Within-microenvironment exposure to particulate matter and health effects in children with asthma: a pilot study utilizing real-time personal monitoring with GPS interface.

BACKGROUND: Most particulate matter (PM) and health studies in children with asthma use exposures averaged over the course of a day and do not take into account spatial/temporal variability that presumably occurs as children move from home, into transit and then school microenvironments. The objectives of this work were to identify increases in morning PM exposure occurring within home, transit and school microenvironments and determine their associations with asthma-related inflammation and rescue medication use. METHODS: In 2007-2008, thirty Denver-area schoolchildren with asthma performed personal PM exposure monitoring using a real-time sensor integrated with a geographic information system (GIS) to apportion exposures to home, transit and school microenvironments. Concurrently, daily monitoring of the airway inflammatory biomarker urinary leukotriene E4 (uLTE4) and albuterol usage was performed. RESULTS: Mean PM exposures each morning were relatively well correlated between microenvironments for subject samples (0.3 < r < 0.8), thus limiting use of this exposure metric to attribute health effects to PM exposure in specific microenvironments. Within-microenvironment increases in exposure, such as would be characterized by one or a series of transient spikes or a sustained increase in concentration (exposure event), however, were not strongly correlated between microenvironments (|r| < 0.25). On days when children were exposed to a ≥ 5µg/m3 exposure event during transit, they demonstrated a 24.0 % increase in uLTE4 (95 % CI: 1.5 %, 51.5 %) and a 9.7 % (-5.9 %, 27.9 %) increase in albuterol usage compared to days without transit exposure events. Associations between exposure events and health outcomes in home and school microenvironments tended to be positive as well, but weaker than for transit. CONCLUSIONS: School children with asthma moving across morning microenvironments experience spatially heterogeneous PM exposures with potentially varying health effects.

Predictors of asthma control and lung function responsiveness to step 3 therapy in children with uncontrolled asthma.

BACKGROUND: Predictors of improvement in asthma control and lung function to step 3 therapy in children with persistent asthma have not been identified despite reported heterogeneity in responsiveness. OBJECTIVE: We sought to evaluate potential predictors of asthma control and lung function responsiveness to step 3 therapy. METHODS: A post hoc analysis from the Best Add-On Giving Effective Response (BADGER) study tested the association between baseline biological, asthma control, pulmonary function, and demographic markers and responsiveness to step-up to a higher dose of inhaled corticosteroid (ICS step-up therapy) or addition of leukotriene receptor antagonist (LTRA step-up therapy) or long-acting ß2-agonist (LABA step-up therapy). RESULTS: In multivariate analyses higher impulse oscillometry reactance area was associated (P = .048) with a differential FEV1 response favoring LABA over ICS step-up therapy, whereas higher urinary leukotriene E4 levels were marginally (P = .053) related to a differential FEV1 response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS with LTRA step-up therapy were not apparent, probably because of suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV1 and asthma control day predictors, suggesting distinct mechanisms related to lung function and asthma control day responses. CONCLUSION: Levels of impulse oscillometry reactance area indicating peripheral airway obstruction and urinary leukotriene E4 levels indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up therapy. Further studies with physiologic, genetic, and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.

Regression calibration for models with two predictor variables measured with error and their interaction, using instrumental variables and longitudinal data.

