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

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, B.; 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, C. E.; 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.; 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.; Wallen-Nielsen, E.; van Veen, I.; Weersink, E.; Wilson, S. J.; Yasinska, V.; Zervas, E.; Ziolkowska-Graca, B.

doi:10.1183/13993003.00142-2021

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.