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Introduction Faced with the challenges of climate change, countries are seeking to decarbonise their economies. A greater understanding of what comprises the carbon footprint of care in healthcare systems will identify potential strategies for reduction of greenhouse gas (GHG) emissions. In respiratory care, the focus has been on preventer inhalers, thereby omitting contributions from other aspects such as healthcare resource utilisation (HCRU) and reliever inhaler use. The healthCARe-Based envirONmental cost of treatment (CARBON) programme aims to provide a broader understanding of the carbon footprint associated with respiratory care. Methods CARBON will quantify the carbon footprint of medications and HCRU among approximately 2.5 million patients with respiratory diseases from seven ongoing studies spanning more than 40 countries. Across studies, to obtain the carbon footprint of all inhaled, oral, and injectable medications, SimaPro life cycle assessment software modelling resource and energy consumption data, in addition to Ecoinvent(R) data sets and certified published studies, will be used. The carbon footprint of HCRU in the United Kingdom will be estimated by applying the methodology and data obtained from the Sustainable Healthcare Coalition Care Pathway Guidance. Planned Outcomes In asthma, CARBON studies will quantify GHG emissions associated with well-controlled versus not well-controlled asthma, the contribution of short-acting beta(2)-agonist (SABA) reliever inhalers (and their potential overuse) to the carbon footprint of care, and how implementation of treatment guidelines can drive improved outcomes and footprint reduction. In chronic obstructive pulmonary disease (COPD), CARBON studies will assess the impact of exacerbation history on GHG emissions associated with HCRU and SABA use in subsequent years and estimate the carbon footprint associated with all aspects of COPD care. Conclusion CARBON aims to show that the principle of evidence-led care focused on improvement of clinical outcomes has the potential to benefit patients and the environment.

Background The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines. Methods We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995. Findings Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to

Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)—a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)—are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.

IntroductionOral corticosteroids (OCS) for asthma are associated with increased risks of developing adverse outcomes (adverse outcomes); no previous study has focused exclusively on intermittent OCS use.MethodsThis historical (2008–2019) UK cohort study using primary care medical records from two anonymised, real-life databases (OPCRD and CPRD) included patients aged≥4 years with asthma receiving only intermittent OCS. Patients were indexed on their first recorded intermittent OCS prescription for asthma and categorised by OCS prescribing patterns: one-off (single), less frequent (≥90 day gap) and frequent (2-agonist (SABA) prescriptions using a multivariable Cox-proportional hazard model.FindingsOf 476 167 eligible patients, 41.7%, 26.8% and 31.6% had one-off, less frequent and frequent intermittent OCS prescribing patterns, respectively. Risk of any AO increased with increasingly frequent patterns of intermittent OCS versus non-OCS (HR; 95% CI: one-off 1.19 (1.18 to 1.20), less frequent 1.35 (1.34 to 1.36), frequent 1.42 (1.42 to 1.43)), and was consistent across age, GINA treatment step and ICS and SABA subgroups. The highest risks of individual OCS-related adverse outcomes with increasingly frequent OCS were for pneumonia and sleep apnoea.ConclusionA considerable proportion of patients with asthma receiving intermittent OCS experienced a frequent prescribing pattern. Increasingly frequent OCS prescribing patterns were associated with higher risk of OCS-related adverse outcomes. Mitigation strategies are needed to minimise intermittent OCS prescription in primary care.

Enrico de Nigris,1 Catrin Treharne,2 Nick Brighton,2 Ulf Holmgren,3 Andrew Walker,4 John Haughney5 1Formerly of Global Product and Portfolio Strategy, AstraZeneca, Cambridge, UK; 2Formerly of Health Economic Modelling, Regulatory and Access, Parexel International, London, UK; 3Real World Science and Digital, BioPharmaceuticals Medical, AstraZeneca, Gothenburg, Sweden; 4Salus Alba, Glasgow, UK; 5Clinical Research Facility, Queen Elizabeth University Hospital, Glasgow, UKCorrespondence: Ulf Holmgren, AstraZeneca, Pepparedsleden 1, Gothenburg, SE-431 83, Sweden, Tel +46 0 317 761 424, Email ulf.holmgren@astrazeneca.comBackground: In the 52-week ETHOS study (NCT02465567), fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) reduced moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations versus fixed-dose long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) or inhaled corticosteroid (ICS)/LABA dual therapies. Here, ETHOS data were used to estimate the long-term cost-effectiveness of BGF versus LAMA/LABA and ICS/LABA dual therapies in the United Kingdom.Methods: Costs, exacerbations, quality-adjusted life-years (QALYs), and LYs were extrapolated using a Markov model that considered disease severity progression, risk of moderate and severe exacerbations, adverse events, and treatment discontinuation in patients with moderate-to-very severe COPD receiving BGF 320/14.4/10 μg, the LAMA/LABA glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg (GFF), or the ICS/LABA budesonide/formoterol fumarate dihydrate 320/10 μg (BFF). Utilities for COPD severity states were estimated using EuroQol 5-dimension 5-level data from ETHOS. Exacerbation disutilities were sourced from published literature. Healthcare resource utilization was based on ETHOS data, published literature, key external experts’ input, and informed assumptions. Unit costs came from the UK National Health Service Schedule of Reference Costs, Unit Costs of Health and Social Care from the Personal Social Services Research Unit, and published literature. A lifetime horizon was considered, with costs, QALYs, and LYs discounted at 3.5% per annum.Results: The incremental cost–utility ratio (ICUR; per QALY gained) was £ 9901 for BGF versus GFF and £ 2164 for BGF versus BFF. The probability of treatments being cost-effective at the conventional UK-adopted willingness-to-pay threshold of ICUR

