Genetic and epigenetic susceptibility of airway inflammation to PM2.5 in school children: new insights from quantile regression.

BACKGROUND: The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation that has proved to be useful in investigations of genetic and epigenetic airway susceptibility to ambient air pollutants. For example, susceptibility to airway inflammation from exposure to particulate matter with aerodynamic diameter < =2.5 µm (PM2.5) varies by haplotypes and promoter region methylation in inducible nitric oxide synthase (iNOS encoded by NOS2). We hypothesized that PM2.5 susceptibility associated with these epigenetic and genetic variants may be greater in children with high FeNO from inflamed airways. In this study, we investigated genetic and epigenetic susceptibility to airborne particulate matter by examining whether the joint effects of PM2.5, NOS2 haplotypes and iNOS promoter methylation significantly vary across the distribution of FeNO in school children. METHODS: The study included 940 school children in the southern California Children's Health Study who provided concurrent buccal samples and FeNO measurements. We used quantile regression to examine susceptibility by estimating the quantile-specific joint effects of PM2.5, NOS2 haplotype and methylation on FeNO. RESULTS: We discovered striking differences in susceptibility to PM2.5 in school children. The joint effects of short-term PM2.5 exposure, NOS2 haplotypes and methylation across the FeNO distribution were significantly larger in the upper tail of the FeNO distribution, with little association in its lower tail, especially among children with asthma and Hispanic white children. CONCLUSION: School-aged children with higher FeNO have greater genetic and epigenetic susceptibility to PM2.5, highlighting the importance of investigating effects across the entire distribution of FeNO.

Traffic-related air pollution and alveolar nitric oxide in southern California children.

Mechanisms for the adverse respiratory effects of traffic-related air pollution (TRAP) have yet to be established. We evaluated the acute effects of TRAP exposure on proximal and distal airway inflammation by relating indoor nitric oxide (NO), a marker of TRAP exposure in the indoor microenvironment, to airway and alveolar sources of exhaled nitric oxide (FeNO).FeNO was collected online at four flow rates in 1635 schoolchildren (aged 12-15 years) in southern California (USA) breathing NO-free air. Indoor NO was sampled hourly and linearly interpolated to the time of the FeNO test. Estimated parameters quantifying airway wall diffusivity (DawNO) and flux (J'awNO) and alveolar concentration (CANO) sources of FeNO were related to exposure using linear regression to adjust for potential confounders.We found that TRAP exposure indoors was associated with elevated alveolar NO. A 10 ppb higher indoor NO concentration at the time of the FeNO test was associated with 0.10 ppb higher average CANO (95% CI 0.04-0.16) (equivalent to a 7.1% increase from the mean), 4.0% higher J'awNO (95% CI -2.8-11.3) and 0.2% lower DawNO (95% CI -4.8-4.6).These findings are consistent with an airway response to TRAP exposure that was most marked in the distal airways.

Spirometry effects on conventional and multiple flow exhaled nitric oxide in children.

OBJECTIVE: Clinical and research settings often require sequencing multiple respiratory tests in a brief visit. Guidelines recommend measuring the concentration of exhaled nitric oxide (FeNO) before spirometry, but evidence for a spirometry carryover effect on FeNO is mixed. Only one study has investigated spirometry carryover effects on multiple flow FeNO analysis. The objective of this study was to evaluate evidence for carryover effects of recent spirometry on three exhaled NO summary measures: FeNO at 50 ml/s, airway wall NO flux [J'awNO] and alveolar NO concentration [CANO] in a population-based sample of schoolchildren. METHODS: Participants were 1146 children (191 with asthma), ages 12-15, from the Southern California Children's Health Study who performed spirometry and multiple flow FeNO on the same day. Approximately, half the children performed spirometry first. Multiple linear regression was used to estimate differences in exhaled NO summary measures associated with recent spirometry testing, adjusting for potential confounders. RESULTS: In the population-based sample, we found no evidence of spirometry carryover effects. However, for children with asthma, there was a suggestion that exhaled NO summary measures assessed ≤6 min after spirometry were lower (FeNO: 25.8% lower, 95% CI: -6.2%, 48.2%; J'awNO: 15.1% lower 95% CI: -26.5%, 43.0%; and CANO 0.43 parts per billion lower, 95% CI: -0.12, 0.98). CONCLUSIONS: In clinical settings, it is prudent to assess multiple flow FeNO before spirometry. In studies of healthy subjects, it may not be necessary to assess FeNO first.

