Person:

Celli, Bartolome

Background: Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552). Methods and Findings: Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-(\alpha) levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice. Conclusions: Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.

Patients with chronic obstructive pulmonary disease (COPD) who are defined as frequent exacerbators suffer with 2 or more exacerbations every year. The molecular mechanisms responsible for this phenotype are poorly understood. We investigated gene expression profile patterns associated with frequent exacerbations in sputum and blood cells in a well-characterised cohort. Samples from subjects from the ECLIPSE COPD cohort were used; sputum and blood samples from 138 subjects were used for microarray gene expression analysis, while blood samples from 438 subjects were used for polymerase chain reaction (PCR) testing. Using microarray, 150 genes were differentially expressed in blood (>±1.5 fold change, p≤0.01) between frequent compared to non-exacerbators. In sputum cells, only 6 genes were differentially expressed. The differentially regulated genes in blood included downregulation of those involved in lymphocyte signalling and upregulation of pro-apoptotic signalling genes. Multivariate analysis of the microarray data followed by confirmatory PCR analysis identified 3 genes that predicted frequent exacerbations; B3GNT, LAF4 and ARHGEF10. The sensitivity and specificity of these 3 genes to predict the frequent exacerbator phenotype was 88% and 33% respectively. There are alterations in systemic immune function associated with frequent exacerbations; down-regulation of lymphocyte function and a shift towards pro-apoptosis mechanisms are apparent in patients with frequent exacerbations.

QUESTION A 6-second spirometry test is easier than full exhalations. We compared the reliability of the ratio of the Forced expiratory volume in 1 second/Forced expiratory volume in 6 seconds (FEV1/FEV6) to the ratio of the FEV1/Forced vital capacity (FEV1/FVC) for the detection of airway obstruction. METHODS The PLATINO population-based survey in individuals aged 40 years and over designed to estimate the prevalence of post-Bronchodilator airway obstruction repeated for the same study participants after 5–9 years in three Latin-American cities. RESULTS Using the FEV1/FVC<Lower limit of normal (LLN) index, COPD prevalence apparently changed from 9.8 to 13.2% in Montevideo, from 9.7 to 6.0% in São Paulo and from 8.5 to 6.6% in Santiago, despite only slight declines in smoking prevalence (from 30.8% to 24.3%). These changes were associated with differences in Forced expiratory time (FET) between the two surveys. In contrast, by using the FEV1/FEV6 to define airway obstruction, the changes in prevalence were smaller: 9.7 to 10.6% in Montevideo, 8.6 to 9.0% in São Paulo, and 7.5 to 7.9% in Santiago. Changes in the prevalence of COPD with criteria based on FEV1/FVC correlated strongly with changes in the FET of the tests (R2 0.92) unlike the prevalence based on a low FEV1/FEV6 (R2 = 0.40). CONCLUSION The FEV1/FEV6 is a more reliable index than FEV1/FVC because FVC varies with the duration of the forced exhalation. Reporting FET and FEV1/FEV6<LLN helps to understand differences in prevalence of COPD obtained from FEV1/FVC-derived indices.

Background: FEV1 is universally used as a measure of severity in COPD. Current thresholds are based on expert opinion and not on evidence. Objectives: We aimed to identify the best FEV1 (% predicted) and dyspnea (mMRC) thresholds to predict 5-yr survival in COPD patients. Design and Methods We conducted a patient-based pooled analysis of eleven COPD Spanish cohorts (COCOMICS). Survival analysis, ROC curves, and C-statistics were used to identify and compare the best FEV1 (%) and mMRC scale thresholds that predict 5-yr survival. Results: A total of 3,633 patients (93% men), totaling 15,878 person-yrs. were included, with a mean age 66.4±9.7, and predicted FEV1 of 53.8% (±19.4%). Overall 975 (28.1%) patients died at 5 years. The best thresholds that spirometrically split the COPD population were: mild ≥70%, moderate 56–69%, severe 36–55%, and very severe ≤35%. Survival at 5 years was 0.89 for patients with FEV1≥70 vs. 0.46 in patients with FEV1 ≤35% (H.R: 6; 95% C.I.: 4.69–7.74). The new classification predicts mortality significantly better than dyspnea (mMRC) or FEV1 GOLD and BODE cutoffs (all p<0.001). Prognostic reliability is maintained at 1, 3, 5, and 10 years. In younger patients, survival was similar for FEV1 (%) values between 70% and 100%, whereas in the elderly the relationship between FEV1 (%) and mortality was inversely linear. Conclusions: The best thresholds for 5-yr survival were obtained stratifying FEV1 (%) by ≥70%, 56–69%, 36–55%, and ≤35%. These cutoffs significantly better predict mortality than mMRC or FEV1 (%) GOLD and BODE cutoffs.

