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.

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.

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.

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.

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.

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.

Network Analysis of Lung Transcriptomics Reveals a Distinct B-Cell Signature in Emphysema.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by a combination of airways disease (bronchiolitis) and parenchymal destruction (emphysema), whose relative proportion varies from patient to patient. OBJECTIVES: To explore and contrast the molecular pathogenesis of emphysema and bronchiolitis in COPD. METHODS: We used network analysis of lung transcriptomics (Affymetrix arrays) in 70 former smokers with COPD to compare differential expression and gene coexpression in bronchiolitis and emphysema. MEASUREMENTS AND MAIN RESULTS: We observed that in emphysema (but not in bronchiolitis) (1) up-regulated genes were enriched in ontologies related to B-cell homing and activation; (2) the immune coexpression network had a central core of B cell-related genes; (3) B-cell recruitment and immunoglobulin transcription genes (CXCL13, CCL19, and POU2AF1) correlated with emphysema severity; (4) there were lymphoid follicles (CD20(+)IgM(+)) with active B cells (phosphorylated nuclear factor-κB p65(+)), proliferation markers (Ki-67(+)), and class-switched B cells (IgG(+)); and (5) both TNFRSF17 mRNA and B cell-activating factor protein were up-regulated. These findings were by and large reproduced in a group of patients with incipient emphysema and when patients with emphysema were matched for the severity of airflow limitation of those with bronchiolitis. CONCLUSIONS: Our study identifies enrichment in B cell-related genes in patients with COPD with emphysema that is absent in bronchiolitis. These observations contribute to a better understanding of COPD pathobiology and may open new therapeutic opportunities for patients with COPD.

International Society of Human and Animal Mycology (ISHAM)-ITS reference DNA barcoding database--the quality controlled standard tool for routine identification of human and animal pathogenic fungi.

Human and animal fungal pathogens are a growing threat worldwide leading to emerging infections and creating new risks for established ones. There is a growing need for a rapid and accurate identification of pathogens to enable early diagnosis and targeted antifungal therapy. Morphological and biochemical identification methods are time-consuming and require trained experts. Alternatively, molecular methods, such as DNA barcoding, a powerful and easy tool for rapid monophasic identification, offer a practical approach for species identification and less demanding in terms of taxonomical expertise. However, its wide-spread use is still limited by a lack of quality-controlled reference databases and the evolving recognition and definition of new fungal species/complexes. An international consortium of medical mycology laboratories was formed aiming to establish a quality controlled ITS database under the umbrella of the ISHAM working group on "DNA barcoding of human and animal pathogenic fungi." A new database, containing 2800 ITS sequences representing 421 fungal species, providing the medical community with a freely accessible tool at http://www.isham.org/ and http://its.mycologylab.org/ to rapidly and reliably identify most agents of mycoses, was established. The generated sequences included in the new database were used to evaluate the variation and overall utility of the ITS region for the identification of pathogenic fungi at intra-and interspecies level. The average intraspecies variation ranged from 0 to 2.25%. This highlighted selected pathogenic fungal species, such as the dermatophytes and emerging yeast, for which additional molecular methods/genetic markers are required for their reliable identification from clinical and veterinary specimens.

Network medicine, multimorbidity and the lung in the elderly.

Noncommunicable diseases, including cardiovascular, metabolic and respiratory diseases, among others, are the major medical challenge of the 21st century. Most noncommunicable diseases are related to the ageing process and often co-occur in the same individual. However, it is unclear whether the index disease is somehow influencing the development of the other ones (comorbidity) or whether all of them (including the index disease) simply represent the clinical expression of pathological ageing (multimorbidity). The pathobiology of ageing, chronic obstructive pulmonary disease (COPD) and concomitant disorders is complex. A new field of research, known as systems biology if applied to model systems or network medicine if applied to human beings, has emerged over the past decade or so, to address biological complexity in a holistic, integrated way. It offers, therefore, great potential to decipher the relationship between ageing, COPD and comorbidities/multimorbidities. In this State of the Art review we present the basic concepts of systems biology, use some examples to illustrate the potential of network medicine to address complex medical problems, and review some recent publications that show how a systems-based research strategy can contribute to improve our understanding of multimorbidity and age-related respiratory diseases.