Regression calibration provides a way to obtain unbiased estimators of fixed effects in regression models when one or more predictors are measured with error. Recent development of measurement error methods has focused on models that include interaction terms between measured-with-error predictors, and separately, methods for estimation in models that account for correlated data. In this work, we derive explicit and novel forms of regression calibration estimators and associated asymptotic variances for longitudinal models that include interaction terms, when data from instrumental and unbiased surrogate variables are available but not the actual predictors of interest. The longitudinal data are fit using linear mixed models that contain random intercepts and account for serial correlation and unequally spaced observations. The motivating application involves a longitudinal study of exposure to two pollutants (predictors) - outdoor fine particulate matter and cigarette smoke - and their association in interactive form with levels of a biomarker of inflammation, leukotriene E4 (LTE 4 , outcome) in asthmatic children. Because the exposure concentrations could not be directly observed, we used measurements from a fixed outdoor monitor and urinary cotinine concentrations as instrumental variables, and we used concentrations of fine ambient particulate matter and cigarette smoke measured with error by personal monitors as unbiased surrogate variables. We applied the derived regression calibration methods to estimate coefficients of the unobserved predictors and their interaction, allowing for direct comparison of toxicity of the different pollutants. We used simulations to verify accuracy of inferential methods based on asymptotic theory.

Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children.

RATIONALE: The effect of endotoxin on asthma morbidity in urban populations is unclear. OBJECTIVES: To determine if indoor pollutant exposure modifies the relationships between indoor airborne endotoxin and asthma health and morbidity. METHODS: One hundred forty-six children and adolescents with persistent asthma underwent repeated clinical assessments at 0, 3, 6, 9, and 12 months. Home visits were conducted at the same time points for assessment of airborne nicotine, endotoxin, and nitrogen dioxide (NO2) concentrations. The effect of concomitant pollutant exposure on relationships between endotoxin and asthma outcomes were examined in stratified analyses and statistical models with interaction terms. MEASUREMENTS AND MAIN RESULTS: Both air nicotine and NO2 concentrations modified the relationships between airborne endotoxin and asthma outcomes. Among children living in homes with no detectable air nicotine, higher endotoxin was inversely associated with acute visits and oral corticosteroid bursts, whereas among those in homes with detectable air nicotine, endotoxin was positively associated with these outcomes (interaction P value = 0.004 and 0.07, respectively). Among children living in homes with lower NO2 concentrations (<20 ppb), higher endotoxin was positively associated with acute visits, whereas among those living in homes with higher NO2 concentrations, endotoxin was negatively associated with acute visit (interaction P value = 0.05). NO2 also modified the effect of endotoxin on asthma symptom outcomes in a similar manner. CONCLUSIONS: The effects of household airborne endotoxin exposure on asthma are modified by coexposure to air nicotine and NO2, and these pollutants have opposite effects on the relationships between endotoxin and asthma-related outcomes.

The response of children with asthma to ambient particulate is modified by tobacco smoke exposure.

RATIONALE: Ambient particulate matter concentrations have been positively associated with urinary leukotriene E(4) (LTE(4)) levels and albuterol usage in children with asthma but interactions with environmental tobacco smoke (ETS) exposure have not been demonstrated despite obvious exposure to both pollutants in an urban setting. OBJECTIVES: To assess the health effects of concurrent ETS and ambient particulate matter exposure in children with asthma. METHODS: Albuterol usage and LTE(4) levels were monitored in 82 urban schoolchildren with asthma over three consecutive fall to spring school periods. Concentrations of morning maximum ambient particulate matter <2.5 µm in aerodynamic diameter (mmPM(2.5)) and urine cotinine levels were also measured daily. MEASUREMENTS AND MAIN RESULTS: Albuterol usage and LTE(4) were related to mmPM(2.5) concentrations on days when urine cotinine levels were low (<10 ng/ml/mg creatinine); on these days, mean albuterol usage and LTE(4) increased up to 5 or 6% per 10 µg/m(3) increase in mmPM(2.5). In contrast, no significant relationship was observed when cotinine was high, although mean albuterol usage and LTE(4) levels were greater in this case. Model fits for LTE(4) levels as a function of mmPM(2.5) concentrations were improved when mmPM(2.5) concentrations were logged, suggesting a nonlinear dose-response relationship between particulate matter exposure concentrations and airway mediators of asthma, for which the relationship tends to flatten at higher concentrations. CONCLUSIONS: This study suggests that ETS modifies the acute effects of low-level ambient PM(2.5) exposure on childhood asthma. This negative interaction, the smaller effect of particulate matter exposure in children exposed to higher ETS, may be related to a nonlinear dose-response relationship between asthma mediators and particulate exposures.

