2025

L R Caley, L Gillgrass , C Zagoya, H Saumtally, F Duckstein, White H 4, J G Mainz, D G Peckham. Longer term follow-up of abdominal symptoms (CFAbd-Score) after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis. J Cyst Fibros. 2025 Jan 14:S1569-1993(25)00010-4. doi: 10.1016/j.jcf.2025.01.010. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39814671/

Background: Whether improvements in gastrointestinal (GI) symptoms observed with Elexacaftor/Tezacaftor/Ivacaftor (ETI) treatment are sustained in the longer-term requires exploration. This study investigated how GI-symptoms change with longer-term ETI use in pancreatic insufficient adults with cystic fibrosis (awCF).
Methods: Participants completed up to three abdominal symptom questionnaires, employing the validated CFAbd-Score. Changes in total CFAbd-Score and its five domains, pain, gastroesophageal reflux-disease (GERD), disorders of bowel movement (DBM), disorders of appetite (DA) and quality of life (QOL), were analysed pre-ETI (T0) and at ≤1.5 years (T1) and 2-4 years of ETI-therapy (T2).
Results: A total of 165 CFAbd-Scores from 68 participants were analysed (median age: 34 years; IQR: 28-39). Total CFAbd-Score significantly (p < 0.05) and clinically meaningfully decreased from 20.4 ± 1.6 pre-ETI (median:40 weeks pre-treatment) to 15.3 ± 1.9 and 16.8 ± 1.6 at T1 (median: 25 weeks of ETI) and T2 (median: 148 weeks of ETI), respectively. The CFAbd-Score´s domains DA and QoL only significantly decreased between T0 and T1, whereas DBM only significantly decreased after 2-4 years of ETI therapy (T2). GERD scores were significantly lower at both T1 and T2.

Conclusion: While GI symptoms in awCF significantly improve within the first 1.5 years of ETI-therapy, they appear to somewhat wane with longer-term use, despite GI-symptom burden still being lower compared to pre-ETI. However, we cannot differentiate whether this results from reduced adherence, a decrease in ETI effects, or long-term changes in diet, gut microbiota or symptom perception. The longer-term impact of ETI and other potential modulator therapies on GI symptoms requires ongoing monitoring.

Laura Caley is a Research Fellow at the Leeds Institute of Medical Research, University of Leeds, School of Medicine, Leeds, United Kingdom.

Connett Gj, Maguire S, Larcombe Tc, Scanlan N, Shinde Ss, Muthukumarana T , Bevan A , Keogh Rh, Legg Jp. Real-world impact of Elexacaftor-Tezacaftor-Ivacaftor treatment in young people with Cystic Fibrosis: A longitudinal study. Respir Med. 2025 Jan:236:107882. doi: 10.1016/j.rmed.2024.107882. Epub 2024 Nov 22.: DOI: 10.1016/j.rmed.2024.107882  pubmed.ncbi.nlm.nih.gov/39581272/

Background: Elexacaftor, Tezacaftor, Ivacaftor (ETI) became available in the UK in August 2020 to treat people with Cystic Fibrosis (CF) aged >12 years. We report a real-world study of clinical outcomes in young people treated with ETI at our CF centre within the first two years of its availability.
Methods: Participants aged 12-17 were identified within our clinic, with demographic data supplemented by the UK CF registry. Comprehensive outcome data spanning two years pre- and two years post-initiation of CFTR modulators were compiled from various local sources, including patient records, medication delivery logs, and clinical notes.
Results: Of the 62 patients started on ETI (32 male, mean age 13.3 years), most (76 %) were homozygous for the F508del mutation. Three discontinuations occurred: one pregnancy, two related to side effects. Adherence was high (Proportion of Days covered >90 % both years). Following ETI initiation there was a significant increase in mean FEV1% (+11.7 units; 95 % CI 7.4-15.6), sustained throughout the two-year treatment period. There was no association between baseline lung function and the degree of improvement or rate of decline post-treatment. Improvements were similar for all treatable genotypes. BMI z-score increased by 0.25 units after four months of treatment, returning to baseline by 24 months. Intravenous antibiotic use decreased by 88 % (median IV days/year reduced from 32 to 4 days, p < 0.01).

