INTRODUCTION:Italian Cystic Fibrosis Registry (ICFR) collects data of people with cystic fibrosis through the collaboration with Italian CF referral and support Centres (Italian law 548/93). It aims at analysing medium and long-term clinical and epidemiological trends, identifying healthcare needs at regional and national levels, contributing to healthcare programs and resource allocation (sharing the population of FC centres with the Ministry of Health). Finally, the RIFC shares some of its data with the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) to better define the number of people with cystic fibrosis with early access to specific treatments with innovative therapies. Moreover, ICFR data are shared with the European CF Patients' Registry (ECFSPs' Registry) to contribute to the estimation of the European incidence of the pathology and to bridge knowledge gaps on specific topics as well as to the adoption of common strategies for the standardized collection of data on people with cystic fibrosis. OBJECTIVES:The objective of this report is to provide updated data from ICFR for the years 2023 and 2024. It is essential to consider that the analyses and specific studies carried out refer to a limited number of variables collected in the Registry, and that the selection of the topics covered in the chapters of this report was agreed by the scientific committee of the ICFR. STUDY DESIGN:The analyses and results presented in this report pertain to people with cystic fibrosis currently under care Italian National Referral Centres (CRR) and Support Centres (SS) for Cystic Fibrosis and Paediatric Hospital 'Bambino Gesù' (OPBG). Data are collected using web-based software adopted by almost all participating centres, except for the centres in Verona (which also includes the data from Treviso and Rovereto) and Messina, where data collection is carried out using a different software. The submitted data are then subject to both quantitative and qualitative quality control (QC) procedures, aimed at verifying the consistency and continuity of the information previously transmitted and shared with the European CF Registry. SETTING AND PARTICIPANTS:In the two-year period 2023-2024, 28 and 27 CF Centres, respectively, submitted their data to ICFR. However, the information from the two CF centres in Sardinia is still partial, since the data provided is limited to a small number of people with cystic fibrosis from 2023. RESULTS:The results section provides a comprehensive overview of various aspects of CF epidemiology and people with cystic fibrosis characteristics. 1. Demography: in 2023 and 2024, 6,127 and 6,182 people with cystic fibrosis were, respectively, included in the ICFR (median ages of 24.1 and 24.9 years). On average, 52.2% of people with cystic fibrosis are male, and most of the population (65.3%) is older than 18 years. This reflects the growth of the adult population, the number of paediatric people with cystic fibrosis remains almost unchanged compared to previous years. 2. DIAGNOSES:in 2024, 66.5% of the Italian CF population received a diagnosis before reaching two years of age, 61.8% within the first year of life, while 15.5% of diagnoses were made in adulthood (>18 years). New diagnoses were 103 in 2023 and 134 in 2024, with an incidence of 1 in 5,587 live births in 2023 and 1 in 8,808 in 2024. 3. GENETICS:the genetic analysis of people with cystic fibrosis was performed in 99.9% of cases. The results allowed the characterization of at least one of the two alleles in 6,040 individuals (97.7%). The most frequent variant in Italy, consistent with previous years, is F508del, present in 43.6% of cases. A higher frequency, compared with other European countries, is also confirmed for the genetic variants N1303K, G542X, and 2789+5G>A. Only 1.3% of alleles carry a CFTR gene variant that has not yet been identified (unknown). 4. Lung function: lung function, measured by percent predicted FEV1%p, declined progressively before adulthood. In detail, 96.4% (in 2023) and 95.5% (in 2024) of paediatric people with cystic fibrosis aged between 6 and 17 maintain a FEV1%p>=70%. On the other hand, the percentage of paediatric people with cystic fibrosis with severely impaired respiratory function (FEV1%p<40%) is 0.2% (2023) and 0.1% (2024). In the adult population, FEV1%p values are encouraging, with an increasing proportion of people with cystic fibrosis showing preserved lung function (85.7% in 2023 and 87.1% in 2024). This report introduces a brief focus on pulmonary exacerbations, which decreased between 2023 and 2024 (from 19.8% to 15.4%; recurrent forms from 8.6% to 4.9%), with reductions across all age groups, though less marked in those over 40. The most affected remain children (1-6 years) and those over 55; the 4.9% with recurrent episodes represent the priority for therapeutic optimization. Overall, trends in respiratory function suggest a progressive improvement in health status among the adult population, likely associated with the increasing use of new targeted pharmacological therapies. 