Prospective Detection of Early Lung Cancer in Patients With COPD in Regular Care by Electronic Nose Analysis of Exhaled Breath.

BACKGROUND: Patients with COPD are at high risk of lung cancer developing, but no validated predictive biomarkers have been reported to identify these patients. Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for early detection of lung cancer in patients with COPD. RESEARCH QUESTION: Can eNose technology be used for prospective detection of early lung cancer in patients with COPD? STUDY DESIGN AND METHODS: BreathCloud is a real-world multicenter prospective follow-up study using diagnostic and monitoring visits in day-to-day clinical care of patients with a standardized diagnosis of asthma, COPD, or lung cancer. Breath profiles were collected at inclusion in duplicate by a metal-oxide semiconductor eNose positioned at the rear end of a pneumotachograph (SpiroNose; Breathomix). All patients with COPD were managed according to standard clinical care, and the incidence of clinically diagnosed lung cancer was prospectively monitored for 2 years. Data analysis involved advanced signal processing, ambient air correction, and statistics based on principal component (PC) analysis, linear discriminant analysis, and receiver operating characteristic analysis. RESULTS: Exhaled breath data from 682 patients with COPD and 211 patients with lung cancer were available. Thirty-seven patients with COPD (5.4%) demonstrated clinically manifest lung cancer within 2 years after inclusion. Principal components 1, 2, and 3 were significantly different between patients with COPD and those with lung cancer in both training and validation sets with areas under the receiver operating characteristic curve of 0.89 (95% CI, 0.83-0.95) and 0.86 (95% CI, 0.81-0.89). The same three PCs showed significant differences (P < .01) at baseline between patients with COPD who did and did not subsequently demonstrate lung cancer within 2 years, with a cross-validation value of 87% and an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.84-0.95). INTERPRETATION: Exhaled breath analysis by eNose identified patients with COPD in whom lung cancer became clinically manifest within 2 years after inclusion. These results show that eNose assessment may detect early stages of lung cancer in patients with COPD.

Regional implementation of atrial fibrillation screening: benefits and pitfalls.

Aims: Despite general awareness that screening for atrial fibrillation (AF) could reduce health hazards, large-scale implementation is lagging behind technological developments. As the successful implementation of a screening programme remains challenging, this study aims to identify facilitating and inhibiting factors from healthcare providers' perspectives. Methods and results: A mixed-methods approach was used to gather data among practice nurses in primary care in the southern region of the Netherlands to evaluate the implementation of an ongoing single-lead electrocardiogram (ECG)-based AF screening programme. Potential facilitating and inhibiting factors were evaluated using online questionnaires (N = 74/75%) and 14 (of 24) semi-structured in-depth interviews (58.3%). All analyses were performed using SPSS 26.0. In total, 16 682 screenings were performed on an eligible population of 64 000, and 100 new AF cases were detected. Facilitating factors included 'receiving clear instructions' (mean ± SD; 4.12 ± 1.05), 'easy use of the ECG-based device' (4.58 ± 0.68), and 'patient satisfaction' (4.22 ± 0.65). Inhibiting factors were 'time availability' (3.20 ± 1.10), 'insufficient feedback to the practice nurse' (2.15 ± 0.89), 'absence of coordination' (54%), and the 'lack of fitting policy' (32%). Conclusion: Large-scale regional implementation of an AF screening programme in primary care resulted in a low participation of all eligible patients. Based on the perceived barriers by healthcare providers, future AF screening programmes should create preconditions to fit the intervention into daily routines, appointing an overall project lead and a General Practitioner (GP) as a coordinator within every GP practice.

Identification of recent exacerbations in COPD patients by electronic nose.

