[Chronic Obstructive Pulmonary Disease]. / Enfermedad pulmonar obstructiva crónica.

Chronic Obstructive Pulmonary Disease (COPD) is related to smoking as the main etiological agent although there are other risk factors that can interact influencing the development of the disease. The definition of COPD is based on three points: the presence of persistent respiratory symptoms, exposure to risk agents, and a non-reversible obstructive spirometric ratio. Forced spirometry with a bronchodilator test is necessary to confirm the diagnosis of COPD, however, attempts are being made to develop alternative methods for screening given the current significant underdiagnosis of this pathology.In order to advance in a more personalized medicine for the patient, classification tools have been adopted such as clinical phenotypes and treatable traits, allowing treatments to be adapted according to the characteristics of the patients. Non-pharmacological treatment (smoking cessation, vaccination, physical exercise...) are essential for the management of the disease, as well as pharmacological treatment based on clinical phenotypes. Eosinophils have become a key marker when establishing treatment with inhaled glucocorticoids.In the follow-up of the disease, it is very relevant to evaluate the degree of control being a fundamental element the absence of exacerbations given their implications in mortality, morbidity and quality of life of patients. More studies are needed to better define the phenotypes of exacerbations and their biomarkers.

ERS statement: a core outcome set for clinical trials evaluating the management of COPD exacerbations.

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use.

Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD.

Accelerated ageing is implicated in the pathogenesis of respiratory diseases as chronic obstructive pulmonary disease (COPD), but recent evidence indicates that the COPD can have roots early in life. Here we hypothesise that the accelerated ageing markers might have a role in the pathobiology of young COPD. The objective of this study was to compare two hallmarks of ageing, telomere length (TL), and mitochondrial DNA copy number (mtDNA-CN, as a surrogate marker of mitochondrial dysfunction) in young (≤ 50 years) and old (>50 years) smokers, with and without COPD. Both, TL and mtDNA-CN were measured in whole blood DNA by quantitative PCR [qPCR] in: (1) young ever smokers with (n = 81) or without (n = 166) COPD; and (2) old ever smokers with (n = 159) or without (n = 29) COPD. A multivariable linear regression was used to assess the association of TL and mtDNA-CN with lung function. We observed that in the entire study population, TL and mtDNA-CN decreased with age, and the former but not the latter related to FEV1/FVC (%), FEV1 (% ref.), and DLCO (% ref.). The short telomeres were found both in the young and old patients with severe COPD (FEV1 <50% ref.). In addition, we found that TL and mtDNA-CN were significantly correlated, but their relationship was positive in younger while negative in the older patients with COPD, suggesting a mitochondrial dysfunction. We conclude that TL, but not mtDNA-CN, is associated with the lung function impairment. Both young and old patients with severe COPD have evidence of accelerated ageing (shorter TL) but differ in the direction of the correlation between TL and mtDNA-CN in relation to age.

Discriminant Performance of Dysexecutive and Frontal Release Signs for Delirium in Patients With High Dementia Prevalence: Implications for Neural Network Impairment.

BACKGROUND: Prevalence of signs of abnormal executive function (EF) and primitive reflexes (PR) with delirium in older hospitalized patients with or without comorbid dementia has not been reported. OBJECTIVE: To describe prevalence of signs of EF deficits and PR in older inpatients and their discriminant value for delirium while accounting for dementia. METHODS: Participants were evaluated for delirium using the Diagnostic and Statistical Manual of Mental Disorders 5th edition and the Delirium Rating Scale Revised-98, dementia using Informant Questionnaire on Cognitive Decline in the Elderly, and signs of PR (n = 5) and EF deficits (n = 3) using bedside neuropsychiatric examination. Three indices (PR, EF, and Combined) and 4 diagnostic groups were created for correlational and discriminant analyses. RESULTS: Correlations of indices were higher with the Delirium Rating Scale Revised-98 than with the Informant Questionnaire on Cognitive Decline in the Elderly and even higher in those with dementia, especially the Combined index (Delirium Frontal Index). Among individual signs, glabellar and Simple Luria Hand Sequence were most common in delirium and the best for delirium discrimination irrespective of dementia status. The Combined index had about 80% sensitivity and specificity at the ≥2 cutoff in the whole cohort (positive and negative predictive values and likelihood ratios: PPV 50.0%, NPV 93.8%, +LR 3.82, -LR 0.25). The Combined index also had the best performance on discriminating delirium in dementia patients at the ≥3 cutoff, with about 80% for both sensitivity and specificity. CONCLUSIONS: PR and EF deficit signs are consistent with reduced neural network integration during delirium, even worse in those with dementia whose baseline structural injury impairs network connectivity with frontal regions. We recommend simple bedside assessment of PR and EF signs to help assess for delirium as an indicator of cerebral cortical neural network impairment in older persons.