5. Nutrition: ICFR data confirm the critical nature of the first months of life, which usually precede the definitive diagnosis of CF and the subsequent initiation of specialized care. In the 12-17 years age group, the median body max index (BMI) z-score is close to zero, documenting an adequate nutritional status in half of the subjects. The proportion of malnourished males was 6.2% and 5%, while among females it was 2.3% and 2.6%, respectively, in 2023 and 2024. In the >=18 years age group, a higher percentage of underweight BMI is observed among females (9% in 2023 and 8% in 2024) compared with males (4.2% and 4.4% in 2023 and 2024, respectively). 6. COMPLICATIONS:in 2024, in both paediatric and adult people with cystic fibrosis, the most frequent complications were the same, but occurred at different rates, such as CF-related liver disease (24.1% and 49.4%, respectively), diabetes (3.8% and 26%), and osteoporosis (4.2% and 18.7%). A total of 50 people with cystic fibrosis with cancer were recorded in 2023 and 2024, of whom 4 were of paediatric age. 7. Transplantation: over the two-year period, 21 people with cystic fibrosis underwent double-lung transplantation, with median ages of 36.2 e 36.8 years in 2023 and 2024, respectively, with ages ranging from 15.1 to 64.7 years across the two years. 8. Microbiology: in 2024, the prevalence of adult people with cystic fibrosis with chronic Pseudomonas aeruginosa infection is 30.1%, while in paediatric people with cystic fibrosis is 5.5%. The prevalence of Staphylococcus aureus infections is 28.7% and 26.4%, respectively, in adults and paediatric people with cystic fibrosis; prevalence of infections of Burkholderia cepacia is 1.6% and 0.2%. 9. MORTALITY:in the two-year period, ICFR data show that 36 people with cystic fibrosis died (16 males and 20 females), with median ages at death of 48.3 years in 2023 and 57.2 years in 2024 (excluding transplanted people with cystic fibrosis). The crude mortality rate ranged from 3.1‰ in 2023 to 2.8‰ in 2024; excluding transplant recipients, the crude rate was 1.6‰ and 1.0‰ in the respective years. 10. Motherhood and fatherhood: over the two-year period, 80 pregnancies were recorded, of which 62 were successfully completed (77.5%). Additionally, 22 pregnancies were still ongoing as of 31.12.2024. In 2024, 25 people with cystic fibrosis became fathers. CONCLUSIONS:The present report updates data published in previous years thus summarizing 2023 and 2024 results. The number of registered people with cystic fibrosis was 6,127 in 2023 and 6,182 in 2024. Population coverage estimates for 2024 to be around 98%. Over the two-year period 2023-2024, the number and percentage of people with cystic fibrosis aged over 18 years increased. In detail, the ICFR recorded 3,927 adult people with cystic fibrosis (64.1%) in 2023 and 4,034 (65.3%) in 2024. An increase in the median age of Italian people with cystic fibrosis has been observed over time, reaching 24.9 years in 2024. The absolute number of new diagnoses per year is comparable with that of the previous biennium (237 vs 234); the percentage of new diagnosis in adulthood was 39.6% in 2024. In 2024, the median age at diagnosis was 3.9 months; 61.8% of subjects are diagnosed within the first year of life; 95.1% of them were identified through neonatal screening. Analysis of different CFTR genotypes in the Italian CF population confirms the high allelic variability observed in Italy, with a substantial proportion of subjects not eligible for CFTR modulator therapy. Regarding respiratory function, findings are consistent with previous reports, showing an increasing percentage of subjects under the age of 18 with a normal respiratory function. This marked improvement observed in the adult population seems to be mainly due to the introduction of highly effective CFTR modulator therapies in Italy from 2021. In 2024, a reduction in the percentage of chronic Pseudomonas aeruginosa infection was observed in both adults (30.1% vs 38.8% in 2020) and paediatric people with cystic fibrosis (5.5% vs 7.6% in 2020). Liver disease remains the most frequent complication in both paediatric and adult populations, affecting 24.1% and 49.4% of people with cystic fibrosis, respectively. During the two-year period, 36 people with cystic fibrosis died with a median age at death between 48.3 and 57.2 years (transplant people with cystic fibrosis excluded). Only one transplanted people with cystic fibrosis under the age of 18 died in the period 2023 and 2024, confirming once again that mortality in paediatric age is a rare event. Finally, for the first time, this report introduces data related to maternity and paternity, highlighting that in more than 77% of cases pregnancies were successful; as well as estimates of tumour and pulmonary exacerbations incidence as possible complications.