Introduction The Fostair® 100/6 (BDP/FF) pressurized metered-dose inhaler, delivering an extrafine formulation, is licensed for asthma and COPD in the UK. However, its real-life effectiveness for COPD has not been evaluated. This study compared the clinical effectiveness of BDP/FF against other licensed ICS/LABA combination inhalers: the Seretide® Accuhaler® (FP/SAL) and the Symbicort® Turbohaler® (BUD/FF). Methods A matched historical cohort study was conducted using records of patients with diagnostic codes for COPD from the Optimum Patient Care Research Database (OPCRD). Patients who had received BDP/FF as their first ICS/LABA were matched 1:1 with patients who had received FP/SAL or BUD/FF, resulting in two matched comparisons. Additional analysis was conducted on patients who had never had diagnostic codes for asthma. Noninferiority in terms of the proportion of patients with moderate/severe COPD exacerbations on the different inhalers in the following year was assessed. Noninferiority was achieved if the upper CI limit were ≤1.2. Results This study included 537 and 540 patient pairs in the BDP/FF vs FP/SAL cohort and the BDP/FF vs BUD/FF cohort, respectively. The proportion of patients with COPD exacerbations in the BDP/FF group was not significantly different from either the FP/SAL (68.7% vs 70.2%, AOR 0.89, 95% CI 0.67–1.19) or BUD/FF group (68.5% vs 69.4%, AOR 0.79, 95% CI 0.58–1.08). Noninferiority of BDP/FF in preventing COPD exacerbations was fulfilled in both comparisons. In patients without asthma, BDP/FF was also noninferior to BUD/FF (proportion with COPD exacerbations, 67.8% vs 64.7%, AOR 0.79, 95% CI 0.51–1.1997). Additionally, a significantly lower proportion of patients prescribed BDP/FF had COPD exacerbations than FP/SAL (64.8% vs 73.7%, AOR 0.64 95% CI 0.43–0.96). Conclusion Initiating ICS/LABA treatment of COPD with extrafine-formulation BDP/FF was noninferior in preventing moderate/severe exacerbations compared to FP/SAL and BUD/FF.

Acknowledgments: The iHARP database was funded by unrestricted grants from Mundipharma International Limited and Optimum Patient Care Global Ltd, which is a social enterprise that focuses on quality improvement in clinical practice. The sponsor was not involved in data analysis or the interpretation of the results.

BACKGROUND: The Asthma Daytime Symptom Diary (ADSD) and the Asthma Nighttime Symptom Diary (ANSD) were developed to meet the need for standardized patient-reported measures of asthma symptoms to assess treatment trial outcomes in adults and adolescents. OBJECTIVE: To determine scoring and evaluate the measurement properties of the ADSD/ANSD. METHODS: Adolescents (12-17 years) and adults (18 + years) with asthma completed draft 8-item electronic versions of the ADSD/ANSD for 10 days alongside the Adult Asthma Symptom Daily Scales (AASDS) and a Patient Global Impression of Severity (PGIS). Using classical and modern psychometric methods, initial analyses evaluated the performance of ADSD/ ANSD items to inform scoring. Subsequent analyses evaluated the reliability and validity of ADSD/ANSD scores. RESULTS: A demographically and clinically diverse sample (n = 130 adolescents; n = 89 adults) was recruited. Item performance was generally strong. However, items assessing chest pressure and mucus/phlegm demonstrated redundancy and poorer performance and were removed. Principal-components analysis, confirmatory factor analysis, and item response theory supported combining items to form 6-item total ADSD/ANSD scores. Internal consistency (alpha = 0.94-0.95) and test-retest reliability (intraclass correlation coefficient = 0.86-0.95) were strong. Strong correlations (r = 0.72-0.80) were observed between ADSD scores and AASDS items assessing asthma symptom frequency, bother, and impact on activities. Significant differences (P < .001) in mean ADSD/ANSD scores were observed between groups categorized by asthma severity (PGIS), asthma control, inhaler use, nebulizer use, activity limitations, and nighttime awakenings. CONCLUSIONS: The ADSD/ANSD items and scores demonstrated strong reliability and validity. Implementation of the measures in interventional studies will enable the evaluation of responsiveness and meaningful within-patient change. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

Background: \ud Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hearafter referred to as BNT).\ud \ud Methods: \ud COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130.\ud \ud Findings: \ud Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44–61) in the younger age group and 76 years (73–78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41–59) in the younger age group and 78 years (75–82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5–2·3) in the half VLA group to 32·3 (24·8–42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7–1·6) for ChAd to 3·6 (2·4–5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0–1·5) in the half VLA group to 11·5 (9·4–14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7–1·6) for half VLA to 4·7 (3·1–7·1) for m1273. The results were similar between those aged 30–69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30–69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273.\ud \ud Interpretation: \ud All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination.\ud \ud Funding: \ud UK Vaccine Taskforce and National Institute for Health Research.

