Biomedicines

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9 pages, 538 KiB

Open AccessEditorial

Chronic Obstructive Pulmonary Disease: The Present and Future

by Aditya Krishnan and Alice M. Turner

Biomedicines 2022, 10(2), 499; https://doi.org/10.3390/biomedicines10020499 - 20 Feb 2022

Cited by 6 | Viewed by 2833

Abstract

Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition associated with smoking and is predicted to become a leading cause of death in the current decade [...] Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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Research

Jump to: Editorial, Review, Other

18 pages, 3853 KiB

Open AccessArticle

Systemic Inflammatory Biomarkers Define Specific Clusters in Patients with Bronchiectasis: A Large-Cohort Study

by Xuejie Wang, Carmen Villa, Yadira Dobarganes, Casilda Olveira, Rosa Girón, Marta García-Clemente, Luis Máiz, Oriol Sibila, Rafael Golpe, Rosario Menéndez, Juan Rodríguez-López, Concepción Prados, Miguel Angel Martinez-García, Juan Luis Rodriguez, David de la Rosa, Xavier Duran, Jordi Garcia-Ojalvo and Esther Barreiro

Biomedicines 2022, 10(2), 225; https://doi.org/10.3390/biomedicines10020225 - 21 Jan 2022

Cited by 4 | Viewed by 3680

Abstract

Differential phenotypic characteristics using data mining approaches were defined in a large cohort of patients from the Spanish Online Bronchiectasis Registry (RIBRON). Three differential phenotypic clusters (hierarchical clustering, scikit-learn library for Python, and agglomerative methods) according to systemic biomarkers: neutrophil, eosinophil, and lymphocyte [...] Read more.

Differential phenotypic characteristics using data mining approaches were defined in a large cohort of patients from the Spanish Online Bronchiectasis Registry (RIBRON). Three differential phenotypic clusters (hierarchical clustering, scikit-learn library for Python, and agglomerative methods) according to systemic biomarkers: neutrophil, eosinophil, and lymphocyte counts, C reactive protein, and hemoglobin were obtained in a patient large-cohort (n = 1092). Clusters #1–3 were named as mild, moderate, and severe on the basis of disease severity scores. Patients in cluster #3 were significantly more severe (FEV₁, age, colonization, extension, dyspnea (FACED), exacerbation (EFACED), and bronchiectasis severity index (BSI) scores) than patients in clusters #1 and #2. Exacerbation and hospitalization numbers, Charlson index, and blood inflammatory markers were significantly greater in cluster #3 than in clusters #1 and #2. Chronic colonization by Pseudomonas aeruginosa and COPD prevalence were higher in cluster # 3 than in cluster #1. Airflow limitation and diffusion capacity were reduced in cluster #3 compared to clusters #1 and #2. Multivariate ordinal logistic regression analysis further confirmed these results. Similar results were obtained after excluding COPD patients. Clustering analysis offers a powerful tool to better characterize patients with bronchiectasis. These results have clinical implications in the management of the complexity and heterogeneity of bronchiectasis patients. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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13 pages, 2667 KiB

Open AccessArticle

Red Blood Cell-Derived Iron Alters Macrophage Function in COPD

by James M. Baker, Molly Hammond, Josiah Dungwa, Rajesh Shah, Angeles Montero-Fernandez, Andrew Higham, Simon Lea and Dave Singh

Biomedicines 2021, 9(12), 1939; https://doi.org/10.3390/biomedicines9121939 - 17 Dec 2021

Cited by 13 | Viewed by 3194

Abstract

Lung macrophage iron levels are increased in COPD patients. Lung macrophage iron levels are thought to be increased by cigarette smoke, but the role of red blood cells (RBCs) as a source of iron has not been investigated. We investigate RBCs as a [...] Read more.

