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Biomedicines
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COPD Phenotypes and Treatable Traits: From Bench to Bedside
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COPD Phenotypes and Treatable Traits: From Bench to Bedside

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 25750

Special Issue Editors

Dr. Zsofia Lazar

E-Mail Website
Guest Editor
Department of Pulmonology, Semmelweis University, Budapest, Hungary
Interests: chronic obstructive pulmonary disease; exacerbation; biomarker; exhaled breath analysis
Dr. Alexander Mathioudakis

E-Mail Website
Guest Editor
Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
Interests: airway diseases

Special Issue Information

Dear Colleagues,

Chronic obstructive pulmonary disease (COPD) remains a leading cause of death and disability in the absence of treatments with disease modifying capacity. The development of effective treatments, both for stable COPD and exacerbations, is hampered by the significant complexity and heterogeneity of the disease, which is caused by the multi-faceted pathways in the disease pathomechanism, as well as the complex interplay with other disease entities. As a result, extensive research is focusing on the characterization of the different COPD subtypes, to allow for the introduction of precision medicine interventions. This process is facilitated by the identification and clinical validation of biomarkers, phenotypes and treatable traits.

This Special Issue aims to bridge the continuum (or, unfortunately, in some cases the gap) among basic, translational, clinical, and methodological research that is urgently needed to inform novel precision medicine interventions, to improve the short- and long-term outcomes of both stable COPD and exacerbations. More specifically, this issue seeks studies and opinions around the pathophysiology, mechanisms, prognosis of specific phenotypes or treatable traits (pulmonary, extrapulmonary) of stable and exacerbated COPD, as well as studies on therapeutic biomarkers and precision medicine interventions. We will also accept studies focusing on the methodology of precision medicine interventions around COPD.

We cordially invite colleagues with interest in this inspiring research field, to submit original research or review articles to broaden the current knowledge on the phenotypes and treatable traits of COPD.

Dr. Zsofia Lazar
Dr. Alexander G. Mathioudakis
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • COPD
  • emphysema
  • chronic bronchitis
  • co-morbidities
  • exacerbation
  • treatable traits
  • disease endotype
  • disease phenotype
  • biomarkers

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Published Papers (6 papers)

