Cystic fibrosis

Danahay H., McCarthy C., Schofield T., Fox R., Charlton H., Lilley S., Sabater J., Salathe M., Baumlin N., Collingwood S.P., Gosling M.

Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed?

Luan X., Henao Romero N., Campanucci V.A., Le Y., Mustofa J., Tam J.S., Ianowski J.P.

Chen Y., Charbonnier J., Andrinopoulou E., Sly P.D., Stick S.M., Tiddens H.A.

COMBAT-CF showed that children aged 0-3 years treated with azithromycin did clinically better than placebo but there was no effect on CT-scores. We reanalysed CTs using an automatic bronchus-artery (BA) analysis.Inspiratory and expiratory CTs at 12 and 36 months were analysed. BA-analysis measures BA-diameters: bronchial outer wall (Bout), bronchial inner wall (Bin), artery (A), and bronchial wall thickness (Bwt) and computes BA-ratios: Bout/A and Bin/A for bronchial widening, Bwt/A and Bwa/Boa (bronchial wall area/bronchial outer area) for bronchial wall thickening. Low attenuation regions (LAR) were analysed using an automatic method. Mixed-effect model was used to compare BA-outcomes at 36 months between treatment groups.228 CTs (59 placebo; 66 azithromycin) were analysed. The azithromycin group had lower Bwa/Boa (p = 0.0034) and higher Bin/A (p = 0.001) relative to placebo. Bout/A (p = 0.0088) was higher because of a reduction in artery diameters which correlated to a reduction in LAR.Azithromycin-treated infants with CF show a reduction in bronchial wall thickness and possibly a positive effect on lung perfusion.

Stahl M., Dohna M., Graeber S.Y., Sommerburg O., Renz D.M., Pallenberg S.T., Voskrebenzev A., Schütz K., Hansen G., Doellinger F., Steinke E., Thee S., Röhmel J., Barth S., Rückes-Nilges C., et. al.

BackgroundWe recently demonstrated that elexacaftor/tezacaftor/ivacaftor (ETI) improves the lung clearance index (LCI) and abnormalities in lung morphology detected by magnetic resonance imaging (MRI) in adolescent and adult patients with cystic fibrosis (CF). However, real-world data on the effect of ETI on these sensitive outcomes of lung structure and function in school-age children with CF have not been reported. The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children aged 6–11 years with CF and one or twoF508delalleles.MethodsThis prospective, observational, multicentre, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and 3 months after initiation of ETI.ResultsA total of 107 children with CF including 40 heterozygous forF508deland a minimal function mutation (F/MF) and 67 homozygous forF508del(F/F) were enrolled in this study. Treatment with ETI improved the median (interquartile range (IQR)) LCI in F/MF (−1.0 (−2.0– −0.1); p<0.01) and F/F children (−0.8 (−1.9– −0.2); p<0.001) from 3 months onwards. Further, ETI improved the median (IQR) MRI global score in F/MF (−4.0 (−9.0–0.0); p<0.01) and F/F children (−3.5 (−7.3– −0.8); p<0.001).ConclusionsETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least oneF508delallele in a real-world setting. Our results support early initiation of ETI to reduce or even prevent lung disease progression in school-age children with CF.

Loske J., Völler M., Lukassen S., Stahl M., Thürmann L., Seegebarth A., Röhmel J., Wisniewski S., Messingschlager M., Lorenz S., Klages S., Eils R., Lehmann I., Mall M.A., Graeber S.Y., et. al.

Donaldson S.H., Corcoran T.E., Pilewski J.M., Laube B.L., Mogayzel P., Ceppe A., Wu J., Zeman K., Rowe S.M., Nichols D.P., Gifford A.H., Bennett W.D., Mayer-Hamblett N.

Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA. These results suggest that pwCF on ETI with mild lung disease do not experience a subclinical deterioration in MCC that could later impact health outcomes after discontinuing HS, and in fact may benefit from improved MCC after stopping DA treatment.

Taylor-Cousar J.L., Janney R., Middleton P.G., Jain R., Nightingale J., West N.E., Shteinberg M., Velez D., Kazmerski T.M.

