Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Epinephrine (adrenaline) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis.

BACKGROUND: International asthma guidelines recommend against epinephrine (adrenaline) administration in acute asthma unless associated with anaphylaxis or angio-oedema. However, administration of intramuscular epinephrine in addition to nebulised selective ß2-agonist is recommended for acute severe or life-threatening asthma in many prehospital guidelines. We conducted a systematic review to determine the efficacy of epinephrine in comparison to selective ß2-agonist in acute asthma. METHODS: We included peer-reviewed publications of randomised controlled trials (RCTs) that enrolled children or adults in any healthcare setting and compared epinephrine by any route to selective ß2-agonist by any route for an acute asthma exacerbation. The primary outcome was treatment failure, including hospitalisation, need for intubation or death. RESULTS: Thirty-eight of 1140 studies were included. Overall quality of evidence was low. Seventeen studies contributed data on 1299 participants to the meta-analysis. There was significant statistical heterogeneity, I2=56%. The pooled Peto's OR for treatment failure with epinephrine versus selective ß2-agonist was 0.99 (0.75 to 1.32), p=0.95. There was strong evidence that recruitment age group was associated with different estimates of the odds of treatment failure; with studies recruiting adults-only having lower odds of treatment failure with epinephrine. It was not possible to determine whether epinephrine in addition to selective ß2-agonist improved outcomes. CONCLUSION: The low-quality evidence available suggests that epinephrine and selective ß2-agonists have similar efficacy in acute asthma. There is a need for high-quality double-blind RCTs to determine whether addition of intramuscular epinephrine to inhaled or nebulised selective ß2-agonist improves outcome. PROSPERO REGISTRATION NUMBER: CRD42017079472.

Metabolomic changes related to airway inflammation, asthma pathogenesis and systemic activity following inhaled fluticasone furoate/vilanterol: a randomized controlled trial.

BACKGROUND: Fluticasone furoate/vilanterol trifenatate (FF/VI) is an inhaled therapy for the treatment of asthma, with a prolonged duration of anti-inflammatory and bronchodilatory action. This study investigated the global metabolomic and lipidomic profile following treatment with FF/VI or placebo and assessed whether changes correlated with exhaled nitric oxide levels as a measure of airway inflammation. METHODS: This was a single-center, randomized, double-blind, placebo-controlled, two-period, crossover, repeat-dose study. Adults with asthma (forced expiratory volume in 1 s ≥ 60% predicted; fraction of exhaled nitric oxide [FeNO] > 40 parts per billion) received once-daily FF/VI 100 µg/25 µg or placebo for 14 days, followed by a 21-day washout period. Serum samples were taken at pre-dose (T1), and 15 and 21 days (T2 and T3, respectively) post dose in each period. The metabolomic and lipidomic profiles were analyzed by liquid chromatography with tandem mass spectrometry and polar liquid chromatography platforms, and ions were matched to a library of standards for metabolite identification and quantification. FeNO values at each timepoint were evaluated for correlations with the biochemical data. RESULTS: Of 27 randomized participants (mean age 24.5 years, 63% male), 26 provided serum samples for metabolomic analysis. A total of 1969 metabolites were identified, 1634 of which corresponded to a named structure in a reference library. Treatment-related changes in the metabolome were generally subtle, with a modest increase in metabolite perturbations across timepoints. The percentage of metabolites with significant changes (p < 0.05 for all) (increases↑/decreases↓) versus placebo were: 2.1% (1.1%↑/1.0%↓), 6.7% (0.46%↑/6.2%↓) and 11.8% (0.86%↑/10.9%↓) at T1, T2 and T3, respectively. Treatment with FF/VI reduced FeNO levels by 60%, whereas the systemic intermediates involved in NO biosynthesis remained unaffected. Evidence of systemic anti-inflammatory activity was seen in complex lipid pathways, suggesting reduced phospholipase-A2 activity, but without downstream impact on free fatty acids or inflammatory mediators. Consistent with the pathogenesis of asthma, there was evidence of higher fatty acid ß-oxidation and lower glycolysis in the placebo arm; this pattern was reversed in the treatment arm. CONCLUSIONS: Despite the prolonged airway anti-inflammatory action of FF/VI, this was accompanied by only subtle systemic metabolomic and lipidomic changes. Trial registration Prospectively registered on ClinicalTrials.gov registry number NCT02712047.