Delirium diagnostic tool-provisional (DDT-Pro) scores in delirium, subsyndromal delirium and no delirium.

OBJECTIVE: To evaluate whether the Delirium Diagnostic Tool-Provisional (DDT-Pro), a 0-9 point scale with three items each representing symptoms from delirium's three core domains, differentiates subsyndromal delirium (SSD) from delirium and no delirium. METHODS: We applied cluster analyses of DDT-Pro scores from 200 consecutive inpatients using three reference standards for delirium diagnosis to determine DDT-Pro cutoff values for delirium, SSD and no delirium groups. Clinical validators and DDT-Pro item scores were compared among groups. RESULTS: DDT-Pro SSD range was 6-7 (n = 54), with no delirium having higher scores (n = 98) and delirium lower (n = 48). Dementia prevalence in the SSD group (40.7%) was intermediate between no delirium (20.4%) and delirium (66.7%). SSD and delirium groups were more affected than no delirium regarding medical comorbidities, hospital stay (no delirium <1 week, SSD and delirium >1 week) and mortality (SSD = 7.4%, delirium = 18.8%, no delirium = 1%). Values for motor subtypes, frontal lobe signs, and DRS-R98 in the SSD group were intermediate between no delirium and delirium, as well as for the DDT-Pro items (all p < 0.05). CONCLUSIONS: All DDT-Pro items, which represent the three delirium core domains, are important for SSD diagnosis. Patients scoring in the SSD 6-7 range have significant clinical and prognostic features and deserve clinical attention.

DNA barcodes, morphology and geographic distribution confirm a new butterfly species in the genus Rhamma (Lepidoptera: Lycaenidae).

We diagnose a new butterfly species from the Belmira paramo in the central cordillera of the Colombian Andes. We infer from the barcoding analysis, wing pattern, morphology and distribution that this entity is not a geographical variation or subspecies of any named lycaenid, and it is described herein as Rhamma eleonorae sp. nov. Adult specimens and female genitalia are illustrated and compared with R. arria (Hewitson, 1870) and R. oxida (Hewitson, 1870), the most closely related taxa based on similarities of wing pattern and COI sequences.

Core outcome set for the management of acute exacerbations of chronic obstructive pulmonary disease: the COS-AECOPD ERS Task Force study protocol.

Randomised controlled trials (RCTs) on the management of COPD exacerbations evaluate heterogeneous outcomes, often omitting those that are clinically important and patient relevant. This limits their usability and comparability. A core outcome set (COS) is a consensus-based minimum set of clinically important outcomes that should be evaluated in all RCTs in specific areas of health care. We present the study protocol of the COS-AECOPD ERS Task Force, aiming to develop a COS for COPD exacerbation management, that could remedy these limitations. For the development of this COS we follow standard methodology recommended by the COMET initiative. A comprehensive list of outcomes is assembled through a methodological systematic review of the outcomes reported in relevant RCTs. Qualitative research with patients with COPD will also be conducted, aiming to identify additional outcomes that may be important to patients, but are not currently addressed in clinical research studies. Prioritisation of the core outcomes will be facilitated through an extensive, multi-stakeholder Delphi survey with a global reach. Selection will be finalised in an international, multi-stakeholder meeting. For every core outcome, we will recommend a specific measurement instrument and standardised time points for evaluation. Selection of instruments will be based on evidence-informed consensus. Our work will improve the quality, usability and comparability of future RCTs on the management of COPD exacerbations and, ultimately, the care of patients with COPD. Multi-stakeholder engagement and societal support by the European Respiratory Society will raise awareness and promote implementation of the COS.

