Chronic Obstructive Pulmonary Disease (COPD)

Research group Magnus Sköld

Professor/senior physician

Magnus Sköld

Phone: 08-517 748 43
Organizational unit: Forskargrupp M Sköld

Our research group focuses on clinical research on common respiratory disorders. We study well characterized patient cohorts carefully phenotyped and we use various laboratory techniques, collaborating with a number of laboratories both within Karolinska Institutet and other universities including international. 

Characterization of the patients is crucial and includes symptoms (questionnaires), lung function tests (spirometry, body plethysmography, diffusion capacity, and impulse oscillometry), imaging (Chest X-ray and computer tomography), 6 minutes walk test, echocardiography and blood chemistry. Sampling of biological material from the lung is performed by fiberoptic bronchoscopy where tissues and cells from the large and from the small airways are harvested.

We are interested in exploring inflammatory mechanisms in the lung and systemically in common respiratory disorders. Specifically the link between the inflammatory response and development of structural changes (remodeling) in the lung is explored. We collaborate with a number of highly skilled labs depending on our research questions, using a various methods including immunohistochemistry, flow cytometry, PCR, cell culture techniques and omics methods.

Chronic Obstructive Lung Disease (COPD)

COPD is a disease with a prevalence of 10% and it is increasing with age. The patients experience dyspnoea, cough but have also co-morbidities and systemic manifestations. There are obvious gender differences both in the epidemiology and in the clinical presentation of the disease. In addition, manifestations of COPD caused by chronic cigarette smoking also vary between different individuals of the same sex. This leads to the consequence that COPD patients differ in particular with regard to emphysema, bronchitis, bronchiolitis, reversibility of bronchodilators rate of exacerbations and systemic involvement. The reasons for development of these various responses to cigarette-smoke exposure are largely unknown. 

Stable COPD

In a cohort of 40 COPD-patients, 40 smokers with normal lung function and 40 neversmokers (Karolinska COSMIC study) we have made significant attempts, by performing bronchoscopy, to characterize inflammation and structural changes in various levels in the airways as well as in the systemic circulation. A 9-year follow-up has recently been initiated where the COSMIC cohort are invited to the clinic for symptoms registration, spirometry and high resolution computed tomography. The study will, in particular, gain knowledge on predisposing factors for developing of airway obstruction in smokers.

COPD exacerbations

In COPD patients with exacerbations have increased risk of hospitalization and mortality. In a planned project together with St Gorans Hospital, we will characterize patients with acute COPD exacerbations (EXATOX study). Blood sampling will be performed both during and three months after acute exacerbations. We will collect cells, plasma and serum for analysis of biomarkers with a variety of methods including omics. Findings will be correlated to clinical parameters. The study will increase our knowledge on the pathophysiology of COPD exacerbations.

Chronic airway obstruction associated to prematurity

Risk factors for chronic airway obstruction are low birth weight and premature birth. In collaboration with Sachs´ Childrens Hospital, Södersjukhuset, Stockholm, adult prematurely born children with and without bronchopulmonary dysplasia (PBD) are compared with mild asthmatics and matched healthy neversmokers in a cross-sectional study (LUNAPRE-study). Bronchoscopy, imaging, lung function tests, echocardiography is, among other methods, used. The study will explore one explanation to chronic airway obstruction not caused by tobacco smoke. The clinical part is likely to be finished 2016/2017.

Chronic airway obstruction in neversmokers (BRONCHO-SCAPIS study)

Recently, it has become evident that chronic airway obstruction in never-smokers is more prevalent than previously known. In this national multicenter study we will identify factors associated with chronic airway obstruction in never-smokers and to determine the molecular mechanisms of this disease in order to find potential targets for intervention. Also, we will identify prognostic markers in early stages of disease.