Severe asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings.

Severe asthma imposes a significant burden on individuals, families and the healthcare system. Treatment is complex, due to disease heterogeneity, comorbidities and complexity in care pathways. New approaches and treatments improve health outcomes for people with severe asthma. However, emerging multidimensional and targeted treatment strategies require a reorganisation of asthma care. Consensus is required on how reorganisation should occur and what areas require further research. The Centre of Excellence in Severe Asthma convened three forums between 2015 and 2018, hosting experts from Australia, New Zealand and the UK. The forums were complemented by a survey of clinicians involved in the management of people with severe asthma. We sought to: (i) identify areas of consensus among experts; (ii) define activities and resources required for the implementation of findings into practice; and (iii) identify specific priority areas for future research. Discussions identified areas of unmet need including assessment and diagnosis of severe asthma, models of care and treatment pathways, add-on treatment approaches and patient perspectives. We recommend development of education and training activities, clinical resources and standards of care documents, increased stakeholder engagement and public awareness campaigns and improved access to infrastructure and funding. Further, we propose specific future research to inform clinical decision-making and develop novel therapies. A concerted effort is required from all stakeholders (including patients, healthcare professionals and organisations and government) to integrate new evidence-based practices into clinical care and to advance research to resolve questions relevant to improving outcomes for people with severe asthma.

Engaging Maori with qualitative healthcare research using an animated comic.

This article reports an effective strategy for recruiting patients with asthma to a qualitative study using an animated comic advertised on social media. An ad spend of NZ$432 on Facebook resulted in 101 study enquiries, and 27 participants taking part in the focus groups, of which 16 (56%) were Maori, the Indigenous Peoples of New Zealand. Representation of Maori amongst participants was over five times higher than their proportion in the local population (9.7%), resulting in data fulfilling the principle of equal explanatory power, an approach to research which can help advance Maori health development and address inequity. The success of this campaign is of particular interest for health researchers in New Zealand where Maori continue to be disproportionately affected by poorer health outcomes compared with non-Maori, particularly those with asthma. Approaches that better engage and support participation of under-represented communities in clinical research are of wider global interest. We reflect on the recruitment strategy and outcomes within a Kaupapa Maori framework, explore how this can be applied more widely in healthcare, and suggest direction for future study and implementation. Lay summary We designed an animated comic to advertise a study for patients with asthma. This was shared locally with a Facebook ad. The approach was highly engaging with the public, and resulted in rapid recruitment. Interestingly, participation of Maori (the Indigenous People of New Zealand) was over five times higher than their proportion in the local population. Maori have poorer health outcomes and increased barriers to healthcare access compared with non-Maori, particularly those with asthma. Approaches which can engage and support under-represented communities to participate in clinical research are of wider global interest. In this article, we reflect on the recruitment strategy and outcomes, and suggest direction for future study and implementation.

Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial.

BACKGROUND: In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting ß-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting ß-agonist (SABA) reliever therapy. We investigated the efficacy of combination budesonide-formoterol reliever therapy compared with maintenance budesonide plus as-needed terbutaline. METHODS: We did a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial at 15 primary care or hospital-based clinical trials units and primary care practices in New Zealand. Participants were adults aged 18-75 years with a self-reported doctor's diagnosis of asthma who were using SABA for symptom relief with or without maintenance low to moderate doses of inhaled corticosteroids in the previous 12 weeks. We randomly assigned participants (1:1) to either reliever therapy with budesonide 200 µg-formoterol 6 µg Turbuhaler (one inhalation as needed for relief of symptoms) or maintenance budesonide 200 µg Turbuhaler (one inhalation twice daily) plus terbutaline 250 µg Turbuhaler (two inhalations as needed). Participants and investigators were not masked to group assignment; the statistician was masked for analysis of the primary outcome. Six study visits were scheduled: randomisation, and weeks 4, 16, 28, 40, and 52. The primary outcome was the number of severe exacerbations per patient per year analysed by intention to treat (severe exacerbations defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids). Safety analyses included all participants who had received at least one dose of study treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616000377437. FINDINGS: Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment and included 885 eligible participants in the analysis: 437 assigned to budesonide-formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. Severe exacerbations per patient per year were lower with as-needed budesonide-formoterol than with maintenance budesonide plus terbutaline as needed (absolute rate per patient per year 0·119 vs 0·172; relative rate 0·69, 95% CI 0·48-1·00; p=0·049). Nasopharyngitis was the most common adverse event in both groups, occurring in 154 (35%) of 440 patients receiving as-needed budesonide-formoterol and 144 (32%) of 448 receiving maintenance budesonide plus terbutaline as needed. INTERPRETATION: In adults with mild to moderate asthma, budesonide-formoterol used as needed for symptom relief was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline. The findings support the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid-formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma. FUNDING: Health Research Council of New Zealand.

