We previously reported that asthmatic children with GSTM1 null genotype may be more susceptible to the acute effect of ozone on the small airways and might benefit from antioxidant supplementation. This study aims to assess the acute effect of ozone on lung function (FEF25-75) in asthmatic children according to dietary intake of vitamin C and the number of putative risk alleles in three antioxidant genes: GSTM1, GSTP1 (rs1695), and NQO1 (rs1800566).
257 asthmatic children from two cohort studies conducted in Mexico City were included. Stratified linear mixed models with random intercepts and random slopes on ozone were used. Potential confounding by ethnicity was assessed. Analyses were conducted under single gene and genotype score approaches.
The change in FEF25-75 per interquartile range (60 ppb) of ozone in persistent asthmatic children with low vitamin C intake and GSTM1 null was −91.2 ml/s (p = 0.06). Persistent asthmatic children with 4 to 6 risk alleles and low vitamin C intake showed an average decrement in FEF25-75 of 97.2 ml/s per 60 ppb of ozone (p = 0.03). In contrast in children with 1 to 3 risk alleles, acute effects of ozone on FEF25-75 did not differ by vitamin C intake.
Our results provide further evidence that asthmatic children predicted to have compromised antioxidant defense by virtue of genetic susceptibility combined with deficient antioxidant intake may be at increased risk of adverse effects of ozone on pulmonary function.
Air pollution; Asthmatic children; Antioxidant genes; Mexico City; Vitamin C
The innate immune pathway is important in the pathogenesis of asthma and eczema. However, only a few variants in these genes have been associated with either disease. We investigate the association between polymorphisms of genes in the innate immune pathway with childhood asthma and eczema. In addition, we compare individual associations with those discovered using a multivariate approach.
Using a novel method, case control based association testing (C2BAT), 569 single nucleotide polymorphisms (SNPs) in 44 innate immune genes were tested for association with asthma and eczema in children from the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. The screening algorithm was used to identify the top SNPs associated with asthma and eczema. We next investigated the interaction of innate immune variants with asthma and eczema risk using Bayesian networks.
After correction for multiple comparisons, 7 SNPs in 6 genes (CARD25, TGFB1, LY96, ACAA1, DEFB1, and IFNG) were associated with asthma (adjusted p-value<0.02), while 5 SNPs in 3 different genes (CD80, STAT4, and IRAKI) were significantly associated with eczema (adjusted p-value < 0.02). None of these SNPs were associated with both asthma and eczema. Bayesian network analysis identified 4 SNPs that were predictive of asthma and 10 SNPs that predicted eczema. Of the genes identified using Bayesian networks, only CD80 was associated with eczema in the single-SNP study. Using novel methodology that allows for screening and replication in the same population, we have identified associations of innate immune genes with asthma and eczema. Bayesian network analysis suggests that additional SNPs influence disease susceptibility via SNP interactions.
Our findings suggest that innate immune genes contribute to the pathogenesis of asthma and eczema, and that these diseases likely have different genetic determinants.
asthma; Bayesian network; genetic association; eczema; innate immunity
Background: Epidemiological studies have assessed T-wave alternans (TWA) as a possible mechanism of cardiac arrhythmias related to air pollution in high-risk subjects and have reported associations with increased TWA magnitude.
Objective: In this controlled human exposure study, we assessed the impact of exposure to concentrated ambient particulate matter (CAP) and ozone (O3) on T-wave alternans in resting volunteers without preexisting cardiovascular disease.
Methods: Seventeen participants without preexisting cardiovascular disease were randomized to filtered air (FA), CAP (150 μg/m3), O3 (120 ppb), or combined CAP + O3 exposures for 2 hr. Continuous electrocardiograms (ECGs) were recorded at rest and T-wave alternans (TWA) was computed by modified moving average analysis with QRS alignment for the artifact-free intervals of 20 beats along the V2 and V5 leads. Exposure-induced changes in the highest TWA magnitude (TWAMax) were estimated for the first and last 5 min of each exposure (TWAMax_Early and TWAMax_Late respectively). ΔTWAMax (Late–Early) were compared among exposure groups using analysis of variance.