This National project was in 2016 awarded the annual big research grant (SEK 15 000 000) from the Swedish Heart-Lung Foundation. The project are based on a national population-based cohort (SCAPIS) including 30 000 well characterized individuals. In this group, we will identify individuals with chronic airway obstruction who have never smoked. These patients, and appropriate control groups, will be invited to each clinic for in-depth clinical characterization. Associating factors, including occupational and environmental, will be identified. Bronchoscopy will be performed, with the aim of collecting airways and lung samples. Molecular phenotyping including identification of T cell subsets, immunohistochemistry and "omics" strategies will take place. A research network including six university hospitals in Sweden (Umeå, Uppsala, Stockholm, Linköping, Gothenburg, Lund) have been formed and the study is planned to start-up in late 2016.

Idiopathic pulmonary fibrosis (IPF)

Idiopathic pulmonary fibrosis (IPF) is a deadly, progressive form of lung fibrosis, with a reported median survival of 2-5 year. The disease is characterized by progressive cough and dyspnoea and the disease result in increased healthcare resources utilization and high direct medical costs. An estimation of incidence is 7-16/100.000 and a prevalence of 14-42 /100.000. The prevalence of IPF in Sweden is, however, unknown and there is therefore a need to establish new tools to characterize this disease to enable a rational allocation of resources inside the national health-care program. We also need to build up a solid platform to enable translational research to detect new biomarkers and new therapy targets. 

The program will target the goal to create a national registry for IPF and a highly qualified translational centre for the diagnosis and care of IPF and rare lung diseases in Stockholm. We have started to build-up a national registry including pulmonary departments throughout the country. We use the same registry platform as in Finland, and a comparative study between the two countries is underway. In addition, the set up of a biobank to collect biological samples from patients with IPF for research purposes is in progress. Currently, we collect blood cells and serum/plasma, but in a near future we will include samples from the upper and lower respiratory tract and surgical specimens obtained by video-assisted techniques. This sub-project will provide not only basic data on incidence and prevalence of IPF in Sweden, but also, in a longer perspective, shed light on inflammatory and fibrotic mechanisms on this devastating model of an interstitial lung disease.

The research group

Magnus Sköld, Group leader, Professor of Respiratory Medicine, MD, PhD, Karolinska Institutet, Senior Consultant, Lung-Allergy Clinic, Karolinska University Hospital Solna

Giovanni Ferrara, , MD, PhD, Senior Consultant, Lung-Allergy Clinic, Karolinska University Hospital Solna

Reza Karimi, MD, PhD, Senior Consultant, Lung-Allergy Clinic, Karolinska University Hospital Solna

Ioanna Kotortsi, MD, ST Respiratory Medicine, Lung-Allergy Clinic, Karolinska University Hospital Solna

Petra Um Bergström, PhD-student, MD, Senior Consultant, Pediatric Clinic, Sachs´ Childrens Hospital, Södersjukhuset, Stockholm

Ida Pesonen, MD, ST Respiratory Medicine, Lung-Allergy Clinic, Karolinska University Hospital Solna

Sven Nyren, MD, PhD, Senior Consultant, Dept Molecular Medicine and Surgery, Karolinska Institutet, Radiology,  Karolinska University Hospital Solna

Maria Ahlsén, PhD, national study co-ordinator BRONCHO-SCAPIS

Lisa Carlson, RN, research nurse, co-ordinator Swedish National IPF registry

Heta Merikallio, PhD, post doc, Division of Respiratory Medicine, Dept Medicine Solna

Heléne Blomqvist, research nurse, co-ordinator BRONCHO-SCAPIS, clinical part

Benita Dahlberg, BMA, co-ordinator BRONCHO-SCAPIS, laboratory part

Benita Engvall, BMA, co-ordinator BRONCHO-SCAPIS

Margitha Dahl, RN, research nurse

Gunnel de Forest, RN, research nurse

Eva-Marie Karlsson, research administrator


Swedish Heart-Lung Foundation, ALF Medicine (Karolinska Institutet and Stockholm County Council), Swedish Asthma and Allergy Foundation, King Gustaf V and Queen Victorias Freemasons Foundation, Swedish Medical Research Council, Karolinska Institutet.