Most males with cystic fibrosis (mwCF) are infertile but with CF transmembrane conductance regulator (CFTR) modulator-conferred benefits, more are utilizing assisted reproductive technologies (ART). Administration of normal human doses of modulators in animal reproductive models caused no genotoxicity; no human data exists. Potential health decline following modulator discontinuation makes the decision to withhold therapy during reproduction challenging.From August-October 2021, international CF clinicians completed an anonymous questionnaire regarding mwCF who used modulators during reproduction.We received 42 surveys for mwCF with partner pregnancies. Forty of 42 mwCF utilized ART; 35 continued modulators during sperm retrieval and 40/42 during partner pregnancy. One of four males who discontinued modulators experienced clinical deterioration. First trimester miscarriages occurred in 11.9 % of partner pregnancies. No congenital anomalies were reported.Use of CFTR modulators during reproduction and partner pregnancy in mwCF did not result in a higher-than-expected miscarriage rate nor congenital anomalies.

Guo J., King I., Hill A.

AbstractBackgroundElexacaftor/tezacaftor/ivacaftor (ETI) has revolutionized cystic fibrosis (CF) treatment. However, previous research has demonstrated profound global disparities in diagnosis and treatment access. If unaddressed, these threaten to widen existing health inequities. Therefore, in this analysis we aimed to reappraise gaps and evaluate progress in diagnosis and treatment equity in high‐income (HIC) versus low‐ and middle‐income countries (LMICs).MethodsEstimates of the global CF population were made in 158 countries using patient registries, systematic literature searches, and an international survey of 14 CF experts. Estimates of the global burden of undiagnosed CF were made using epidemiological studies identified in literature searches and registry coverage data. The proportion of people receiving ETI was estimated using publicly available revenue data and a survey of 23 national drug pricing databases.Results188,336 (163,421–209,204) people are estimated to have CF in 96 countries. Of these, 112,955 (60%) were diagnosed and 51,322 (27%) received ETI. The undiagnosed patient burden is estimated to be 75,381 people, with 82% in LMICs. ETI is reimbursed in 35 HICs, but only one LMIC. Four years after approval, there are 14,911 people diagnosed with CF who live in a country where ETI is inaccessible. This increases to 76,199 when including the estimated undiagnosed population.ConclusionsEquitable access to CFTR modulators must become a top priority for the international CF community. ETI costs up to $322,000 per year but could be manufactured for $5000 to allow access under a voluntary license. Given the extent of disparities, other mechanisms to improve access that circumvent the manufacturer should also be considered.

Graziano S., Boldrini F., Pellicano G.R., Milo F., Majo F., Cristiani L., Montemitro E., Alghisi F., Bella S., Cutrera R., Fiocchi A.G., Quittner A., Tabarini P.

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. Women reported more side effects than men (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. Women reported more side effects than men. pwCF should be followed up systematically to assess the frequency of side effects after starting this new modulator. 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. How does ETI affect mental health, cognitive processing, neuropsychological side effects, GI symptoms, and health-related quality of life over time? 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. 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. Women reported more side effects than men (ie, insomnia, headache, concentration problems, brain fog). 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. Women reported more side effects than men. pwCF should be followed up systematically to assess the frequency of side effects after starting this new modulator.

Bechtella L., Chunsheng J., Fentker K., Ertürk G.R., Safferthal M., Polewski Ł., Götze M., Graeber S.Y., Vos G.M., Struwe W.B., Mall M.A., Mertins P., Karlsson N.G., Pagel K.

AbstractThe dense O-glycosylation of mucins plays an important role in the defensive properties of the mucus hydrogel. Aberrant glycosylation is often correlated with inflammation and pathology such as COPD, cancer, and Crohn’s disease. The inherent complexity of glycans and the diversity in the O-core structure constitute fundamental challenges for the analysis of mucin-type O-glycans. Due to coexistence of multiple isomers, multidimensional workflows such as LC-MS are required. To separate the highly polar carbohydrates, porous graphitized carbon is often used as a stationary phase. However, LC-MS workflows are time-consuming and lack reproducibility. Here we present a rapid alternative for separating and identifying O-glycans released from mucins based on trapped ion mobility mass spectrometry. Compared to established LC-MS, the acquisition time is reduced from an hour to two minutes. To test the validity, the developed workflow was applied to sputum samples from cystic fibrosis patients to map O-glycosylation features associated with disease.

