Abstract
Rationale Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids (PDO) with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC).
Methods We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed effect models and multivariable logistic regression to estimate the association of FIS with long-term FEV1pp decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC.
Results FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95%CI: 0.11%–0.54%; p=0.004) per 1000-points change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR: 0.18, 95%CI: 0.07–0.46, p<0.001), CF-related liver disease (adjusted OR: 0.18, 95%CI: 0.06–0.54, p=0.002) and diabetes (adjusted OR: 0.34, 95%CI: 0.12–0.97, p=0.044). These associations were absent for SCC.
Conclusion This study exemplifies the prognostic value of a PDO-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Muilwijk has nothing to disclose.
Conflict of interest: Dr. de Poel has nothing to disclose.
Conflict of interest: Dr. van Mourik reports financial compensation (money to instituation) from Vertex for participation in a webinar, outside the submitted work.
Conflict of interest: Dr. Suen has nothing to disclose.
Conflict of interest: Dr. Vonk has nothing to disclose.
Conflict of interest: Dr. Brunsveld has nothing to disclose.
Conflict of interest: Dr. Kruisselbrink has nothing to disclose.
Conflict of interest: Dr. Oppelaar has nothing to disclose.
Conflict of interest: Dr. Hagemeijer has nothing to disclose.
Conflict of interest: Dr. Berkers has nothing to disclose.
Conflict of interest: Dr. de Winter-de Groot has nothing to disclose.
Conflict of interest: Dr. Michel has nothing to disclose.
Conflict of interest: Mr. Jans has nothing to disclose.
Conflict of interest: Dr. van Panhuis has nothing to disclose.
Conflict of interest: Dr. van der Eerden has nothing to disclose.
Conflict of interest: Dr. van der Meer has nothing to disclose.
Conflict of interest: Dr. Roukema has nothing to disclose.
Conflict of interest: Dr. Dompeling has nothing to disclose.
Conflict of interest: Dr. Weersink has nothing to disclose.
Conflict of interest: Dr. Koppelman reports grants from Lung Foundation of the Netherlands, Vertex Pharmaceuticals, UBBO EMMIUS foundation, GSK, TEVA the Netherlands, TETRI Foundation, European Union (H2020) , outside the submitted work; and he has participated in advisory boards meetings to GSK and PURE-IMS outside the submitted work (Money to institution).
Conflict of interest: Dr. Vries has nothing to disclose.
Conflict of interest: Dr. Zomer-van Ommen has nothing to disclose.
Conflict of interest: Dr. Eijkemans has nothing to disclose.
Conflict of interest: Dr. van der Ent reports grants from GSK, grants from Nutricia, grants from TEVA, grants from Gilead, grants from Vertex, grants from ProQR, grants from Proteostasis, grants from Galapagos NV, grants from Eloxx, outside the submitted work; In addition, Dr. van der Ent has a patent 10006904 with royalties paid.
Conflict of interest: Dr. Beekman reports grants from Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries and Galapagos , outside the submitted work; In addition, Dr. Beekman has a patent patent(s) related to the FIS-assay with royalties paid to J.M. Beekman and C.K. van der Ent.
Conflict of interest: Dr. de Winter-de Groot has nothing to disclose.
Conflict of interest: Dr. Michel has nothing to disclose.
- Received February 17, 2021.
- Accepted December 23, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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