Beyond spirometryꓽ additional criteria to establish CFTR modulator efficacy in people with Cystic Fibrosis

This thesis shows how CFTR functional testing can help in estimating the effects of a certain CFTR mutation and the effects of CFTR modulators on an individual basis, and how additional clinical follow up parameters apart from lung function can help evaluations of treatment effects in the clinical setting. In chapter two we focus on 5T, a mutation of varying clinical consequence. We used NPD, sweat test and clinical parameters to evaluate the severity of consequences of the mutation. We show that it is important in the evaluation of individuals with 5T to not only include TG repeats in the genetic evaluation, but also to make use of multiple clinical tools and signs in the evaluation of these patients, as expression of clinical problems varies greatly among patients with this splicing mutation. In chapter three we explore how Ussing measurements of treatment effect in cultured nasal cells of individual patients correlates to clinical effects in these patients. As the in vitro and in vivo measurements are correlated, it could be a useful option for in vivo prediction of in vivo treatment effects in the future, as a patient-friendly and feasible addition to rectal organoids. Chapter four provides illustration of how various methods of CFTR functional measurement (FIS in rectal organoids and Ussing in nasal cells) as well as follow up modalities were applied in the case of an individual pwCF who was found eligible for treatment with ELE/TEZ/IVA based on CFTR functional measurements and had a favorable response. In chapter five we studied a group of F508del homozygous patients starting LUM/IVA while their ppFEV1 was 90 or higher. While their lung function hardly changed, we did see changes in BMI, sweat test, exacerbation rate and quality of life scores, suggesting that relevant effects also applied to this subset of CF patients and that it is important to focus on more than FEV1 alone during follow up after start of modulating therapy. Chapter six provides a closer look at another follow up parameter used with CFTR modulators: sweat chloride testing. We described the decrease in sweat chloride levels in F508del homozygous patients starting LUM/IVA. We found that age and weight did not have a relevant influence on the magnitude of sweat chloride response, however sex did; the response in females was larger than in males. Chapter seven evaluates Brody scores calculated from CT scans of F508del/S1251N patients before start of ivacaftor treatment, and correlation of this score to the lung function response on treatment. We found that patients with a higher Brody score had more improvement in lung function on therapy, suggesting in this group with relatively well-preserved lungs, that the patients with most limited lung damage had less room for improvement of their lung function upon start of treatment. Chapter eight describes a group of CF patients with severe lung damage who started ELE/TEZ/IVA on compassionate use basis, and the treatments effects on the short and longer term. A drastic response on CT scan was seen in these patients with reduction of mucus plugging and peribronchial thickening, as well as a moderate response in FEV1 and good response in BMI and exacerbation rate. Overall this group of patients respond less in lung function, but on other outcomes just as well as CF patients starting treatment with moderately affected lungs. Chapter nine provides an overview of relevant questions that people with CF may have before starting highly effective CFTR modulating therapy. These questions are addressed one by one with the available evidence at that time, to provide a tool for clinicians discussing commencement of therapy with their patient.

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