Background The B.1.1.7 (Alpha) SARS-CoV-2 variant of concern was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between the B.1.1.7 lineage infection and increased 28-day mortality. However, to date none have addressed the impact of infection on severity of illness or the need for oxygen or ventilation. Methods In this prospective clinical cohort sub-study of the COG-UK consortium, 1475 samples from hospitalised and community cases collected between the 1st November 2020 and 30th January 2021 were collected. These samples were sequenced in local laboratories and analysed for the presence of B.1.1.7-defining mutations. We prospectively matched sequence data to clinical outcomes as the lineage became dominant in Scotland and modelled the association between B.1.1.7 infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no support, 2. oxygen, 3. ventilation and 4. death. Additionally, we calculated an estimate of the growth rate of B.1.1.7-associated infections following introduction into Scotland using phylogenetic data. Results B.1.1.7 was responsible for a third wave of SARS-CoV-2 in Scotland, and rapidly replaced the previously dominant second wave lineage B.1.177) due to a significantly higher transmission rate (∼5 fold). Of 1475 patients, 364 were infected with B.1.1.7, 1030 with B.1.177 and 81 with other lineages. Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (B.1.1.7 versus non-B.1.1.7). Viral load was higher in B.1.1.7 samples than in non-B.1.1.7 samples as measured by cycle threshold (Ct) value (mean Ct change: -2.46, 95% CI: -4.22, -0.70). Conclusions The B.1.1.7 lineage was associated with more severe clinical disease in Scottish patients than co-circulating lineages. Funding COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute. Funding was also provided by UKRI through the JUNIPER consortium (grant number MR/V038613/1). Sequencing and bioinformatics support was funded by the Medical Research Council (MRC) core award (MC UU 1201412).

Earlier detection of lung cancer is possible, but difficult and costly to achieve. Screening with Low Dose Computed Tomography (LDCT)scanning has been shown to reduce mortality by 20-25% over the past decade but uptake amongst those most likely to suffer the disease has been slow. Resource constraints and a high false positive rate have also limited adoption of LDCT in many health systems. Targeted screening of people most likely to benefit using a range of biomarkers may be one way to improve the yield and reduce the resource requirements of LDCT. Autoantibodies, which amplify the signal produced by cancer derived proteins, are present in the blood of people mounting an immune response to cancer are a potential way to select those at highest risk. We have followed up 12 208 people enrolled in the ECLS trial for three years and shown that the specificity for early stage (I &II) disease is 90.3% throughout that period. More cancers were detected in the control than the intervention arm of the trial (101V 83). Sensitivity was 77.8% after 6 months and dropped to 46.4% after 3 years. At the end of three years the hazard ratios (95%CI) for All Cause, Cancer Specific and Lung Cancer Mortality was 0.82(0.67-1.01), 0.72(0.54-0.97) and 0.70(0.46-1.08) respectively for those randomised to Early CDT testing. As a range of treatment modalities become increasingly more effective it is even more important to target LDCT on those most likely to have early stage disease. Autoantibody testing may be one method of targeting early detection on those most likely to benefit.

Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines based on updated variants are likely to be required over time to prevent productive infection. This study also suggests that two dose regimes of vaccine are required for maximal BNT162b2 and ChAdOx1-induced immunity.

Mafalda Ramos,1 Mark Lamotte,1 Laetitia Gerlier,1 Per Svangren,2 Anna Miquel-Cases,3 John Haughney4 1Real World Evidence Solutions, IQVIA, 1930 Zaventem, Belgium; 2Core Respiratory, Global Product and Portfolio Strategy – Global Payer Evidence and Pricing, AstraZeneca Gothenburg R&D, SE-431 83 Mölndal, Sweden; 3Global Price and Reimbursement, Global Payer Evidence and Pricing, AstraZeneca Gothenburg R&D, Cambridge CB2 8PA, UK; 4Academic Primary Care Division of Applied Health Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK Background: While the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines advise exercise to reduce disease progression, little investment in promoting physical activity (PA) is made by health care authorities. The purpose of this study was to estimate the cost-effectiveness of regular PA vs sedentary lifestyle in people with COPD in the UK.Methods: Efficacy, quality of life, and economic evidence on the PA effects in COPD patients were retrieved from literature to serve as input for a Markov microsimulation model comparing a COPD population performing PA vs a COPD population with sedentary lifestyle. The GOLD classification defined the model health states. For the base case, the cost of PA was estimated at zero, a lifetime horizon was used, and costs and effects were discounted at 3.5%. Analyses were performed from the UK National Health Service (NHS) perspective. Uncertainty around inputs and assumptions were explored via scenario and sensitivity analyses, including a cost threshold analysis. Outcomes were cost/quality-adjusted life year (QALY) gained and cost/year gained.Results: Based on our model, the effects of PA in the UK COPD population would be lower mortality (-6%), fewer hospitalizations (-2%), gains in years (+0.82) and QALYs (+0.66), and total cost savings of £2,568. The cost/QALY and cost/year gained were dominant. PA was cost-saving at costs

