Exhaled nitric oxide, susceptibility and new-onset asthma in the Children's Health Study.
ABSTRACT: A substantial body of evidence suggests an aetiological role of inflammation, and oxidative and nitrosative stress in asthma pathogenesis. Exhaled nitric oxide fraction (F(eNO)) may provide a noninvasive marker of oxidative and nitrosative stress, and aspects of airway inflammation. We examined whether children with elevated F(eNO) are at increased risk for new-onset asthma. We prospectively followed 2,206 asthma-free children (age 7-10 yrs) who participated in the Children's Health Study. We measured F(eNO) and followed these children for 3 yrs to ascertain incident asthma cases. Cox proportional hazard models were fitted to examine the association between F(eNO) and new-onset asthma. We found that F(eNO) was associated with increased risk of new-onset asthma. Children in the highest F(eNO) quartile had more than a two-fold increased risk of new-onset asthma compared to those with the lowest quartile (hazard ratio 2.1, 95% CI 1.3-3.5). This effect did not vary with the child's history of respiratory allergic symptoms. However, the effect of elevated F(eNO) on new-onset asthma was most apparent among those without a parental history of asthma. Our results indicate that children with elevated F(eNO) are at increased risk for new-onset asthma, especially if they have no parental history of asthma.
Project description:This study aimed to examine the separate effects of maternal and paternal history on the onset of asthma in children and evaluate the relationship between age of asthma onset in parents and risk of asthma in their children.We used data from the third National Health and Nutrition Examination Survey. We developed new continuous standardized scores for survey data to quantify parental history that incorporated both the occurrence of asthma and the age at onset, and associated these scores with asthma risk in the children. The association analysis was adjusted for sex and obesity status.Children with maternal history have elevated asthma risk (hazard ratio of 3.71, 95% CI: 1.19-11.60) than those without, and those whose mothers had earlier age of onset have increased risk of asthma compared to those whose mothers had later age of onset. On the contrary, paternal history had a relatively smaller effect that may be only detectable in larger samples (hazard ratio of 2.17, 95% CI: 0.69-6.79).Maternal asthma history was strongly associated with the onset of asthma in the second generation, and children whose mother had an earlier age of onset had an increased risk of 3.71. For an approximately 10-year decrease in mother's age at onset of asthma, the risk of asthma for the offspring increased by 1.37-fold. Using our new risk scores led to smaller standard errors and thus more precise estimates than using a binary indicator.
Project description:This study describes the clinical characteristics and corticosteroid responsiveness of children with difficult asthma (DA). We hypothesised that complete corticosteroid responsiveness (defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction (F(eNO)) and no bronchodilator responsiveness (BDR <12%)) is uncommon in paediatric DA. We report on 102 children, mean+/-sd age 11.6+/-2.8 yrs, with DA in a cross-sectional study. 89 children underwent spirometry, BDR and F(eNO) before and after 2 weeks of systemic corticosteroids (corticosteroid response study). Bronchoscopy was performed after the corticosteroid trial. Of the 102 patients in the cross-sectional study, 88 (86%) were atopic, 60 (59%) were male and 52 (51%) had additional or alternative diagnoses. Out of the 81 patients in the corticosteroid response study, nine (11%) were complete responders. Of the 75 patients with symptom data available, 37 (49%) responded symptomatically, which was less likely if there were smokers in the home (OR 0.31, 95% CI 0.02-0.82). Of the 75 patients with available spirometry data, 35 (46%) had normal spirometry, with associations being BAL eosinophilia (OR 5.43, 95% CI 1.13-26.07) and high baseline forced expiratory volume in 1 s (FEV(1)) (OR 1.08, 95% CI 1.02-1.12). Of these 75 patients, BDR data were available in 64, of whom 36 (56%) had <12% BDR. F(eNO) data was available in 70 patients, of whom 53 (75%) had normal F(eNO). Airflow limitation data was available in 75 patients, of whom 17 (26%) had persistent airflow limitation, which was associated with low baseline FEV(1) (OR 0.93, 95% CI 0.90-0.97). Only 11% of DA children exhibited complete corticosteroid responsiveness. The rarity of complete corticosteroid responsiveness suggests alternative therapies are needed for children with DA.
