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Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pulmonology".

Deadline for manuscript submissions: closed (30 October 2019) | Viewed by 32712

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Special Issue Editor

Prof. Dr. Lies Lahousse

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Guest Editor

Department Bioanalysis, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
Interests: pharmacoepidemiology; pharmacogenetics; precision medicine; multimorbidity; COPD; asthma

Special Issue Information

Dear Colleagues,

For patients with chronic obstructive pulmonary disease (COPD), bronchodilators are the mainstay of treatment since these reduce exacerbations and improve breathlessness and lung function. However, COPD is a complex, heterogeneous disease, and beyond breathing difficulties, specific systemic effects and comorbidities dominate patients’ quality of life and mortaility risk. Therefore, to improve the care of patients with complex chronic respiratory diseases, we need to enhance our understanding of the heterogeneity among phenotypes, endotypes, and underlying genetics.

The identification of traitable traits can indeed foster more personalized assessment and treatment to improve health outcomes of patients with COPD. Methodological challenges for precision medicine in COPD can be found in difficulties in defining phenotypes, identifying endotypes, finding good biomarkers, and observing a representative large sample size for sufficient time. In addition, there are barriers to implement precision medicine for COPD patients in clinical practice including difficulties to define simple strategies, build good algorithms, monitor therapeutic responses, enhance therapy adherence, implement a holistic approach, or provide integrated personalized care.

Therefore, we would like to move this field forward and invite original research, meta-analysis, and state-of-the-art reviews on methodological challenges for precision medicine in COPD. Examples include pharmacoepidemiological studies, meta-analyses of clinical trials studying the effectiveness of pharmacological therapies for COPD, and novel data or concepts on integrating more personalized care for patients with COPD in clinical practice.

This Special Issue aims to advance precision medicine for patients with COPD by identifying and solving methodological challenges in phenotyping, endotyping, and translating research to clinical care. We are happy to receive your submissions to move precision medicine forward.

Prof. Dr. Lies Lahousse
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

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

precision medicine
pharmacoepidemiology
personalized care
therapy adherence
COPD asthma

Published Papers (9 papers)

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Research

Jump to: Review

7 pages, 632 KiB

Open AccessArticle

Real-Life Patterns of Exacerbations While on Inhaled Corticosteroids and Long-Acting Beta Agonists for Asthma over 15 Years

by Michael J. McGeachie, Alberta L. Wang, Sharon M. Lutz, Joanne E. Sordillo, Scott T. Weiss, Kelan G. Tantisira, Carlos Iribarren, Meng X. Lu and Ann Chen Wu

J. Clin. Med. 2020, 9(3), 819; https://doi.org/10.3390/jcm9030819 - 18 Mar 2020

Cited by 4 | Viewed by 2706

Abstract

Asthma affects more than 300 million people in the world, costs over $80 billion annually in the United States, and is efficaciously treated with inhaled corticosteroids (ICS). To our knowledge, no studies have examined the real-world effectiveness of ICS, including the combination therapy consisting of ICS and long-acting beta agonists (LABAs), and patterns of use over a 15-year time period. We used data from the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort which comprises longitudinal electronic health record data of over 100,000 people. Data included longitudinal asthma-related events, such as ambulatory office visits, hospitalizations, emergency department (ED) visits, and fills of ICS and ICS–LABA combination. Asthma exacerbations were defined as an asthma-related ED visit, hospitalization, or oral corticosteroid (OCS) burst. We used an expected-value approach to determine ICS and ICS–LABA coverage over exacerbation events. We compared rates of exacerbation of subjects on ICS or ICS–LABAs to their own rates of exacerbation when off controller medications. We found ICS–LABA therapy had significant effects, reducing all types of exacerbations per day by a factor of 1.76 (95% CI (1.06, 2.93), p = 0.03) and, specifically, bursts per day by a factor of 1.91 (95% CI (1.04, 3.53), p = 0.037). In conclusion, ICS–LABA therapy was significantly associated with fewer asthma-related exacerbations in a large population of individuals with asthma who were followed for 15 years. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

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10 pages, 1600 KiB

Open AccessCommunication

LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

by Jürgen Knobloch, David Jungck, Juliane Kronsbein, Erich Stoelben, Kazuhiro Ito and Andrea Koch