Chronic Pseudomonas aeruginosa colonisation leads to lung deterioration and poor prognosis in people with cystic fibrosis (pwCF). Early and aggressive therapies can achieve P. aeruginosa eradication, which may recur later. Therefore, determining whether it has resisted therapy or has been newly acquired may guide subsequent treatment(s). This information is crucial also for patients treated with CFTR modulators representing P. aeruginosa after prolonged negativity and to confirm chronic infections. We evaluated the ability of Fourier-transform infrared (FT-IR) spectroscopy to determine intra-patient isoclonality for 103 P. aeruginosa strains isolated from 36 pwCF. Two were chronically and two intermittently colonised; twelve were on modulators with a past P. aeruginosa colonisation; and twenty received eradication therapy, ten of whom were also treated with modulators. FT-IR data were validated by Whole Genome Sequencing (WGS) identification of Sequence Type. FT-IR identified persistence of P. aeruginosa in 24 patients, with a WGS-confirmed positive predictive value of 100% and diagnostic accuracy of 94%. The eradication therapy success rate was 45%, and the time to P. aeruginosa reappearance was similar in both patients with failed eradication treatment and those who initially cleared the infection but later acquired a new strain. Nine patients in modulators showed persistent infections. FT-IR can rapidly determine the clonality of P. aeruginosa isolates, allowing discrimination of recurring versus new infections both in patients with established colonisations and those subjected to eradication therapy representing P. aeruginosa. By overcoming the time-based criteria used to define new infections and by providing the actual success rate of eradication therapies, FT-IR can effectively contribute to the development of efficient therapeutic strategies.

Background/Objectives: Cystic fibrosis (CF) is a multi-system disorder characterized by chronic respiratory failure, malnutrition, and impaired growth. Achieving linear growth above the 50th percentile is associated with better pulmonary outcomes. Since October 2022, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been approved in Italy for children aged ≥6 years. However, data on its impact on height velocity (HV) remain lacking. This study aims to evaluate growth patterns by HV and explore differences according to the CFTR variant genotype. Methods: We conducted a prospective single-center study at the CF Unit of Bambino Gesù Children’s Hospital involving 24 children aged 6–11 years eligible for ETI treatment. Baseline assessments included height, weight, body mass index (BMI), bone mineral density (BMD), body composition (via bioelectrical impedance analysis, BIA), and muscle strength (one-minute sit-to-stand test (1STST)). Height, weight, HV, and BMI standard deviation scores (SDS) were calculated for the 6 months before and after ETI initiation. Results: The mean age of the cohort was 8.7 ± 1.9 years (F/M: 12/12), with most patients naïve to CFTR modulators. A significant increase in HV was observed post-ETI: from 4.2 ± 2.0 cm/year (−1.96 ± 2.4 SDS) in the 6 months before treatment to 7.1 ± 3.0 cm/year (+1.5 ± 3.7 SDS) after treatment initiation (p < 0.0001). Patients with F508del/minimal function (F/MF) genotypes (n = 11) showed significantly greater HV compared to those with F508del/F508del (F/F, n = 5) and F508del/residual function (F/RF, n = 8) genotypes (p < 0.0001). No significant differences were observed among genetic groups in baseline BMD or lean mass. Conclusions: ETI treatment significantly and rapidly improves HV in children with CF, particularly in those with F/MF genotypes. These findings underscore the role of CFTR modulator therapy in promoting linear growth, a key indicator of health in pediatric CF populations.

