2024

 Jean-Pierre Amoakon, Goutham Mylavarapu, Raouf S Amin, Anjaparavanda P Naren. Pulmonary Vascular Dysfunctions in Cystic Fibrosis.  Review  Physiology (Bethesda). 2024 Mar 19.  doi: 10.1152/physiol.00024.2023. Online ahead of print. 38501963 pubmed.ncbi.nlm.nih.gov/38501963/

Jean-Pierre Amoakon LinkedIn

Cystic Fibrosis (CF) is an inherited disorder caused by a deleterious mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Given that the CFTR protein is a chloride channel expressed on a variety of cells throughout the human body, mutations in this gene impact several organs, particularly the lungs. For this very reason, research regarding CF disease and CFTR function has historically focused on the lung airway epithelium. Nevertheless, it has been discovered more than two decades ago that CFTR is also expressed and functional on endothelial cells. Despite the great strides that have been made in understanding the role of CFTR in the airway epithelium, the role of CFTR in the endothelium remains unclear. Considering that the airway epithelium and endothelium work in tandem to allow gas exchange, it becomes very crucial to understand how a defective CFTR protein can impact the pulmonary vasculature and overall lung function. Fortunately, more recent research has been dedicated to elucidating the role of CFTR in the endothelium. As a result, several vascular dysfunctions associated with CF disease have come to light. Here, we summarize the current knowledge on pulmonary vascular dysfunctions in CF and discuss applicable therapies.

Jean-Pierre Amoakon is a researcher at Systems Biology and Physiology, University of Cincinnati, Cincinnati, Ohio, United States

Catherine R Armbruster, Yasmin K Hilliam, Anna C Zemke, Samar Atteih, Christopher W Marshall, John Moore, Junu Koirala, Leah Krainz, Jordan R Gaston , Stella E Lee, Vaughn S Cooper, Jennifer M Bomberger.  Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis.  mBio. 2024 Apr 2:e0051924.  doi: 10.1128/mbio.00519-24.  Online ahead of print.  pubmed.ncbi.nlm.nih.gov/38564694/

Catherine R Armbruster
Dartmouth medicine

Today, more than 90% of people with cystic fibrosis (pwCF) are eligible for the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy called elexacaftor/tezacaftor/ivacaftor (ETI) and its use is widespread. Given the drastic respiratory symptom improvement experienced by many post-ETI, clinical studies are already underway to reduce the number of respiratory therapies, including antibiotic regimens, that pwCF historically relied on to combat lung disease progression. Early studies suggest that bacterial burden in the lungs is reduced post-ETI, yet it is unknown how chronic Pseudomonas aeruginosa populations are impacted by ETI. We found that pwCF remain infected throughout their upper and lower respiratory tract with their same strain of P. aeruginosa post-ETI, and these strains continue to evolve in response to the newly CFTR-corrected airway. Our work underscores the continued importance of CF airway microbiology in the new era of highly effective CFTR modulator therapy.
Importance: The highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

Catherine Armbruster is in the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.and the Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.

C J Bathgate, D A Fedele, E M Tillman, J He 4 , R S Everhart , L R Reznikov, F F Liu , K Kirby , K Raffensperger , K Traver , K A Riekert  , S W Powers  , A M Georgiopoulos. Elexacaftor/tezacaftor/ivacaftor and mental health: A workshop report from the Cystic Fibrosis Foundation’s Prioritizing Research in Mental Health working group.Review J Cyst Fibros. 2024 Nov 26:S1569-1993(24)01814-9. doi: 10.1016/j.jcf.2024.11.006. Online ahead of print. Free article.pubmed.ncbi.nlm.nih.gov/39592379/

C J Bathgate
National Jewish Health

Background: This report summarizes the 2023 inaugural annual meeting of the Cystic Fibrosis Foundation’s Prioritizing Research in Mental Health (PRIME) working group. This workshop focused on mental health and elexacaftor/tezacaftor/ivacaftor (ETI).
Methods: We reviewed existing literature and identified key gaps and study design considerations in preclinical work, pharmacokinetics/pharmacodynamics, mood/anxiety, quality of life/self-perception, neuropsychological symptoms, sleep, and symptom management.
Results: Limited studies have identified behavioral changes with modulator exposure in rodent models of depression, anxiety, and cognition. Longitudinal human studies reporting mean changes generally show no change or improvement. However, case reports and single-center studies identify subgroups reporting new or worsening symptoms.
Conclusions: Future studies should focus on understanding the role of CFTR in the nervous system, defining ETI impacts in preclinical models, and mechanistic investigations. Innovative methods with larger samples and comprehensive assessments are needed to determine the incidence of new/worsening symptoms throughout the lifespan and effective management strategies.

C J Bathgate is a clinical psychologist in the Department of Medicine National Jewish Health, Denver, CO, USA.