Recent Publications Magnus Sköld

Health effects of a subway environment in healthy volunteers.
Klepczyńska Nyström A, Svartengren M, Grunewald J, Pousette C, Rödin I, Lundin A, et al
Eur. Respir. J. 2010 Aug;36(2):240-8

Limited airway effects in mild asthmatics after exposure to air pollution in a road tunnel.
Larsson B, Grunewald J, Sköld C, Lundin A, Sandström T, Eklund A, et al
Respir Med 2010 Dec;104(12):1912-8

Remodeling in asthma and COPD--differences and similarities.
Sköld C
Clin Respir J 2010 May;4 Suppl 1():20-7

Tenascin-C and alpha-smooth muscle actin positive cells are increased in the large airways in patients with COPD.
Löfdahl M, Kaarteenaho R, Lappi-Blanco E, Tornling G, Sköld M
Respir. Res. 2011 Apr;12():48

Asthmatics exhibit altered oxylipin profiles compared to healthy individuals after subway air exposure.
Lundström S, Levänen B, Nording M, Klepczynska-Nyström A, Sköld M, Haeggström J, et al
PLoS ONE 2011 ;6(8):e23864

Assessing recent smoking status by measuring exhaled carbon monoxide levels.
Sandberg A, Sköld C, Grunewald J, Eklund A, Wheelock
PLoS ONE 2011 ;6(12):e28864

Cell recovery in bronchoalveolar lavage fluid in smokers is dependent on cumulative smoking history.
Karimi R, Tornling G, Grunewald J, Eklund A, Sköld C
PLoS ONE 2012 ;7(3):e34232

Bronchoalveolar lavage results are independent of season, age, gender and collection site.
Olsen H, Grunewald J, Tornling G, Sköld C, Eklund A
PLoS ONE 2012 ;7(8):e43644

Gender differences in the bronchoalveolar lavage cell proteome of patients with chronic obstructive pulmonary disease.
Kohler M, Sandberg A, Kjellqvist S, Thomas A, Karimi R, Nyrén S, et al
J. Allergy Clin. Immunol. 2013 Mar;131(3):743-51

Altered microRNA profiles in bronchoalveolar lavage fluid exosomes in asthmatic patients.
Levänen B, Bhakta N, Torregrosa Paredes P, Barbeau R, Hiltbrunner S, Pollack J, et al
J. Allergy Clin. Immunol. 2013 Mar;131(3):894-903

Increased intraepithelial (CD103+) CD8+ T cells in the airways of smokers with and without chronic obstructive pulmonary disease.
Mikko M, Forsslund H, Cui L, Grunewald J, Wheelock A, Wahlström J, et al
Immunobiology 2013 Feb;218(2):225-31

Review of IPF diagnosis and management recommendations in Europe.
Xaubet A, Behr J, Bendstrup E, Cottin V, Hirani N, Kähler C, et al
Sarcoidosis Vasc Diffuse Lung Dis 2013 Dec;30(4):249-61

Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis.
Reynisdottir G, Karimi R, Joshua V, Olsen H, Hensvold A, Harju A, et al
2014 Jan;66(1):31-9

Distribution of T-cell subsets in BAL fluid of patients with mild to moderate COPD depends on current smoking status and not airway obstruction.
Forsslund H, Mikko M, Karimi R, Grunewald J, Wheelock , Wahlström J, et al
Chest 2014 Apr;145(4):711-22

Lung cancer-associated myofibroblasts reveal distinctive ultrastructure and function.
Karvonen H, Lehtonen S, Sormunen R, Lappi-Blanco E, Sköld C, Kaarteenaho R
J Thorac Oncol 2014 May;9(5):664-74