Patients’ peak inspiratory flow rate (PIFR) may help clinicians select a suitable inhaler device. The In-Check® device has gained some status as a simple tool to estimate PIFR (scale reflecting inhaler resistance from R0 to R5). It has been suggested that some patients with asthma may not be able to generate sufficient PIFR with high resistance devices (R5) to satisfy the minimum requirements of 30 L/min. We conducted a prospective service evaluation study to identify what proportion of patients with asthma are able to generate a correct PIFR at In-Check device R0-R5 resistance settings and what the phenotypical features of those patients are. As part of UK general practice asthma review service, sequential patients were recruited from 41 centres by 10 respiratory specialist nurses. Patients had PIFR checked at the resistance corresponding to their current preventer inhaler device, at R5 (high resistance dry powder inhaler (DPI) setting), and, at R0 (no resistance, pressurised metered dose inhaler (pMDI) setting. Correct PIFR (pass) was defined for R5 as 30–90 L/min, and, for R0 as 20–60 L/min. 994 adults (female 64.3%) were included, of whom 90.4% currently used a preventer inhaler (71.5% MDI (R0), 0% R1, 6.3% R2, 14.5% R3, 4.9% R4, 2.8% R5). 93.7% of patients passed at R5 resistance, compared to 70.5% at R0 (p 71 years) 90.2% passed at R5 compared to 71.0% at R0. Conclusion Patients with asthma can achieve adequate inspiratory flow 30–90 L/min with high resistance DPI (R5).

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. \ud \ud \ud METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. \ud \ud \ud FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. \ud \ud \ud INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. \ud \ud \ud FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Background: Exacerbations are an important driver of disease progression in COPD and are a key target for patient management. An observational retrospective cohort Study of HEalthcare Resource utiLisation related to exacerbatiOns in patients with COPD (SHERLOCK; D5980R00014) evaluated the clinical impact of exacerbations in primary care patients. Objective: To evaluate associations between exacerbation history and subsequent exacerbations in COPD. Methods: Patients in NHS Scotland ≥40 years of age with COPD were stratified by exacerbation history in the prior year: Group A (none), B (1 moderate), C (1 severe) and D (≥2 moderate and/or severe). Exacerbation rate and type were assessed over 3 years. Rate ratios (RR) were calculated versus the patients in Group A. Results: Overall, 22,462 patients were included. Over 1 year, moderate or severe exacerbation rates for the groups were 0.69 (A), 1.20 (B) and 1.27 (C) per person per year (Table). Patients with prior exacerbations had an increased likelihood of moderate or severe exacerbation during follow-up (B+C: 71%; B: 70%; C: 87%) versus patients in Group A. Data remained consistent over 3 years. Conclusions: In patients with COPD, increased likelihood and rate of subsequent exacerbation was observed after one prior exacerbation. Targeting patients with an exacerbation history may reduce related healthcare costs and support decision-makers with demand planning.

BACKGROUND: Patients' peak inspiratory flow rate (PIFR) may help clinicians select an inhaler device. OBJECTIVE: To determine the proportion of patients with asthma who could generate correct PIFRs at different inhaler resistance settings. METHODS: During a UK asthma review service, patients' PIFR was checked at resistance settings matching their current preventer inhaler device, at R5 (high resistance dry powder inhaler (DPI)) and at R0 (low resistance, pressurised metered dose inhaler (pMDI)). Correct PIFR ('pass') was defined for R5 as 30-90 L/min and for R0 as 20-60 L/min. A logistic regression model examined the independent predictors of incorrect PIFR ('fail') at R5 and R0. Asthma severity was assessed retrospectively from treatment level. RESULTS: A total of 994 adults (female 64.3%) were included, of whom 90.4% currently used a preventer inhaler (71.5% pMDI). PIFR pass rates were: 93.7% at R5 compared with 70.5% at R0 (p60 L/min), and 20% of patients currently using pMDI failed for this reason. Independent risk factors for failing R5 were: female gender, older age group and current preventer pMDI; and for failing R0 included: male gender, younger age group, current preventer DPI and mild versus severe asthma. CONCLUSIONS: This study demonstrates that most patients with asthma can achieve adequate inspiratory flow to activate high resistance DPIs, whereas approximately a third of patients breathe in too fast to achieve recommended inspiratory flows for correct pMDI use, including one fifth of patients who currently use a pMDI preventer.

