Matthew J. Peters

Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations

This randomised, double‐blind, 6‐month study compared budesonide/formoterol for maintenance and relief with salmeterol/fluticasone and a fixed maintenance dose of budesonide/formoterol, both with terbutaline for relief. Following a 2‐week run‐in, 3335 symptomatic adults and adolescents (mean FEV1 73% predicted, mean inhaled corticosteroid dose 745 μg/day) received budesonide/formoterol 160/4.5 μg one inhalation bid plus additional inhalations as needed, salmeterol/fluticasone 25/125 μg two inhalations bid plus as‐needed terbutaline or budesonide/formoterol 320/9 μg one inhalation bid plus as‐needed terbutaline. Budesonide/formoterol for maintenance and relief prolonged the time to first severe exacerbation requiring hospitalisation, emergency room treatment or oral steroids (primary variable) vs. fixed‐dose salmeterol/fluticasone and budesonide/formoterol (p = 0.0034 and p = 0.023 respectively; log‐rank test). Exacerbation rates were 19, 16 and 12 events/100 patients/6 months for salmeterol/fluticasone, fixed‐dose budesonide/formoterol and budesonide/formoterol for maintenance and relief, respectively, [rate reduction vs. fixed‐dose salmeterol/fluticasone (0.61; 95% CI 0.49–0.76, p < 0.001) and vs. fixed‐dose budesonide/formoterol (0.72; 95% CI 0.57–0.90, p = 0.0048)]. Budesonide/formoterol maintenance and relief patients used less inhaled corticosteroid vs. salmeterol/fluticasone and fixed‐dose budesonide/formoterol patients. All treatments provided similar marked improvements in lung function, asthma control days and asthma‐related quality of life. Budesonide/formoterol for maintenance and relief reduces asthma exacerbations and maintains similar daily asthma control at a lower overall drug load compared with fixed‐dose salmeterol/fluticasone and budesonide/formoterol.

Full blood count parameters for the detection of asthma inflammatory phenotypes

In asthma, the airway inflammatory phenotype influences clinical characteristics and treatment response. Although induced sputum is the gold standard test for phenotyping asthma, a more accessible method is needed for clinical practice.

Effect of simulated commercial flight on oxygenation in patients with interstitial lung disease and chronic obstructive pulmonary disease

Background: Commercial aircraft cabins provide a hostile environment for patients with underlying respiratory disease. Although there are algorithms and guidelines for predicting in-flight hypoxaemia, these relate to chronic obstructive pulmonary disease (COPD) and data for interstitial lung disease (ILD) are lacking. The purpose of this study was to evaluate the effect of simulated cabin altitude on subjects with ILD at rest and during a limited walking task. Methods: Fifteen subjects with ILD and 10 subjects with COPD were recruited. All subjects had resting arterial oxygen pressure (Pao2) of >9.3 kPa. Subjects breathed a hypoxic gas mixture containing 15% oxygen with balance nitrogen for 20 minutes at rest followed by a 50 metre walking task. Pulse oximetry (Spo2) was monitored continuously with testing terminated if levels fell below 80%. Arterial blood gas tensions were taken on room air at rest and after the resting and exercise phases of breathing the gas mixture. Results: In both groups there was a statistically significant decrease in arterial oxygen saturation (Sao2) and Pao2 from room air to 15% oxygen at rest and from 15% oxygen at rest to the completion of the walking task. The ILD group differed significantly from the COPD group in resting 15% oxygen Sao2, Pao2, and room air pH. Means for both groups fell below recommended levels at both resting and when walking on 15% oxygen. Conclusion: Even in the presence of acceptable arterial blood gas tensions at sea level, subjects with both ILD and COPD fall below recommended levels of oxygenation when cabin altitude is simulated. This is exacerbated by minimal exercise. Resting sea level arterial blood gas tensions are similarly poor in both COPD and ILD for predicting the response to simulated cabin altitude.

