Engaging stakeholders to level up COPD care in LMICs: lessons learned from the "Breathe Well" programme in Brazil, China, Georgia, and North Macedonia.

BACKGROUND: Effective stakeholder engagement in health research is increasingly being recognised and promoted as an important pathway to closing the gap between knowledge production and its use in health systems. However, little is known about its process and impacts, particularly in low-and middle-income countries. This opinion piece draws on the stakeholder engagement experiences from a global health research programme on Chronic Obstructive Pulmonary Disease (COPD) led by clinician researchers in Brazil, China, Georgia and North Macedonia, and presents the process, outcomes and lessons learned. MAIN BODY: Each country team was supported with an overarching engagement protocol and mentored to develop a tailored plan. Patient involvement in research was previously limited in all countries, requiring intensive efforts through personal communication, meetings, advisory groups and social media. Accredited training programmes were effective incentives for participation from healthcare providers; and aligning research findings with competing policy priorities enabled interest and dialogue with decision-makers. The COVID-19 pandemic severely limited possibilities for planned engagement, although remote methods were used where possible. Planned and persistent engagement contributed to shared knowledge and commitment to change, including raised patient and public awareness about COPD, improved skills and practice of healthcare providers, increased interest and support from clinical leaders, and dialogue for integrating COPD services into national policy and practice. CONCLUSION: Stakeholder engagement enabled relevant local actors to produce and utilise knowledge for small wins such as improving day-to-day practice and for long-term goals of equitable access to COPD care. For it to be successful and sustained, stakeholder engagement needs to be valued and integrated throughout the research and knowledge generation process, complete with dedicated resources, contextualised and flexible planning, and commitment.

Randomised controlled trial testing effectiveness of feedback about lung age or exhaled CO combined with very brief advice for smoking cessation compared to very brief advice alone in North Macedonia: findings from the Breathe Well group.

INTRODUCTION: In 2019, smoking prevalence in North Macedonia was one of the world's highest at around 46% in adults. However, access to smoking cessation treatment is limited and no co-ordinated smoking cessation programmes are provided in primary care. METHODS: We conducted a three parallel-armed randomised controlled trial (n = 1368) to investigate effectiveness and cost-effectiveness of lung age (LA) or exhaled carbon monoxide (CO) feedback combined with very brief advice (VBA) to prompt smoking cessation compared with VBA alone, delivered by GPs in primary care in North Macedonia. All participants who decided to attempt to quit smoking were advised about accessing smoking cessation medications and were also offered behavioural support as part of the "ACT" component of VBA. Participants were aged ≥ 35 years, smoked ≥ 10 cigarettes per day, were recruited from 31 GP practices regardless of motivation to quit and were randomised (1:1:1) using a sequence generated before the start of recruitment. The primary outcome was biochemically validated 7-day point prevalence abstinence at 4 weeks (wks). Participants and GPs were not blinded to allocation after randomisation, however outcome assessors were blind to treatment allocation. RESULTS: There was no evidence of a difference in biochemically confirmed quitting between intervention and control at 4wks (VBA + LA RR 0.90 (97.5%CI: 0.35, 2.27); VBA + CO RR 1.04 (97.5%CI: 0.44, 2.44)), however the absolute number of quitters was small (VBA + LA 1.6%, VBA + CO 1.8%, VBA 1.8%). A similar lack of effect was observed at 12 and 26wks, apart from in the VBA + LA arm where the point estimate was significant but the confidence intervals were very wide. In both treatment arms, a larger proportion reported a reduction in cigarettes smoked per day at 4wks (VBA + LA 1.30 (1.10, 1.54); VBA + CO 1.23 (1.03, 1.49)) compared with VBA. The point estimates indicated a similar direction of effect at 12wks and 26wks, but differences were not statistically significant. Quantitative process measures indicated high fidelity to the intervention delivery protocols, but low uptake of behavioural and pharmacological support. VBA was the dominant intervention in the health economic analyses. CONCLUSION: Overall, there was no evidence that adding LA or CO to VBA increased quit rates. However, a small effect cannot be ruled out as the proportion quitting was low and therefore estimates were imprecise. There was some evidence that participants in the intervention arms were more likely to reduce the amount smoked, at least in the short term. More research is needed to find effective ways to support quitting in settings like North Macedonia where a strong smoking culture persists. TRIAL REGISTRATION: The trial was registered at http://www.isrctn.com (ISRCTN54228638) on the 07/09/2018.

