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.

Evaluating the Feasibility of a Community Pharmacy-Delivered Behaviour Change Intervention to Reduce Reliever Reliance in Asthma.

Purpose: The aim of this study was to evaluate the feasibility of a community pharmacy-delivered intervention to shift patients' beliefs about short-acting beta2 agonists (SABA) in asthma management. The study targeted individual beliefs about SABA and assessed actual SABA use, focusing on reducing SABA use as well as adherence to inhaled corticosteroids (ICS) as a preventive measure. Patients and Methods: This non-randomized, before-and-after feasibility study enrolled participants with asthma from four community pharmacies in Auckland, New Zealand. Eligible participants were aged 18 years and above and were prescribed a SABA for their asthma. The intervention included the SABA reliance questionnaire to determine the degree of SABA reliance, verbal discussions with pharmacists personalised according to the degree of SABA reliance identified, and referral to general practitioners as appropriate. Results: Of the 44 patients who consented into the study, 19 were in the control group and 16 in the intervention group. Recruitment and retention were modest, with 10 control and five intervention participants completing the 90-day follow-up. Although not statistically significant, preliminary results indicated reduced SABA reliance and increased ICS adherence in the intervention group, and reduced SABA refill. Feedback showed that 78% of intervention participants found the information easy to understand, and 56% expressed intent to consult their general practitioners. Pharmacy staff found the intervention feasible but noted time constraints as a barrier to intervention delivery. Conclusion: The study demonstrates that a community pharmacy-delivered intervention is feasible and acceptable to both patients and pharmacists. While preliminary results show a positive effect on reducing SABA reliance and improvement of ICS adherence, the results were not statistically significant due to the small numbers recruited. This suggests a larger randomised trial is indicated. This intervention holds promise for addressing the over-reliance on SABA in asthma management and improving adherence to preventive therapies.

Taking Charge After Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Randomized Controlled Feasibility Trial of a Psychologically Informed Self-Management Intervention.

Purpose: Few interventions improve outcomes for people with Chronic Obstructive Pulmonary Disease (COPD), particularly higher risk groups such as those admitted to hospital with an acute exacerbation of COPD (AECOPD). The aim of the study was to test the feasibility and acceptability of a modified version of the Take Charge program in people after AECOPD and to determine the potential to improve self-reported limitations, health-related quality of life and reduce future hospitalizations. Patients and Methods: A prospective, parallel group randomized trial with blinded endpoint assessment. Participants had been discharged from hospital with a diagnosis of AECOPD and were randomized to receive either a single 60-90 minute session of "Take Charge for COPD" from a trained facilitator in their own home or usual care. Take Charge is a "talking therapy" that encourages a sense of purpose, autonomy, mastery, and connectedness with others. The primary outcome was the rate of moderate or severe episodes of AECOPD in the subsequent 12 months. Results: Fifty-six people were randomized (study target 60): predominantly European (71%), female (61%), older (mean [SD] age 70 [11] years), and non-smokers (89%). Charlson Comorbidity Index mean (SD) score was 2.3 (1.6) indicating mild to moderate comorbidity severity. There were 85 moderate or severe AECOPD episodes in the 12 months after the index admission for the Take Charge participants and 84 episodes in the control group (relative rate 0.93; 95% confidence interval (CI) 0.69 to 1.26). COPD Clinical Questionnaire (CCQ) scores were significantly lower (better) in the Take Charge group (mean difference -1.26; 95% CI -2.06 to -0.45). Conclusion: The Take Charge intervention proved feasible with a population of people recently discharged from hospital with AECOPD. The direction of change in the primary outcome and some secondary outcomes suggest that an adequately powered study is justified.

Prevention of Re-Hospitalization for Acute Exacerbations: Perspectives of People with Chronic Obstructive Pulmonary Disease: A Qualitative Study.

