Christene R. McLachlan

Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship

Exhaled nitric oxide (eNO) is an easily measured marker of airway inflammation. This study was undertaken to evaluate the usefulness of serial eNO in investigating the dose-response relationship for inhaled beclomethasone (BDP), and to compare eNO with other markers of airway inflammation. Following withdrawal of inhaled corticosteroid (ICS) therapy, 65 patients entered a double-blind, parallel-group, placebo-controlled trial of 50, 100, 200 or 500 µg·BDP·day−1 for eight weeks. eNO and spirometry were performed weekly and a hypertonic saline challenge with sputum induction was performed at the beginning and end of treatment. The relationship between the dose of ICS and changes in eNO and forced expiratory volume in one second (FEV1) was linear at 1 week and at the end of treatment. A linear dose-response relationship was also seen for sputum eosinophils. Changes in eNO correlated significantly with changes in sputum eosinophils. Changes in the provocative dose of saline causing a 15% fall in FEV1 saline did not differ across the treatment groups nor did they correlate with changes in other measurements. Exhaled nitric oxide may be used to assess the dose-response relationship for the anti-inflammatory effects of inhaled beclomethasone. The relationship found in this study was linear over the dose range 0–500 µg·day−1 soon after commencing therapy and continued over time.

Effects of cannabis on lung function: a population-based cohort study

The effects of cannabis on lung function remain unclear and may be different from those of tobacco. We compared the associations between use of these substances and lung function in a population-based cohort (n = 1,037). Cannabis and tobacco use were reported at ages 18, 21, 26 and 32 yrs. Spirometry, plethysmography and carbon monoxide transfer factor were measured at 32 yrs. Associations between lung function and exposure to each substance were adjusted for exposure to the other substance. Cumulative cannabis use was associated with higher forced vital capacity, total lung capacity, functional residual capacity and residual volume. Cannabis was also associated with higher airway resistance but not with forced expiratory volume in 1 s, forced expiratory ratio or transfer factor. These findings were similar among those who did not smoke tobacco. In contrast, tobacco use was associated with lower forced expiratory volume in 1 s, lower forced expiratory ratio, lower transfer factor and higher static lung volumes, but not with airway resistance. Cannabis appears to have different effects on lung function from those of tobacco. Cannabis use was associated with higher lung volumes, suggesting hyperinflation and increased large-airways resistance, but there was little evidence for airflow obstruction or impairment of gas transfer.

Systemic inflammation and lung function in young adults

Background: Impaired lung function is associated with systemic inflammation and is a risk factor for cardiovascular disease in older adults. It is unknown when these associations emerge and to what extent they are mediated by smoking, chronic airways disease, and/or established atherosclerosis. We explored the association between the forced expiratory volume in one second (FEV1) and the systemic inflammatory marker C-reactive protein (CRP) in young adults. Methods: Associations between spirometric lung function and blood CRP were assessed in a population based birth cohort of approximately 1000 New Zealanders at ages 26 and 32 years. Analyses adjusted for height and sex to account for differences in predicted lung function and excluded pregnant women. Results: There were significant inverse associations between FEV1 and CRP at both ages. Similar results were found for the forced vital capacity. These associations were similar in men and women and were independent of smoking, asthma, and body mass index. Conclusions: Reduced lung function is associated with systemic inflammation in young adults. This association is not related to smoking, asthma, or obesity. The reasons for the association are unexplained, but the findings indicate that the association between lower lung function and increased inflammation predates the development of either chronic lung disease or clinically significant atherosclerosis. The association between poor lung function and cardiovascular disease may be mediated by an inflammatory mechanism.

Relationship between socioeconomic status and asthma: a longitudinal cohort study

Background: There is conflicting information about the relationship between asthma and socioeconomic status, with different studies reporting no, positive, or inverse associations. Most of these studies have been cross sectional in design and have relied on subjective markers of asthma such as symptoms of wheeze. Many have been unable to control adequately for potential confounding factors. Methods: We report a prospective cohort study of approximately 1000 individuals born in Dunedin, New Zealand in 1972–3. This sample has been assessed regularly throughout childhood and into adulthood, with detailed information collected on asthma symptoms, lung function, airway responsiveness, and atopy. The prevalence of these in relation to measures of socioeconomic status were analysed with and without controls for potential confounding influences including parental history of asthma, smoking, breast feeding, and birth order using cross sectional time series models. Results: No consistent association was found between childhood or adult socioeconomic status and asthma prevalence, lung function, or airway responsiveness at any age. Having asthma made no difference to educational attainment or socioeconomic status by age 26. There were trends to increased atopy in children from higher socioeconomic status families consistent with previous reports. Conclusions: Socioeconomic status in childhood had no significant impact on the prevalence of asthma in this New Zealand born cohort. Generalisation of these results to other societies should be done with caution, but our results suggest that the previously reported associations may be due to confounding.

