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2. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Author

Mikus, M.S. Kolmert, J. Andersson, L.I. Östling, J. Knowles, R.G. Gómez, C. Ericsson, M. Thörngren, J.-O. Khoonsari, P.E. Dahlén, B. Kupczyk, M. de Meulder, B. Auffray, C. Bakke, P.S. Beghe, B. Bel, E.H. Caruso, M. Chanez, P. Chawes, B. Fowler, S.J. Gaga, M. Geiser, T. Gjomarkaj, M. Horváth, I. Howarth, P.H. Johnston, S.L. Joos, G. Krug, N. Montuschi, P. Musial, J. Niżankowska-Mogilnicka, E. Olsson, H.K. Papi, A. Rabe, K.F. Sandström, T. Shaw, D.E. Siafakas, N.M. Uhlén, M. Riley, J.H. Bates, S. Middelveld, R.J.M. Wheelock, C.E. Chung, K.F. Adcock, I.M. Sterk, P.J. Djukanovic, R. Nilsson, P. Dahlén, S.-E. James, A. Ahmed, H. Balgoma, D. Bansal, A.T. Baribaud, F. Bigler, J. Billing, B. Bisgaard, H. Boedigheimer, M.J. Bønnelykke, K. Brandsma, J. Brinkman, P. Bucchioni, E. Burg, D. Bush, A. Chaiboonchoe, A. Checa, T. Compton, C.H. Corfield, J. Cunoosamy, D. D’Amico, A. Emma, R. Erpenbeck, V.J. Erzen, D. Fichtner, K. Fitch, N. Fleming, L.J. Formaggio, E. Frey, U. Gahlemann, M. Goss, V. Guo, Y.-K. Hashimoto, S. Haughney, J. Hedlin, G. Hekking, P.-P.W. Higenbottam, T. Hohlfeld, J.M. Holweg, C.T.J. Knox, A.J. Konradsen, J. Lazarinis, N. Lefaudeux, D. Li, T. Loza, M.J. Lutter, R. Manta, A. Masefield, S. Matthews, J.G. Mazein, A. Meiser, A. Miralpeix, M. Mores, N. Murray, C.S. Myles, D. Naz, S. Nordlund, B. Pahus, L. Pandis, I. Pavlidis, S. Postle, A. Powel, P. Rao, N. Reinke, S. Roberts, A. Roberts, G. Rowe, A. Schofield, J.P.R. Seibold, W. Selby, A. Sigmund, R. Singer, F. Sjödin, M. Skipp, P.J. Sousa, A.R. Sun, K. Thornton, B. Uddin, M. van Aalderen, W.M. van Geest, M. Vestbo, J. Vissing, N.H. Wagener, A.H. Wagers, S.S. Weiszhart, Z. Wheelock, C.E. Wheelock, Å. Wilson, S.J. Yasinska, V. Brusselle, G.G. Campbell, D.A. Contoli, M. Damm, K. de Rudder, I. Delin, I. Devautour, C. Duplaga, M. Eduards, M. Ek, A. Ekström, T. Figiel, E. Gaber, F. Gauw, S. Gawlewicz-Mroczka, A. Gerding, D. Haque, S. Hewitt, L. Hiemstra, P.S. Holgate, S.T. Holloway, J. Kania, A. Kanniess, F. Karlsson, Ö. Kips, J.C. Kumlin, M. Lantz, A.-S. Lazarinis, N. Magnussen, H. Mallia, P. Martling, I. Meziane, L. Oikonomidou, E. Olsson, M. Pace, E. Papadopouli, E. Papadopoulos, N. Plataki, M. Profita, M. Reinius, L.E. Richter, K. Robinson, D.S. Romagnoli, M. Samara, K. Schelfhout, V. Skedinger, M. Stamataki, E. ten Brinke, A. Vachier, I. Wallén-Nielsen, E. van Veen, I. Weersink, E. Wilson, S.J. Yasinska, V. Zervas, E. Ziolkowska-Graca, B. U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group BIOAIR (Longitudinal Assessment of Clinical Course Biomarkers in Severe Chronic Airway Disease) Consortium

Abstract

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA. © 2022 European Respiratory Society. All rights reserved.

