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3. FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes

Author

de Poel, E., Spelier, S., Hagemeijer, M. C., van Mourik, P., Suen, S. W.F., Vonk, A. M., Brunsveld, J. E., Ithakisiou, G. N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K. M., Heida-Michel, S., Jans, S. R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E. J.M., Koppelman, G. H., Blaazer, A. R., Muijlwijk-Koezen, J. E., van der Ent, C. K., Beekman, J. M., de Poel, E., Spelier, S., Hagemeijer, M. C., van Mourik, P., Suen, S. W.F., Vonk, A. M., Brunsveld, J. E., Ithakisiou, G. N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K. M., Heida-Michel, S., Jans, S. R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E. J.M., Koppelman, G. H., Blaazer, A. R., Muijlwijk-Koezen, J. E., van der Ent, C. K., and Beekman, J. M.

Abstract

Background: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF. Methods: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators. Results: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy. Conclusion: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies. One-sentence summary: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

Published
2023
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4. FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes

Author

Longziekten onderzoek 2, Child Health, Arts Assistenten Longziekten, Beleid & Communicatie, CTI, Translational Neuroscience, Revalidatiegeneeskunde Onderwijs, Longziekten patientenzorg, Afdeling Hartcatheterisatie, Epi Kanker Team A, Longziekten, Speerpunt Child Health, Infection & Immunity, Onderzoek, Regenerative Medicine and Stem Cells, de Poel, E., Spelier, S., Hagemeijer, M. C., van Mourik, P., Suen, S. W.F., Vonk, A. M., Brunsveld, J. E., Ithakisiou, G. N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K. M., Heida-Michel, S., Jans, S. R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E. J.M., Koppelman, G. H., Blaazer, A. R., Muijlwijk-Koezen, J. E., van der Ent, C. K., Beekman, J. M., Longziekten onderzoek 2, Child Health, Arts Assistenten Longziekten, Beleid & Communicatie, CTI, Translational Neuroscience, Revalidatiegeneeskunde Onderwijs, Longziekten patientenzorg, Afdeling Hartcatheterisatie, Epi Kanker Team A, Longziekten, Speerpunt Child Health, Infection & Immunity, Onderzoek, Regenerative Medicine and Stem Cells, de Poel, E., Spelier, S., Hagemeijer, M. C., van Mourik, P., Suen, S. W.F., Vonk, A. M., Brunsveld, J. E., Ithakisiou, G. N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K. M., Heida-Michel, S., Jans, S. R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E. J.M., Koppelman, G. H., Blaazer, A. R., Muijlwijk-Koezen, J. E., van der Ent, C. K., and Beekman, J. M.

Published
2023

5. First study results of the P4O2 long COVID cohort

Author

Baalbaki, N, primary, Blankestijn, J, additional, Abdel-Aziz, M, additional, De Backer, J, additional, Bazdar, S, additional, Beekers, I, additional, Beijers, R, additional, Van Den Bergh, J, additional, Bloemsma, L, additional, Bogaard, H J, additional, Van Bragt, J, additional, Van Den Brink, V, additional, Charbonnier, J P, additional, Cornelissen, M, additional, Dagelet, Y, additional, Davies, E H, additional, Van Der Does, A, additional, Downward, G, additional, Van Drunen, C, additional, Gach, D, additional, Geelhoed, M, additional, Glastra, J, additional, Golebski, K, additional, Heijink, I, additional, Holtjer, J, additional, Holverda, S, additional, Houweling, L, additional, Jacobs, J, additional, Jonker, R, additional, Kos, R, additional, Langen, R, additional, Van Der Lee, I, additional, Leliveld, A, additional, Mohamed Hoesein, F, additional, Neerincx, A, additional, Noij, L, additional, Olsson, J, additional, Van De Pol, M, additional, Pouwels, S, additional, Rolink, E, additional, Rutgers, M, additional, Șahin, H, additional, Schaminee, D, additional, Schols, A, additional, Schuurman, L, additional, Skipp, P, additional, Slingers, G, additional, Smeenk, O, additional, Sondermeijer, B, additional, Tamarit, M, additional, Verkouter, I, additional, Vermeulen, R, additional, De Vries, R, additional, Weersink, E, additional, Van De Werken, M, additional, De Wit-Van De Wijck, Y, additional, Young, S, additional, Nossent, E, additional, and Maitland-Van Der Zee, A, additional

