5.482 Journal of Cystic Fibrosis The Official Journal of the European Cystic Fibrosis Society www.ECFS.eu Volume 21 Issue 1 January 2022 ISSN 1569-1993 In this Issue: Cardiovascular complications in cystic fibrosis: A review of the literature June 2022 Volume 21, S 1 Abstracts of the 45th European Cystic Fibrosis Conference – 2022 47 European Cystic Fibrosis Conference 5–8 June 2024 June 2024 Supplement: Volume 23, Suppl. 1 527
Editorial Board Editor-in-Chief: Patrick Flume, Medical University of South Carolina, Charleston, South Carolina, USA Deputy Editors: Carlo Castellani, IRCCS Instituto Giannina Gaslini, Cystic Fibrosis Centre, Genoa, Italy Jane Davies, National Heart & Lung Institute, Imperial College London and Royal Brompton and Harefield NHS Foundation Trust, London, UK Editorial Board: Scott Blackman, USA Pierre-Régis Burgel, France Scott Donaldson, USA Aleksander Edelman, France Pascale Fanen, France Carlos Farinha, Portugal Sonya Heltshe, USA Niels Høiby, Denmark Dominic Hughes, UK Andrea Kelly, USA Susannah King, Australia Paul McCray, USA Marianne Muhlebach, USA KeithOoi, Australia Nicoletta Pedemonte, Italy Gerald Pier, USA Felix Ratjen, Canada Kristin A. Riekert, USA Dorota Sands, Poland Rhonda Szczesniak, USA Anne Stephenson, Canada Cliff Taggart, UK Jennifer Taylor-Cousar, USA DaanTouw, The Netherlands Michael Tunney, N. Ireland Donald Van Devanter, USA Valerie Waters, Canada Michael Wilschanski, Israel Jeffrey Wine, USA Editor In Chief, Cystic Fibrosis Research News: Harry Heijerman, University Medical Center Utrecht, The Netherlands Previous Editors-in-Chief: Harry Heijerman, University Medical Center Utrecht, The Netherlands Gerd Döring, University of Tübingen, Tübingen, Germany ScottBell, The Prince Charles Hospital, Queensland, Australia Amsterdam — Boston — London — New York — Oxford — Paris — Philadelphia — San Diego — St. Louis — Tokyo
Volume 21 (2022) Publication of this Abstract Book was supported by the European Cystic Fibrosis Society. Abstracts of the 47th European Cystic Fibrosis Conference 5–8 June 2024 Glasgow, United Kingdom Volume 23, Supplement 1 (2024)
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Contents, Volume 17 (2018) Supplement Abstracts of the 40th European Cystic Fibrosis Conference Seville, Spain, 7–10 June 2017 Workshops S1 Workshop 1. Old and new thoughts on antibiotics ............................................................................ S1 Workshop 2. Nutrition: from daily practice to enzymes for the future ............................................ S3 Workshop 3. New therapies targeting the airway surface ................................................................. S4 Workshop 4. New insights from inflammation and immunology...................................................... S6 Workshop 5. Anxiety and depression: a family affair ........................................................................ S7 Workshop 6. CFTR dysfunction: what happens where? ..................................................................... S9 Workshop 7. Microbiome analysis in CF: what’s new in lung and gut?............................................ S11 Workshop 8. CT and MRI, where are we? Ready yet for the clinics? ................................................ S12 Workshop 9. Exercise and correlations with other outcomes............................................................ S14 Workshop 10. The impact of CF: high mountains – deep valleys ...................................................... S16 Workshop 11. Newborn screening and diagnostic advances .............................................................. S17 Workshop 12. Bone health, glucose metabolism and CFRD ............................................................... S19 Workshop 13. Rescuing CFTR: new developments ............................................................................. S20 Workshop 14. Basic pathogenesis: Pseudomonas, microbiota interaction and viruses...................... S22 Workshop 15. New lung function methods to monitor disease and treatment ................................ S24 Workshop 16. Understanding and teaching, a knowledge network................................................... S26 Workshop 17. CF related liver disease and pancreatic insufficiency: can we do better? .................. S28 Workshop 18. CFTR: Functional tests for therapeutic interventions.................................................. S29 Workshop 20. Evolving epidemiology and risk factors for lung infection......................................... S31 Workshop 21. How to personalise chest physiotherapy? ................................................................... S32 Workshop 23. Insights from registries and cohorts............................................................................ S34 ePS01. Screening and Diagnosis ........................................................................................................... S36 ePS02. The CF team in development ................................................................................................... S39 ePS03. New treatments ........................................................................................................................ S41 ePS04. Multi-tasking physiotherapists: managing hygiene, pain, exercise, . . . .................................. S43 1 23 2024 Abstracts of the 47th European Cystic Fibrosis Conference – 2024 5–8 June 2024 Glasgow, United Kingdom Workshops ���������������������������������������������������������������������������������������������������������������������������������������������������������������������� S1 WS01 – Measuring impact in cystic fibrosis treatment....................................................................................................S1 WS02 – Seeing the bigger picture: regional and genetic drivers of health inequality............................................S3 WS03 – Modernizing psychosocial assessment and care within the CFTR Modulator landscape......................S5 WS04 – Exploring latest breakthroughs in gastroenterology and cystic fibrosis liver disease in cystic fibrosis.............................................................................................................................................................S7 WS05 – Novel approaches and outcomes in CFTR therapeutics.....................................................................................S9 WS06 – Where are we with new therapeutic approaches?...........................................................................................S11 WS07 – Ageing in cystic fibrosis: diabetes, cardiovascular risk and outcomes of pregnancy............................S12 WS08 – Optimising physiotherapy practice – insights into current management................................................S14 WS09 – New insights into cystic fibrosis microbiology..................................................................................................S16 WS10 – Evaluating the outcomes of novel CFTR-targeted therapies..........................................................................S18 WS11 – Diagnosing cystic fibrosis and screening for complications.........................................................................S20 WS12 – Innovations in nutrition and dietetics for cystic fibrosis management.....................................................S22 WS13 – Inflammation and infection discovery science.................................................................................................S23 WS14 – Understanding the role of CFTR and the effects of CFTR-modulating drugs on tissue function: from lungs to bones and beyond........................................................................................................S25 WS15 – Expanding the knowledge on CFTR modulators...............................................................................................S27 WS16 – Deep dive into difficult infections.........................................................................................................................S29 WS17 – Measuring disease activity in cystic fibrosis lung disease..............................................................................S31 ePoster Sessions �����������������������������������������������������������������������������������������������������������������������������������������������������������S34 ePoster Session 1 – Advances in exercise interventions in the management of cystic fibrosis.........................S34 ePoster Session 2 – Managing complexity of cystic fibrosis challenges...................................................................S37 ePoster Session 3 – Managing cystic fibrosis pathogens................................................................................................S40 ePoster Session 4 – How to manage lung disease?..........................................................................................................S43 ePoster Session 5 – New insights in cystic fibrosis liver disease and optimising nutritional care in cystic fibrosis.....................................................................................................................................S47 ePoster Session 6 – Broad insights from registries and observational studies.......................................................S50 ePoster Session 7 – Inflammation and pulmonary outcomes in cystic fibrosis.....................................................S53
This abstract book has been produced electronically by Elsevier B.V., and is also available on USB. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier or the European Cystic Fibrosis Society for any injury and/ or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Although all advertising material is expected to conform to ethical and medical standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. ePoster Session 8 – Evolution of physiotherapy in the post ETI era...........................................................................S56 ePoster Session 9 – Understanding CFTR function and developing new treatment targets...............................S60 ePoster Session 10 – Modulation of CFTR: from bench to bedside.............................................................................S63 Poster Sessions �������������������������������������������������������������������������������������������������������������������������������������������������������������S66 Diagnosis/Screening. ................................................................................................................................................................. S66 Genetics..........................................................................................................................................................................................S74 Cell