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2.  Lung Clearance Index as an Outcome Measure for Clinical Trials in Young Children with Cystic Fibrosis. A Pilot Study Using Inhaled Hypertonic Saline 
Rationale: Lung clearance index (LCI), measured by multiple breath washout (MBW), is a noninvasive measure of ventilation inhomogeneity that holds promise as an objective physiologic endpoint for clinical trials in infants and preschool children with cystic fibrosis (CF).
Objectives: To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers.
Methods: The Infant Study of Inhaled Saline trial was a multicenter, randomized, controlled trial of hypertonic (7%) versus isotonic (0.9%) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age. LCI measurements were performed in a single-center pilot substudy at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas. LCI measurements were standardized using published normative data (zLCI) to account for height-related changes in LCI during early childhood. A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect.
Measurements and Main Results: A total of 27 participants were randomized; 25 participants, aged (median [range]) 2.6 (0.34–4.95) years, had acceptable baseline and follow-up LCI measures. On average, LCI decreased in the hypertonic saline group (n = 12) by 1.19 z-scores units (95% confidence interval [CI] = −2.46 to 0.06), and remained stable in the isotonic saline group (n = 13) at 0.81 (95% CI = −0.40 to 2.02). A significant treatment effect was observed for zLCI (2.01; 95% CI = 0.26 to 3.76; P = 0.025).
Conclusions: MBW testing is feasible in an interventional study in infants and preschool children with CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies.
Clinical trial registered with (NCT00709280).
PMCID: PMC3778738  PMID: 23742699
cystic fibrosis; lung clearance index; infant; hypertonic saline; preschool child
3.  Asymmetric Dimethylarginine in Chronic Obstructive Pulmonary Disease (ADMA in COPD) 
l-Arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in l-arginine metabolism, contributes to airways obstruction in asthma and cystic fibrosis. Herein, we assessed l-arginine metabolism in airways of patients with chronic obstructive pulmonary disease (COPD). Lung function testing, measurement of fractional exhaled NO (FeNO) and sputum NO metabolites, as well as quantification of l-arginine metabolites (l-arginine, l-ornithine, l-citrulline, ADMA and symmetric dimethylarginine) using liquid chromatography-mass spectrometry (LC-MS) were performed. Concentrations of l-ornithine, the product of arginase activity, correlated directly with l-arginine and ADMA sputum concentrations. FeNO correlated directly with pre- and post-bronchodilator forced expiratory volume in one second (FEV1). Sputum arginase activity correlated inversely with total NO metabolite (NOx) and nitrite concentrations in sputum, and with pre- and post-bronchodilator FEV1. These findings suggest that ADMA in COPD airways results in a functionally relevant shift of l-arginine breakdown by the NO synthases towards the arginase pathway, which contributes to airway obstruction in these patients.
PMCID: PMC4013615  PMID: 24727374
arginine metabolism; nitric oxide; asymmetric dimethylarginine; arginase; pulmonary function; airway obstruction; l-ornithine
6.  A new exposure metric for traffic-related air pollution? An analysis of determinants of hopanes in settled indoor house dust 
Environmental Health  2013;12:48.
Exposure to traffic-related air pollution (TRAP) can adversely impact health but epidemiologic studies are limited in their abilities to assess long-term exposures and incorporate variability in indoor pollutant infiltration.
In order to examine settled house dust levels of hopanes, engine lubricating oil byproducts found in vehicle exhaust, as a novel TRAP exposure measure, dust samples were collected from 171 homes in five Canadian cities and analyzed by gas chromatography–mass spectrometry. To evaluate source contributions, the relative abundance of the highest concentration hopane monomer in house dust was compared to that in outdoor air. Geographic variables related to TRAP emissions and outdoor NO2 concentrations from city-specific TRAP land use regression (LUR) models were calculated at each georeferenced residence location and assessed as predictors of variability in dust hopanes.
Hopanes relative abundance in house dust and ambient air were significantly correlated (Pearson’s r=0.48, p<0.05), suggesting that dust hopanes likely result from traffic emissions. The proportion of variance in dust hopanes concentrations explained by LUR NO2 was less than 10% in Vancouver, Winnipeg and Toronto while the correlations in Edmonton and Windsor explained 20 to 40% of the variance. Modeling with household factors such as air conditioning and shoe removal along with geographic predictors related to TRAP generally increased the proportion of explained variability (10-80%) in measured indoor hopanes dust levels.
Hopanes can consistently be detected in house dust and may be a useful tracer of TRAP exposure if determinants of their spatiotemporal variability are well-characterized, and when home-specific factors are considered.
PMCID: PMC3711892  PMID: 23782977
Air pollution; Dust; Exposure assessment; Hopanes; Land use regression; Traffic
7.  Bronchodilator Responsiveness in Wheezy Infants and Toddlers is Not Associated with Asthma Risk Factors 
Pediatric Pulmonology  2011;47(5):421-428.
There are limited data assessing bronchodilator responsiveness (BDR) in infants and toddlers with recurrent wheezing, and factors associated with a positive response.
In a multicenter study of children ≤ 36 months old we assessed the prevalence of and factors associated with BDR among infants/toddlers with recurrent episodes of wheezing.
Forced expiratory flows and volumes using the raised-volume rapid thoracic compression method were measured in 76 infants/toddlers (mean (sd) age 16.8 (7.6) mos.) with recurrent wheezing before and after administration of albuterol. Prior history of hospitalization or emergency department treatment for wheezing, use of inhaled or systemic corticosteroids, physician treatment of eczema, environmental tobacco smoke exposure, and family history of asthma or allergic rhinitis were ascertained.