Published
2023
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7. Real-world effectiveness of reslizumab in patients with severe eosinophilic asthma – “first initiators” and “switchers”

Author

Hashimoto, S, primary, Kroes, J A, additional, Eger, K, additional, Mau-Asam, P, additional, Hofstee, H B, additional, Bendien, S A, additional, Braunstahl, G, additional, Broeders, M E, additional, Imming, L M, additional, Langeveld, B, additional, Maitland-Van Der Zee, A H, additional, Oud, K T, additional, Patberg, K W, additional, Smeenk, F W, additional, Romme, E A, additional, Van Bezouw, M J, additional, Van De Ven, M J, additional, Van Veen, A, additional, Van Velzen, E, additional, Van Veen, I H, additional, Weersink, E J, additional, Ten Brinke, A, additional, Sont, J K, additional, Bel, E H, additional, and Team, R A P S O D I, additional

Published
2022
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9. Airway inflammation before and after bronchial thermoplasty

Author

Goorsenberg, A W, primary, Wijsman, P C, additional, Ravi, A, additional, D'Hooghe, J N, additional, Dierdorp, B S, additional, Dekker, T, additional, Van Schaik, C C, additional, Ten Hacken, N H, additional, Shah, P L, additional, Weersink, E J, additional, Bel, E H, additional, Annema, J T, additional, Lutter, R, additional, and Bonta, P I, additional

Published
2022
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11. Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Author

de Poel, E., Spelier, S., Suen, S. W.F., Kruisselbrink, E., Graeber, S. Y., Mall, M. A., Weersink, E. J.M., van der Eerden, M. M., Koppelman, G. H., van der Ent, C. K., Beekman, J. M., de Poel, E., Spelier, S., Suen, S. W.F., Kruisselbrink, E., Graeber, S. Y., Mall, M. A., Weersink, E. J.M., van der Eerden, M. M., Koppelman, G. H., van der Ent, C. K., and Beekman, J. M.

Abstract

Background: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation. Methods: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. Results: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. Conclusions: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.

Published
2022

12. Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Author

Longziekten onderzoek 2, CTI, Longziekten patientenzorg, Speerpunt Child Health, Child Health, Infection & Immunity, Onderzoek, Regenerative Medicine and Stem Cells, de Poel, E., Spelier, S., Suen, S. W.F., Kruisselbrink, E., Graeber, S. Y., Mall, M. A., Weersink, E. J.M., van der Eerden, M. M., Koppelman, G. H., van der Ent, C. K., Beekman, J. M., Longziekten onderzoek 2, CTI, Longziekten patientenzorg, Speerpunt Child Health, Child Health, Infection & Immunity, Onderzoek, Regenerative Medicine and Stem Cells, de Poel, E., Spelier, S., Suen, S. W.F., Kruisselbrink, E., Graeber, S. Y., Mall, M. A., Weersink, E. J.M., van der Eerden, M. M., Koppelman, G. H., van der Ent, C. K., and Beekman, J. M.

Published
2022

13. 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

14. 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

16. 665: Forskolin-induced intestinal organoid swelling predicts long-term cystic fibrosis disease progression

Author

Muilwijk, D., primary, de Poel, E., additional, van Mourik, P., additional, Suen, S., additional, Vonk, A., additional, Brunsveld, J., additional, Kruisselbrink, E., additional, Oppelaar, H., additional, Hagemeijer, M., additional, Berkers, G., additional, de Winter-de Groot, K., additional, Michel, S., additional, Jans, S., additional, van Panhuis, H., additional, van der Eerden, M., additional, van der Meer, R., additional, Roukema, J., additional, Dompeling, E., additional, Weersink, E., additional, Koppelman, G., additional, Vries, R., additional, Zomer-van Ommen, D., additional, Eijkemans, R., additional, van der Ent, C., additional, and Beekman, J., additional

Published
2021
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19. Characteristics and treatment regimens across ERS SHARP severe asthma registries