Biology/Physiology............................................................................................................................................................S78 Clinical Trials/New Therapies.................................................................................................................................................S80 Pulmonology/Inflammation/Immunology......................................................................................................................... S98 Epidemiology/Registry.............................................................................................................................................................S116 Microbiology/Antibiotics. ...................................................................................................................................................... S129 Gastroenterology/Liver Disease/Endocrinology/Metabolic Complications............................................................S150 Nutrition/Growth...................................................................................................................................................................... S167 Nursing/Psychosocial Issues..................................................................................................................................................S181 Physiotherapy............................................................................................................................................................................ S203 Author Index ������������������������������������������������������������������������������������������������������������������������������������������������������������ S215
Workshops WS01–Measuring impact in cystic fibrosis treatment WS01.01 Clinical validation of automated vs manual PRAGMA-CF CT score in children with CF P. Raut1, Y. Chen1, E. Andrinopoulou2, C. Wainwright3, H. Tiddens1, D. Caudri1. 1Erasmus Medical Center, Pediatric Pulmonology and Radiology & Nuclear Medicine, Rotterdam, Netherlands; 2Erasmus Medical Center, Department of Biostatistics and Department of Epidemiology, Rotterdam, Netherlands; 3Child Health Research Centre, University of Queensland, South Brisbane, Queensland, Australia Introduction: The PRAGMA-CF is a well-validated manual chest CT scoring system to quantify relevant components of structural airway damage in CF. We aim to validate a newly developed automated PRAGMA-CF scoring algorithm, by comparing it to the manual scores. Material and methods: Data from the Australian CF-FAB study were used, including 120 children aged 9–18 years with in total 225 inspiratory CT’s. Manual PRAGMA score was performed by an experienced observer, including 4 subscores %Bronchiectasis (%BE), %Mucus plugging (%MP), % Airway wall thickening (%AWT), %Atelectasis (%AT), and composite % Disease (%DIS = %BE+%MP+%AWT). Scans were then analyzed with the AIbased automated PRAGMA-CF algorithm, part of the LungQTM platform, identifying %BE, %AWT and %DIS. %MP and %AT are not yet available in the automated score. The manual score is performed on 10 randomly selected CT slices. The automated analysis can mimic this, or analyze all available slices. Results were compared using descriptive statistics, scatterplots and Pearson correlation coefficients. Results: 185 scans were analyzed with both methods. Manual scores ranged %BE 0–20%, %DIS0–35%, and %AWT 0–15%, while for the automated scores this was 0–10% (%BE), 0–15% (%DIS) and 0–10% (%AWT). Correlation was very high for %BE (0.86 (CI95%: 0.82–0.90, p < 0.001) and %DIS (0.86 (CI95%: 0.82–0.89, p < 0.001), but weak for %AWT (0.30 (CI95%: 0.16–0.43, p < 0.001). The manual score estimated %BE and %DIS higher than the automated score, with a scaling factor of about 2. No differences were found comparing analysis in 10 selected slices vs. all available slices in the automated analysis. Conclusion: The newly developed automated PRAGMA-CF score has an excellent correlation with %BE and %DIS of the manual PRAGMA-CF, but outcomes show systematic differences with the manual PRAGMA scores. Our results show that the automated PRAGMA-CF has great potential to score structural airway damage in larger cohorts of CF patients. WS01.02 Dynamic chest radiography in people with cystic fibrosis – a new method of measuring simple lung function D. Green1,2, T. Fitzmaurice2,1, F. Frost2,1, D. Nazareth1,2, M. Walshaw1,2. 1Liverpool Heart and Chest Hospital, Respiratory, Liverpool, United Kingdom; 2University of Liverpool, Liverpool, United Kingdom Objectives: Traditional spirometry involves forced maneuvers that are unphysiological, and the use of a mouthpiece alters normal breathing. Dynamic Chest radiography (DCR) is a novel cinematic imaging technique that visualizes the thorax in motion over 10–20 seconds without using forced maneuvers or a mouthpiece, with a radiation dose similar to a standard chest film. We wished to investigate the relationship between DCR and spirometry. Methods: Using DCR, a semi-automated calculation of projected lung area (PLA) throughout inspiration and expiration was made, where PLA was recorded at its maximum during inspiration (PLAmax) and minimum during expiration (PLAmin). Percentage change between these points was also recorded. We compared this with traditional spirometry recorded within 24 hours of DCR acquisition in 20 adult people with cystic fibrosis (pwCF). Results: The mean (SD) FEV1was 70.9 (23.4) % predicted. Mean (SD) PLAmax andPLAminwas 44164.2 (7873) mm2and 