly population living in Steubenville, Ohio was associated with an increase in eNO, although the association was not statistically significant.
We did not observe any statistically significant association between ambient SO2 and eNO. However, researchers should be cautious when interpreting this. In this study, the daily average concentration was 5.3 ppb. The EPA air quality standards for the SO2 24-hour average is 140 ppb. The low levels of ambient SO2 may have provided a narrow pollution range for this study, thus limiting our ability to fully explore the relation between exposure to ambient SO2 and eNO.
We observed negative associations between ambient O3
and eNO. This observation is in line with those reported from a recent study. Adamkiewicz et al11
have observed a negative association (not statistically significant) between 24-hour O3
exposures and eNO in an elderly population. Several other studies have also confirmed that eNO levels are reduced in habitual smokers as well as passive smokers.31
The mechanism for the negative associations between ambient O3
exposure and eNO is unclear, and little is known about the effect of O3
exposure on eNO in patients with persistent asthma. However, it is possible for O3
, as a potent oxidant, to react rapidly with NO, yielding the harmful oxidant peroxynitrite.32
This rapid chemical reaction between O3
and NO could occur both in airways and in the system of the ANORA. The ambient O3
may also increase breakdown of NO or damage to NO producing epithelial cells.31
However, we could not clarify these mechanisms in this study. Last, the inverse association with O3
is likely to be spurious because of modeling year-round exposure, although our model analyses controlled for season. Ozone is a seasonal pollutant (ie, not present in high levels from November to April in many parts of the country), and previous analyses of ozone and potential health effects have often showen much stronger effects of ozone when the analyses were restricted to the warm months (May through October).
This study is limited in several respects. First, we did not have data on factors that are known or suspected to affect respiratory health. These factors are environmental tobacco smoke, indoor air pollution sources, working environment, and time-activity pattern. In addition, time-activity patterns can vary with pollutant levels (eg, more time outdoors in high-ozone summer months than during the low-ozone winter months). Similarly, there may be greater indoor air pollution exposure during winter months. Nevertheless, the estimated effects are unlikely to be confounded significantly by these factors because they do not vary with daily pollution exposures.33
Second, exposure misclassification is a major limitation of environmental epidemiologic research and is clearly applicable to this study. This is because we did not have personal exposure data and because, shared by most panel studies, we used stationary air monitoring data as a surrogate of personal exposure. However, it has been well documented that ambient particles are distributed uniformly within a region, especially extra fine particles but not coarse particles (PM10
is a measure of both coarse and fine particles).34
Other researchers have also found that indoor NO2
correlated highly with outdoor NO2
Third, time-dependent covariates, aeroallergens (ie, fungi and pollen) and viral respiratory infections, are potential confounders. However, previous studies did not find confounding by outdoor fungi and pollen.36–37
In addition, we expect that we can, at least partially, remove such confounding by temporal filtering of the regression model analyses because the levels of aeroallergens generally follow seasonal weather patterns.38
As for the viral respiratory infections, introducing it into the regression model did not substantially alter the associations between pollutants and health outcomes.25,39
Nevertheless, we conducted supplement analyses by constricting data analyses on the nonepidemic winter seasons and did not find any significant change of the estimated effects.
Ambient air pollution levels below the current US National Ambient Air Quality Standard may still enhance airway inflammation among patients with persistent asthma, even on typical asthma medications.