Molecular profiling of exhaled breath by electronic nose (eNose) might be suitable as a noninvasive tool that can help in monitoring of clinically unstable COPD patients. However, supporting data are still lacking. Therefore, as a first step, this study aimed to determine the accuracy of exhaled breath analysis by eNose to identify COPD patients who recently exacerbated, defined as an exacerbation in the previous 3 months. Data for this exploratory, cross-sectional study were extracted from the multicentre BreathCloud cohort. Patients with a physician-reported diagnosis of COPD (n=364) on maintenance treatment were included in the analysis. Exacerbations were defined as a worsening of respiratory symptoms requiring treatment with oral corticosteroids, antibiotics or both. Data analysis involved eNose signal processing, ambient air correction and statistics based on principal component (PC) analysis followed by linear discriminant analysis (LDA). Before analysis, patients were randomly divided into a training (n=254) and validation (n=110) set. In the training set, LDA based on PCs 1-4 discriminated between patients with a recent exacerbation or no exacerbation with high accuracy (receiver operating characteristic (ROC)-area under the curve (AUC)=0.98, 95% CI 0.97-1.00). This high accuracy was confirmed in the validation set (AUC=0.98, 95% CI 0.94-1.00). Smoking, health status score, use of inhaled corticosteroids or vital capacity did not influence these results. Exhaled breath analysis by eNose can discriminate with high accuracy between COPD patients who experienced an exacerbation within 3 months prior to measurement and those who did not. This suggests that COPD patients who recently exacerbated have their own exhaled molecular fingerprint that could be valuable for monitoring purposes.

Effectiveness of intensive practice nurse counselling versus brief general practitioner advice, both combined with varenicline, for smoking cessation: a randomized pragmatic trial in primary care.

AIMS: To study the effectiveness of intensive counselling by a practice nurse (PN) versus brief advice by a general practitioner (GP), each combined with pharmacotherapy, for 6 months' tobacco abstinence (primary outcome). Secondary outcomes included 12-month abstinence, medication adherence and incremental costs per life-year gained. DESIGN: A multi-site (n = 10), two-group, parallel, pragmatic randomized controlled trial. SETTING: A network of primary health-care centres in the Netherlands. PARTICIPANTS: A total of 295 adult daily smokers (mean age = 48 years; mean cigarettes/day = 19). INTERVENTION AND COMPARATOR: Patients were randomized to receive individual counselling by a practice nurse (PN) (n = 149) or brief advice by a general practitioner (GP) (146). All patients received 12 weeks of open-label varenicline. MEASUREMENTS: The primary outcome was prolonged biochemically validated abstinence from weeks 9 to 26 after treatment initiation. Secondary outcomes included abstinence from weeks 9 to 52, good dosing adherence (> 80% days taken) and incremental costs per life-year gained. FINDINGS: Abstinence rates in the PN versus GP groups were 32.2% (n = 48) versus 39.0% [n = 57; odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.44-1.16] from weeks 9 to 26 and 25.5% (n = 38) versus 28.8% (n = 42; OR = 0.84, 95% CI = 0.50-1.43) from weeks 9 to 52, respectively. Values of the Bayes factor indicated that the PN and GP were equally effective. Good dosing adherence was significantly lower in the PN (45.5%, n = 56/123) than in the GP group (62.0%, n = 75/121; OR = 0.45, 95% CI = 0.26-0.77), and the incremental costs per life-year gained were -€416.10. CONCLUSIONS: Among people seeking help to stop smoking from their general practice, one-off brief advice from a general practitioner appears to be as effective as several sessions of behavioural support from a practice nurse when smoking cessation medication is provided.

Introduction of the DiaGene study: clinical characteristics, pathophysiology and determinants of vascular complications of type 2 diabetes.