Purpose: Current guidelines for prevention of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) reflect clinical understanding of the causes of exacerbations but with a limited recognition of person-specific contributing factors. As part of a randomized trial of a person-centered intervention aiming to promote self-determination, we describe personal perspectives of those with chronic obstructive pulmonary disease (COPD) on what they saw as the causes and best ways to stay well and prevent rehospitalization after an AECOPD. Patients and Methods: Twelve participants (mean age 69.3 years, six female, six male; eight New Zealand European, two Maori, one Pacific, and one other) were interviewed about their experiences of staying well and out of hospital. Data were collected via individual semi-structured interviews one year following an index hospital admission for AECOPD and focused on the participants' views and experiences of their health condition, their beliefs about staying well, and the causes of and factors preventing further exacerbations and hospitalizations. Data were analyzed using constructivist grounded theory methods. Results: Three main themes were identified that described participants' views on what helped or hindered them to stay well and out of hospital: 1) Being Positive: The importance of having a positive mindset; 2) Being Proactive: Practical steps to reduce the risk of, and consequences from, episodes of AECOPD; and 3) Being in Control: Feeling in command of one's life and health. Each of these was affected by Being Connected: The influence of significant others, particularly close family. Conclusion: This research expands our understanding of how patients manage COPD and adds patient perspectives to current knowledge on how to prevent recurrent AECOPD. Programs which promote self-efficacy and positivity would be beneficial additions to AECOPD prevention strategies, as could the inclusion of family or significant others in wellbeing plans.

A survey of adult respiratory and sleep services in Aotearoa New Zealand: inequities in the provision of adult respiratory and sleep services.

AIMS: The New Zealand "Standards for Adult Respiratory and Sleep Services" were published by the Ministry of Health in 2004. A 2006 survey demonstrated major gaps in the staffing and service provision and significant variation between district health boards (DHBs). We repeated this survey in 2019/20 in order to highlight issues which should be addressed as part of health service reforms. METHODS: Survey of all adult DHB respiratory services assessing staffing and service provision. RESULTS: There is marked regional variation in staffing levels for all specialist clinicians. There are 1.18 FTE/100,000 population respiratory physicians, which is well below Australian and United Kingdom levels. Two hundred thousand people in New Zealand do not have access to a local respiratory physician. For provided services we found a four-fold variation between DHBs for CPAP treatments, six-fold for oxygen services, and eight-fold for pulmonary rehabilitation. CONCLUSION: The place of residence of New Zealanders determines access to respiratory services. There are inequities in access, with little progress made since 2006. Data on health outcomes are required. The restructure of the health service must rectify this situation. The need to end a "postcode lottery" is demonstrated when reviewing current respiratory services in New Zealand.

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.

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.

Rhinothermy delivered by nasal high flow therapy in the treatment of the common cold: a randomised controlled trial.

BACKGROUND: The common cold is the most common infectious disease affecting humans and has a substantial economic impact on society. Human rhinoviruses, which cause almost two-thirds of colds, have demonstrated temperature-dependent replication which is optimal between 33°C and 35°C. METHODS: This randomised, single-blind, parallel-group trial completed at a single-centre in New Zealand, recruited 170 participants aged 18-75 years (mean age 27.5 years) who were within 48 hours of common cold symptom onset and had a symptom score (the Modified Jackson Score (MJS)) ≥7 and a negative point-of-care test for influenza. Participants were blinded to the intervention and randomised (1:1) to 5 days of either nasal high flow rhinothermy (rNHF) (100% humidified air delivered at 35 L/min and 41°C for 2 hours daily) (n=85) or 'sham' rhinothermy (100% humidified air delivered at 10 L/min and 31°C for 10 min daily) (n=85) and completed daily symptom diaries, which included the MJS, for 14 days, to investigate whether rNHF reduced common cold symptom severity and duration compared with 'sham' rhinothermy. RESULTS: An intention-to-treat superiority analysis included all randomised participants and showed no difference between treatment groups for the primary outcome, the day 4 MJS analysed by analysis of covariance: mean (SD) 6.33 (3.97) for rNHF vs 5.8 (3.15) for 'sham'; estimated difference (95% CI) 0.37 (-0.69 to 1.42), p=0.49. There was no difference in time until resolution of symptoms: mean (SD) 5.96 (4.47) days for rNHF vs 6.42 (4.09) days for 'sham'; estimated difference (95% CI) 1.02 (0.75 to 1.38), p=0.91. There were no serious adverse events related to the study treatments. CONCLUSIONS: This well-powered, single-blind randomised controlled trial does not provide evidence that 5 days of rNHF (100% humidified air heated to 41°C delivered at 35 L/min for 2 hours daily) reduces common cold symptom severity or duration. However, investigation of rNHF in the treatment of influenza is warranted. TRIAL REGISTRATION NUMBER: ACTRN12617001340325.