Factors affecting exhaled nitric oxide measurements: the effect of sex

BackgroundExhaled nitric oxide (FENO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect FENO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting FENO in a well characterised adult population.MethodsData were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on FENO were explored by unadjusted and adjusted linear regression analyses.ResultsThe effect of sex on FENO was both statistically and clinically significant, with FENO levels approximately 25% less in females. Overall, current smoking reduced FENO up to 50%, but this effect occurred predominantly in those who smoked on the day of the FENO measurement. Atopy increased FENO by 60%. The sex-related differences in FENO remained significant (p < 0.001) after controlling for all other significant factors affecting FENO.ConclusionEven after adjustment, FENO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.

Leptin, adiponectin, and asthma: findings from a population-based cohort study

BACKGROUND Obesity is thought to increase the risk of asthma, especially in women. It has been proposed that this association could be due to the immune-modulating effect of adipokines secreted by adipose tissue. OBJECTIVE To investigate whether aspects of the asthma phenotype are associated with higher levels of the proinflammatory adipokine leptin and lower levels of the anti-inflammatory adipokine adiponectin in a cross-sectional analysis of a group of young adults. METHODS Associations between leptin and adiponectin and a diagnosis of asthma, symptoms of wheeze, bronchodilator response, airflow obstruction, and exhaled nitric oxide were evaluated by logistic or linear regression in a population-based birth cohort of approximately 1,000 men and women aged 32 years. Further analyses adjusted for smoking and body fat. RESULTS There were no significant associations between leptin and any of the markers of the asthma phenotype in either men or women. In men, higher levels of adiponectin were associated with lower levels of exhaled nitric oxide but an increased risk of bronchodilator responsiveness. The inverse association with exhaled nitric oxide remained significant after adjustment for body fat, but the association with bronchodilator responsiveness did not. Adiponectin levels were not associated with any markers of asthma in women. CONCLUSIONS The inverse association between adiponectin and exhaled nitric oxide in men warrants further investigation. However, the findings indicate that levels of leptin and adiponectin are unlikely to mediate the previously observed association between obesity and asthma.

Bronchoprotective and bronchodilator effects of single doses of (S)-salbutamol, (R)-salbutamol and racemic salbutamol in patients with bronchial asthma

AbstractObjectives: The drug salbutamol is used as a 50: 50 racemic mixture of its two enantiomers, (R)- and (S)-salbutamol. Previous studies suggest that the (R)-enantiomer is active, and the (S)-enantiomer is either inert or may be responsible for adverse effects. The aim of the study was to measure the protection given against methacholine (MCh) and adenosine monophosphate (AMP) by (R)-, (S)- and rac-salbutamol and their bronchodilator effects. Methods: A double-blind, placebo-controlled, four-way cross-over study was performed in subjects with mild to moderate asthma. There were three groups: AMP30 (n = 10), MCh30 (n = 13) and MCh180 (n = 10). The groups received AMP or MCh challenges at either 30 min or 180 min after each of four pretreatments: 100 μg (S)-salbutamol, 100 μg (R)- salbutamol, 200 μg rac-salbutamol or placebo (normal saline), each administered via nebuliser. Spirometry was measured at 30, 60, 90, 120, 150 and 180 min in the MCh180 group. Results: (R)- and rac-salbutamol showed equivalent bronchoprotective effects at 30 min. PC20AMP increased by 3.22 (1.86) and 3.41 (2.15) doubling doses (P < 0.001) and PC20MCh increased by 2.86 (1.09) and 2.75 (0.89) (P < 0.001) respectively. (S)-salbutamol caused no equivalent effect. There was no significant effect at 180 min. No hyper-responsiveness occurred after treatment with (S)-salbutamol. The mean increase in forced expiratory volume in 1 s (FEV1) was 12.4% (6.8%) with (R)- and 12.0% (7.7%) with rac-salbutamol at 90 min. No significant change in FEV1 occurred with (S)-salbutamol. Conclusions: These results confirm other recent findings that the bronchoprotective and bronchodilator effects of salbutamol are attributable to its (R)-enantiomer. No adverse effects were noted after single doses of (S)-salbutamol.