Published
2022

3. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Author

Mikus, M. S., Kolmert, J., Andersson, L. I., Ostling, J., Knowles, R. G., Gomez, C., Ericsson, M., Thorngren, J. -O., Khoonsari, P. E., Dahlen, B., Kupczyk, M., de Meulder, B., Auffray, C., Bakke, P. S., Beghe, Bianca, Bel, E. H., Caruso, M., Chanez, P., Chawes, B., Fowler, S. J., Gaga, M., Geiser, T., Gjomarkaj, M., Horvath, I., Howarth, P. H., Johnston, S. L., Joos, G., Krug, N., Montuschi, P., Musial, J., Nizankowska-Mogilnicka, E., Olsson, H. K., Papi, A., Rabe, K. F., Sandstrom, T., Shaw, D. E., Siafakas, N. M., Uhlen, M., Riley, J. H., Bates, S., Middelveld, R. J. M., Wheelock, C. E., Chung, K. F., Adcock, I. M., Sterk, P. J., Djukanovic, R., Nilsson, P., Dahlen, S. -E., James, A., Ahmed, H., Balgoma, D., Bansal, A. T., Baribaud, F., Bigler, J., Billing, B., Bisgaard, H., Boedigheimer, M. J., Bonnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Chaiboonchoe, A., Checa, T., Compton, C. H., Corfield, J., Cunoosamy, D., D'Amico, A., Emma, R., Erpenbeck, V. J., Erzen, D., Fichtner, K., Fitch, N., Fleming, L. J., Formaggio, E., Frey, U., Gahlemann, M., Goss, V., Guo, Y. -K., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P. -P. W., Higenbottam, T., Hohlfeld, J. M., Holweg, C. T. J., Knox, A. J., Konradsen, J., Lazarinis, N., Lefaudeux, D., Li, T., Loza, M. J., Lutter, R., Manta, A., Masefield, S., Matthews, J. G., Mazein, A., Meiser, A., Miralpeix, M., Mores, N., Murray, C. S., Myles, D., Naz, S., Nordlund, B., Pahus, L., Pandis, I., Pavlidis, S., Postle, A., Powel, P., Rao, N., Reinke, S., Roberts, A., Roberts, G., Rowe, A., Schofield, J. P. R., Seibold, W., Selby, A., Sigmund, R., Singer, F., Sjodin, M., Skipp, P. J., Sousa, A. R., Sun, K., Thornton, B., Uddin, M., van Aalderen, W. M., van Geest, M., Vestbo, J., Vissing, N. H., Wagener, A. H., Wagers, S. S., Weiszhart, Z., Wheelock, A., Wilson, S. J., Yasinska, V., Brusselle, G. G., Campbell, D. A., Contoli, M., Damm, K., de Rudder, I., Delin, I., Devautour, C., Duplaga, M., Eduards, M., Ek, A., Ekstrom, T., Figiel, E., Gaber, F., Gauw, S., Gawlewicz-Mroczka, A., Gerding, D., Haque, S., Hewitt, L., Hiemstra, P. S., Holgate, S. T., Holloway, J., Kania, A., Kanniess, F., Karlsson, O., Kips, J. C., Kumlin, M., Lantz, A. -S., Magnussen, H., Mallia, P., Martling, I., Meziane, L., Oikonomidou, E., Olsson, M., Pace, E., Papadopouli, E., Papadopoulos, N., Plataki, M., Profita, M., Reinius, L. E., Richter, K., Robinson, D. S., Romagnoli, M., Samara, K., Schelfhout, V., Skedinger, M., Stamataki, E., ten Brinke, A., Vachier, I., Wallen-Nielsen, E., van Veen, I., Weersink, E., Zervas, E., and Ziolkowska-Graca, B.

