Patterns and determinants of exhaled nitric oxide trajectories in schoolchildren over a 7-year period.

Fractional exhaled nitric oxide (F ENO50 ), a marker of allergic airway inflammation, is used in respiratory research and asthma clinical care; however, its trajectory with increasing age during childhood has not been well characterised. We examined F ENO50 longitudinally during a period of important somatic growth to describe trajectories across childhood and adolescence in healthy participants and evaluate clinical factors as potential determinants of trajectories.F ENO50 was collected at six visits over 8 years in a population-based cohort of 1791 schoolchildren without asthma (median age at entry 8.4 years). Smooth sex-specific F ENO50 trajectories were estimated using generalised additive mixed models, with participant-level random effects. We evaluated whether sex-specific trajectories were influenced by race/ethnicity, body mass index (BMI) percentile, allergic rhinitis or puberty.Different F ENO50 patterns were observed by sex in later childhood and several factors were associated with either F ENO50 level or change in F ENO50 as participants aged. F ENO50 -age trajectories were similar by sex until age ∼11.5 years, after which males had greater F ENO50 change than females. This divergence in F ENO50 -age trajectories coincides with puberty. Males with higher starting BMI percentile had attenuated F ENO50 -age slopes. Among males, F ENO50 levels were lower in non-Hispanic white subjects. Among both sexes, participants with rhinitis had higher F ENO50 F ENO50 levels within individuals tracked over time; however, there was considerable variation in F ENO50 patterns across participants.F ENO50 trajectories from longitudinal data provide evidence of sex differences coinciding with puberty, suggesting potential hormone link. Improved understanding of determinants of F ENO50 trajectories is needed to realise the potential for using individualised predicted F ENO50 trajectories.

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.

Impact of different fixed flow sampling protocols on flow-independent exhaled nitric oxide parameter estimates using the Bayesian dynamic two-compartment model.

Exhaled nitric oxide (FeNO) is an established respiratory biomarker with clinical applications in the diagnosis and management of asthma. Because FeNO depends strongly on the flow (exhalation) rate, early protocols specified that measurements should be taken when subjects exhaled at a fixed rate of 50 ml/s. Subsequently, multiple flow (or "extended") protocols were introduced which measure FeNO across a range of fixed flow rates, allowing estimation of parameters including Caw NO and CA NO which partition the physiological sources of NO into proximal airway wall tissue and distal alveolar regions (respectively). A recently developed dynamic model of FeNO uses flow-concentration data from the entire exhalation maneuver rather than plateau means, permitting estimation of Caw NO and CA NO from a wide variety of protocols. In this paper, we use a simulation study to compare Caw NO and CA NO estimation from a variety of fixed flow protocols, including: single maneuvers (30, 50,100, or 300 ml/s) and three established multiple maneuver protocols. We quantify the improved precision with multiple maneuvers and the importance of low flow maneuvers in estimating Caw NO. We conclude by applying the dynamic model to FeNO data from 100 participants of the Southern California Children's Health Study, establishing the feasibility of using the dynamic method to reanalyze archived online FeNO data and extract new information on Caw NO and CA NO in situations where these estimates would have been impossible to obtain using traditional steady-state two compartment model estimation methods.

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.

Bayesian estimation of physiological parameters governing a dynamic two-compartment model of exhaled nitric oxide.

The fractional concentration of nitric oxide in exhaled breath (feNO) is a biomarker of airway inflammation with applications in clinical asthma management and environmental epidemiology. feNO concentration depends on the expiratory flow rate. Standard feNO is assessed at 50 mL/sec, but "extended NO analysis" uses feNO measured at multiple different flow rates to estimate parameters quantifying proximal and distal sources of NO in the lower respiratory tract. Most approaches to modeling multiple flow feNO assume the concentration of NO throughout the airway has achieved a "steady-state." In practice, this assumption demands that subjects maintain sustained flow rate exhalations, during which both feNO and expiratory flow rate must remain constant, and the feNO maneuver is summarized by the average feNO concentration and average flow during a small interval. In this work, we drop the steady-state assumption in the classic two-compartment model. Instead, we have developed a new parameter estimation approach based on measuring and adjusting for a continuously varying flow rate over the entire feNO maneuver. We have developed a Bayesian inference framework for the parameters of the partial differential equation underlying this model. Based on multiple flow feNO data from the Southern California Children's Health Study, we use observed and simulated NO concentrations to demonstrate that our approach has reasonable computation time and is consistent with existing steady-state approaches, while our inferences consistently offer greater precision than current methods.

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.

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.

Effects of ambient air pollutants on asthma medication use and wheezing among fourth-grade school children from 12 Southern California communities enrolled in The Children's Health Study.