What matters most to patients when choosing treatment for mild-moderate asthma? Results from a discrete choice experiment.

BACKGROUND: An as-needed combination preventer and reliever regimen was recently introduced as an alternative to conventional daily preventer treatment for mild asthma. In a subgroup analysis of the PRACTICAL study, a pragmatic randomised controlled trial of budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild asthma, we recently reported that about two-thirds preferred as-needed combination preventer and reliever therapy. The aim of this study was to determine the relative importance of attributes associated with these two asthma therapies in this subgroup of participants who indicated their preferred treatment in the PRACTICAL study. METHODS: At their final study visit, a subgroup of participants indicated their preferred treatment and completed a discrete choice experiment using the Potentially All Pairwise RanKings of all possible Alternatives method and 1000minds software. Treatment attributes and their levels were selected from measurable study outcomes, and included: treatment regimen, shortness of breath, steroid dose and likelihood of asthma flare-up. RESULTS: The final analysis dataset included 288 participants, 64% of whom preferred as-needed combination preventer and reliever. Of the attributes, no shortness of breath and lowest risk of asthma flare-up were ranked highest and second highest, respectively. However, the relative importance of the other two attributes varied by preferred therapy: treatment regimen was ranked higher by participants who preferred as-needed treatment than by participants who preferred maintenance treatment. CONCLUSIONS: Knowledge of patient preferences for treatment attributes together with regimen characteristics can be used in shared decision-making regarding choice of treatment for patients with mild-moderate asthma. TRIAL REGISTRATION NUMBER: ACTRN12616000377437.

Self-titration of inhaled corticosteroid and ß2-agonist in response to symptoms in mild asthma: a pre-specified analysis from the PRACTICAL randomised controlled trial.

INTRODUCTION: In mild asthma, as-needed budesonide-formoterol is superior or noninferior to maintenance budesonide plus as-needed short-acting ß2-agonist in reducing severe exacerbations. In this pre-specified analysis, we investigated patterns of inhaled corticosteroid (ICS) and ß2-agonist use in PRACTICAL, a randomised controlled trial. METHODS: Participants were randomised 1:1 to as-needed budesonide-formoterol (200/6 µg Turbuhaler, one actuation) or maintenance budesonide (200 µg Turbuhaler, one actuation twice a day) with as-needed terbutaline (250 µg, two actuations) for 52 weeks. 110 participants had electronic monitors attached to their study inhalers which captured the time and date of every actuation. Key outcome measures were patterns of ICS and ß2-agonist use. One actuation of budesonide-formoterol was considered to be an equivalent bronchodilator dose as two actuations of terbutaline. RESULTS: Participants randomised to as-needed budesonide-formoterol had more days with no ICS use compared with maintenance budesonide (median total days of no use 156 versus 22 days, respectively), lower median daily budesonide dose (164 versus 328 µg, respectively) and a greater median number of days of ≥4 budesonide actuations (4 versus 1 days, respectively). Participants randomised to as-needed budesonide-formoterol took higher equivalent doses of ß2-agonist both overall (median number of actuations 0.8 versus 0.3 per day, respectively) and in response to worsening asthma (total number of "overuse days" of >8 or >16 actuations of budesonide-formoterol or terbutaline 33 versus 10 days, respectively). CONCLUSIONS: The timing of ICS dose when self-titrated to ß2-agonist use is more important than total ICS dose in reducing severe exacerbation risk in mild asthma, when associated with greater overall use of as-needed ß2-agonist.