New Zealand COPD Guidelines: Quick Reference Guide.

The purpose of the Asthma and Respiratory Foundation of New Zealand's COPD Guidelines: Quick Reference Guide is to provide simple, practical, evidence-based recommendations for the diagnosis, assessment, and management of chronic obstructive pulmonary disease (COPD) in clinical practice. The intended users are health professionals responsible for delivering acute and chronic COPD care in community and hospital settings, and those responsible for the training of such health professionals.

ICS-formoterol reliever versus ICS and short-acting ß2-agonist reliever in asthma: a systematic review and meta-analysis.

BACKGROUND: The Global Initiative for Asthma recommends as-needed inhaled corticosteroid (ICS)-formoterol as an alternative to maintenance ICS plus short-acting ß2-agonist (SABA) reliever at step 2 of its stepwise treatment algorithm. Our aim was to assess the efficacy and safety of these two treatment regimens, with a focus on prevention of severe exacerbation. METHODS: We performed a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing as-needed ICS-formoterol with maintenance ICS plus SABA. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov were searched from database inception to 12 December 2019. The primary outcome was time to first severe exacerbation. RCTs were excluded if they used as-needed budesonide-formoterol as part of a maintenance and reliever regimen, or did not report on severe exacerbations. The review is registered with PROSPERO (identifier number CRD42020154680). RESULTS: Four RCTs (n=8065 participants) were included in the analysis. As-needed ICS-formoterol was associated with a prolonged time to first severe exacerbation (hazard ratio 0.85, 95% CI 0.73-1.00; p=0.048) and reduced daily ICS dose (mean difference -177.3 µg, 95% CI -182.2--172.4 µg). Asthma symptom control was worse in the as-needed group (Asthma Control Questionnaire-5 mean difference 0.12, 95% CI 0.09-0.14), although this did not meet the minimal clinically important difference of 0.50 units. There was no significant difference in serious adverse events (OR 1.07, 95% CI 0.84-1.36). CONCLUSION: As-needed ICS-formoterol offers a therapeutic alternative to maintenance low-dose ICS plus SABA in asthma and may be the preferred option when prevention of severe exacerbation is the primary aim of treatment.

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.

Combination budesonide/formoterol inhaler as sole reliever therapy in Maori and Pacific people with mild and moderate asthma.

AIM: In the PRACTICAL study, as-needed budesonide/formoterol reduced the rate of severe exacerbations compared with maintenance budesonide plus as-needed terbutaline. In a pre-specified analysis we analysed the efficacy in Maori and Pacific peoples, populations with worse asthma outcomes. METHOD: The PRACTICAL study was a 52-week, open-label, parallel group, randomised controlled trial of 890 adults with mild to moderate asthma, who were randomised to budesonide/formoterol Turbuhaler 200/6mcg one actuation as required or budesonide Turbuhaler 200mcg one actuation twice daily and terbutaline Turbuhaler 250mcg two actuations as required. The primary outcome was rate of severe exacerbations. The analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable. RESULTS: Seventy-two participants (8%) identified as Maori, 36 participants (4%) as Pacific ethnicity. There was no evidence that ethnicity was an effect modifier for severe exacerbations (P interaction 0.70). CONCLUSION: The reduction in severe exacerbation risk with budesonide-formoterol reliever compared with maintenance budesonide was similar in Maori and Pacific adults compared with New Zealand European/Other.

Patient preferences for asthma management: a qualitative study.

OBJECTIVE: Preference for asthma management and the use of medications is motivated by the interplay between lived experiences of asthma and patients' attitudes towards medications. Many previous studies have focused on individual aspects of asthma management, such as the use of preventer and reliever inhalers. The aim of this qualitative study was to explore the preferences of patients with mild-moderate asthma for asthma management as a whole and factors that influenced these preferences. DESIGN: A qualitative study employing qualitative descriptive analysis situated within a constructionist epistemology to analyse transcribed audio recordings from focus groups. SETTING: Three locations within the greater Wellington area in New Zealand. PARTICIPANTS: Twenty-seven adults with self-reported doctor's diagnosis of asthma, taking short-acting beta-agonists alone or inhaled corticosteroids with or without long-acting beta2-agonist, who had used any inhaled asthma medication within the last month. RESULTS: Four key areas described preferences for asthma management. Preferences for self-management: participants wanted to be in control of their asthma and developed personal strategies to achieve this. Preferences for the specific medications or treatment regimen: participants preferred regimens that were convenient and reliably relieved symptoms. Preferences for inhaler devices: devices that had dose counters and were easy to use and portable were important. Preferences for asthma services: participants wanted easier access to their inhalers and to be empowered by their healthcare providers. Participant preferences within each of these four areas were influenced by the impact asthma had on their life, their health beliefs, emotional consequences of asthma and perceived barriers to asthma management. CONCLUSIONS: This study illustrates the interaction of the lived experience of asthma, factors specific to the individual, and factors relating to asthma treatments in shaping patient preferences for asthma management. This aids our understanding of preferences for asthma management from the patient perspective. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000601134).

