Nathan Rabinovitch

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.

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.

Effect of budesonide aqueous nasal spray on hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis

BACKGROUND Intranasal corticosteroids are safe and effective for treating allergic rhinitis in adults. Since children may receive more systemic corticosteroid on a dose-per-weight basis than adults, the safety of corticosteroid therapy in pediatric patients is an important issue. OBJECTIVE To determine the effects of treatment with budesonide aqueous nasal spray using the recommended once-daily dose for adults and children 6 years and older on hypothalamic-pituitary-adrenal (HPA) axis function in pediatric patients with allergic rhinitis. METHODS In a 6-week, multicenter, double-blind, placebo-controlled study, 78 patients aged 2 to 5 years with allergic rhinitis were treated with budesonide aqueous nasal spray (64 microg/d) or placebo. Mean change in morning plasma cortisol levels from baseline to study end 0, 30, and 60 minutes after low-dose (10-microg) cosyntropin stimulation and mean change in the difference from 0 to 30 minutes and from 0 to 60 minutes after cosyntropin stimulation were used to evaluate HPA axis function. RESULTS Mean change from baseline to study end in plasma cortisol levels 0, 30, and 60 minutes after cosyntropin stimulation and the difference from 0 to 30 minutes and from 0 to 60 minutes were not significantly different between the treatment and placebo groups (P > .05 for all). At the end of the study, 3 budesonide aqueous nasal spray and 6 placebo patients were classified as having subnormal HPA axis function. The safety and tolerability profile of budesonide aqueous nasal spray was comparable to that of placebo. CONCLUSIONS Administration of budesonide aqueous nasal spray for 6 weeks was well tolerated and safe and had no measurable suppressive effects on HPA axis function in patients aged 2 to 5 years with allergic rhinitis.

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.

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.

Estimating effects of ambient PM2.5 exposure on health using PM2.5 component measurements and regression calibration

Most air pollution and health studies conducted in recent years have examined how a health outcome is related to pollution concentrations from a fixed outdoor monitor. The pollutant effect estimate in the health model used indicates how ambient pollution concentrations are associated with the health outcome, but not how actual exposure to ambient pollution is related to health. In this article, we propose a method of estimating personal exposures to ambient PM2.5 (particulate matter less than 2.5 μm in diameter) using sulfate, a component of PM2.5 that is derived primarily from ambient sources. We demonstrate how to use regression calibration in conjunction with these derived values to estimate the effects of personal ambient PM2.5 exposure on a continuous health outcome, forced expiratory volume in 1 s (FEV1), using repeated measures data. Through simulation, we show that a confidence interval (CI) for the calibrated estimator based on large sample theory methods has an appropriate coverage rate. In an application using data from our health study involving children with moderate to severe asthma, we found that a 10 μg/m3 increase in PM2.5 was associated with a 2.2% decrease in FEV1 at a 1-day lag of the pollutant (95% CI: 0.0–4.3% decrease). Regressing FEV1 directly on ambient PM2.5 concentrations from a fixed monitor yielded a much weaker estimate of 1.0% (95% CI: 0.0–2.0% decrease). Relatively small amounts of personal monitor data were needed to calibrate the estimate based on fixed outdoor concentrations.

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.

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 β₂-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.

Leukotriene-E4 in human urine: Comparison of on-line purification and liquid chromatography-tandem mass spectrometry to affinity purification followed by enzyme immunoassay

A new analytical method suitable for high throughput measurements of LTE(4) in human urine is described. The methodology utilizes on-line enrichment and liquid chromatography/tandem mass spectrometry (LC/MS/MS). The novel LC/MS/MS method is rapid, linear from 5 to 500pg/ml in spiked urine samples of both healthy and asthmatic subjects and more accurate and precise than enzyme immunoassay (EIA) and previous LC/MS/MS methods. Results from sample integrity experiments and preliminary values of urinary LTE(4) from healthy adults and children are reported.

Expression of Functional Activating and Inhibitory Fcγ Receptors on Human B Cells

Background: The CD32 (FcγII) receptor is involved in the regulation of the B cell response to antigen. The sole Fc receptor demonstrated in mice is the inhibitory FcγIIB receptor. Crosslinking this receptor does not lead to downstream signaling or cell activation. Instead, when immune complexes bind to Fcy on murine B cells, cell activation through the B cell antigen receptor is attenuated. The objective of this study was to evaluate the expression of the FcγII receptor and the response to immune complex stimulation in human B cells. Methods: Human lymphoblastoid, peripheral and tonsillar B cells were stained with anti-CD32 antibodies IV.3 and 8.26 to determine the relative expression of the activating (FcγIIA) and inhibitory (FcγIIB) isoforms of CD32. Tetanus immune complexes were added to B cells and the activation of c-Jun amino-terminal kinase was assayed. Results: Unlike murine cells, human B cells express high levels of the activating form of the Fcγ receptor IIA. Addition of immune complexes to peripheral B cells resulted in signaling of Jun kinase, an important downstream kinase involved in the regulation of B cell function. The level of expression of FcγIIA on human B cells was not uniform, but depended on activation status. Peripheral blood B cells expressed high levels of FcγIIA, while tonsillar B cells predominantly expressed FcγIIB. Furthermore, when peripheral B cells were activated, the expression of FcγIIA relative to FcγIIB decreased. Conclusion: The response of human B cells to binding of immune complexes depends on the relative expression of activating (FcγIIA) versus inhibitory (FcγIIB) receptors.