BACKGROUND: Type 2 diabetes is a major healthcare problem. Glucose-, lipid-, and blood pressure-lowering strategies decrease the risk of micro- and macrovascular complications. However, a substantial residual risk remains. To unravel the etiology of type 2 diabetes and its complications, large-scale, well-phenotyped studies with prospective follow-up are needed. This is the goal of the DiaGene study. In this manuscript, we describe the design and baseline characteristics of the study. METHODS: The DiaGene study is a multi-centre, prospective, extensively phenotyped type 2 diabetes cohort study with concurrent inclusion of diabetes-free individuals at baseline as controls in the city of Eindhoven, The Netherlands. We collected anthropometry, laboratory measurements, DNA material, and detailed information on medication usage, family history, lifestyle and past medical history. Furthermore, we assessed the prevalence and incidence of retinopathy, nephropathy, neuropathy, and diabetic feet in cases. Using logistic regression models, we analyzed the association of 11 well known genetic risk variants with type 2 diabetes in our study. RESULTS: In total, 1886 patients with type 2 diabetes and 854 controls were included. Cases had worse anthropometric and metabolic profiles than controls. Patients in outpatient clinics had higher prevalence of macrovascular (41.9% vs. 34.8%; P = 0.002) and microvascular disease (63.8% vs. 20.7%) compared to patients from primary care. With the exception of the genetic variant in KCNJ11, all type 2 diabetes susceptibility variants had higher allele frequencies in subjects with type 2 diabetes than in controls. CONCLUSIONS: In our study population, considerable rates of macrovascular and microvascular complications are present despite treatment. These prevalence rates are comparable to other type 2 diabetes populations. While planning genomics, we describe that 11 well-known type 2 diabetes genetic risk variants (in TCF7L2, PPARG-P12A, KCNJ11, FTO, IGF2BP2, DUSP9, CENTD2, THADA, HHEX, CDKAL1, KCNQ1) showed similar associations compared to literature. This study is well-suited for multiple omics analyses to further elucidate disease pathophysiology. Our overall goal is to increase the understanding of the underlying mechanisms of type 2 diabetes and its complications for developing new prediction, prevention, and treatment strategies.

Should the diagnosis of COPD be based on a single spirometry test?

Clinical guidelines indicate that a chronic obstructive pulmonary disease (COPD) diagnosis is made from a single spirometry test. However, long-term stability of diagnosis based on forced expiratory volume in 1 s over forced vital capacity (FEV1/FVC) ratio has not been reported. In primary care subjects at risk for COPD, we investigated shifts in diagnostic category (obstructed/non-obstructed). The data were from symptomatic 40+ years (ex-)smokers referred for diagnostic spirometry, with three spirometry tests, each 12±2 months apart. The obstruction was based on post-bronchodilator FEV1/FVC < lower limit of normal (LLN) and <0.70 (fixed ratio). A total of 2,352 subjects (54% male, post-bronchodilator FEV1 76.5% predicted) were studied. By LLN definition, 32.2% were obstructed at baseline, but 32.2% of them were no longer obstructed at years 1 and/or 2. By fixed ratio, these figures were 46.6 and 23.8%, respectively. Overall, 14.3% of subjects changed diagnostic category by 1 year and 15.4% by 2 years when applying the LLN cut-off, and 15.1 and 14.6% by fixed ratio. Change from obstructed to non-obstructed was more likely for patients with higher body mass index (BMI) and baseline short-acting bronchodilator (SABA) users, and less likely for older subjects, those with lower FEV1% predicted, baseline inhaled steroid users, and current smokers or SABA users at year 1. Change from non-obstructed to obstructed was more likely for males, older subjects, current smokers and patients with lower baseline FEV1% predicted, and less likely for those with higher baseline BMI. Up to one-third of symptomatic (ex-)smokers with baseline obstruction on diagnostic spirometry had shifted to non-obstructed when routinely re-tested after 1 or 2 years. Given the implications for patients and health systems of a diagnosis of COPD, it should not be based on a single spirometry test.

Impact of switching to new spirometric reference equations on severity staging of airflow obstruction in COPD: a crosssectional observational study in primary care.

BACKGROUND: Severity of airflow obstruction in chronic obstructive pulmonary disease (COPD) is based on forced expiratory volume in one second expressed as percentage predicted (FEV1%predicted) derived from reference equations for spirometry results. AIMS: To establish how switching to new spirometric reference equations would affect severity staging of airflow obstruction in the Dutch primary care COPD patient population. METHODS: Spirometry tests of 3,370 adults aged >40 years with obstruction (postbronchodilator FEV1/forced vital capacity (FVC) <0.70) were analysed. The presence and severity of obstruction were defined using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Postbronchodilator FEV1%predicted was calculated using three reference equations: corrected European Community of Steel and Coal (ECSC) (currently recommended in Dutch primary care), Swanney et al., and Global Lung Initiative (GLI). Discordances between severity classifications based on these equations were analysed. RESULTS: We studied 1,297 (38.5%) females and 2,073 males. Application of contemporary reference equations (i.e. Swanney and GLI) changed the GOLD severity stages obtained with the ECSC equations, mostly into milder stages. Severity of airflow obstruction was staged differently in 14.0% and 6.3%, respectively, when the Swanney et al. and GLI reference equations were applied. CONCLUSIONS: Compared with the (corrected) ECSC equations, switching to more contemporary reference equations would result in lower FEV1 predicted values and affect interpretation of spirometry by reclassifying 6-14% of primary care COPD patients into different (mostly milder) severity stages. If and how this will affect GPs' treatment choices in individual patients with COPD requires further investigation.

