Jan Willem J. Lammers

Recognising heart failure in elderly patients with stable chronic obstructive pulmonary disease in primary care: cross sectional diagnostic study

Abstract Objective To determine which clinical variables provide diagnostic information in recognising heart failure in primary care patients with stable chronic obstructive pulmonary disease (COPD) and whether easily available tests provide added diagnostic information. Design Cross sectional diagnostic study. Setting 51 primary care practices. Participants 1186 patients aged  65 years with COPD diagnosed by their general practitioner who did not have a diagnosis of heart failure confirmed by a cardiologist. Main outcome measures Independent diagnostic variables for concomitant heart failure in primary care patients with stable COPD. Results 405 patients (34% of eligible patients) underwent a systematic diagnostic investigation, which resulted in 83 (20.5%) receiving a new diagnosis of concomitant heart failure. Independent clinical variables for concomitant heart failure were a history of ischaemic heart disease, high body mass index, laterally displaced apex beat, and raised heart rate (area under the receiver operating characteristic curve (ROC area) 0.70, 95% confidence interval 0.64 to 0.76). Addition of measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) to the reduced “clinical model” had the largest added diagnostic value, with a significant increase of the ROC area to 0.77 (0.71 to 0.83), followed by electrocardiography (0.75, 0.69 to 0.81). C reactive protein and chest radiography had limited added value. A simplified diagnostic model consisting of the four independent clinical variables plus NT-proBNP and electrocardiography was developed. Conclusions A limited number of items easily available from history and physical examination, with addition of NT-proBNP and electrocardiography, can help general practitioners to identify concomitant heart failure in individual patients with stable COPD.

The Diagnostic Value of Physical Examination and Additional Testing in Primary Care Patients With Suspected Heart Failure

Background— Early diagnosis of nonacute heart failure is crucial because prompt initiation of evidence-based treatment can prevent or slow down further progression. To diagnose new-onset heart failure in primary care is challenging. Methods and Results— This is a cross-sectional diagnostic accuracy study with external validation. Seven hundred twenty-one consecutive patients suspected of new-onset heart failure underwent standardized diagnostic work-up including chest x-ray, spirometry, ECG, N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement, and echocardiography in specially equipped outpatient diagnostic heart failure clinics. The presence of heart failure was determined by an outcome panel using the initial clinical data and 6-month follow-up data, blinded to biomarker data. Of the 721 patients, 207 (28.7%) had heart failure. The combination of 3 items from history (age, coronary artery disease, and loop diuretic use) plus 6 from physical examination (pulse rate and regularity, displaced apex beat, rales, heart murmur, and increased jugular vein pressure) showed independent diagnostic value (c-statistic 0.83). NT-proBNP was the most powerful supplementary diagnostic test, increasing the c-statistic to 0.86 and resulting in net reclassification improvement of 69% (P<0.0001). A simplified diagnostic rule was applied to 2 external validation datasets, resulting in c- statistics of 0.95 and 0.88, confirming the results. Conclusions— In this study, we estimated the quantitative diagnostic contribution of elements of the history and physical examination in the diagnosis of heart failure in primary care outpatients, which may help to improve clinical decision making. The largest additional quantitative diagnostic contribution to those elements was provided by measurement of NT-proBNP. For daily practice, a diagnostic rule was derived that may be useful to quantify the probability of heart failure in patients with new symptoms suggestive of heart failure.

The impact of concurrent heart failure on prognosis in patients with chronic obstructive pulmonary disease

To compare prognosis in patients with chronic obstructive pulmonary disease (COPD) with or without concomitant heart failure.

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10−6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

The relationship between lung function impairment and quantitative computed tomography in chronic obstructive pulmonary disease.