Results: Mean ± SD values for ΔTWAMax were –2.1 ± 0.4, –2.7 ± 1.1, –1.9 ± 1.5, and –1.2 ± 1.5 in FA, CAP, O3, and CAP + O3 exposure groups, respectively. No significant differences were observed between pollutant exposures and FA.
Conclusion: In our study of 17 volunteers who had no preexisting cardiovascular disease, we did not observe significant changes in T-wave alternans after 2-hr exposures to CAP, O3, or combined CAP + O3. This finding, however, does not preclude the possibility of pollution-related effects on TWA at elevated heart rates, such as during exercise, or the possibility of delayed responses.
air pollution; arrhythmia; controlled exposure; ozone; particulate matter; T-wave alternans
Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma.
Assess the influence of prenatal vitamin D status on immune function at birth.
In an inner-city birth cohort of 568 newborns, 520 of whom had at least one atopic parent, we measured umbilical cord (UC) plasma concentration of 25-hydroxy vitamin D (25(OH)D) and the cytokine responses of UC blood mononuclear cells (UCMCs) to stimuli including phytohemaglutinin (PHA), lipopolysaccharide (LPS), and peptidoglycan (PG). In a subset, UCMC expression of regulatory T-cell markers and the suppressive activity of CD4+CD25+ UCMCs was measured.
The 25th, 50th, and 75th percentiles of UC plasma 25(OH)D level were 15.0, 20.2, and 25.6 ng/mL, respectively. Most cytokine responses of UCMC were not correlated with UC 25(OH)D concentration; however, IFN-γ release after LPS stimulation was weakly positively correlated with UC 25(OH)D concentration (r = 0.11, p =0.01). PHA responses were not significantly correlated with 25(OH)D concentration. The UC plasma 25(OH)D concentration was inversely related to the number of CD25+ (r= -0.20, p=0.06), CD25Bright (r= -0.21, p=0.05), and CD25+FoxP3 (r= -0.29, p=0.06) cells as a proportion of CD4+ T cells in UC blood (r = -0.26, p = 0.04) but not to the suppressive activity of CD4+CD25+ cells (r=0.17, p=0.22).
Conclusion and Clinical Relevance
UC 25(OH)D concentration was not correlated with most UCMC cytokine responses to multiple stimuli. There was a suggestion of a weakly positive correlation with IFN-γ release after LPS stimulation. The proportions of CD25+, CD25bright, and CD25+FoxP3 cells to total CD4+ T cells were inversely correlated with UC 25(OH)D concentration. Our findings suggest that higher vitamin D levels at birth may be associated with a lower number of T regulatory cells. Vitamin D status in utero may influence immune regulation in early life.
Current evidence supports a role for gut colonization in promoting and maintaining a balanced immune response in early life. An altered or less diverse gut microbiota composition has been associated with atopic diseases and/or obesity. Moreover, certain gut microbial strain or strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. However, there has been no fully adequate longitudinal study of the relation between the neonatal gut microbiota and the development of allergic diseases (e.g., atopic asthma) and obesity. The emergence of promising experimental studies has led to several clinical trials of probiotics (live bacteria given orally that allow for intestinal colonization) in humans. Probiotic trials thus far have failed to show a consistent preventive or therapeutic effect on asthma or obesity. Previous trials of probiotics have been limited by small sample size, short duration of follow-up, or lack state-of-the art analyses of the gut microbiota. Finally, there is emerging evidence that the vitamin D pathway may be important in gut homeostasis and in the signaling between the microbiota and the host. Given the complexity of the gut micriobiota, additional research is needed before we can confidently establish whether its manipulation in early life can prevent or treat asthma and/or obesity.
microbiota; asthma; obesity; allergic; eczema; vitamin D; probiotics; cytokines
Studies on airway inflammation, measured as fraction exhaled nitric oxide (FENO), have focused on its relation to control of asthma, but the contribution of allergen exposure to elevation of FENO is unknown.
We evaluated (1) whether FENO was elevated in children with allergic sensitization or asthma; (2) whether specific allergen exposure increased FENO levels in sensitized, but not in unsensitized children; and (3) whether sedentary behavior increased FENO, independent of allergen exposures.