Diagnostic accuracy of primary care asthma/COPD working hypotheses, a real life study.

UNLABELLED: Misdiagnoses are inevitable when working hypotheses of asthma/COPD of General Practitioners (GPs) are not checked by spirometry. To reduce misdiagnoses, Asthma/COPD-support services (AC-services) offer support by performing spirometry assessed together with written medical history by consulting pulmonologists. RESEARCH QUESTIONS: Which criteria do GPs use to justify their asthma/COPD working hypotheses? How do diagnostic assessments by an AC-service change GPs' working hypotheses? Do GPs' justifications for their working hypotheses influence the extent to which working hypotheses correspond with diagnoses given by an AC-service? METHOD: We investigated the working hypotheses of 17 GPs for 284 patients with respiratory problems and their justifications: "clinical symptoms", "office spirometry", or "specialist's correspondence". Working hypotheses were compared with diagnoses given by an AC-service, and the influence of the different justifications categories on diagnostic accuracy of the working hypotheses was described. RESULTS: 49% of the working hypothesis were only based on clinical information, 21% were also based on office spirometry. For 30% additional specialist information was available. 50% of the working hypotheses were confirmed by the AC-service. The working hypothesis asthma was confirmed more frequently (62%) than the working hypothesis COPD (40%). The justifications for the working hypotheses given by GPs did not influence these results. CONCLUSION: Diagnostic assessments of the AC-service differed significantly from the working hypotheses of GPs, even when these were based on previous specialists' correspondence or on office spirometry. To optimize the diagnoses in primary care, diagnostic support of an AC-service is recommended for all primary care patients with respiratory problems.

Lung function decline in relation to diagnostic criteria for airflow obstruction in respiratory symptomatic subjects.

BACKGROUND: Current COPD guidelines advocate a fixed < 0.70 FEV1/FVC cutpoint to define airflow obstruction. We compared rate of lung function decline in respiratory symptomatic 40+ subjects who were 'obstructive' or 'non-obstructive' according to the fixed and/or age and gender specific lower limit of normal (LLN) FEV1/FVC cutpoints. METHODS: We studied 3,324 respiratory symptomatic subjects referred to primary care diagnostic centres for spirometry. The cohort was subdivided into four categories based on presence or absence of obstruction according to the fixed and LLN FEV1/FVC cutpoints. Postbronchodilator FEV1 decline served as primary outcome to compare subjects between the respective categories. RESULTS: 918 subjects were obstructive according to the fixed FEV1/FVC cutpoint; 389 (42%) of them were non-obstructive according to the LLN cutpoint. In smokers, postbronchodilator FEV1 decline was 21 (SE 3) ml/year in those non-obstructive according to both cutpoints, 21 (7) ml/year in those obstructive according to the fixed but not according to the LLN cutpoint, and 50 (5) ml/year in those obstructive according to both cutpoints (p = 0.004). CONCLUSION: This study showed that respiratory symptomatic 40+ smokers and non-smokers who show FEV1/FVC values below the fixed 0.70 cutpoint but above their age/gender specific LLN value did not show accelerated FEV1 decline, in contrast with those showing FEV1/FVC values below their LLN cutpoint.

Effect of lifestyle intervention for people with diabetes or prediabetes in real-world primary care: propensity score analysis.

