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  • 1.
    Ellingsen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Chronic obstructive pulmonary disease: exacerbations and mortality: Prognostic value of biomarkers and comorbidities2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. COPD is associated with systemic inflammation, and comorbidities are common. A characteristic feature is acute exacerbations (AECOPDs), i.e., episodes of worsening symptoms. AECOPDs are associated with increased mortality.

    Aim: To find prognostic risk factors for COPD mortality and AECOPDs, focusing on comorbidities and inflammatory biomarkers.

    Methods: In Paper I, associations between comorbidities, pharmacological treatment, and mortality were analysed in a real-world cohort of almost 18,000 primary care COPD patients. Data from medical records and national registers were analysed in Cox proportional hazards regressions.

    Papers II–IV were based on the Tools Identifying Exacerbations (TIE) cohort study of 572 COPD patients recruited from primary and secondary care in three Swedish regions. Participants were invited to three yearly visits, including phlebotomy, spirometry, and health questionnaires.

    In Paper II, the ability of blood neutrophil-to-lymphocyte ratio (NLR) and eosinophils (B-Eos) to predict AECOPDs was analysed with mixed-effects logistic regressions.

    In Paper III, the ability of C-reactive protein (CRP), fibrinogen, blood leukocytes (B-Leu), and four blood cell indices to predict AECOPDs was analysed with ordinal logistic regressions.

    In Paper IV, an algorithm for clinical phenotyping previously developed to predict mortality was studied. The algorithm’s ability to predict AECOPDs and mortality was analysed with Cox proportional hazards regressions; additionally, the identified phenotypes were analysed concerning differences in blood-based inflammatory biomarkers.

    Results: Several comorbidities, including heart diseases, were associated with increased mortality risk. Some pharmacological treatments were associated with increased or decreased mortality risk (Paper I). NLR, B-Eos, CRP, fibrinogen, and B-Leu (Papers II–III) predicted AECOPDs after adjustment for confounders, whereas other blood cell indices were of limited value (Paper III). The clinical phenotyping algorithm predicted AECOPDs and mortality, and the phenotypes had different patterns of inflammatory biomarkers (Paper IV).

    Conclusions: Comorbidities, particularly heart diseases, are substantial risk factors for mortality in COPD and should be an integral part of management of COPD patients. NLR, B-Eos, CRP, fibrinogen, and B-Leu are independent predictors of AECOPDs and should be further investigated as parts of, e.g., risk prediction tools. A previously developed algorithm for clinical phenotyping predicts mortality and AECOPDs.

    List of papers
    1. Impact of Comorbidities and Commonly Used Drugs on Mortality in COPD - Real-World Data from a Primary Care Setting
    Open this publication in new window or tab >>Impact of Comorbidities and Commonly Used Drugs on Mortality in COPD - Real-World Data from a Primary Care Setting
    Show others...
    2020 (English)In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 15, p. 235-245Article in journal (Refereed) Published
    Abstract [en]

    Background: Life expectancy is significantly shorter for patients with chronic obstructive pulmonary disease (COPD) than the general population. Concurrent diseases are known to infer an increased mortality risk in those with COPD, but the effects of pharmacological treatments on survival are less established. This study aimed to examine any associations between commonly used drugs, comorbidities and mortality in Swedish real-world primary care COPD patients.

    Methods: Patients with physician-diagnosed COPD from a large primary care population were observed retrospectively, utilizing primary care records and mandatory Swedish national registers. The time to all-cause death was assessed in a stepwise multiple Cox proportional hazards regression model including demography, socioeconomic factors, exacerbations, comorbidities and medication.

    Results: During the observation period (1999-2009) 5776 (32.5%) of 17,745 included COPD patients died. Heart failure (hazard ratio [HR]: 1.88, 95% confidence interval [CI]: 1.74-2.04), stroke (HR: 1.52, 95% CI: 1.40-1.64) and myocardial infarction (HR: 1.40, 95% CI: 1.24-1.58) were associated with an increased risk of death. Use of inhaled corticosteroids (ICS; HR: 0.79, 95% CI: 0.66-0.94), beta-blockers (HR: 0.86, 95% CI: 0.76-0.97) and acetylsalicylic acid (ASA; HR: 0.87, 95% CI: 0.77-0.98) was dose-dependently associated with a decreased risk of death, whereas use of long-acting muscarinic antagonists (LAMA; HR: 1.33, 95% CI: 1.14-1.55) and N-acetylcysteine (NAC; HR: 1.26, 95% CI: 1.08-1.48) were dose-dependently associated with an increased risk of death in COPD patients.

    Conclusion: This large, retrospective, observational study of Swedish real-world primary care COPD patients indicates that coexisting heart failure, stroke and myocardial infarction were the strongest predictors of death, underscoring the importance of timely recognition and treatment of comorbidities. A decreased risk of death associated with the use of ICS, beta-blockers and ASA, and an increased risk associated with the use of LAMA and NAC, was also found.