32577.4 (8355) mm2respectively. The mean (SD) percentage change in PLA between PLAmax andPLAminwas 25.92% (9.1). There was a significant correlation between lung function in the form of FEV1 and percentage change of PLAmax to PLAmin (r=0.69, p < 0.0001) and also FEV1 and expiratory PLAmin (r=−0.44, p-0.0006). There was however no significant correlation between FEV1and inspiratory PLAmax (r=−0.13, p = 0.33). Conclusion: DCR metrics correlate with simple lung function in pwCF. DCRs are quick to perform, impart a low radiation dose, and may be better tolerated by pwCF than conventional spirometry. Given the unphysiological nature of forced maneuvers in the measurement of lung function, we are further exploring the utility of DCR in pwCF. WS01.03 Effects of elexacaftor/tezacaftor/ivacaftor in lung transplant recipients with cystic fibrosis: the Dutch national KOALA study J.P. van Gemert1, B. Luijk2, M.E. Hellemons3, K.A. Visser1, C. Hansen4, R. van der Meer5, T. Gan1, H. van der Vaart1, O.W. Akkerman1, W.N. Steenhuis1, M. Verkleij6, H.G.M. Heijerman2, E.A.M. Verschuuren1. 1University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, Netherlands; 2University Medical Center Utrecht, Department of Respiratory Medicine, Utrecht, Netherlands; 3Erasmus University, Department of Respiratory Diseases, Rotterdam, Netherlands; 4University Medical Center Groningen, Department of Clinical Pharmacy & Pharmacology, Groningen, Netherlands; 5Haga Teaching Hospital, Department of Pulmonology, The Hague, Netherlands; 6Amsterdam UMC location University of Amsterdam, Child and Adolescent Psychiatry & Psychosocial Care, Amsterdam, Netherlands Objectives: So far, the administration of Elexacaftor/Tezacaftor/Ivacaftor (ETI) to people with Cystic Fibrosis (PwCF) after lung transplantation (LTx) has been restrained due to uncertainties regarding efficacy, concerns about drug interactions, and costs. Given the multisystemic nature of CF and the persistence of extrapulmonary symptoms post-LTx, this study aims to investigate the relevant benefits of ETI for PwCF after LTx. Methods: Between 1-11-2022 and 1-11-2023 ETI was offered to eligible PwCF after LTx with at least one F508del mutation in 3 Dutch LTx centers. PwCF were considered eligible if they had either underweight (BMI ≤ 19 kg/m²), chronic sinus disease, poor control of CF-related diabetes, gastrointestinal (GI) manifestations or chronic lung allograft dysfunction. BMI, HbA1c, SNOT-22 score, GI Symptom Tracker, CF QuestionnaireRevised (CFQ-R), FEV1, renal function, changes in calcineurin inhibitor (CNI) doses and levels were compared between baseline and 3 months use of ETI. Results: Fifty-five PwCF after LTx with a median age of 42 (IQR 34–49), 31 male (62%), median 11 years after LTx, were included. Five (9%) were excluded because of discontinuation of ETI due to side effects. Three month Journal of Cystic Fibrosis 23S1 (2024) S1–S33
follow-up was completed by 50 PwCF after LTx and showed a decrease in SNOT-22 score (p< 0.001) and GI symptoms (all 4 items, p< 0.05) and an increase in BMI (p= 0.012) and CFQ-R (6 out of 12 items, p< 0.05). There was no effect on HbA1c (p= 0.312) and FEV1 (p= 0.076). A decline in GGT (p= 0.023), but no change on other liver tests was found. Median CNI daily dose was reduced from 6 mg to 4 mg (p< 0.001), with stable CNI trough levels. Renal function declined (p= 0.01) from EGFR 68.0 (IQR 47.8–85.25) to 62.5 ml/min 1.73 m² (IQR 42.8–78.5). Conclusion: ETI is beneficial in 91% of PwCF after LTx, with favourable effects on chronic sinus disease, GI symptoms, BMI and quality of life. However, side effects may occur and careful monitoring of renal function is recommended. WS01.04 Real-world outcomes in people with cystic fibrosis (pwCF) treated with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) with up to three years of follow-up J.K. Bower1, C.-Y. Chang1, G. Sahota1, A. Chin1, N. Ahluwalia1, H. Zheng1, T.G. Weinstock1, J. Ostrenga2, N. Regenfuß3, L. Naehrlich4. 1Vertex Pharmaceuticals Incorporated, Boston, United States; 2Cystic Fibrosis Foundation, Boston, United States; 3University Medical Center Mainz, Interdisciplinary Center for Clinical Trials (IZKS), Mainz, Germany; 4JustusLiebig-University Giessen, Department of Pediatrics, Giessen, Germany Objective: To understand long-term effects of real-world ELX/TEZ/IVA use, a five-year post-authorisation safety study is ongoing. We report updated results from the third annual interim analysis (IA). Methods: Data through 2022 from the US CF Foundation Patient Registry and German CF Registry for pwCF initiating ELX/TEZ/IVA from 2019–20 in the US and 2020–21 in Germany were included. Posttreatment patterns in pulmonary exacerbations (PEx), hospitalisations, percent predicted FEV1 (ppFEV1), and bacterial culture data were compared to five years (yrs) pretreatment. Death and lung transplant rates were assessed relative to 2019 data for pwCF aged≥12 yrs with one or more F508del allele. Results: Overall, 16,109 pwCF in the US and 2,861 pwCF in Germany were included; 74% of US cohort (n = 11,963) and 51% of German cohort (n = 1,465) had more than two yrs posttreatment data. PEx frequency decreased and remained lower than baseline; cumulative mean PEx/ person/yr posttreatment was 76% lower relative to yr before treatment initiation in US and 70% lower in Germany. Any-cause hospitalisation results were similar to PEx results. Mean ppFEV1 increased posttreatment and remained higher than baseline in year three (US: +8.2 percentage points [95% CI 8.0–8.4]; Germany: +10.2 percentage points [95% CI 9.7– 10.8]). Prevalence of pulmonary pathogens (e.g., Pseudomonas aeruginosa, Staphylococcus aureus) decreased posttreatment. In the US, death rate was 0.63%/yr (62% lower than 2019) and lung transplant rate was 0.15%/yr (86% lower than 2019). In Germany, death rate was 0.13%/yr (84% lower than 2019) and lung transplant rate was 0.04%/yr (96% lower than 2019). No new safety concerns were identified. Conclusion: This IA of the largest real-world cohorts of pwCF treated with ELX/TEZ/IVA shows the disease-modifying benefits of ELX/TEZ/IVA, including sustained improvements in survival, lung transplant rate, lung function, PEx and hospitalisation frequency, and prevalence of bacterial pathogens. WS01.05 Long-term real-world outcomes of CFTR modulation with ivacaftor in adult cystic fibrosis patients with the G551D mutation; 8 years single center real-world study H.I.S. Ibrahim1,2, K. Deasy1,2, M. McCarthy1, J. Dorgan1, C. Fleming1, C. Howlett1, K. Cronin1, E. O’Riordan 1, J. Mansfield1, S. Twohig1, T. Vagg1,2, D.M. Murphy1,2, B.J. Plant1,2. 1Cork Adult Cystic Fibrosis Centre, Cork University Hospital & University College Cork, Cork, Ireland; 2The HRB funded Clinical Research Facility, University College Cork, Cork, Ireland Clinical trials and real-world studies highlighted the benefits of ivacaftor in cystic fibrosis (CF) patients with G551D mutation. Data pertaining to the long-term effect of CFTR modulators beyond 5 years of treatment is limited. We conducted a one-time point data collection at 8 years of treatment with ivacaftor in 25 adult CF patients with G551D CFTR mutation. Clinical parameters (including percent of predicted forced expiratory volume in 1 second (ppFEV1), modified shuttle walk test, body mass index (BMI), exacerbations frequency), and sweat chloride were compared to baseline and 1 year of treatment. The mean age of our cohort was 30.5 years. The improvement in ppFEV1 of 10.79 percentage point (p < 0.0001) seen during the first year of treatment was followed by a significant decline at 8 years (mean of differences was −11.09% between 1 and 8 year of treatment, p = 0.0005). The improvement in the modified shuttle walk test of 68.43 meters (p = 0.021) seen during the first year of treatment was lost at 8 years of treatment. The significant reduction in sweat chloride during the first year of treatment (mean of difference −58.12 mmol/L, p < 0.0001) is sustained at 8 years (mean of difference −52.44 mmol/L compared to baseline, p < 0.0001). The mean BMI of our study cohort improved from a baseline of 20.28 to 21.76 at 1 year, to 22.7 at 8 years of treatment. The mean exacerbation frequency at 1 year of treatment dropped from 1 to 0.17 (p = 0.0048), but increased to 0.66 at 8 years (mean of difference was 0.49 between 8 year and 1 year, p = 0.038). In a cohort of adult CF patients, the initial improvements in ppFEV1 and walk test, and the reductions in IV antibiotics courses seen at 1 year of ivacaftor treatment were not sustained at 8 years, in spite of sustained restoration of CFTR function measured by sweat chloride. Understanding the factors influencing long term effectiveness of CFTR modulation is paramount to prolong the initial beneficial effects and improve survival in CF. WS01.06 Evaluating trends in cardiovascular events in people with cystic fibrosis before and after elexacaftor/tezacaftor/ivacaftor initiation – a retrospective review in federated electronic healthcare record A. Chan1,2, D. Green3,4, D. Nazareth3,4, G.Y. Lip2,5, D.Wat3,4, F. Frost3,4. 1Liverpool Heart and Chest Hospital, Pharmacy Department, Liverpool, United Kingdom; 2Liverpool Centre for Cardiovascular Science, Liverpool, United Kingdom; 3Liverpool Heart and Chest Hospital, Department of Respiratory Medicine, Liverpool, United Kingdom; 4University of Liverpool, Liverpool, United Kingdom; 5Liverpool Heart and Chest Hospital, Department of Cardiology, Liverpool, United Kingdom Background: As people with cystic fibrosis (pwCF) grow older, there is an increasing concern regarding long-term cardiovascular risk. However, little is known about the risk of cardiovascular disease in people receiving CFTR modulator therapy, i.e. elexacaftor/tezacaftor/ivacaftor (ETI). We therefore investigated the frequency of cardiovascular events in pwCF receiving ETI within TriNetX, a global federated healthcare data network with real-time access to anonymised international electronic healthcare records, and hypothesised the marked improvements in inflammation associated with ETI may result in reduced cardiovascular events. Methods: We investigated the incidence of major adverse cardiovascular events(MACE), including left-side heart failure and heart attacks; and atrial fibrillation (AF), that occurred annually between November 2016 and October 2019 (pre-ETI initiation) and between November 2019 and October 2023 (post-ETI initiation) of 4810 adult pwCF who are currently taking ETI on TriNetX. The data including demographic details, cardiovascular-related medications and individual cardiovascular-related diagnoses, were captured. Results: Overall MACE-AF was low in pwCF but annualised MACE-AF incidence increased over the study period, tripling in the post-ETI era compared to four years pre-ETI initiation (0.45% vs 1.54% respectively). pwCF diagnosed with hypertension increased to a similar degree (15 vs 49), as did ischaemic heart disease (10 vs 38). These increases were accompanied by an increase in people receiving cardiovascular medications. Discussion: Cardiac disease remains rare in CF but appeared to be increasing prior to ETI and has continued to increase after the initiation of ETI. Despite the profound anti-inflammatory effects of ETI use, we found no evidence of reduced MACE-AF after ETI initiation. Research should focus on identifying cardiovascular risk factors and enabling the implementation of suitable risk stratification measures. Workshops / Journal of Cystic Fibrosis 23S1 (2024) S1–S33 S2