BACKGROUND:Cystic fibrosis (CF) is a genetic disease caused by CFTR protein dysfunction. Elexacaftor/tezacaftor/ivacaftor (ETI) shows promise in improving outcomes for people with CF (pwCF) with Phe508del combined with gating (F/G) or residual function (F/RF) mutations, though real-world evidence remains scarce. OBJECTIVES:This study evaluated the effectiveness and safety of ETI therapy in pwCF with F/G and F/RF genotypes in real-world settings. METHODS:A multicentre, retrospective study enrolled 78 pwCF (24 F/G and 54 F/RF) receiving ETI after prior CFTR modulator treatments (ivacaftor and tezacaftor/ivacaftor). Endpoints included changes in ppFEV1, sweat chloride concentration (SCC), CFQ-R respiratory domain scores, body mass index (BMI), pulmonary exacerbations (PEx), and antibiotic use over 24 weeks. Safety was assessed via self-reported adverse events. RESULTS:ETI improved ppFEV1 (mean increase: 3.8; 95 % CI, 1.8-5.8), SCC (mean decrease: -23.7 mmol/L; 95 % CI, -28.6 to -18.9), and CFQ-R scores (median improvement: 9.4 points; p < 0.05). BMI increased (mean change: 0.41 kg/m2; 95 % CI, 0.05-0.76), while PEx and antibiotic use decreased by 65.2 % and >50 %, respectively (p < 0.001). Subgroup analysis revealed greater ppFEV1 improvement in F/G patients (6.0 points; 95 % CI, 2.6-9.4) compared to F/RF patients (2.8 points; 95 % CI, 0.4-5.2). No serious adverse events were reported. CONCLUSIONS:ETI therapy provides significant clinical benefits in pwCF with F/G and F/RF genotypes, including improved lung function, SCC normalization, and reduced PEx, compared with previous modulator treatments. Further research is needed to confirm long-term outcomes.

BACKGROUND:The prognosis for people with Cystic Fibrosis (CF) has significantly improved due to the introduction of CF Transmembrane Regulator (CFTR) modulators. This study aims to analyze pregnancies and related outcomes in Italian women with CF while also identifying current and potential future challenges. METHODS:This retrospective study utilized data from the Italian cystic fibrosis Registry (ICFR), focusing on pregnancies occurring between 2016 and 2023. Key clinical variables assessed included genotype, age at conception, body mass index, percent predicted forced respiratory volume (ppFEV₁), presence of CF-related diabetes (CFRD), and CFTR modulator therapy. The outcomes analyzed were pulmonary function and BMI as a surrogate of nutritional status before and after pregnancy, as well as preterm birth rate, birthweight, and mode of delivery. RESULTS:Between 2016 and 2023, the ICFR reported 172 pregnancies, of which 148 (86.0 %) were carried to term. The median age at conception was 31.8 years (range: 17.0-43.9), median BMI 21.6 kg/m² (range: 16.5-38.9), and median ppFEV₁ 79.7 (range: 29.0-120.4). CFRD was present in 32 women (21.6 %), and 55 (37.2 %) were receiving CFTR modulator therapy. Better clinical status at the beginning of pregnancy was observed in 2016-23 period, with a higher mean ppFEV1, in the mean age at conception and in the mean BMI value. In the present study, only a limited number of women were in severe clinical condition (<5 % had a severe ppFEV1 value or a BMI showing a malnutrition status). The overall preterm birth (<37 weeks gestation) was 24.1 % (34 cases), higher in women with CFRD (40.6 %) and lowest in those receiving CFTRm (22.7 %). Median birthweight was 2,990 g (range: 800-4,155 g). The overall cesarean section rate was 54.9 %, peaking at 81.2 % in women with CFRD. CONCLUSION:Understanding national pregnancy trends and outcomes is essential for informing effective public health strategies and improving maternal-infant wellbeing. An increasing number of women with CF are achieving successful pregnancies and delivering healthy babies. It is essential to provide women treated with CFTR modulators with up-to-date information regarding the safety of these therapies during pregnancy and breastfeeding.