Author

van Bragt, J. J. M. H., Adcock, I. M., Bel, E. H. D., Braunstahl, G. -J., Ten Brinke, A., Busby, J., Canonica, G. W., Cao, H., Chung, K. F., Csoma, Z., Dahlen, B., Davin, E., Hansen, S., Heffler, E., Horvath, I., Korn, S., Kots, M., Kuna, P., Kwon, N., Louis, R., Plaza, V., Porsbjerg, C., Ramos-Barbon, D., Richards, L. B., Skrgat, S., Sont, J. K., Vijverberg, S. J. H., Weersink, E. J. M., Yasinska, V., Wagers, S. S., Djukanovic, R., Maitland-van der Zee, A. H., Nucera, Eleonora, Nucera E (ORCID:0000-0002-0565-7680), van Bragt, J. J. M. H., Adcock, I. M., Bel, E. H. D., Braunstahl, G. -J., Ten Brinke, A., Busby, J., Canonica, G. W., Cao, H., Chung, K. F., Csoma, Z., Dahlen, B., Davin, E., Hansen, S., Heffler, E., Horvath, I., Korn, S., Kots, M., Kuna, P., Kwon, N., Louis, R., Plaza, V., Porsbjerg, C., Ramos-Barbon, D., Richards, L. B., Skrgat, S., Sont, J. K., Vijverberg, S. J. H., Weersink, E. J. M., Yasinska, V., Wagers, S. S., Djukanovic, R., Maitland-van der Zee, A. H., Nucera, Eleonora, and Nucera E (ORCID:0000-0002-0565-7680)

Abstract

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m-2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day-1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day-1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Published
2020

20. Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma

Author

Onderzoek Longziekten, MS MDL 1, Longziekten, Infection & Immunity, de Nijs, S B, Krop, E J M, Portengen, L, Rijssenbeek-Nouwens, L H, de Vries, D, Weersink, E J M, Heijerman, H G M, Heederik, D J J, Lammers, J W J, Onderzoek Longziekten, MS MDL 1, Longziekten, Infection & Immunity, de Nijs, S B, Krop, E J M, Portengen, L, Rijssenbeek-Nouwens, L H, de Vries, D, Weersink, E J M, Heijerman, H G M, Heederik, D J J, and Lammers, J W J

Published
2020

22. Three phenotypes of adult-onset asthma

Author

Amelink, M., de Nijs, S. B., de Groot, J. C., van Tilburg, P. M. B., van Spiegel, P. I., Krouwels, F. H., Lutter, R., Zwinderman, A. H., Weersink, E. J. M., ten Brinke, A., Sterk, P. J., and Bel, E. H.

Published
2013
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27. A case-control study of the relation between plasma selenium and asthma in European populations: a GA2LEN project

Author

Burney, P., Potts, J., Makowska, J., Kowalski, M., Phillips, J., Gnatiuc, L., Shaheen, S., Joos, G., Van Cauwenberge, P., van Zele, T., Verbruggen, K., van Durme, Y., Derudder, I., Wohrl, S., Godnic-Cvar, J., Salameh, B., Skadhauge, L., Thomsen, G., Zuberbier, T., Bergmann, K. C., Heinzerling, L., Renz, H., Al-Fakhri, N., Kosche, B., Hildenberg, A., Papadopoulos, N. G., Xepapadaki, P., Zannikos, K., Gjomarkaj, M., Bruno, A., Pace, E., Bonini, S., Bresciani, M., Gramiccioni, C., Fokkens, W., Weersink, E. J. M., Carlsen, K.-H., Bakkeheim, E., Loureiro, C., Villanueva, C. M., Sanjuas, C., Zock, J.-P., Lundback, B., and Janson, C.