WS02–Seeing the bigger picture: regional and genetic drivers of health inequality WS02.01 Health inequality in Europe in cystic fibrosis people I. Sermet-Gaudelus1, A.L. Orenti2, E. Hatziagorou3, E. Bakkeheim4, E. Kerem5, L. Nearhrlich6, ECFSPR Steering Group7. 1INSERM, Institut Necker Enfants Malades, Paris, France; 2Department of Clinical Sciences and Community Health, Laboratory of Medical Statistics, Biometry and Epidemiology“G.A. Maccacaro,” University of Milan;, European Cystic Fibrosis Society, Karup, Denmark, Milan, Italy; 3Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 4National Resource Centre for Cystic Fibrosis, Oslo University Hospital, Oslo, Norway; 5Department of Pediatrics and CF Center, Hebrew University Medical School, Hadassah Medical Center, Jerusalem, Israel; 6Department of Pediatrics, Justus-LiebigUniversity Giessen, Giessen, Germany; 7European Cystic Fibrosis Society, Karup, Denmark Objectives: Disparity in health delivery stands as a prominent challenge in European public health policy. While advancements in research and medical care have positively affected cystic fibrosis (CF) outcomes in higher-income countries, the situation remains troubling in lower-income European countries. We aimed to assess variations in survival and key disease indicators among people with CF (pwCF) homozygous for F508del based on the socioeconomic status of their country of residence in Europe in 2021, identify immediate determinants of geographic differences, and propose feasible interventions. Methods: We analysed 2021 data from 17,181 CF patients homozygous for F508del across 38 European countries in the European Cystic Fibrosis Society Patient Registry. Lung-transplanted patients were excluded. Our focus was on assessing survival and main CF disease indicators by Gross National Income (GNI) per capita, serving as a marker for economic differences within Europe. Results: 17,181 pwCF aged≤40 years were included. Of these, 12% lived in lower income countries (GNI≤17,000), 15% lived in middle income (17,000<GNI<40,000), 73% in higher income countries. In 2021, at all ages, pwCF living in lower income countries exhibited significantly lower median survival age, reduced ppFEV1, higher rates of chronicPseudomonas aeruginosa (Pa) colonization and a higher percentage of underweight individuals compared to their counterparts in middle and higher-income countries. Model simulations indicated that enhancing nutritional status and reducing Pa colonization increased survival by a mean of 15 years in lower-income countries. Conclusion: While socioeconomic status proves challenging to modify, reducing undernutrition and Pa colonization rates in lower-income countries significantly influence survival among CF patients. WS02.02 Worldwide prevalence of F508del and rareCFTRvariants responsive to elexacaftor/tezacaftor/ivacaftor P.-R. Burgel1, A. Orenti2, L. Cromwell3, A. Stephenson4,5, on behalf of the ECFS patient registry scientific committee and the CF Registry Global Collaboration. 1Université Paris-Cité and Assistance Publique Hôpitaux de Paris, National CF Reference Center, Paris Cedex 14, France; 2Università degli Studi di Milano, Department of Clinical Sciences and Community Health, Laboratory of Medical Statistics, Biometry and Epidemiology “G. A. Maccacaro,” Milano, Italy; 3Cystic Fibrosis Foundation Patient Registry, Bethesda, United States; 4St. Michael’s Hospital, Toronto, Canada; 5Cystic Fibrosis Canada, Toronto, Canada Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is approved in people with CF (pwCF) with at least one F508del variant. Additionally, invitrodata led the US Food and Drug Administration (FDA) to approve ETI for 177 rare CFTR variants. The French Compassionate Program identified 7 additional variants not belonging to the FDA list but responsive to ETI. Our objective was to examine the impact of expanding the label of ETI to rare CFTR variants on the number of eligible pwCF. Methods: Data were obtained from the ECFS patient registry (ECFSPR) and from National Registries in non-European Countries. PwCF were classified according to five mutually-exclusive categories: 1) At least one F508del 2) At least one of the 177 FDA-approved variants 3) At least one of the 7 variants identified in the French Compassionate Program 4) Two variants known to result in no CFTR protein 5) all other variant combinations. The first 3 groups were considered responsive to ETI, group 4 was non responsive and group 5 was undetermined responsiveness. Results: Data were obtained from 40 countries (n = 52367 pwCF) in the ECFSPR, US (n = 30870), Canada (n = 4187), Australia (n = 3546), Brazil (n = 3375) and South Africa (n = 480), totalling 94825 pwCF. Among them, 77218 (81.5%) had at least one F508del, 6014 (6.3%) at least one FDAapproved variants, and 2858 (3.0%) at least one of the 7 French Compassionate variants. Two variants resulting in no CFTR protein were found in 3327 (3.5%) and other variant combinations were found in 5408 (5.7%). PwCF with at least one F508del variant represented 30% to 95% in individual countries, and expanding the eligibility to non F508del variants resulted in an absolute increase that was greatest in countries with low F508del prevalence. Conclusion: Expanding the label of ETI to rare CFTR variants identified as ETI responsive based on in vitro and/or real-word data will reduce the % of pwCF not eligible to CFTR modulators <10%, with large variability between countries. WS02.03 Disease burden in people with cystic fibrosis according to CFTR genotype and eligibility to CFTR modulator therapy: a ECFS Patient Registry analysis I. Tomarelli1,2, A. Orenti3, P.