Associations of children's lung function with ambient air pollution: joint effects of regional and near-roadway pollutants.

BACKGROUND: Previous studies have reported adverse effects of either regional or near-roadway air pollution (NRAP) on lung function. However, there has been little study of the joint effects of these exposures. OBJECTIVES: To assess the joint effects of NRAP and regional pollutants on childhood lung function in the Children's Health Study. METHODS: Lung function was measured on 1811 children from eight Southern Californian communities. NRAP exposure was assessed based on (1) residential distance to the nearest freeway or major road and (2) estimated near-roadway contributions to residential nitrogen dioxide (NO2), nitric oxide (NO) and total nitrogen oxides (NOx). Exposure to regional ozone (O3), NO2, particulate matter with aerodynamic diameter <10 µm (PM10) and 2.5 µm (PM2.5) was measured continuously at community monitors. RESULTS: An increase in near-roadway NOx of 17.9 ppb (2 SD) was associated with deficits of 1.6% in forced vital capacity (FVC) (p=0.005) and 1.1% in forced expiratory volume in 1 s (FEV1) (p=0.048). Effects were observed in all communities and were similar for NO2 and NO. Residential proximity to a freeway was associated with a reduction in FVC. Lung function deficits of 2-3% were associated with regional PM10 and PM2.5 (FVC and FEV1) and with O3 (FEV1), but not NO2 across the range of exposure between communities. Associations with regional pollution and NRAP were independent in models adjusted for each. The effects of NRAP were not modified by regional pollutant concentrations. CONCLUSIONS: The results indicate that NRAP and regional air pollution have independent adverse effects on childhood lung function.

Longitudinal effects of air pollution on exhaled nitric oxide: the Children's Health Study.

OBJECTIVES: To assess the effects of long-term variations in ambient air pollutants on longitudinal changes in exhaled nitric oxide (FeNO), a potentially useful biomarker of eosinophilic airway inflammation, based on data from the southern California Children's Health Study. METHODS: Based on a cohort of 1211 schoolchildren from eight Southern California communities with FeNO measurements in 2006-2007 and 2007-2008, regression models adjusted for short-term effects of air pollution were fitted to assess the association between changes in annual long-term exposures and changes in FeNO. RESULTS: Increases in annual average concentrations of 24-h average NO2 and PM2.5 (scaled to the IQR of 1.8 ppb and 2.4 µg/m(3), respectively) were associated with a 2.29 ppb (CI 0.36 to 4.21; p=0.02) and a 4.94 ppb (CI 1.44 to 8.47; p=0.005) increase in FeNO, respectively, after adjustments for short-term effects of the respective pollutants. In contrast, changes in annual averages of PM10 and O3 were not significantly associated with changes in FeNO. These findings did not differ significantly by asthma status. CONCLUSIONS: Changes in annual average exposure to current levels of ambient air pollutants are significantly associated with changes in FeNO levels in children, independent of short-term exposures and asthma status. Use of this biomarker in population-based epidemiological research has great potential for assessing the impact of changing real world mixtures of ambient air pollutants on children's respiratory health.

Allergic inflammation in the human lower respiratory tract affected by exposure to diesel exhaust.