Project description:There has been no longitudinal study of the relation between concurrent exposure to dust mite allergen and endotoxin in early life and asthma and atopy at school age.To examine the relation between exposure to dust mite allergen and endotoxin at age 2 to 3 months and asthma, wheeze, and atopy in high-risk children.Birth cohort study of 440 children with parental history of atopy in the Boston metropolitan area.In multivariate analyses, early exposure to high levels of dust mite allergen (> or =10 microg/g) was associated with increased risks of asthma at age 7 years (odds ratio [OR], 3.0; 95% CI, 1.1-7.9) and late-onset wheeze (OR, 5.0; 95% CI, 1.5-16.4). Exposure to endotoxin levels above the lowest quartile at age 2 to 3 months was associated with reduced odds of atopy at school age (OR, 0.5; 95% CI, 0.2-0.9). In contrast with its inverse association with atopy, endotoxin exposure in early life was associated with an increased risk of any wheeze between ages 1 and 7 years that did not change significantly with time (hazard ratio for each quartile increment in endotoxin levels, 1.23; 95% CI, 1.07-1.43).Among children at risk of atopy, early exposure to high levels of dust mite allergen is associated with increased risks of asthma and late-onset wheeze. In these children, endotoxin exposure is associated with a reduced risk of atopy but an increased risk of wheeze.Early endotoxin exposure may be a protective factor against atopy but a risk factor for wheeze in high-risk children.
Project description:OBJECTIVE:HIV disrupts host defense mechanisms and maintains chronic inflammation in the lung. Nitric oxide is a marker of lung inflammation and can be measured in the exhaled air. We investigated the relationship between exhaled nitric oxide (eNO), HIV status and airway abnormalities in perinatally HIV-infected children aged 6-19 years. DESIGN:A cross-sectional study. METHODS:HIV-infected individuals on antiretroviral therapy and HIV-uninfected children with no active tuberculosis (TB) or acute respiratory tract infection were recruited from a public hospital in Harare, Zimbabwe. Clinical history was collected and eNO testing and spirometry was performed. The association between eNO and explanatory variables (HIV, FEV1 z-score, CD4 cell count, viral load, history of TB) was investigated using linear regression analysis adjusted for age, sex and time of eNO testing. RESULTS:In total, 222 HIV-infected and 97 HIV-uninfected participants were included. Among HIV-infected participants, 57 (25.7%) had a history of past TB; 56 (25.2%) had airway obstruction, but no prior TB. HIV status was associated with lower eNO level [mean ratio 0.79 (95% confidence interval, 95% CI 0.65-0.97), P?=?0.03]. Within the HIV-infected group, history of past TB was associated with lower eNO levels after controlling for age, sex and time of eNO testing [0.79 (95% CI 0.67-0.94), P?=?0.007]. CONCLUSION:HIV infection and history of TB were associated with lower eNO levels. eNO levels may be a marker of HIV and TB-induced alteration in pulmonary physiology; further studies focused on potential causes for lower eNO levels in HIV and TB are warranted.
Project description:Background:The aim of this study was to identify patients who benefit most from exhaled nitric oxide fraction (F ENO)-driven asthma management in primary care, based on prespecified subgroups with different levels of F ENO. Methods:We used data from 179 adults with asthma from a 12-month primary care randomised controlled trial with 3-monthly assessments of F ENO, asthma control, medication usage, costs of medication, severe asthma exacerbations and quality of life. In the original study, patients were randomised to either a symptom-driven treatment strategy (controlled asthma (Ca) strategy) or a F ENO+symptom-driven strategy (FCa). In both groups, patients were categorised by their baseline level of F ENO as low (<25?ppb), intermediate (25-50?ppb) and high (>50?ppb). At 12 months, we compared, for each prespecified F ENO subgroup, asthma control, asthma-related quality of life, medication usage, and costs of medication between the Ca and FCa strategy. Results:We found a difference between the Ca and FCa strategy for the mean dosage of beclomethasone strategy of 223 µg (95% CI 6-439), p=0.04) and for the total costs of asthma medication a mean reduction of US$159 (95% CI US$33-285), p=0.03) in patients with a low baseline F ENO level. No differences were found for asthma control, severe asthma exacerbations and asthma-related quality of life in patients with a low baseline F ENO level. Furthermore, in patients with intermediate or high level of F ENO, no differences were found. Conclusions:In primary care, F ENO-driven asthma management is effective in patients with a low F ENO level, for whom it is possible to down-titrate medication, while preserving asthma control and quality of life.