At age 12, in a birth cohort of children with parental history of allergy or asthma, we measured bed dust allergen (dust mite, cat, cockroach) by ELISA; specific allergic sensitization primarily by specific IgE ; and respiratory disease (current asthma, rhinitis, and wheeze) and hours of TV viewing/video game playing by questionnaire. Children performed spirometry maneuvers before and after bronchodilator responses, and had FENO measured using electrochemical detection methods (NIOX MINO).
FENO was elevated in children with current asthma (32.2 ppb), wheeze (27.0 ppb), or rhinitis (23.2ppb) as compared to individuals without these respective symptoms/diagnoses (16.4 ppb to 16.6 ppb, p< 0.005 for all comparisons). Allergic sensitization to indoor allergens (cat, dog, dust mite) predicted higher levels of FENO, and explained one third of the variability of FENO. FENO levels were highest in children both sensitized and exposed to dust mite. Greater than 10 hours of weekday TV viewing was associated with a 0.64 log increase in FENO, after controlling indoor allergen exposure, BMI and allergic sensitization.
Allergen exposures and sedentary behavior (TV viewing/ video game playing), may increase airway inflammation, measured as FENO.
Asthma; dust mite; cat; allergens; exhaled NO; allergic sensitization; home environment
Background: Diabetes increases the risk of hypertension and orthostatic hypotension and raises the risk of cardiovascular death during heat waves and high pollution episodes.
Objective: We examined whether short-term exposures to air pollution (fine particles, ozone) and heat resulted in perturbation of arterial blood pressure (BP) in persons with type 2 diabetes mellitus (T2DM).
Methods: We conducted a panel study in 70 subjects with T2DM, measuring BP by automated oscillometric sphygmomanometer and pulse wave analysis every 2 weeks on up to five occasions (355 repeated measures). Hourly central site measurements of fine particles, ozone, and meteorology were conducted. We applied linear mixed models with random participant intercepts to investigate the association of fine particles, ozone, and ambient temperature with systolic, diastolic, and mean arterial BP in a multipollutant model, controlling for season, meteorological variables, and subject characteristics.
Results: An interquartile increase in ambient fine particle mass [particulate matter (PM) with an aerodynamic diameter of ≤ 2.5 μm (PM2.5)] and in the traffic component black carbon in the previous 5 days (3.54 and 0.25 μg/m3, respectively) predicted increases of 1.4 mmHg [95% confidence interval (CI): 0.0, 2.9 mmHg] and 2.2 mmHg (95% CI: 0.4, 4.0 mmHg) in systolic BP (SBP) at the population geometric mean, respectively. In contrast, an interquartile increase in the 5-day mean of ozone (13.3 ppb) was associated with a 5.2 mmHg (95% CI: –8.6, –1.8 mmHg) decrease in SBP. Higher temperatures were associated with a marginal decrease in BP.
Conclusions: In subjects with T2DM, PM was associated with increased BP, and ozone was associated with decreased BP. These effects may be clinically important in patients with already compromised autoregulatory function.
air pollution; ambient temperature; blood pressure; diabetes mellitus; epidemiology; ozone; particles
Few prospective data link early childhood adiposity with asthma-related symptoms.
We sought to examine the associations of weight-for-length (WFL) at age 6 months with incidence of wheezing by age 3 years.
We studied 932 children in a prospective cohort of children. The main outcome was recurrent wheezing, which was defined as parents’ report of wheezing between 2 and 3 years of age plus wheezing in either year 1 or 2 of life. Secondary outcomes included any wheezing from 6 months to 3 years and current asthma. We used multiple logistic regression to examine associations of 6-month WFL z scores with these outcomes.
At 6 months, the infants’ mean WFL z score was 0.68 (SD, 0.94; range −2.96 to 3.24). By age 3 years, 14% of children had recurrent wheezing. After adjustment for a variety of potential confounders, we found that each 1-unit increment in 6-month WFL z score was associated with greater odds of recurrent wheezing (odds ratio [OR], 1.46; 95% CI, 1.11–1.91) and any wheezing (OR, 1.23; 95% CI, 1.03–1.48). We observed a weaker association between 6-month WFL z score and current asthma (OR, 1.22; 95% CI, 0.94–1.59).