Lung density on high resolution computer tomography (HRCT) reflects degree of inflammation in smokers.
Karimi R, Tornling G, Forsslund H, Mikko M, Wheelock , Nyrén S, et al
Respir. Res. 2014 Feb;15():23

Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation.
Ytterberg A, Joshua V, Reynisdottir G, Tarasova N, Rutishauser D, Ossipova E, et al
Ann. Rheum. Dis. 2015 Sep;74(9):1772-7

Interleukin-26 in antibacterial host defense of human lungs. Effects on neutrophil mobilization.
Che K, Tengvall S, Levänen B, Silverpil E, Smith M, Awad M, et al
Am. J. Respir. Crit. Care Med. 2014 Nov;190(9):1022-31

Organisation of diagnosis and treatment of idiopathic pulmonary fibrosis and other interstitial lung diseases in the Nordic countries.
Bendstrup E, Hyldgaard C, Altraja A, Sjåheim T, Myllärniemi M, Gudmundsson G, et al
Eur Clin Respir J 2015 ;2():

Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis.
Reynisdottir G, Olsen H, Joshua V, Engström M, Forsslund H, Karimi R, et al
Ann. Rheum. Dis. 2016 Sep;75(9):1722-7

Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD.
Balgoma D, Yang M, Sjödin M, Snowden S, Karimi R, Levänen B, et al
Eur. Respir. J. 2016 Jun;47(6):1645-56

Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis.
Lehtonen S, Veijola A, Karvonen H, Lappi-Blanco E, Sormunen R, Korpela S, et al
Respir. Res. 2016 Feb;17():14

Vital capacity and COPD: the Swedish CArdioPulmonary bioImage Study (SCAPIS).
Torén K, Olin A, Lindberg A, Vikgren J, Schiöler L, Brandberg J, et al
Int J Chron Obstruct Pulmon Dis 2016 ;11():927-33

Idiopathic pulmonary fibrosis in Sweden: report from the first year of activity of the Swedish IPF-Registry.
Ferrara G, Carlson L, Palm A, Einarsson J, Olivesten C, Sköld M
Eur Clin Respir J 2016 ;3():31090

Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial.
Behr J, Bendstrup E, Crestani B, Günther A, Olschewski H, Sköld C, et al
Lancet Respir Med 2016 Jun;4(6):445-53

A retrospective chart review of pirfenidone-treated patients in Sweden: the REPRIS study.
Sköld C, Janson C, Elf , Fiaschi M, Wiklund K, Persson H
Eur Clin Respir J 2016 ;3():32035

Forsslund H, Yang M, Mikko M, Karimi R, Nyrén S, Engvall B,  Grunewald J,  Merikallio H,  Kaarteenaho R, Wahlström J,  Wheelock ÅM, Sköld CM. Gender differences in the T-cell profiles of the airways in COPD associate with clinical phenotypes. Internat J COPD (2016) in press.

Recent publications Giovanni Ferrara

Idiopathic pulmonary fibrosis in Sweden: report from the first year of activity of the Swedish IPF-Registry.
Ferrara G, Carlson L, Palm A, Einarsson J, Olivesten C, Sköld M
Eur Clin Respir J 2016 ;3():31090

T-Cell Therapy: Options for Infectious Diseases.
Parida S, Poiret T, Zhenjiang L, Meng Q, Heyckendorf J, Lange C, et al
Clin. Infect. Dis. 2015 Oct;61Suppl 3():S217-24

Macrolides for chronic asthma.
Kew K, Undela K, Kotortsi I, Ferrara G
Cochrane Database Syst Rev 2015 Sep;(9):CD002997

Recurrent respiratory infections and unusual radiology: a woman with Kartagener's syndrome.
Ronnevi C, Ortiz-Villalon C, Pawlowski J, Ferrara G
BMJ Case Rep 2015 Sep;2015():

