BACKGROUND:Since 2018, important advancements in the medical care of people with cystic fibrosis, particularly the introduction and widespread use of highly effective cystic fibrosis transmembrane conductance regulator modulators, have contributed to the adult cystic fibrosis population growing substantially and has led to an increased need for tailored health-care approaches. Our study aimed to analyse the extent to which the clinical characteristics and treatment outcomes of adults with cystic fibrosis have evolved from 2014 to 2024. METHODS:The European Cystic Fibrosis Society Patient Registry (ECFSPR), collects annual data for more than 55 000 people with cystic fibrosis. Longitudinal data from 20 countries in Europe with high patient coverage (>85%) from 2014 to 2024 were analysed, representing 80% of the whole ECFSPR cohort. Differences in annual cross-sectional estimates were assessed using regression models. FINDINGS:Between 2014 and 2024, the number of adults with cystic fibrosis increased by 45·0%, from 50·9% to 60·5% of the total cystic fibrosis population. The number of adults older than 30 years nearly doubled. Among adults with cystic fibrosis who had not received a transplant, mean percent predicted FEV1 improved from 66·1% to 78·8% (p<0·0001), with most of the gain occurring after 2020. Chronic Pseudomonas aeruginosa infection declined significantly (p<0·0001), whereas mean BMI increased significantly (p<0·0001), halving the proportion of individuals who are underweight. Age-related complications, such as malignancy, increased, whereas cystic fibrosis-specific complications and insulin-treated diabetes declined. The largest improvements were observed in individuals with at least one variant responsive to elexacaftor-tezacaftor-ivacaftor (ETI). The uptake of ETI increased from 2% in 2019 to 71% in 2024, associated with improvements in health indicators. INTERPRETATION:From 2014 to 2024, the adult cystic fibrosis population in Europe expanded substantially due to marked improvements in treatment, particularly following the availability of ETI triple therapy from 2018-19 onwards. The growing number of people with CF surviving to adulthood is consistent with substantial effects from improved care and cystic fibrosis transmembrane conductance regulator modulators, such as ETI, and highlight evolving care needs of people with cystic fibrosis. FUNDING:None.

BACKGROUND:Cystic fibrosis (CF) transplant recipients infected with SARS-CoV-2 are at high risk for hospitalization or death. We aimed to (1) assess whether time since solid organ transplantation impacts severity of SARS-CoV-2 infection and (2) to evaluate the impact of SARS-CoV-2 infection on the slope of lung function trajectory. METHODS:This is a retrospective international cohort study of individuals with CF post-solid organ transplant with a confirmed SARS-CoV-2 infection between January 2020 and December 2021. The primary outcome was death or hospitalization. The secondary outcome was change in lung function trajectory following infection. To assess the impact of time from transplant on the primary outcome, logistic regression was performed while lung function trajectory was assessed using a linear mixed-effects model. RESULTS:A total of 526 SARS-CoV-2 infections from 19 countries were recorded. The median age at time of infection was 36 years (IQR 29-44). Median time since transplant was 5.8 years (IQR 3.3-10.8). The timing of transplant relative to infection was not significantly associated with hospitalization or death (OR 0.975 CI 0.928-1.025). A higher baseline ppFEV1 was associated with a decreased odds of death or hospitalization (OR 0.989, 95% CI 0.983, 0.995). In a subgroup of participants, lung function trajectory did not change significantly in the year following SARS-CoV-2 infection. CONCLUSIONS:In a diverse global post-transplant CF population, the timing of transplantation was not significantly associated with severe outcomes following SARS-CoV-2 infection. Those with more severe lung disease were at increased risk for worse outcomes and should be monitored closely.