Infants with higher WFL z scores at 6 months of age had a greater risk of recurrent wheezing by age 3 years. It is unclear whether the relationship of infant adiposity and early-life wheeze extends to allergic asthma or wheeze that can persist into later childhood. Our findings suggest that early interventions to prevent excess infant adiposity might help reduce children’s risk of asthma-related symptoms.
Asthma; wheeze; adiposity; children; prospective study
Children spend a significant amount of time in school. Little is known about the role of allergen exposure in school environments and asthma morbidity.
The School Inner-City Asthma (SICAS) is an NIH funded prospective study evaluating the school/classroom specific risk factors and asthma morbidity among urban children
This paper describes the design, methods, and important lessons learned from this extensive investigation. A single center is recruiting 500 elementary school aged children, all of whom attend inner-city, metropolitan schools. The primary hypothesis is that exposure to common indoor allergens in the classroom will increase the risk of asthma morbidity in children with asthma, even after controlling for home allergen exposures. The protocol includes screening surveys of entire schools and baseline eligibility assessments obtained in the spring prior to the academic year. Extensive baseline clinical visits are being conducted among eligible children with asthma during the summer prior to the academic school year. Environmental classroom/school assessments including settled dust and air sampling for allergen, mold, air pollution, and inspection data are collected twice during the academic school year and one home dust sample linked to the enrolled student. Clinical outcomes are measured every 3 months during the academic school year.
The overall goal of SICAS is to complete the first study of its kind to better understand school-specific urban environmental factors on childhood asthma morbidity. We also discuss the unique challenges related to school-based urban research and lessons being learned from recruiting such a cohort.
asthma; questionnaires; schools; child
Rationale: Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17% of U.S. adults, and may be more prevalent in poor urban environments. SDB and air pollution have been linked to increased cardiovascular diseases and mortality, but the association between pollution and SDB is poorly understood.
Objectives: We used data from the Sleep Heart Health Study (SHHS), a U.S. multicenter cohort study assessing cardiovascular and other consequences of SDB, to examine whether particulate air matter less than 10 μm in aerodynamic diameter (PM10) was associated with SDB among persons 39 years of age and older.
Methods: Using baseline data from SHHS urban sites, outcomes included the following: the respiratory disturbance index (RDI); percentage of sleep time at less than 90% O2 saturation; and sleep efficiency, measured by overnight in-home polysomnography. We applied a fixed-effect model containing a city effect, controlling for potential predictors. In all models we included both the 365-day moving averages of PM10 and temperature (long-term effects) and the differences between the daily measures of these two predictors and their 365-day average (short-term effects).
Measurements and Main Results: In summer, increases in RDI or percentage of sleep time at less than 90% O2 saturation, and decreases in sleep efficiency, were all associated with increases in short-term variation in PM10. Over all seasons, we found that increased RDI was associated with an 11.5% (95% confidence interval: 1.96, 22.01) increase per interquartile range increase (25.5°F) in temperature.
Conclusions: Reduction in air pollution exposure may decrease the severity of SDB and nocturnal hypoxemia and may improve cardiac risk.
particulate matter; sleep-disordered breathing; sleep architecture
The rise in asthma prevalence over the last few decades may be due changes in pre-natal or early life environment including maternal diet during pregnancy. Previous studies have found associations between individual foods or nutrients consumed during pregnancy and asthma or wheeze in children, but these may be confounded by overall dietary pattern.
To determine if overall maternal dietary pattern during pregnancy is associated with recurrent wheeze in children.
1376 mother-infant pairs from Project Viva, a longitudinal pre-birth cohort, who had responses for food frequency questionnaires in the 1st and 2nd trimester and outcome data at 3 years of age were included. Multivariable logistic regression was used to look at associations between dietary pattern and the primary outcome of recurrent wheeze at 3 years. Overall dietary pattern was examined using Mediterranean diet score, Alternate Healthy Eating Index modified for pregnancy (AHEI-P), and principal components analysis to look at Western and Prudent diets.