Validation of the Delirium Diagnostic Tool-Provisional (DDT-Pro) With Medical Inpatients and Comparison With the Confusion Assessment Method Algorithm.

OBJECTIVE: Delirium remains underdetected as a result of its broad constellation of symptoms and the inadequate neuropsychiatric expertise of most medical-surgical clinicians. Brief, accurate tools are needed to enhance detection. METHODS: The authors extended validation of the Delirium Diagnostic Tool-Provisional (DDT-Pro), originally validated in a study of inpatients with traumatic brain injury for diagnosis of delirium by nonexpert clinicians, for 200 general medical inpatients in Colombia. The three structured, quantitatively rated items in DDT-Pro represent the three core delirium domains. RESULTS: High interrater reliability between physician and nurse (0.873) administrators, internal consistency (>0.81), and content validity were found. Compared with independent reference standard diagnosis with DSM-5 or the Delirium Rating Scale-Revised-98, the area under the receiver operating characteristic (ROC) curve (global diagnostic accuracy) range was 93.8%-96.3%. ROC analysis revealed the same cutoff score (≤6) as that for the original study, with somewhat lower sensitivities of 88.0%-90.0% and specificities of 85.3%-81.2% (independent expert physician or nurse ratings). Even when rated by a trained expert physician, the original version of the Confusion Assessment Method algorithm (CAM-A) performed moderately, with lower sensitivities (61.8%-70.0%) than the DDT-Pro (88.0%-100%) and somewhat higher specificities (84.8%-95.3% versus 67.4%-86.7%), with values depending on dementia status, reference standard, and rater type. Accuracies for the DDT-Pro and CAM-A were comparable (DDT-Pro: 83.0%-87.5% versus CAM-A: 87.5%-88.5%), although lower in the dementia subgroup, especially for CAM-A. However, these tools were significantly discordant, especially in negative cases, which suggests that they do not detect diagnosis of patients in the same way. CONCLUSIONS: The DDT-Pro had high validity and reliability in provisional delirium diagnosis by physicians and nonexpert clinicians, although further validation is warranted before widespread use can be recommended.

Environmental Surveillance of Polioviruses in Armenia, Colombia before Trivalent Oral Polio Vaccine Cessation.

Although acute flaccid paralysis (AFP) surveillance is the "gold standard" for detecting cases of polio, environmental surveillance can provide supplementary information in the absence of paralytic poliomyelitis cases. This study aimed to detect the introduction and/or circulation of wild poliovirus or vaccine-derived polioviruses (VDPV) in wastewater, covering a significant population of Armenia, Colombia, before trivalent oral polio vaccine (OPV) cessation. Between March and September 2015, 24 wastewater samples were collected from eight study sites in eight communes of Armenia, Colombia. Virus detection and characterization were performed using both cell culture (i.e., RD or L20B cells) and RT-PCR. Polioviruses were isolated in 11 (45.8%) of 24 wastewater samples. All isolates were identified as Sabin strains (type 1 = 9, type 3 = 2) by intratypic differentiation. Type 2 poliovirus was not detected in any of the samples. No wild poliovirus or VDPV was detected among the isolates. Non-polio enterovirus was identified in 8.3% (2/24) of the samples. This study revealed the excretion of Sabin poliovirus from OPV-immunized individuals, as well as the absence of VDPV and wild poliovirus in wastewaters of Armenia, Colombia. This confirms that environmental surveillance is an effective method, as an additional support to AFP surveillance, to monitor poliovirus during the OPV-to-IPV (inactivated polio vaccine) transition period.