Patient preferences for symptom-driven or regular preventer treatment in mild to moderate asthma: findings from the PRACTICAL study, a randomised clinical trial.

Symptom-driven low-dose inhaled corticosteroid-formoterol is safe and effective in mild asthma and has been recommended as one of the preferred treatment regimens at steps 1 and 2 in the 2019 update of the Global Initiative for Asthma. However, there are no data on patient preferences for this regimen.A subgroup of participants in the PRACTICAL study (ACTRN12616000377437), a randomised controlled trial comparing symptom-driven budesonide-formoterol with maintenance budesonide plus as-needed terbutaline completed a survey on treatment preferences, satisfaction, beliefs and experience at their final study visit.306 (75%) out of 407 eligible participants completed the survey. Regimen preference was strongly associated with randomised treatment, as were preferences for and beliefs about preventer inhaler use. Combination preventer and reliever as-needed therapy was preferred by 135 (90%, 95% CI 85.2-94.8%) out of 150 who were randomised to as-needed budesonide-formoterol, and by 63 (40%, 95% CI 32.7-48.1%) out of 156 who were randomised to maintenance budesonide. By contrast, twice-daily preventer inhaler with a reliever inhaler as required was preferred by 15 (10%) out of 150 of those randomised to as-needed budesonide-formoterol and 93 (60%) out of 156 of those randomised to maintenance budesonide. Satisfaction with all study inhalers was high. Of patients randomised to as-needed budesonide-formoterol 92% (n=138) were confident using it as a reliever at the end of the study.Although most participants preferred the regimen to which they had been randomised, this association was much stronger for those randomised to budesonide-formoterol as needed, indicating that most patients preferred as-needed corticosteroid-formoterol therapy if they had experienced it.

Pre-apneic capnography waveform abnormalities during procedural sedation and analgesia.

Capnography monitoring is recommended for use during procedural sedation. This study examined associations between capnography waveform abnormalities and the onset of apnea. Capnography waveforms from a sample of 102 participants undergoing moderate procedural sedation with bolus doses of midazolam and fentanyl were analyzed using a mixed effects Cox model. Patients were at increased risk of apnea (classified as end-tidal carbon dioxide concentration of zero) while demonstrating a capnography waveform abnormality classified as hypopnea (more than 10% increase or decrease from baseline end-tidal carbon dioxide concentration) (Hazard Ratio 2.14; 95% CI 1.75 to 2.62). Risk of apnea was not increased during capnography waveform abnormalities classified as bradypnea (capnography-derived respiratory rate less than 8 breaths/min) (Hazard Ratio 0.64; 95% CI 0.33 to 1.25). These estimates were similar when apneic episodes were defined as only those that lasted more than 20 s duration. Deciphering which capnography waveform abnormalities should promote intervention (and therefore alarms to signal the event to clinicians) from those that do not is an essential step towards successful implementation of this technology into practice. Our results indicate that using information about the history of previous capnography waveform abnormalities may be a promising solution to assist prediction of apneic episodes.

Accuracy and precision of transcutaneous carbon dioxide monitoring: a systematic review and meta-analysis.

BACKGROUND: Transcutaneous carbon dioxide (TcCO2) monitoring is a non-invasive alternative to arterial blood sampling. The aim of this review was to determine the accuracy and precision of TcCO2 measurements. METHODS: Medline and EMBASE (2000-2016) were searched for studies that reported on a measurement of PaCO2 that coincided with a measurement of TcCO2. Study selection and quality assessment (using the revised Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2)) were performed independently. The Grading Quality of Evidence and Strength of Recommendation approach was used to summarise the strength of the body of evidence. Pooled estimates of the mean bias between TcCO2 and PaCO2 and limits of agreement with outer 95% CIs (termed population limits of agreement) were calculated. RESULTS: The mean bias was -0.1 mm Hg and the population limits of agreement were -15 to 15 mm Hg for 7021 paired measurements taken from 2817 participants in 73 studies, which was outside of the clinically acceptable range (7.5 mm Hg). The lowest PaCO2 reported in the studies was 18 mm Hg and the highest was 103 mm Hg. The major sources of inconsistency were sensor location and temperature. The population limits of agreement were within the clinically acceptable range across 3974 paired measurements from 1786 participants in 44 studies that applied the sensor to the earlobe using the TOSCA and Sentec devices (-6 to 6 mm Hg). CONCLUSION: There are substantial differences between TcCO2 and PaCO2 depending on the context in which this technology is used. TcCO2 sensors should preferentially be applied to the earlobe and users should consider setting the temperature of the sensor higher than 42°C when monitoring at other sites. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO; CRD42017057450.