INTRODUCTION Progressive airway disease with recurrent infections is a hallmark of cystic fibrosis (CF). While Pseudomonas aeruginosa and Staphylococcus aureus are the most common pathogens, emerging bacteria such as Stenotrophomonas maltophilia (SM), non-tuberculous mycobacteria, and Achromobacter species are increasingly identified. SM, a gram-negative bacterium, has been cultured from the sputum of people with CF (pwCF) with variable prevalence across countries. While its role remains debated, a 2012 review suggests that chronic SM may be a marker of more severe lung disease [1]. The clinical impact of Stenotrophomonas maltophilia in European pwCF remains underexplored, highlighting the need for better epidemiological data to guide research and care. AIMS Aims of this study are to estimate the prevalence and incidence of SM in Europe, to compare the clinical characteristics of pwCF according to their SM infection status and to characterize the most common patterns of infection during a period of 6 years (2018-2023). METHODS This longitudinal study is based on data provided by the European Cystic Fibrosis Society Patient Registry (ECFSPR), which collects demographic and clinical data of pwCF from 42 countries in Europe. Data are collected annually, according to specific inclusion criteria and standardized definitions. In the ECFSPR, SM status is classified as negative, intermittent, or chronic, based on standardized criteria [2]. Demographics and clinical outcomes within SM-negative, intermittent, and chronic groups in 2023 were described and the differences among groups were assessed using Pearson’s Chi-squared test for categorical and Kruskal-Wallis test for continuous variables. SM overall incidence and prevalence from 2008 to 2023 were computed. Prevalence was the proportion of infected (both intermittent and chronic together) in each year, while incidence was the number of newly infected individuals divided by those uninfected in the previous year. To assess whether trends in prevalence and incidence over time were statistically significant, logistic regression models were applied, using infection status as the response variable and calendar year as a continuous explanatory variable. Additional models were then fitted, accounting for time of introduction of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators and COVID-19 pandemic (pre- or post- period). Chronic and intermittent SM infection were used as response variables in further logistic regression models to assess whether a significant trend existed with age at follow-up, included as a continuous explanatory variable, also accounting for CFTR modulator use. Infection patterns from 2018–2023 were used to classify patients accordingly. Analyses were run using R Core Team versions 4.5.0. RESULTS In 2023, ECFSPR included 52977 pwCF, of whom 51566 (97.3%) had complete information regarding SM infection status. The overall prevalence of SM (including both chronic and intermittent cases) in 2023 ranged from 0.26% in Romania to 19.3% in Serbia, accounting for 5.0% (95% CI: 4.8 to 5.2) across Europe. Four small countries did not report any SM detection. Age, gender, BMI in adults, BMI z-score in children, and the country’s income category (all p<.05) differed across the three infection groups: SM-negative (49010, 95%), intermittent (2000, 3.9%), and chronic (556, 1.1%). SM-chronic had the highest median age (28.7y) and lowest BMI (22.1 kg/m2), while SM-intermittent were the youngest (16.5y), and SM-negative had the highest BMI (22.5 kg/m2). In contrast, genotype (p=0.7) and use of pancreatic enzymes (p=0.2) showed no significant differences. All concomitant infections—chronic P. aeruginosa, chronic S. aureus, MRSA, H. influenzae, Achromobacter spp., and nontuberculous mycobacteria—differed significantly across groups (all p<.001), with highest prevalence in those chronically infected with SM; only chronic Burkholderia cepacia complex showed a borderline difference (p=.041). The prevalence of SM increases significantly with age (p<.001) in both the unadjusted model and the model adjusted with CFTR modulator use. The unadjusted model showed no significant trend in SM prevalence over time (p=0.609); however, after adjusting for CFTR modulator/COVID period (≤2019 vs >2019), a significant trend was observed (p<.001); furthermore, the stratified analysis revealed a significant rise in SM prevalence from 2008 to 2019 (p<.001), followed by a significant decline from 2020 to 2023 (p<.001). Among 32,724 pwCF, 64 distinct infection patterns were identified. Most (24,594, 75.2%) showed no infection, while 24.8% (8,130) showed infection in at least one year and 11.1% (3640) for at least 2 years. Specifically, one year (13.7%), two years (5.3%), three years (2.8%), four years (1.5%), five years (0.8%), and six years (0.6%). Only 1.6% (524) of pwCF showed a continuous infection, remaining positive through 2023. CONCLUSIONS This large multinational analysis offers a detailed view of SM infection in the European CF population, revealing that while most individuals remained uninfected, nearly one-quarter experienced infection between 2018 and 2023. Chronic infection was strongly age-associated and consistently linked to a higher burden of co-infections. The shifting temporal trends—marked by a rise in prevalence up to 2019 and a subsequent decline during the CFTR modulator and post-COVID era—suggest that both medical advancements and broader changes in healthcare practices may significantly shape SM epidemiology. These findings highlight the need for continued surveillance to guide care and inform future research.