Lung macrophage iron levels are increased in COPD patients. Lung macrophage iron levels are thought to be increased by cigarette smoke, but the role of red blood cells (RBCs) as a source of iron has not been investigated. We investigate RBCs as a potential source of alveolar iron in COPD, and determine the effect of RBC-derived iron on macrophage function. We used lung tissue sections to assess RBC coverage of the alveolar space, iron and ferritin levels in 11 non-smokers (NS), 15 smokers (S) and 32 COPD patients. Lung macrophages were isolated from lung resections (n = 68) and treated with hemin or ferric ammonium citrate (50, 100 or 200 μM). Lung macrophage phenotype marker gene expression was measured by qPCR. The phagocytosis of Non-typeable Haemophilus influenzae (NTHi) was measured by flow cytometry. Cytokine production in response to NTHi in iron-treated macrophages was measured by ELISA. Lung macrophage iron levels were significantly correlated with RBC coverage of the alveolar space (r = 0.31, p = 0.02). Furthermore, RBC coverage and lung macrophage iron were significantly increased in COPD patients and correlated with airflow obstruction. Hemin treatment downregulated CD36, CD163, HLA-DR, CD38, TLR4, CD14 and MARCO gene expression. Hemin-treated macrophages also impaired production of pro-inflammatory cytokines in response to NTHi exposure, and decreased phagocytosis of NTHi (200 μM: 35% decrease; p = 0.03). RBCs are a plausible source of pulmonary iron overload in COPD. RBC-derived iron dysregulates macrophage phenotype and function. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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19 pages, 2299 KiB

Open AccessArticle

Assessing Treatment Success or Failure as an Outcome in Randomised Clinical Trials of COPD Exacerbations. A Meta-Epidemiological Study

by Alexander G. Mathioudakis, Sachin Ananth, Thomas Bradbury, Balazs Csoma, Pradeesh Sivapalan, Elizabeth Stovold, Gustavo Fernandez-Romero, Zsofia Lazar, Gerard J. Criner, Christine Jenkins, Alberto Papi, Jens-Ulrik Jensen, Jørgen Vestbo and on behalf of the DECODE-NET

Biomedicines 2021, 9(12), 1837; https://doi.org/10.3390/biomedicines9121837 - 5 Dec 2021

Cited by 8 | Viewed by 3844

Abstract

A recently published ERS core outcome set recommends that all trials of COPD exacerbation management should assess the treatment success (or “cure” of the exacerbation), defined as a dichotomous measure of the overall outcome of an exacerbation. This methodological systematic review describes and [...] Read more.

A recently published ERS core outcome set recommends that all trials of COPD exacerbation management should assess the treatment success (or “cure” of the exacerbation), defined as a dichotomous measure of the overall outcome of an exacerbation. This methodological systematic review describes and compares the instruments that were used to assess treatment success or failure in 54 such RCTs, published between 2006–2020. Twenty-three RCTs used composite measures consisting of several undesirable outcomes of an exacerbation, together defining an overall unfavourable outcome, to define treatment failure. Thirty-four RCTs used descriptive instruments that used qualitative or semi-quantitative descriptions to define cure, marked improvement, improvement of the exacerbation, or treatment failure. Treatment success and failure rates among patients receiving guidelines-directed treatments at different settings and timepoints are described and could be used to inform power calculations in future trials. Descriptive instruments appeared more sensitive to treatment effects compared to composite instruments. Further methodological studies are needed to optimise the evaluation of treatment success/failure. In the meantime, based on the findings of this systematic review, the ERS core outcome set recommends that cure should be defined as sufficient improvement of the signs and symptoms of the exacerbation such that no additional systemic treatments are required. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 5643 KiB

Open AccessArticle

Determinants of Pulmonary Emphysema Severity in Taiwanese Patients with Chronic Obstructive Pulmonary Disease: An Integrated Epigenomic and Air Pollutant Analysis

by Sheng-Ming Wu, Wei-Lun Sun, Kang-Yun Lee, Cheng-Wei Lin, Po-Hao Feng, Hsiao-Chi Chuang, Shu-Chuan Ho, Kuan-Yuan Chen, Tzu-Tao Chen, Wen-Te Liu, Chien-Hua Tseng and Oluwaseun Adebayo Bamodu

Biomedicines 2021, 9(12), 1833; https://doi.org/10.3390/biomedicines9121833 - 4 Dec 2021

Cited by 4 | Viewed by 2827

Abstract

Background: Chronic obstructive pulmonary disease (COPD) continues to pose a therapeutic challenge. This may be connected with its nosological heterogeneity, broad symptomatology spectrum, varying disease course, and therapy response. The last three decades has been characterized by increased understanding of the pathobiology of [...] Read more.