Burgel P., Southern K.W., Addy C., Battezzati A., Berry C., Bouchara J., Brokaar E., Brown W., Azevedo P., Durieu I., Ekkelenkamp M., Finlayson F., Forton J., Gardecki J., Hodkova P., et. al.

Abstract This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey.

Beswick D.M., Khatiwada A., Miller J.E., Humphries S.M., Wilson A., Vladar E.K., Lynch D.A., Taylor-Cousar J.L.

•HEMT improves multiple measures of sinusitis through 2 years of therapy in adults.•Sinus CT scans analyzed via machine learning methods and sinus symptoms improved.•Health utility increased and productivity loss decreased with 24 months of HEMT.•HEMT initiated in adulthood did not fully resolve chronic rhinosinusitis in adults.

Tewkesbury D.H., Scott J., Barry P.J., Bright-Thomas R.J., Hanley K.P., Athwal V., Jones A.M.

Background There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults. Methods Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I. Results The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17–25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01). Conclusions Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.

Cazier P., Chassagnon G., Dhote T., Da Silva J., Kanaan R., Honore I., Carlier N., Revel M., Canniff E., Martin C., Burgel P.

BackgroundThis study sought to evaluate the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on lung structural abnormalities in adults with cystic fibrosis (awCF) with a specific focus on the reversal of bronchial dilatations.MethodsChest computed tomography (CT) performed prior to, and ≥12 months after initiation of ETI were visually reviewed for possible reversal of bronchial dilatations. AwCF with and without reversal of bronchial dilatation (the latter served as controls with 3 controls per case) were selected. Visual Brody score, bronchial and arterial diameters, and lung volume were measured on CT.ResultsReversal of bronchial dilatation was found in 12/235 (5%) awCF treated with ETI. Twelve awCF with and 36 without reversal of bronchial dilatations were further analyzed (male=56%, mean age=31.6±8.5 years,F508del/F508del CFTR=54% and mean %predicted forced expiratory volume in 1 s=58.8%±22.3). The mean±sdBrody score improved overall from 79.4±29.8 to 54.8±32.3 (p<0.001). Reversal of bronchial dilatations was confirmed by a decrease in bronchial lumen diameter in cases from 3.9±0.9 mm to 3.2±1.1 mm (p<0.001), whereas it increased in awCF without reversal of bronchial dilatation (from 3.5±1.1 mm to 3.6±1.2 mm, p=0.002). Reversal of bronchial dilatations occurred in cylindrical (not varicose or saccular) bronchial dilatations. Lung volumes decreased by −6.6±10.7% in awCF with reversal of bronchial dilatation but increased by +2.3±9.6% in controls (p=0.007).ConclusionAlthough bronchial dilatations are generally considered irreversible, ETI was associated with reversal, which was limited to the cylindrical bronchial dilatations subtype, and occurred in a small subset of awCF. Initiating ETI earlier in life may reverse early bronchial dilatations.

Kerem E., Orenti A., Adamoli A., Hatziagorou E., Naehrlich L., Sermet-Gaudelus I.