The most commonly used regression method to analyse Length and Weight data of fishes is Ordinary Least Squares (OLS). The OLS method, however, relies on assumptions that data is normally distributed and free from outliers maybe due to measurement or recording errors. Outliers are often encountered in Length-Weight data and can lead to spurious parameter estimates and potentially erroneous analyses. Robust Regression (RR) is a statistical method that can identify and account for (down-weight) outliers. Using Length-Weight data from 2 species of fishes, we demonstrate the application of RR models and their superior performance over OLS both in identifying outliers, accounting for them and estimating equation parameters. A recently developed RR method called Multiple Options (MO) performed especially well, generating a useful plot for inspection of outlier data. The results of this study suggest that the entire problem of outliers in analysing Length-Weight data can be circumvented by using RR methods. We recommend future studies of Length-Weight relationships in fishes use RR methods to estimate model parameters rather than the OLS method.

Patient registries are valuable tools for epidemiological research, especially for rare diseases, and a high level of data quality is essential but not always demonstrated. Although crucial, the quality management process in patient registries rarely includes data validation. The European Cystic Fibrosis Society Patient Registry (ECFSPR) collects clinical data about people with cystic fibrosis (pwCF) in Europe (as defined by the World Health Organisation (WHO) European region). This on-site data validation project was conducted by the ECFSPR to assess feasibility of the project, data accuracy and identify areas for improvement. From November 2018 to April 2024 the ECFSPR visited centres to validate data on-site, assessing the accuracy and validity of source data for key variables related to demographics, diagnosis, organ transplant and annual disease progression. We compared data submitted to ECFSPR with medical health records (MHR) at participating centres; standardised variable definitions are used for the ECFSPR data. Accuracy (incl. validity) was expressed as the percentage of validated data points that match the MHR. We validated source data on-site in 34 of 40 (85

Introduction Cystic fibrosis (CF) is a heterogeneous multisystemic disease. Despite considerable improvement in survival, CF remains a life-shortening disease with respiratory failure as the main cause of death. In 2020, elexacaftor/tezacaftor/ivacaftor (ETI) became available as a new highly effective CFTR-modulator therapy targeting the basic protein defect for people with a specific gene variant, and it was shown to improve lung function respiratory symptoms, and other clinical outcomes, including pulmonary exacerbations (PEx) [1]. However, despite the reduced frequency of PEx, these events remain an important driver of morbidity and mortality in people with CF (pwCF) [2]: in 2023, 16% of adults with CF in Europe experienced at least one PEx during the year [3]. The full extent of CFTR modulators effect on chronic airway infections and the recurrent PEx, especially in the long-term, remains uncertain with some studies reporting inconsistent results [4]. Objectives This study aimed to evaluate the real-world effectiveness of ETI therapy on PEx frequency in pwCF followed up between 2018 and 2023, using data from the European Cystic Fibrosis Society Patient Registry (ECFSPR). Specifically, a longitudinal comparison was conducted to evaluate the effectiveness of the new CFTR-modulator therapy on the number of PEx and the prevalence of chronic infections over time. Methods Data were obtained from the ECFSPR, a population-based Registry that collects clinical and demographic data on an annual basis according to agreed definitions of a common set of variables from Centres and national Registries in Europe and neighbouring countries from 2008 to 2023 [9]. To determine the effectiveness of ETI on PEx and chronic infections, a retrospective and longitudinal comparison from 2018 to 2023 was implemented. The