Urinary leukotriene E4 levels identify children with tobacco smoke exposure at risk for asthma exacerbation.

BACKGROUND: Children with asthma exposed to secondhand smoke (SHS) might be at higher risk for severe exacerbations, but biomarkers of susceptibility to SHS exposure have not been previously reported. OBJECTIVES: We sought to assess the usefulness of urinary leukotriene E(4) (uLTE4) levels in the prediction of increased risk of severe asthma exacerbations requiring emergency department (ED) or urgent care (UC) visits. METHODS: Forty-four schoolchildren with moderate-to-severe asthma receiving inhaled corticosteroids were followed for 5 months with repeated measurements of uLTE4 and monitoring of ED and UC visits. SHS exposure status was determined by using prestudy questionnaires and repeated measurements of urinary cotinine during the study. RESULTS: Nine (45%) of 20 children with SHS exposure experienced a severe exacerbation requiring an ED or UC visit compared with 3 (12.5%) of 24 children without significant SHS exposure (relative risk, 3.6; 95% CI, 1.1-11.5; P = .02). The uLTE4 level was a significant predictor of exacerbation risk in children exposed to SHS (area under the curve, 0.85; P = .003). Other predictors, such as nighttime symptom frequency, prebronchodilator and postbronchodilator lung function, and exhaled nitric oxide levels, were not related to exacerbations in this group. uLTE4 levels at or greater than 106 pg/mg achieved 67% (6/9) sensitivity and 100% (11/11) specificity for predicting children with SHS exposure who required an ED or UC visit. CONCLUSIONS: Children exposed to SHS are at increased risk for severe asthma exacerbations, despite use of inhaled corticosteroids. uLTE4 levels identify children exposed to SHS at high risk for asthma exacerbations.

Pearls and pitfalls of implementing LEAP strategy for peanut: A case report.

Early introduction of peanut in infants at high risk has been widely adopted and implemented in pediatric outpatient clinics since 2017. It is often overlooked that almost 2% of infants went on to develop peanut allergy despite regular consumption in a previous study. Here we described a case of anaphylaxis to peanut in a 6-month-old infant after a negative skin-prick test result, supervised introduction in the clinic, and successful home consumption, which, to our knowledge, has only previously been described once in the literature.

Environmental pollution and lung effects in children.

PURPOSE OF REVIEW: Studies over the last 2 years have added important new information on the relationship between air pollution and asthma incidence and severity. RECENT FINDINGS: Outdoor air pollution has been associated with asthma exacerbations, including emergency department visits and hospitalizations, as well as with the onset of asthma. Possible mechanisms mediating both incidence and severity effects include the induction of oxidative stress, and/or allergic sensitization, as well as increased susceptibility to viral infections. Some of these mechanisms may be occurring in utero including epigenetic changes that may increase risk for development of asthma. Factors related to increased susceptibility for air pollution-related asthma severity include age, season and genetic polymorphisms related to antioxidant enzymes. SUMMARY: Ambient pollution levels may be associated with both asthma incidence and severity. Susceptibility to air pollution may be higher in children with genetic polymorphisms related to the 'oxidant stress pathways'. Potential interventions for susceptible children at risk for asthma development and/or severity include decreased exposure on high air pollution days, especially in the summer months, and antioxidant supplementation. On the population level, changes in school and home zoning to increase distance from busy roadways may help reduce both asthma incidence and severity.

Urinary leukotriene E4/exhaled nitric oxide ratio and montelukast response in childhood asthma.