Project description:Asthma is a growing public health problem in developing countries. However, few studies have studied the role of urbanisation in this phenomenon. It was hypothesised that children living in a peri-urban setting in Peru have higher rates of asthma and allergy than rural counterparts.1441 adolescents aged 13-15 years were enrolled from two settings: a peri-urban shanty town in Lima (n = 725) and 23 rural villages in Tumbes (n = 716). Participants filled in questionnaires on asthma and allergy symptoms, environmental exposures and sociodemographics, and underwent spirometry, and exhaled nitric oxide (eNO) and allergy skin testing. Indoor particulate matter (PM) concentrations were measured in 170 households.Lima adolescents had higher rates of lifetime wheezing (22% vs 10%), current asthma symptoms (12% vs 3%) and physician-diagnosed asthma (13% vs 2%; all p <0.001). Current rhinitis (23% vs 12%), eczema (12% vs 0.4%), atopy (56% vs 38%), personal history of cigarette smoking (7.4% vs 1.3%) and mean indoor PM (31 vs 13 ?g/m(3)) were also higher in Lima (all p < 0.001). The peri-urban environment of Lima was associated with a 2.6-fold greater odds (95% CI 1.3 to 5.3) of asthma in multivariable regression. Forced expiratory volumes were higher and FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) ratios were lower in Lima (all p < 0.001). Higher eNO values in Lima (p < 0.001) were attributable to higher rates of asthma and atopy.Peri-urban adolescents had more asthma, atopy and airways inflammation and were exposed to more indoor pollution. The findings provide evidence of the risks posed to lung health by peri-urban environments in developing countries.
Project description:Although involuntary exposure to maternal smoking during the in utero period and to secondhand smoke are associated with occurrence of childhood asthma, few studies have investigated the role of active cigarette smoking on asthma onset during adolescence.To determine whether regular smoking is associated with the new onset of asthma during adolescence.We conducted a prospective cohort study among 2,609 children with no lifetime history of asthma or wheezing who were recruited from fourth- and seventh-grade classrooms and followed annually in schools in 12 southern California communities. Regular smoking was defined as smoking at least seven cigarettes per day on average over the week before and 300 cigarettes in the year before each annual interview. Incident asthma was defined using new cases of physician-diagnosed asthma.Regular smoking was associated with increased risk of new-onset asthma. Children who reported smoking 300 or more cigarettes per year had a relative risk (RR) of 3.9 (95% confidence interval [95% CI], 1.7-8.5) for new-onset asthma compared with nonsmokers. The increased risk from regular smoking was greater in nonallergic than in allergic children. Regular smokers who were exposed to maternal smoking during gestation had the largest risk from active smoking (RR, 8.8; 95% CI, 3.2-24.0).Regular smoking increased risk for asthma among adolescents, especially for nonallergic adolescents and those exposed to maternal smoking during the in utero period.