Introduction Severe asthma is a debilitating, life-threatening disease associated with substantial global morbidity, mortality, and health care resource utilization. Patients may not receive guideline-directed medical care for severe asthma. Moreover, viable precision-based assessment tools and newer preventive therapies that can reduce the frequency of exacerbations and associated functional impact are underused. As a result, high rates of poorly controlled severe asthma persist, and patient health-related quality of life suffers. Methods In 2019, the Improve Access to Better Care Task Force of the PRECISION Steering Committee set out to develop a global template on quality standards for severe asthma care to support improved access to and delivery of quality care. This Quality Standard is grounded in the vast body of published evidence available for severe asthma care, published clinical guidelines (i.e., from the Global Initiative for Asthma in 2019 and the European Respiratory Society/American Thoracic Society in 2014), and the 2018 PRECISION-supported Charter to Improve Patient Care in Severe Asthma. Results The Quality Standard developed emphasizes four key elements aimed at optimizing clinical care and outcomes in severe asthma: (1) organization of services, (2) timely identification and referral for suspected severe asthma, (3) specialized assessment and management of severe asthma to optimize outcomes, and (4) patient-centric care and shared decision-making that is reflective of the patient’s expectations, priorities, and values. Four key Quality Statements are provided, along with quality metrics and strategies for local adaptation to optimize implementation. Conclusion This Global Quality Standard is intended to mobilize policymakers, health care providers, and patient advocacy groups to build consensus on the definition and expectations of quality care in severe asthma, to promote patient-centric care, to identify gaps in care and areas for improvement, and systematically implement improvement measures and outcomes and to reduce the burden of illness for patients with severe asthma., Plain Language Summary Although only 10% of patients with asthma have severe disease, these patients use up to half of all health care resources used to treat asthma. For the patient, severe asthma is associated with substantial morbidity, increased risk of death, and poor quality of life. Effective treatments for severe asthma are available, yet access to these treatments varies for many patients around the globe, and they are not always used effectively when available. A task force of leading global asthma experts was recently assembled to develop global standards to support improved access and delivery of quality care for patients with severe asthma. The task force identified four key elements to optimize management and outcomes: (1) coordination of services, (2) timely detection and referral of patients with severe asthma, (3) use of guideline-recommended assessments and therapies, and (4) integration of patient expectations and values when making treatment decisions. This Quality Standard details each of these elements by providing supporting rationale, ways to measure improvements in each area, and strategies to implement these elements at local clinics around the world. Ultimately, this Quality Standard is intended to help policymakers, health care providers, patient advocacy groups, and other key stakeholders build consensus on the requirements for quality care in severe asthma to improve patient care while also reducing the overall global burden of severe asthma.

Factors related to the discrepancy between patient-perceived and actual disease control remain unclear. Identifying patients at risk of overestimation of asthma control remains elusive. This study aimed to (i) investigate the relationship between patient-reported and actual level of asthma control (ii), compare the characteristics between patients who believe their asthma is well controlled that accurately report 'well-controlled' asthma with those that do not, and (iii) identify factors associated with inaccurately reported 'well-controlled' asthma. A historical, multinational, cross-sectional study using data from the iHARP (initiative Helping Asthma in Real-life Patients) review service for adults with asthma prescribed fixed-dose combination therapy. Data from 4274 patients were analysed. A major discrepancy between patient-reported and Global Initiative for Asthma defined asthma control was detected; 71.1% of patients who reported 'well-controlled' asthma were inaccurate in their perception despite receiving regular maintenance therapy. Significant differences were noted in age, gender, body mass index, education level, medication use, side effects, attitudes to preventer inhaler use, inhaler technique review and respiratory specialist review between patients who accurately reported 'wellcontrolled' asthma and those who did not. Independent risk factors associated with inaccurately reported 'well-controlled' asthma were: having taken a maximum of 5-12 puffs or more of reliever inhaler on at least one day within the previous 4 weeks; being female; having seen a respiratory specialist more than a year ago (rather than in the previous year); and having required oral corticosteroids for worsening asthma in the previous year. The study highlighted the significant hidden burden associated with under-recognition of poor asthma control, on the part of the patient and the need for targeted interventions designed to address the continuing discrepancy between perceived and actual disease control., The International Primary Care Respiratory Group (IPCRG) has facilitated the publication of this paper. The iHARP database was funded by unrestricted grants from Mundipharma International Limited and Optimum Patient Care Global Ltd, which is a social enterprise that focuses on quality improvement in clinical practice. The sponsor was not involved in data analysis or the interpretation of the results.

Objective Asthma has a substantial impact on quality of life and health care resources. The identification of a more cost-effective, yet equally efficacious, treatment could positively influence the economic burden of this disease. Fluticasone propionate/Formoterol (FP/FOR) may be as effective as Fluticasone Salmeterol (FP/SAL). We evaluated non-inferiority of asthma control in terms of the proportion of patients free from exacerbations, and conducted a cost impact analysis. Methods This historical, matched cohort database study evaluated two treatment groups in the Optimum Patient Care Research Database in the UK: 1) an FP/FOR cohort of patients initiating treatment with FP/FOR or changing from FP/SAL to FP/FOR and; 2) an FP/SAL cohort comprising patients initiating, or remaining on FP/SAL pMDI combination therapy. The main outcome evaluated non-inferiority of effectiveness (defined as prevention of severe exacerbations, lower limit of the 95% confidence interval (CI) of the mean difference between groups in patient proportions with no exacerbations is −3.5% or higher) in patients treated with FP/FOR versus FP/SAL. Results After matching 1:3, we studied a total of 2472 patients: 618 in the FP/FOR cohort (174 patients initiated on FP/FOR and 444 patients changed to FP/FOR) and 1854 in the FP/SAL cohort (522 patients initiated FP/SAL and 1332 continued FP/SAL). The percentage of patients prescribed FP/FOR met non-inferiority as the adjusted mean difference in proportion of no severe exacerbations (95%CI) was 0.008 (−0.032, 0.047) between the two cohorts. No other significant differences were observed except acute respiratory event rates, which were lower for patients prescribed FP/FOR (rate ratio [RR] 0.82, 95% CI 0.71, 0.94). Conclusions Changing to, or initiating FP/FOR combination therapy, is associated with a non-inferior proportion of patients who are severe exacerbation-free at a lower average annual cost compared with continuing or initiating treatment with FP/SAL.