Objective The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. Study design This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. Results Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n = 85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026). Conclusions This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

Background: Italy initiated elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (pwCF) in July 2021. It has led to dramatic improvements in lung function, BMI, sweat chloride, and respiratory symptoms. However, few data are available on side effects or effects on a broad range of outcomes. Research question: How does ETI affect mental health, cognitive processing, neuropsychological side effects, GI symptoms, and health-related quality of life over time? Study design and methods: This was a prospective, "real-world" longitudinal study. Participants were recruited consecutively and evaluated at initiation (T0) and after 1 month, 3 months, and 6 months of starting treatment. Assessments included depression (nine-item Patient Health Questionnaire), anxiety (seven-item Generalized Anxiety Disorder), cognition (Symbol Digit Modalities Test), GI Symptom Tracker, and health-related quality of life (Cystic Fibrosis Questionnaire-Revised). Based on literature, an ad hoc questionnaire was developed to assess side effects: insomnia, headache, memory problems, "brain fog," and concentration problems. Following descriptive analyses, longitudinal data were analyzed by using mixed models for repeated measures, controlling for age and sex when appropriate. Results: Ninety-two consecutive pwCF (female/male, 46/46; mean age, 25.4 years) participated. FEV1 increased initially and then remained stable. BMI also increased significantly from T0 to 6 months (P < .01). Depression improved from T0 to 1 month (P < .001); however, no changes in anxiety were found. Cognitive processing improved from T0 to subsequent assessments. Positive changes were reported on the GI Symptom Tracker for stools and adherence challenges, although no changes were found for abdominal pain and digestion. Side effects occurred in 10% to 29%, with no reduction over time; insomnia increased significantly across time. Female participants reported more side effects than male participants (ie, insomnia, headache, concentration problems, brain fog). Interpretation: This prospective study evaluated the effects of ETI using multiple measures. Significant improvements were found in many domains; however, side effects were reported by a substantial proportion of pwCF, with no improvements over time. Female participants reported more side effects than male participants. pwCF should be followed up systematically to assess the frequency of side effects after starting this new modulator.

BackgroundPrimary ciliary dyskinesia (PCD) is considered a rare cause of chronic rhinosinusitis with nasal polyposis (CRSwNP), which is reported in 6% of children with PCD. The forms of PCD associated with the variants of the GAS8 gene identified so far seem to be linked to recurrent respiratory infections (sinusitis, otitis, and bronchiectasis) without situs inversus.Case presentationWe report a case of an 11-year-old girl with recurrent otitis media, productive cough, and chronic rhinosinusitis with nasal polyposis with homozygosity for a novel nonsense mutation in the GAS8.ConclusionChildren with CRSwNP should be treated in a multidisciplinary manner (ENT, pulmonologist, allergist, pathologist, pediatrician, and geneticist) because nasal polyposis often hides etiologies that must be recognized.

INTRODUCTION:Italian Cystic Fibrosis Registry (ICFR) collects data of patients with cystic fibrosis (CF) through the collaboration with Italian CF referral and support Centres (Italian law 548/93). It aims at analysing medium and long-term clinical and epidemiological trends, identifying healthcare needs at regional and national levels, contributing to healthcare programmes, and resource allocation. Italian data are also compared at international level through the collaboration with the European CF Registry for sharing epidemiological data on general aspects like CF epidemiology and specific topics such as the use of CFTR modulators.OBJECTIVES:The purpose of this Report is to provide updated demographic and clinical data of the Italian FC population for the years 2021 and 2022, to contribute essential information for the implementation of projects aimed at improving the management of patients affected by this disease.DESIGN:Analyses and results presented in this Report pertain to patients currently under care at Italian National Referral and Support Centres for Cystic Fibrosis and Paediatric Hospital 'Bambino Gesù' in the 2021-2022 period. Data were submitted by clinical Centres through a dedicated web-based software and underwent dual quality control (QC) measures: automated quantitative QC within the software and secondary QC at the European level before the integration into the European Cystic Fibrosis Registry. These measures ensure data completeness, accuracy, and longitudinal consistency with European core data.SETTING AND PARTICIPANTS:A total of 27 CF Centres, including referral and support centres, as well as 'Bambino Gesù' Children's Hospital CF centre, submitted their data to ICFR for the years 2021-2022. Althourgh CF Centres in Verona and Messina do not use the ICFR software, their data are centrally collected and subsequently forwarded to the European Registry. Data from service centres in Treviso and Rovereto are transmitted via the Verona CF Centre. Data from Sardinia Centre are currently unavailable.RESULTS:The results section provides a comprehensive overview of various aspects of CF epidemiology and patient characteristics. 