None of these dietary patterns was associated with the primary outcome of recurrent wheeze in children in either the crude or in the multivariable models (multivariable model: OR per one point increase Mediterranean diet 0.98 [95% CI 0.89, 1.08] AHEI-P 1.07 [0.87, 1.30] Prudent 1.02 [0.83, 1.26] Western 0.98 [0.81, 1.19]).
Overall dietary pattern during pregnancy is not associated with recurrent wheeze in this cohort. Maternal intake of individual nutrients may be more important determinants ofoffspring wheeze-associated illness than is dietary pattern.
asthma; dietary pattern; Mediterranean diet; healthy diet; principal components; childhood wheeze; pregnancy
Particulate pollution has been linked to risk of cardiac death; possible mechanisms include pollution-related increases in cardiac electrical instability. T-wave alternans (TWA) is a marker of cardiac electrical instability measured as differences in the magnitude between adjacent T waves. In a repeated-measures study of 48 patients aged 43-75 years, we investigated associations of ambient and home indoor particulate pollution including black carbon (BC) and report of traffic exposure, with changes in half-hourly maximum TWA (TWA-MAX), measured by 24 hour Holter electrocardiogram monitoring. Each patient was observed up to 4 times within one year after percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease for a total of 5,830 half-hour observations. Diary data for each half-hour period defined whether the patient was home or not home, or in traffic. Increases in TWA-MAX were independently associated both with the previous 2-h mean ambient BC (2.1%; 95% C.I.: 0.9-3.3) and with being in traffic in the previous 2 hours (6.1%; 95% C.I.: 3.4-8.8). When subjects were home, indoor home BC effects were largest and most precise; when subjects were away from home, ambient central site BC effects were strongest. Increases in pollution increased the odds of TWA-MAX ≥ 75th percentile (OR 1.4; 95% CI: 1.2-1.6 for 1 μg/m3 increase in 6-h mean BC). In conclusion, following hospitalization for coronary artery disease, being in traffic, and short-term ambient or indoor BC exposures increase TWA, a marker of cardiac electrical instability.
Air pollution; coronary disease; myocardial infarction; T-wave alternans; circadian rhythm
Frequently, exposure data are measured over time on a grid of discrete values that collectively define a functional observation. In many applications, researchers are interested in using these measurements as covariates to predict a scalar response in a regression setting, with interest focusing on the most biologically relevant time window of exposure. One example is in panel studies of the health effects of particulate matter (PM), where particle levels are measured over time. In such studies, there are many more values of the functional data than observations in the data set so that regularization of the corresponding functional regression coefficient is necessary for estimation. Additional issues in this setting are the possibility of exposure measurement error and the need to incorporate additional potential confounders, such as meteorological or co-pollutant measures, that themselves may have effects that vary over time. To accommodate all these features, we develop wavelet-based linear mixed distributed lag models that incorporate repeated measures of functional data as covariates into a linear mixed model. A Bayesian approach to model fitting uses wavelet shrinkage to regularize functional coefficients. We show that, as long as the exposure error induces fine-scale variability in the functional exposure profile and the distributed lag function representing the exposure effect varies smoothly in time, the model corrects for the exposure measurement error without further adjustment. Both these conditions are likely to hold in the environmental applications we consider. We examine properties of the method using simulations and apply the method to data from a study examining the association between PM, measured as hourly averages for 1–7 days, and markers of acute systemic inflammation. We use the method to fully control for the effects of confounding by other time-varying predictors, such as temperature and co-pollutants.
Air pollution; Functional data analysis; Markov chain Monte Carlo; Mixture prior; Panel study; Particulate matter; Wavelets
Rationale: Stress-elicited disruption of immunity begins in utero.
Objectives: Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n = 557 families).
Methods: Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age).
Measurements and Main Results: Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than $15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-α to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN-γ.
Conclusions: Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children.
psychological stress; cord blood; cytokines; innate; adaptive
The environment is suspected to play an important role in the development of childhood asthma. Cohort studies are a powerful observational design for studying exposure–response relationships, but their power depends in part upon the accuracy of the exposure assessment.
The purpose of this paper is to summarize and discuss issues that make accurate exposure assessment a challenge and to suggest strategies for improving exposure assessment in longitudinal cohort studies of childhood asthma and allergies.