Serum reactome induced by Bordetella pertussis infection and Pertussis vaccines: qualitative differences in serum antibody recognition patterns revealed by peptide microarray analysis.
Valentini D, Ferrara G, Advani R, Hallander H, Maeurer M
BMC Immunol. 2015 Jul;16():40

Acute exacerbation of idiopathic pulmonary fibrosis: a clinical review.
Luppi F, Cerri S, Taddei S, Ferrara G, Cottin V
Intern Emerg Med 2015 Jun;10(4):401-11

Extra-pulmonary tuberculosis and Xpert® MTB/RIF: all about meta-analyses?
O'Grady J, Kik S, Ferrara G
Int. J. Tuberc. Lung Dis. 2015 Mar;19(3):254

No association between Birt-Hogg-Dubé syndrome skin fibrofolliculomas and the first 10 described human polyomaviruses or human papillomaviruses.
Bradley M, Nordfors C, Vlastos A, Ferrara G, Ramqvist T, Dalianis T
Virology 2014 Nov;468-470():244-7

Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial.
Skrahin A, Ahmed R, Ferrara G, Rane L, Poiret T, Isaikina Y, et al
Lancet Respir Med 2014 Feb;2(2):108-22

Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children.
Kew K, Karner C, Mindus S, Ferrara G
Cochrane Database Syst Rev 2013 Dec;(12):CD009019

Chronic empyema: importance of preventing complications in the management of pleural effusions.
Molander V, Diakopoulou M, Orre L, Ferrara G
BMJ Case Rep 2013 Aug;2013():

Linezolid to treat extensively drug-resistant TB: retrospective data are confirmed by experimental evidence.
Sotgiu G, Centis R, D'Ambrosio L, Spanevello A, Migliori G,
Eur. Respir. J. 2013 Jul;42(1):288-90

Severe pneumonia after intravesical BCG instillation in a patient with invasive bladder cancer: case report and literature review.
Caramori G, Artioli D, Ferrara G, Cazzuffi R, Pasquini C, Libanore M, et al
Monaldi Arch Chest Dis 2013 Mar;79(1):44-8

Isoniazid preventive treatment: predictors of adverse events and treatment completion.
Codecasa L, Murgia N, Ferrarese M, Delmastro M, Repossi A, Casali L, et al
Int. J. Tuberc. Lung Dis. 2013 Jul;17(7):903-8

Intra-abdominal bleeding during treprostinil infusion in a patient with pulmonary arterial hypertension.
Mindus S, Pawlowski J, Nisell M, Ferrara G
BMJ Case Rep 2013 Feb;2013():

Intravenous immunoglobulin (IVIg) for refractory and difficult-to-treat infections.
Ferrara G, Zumla A, Maeurer M
Am. J. Med. 2012 Oct;125(10):1036.e1-8

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis.
Sotgiu G, Centis R, D'Ambrosio L, Alffenaar J, Anger H, Caminero J, et al
Eur. Respir. J. 2012 Dec;40(6):1430-42

Risk factors associated with pulmonary tuberculosis: smoking, diabetes and anti-TNFα drugs.
Ferrara G, Murray M, Winthrop K, Centis R, Sotgiu G, Migliori G, et al
Curr Opin Pulm Med 2012 May;18(3):233-40

Trends and challenges in tuberculosis in a medium-sized southern European setting.
Pasticci M, Mazzolla R, Mercuri A, Gamboni G, Bombaci J, Tiecco C, et al
Int. J. Tuberc. Lung Dis. 2012 May;16(5):645-8

Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children.
Lasserson T, Ferrara G, Casali L
Cochrane Database Syst Rev 2011 Dec;(12):CD004106

Xpert MTB/RIF test for tuberculosis.
Ferrara G, O'Grady J, Zumla A, Maeurer M
Lancet 2011 Aug;378(9790):482; author reply 482-3

Screening of immigrants in the UK for latent tuberculosis.
McNerney R, Ferrara G, O'Grady J, Maeurer M, Zumla A
Expert Rev Respir Med 2011 Aug;5(4):483-6