    Place, publisher, year, edition, pages
    DOVE MEDICAL PRESS LTD, 2020
    Keywords
    observational, LAMA, inhaled corticosteroids, beta-blockers, acetylsalicylic acid, chronic obstructive pulmonary disease
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-407514 (URN)10.2147/COPD.S231296 (DOI)000515171300001 ()32099348 (PubMedID)
    Funder
    AstraZeneca
    Available from: 2020-03-25 Created: 2020-03-25 Last updated: 2024-02-22Bibliographically approved
    2. Neutrophil-to-lymphocyte ratio, blood eosinophils and COPD exacerbations: a cohort study
    Open this publication in new window or tab >>Neutrophil-to-lymphocyte ratio, blood eosinophils and COPD exacerbations: a cohort study
    Show others...
    2021 (English)In: ERJ Open Research, E-ISSN 2312-0541, Vol. 7, no 4Article in journal (Refereed) Published
    Abstract [en]

    Background Blood neutrophil-to-lymphocyte ratio (NLR) and blood eosinophils (B-Eos) are emerging biomarkers in COPD. This study examined whether they could predict acute exacerbations of COPD (AECOPDs), and determined their longitudinal stability.Methods In this closed cohort study, Swedish subjects with spirometry-verified COPD attended three yearly visits in a stable phase of the disease. Blood cell counts, spirometry and questionnaire-assessed AECOPD-history (worsening of COPD leading to an unscheduled visit and/or use of antibiotics and/or oral corticosteroids) were collected at each visit.Results Of 466 included subjects 57% were female. Baseline mean±sd forced expiratory volume in 1 s was 58±17% predicted. High NLR (≥3.0) was more common in subjects with previous AECOPDs than in those without (33.5% versus 20.4%, p=0.002). In two-level mixed-effects logistic regression models adjusted for confounders, NLR as a continuous variable (OR 1.20, 95% CI 1.04–1.38) and B-Eos ≥300 cells·µL−1 (OR 1.54, 95% CI 1.06–2.24) were associated with future AECOPDs. In 386 subjects with blood cell data available at all three visits, the intraclass correlation coefficient for NLR was 0.61 (95% CI 0.56–0.66) and for B-Eos 0.69 (95% CI 0.64–0.73). NLR was persistently ≥3.0 in 10.6% and B-Eos was persistently ≥300 cells·µL−1 in 15.3%.Conclusions Stable phase NLR and B-Eos were associated with future AECOPDs. NLR on its own is probably not useful to predict AECOPDs but might be included in a risk scoring index. A minority of subjects with COPD had persistently elevated stable-phase NLR or B-Eos, and the biomarkers showed fair longitudinal reliability.

    Place, publisher, year, edition, pages
    ERS Publications, 2021
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-463033 (URN)10.1183/23120541.00471-2021 (DOI)000769759500054 ()34988219 (PubMedID)
    Funder
    Swedish Heart Lung Foundation
    Available from: 2022-01-04 Created: 2022-01-04 Last updated: 2024-02-22Bibliographically approved
    3. CRP, fibrinogen, leukocytes, and blood cell indices as prognostic biomarkers of future COPD exacerbation frequency: the TIE cohort study
    Open this publication in new window or tab >>CRP, fibrinogen, leukocytes, and blood cell indices as prognostic biomarkers of future COPD exacerbation frequency: the TIE cohort study
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Respiratory Medicine and Allergy
    Research subject
    Lung Medicine
    Identifiers
    urn:nbn:se:uu:diva-523300 (URN)
    Available from: 2024-02-20 Created: 2024-02-20 Last updated: 2024-02-26
    4. Clinical phenotypes predict exacerbations of COPD: the TIE cohort study
    Open this publication in new window or tab >>Clinical phenotypes predict exacerbations of COPD: the TIE cohort study
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Respiratory Medicine and Allergy
    Research subject
    Lung Medicine
    Identifiers
    urn:nbn:se:uu:diva-523302 (URN)
    Available from: 2024-02-22 Created: 2024-02-22 Last updated: 2024-02-22
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  • 2.
    Ellingsen, Jens
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Bröms, Kriistina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Lisspers, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Högman, Marieann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Longitudinal measurements of blood eosinophils in relation to COPD outcomes2018In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 52Article in journal (Other academic)
  • 3.
    Ellingsen, Jens
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Bröms, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Farkhooy, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Hårdstedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna.
    Högman, Marieann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lisspers, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Palm, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Clinical phenotypes predict exacerbations of COPD: the TIE cohort studyManuscript (preprint) (Other academic)
  • 4.
    Ellingsen, Jens
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Bröms, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Hårdstedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna.
    Högman, Marieann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lisspers, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Palm, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    CRP, fibrinogen, leukocytes, and blood cell indices as prognostic biomarkers of future COPD exacerbation frequency: the TIE cohort studyManuscript (preprint) (Other academic)
  • 5.
    Ellingsen, Jens
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Bröms, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Lisspers, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Högman, Marieann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Neutrophil-to-lymphocyte ratio, blood eosinophils and COPD exacerbations: a cohort study2021In: ERJ Open Research, E-ISSN 2312-0541, Vol. 7, no 4Article in journal (Refereed)
    Abstract [en]