Exposures of interest need to be prioritized, because a single study cannot measure all potentially relevant exposures. Hypotheses need to be based on proposed mechanisms, critical time windows for effects, prior knowledge of physical, physiologic, and immunologic development, as well as genetic pathways potentially influenced by the exposures. Modifiable exposures are most important from the public health perspective. Given the interest in evaluating gene–environment interactions, large cohort sizes are required, and planning for data pooling across independent studies is critical. Collection of additional samples, possibly through subject participation, will permit secondary analyses. Models combining air quality, environmental, and dose data provide exposure estimates across large cohorts but can still be improved.
Exposure is best characterized through a combination of information sources. Improving exposure assessment is critical for reducing measurement error and increasing power, which increase confidence in characterization of children at risk, leading to improved health outcomes.
childhood asthma; cohort studies; exposure assessment
Measurement of fungal and bacterial biomarkers can be costly, but it is not clear whether home characteristics can be used as a proxy of these markers, particularly if the purpose is to differentiate specific classes of biologic exposures that have similar sources but may have different effects on allergic disease risk.
We evaluated home characteristics as predictors of multiple microbial biomarkers, with a focus on common and unique determinants and with attention to the extent of their explanatory ability.
In 376 Boston-area homes enrolled in a cohort study of home exposures and childhood asthma, we assessed the relationship between home characteristics gathered by questionnaire and measured gram-negative bacteria (GNB) (endotoxin and C10:0, C12:0, and C14:0 3-hydroxy fatty acids), gram-positive bacteria (GPB) (N-acetyl muramic acid), and fungal biomarkers [ergosterol and (1→6) branched, (1→3) β-d glucans] in bed and family room dust.
Home characteristics related to dampness were significant predictors of all microbial exposures; water damage or visible mold/mildew in the home was associated with a 20–66% increase in GNB levels. Report of cleaning the bedroom at least once a week was associated with reduced GNB, GPB, and fungi. Presence of dogs or cats predicted increases in home bacteria or fungi. The proportion of variance in microbial biomarkers explained by home characteristics ranged from 4.2% to 19.0%.
Despite their associations with multiple microbial flora, home characteristics only partially explain the variability in microbial biomarker levels and cannot substitute for specific microbial measurements in studies concerned with distinguishing effects of specific classes of microbes.
bacteria; dampness; fungi; home characteristics; indoor exposure; respiratory health
Immunologic responses at birth likely relate to subsequent risks for allergic diseases and wheezing in infancy; however, the influences of parental characteristics and prenatal factors on neonatal immune responses are incompletely understood.
This study investigates potential correlations between urban parental, prenatal and perinatal factors on innate and adaptive stimuli-induced cytokine responses.
560 and 49 children of parents with and without allergic disease or asthma, respectively, were enrolled into a prospective birth cohort study (Urban Environment and Childhood Asthma [URECA]). Cord blood mononuclear cells were incubated with innate and adaptive immune stimuli, and cytokine responses (ELISA) were compared to season of birth, parental characteristics, in-utero stressors, and fetal growth.
Many cytokine responses varied by season of birth, including 2–3 fold fluctuations with specific IFN-α and IFN-γ responses. Birthweight was inversely associated with IFN-γ responses to RSV (R=−0.16), but positively associated with IL-8 responses to a variety of innate stimuli (R=0.08–0.12). Respiratory syncytial virus (RSV) induced cytokine responses were 21–54% lower in children of mothers with asthma. Cytokine responses were generally lower in babies born to parents with allergy/asthma.
Innate cytokine responses are associated with parental allergic or airway disease, somatic fetal growth, ethnicity, and season of birth. Collectively, these findings suggest that urban prenatal exposures and familial factors affect the development of the fetal immune system.
Prenatal influences that disturb normal immune development might establish the patterns that are associated with recurrent wheezing in infants and preschoolers, and later as allergy and asthma in school-age children.