Feasibility of a pulmonary rehabilitation programme for patients with symptomatic chronic obstructive pulmonary disease in Georgia: a single-site, randomised controlled trial from the Breathe Well Group.

OBJECTIVES: To assess the feasibility of delivering a culturally tailored pulmonary rehabilitation (PR) programme and conducting a definitive randomised controlled trial (RCT). DESIGN: A two-arm, randomised feasibility trial with a mixed-methods process evaluation. SETTING: Secondary care setting in Georgia, Europe. PARTICIPANTS: People with symptomatic spirometry-confirmed chronic obstructive pulmonary disease recruited from primary and secondary care. INTERVENTIONS: Participants were randomised in a 1:1 ratio to a control group or intervention comprising 16 twice-weekly group PR sessions tailored to the Georgian setting. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility of the intervention and RCT were assessed according to: study recruitment, consent and follow-up, intervention fidelity, adherence and acceptability, using questionnaires and measurements at baseline, programme end and 6 months, and through qualitative interviews. RESULTS: The study recruited 60 participants (as planned): 54 (90%) were male, 10 (17%) had a forced expiratory volume in 1 second of ≤50% predicted. The mean MRC Dyspnoea Score was 3.3 (SD 0.5), and mean St George's Respiratory Questionnaire (SGRQ) 50.9 (SD 17.6). The rehabilitation specialists delivered the PR with fidelity. Thirteen (43.0%) participants attended at least 75% of the 16 planned sessions. Participants and rehabilitation specialists in the qualitative interviews reported that the programme was acceptable, but dropout rates were high in participants who lived outside Tbilisi and had to travel large distances. Outcome data were collected on 63.3% participants at 8 weeks and 88.0% participants at 6 months. Mean change in SGRQ total was -24.9 (95% CI -40.3 to -9.6) at programme end and -4.4 (95% CI -12.3 to 3.4) at 6 months follow-up for the intervention group and -0.5 (95% CI -8.1 to 7.0) and -8.1 (95% CI -16.5 to 0.3) for the usual care group at programme end and 6 months, respectively. CONCLUSIONS: It was feasible to deliver the tailored PR intervention. Approaches to improve uptake and adherence warrant further research. TRIAL REGISTRATION NUMBER: ISRCTN16184185.

Community lung health service design for COPD patients in China by the Breathe Well group.

COPD is increasingly common in China but is poorly understood by patients, medications are not used as prescribed and there is no access to recommended non-pharmacological treatment. We explored COPD patients' and general practitioners' (GPs) knowledge of COPD, views on its management and the acceptability of a flexible lung health service (LHS) offering health education, exercise, self-management, smoking cessation and mental health support. Using a convergent mixed methods design, data were collected from patients and GPs using focus groups (FGs) in four Chinese cities, questionnaires were also used to collect data from patients. FGs were audio-recorded and transcribed. Quantitative data were analysed descriptively, thematic framework analysis was used for the qualitative data. Two-hundred fifty-one patients completed the questionnaire; 39 patients and 30 GPs participated in ten separate FGs. Three overarching themes were identified: patients' lack of knowledge/understanding of COPD, current management of COPD not meeting patients' needs and LHS design, which was well received by patients and GPs. Participants wanted COPD education, TaiChi, psychological support and WeChat for social support. 39% of survey responders did not know what to do when their breathing worsened and 24% did not know how to use their inhalers. 36% of survey respondents requested guided relaxation. Overall, participants did not fully understand the implications of COPD and current treatment was sub-optimal. There was support for developing a culturally appropriate intervention meeting Chinese patients' needs, health beliefs, and local healthcare delivery. Further research should explore the feasibility of such a service.