BACKGROUND: A subset of children with asthma respond better to leukotriene receptor antagonists than to inhaled corticosteroids. Information is needed to identify children with these preferential responses. OBJECTIVE: We sought to determine whether the ratio of urinary leukotriene E(4) (LTE(4)) to fractional exhaled nitric oxide (FE(NO)) delineates children with preferential responsiveness to montelukast compared with fluticasone propionate (FP) therapy. METHODS: Data from 318 children with mild-to-moderate asthma enrolled in 2 National Heart, Lung, and Blood Institute Childhood Asthma Research and Education Network studies (Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid [CLIC] and the Pediatric Asthma Controller Trial [PACT]) were analyzed. The association between LTE(4)/FE(NO) ratios at baseline and improved lung function or asthma control days (ACDs) with montelukast and FP therapy was determined, and phenotypic characteristics related to high ratios were assessed. RESULTS: LTE(4)/FE(NO) ratios were associated with a greater response to montelukast than FP therapy for FEV(1) measurements (2.1% increase per doubling of ratio, P = .001) and for ACDs per week (0.3-ACD increase, P = .009) in the CLIC study. In PACT the ratio was associated with greater ACD responsiveness to MT than FP therapy (0.6 ACD increase, P=.03) [corrected]. In a combined study analysis, LTE(4): FE(NO) ratios were associated with greater response to MT than FP therapy for FEV(1) (1.8% increase, P =.0005) and ACDs (0.4 increase, P =.001)[corrected].Children with LTE(4)/FE(NO) ratios at or above the 75th percentile were likely (P < .05) to be younger and female and exhibit lower levels of atopic markers and methacholine reactivity. CONCLUSION: LTE(4)/FE(NO) ratios predict a better response to montelukast than FP therapy in children with mild-to-moderate asthma.

A statistical model for under- or overdispersed clustered and longitudinal count data.

We propose a likelihood-based model for correlated count data that display under- or overdispersion within units (e.g. subjects). The model is capable of handling correlation due to clustering and/or serial correlation, in the presence of unbalanced, missing or unequally spaced data. A family of distributions based on birth-event processes is used to model within-subject underdispersion. A computational approach is given to overcome a parameterization difficulty with this family, and this allows use of common Markov Chain Monte Carlo software (e.g. WinBUGS) for estimation. Application of the model to daily counts of asthma inhaler use by children shows substantial within-subject underdispersion, between-subject heterogeneity and correlation due to both clustering of measurements within subjects and serial correlation of longitudinal measurements. The model provides a major improvement over Poisson longitudinal models, and diagnostics show that the model fits well.

Methylation of cysteinyl leukotriene receptor 1 genes associates with lung function in asthmatics exposed to traffic-related air pollution.

Air pollution is associated with early declines in lung function and increased levels of asthma-related cysteinyl leukotrienes (CysLT) but a biological pathway linking this rapid response has not been delineated. In this randomized controlled diesel exhaust (DE) challenge study of 16 adult asthmatics, increased exposure-attributable urinary leukotriene E4 (uLTE4, a biomarker of cysteinyl leukotriene production) was correlated (p = 0.04) with declines in forced expiratory volume in 1-second (FEV1) within 6 hours of exposure. Exposure-attributable uLTE4 increases were correlated (p = 0.02) with increased CysLT receptor 1 (CysLTR1) methylation in peripheral blood mononuclear cells which, in turn, was marginally correlated (p = 0.06) with decreased CysLTR1 expression. Decreased CysLTR1 expression was, in turn, correlated (p = 0.0007) with FEV1 declines. During the same time period, increased methylation of GPR17 (a negative regulator of CysLTR1) was observed after DE exposure (p = 0.02); this methylation increase was correlated (p = 0.001) with decreased CysLTR1 methylation which, in turn, was marginally correlated (p = 0.06) with increased CysLTR1 expression; increased CysLTR1 expression was correlated (p = 0.0007) with FEV1 increases. Collectively, these data delineate a potential mechanistic pathway linking increased DE exposure-attributable CysLT levels to lung function declines through changes in CysLTR1-related methylation and gene expression.

