Predicting steroid responsiveness in patients with asthma using exhaled breath profiling.

BACKGROUND: Exhaled breath contains disease-dependent volatile organic compounds (VOCs), which may serve as biomarkers distinguishing clinical phenotypes in asthma. Their measurement may be particularly beneficial in relation to treatment response. OBJECTIVE: Our aim was to compare the performance of electronic nose (eNose) breath analysis with previously investigated techniques (sputum eosinophils, exhaled nitric oxide (FeNO) and airway hyperresponsiveness) to discriminate asthma from controls and identify steroid responsiveness in steroid-free patients. Trial registration ACTRN12613000038796. METHODS: Twenty-five patients with mild/moderate asthma had their inhaled steroid treatment discontinued until loss of control or 28 days. They were subsequently treated with oral prednisone 30 mg/day for 14 days. Steroid responsiveness was defined as an increase of either > 12% FEV1 or > 2 doubling doses PC20 AMP. Steroid-free assessment of sputum eosinophils, FeNO and exhaled breath VOCs were used to construct algorithms predicting steroid responsiveness. Performance characteristics were compared by ROC analysis. RESULTS: The eNose discriminated between asthma and controls (area under the curve = 0.766 ± 0.14; P = 0.002) with similar accuracy to FeNO (0.862 ± 0.12; P < 0.001) and sputum eosinophils (0.814 ± 0.15; P < 0.001). Steroid responsiveness was predicted with greater accuracy by VOC-analysis (AUC = 0.883 ± 0.16; P = 0.008) than FeNO (0.545 ± 0.28; P = 0.751) or sputum eosinophils (0.610 ± 0.29; P = 0.441). CONCLUSIONS AND CLINICAL RELEVANCE: Breath analysis by eNose can identify asthmatic patients and may be used to predict their response to steroids with greater accuracy than sputum eosinophils or FeNO. This implies a potential role for breath analysis in the tailoring of treatment for asthma patients.

The effect of adiposity measured by dual-energy X-ray absorptiometry on lung function.

Respiratory function is impaired in obesity but there are limitations with body mass index and skin-fold thickness in assessing this effect. The present authors hypothesised that the regional distribution of body fat and lean mass, as measured by dual-energy X-ray absorptiometry (DXA), might be more informative than conventional measurements of total body fat. In total, 107 subjects (55 female, 51.4%) aged 20-50 yrs with no respiratory disease were recruited. Respiratory function tests, anthropometric measurements and a DXA scan were performed. Partial correlation and linear regression analyses were used to explore the effect of adiposity and lean body mass on respiratory function. The majority of respiratory function parameters were significantly correlated with DXA and non-DXA measurements of body fat. Neither thoracic nor abdominal fat had a greater effect. There were some differences in the effect of adiposity between the sexes. Respiratory function was negatively associated with lean body mass in females but positively associated in males. This disappeared after adjustment in females but remained in males. The effects of thoracic and abdominal body fat on respiratory function are comparable but cannot be separated from one another.

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.

Bronchodilator tolerance: the impact of increasing bronchoconstriction.

Chronic exposure to beta-agonists causes tolerance to their bronchodilator effects, which is best demonstrated during acute bronchoconstriction. The aim of the present study was to assess whether tolerance becomes more evident with increasing bronchoconstriction, as might occur in acute asthma. In a randomised, double-blind, placebo-controlled, crossover study comprising 15 patients, the treatments were salbutamol 400 microg q.i.d. or placebo given via Diskhaler for 28 days with a 2-week washout between treatments. Patients attended on days 14, 21 and 28. Bronchoconstriction was induced on two of these three occasions to achieve a reduction in the forced expiratory volume in one second (FEV1) of 0 (no methacholine), 15 and 30% (using methacholine) in a randomised order. Immediately after this, salbutamol 100 microg, 100 microg and 200 microg was inhaled at 0, 5, and 10 min. FEV1 was measured over 40 min. Dose/response curves were plotted and values for the area under the curve (AUC)0-40 FEV1 were compared between treatments and by degree of bronchoconstriction. Regular salbutamol resulted in attenuation of the acute response to beta-agonist, which was increasingly evident with greater bronchoconstriction. With a reduction in FEV1 of 0, 15 and 30%, the AUC0-40 FEV1 with salbutamol were 11.2, -14.6 and -35.7% respectively, compared to placebo. There was a linear relationship between the magnitude of bronchoconstriction and the between-treatment differences in AUC0-40 FEV1. Increasing bronchoconstriction conferred greater susceptibility to the effects of bronchodilator tolerance.

House dust mite allergen levels in university student accommodation in Dunedin.