To improve understanding of human health risks from exposure to diesel exhaust particles (DEP*), we tested whether immunologic effects previously observed in the human nose also occur in the lower airways. Our overall hypothesis was that cell influx and production of cytokines, chemokines, immunoglobulin E (IgE), and other mediators, which would be measurable in sputum and blood, occur in people with asthma after realistic controlled exposures to diesel exhaust (DE). In Phase 1 we tested for direct effects of DE in subjects with clinically undifferentiated mild asthma. In Phase 2 we tested whether DE exposure would exacerbate response to inhaled cat allergen in subjects with both asthma and cat sensitivity. The exposure facility was a controlled-environment chamber supplied with DE from an idling medium-duty truck with ultra-low-sulfur fuel and no catalytic converter. We exposed volunteers for 2 hours with intermittent exercise to exhaust with DEP mass concentration near 100 microg/m3. Exposures to nitrogen dioxide (NO2) near 0.35 ppm (similar to its concentration in DE) and to filtered air (FA) served as controls. Blood was drawn before exposure on day 1 and again the next morning (day 2). Sputum was induced only on day 2. Bronchial reactivity was measured -1 hour after exposure ended. Supplementary endpoints included measures of blood coagulation status, cardiopulmonary physiology, and symptoms. Each phase employed 15 subjects with asthma; 3 subjects participated in both phases. In Phase 1, airway reactivity was measured with inhaled methacholine; in Phase 2, with inhaled cat allergen. We found little biologic response to DE exposure compared with exposure to control atmospheres. In Phase 1, interleukin 4 (IL-4) in sputum showed an estimated 1.7-fold increase attributable to DE exposure, which was close to statistical significance; airway resistance increased modestly but significantly on day 2 after DE exposure; and nonspecific symptom scores increased significantly during DE exposure. In Phase 2, indicators of airway inflammation in sputum showed a possibly meaningful response: polymorphonuclear leukocytes (PMNs) and eosinophils increased after DE exposure, whereas macrophages decreased. IgE in sputum and the bronchoconstrictive response to cat allergen varied significantly between atmospheres, but not in patterns consistent with our primary hypothesis. Symptom score changes relatable to DE exposure were smaller than those in Phase 1 and not statistically significant. Controlled exposures, lasting 2 hours with intermittent exercise, to diluted DE at a particle mass concentration of 100 microg/m3 did not evoke clear and consistent lower-airway or systemic immunologic or inflammatory responses in mildly asthmatic subjects, with or without accompanying challenge with cat allergen. Likewise, these DE exposures did not significantly increase nonspecific or allergen-specific bronchial reactivity. A few isolated statistically significant or near-significant changes were observed during and after DE exposure, including increases in nonspecific symptoms (e.g., headache, nausea) suggestive of subtle, rapid-onset systemic effects. It is possible the lower respiratory tract is more resistant than the nose to adjuvant effects of diesel particles on allergic inflammation, so that no meaningful effects occur under exposure conditions like these. Alternatively, the experimental conditions may have been near a threshold for finding effects. That is, important lower respiratory effects may occur but may be detectable experimentally with slightly higher DEP concentrations, longer exposures, more invasive testing (e.g., bronchoalveolar lavage), or more susceptible subjects. However, ethical and practical barriers to such experiments are considerable.

A review of controlled human SO2 exposure studies contributing to the US EPA integrated science assessment for sulfur oxides.

Laboratory studies involving intentional and highly controlled exposures to air pollutants among groups of human volunteers provide valuable information related to the potential health effects of pollutants regulated under the US Clean Air Act. These controlled human exposure studies often provide biological plausibility for the associations between air-pollutant concentration and a given health endpoint observed in epidemiologic investigations. In some cases, results from human laboratory studies provide evidence of a relevant health effect at ambient or near-ambient concentrations and thus directly support the selection of air quality standard levels. In the recently completed review of the US National Ambient Air Quality Standards (NAAQS) for sulfur dioxide (SO2), the US Environmental Protection Agency (EPA) concluded that short-term exposures to SO2 are causally associated with an increase in respiratory morbidity. This determination was based in large part on findings from laboratory studies of controlled exposures to SO2 among small groups of asthmatic individuals. The purpose of this review is to concisely present an overview of the evidence from controlled human exposure studies of SO2-induced respiratory health effects following short-term exposures. While the majority of these studies were conducted over 20 years ago, the findings and insights gained from this work continues to play an integral role in evaluating the respiratory effects of ambient exposures to SO2.

Analysis of the concentration-respiratory response among asthmatics following controlled short-term exposures to sulfur dioxide.

Some of the most compelling evidence of sulfur dioxide (SO(2))-induced respiratory morbidity is derived from a large body of studies involving controlled short-term exposures among groups of asthmatic volunteers. These studies were extensively cited in the recently completed review of the primary National Ambient Air Quality Standards for SO(2). Although it is clear from these investigations that exposure to SO(2) may result in a significant increase in bronchoconstriction, there is uncertainty regarding the range of concentrations over which this respiratory response occurs. The objective of this study was to better characterize the concentration-response relationship between SO(2) and measures of bronchoconstriction using individual subject lung function response data. In reviewing studies of asthmatics exposed to SO(2) during 5- to 10-min periods of elevated ventilation, we observed clear and consistent evidence of an increase in the bronchoconstrictive response to SO(2) with increasing exposure concentrations between 0.2 and 1.0 ppm. In a subsequent analysis of individual subject data, it was found that those asthmatics experiencing SO(2)-induced respiratory effects at relatively high exposure concentrations are also more likely than nonresponders to experience similar effects after exposure to lower SO(2) concentrations (≤0.4 ppm). Although the clinical significance of these effects is unsettled, the findings provide additional support to epidemiologic evidence of an association between ambient SO(2) concentration and various measures of respiratory morbidity in the general population.