Atopy; immune response; cord blood; birth cohort; gestational age; cytokines
Spatial cluster detection has become an important methodology in quantifying the effect of hazardous exposures. Previous methods have focused on cross-sectional outcomes that are binary or continuous. There are virtually no spatial cluster detection methods proposed for longitudinal outcomes. This paper proposes a new spatial cluster detection method for repeated outcomes using cumulative geographic residuals. A major advantage of this method is its ability to readily incorporate information on study participants relocation, which most cluster detection statistics cannot. Application of these methods will be illustrated by the Home Allergens and Asthma prospective cohort study analyzing the relationship between environmental exposures and repeated measured outcome, occurrence of wheeze in the last 6 months, while taking into account mobile locations.
Asthma; Cumulative residuals; Repeated measured; Spatial cluster detection; Wheeze
While some evidence suggests that antigen sensitization may begin prenatally, the influence of maternal allergen exposure during pregnancy has not been fully elucidated.
We examined the relationship between prenatal maternal aeroallergen exposure and cord blood total immunoglobulin E (IgE) and the potential mediating/indirect effect of maternal immune response.
This study was performed in 301 mother-infant pairs enrolled in the Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project, a study examining the effects of prenatal and early life social and physical environmental exposures on urban asthma risk. Dust samples collected prenatally from mothers’ bedrooms were analyzed for cockroach and dust mite allergens. Cord blood was analyzed for total IgE and maternal serum collected during pregnancy for total and specific IgE. We assessed the relationship between prenatal exposure and cord blood total IgE and the potential mediation effect adjusting for maternal age, race, education, smoking status and dust collection season; and child’s gender and season of birth.
In multivariate models, elevated prenatal dust mite levels (> 0.2 µg/g) increased cord blood IgE concentrations by 29% (p=0.08) and continuous dust mite concentration was associated with a significant non-linear increase in cord blood IgE (p=0.02). Elevated prenatal exposure to cockroach allergen (> 2 U/g) was not associated with cord blood IgE, but showed a significant indirect relationship through maternal total IgE (β=0.23; 95% CI: 0.08, 0.41).
These results demonstrate that maternal prenatal exposure to household allergens may impact cord blood IgE albeit the underlying mechanism may be allergen-specific.
Maternal prenatal inhalant allergen exposure may precipitate infant immune response although the pathway of the effect may differ by allergen.
Prenatal exposure to dust mite was associated with increased cord blood total IgE whereas the relationship between prenatal cockroach exposure and total cord blood IgE was only observed through the indirect effect of maternal allergic response.
Allergen; Dust Mite; Cockroach; Maternal; Prenatal; Cord Blood; Immunoglobulin E; IgE; Urban
Ambient particulate pollution and traffic have been linked to myocardial infarction and cardiac death risk. Possible mechanisms include autonomic cardiac dysfunction.
In a repeated-measures study of 46 patients 43–75 years of age, we investigated associations of central-site ambient particulate pollution, including black carbon (BC) (a marker for regional and local traffic), and report of traffic exposure with changes in half-hourly averaged heart rate variability (HRV), a marker of autonomic function measured by 24-hr Holter electrocardiogram monitoring. Each patient was observed up to four times within 1 year after a percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease (4,955 half-hour observations). For each half-hour period, diary data defined whether the patient was home or not home, or in traffic.
A decrease in high frequency (HF; an HRV marker of vagal tone) of −16.4% [95% confidence interval (CI), −20.7 to −11.8%] was associated with an interquartile range of 0.3-μg/m3 increase in prior 5-day averaged ambient BC. Decreases in HF were independently associated both with the previous 2-hr averaged BC (−10.4%; 95% CI, −15.4 to −5.2%) and with being in traffic in the previous 2 hr (−38.5%; 95% CI, −57.4 to −11.1%). We also observed independent responses for particulate air matter with aerodynamic diameter ≤ 2.5 μm and for gases (ozone or nitrogen dioxide).
After hospitalization for coronary artery disease, both particulate pollution and being in traffic, a marker of stress and pollution, were associated with decreased HRV.
air pollution; cardiac event; heart rate variability; myocardial infarction; traffic
Systemic inflammation may be one of the mechanisms mediating the association between ambient air pollution and cardiovascular morbidity and mortality. Interleukin-6 (IL-6) and fibrinogen are biomarkers of systemic inflammation that are independent risk factors for cardiovascular disease.