Background: Chronic obstructive pulmonary disease (COPD) continues to pose a therapeutic challenge. This may be connected with its nosological heterogeneity, broad symptomatology spectrum, varying disease course, and therapy response. The last three decades has been characterized by increased understanding of the pathobiology of COPD, with associated advances in diagnostic and therapeutic modalities; however, the identification of pathognomonic biomarkers that determine disease severity, affect disease course, predict clinical outcome, and inform therapeutic strategy remains a work in progress. Objectives: Hypothesizing that a multi-variable model rather than single variable model may be more pathognomonic of COPD emphysema (COPD-E), the present study explored for disease-associated determinants of disease severity, and treatment success in Taiwanese patients with COPD-E. Methods: The present single-center, prospective, non-randomized study enrolled 125 patients with COPD and 43 healthy subjects between March 2015 and February 2021. Adopting a multimodal approach, including bioinformatics-aided analyses and geospatial modeling, we performed an integrated analysis of selected epigenetic, clinicopathological, geospatial, and air pollutant variables, coupled with correlative analyses of time-phased changes in pulmonary function indices and COPD-E severity. Results: Our COPD cohort consisted of 10 non-, 57 current-, and 58 ex-smokers (median age = 69 ± 7.76 years). Based on the percentages of low attenuation area below − 950 Hounsfield units (%LAA_-950insp), 36 had mild or no emphysema (%LAA_-950insp < 6), 22 were moderate emphysema cases (6 ≤ %LAA_-950insp < 14), and 9 presented with severe emphysema (%LAA-950insp ≥ 14). We found that BMI, lnc-IL7R, PM_2.5, PM₁₀, and SO₂ were differentially associated with disease severity, and are highly-specific predictors of COPD progression. Per geospatial levels, areas with high BMI and lnc-IL7R but low PM_2.5, PM₁₀, and SO₂ were associated with fewer and ameliorated COPD cases, while high PM_2.5, PM₁₀, and SO₂ but low BMI and lnc-IL7R characterized places with more COPD cases and indicated exacerbation. The prediction pentad effectively differentiates patients with mild/no COPD from moderate/severe COPD cases, (mean AUC = 0.714) and exhibited very high stratification precision (mean AUC = 0.939). Conclusion: Combined BMI, lnc-IL7R, PM_2.5, PM₁₀, and SO₂ levels are optimal classifiers for accurate patient stratification and management triage for COPD in Taiwan. Low BMI, and lnc-IL7R, with concomitant high PM_2.5, PM₁₀, and SO₂ levels is pathognomonic of exacerbated/aggravated COPD in Taiwan. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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13 pages, 1269 KiB

Open AccessArticle

The Association between Use of ICS and Psychiatric Symptoms in Patients with COPD—A Nationwide Cohort Study of 49,500 Patients

by Alexander Jordan, Pradeesh Sivapalan, Josefin Eklöf, Jakob B. Vestergaard, Howraman Meteran, Mohamad Isam Saeed, Tor Biering-Sørensen, Anders Løkke, Niels Seersholm and Jens Ulrik Stæhr Jensen

Biomedicines 2021, 9(10), 1492; https://doi.org/10.3390/biomedicines9101492 - 18 Oct 2021

Cited by 4 | Viewed by 2895

Abstract

Psychiatric side effects are well known from treatment with systemic corticosteroids. It is, however, unclear whether inhaled corticosteroids (ICS) have psychiatric side effects in patients with COPD. We conducted a nationwide cohort study in all Danish COPD outpatients who had respiratory medicine specialist-verified [...] Read more.