Exhaled nitric oxide in a population-based study of southern California schoolchildren.

BACKGROUND: Determinants of exhaled nitric oxide (FeNO) need to be understood better to maximize the value of FeNO measurement in clinical practice and research. Our aim was to identify significant predictors of FeNO in an initial cross-sectional survey of southern California schoolchildren, part of a larger longitudinal study of asthma incidence. METHODS: During one school year, we measured FeNO at 100 ml/sec flow, using a validated offline technique, in 2568 children of age 7-10 yr. We estimated online (50 ml/sec flow) FeNO using a prediction equation from a separate smaller study with adjustment for offline measurement artifacts, and analyzed its relationship to clinical and demographic characteristics. RESULTS: FeNO was lognormally distributed with geometric means ranging from 11 ppb in children without atopy or asthma to 16 ppb in children with allergic asthma. Although effects of atopy and asthma were highly significant, ranges of FeNO for children with and without those conditions overlapped substantially. FeNO was significantly higher in subjects aged > 9, compared to younger subjects. Asian-American boys showed significantly higher FeNO than children of all other sex/ethnic groups; Hispanics and African-Americans of both sexes averaged slightly higher than non-Hispanic whites. Increasing height-for-age had no significant effect, but increasing weight-for-height was associated with decreasing FeNO. CONCLUSION: FeNO measured offline is a useful biomarker for airway inflammation in large population-based studies. Further investigation of age, ethnicity, body-size, and genetic influences is needed, since they may contribute to substantial variation in FeNO.

Exposures of healthy and asthmatic volunteers to concentrated ambient ultrafine particles in Los Angeles.

Adult volunteers (17 healthy, 14 asthmatic) were exposed in a controlled environmental chamber to concentrated ultrafine particles (UFP) collected in a Los Angeles suburb with substantial motor vehicle pollution. Exposures lasted 2 h with intermittent exercise. Inhaled particle counts (mean 145,000/cm(3), range 39,000-312,000) were typically 7-8 times higher than ambient levels. Mass concentrations (mean 100 microg/m(3), range 13-277) were not highly correlated with counts. Volunteers were evaluated for lung function, symptoms, exhaled nitric oxide (eNO), Holter electrocardiography, and inflammatory markers in peripheral blood and induced sputum. Relative to control (filtered air) studies, UFP exposures were associated with a 0.5% mean fall in arterial O(2) saturation estimated by pulse oximetry (p < .01), a 2% mean fall in forced expired volume in 1 sec (FEV(1)) the morning after exposure (p < .05), and a transient slight decrease in low-frequency (sympathetic) power in Holter recordings during quiet rest (p < .05). Healthy and asthmatic subjects were not significantly different across most endpoints. Thus, this initial experimental study of human volunteers exposed to concentrated Los Angeles area ambient UFP showed some acute deleterious cardiopulmonary responses, which, although generally small and equivocal as in previous studies of larger sized concentrated ambient particles, might help to explain reported adverse health effects associated with urban particulate pollution.

Generation and characterization of diesel exhaust in a facility for controlled human exposures.

An idling medium-duty diesel truck operated on ultralow sulfur diesel fuel was used as an emission source to generate diesel exhaust for controlled human exposure. Repeat tests were conducted on the Federal Test Procedure using a chassis dynamometer to demonstrate the reproducibility of this vehicle as a source of diesel emissions. Exhaust was supplied to a specially constructed exposure chamber at a target concentration of 100 microg x m(-3) diesel particulate matter (DPM). Spatial variability within the chamber was negligible, whereas emission concentrations were stable, reproducible, and similar to concentrations observed on the dynamometer. Measurements of nitric oxide, nitrogen dioxide, carbon monoxide, particulate matter (PM), elemental and organic carbon, carbonyls, trace elements, and polycyclic aromatic hydrocarbons were made during exposures of both healthy and asthmatic volunteers to DPM and control conditions. The effect of the so-called "personal cloud" on total PM mass concentrations was also observed and accounted for. Conventional lung function tests in 11 volunteer subjects (7 stable asthmatic) did not demonstrate a significant change after 2-hr exposures to diesel exhaust. In summary, we demonstrated that this facility can be effectively and safely used to evaluate acute responses to diesel exhaust exposure in human volunteers.