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.

Asthma and Respiratory Foundation NZ Adolescent and Adult Asthma Guidelines 2020: a quick reference guide.

The purpose of the 2020 Asthma and Respiratory Foundation NZ Adolescent and Adult Asthma Guidelines is to provide simple, practical and evidence-based recommendations for the diagnosis, assessment and management of asthma in adolescents and adults (aged 12 and over) in a quick reference format. The intended users are health professionals responsible for delivering asthma care in the community and hospital settings, and those responsible for the training of such health professionals. The main changes in the 2020 update are: 1) combining the recommendations for both adolescents and adults in a single document, 2) the recommendation to avoid SABA-only treatment in the long-term management of asthma, 3) the use of budesonide/formoterol reliever, with or without maintenance budesonide/formoterol, is preferred to SABA reliever, with or without maintenance ICS or ICS/LABA, across the spectrum of asthma severity, 4) introduction of the terminology 'anti-inflammatory reliever (AIR)' therapy to describe the use of budesonide/formoterol as a reliever medication, with or without maintenance budesonide/ formoterol therapy. This approach encompasses and extends the 'Single combination ICS/LABA inhaler Maintenance And Reliever Therapy' (SMART) approach recommended in the previous guideline, 5) the inclusion of two stepwise management algorithms, 6) a clinical allergy section, 7) the role of LAMA therapy in severe asthma, 8) the role of omalizumab in severe allergic asthma and mepolizumab in severe eosinophilic asthma, 9) an appendix detailing educational materials.

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.

Skeletal muscle microvasculature response to ß-adrenergic stimuli is diminished with cardiac surgery.

BACKGROUND: Cardiac surgery and cardiopulmonary bypass are associated with alterations in blood pressure in the perioperative period, which, if uncontrolled, can result in end organ damage or dysfunction. Microvessels, significant contributors to blood pressure, both in the myocardium and peripheral skeletal muscle, have diminished responsiveness to major mediators of vascular tone, including thromboxane and serotonin after cardiopulmonary bypass. Responsiveness of these vessels to ß-adrenergic stimulation, a major mediator of vascular tone, has not yet been studied. In this report, we investigated the role of ß-adrenergic receptors in vascular tone regulation in human skeletal muscle microvessels before and after ß-adrenergic stimulation. METHODS: Skeletal muscle microvessels were isolated from patients undergoing cardiac surgery before and after cardiopulmonary bypass. Vessels were exposed in an ex vivo model to the ß-adrenergic agonist isoproterenol, or the direct adenylyl cyclase activator, forskolin, and the selective ß-receptor antagonist ICI18.551 hydrochloride plus isoproterenol. Immunofluorescence of ß receptors and Western blotting were also performed. RESULTS: Microvessels showed diminished responsiveness to isoproterenol (10-6 to 10-4M) after cardiopulmonary bypass (n = 8/group, P = .01). Pretreatment with the selective ß-2 blocker ICI18.551 (10-6M) prevented isoproterenol-induced microvascular relaxation (P = .001). Forskolin-induced relaxation response was also significantly diminished after cardiopulmonary bypass (n = 4/group, P < .05 versus before cardiopulmonary bypass). No significant changes in the total protein expression of ß-1, ß-2, and ß-3 receptors were detected by western blotting or immunofluorescence. CONCLUSION: Microvessels isolated from human skeletal muscle show diminished responsiveness to isoproterenol and its downstream activator forskolin after cardiopulmonary bypass, suggesting there is an alteration in ß-adrenergic receptor responsive in adenylate cyclase. The relaxation response to isoproterenol was via activation ß-2 receptors without changes in ß-adrenergic receptor abundance.