We investigated the association between ambient air pollution and systemic inflammation using baseline measurements of IL-6 and fibrinogen from controlled human exposure studies.
In this retrospective analysis we used repeated-measures data in 45 nonsmoking subjects. Hourly and daily moving averages were calculated for ozone, nitrogen dioxide, sulfur dioxide, and particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5). Linear mixed-model regression determined the effects of the pollutants on systemic IL-6 and fibrinogen. Effect modification by season was considered.
We observed a positive association between IL-6 and O3 [0.31 SD per O3 interquartile range (IQR); 95% confidence interval (CI), 0.08–0.54] and between IL-6 and SO2 (0.25 SD per SO2 IQR; 95% CI, 0.06–0.43). We observed the strongest effects using 4-day moving averages. Responses to pollutants varied by season and tended to be higher in the summer, particularly for O3 and PM2.5. Fibrinogen was not associated with pollution.
This study demonstrates a significant association between ambient pollutant levels and baseline levels of systemic IL-6. These findings have potential implications for controlled human exposure studies. Future research should consider whether ambient pollution exposure before chamber exposure modifies IL-6 response.
air pollution; epidemiology; fibrinogen; inflammation; interleukin-6
The association of particulate matter (PM) with cardiovascular morbidity and mortality is well documented. PM-induced ischemia is considered a potential mechanism linking PM to adverse cardiovascular outcomes.
Methods and Results
In a repeated-measures study including 5,979 observations on 48 patients aged 43–75 years, we investigated associations of ambient pollution with ST-segment level changes averaged over half-hour periods, measured in the modified V5 position by 24-hr Holter electrocardiogram monitoring. Each patient was observed up to 4 times within one year after a percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease without acute coronary syndrome. Elevation in fine particles (PM2.5) and black carbon (BC) levels predicted depression of half-hour averaged ST-segment levels. An interquartile increase in the previous 24-h mean BC level was associated with a 1.50-fold increased in risk of ST-segment depression ≥0.1 mm (95% CI: 1.19, 1.89) and a −0.031 mm (95% CI: −0.042, −0.019) decrease in half-hour averaged ST-segment level (continuous outcome). Effects were greatest within the first month after hospitalization, and for patients with myocardial infarction during hospitalization or with diabetes.
ST-segment depression is associated with increased exposure to PM2.5 and BC in cardiac patients. The risk of pollution-associated ST-segment depression may be greatest in those with myocardial injury in the first month after the cardiac event.
air pollution; particles; cardiovascular diseases; myocardial infarction; ST-segment depression
Human controlled-exposure studies have assessed the impact of ambient fine particulate matter on cardiac autonomic function measured by heart rate variability (HRV), but whether these effects are modified by concomitant ozone exposure remains unknown.
In this study we assessed the impact of O3 and particulate matter exposure on HRV in humans.
In a crossover design, 50 subjects (19–48 years of age) were randomized to 2-hr controlled exposures to filtered air (FA), concentrated ambient particles (CAPs), O3, or combined CAPs and ozone (CAPs + O3). The primary end point was change in HRV between the start and end of exposure. Secondary analyses included blood pressure (BP) responses, and effect modification by asthmatic status.
Achieved mean CAPs and O3 exposure concentrations were 121.6 ± 48.0 μg/m3 and 113.9 ± 6.6 ppb, respectively. In a categorical analysis, exposure had no consistent effect on HRV indices. However, the dose–response relationship between CAPs mass concentration and HRV indices seemed to vary depending on the presence of O3. This heterogeneity was statistically significant for the low-frequency component of HRV (p = 0.02) and approached significance for the high-frequency component and time-domain measures of HRV. Exposure to CAPs + O3 increased diastolic BP by 2.0 mmHg (SE, 1.2; p = 0.02). No other statistically significant changes in BP were observed. Asthmatic status did not modify these effects.
The potentiation by O3 of CAPs effects on diastolic BP and possibly HRV is of small magnitude in young adults. Further studies are needed to assess potential effects in more vulnerable populations.
asthma; blood pressure; heart rate variability; ozone; particulate matter