Roger Escamilla

Clinical COPD phenotypes: a novel approach using principal component and cluster analyses

Classification of chronic obstructive pulmonary disease (COPD) is usually based on the severity of airflow limitation, which may not reflect phenotypic heterogeneity. Here, we sought to identify COPD phenotypes using multiple clinical variables. COPD subjects recruited in a French multicentre cohort were characterised using a standardised process. Principal component analysis (PCA) was performed using eight variables selected for their relevance to COPD: age, cumulative smoking, forced expiratory volume in 1 s (FEV1) (% predicted), body mass index, exacerbations, dyspnoea (modified Medical Research Council scale), health status (St George’s Respiratory Questionnaire) and depressive symptoms (hospital anxiety and depression scale). Patient classification was performed using cluster analysis based on PCA-transformed data. 322 COPD subjects were analysed: 77% were male; median (interquartile range) age was 65.0 (58.0–73.0) yrs; FEV1 was 48.9 (34.1–66.3)% pred; and 21, 135, 107 and 59 subjects were classified in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1, 2, 3 and 4, respectively. PCA showed that three independent components accounted for 61% of variance. PCA-based cluster analysis resulted in the classification of subjects into four clinical phenotypes that could not be identified using GOLD classification. Importantly, subjects with comparable airflow limitation (FEV1) belonged to different phenotypes and had marked differences in age, symptoms, comorbidities and predicted mortality. These analyses underscore the need for novel multidimensional COPD classification for improving patient care and quality of clinical trials.

Clinical COPD phenotypes identified by cluster analysis: validation with mortality

To the Editors: Because forced expiratory volume in 1 s is a poor descriptor of chronic obstructive pulmonary disease (COPD) heterogeneity [1], interest has emerged regarding the identification of clinically relevant COPD phenotypes [2, 3]. We recently reported the usefulness of applying mathematical models ( i.e. principal component and cluster analyses) to multiple variables for the identification of clinical phenotypes in a cohort of COPD subjects [4]. These original analyses allowed the description of four COPD groups, which we called “clinical COPD phenotypes” [4]. This terminology was based on the classical definition of “phenotype”, referring to the observable characteristics (including respiratory manifestations and comorbidities) of patients. Recently, a panel of experts proposed the following modified definition for clinical COPD phenotypes: “a single or combination of disease attributes that describes differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)” [2 …

Alternative processing of the U2 small nuclear RNA produces a 19-22nt fragment with relevance for the detection of non-small cell lung cancer in human serum.

RNU2 exists in two functional forms (RNU2-1 and RNU2-2) distinguishable by the presence of a unique 4-bases motif. Detailed investigation of datasets obtained from deep sequencing of five human lung primary tumors revealed that both forms express at a high rate a 19–22nt fragment (miR-U2-1 and -2) from its 3′ region and contains the 4-bases motif. Deep sequencing of independent pools of serum samples from healthy donors and lung cancer patients revealed that miR-U2-1 and -2 are pervasively processed in lung tissue by means of endonucleolytic cleavages and stably exported to the blood. Then, microarrays hybridization experiments of matched normal/tumor samples revealed a significant over-expression of miR-U2-1 in 14 of 18 lung primary tumors. Subsequently, qRT-PCR of miR-U2-1 using serum from 62 lung cancer patients and 96 various controls demonstrated that its expression levels identify lung cancer patients with 79% sensitivity and 80% specificity. miR-U2-1 expression correlated with the presence or absence of lung cancer in patients with chronic obstructive pulmonary disease (COPD), other diseases of the lung – not cancer, and in healthy controls. These data suggest that RNU2-1 is a new bi-functional ncRNA that produces a 19–22nt fragment which may be useful in detecting lung cancer non-invasively in high risk patients.

Real-life use of inhaled corticosteroids in COPD patients versus the GOLD proposals: a paradigm shift in GOLD 2011?

To the Editor: Clinical trials in chronic obstructive pulmonary disease (COPD) patients have shown that the long-term use of inhaled corticosteroids (ICS) in COPD patients reduced the number of exacerbations per patient per year and improved health status [1]. Early studies have suggested increased ICS efficacy in patients with low lung function and frequent exacerbations [2]. The efficacy was reinforced when ICS was used in conjunction with long-acting β2-agonists (LABA) [3]. In most countries, health authorities approved ICS/LABA combinations in COPD patients with severe airflow impairment and frequent exacerbations, as also recommended in the Global Initiative for Obstructive Lung Disease (GOLD) 2007 document [4]. However, several surveys found poor adherence to this proposal among primary care physicians and pulmonologists in “real life”, ICS being often prescribed at a milder stage of the disease. The GOLD 2011 document proposed a new multidimensional system for the assessment and management of patients with COPD [5]. This system classifies COPD patients into four categories (A, B, C and D) based on the level of symptoms (dyspnoea or global clinical impact) and the risk of future exacerbations, as assessed using the severity of airflow limitation and the past history …

Relationship between blood eosinophils, clinical characteristics, and mortality in patients with COPD