Conclusions: ETI use in adolescents in a real-world setting led to sustained improvements in health outcomes, consistent with those seen in open trial extension studies.

Prof. Garry Connett is at the National Institute for Health Research, Southampton Respiratory Biomedical Research Centre, University Hospitals Southampton NHS Foundation Trust, Southampton, UK; Southampton Children’s Hospital, University Hospitals Southampton NHS Foundation Trust, Southampton, UK.

Dorina Dobi , Nicoletta Loberto, Laura Mauri, Rosaria Bassi , Elena Chiricozzi, Giulia Lunghi, Massimo Aureli. Effect of CFTR modulators Elexacaftor/Tezacaftor/Ivacaftor on lipid metabolism in human bronchial epithelial cells. Glycoconj J. 2025 Jan 11. doi: 10.1007/s10719-024-10174-7. pubmed.ncbi.nlm.nih.gov/39797966/

Cystic Fibrosis (CF) is a life-threatening hereditary disease resulting from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that encodes a chloride channel essential for ion transport in epithelial cells. Mutations in CFTR, notably the prevalent F508del mutation, impair chloride transport, severely affecting the respiratory system and leading to recurrent infections. Recent therapeutic advancements include CFTR modulators such as ETI, a combination of two correctors (Elexacaftor and Tezacaftor) and a potentiator (Ivacaftor), that can improve CFTR function in patients with the F508del mutation. This study investigated ETI’s impact on the maturation of the mutated CFTR, the expression levels of its scaffolding proteins, and lipid composition of cells using bronchial epithelial cell lines expressing both wild-type and F508del CFTR. Our findings revealed that ETI treatment enhances CFTR and its scaffolding proteins expression and aids in rescuing mature F508del CFTR, causing also significant alterations in the lipid profile including reduced levels of lactosylceramide and increased content of gangliosides GM1 and GD1a

These changes were linked to ETI’s influence on enzymes involved in the sphingolipid metabolism, in particular GM3 synthase and sialidase. Through this work, we aim to deepen understanding CFTR interactions with lipids, and to elucidate the mechanisms of action of CFTR modulators. Our findings may support the development of potential therapeutic strategies contributing to the ongoing efforts to design effective correctors and potentiators for CF treatment.

Dorina Dobi is in the Department of Medical Biotechnology and Translational Medicine, University of Milano, Milan, Italy.

Rebecca Dobra, Christopher Short, Kiyo Wong, Clare Saunders, Mary Abkir, Samantha Irving, Jane C Davies. Utility and interpretation of multiple breath washout in children with cystic fibrosis. Arch Dis Child Educ Pract Ed. 2025 Jan 13:edpract-2024-328203. doi: 10.1136/archdischild-2024-328203. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39805677/

Transformative changes in the health of children with cystic fibrosis (CF) mean that more sensitive outcome measures are needed to monitor paediatric CF lung disease. Multiple breath washout (MBW) and its primary readout lung clearance index are gaining increasing traction as an endpoint for clinical trials in the CF space and show promise as a clinical investigation. In this article, we use four clinically based questions to explore what MBW can and cannot (yet) do and highlight some of its strengths and weaknesses as an investigation. We end by discussing how we can increase the utility of MBW as an investigation in children with CF.

Rebecca Dobra is at the National Heart and Lung Institute, Imperial College London, London, UK and the Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK.

Jennifer L Goralski , Asha N Talati, Emily E Hardisty, Neeta L Vora. Pregnancy in People With Cystic Fibrosis Treated With Highly Effective Modulator Therapy. Review Obstet Gynecol. 2025 Jan 1;145(1):47-54. doi: 10.1097/AOG.0000000000005732. Epub 2024 Sep 19. pubmed.ncbi.nlm.nih.gov/39666984/

With improvements in overall health attributable to newly available medications called highly effective modulator therapy, an increasing number of people with cystic fibrosis (CF) are pursuing pregnancy. However, the safety of these medications for pregnant people with CF and the fetus remains largely unknown. Limited data demonstrate a decline in patients’ health and well-being after withdrawal of highly effective modulator therapy during pregnancy; however, both animal and human studies suggest an association between highly effective modulator therapy and cataracts in the offspring that requires further investigation. Use of highly effective modulator therapy can also affect the results of newborn screening and may influence fetal outcomes among fetuses affected by CF as a result of transplacental passage of highly effective modulator therapy. An ongoing prospective cohort study will likely provide more information for pregnant people with CF. Until then, multidisciplinary counseling continues to be critical for people with CF who are of reproductive age.