Tuberculosis in prisons: anatomy of global neglect.
O'Grady J, Maeurer M, Atun R, Abubakar I, Mwaba P, Bates M, et al
Eur. Respir. J. 2011 Oct;38(4):752-4

A decade of interferon-γ release assays: quest for the holy grail to diagnose latent infection with mycobacterium tuberculosis?
Ferrara G, Parida S, Zumla A, Richeldi L, Maeurer M
Am. J. Respir. Crit. Care Med. 2011 Jun;183(12):1732

The best on infections: update from the 2010 ERS Congress.
Miravitlles M, Sotgiu G, Dimopoulos G, Rohde G, Centis R, Ferrara G, et al
Eur. Respir. J. 2011 Aug;38(2):450-5

A multicentre evaluation of the accuracy and performance of IP-10 for the diagnosis of infection with M. tuberculosis.
Ruhwald M, Dominguez J, Latorre I, Losi M, Richeldi L, Pasticci M, et al
Tuberculosis (Edinb) 2011 May;91(3):260-7

Tuberculosis in prisons in sub-Saharan Africa--the need for improved health services, surveillance and control.
O'Grady J, Hoelscher M, Atun R, Bates M, Mwaba P, Kapata N, et al
Tuberculosis (Edinb) 2011 Mar;91(2):173-8

Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis.
Diel R, Goletti D, Ferrara G, Bothamley G, Cirillo D, Kampmann B, et al
Eur. Respir. J. 2011 Jan;37(1):88-99

TB or not TB: update from the ERS Respiratory Infection Assembly 10.
Miravitlles M, Ferrara G, Lange C, Dimopoulos G, Rohde G, Blasi F, et al
Eur. Respir. J. 2010 Sep;36(3):665-70

Research group Åsa Wheelock

Senior researcher

Åsa Wheelock

Phone: 08-517 706 64
Organizational unit: Group Wheelock

COPD and gender

Chronic Obstructive Pulmonary Disease (COPD) is a global health problem of pandemic proportion and a leading cause of morbidity and mortality worldwide. Recent epidemiological studies indicate significant gender differences in susceptibility, with post-menopausal women being at greatest risk.

COPD is primarily an inflammatory disease of the peripheral airways, characterized by infiltration of macrophages and T lymphocytes. Besides smoking cessation, no efficacious treatments currently exist neither to prevent the inflammatory progression of COPD nor the progressive decline in lung function. The inflammation-induced tissue damage and subsequent remodelling invariably lead to impaired lung function and subsequent morbidity and mortality. Treatments with inhaled glucocorticoids, which are used to maintain most asthma patients, are largely ineffective in COPD patients. In macrophages from control subjects and healthy smokers, the release of inflammatory mediators is inhibited by corticosteroids, while corticosteroids remain inefficacious in macrophages of COPD patients.

The main objective of this project is to study gender differences critical for the pathophysiology of COPD, specifically by studying protein mediators from the lower airways. It is clear that multiple inflammatory mediators originating from several different inflammatory cell phenotypes are involved in the chronic inflammation and structural changes characteristic for COPD. However, the complex interplay between these inflammatory cells and their sequential appearance in the progression of the disease has not been elucidated. To this end, we are using proteomics profiling to identify protein mediators relevant for disease progression. Specifically, alterations in the proteomes of the individual inflammatory cell types involved in COPD as well as airway epithelial cells and airway exudates collected during fiberbronchoscopy of human volunteers are subject for investigation.The overall aim of these studies is to discover biomarkers of disease and susceptibility of COPD. Eventually, such biomarkers may result in improved techniques for early diagnosis of COPD, as well as novel pharmaceutical targets for the treatment of this debilitating disease.

Most importantly, the findings from these studies will lead to the elucidation of gender-associated differences in the toxicological and pathological response to the major health hazard in our society, tobacco smoke, thus representing an important step towards personalized medicine.