Background: Reliance on and overuse of short-acting beta-agonists (SABA ROU) increases the risk of asthma attacks1 and is recognised by GINA as a key issue in asthma management. Patient beliefs can drive SABA ROU – assessing these can identify those at risk of ROU. Aim: To assess patient beliefs influencing SABA ROU and whether such beliefs can be changed by brief, behaviourally-intelligent messages. Method: 446 people with self-reported asthma, recruited via Amazon mTurk, completed validated questionnaires assessing perceptions of SABA and anti-inflammatory reliever (Necessity Beliefs and Concerns)2 and reported adherence. We examined whether beliefs about SABA and anti-inflammatory reliever were amenable to change in a subset of 55 patients who, after completing the baseline questionnaires, were exposed to brief messages designed to change their beliefs. The questionnaire assessments were repeated immediately after exposure to the messages, and 2 weeks later. Results: Many patients held beliefs about SABA that were consistent with over-reliance. For example, 71.7% (320/446) believed that ‘using their reliever was the best way to ‘keep on top of their asthma’ and 59.9% (267/446) agreed that ‘the benefits of the reliever markedly outweighs any risks’. Over-reliance on SABA correlated with low adherence to inhaled corticosteroids (p Conclusion: Patient beliefs driving SABA ROU are amenable to change using brief behaviourally-intelligent messages. References: 1. Pavord et al. Lancet 2018;391:350-400. 2. Horne et al. Psychology & Health 1999;14:1-24.

Background: The KRONOS trial (NCT02497001) demonstrated the efficacy of BGF MDI versus LAMA/LABA and ICS/LABA dual therapies over 24 weeks. Modelling can be used to extrapolate trial data to estimate long-term clinical outcomes in order to inform treatment guidelines and reimbursement decisions. Objective: To estimate the lifetime clinical effectiveness of BGF MDI versus LAMA/LABA (glycopyrrolate/formoterol fumarate MDI) and ICS/LABA (budesonide/formoterol dry powder inhaler) therapies in patients with moderate-to-very severe COPD. Methods: Using data from KRONOS and published literature, a Markov model was developed to simulate the natural history of patients recruited in KRONOS and to extrapolate average lifetime clinical outcomes. Health states were defined based on airflow limitation (FEV1 % predicted; moderate/severe/very severe) and exacerbation history (none/moderate/severe). Probabilities for transitions between COPD severity states and exacerbation rates were estimated from KRONOS data. Outcomes included life years (LYs), quality-adjusted LYs (QALYs) and exacerbations. Results: Total LYs and QALYs for a patient on BGF MDI (9.19 and 6.85) indicated a benefit compared to ICS/LABA (8.79 and 6.47) and LAMA/LABA (8.66 and 6.41). Similarly, both moderate and severe lifetime exacerbations were lowest for BGF MDI (3.46 and 0.74) followed by ICS/LABA (4.97 and 0.99) and LAMA/LABA (6.86 and 1.58). Conclusions: Modelling using KRONOS data demonstrated better outcomes with BGF MDI versus dual therapies over a lifetime, particularly in reducing exacerbations, for patients with COPD.

Background Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1–5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD. Objective To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation. Design A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial. Setting The trial was conducted in 121 UK primary and secondary care sites. Participants People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of Interventions Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status. Primary outcome The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs. Results A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV1 was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV1), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms. Limitations A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment (n = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study. Conclusion For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses. Future work To promote consideration of the findings of this trial in national and international COPD guidelines. Trial registration Current Controlled Trials ISRCTN27066620. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 37. See the NIHR Journals Library website for further project information.

Fractional exhaled nitric oxide (FeNO) is the only available point of care test to assess type-2 inflammation in asthma. In making a diagnosis of asthma, FeNO should be used together with blood eosinophils and spirometry, alongside a history. Raised FeNO in conjunction with blood eosinophilia are treatable traits of type 2 inflammation in asthma, which in turn may guide personalised management. A FeNO suppression test can be used to assess adherence and device use with ICS therapy. Furthermore FeNO may be used to provide feedback to patients in response to ICS, especially when spirometry is normal. FeNO may facilitate appropriate referral to secondary care for more definitive specialist investigations. In summary, FeNO is cost effective in the diagnosis and management of asthma and should be incorporated into primary and secondary care as part of routine clinical practice.