Jennifer L Goralski is in the Division of Pulmonary and Critical Care Medicine, the Division of Pediatric Pulmonology, and the Division of Maternal Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Niels Høiby. Cystic fibrosis and the clinical biofilm revolution. A survey of the Danish CF Center’s contribution. Biofilm 2024 Dec 20:9:100246. doi: 10.1016/j.bioflm.2024.100246. eCollection 2025 Jun.  pubmed.ncbi.nlm.nih.gov/39811797/

Biofilm infections are chronic infections which are difficult to diagnose. Biofilm infections are tolerant to antibiotics and the defense mechanisms of the host. Patients with the genetic disease cystic fibrosis (CF) produce viscid mucus in the respiratory tract and therefore suffer from chronic biofilm infections in their lungs and paranasal sinuses. The most important microorganism is the mucoid phenotype of Pseudomonas aeruginosa which causes chronic biofilm infections in the lungs of CF patients and untreated patients succumb as children if they contact this biofilm infection. Since CF patients are treated in CF Centers all over the world, it is possible to do longitudinal studies on epidemiology, pathophysiology, diagnosis, prevention and treatment of P. aeruginosa biofilm infection which is not possible if such patients are not followed in specialized centers. This survey describes the research through several decades in the Danish CF Center in Copenhagen which have changed the epidemiology, treatment, prophylaxis and prognosis of CF patients worldwide. Based on these results ESCMID Guidelines for diagnosis and treatment of biofilm infections were published which have influenced biofilm research and treatment in other areas.

Niels Hoiby is with the European Society for Clinical Microbiology and Infectious Disease Study Group for Biofilms (ESGB), Switzerland; the Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Denmark and the
Institute of Immunology and Microbiology, Panum Institute, University of Copenhagen, Denmark.Chiara

Chiara Lanfranchi , Gianfranco Alicandro , Lisa Cariani, Beatrice Silvia Orena, Andrea Gramegna , Carmela Rizza, Francesco Blasi , Valeria Daccò. Respiratory Outcomes and Aspergillus Serology Following Elexacaftor/Tezacaftor/Ivacaftor Therapy in People with Cystic Fibrosis and a History of Aspergillus fumigatus Infection. Lung
. 2025 Jan 6;203(1):24. doi: 10.1007/s00408-024-00781-4.   pubmed.ncbi.nlm.nih.gov/39762638/

Purpose: The study evaluated the effects of elexacaftor/tezacaftor/ivacaftor (ETI) therapy in people with cystic fibrosis (pwCF) and a clinical history of Aspergillus fumigatus (AF) infection.
Methods: This prospective cohort study included pwCF who initiated ETI therapy and had received antifungal treatment in the preceding five years due to allergic bronchopulmonary aspergillosis (ABPA group) or other AF-related clinical manifestations (AF group). A control group of pwCF with no prior respiratory cultures positive for AF was also included. Changes from baseline to 12 months in spirometry measures and lung clearance index (LCI2.5), as well as respiratory colonization by AF, were compared across groups. Annual fold changes in the geometric mean of immunological markers were estimated using generalized estimating equations with a piecewise linear spline model, fitted to data collected from three years before to one-year post-ETI.
Results: The study included 16 patients in the ABPA group, 47 in the AF group, and 45 controls. Spirometry and LCI2.5 improvements were comparable across groups. Positive respiratory cultures decreased from 43.8 to 18.8% in the ABPA group (p = 0.30), and from 78.7 to 23.4% in the AF group (p < 0.001). Total IgE and IgG anti-AF decreased in both the ABPA and the AF groups, with annual reductions of 20-42%. No ABPA episodes occurred during ETI therapy.

Conclusion: During ETI therapy, pulmonary outcomes improved, AF colonization and sensitization decreased, and no episodes of ABPA were observed in pwCF with a clinical history of AF infection

Chiara Lanfranchi is in the Mother and Child Department, Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy.