Psychiatric side effects are well known from treatment with systemic corticosteroids. It is, however, unclear whether inhaled corticosteroids (ICS) have psychiatric side effects in patients with COPD. We conducted a nationwide cohort study in all Danish COPD outpatients who had respiratory medicine specialist-verified COPD, age ≥40 years, and no previous cancer. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder were assessed by Cox proportional hazards models. We observed a dose-dependent increase in the risk of antidepressant-use with ICS cumulated dose (HR 1.05, 95% CI 1.03–1.07, p = 0.0472 with low ICS exposure, HR 1.10, 95% CI 1.08–1.12, p < 0.0001 with medium exposure, HR 1.15, 95% CI 1.11–1.15, p < 0.0001 with high exposure) as compared to no ICS exposure. We found a discrete increased risk of admission to psychiatric hospitals in the medium and high dose group (HR 1.00, 95% CI 0.98–1.03, p = 0.77 with low ICS exposure, HR 1.07, 95% CI 1.05–1.10, p < 0.0001 with medium exposure, HR 1.13, 95% CI 1.10–1.15, p < 0.0001 with high exposure). The association persisted when stratifying for prior antidepressant use. Thus, exposure to ICS was associated with a small to moderate increase in antidepressant-use and psychiatric admissions. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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16 pages, 1133 KiB

Open AccessArticle

Systemic Profiles of microRNAs, Redox Balance, and Inflammation in Lung Cancer Patients: Influence of COPD

by Liyun Qin, Maria Guitart, Víctor Curull, Albert Sánchez-Font, Xavier Duran, Jun Tang, Mireia Admetlló and Esther Barreiro

Biomedicines 2021, 9(10), 1347; https://doi.org/10.3390/biomedicines9101347 - 29 Sep 2021

Cited by 4 | Viewed by 2729

Abstract

Lung cancer (LC) risk increases in patients with chronic respiratory diseases (COPD). MicroRNAs and redox imbalance are involved in lung tumorigenesis in COPD patients. Whether systemic alterations of those events may also take place in LC patients remains unknown. Our objectives were to [...] Read more.

Lung cancer (LC) risk increases in patients with chronic respiratory diseases (COPD). MicroRNAs and redox imbalance are involved in lung tumorigenesis in COPD patients. Whether systemic alterations of those events may also take place in LC patients remains unknown. Our objectives were to assess the plasma levels of microRNAs, redox balance, and cytokines in LC patients with/without COPD. MicroRNAs (RT-PCR) involved in LC, oxidized DNA, MDA-protein adducts, GSH, TEAC, VEGF, and TGF-beta (ELISA) were quantified in plasma samples from non-LC controls (n = 45), LC-only patients (n = 32), and LC-COPD patients (n = 91). In LC-COPD patients compared to controls and LC-only, MDA-protein adduct levels increased, while those of GSH decreased, and two patterns of plasma microRNA were detected. In both LC patient groups, miR-451 expression was downregulated, while those of microRNA-let7c were upregulated, and levels of TEAC and TGF-beta increased compared to the controls. Correlations were found between clinical and biological variables. A differential expression profile of microRNAs was detected in patients with LC. Moreover, in LC patients with COPD, plasma oxidative stress levels increased, whereas those of GSH declined. Systemic oxidative and antioxidant markers are differentially expressed in LC patients with respiratory diseases, thus implying its contribution to the pathogenesis of tumorigenesis in these patients. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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14 pages, 1598 KiB

Open AccessEditor’s ChoiceArticle

Airway Bacteria Quantification Using Polymerase Chain Reaction Combined with Neutrophil and Eosinophil Counts Identifies Distinct COPD Endotypes

by Augusta Beech, Simon Lea, Jian Li, Natalie Jackson, Alex Mulvanny and Dave Singh

Biomedicines 2021, 9(10), 1337; https://doi.org/10.3390/biomedicines9101337 - 27 Sep 2021

Cited by 15 | Viewed by 2577

Abstract

Background: Chronic obstructive pulmonary disease (COPD) inflammatory endotypes are associated with different airway microbiomes. We used quantitative polymerase chain reaction (qPCR) analysis of sputum samples to establish the bacterial load upper limit in healthy controls; these values determined the bacterial colonisation prevalence in [...] Read more.