-R. Burgel4,5,6, A. Gramegna1,2, F. Blasi1,2, ECFSPR Steering Group. 1Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Internal Medicine Dept, Respiratory Unit and Cystic Fibrosis Adult Centre, Milano, Italy; 2University of Milan, Dept Pathophisiology and Transplantation, Milan, Italy; 3University of Milan, Dept of Clinical Sciences and Community Health, Laboratory of Medical Statistics, Biometry and Epidemiology “G. A. Maccacaro”, Milan, Italy; 4Université Paris-Cité, Institut Cochin, Inserm U 1016, Paris, France; 5Respiratory Medicine and Cystic Fibrosis National Reference Centre, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; 6ERN-Lung CF Network, Frankfurt, Germany Introduction: The survival rate in cystic fibrosis (CF) has recently improved, largely due to CFTR modulators (CFTRm). However, only people with CF (pwCF) with selected CFTR genotypes are eligible CFTRm, Table: (abstract: WS01.06). Year Pre-ETI Annual incidence of MACE-AF % Age (years) SD BMI BMI SD No. of pwCF onCVmeds Heart Failure Atrial Fibrillation Hypertension Ischaemic Heart Disease 2016 22 0.4574% 44.9 16.7 24 4.48 22 13 14 15 10 Nov 2015–Oct 2016 2017 41 0.8524% 42.5 15.8 25 6.24 41 23 23 33 24 Nov 2016–Oct 2017 2018 47 0.9771% 44.3 18.2 23.9 4.97 44 26 27 36 28 Nov 2017–Oct 2018 2019 46 0.9563% 44 19.4 23.1 4.1 44 24 28 33 32 Nov 2018–Oct 2019 Post-ETI 2020 54 1.1227% 45 17.2 23.8 5 50 27 33 36 30 Nov 2019–Oct 2020 2021 61 1.2682% 43.7 18.1 23 4.36 58 29 35 32 45 Nov 2020–Oct 2021 2022 65 1.3514% 46.7 17 22.8 4.91 62 35 31 43 30 Nov 2021–Oct 2022 2023 74 1.5385% 46.4 18.6 23 4.59 72 41 29 49 38 Nov 2022–Oct 2023 Workshops / Journal of Cystic Fibrosis 23S1 (2024) S1–S33 S3
and eligibility varies with local regulatory authorities. This study aims to assess the disease burden of pwCF according to CFTRgenotype. Methods: We conducted a cross-sectional observational study using data from the 2019 ECFS Patient Registry (ECFSPR). We categorized pwCF who into five mutually exclusive subgroups: 1) patients with at least one p. Phe508del variant (F-any); 2) patients with CFTR genotypes approved by the FDA for ETI therapy (FDA approved); 3) patients with CFTR genotypes included in the French compassionate program (French compassionate); 4) patients with two variants producing no CFTR protein, e.g. stop codon mutations (non-responsive) and 5) patients with CFTR genotypes not included in the previous groups (other). We analyzed clinical features, comorbidities, treatment, and survival for each group. Results: 49,895 patients were included: 40,032 (F-any), 2,9101 (FDA approved), 1,712 (French compassionate), 2,079 (non-responsive), 3,162 (other). Non-responsive group had the most severe clinical characteristics, while the French compassionate had worse outcomes than the FDAapproved subgroup: FEV1pp (81.5% vs 88.1%); comorbidities (pancreatic insufficiency, 59.4% vs 45.3%; CFRD, 9.3% vs 4.6%); BMI (z-score −0.15 vs −0.01); antibiotic (inhaled, 38.2% vs 23.9%; i.v. 31.1% vs 22.5%); O2 therapy (4.2% vs 2.6%); death (1.3% vs 0.2%). Conclusion: Approximately 10% of CF patients lack eligibility to CFTRm therapies according to current EMA label, limited to F508del. PwCF with variants expected to respond to ETI (including FDA-approved and French Compassionate groups) have substantial disease burden. The extension of the label to the French compassionate group would benefit patients with worse clinical outcomes. WS02.04 Elexacaftor/tezacaftor/ivacaftor improved lung function and reduced exacerbations among individuals with rare, FDA-approved, CFTR variants in the United States E. Cromwell1, J. Ostrenga1, D.B. Sanders2,W.Morgan3, C. Castellani4, R. Szczesniak5, P.-R. Burgel6. 1Cystic Fibrosis Foundation, Patient Registry Research, Bethesda, United States; 2Indiana University, Indianapolis, United States; 3Arizona State University, Pulmonary and Sleep Medicine, Tucson, United States; 4IRCCS Istituto Giannina Gaslini, Genova, Italy; 5University of Cincinnati, Cincinnati, United States; 6Université Paris Cité, Paris, France Objectives: In December 2020, the United States (US) Food and Drug Administration used in vitro data to extend the label of elexacaftor/ tezacaftor/ivacaftor (ETI) to people with cystic fibrosis (CF) who have at least one of 177 rare CFTRvariants. We used the US CF Foundation Patient Registry to describe the clinical response to ETI among individuals with no F508del variant and at least one of these 177 rare variants. Methods: We implemented a pre/post comparison using date of first ETI prescription to define period of exposure; measures reported in the year preceding and following prescription were included. Linear regression with generalized estimating equations was used to estimate the ETI effect for