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Research

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12 pages, 1075 KiB  
Article
Biomarkers of Clot Activation and Degradation and Risk of Future Major Cardiovascular Events in Acute Exacerbation of COPD: A Cohort Sub-Study in a Randomized Trial Population
by Peter Kamstrup, Jannie Marie Bülow Sand, Charlotte Suppli Ulrik, Julie Janner, Christian Philip Rønn, Sarah Rank Rønnow, Diana Julie Leeming, Sidse Graff Jensen, Torgny Wilcke, Alexander G. Mathioudakis, Marc Miravitlles, Therese Lapperre, Elisabeth Bendstrup, Ruth Frikke-Schmidt, Daniel D. Murray, Theis Itenov, Apostolos Bossios, Susanne Dam Nielsen, Jørgen Vestbo, Tor Biering-Sørensen, Morten Karsdal, Jens-Ulrik Jensen and Pradeesh Sivapalanadd Show full author list remove Hide full author list
Biomedicines 2022, 10(8), 2011; https://doi.org/10.3390/biomedicines10082011 - 19 Aug 2022
Cited by 1 | Viewed by 2475
Abstract
Cardiovascular diseases are common in patients with chronic obstructive pulmonary disease (COPD). Clot formation and resolution secondary to systemic inflammation may be a part of the explanation. The aim was to determine whether biomarkers of clot formation (products of von Willebrand Factor formation [...] Read more.
Cardiovascular diseases are common in patients with chronic obstructive pulmonary disease (COPD). Clot formation and resolution secondary to systemic inflammation may be a part of the explanation. The aim was to determine whether biomarkers of clot formation (products of von Willebrand Factor formation and activation) and clot resolution (product of fibrin degeneration) during COPD exacerbation predicted major cardiovascular events (MACE). The cohort was based on clinical data and biobank plasma samples from a trial including patients admitted with an acute exacerbation of COPD (CORTICO-COP). Neo-epitope biomarkers of formation and the activation of von Willebrand factor (VWF-N and V-WFA, respectively) and cross-linked fibrin degradation (X-FIB) were assessed using ELISAs in EDTA plasma at the time of acute admission, and analyzed for time-to-first MACE within 36 months, using multivariable Cox proportional hazards models. In total, 299/318 participants had samples available for analysis. The risk of MACE for patients in the upper quartile of each biomarker versus the lower quartile was: X-FIB: HR 0.98 (95% CI 0.65–1.48), VWF-N: HR 1.56 (95% CI 1.07–2.27), and VWF-A: HR 0.78 (95% CI 0.52–1.16). Thus, in COPD patients with an acute exacerbation, VWF-N was associated with future MACE and warrants further studies in a larger population. Full article
(This article belongs to the Special Issue COPD Phenotypes and Treatable Traits: From Bench to Bedside)
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10 pages, 1968 KiB  
Article
Relationships between Airway Remodeling and Clinical Characteristics in COPD Patients
by Andrew Higham, Josiah Dungwa, Natalie Jackson and Dave Singh
Biomedicines 2022, 10(8), 1992; https://doi.org/10.3390/biomedicines10081992 - 17 Aug 2022
Cited by 4 | Viewed by 2013
Abstract
Background: Airway remodeling is a cardinal feature of chronic obstructive pulmonary disease (COPD) pathology. However, inconsistent findings have been reported regarding the nature of proximal airway remodeling in COPD. This is likely due to the heterogeneity of COPD. This study investigated the [...] Read more.
Background: Airway remodeling is a cardinal feature of chronic obstructive pulmonary disease (COPD) pathology. However, inconsistent findings have been reported regarding the nature of proximal airway remodeling in COPD. This is likely due to the heterogeneity of COPD. This study investigated the histopathological features of airway remodeling in bronchial biopsies of COPD patients compared to smoking controls (S). We tested the hypothesis that histopathological features in bronchial biopsies relate to clinical characteristics in COPD patients, focusing on smoking status, symptom burden, lung function, exacerbation risk and inhaled corticosteroid (ICS) use. Methods: We recruited 24 COPD patients and 10 S. We focused on reticular basement membrane thickness (RBM), surface immunoglobulin A (IgA) expression, goblet cell numbers (periodic acid-Schiff [PAS]+), sub-mucosal remodeling markers including collagen 4, 6 and laminin expression, and inflammatory cell counts (CD45+). Results: RBM thickness was increased in frequent exacerbators, IgA expression was reduced in COPD patients with worse lung function, and goblet cell numbers were increased in COPD patients compared to S but with no difference between the COPD subgroups. Collagen 4 expression was associated with higher symptom burden and worse quality of life. Sub-mucosal inflammatory cell counts were increased in COPD non-inhaled corticosteroid (ICS) users compared to ICS users and S. Conclusion: We observed relationships between the histopathological features of airway remodeling and clinical characteristics in COPD patients. Our data highlight the influence of clinical heterogeneity on diverse patterns of airway remodeling in COPD patients. Full article
(This article belongs to the Special Issue COPD Phenotypes and Treatable Traits: From Bench to Bedside)
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20 pages, 3092 KiB  
Article
Validation of Sputum Biomarker Immunoassays and Cytokine Expression Profiles in COPD
by Alex Mulvanny, Caroline Pattwell, Augusta Beech, Thomas Southworth and Dave Singh
Biomedicines 2022, 10(8), 1949; https://doi.org/10.3390/biomedicines10081949 - 11 Aug 2022
Cited by 11 | Viewed by 2819
Abstract
Immunoassays are commonly used to assess airway inflammation in sputum samples from chronic obstructive pulmonary disease (COPD) patients. However, assay performance and validation in this complex matrix is inconsistently reported. The aim of this study was to assess the suitability of various immunoassays [...] Read more.
Immunoassays are commonly used to assess airway inflammation in sputum samples from chronic obstructive pulmonary disease (COPD) patients. However, assay performance and validation in this complex matrix is inconsistently reported. The aim of this study was to assess the suitability of various immunoassays for use with sputum samples, followed by use of validated immunoassays to evaluate biomarker levels in COPD patients. Assays were assessed for recombinant reference standard suitability, optimal sample dilution, standard recovery in the biological matrix and reproducibility. Validated assays were used to assess sputum supernatants in Cohort A (n = 30 COPD, n = 10 smokers, n = 10 healthy) and Cohort B (n = 81 COPD, n = 15 smokers, n = 26 healthy). Paired baseline and exacerbation samples from 14 COPD patients were assessed in cohort A, and associations with sputum cell counts and bacterial colonisation investigated in cohort B. 25/32 assays passed validation; the primary reason for validation failure was recombinant reference standard suitability and sample dilution effects. Interleukin (IL-)6 and IL-8 were significantly increased in COPD patients compared to healthy subjects and smokers for both cohorts. Tumour necrosis factor (TNF)α and IL-1β were higher in COPD compared to smokers using one immunoassay but not another, partly explained by different absolute recovery rates. IL-1β, IL-2, IL-4, IL-8, IL-17A, Granulocyte colony stimulating factor (G-CSF), Interferon (IFN-)γ, Interferon gamma induced protein (IP-)10, Macrophage inflammatory protein (MIP)-1α, MIP-1β and TNF-α levels correlated with sputum neutrophil percentage in COPD patients. IL-1β, IL-4, IL-8, G-CSF and IFN-γ levels were associated with Haemophilus influenzae colonisation in COPD patients. Current smokers had lower levels of IL-1β, IL-4, IL-8, G-CSF, IFN-γ, IP-10, Monocyte chemoattractant protein (MCP)-1, MIP-1α, MIP-1β and TNF-α. Validated immunoassays applied to sputum supernatants demonstrated differences between COPD patients and controls, the effects of current smoking and associations between Haemophilus influenzae colonisation and higher levels of selected cytokines. Immunoassay validation enabled inflammatory mediators associated with different COPD characteristics to be determined. Full article
(This article belongs to the Special Issue COPD Phenotypes and Treatable Traits: From Bench to Bedside)
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Review