Background: Chronic obstructive pulmonary disease (COPD) inflammatory endotypes are associated with different airway microbiomes. We used quantitative polymerase chain reaction (qPCR) analysis of sputum samples to establish the bacterial load upper limit in healthy controls; these values determined the bacterial colonisation prevalence in a longitudinal COPD cohort. Bacteriology combined with sputum inflammatory cells counts were used to investigate COPD endotypes. Methods: Sixty COPD patients and 15 healthy non-smoking controls were recruited. Sputum was analysed by qPCR (for Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Psuedomonas aeruginosa) and sputum differential cell counts at baseline and 6 months. Results: At baseline and 6 months, 23.1% and 25.6% of COPD patients were colonised with H. influenzae, while colonisation with other bacterial species was less common, e.g., S. pneumoniae—1.9% and 5.1%, respectively. H. influenzae + ve patients had higher neutrophil counts at baseline (90.1% vs. 67.3%, p < 0.01), with similar results at 6 months. COPD patients with sputum eosinophil counts ≥3% at ≥1 visit rarely showed bacterial colonisation. Conclusions: The prevalence of H. influenzae colonisation was approximately 25%, with low colonisation for other bacterial species. H. influenzae colonisation was associated with sputum neutrophilia, while eosinophilic inflammation and H. influenzae colonisation rarely coexisted. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 2008 KiB

Open AccessArticle

Iron Replacement and Redox Balance in Non-Anemic and Mildly Anemic Iron Deficiency COPD Patients: Insights from a Clinical Trial

by Maria Pérez-Peiró, Clara Martín-Ontiyuelo, Anna Rodó-Pi, Lucilla Piccari, Mireia Admetlló, Xavier Durán, Diego A. Rodríguez-Chiaradía and Esther Barreiro

Biomedicines 2021, 9(9), 1191; https://doi.org/10.3390/biomedicines9091191 - 10 Sep 2021

Cited by 10 | Viewed by 3046

Abstract

In COPD patients, non-anemic iron deficiency (NAID) is a common systemic manifestation. We hypothesized that in COPD patients with NAID, iron therapy may improve systemic oxidative stress. The FACE (Ferinject assessment in patients with COPD and iron deficiency to improve exercise tolerance) study [...] Read more.

In COPD patients, non-anemic iron deficiency (NAID) is a common systemic manifestation. We hypothesized that in COPD patients with NAID, iron therapy may improve systemic oxidative stress. The FACE (Ferinject assessment in patients with COPD and iron deficiency to improve exercise tolerance) study was a single-blind, unicentric, parallel-group, placebo-controlled clinical trial (trial registry: 2016-001238-89). Sixty-six patients were enrolled (randomization 2:1): iron arm, n = 44 and placebo arm, n = 22, with similar clinical characteristics. Serum levels of 3-nitrotyrosine, MDA-protein adducts, and reactive carbonyls, catalase, superoxide dismutase (SOD), glutathione, Trolox equivalent antioxidant capacity (TEAC), and iron metabolism biomarkers were quantified in both groups. In the iron-treated patients compared to placebo, MDA-protein adducts and 3-nitrotyrosine serum levels significantly declined, while those of GSH increased and iron metabolism parameters significantly improved. Hepcidin was associated with iron status parameters. This randomized clinical trial evidenced that iron replacement elicited a decline in serum oxidative stress markers along with an improvement in GSH levels in patients with stable severe COPD. Hepcidin may be a surrogate biomarker of iron status and metabolism in patients with chronic respiratory diseases. These findings have potential clinical implications in the management of patients with severe COPD. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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11 pages, 1084 KiB

Open AccessArticle

Impact of Frailty on Hippocampal Volume in Patients with Chronic Obstructive Pulmonary Disease

by Shun Takahashi, Tsunahiko Hirano, Kasumi Yasuda, Tomohiro Donishi, Kazuyoshi Suga, Keiko Doi, Keiji Oishi, Shuichiro Ohata, Yoriyuki Murata, Yoshikazu Yamaji, Maki Asami-Noyama, Nobutaka Edakuni and Kazuto Matsunaga

Biomedicines 2021, 9(9), 1103; https://doi.org/10.3390/biomedicines9091103 - 28 Aug 2021

Cited by 8 | Viewed by 2717

Abstract

Brain frailty may be related to the pathophysiology of poor clinical outcomes in chronic obstructive pulmonary disease (COPD). This study examines the relationship between hippocampal subfield volumes and frailty and depressive symptoms, and their combined association with quality of life (QOL) in patients [...] Read more.