Randomised trial of an inhaled β2 agonist, inhaled corticosteroid and their combination in the treatment of asthma

BACKGROUND Although many asthmatic patients are treated with a combination of β2 agonist and corticosteroid inhalers, the clinical effects of combining the drugs are unknown. Studies on the early asthmatic response to allergen suggest that β2 agonists may reduce the benefit of inhaled corticosteroids. A study of the effects of combining the drugs on asthma control was undertaken. METHODS Sixty one subjects with mild to moderate asthma were randomised to a double blind crossover comparison of inhaled budesonide (200–400 μg twice daily), terbutaline (500–1000 μg four times daily), combined treatment, and placebo. Each treatment was given for six weeks following a four week washout period. Ipratropium was used for symptom relief. Treatments were ranked from worst (1) to best (4) based on need for oral steroid, mean morning peak flow, nocturnal awakening, ipratropium use, and asthma symptoms. Lung function and bronchial hyperresponsiveness were measured before and after each treatment. RESULTS Evaluable data for all four treatments were obtained from 47 subjects. The mean rank of each treatment was: placebo = 2.05; terbutaline = 2.13; budesonide = 2.48; combined treatment = 3.34. Combined treatment was ranked significantly better than any other treatment (p<0.01). Mean (95% CI) morning and evening peak flows were 14 (5 to 23) and 24 (15 to 34) l/min higher, respectively, during combined treatment than during budesonide, and 27 (17 to 37) and 15 (7 to 23) l/min higher than during terbutaline. Asthma symptoms tended to be least frequent during combined treatment but were not significantly different from budesonide alone. There was no significant difference between combined treatment and budesonide alone for lung function and bronchial hyperresponsiveness. CONCLUSIONS In this group of mild to moderate asthmatic subjects the combination of β2 agonist and corticosteroid gave better asthma control than either treatment alone. There was no evidence that regular β2 agonist treatment impaired the beneficial effect of inhaled corticosteroid.

The Influence of Polymorphism at Position 16 of the β2-Adrenoceptor on the Development of Tolerance to β-Agonist

Polymorphism at position 16 of the β2-adrenoceptor alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to (3-agonist in homozygous Gly-16 patients with patients harboring the “wild” genotype (homozygous Arg-16) during regular treatment with salmeterol. In a prospective, randomized, double blind, placebo controlled, cross over study, 20 subjects with mild to moderate asthma (10 Gly-16, 10 Arg-16) received 2 weeks of treatment with inhaled salmeterol 100 μg b.i.d. Thereafter, dose responses to inhaled salbutamol were constructed for forced expiratory volume in 1 sec (FEV1), heart rate, QTc interval, serum potassium and glucose, and finger tremor. The protective effect of salbutamol against adenosine monophosphate (AMP) challenge was also measured. Salmeterol resulted in a significant reduction in the area under curve (AUC) for FEV1 (p = 0.01), heart rate (p = 0.01), QTc interval (p = 0.01), and tremor (p = 0.05), and in the maximum responses for FEV1 (p = 0.05), heart rate (p = 0.02), and glucose (p = 0.02). The protective effect of salbutamol against AMP was reduced by 3.61 doubling doses (p < 0.001). However, differences between Gly-16 and Arg-16 patients were small and nonsignificant. Thus, although tolerance is influenced in vitro by polymorphism of the β2-adrenoceptor, the magnitude of between genotype differences in vivo is unlikely to be significant.

Association between exhaled nitric oxide and systemic inflammatory markers

BACKGROUND Asthma is an inflammatory condition of the airways, and there is some evidence to suggest that it is associated with a systemic inflammatory response, as measured by C-reactive protein (CRP) and fibrinogen. Exhaled nitric oxide is a noninvasive measure of asthmatic airway inflammation. OBJECTIVE To determine if there is an association between exhaled nitric oxide and these systemic inflammatory markers. METHODS The Dunedin Multidisciplinary Health and Development Study is a birth cohort of approximately 1,000 individuals born between April 1, 1972, and March 31, 1973. At the age of 32 years, study members were assessed for diagnosis of asthma, atopy by skin prick testing, smoking, body mass index, exhaled nitric oxide, high-sensitivity serum CRP, and plasma fibrinogen level. RESULTS There was no significant association between exhaled nitric oxide and CRP (P = .99). There was a trend to an inverse association between exhaled nitric oxide and fibrinogen (P = .049), but this was not significant after adjusting for smoking and use of corticosteroids or after further adjustment for body mass index and atopy (P = .71). CONCLUSION In this population-based sample of young adults, there was no association between airway inflammation, as measured by exhaled nitric oxide, and systemic inflammation, as measured by either CRP or fibrinogen.