Subjects
Blood Proteins, Humans, Inflammation, Proteomics, Severity of Illness Index, Steroids, Asthma, Quality of Life
Published
2022

4. Frequent exacerbators - a distinct phenotype of severe asthma

Author

Kupczyk, M. ten Brinke, A. Sterk, P.J. Bel, E.H. Papi, A. Chanez, P. Nizankowska-Mogilnicka, E. Gjomarkaj, M. Gaga, M. Brusselle, G. Dahlén, B. Dahlén, S.-E. Weersink, E. Papadopoulos, N. Oikonomidou, E. Zervas, E. Contoli, M. Pauwels, R.A. Joos, G.F. de Rudder, I. Schelfhout, V. Richter, K. Gerding, D. Magnussen, H. Siafakas, N.M. Tzortzaki, E. Samara, K. Plataki, M. Papadopouli, E. Szczeklik, A. Ziolkowska-Graca, B. Kania, A. Gawlewicz-Mroczka, A. Duplaga, M. Figiel, E. Rabe, K.F. Hiemstra, P.S. Gauw, S. van Veen, I. Kips, J.C. Johnston, S.L. Mallia, P. Campbell, D.A. Robinson, D.S. Kanniess, F. Fabbri, L.M. Romagnoli, M. Vachier, I. Devautour, C. Meziane, L. Vignola, A.M. Pace, E. Profita, M. Holgate, S.T. Howarth, P.H. Wilson, S.J. Hewitt, L. Holoway, J.

Abstract

Background: Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. Objective: The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. Methods: Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. Results: During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 μg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1/FVC ratio (-0.07 vs. -0.01 ΔFEV1/FVC, frequent vs. non-frequent, respectively, P 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). Conclusion and Clinical Relevance: We were able to distinguish and characterize a subphenotype of asthma subjects - frequent exacerbators - who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice. © 2013 John Wiley & Sons Ltd.

Published
2014

5. Detection of exacerbations in asthma based on electronic diary data : results from the 1-year prospective BIOAIR study

Author

Kupczyk, M., Haque, S., Sterk, P. J., Nizankowska-Mogilnicka, E., Papi, A., Bel, E. H., Chanez, P., Dahlen, B., Gaga, M., Gjomarkaj, M., Howarth, P. H., Johnston, S. L., Joos, G. F., Kanniess, F., Tzortzaki, E., James, A., Middelveld, R. J. M., Dahlen, S.-E., Weersink, E., Papadopoulos, N., Oikonomidou, E., Zervas, E., Contoli, M., Pauwels, R. A., Brusselle, G., de Rudder, I., Schelfhout, V., Richter, K., Gerding, D., Magnussen, H., Siafakas, N. M., Samara, K., Plataki, M., Papadopouli, E., Szczeklik, A., Ziolkowska-Graca, B., Kania, A., Gawlewicz-Mroczka, A., Duplaga, M., Figiel, E., Rabe, K. F., Hiemstra, P. S., Gauw, S., van Veen, I., Kips, J. C., Mallia, P., Campbell, D. A., Robinson, D. S., Fabbri, L. M., Romagnoli, M., Vachier, I., Devautour, C., Meziane, L., Maurizio Vignola, A., Pace, E., Profita, M., Holgate, S. T., Wilson, S. J., Hewitt, L., Holoway, J., Damm, K., Delin, I., Eduards, M., Ek, A., Ekstrom, T., Gulich, A., Johansson, L. E., Karlsson, O., Kumlin, M., Martling, I., Skedinger, M., Amsterdam institute for Infection and Immunity, and Pulmonology

Subjects
2. Zero hunger, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Exacerbation, business.industry, medicine.disease, Electronic diary, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Asthma Control Questionnaire, medicine, Sputum, Medical history, 030212 general & internal medicine, medicine.symptom, business, Body mass index, Lung function, Asthma
Abstract

Background Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation. Methods In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation. Results Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils ≥3%, body mass index >25 and low quality of life (St George9s Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p Conclusions Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control.

Published
2013

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