Brain frailty may be related to the pathophysiology of poor clinical outcomes in chronic obstructive pulmonary disease (COPD). This study examines the relationship between hippocampal subfield volumes and frailty and depressive symptoms, and their combined association with quality of life (QOL) in patients with COPD. The study involved 40 patients with COPD. Frailty, depressive symptoms and QOL were assessed using Kihon Checklist (KCL), Hospital Anxiety and Depression Scale (HADS), and World Health Organization Quality of Life Assessment (WHO/QOL-26). Anatomical MRI data were acquired, and volumes of the hippocampal subfields were obtained using FreeSurfer (version 6.0). Statistically, HADS score had significant association with WHO/QOL-26 and KCL scores. KCL scores were significantly associated with volumes of left and right whole hippocampi, presubiculum and subiculum, but HADS score had no significant association with whole hippocampi or hippocampal subfield volumes. Meanwhile, WHO/QOL-26 score was significantly associated with volume of the left CA1. There was a significant association between frailty, depression, and QOL. Hippocampal pathology was related to frailty and, to some extent, with QOL in patients with COPD. Our results suggest the impact of frailty on hippocampal volume and their combined associations with poor QOL in COPD. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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10 pages, 1124 KiB

Open AccessArticle

Systemic Corticosteroids and the Risk of Venous Thromboembolism in Patients with Severe COPD: A Nationwide Study of 30,473 Outpatients

by Ema Rastoder, Pradeesh Sivapalan, Josefin Eklöf, Mohamad Isam Saeed, Alexander Svorre Jordan, Howraman Meteran, Louise Tønnesen, Tor Biering-Sørensen, Anders Løkke, Niels Seersholm, Thyge Lynghøj Nielsen, Jørn Carlsen, Julie Janner, Nina Godtfredsen, Uffe Bodtger, Christian B. Laursen, Ole Hilberg, Filip K. Knop, Helene Priemé, Truls Sylvan Ingebrigtsen, Vibeke Gottlieb, Jon Torgny Wilcke and Jens Ulrik Stæhr Jensen Show full author list Hide full author list

Biomedicines 2021, 9(8), 874; https://doi.org/10.3390/biomedicines9080874 - 23 Jul 2021

Cited by 5 | Viewed by 3099

Abstract

Due to frequent exacerbations, many patients with chronic obstructive pulmonary disease (COPD) are exposed to oral corticosteroids (OCS), which may be thrombogenic. We evaluated the risk of hospitalisation with venous thromboembolism (VTE) and death in patients with acute exacerbation of COPD (AECOPD) treated [...] Read more.

Due to frequent exacerbations, many patients with chronic obstructive pulmonary disease (COPD) are exposed to oral corticosteroids (OCS), which may be thrombogenic. We evaluated the risk of hospitalisation with venous thromboembolism (VTE) and death in patients with acute exacerbation of COPD (AECOPD) treated with long and short OCS regimens. In this nationwide cohort study of 30,473 COPD outpatients treated for AECOPD, we compared the risk of VTE hospitalisation and all-cause mortality within 6 months in OCS dose of >250 mg vs. ≤250 mg. A multivariable Cox proportional hazard regression was used to estimate the risk. The incidence of VTE hospitalisations was 0.23%. A long OCS treatment course was associated with an increased risk of VTE compared to a short course (hazard ratio (HR) 1.69, [95% confidence interval (CI) 1.05 to 2.72], p < 0.031). A higher risk of all-cause mortality was seen in the group of COPD patients treated with a long OCS course (HR 1.71, [95% CI 1.63 to 1.79], p < 0.0001). The risk of reported VTE hospitalisation was higher among AECOPD patients treated with long courses of OCS, but the absolute risk was low, suggesting under-reporting of the condition. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 3210 KiB

Open AccessFeature PaperArticle

Pulmonary MicroRNA Changes Alter Angiogenesis in Chronic Obstructive Pulmonary Disease and Lung Cancer

by Clara E. Green, Joseph Clarke, Roy Bicknell and Alice M. Turner

Biomedicines 2021, 9(7), 830; https://doi.org/10.3390/biomedicines9070830 - 16 Jul 2021

Cited by 15 | Viewed by 2816

Abstract

The pulmonary endothelium is dysfunctional in chronic obstructive pulmonary disease (COPD), a known risk factor for lung cancer. The pulmonary endothelium is altered in emphysema, which is disproportionately affected by cancers. Gene and microRNA expression differs between COPD and non-COPD lung. We hypothesised [...] Read more.