J. Clin. Med. 2019, 8(12), 2058; https://doi.org/10.3390/jcm8122058 - 22 Nov 2019

Cited by 13 | Viewed by 3157

Abstract

Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophilic inflammation. Neutralization of non-type 2/IL-8-associated airway inflammation by reversion of its corticosteroid-resistance might be a future strategy for other phenotypes. Human airway smooth muscle cells (HASMCs) produce corticosteroid-insensitive IL-8 in response to TNFα or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-β2-agonists (LABAs) reverse the corticosteroid-insensitivity of IL-8 by p38MAPK inhibition in HASMCs. Cultivated HASMCs from COPD subjects were pre-incubated with formoterol, salmeterol, fluticasone-propionate, BIRB796 (p38MAPKα, -γ, -δ inhibitor), and/or SB203580 (p38MAPKα and -β inhibitor) before stimulation with TNFα or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNFα- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNFα-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNFα-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNFα induced p38MAPKα and -γ activity. LPS induced p38MAPKα activity. Formoterol reduced TNFα-induced p38MAPKγ and LPS-induced p38MAPKα activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPKγ in stable disease and via p38MAPKα in exacerbations. Our pre-clinical data indicate a utility for also adding ICS in non-type 2 inflammatory COPD phenotypes to bronchodilator therapy. Depending on phenotype and disease stage, isoform-specific p38MAPK blockers might also reverse corticosteroid-resistance in COPD. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

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12 pages, 242 KiB

Open AccessArticle

Cross-Sectional and Longitudinal Associations between Peak Expiratory Flow and Frailty in Older Adults

by Caterina Trevisan, Debora Rizzuto, Stefania Maggi, Giuseppe Sergi, Anna-Karin Welmer and Davide Liborio Vetrano

J. Clin. Med. 2019, 8(11), 1901; https://doi.org/10.3390/jcm8111901 - 07 Nov 2019

Cited by 13 | Viewed by 2685

Abstract

Peak expiratory flow (PEF) has been linked to several health-related outcomes in older people, but its association with frailty is still unclear. This study investigates the association between PEF and prevalent and incident frailty in older adults. Data come from 2559 community-dwelling participants (age ≥ 60 years) of the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Baseline PEF was expressed as standardized residual (SR) percentiles. Frailty was assessed at baseline and over six years, according to the Fried criteria. Associations between PEF and frailty were estimated cross-sectionally through logistic regressions, and longitudinally by multinomial logistic regression, considering death as alternative outcome. Obstructive respiratory diseases and smoking habits were treated as potential effect modifiers. Our cross-sectional results showed that the 10th–49th and <10th PEF SR percentile categories were associated with three- and five-fold higher likelihood of being frail than the 80th–100th category. Similar estimates were confirmed longitudinally, i.e., adjusted OR = 3.11 (95% CI: 1.61–6.01) for PEF SR percentiles < 10th, compared with 80th–100th percentiles. Associations were enounced in participants without physical deficits, and tended to be stronger among those with baseline obstructive respiratory diseases, and, longitudinally, also among former/current smokers. These findings suggest that PEF is a marker of general robustness in older adults, and its reduction exceeding that expected by age is associated with frailty development. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

12 pages, 921 KiB

Open AccessArticle

β₂-Adrenergic Receptor (ADRB2) Gene Polymorphisms and Risk of COPD Exacerbations: The Rotterdam Study

by Leila Karimi, Lies Lahousse, Mohsen Ghanbari, Natalie Terzikhan, André G. Uitterlinden, Johan van der Lei, Guy G. Brusselle, Bruno H. Stricker and Katia M. C. Verhamme

J. Clin. Med. 2019, 8(11), 1835; https://doi.org/10.3390/jcm8111835 - 01 Nov 2019

Cited by 12 | Viewed by 2668

Abstract

The role of the β₂-adrenergic receptor (ADRB2) gene in patients with chronic obstructive pulmonary disease (COPD) is unclear. We investigated the association between ADRB2 variants and the risk of exacerbations in COPD patients treated with inhaled β₂-agonists. Within the Rotterdam Study, a population-based cohort study, we followed 1053 COPD patients until the first COPD exacerbation or end of follow-up and extracted rs1042713 (16Arg > Gly) and rs1042714 (27Gln > Glu) in ADRB2. Exposure to inhaled β₂-agonists was categorized into current, past, or non-use on the index date (date of COPD exacerbation for cases and on the same day of follow-up for controls). COPD exacerbations were defined as acute episodes of worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate exacerbations), or hospitalization (severe exacerbations). The associations between ADRB2 variants and COPD exacerbations were assessed using Cox proportional hazards models, adjusting for age, sex, use of inhaled corticosteroids, daily dose of β₂-agonists, and smoking. In current users of β₂-agonists, the risk of COPD exacerbation decreased by 30% (hazard ratio (HR); 0.70, 95% CI: 0.59–0.84) for each copy of the Arg allele of rs1042713 and by 20% (HR; 0.80, 95% CI: 0.69–0.94) for each copy of the Gln allele of rs1042714. Furthermore, current users carrying the Arg16/Gln27 haplotype had a significantly lower risk (HR; 0.70, 95% CI: 0.59–0.85) of COPD exacerbation compared to the Gly16/Glu27 haplotype. In conclusion, we observed that the Arg16/Gln27 haplotype in ADRB2 was associated with a reduced risk of COPD exacerbation in current users of inhaled β₂-agonists. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