Determinants of Children's Exhaled Nitric Oxide: New Insights from Quantile Regression.

While the fractional concentration of exhaled nitric oxide (FeNO) has proven useful in asthma research, its exact role in clinical care remains unclear, in part due to unexplained inter-subject heterogeneity. In this study, we assessed the hypothesis that the effects of determinants of the fractional concentration of exhaled nitric oxide (FeNO) vary with differing levels of FeNO. In a population-based cohort of 1542 school children aged 12-15 from the Southern California Children's Health Study, we used quantile regression to investigate if the relationships of asthma, socio-demographic and clinical covariates with FeNO vary across its distribution. Differences in FeNO between children with and without asthma increased steeply as FeNO increased (Estimated asthma effects (in ppb) at selected 20th, 50th and 80th percentiles of FeNO are 2.4, 6.3 and 22.2, respectively) but the difference was steeper with increasing FeNO in boys and in children with active rhinitis (p-values<0.01). Active rhinitis also showed significantly larger effects on FeNO at higher concentrations of FeNO (Estimated active rhinitis effects (in ppb) at selected 20th, 50th and 80th percentiles of FeNO are 2.1, 5.7 and 14.3, respectively). Boys and children of Asian descent had higher FeNO than girls and non-Hispanic whites; these differences were significantly larger in those with higher FeNO (p-values<0.01). In summary, application of quantile regression techniques provides new insights into the determinants of FeNO showing substantially varying effects in those with high versus low concentrations.

Asthma symptoms in Hispanic children and daily ambient exposures to toxic and criteria air pollutants.

Although acute adverse effects on asthma have been frequently found for the U.S. Environmental Protection Agency's principal criteria air pollutants, there is little epidemiologic information on specific hydrocarbons from toxic emission sources. We conducted a panel study of 22 Hispanic children with asthma who were 10-16 years old and living in a Los Angeles community with high traffic density. Subjects filled out symptom diaries daily for up to 3 months (November 1999 through January 2000). Pollutants included ambient hourly values of ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide and 24-hr values of volatile organic compounds (VOCs), particulate matter with aerodynamic diameter < 10 microm (PM10, and elemental carbon (EC) and organic carbon (OC) PM10 fractions. Asthma symptom severity was regressed on pollutants using generalized estimating equations, and peak expiratory flow (PEF) was regressed on pollutants using mixed models. We found positive associations of symptoms with criteria air pollutants (O3, NO2, SO2, PM10), EC-OC, and VOCs (benzene, ethylbenzene, formaldehyde, acetaldehyde, acetone, 1,3-butadiene, tetrachloroethylene, toluene, m,p-xylene, and o-xylene). Selected adjusted odds ratios for bothersome or more severe asthma symptoms from interquartile range increases in pollutants were, for 1.4 ppb 8-hr NO2, 1.27 [95% confidence interval (CI), 1.05-1.54]; 1.00 ppb benzene, 1.23 (95% CI, 1.02-1.48); 3.16 ppb formaldehyde, 1.37 (95% CI, 1.04-1.80); 37 microg/m3 PM10, 1.45 (95% CI, 1.11-1.90); 2.91 microg/m3 EC, 1.85 (95% CI, 1.11-3.08); and 4.64 microg/m3 OC, 1.88 (95% CI, 1.12-3.17). Two-pollutant models of EC or OC with PM10 showed little change in odds ratios for EC (to 1.83) or OC (to 1.89), but PM10 decreased from 1.45 to 1.0. There were no significant associations with PEF. Findings support the view that air toxins in the pollutant mix from traffic and industrial sources may have adverse effects on asthma in children.

Impact of respiratory illness on expiratory flow rates in normal, asthmatic, and allergic children.