The pulmonary endothelium is dysfunctional in chronic obstructive pulmonary disease (COPD), a known risk factor for lung cancer. The pulmonary endothelium is altered in emphysema, which is disproportionately affected by cancers. Gene and microRNA expression differs between COPD and non-COPD lung. We hypothesised that the alteration in microRNA expression in the pulmonary endothelium contributes to its dysfunction. A total of 28 patients undergoing pulmonary resection were recruited and endothelial cells were isolated from healthy lung and tumour. MicroRNA expression was compared between COPD and non-COPD patients. Positive findings were confirmed by quantitative polymerase chain reaction (qPCR). Assays assessing angiogenesis and cellular migration were conducted in Human Umbilical Vein Endothelial Cells (n = 3–4) transfected with microRNA mimics and compared to cells transfected with negative control RNA. Expression of miR-181b-3p, miR-429 and miR-23c (all p < 0.05) was increased in COPD. Over-expression of miR-181b-3p was associated with reduced endothelial sprouting (p < 0.05). miR-429 was overexpressed in lung cancer as well and exhibited a reduction in tubular formation. MicroRNA-driven changes in the pulmonary endothelium thus represent a novel mechanism driving emphysema. These processes warrant further study to determine if they may be therapeutic targets in COPD and lung cancer. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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13 pages, 936 KiB

Open AccessArticle

Risk of Chronic Obstructive Pulmonary Disease Exacerbation in Patients Who Use Methotrexate—A Nationwide Study of 58,580 Outpatients

by Christina Marisa Bergsøe, Pradeesh Sivapalan, Mohamad Isam Saeed, Josefin Eklöf, Zaigham Saghir, Rikke Sørensen, Tor Biering-Sørensen and Jens-Ulrik Stæhr Jensen

Biomedicines 2021, 9(6), 604; https://doi.org/10.3390/biomedicines9060604 - 26 May 2021

Cited by 4 | Viewed by 4217

Abstract

Patients with severe chronic obstructive pulmonary disease (COPD) experience frequent acute exacerbations and require repeated courses of corticosteroid therapy, which may lead to adverse effects. Methotrexate (MTX) has anti-inflammatory properties. The objective of this study was to describe the risk of COPD exacerbation [...] Read more.

Patients with severe chronic obstructive pulmonary disease (COPD) experience frequent acute exacerbations and require repeated courses of corticosteroid therapy, which may lead to adverse effects. Methotrexate (MTX) has anti-inflammatory properties. The objective of this study was to describe the risk of COPD exacerbation in patients exposed to MTX. In this nationwide cohort study of 58,580 COPD outpatients, we compared the risk of hospitalization-requiring COPD exacerbation or death within 180 days in MTX vs. non-MTX users in a propensity-score matched study population as well as an unmatched cohort, in which we adjusted for confounders. The use of MTX was associated with a reduction in risk of COPD exacerbation in the propensity-score matched population at 180 days follow-up (HR 0.66, CI 0.66–0.66, p < 0.001). Similar results were shown in our sensitivity analyses at 180-day follow-up on unmatched population and 365-day follow-up on matched and unmatched population (HR 0.76 CI 0.59–0.99, HR 0.81 CI 0.81–0.82 and HR 0.92 CI 0.76–1.11, respectively). MTX was associated with a lower risk of COPD exacerbation within the first six months after study entry. The finding seems biologically plausible and could potentially be a part of the management of COPD patients with many exacerbations. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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Review

Jump to: Editorial, Research, Other

13 pages, 1172 KiB

Open AccessReview

Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine

by Laura Carrasco-Hernández, Esther Quintana-Gallego, Carmen Calero, Rocío Reinoso-Arija, Borja Ruiz-Duque and José Luis López-Campos

Biomedicines 2021, 9(10), 1437; https://doi.org/10.3390/biomedicines9101437 - 10 Oct 2021

Cited by 12 | Viewed by 3332

Abstract

In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially [...] Read more.