BACKGROUND: Many lifestyle interventions for patients with prediabetes or type 2 diabetes mellitus (T2DM) have been investigated in randomised clinical trial settings. However, the translation of these programmes into primary care seems challenging and the prevalence of T2DM is increasing. Therefore, there is an urgent need for lifestyle programmes, developed and shown to be effective in real-world primary care. We evaluated a lifestyle programme, commissioned by the Dutch government, for patients with prediabetes or type 2 diabetes in primary care. METHODS: We performed a retrospective comparative medical records analysis using propensity score matching. Patients with prediabetes or T2DM were selected from ten primary healthcare centres. Patients who received the lifestyle intervention (n = 186) were compared with a matched group of patients who received usual care (n = 2632). Data were extracted from the electronic primary care records. Propensity score matching was used to control for confounding by indication. Outcome measures were exercise level, BMI, HbA1c, fasting glucose, systolic and diastolic blood pressure, total cholesterol, HDL and LDL cholesterol and triglycerides and the follow-up period was one year. RESULTS: There was no significant difference at follow-up in any outcome measure between either group. The reduction at one year follow-up of HbA1c and fasting glucose was positive in the intervention group compared with controls, although not statistically significant (-0.12%, P = 0.07 and -0.17 mmol/l, P = 0.08 respectively). CONCLUSIONS: The effects of the lifestyle programme in real-world primary care for patients with prediabetes or T2DM were small and not statistically significant. The attention of governments for lifestyle interventions is important, but from the available literature and the results of this study, it must be concluded that improving lifestyle in real-world primary care is still challenging.

Diagnostic assessments of spirometry and medical history data by respiratory specialists supporting primary care: are they reliable?

AIM: To determine the intra- and inter-observer reliability of respiratory specialists' diagnostic assessments of spirometry and written medical history data obtained from primary care. METHOD: Five respiratory specialists assessed spirometry data and the history of 156 patients randomly selected from referrals to an asthma/COPD-service. The inter-observer reliability was evaluated. After six months, all specialists repeated the assessments and the intraobserver reliability was evaluated. RESULTS: The diagnostic assessments for all patients had reasonable intra- and inter-observer reliability, resulting in a Cohen's kappa (kappa) of 0.67 and 0.66 respectively. The intra-observer reliability for assessing the need for additional diagnostic examinations had an average kappa 0.56 for new patients and an average kappa 0.39 for follow-up examinations. The assessments of clinical stability in follow-up patients--on which therapeutic advice was based--were inconsistent. CONCLUSION: GPs who are reluctant to perform or interpret spirometry themselves may be supported diagnostically by respiratory specialists in an asthma/COPD-service. The reliability of this advice varies. More appropriate criteria for assessing clinical stability in patients with asthma and COPD are necessary to improve the reliability of the therapeutic advice.

The validity of diagnostic support of an asthma/COPD service in primary care.

BACKGROUND: To support GPs in diagnosing and monitoring their patients with asthma/chronic obstructive pulmonary disease (COPD), 'asthma/COPD services' have been developed. Within these services, pulmonologists perform structured diagnostic and therapeutic assessments based on the combination of written history data and spirometry. AIM: This study determines the validity of the diagnosis and advice when assessed using only written information. DESIGN OF STUDY: The results of the diagnostic procedures of an asthma/COPD service were compared with the results of regular office consultations by pulmonologists. SETTING: From January until August 2004, two pulmonologists examined 80 randomly selected patients referred to an asthma/COPD service in Eindhoven, the Netherlands. METHOD: Concordance was analysed between diagnosis and advice based on written spirometry and history data, with assessments based on live consultations with the same patients by pulmonologists. RESULTS: The validity of the assessed diagnosis was high (Cohen's kappa = 0.82). When the diagnosis was uncertain, the advice for medical treatment scored low in validity (Cohen's kappa = 0.39). The advice for additional diagnostic examinations had a high internal validity: in half of the patients, uncertainty in diagnosis turned into a definite diagnosis of asthma/COPD, or another cause for the complaints of the patient was revealed; in the other half, the diagnosis of asthma/COPD could be rejected. CONCLUSIONS: A structured asthma/COPD service offering diagnosis and diagnostic advice assessed from written spirometry and history data is a new and valid facility that can support the GP who faces the complicated diagnostic procedures in a progressive number of patients with asthma/COPD.