Patient overreliance on short-acting betaTo develop and validate a brief questionnaire to elicit patients' perceptions of SABA (eg, belief that asthma is best managed by SABA alone) that could lead them to be overly reliant on SABA.The 5-item SABA Reliance Questionnaire (SRQ) was adapted from the well-validated Beliefs about Medicines Questionnaire assessing patient perceptions of the importance of, and necessity for, SABA in managing their asthma. The psychometric properties of the questionnaire were studied using Amazon Mechanical Turk, an online survey platform, in 446 people with self-reported asthma. Internal reliability and criterion-related validity were assessed on the basis of relationships between SRQ scores and other variables, including self-reported adherence to ICSs and perceived importance of reliever inhalers.Internal reliability was good with Cronbach α = 0.74. Criterion-related validity was demonstrated by an inverse correlation between SRQ scores and self-reported adherence to ICSs (r = -0.291; P.0001), and significant correlation between SRQ scores and perceived reliever importance (r = 0.216; P.0001), as well as by significant differences in SRQ scores between those with high and those with low self-reported ICS adherence (adherence to ICS t = 4.825; P.0001).The SRQ demonstrated acceptable internal reliability, and criterion validity, supporting its potential use as a pragmatic tool for identifying patients whose beliefs are indicative of overreliance on SABA for asthma.

Background Despite the widespread availability of patient-reported asthma questionnaires, instruments developed in accordance with present regulatory expectations are lacking. To address this gap, the Patient-Reported Outcome (PRO) Consortium's Asthma Working Group has developed a patient-reported asthma daily symptom diary (ADSD) for use in clinical research to assess outcomes and support medical product labeling claims in adults and adolescents with asthma. Objectives To summarize the qualitative research conducted to inform the initial development of the ADSD and to provide evidence for content validity of the instrument in accordance with the Food and Drug Administration's PRO Guidance. Methods Research informing the initial development and confirming the content validity of the ADSD is summarized. This comprised a review of published qualitative research, semi-structured concept elicitation interviews (n = 55), and cognitive interviews (n = 65) with a diverse and representative sample of adults and adolescents with a clinician-confirmed diagnosis of asthma in the United States to understand the asthma symptom experience and to assess the relevance and understanding of the newly developed ADSD. Results From the qualitative literature review and concept elicitation interviews, eight core asthma symptoms emerged. These were broadly categorized as breathing symptoms (difficulty breathing, shortness of breath, and wheezing), chest symptoms (chest tightness, chest pain, and pressure/weight on chest), and cough symptoms (cough and the presence of mucus/phlegm). Conceptual saturation was achieved and differences in the experience of participants according to socio-demographic or clinical characteristics were not observed. Subsequent testing of the ADSD confirmed participant relevance and understanding. Conclusions The ADSD is a new patient-reported asthma symptom diary developed in accordance with the Food and Drug Administration's PRO Guidance. Evidence to date supports the content validity of the instrument. Item performance, reliability, and construct validity will be assessed in future quantitative research.

Importance Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration isrctn.org Identifier: ISRCTN27066620.

Background: While the GOLD guidelines advise exercise to reduce disease progression, little investment in promoting physical activity (PA) is made by healthcare authorities. Objective: To estimate the cost-effectiveness of regular PA vs sedentary lifestyle in COPD patients of the UK. Methods: Efficacy, quality of life, and economic evidence on the PA effects in COPD patients was retrieved from literature. These data served as input for a Markov microsimulation model comparing a COPD population performing PA vs a COPD population with a sedentary lifestyle. The GOLD classification defined the model health states. For the base case, the cost of PA was estimated at zero, a lifetime horizon was used and costs and effects were discounted at 3.5%. Analyses were performed from the UK NHS perspective. Uncertainty around inputs and assumptions was explored via scenario and sensitivity analyses, including a cost threshold analysis. Outcomes were cost/quality-adjusted-life-year (QALY) gained and cost/year gained. Results: In the base case, PA resulted in lower mortality (-6%) and number of hospitalisations (-2%), gains in years (+0.82) and QALYs (+0.66), and savings in total costs (-£2,568). The cost/QALY and cost/year gained were dominant. PA was cost-saving at costs Conclusions: Including PA in the management of COPD patients of the UK leads to long-term clinical benefits. If the NHS only promotes exercise via medical advice, this would lead to healthcare costs savings. If the NHS chose to fund PA, it would still likely lead to a cost-effective intervention.