Investigating primary healthcare practitioners' barriers and enablers to referral of patients with COPD to pulmonary rehabilitation: a mixed-methods study using the Theoretical Domains Framework.

OBJECTIVES: Pulmonary rehabilitation (PR) is a highly effective, recommended intervention for patients with chronic obstructive pulmonary disease (COPD). Using behavioural theory within mixed-methods research to understand why referral remains low enables the development of targeted interventions in order to improve future PR referral. DESIGN: A multiphase sequential mixed-methods study. SETTING: United Kingdom (UK). PARTICIPANTS: 252 multiprofessional primary healthcare practitioners (PHCPs). MEASURES: Phase 1: semistructured interviews. Phase 2: a 54-item paper and online questionnaire, based on the Theoretical Domains Framework (TDF). Content and descriptive analysis utilised. Data mixed at two points: instrument design and interpretation. RESULTS: 19 PHCPs took part in interviews and 233 responded to the survey. Integrated results revealed that PHCPs with a post qualifying respiratory qualification (154/241; 63.9%) referred more frequently (91/154; 59.1%) than those without (28/87; 32.2%). There were more barriers than enablers for referral in all 13 TDF domains. Key barriers included: infrequent engagement from PR provider to referrer, concern around patient's physical ability and access to PR (particularly for those in work), assumed poor patient motivation, no clear practice referrer and few referral opportunities. These mapped to domains: belief about capabilities, social influences, environment, optimism, skills and social and professional role. Enablers to referral were observed in knowledge, social influences memory and environment domains. Many PHCPs believed in the physical and psychological value of PR. Helpful enablers were out-of-practice support from respiratory interested colleagues, dedicated referral time (annual review) and on-screen referral prompts. CONCLUSIONS: Referral to PR is complex. Barriers outweighed enablers. Aligning these findings to behaviour change techniques will identify interventions to overcome barriers and strengthen enablers, thereby increasing referral of patients with COPD to PR.

Performance of the EQ-5D-5L Plus Respiratory Bolt-On in the Birmingham Chronic Obstructive Pulmonary Disease Cohort Study.

OBJECTIVES: A respiratory bolt-on dimension for the EQ-5D-5L has recently been developed and valued by the general public. This study aimed to validate the EQ-5D-5L plus respiratory dimension (EQ-5D-5L+R) in a large group of patients with chronic obstructive pulmonary disease (COPD). METHODS: Validation was undertaken with data from the Birmingham COPD Cohort Study, a longitudinal UK study of COPD primary care patients. Data on the EQ-5D-5L+R were collected from 1008 responding participants during a follow-up questionnaire in 2017 and combined with (previously collected) data on patient and disease characteristics. Descriptive and correlation analyses were performed on the EQ-5D-5L+R dimensions and utilities, in relation to COPD characteristics and compared with the EQ-5D-5L without respiratory dimension. Multivariate regression models were estimated to test whether regression coefficients of clinical characteristics differed between the EQ-5D-5L+R utility and the EQ-5D-5L utility. RESULTS: Correlation coefficients for the EQ-5D-5L+R utility with COPD parameters were slightly higher than the EQ-5D-5L utility. Both instruments displayed discriminant validity but analyses in clinical subgroups of patients showed larger absolute differences in utilities for the EQ-5D-5L+R. In the multivariate analyses, only the coefficient for the COPD Assessment Test score was higher for the model using the EQ-5D-5L+R utility as outcome. CONCLUSIONS: This study showed that the addition of a respiratory domain to the EQ-5D-5L led to small improvements in the instrument's performance. Comparability of the EQ-5D across diseases, currently considered one of its strengths, would have to be traded off against a modest improvement in utility difference when adding the respiratory dimension.

Accuracy and cost-effectiveness of different screening strategies for identifying undiagnosed COPD among primary care patients (≥40 years) in China: a cross-sectional screening test accuracy study: findings from the Breathe Well group.