BackgroundPrognosis and disease severity in cystic fibrosis (CF) is linked to declining lung function. To characterize lung function by the number of adults in countries with different level of Gross National Income (GNI), data from the European Cystic Fibrosis Society Patient Registry was utilized.MethodsAnnual data including age, forced expiratory volume in 1 s (FEV1), anthropometry, genotype, respiratory cultures and CF related diabetes (CFRD) were retrieved between 2011 and 2021. All countries were stratified into GNI per capita to reflect differences within Europe.FindingsA consistent improvement in FEV1percent of predicted (FEV1pp) and survival was observed among the 47 621 people with CF (pwCF), including subjects with chronicPseudomonas aeruginosa, CFRD, and/or undernutrition. Mean values of FEV1pp changed from 85 to 94.2 for children and from 63.6 to 74.7 for adults. FEV1pp further increased among those carrying the F508del mutation in 2021, when elexacaftor\tezacaftor\ivacaftor (ETI) was available. The number of adult pwCF increased from 13 312 in 2011 to 21 168 in 2021, showing a 60% increase. PwCF living in European countries with lower income (LIC) did not demonstrate a significant annual increase in FEV1pp or in number of adults.InterpretationThis pan-European analysis demonstrates a consistent improvement in FEV1pp, number of adult pwCF and survival over the last decade only in European higher and middle-income countries. An urgent action is needed in the LIC where such improvement was not observed. The notable improvement observed pwCF carrying the F508del mutation emphasizes the need to develop treatments for all CF mutations.

Kekeç H., Eyüboğlu T.Ş., Aslan A.T., Hocoğlu Z.İ., Yalçın E., Sunman B., Yavuz B.Ç., Şen V., Savaş S., Kılınç A.A., Başkan A.K., Yazan H., Ünal G., Canıtez Y., Sapan N., et. al.

Parisi G.F., Terlizzi V., Manti S., Papale M., Pecora G., Presti S., Tosto M., Leonardi S.

Cystic fibrosis (CF), a genetic disorder characterized by mutations in the CFTR gene, has seen significant advances in treatment through cutting-edge approaches such as gene therapy and personalized medicine. This review examines the current and emerging strategies shaping CF care, focusing on novel therapies that target the root cause of CF and optimize patient outcomes. CFTR modulators have transformed cystic fibrosis management by enhancing protein function for specific mutations, leading to improved lung function and quality of life. Concurrently, gene therapy offers transformative potential by aiming to correct CFTR mutations using tools like CRISPR/Cas9 or prime editing, though challenges remain in delivery and long-term efficacy. The integration of precision medicine, facilitated by genomic and computational technologies, allows for personalized treatment plans that account for genetic variability and disease severity. Complementing these approaches, holistic management emphasizes the importance of psychological support and nutritional optimization, acknowledging CF’s multi-system impact. Future directions include exploring anti-inflammatory agents and microbiome modulation to further mitigate disease morbidity. However, global disparities in treatment access continue to challenge equitable healthcare delivery, underscoring the need for policy reform and international cooperation. By synthesizing these developments, this review highlights the transformative potential of modern CF treatments, advocating for continued innovation and global healthcare equity, with the ultimate goal of dramatically improving life expectancy and quality of life for individuals with CF.

Venditto L., Tosco A., Sepe A., Castaldo A., Cimbalo C., Fevola C., Di Maurizio M., Baggi R., Avenali S., Terlizzi V.

Background/Objectives: Cystic Fibrosis (CF) is an autosomal recessive genetic disorder caused by variants in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Recently, a targeted therapy for CF has been developed, represented by the CFTR modulators that enhance or restore the function of the CFTR protein. The most recent is the combination of three modulators, Elexacaftor, Tezacaftor, and Ivacaftor (ETI). This study describes the presentation, management, and follow-up of tracheal diverticulum (TD) in pwCF receiving ETI therapy. Methods: This retrospective study included people with CF (pwCF) on ETI treatment and followed up in two CF Italian centers who developed an asymptomatic TD, diagnosed incidentally at chest CT scan. Results: Among 268 pwCF receiving ETI, three (1.19%) were diagnosed with TD identified after chest CT and were included in this study. Endoscopic confirmation was obtained in one patient. All patients were on inhaled colistimethate, two of them for chronic Pseudomonas aeruginosa colonization, and one undergoing eradication therapy. Conclusions: TD may be identified in chest CT obtained in pwCF in treatment with ETI. Further studies and a longer follow up are needed to confirm these findings.

Gryspeert K., Dipalo L.L., Da Silva Cunha A.L., Bulcaen M., Ensinck M.M., Carlon M.S.