Occurrence of Ochroconis and Verruconis species in clinical specimens from the United States.

Ochroconis is a dematiaceous fungus able to infect immunocompetent people. Recently, the taxonomy of the genus has been reevaluated, and the most relevant species, Ochroconis gallopava, was transferred to the new genus Verruconis. Due to the important clinical implications of these fungi and based on the recent classification, it was of interest to know the spectra of Ochroconis and Verruconis species in clinical samples received in a reference laboratory in the United States. A set of 51 isolates was identified morphologically and molecularly based on sequence analyses of the nuclear ribosomal RNA (nrRNA), actin, and ß-tubulin genes. Verruconis gallopava was the most common species (68.6%), followed by Ochroconis mirabilis (21.5%). One isolate of Ochroconis cordanae was found, being reported for the first time in a clinical setting. The most common anatomical site of isolation was the lower respiratory tract (58.8%), followed by superficial and deep tissues at similar frequencies (21.6 and 19.6%, respectively). Interestingly, three new species were found, which are Ochroconis olivacea and Ochroconis ramosa from clinical specimens and Ochroconis icarus of an environmental origin. The in vitro antifungal susceptibilities of eight antifungal drugs against the Ochroconis isolates revealed that terbinafine and micafungin were the most active drugs.

Influence of previous use of inhaled corticoids on the development of pleural effusion in community-acquired pneumonia.

RATIONALE: Previous use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease has been associated with increased risk of community-acquired pneumonia. However, ICS have been associated with fewer pneumonia complications and decreased risk of pneumonia-related mortality. OBJECTIVES: The objective of the study was to assess the influence of previous use of ICS on the incidence of parapneumonic effusion in patients with different baseline respiratory disorders. METHODS: We conducted a single-center cohort study of 3,612 consecutively collected patients diagnosed with community-acquired pneumonia. We assessed clinical, radiographic, and pleural-fluid chemistry and microbiologic variables. Patients were classified according to whether or not they received prior ICS treatment. MEASUREMENTS AND MAIN RESULTS: A total of 633 patients (17%) were treated with corticosteroids before the diagnosis of pneumonia (chronic obstructive pulmonary disease, 54%; asthma, 13%). Incidence of parapneumonic effusion was lower in patients with ICS use compared with non-ICS patients (5% vs. 12%; P < 0.001). After matching according to propensity scores (n = 640), prior treatment with corticosteroids was still significantly associated with a lower incidence of parapneumonic effusion (odds ratio, 0.40; 95% confidence interval, 0.23-0.69; P = 0.001) compared with patients without ICS treatment. Prior ICS treatment was associated with higher levels of glucose (P = 0.003) and pH (P = 0.02), and lower levels of protein (P = 0.01) and lactic acid dehydrogenase (P = 0.007) in the pleural fluid. CONCLUSIONS: Prior treatment with ICS in a population of patients with different respiratory chronic disorders who develop pneumonia is associated with lower incidence of parapneumonic effusion.

In vitro antifungal susceptibility of clinical isolates of Arthrographis kalrae, a poorly known opportunistic fungus.

The in vitro antifungal activity of amphotericin B (AMB), itraconazole, voriconazole, posaconazole, terbinafine (TRB), caspofungin, anidulafungin and micafungin were evaluated by a broth microdilution technique against 22 isolates of Arthrographis kalrae of clinical origin. TRB showed the highest activity, followed by the azoles, particularly posaconazole. AMB exerted low activity whereas the echinocandins showed almost no antifungal activity.

Acremonium with catenate elongate conidia: phylogeny of Acremonium fusidioides and related species.