To investigate the effects of 12 monthly average air pollution levels on monthly prevalence of respiratory morbidity, the authors examined retrospective questionnaire data on 2034 4th-grade children from 12 Southern California communities that were enrolled in The Children's Health Study. Wheezing during the spring and summer months was associated with community levels of airborne particulate matter with a diameter < or = 10 microm (PM10) (odds ratio (OR) = 2.91; 95% confidence interval (CI) = 1.46-5.80), but was not associated with community levels of ozone, nitrogen dioxide, PM2.5 (diameter < or = 2.5), nitric acid, or formic acid. Logistic regression was performed on data stratified into two seasonal groups, spring/summer and fall/winter. Among asthmatics, the monthly prevalence of asthma medication use was associated with monthly levels of ozone, nitric acid, and acetic acid (OR = 1.80 [95%CI = 1.19-2.70]; OR = 1.80 [95%CI = 1.23-2.65]; OR = 1.57 [95% CI = 1.11-2.21]; respectively). Asthma medication use was more prevalent among children who spent more time outdoors--with consequential exposure to ozone--than among children who spent more time indoors (OR = 3.07 [95%CI = 1.61-5.86]; OR = 1.31 [95%CI = 0.47-2.71]; respectively). The authors concluded that monthly variations in some ambient air pollutants were associated with monthly respiratory morbidity among school children.

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.

Multiple-flow exhaled nitric oxide, allergy, and asthma in a population of older children.

UNLABELLED: "Extended" (multiple-flow) measurements of exhaled nitric oxide (FeNO) potentially can distinguish proximal and distal airway inflammation, but have not been evaluated previously in large populations. We performed extended NO testing within a longitudinal study of a school-based population, to relate bronchial flux (J'awNO) and peripheral NO concentration (CalvNO) estimates with respiratory health status determined from questionnaires. We measured FeNO at 30, 50, 100, and 300 ml/sec in 1,640 subjects aged 12-15 from eight communities, then estimated J'awNO and CalvNO from linear and nonlinear regressions of NO output versus flow. J'awNO, as well as FeNO at all flows, showed influences of asthma, allergy, Asian or African ancestry, age, and height (positive), and of weight (negative), generally corroborating past findings. By contrast, CalvNO results were inconsistent across different extended NO regression models, and appeared more sensitive to small measurement artifacts. CONCLUSIONS: Extended NO testing is feasible in field surveys of young populations. In interpreting results, size, age, and ethnicity require attention, as well as instrumental and environmental artifacts. J'awNO and conventional FeNO provide similar information, probably reflecting proximal airway inflammation. CalvNO may give additional information relevant to peripheral airway, alveolar, or systemic pathology. However, it needs additional research, including testing of populations with independently verifiable peripheral or systemic pathology, to optimize measurement technique and interpretation.

Residential traffic-related pollution exposures and exhaled nitric oxide in the children's health study.

BACKGROUND: The fractional concentration of nitric oxide in exhaled air (FeNO) potentially detects airway inflammation related to air pollution exposure. Existing studies have not yet provided conclusive evidence on the association of FeNO with traffic-related pollution (TRP). OBJECTIVES: We evaluated the association of FeNO with residential TRP exposure in a large cohort of children. METHODS: We related FeNO measured on 2,143 children (ages 7-11 years) who participated in the Southern California Children's Health Study (CHS) to five classes of metrics of residential TRP: distances to freeways and major roads; length of all and local roads within circular buffers around the home; traffic densities within buffers; annual average line source dispersion modeled nitrogen oxides (NOx) from freeways and nonfreeway roads; and predicted annual average nitrogen oxide, nitrogen dioxide, and NOx from a model based on intracommunity sampling in the CHS. RESULTS: In children with asthma, length of roads was positively associated with FeNO, with stronger associations in smaller buffers [46.7%; 95% confidence interval (CI), 14.3-88.4], 12.4% (95% CI, -8.8 to 38.4), and 4.1% (95% CI, -14.6 to 26.8) higher FeNO for 100-, 300-, and 1,000-m increases in the length of all roads in 50-, 100-, and 200-m buffers, respectively. Other TRP metrics were not significantly associated with FeNO, even though the study design was powered to detect exposures explaining as little as 0.4% of the variation in natural log-transformed FeNO (R2 = 0.004). CONCLUSION: Length of road was the only indicator of residential TRP exposure associated with airway inflammation in children with asthma, as measured by FeNO.

Relationships of online exhaled, offline exhaled, and ambient nitric oxide in an epidemiologic survey of schoolchildren.

UNLABELLED: Field measurements of exhaled nitric oxide (FeNO) and ambient nitric oxide (NO) are useful to assess both respiratory health and short-term air pollution exposure. Online real-time measurement maximizes data quality and comparability with clinical studies, but offline delayed measurement may be more practical for large epidemiological studies. To facilitate cross-comparison in larger studies, we measured FeNO and concurrent ambient NO both online and offline in 362 children at 14 schools in 8 Southern California communities. Offline breath samples were collected in bags at 100 ml/s expiratory flow with deadspace discard; online FeNO was measured at 50 ml/s. Scrubbing of ambient NO from inhaled air appeared to be nearly 100% effective online, but 50-75% effective offline. Offline samples were stored at 2-8 degrees C and analyzed 2-26 h later at a central laboratory. Offline and online FeNO showed a nearly (but not completely) linear relationship (R(2)=0.90); unadjusted means (ranges) were 10 (4-94) and 15 (3-181) p.p.b., respectively. Ambient NO concentration range was 0-212 p.p.b. Offline FeNO was positively related to ambient NO (r=0.30, P<0.0001), unlike online FeNO (r=0.09, P=0.08), indicating that ambient NO artifactually influenced offline measurements. Offline FeNO differed between schools (P<0.001); online FeNO did not (P=0.26), suggesting artifacts related to offline bag storage and transport. Artifact effects were small in comparison with between-subject variance of FeNO. An empirical statistical model predicting individual online FeNO from offline FeNO, ambient NO, and lag time before offline analysis gave R(2)=0.94. Analyses of school or age differences yielded similar results from measured or model-predicted online FeNO. CONCLUSIONS: Either online or offline measurement of exhaled NO and concurrent ambient NO can be useful in field epidemiology. Influence of ambient NO on exhaled NO should be examined carefully, particularly for offline measurements.