Change in biomarkers of type-2 inflammation following severe exacerbations of asthma.

We investigated the time course of change of type-2 asthma biomarkers after a severe asthma exacerbation. Blood eosinophils were lowest immediately after treatment was initiated (0.07 vs 0.33×109/L, p<0.001) while serum IgE levels were at their highest (339 vs 249 U/L, p<0.001). Fractional exhaled Nitric Oxide levels were lowest 2 weeks after treatment (23 vs 33 ppb, p=0.06) and serum periostin levels were lowest 1 week after treatment (45·9 vs 50·9 ng/mL, p<0.001). A delay of 4-8 weeks following a severe exacerbation is required if these biomarkers are used to guide the ongoing management of patients with asthma. TRIAL REGISTRATION NUMBER: Post-results; The Australia New Zealand Trial Registry, >ACTRN12614000443695.

Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under International Workshop report.

"Treatable traits" have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each individual to improve outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.

Nasal high-flow therapy compared with non-invasive ventilation in COPD patients with chronic respiratory failure: A randomized controlled cross-over trial.

BACKGROUND AND OBJECTIVE: Non-invasive ventilation (NIV) is part of the standard of care for hypercapnic respiratory failure secondary to COPD, but may be poorly tolerated. Preliminary evidence suggests nasal high-flow (NHF) therapy may improve hypercapnia in COPD and be well tolerated. We compared NHF and NIV in people with COPD and chronic hypercapnic respiratory failure. METHODS: Single-blind randomized controlled two-way cross-over single-centre trial was conducted in New Zealand. Twenty-four participants with stable hypercapnic COPD received: NHF at 45 L/min and NIV at 15/4 cm H2 O, each for 60 min with a 15-min washout in between. The primary outcome was transcutaneous partial pressure of carbon dioxide (PtCO2 ) at 60 min, adjusted for baseline. RESULTS: NIV reduced the PtCO2 more than NHF (mean (SD) at 60 min by -5.3 (5.0) vs -2.5 (3.5) mm Hg; difference: -2.8 (-5.0 to -0.5) P = 0.021). Difference across all time points was -2.5 mm Hg (95% CI -4.5 to -0.5, P = 0.016). There was no significant difference in the proportion of participants with a reduction of PtCO2 ≥ 4 or ≥ 8 mm Hg. Participants rated NHF significantly better for ease of application, comfort and fit. CONCLUSION: In stable COPD patients with chronic hypercapnia, NIV resulted in a greater reduction in PtCO2 compared with NHF, which was of uncertain clinical significance. NHF was better tolerated than NIV and may be a therapeutic option for some people with hypercapnic respiratory failure. CLINICAL TRIAL REGISTRATION: ACTRN12616001701415 at www.anzctr.org.au.

Anti-inflammatory duration of action of fluticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial.

BACKGROUND: Fluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action. METHODS: A single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naïve adults with asthma. Participants with an FEV1 ≥ 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation. RESULTS: In the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42-212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61-0.86) with the maximum reduction occurring at day 14, 0.32 (0.27-0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59-1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment. CONCLUSIONS: The anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma. Funding GlaxoSmithKline (201499). TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov registry number NCT02712047 .

Treatable traits of chronic airways disease.