OBJECTIVES: To examine the accuracy and cost-effectiveness of various chronic obstructive pulmonary disease (COPD) screening tests and combinations within a Chinese primary care population. DESIGN: Screening test accuracy study. SETTING: Urban and rural community health centres in four municipalities of China: Beijing (north), Chengdu (southwest), Guangzhou (south) and Shenyang (northeast). PARTICIPANTS: Community residents aged 40 years and above who attended community health centres for any reason were invited to participate. 2445 participants (mean age 59.8 (SD 9.6) years, 39.1% (n=956) male) completed the study (February-December 2019), 68.9% (n=1684) were never-smokers and 3.6% (n=88) had an existing COPD diagnosis. 13.7% (n=333) of participants had spirometry-confirmed airflow obstruction. INTERVENTIONS: Participants completed six index tests (screening questionnaires (COPD Diagnostic Questionnaire, COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE), Chinese Symptom-Based Questionnaire (C-SBQ), COPD-SQ), microspirometry (COPD-6), peak flow (model of peak flow meters used in the study (USPE)) and the reference test (ndd Easy On-PC). PRIMARY AND SECONDARY OUTCOMES: Cases were defined as those with forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) below the lower limit of normal (LLN-GLI) on the reference test. Performance of individual screening tests and their combinations was evaluated, with cost-effectiveness analyses providing cost per additional true case detected. RESULTS: Airflow measurement devices (sensitivities 64.9% (95% CI 59.5% to 70.0%) and 67.3% (95% CI 61.9% to 72.3%), specificities 89.7% (95% CI 88.4% to 91.0%) and 82.6% (95% CI 80.9% to 84.2%) for microspirometry and peak flow, respectively) generally performed better than questionnaires, the most accurate of which was C-SBQ (sensitivity 63.1% (95% CI 57.6% to 68.3%) specificity 74.2% (95% CI 72.3% to 76.1%)). The combination of C-SBQ and microspirometry used in parallel maximised sensitivity (81.4%) (95% CI 76.8% to 85.4%) and had specificity of 68.0% (95% CI 66.0% to 70.0%), with an incremental cost-effectiveness ratio of £64.20 (CNY385) per additional case detected compared with peak flow. CONCLUSIONS: Simple screening tests to identify undiagnosed COPD within the primary care setting in China is possible, and a combination of C-SBQ and microspirometry is the most sensitive and cost-effective. Further work is required to explore optimal cut-points and effectiveness of programme implementation. TRIAL REGISTRATION NUMBER: ISRCTN13357135.

Study to evaluate the effectiveness and cost-effectiveness of different screening strategies for identifying undiagnosed COPD among residents (≥40 years) in four cities in China: protocol for a multicentre cross-sectional study on behalf of the Breathe Well group.

INTRODUCTION: The latest chronic obstructive pulmonary disease (COPD) epidemiology survey in China estimated that there were 99 million potential COPD patients in the country, the majority of whom are undiagnosed. Screening for COPD in primary care settings is of vital importance for China, but it is not known which strategy would be the most suitable for adoption in primary care. Studies have been conducted to test the accuracy of questionnaires, expiratory peak flow meters and microspirometers to screen for COPD, but no study has directly evaluated and compared the effectiveness and cost-effectiveness of these methods in the Chinese setting. METHODS AND ANALYSIS: We present the protocol for a multicentre cross-sectional study, to be conducted in eight community hospitals from four cities among Chinese adults aged 40 years or older to investigate the effectiveness and cost-effectiveness of different case-finding methods for COPD, and determine the test performance of individual and combinations of screening tests and strategies in comparison with quality diagnostic spirometry. Index tests are screening questionnaires (COPD Diagnostic Questionnaire (CDQ), COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk Questionnaire (CAPTURE), symptom-based questionnaire, COPD Screening Questionnaire (COPD-SQ)), microspirometer and peak flow. Each participant will complete all of these tests in one assessment. The primary analysis will compare the performance of a screening questionnaire with a handheld device. Secondary analyses will include the comparative performance of each index test, as well as a comparison of strategies where we use a screening questionnaire and a handheld device. Approximately 2000 participants will be recruited over 9 to 12 months. ETHICS AND DISSEMINATION: The study has been approved by Peking University Hospital and University of Birmingham. All study participants will provide written informed consent. Study results will be published in appropriate journal and presented at national and international conferences, as well as relevant social media and various community/stakeholder engagement activities. TRIAL REGISTRATION NUMBER: ISRCTN13357135.