Multi-level immune response network in mild-moderate Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is associated with an abnormal pulmonary and systemic immune response to tobacco smoking. Yet, how do immune cells relate within and between these two biological compartments, how the pulmonary infiltrate influences the lung transcriptome, and what is the role of active smoking vs. presence of disease is unclear. METHODS: To investigate these questions, we simultaneously collected lung tissue and blood from 65 individuals stratified by smoking habit and presence of the disease. The immune cell composition of both tissues was assessed by flow cytometry, whole lung transcriptome was determined with Affymetrix arrays, and we used Weighted Gene Co-expression Network Analysis (WGCNA) to integrate results. RESULTS: Main results showed that: (1) current smoking and the presence of COPD were both independently associated with a reduction in the proportion of lung T cells and an increase of macrophages, specifically those expressing CD80 + CD163+; (2) changes in the proportion of infiltrating macrophages, smoking status or the level of airflow limitation were associated to different WGCNA modules, which were enriched in iron ion transport, extracellular matrix and cilium organization gene ontologies; and, (3) circulating white blood cells counts were correlated with lung macrophages and T cells. CONCLUSIONS: Mild-moderated COPD lung immune infiltrate is associated with the active smoking status and presence of disease; is associated with changes in whole lung tissue transcriptome and marginally reflected in blood.

Smoking Impairs the Immunomodulatory Capacity of Lung-Resident Mesenchymal Stem Cells in Chronic Obstructive Pulmonary Disease.

Tobacco smoking is the main environmental risk factor for chronic obstructive pulmonary disease (COPD), but not all smokers develop the disease. A population of lung-resident mesenchymal stem cells (LR-MSCs) exist in healthy lungs, but how tobacco smoking affects them and their role in COPD have not been assessed yet. Using a sphere-based culture technique, we isolated LR-MSCs from lung tissue obtained from nonsmokers and current and former smokers with and without COPD (n = 53). The cells were characterized by flow cytometry and Affymetrix arrays. Their immunomodulatory capacity was assessed in vitro using cocultures with T cells and after preincubation with 2.5% and 5% cigarette smoke extract. We were able to isolate LR-MSCs expressing similar phenotypic markers in all of the study groups. LR-MSCs from current smokers with COPD expressed different levels of CX3CL1 and CCL5 cytokines, and were unable to modulate CD8+ T-cell proliferation. Preincubation of LR-MSCs with cigarette smoke extract reduced their immunomodulatory capacity. In conclusion, 1) LR-MSCs can be isolated in similar amounts from never-smokers and smokers with and without COPD; 2) their immunomodulatory capacity is impaired in current smokers with COPD, but not in those with normal lung function; and 3) this is reversible after smoking cessation and is reproducible in vitro.

Do sputum or circulating blood samples reflect the pulmonary transcriptomic differences of COPD patients? A multi-tissue transcriptomic network META-analysis.

BACKGROUND: Previous studies have identified lung, sputum or blood transcriptomic biomarkers associated with the severity of airflow limitation in COPD. Yet, it is not clear whether the lung pathobiology is mirrored by these surrogate tissues. The aim of this study was to explore this question. METHODS: We used Weighted Gene Co-expression Network Analysis (WGCNA) to identify shared pathological mechanisms across four COPD gene-expression datasets: two sets of lung tissues (L1 n = 70; L2 n = 124), and one each of induced sputum (S; n = 121) and peripheral blood (B; n = 121). RESULTS: WGCNA analysis identified twenty-one gene co-expression modules in L1. A robust module preservation between the two L datasets was observed (86%), with less preservation in S (33%) and even less in B (23%). Three modules preserved across lung tissues and sputum (not blood) were associated with the severity of airflow limitation. Ontology enrichment analysis showed that these modules included genes related to mitochondrial function, ion-homeostasis, T cells and RNA processing. These findings were largely reproduced using the consensus WGCNA network approach. CONCLUSIONS: These observations indicate that major differences in lung tissue transcriptomics in patients with COPD are poorly mirrored in sputum and are unrelated to those determined in blood, suggesting that the systemic component in COPD is independently regulated. Finally, the fact that one of the preserved modules associated with FEV1 was enriched in mitochondria-related genes supports a role for mitochondrial dysfunction in the pathobiology of COPD.