We examined the effects of current respiratory illness (RI) on pulmonary function (PF) in 1,103 subjects who underwent spirometry at schools twice within a 4-month period. Before spirometry, subjects were asked if they had a "cold or other chest illness" during the previous month, and if so, whether they had fully recovered. Those who had not recovered were considered to have an RI. We found that children without RI at their first PF test who reported RI on retest had significantly lower forced expiratory volume in 1 sec (FEV(1)) (-0.8%), peak expiratory flow rate (PEFR) (-2.2%), forced expiratory flow between 25-75% of vital capacity (FEF(25-75)) (-3.5%), and forced expiratory flow at 75% of vital capacity (FEF(75)) (-5.1%) than those without RI on both test and retest. Restriction of subjects to those without a history of doctor-diagnosed asthma did not appreciably change these findings. Children with hay fever had significantly larger RI-associated decreases for FEV(1), FEF(25-75), and FEF(75), but not PEFR, than those without hay fever. Among asthmatic subjects, those with active asthma had larger RI-associated decreases in FEF(25-75) and FEF(75), but not PEFR, than those without asthma. There was limited evidence that small airway losses were greater in children less than 12.5 years old. We conclude that RI in children who are well enough to attend school may reduce expiratory flow rates. These effects are greater for children with active asthma or hay fever than in those without, and may be inversely related to age.

Respiratory symptoms and peak expiratory flow in children with asthma in relation to volatile organic compounds in exhaled breath and ambient air.

Indoor volatile organic compounds (VOCs) have been associated with asthma, but there is little epidemiologic work on ambient exposures, and no data on relationships between respiratory health and exhaled breath VOCs, which is a biomarker of VOC exposure. We recruited 26 Hispanic children with mild asthma in a Los Angeles community with high VOC levels near major freeways and trucking routes. Two dropped out, three had invalid peak expiratory flow (PEF) or breath VOC data, leaving 21. Children filled out symptom diaries and performed PEF maneuvers daily, November 1999-January 2000. We aimed to collect breath VOC samples on asthma episode and baseline symptom-free days, but six subjects only gave samples on symptom-free days. We analyzed 106 breath samples by GC-MS. Eight VOCs were quantifiable in >75% of breath samples (benzene, methylene chloride, styrene, tetrachloroethylene, toluene, m,p-xylene, o-xylene, and p-dichlorobenzene). Generalized estimating equation and mixed linear regression models for VOC exposure-response relationships controlled for temperature and respiratory infections. We found marginally positive associations between bothersome or more severe asthma symptoms and same day breath concentrations of benzene [odds ratio (OR) 2.03, 95% confidence interval (CI) 0.80, 5.11] but not other breath VOCs. Ambient petroleum-related VOCs measured on the same person-days as breath VOCs showed notably stronger associations with symptoms, including toluene, m,p-xylene, o-xylene, and benzene (OR 5.93, 95% CI 1.64, 21.4). On breath sample days, symptoms were also associated with 1-h ambient NO(2), OR 8.13 (1.52, 43.4), and SO(2), OR 2.36 (1.16, 4.81). Consistent inverse relationships were found between evening PEF and the same ambient VOCs, NO(2), and SO(2). There were no associations with O(3). Given the high traffic density of the region, stronger associations for ambient than for breath VOCs suggest that ambient VOC measurements were better markers for daily exposure to combustion-related compounds thought to be causally related to acute asthma. Alternatively, the low sample size of symptom responses (15-21 responses per 108 breath samples) may have led to the nonsignificant results for breath VOCs.

Controlled exposures of healthy and asthmatic volunteers to concentrated ambient particles in metropolitan Los Angeles.

Epidemiologic studies report health effects associated with exposure to ambient particulate matter (PM), but underlying biologic mechanisms remain unclear. We evaluated pulmonary and systemic effects in twelve healthy human adult and twelve asthmatic volunteers exposed once for 2 hours in a whole-body chamber to approximately 200 microg/m3 concentrated ambient particles (CAPs) in the fine (< 2.5 microm) size range and once to filtered air. Neither healthy nor asthmatic subjects showed significant changes in symptoms, spirometry, or routine hematologic measurements attributable to CAPs exposure compared with filtered air. Both groups showed CAPs-related (1) decreases of columnar cells in induced sputum after exposure, (2) increases in certain blood mediators of inflammation (ie, soluble intercellular adhesion molecule 1 [ICAM-1] and interleukin [IL] 6 [marginally significant in asthmatic subjects only]), and (3) parasympathetic stimulation of heart rate variability (HRV). In the asthmatic group, systolic blood pressure modestly increased during filtered air exposure and decreased during CAPs exposure, whereas the pattern was reversed in the healthy group. In summary, this study measured a large number and wide range of biologic endpoints on a relatively small number of healthy and asthmatic volunteers and found few biologic endpoints that responded to CAPs and filtered air exposures with significantly different values. However, observed changes in some mediators of inflammation in blood and changes in HRV were consistent with PM-related effects reported from epidemiologic studies. They suggest that exposure to concentrated PM 2.5 pm or smaller in aerodynamic diameter (PM2.5) tends to elicit more systemic than pulmonary effects. This investigation is one of the first to apply concentrator-exposure technology in a high-risk group (subjects with asthma). Further studies of responses to CAPs that involve other biologic endpoints, other PM size modes, and subjects with other risk factors are needed.