1.Demography: in 2021 and 2022, 5,977 and 6,077 CF patients were respectively included in the ICFR, with median ages of 23.3 and 23.7 years. The prevalence rates were 10.1 and 10.3 per 100,000 residents in Italy for the respective years, with males comprising 51.6% on average. The distribution by age showed a higher frequency among patients aged 7 to 35 years; adult patients constituted 63.5% on average in both years. 2. Diagnosis: most CF patients were diagnosed before the age of two (mean value 57.9%), with a significant percentage diagnosed in adult age (35.4% in 2021 and 25.6% in 2022). 3.New diagnoses: there were 113 new diagnoses in 2021 and 121 in 2022, with estimated incidences of 1 in 9,097 living births in 2021 and 1 in 6,232 in 2022. 4. Genetics: genetic analyses were conducted on 99.9% of patients, revealing CFTR gene mutations in over 98% of cases. The F508del mutation was the most common (44% of alleles in 2021), with 18% of patients having at least one "residual function" mutation. Gating mutations were present in 3.4% of Italian patients, while 20% had at least one-stop codon mutation. 5.Lung function: lung function, measured by percent predicted (pp)FEV1 (Forced Expiratory Volume in the first second) progressively declined before adulthood, with the majority of paediatric patients (92.8% in 2021 and 93.8% in 2022) maintaining a ppFEV1≥70%. 6.Nutrition: critical periods for nutrition were identified as the first 6 months of life and adolescence, with higher prevalence of malnourished male adolescents compared to females. Suboptimal BMI values were more common in adult females (28.7% in 2021 and 26.9% in 2022) compared to males (14.2% in 2021 and 12.6% in 2022). 7. Complications: CF-related liver disease without cirrhosis was prevalent in patients under 18 years (21.9% in 2021 and 21.2 in 2022), while CF-related diabetes was most frequent in adults (24.2%). 8.Transplantation: over the two-year period, 28 patients underwent double-lung transplantation, with median ages of 29.1 in 2021 and 35.3 in 2022, respectively. Median waiting times ranged from 9.4 to 11.6 months. 9.Microbiology: chronic Pseudomonas aeruginosa infection affected 37.2% of adult patients in 2021 and 36.0% in 2022, compared to 7.4% and 6.5% in paediatric patients. Staphylococcus aureus infection rates were 34.6% and 42.2% in 2021 among adults and 34.4% and 36.7% in 2022 among paediatric patients. 10. Mortality: a total of 34 patients died during the 2021-22 period (19 females, 15 males), with median ages at death of 43.7 years in 2021 and 46 years in 2022 (excluding transplanted patients).CONCLUSIONS:The present Report is an update of the data published in the past years and summarizes the main epidemiological and clinical data regarding Italian CF subjects in the years 2021 and 2022. The number of patients registered in 2021 was 5,977, while in 2022 was 6,077. The population coverage estimates for 2022 to be around 97%. In 2020, 60.5% of patients were older than 18 years, in 2022 adult patients account for 63.5% of the Italian CF population. Over the years, therefore, an increase in the median age of Italian CF patients has been observed, reaching 23.7 years in 2022. The absolute number of new diagnoses per year remains substantially unchanged over the years (a total of 234 in the period under review). The median age at diagnosis in 2022 was 2.5 months, 62.6% of subjects are really diagnosed within the first year of life and almost 90% of them are diagnosed through neonatal screening. In 2022, almost all patients underwent genetic analysis (99.9%). Data collected confirm the great variability among Italian CF patients. As regards respiratory function, what is reported in previous reports is here confirmed, with an ever-increasing percentage of subjects under the age of 18 having normal respiratory function, moreover, less than 1% of paediatric patients has a severe lung function (ppFEV1<40). The marked improvement in this indicator in the adult population seems to be mainly due to the introduction from 2021 in Italy of therapy with highly effective CFTR modulators. At the same time, the close positive correlation between nutritional status and respiratory function is confirmed for the adult population. As regards chronic infection by Pseudomonas aeruginosa, in 2022, a reduction in the percentage of chronic infection is observed both among adults (36% vs 38.8% in 2020) and in paediatric patients (6.5% vs 7.6% in 2020). The most frequent complication in both paediatric and adult populations is liver disease (respectively, in 24.2% and 41.3% of subjects). In the two-year period, 34 patients died; their median age at death was between 43 and 46 years (transplant patients excluded); only two patients under the age of 18 died in the period 2021 and 2022, confirming once again that mortality in paediatric age is a rare event. The data presented in this Report shows how the register can be a national and international point of reference for CF patients and the scientific community, a tool for describing the Italian CF population over the years, and a starting point for planning epidemiological studies and clinical studies.