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12 pages, 1486 KiB

Open AccessArticle

Prevalence of Asthma and COPD and Blood Eosinophil Count in a Middle-Aged Belgian Population

by Sara R. A. Wijnant, Lies Lahousse, Marc L. De Buyzere, Guy G. Brusselle and Ernst R. Rietzschel

J. Clin. Med. 2019, 8(8), 1122; https://doi.org/10.3390/jcm8081122 - 28 Jul 2019

Cited by 12 | Viewed by 6926

Abstract

Various phenotypes exist in asthma and Chronic Obstructive Pulmonary Disease (COPD). These are important to identify in order to guide treatment decisions. We aim to investigate the prevalence and clinical characteristics of obstructive airway diseases in the middle-aged population. We estimated the prevalence of COPD and/or asthma in the Asklepios cohort study (Belgium), using information from the third European Community Respiratory Health Survey (ECRHS3), medical records, and spirometry. Respiratory symptoms, respiratory medication, and current disease status distinguished clinical from sub-clinical cases. In addition, we compared the blood eosinophil count/µL (median [IQR]) between cases and controls. Of the 2221 participants (mean age 56.1 ± 5.9 years; 48.7% males), 138 (6.2%) participants had clinical current asthma, 22 (1.0%) participants had sub-clinical ever asthma, 102 (4.6%) had sub-clinical spirometry-defined COPD, 104 (4.6%) participants had clinical spirometry-confirmed COPD, and 11 (0.5%) had asthma and COPD overlap (ACO). Clinical current asthma (160.0 [110.0–250.0]), sub-clinical ever asthma (170.0 [110.0–230.0]), and clinical COPD (160.0 [110.0–220.0])—but less sub-clinical COPD (140.0 [90.0–210.0])—had higher eosinophil counts, compared to controls (130.0 [80.0–200.0]). We conclude that obstructive airway diseases are prevalent in the middle-aged Asklepios cohort. Moreover, the systemic eosinophil count is increased in clinical COPD cases, and in asthma cases regardless of clinical remission. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

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14 pages, 915 KiB

Open AccessArticle

Low Vitamin K Status Is Associated with Increased Elastin Degradation in Chronic Obstructive Pulmonary Disease

by Ianthe Piscaer, Jody M. W. van den Ouweland, Kristina Vermeersch, Niki L. Reynaert, Frits M. E. Franssen, Spencer Keene, Emiel F. M. Wouters, Wim Janssens, Cees Vermeer and Rob Janssen

J. Clin. Med. 2019, 8(8), 1116; https://doi.org/10.3390/jcm8081116 - 27 Jul 2019

Cited by 28 | Viewed by 4413

Abstract

Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and is partially regulated by Matrix Gla Protein (MGP), via a vitamin K-dependent pathway. The aim was to assess vitamin K status in COPD as well as associations between vitamin K status, elastin degradation, lung function parameters and mortality. A total of 192 COPD patients and 186 age-matched controls were included. In addition to this, 290 COPD patients from a second independent longitudinal cohort were also included. Vitamin K status was assessed by measuring plasma inactive MGP levels and rates of elastin degradation by measuring plasma desmosine levels. Reduced vitamin K status was found in COPD patients compared to smoking controls (p < 0.0005) and controls who had never smoked (p = 0.001). Vitamin K status was inversely associated with desmosine (cohort 1: p = 0.001; cohort 2: p = 0.004). Only few significant associations between vitamin K status and lung function parameters were found. Mortality was higher in COPD patients within the quartile with the lowest vitamin K status compared to those within the other quartiles (hazard ratio 1.85, 95% confidence interval (CI), 1.21–2.83, p = 0.005). In conclusion, we demonstrated reduced vitamin K status in COPD and an inverse association between vitamin K status and elastin degradation rate. Our results therefore suggest a potential role of vitamin K in COPD pathogenesis. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

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10 pages, 416 KiB

Open AccessArticle

Patterns and Predictors of Recovery from Poor Health Status Measured with the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test in Patients with Stable COPD: A Longitudinal Study

by Francesc Medina-Mirapeix, Roberto Bernabeu-Mora, Maria Piedad Sánchez-Martínez, Mariano Gacto-Sánchez, Rodrigo Martín San Agustín and Joaquina Montilla-Herrador