Using the published upper limit of normal for post bronchodilator change (FEV0.5 ≥ 13% and/or FEF25–75 ≥ 24%) in healthy infants, 24% (n=18) of children in our study exhibited BDR. The BDR response was not associated with any clinical factor other than body size. Dichotomizing subjects into responders (defined by published limits of normal)or by quartile to identify children with the greatest change from baseline (4th quartile vs. other) did not identify any other factor associated with BDR.
Approximately one quarter of infants/toddlers with recurrent wheezing exhibited BDR at their clinical baseline. However, BDR in wheezy infants/toddlers was not associated with established clinical asthma risk factors.
PMCID: PMC3325342  PMID: 22006677
recurrent wheezing; infants; pulmonary function; raised-volume rapid thoracoabdominal compression; bronchodilator responsiveness; asthma
8.  Multiple Breath Nitrogen Washout: A Feasible Alternative to Mass Spectrometry 
PLoS ONE  2013;8(2):e56868.
The lung clearance index (LCI), measured by multiple breath washout (MBW), reflects global ventilation inhomogeneity and is a sensitive marker of early cystic fibrosis (CF) lung disease. Current evidence is based on a customized mass spectrometry system that uses sulfur hexafluoride (SF6) as a tracer gas, which is not widely available. Nitrogen (N2) washout may be better suited for clinical use and multi-center trials.
To compare the results obtained from a N2 washout system to those generated by the SF6 based system in healthy children and children with CF.
Children with CF were recruited from outpatient clinics; healthy children were recruited from the Research4Kids online portal. Participants performed MBWSF6 (Amis 2000, Innovision, Denmark) and MBWN2 (ExhalyzerD, EcoMedics, Switzerland) in triplicate, in random order on the same day. Agreement between systems was assessed by Bland-Altman plot.
Sixty-two healthy and 61 children with CF completed measurements on both systems. In health there was good agreement between systems (limits of agreement −0.7 to 1.9); on average N2 produced higher values of LCI (mean difference 0.58 (95% CI 0.42 to 0.74)). In CF the difference between systems was double that in health with a clear bias towards disproportionately higher LCIN2 compared to LCISF6 at higher mean values of LCI.
LCIN2 and LCISF6 have similar discriminative power and intra-session repeatability but are not interchangeable. MBWN2 offers a valid new tool to investigate early obstructive lung disease in CF, but requires independent normative values.
PMCID: PMC3574055  PMID: 23457632
9.  A retrospective cross-sectional study of risk factors and clinical spectrum of children admitted to hospital with pandemic H1N1 influenza as compared to influenza A 
BMJ Open  2012;2(2):e000310.
To compare risk factors for severe disease as measured by admission to hospital and intensive care unit (ICU) and other clinical outcomes in children with pandemic H1N1 (pH1N1) versus those with seasonal influenza.
Retrospective analysis of children admitted to hospital with pH1N1 versus seasonal influenza A.
Canadian tertiary referral children's hospital.
All laboratory-identified cases of pH1N1 in children younger than 18 years admitted to hospital in 2009 (n=176) and all seasonal influenza A cases admitted to hospital from influenza seasons 2004–2005 to 2008–2009 (n=200). Children with onset of symptoms more than 3 days after admission were excluded.
Primary and secondary outcome measures
Primary outcomes include admission to hospital and ICU and need for mechanical ventilation. Secondary outcomes include length of stay in hospital and duration of supplemental oxygen requirement.
Children admitted with pH1N1 were older than seasonal influenza A admissions (hospital admission: 6.5 vs 3.3 years, p<0.01; ICU admission: 7.3 vs 3.6 years, p=0.02). Children hospitalised with pH1N1 were more likely to have a pre-existing diagnosis of asthma (15% vs 5%, p<0.01); however, there was no difference in the severity of pre-existing asthma between the two groups. After controlling for obesity, asthma (OR 4.59, 95% CI 1.42 to 14.81) and age ≥5 years (OR 2.87, 95% CI 1.60 to 5.16) were more common risk factors in admitted children with pH1N1. Asthma was a significant predictor of the need for intensive care in patients with pH1N1 (OR 4.56, 95% CI 1.16 to 17.89) but not in patients with seasonal influenza A.
While most pH1N1 cases presented with classic influenza-like symptoms, risk factors for severe pH1N1 disease differed from seasonal influenza A. Older age and asthma were associated with increased admission to hospital and ICU for children with pH1N1.
Article summary
Article focus
Young age and underlying medical conditions have traditionally been considered risk factors for severe influenza in children.
Children admitted with pH1N1 influenza are more likely to have asthma; however, the impact of asthma severity is unknown.
Key messages
The presence of asthma and increased age, but not severity of asthma, were more common risk factors for hospitalisation with severe H1N1 influenza than with seasonal influenza A.
These results suggest that in future pandemics, certain high-risk groups may be more adversely affected than expected with seasonal influenza.
Treatment of pH1N1 influenza with oseltamivir did not appear to be associated with differing outcomes or severity of disease.
Strengths and limitations of this study
The strength of this study is that it compares a large number of children admitted with microbiologically confirmed pH1N1 to those admitted over 5 years with seasonal influenza A. For each admitted child with suspected asthma, at least two physicians reviewed the case to confirm a diagnosis of pre-existing asthma and to grade the asthma as mild, moderate or severe.
The main limitations of this study include its retrospective design, single-centre site, the inability to calculate population-based rates and that the number of admitted patients with asthma, particularly to ICU, was small.
PMCID: PMC3307038  PMID: 22411932
10.  Asthma: epidemiology, etiology and risk factors 
PMCID: PMC2764772  PMID: 19752106

Results 1-11 (11)