Impact of COPD case finding on clinical care: a prospective analysis of the TargetCOPD trial.

OBJECTIVES: To investigate the impact of chronic obstructive pulmonary disease (COPD) case finding on clinical care. DESIGN: We conducted a prospective observational analysis of data from a pragmatic cluster randomised controlled trial in primary care in the West Midlands, UK (TargetCOPD). This compared alternative methods of COPD case finding against usual care. Data were extracted from electronic healthcare records and self-reported questionnaires for a subset of patients with newly diagnosed COPD. SETTING: 50 general practices that participated in the TargetCOPD trial. PARTICIPANTS: Patients aged 40-79 years newly identified with COPD by targeted case finding or by usual care, from 10 August 2012 to 22 June 2014. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was addition to a COPD register by the end of the trial. The secondary outcome was a clinical care score, derived from the sum of clinical assessments and relevant interventions. Associations between participant characteristics and the primary and secondary outcomes were assessed using multilevel regression. RESULTS: 857 patients identified with COPD by case finding and 764 by usual care were included. Only 21.2% of case-found patients had been added to a COPD register, compared with 92.7% of those diagnosed by usual care. The odds of being added were greater in smokers (adjusted OR 8.68, 95% CI 2.53 to 29.8), and in those with lower percentage of predicted forced expiratory volume in 1 s (adjusted OR 0.96 per percentage rise, 95% CI 0.95 to 0.98). Patients who had been added to a COPD register had a significantly higher clinical care score (mean difference 5.06, 95% CI 4.36 to 5.75). CONCLUSIONS: Only one in five case-found patients had been registered with COPD. Patients added to a COPD register received significantly higher levels of appropriate clinical care. TRIAL REGISTRATION NUMBER: ISRCTN14930255; Post-results.

Referral of patients with chronic obstructive pulmonary disease to pulmonary rehabilitation: a qualitative study of barriers and enablers for primary healthcare practitioners.

BACKGROUND: Pulmonary rehabilitation (PR) is a cost-effective, internationally recommended intervention for patients with chronic obstructive pulmonary disease (COPD). Referral is predominately led by primary healthcare practitioners (PHCPs), but referral and patient uptake is poor. AIM: To understand barriers and enablers for PHCPs when considering patient referral to PR, to explore the influence of patient characteristics, and to understand how referral rates may be increased. DESIGN AND SETTING: PHCPs who care for and refer patients with COPD to PR were purposively selected from general practices across Cambridgeshire and Peterborough, and the West Midlands. METHOD: A qualitative study. Semi-structured interviews were undertaken to theme saturation, exploring PR referral. Images depicting patients with varying COPD severity were used to stimulate memory and associative recall. Interviews were recorded, transcribed verbatim, and analysed using rapid qualitative analysis. RESULTS: A total of 19 PHCPs were interviewed. Barriers to PR referral included limited awareness of the clinical benefits, little knowledge of local PR providers, consultation time constraints, and presumed low patient motivation. While practice nurses had the greatest knowledge, they still described difficulty in promoting PR. PHCPs frequently described assessing patient suitability based on presumed accessibility, social, and disease-specific characteristics rather than the clinical benefits of PR. Referrals were facilitated by financial incentives for the practice and positive feedback from patients and providers. CONCLUSION: There were more barriers to PR referral than enablers. Providers must engage better with PHCPs, patients with COPD, and carers, and actively promote PR. Increasing PHCPs' awareness of the benefits of PR, financial incentives, and alternative referral pathways should be considered.