PURPOSE OF REVIEW: To describe the rationale on which the treatable traits approach to the management of airways disease is based and the issues that need to be considered for its implementation in clinical practice. RECENT FINDINGS: In clinical practice, treatable traits can be classified according to both endotypes and phenotypes, broadly grouped within pulmonary, extrapulmonary, environmental and behavioural factors. Specific investigations and treatments are undertaken for each of the traits rather than a 'one size fits all' stepwise approach to pharmacological treatment which currently represents the core of asthma and chronic obstructive pulmonary disease (COPD) guidelines. Although there is strong evidence of the benefit of the treatable traits approach to specific traits in asthma and/or COPD, there is uncertainty regarding the preferred method of implementation, efficacy and cost-effectiveness of multidimensional intervention programmes in clinical practice. It is likely that 'master protocols' for randomized controlled trials will be required to evaluate such multiple interventions in broad populations of patients with airways disease. SUMMARY: Current evidence suggests that the precision medicine approach based on the identification and treatment of treatable traits is preferable to a 'one-size-fits-all' stepwise approach to the treatment of airways disease, although high-quality evidence to guide the practical application of this multidimensional management strategy is now required. VIDEO ABSTRACT.

Impaired coronary contraction to phenylephrine after cardioplegic arrest in diabetic patients.

BACKGROUND: We have previously found that hyperkalemic cardioplegic arrest in the setting of cardiopulmonary bypass (CP/CPB) is associated with impairment of the coronary arteriolar response to phenylephrine in nondiabetic (ND) patients. We hypothesized that diabetes may alter coronary arteriolar response to alpha-1 adrenergic agonist in the setting of CP/CPB. In this study, we further investigated the effects of diabetes on the altered coronary arteriolar response to phenylephrine in patients undergoing cardiac surgery. METHODS: Coronary arterioles (90-150 µm in diameter) were harvested pre- and post-CP/CPB from the ND and diabetic mellitus (DM) patients (n = 8/group) undergoing cardiac surgery. In-vitro microvascular reactivity was examined in response to phenylephrine. The protein expression/localization of the alpha-1 adrenergic receptors in the atrial myocardium was measured by Western blotting and immunohistochemistry. RESULTS: Phenylephrine (10-9 to 10-4 M) induced a dose-dependent contractile response in both ND and DM vessels pre- and post-CP/CPB. There was no significant difference in the pre-CP/CPB contractile responses to phenylephrine between ND and DM groups. The post-CP/CPB contractile response was significantly diminished in both ND and DM groups compared with the respective pre-CP/CPB response (P < 0.05 versus pre-CP/CPB). This diminished contractile response was more pronounced in vessels from DM patients compared with vessels from ND patients (P < 0.05 versus ND). There were no significant differences in the protein expression of alpha-1A and alpha-1B receptors in the atrial myocardium between the ND and DM groups or tissue harvested pre- or post-CP/CPB. CONCLUSIONS: Diabetes is associated with a decreased contractile response of coronary arterioles to phenylephrine in the setting of CP/CPB versus that observed in ND patients. This alteration may contribute to the vasomotor dysfunction of coronary microcirculation seen early after CP/CPB in patients with diabetes.

Nasal high flow therapy and PtCO2 in stable COPD: A randomized controlled cross-over trial.

BACKGROUND AND OBJECTIVE: Hypercapnia is associated with worse clinical outcomes in exacerbations of COPD. The present study aimed to determine the effects of nasal high flow (NHF) therapy on transcutaneous partial pressure of carbon dioxide (PtCO2 ) in stable COPD patients. METHODS: In a single-blind randomized controlled cross-over trial, 48 participants with COPD were allocated in random order to all of four 20 min interventions: NHF at 15 L/min, 30 L/min and 45 L/min or breathing room air with each intervention followed by a washout period of 15 min. The primary outcome measure was PtCO2 at 20 min, adjusted for baseline PtCO2 . Secondary outcomes included respiratory rate at 20 min, adjusted for baseline. RESULTS: The mean (95% CI) change in PtCO2 at 20 min was -0.6 mm Hg (-1.1 to 0.0), P = 0.06; -1.3 mm Hg (-1.9 to 0.8), P < 0.001; and -2.4 mm Hg (-2.9 to -1.8), P < 0.001; for NHF at 15 L/min, 30 L/min and 45 L/min compared with room air, respectively. The mean (95% CI) change in respiratory rate at 20 min was -1.5 (-2.7 to -0.3), P = 0.02; -4.1 (-5.3 to -2.9), P < 0.001; and -4.3 (-5.5 to -3.1), P < 0.001; breaths per minute compared with room air, respectively. CONCLUSION: NHF results in a small flow-dependent reduction in PtCO2 and respiratory rate in patients with stable COPD.