analysis included the following variables: total number of days of intravenous antibiotics (IV Abx), including those performed both in hospital and at home (as a proxy for PEx), number of days of IV Abx performed exclusively in hospital, total number of days in hospital for any cause and the presence of chronic infections, including Pseudomonas aeruginosa, Burkholderia Cepacia Complex and Staphylococcus aureus. The first three variables were analysed both as continuous and as categorical (≥1 day vs. 0 days). The chronic infections were instead categorized as the presence of at least one infection versus no infection. To assess whether there were significant differences between the paired periods before and after treatment, the Wilcoxon signed-rank test and McNemar's test for paired data were used, as the same pwCF were evaluated at two time points. All analyses were performed using R software. Results The study included pwCF aged 12-60 years; pwCF who underwent solid organ transplants were excluded. Participants had either an F508del homozygous genotype or were F508del heterozygous with a minimal function variant The analyses were restricted to those who started ETI modulator therapy in 2020 (N= 6,628). Only people with available data on the number of days on IV Abx therapy administered at home and in hospital were considered, resulting in a final study population of 4,602 pwCF. Comparison of two years before and two years after starting ETI showed that the percentage of pwCF with at least one day on IV Abx decreased significantly from 64% to 23% (p<0.001), the percentage of pwCF with at least one day on IV Abx in hospital decreased from 50% to 16% (p<0.001) and, in parallel, that the percentage of pwCF hospitalized dropped from 56% to 24% (p<0.001). Also considering the corresponding variables as continuous, all the differences remain statistically significant. Notably, these improvements measured by total days on IV antibiotics and related variables persisted through three years post-ETI initiation. The prevalence of at least one chronic infection significantly decreased from 67.8% to 36.8% after 2 years of ETI therapy (p<0.001). Number of chronic infections further decreased to 34.5% after 3 years of treatment. Conclusions This analysis of the ECFSPR data demonstrates a marked reduction in PEx after the introduction of the new highly effective CFTR-modulator therapy. The introduction of ETI significantly reduced the clinical burden in pwCF, with decreases of days on IV Abx, hospitalizations and chronic infections. These benefits were observed consistently after 3 years of therapy. Further steps will include the implementation of statistical models to study changes in days on IV Abx as well as in other clinical outcomes before and after ETI.

Multiple breath washout (MBW) and its primary output, lung clearance index (LCI), sensitively measure ventilation inhomogeneity in cystic fibrosis (CF). This study aimed to characterize real-world MBW use in Europe through retrospective analysis of 2023 data from the European Cystic Fibrosis Society Patient Registry (ECFSPR). We determined the proportions of people with (pwCF) with one MBW measurement in 2023 by age group, lung function, country and device used. We analysed data from 39,986 non-transplanted paediatric and adult pwCF from 40 countries. Overall, 10 % of pwCF had an MBW measurement in 2023. MBW was performed in 22 countries and in 12 % of pwCF in those countries. Austria had the highest overall MBW use (39 % of pwCF). The highest proportions of pwCF who had MBW were aged 6-11 years (23 %) and 12-17 years (23 %). MBW was mostly used in pwCF with normal (19 %) or mildly impaired (10 %) percent predicted forced expiratory volume in one second. The Eco Medics Exhalyzer® D N2 was the most commonly used device (83 %). MBW is not yet routinely used in CF care in many European countries, presenting a window of opportunity to standardise MBW devices, software, and data quality control processes. This will ensure the accuracy and reliability of LCI measurements across different centres and devices, and facilitate MBW implementation in research and in care.

BackgroundLumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR).MethodsThe LUM/IVA cohort included children in the ECFSPR who started LUM/IVA between 15 January 2019 and 31 December 2020. Longitudinal trends in growth parameters, pulmonary exacerbations, hospitalizations, safety outcomes, and other effectiveness outcomes in the LUM/IVA cohort were compared to those in two modulator-naïve cohorts: (i) matched concurrent cohort heterozygous for F508del and a minimal function mutation (F/MF concurrent comparator cohort) and (ii) matched concurrent cohort with the F/F genotype from countries without commercial access to LUM/IVA as of 2020 (F/F concurrent comparator cohort).ResultsThe LUM/IVA cohort matched to the F/MF concurrent comparator cohort had 681 children and the LUM/IVA cohort matched to the F/F concurrent comparator cohort had 183 children. LUM/IVA cohorts had increases in body mass index percentiles relative to the matched F/MF and F/F concurrent comparator cohorts (mean difference in change from baseline: 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively). Increases in height and weight percentiles were also observed in the LUM/IVA cohort relative to the F/MF and F/F concurrent comparator cohorts. Reductions in pulmonary exacerbations and hospitalizations relative to baseline and the F/F concurrent comparator cohort were seen in 2021.ConclusionsThis interim analysis showed favorable trends in clinical outcomes, including growth parameters, pulmonary exacerbations, and hospitalizations, suggesting an early beneficial effect of LUM/IVA treatment in children aged 2 through 5 years at treatment initiation.

Background: The robust regression is rarely used in the statistical analyses in comparison with the Ordinary Least Squares regression and the Weighted Regression. In addition, in the frequent case of the heteroskedasticity of the residuals, a weighted regression carried out once is the main suggestion of the statistical books and the resulting reduced heteroscedasticity is usually considered sufficiently satisfactory. Methods: We showed the OLS regression analysis on data simulated with a well evident heteroskedasticity and an ad hoc outlier, followed by a weighted regression iteratively carried out by using iteratively reweighted least squares, an estimation method used also in several procedures of the robust regression analysis. Therefore, the link between the iteratively performed weighted regression and the robust regression becomes immediate. Furthermore, the same data have been analysed using some robust regression procedures.Results: It has been shown that in a simulated sample of heteroscedastic data with and without an obvious artificially created outlier the weighted regression performs worse with more biased parameter estimates than robust regression procedures (such as the robust MO procedure) as the presence of the outlier is not adequately neutralized. Discussion: In presence of a heteroskedastic pattern of the residuals, the suggestion to use robust regression procedures which can also deal with the almost sure presence of outliers seems more sensible. Among the robust regression procedures carried out, the performance of the robust MO procedure appears particularly appealing since it allows biostatisticians a more reasoned management of the outliers shown in a very illustrative “ad hoc” plot. Robust regression procedures represent a sensible alternative to OLS regression taking into account that its assumptions are practically not always fulfilled and that outliers, which are almost certainly present, are not only difficult to handle in classical OLS regression but can also provide highly biased estimates.

Background:Association between dependence on oxygen therapy (OT) and natural disease progression in people with cystic fibrosis (pwCF) has not been estimated yet. The aim of this study is to understand the prognosis for pwCF on OT, evaluating how the transition probabilities from being alive without lung transplantation (LTx) to LTx and to death, and from being alive after LTx to death change in pwCF with and without OT.Methods:We used 2008-2017 data from the 35-country European CF Society Patient Registry. A multi-state model was fitted to assess the effects of individual risk factors on transition probabilities.Results:We considered 48,343 pwCF aged from 6 to 50 years. OT (HR 5.78, 95% CI: 5.32-6.29) and abnormal FEV1 (HR 6.41, 95% CI: 5.28-7.79) were strongly associated with the probability of having LTx; chronic infection with Burkholderia cepacia complex (HR 3.19, 95% CI: 2.78-3.67), abnormal FEV1 (HR 5.00, 95% CI: 4.11-6.08) and the need for OT (HR 4.32, 95% CI: 3.93-4.76) showed the greatest association with the probability of dying without LTx. Once pwCF received LTx, OT (HR 1.75, 95% CI: 1.41-2.16) and abnormal FEV1 (HR 1.63, 95% CI: 1.18-2.25) were the main factors associated with the probability of dying. An association of gross national income with the probability of receiving LTx and with the probability of dying without LTx was also found.Conclusion:Oxygen therapy is associated with poor survival in pwCF with and without LTx; harmonization of CF care throughout European countries and minimization of the onset of pulmonary gas exchange abnormalities using all available means remains of paramount importance.