Clinical characteristics of patients newly diagnosed with COPD by the fixed ratio and lower limit of normal criteria: a cross-sectional analysis of the TargetCOPD trial.

Background: Consensus on the definition of airflow obstruction to diagnose COPD remains unresolved. Methods: We undertook systematic case finding for COPD in primary care using the fixed ratio (FR) criterion (forced expiratory volume in 1 s/forced vital capacity [FEV1/FVC] <0.7) for defining airflow obstruction and also using the lower limit of normal (LLN). We then compared the clinical characteristics of those identified by the 2 criteria. Results: A total of 3,721 individuals reporting respiratory symptoms were invited for spirometry. A total of 2,607 attended (mean age 60.4 years, 52.8% male, 29.8% current smokers) and 32.6% had airflow obstruction by FR ("FR+") and 20.2% by LLN ("LLN+"). Compared with the LLN+/FR+ group, the LLN-/FR+ group (12.4%) was significantly older, had higher FEV1 and FEV1/FVC, lower COPD assessment test scores, and less cough, sputum, and wheeze, but was significantly more likely to report a diagnosis of heart disease (14.2% versus 6.9%, p<0.001). Compared with the LLN+/FR+ group, the LLN-/FR- group was younger, had a higher body mass index, fewer pack-years, a lower prevalence of respiratory symptoms except for dyspnea, and lower FVC and higher FEV1. The probability of known heart disease was significantly lower in the LLN+/FR+ group compared with those with preserved lung function (LLN-/FR-) (adjusted odds ratio 0.62, 95% CI: 0.43-0.90) but this was not seen in the LLN-/FR+ group (adjusted odds ratio 0.90, 95% CI: 0.63-1.29). Conclusion: In symptomatic individuals, defining airflow obstruction by FR instead of LLN identifies a significant number of individuals who have less respiratory and more cardiac clinical characteristics.

Case-finding for COPD in primary care: a qualitative study of patients' perspectives.

Background: COPD is a leading cause of morbidity and mortality, yet it remains largely under-diagnosed. Case-finding is encouraged by many professionals, but there is a lack of information on the patients' views and perspectives. Patients and methods: Semistructured interviews were conducted with adults, aged 40 years or older with a history of smoking, who were eligible and invited for case-finding for COPD as a part of a large UK primary care trial. Patients, including those who consented or declined participation and those with and without COPD after screening, were interviewed. Interviews were transcribed and analyzed using the framework method. Results: The 43 interviews revealed the following two main categories of themes: patients' views on COPD case-finding and barriers to case-finding. Overall, case-finding was deemed important and beneficial. Participants highlighted the need for screening activities to be convenient for patients but perceived that general practitioners (GPs) lacked the time and accessing appointments was difficult. Desire for a health check among symptomatic patients facilitated participation in case-finding. Psychological barriers to engagement included denial of ill health or failure to recognize symptoms, fear of the "test", and lung symptoms being low on the hierarchy of patient health complaints. Mechanical barriers included providing care for another person (and therefore being too busy), being unable to access GP appointments, and lacking feedback of spirometry results or communication of the diagnosis. Conclusion: Patient engagement with case-finding may be limited by denial or lack of recognition of symptoms and physical barriers to attendance. Increasing public awareness of COPD risk factors and early symptoms may enhance case-finding.

Barriers and enablers of physical activity engagement for patients with COPD in primary care.

BACKGROUND: Given that physical activity (PA) has a positive impact on COPD symptoms and prognosis, this study examined the factors that both encourage and limit participation in PA for individuals with COPD in a primary care setting from the perspective of social cognitive theory. METHODS: A purposive sample of 26 individuals with a range of COPD severity (age range: 50-89 years; males =15) were recruited from primary care to participate in one of four focus groups. Thematic analysis was undertaken to identify key concepts related to their self-efficacy beliefs. RESULTS: Several barriers and enablers closely related to self-efficacy beliefs and symptom severity were identified. The main barriers were health related (fatigue, mobility problems, breathing issues caused by the weather), psychological (embarrassment, fear, frustration/disappointment), attitudinal (feeling in control of their condition, PA perception, older age perception), and motivational. The main enabling factors were related to motivation (autonomous or controlled), attitudes, self-regulation, and performance accomplishments. CLINICAL IMPLICATIONS: When designing interventions for individuals with COPD, it is important to understand the patient-specific social cognitive influences on PA participation. This information can then inform individually tailored management planning.