Steinke E., Bauman G., Steffen I.G., Schobert I.T., Thee S., Syunyaeva Z., Roehmel J., Posch H., Fahlenkamp U.L., Scale C., Veldhoen S., Bieri O., Wielpütz M.O., Mall M.A., Stahl M., et. al.

BackgroundEstablished morpho-functional chest magnetic resonance imaging (MRI) detects abnormalities in lung morphology and perfusion in people with cystic fibrosis (pwCF) using a dedicated scoring system. Functional assessment is performed using contrast-enhanced (CE) perfusion MRI. Novel matrix pencil decomposition MRI (MP-MRI) is a contrast agent-free alternative, but further validation of this technique is needed.ObjectivesThe aim of this study was to evaluate the applicability of the validated morpho-functional chest MRI score for CE perfusion and MP perfusion MRI in a multireader approach.MethodsTwenty-seven pwCF (mean age 20.8 years, range 8.4–45.7 years) underwent morpho-functional MRI including CE perfusion and MP perfusion MRI in the same examination. Nine blinded chest radiologists of different experience levels assessed lung perfusion and applied the validated chest MRI score to CE- and MP-MRI. Inter-reader agreement of perfusion scores in CE- and MP-MRI were compared with each other and with the MRI morphology score. Differences according to the readers’ experience were also analyzed.ResultsThe CE perfusion scores were overall lower than the MP perfusion scores (6.2 ± 3.3 vs. 6.9 ± 2.0; p &lt; 0.05) with a strong correlation between both perfusion scores (r = 0.74; p &lt; 0.01). The intraclass correlation coefficient (ICC) as measure for inter-reader agreement was good and significant for both perfusion scores, but higher for the CE perfusion score (0.75, p &lt; 0.001) than for MP perfusion scores (0.61, p &lt; 0.001). The Bland–Altman analysis revealed a difference in CE and MP perfusion scores with more extreme values in CE perfusion scores compared to MP perfusion scores (r = 0.62, p &lt; 0.001). The morphology score showed a moderate to good correlation with the CE perfusion score (r = 0.73, p &lt; 0.01) and the MP perfusion score (r = 0.55, p &lt; 0.01). We did not find a difference in scoring according to the radiological experience level.ConclusionThe established chest MRI score can be applied both to validated CE and novel MP perfusion MRI with a good interreader reliability. The remaining difference between CE and MP-MRI scores may be explained by a lack of routine in visual analysis of MP-MRI and may favor an automated analysis for use of MP-MRI as a noninvasive outcome measure.

Hart M., Kumar M., Goswami H.B., Harris W.T., Skopelja-Gardner S., Swiatecka-Urban A.

Abstract Cystic fibrosis (CF) is a life-shortening multisystem disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, causing the most devastating phenotypes in the airway and pancreas. Significant advances in treatment for CF lung disease, including the expanded use of high-efficiency modulator therapies (HEMT) such as Trikafta, have dramatically increased both quality of life and life expectancy for people with CF (PwCF). With these advances, long-term extrapulmonary manifestations are more frequently recognized. Pseudo-Barter syndrome, acute kidney injury (AKI) induced by medications or dehydration, amyloidosis, nephrolithiasis, and IgA and diabetic nephropathies have been previously reported in PwCF. Newer data suggest that chronic kidney disease (CKD) is a new morbidity in the aging CF population, affecting 19% of people over age 55. CKD carries a high risk of premature death from cardiovascular complications. Studies suggest that CFTR dysfunction increases kidneys’ vulnerability to injury caused by the downstream effects of CF. Improving the mutant CFTR function by HEMT may help to tease apart the kidney responses resulting from extrinsic factors and those intrinsically related to the CFTR gene mutations. Additionally, given the novelty of HEMT approaches, the potential off-target effects of their long-term use are currently unknown. We review the evolving kidney complications in PwCF and propose the term CF-related kidney disease. We hope this review will increase awareness about the changing phenotype of kidney dysfunction in PwCF and help prevent morbidity related to this condition. Graphical abstract

Lucca F., Volpi S., Ros M., Fabrizzi B., Meneghelli I., Bordicchia M., Buniotto F., Lancini A., Brignole C., Pauro F., Bezzerri V., Cipolli M.