Amalia S Magaret, Sonya L Heltshe. Need for re-assessment of impact of repeated pregnancy on lung health in cystic fibrosis. Respir Med. 2025 Jan:236:107890. doi: 10.1016/j.rmed.2024.107890. Epub 2024 Nov 28. pubmed.ncbi.nlm.nih.gov/39615801/

Amalia S Magaret is Faculty Director at the University of Washington Depts of Pediatrics and Biostatistics, United States; Seattle Children’s Research Institute, United States.

Lucy Perrem, Stephanie Jeanneret-Manning, Stephanie D Davis , Margaret Rosenfeld, Todd Edwards, Sanja Stanojevic, Felix Ratjen. Does using the Lung Clearance Index (LCI) inform clinical decisions in children with cystic fibrosis? J Cyst Fibros. 2025 Jan 11:S1569-1993(24)01852-6. doi: 10.1016/j.jcf.2024.12.001. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39800642/

Introduction: The Lung Clearance Index (LCI) is an established research test, but its role in clinical decision-making is not well defined. This study estimated the proportion of treatment decisions that are changed or supported by the added information provided by LCI.
Methods: A mixed methods prospective observational study was conducted in North America. Providers were invited to participate in a clinical vignette survey consisting of 10 hypothetical scenarios involving pediatric cystic fibrosis (CF) management. First, they made a clinical decision based on information captured in routine clinical visits. Then, the LCI value was made available, and providers were asked whether the LCI changed or supported their decision. A prospective study was also conducted at three CF centres to determine how often physicians make pulmonary treatment decisions at CF clinic visits and how often they perceive additional lung function data would be helpful for these decisions.
Results: We received 522 vignette responses from 62 participants. LCI changed the decision in 18.4 % of cases, supported the decision in 57.1 % and did not impact the decision in 24.5 %. Data from patient encounters in the prospective study demonstrated that changes to pulmonary treatments were considered in 98/322 (30.4 %) visits; additional lung function information could potentially have helped in 64.3 % of the treatment decisions.

Conclusion: LCI changes or supports a significant proportion of treatment decisions. Providers perceive that additional information about lung function could be helpful at the majority of encounters where changes in treatment are considered.

Lucy Perrem is a paediatric pulmonologist at  Children’s Health Ireland, Dublin, Ireland; University College Dublin, Dublin 4, Ireland.

Karuna Sapru, Joanna Wilkinson, Anthony K Webb, Muhammad Akhtar, Rowland J Bright-Thomas. Success Rates of Assisted Reproduction for Men With Cystic Fibrosis. Pediatr Pulmonol. 2025 Jan;60(1):e27472. doi: 10.1002/ppul.27472.  pubmed.ncbi.nlm.nih.gov/39812352/

Background: The vast majority of men with CF (mwCF) are infertile. Improvements in assisted reproductive technology (ART) have made it possible for these patients to become biological fathers.
Methods: Data were examined for all male CF patients attending a large adult CF center over a 23-year period. Azoospermia was confirmed via laboratory analysis of semen and was defined as complete absence of sperm in the ejaculate. Outcome of surgical sperm retrieval (SSR) procedure, post SSR complications, success rate of intracytoplasmic sperm injection (ICSI) and embryo transfer and subsequent live births were evaluated.
Results: Seventy-one mwCF with proven azoospermia were referred to fertility services over the study period. Mean (SD) percentage predicted forced expiratory volume in 1 second (ppFEV1) 67.86 ( ± 25.3), body mass index (BMI) 24.3 ( ± 3.7) kg/m2. Seventy (98.5%) of these men underwent and had successful SSR. 67/71 (94%) couples proceeded to have ICSI post SSR. 11 couples had failed egg fertilisation, implantation, or early miscarriage. 56/67 couples (84%) went on to have live births. To date 10/71 (14%) mwCF referred for fertility treatment have died. Mean ppFEV1 and BMI of mwCF who survived was higher than those who died; FEV1 72.8% ( ± 23.4) versus 38% ( ± 12.0) (p < 0.001), BMI 25.0 ( ± 3.5) kg/m2 versus 20.3 ( ± 2.2) kg/mg2 (p < 0.001).
Conclusion: This is the largest study to investigate success rate of fertility treatment in mwCF and demonstrates that fertility treatment is successful in greater than 75% of patients referred. Clinical status and prognosis remain important factors when considering referral to fertility services.