Cystic fibrosis (CF) is a multisystem disorder characterized by progressive respiratory deterioration, significantly impacting both quality of life and survival. Over the years, lung ultrasound (LUS) has emerged as a promising tool in pediatric respiratory due to its safety profile and ease at the bedside. In the era of highly effective CF modulator therapies and improved life expectancy, the use of non-ionizing radiation techniques could become an integral part of CF management, particularly in the pediatric population. The present review explores the potential role of LUS in CF management based on available data, analyzing all publications from January 2015 to January 2024, focusing on two key areas: LUS in CF pulmonary exacerbation and its utility in routine clinical management. Nonetheless, LUS exhibits a robust correlation with computed tomography (CT) scans and serves as an additional, user-friendly imaging modality in CF management, demonstrating high specificity and sensitivity in identification, especially in consolidations and atelectasis in the CF population. Due to its ability, LUS could be an instrument to monitor exacerbations with consolidations and to establish therapy duration and monitor atelectasis over time or their evolution after therapeutic bronchoalveolar lavage. On the basis of our analysis, sufficient data emerged showing a good correlation between LUS score and respiratory function tests. Good sensitivity and specificity of the methodology have been found in rare CF pulmonary complications such as effusion and pneumothorax. Regarding its use in follow-up management, the literature reports a moderate correlation between LUS scores and the type, extent, and CT severity score of bronchiectasis. A future validation of ultrasound scores specifically in CF patients could improve the use of LUS to identify pulmonary exacerbations and monitor disease progression. However, further research is needed to comprehensively establish the role of LUS in the CF population, particularly in elucidating its broader utility and long-term impact on patient care.

Hypoxia contributes to the exaggerated yet ineffective airway inflammation that fails to oppose infections in cystic fibrosis (CF). However, the potential for impairment of essential immune functions by HIF-1 alpha (hypoxia-inducible factor 1 alpha) inhibition demands a better comprehension of downstream hypoxia-dependent pathways that are amenable for manipulation. We assessed here whether hypoxia may interfere with the activity of AhR (aryl hydrocarbon receptor), a versatile environmental sensor highly expressed in the lungs, where it plays a homeostatic role. We used murine models of Aspergillus fumigatus infection in vivo and human cells in vitro to define the functional role of AhR in CF, evaluate the impact of hypoxia on AhR expression and activity, and assess whether AhR agonism may antagonize hypoxia-driven inflammation. We demonstrated that there is an important interferential cross-talk between the AhR and HIF-1 alpha signaling pathways in murine and human CF, in that HIF-1 alpha induction squelched the normal AhR response through an impaired formation of the AhR:ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF-1 beta heterodimer. However, functional studies and analysis of the AhR genetic variability in patients with CF proved that AhR agonism could prevent hypoxia-driven inflammation, restore immune homeostasis, and improve lung function. This study emphasizes the contribution of environmental factors, such as infections, in CF disease progression and suggests the exploitation of hypoxia:xenobiotic receptor cross-talk for antiinflammatory therapy in CF.