Background: Cystic Fibrosis is an inherited disorder caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene, encoding a chloride and bicarbonate channel widely expressed in epithelia. Loss of CFTR function leads to dehydration of the epithelium surface with thicker mucus secretions from tissues. The lungs, pancreas, liver, intestines, and sweat glands are the most common affected organs. However, pulmonary disease remains the main cause of morbidity and mortality. Fortunately, elexacaftor/tezacaftor/ivacaftor (ETI) therapy is showing unprecedented clinical benefits in patients with Cystic Fibrosis (CF) carrying at least one F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. However, almost 35% of the CF population living in the Mediterranean area still lacks effective CFTR modulator therapies because of the elevated incidence of patients with (pw)CF harboring CFTR rare mutations (RMs), different from F508del. Methods: Twenty-three pwCF harboring RM including the N1303K underwent off-label ETI treatment for 6-12 months. Respiratory function in terms of FEV1 and FVC was measured after 3, 6, and 12 months of treatment. In addition, we analyzed sweat chloride concentration, body mass index (BMI), and quality of life before and after treatment. Possible adverse effects were recorded. Results: All patients included in this off-label program displayed a substantial improvement in respiratory function. In particular, patients carrying the N1303K mutation showed an improvement in FEV1 and FVC similar to that observed in subjects harboring the F508del mutation, although sweat chloride concentration was not significantly decreased. No severe adverse effect was reported. Conclusions: This study strengthens the clinical efficacy of ETI in pwCF harboring the N1303K and other CFTR rare variants. Since these CFTR RMs have not been approved for ETI therapy in Europe, this study may promote the inclusion of these variants in the list of CFTR mutations responsive to ETI.

Villella V.R., Castaldo A., Scialò F., Castaldo G.

A critical challenge in the age of advanced modulator therapies is to understand and determine how effectively chronic oxidative stress and oxidative stress-induced inflammation can be reversed and physiological balance restored when CFTR function is pharmacologically improved. The triple therapy with elexacaftor–tezacaftor–ivacaftor (ETI) suggests that CFTR activity in individuals with at least one F508del mutation can be partially restored to about 50% of normal levels. Although incomplete, the partial recovery of CFTR function has been shown to drastically lower sputum pathogen content, enhance microbiome diversity, and lower inflammation markers within the first year of treatment in adolescents and adults with cystic fibrosis. However, despite these advancements, residual airway infection, oxidative stress and inflammation persist, with levels similar to other chronic lung conditions, like non-CF bronchiectasis. This persistence highlights the necessity for innovative antioxidant and anti-inflammatory treatments, in particular for individuals with advanced lung disease. To address this issue, emerging multi-omics technologies offer valuable tools to investigate the impact of modulator therapies on various molecular pathways. By analyzing changes in gene expression, epigenetic modifications, protein profiles and metabolic processes in airway-derived samples, it could be possible to uncover the mechanisms driving persistent oxidative stress and inflammation. These insights could pave the way for identifying new therapeutic targets to fully restore airway health and overall physiological balance.

Hoppe J.E., Kasi A.S., Pittman J.E., Jensen R., Thia L.P., Robinson P., Tirakitsoontorn P., Ramsey B., Mall M.A., Taylor-Cousar J.L., McKone E.F., Tullis E., Salinas D.B., Zhu J., Chen Y., et. al.

Cereghetti G.M., Christe A.

Abstract Airways and inhalational diseases represent a significant portion of respiratory pathologies, with chronic respiratory diseases being the third leading cause of death globally in 2019. Computed tomography (CT), particularly high-resolution CT (HRCT), is the gold standard for diagnosing and assessing airway diseases. HRCT allows visualization of key patterns such as airway wall thickening, bronchiectasis, bronchiolitis, and mosaic perfusion. While chest radiography provides rapid preliminary assessment, especially in emergencies, it has lower sensitivity and specificity compared to CT due to its two-dimensional nature. HRCT is crucial for detecting inhalational lung diseases and diagnosing occupational lung diseases (OLD). This overview presents CT imaging appearances, etiology, pathophysiology, and pathology of various airways and inhalational diseases, including tracheal pathologies. It highlights key diagnostic features and considerations for radiologists, emphasizing the role of HRCT in accurately depicting disease processes in small airways and occasionally leading to specific diagnoses among clinically relevant possibilities.