Oxygen versus air-driven nebulisers for exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: In exacerbations of chronic obstructive pulmonary disease, administration of high concentrations of oxygen may cause hypercapnia and increase mortality compared with oxygen titrated, if required, to achieve an oxygen saturation of 88-92%. Optimally titrated oxygen regimens require two components: titrated supplemental oxygen to achieve the target oxygen saturation and, if required, bronchodilators delivered by air-driven nebulisation. The effect of repeated air vs oxygen-driven bronchodilator nebulisation in acute exacerbations of chronic obstructive pulmonary disease is unknown. We aimed to compare the effects of air versus oxygen-driven bronchodilator nebulisation on arterial carbon dioxide tension in exacerbations of chronic obstructive pulmonary disease. METHODS: A parallel group double-blind randomised controlled trial in 90 hospital in-patients with an acute exacerbation of COPD. Participants were randomised to receive two 2.5 mg salbutamol nebulisers, both driven by air or oxygen at 8 L/min, each delivered over 15 min with a 5 min interval in-between. The primary outcome measure was the transcutaneous partial pressure of carbon dioxide at the end of the second nebulisation (35 min). The primary analysis used a mixed linear model with fixed effects of the baseline PtCO2, time, the randomised intervention, and a time by intervention interaction term; to estimate the difference between randomised treatments at 35 min. Analysis was by intention-to-treat. RESULTS: Oxygen-driven nebulisation was terminated in one participant after 27 min when the PtCO2 rose by > 10 mmHg, a predefined safety criterion. The mean (standard deviation) change in PtCO2 at 35 min was 3.4 (1.9) mmHg and 0.1 (1.4) mmHg in the oxygen and air groups respectively, difference (95% confidence interval) 3.3 mmHg (2.7 to 3.9), p < 0.001. The proportion of patients with a PtCO2 change ≥4 mmHg during the intervention was 18/45 (40%) and 0/44 (0%) for oxygen and air groups respectively. CONCLUSIONS: Oxygen-driven nebulisation leads to an increase in PtCO2 in exacerbations of COPD. We propose that air-driven bronchodilator nebulisation is preferable to oxygen-driven nebulisation in exacerbations of COPD. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry number ACTRN12615000389505 . Registration confirmed on 28/4/15.

Phenotypes of symptomatic airways disease in China and New Zealand.

It is uncertain whether phenotypes of asthma and chronic obstructive pulmonary disease (COPD) vary between populations with different genetic and environmental characteristics. Here, our objective was to compare the phenotypes of airways disease in two separate populations.This was a cross-sectional observational study in adult populations from New Zealand and China. Participants aged 40-75 years who reported wheeze and breathlessness in the last 12 months were randomly selected from the general population and underwent detailed characterisation. Complete data for cluster analysis were available for 345 participants. Hierarchical cluster analysis was undertaken, based on 12 variables: forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity ratio, bronchodilator reversibility, peak expiratory flow variability, transfer coefficient of the lung for carbon monoxide, exhaled nitric oxide fraction, total IgE, C-reactive protein, age of symptom onset, body mass index, health status and cigarette smoke exposure.Cluster analysis of the combined dataset described five phenotypes: "severe late-onset asthma/COPD overlap group", "moderately severe early-onset asthma/COPD overlap group", "moderate to severe asthma group with type 2 predominant disease", and two groups with minimal airflow obstruction, differentiated by age of onset. Separate analyses by country showed similar patterns; however, a distinct obese/comorbid group was observed in the New Zealand population.Cluster analysis of adults with symptomatic airways disease suggests the presence of similar asthma/COPD overlap phenotypes within populations with different genetic and environmental characteristics, and an obese/comorbid phenotype in a Western population.