In patients with COPD, there is controversy regarding the association of blood eosinophil (Eos) levels with 1) exacerbation frequency and 2) the effect of inhaled corticosteroids for prevention of exacerbations. To determine whether Eos define subgroups of patients exhibiting attributes of COPD clinical phenotypes, we compared clinical features and mortality rates in COPD patients from the Initiatives BPCO French cohort categorized using different thresholds of blood Eos levels. The following data were collected at inclusion: medical and smoking history, occupational exposures, dyspnea, cough and sputum production, exacerbations in the previous year, history of allergy and asthma, nasal symptoms, body mass index, St George Respiratory Questionnaire (SGRQ) total score, post-bronchodilator spirometry, comorbidities, and medications. Three-year survival between groups was compared using Kaplan–Meier analysis. Three sets of analyses were performed to compare patients with ≥2% versus <2%, ≥3% versus <3%, and ≥4% versus <4% Eos. Eos was available in 458 patients (mean age: 62 years, 72% male, mean forced expiratory volume in 1 second: 51% pred), including 235 patients with Eos ≥2% (49%), 149 with Eos ≥3% (33%), and 90 with Eos ≥4% (20%). For all cutoffs, there was no difference between Eos+ and Eos− groups in univariate analyses except for diabetes and SGRQ score (more frequent and more impaired, respectively, in lower Eos categories). In particular, there was no difference in exacerbation rate, history of asthma, or three-year survival. In conclusion, regardless of the cutoff, Eos+ COPD patients exhibited no specific characteristic in terms of symptoms, lung function, exacerbation rate, and prognosis. These findings suggest that the association of higher Eos with exacerbations reported in previous studies could be population specific, which does not support generalizing the use of Eos as a biomarker for COPD phenotyping.

Impact of gender on COPD expression in a real-life cohort

Reports regarding gender-related differences in COPD expression have provided conflicting results. In the French Initiatives BPCO real-world cohort, which contained 688 patients (146 women) when data were extracted, women were matched with men (1:3 ratio: n = 107:275) on age (5-year intervals) and FEV1 (5% predicted intervals) and comparisons were performed using univariate logistic regressions. For a given age and level of airflow obstruction, women with COPD had higher BOD scores due to more pronounced dyspnea and lower BMI, suggesting worse prognosis, and were more likely to exhibit anxiety, suggesting the need for specific assessment and care.

Asthma–COPD overlap syndrome (ACOS) vs ‘pure’ COPD: a distinct phenotype?

Some studies suggest that asthma–COPD overlap syndrome (ACOS) is associated with worse outcomes than chronic obstructive pulmonary disease (COPD). The goal of this study was to further explore the clinical characteristics and survival of patients with ACOS identified in a real‐life cohort of patients with COPD.

Association between occupational exposure and the clinical characteristics of COPD

BackgroundThe contribution of occupational exposures to COPD and their interaction with cigarette smoking on clinical pattern of COPD remain underappreciated. The aim of this study was to explore the contribution of occupational exposures on clinical pattern of COPD.MethodsCross-sectional data from a multicenter tertiary care cohort of 591 smokers or ex-smokers with COPD (median FEV1 49%) were analyzed. Self-reported exposure to vapor, dust, gas or fumes (VDGF) at any time during the entire career was recorded.ResultsVDGF exposure was reported in 209 (35%) subjects aged 31 to 88 years. Several features were significantly associated with VDGF exposure: age (median 68 versus 64 years, p < 0.001), male gender (90% vs 76%; p < 0.0001), reported work-related respiratory disability (86% vs 7%, p < 0.001), current wheezing (71% vs 61%, p = 0.03) and hay fever (15.5% vs 8.5%, p < 0.01). In contrast, current and cumulative smoking was less (p = 0.01) despite similar severity of airflow obstruction.ConclusionIn this patient series of COPD patients, subjects exposed to VDGF were older male patients who reported more work-related respiratory disability, more asthma-like symptoms and atopy, suggesting that, even in smokers or ex-smokers with COPD, occupational exposures are associated with distinct patients characteristics.

Undiagnosed airflow limitation in patients at cardiovascular risk.

BACKGROUND Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) share risk factors and impair each others prognosis. AIMS To assess the prevalence of airflow limitation (AL) compatible with COPD in a population at cardiovascular risk and to identify determinants of AL. METHODS All consecutive patients referred to the cardiovascular prevention unit of a university hospital in 2009 were studied in a cross-sectional analysis. Patients answered questionnaires on socioeconomic status, medical history and lifestyle, and underwent extensive physical examinations, biological measures and spirometry testing. AL was defined as FEV1/FVC<0.70, without any history of asthma. Determinants of AL were assessed using logistic regression. RESULTS The sample comprised 493 participants (mean age 57.4±11.1 years); 60% were men, 18% were current smokers, 42% were ex-smokers and 10% of patients had a history of CVD. Ten-year risk of coronary heart disease (CHD) according to the Framingham equation was intermediate (10-20%) for 25% of patients and high (>20%) for 10%. Prevalence of AL was 5.9% (95% confidence interval [CI] 4.0-8.3%) in the whole population and 4.3% (2.6-6.6%) among subjects in primary cardiovascular prevention. AL was independently associated with CVD (adjusted odds ratio 4.18, 95% CI 1.72-10.15; P=0.002) but not with Framingham CHD risk. More than 80% of patients screened with AL had not been diagnosed previously and more than one in two patients was asymptomatic. CONCLUSION Patients with CVD are at increased risk of AL and thus should benefit from AL screening as they are frequently asymptomatic.

Association of chronic nasal symptoms with dyspnoea and quality-of-life impairment in chronic obstructive pulmonary disease.

Previous studies suggested that chronic nasal symptoms (CNS) are frequent in chronic obstructive pulmonary disease (COPD) subjects, but their contribution to dyspnoea and quality‐of‐life (QoL) impairment is not clearly established.