Graeber S.Y., Sommerburg O., Yu Y., Berges J., Hirtz S., Scheuermann H., Berger J., Duerr J., Mall M.A.

ObjectiveIntestinal current measurement (ICM) provides a sensitive bioassay for assessment of cystic fibrosis transmembrane conductance regulator (CFTR) function in rectal biopsies ex vivo and is used as a diagnostic tool for cystic fibrosis (CF). Furthermore, ICM was shown to be sensitive to detect pharmacological rescue of CFTR function by CFTR modulators in people with CF carrying responsive CFTR mutations. Results from clinical trials of CFTR modulators across age groups indicate that CFTR function in the sweat duct may be age-dependent with children reaching higher levels than adults. However, little is known about age dependency of CFTR function in the intestinal epithelium.MethodsWe investigated CFTR-mediated chloride secretion in rectal biopsies from 258 people without CF and 72 people with pancreatic-insufficient CF from 1 month to 68 years of age. Change in transepithelial short-circuit current in response to cyclic adenosine monophosphate (cAMP)-mediated (100 μM IBMX, 1 µM forskolin, basolateral) and cholinergic (100 μM carbachol, basolateral) stimulation was assessed as a readout for CFTR function using perfused micro-Ussing chambers. Furthermore, quantitative real-time PCR of CFTR and morphometric analysis of epithelial cells lining the crypts and surface of the rectal mucosa were performed to assess regulation at the levels of gene expression and epithelial cell densities.ResultsWe found that CFTR-mediated chloride secretion across rectal tissues, as determined from cAMP-mediated as well as cholinergic chloride-secretory responses was highest during infancy and early childhood and declined with age in people without CF (both P &lt; 0.001). Although, there was no difference in cAMP-mediated currents in people with CF, potassium-secretory responses induced by cholinergic stimulation were also reduced with increasing age. Transcript analyses showed that CFTR mRNA expression was slightly increased with increasing age in people without CF (P &lt; 0.05). Morphometric analyses demonstrated that CFTR expressing colonocytes at the crypt base were decreased with age (P &lt; 0.05). A secondary analysis of the ICM data of our previous studies on the effects of lumacaftor/ivacaftor on CFTR function in F508del -homozygous people with CF aged 12 years and older and 2–11 year old children showed correlations of the change in cAMP-mediated and cholinergic chloride secretory response with the age of people with CF (P &lt; 0.01 and P &lt; 0.05, respectively).ConclusionThese results demonstrate that CFTR function in the rectal epithelium is reduced with increasing age and indicate that this change is likely due to a decline in the number of secretory colonocytes at the crypt base. These findings suggest that differences in CFTR expressing cells may explain increased functional responses to CFTR modulator therapies in children compared to adult people with CF.

Serrano D., Uzumcu A., Gerstein M., Ayasse N.D., Engstrom E., Barnes F.B., Iaconangelo C., Thorat T., McGarry L.J., Sermet-Gaudelus I.