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14 pages, 2500 KiB  
Review
Combined Pulmonary Fibrosis and Emphysema: Comparative Evidence on a Complex Condition
by Diana Calaras, Alexander G. Mathioudakis, Zsofia Lazar and Alexandru Corlateanu
Biomedicines 2023, 11(6), 1636; https://doi.org/10.3390/biomedicines11061636 - 4 Jun 2023
Cited by 7 | Viewed by 11948
Abstract
Combined pulmonary fibrosis and emphysema (CPFE) is a clinical syndrome characterized by upper lobe emphysema and lower lobe fibrosis manifested by exercise hypoxemia, normal lung volumes, and severe reduction of diffusion capacity of carbon monoxide. It has varying prevalence worldwide with a male [...] Read more.
Combined pulmonary fibrosis and emphysema (CPFE) is a clinical syndrome characterized by upper lobe emphysema and lower lobe fibrosis manifested by exercise hypoxemia, normal lung volumes, and severe reduction of diffusion capacity of carbon monoxide. It has varying prevalence worldwide with a male predominance, and with smoking history of more than 40 pack-years being a common risk factor. The unique imaging features of CPFE emphasize its distinct entity, aiding in the timely detection of pulmonary hypertension and lung cancer, both of which are common complications. High-resolution computed tomography (HRCT) is an important diagnostic and prognostic tool, while lung cancer is an independent factor that alters the prognosis in CPFE patients. Treatment options for CPFE are limited, but smoking cessation, usual treatments of pulmonary fibrosis and emphysema, and avoidance of environmental exposures are encouraged. Full article
(This article belongs to the Special Issue COPD Phenotypes and Treatable Traits: From Bench to Bedside)
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13 pages, 791 KiB  
Review
Time-Updated Phenotypic Guidance of Corticosteroids and Antibiotics in COPD: Rationale, Perspective and a Proposed Method
by Alexander Jordan, Pradeesh Sivapalan, Valdemar Rømer and Jens-Ulrik Jensen
Biomedicines 2023, 11(5), 1395; https://doi.org/10.3390/biomedicines11051395 - 8 May 2023
Cited by 2 | Viewed by 2249
Abstract
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with distinct phenotypes, each having distinct treatment needs. Eosinophilic airway inflammation is present in a subset of COPD patients in whom it can act as a driver of exacerbations. Blood eosinophil counts are a [...] Read more.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with distinct phenotypes, each having distinct treatment needs. Eosinophilic airway inflammation is present in a subset of COPD patients in whom it can act as a driver of exacerbations. Blood eosinophil counts are a reliable way to identify patients with an eosinophilic phenotype, and these measurements have proven to be successful in guiding the use of corticosteroids in moderate and severe COPD exacerbations. Antibiotic use in COPD patients induces a risk of Clostridium difficile infection, diarrhea, and antibiotic resistance. Procalcitonin could possibly guide antibiotic treatment in patients admitted with AECOPD. Current studies in COPD patients were successful in reducing exposure to antibiotics with no changes in mortality or length of stay. Daily monitoring of blood eosinophils is a safe and effective way to reduce oral corticosteroid exposure and side effects for acute exacerbations. No evidence on time-updated treatment guidance for stable COPD exists yet, but a current trial is testing an eosinophil-guided approach on inhaled corticosteroid use. Procalcitonin-guided antibiotic treatment in AECOPD shows promising results in safely and substantially reducing antibiotic exposure both in time-independent and time-updated algorithms. Full article
(This article belongs to the Special Issue COPD Phenotypes and Treatable Traits: From Bench to Bedside)
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12 pages, 512 KiB  
Review
Blood Eosinophils and Exhaled Nitric Oxide: Surrogate Biomarkers of Airway Eosinophilia in Stable COPD and Exacerbation
by Balazs Antus and Imre Barta
Biomedicines 2022, 10(9), 2128; https://doi.org/10.3390/biomedicines10092128 - 30 Aug 2022
Cited by 7 | Viewed by 2705
Abstract
In recent years, tremendous efforts have been devoted to characterizing the inflammatory processes in chronic obstructive pulmonary disease (COPD) in order to provide more personalized treatment for COPD patients. While it has proved difficult to identify COPD-specific inflammatory pathways, the distinction between eosinophilic [...] Read more.
In recent years, tremendous efforts have been devoted to characterizing the inflammatory processes in chronic obstructive pulmonary disease (COPD) in order to provide more personalized treatment for COPD patients. While it has proved difficult to identify COPD-specific inflammatory pathways, the distinction between eosinophilic and non-eosinophilic airway inflammation has gained clinical relevance. Evidence has shown that sputum eosinophil counts are increased in a subset of COPD patients and that these patients are more responsive to oral or inhaled corticosteroid therapy. Due to feasibility issues associated with sputum cell profiling in daily clinical practice, peripheral blood eosinophil counts and fractional exhaled nitric oxide levels have been evaluated as surrogate biomarkers for assessing the extent of airway eosinophilia in COPD patients, both in stable disease and acute exacerbations. The diagnostic value of these markers is not equivalent and depends heavily on the patient’s condition at the time of sample collection. Additionally, the sensitivity and specificity of these tests may be influenced by the patient’s maintenance treatment. Overall, eosinophilic COPD may represent a distinct disease phenotype that needs to be further investigated in terms of prognosis and treatment outcomes. Full article
(This article belongs to the Special Issue COPD Phenotypes and Treatable Traits: From Bench to Bedside)
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