Background Cystic fibrosis (CF) is a multi-system disease that causes chronic respiratory failure, malnutrition and poor growth as a result of a negative energy balance due to maldigestion and malabsorption. Achieving linear growth and height above the 50 th percentile is associated with improved lung function. In October 2022, the use of Elexacaftor/Tezacaftor/Ivacaftor (ETI) was approved for children with CF from the age of 6 years. Analyses on the effect of ETI on height velocity (HV) are not usually available from trial and real life data and our work aims to study growth pattern by HV. A secondary aim was to check for any differences according to the CFTR variants severity. Methods We conducted a single-center prospective study at the CF Unit of the Bambino Gesù Children’s Hospital, including children aged 6-11 years who were eligible for ETI. The whole population of 24 people with CF (pwCF) underwent evaluation of height, weight, body mass index (BMI), bone mineral density (BMD), body composition analysis with bioelectrical impedance analysis (BIA), and muscle weakness using the one-minute sit-to-stand test (1STST) before starting the new drug. Height, weight, height velocity (HV), BMI standard deviation scores (SDS) were calculated for both 6 months before and 6 months after the start of ETI treatment. Results The mean age of the population was 8.7 years (SD 1.87), with a balanced gender distribution (F/M 12/12) and majority naïve to previous CFTR modulators. We found a significant difference in the growth rate achieved when comparing the calculated mean HV between T (-6 months) and T0 (4.2±2.0 cm/year; -1.96±2.4 SDS) with the HV between T0 and T (+6 months) (7.1±3.0 cm/year; +1.5±3.7 SDS) (p<0.0001). The group with F508del/minimal function mutations (F/MF) – 15 pwCF – had a higher average speed than those with homozygous F508del (F/F) – 5 pts – and those with F508del/residual function mutations (F/RF) – 4 pts – ( p< 0.0001). We found no significant differences in the three different genetic groups concerning BMD and initial lean mass. Conclusion The results highlight the benefit of ETI in the pediatric CF population, particularly by increasing the HV in children aged 6-11, especially those with the F/MF genotype. This study further emphasizes the impact of CFTR restoration on a fundamental aspect of the CF child’s well-being, growth.

In conclusion, our data suggest that subjects with genotype 5T;TG12/VVCC likely have a very low risk of progressing to CF, as compared to those with F508del/5T;TG12. 4 This observation could lead to differentiate follow up in presence of at least one 5T;TG12. Knowing these data is crucial to offer a useful counseling for CRMS/CFSPID infants and for non‐CF adults with CBAVD alone. Anyway further data are needed to evaluate the outcomes after a longer follow up.

CFTR modulators (CFTRm) were introduced recently but they are already profoundly changing Cystic Fibrosis (CF) landscape. This survey was conducted in 2018 to evaluate how their perception and use evolved in Italy, with focus on factors that could influence physician treatment decisions. Response rate was 75.6% and the majority of physicians (81%) had been working in CF for over 5 years. While traditional parameters such as lung function and nutritional status remain key evaluation criteria in relation to initiation and monitoring of CFTRm, pulmonary exacerbations ranked at least at the same level of importance in both pediatric and adolescent/adult patients homozygous for F508del, as well as those with residual function mutations. Increasing interest is shown for tools that can help detect early manifestations of disease such as Lung Clearance Index and imaging. Patient-related outcomes, such as ability to conduct daily activities, are also deemed relevant in decision to start and continue CFTRm. Physician decision to initiate treatment according to clinical presentation was similar in all groups, showing that more importance was given to severity/instability of disease rather than mutation type or age range. A relatively low percentage of physicians would treat asymptomatic patients, in particular very young or those with residual function mutations, showing reluctance to treat early in some patient groups in the absence of clear manifestations of CF. Increasing experience with CFTRm will allow to gain more long term evidence and will help shape new guidelines.