J. Clin. Med. 2019, 8(7), 946; https://doi.org/10.3390/jcm8070946 - 29 Jun 2019

Cited by 3 | Viewed by 2199

Abstract

Recent recommendations for chronic obstructive pulmonary disease (COPD) suggest that evaluation and management should focus on patient health status. Despite the frequency of poor health status and its negative impact on patients with COPD, little is known about how poor or non-poor health status persists and/or remits over time or what factors might predict recovery from a poor health status. The aim was to determine the likelihood of transitioning between poor and non-poor health status in patients with stable COPD followed for 2 years and to investigate factors that might predict recovery from poor health status. We prospectively included 137 patients with stable COPD (mean age, 66.9 years ± 8.3). Health status was measured at baseline and after 1 and 2 years with the COPD assessment test (CAT). Higher scores indicated worse health status, and 10 was the cut-off score for discriminating between non-poor and poor health status. The likelihoods of annual transitions to new episodes and recovery were calculated. We evaluated demographic, non-respiratory, and respiratory variables as potential predictors with generalized estimating equations. At baseline, 37 patients (27%) reported non-poor health status. Within the group of patients displaying poor health status at the beginning of the year, 176 annual transitions were identified during the study period: 15.9% were transitions to recovery from poor health status. In contrast, of the 70 transitions from a starting non-poor health status, 32.4% worsened. Predictors of transitions to recovery were: current non-smoker status (odds ratio (OR) = 3.88; 95% confidence interval (CI): 0.64–5.54) and handgrip strength (OR = 1.08; 95% CI: 1.00–1.16). This study suggests that self-reported health status, measured with the CAT, has a dynamic nature in patients with COPD. Annual transitions towards recovery from poor health status are most likely among current non-smoking patients and those with high handgrip strength. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

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Review

Jump to: Research

12 pages, 1024 KiB

Open AccessReview

Challenges to the Application of Integrated, Personalized Care for Patients with COPD—A Vision for the Role of Clinical Information

by Lowie E.G.W. Vanfleteren, Alex J. van ‘t Hul, Katarzyna Kulbacka-Ortiz, Anders Andersson, Anders Ullman and Martin Ingvar

J. Clin. Med. 2020, 9(5), 1311; https://doi.org/10.3390/jcm9051311 - 02 May 2020

Cited by 9 | Viewed by 3796

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease defined by airflow limitation and characterized by a spectrum of treatable and untreatable pulmonary and extra-pulmonary disease characteristics. Nonpharmacological management related to physical activity, physical capacity, body composition, breathing and energy-saving techniques, coping strategies, and self-management is as important as its pharmacological management. Most patients with COPD carry other chronic diagnoses and this poses a key challenge, as it lowers the quality of life, increases mortality, and impacts healthcare consumption. A personalized, multi-, and interprofessional approach is key. Today, healthcare is poorly organized to meet this complexity with the isolation between care levels, logic silos of the different healthcare professions, and lack of continuity of care along the patient’s journey with the healthcare system. In order to meet the criteria for integrated, personalized care for COPD, the structural capabilities of healthcare to support a comprehensive approach and continuity of care needs improvement. COPD is preeminently a disease that requires a transition from a reactive single-specialty approach to a proactive interprofessional approach. In this study, we discuss the issues that need to be addressed when moving from current health care practice to a person-centered model where the care processes and information are aligned to the individual personal needs of the patient. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

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8 pages, 423 KiB

Open AccessReview

Reassessing the Role of Eosinophils as a Biomarker in Chronic Obstructive Pulmonary Disease

by Mariaenrica Tinè, Davide Biondini, Umberto Semenzato, Erica Bazzan, Manuel G. Cosio, Marina Saetta and Graziella Turato

J. Clin. Med. 2019, 8(7), 962; https://doi.org/10.3390/jcm8070962 - 02 Jul 2019

Cited by 18 | Viewed by 3504

Abstract

Blood eosinophils measurement, as proxy for tissue eosinophils, has become an important biomarker for exacerbation risk and response to inhaled corticosteroids (ICS) in Chronic Obstructive Pulmonary Disease (COPD). Its use to determine the pharmacological approach is recommended in the latest COPD guidelines. The potential role of blood eosinophils is mainly based on data derived from post-hoc and retrospective analyses that showed an association between increased blood eosinophils and risk of exacerbations, as well as mitigation of this risk with ICS. Yet other publications, including studies in real life COPD, do not confirm these assumptions. Moreover, anti-eosinophil therapy targeting interleukin (IL)-5 failed to reduce exacerbations in COPD patients with high blood eosinophils, which casts significant doubts on the role of eosinophils in COPD. Furthermore, a reduction of eosinophils might be harmful since COPD patients with relatively high eosinophils have better pulmonary function, better life quality, less infections and longer survival. These effects are probably linked to the role of eosinophils in the immune response against pathogens. In conclusion, in COPD, high blood eosinophils are widely used as a biomarker for exacerbation risk and response to ICS. However, much is yet to be learned about the reasons for the high eosinophil counts, their variations and their controversial effects on the fate of COPD patients. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease: Methodological Challenges for Precision Medicine)

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