AIM: To quantify the levels of Dermatophagoides pteronyssinus (Der p1) in different university student accommodation in Dunedin, and to assess relationships with housing characteristics and housekeeping practices. METHODS: Dwellings (n=178) were randomly selected from a database of first year university students in Dunedin. Dust samples were collected from both bed and the bedroom floor by standardised procedures. Der p1 levels were quantified by monoclonal antibody ELISA techniques. Details of housing characteristics, occupancy and housekeeping practices were obtained by questionnaire. RESULTS: Geometric mean (95% confidence intervals) Der p1 allergen levels from bedroom floors were: family homes (n=61) 5.58 (3.73-8.36) microg/g; student flats (n=43) 3.89 (2.49-6.07) microg/g; halls of residence (n=74) 0.26 (0.16-0.43) microg/g. Der p1 allergen levels from beds were: family homes 15.85 (9.78-26.57) microg/g; student flats 10.5 (6.41-17.19) microg/g; halls of residence 3.25 (2.33-4.54) microg/g. In all accommodation lower levels of Der p1 were found on the floor compared to the bed (p<0.005). Halls of residence had significantly lower Der p1 levels in both bed and floor (p<0.0005). Higher levels of Der p1 were associated with longer duration of occupancy, a history of condensation or mold in the accommodation, failure to use a hot wash for sheets, mattress age greater than one year and infrequent vacuuming of the bedroom floor. CONCLUSIONS: Wide variations in Der p1 levels were observed between different forms of student accommodation. Higher levels of Der p1 are found in family homes than in student flats or halls of residence.

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 microg x BDP x 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 microg x day(-1) soon after commencing therapy and continued over time.

The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control.

Exhaled nitric oxide (eNO) levels are increased in untreated or unstable asthma and measurements can be made easily. Our aim was to assess the usefulness of eNO for diagnosing and predicting loss of control (LOC) in asthma following steroid withdrawal. Comparisons were made against sputum eosinophils and airway hyperresponsiveness (AHR) to hypertonic saline (4.5%). Seventy-eight patients with mild/moderate asthma had their inhaled steroid therapy withdrawn until LOC occurred or for a maximum of 6 wk. Sixty (77.9%) developed LOC. There were highly significant correlations between the changes in eNO and symptoms (p < 0.0001), FEV(1) (p < 0.002), sputum eosinophils (p < 0.0002), and saline PD(15) (p < 0.0002), and there were significant differences between LOC and no LOC groups. Both single measurements and changes of eNO (10 ppb, 15 ppb, or an increase of > 60% over baseline) had positive predictive values that ranged from 80 to 90% for predicting and diagnosing LOC. These values were similar to those obtained using sputum eosinophils and saline PD(15) measurements. We conclude that eNO measurements are as useful as induced sputum analysis and AHR in assessing airway inflammation, with the advantage that they are easy to perform.

Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol.

Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction. This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist, formoterol. The modifying effect of intravenous corticosteroid was also studied. Ten asthmatic subjects (using inhaled steroids) participated in a randomised, double-blind, placebo-controlled, cross-over study. Formoterol 12 microg b.i.d. or matching placebo was given for 10-14 days with >2 weeks washout. Following each treatment, patients underwent a methacholine challenge to induce a fall in forced expired volume in one second (FEV1) of at least 20%, then salbutamol 100 microg, 100 microg, and 200 microg was inhaled via a spacer at 5 min intervals, with a further 400 microg at 45 min. After a third single-blind formoterol treatment period, hydrocortisone 200 mg was given intravenously prior to salbutamol. Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry. Regular formoterol resulted in a significantly lower FEV1 after salbutamol at each time point compared to placebo (p<0.01). The area under the curves (AUCs) for 15 (AUC0-15) and 45 (AUC0-45) min were 28.8% and 29.5% lower following formoterol treatment (p<0.001). Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration. It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol. This bronchodilator tolerance is evident in circumstances of acute bronchconstriction.

Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment.

There is uncertainty about the development of airway tolerance to beta-agonists and the phenomenon of rebound bronchoconstriction on beta-agonist withdrawal. We have recently completed a study of the regular terbutaline and budesonide treatment in asthma. We report our observations on the effect of starting and stopping terbutaline treatment on morning and evening peak flows. The study was a randomized four-way, double-dummy, cross-over comparison of regular inhaled terbutaline (500-1000 microg four times daily), budesonide, combined treatment and matching placebo. Each treatment was given for 6 weeks following a 4 week single-blind placebo washout. Ipratropium was used for symptom relief. No other asthma medication was permitted during either the treatment or wash-out periods. Evaluable data were obtained from 52 subjects for both placebo and terbutaline treatment. Changes in mean morning and evening peak flows during terbutaline treatment were compared to the baseline peak flows during the last 2 weeks of the preceding washout. The peak flow changes on stopping terbutaline were also analysed. Mean morning peak flow was not significantly different during terbutaline treatment when compared to either baseline or placebo treatment. Evening peak flows were significantly higher during terbutaline treatment [mean increase 23.1 l min(-1) (95% CI = 18.8, 27.4)]. Analysis of the peak flow changes on a day-by-day basis revealed an initial increase in morning peak flows for the first 2 days of treatment of 19.2 and 13.41 min(-1) [increases of 25.0 and 17.31 min(-1) in comparison with the corresponding values during placebo (P<0.01)] followed by a return to baseline. The increase in evening peak flows was also greater for the first 2 days of treatment than for the remainder of the treatment period (P<0.01). On ceasing terbutaline treatment there was a fall in mean morning peak flow below the baseline on the following morning of 21.6 l min(-1) (P<0.05 compared to placebo). The temporary increase in morning peak flows and greater than expected rise in evening peak flows for the first 2 days of treatment suggest the development of tolerance to the bronchodilator effect of terbutaline. Similarly, the fall in morning peak flows on treatment withdrawal suggests rebound bronchoconstriction. These effects are likely to be mediated by downregulation of the beta-receptor during treatment. The clinical significance of these changes is uncertain in view of the stability of overall asthma control during terbutaline treatment, but sudden withdrawal of beta-agonist treatment could conceivably lead to a deterioration in asthma control.

Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma.

Previous studies have shown that the regular administration of short acting beta-agonists can be associated with adverse effects on airway caliber and bronchial hyperresponsiveness (BHR) and that this may occur through a proinflammatory mechanism. The aim was to explore possible adverse effects of high-dose beta-agonist therapy and to assess any adverse interaction with corticosteroids. We undertook a randomized, crossover study to investigate the effects of 6 wk of treatment with regular terbutaline (1 mg four times a day), regular budesonide (400 microg twice a day), combined treatment, and placebo in subjects with mild to moderate asthma. Major endpoints were PD(15) saline, PD(20) methacholine, and induced sputum differential cell counts. Thirty-four subjects were randomized and 28 completed the study. PD(15) saline decreased on terbutaline alone compared with placebo treatment and on combined treatment compared with budesonide alone (mean fold decrease of 0.57 [95% CI = 0.36, 0.90] and 0.65 [95% CI = 0.43, 0.97], respectively). PD(20) methacholine was not affected by the use of terbutaline either alone or in combination with budesonide. The percentage of eosinophils in induced sputum increased during terbutaline treatment alone compared with placebo (median 8.3% versus 4.4%, p = 0.049). The addition of terbutaline to budesonide did not affect the percentage of eosinophils compared with budesonide treatment alone. These findings support the hypothesis that short-acting beta-agonists have a permissive effect on airway inflammation and that when used in high dose there may be an unfavorable interaction with inhaled corticosteroids.

The influence of polymorphism at position 16 of the beta2-adrenoceptor on the development of tolerance to beta-agonist.

Polymorphism at position 16 of the beta2-adrenoceptor alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to beta-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 microg 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 beta2-adrenoceptor, the magnitude of between-genotype differences in vivo is unlikely to be significant.

Tolerance to beta-agonists during acute bronchoconstriction.

Previous reports suggest that regular use of beta-agonists does not lead to tolerance to their bronchodilator effects. However, most studies have been conducted in stable asthma. This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction. Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline (1 mg q.i.d.), budesonide (400 microg, b.i.d.), both drugs or placebo in a randomized, double-blind, cross-over study. After each treatment methacholine was administered to induce a 20% fall in the forced expiratory volume in one second (FEV1). The response to inhaled salbutamol 100, 100, 200 microg at 5 min intervals) was then measured. Dose-response curves were compared using an analysis of covariance. Pre-methacholine FEV1, the highest pre-methacholine FEV1, the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20% fall in FEV1 (PD20) were used as covariates. There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment: the mean (95% confidence intervals (CI)) area under the dose-response curve was reduced by 36% (24, 47) compared to placebo (p<0.0001). The reduction in bronchodilator response was not affected by concomitant treatment with budesonide. Significant tolerance to the bronchodilator effect of inhaled beta-agonists may be demonstrated when tested during acute bronchoconstriction. Continuous treatment with inhaled beta-agonists may lead to a reduced response to emergency beta-agonist treatment during asthma exacerbations.

Randomised trial of an inhaled beta2 agonist, inhaled corticosteroid and their combination in the treatment of asthma.

BACKGROUND: Although many asthmatic patients are treated with a combination of beta2 agonist and corticosteroid inhalers, the clinical effects of combining the drugs are unknown. Studies on the early asthmatic response to allergen suggest that beta2 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 microg twice daily), terbutaline (500-1000 microg 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 beta2 agonist and corticosteroid gave better asthma control than either treatment alone. There was no evidence that regular beta2 agonist treatment impaired the beneficial effect of inhaled corticosteroid.

Jaundice in full term healthy neonates--a population study.

A geographically based population of 498 full term, appropriate for gestational age, healthy, singleton neonates was used to study the effect of obstetric and nursery practices on the occurrence of neonatal jaundice. At 3-4 days 56% of babies became visibly jaundiced (plasma bilirubin (PB) greater than 100 mumol/l) and 10% were hyperbilirubinaemic (PB greater than 200 mumol/l). Less mature babies, those slow to pass meconium and those who had lost weight at 4 and 7 days were more likely to be jaundiced. Obstetric practices, drugs given during labour, mother's or baby's blood group, natural illumination, plethora, extravasated blood or mode of feeding were found to have no effect. No benefit from giving supplementary milk or dextrose to breast fed babies was discovered. At 6-7 days at least 9% of babies, all but one of whom were breast fed, were visibly jaundiced. The frequency of prolonged jaundice (breast milk jaundice) was 3.8% of breast fed babies at 3 weeks and zero by 7 weeks. The proportion of babies receiving phototherapy was 2.2%.