B cell–adaptive immune profile in emphysema-predominant chronic obstructive pulmonary disease

Cigarette smoke, the major risk factor for COPD in developed countries, causes pulmonary inflammation that persists long after smoking cessation, suggesting self-perpetuating adaptive immune responses similar to those that occur in autoimmune diseases. Increases in the number and size of B cell–rich lymphoid follicles (LFs) have been shown in patients in severe stages of COPD (4), and increased B-cell products (autoantibodies) have been observed in the blood and lungs of patients with COPD (5, 6). Oligoclonal rearrangement of the immunoglobulin genes has been observed in B cells isolated from COPD LFs, suggesting that a specific antigenic stimulation drives B-cell proliferation. Consistently, we have shown that in the COPD lung, there is an overexpression of BAFF (B-cell activation factor of the TNF family), which is a key regulator of B-cell homeostasis in several autoimmune diseases (7) and is involved in the growth of LFs in COPD. However, a network analysis of lung transcriptomics showed that a prominent B-cell molecular signature characterized emphysema preferentially but was absent in AD independently of the degree of airflow limitation (8). In the current study, we investigated the correlation between B-cell responses in lung tissue from patients with COPD and healthy smokers, and the extent of emphysema versus airflow limitation

Plasma metabolomics and clinical predictors of survival differences in COPD patients

Background: Plasma metabolomics profile (PMP) in COPD has been associated with clinical characteristics, but PMP’s relationship to survival has not been reported. We determined PMP differences between patients with COPD who died an average of 2 years after enrollment (Non-survivors, NS) compared to those who survived (S) and also with age matched controls (C). Methods: We studied prospectively 90 patients with severe COPD and 30 controls. NS were divided in discovery and validation cohorts (30 patients each) and the results compared to the PMP of 30 S and C. All participants completed lung function tests, dyspnea scores, quality of life, exercise capacity, BODE index, and plasma metabolomics by liquid and gas chromatography / mass spectometry (LC/MS, LC/MS2 , GC/MS). Statistically, we used Random Forest Analysis (RFA) and Support Vector Machine (SVM) to determine metabolites that differentiated the 3 groups and compared the ability of metabolites vs. clinical characteristics to classify patients into survivors and non-survivors. Results: There were 79 metabolites statistically different between S and NS [p < 0.05 and false discovery rate (q value) < 0.1]. RFA and SVM classification of COPD survivors and non-survivors had a predicted accuracy of 74 and 85% respectively. Elevation of tricyclic acid cycle intermediates branched amino acids depletion and increase in lactate, fructose and xylonate showed the most relevant differences between S vs. NS suggesting alteration in mitochondrial oxidative energy generation. PMP had similar predictive power for risk of death as information provided by clinical characteristics. Conclusions: A plasma metabolomic profile characterized by an oxidative energy production difference between survivors and non-survivors was observed in COPD patients 2 years before death

Chronic obstructive pulmonary disease (COPD) as a disease of early aging: evidence from the epiChron cohort

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

Somatotypes trajectories during adulthood and their association with COPD phenotypes

Rationale: Chronic obstructive pulmonary disease (COPD) comprises distinct phenotypes, all characterised by airflow limitation. Objectives: We hypothesised that somatotype changes – as a surrogate of adiposity – from early adulthood follow different trajectories to reach distinct phenotypes. Methods: Using the validated Stunkard’s Pictogram, 356 COPD patients chose the somatotype that best reflects their current body build and those at ages 18, 30, 40 and 50 years. An unbiased group-based trajectory modelling was used to determine somatotype trajectories. We then compared the current COPD-related clinical and phenotypic characteristics of subjects belonging to each trajectory. Measurements and main results: At 18 years of age, 88% of the participants described having a lean or medium somatotype (estimated body mass index (BMI) between 19 and 23 kg·m−2 ) while the other 12% a heavier somatotype (estimated BMI between 25 and 27 kg·m−2 ). From age 18 onwards, five distinct trajectories were observed. Four of them demonstrating a continuous increase in adiposity throughout adulthood with the exception of one, where the initial increase was followed by loss of adiposity after age 40. Patients with this trajectory were primarily females with low BMI and DLCO (diffusing capacity of the lung for carbon monoxide). A persistently lean trajectory was seen in 14% of the cohort. This group had significantly lower forced expiratory volume in 1 s (FEV1), DLCO, more emphysema and a worse BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) score thus resembling the multiple organ loss of tissue (MOLT) phenotype. Conclusions: COPD patients have distinct somatotype trajectories throughout adulthood. Those with the MOLT phenotype maintain a lean trajectory throughout life. Smoking subjects with this lean phenotype in early adulthood deserve particular attention as they seem to develop more severe COPD