Hiperplasia difusa idiopática de células neuroendocrinas como causa de tos crónica / Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Causing Chronic Cough

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Characterization, localization and comparison of c-Kit+ lung cells in never smokers and smokers with and without COPD.

BACKGROUND: c-Kit + lung stem cells have been described in the human healthy lung. Their potential relation with smoking and/or chronic obstructive pulmonary disease (COPD) is unknown. METHODS: We characterized and compared c-Kit+ cells in lung tissue of 12 never smokers (NS), 15 smokers with normal spirometry (S) and 44 COPD patients who required lung resectional surgery. Flow cytometry (FACS) was used to characterize c-Kit+ cells in fresh lung tissue disaggregates, and immunofluorescence (IF) for further characterization and to determine their location in OCT- embedded lung tissue. RESULTS: We identified 4 c-Kit+ cell populations, with similar proportions in NS, S and COPD: (1) By FACS, c-Kithigh/CD45+ cells (4.03 ± 2.97% (NS), 3.96 ± 5.30% (S), and 5.20 ± 3.44% (COPD)). By IF, these cells were tryptase+ (hence, mast cells) and located around the airways; (2) By IF, c-Kitlow/CD45+/triptase- (0.07 ± 0.06 (NS), 0.03 ± 0.02 (S), and 0.06 ± 0.07 (COPD) cells/field), which likely correspond to innate lymphoid cells; (3) By FACS, c-Kitlow/CD45-/CD34+ (0.95 ± 0.84% (NS), 1.14 ± 0.94% (S) and 0.95 ± 1.38% (COPD)). By IF these cells were c-Kitlow/CD45-/CD31+, suggesting an endothelial lineage, and were predominantly located in the alveolar wall; and, (4) by FACS, an infrequent c-Kitlow/CD45-/CD34- population (0.09 ± 0.14% (NS), 0.08 ± 0.09% (S) and 0.08 ± 0.11% (COPD)) compatible with a putative lung stem cell population. Yet, IF failed to detect them and we could not isolate or grow them, thus questioning the existence of c-Kit+ lung stem-cells. CONCLUSIONS: The adult human lung contains a mixture of c-Kit+ cells, unlikely to be lung stem cells, which are independent of smoking status and/or presence of COPD.

Distribution, temporal stability and association with all-cause mortality of the 2017 GOLD groups in the ECLIPSE cohort.

BACKGROUND: In 2017, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposed a new classification of patients with chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS: We contrasted the distribution of COPD patients according to GOLD 2017 and 2011 classifications, the temporal stability of the 2017 groups during 3 years follow-up and their association with all-cause mortality in the ECLIPSE cohort. RESULTS: We found that GOLD 2017: (1) switched a substantial proportion of GOLD 2011C and D patients to A and B groups at recruitment; (2) about half of A, B and D patients remained in the same group at the end of follow-up, whereas 74% of C patients (the smallest group of all) changed, either because exacerbation rate decreased or dyspnea increased; and, (3) all-cause mortality by group was not significantly different between GOLD 2011 and 2017. Of note, mortality in B (16%) and D patients (18%) was similar, both with similar severity of airflow limitation, the best individual mortality risk factor. CONCLUSIONS: These results illustrate the cross-sectional and longitudinal effects of excluding FEV1 from GOLD 2017, and highlight both the clinical relevance of symptom assessment in the management of COPD and the prognostic capacity of FEV1.

