Who Are the Children with Asthma Most Susceptible to Air Pollution?

In this issue of the AJRCCM (pp. 1098-1105), Rabinovitch and colleagues (1) show a positive association between fine-particulate air pollution and a biomarker of airway inflammation, urinary leukotriene E^sub 4^ (LTE^sub 4^), in 73 schoolchildren with asthma. LTE^sub 4^ is a stable product of the cysteinyl leukotrienes C4 and D4, which are produced by inflammatory cells, including eosinophils, and have bronchoconstrictive and proinflammatory properties. Specifically, the authors of this article found that urinary LTE^sub 4^ was associated with morning hourly ambient exposure to particulate matter of less than 2.5

Many epidemiologic studies have shown associations of asthma hospital admissions and emergency department visits with 24-hour average PM levels below the current U.S. National Ambient Air Quality Standards (NAAQS) (2). This could be partly explained by unmeasured short-term PM^sub 2.5^ excursions above or even below the current 24-hour standard, which is 65 µg/m^sup 3^ (2). The Denver findings were for morning means, ranging up to only 30 µg/m^sup 3^, on days when 24-hour PM^sub 2.5^ concentrations were no greater than 12 µg/m^sup 3^. For more on the current controversy regarding the NAAQS, see Rom and Samet (3).

Other epidemiologic studies have shown associations between acute asthma outcomes in children and short-term peaks in PM^sub 2.5^ or PM^sub 2.5^ exposure in the hours immediately preceding the outcome measurements, including exhaled NO (4), asthma symptoms (5), and FEV^sub 1^ (6). It is conceivable that children exposed over short periods to high concentrations of particles are at risk for acute asthma exacerbations, even if they spend most of the day in "low pollution" environments well below the NAAQS.

A strength of the panel study design of the Denver study is that through repeated measures, each subject can serve as his or her own control. This design is well suited to detect susceptible subgroups or individuals since within-subject exposure-response relationships can be determined with great precision. One susceptibility factor revealed in this study was that associations were stronger for shorter children. This may be due to greater fractional deposition of particles due to higher respiratory rates and smaller airways combined with airway obstruction. Increased deposition among individuals with asthma is particularly higher for ultrafine particles (< 0.1 µm) (7). These particles have higher number concentration and surface area in urban aerosols than do larger particles (8). The large surface area carries disproportionately high concentrations per unit mass of redox active organic compounds and transition metals that can induce oxidative stress and subsequent airway inflammation (8, 9). Ultrafine particles generated from tailpipe emissions near roadways are particularly rich in redox active chemicals (8). Therefore, groups of children with asthma at high risk from air pollution are those who live near high-density traffic or industrial pollutant sources, and who often have the least access to medical care due to poverty (10).

The findings of the Denver study (1) point to the importance of air pollutants in causing acute airway responses in subjects with persistent asthma, most of whom were on inhaled corticosteroids. Other panel studies have also shown stronger pollutant associations in subjects with persistent asthma symptoms receiving antiinflammatory medications, whereas some have instead found stronger associations in subjects not receiving antiinflammatory medications (reviewed in References 1, 4, and 5). Rabinovitch and colleagues (1) also found that subjects with more severe asthma had stronger associations between morning PM^sub 2.5^ and subsequent bronchodilator use.

Previous studies have revealed other plausible susceptibility factors in children with asthma. Boys allergic to indoor allergens show an increase in FEV^sub 1^ decrements in relation to personal hourly PM exposures (6). Children born prematurely or with low birth weight have increased asthma symptoms and decreased PEF in relation to elevations in outdoor ozone (11). Genetic polymorphisms related to oxidative stress are also anticipated to be modifiers of responses to air pollutants (12), and gene-environment interactions are detectable using repeated measures (13).

Accurately measured within-subject changes in exposure, especially from the use of personal exposure monitors, can also unmask differences in susceptibility. Susceptibility, in this case, can be either biological susceptibility to toxic pollutant components or simply higher personal exposures, despite low background concentrations. In this regard, another specific design advantage in the Denver study that mitigated the lack of personal exposure measurements was the research setting. Because children are expected to have time-activity patterns that place them close to air pollutant sources (e.g., traffic), outdoor stationary site measurements are expected to misclassify true exposure. However, conditions of exposure for subjects in the Denver study were likely routine in that morning air pollutant exposures were measured only on school days, and this measurement directly preceded outcome measurements in one school. Presumably, subjects had repeating patterns of commuting to the school in the morning. Higher PM^sub 2.5^ concentrations in the morning were likely due to rush hour traffic. However, there was no assessment of in-vehicle exposures during the commute, or measurements of particle components or other characteristics. Although there is a growing literature on the relationship between asthma outcomes and the proximity of a subject's home and school to high traffic density (14, 15), few studies have evaluated the respiratory health effects of in-vehicle exposures, and none yet have for these effects in children with asthma. High concentrations of ultrafine particles have been measured in vehicles, especially on freeways (8).

Studies of older children with asthma suggest a number of intrinsic and extrinsic factors that enhance susceptibility to air pollutants. Questions that remain unanswered regard the interlacing biological and environmental determinants of susceptibility to asthma onset. This will require studying the impact of toxic air pollutants on in utero, postnatal, and early-childhood development, times of immunologic (14) and metabolic vulnerability (16).

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