Smoking and obstructive lung dysfunction in persons with chronic spinal cord injury.

BACKGROUND: Persons with higher-level spinal cord injury (SCI) have reduced vital capacity and increased risk of respiratory symptoms and illness, with smokers experiencing excess vital capacity losses. To date, obstructive lung dysfunction, the most prominent effect of smoking in the able-bodied population, has not been characterized in persons with SCI. OBJECTIVE: To determine whether smokers and/or nonsmokers with SCI are at increased risk to develop obstructive lung dysfunction, as measured by the ratio of forced expired volume in 1 second to forced vital capacity (FEV1/FVC). METHODS: Regression analyses on cross-sectional data from routine clinical testing of outpatients followed at the Bronx Veterans Affairs Medical Center in metropolitan New York (NY) and Rancho Los Amigos National Rehabilitation Center in metropolitan Los Angeles (LA) tested the relationship of FEV1/FVC (percentage of predicted normal value) to age, SCI characteristics, and smoking status. RESULTS: NY current smokers showed a significant (P < 0.01) excess decline in FEV1/FVC with increasing age; 35% fell below normal limits compared with 16% of NY former and never smokers. LA current smokers, who were generally younger and smoking less, showed a less clear age-related decline. Never smokers in NY or LA showed no age-related decline beyond that expected in the general population. Former smokers resembled never smokers, except that NY paraplegics showed borderline-significant (P = 0.09) excess age-related decline, which was less than that in NY current smokers. CONCLUSION: Smokers with SCI appeared to be at excessive risk for obstructive lung diseases. Smoking cessation appeared to reduce the risk substantially. Careful longitudinal studies are needed to confirm these findings.

Exhaled nitric oxide: sources of error in offline measurement.

Delayed offline measurement of exhaled nitric oxide (eNO), although useful in environmental and clinical research, is limited by the instability of stored breath samples. The authors characterized sources of instability with the goal of minimizing them. Breath and other air samples were stored under various conditions, and NO levels were measured repeatedly over 1-7 d. Concentration change rates varied positively with temperature and negatively with initial NO level, thus "stable" levels reflected a balance of NO-adding and NO-removing processes. Storage under refrigeration for a standardized period of time can optimize offline eNO measurement, although samples at room temperature are effectively stable for several hours.

Estimation of parameters in the two-compartment model for exhaled nitric oxide.

The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation that is being increasingly considered in clinical, occupational, and epidemiological applications ranging from asthma management to the detection of air pollution health effects. FeNO depends strongly on exhalation flow rate. This dependency has allowed for the development of mathematical models whose parameters quantify airway and alveolar compartment contributions to FeNO. Numerous methods have been proposed to estimate these parameters using FeNO measured at multiple flow rates. These methods--which allow for non-invasive assessment of localized airway inflammation--have the potential to provide important insights on inflammatory mechanisms. However, different estimation methods produce different results and a serious barrier to progress in this field is the lack of a single recommended method. With the goal of resolving this methodological problem, we have developed a unifying framework in which to present a comprehensive set of existing and novel statistical methods for estimating parameters in the simple two-compartment model. We compared statistical properties of the estimators in simulation studies and investigated model fit and parameter estimate sensitivity across methods using data from 1507 schoolchildren from the Southern California Children's Health Study, one of the largest multiple flow FeNO studies to date. We recommend a novel nonlinear least squares model with natural log transformation on both sides that produced estimators with good properties, satisfied model assumptions, and fit the Children's Health Study data well.