AbstractObjectivesTo determine the relationship between lung function impairment and quantitative computed tomography (CT) measurements of air trapping and emphysema in a population of current and former heavy smokers with and without airflow limitation.MethodsIn 248 subjects (50 normal smokers; 50 mild obstruction; 50 moderate obstruction; 50 severe obstruction; 48 very severe obstruction) CT emphysema and CT air trapping were quantified on paired inspiratory and end-expiratory CT examinations using several available quantification methods. CT measurements were related to lung function (FEV1, FEV1/FVC, RV/TLC, Kco) by univariate and multivariate linear regression analysis.ResultsQuantitative CT measurements of emphysema and air trapping were strongly correlated to airflow limitation (univariate r-squared up to 0.72, p < 0.001). In multivariate analysis, the combination of CT emphysema and CT air trapping explained 68-83% of the variability in airflow limitation in subjects covering the total range of airflow limitation (p < 0.001).ConclusionsThe combination of quantitative CT air trapping and emphysema measurements is strongly associated with lung function impairment in current and former heavy smokers with a wide range of airflow limitation.Key Points• CT helps to automatically assess lung disease in heavy smokers • CT quantitatively measures emphysema and small airways disease in heavy smokers • CT air trapping and CT emphysema are associated with lung function impairment

Symptoms of influenza virus infection in hospitalized patients

BACKGROUND During influenza outbreaks, fever and cough are the most accurate symptoms in predicting influenza virus infection in the community. OBJECTIVE To determine the usefulness of fever, cough, and other symptoms for diagnosing influenza virus infection in hospitalized patients. DESIGN Prospective cohort study. SETTING Three wards (pulmonology, internal medicine and infectious diseases, and geriatrics) of a tertiary care hospital in the Netherlands. PATIENTS All patients staying in the wards during peak national influenza activity in the 2005-2006 and 2006-2007 influenza seasons. METHODS During peak influenza activity, the presence of fever, cough, and/or other symptoms possibly associated with influenza was monitored for all patients, and nose and throat swab samples were taken twice weekly for virologic analysis. RESULTS Of 264 patients, 23 (9%) tested positive for influenza virus. The positive predictive value of fever and cough for the diagnosis of influenza virus infection was 23% (95% confidence interval, 0%-62%), and the sensitivity was 35% (95% confidence interval, 11%-58%). The combination of symptoms with the highest positive predictive value (40%) was that of cough, chills, and obstructed nose or coryza. The combination of cough and chills or fever had the highest sensitivity (60%). None of the combinations of symptoms had both a positive predictive value and a sensitivity higher than 40%. CONCLUSIONS Both the sensitivity and the positive predictive value of fever, cough, and/or other symptoms for the diagnosis of influenza virus infection in hospitalized patients are low. The use of these common symptoms for treatment decisions and infection control management will probably be insufficient to contain a nosocomial outbreak, because many influenza cases will remain unidentified.

Conventional Influenza Vaccination Is Not Associated with Complications in Working-Age Patients with Asthma or Chronic Obstructive Pulmonary Disease

Abstract By using a nested case-control design, the authors studied the effectiveness of the influenza vaccine in reducing severe and fatal complications in 4,241 and 5,966 primary care, working-age patients aged 18–64 years who had asthma or chronic obstructive pulmonary disease during the 1998–1999 and 1999–2000 influenza epidemics in the Netherlands. Patients developing fatal or nonfatal exacerbations of lung disease, pneumonia, congestive heart failure, or myocardial infarction during either epidemic were considered cases. For each case, four age- and sex-matched controls were randomly sampled, and patient records were reviewed. Conditional logistic regression and propensity scores were used to assess vaccine effectiveness after adjustment for confounding factors. In seasons one and two, respectively, 87% (47/54) and 85% (171/202) of the cases and 74% (155/210) and 75% (575/766) of the controls had been vaccinated. After adjustments, vaccination was not associated with reductions in complications (season one: odds ratio = 0.95, 95% confidence interval (CI): 0.26, 3.48; season two: odds ratio = 1.07, 95% CI: 0.59, 1.96; pooled odds ratio = 1.07, 95% CI: 0.63, 1.80). Because influenza vaccination appeared not to be associated with a clinically relevant reduction in severe morbidity, other measures need to be explored.