Karuna Sapru is in the Dept. of Respiratory Medicine, Manchester Adult Cystic Fibrosis Centre, North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Shad Christina , Paal Michael , Habler Katharina , Scherf-Clavel Oliver, Breuling Magdalena, Berger Christiane, Naehrig Susanne. Therapeutic drug monitoring of elexacaftor, tezacaftor, and ivacaftor before, during, and after pregnancy in women with cystic fibrosis: An observational study Respir Med . 2025 Jan:236:107868.doi: 10.1016/j.rmed.2024.107868. Epub 2024 Nov 19.  pubmed.ncbi.nlm.nih.gov/39566645/

Christina Shad
LinkedIn

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved health and increased life expectancy in many patients with cystic fibrosis (pwCF). Family planning issues have become more important since then. Many women decide to remain on modulator therapy during pregnancy despite insufficient evidence-based recommendations for continuing ETI during pregnancy and lactation.
Methods: In this retrospective observational report, we present data on maternal serum concentrations of ETI, assessed via a therapeutic drug monitoring (TDM) program established at our CF center for adults. Blood was taken during routine visits. We retrospectively analyzed the corresponding predicted forced expiratory volume in 1 s (ppFEV₁), at five time points before, during, and after pregnancy.
Results: Of seven ETI-exposed pregnancies in six women between February 2021 and September 2023, the intake of ETI resulted in no maternal complications and healthy offspring. The dose was reduced in all women, 71.4 % before and 28.6 % during pregnancy, primarily as a result of side effects and/or increased ETI concentrations. Despite dose reductions, serum concentrations showed a broad distribution, with values below, within, and above the C_max range according to the pharmacokinetic data in the manufacturer’s product characteristics. Pulmonary function largely remained stable without pulmonary exacerbations requiring intravenous antibiotic treatment.

Edith T Zemanick, Bonnie Ramsey, Dorota Sands, Edward F McKone, Isabelle Fajac , Jennifer L Taylor-Cousar , Marcus A Mall  , Michael W Konstan  , Nitin Nair , Jiaqiang Zhu , Emilio Arteaga-Solis  Fredrick Van Goor  , Lisa McGarry , Valentin Prieto-Centurion  , Patrick R Sosnay  , Carmen Bozic , David Waltz , Nicole Mayer-Hamblett.   Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment. J Cyst Fibros. 2025 Jan 3:S1569-1993(24)01854-X. doi: 10.1016/j.jcf.2024.12.006. Online ahead of print. J Cyst Fibros. 2025 Jan 3:S1569-1993(24)01854-X. doi: 10.1016/j.jcf.2024.12.006. Online ahead of print.

Background: Highly effective CFTR modulators improve CFTR function and lead to dramatic improvements in health outcomes in many people with cystic fibrosis (pwCF). The relationship between measures of CFTR function, such as sweat chloride concentration, and clinical outcomes in pwCF treated with CFTR modulators is poorly defined. We conducted analyses to better understand the relationships between sweat chloride and CFTR function in vitro, and between sweat chloride and clinical outcomes following CFTR modulator treatment.
Methods: Mean sweat chloride values in healthy people, CF carriers, and pwCF treated with CFTR modulators at different doses were compared to chloride transport in corresponding human bronchial epithelial (HBE) cells. A pooled analysis of phase 3 CFTR modulator studies was performed to evaluate the relationship between attained values of sweat chloride and improvements in lung function, body mass index (BMI), patient reported outcomes, pulmonary exacerbations, and lung function change over time.
Results: Sweat chloride concentrations in vivo correlated strongly with CFTR-dependent chloride current in HBE cells in vitro. Sweat chloride values of <30 mmol/L and ≥30 to <60 mmol/L in pwCF following CFTR modulator treatment were associated with better clinical outcomes than sweat chloride ≥60 to <80 mmol/L and ≥80 mmol/L.

Conclusions: In pwCF treated with CFTR modulators, lower sweat chloride levels (reflecting greater CFTR function) are associated with better clinical outcomes. These results support the therapeutic strategy of further restoring CFTR function towards normal, as reflected in lowering sweat chloride to below the diagnostic threshold for CF (<60 mmol/L) and to normal (<30 mmol/L), with CFTR modulators.

Edith T Zemanick  is in the Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado, Aurora, CO, U