In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein’s dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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19 pages, 1195 KiB

Open AccessReview

Inhaled Corticosteroids and the Lung Microbiome in COPD

by Holly R. Keir, Marco Contoli and James D. Chalmers

Biomedicines 2021, 9(10), 1312; https://doi.org/10.3390/biomedicines9101312 - 24 Sep 2021

Cited by 24 | Viewed by 4573

Abstract

The Global Initiative for Chronic Obstructive Lung Disease 2021 Report recommends inhaled corticosteroid (ICS)-containing regimens as part of pharmacological treatment in patients with chronic obstructive lung disease (COPD) and frequent exacerbations, particularly with eosinophilic inflammation. However, real-world studies reveal overprescription of ICS in [...] Read more.

The Global Initiative for Chronic Obstructive Lung Disease 2021 Report recommends inhaled corticosteroid (ICS)-containing regimens as part of pharmacological treatment in patients with chronic obstructive lung disease (COPD) and frequent exacerbations, particularly with eosinophilic inflammation. However, real-world studies reveal overprescription of ICS in COPD, irrespective of disease presentation and inflammatory endotype, leading to increased risk of side effects, mainly respiratory infections. The optimal use of ICS in COPD therefore remains an area of intensive research, and additional biomarkers of benefit and risk are needed. Although the interplay between inflammation and infection in COPD is widely acknowledged, the role of the microbiome in shaping lower airway inflammation has only recently been explored. Next-generation sequencing has revealed that COPD disease progression and exacerbation frequency are associated with changes in the composition of the lung microbiome, and that the immunosuppressive effects of ICS can contribute to potentially deleterious airway microbiota changes by increasing bacterial load and the abundance of potentially pathogenic taxa such as Streptococcus and Haemophilus. Here, we explore the relationship between microbiome, inflammation, ICS use and disease phenotype. This relationship may inform the benefit:risk assessment of ICS use in patients with COPD and lead to more personalised pharmacological management. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 2814 KiB

Open AccessSystematic Review

A Systematic Review and Meta-Analysis of the Prevalence and Impact of Pulmonary Bacterial Colonisation in Stable State Chronic Obstructive Pulmonary Disease (COPD)

by Michael N. Armitage, Daniella A. Spittle and Alice M. Turner

Biomedicines 2022, 10(1), 81; https://doi.org/10.3390/biomedicines10010081 - 31 Dec 2021

Cited by 11 | Viewed by 3940

Abstract

Background: Half of acute exacerbations of COPD are due to bacterial infection, and the other half are likely influenced by microbial colonisation. The same organisms commonly cultured during acute exacerbations are often found in the sputum of patients during stability. A robust assessment [...] Read more.

Background: Half of acute exacerbations of COPD are due to bacterial infection, and the other half are likely influenced by microbial colonisation. The same organisms commonly cultured during acute exacerbations are often found in the sputum of patients during stability. A robust assessment of the prevalence of potentially pathogenic microorganisms (PPMs) in the sputum of stable COPD patients may help to inform the targeted prevention of exacerbation by these organisms. Methods: A systematic review and meta-analysis was carried out to determine the prevalence of PPMs in patients with COPD in the stable state. Meta-analysis of prevalence was carried out using the Freeman–Tukey double arcsine transformation random effects model, and sub-group analysis was performed for sputum modality. Prevalence of total and individual PPMs was calculated from patient-level data from individual studies. Results: Pooled prevalence of PPMs identified by sputum culture was found to be 41% (95% CI 36–47%). Significant heterogeneity was found across all studies, which can likely be attributed to inconsistent measuring and reporting of PPMs. The most commonly reported organisms were H. influenzae, M catarrhalis, S. pneumoniae, S. aureus, and P. aeruginosa. Declining lung function was weakly correlated with prevalence of PPMs. Conclusion: The airways of patients with COPD are colonised with PPMs during the stable state in almost half of patients. A complex relationship likely exists between the microbiome in the stable state and the phenotype of COPD patients. Targeted microbial therapy for preventing exacerbations of COPD should carefully consider the stable microbiome as well as the exacerbated. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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