Time to and factors associated with initiation of biological therapy in patients with rheumatoid arthritis in Colombia / Tiempo y factores asociados con el inicio de terapia biológica con antirreumáticos modificadores de enfermedad en pacientes con Artritis Reumatoide en Colombia

ABSTRACT Aims: To determine the time Colombian patients with rheumatoid arthritis (RA) are treated with non-biological disease-modifying antirheumatic drugs (DMARDs) before changing to biological therapy. Methods: A retrospective cohort study that collected information about the start of antirheumatic treatment in patients of all ages with a diagnosis of RA until the change to biological DMARD therapy. Survival analysis using Kaplan-Meier curves, from 1 January 2007 until 31 December 2013 by SPSS 23.0 for Windows, was made. Results: A total of 3880 patients (75.3% women) with a mean age of 51.3 years started non-biological DMARDs. After 5 years, 234 patients (6.0%) initiated biological DMARD therapy in 17.5 ± 13.9 months. The use of glucocorticoids (OR: 2.49; 95% CI: 1.658-3.732), having any comedication (OR: 1.83; 95%CI: 1.135-2.966) and being treated in the city of Bogota (OR: 2.30; 95%CI: 1.585-3.355) or in the cities of the Colombian Atlantic coast (OR: 2.848; 95%CI: 1.468-5.524) were associated with a higher likelihood of biological DMARD initiation. Whereas the initiation of therapy with methotrexate (OR: 0.04; 95% CI: 0.014-0.108; p < 0.001) or chloroquine (OR: 0.13; 95% CI: 0.092-0.187; p < 0.001) or receiving antihypertensive medication (OR: 0.64; 95% CI: 0.421-0.960; p = 0.031) was associated with a significant reduce in likelihood. Conclusion: After 5 years of non-biological DMARD therapy, 6.0% of people with RA started biological DMARDs. Receiving glucocorticoids, having any comedication, being treated in Bogota City or cities of the Colombian Atlantic coast affected the probability of switching to biological therapy in these patients.

RESUMEN Objetivo: Determinar el tiempo transcurrido desde que pacientes de Colombia con artritis reumatoide (AR) en tratamiento con fármacos antirreumáticos modificadores de enfermedad no biológicos (FAMEs) cambian a terapia con biológicos. Materiales y métodos: Estudio de cohorte retrospectiva que recogió información sobre inicio de tratamiento antirreumático en pacientes de todas las edades con diagnóstico de AR hasta que pasaron a terapia con FAMEs biológicos. Se hizo un análisis de sobrevida, utilizando curvas de Kaplan-Meier, desde el 1 de enero de 2007 hasta el 31 de diciembre de 2013 mediante SPSS 23.0 para Windows. Resultados: Un total de 3880 pacientes iniciaron terapia con FAMEs no biológicos, (75,3% fueron mujeres) con una edad media de 51,3 anos. Tras cinco años de seguimiento, 234 pacientes (6,0%) iniciaron FAMEs biológicos en promedio a los 17,5 ± 13,9 meses. El uso de corticoides (OR: 2,49; IC95%: 1,658-3,732; p<0,001), recibir alguna comedicación (OR: 1,83; IC95%: 1,135-2,966), ser tratado en Bogotá (OR: 2,30; IC95%: 1,585-3,355), en las ciudades de la costa Atlántica (OR: 2,848; IC95%: 1,468-5,524) estuvieron asociados con una mayor probabilidad de inicio de biológicos mientras que el uso de metotrexate (OR: 0,04; IC95%: 0,014-0,108) o cloroquina (OR: 0,13; IC95%: 0,092-0,187) o recibir medicación antihipertensiva (OR: 0,64; IC95%: 0,421-0,960) redujeron la posibilidad. Conclusiones: Después de cinco años de terapia antirreumática convencional, un 6,0% de pacientes con AR inició terapia con FAMEs biológicos. Recibir corticoides, recibir comedicación, ser tratado en Bogotá o la costa Atlántica afectan la probabilidad de cambiar a terapia biológica.