Health effects of concurrent ambient and tobacco smoke-derived particle exposures at low concentrations in children with asthma.

Exposure to particulate matter less than 2.5 microns from either ambient pollution (AMB-PM2.5) or secondhand smoke (SHS-PM2.5) have been associated with asthma worsening, but there is little information on effects and relative potency with concurrent exposures. We studied health effects of concurrent exposures to AMB-PM2.5 and SHS-PM2.5 over a 6-year period in schoolchildren with asthma. Regression calibration with instrumental variables (RCIV) was utilized to estimate effects of personal exposure to low-level SHS and AMB-PM2.5 on daily albuterol usage and urinary leukotriene E4 (uLTE4; a biomarker of asthma-related inflammation) using urine cotinine and concentrations from fixed and personal pollution monitors. Each IQR increase in SHS-PM2.5 exposure was associated with a 6.7% increase (95% CI: 1.0-12.8%) in uLTE4 on the same day and 9.4% increase (95% CI: -2.6 to 22.7%) in albuterol use the next day, when children were co-exposed to mean levels of AMB-PM2.5. The dose-response relationship between health outcomes and one pollutant was higher at lower levels of the other pollutant. For example, at lower levels of predicted SHS-PM2.5 exposure, increases in health outcomes per IQR increase in AMB-PM2.5 ranged between 2 and 5%, but were negligible at higher SHS-PM2.5 levels. Comparing at equivalent co-exposure levels, SHS-PM2.5 was 1.6 times more potent than AMB-PM2.5 for uLTE4 (95% CI: 1.1-2.3); estimates for albuterol usage were similar but less significant. Effects at mean co-exposure levels were closer [SHS to AMB-PM2.5 potency ratio = 1.2 (95% CI: 0.9-1.5) for uLTE4 and 1.2 (95% CI: 0.7-1.9) for albuterol usage]. In summary, concurrent exposure to relatively low levels of SHS and AMB-PM2.5 were associated with health outcomes in asthmatic schoolchildren. Dose responses varied with changes in the relative amounts of each pollutant; SHS-PM2.5 was observed to be more potent than AMB-PM2.5 when co-exposure levels were equivalent.

Exposure to tobacco smoke increases leukotriene E4-related albuterol usage and response to montelukast.

BACKGROUND: Cysteinyl leukotrienes (CysLTs) are important mediators of asthma in children. Predictors of susceptibility to CysLT effects have not been developed. OBJECTIVES: To identify susceptibility markers to CysLT effects and montelukast response. METHODS: Twenty-seven schoolchildren were followed for 5 months with measurements of urinary leukotriene E4 (LTE(4)), cotinine, fractional exhaled nitric oxide (FENO), and monitoring of albuterol use. After a baseline run-in, children were randomized to receive daily montelukast or placebo without change in their current controller medications. RESULTS: At baseline, a significant (P = .003) positive association was observed between LTE(4) levels and albuterol use 2 days later. LTE(4)-related albuterol usage (ie, change per interquartile increase in LTE(4)) declined significantly after montelukast treatment (12% decline; P = .0005 for relative difference between intervals) but not placebo (2% increase; P = .80). Declines in LTE(4)-related albuterol usage between intervals tended to be greater in girls (P = .01 for girls; P = .21 for boys; P = .07 for interaction) and were greater among children with higher cotinine levels (P = .01 for high cotinine group; P = .17 for low cotinine group; P = .04 for interaction). Children with high LTE(4) levels relative to FENO demonstrated significant (P = .05) declines in LTE(4)-related albuterol usage between intervals (P = .89 for low ratio group; P = .25 for interaction). CONCLUSION: Increased individual CysLT levels are associated with subsequent albuterol usage. CysLT-related albuterol usage and montelukast responsiveness are increased in children exposed to tobacco smoke and tend to be greater in girls than boys. Measurement of LTE(4) to FENO ratios may help predict susceptibility to montelukast.