Targeted case finding for chronic obstructive pulmonary disease versus routine practice in primary care (TargetCOPD): a cluster-randomised controlled trial.

BACKGROUND: Many individuals with chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide. Health-care organisations are implementing case-finding programmes without good evidence of which are the most effective and cost-effective approaches. We assessed the effectiveness and cost-effectiveness of two alternative approaches to targeted case finding for COPD compared with routine practice. METHODS: In this cluster-randomised controlled trial, participating general practices in the West Midlands, UK, were randomly assigned (1:1), via a computer-generated block randomisation sequence, to either a targeted case-finding group or a routine care group. Eligible patients were ever-smokers aged 40-79 years without a previously recorded diagnosis of COPD. Patients in the targeted case-finding group were further randomly assigned (1:1) via their household to receive either a screening questionnaire at the general practitioner (GP) consultation (opportunistic) or a screening questionnaire at the GP consultation plus a mailed questionnaire (active). Respondents reporting relevant respiratory symptoms were invited for post-bronchodilator spirometry. Patients, clinicians, and investigators were not masked to allocation, but group allocation was concealed from the researchers who performed the spirometry assessments. Primary outcomes were the percentage of the eligible population diagnosed with COPD within 1 year (defined as post-bronchodilator forced expiratory volume in 1 s [FEV1] to forced vital capacity [FVC] ratio <0·7 in patients with symptoms or a new diagnosis on their GP record) and cost per new COPD diagnosis. Multiple logistic and Poisson regression were used to estimate effect sizes. Costs were obtained from the trial. This trial is registered with ISRCTN, number ISRCTN14930255. FINDINGS: From Aug 10, 2012, to June 22, 2014, 74 818 eligible patients from 54 diverse general practices were randomly assigned and completed the trial. At 1 year, 1278 (4%) cases of COPD were newly detected in 32 789 eligible patients in the targeted case-finding group compared with 337 (1%) cases in 42 029 patients in the routine care group (adjusted odds ratio [OR] 7·45 [95% CI 4·80-11·55], p<0·0001). The percentage of newly detected COPD cases was higher in the active case-finding group (822 [5%] of 15 378) than in the opportunistic case-finding group (370 [2%] of 15 387; adjusted OR 2·34 [2·06-2·66], p<0·0001; adjusted risk difference 2·9 per 100 patients [95% CI 2·3-3·6], p<0·0001). Active case finding was more cost-effective than opportunistic case finding (£333 vs £376 per case detected, respectively). INTERPRETATION: In this well established primary care system, routine practice identified few new cases of COPD. An active targeted approach to case finding including mailed screening questionnaires before spirometry is a cost-effective way to identify undiagnosed patients and has the potential to improve their health. FUNDING: National Institute for Health Research.

TargetCOPD: a pragmatic randomised controlled trial of targeted case finding for COPD versus routine practice in primary care: protocol.