Project description:BACKGROUND:Infancy is a developmental stage with heightened susceptibility to environmental influences on the risk of chronic childhood disease. Few birth cohort studies have detailed measures of fungal diversity data in infants' bedrooms, limiting the potential to measure long-term associations of these complex exposures with development of asthma or allergy. OBJECTIVE:We evaluated the relation of home fungal levels in infancy to repeated measures of wheeze and development of asthma and rhinitis by age 13, and sensitization by age 12 years. METHODS:In the Epidemiology of Home Allergens and Asthma prospective birth cohort study, we recruited 408 children with family history of allergic disease or asthma. When children were aged 2-3 months, we measured culturable fungi in bedroom air and dust, and in outdoor air. Main outcomes included ascertainment of symptoms/disease onset by questionnaire from birth through age 13. We estimated hazard ratios and, for wheeze and sensitization, odds ratios for an interquartile increase in log-transformed fungal concentrations, adjusting for other outcome predictors and potential confounders. RESULTS:Elevated levels of yeasts in bedroom floor dust were associated with reduced: i) wheeze at any age; ii) fungal sensitization; and iii) asthma development by age 13 (hazard ratio (HR) = 0.86; 95% confidence interval (CI), [0.75 to 0.98]). Outdoor airborne Cladosporium and dustborne Aspergillus predicted increased rhinitis. Risk of fungal sensitization by age 12, in response to environmental Alternaria and Aspergillus, was elevated in children with a maternal history of fungal sensitization. CONCLUSIONS AND CLINICAL RELEVANCE:Despite the irritant and allergenic properties of fungi, early-life elevated dust yeast exposures or their components may be protective against allergy and asthma in children at risk for these outcomes. Ascertainment of fungal components associated with immunoprotective effects may have therapeutic relevance for asthma.
Project description:We assessed the effect of daily variations in ambient air pollutants on exhaled nitric oxide fraction (F(eNO)) using data from a cohort of school children with large differences in air pollutant exposures from the Children's Health Study. Based on a cohort of 2,240 school children from 13 Southern Californian communities, cumulative lagged average regression models were fitted to determine the association between F(eNO) and ambient air pollution levels from central site monitors with lags of up to 30 days prior to F(eNO) testing. Daily 24-h cumulative lagged averages of particles with a 50% cut-off aerodynamic diameter of 2.5 µm (PM?.?; over 1-8 days) and particles with a 50% cut-off aerodynamic diameter of 10 µm (PM??; over 1-7 days), as well as 10:00-18:00 h cumulative lagged average of O? (over 1-23 days) were significantly associated with 17.42% (p<0.01), 9.25% (p<0.05) and 14.25% (p<0.01) higher F(eNO) levels over the interquartile range of 7.5 ?g·m?³, 12.97 ?g·m?³ and 15.42 ppb, respectively. The effects of PM?.?, PM?? and O? were higher in the warm season. The particulate matter effects were robust to adjustments for effects of O? and temperature and did not vary by asthma or allergy status. In summary, short-term increases in PM?.?, PM?? and O? were associated with airway inflammation independent of asthma and allergy status, with PM?? effects significantly higher in the warm season.
Project description:BACKGROUND: Because of shifts in the gender ratio and incidence and remission rates of asthma during the teen ages, the methodology of incidence studies among teenagers is important, i.e. if the time intervals between surveys are too long, the incident cases might not be properly identified. The aim was to study the impact of study design on the incidence rates of asthma and wheeze during the teen ages. METHODS: In a study about asthma and allergic diseases within the OLIN studies (Obstructive Lung Disease in northern Sweden), a cohort of school children (n = 3,430) was followed annually by questionnaire from age 8 yrs. In the endpoint survey (age 18 yrs) 2,582 (75% of original responders) participated. Incident cases from age 12-18 yrs were identified by two methods: annual questionnaire reports (AR) and baseline-endpoint surveys only (BE). RESULTS: The cumulative incidence of asthma and wheeze was significantly higher based on AR compared to BE. Compared to the incidence rates based on all the annual surveys, the calculated average annual rates based on BE were in general lower both among the boys and among the girls. There were no differences between boys and girls in incidence rates of asthma or wheeze during the early teen years. However, from the age of 15 years, the annual incidence rates were significantly or borderline significantly higher among girls than boys. At onset, the additional cases of current asthma identified by AR had significantly less severe asthma than those identified in BE (p < 0.02). CONCLUSION: the size of the incidence of asthma and wheeze during the teen ages was influenced by study design. By using the conventional prospective study design with longer follow-up time, the incidence was underestimated.