Effect of an integrated primary care model on the management of middle-aged and old patients with obstructive lung diseases.

OBJECTIVE: To investigate the effect of a primary care model for COPD on process of care and patient outcome. DESIGN: Controlled study with delayed intervention in control group. SETTING: The GP delegates tasks to a COPD support service (CSS) and a practice nurse. The CSS offers logistic support to the practice through a patient register and recall system for annual history-taking and lung function measurement. It also forms the link with the chest physician for diagnostic and therapeutic advice. The practice nurse's most important tasks are education and counselling. SUBJECTS: A total of 44 practices (n =22 for intervention and n =22 for control group) and 260 of their patients > or = 40 years with obstructive lung diseases. RESULTS: Within the intervention group planned visits increased from 16% to 44% and from 19% to 25% in the control condition (difference between groups p =0.014). Annual lung function measurement rose from 17% to 67% in the intervention and from 11% to 18% in the control group (difference between groups p =0.001). Compared with control, more but not statistically significant smokers received periodic advice to quit smoking (p =0.16). At baseline 41% of the intervention group were using their inhalers correctly and this increased to 54% after two years; it decreased in the control group from 47 to 29% (difference between groups p =0.002). The percentage of patients without exacerbation did not change significantly compared with the control condition. The percentage of the intervention group not needing emergency medication rose from 79% to 84% but decreased in the controls from 81 to 76% (difference between groups p =0.08). CONCLUSION: Combining different disciplines in one model has a positive effect on compliance with recommendations for monitoring patients, and improves the care process and some patient outcomes.

Logistic support service improves processes and outcomes of diabetes care in general practice.

BACKGROUND: Guidelines for type 2 diabetes care in general practice are well known and accepted, but the implementation falls short. OBJECTIVE: To implement these guidelines by introducing a diabetes support service (DSS) to support the care delivered by the GP. METHODS: A controlled, non-randomised study with delayed intervention in the control group; 78 GPs (n=51 for the intervention and n=21 for the control group) in the south of the Netherlands and 613 of their type 2 diabetic patients participated. Data were collected on the frequency, content and results of the check-ups (fasting blood glucose, HbA1c, cholesterol, cholesterol/HDL ratio, triglycerides, creatinine, blood pressure, fundus photography, foot examination, body mass index and smoking status) for 3 years. The year before signing up with the DSS was taken for the pre-measurements and after 2 years of DSS the post-measurements took place. The effect of the DSS was analysed in a mixed model with repeated measurement covariance structure. RESULTS: At baseline the intervention and control group did not differ in control frequency and outcome (HbA1c). After the intervention the percentage of patients that attended four or more quarterly check-ups (with at least testing of fasting blood glucose or HbA1c) increased from 59 to 78%. In contrast, the frequency of check-ups in the control group remained constant. This effect was significant. The HbA1c remained the same in the intervention group while there was a significant deterioration in the HbA1c in the control group. CONCLUSION: Simple logistic support by the DSS proved to have the capacity to implement type 2 diabetes guidelines in general practice.

The feasibility of a primary care model for the management of COPD.

AIMS: To investigate the feasibility of a primary care model to improve the management of COPD. METHODS: An intervention study on 1,497 patients with documented COPD from 22 general practices, involving 11 practice nurses and a COPD Support Service (CSS). Outcome measures included the successful delegation of tasks from general practitioners (GPs) to the CSS and practice nurse, and performance in daily practice according to the model components -- keeping a patient register with a recall system, periodical history taking and lung function measurements, asking diagnostic and therapeutic advice, and performing regular follow-up visits with education and counselling. RESULTS: In the 22 general practices, all components of the model were performed systematically, with the exception of 'asking for diagnostic and therapeutic advice' which occurred in 10 practices only. Of the 1,497 patients, 374 (25%) were treated by chest physicians. Of the remaining patients 88% were included in the primary care model and 12% refused regular follow-up. CONCLUSION: This primary care model for COPD management proved to be very feasible; GPs delegated the tasks, almost all patients were included in the control system, and a large majority of patients accepted follow-up according to the model.