The European Cystic Fibrosis Society Patient Registry (Registry) contains data of over 50,000 patients from 40 countries. High quality data is essential for epidemiological research, pharmacovigilance studies and the annual reports. We compared the Registry data from 2021 with the patient health record (random patient list generated by the Registry statisticians), and validated a subset of variables (demographics, genotype, anthropometric data, lung function, microbiology, medications and complications). In 2022, we visited 4 established national registries (in Czech Republic, Germany, Ireland, the Netherlands) and 3 countries, that input data directly in the Registry's software (Croatia, Luxembourg and Slovakia). Of the 598 patients checked (6% of total patients in these countries), Transplantation, Burkholderia infections, Medications, Hemoptysis were 96–100% accurate. Lung function, Pseudomonas infections, Inhaled antibiotics, Liver disease had an accuracy of 90–95%, while genetic and anthropometric data were 85–89% accurate. The overall accuracy of data for 2021 is 94%. Factors that influence accuracy are organisation of the data collection process, quality of documentation available in the hospital and, for national registries, the software. We gained insight into the local documentation procedures, software, and identified areas that would benefit from revision or additional support, at both Registry and local level. The high quality of the Registry data is reflected by data validation. To further optimise data quality we advocate structured documentation of patient data and provide regular training on the variable definitions and parameters for the users.

Background: Achromobacter species are emerging pathogens isolated from respiratory samples of Patients with cystic fibrosis (pwCF) causing growing concerns in the CF community . The epidemiology and the clinical impact of Achromobacter in CF is unclear since data are restricted to small case control studies or selected populations .Aim: To characterize the effect of Achromobacter respiratory infection on CF lung disease.Methods: European CF Society Patient Registry data was analysed for association between Achromobacter infection and demographic/clinical characteristics and outcomes of pwCF. Results: Of eligible 38,795 patients, Achromobacter infection was reported in 2,093 (prevalence (95% CI) of 5.40% (5.17 -5.62). The prevalence varied significantly between the countries and increased with age peaking at the age 20-30. Achromobacter infection was more prevalent in pwCF carrying class minimal function mutations, having worse nutrition or lower pulmonary function, and more patients inhaled an-tibiotics against P. aeruginosa. Patient infected with Achromobacter had similar pulmonary function and BMI to patients infected with P. aeruginosa at all age groups. Being infected with both bacteria was asso-ciated with significantly lower pulmonary function and BMI at all age groups.Conclusions: Achromobacter infection was associated with disease severity similar to infection with P. aeruginosa. Being infected with both bacteria is associated with even more severe disease. This suggests to study if eradication will improve the outcome of pwCF. (c) 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Objectives LUM/IVA has been shown to be safe and effective in people with CF, including children. This registry-based study evaluated long-term efficacy and safety of LUM/IVA in children aged 2 through 5 years at treatment initiation. Methods LUM/IVA cohorts included children with CF homozygous for F508del (F/F) in the European CF Society Patient Registry who initiated LUM/IVA therapy between 15 January 2019 (approval) and 31 December 2020. Longitudinal trends in key outcomes were compared to 3 modulator-naïve cohorts: matched concurrent cohort of children heterozygous for F508del and minimal function mutation (F/MF) from same countries (AT,LU,DK,FR,IE,NL,SE,SI,CH,UK,DE) as LUM/IVA cohort (F/MF comparator [COMP]); matched concurrent cohort of F/F children from countries (HR,IT,CZ,LT,NO,PL) without commercial access to LUM/IVA as of 2020 (F/F COMP); and a historical cohort of F/F children from the same countries as LUM/IVA cohort. Results LUM/IVA cohort matched to F/MF COMP included 681 children and LUM/IVA cohort matched to F/F COMP included 183 children. As of 31 December 2021, >90% remained on treatment (mean exposure 23 months). LUM/IVA cohorts had increases in BMI percentiles relative to F/MF COMP and F/F COMP (mean difference in absolute change from baseline 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively) as well as to historical cohort, and reductions in pulmonary exacerbations (table 1) and hospitalizations relative to baseline, and relative to the F/F COMP in 2021. Interim results from this study support the benefits of LUM/IVA initiation in children with CF aged 2 through 5 years. Please refer to page A283 for declarations of interest related to this abstract.