Gaps in Optimal Care for Lung Cancer

Purpose: Lung cancer is the leading cause of cancer death in Australia, but little is known about how Australian patients with this disease are managed. Methods: Lung cancer patients diagnosed from November 1, 2001 to December 31, 2002 were identified through the population-based New South Wales Central Cancer Registry. Information was collected on diagnosis, staging, referrals, and treatment. Cross-tabulations and logistic regression examined factors related to not receiving cancer-specific therapy. Results: There were 2931 potentially eligible patients registered by the Central Cancer Registry and completed questionnaires were obtained for 1812 patients (62%); median age 71 years and 66% men. The pathology was non-small cell in 71%, small cell in 15% and not confirmed in 13% of patients. Eleven percent of patients did not see a lung cancer specialist and 33% received no cancer-specific therapy after initial diagnosis. Treatment utilization rates were 17% for surgery, 39% for radiotherapy, and 30% for chemotherapy. Factors significantly associated with having no cancer-specific therapy included female gender, older age, weight loss, poorer performance status, advanced or unknown disease stage, and consultation with a low patient volume lung cancer specialist or a non-lung cancer specialist. The median survival was 172 days and 2-year crude survival was 17%. Conclusions: Treatment patterns were in broad concordance with present national guidelines. Nevertheless, a significant proportion of lung cancer patients did not receive cancer-specific therapy. Treatment decisions should be multidisciplinary and decision-makers should include experienced lung cancer specialists.

Ventilation heterogeneity predicts asthma control in adults following inhaled corticosteroid dose titration

BACKGROUND Asthma guidelines recommend inhaled corticosteroid (ICS) dose titration for patients on the basis of an assessment of current asthma control. However, the physiological determinants of asthma symptom control are poorly understood and spirometry is a poor predictor of symptomatic response. OBJECTIVE To determine the role of small airway measurements in predicting the symptom response following ICS dose titration. METHODS Adult asthmatic patients had the Asthma Control Questionnaire (ACQ) scores and lung function measured at baseline and after 8 weeks. Tests included spirometry, plethysmography, sputum cell count, exhaled nitric oxide, airway hyperresponsiveness to mannitol, respiratory system mechanics using the forced oscillation technique, and ventilation heterogeneity using the multiple breath nitrogen washout. The parameters ventilation heterogeneity in convection-dependent airways and ventilation heterogeneity in diffusion-dependent airways were derived as measures of ventilation heterogeneity in the small airways. The dose of ICS was doubled if the ACQ score was greater than or equal to 1.5 (uptitration) and quartered if the ACQ score was less than 1.5 (downtitration). The relationships between baseline physiological parameters and the change in the symptom-only 5-item ACQ (deltaACQ-5) were examined by using Spearman correlations, forward stepwise linear regressions, and receiver operator curve analyses. RESULTS ICS dose uptitration (n= 20) improved ACQ-5 scores (1.76 to 1.16; P= .04). Baseline fraction of exhaled nitric oxide (r= -0.55; P= .01) and ventilation heterogeneity in convection-dependent airways (r= -0.64; P= .002) correlated with deltaACQ-5, but ventilation heterogeneity in convection-dependent airways was the only independent predictor (r(2) = 0.34; P = 0.007). ICS dose downtitration (n= 41) worsened ACQ-5 scores (0.46 to 0.80; P< .001), with 29% of the patients having a deltaACQ-5 of greater than 0.5. Only baseline ventilation heterogeneity in diffusion-dependent airways correlated with deltaACQ-5 (r= 0.40; P= .009) and identified subjects with deltaACQ-5 of greater than 0.5 (receiver operator curve area under the curve= 0.78; P= .0003). CONCLUSIONS Ventilation heterogeneity predicts symptomatic responses to ICS dose titration. Worse small airways function predicts symptomatic improvement to ICS dose uptitration and loss of symptom control during downtitration.

Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial

BACKGROUND Exacerbations of asthma cause a substantial global illness burden. Adults with uncontrolled persistent asthma despite maintenance treatment require additional therapy. Since macrolide antibiotics can be used to treat persistent asthma, we aimed to assess the efficacy and safety of oral azithromycin as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator. METHODS We did a randomised, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in adults (≥18 years) with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Patients were randomly assigned (1:1) to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Patients were centrally allocated using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Primary efficacy endpoints were the rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analysed on an intention-to-treat basis. The trial is registered at the Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235. FINDINGS Between June 12, 2009, and Jan 31, 2015, 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). Azithromycin reduced asthma exacerbations (1·07 per patient-year [95% CI 0·85-1·29]) compared with placebo (1·86 per patient-year [1·54-2·18]; incidence rate ratio [IRR] 0·59 [95% CI 0·47-0·74]; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 [61%] patients in the placebo group vs 94 [44%] patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 [95% CI 0·21-0·52]; p=0·001). Diarrhoea was more common in azithromycin-treated patients (72 [34%] vs 39 [19%]; p=0·001). INTERPRETATION Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma. FUNDING National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust.

Short-form Sun-style T'ai Chi as an exercise training modality in people with COPD

The aims of the study were to determine the effect of short-form Sun-style t’ai chi (SSTC) (part A) and investigate exercise intensity of SSTC (part B) in people with chronic obstructive pulmonary disease (COPD). Part A: after confirmation of eligibility, participants were randomly allocated to either the t’ai chi group or control group (usual medical care). Participants in the t’ai chi group trained twice weekly for 12 weeks. Part B: participants who had completed training in the t’ai chi group performed a peak exercise test (incremental shuttle walk test) and SSTC while oxygen consumption (VO2) was measured. Exercise intensity of SSTC was determined by the per cent of VO2 reserve. Of 42 participants (mean±sd forced expiratory volume in 1 s 59±16% predicted), 38 completed part A and 15 completed part B. Compared to control, SSTC significantly increased endurance shuttle walk time (mean difference 384 s, 95% CI 186–510); reduced medial-lateral body sway in semi-tandem stand (mean difference -12.4 mm, 95% CI -21– -3); and increased total score on the chronic respiratory disease questionnaire (mean difference 11 points, 95% CI 4–18). The exercise intensity of SSTC was 53±18% of VO2 reserve. SSTC was an effective training modality in people with COPD achieving a moderate exercise intensity which meets the training recommendations.

Ground walk training improves functional exercise capacity more than cycle training in people with chronic obstructive pulmonary disease (COPD): a randomised trial

QUESTIONS Does an eight-week program of walk training improve endurance walking capacity in people with COPD compared to cycle training? Does walk training improve peak walking capacity, cycle capacity, and quality of life compared to cycle training? Is the endurance shuttle walk test (ESWT) responsive to change in walking capacity elicited by exercise training? DESIGN Randomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis. PARTICIPANTS 36 people with stable COPD recruited with four dropouts. INTERVENTION Participants were randomised into either a walk or cycle training group. Both groups trained indoors for 30 to 45 minutes per session, three times weekly over eight weeks at Concord Hospital. Training intensities were based on baseline peak exercise tests and progressed as able. OUTCOME MEASURES The primary outcome was endurance walking capacity measured by the ESWT. Secondary outcomes included peak walking capacity, peak and endurance cycle capacity, and health-related quality of life. Measures were taken at baseline (Week 0) and following training (Week 8). RESULTS The walk training group increased their endurance walking time by 279 seconds (95% CI 70 to 483) more than the cycle training group. No significant differences between the groups were found for any other outcome. CONCLUSION Ground walk training increased endurance walking capacity more than cycle training and was similar to cycle training in improving peak walking capacity, peak and endurance cycle capacity and quality of life. This study provides evidence for ground walking as a mode of exercise training in pulmonary rehabilitation programs.