ppFEV1, BMI (in adults) and weight percentile (in children) and negative binomial regression to estimate the impact of ETI on rate of IV-treated pulmonary exacerbations. Results: 818 individuals reported an ETI prescription; those with at least one G551D allele accounted for 21% of the study population and 34% had a prior ivacaftor prescription. Overall, ppFEV1 increased 3.4 percentage points (95% confidence interval (CI): 2.2; 4.5) after ETI. The change in ppFEV1 for those with an ivacaftor prescription within 180 days of ETI (n = 236) was 3.3 (95% CI: 1.4; 5.2). The rate of IV-treated pulmonary exacerbations declined by 54% (rate ratio: 0.46, 95% CI: 0.37; 0.57) after initiation of ETI; the effect was not modified by ivacaftor prescription or G551D status. No difference was detected in BMI or weight percentile. The proportion of subjects classified as underweight decreased from 7.4% pre ETI to 4.8% post-ETI. Conclusions: The increase in FEV1 and reduction in pulmonary exacerbations treated with IV antibiotics following ETI initiation in pwCF with at least one of the 177 FDA-approved variants supports relying oninvitrodata to expand the label of ETI. This is particularly relevant as other regulatory agencies begin to address eligibility for ETI treatment. WS02.05 Assessment of respiratory infection following initiation of elexacaftor/ tezacaftor/ivacaftor using the European Cystic Fibrosis Society patient registry M. Pollak1, S. Gambazza2, A. Orenti2, J. van Rens3, V. De Rose4, M. Mei Zahav1, ECFSPR Steering Group. 1Schneider-Children’sMedical Center, Pediatric Pulmonology Institute, Petah Tikva, Israel; 2University of Milan, Department of Clinical Sciences and Community Health, Laboratory of Medical Statistics, Biometry and Epidemiology“G. A. Maccacaro”, Milan, Italy; 3European Cystic Fibrosis Society Patient Registry, Karup, Denmark; 4University of Turin, Department of Molecular Biotechnology and Health Sciences, Turin, Italy Objectives: Elexacaftor/tezacaftor/Ivacaftor (ETI) has improved the quality of life and prognosis for people with Cystic Fibrosis (pwCF). We sought to assess the extent to which ETI can clear microbiological pathogens from the airways as change in infection rate following ETI initiation. Methods: Using the ECFS patient registry, pwCF who initiated ETI therapy between 2019 and 2021 were identified (cases). Microbiological data from one year after ETI was compared to one-year prior initiation. Controls were identified comparing microbiological status of same pwCF in the year before ETI initiation with 2 years earlier. Adjustments were made for sex, age, CFTR mutation group, FEV1 percent predicted, socioeconomical status and previous exposure to other CFTR modulators. Results: We included 15,739 pwCF from 30 countries. The mean (SD) age was 26.9 (11.6) years (53.1% males); 54.9% F508del homozygous, and 1.5% did not carry the F508del mutation. The 2.4% started ETI therapy in 2019, 48.2% in 2020 and 49.5% in 2021. Respectively, the 43% (95% CI: 42.1–43.9; p < 0.001) and 55.6% (95% CI: 54.6–56.6; p < 0.001) of pwCF who had Pseudomonas aeruginosa (Pa) and methicillin-sensitive Staphylococcus aureus (MSSA) turned negative after ETI initiation. Considering controls, only 23.2% and 41.9% eradicated Pa and MSSA, respectively. The percent difference between cases and controls was 19.8% (p < 0.001) and 13.7% (p < 0.001), respectively. These rates remained statistically significant also after adjustment. Similarly, significant clearance rates were seen for methicillin-resistant Staphylococcus aureus, Burkholderia Cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans and Nontuberculous mycobacteria. Conclusion: One-year after ETI initiation, a significant proportion of pwCF had clearance of microbiological lung pathogens, with significant rate differences between cases and controls, supporting the assumption that this is likely due to ETI therapy. WS02.06 Impact of elexacaftor/tezacaftor/ivacaftor on utilisation of maintenance therapies in cystic fibrosis: Danish nationwide register study H.K. Råket1, C.B. Jensen2, S. Jensen-Fangel3, J. Petersen2, E. Jimenez-Solem1, TransformCF Study Group. 1Copenhagen University Hospital, Bispebjerg and Frederiksberg, Dept. of Clinical Pharmacology and Copenhagen Phase IV-Unit, Copenhagen NV, Denmark; 2Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen Phase IV Unit, Department of Clinical Pharmacology and Centre for Clinical Research and Prevention, Copenhagen NV, Denmark; 3Aarhus University Hospital, Department of Infectious Diseases, Aarhus, Denmark Objectives: Elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to substantially improve outcomes in people living with cystic fibrosis (pwCF). Despite guidelines recommending the continuation of most maintenance therapies alongside ETI, its actual influence on these therapies is unclear. This study evaluates ETI’s effect on maintenance therapy utilisation in Danish pwCF. Methods: The study included pwCF who initiated ETI between 2018 and 2022. Utilisation of maintenance therapies was analysed by drug class (e.g., inhaled antibiotics) and individual treatments (e.g., dornase alfa) pre- and post-ETI initiation using National Prescription Registry data. The impact of ETI on use of maintenance therapies was reported as odds ratios (OR) for prescription redemptions using a logistic regression model. Workshops / Journal of Cystic Fibrosis 23S1 (2024) S1–S33 S4
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