    Background Blood neutrophil-to-lymphocyte ratio (NLR) and blood eosinophils (B-Eos) are emerging biomarkers in COPD. This study examined whether they could predict acute exacerbations of COPD (AECOPDs), and determined their longitudinal stability.Methods In this closed cohort study, Swedish subjects with spirometry-verified COPD attended three yearly visits in a stable phase of the disease. Blood cell counts, spirometry and questionnaire-assessed AECOPD-history (worsening of COPD leading to an unscheduled visit and/or use of antibiotics and/or oral corticosteroids) were collected at each visit.Results Of 466 included subjects 57% were female. Baseline mean±sd forced expiratory volume in 1 s was 58±17% predicted. High NLR (≥3.0) was more common in subjects with previous AECOPDs than in those without (33.5% versus 20.4%, p=0.002). In two-level mixed-effects logistic regression models adjusted for confounders, NLR as a continuous variable (OR 1.20, 95% CI 1.04–1.38) and B-Eos ≥300 cells·µL−1 (OR 1.54, 95% CI 1.06–2.24) were associated with future AECOPDs. In 386 subjects with blood cell data available at all three visits, the intraclass correlation coefficient for NLR was 0.61 (95% CI 0.56–0.66) and for B-Eos 0.69 (95% CI 0.64–0.73). NLR was persistently ≥3.0 in 10.6% and B-Eos was persistently ≥300 cells·µL−1 in 15.3%.Conclusions Stable phase NLR and B-Eos were associated with future AECOPDs. NLR on its own is probably not useful to predict AECOPDs but might be included in a risk scoring index. A minority of subjects with COPD had persistently elevated stable-phase NLR or B-Eos, and the biomarkers showed fair longitudinal reliability.

    Download full text (pdf)
    fulltext
  • 6.
    Ellingsen, Jens
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Larsson, Kjell
    Karolinska Inst, Natl Inst Environm Med, Integrat Toxicol, Stockholm, Sweden.
    Lisspers, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Thuresson, Marcus
    Statisticon AB, Uppsala, Sweden.
    Jansson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Impact of Comorbidities and Commonly Used Drugs on Mortality in COPD - Real-World Data from a Primary Care Setting2020In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 15, p. 235-245Article in journal (Refereed)
    Abstract [en]

    Background: Life expectancy is significantly shorter for patients with chronic obstructive pulmonary disease (COPD) than the general population. Concurrent diseases are known to infer an increased mortality risk in those with COPD, but the effects of pharmacological treatments on survival are less established. This study aimed to examine any associations between commonly used drugs, comorbidities and mortality in Swedish real-world primary care COPD patients.

    Methods: Patients with physician-diagnosed COPD from a large primary care population were observed retrospectively, utilizing primary care records and mandatory Swedish national registers. The time to all-cause death was assessed in a stepwise multiple Cox proportional hazards regression model including demography, socioeconomic factors, exacerbations, comorbidities and medication.

    Results: During the observation period (1999-2009) 5776 (32.5%) of 17,745 included COPD patients died. Heart failure (hazard ratio [HR]: 1.88, 95% confidence interval [CI]: 1.74-2.04), stroke (HR: 1.52, 95% CI: 1.40-1.64) and myocardial infarction (HR: 1.40, 95% CI: 1.24-1.58) were associated with an increased risk of death. Use of inhaled corticosteroids (ICS; HR: 0.79, 95% CI: 0.66-0.94), beta-blockers (HR: 0.86, 95% CI: 0.76-0.97) and acetylsalicylic acid (ASA; HR: 0.87, 95% CI: 0.77-0.98) was dose-dependently associated with a decreased risk of death, whereas use of long-acting muscarinic antagonists (LAMA; HR: 1.33, 95% CI: 1.14-1.55) and N-acetylcysteine (NAC; HR: 1.26, 95% CI: 1.08-1.48) were dose-dependently associated with an increased risk of death in COPD patients.

    Conclusion: This large, retrospective, observational study of Swedish real-world primary care COPD patients indicates that coexisting heart failure, stroke and myocardial infarction were the strongest predictors of death, underscoring the importance of timely recognition and treatment of comorbidities. A decreased risk of death associated with the use of ICS, beta-blockers and ASA, and an increased risk associated with the use of LAMA and NAC, was also found.

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