Extended exhaled nitric oxide analysis in field surveys of schoolchildren: a pilot test.

Extended exhaled nitric oxide (eNO) analysis can distinguish proximal and distal airway contributions to FeNO. Thus, it has the potential to detect effects of different environmental influences, allergic phenotypes, and genetic variants on proximal and distal airways. However, its feasibility in field surveys has not been demonstrated, and models for estimating compartmental NO contributions have not been standardized. In this study we verified that extended NO tests can be performed by children in schools, and assessed different analytical models to estimate bronchial flux and alveolar NO concentration. We tested students at a middle school, using EcoMedics NO analyzers with ambient NO scrubbers, at flows of 50 (conventional), 30, 100, and 300 ml/sec, with 2-3 trials at each flow. Data from 65 children were analyzed by two linear and four nonlinear published models, plus a new empirical nonlinear model. Bronchial NO flux estimates from different models differed in magnitude but were strongly correlated (r >or= 0.95), and increased in subjects with allergic asthma. Alveolar concentration estimates differed among models and did not consistently show the same effects of allergy or asthma. A novel index of nonlinear behavior of NO output versus flow was significantly related to asthma status, and not strongly correlated with bronchial flux or alveolar concentration. Field-based extended NO testing of children can yield useful information about NO in different regions of the respiratory tract that is not obtainable from conventional FeNO. Extended NO analysis holds promise for investigating environmental and genetic determinants of regional airway inflammatory states.

TNF-308 modifies the effect of second-hand smoke on respiratory illness-related school absences.

RATIONALE: Exposure to second-hand smoke (SHS) has been associated with increased risk of respiratory illness in children including respiratory illness-related school absences. The role of genetic susceptibility in risk for adverse effects from SHS has not been extensively investigated in children. OBJECTIVE: To determine whether the tumor necrosis factor (TNF) G-308A genotype influences the risk for respiratory illness-related school absences associated with SHS exposure. METHODS: Incident school absences were collected, using an active surveillance system, between January and June 1996, as part of the Air Pollution and Absence Study, a prospective cohort study nested in the Children's Health Study. Buccal cells and absence reports were collected on 1,351 students from 27 elementary schools in California. MEASUREMENTS AND MAIN RESULTS: Illness-related school absences were classified as nonrespiratory and respiratory illness-related, which were further categorized into upper or lower respiratory illness-related absences based on symptoms. The effect of SHS exposure on respiratory illness-related absences differed by TNF genotype (p interaction, 0.02). In children possessing at least one copy of the TNF-308 A variant, exposure to two or more household smokers was associated with a twofold risk of a school absence due to respiratory illness (relative risk, 2.13; 95% confidence interval, 1.34, 3.40) and a fourfold risk of lower respiratory illness-related school absence (relative risk, 4.15; 95% confidence interval, 2.57, 6.71) compared with unexposed children homozygous for the common TNF-308 G allele. CONCLUSIONS: These results indicate that a subgroup of genetically susceptible children are at substantially greater risk of respiratory illness if exposed to SHS.

Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function.

Both in utero exposures to maternal smoking and asthma are associated with chronic deficits in lung function. We hypothesized that in utero exposure affects lung function in children without asthma and synergistically affects children with early onset asthma. To investigate effects of in utero exposure and age at asthma diagnosis on lung function, we examined longitudinal medical history, tobacco smoke exposure, and lung function data from 5,933 participants in the Children's Health Study. We found that children exposed in utero, but without asthma, showed decreased FEV1/FVC, FEF25-75, and FEF25-75/FVC ratio. Among children without in utero exposure, early asthma diagnosis was associated with larger decreases in FEV1, FEF25-75, and FEV1/FVC ratio compared with later diagnosed asthma. Children with in utero exposure alone and early onset asthma showed deficits in FEV1 (-13.6%; 95% confidence interval [CI], -18.9 to -8.2) and FEF25-75 (-29.7%; 95% CI, -37.8 to -20.5) among boys; and FEF25-75 (-26.6%; 95% CI, -36.4 to -15.1) and FEV1/FVC (-9.3%; 95% CI, -12.9 to -5.4) among girls. The absolute differences in FEF25-75 associated with in utero exposure increased with age in children with early onset asthma. We found little evidence for effects from environmental tobacco smoke exposure alone. In summary, deficits in lung function were largest among children with in utero exposure and early onset asthma.