Abstract Background The introduction of the novel therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been effective in improving weight gain in both clinical trials and real-world studies. However, the magnitude of this effect appears to be heterogeneous across patient subgroups. This study aims to identify potential determinants of heterogeneity in weight gain following 6-month ETI therapy. Methods We conducted a multicenter, prospective cohort study enrolling 92 adults with CF at two major CF centers in Italy with follow-up visit at one month and six months from ETI initiation. The treatment’s effect on weight changes was evaluated using mixed effect regression models that included subject-specific random intercepts and fixed effects for potential predictors of treatment response, time and a predictor-by-time interaction term. Results The mean weight gain at six months from the start of treatment was 4.6 kg (95% CI: 2.3–6.9) for the 10 patients with underweight, 3.2 kg (95% CI: 2.3-4.0) for the 72 patients with normal weight, and 0.7 kg (95% CI: -1.6-3.0) for the 10 patients with overweight. After six months of ETI treatment, 8 (80%) of the patients with underweight transitioned to the normal weight category, while 11 (15.3%) of the normal-weight patients became overweight. The major determinants of heterogeneity in weight gain were the baseline BMI and the presence of at least one CFTR residual function mutation, explaining 13% and 8% of the variability, respectively. Conclusions Our results indicate that ETI is highly effective in improving weight gain in underweight subjects with CF. However, our data also suggests the need for close monitoring of excess weight gain to prevent potential cardiometabolic complications.

Nasal polyps (NPs) are rarely reported in childhood and usually represent red flags for systemic diseases, such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and immunodeficiencies. The European Position Paper released in 2020 (EPOS 2020) provided a detailed classification and defined the correct diagnostic and therapeutic approaches. We report a one-year experience of a multidisciplinary team, made up of otorhinolaryngologists, allergists, pediatricians, pneumologists and geneticists, with the aim of ensuring a personalized diagnostic and therapeutic management of the pathology. In 16 months of activity, 53 patients were admitted (25 children with chronic rhinosinusitis with polyposis and 28 with antro-choanal polyp). All patients underwent phenotypic and endo-typic assessment, using proper classification tools for nasal pathology (both endoscopic and radiological), as well as adequate cytological definition. An immuno-allergic evaluation was carried out. Pneumologists evaluated any lower airway respiratory disease. Genetic investigations concluded the diagnostic investigation. Our experience enhanced the complexity of children's NPs. A multidisciplinary assessment is mandatory for a targeted diagnostic and therapeutic pathway.

Respiratory tract exacerbations play a crucial role in progressive lung damage of people with cystic fibrosis, representing a major determinant in the loss of functional lung tissue, quality of life and patient survival. Detection and monitoring of respiratory tract exacerbations are challenging for clinicians, since under- and over-treatment convey several risks for the patient. Although various diagnostic and monitoring tools are available, their implementation is hampered by the current definition of respiratory tract exacerbation, which lacks objective “cut-offs” for clinical and lung function parameters. In particular, the latter shows a large variability, making the current 10% change in spirometry outcomes an unreliable threshold to detect exacerbation. Moreover, spirometry cannot be reliably performed in preschool children and new emerging tools, such as the forced oscillation technique, are still complementary and need more validation. Therefore, lung imaging is a key in providing respiratory tract exacerbation-related structural and functional information. However, imaging encompasses several diagnostic options, each with different advantages and limitations; for instance, conventional chest radiography, the most used radiological technique, may lack sensitivity and specificity in respiratory tract exacerbations diagnosis. Other methods, including computed tomography, positron emission tomography and magnetic resonance imaging, are limited by either radiation safety issues or the need for anesthesia in uncooperative patients. Finally, lung ultrasound has been proposed as a safe bedside option but it is highly operator-dependent and there is no strong evidence of its possible use during respiratory tract exacerbation. This review summarizes the clinical challenges of respiratory tract exacerbations in patients with cystic fibrosis with a special focus on imaging. Firstly, the definition of respiratory tract exacerbation is examined, while diagnostic and monitoring tools are briefly described to set the scene. This is followed by advantages and disadvantages of each imaging technique, concluding with a diagnostic imaging algorithm for disease monitoring during respiratory tract exacerbation in the cystic fibrosis patient.