Distribution and Outcomes of a Phenotype- Based Approach to Guide COPD Management: Results from the CHAIN Cohort

Rationale The Spanish guideline for COPD (GesEPOC) recommends COPD treatment according to four clinical phenotypes: non-exacerbator phenotype with either chronic bronchitis or emphy- sema (NE), asthma-COPD overlap syndrome (ACOS), frequent exacerbator phenotype with emphysema (FEE) or frequent exacerbator phenotype with chronic bronchitis (FECB). How- ever, little is known on the distribution and outcomes of the four suggested phenotypes. Objective We aimed to determine the distribution of these COPD phenotypes, and their relation with one-year clinical outcomes. Methods We followed a cohort of well-characterized patients with COPD up to one-year. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between the four phenotypes. Results Overall, 831 stable COPD patients were evaluated. They were distributed as NE, 550 (66.2%); ACOS, 125 (15.0%); FEE, 38 (4.6%); and FECB, 99 (11.9%); additionally 19 (2.3%) COPD patients with frequent exacerbations did not fulfill the criteria for neither FEE nor FECB. At baseline, there were significant differences in symptoms, FEV 1 and BODE index (all p<0.05). The FECB phenotype had the highest CAT score (17.1±8.2, p<0.05 compared to the other phenotypes). Frequent exacerbator groups (FEE and FECB) were receiving more pharmacological treatment at baseline, and also experienced more exacer- bations the year after (all p<0.05) with no differences in one-year mortality. Most of NE (93%) and half of exacerbators were stable after one year. Conclusions There is an uneven distribution of COPD phenotypes in stable COPD patients, with signifi- cant differences in demographics, patient-centered outcomes and health care resources use

The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel

© 2018 Ward et al. Ubiquitin-specific protease 15 (USP15) regulates important cellular processes, including transforming growth factor β (TGF-β) signaling, mitophagy, mRNA processing, and innate immune responses; however, structural information on USP15's catalytic domain is currently unavailable. Here, we determined crystal structures of the USP15 catalytic core domain, revealing a canonical USP fold, including a finger, palm, and thumb region. Unlike for the structure of paralog USP4, the catalytic triad is in an inactive configuration with the catalytic cysteine ∼10 Å apart from the catalytic histidine. This conformation is atypical, and a similar misaligned catalytic triad has so far been observed only for USP7, although USP15 and USP7 are differently regulated. Moreover, we found that the active-site loops are flexible, resulting in a largely open ubiquitin tail-binding channel. Comparison of the USP15 and USP4 structures points to a possible activation mechanism. Sequence differences between these two USPs mainly map to the S1' region likely to confer specificity, whereas the S1 ubiquitin-binding pocket is highly conserved. Isothermal titration calorimetry monoubiquitin- and linear diubiquitin-binding experiments showed significant differences in their thermodynamic profiles, with USP15 displaying a lower affinity for monoubiquitin than USP4. Moreover, we report that USP15 is weakly inhibited by the antineoplastic agent mitoxantrone in vitro A USP15-mitoxantrone complex structure disclosed that the anthracenedione interacts with the S1' binding site. Our results reveal first insights into USP15's catalytic domain structure, conformational changes, differences between paralogs, and small-molecule interactions and establish a framework for cellular probe and inhibitor development

New GOLD classification: Longitudinal data on group assignment

Rationale: Little is known about the longitudinal changes associated with using the 2013 update of the multidimensional GOLD strategy for chronic obstructive pulmonary disease (COPD). Objective: To determine the COPD patient distribution of the new GOLD proposal and evaluate how this classification changes over one year compared with the previous GOLD staging based on spirometry only. Methods: We analyzed data from the CHAIN study, a multicenter observational Spanish cohort of COPD patients who are monitored annually. Categories were defined according to the proposed GOLD: FEV1%, mMRC dyspnea, COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ), and exacerbations-hospitalizations. One-year follow-up information was available for all variables except CCQ data. Results: At baseline, 828 stable COPD patients were evaluated. On the basis of mMRC dyspnea versus CAT, the patients were distributed as follows: 38.2% vs. 27.2% in group A, 17.6% vs. 28.3% in group B, 15.8% vs. 12.9% in group C, and 28.4% vs. 31.6% in group D. Information was available for 526 patients at one year: 64.2% of patients remained in the same group but groups C and D show different degrees of variability. The annual progression by group was mainly associated with one-year changes in CAT scores (RR, 1.138; 95%CI: 1.074-1.206) and BODE index values (RR, 2.012; 95%CI: 1.487-2.722). Conclusions: In the new GOLD grading classification, the type of tool used to determine the level of symptoms can substantially alter the group assignment. A change in category after one year was associated with longitudinal changes in the CAT and BODE index

Preguntas y respuestas relacionadas con tabaquismo en pacientes con EPOC. Aplicación de metodología con formato PICO

The ALAT and SEPAR Treatment and Control of Smoking Groups have collaborated in the preparation of this document which attempts to answer, by way of PICO methodology, different questions on health interventions for helping COPD patients to stop smoking. The main recommendations are: (i) moderate-quality evidence and strong recommendation for performing spirometry in COPD patients and in smokers with a high risk of developing the disease, as a motivational tool (particularly for showing evidence of lung age), a diagnostic tool, and for active case-finding; (ii) high-quality evidence and strong recommendation for using intensive dedicated behavioral counselling and drug treatment for helping COPD patients to stop smoking; (iii) high-quality evidence and strong recommendation for initiating interventions for helping COPD patients to stop smoking during hospitalization with improvement when the intervention is prolonged after discharge, and (iv) high-quality evidence and strong recommendation for funding treatment of smoking in COPD patients, in view of the impact on health and health economics. © 2017 SEPA

Preguntas y respuestas relacionadas con tabaquismo en pacientes con EPOC. Aplicación de metodología con formato PICO

The ALAT and SEPAR Treatment and Control of Smoking Groups have collaborated in the preparation of this document which attempts to answer, by way of PICO methodology, different questions on health interventions for helping COPD patients to stop smoking. The main recommendations are: (i) moderate-quality evidence and strong recommendation for performing spirometry in COPD patients and in smokers with a high risk of developing the disease, as a motivational tool (particularly for showing evidence of lung age), a diagnostic tool, and for active case-finding; (ii) high-quality evidence and strong recommendation for using intensive dedicated behavioral counselling and drug treatment for helping COPD patients to stop smoking; (iii) high-quality evidence and strong recommendation for initiating interventions for helping COPD patients to stop smoking during hospitalization with improvement when the intervention is prolonged after discharge, and (iv) high-quality evidence and strong recommendation for funding treatment of smoking in COPD patients, in view of the impact on health and health economics. © 2017 SEPA