Objectives: LUM/IVA has been shown to be safe and effective in people with CF, including children. This registry-based study evaluated long-term efficacy and safety of LUM/IVA in children aged 2 through 5 years at treatment initiation. Table(abstract: WS16.04).Annual risk of pulmonary exacerbation leading to hospitalization YearMatched to F/MF COMPMatched to F/F COMPLUM/IVA Cohort (n = 681) Risk, %F/MF Concurrent COMP Cohort (n = 681) Risk, %Relative Risk (95% CI)LUM/IVA Cohort (n = 183) Risk, %F/F Concurrent COMP Cohort (n = 183) Risk, %Relative Risk (95% CI)Baseline (2018)18.714.91.26 (0.99,1.59)22.021.51.02 (0.69, 1.51)Enrollment (2019)1Treatment effect is not expected to be notable during enrollment years.17.313.31.30 (1.01,1.67)16.919.30.88 (0.56, 1.36)Enrollment (2020)1Treatment effect is not expected to be notable during enrollment years., 2Outcome patterns in 2020 and 2021 are potentially affected by the COV1D-19 pandemic.14.39.91.44 (1.07,1.93)13.113.70.96 (0.56, 1.62)202129.210.30.89 (0.64, 1.25)6.021.40.28 (0.14, 0.54)1 Treatment effect is not expected to be notable during enrollment years.2 Outcome patterns in 2020 and 2021 are potentially affected by the COV1D-19 pandemic. Open table in a new tab Methods: LUM/IVA cohorts included children with CF homozygous for F508del (F/F) in the European CF Society Patient Registry who initiated LUM/IVA therapy between 15 January 2019 (approval) and 31 December 2020. Longitudinal trends in key outcomes were compared to 3 modulator-naïve cohorts: matched concurrent cohort of children heterozygous for F508del and minimal function mutation (F/MF) from same countries (AT,LU, DK,FR,IE,NL,SE,SI,CH,UK,DE) as LUM/IVA cohort (F/MF comparator [COMP]); matched concurrent cohort of F/F children from countries (HR, IT,CZ,LT,NO,PL) without commercial access to LUM/IVA as of 2020 (F/F COMP); and a historical cohort of F/F children from the same countries as LUM/IVA cohort. Results: LUM/IVA cohort matched to F/MF COMP included 681 children and LUM/IVA cohort matched to F/F COMP included 183 children. As of 31 December 2021, >90% remained on treatment (mean exposure 23 months). LUM/IVA cohorts had increases in BMI percentiles relative to F/MF COMP and F/F COMP (mean difference in absolute change from baseline 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively) as well as to historical cohort, and reductions in pulmonary exacerbations (Table) and hospitalizations relative to baseline, and relative to the F/F COMP in 2021. Conclusion: Interim results from this study support the benefits of LUM/IVA initiation in children with CF aged 2 through 5 years. #ECFSPR collaborators Andreas Pfleger (AT), Elise Lammertijn* (BE), Duška Tješic?-Drinkovic? (HR), Pavel Dr?evínek (CZ), Milan Macek Jr.* (CZ), Hanne Vebert Olesen (DK), Lydie Lemonnier-Videau (FR), Pierre-Régis Burgel* (FR), Elpis Hatziagorou* (GR), Godfrey Fletcher (IE), Rita Padoan (IT), Annalisa Orenti* (IT), Federico Ambrogi* (IT), Simone Gambazza (IT), Elına Aleksejeva (LV), Anna-Maria Charatsi (LU), Domenique Zomer (NL), Egil Bakkeheim (NO), Lukasz Woz?niacki (PL), Uroš Krivec (SI), Christina Krantz (SE), Anders Lindblad* (SE), Andreas Jung (CH), Sarah Clarke (UK), Siobhán B. Carr* (UK). *ECFSPR Scientific Committee