Supplementation with Qter®and Creatine improves functional performance in COPD patients on long term oxygen therapy

Background: Skeletal muscle dysfunction and poor functional capacity are important extra-pulmonary manifestations of chronic obstructive pulmonary disease (COPD), especially in COPD patients on long-term O2therapy (LTOT). Beside the role of pulmonary rehabilitation, the effect of nutritional interventions is still controversial, and there are knowledge gaps on the effective role of nutraceutical supplementation on hard endpoints. The aim of this study was to investigate the effects of nutritional supplementation with Coenzyme Q10 (QTer®) – a powerful antioxidant with the potential to reduce oxidative stress and improve mitochondrial function − and Creatine on functional, nutritional, and metabolomic profile in COPD patients on long-term O2therapy. Methods: One-hundred and eight patients with COPD from 9 Italian hospitals were enrolled in this double-blinded randomized placebo-controlled clinical study. At baseline and after 2 months of therapy, the patients underwent spirometry, 6-minute walk test (6MWT), bioelectrical impedance analysis, and activities of daily living questionnaire (ADL). Also, dyspnea scores and BODE index were calculated. At both time points, plasma concentration of CoQ10 and metabolomic profiling were measured. Findings: Ninety patients, who randomly received supplementation with QTer®and Creatine or placebo, completed the study. Compared with placebo, supplemented patients showed improvements in 6MWT (51 ± 69 versus 15 ± 91 m, p < 0.05), body cell mass and phase angle, sodium/potassium ratio, dyspnea indices and ADL score. The CoQ10 plasma concentration increased in the supplementation group whereas it did not change in the placebo group. The metabolomics profile also differed between groups. Adverse events were similar in both groups. Interpretation: These results show that in patients with COPD, dietary supplementation with CoQ10 and Creatine improves functional performance, body composition and perception of dyspnea. A systemic increase in some anti-inflammatory metabolites supports a pathobiological mechanism as a reason for these benefits. Further trials should help clarifying the role of QTer®and Creatine supplementation in patients with COPD

A Novel Insight into Adaptive Immunity in Chronic Obstructive Pulmonary Disease B Cell Activating Factor Belonging to the Tumor Necrosis Factor Family

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a disorder characterized by an abnormal inflammatory response that persists even after smoking cessation, yet the underlying mechanisms are not fully understood. OBJECTIVES: To investigate the expression of B-cell activating factor of tumor necrosis factor family (BAFF), a crucial mediator in the crosstalk between innate and adaptive immune responses, in patients with COPD and to explore its correlation with disease severity. METHODS: Using immunohistochemistry, expression of BAFF was examined in lung specimens from 21 smokers with COPD (FEV(1) = 57 \ub1 5% predicted), 14 control smokers (FEV(1) = 99 \ub1 2% predicted) and 8 nonsmokers (FEV(1) = 104 \ub1 4% predicted). BAFF was quantified in alveolar macrophages and alveolar walls, in bronchiolar and parenchymal lymphoid follicles, and in peripheral airways and pulmonary arterioles. MEASUREMENTS AND MAIN RESULTS: In alveolar macrophages and parenchymal lymphoid follicles, BAFF expression was increased in smokers with COPD compared with control smokers and nonsmokers (P < 0.05 for all comparisons). In both compartments, BAFF was also up-regulated in control smokers as compared with nonsmokers (P = 0.03 and P = 0.01). Moreover, BAFF was overexpressed in bronchiolar lymphoid follicles, alveolar walls, peripheral airways, and pulmonary arterioles from smokers with COPD compared with nonsmokers (P < 0.05 for all). Among patients with COPD, BAFF(+) macrophages were inversely related to FEV(1) (P = 0.03, Spearman's rho [r(S)] = -0.48), FEV(1)/FVC (P = 0.02, r(S) = -0.50), and Pa(O(2)) values (P = 0.01, r(S) = -0.55). CONCLUSIONS: This study demonstrated overexpression of BAFF in peripheral lung of patients with COPD, mainly in alveolar macrophages and lymphoid follicles. Moreover, BAFF expression was correlated to the degree of lung function impairment and hypoxia, suggesting that it may have a possible impact on disease severity