Published
2008

28. Abstracts of papers and posters

Author

Anthonio, R. L., Willemsen, A. T. M., Visser, T., van Waarde, A., Elzinga, P., Weemaes, A., Meeder, J. G., Pruim, J., Visser, G., Blanksma, P. K., Vaalburg, W., Bloemen, P. G. M., Henricks, P. A. J., van Bloois, L., van den Tweel, M. C., Nijkamp, F. P., Crommelin, D. J. A., Storm, G., de Boer, A. H., Winter, H. M. I., Lerk, C. F., de Boer, J., Meurs, H., Bottone, A. E., Koopal, M., Visser, J. C., Zaagsma, J., Borger P., Kauffman H. F., Vijgen J. L. J., Postma D. S., Vellenga E., Buckley, Theresa L., Buikema, H., van Gilst, W. H., van Veldhuisen, D. J., de Smet, B. J. G. L., Scholtens, E., Lie, K. I., Wesseling, H., Cheung, P. K., Dijkhuis, F. W. D., Bakker, W. W., Visser, J., Coopes, R. P., Benthem, L., van der Leest, J., Roffel, A. F., Coppes, R. P., Zeilstra, L. J. W., Vissink, A., Konings, A. W. T., Dijkstra, M., Veld, G. In't, Müller, M., van den Berg, G. J., Kuipers, F., Vonk, R. J., Elsinga, P. H., Franssen, E. J. F., van der Graaf, W. T. A., de Vries, E. G. E., Visser, G. M., Vos, M. G., Braker, A. H., Visser, T. J., Visser, G. M., Engels, F., van Houwelingen, A. H., van de Velde, M. J., Gansevoort, R. T., Sluiter, W. J., Hemmelder, M. H., de Zeeuw, D., de Jong, P. E., Gelissen, H. P. M. M., Henning, R. H., Epema, A. H., van Eekeren, J., Hennis, P. J., Den Hertog, A., de Graaf, S. S. N., Kellie, S. J., Bloemhof, H., Johnston, I., Besser, M., Chaseling, R. W., Ouvrier, R. A., Uqes, D. R. A., De Haan, A., Geerligs, H. J., Huchshorn, J. P., Van Scharenburg, G. J. M., Wilschut, J., Haas, M., Kluppel, C. A., Meijer, D. K. F., Moolenaar, F., Heerdink, Eibert R., Leufkens, Hubert G., Herings, Ron M. C., Stricker, Bruno H. Ch., Bakker, Albert, Heesen W. F., Beltman F. W., Smit A. J., May J. F., Meyboom-de Jong B., Duin, M., van den Akker, J., te Pas, M. F. W., van Popta, J. P., Nelemans, S. A., van der Linde, H. J., de Boer, A., Sturmans, F., Hessel, E. M., Van Oosterhout, A. J. M., Hofstra, C. L., Garssen, J., van Loveren, H., Savelkoul, H. F. J., Hoekstra, Y., Weersink, E. J. M., de Jong, J. W., van der Belt-Gritter, B., Jonkman, Lisa M., Kemner, Chantal, Koelega, Harry S., van Engeland, Herman, Verbaten, Marinus N., Kalivianakis, M., Zijlstra, I., Verkade, H. J., Elzinga, H., Stellaard, F., Kamps, J. A. A. M., Swart, P. J., Morselt, H., Scherphof, G. L., Kenemans, J. L., Lorist, M. M., Koopen, N. R., Kraneveld, A. D., Koster, A. Si., Kuipers, M. E., Groenink, M., Huisman, H., Schuitemaker, H., Lau, H. S., van den Broek, I. J. P. M., van Dijk, A., Oostinga, J., Porsius, A. J., Lin, Y., Havinga, R., Meijer, R. J., van der Mark, Th. W., Koëter, G. H., Michels, A. A., Nguyen, V. -T., Bensaude, O., Kampinga, H. H., Mohede, Inge C. M., Van Antoon J. M., Molema, Grietje, Edgington, Thomas S., Thorpe, Philip E., Olinga, P., Sandker, G. W., Slooff, M. J. H., Merema, M. T., Groothuis, G. M. M., Hofman, G., Van Ark, I., Paulussen, J. J. C., Fischer, M. J. E., de Mol, N. J., Janssen, L. H. M., Peters, E. Th. J., van der Werf, G. Th., Haaijer-Ruskamp, F. M., Pinto, Yigal M., Rooks, Gerrit, Grandjean, Jean G., Ebels, Tjark, Schunkert, H., Redegeld, Frank A., Garssen, Johan, van Loveren, Henk, Rigter, Irma M., van Groningen, Muck, Boks, Gertjan J., Tollenaere, Jan P., Trollope, Keith I., Vinter, Jeremy G., Hashjin, Gudarz Sadeghi, Folkerts, Gert, van de Loo, Peet G. F., Santing, R. E., Olymulder, C. G., van der Molen, K., Pasman, Y., Scheerens, Heleen, Van Loveren, Henk, Seppenwoolde-Waasdorp, T. J. A., de Boer, P., Van Engelen, H. M. J., Thijssen, J. H. H., Maes, R. A. A., Smit, J., Smit, J. W., Steen, H., Steurs, M. H., Kuks, P. F. M., Leusink, J. A., Szabó, Balázs M., Crijns, Harry J. G. M., Wiesfeld, Ans C. P., Talsma, H., Borchert, J. C. H., van Steenbergen, M. J., Hennink, W. E., Teeuw, K. B., Cromheecke, H., Schreudering, A., Teisman, B. C. H., Maselbas, W., Wolters-Keulemans, G. T. P., Tieleman, R. G., de Langen, C. D. J., Bel, K., Crijns, H. J. G. M., Grandjean, J., Wijffels, M., Klimp, A. H., van de Meer, P. F., Allessie, M. A., van Patot, H. A. Tissot, de Jongh, B. M., Tuininga, Y. S., Brouwer, J., Haaksma, J., Man in't Veld, A. J., Blomjous, F. J., Vingerhoeds, M. H., Belliot, S. O., Haisma, H. J., Visscher, C. A., Huisman, R. M., Navis, G. J., de Vlieger, J. F., van den Wijngaard, P., Wilting, J., van Heuven-Nolsen, D., Voors, A. A., van Brussel, B. L., Plokker, H. W. M., Van Waardenburg R. C. A. M., Meijer, Prins J., De Vries, C., Mulder N. H., Wierenga, P. K., Wilschut J., Schoen P., and Bron R.