Acremonium is one of the largest and most complex genera of hyphomycetes. Its taxonomy is not yet resolved and the phylogenetic value of the most distinctive morphological features is unknown. The species of this genus produce conidia in chains or form slimy heads or both. We have studied a set of clinical and environmental Acremonium strains morphologically characterized by producing mostly catenate, elongate, more or less fusiform conidia. Based on phenotypic data and in the analysis of the sequences of the ITS region, the D1/D2 domains of the 28S rRNA gene and a fragment of the ß-tubulin gene, three new species morphologically similar to Acremonium fusidioides and belonging to the family Bionectriaceae (Hypocreales) are described and illustrated; they are Acremonium pilosum, Acremonium parvum and Acremonium citrinum. The first species produces two kinds of conidia: clavate with smooth walls and globose with abundant filiform projections. Acremonium parvum is characterized by slow growth and pyriform or slightly lanceolate conidia with an elongate and truncate base. Acremonium citrinum produces a diffusible yellow pigment and obovoid conidia.

Lung function abnormalities are highly frequent in patients with heart failure and preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) is the most prevalent form of heart failure in outpatients. Yet, the pathophysiology of this syndrome is unclear and pharmacological treatment does not improve prognosis. Because breathlessness during activities of daily living is the most frequent complaint of patients with HFPEF, we hypothesised that lung function may be often abnormal in these patients due to either a direct effect of HFPEF and/or shared risk factors. In this study we explore the frequency, type and severity of lung function abnormalities in HFPEF. METHODS: We measured forced spirometry, static lung volumes, pulmonary diffusing capacity (DL(CO)) and arterial blood gases in 69 outpatients with newly diagnosed symptomatic HFPEF. RESULTS: We found that 94% of the patients showed abnormalities in at least one of the lung function measurements obtained: spirometry was abnormal in 59%, DL(CO) in 83% and arterial hypoxaemia was present in 62%. Their severity varied between patients, they were more prevalent in patients with NYHA functional class III/IV, and most often they were undiagnosed and untreated. CONCLUSIONS: Lung function abnormalities are very frequent in HFPEF patients. A greater awareness among clinicians may contribute to improve their management and health status.

Rare arthroconidial fungi in clinical samples: Scytalidium cuboideum and Arthropsis hispanica.

We report the presence of the two arthroconidial anamorphic fungi, Scytalidium cuboideum and Arthropsis hispanica, in clinical samples from the USA. Both fungi were morphologically and molecularly identified. The antifungal susceptibility of four isolates of A. hispanica and five of S. cuboideum to eight antifungal drugs is provided.

Two new species of Acremonium from Spanish soils.

In a survey on the diversity of microfungi in Spanish soils, two new species of Acremonium were found. Both species were characterized as having more or less erect, mostly branched conidiophores bearing whorls of acicular phialides. In addition, one of these species, Acremonium asperulatum, produced abundant chlamydospores and globose rough-walled conidia. The other species, Acremonium variecolor, produced a brownish diffusible pigment and smooth-walled, subglobose conidia with apiculate base; sessile conidia inserted directly on vegetative hyphae also were present. The analysis of the sequences of the ITS region, the D1/D2 domains of the 28S rRNA gene and a fragment of the actin gene revealed relationships of both species with members of the Bionectriaceae (Hypocreales). Genetic differences were observed with morphologically similar species.

[Absence of poliovirus circulation in Colombian departments with vaccination coverage below 80%]. / Ausencia de circulación de poliovirus en departamentos colombianos con coberturas vacunales inferiores a 80%

This study aims to explore a possible silent circulation of wild and vaccine-derived polioviruses in departments of Colombia with polio vaccination coverage of below 80%. The study collected 52 samples of wastewater concentrated as a result of precipitation with polyethylene glycol and sodium chloride. The viral detection was carried out through isolation and the identification through neutralization of the cytopathic effect, as well as through a conventional polymerase chain reaction following reverse transcription. The isolated polioviruses were characterized by the VP1 gene sequence. In two of the 52 samples, there was a presence of the Sabin type 2 poliovirus with more than 99% sequence similarity with the Sabin type 2 strain polio. Circulation of the nonpolio enterovirus was detected in 17.3% of the samples. The serotypes identified corresponded to coxsackievirus B1, echovirus 30, and echovirus 11. No evidence of the spread of either vaccine-derived poliovirus or wild poliovirus was detected in the departments of Colombia with polio coverage lower than 80%.

[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.