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

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          Abstract

          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 20 th, 50 th and 80 th 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 20 th, 50 th and 80 th 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.

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          Most cited references22

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          Traffic, Susceptibility, and Childhood Asthma

          Results from studies of traffic and childhood asthma have been inconsistent, but there has been little systematic evaluation of susceptible subgroups. In this study, we examined the relationship of local traffic-related exposure and asthma and wheeze in southern California school children (5–7 years of age). Lifetime history of doctor-diagnosed asthma and prevalent asthma and wheeze were evaluated by questionnaire. Parental history of asthma and child’s history of allergic symptoms, sex, and early-life exposure (residence at the same home since 2 years of age) were examined as susceptibility factors. Residential exposure was assessed by proximity to a major road and by modeling exposure to local traffic-related pollutants. Residence within 75 m of a major road was associated with an increased risk of lifetime asthma [odds ratio (OR) = 1.29; 95% confidence interval (CI), 1.01–1.86], prevalent asthma (OR = 1.50; 95% CI, 1.16–1.95), and wheeze (OR = 1.40; 95% CI, 1.09–1.78). Susceptibility increased in long-term residents with no parental history of asthma for lifetime asthma (OR = 1.85; 95% CI, 1.11–3.09), prevalent asthma (OR = 2.46; 95% CI, 0.48–4.09), and recent wheeze (OR = 2.74; 95% CI, 1.71–4.39). The higher risk of asthma near a major road decreased to background rates at 150–200 m from the road. In children with a parental history of asthma and in children moving to the residence after 2 years of age, there was no increased risk associated with exposure. Effect of residential proximity to roadways was also larger in girls. A similar pattern of effects was observed with traffic-modeled exposure. These results indicate that residence near a major road is associated with asthma. The reason for larger effects in those with no parental history of asthma merits further investigation.
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            Global map of the prevalence of symptoms of rhinoconjunctivitis in children: The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three.

            Phase One of the International Study of Asthma and Allergies in Childhood (ISAAC) measured the global patterns of prevalence and severity of symptoms of rhinoconjunctivitis in children in 1993-1997. International Study of Asthma and Allergies in Childhood Phase Three was a cross-sectional survey performed 5-10 years after Phase One using the same methodology. Phase Three covered all of the major regions of the world and involved 1 059 053 children of 2 age groups from 236 centres in 98 countries. The average overall prevalence of current rhinoconjunctivitis symptoms was 14.6% for the 13- to 14-year old children (range 1.0-45%). Variation in the prevalence of severe rhinoconjunctivitis symptoms was observed between centres (range 0.0-5.1%) and regions (range 0.4% in western Europe to 2.3% in Africa), with the highest prevalence being observed mainly in the centres from middle and low income countries, particularly in Africa and Latin America. Co-morbidity with asthma and eczema varied from 1.6% in the Indian sub-continent to 4.7% in North America. For 6- to 7-year old children, the average prevalence of rhinoconjunctivitis symptoms was 8.5%, and large variations in symptom prevalence were also observed between regions, countries and centres. Wide global variations exist in the prevalence of current rhinoconjunctivitis symptoms, being higher in high vs low income countries, but the prevalence of severe symptoms was greater in less affluent countries. Co-morbidity with asthma is high particularly in Africa, North America and Oceania. This global map of symptom prevalence is of clinical importance for health professionals.
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              Use of exhaled nitric oxide measurements to guide treatment in chronic asthma.

              International guidelines for the treatment of asthma recommend adjusting the dose of inhaled corticosteroids on the basis of symptoms, bronchodilator requirements, and the results of pulmonary-function tests. Measurements of the fraction of exhaled nitric oxide (FE(NO)) constitute a noninvasive marker that may be a useful alternative for the adjustment of inhaled-corticosteroid treatment. In a single-blind, placebo-controlled trial, we randomly assigned 97 patients with asthma who had been regularly receiving treatment with inhaled corticosteroids to have their corticosteroid dose adjusted, in a stepwise fashion, on the basis of either FE(NO) measurements or an algorithm based on conventional guidelines. After the optimal dose was determined (phase 1), patients were followed up for 12 months (phase 2). The primary outcome was the frequency of exacerbations of asthma; the secondary outcome was the mean daily dose of inhaled corticosteroid. Forty-six patients in the FE(NO) group and 48 in the group whose asthma was treated according to conventional guidelines (the control group) completed the study. The final mean daily doses of fluticasone, the inhaled corticosteroid that was used, were 370 microg per day for the FE(NO) group (95 percent confidence interval, 263 to 477) and 641 microg per day for the control group (95 percent confidence interval, 526 to 756; P=0.003), a difference of 270 microg per day (95 percent confidence interval, 112 to 430). The rates of exacerbation were 0.49 episode per patient per year in the FE(NO) group (95 percent confidence interval, 0.20 to 0.78) and 0.90 in the control group (95 percent confidence interval, 0.31 to 1.49), representing a nonsignificant reduction of 45.6 percent (95 percent confidence interval for mean difference, -78.6 percent to 54.5 percent) in the FE(NO) group. There were no significant differences in other markers of asthma control, use of oral prednisone, pulmonary function, or levels of airway inflammation (sputum eosinophils). With the use of FE(NO) measurements, maintenance doses of inhaled corticosteroids may be significantly reduced without compromising asthma control. Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 July 2015
                2015
                : 10
                : 7
                : e0130505
                Affiliations
                [1 ]Department of Internal Medicine, University of Utah, Salt Lake City, Utah, United States of America
                [2 ]Department of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, United States of America
                [3 ]Veteran Affairs Salt Lake City Health Care System, Salt Lake City, Utah, United States of America
                [4 ]Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America
                [5 ]Department of Psychiatry, Kern Medical Center, Bakersfield, California, United States of America
                University of Athens, GREECE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: KB FDG. Analyzed the data: YZ. Contributed reagents/materials/analysis tools: YZ. Wrote the paper: YZ KB SPE MTS WSL EBR TMB FDG.

                Article
                PONE-D-14-55433
                10.1371/journal.pone.0130505
                4516246
                26214692
                e06aae80-841b-419b-a194-a53f61ae4649
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 19 December 2014
                : 12 March 2015
                Page count
                Figures: 4, Tables: 3, Pages: 13
                Funding
                This work was supported by the National Heart, Lung and Blood Institute (grants 5R01HL61768 and 5R01HL76647); the Southern California Environmental Health Sciences Center (grant 5P30ES007048) funded by the National Institute of Environmental Health Sciences; the Children’s Environmental Health Center (grants 5P01ES009581, R826708-01 and RD831861-01) funded by the National Institute of Environmental Health Sciences and the Environmental Protection Agency; the National Institute of Environmental Health Sciences (grants 5P01ES011627, 1K22ES022987 and R01ES023262); the James H. Zumberge Research and Innovation Fund, and the Hastings Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                Due to ethical and legal restrictions, the raw data underlying this paper cannot be freely available in the public domain. The de-identified data from the Southern California Children Health Study is available to interested researchers upon request, pending ethical approval. Investigators who wish to access the data will be required to submit a brief research protocol, which will be reviewed by the Children’s Health Study Health Data Release Committee and the USC IRB. Recipients must agree to security policies. Please send requests to access this dataset to the corresponding author, Dr. Yue Zhang ( zhang.yue@ 123456hsc.utah.edu ).

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