Published
1994
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29. Inhaled fluticasone

Author

WEERSINK, E J M, MEIJER, R J, KERSTJENS, H A M, and POSTMA, D S

Published
2000

36. 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

39. 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

42. Inhaled fluticasone

Author

POLOSA, R., WEERSINK, E, MEIJER, R, KERSTJENS, H, and POSTMA, D

Subjects
Pulmonary and Respiratory Medicine, Letters to the Editor
Published
2000

43. The relation between paracetamol use and asthma : a GA2LEN European case-control study

Author

Shaheen, S., Potts, J., Gnatiuc, L., Makowska, J., Kowalski, M. L., Joos, G., van Zele, T., van Durme, Y., De Rudder, I., Wöhrl, S., Godnic-Cvar, J., Skadhauge, L., Thomsen, G., Zuberbier, T., Bergmann, K. C., Heinzerling, L., Gjomarkaj, M., Bruno, A., Pace, E., Bonini, S., Fokkens, W., Weersink, E. J. M., Loureiro, C., Todo-Bom, A., Villanueva, C. M., Sanjuas, C., Zock, J-P., Janson, Christer, Burney, P., Shaheen, S., Potts, J., Gnatiuc, L., Makowska, J., Kowalski, M. L., Joos, G., van Zele, T., van Durme, Y., De Rudder, I., Wöhrl, S., Godnic-Cvar, J., Skadhauge, L., Thomsen, G., Zuberbier, T., Bergmann, K. C., Heinzerling, L., Gjomarkaj, M., Bruno, A., Pace, E., Bonini, S., Fokkens, W., Weersink, E. J. M., Loureiro, C., Todo-Bom, A., Villanueva, C. M., Sanjuas, C., Zock, J-P., Janson, Christer, and Burney, P.

Abstract

Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking. As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA(2)LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (20-45 yrs) and place of residence. In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma. These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations.

Published
2008
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44. Open longbiopsie bij ernstig zieke patiënten met onbegrepen longinfiltraten

Author

Weersink, E. J., van den Elshout, F. J., van Leusen, R., Bosch, F. H., and Other departments

Subjects
respiratory system, respiratory tract diseases
Abstract

In three patients, a man aged 34 with aids, a woman aged 67 with recurrent major dyspnoea and a woman aged 73 with chronic lymphatic leukaemia, examination revealed progressive dyspnoea while the chest X-rays showed infiltrative lesions in both lungs. In view of the inadequate response to the treatment administered, an open lung biopsy was performed, following which the diagnosis could be made. Adequate treatment was then started and followed by clinical recovery. It is not clear if open lung biopsy carries higher risks of mortality and morbidity than biopsy by means of flexible bronchoscopy. Open lung biopsy more often leads to a classifying diagnosis. For collection of endobronchial or transbronchial biopsy samples in ununderstood diffuse interstitial lung diseases, flexible bronchoscopy is the method of first choice. Open lung biopsy is a justified supplementary examination, at any rate in severely ill, immunocompromised patients who require adequate therapy without delay

Published
1998

45. Risk Factors Of Asthma Onset In Adulthood

Author

de Nijs, Selma B., primary, Amelink, M, additional, vd Berg, B., additional, Krouwels, F.H., additional, Sterk, Peter J., additional, Weersink, E. J., additional, and Bel, Elisabeth H.D., additional

Published
2012
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