The United Kingdom (UK) National Review of Asthma Deaths (NRAD) (2011–2014) identified a number of contributory risk factors which had not previously been recognized by those caring for people with asthma. Only one of the 19 NRAD recommendations has so far been implemented nationally, and that only partially, and as yet systems are not in place to identify patients at risk of attacks and dying from asthma. In 2015/2016 Bedfordshire Clinical Commissioning Group (CCG) in England, UK, initiated a quality asthma audit of people with asthma to identify some of the risk factors identified in the NRAD report with the aim of optimizing patient care. Fifty (89%) of the General Practices caring for 415,152 patients (27,587 diagnosed with asthma (prevalence 7%; range 4–12%)), participated and the results identified a wide variation in process of care and presence of risk factors including: excess short acting reliever and insufficient preventer prescriptions, failure to issue personal asthma action plans, and to perform annual reviews or check inhaler technique. Identification of these patients involved high-intensity input by trained asthma nurses using sophisticated data extraction software. GP computer systems used in primary care currently do not have the functionally, without the need for manual audit, to implement the NRAD recommendations, starting with the identification of patients at risk. Modifications to existing systems within both primary and secondary care are required in order to prevent unnecessary deaths related to asthma. There is a pressing need to move towards a more pro-active model of care., Asthma: Encouraging proactive care Pro-active disease management for patients with asthma is crucial and could be vastly improved with an overhaul of computer systems in primary care. Following the UK National Review of Asthma Deaths (NRAD) in 2011–2014, multiple mortality risk factors were identified that have yet to be factored into asthma care. The NHS Bedfordshire Clinical Commissioning Group, with support from NSHI and Dr Mark L Levy (Harrow CCG), conducted a manual audit of 50 Bedfordshire doctors’ surgeries to identify relevant NRAD recommendations to optimize patient care. Levy’s team found marked variations in asthma care between the surgeries. Risk factors present included excessive short-acting reliever inhaler prescriptions and inadequate prescribing of preventer inhalers, together with limited implementation of personal asthma plans and annual reviews. The researchers highlight the limitations of existing computer systems for these purposes and recommend an overhaul of asthma tracking and automated alerts.

Background Identifying asthma patients suitable for biologic therapy includes the assessment of blood biomarkers (IgE and eosinophils (EOS)). How they relate to each other is unclear. Methods This retrospective, database study used routinely collected clinical data to identify and evaluate an asthma cohort (classification code for asthma; ≥ 18 years; ≥1 prescription for asthma; ≥1 estimation of serum IgE, in 2 years prior to index date). Distribution into high and low IgE and EOS groups (IgE cut-point: > or ≤75 kU/L; EOS cut point: >or ≤400 μ/L), and characteristics by group are described. Findings In patients with severe asthma (British Thoracic Society Step (BTS) ≥4; N = 884), using maximum recorded IgE/EOS, 33% had high IgE/high EOS, 28% low IgE/low EOS and approximately a fifth each had high IgE/low EOS or low IgE/high EOS. Proportions were similar when EOS values measured 2 or 4 weeks before an exacerbation were excluded. Using EOS/IgE ′same day’ measurements (N = 578) only identified half of the high EOS group. Patients in high IgE groups were more likely to be younger males without comorbid COPD; those in high EOS groups were more likely to be on BTS treatment Step 5 vs 4. The low IgE/low EOS group had the lowest incidence of asthma-related hospital attendances, the highest incidence was observed in the high EOS groups. Conclusion Maximum available EOS measurement irrespective of exacerbations may be relevant when considering therapy. These data showed low IgE/Low EOS to be more benign and high EOS groups at increased risk of frequent, severe exacerbations.

Background Spacers may be compatible but unlicensed for an inhaler device. A prior study showed that co-prescription of unlicensed spacers with non-extrafine (non-EF) beclometasone dipropionate (BDP) asthma therapy was common.1 This study aimed to compare the occurrence of patient-reported inhaled corticosteroid (ICS)-related adverse events (AEs) in patients with asthma co-prescribed the licensed Volumatic or unlicensed Aerochamber spacer with their non-EF BDP therapy. Method A cross-sectional study using completed questionnaires and data extracted from the Optimum Patient Care Research Database including patients with asthma, aged ≤65 years,≥2 prescriptions for non-EF BDP and co-prescription of either a Volumatic or Aerochamber spacer. Patient characterisation was performed for the year prior to receipt of the completed questionnaire. AEs captured via questionnaire included continual sore mouth/throat, oral thrush, hoarse voice, bruising, weight gain and cough. The primary outcome was non-inferiority of the proportion of patient-reported oral candidiasis (reported as oral thrush/hoarse voice). The two spacer groups were compared using logistic regression, adjusted for gender, ICS average dose and smoking status. Non-inferiority was claimed if the upper 95% confidence interval (CI) of the marginal effect estimate was Results Of the patients co-prescribed the licensed Volumatic spacer (n=155), 29.9% reported oral candidiasis, compared to 27.7% of patients co-prescribed the unlicensed Aerochamber device (n=385, p=0.622). The marginal effect estimate was −0.043 (95%CI −0.133, 0.047) and the Aerochamber was determined to be non-inferior to the Volumatic spacer. In terms of the total number of reported AEs, there were no significant differences for the main population (≤65 years) (p=0.797), 16–65 years (p=0.875), Conclusion Co-prescription of the unlicensed Aerochamber spacer with non-EF BDP asthma therapy, in recommended patient groups, does not increase the risk of developing oral candidiasis or other ICS-related AEs, as compared to co-prescription of the licensed, Volumatic device. Reference ICARUS study submitted to PCRS2017.