The effect of a single inhaled dose of a VLA‐4 antagonist on allergen‐induced airway responses and airway inflammation in patients with asthma

Adhesion molecule very late antigen‐4 (VLA‐4) is implicated in the recruitment and activation of inflammatory cells in asthma, including eosinophils, T cells and mast cells. VLA‐4 antagonists have been proposed as a new anti‐inflammatory treatment modality for asthma. Therefore, we investigated whether a single inhaled dose of VLA‐4 antagonist GW559090X could protect against allergen‐induced changes in airway responses and airway inflammation in patients with asthma. We performed a randomized, double‐blind, three‐way crossover study with single inhaled doses of 3 mg of GW559090X, 500 μg of fluticasone propionate (FP) or placebo in 15 patients with mild intermittent asthma, controlled with short‐acting β2‐agonists only. All patients developed a late asthmatic response (LAR) after allergen inhalation during screening. Study medication was administered 30 min prior to allergen challenge. Pre‐dose and 24 h post‐dose PC20 methacholine and levels of exhaled nitric oxide (eNO) were determined. At the given dose, VLA‐4 antagonist GW559090X did not attenuate the early asthmatic response (EAR) when compared with placebo: mean AUC0−2h(± SEM) (%fall h): 27.2 ± 3.7 and 21.9 ± 3.0 respectively (P = 0.33); nor the LAR: mean AUC3−8h(± SEM) (%fall h): 98.8 ± 12.9 and 94.8 ± 6.8 respectively (P = 0.84). However, pretreatment with FP did attenuate both EAR and LAR when compared with placebo: mean AUC0−2h11.6 ± 3.3 (P = 0.024) and mean AUC3−8h 6.3 ± 7.6 (P < 0.001). None of these treatments had an effect on allergen‐induced changes in airway hyper‐responsiveness or eNO levels. These findings suggest that VLA‐4 may not play a major role in allergen‐induced airway responses and inflammation in asthma.

Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) &kgr;&bgr; pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10−9). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-&kgr;&bgr;, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution. This article provides suggestive evidence, but not firm evidence that there is overlap in genetics of asthma and COPD http://ow.ly/we9yE

Distribution of emphysema in heavy smokers: Impact on pulmonary function

PURPOSE To investigate impact of distribution of computed tomography (CT) emphysema on severity of airflow limitation and gas exchange impairment in current and former heavy smokers participating in a lung cancer screening trial. MATERIALS AND METHODS In total 875 current and former heavy smokers underwent baseline low-dose CT (30 mAs) in our center and spirometry and diffusion capacity testing on the same day as part of the Dutch-Belgian Lung Cancer Screening Trial (NELSON). Emphysema was quantified for 872 subjects as the number of voxels with an apparent lowered X-ray attenuation coefficient. Voxels attenuated <-950 HU were categorized as representing severe emphysema (ES950), while voxels attenuated between -910 HU and -950 HU represented moderate emphysema (ES910). Impact of distribution on severity of pulmonary function impairment was investigated with logistic regression, adjusted for total amount of emphysema. RESULTS For ES910 an apical distribution was associated with more airflow obstruction and gas exchange impairment than a basal distribution (both p<0.01). The FEV(1)/FVC ratio was 1.6% (95% CI 0.42% to 2.8%) lower for apical predominance than for basal predominance, for Tlco/V(A) the difference was 0.12% (95% CI 0.076-0.15%). Distribution of ES950 had no impact on FEV(1)/FVC ratio, while an apical distribution was associated with a 0.076% (95% CI 0.038-0.11%) lower Tlco/V(A) (p<0.001). CONCLUSION In a heavy smoking population, an apical distribution is associated with more severe gas exchange impairment than a basal distribution; for moderate emphysema it is also associated with a lower FEV(1)/FVC ratio. However, differences are small, and likely clinically irrelevant.