Down-titration from high-dose combination therapy in asthma: Removal of long-acting β2-agonist

BACKGROUND Asthma guidelines recommend reducing inhaled corticosteroids (ICS) to the minimum effective dose, but the timing of long-acting beta(2)-agonist (LABA) withdrawal is unclear. Recent FDA guidelines recommend LABA withdrawal once asthma is well-controlled. This 13-month double-blind study of patients taking high-dose combination therapy investigated the effect of discontinuation of LABA before ICS down-titration. METHODS Adults using salmeterol/fluticasone combination (SFC) 50/500 microg bd were randomized to SFC 50/500 microg bd or fluticasone propionate (FP) 500 microg bd, with subsequent ICS down-titration 8-weekly using a clinical algorithm. The primary outcome was mean daily FP dose, including ICS for exacerbations. RESULTS 82 subjects were randomized. Asthma was well-controlled at baseline, with mean FEV(1) 84.8% predicted and Asthma Control Questionnaire (ACQ) score 0.9. There was no significant difference in mean daily FP dose (SFC: 721 microg, FP:816 microg, p = 0.3), but final dose was lower with SFC (534 microg cf. 724 microg, p = 0.005). ICS dose was reduced by >or=80% in 41% SFC and 15% FP patients. Ambulatory lung function was significantly higher with SFC, but there were no differences between groups in rescue beta(2)-agonist use, clinic spirometry, airway responsiveness, ACQ, sputum eosinophils or FeNO. Baseline airway responsiveness, and pre-reduction blood eosinophils, were significant predictors of mean daily FP dose and dose reduction failure respectively. CONCLUSIONS Many patients prescribed high-dose combination therapy may be over-treated. Substantial reductions in dose can be achieved with a clinical algorithm, reaching lower FP doses with SFC than FP without losing asthma control or increasing disease activity. TRIAL REGISTRATION This study was commenced before mandatory registration of clinical trials.

Platelet activation in acute pulmonary embolism

Summary.  Background: Platelet activation is implicated in thrombotic disorders, but has not been described in acute clinical pulmonary embolism (PE). Objectives: To investigate the natural history of platelet activation in PE and associated markers of inflammation, thrombosis and cardiac dysfunction. Methods: Thirty‐five consecutive patients (age 62 ±17 years) with acute PE were prospectively enrolled and followed for 6 months. Platelet activation was assessed by flow cytometry [measuring expression of platelet P‐selectin, conformational activation of glycoprotein IIb/IIIa complex (PAC‐1) and formation of platelet–leukocyte complexes] and by plasma soluble P‐selectin. Platelet activation, right ventricular (RV) function (assessed as RV ejection area by transthoracic echocardiography), D‐dimer and high‐sensitivity C‐reactive protein (hs‐CRP) were measured at presentation and repeated over 6 months follow‐up. Results: Soluble P‐selectin (56 ±19 ng mL−1, anovaP < 0.0001) and PAC‐1 (1.5 ± 1.8%, anovaP = 0.005) were mildly but significantly increased in patients with acute PE relative to healthy young men (soluble P‐selectin 33 ± 13 ng mL−1, P < 0.001; PAC‐1 binding 0.5 ± 0.6%, P < 0.01) and age‐matched controls (soluble P‐selectin 31 ± 9 ng mL−1, P < 0.001; PAC‐1 binding 0.4 ±0.4%, P < 0.05). Platelet P‐selectin expression and platelet–leukocyte complexes were not increased during acute PE. Echocardiographic RV ejection area correlated inversely with soluble P‐selectin (r = −0.47, P = 0.007) and positively with platelet P‐selectin (r = 0.49, P = 0.0007), suggesting P‐selectin is shed from activated platelets in proportion to the severity of RV dysfunction. Elevated soluble P‐selectin, D‐dimer and hs‐CRP demonstrated a time‐dependent return to normal during 6 months follow‐up. Conclusion: Platelet activation is evident after acute PE. Platelet activation correlates with the severity of RV dysfunction, and can persist for several months after acute PE.