The Cystic Fibrosis (CF) Impact Questionnaire (CF-IQ) was qualitatively developed to assess the impact of CF in the context of treatment advancements and increased longevity. This study reports the CF-IQ validation. In this noninterventional validation study, people with CF completed the 40-item CF-IQ and validating patient-reported outcome measures (PROMs) via electronic diaries at enrollment (baseline) and at the 4-week follow-up. Validation consisted of modern methods and focus groups to finalize structural validity, and classical methods to assess internal consistency [1–3], test-retest reliability [4,5], concurrent validity [5], and known-groups validity [5] of the CF-IQ. At baseline, 214 adults completed the survey; 193 completed the follow-up survey. Unidimensional item response theory (IRT) models were separately fit to 5 prespecified domains (Control and Burden of CF Treatment Impacts, Physical Activity Impacts, Social Activity Impacts, Emotional Impacts, and Work/School Limitation Impacts). IRT local dependence (LD) statistics identified 17 redundant items. Two independent CF-patient focus groups (14 total patients) confirmed these findings, and the 17 items were dropped. Each domain defined on the final 23 items achieved the criterion of exact model fit as measured by the root mean squared error of approximation (RMSEA, values = 0), Internal consistency (Cronbach’s α) values ranged from 0.81 to 0.89, 4 of 5 domains achieved acceptable test-retest reliability, with intraclass correlation coefficient (ICC) values ≥ 0.7, acceptable concurrent validity was achieved for all domains, and known-groups validity was established. The novel CF-IQ is a psychometrically robust PROM capturing patient-centric impacts of CF in the context of the current standard of care.

Finotti A., Gambari R.

The discovery of the involvement of microRNAs (miRNAs) in cystic fibrosis (CF) has generated increasing interest in the past years, due to their possible employment as a novel class of drugs to be studied in pre-clinical settings of therapeutic protocols for cystic fibrosis. In this narrative review article, consider and comparatively evaluate published laboratory information of possible interest for the development of miRNA-based therapeutic protocols for cystic fibrosis. We consider miRNAs involved in the upregulation of CFTR, miRNAs involved in the inhibition of inflammation and, finally, miRNAs exhibiting antibacterial activity. We suggest that antago-miRNAs and ago-miRNAs (miRNA mimics) can be proposed for possible validation of therapeutic protocols in pre-clinical settings.

Shen T.

The Special Issue “Molecular Mechanisms, Diagnoses, and Treatments of Respiratory Diseases” in the journal Biomedicines compiles critical advancements in the understanding of respiratory diseases, focusing on their molecular mechanisms, diagnostic approaches, and therapeutic strategies [...]

Taccetti G., Terlizzi V., Campana S., Dolce D., Ravenni N., Fevola C., Francalanci M., Galici V., Neri A.S.

Bacterial infections of the lower airways are the main cause of mortality and morbidity in cystic fibrosis. The most frequently isolated pathogens are S. aureus and P. aeruginosa; bacterial co-infections are frequently observed. The aim of this review is to provide, in the current context, the indications regarding the best antibiotic strategy to adopt in subjects affected by CF infected with the most common pathogens. We selected relevant publications (guidelines, systematic reviews and clinical studies published so far on these topics) and we analysed the sampling methods used and antibiotic strategies adopted. Oropharyngeal sampling methods are considered less sensitive for pathogen detection than sputum. In non-expectorating people, induced sputum is considered equivalent to two-lobe bronchoalveolar lavage, which is considered invasive. Antibiotic treatment against the main pathogens can consist in eradication treatment in the early stages of infection, chronic suppressive therapy and treatment of the pulmonary exacerbations. This scheme is valid for P. aeruginosa but remains to be demonstrated for the other pathogens. For S. aureus, no evidence-based therapeutic strategies on how to treat the different stages of bacterial infection have been established with certainty. With regard to the treatment of the other classic pathogens (B. cepacia complex, A. xylosoxidans and S. maltophilia), no evidence-based indications exist and decision is left to the clinician. The recent introduction of highly effective modulators on the CFTR protein, in addition to the favourable effects described in regulatory trials, has led to a reduction in bacterial isolations; the real effect of which in clinical practice has still to be assessed on the basis of scientific data. The reliability of culture examination depends on sampling methods, and expectorated sputum continues to be the best method as it is simple and non-invasive. P. aeruginosa is the pathogen for which antibiotic strategies for the various stages of infection appear best established, and the efficacy of early eradication treatment and chronic suppressive therapy have been underlined in clinical trials and systematic reviews. The recent introduction of modulators into clinical practice, despite their widely described efficacy, has not yet led to suggestions for changes in antibiotic strategies against the pathogens most frequently isolated.