Background: The Global Initiative for Obstructive Lung Diseases (GOLD) defines COPD as a disease that is usually progressive. GOLD also provides a spirometric classification of airflow limitation. However, little is known about the long-term changes of patients in different GOLD grades. Objective: Explore the proportion and characteristics of COPD patients that change their spirometric GOLD grade over long-term follow-up. Methods: Patients alive for at least 8 years since recruitment and those who died with at least 4 years of repeated spirometric measurements were selected from the BODE cohort database. We purposely included the group of non survivors to avoid a “survival selection” bias. The proportion of patients that had a change (improvement or worsening) in their spirometric GOLD grading was calculated and their characteristics compared with those that remained in the same grade. Results: A total of 318 patients were included in the survivor and 217 in the non-survivor groups. Nine percent of survivors and 11% of non survivors had an improvement of at least one GOLD grade. Seventy one percent of survivors and non-survivors remained in the same GOLD grade. Those that improved had a greater degree of airway obstruction at baseline. Conclusions: In this selected population of COPD patients, a high proportion of patients remained in the same spirometric GOLD grade or improved in a long-term follow-up. These findings suggest that once diagnosed, COPD is usually a non-progressive disease.

Background: Aging is an important risk factor for most chronic diseases. Patients with COPD develop more comorbidities than non-COPD subjects. We hypothesized that the development of comorbidities characteristically affecting the elderly occur at an earlier age in subjects with the diagnosis of COPD. Methods and findings We included all subjects carrying the diagnosis of COPD (n = 27,617), and a similar number of age and sex matched individuals without the diagnosis, extracted from the 727,241 records of individuals 40 years and older included in the EpiChron Cohort (Aragon, Spain). We compared the cumulative number of comorbidities, their prevalence and the mortality risk between both groups. Using network analysis, we explored the connectivity between comorbidities and the most influential comorbidities in both groups. We divided the groups into 5 incremental age categories and compared their comorbidity networks. We then selected those comorbidities known to affect primarily the elderly and compared their prevalence across the 5 age groups. In addition, we replicated the analysis in the smokers’ subgroup to correct for the confounding effect of cigarette smoking. Subjects with COPD had more comorbidities and died at a younger age compared to controls. Comparison of both cohorts across 5 incremental age groups showed that the number of comorbidities, the prevalence of diseases characteristic of aging and network’s density for the COPD group aged 56–65 were similar to those of non-COPD 15 to 20 years older. The findings persisted after adjusting for smoking. Conclusion: Multimorbidity increases with age but in patients carrying the diagnosis of COPD, these comorbidities are seen at an earlier age.

The natural history of chronic obstructive pulmonary disease (COPD) is still not well understood. Traditionally believed to be a self-inflicted disease by smoking, now we know that not all smokers develop COPD, that other inhaled pollutants different from cigarette smoke can also cause it, and that abnormal lung development can also lead to COPD in adulthood. Likewise, the inflammatory response that characterizes COPD varies significantly between patients, and not all of them perceive symptoms (mostly breathlessness) similarly. To investigate the variability and determinants of different “individual natural histories” of COPD, we developed a theoretical, multi-stage, computational model of COPD (EASI) that integrates dynamically and represents graphically the relationships between exposure (E) to inhaled particles and gases (smoking), the biological activity (inflammatory response) of the disease (A), the severity (S) of airflow limitation (FEV1) and the impact (I) of the disease (breathlessness) in different clinical scenarios. EASI shows that the relationships between E, A, S and I vary markedly within individuals (through life) and between individuals (at the same age). It also helps to delineate some potentially relevant, but often overlooked concepts, such as disease progression, susceptibility to COPD and issues related to symptom perception. In conclusion, EASI is an initial conceptual model to interpret the longitudinal and cross-sectional relationships between E, A, S and I in different clinical scenarios. Currently, it does not have any direct clinical application, thus it requires experimental validation and further mathematical development. However, it has the potential to open novel research and teaching alternatives.