BACKGROUND: Many people with clinically significant chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide. There are a number of small studies which have examined possible methods of case finding through primary care, but no large RCTs that have adequately assessed the most cost-effective approach. METHODS/DESIGN: In this study, using a cluster randomised controlled trial (RCT) in 56 general practices in the West Midlands, we plan to investigate the effectiveness and cost-effectiveness of a Targeted approach to case finding for COPD compared with routine practice. Using an individual patient RCT nested in the Targeted arm, we plan also to compare the effectiveness and cost-effectiveness of Active case finding using a postal questionnaire (with supplementary opportunistic questionnaires), and Opportunistic-only case finding during routine surgery consultations.All ever-smoking patients aged 40-79 years, without a current diagnosis of COPD and registered with participating practices will be eligible. Patients in the Targeted arm who report positive respiratory symptoms (chronic cough or phlegm, wheeze or dyspnoea) using a brief questionnaire will be invited for further spirometric assessment to ascertain whether they have COPD or not. Post-bronchodilator spirometry will be conducted to ATS standards using an Easy One spirometer by trained research assistants.The primary outcomes will be new cases of COPD and cost per new case identified, comparing targeted case finding with routine care, and two types of targeted case finding (active versus opportunistic). A multilevel logistic regression model will be used to model the probability of detecting a new case of COPD for each treatment arm, with clustering of patients (by practice and household) accounted for using a multi-level structure.A trial-based analysis will be undertaken using costs and outcomes collected during the trial. Secondary outcomes include the feasibility, efficiency, long-term cost-effectiveness, patient and primary care staff views of each approach. DISCUSSION: This will be the largest RCT of its kind, and should inform how best to identify undiagnosed patients with COPD in the UK and other similar healthcare systems. Sensitivity analyses will help local policy-makers decide which sub-groups of the population to target first. TRIAL REGISTRATION: Current controlled trials ISRCTN14930255.

The acute impact of a hematopoietic allograft on lung function and inflammation: a prospective observational study.

BACKGROUND: No studies have investigated the immediate impact of receiving an allogeneic hematopoietic stem cell transplant (HSCT) on pulmonary inflammation or lung function. METHODS: Using a prospective study design, we quantified the changes in these outcome measures in eligible adult individuals in the first six months after receiving an allogeneic hematopoietic stem cell transplant. RESULTS: Between January 2007 and December 2008, 72 patients were eligible to participate in the cohort, and of these 68 (94%) were included in the study. Compared to baseline, pulmonary inflammation as measured by exhaled nitric oxide increased after receiving a HSCT with the largest increment seen at three months (+6.0 ppb, 95%CI: +0.4 to +11.5), and this was sustained at six months. Percent predicted forced expiratory volume in one second decreased over the same period, with the largest decrease observed at six weeks (-5.9%, 95% CI: -8.9 to -2.9), and this was also sustained over a six month period. Similar associations were observed for FVC. A larger increase in exhaled nitric oxide from baseline at six weeks and three months may be associated with decreased mortality (p=0.06, p=0.04 respectively). CONCLUSION: Our data demonstrate that recipients of an allogeneic HSCT experience an increase in biomarkers of pulmonary inflammation and a decrease in lung function in the first six months after the procedure. If independently validated in other study populations, these observations could have potential as a prognostic biomarker for this patient group.

Detection of chronic rejection by quantitative ventilation scintigrams in lung-transplanted patients: a pilot study.

The suspicion of chronic rejection [bronchiolithis obliterans syndrome (BOS)] is usually based on deteriorating forced expired volume in 1 s. It is however, desirable to develop more sensitive methods as increased anti-inflammatory therapy is thought to stop progression of the rejection. The aim of the present study was to develop quantitative tools based on ventilation scintigrams, to diagnose BOS. Sixteen double-lung-transplanted patients participated, six developing BOS and 10 who did not develop BOS. They were investigated with planar posterior-anterior (99m)Tc-Technegas (Tetley Manufacturing Ltd, Sydney, Australia) ventilation scintigraphy at baseline, 6 months to 1 year post-transplantation, and at a follow-up examination 3-4-year post-transplant or in the BOS patients close to the time of the diagnosis. An automatic region of interest (ROI) was drawn on each lung in the scintigraphic image at baseline and also applied to the follow-up investigation. The area inside the ROI was subdivided into stripes 10.8 mm high and squares 10.8 x 10.8 mm wide. Corresponding stripes and squares in baseline and follow-up were analysed regarding differences in relative retention. The results show that the square analysis is superior. Applying chosen cut-off values for square element differences, 6/6 right and 5/6 left BOS lungs were identified and one left and one right lung of patients not developing BOS were misclassified. We conclude that the square element difference appears to be a promising method to diagnose BOS.