Katie J BayfieldOliver WeinheimerAnna MiddletonChristie BoytonRachel FitzpatrickBrendan KennedyAnneliese BlaxlandGeshani JayasuriyaNeil CaplainMark O WielpützLifeng YuCraig J GalbanTerry E RobinsonBrian BartholmaiPer GustafssonDominic FitzgeraldHiran SelvaduraiPaul D Robinson. Comparative sensitivity of early cystic fibrosis lung disease detection tools in school aged children.  J Cyst Fibros . 2024 Sep;23(5):918-925.doi: 10.1016/j.jcf.2024.05.012. Epub 2024 Jul 4.     38969602. pubmed.ncbi.nlm.nih.gov/38969602/

Katie J Bayfield
ResearchGate

Background: Effective detection of early lung disease in cystic fibrosis (CF) is critical to understanding early pathogenesis and evaluating early intervention strategies. We aimed to compare ability of several proposed sensitive functional tools to detect early CF lung disease as defined by CT structural disease in school aged children.
Methods: 50 CF subjects (mean±SD 11.2 ± 3.5y, range 5-18y) with early lung disease (FEV1≥70 % predicted: 95.7 ± 11.8 %) performed spirometry, Multiple breath washout (MBW, including trapped gas assessment), oscillometry, cardiopulmonary exercise testing (CPET) and simultaneous spirometer-directed low-dose CT imaging. CT data were analysed using well-evaluated fully quantitative software for bronchiectasis and air trapping (AT).
Results: CT bronchiectasis and AT occurred in 24 % and 58 % of patients, respectively. Of the functional tools, MBW detected the highest rates of abnormality: Scond 82 %, MBWTG RV 78 %, LCI 74 %, MBWTG IC 68 % and Sacin 51 %. CPET VO2peak detected slightly higher rates of abnormality (9 %) than spirometry-based FEV1 (2 %). For oscillometry AX (14 %) performed better than Rrs (2 %) whereas Xrs and R5-19 failed to detect any abnormality. LCI and Scond correlated with bronchiectasis (r = 0.55-0.64, p < 0.001) and AT (r = 0.73-0.74, p < 0.001). MBW-assessed trapped gas was detectable in 92 % of subjects and concordant with CT-assessed AT in 74 %.
Conclusions: Significant structural and functional deficits occur in early CF lung disease, as detected by CT and MBW. For MBW, additional utility, beyond that offered by LCI, was suggested for Scond and MBW-assessed gas trapping. Our study reinforces the complementary nature of these tools and the limited utility of conventional oscillometry and CPET in this setting.

Katie Bayfield is a Clinical Research Physiologist at The Children’s Hospital at Westmead, Westmead, New South Wales, Australia.

Françoise Simonnet Bisson, Mathieu Fauvernier , Chantal Belleguic, Isabelle Danner Boucher, Dominique Grenet, Rebecca Hamidfar, Dominique Hubert, Julie Macey, Marlène Murris-Espin, Michele Porzio, Sophie Ramel, Quitterie Reynaud, Martine Reynaud-Gaubert, Pierre-Régis Burgel.   Intimacy and sexual life of females with cystic fibrosis.   J Cyst Fibros. 2024 Aug 24:S1569-1993(24)00829-4. doi: 10.1016/j.jcf.2024.08.003. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39183126/
Introduction: The effects of cystic fibrosis (CF) on females’ sexuality have not been described. The aims of the present study were to describe and characterize sexual issues in females with CF.
Methods: We included adult (≥18 years) females with CF currently or previously in a sexual relationship from 11 adult CF centres in France. We collected quantitative data using a modified version of the self-administered Pelvic Incontinence Sexual Questionnaire IUGA-Revised (PISQ-IR). We performed one-to-one interviews using a semi-directive framework in volunteer females to further characterize the effects of CF on sexual life. We summarized answers to questionnaire as percentages and analysed interviews by theme according to discourse analysis method.
Results: Between November 2019 and July 2021, 212 females completed the PISQR-IR, of whom 15 were interviewed. Of the females who completed the questionnaire, 93.4% were concerned about the discomfort, pain, or unpleasantness they experienced during sexual intercourse. The most frequent cause of sexual difficulties was a lack of vaginal lubrication (78.8%), followed by pain (74.1%) and discomfort. Interviews revealed sexual lives that were uncomfortable or painful, unsatisfying or avoided for most females, with a strong impression of being sexually different, incompetent, and betrayed by their bodies in terms of sexual desire.
Conclusion: Sexual difficulties faced by females with CF are highly prevalent. Increasing awareness regarding sex life issues in females with CF appears necessary to improve their management by CF multidisciplinary teams.

Françoise Simonnet Bisson is a Psychologist, Sexologist, at the  Hospices Civils de Lyon, CRCM adultes, Médecine Interne Hôpital Lyon Sud France

Elora Blaisonneau , Brendan Le Daré, Marion Mercerolle , Astrid Bacle , Louise Triquet , Marie-Noëlle Osmont , Chantal Belleguic, Elisabeth Polard. [Adverse effects of the tezacaftor/ivacaftor/elexacaftor combination that may lead to discontinuation: About a series of 10 cases] [Article in French].Therapie
. 2024 Jul 14:S0040-5957(24)00073-8. doi: 10.1016/j.therap.2024.06.005. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/39174453/
The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France).
Materials and methods: A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France.
Results: Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case.
Conclusion: This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of “caftors”, their possible risk factors, and the impact of adjusting dosing modalities.

Elora Blaisonnea is at the Pôle pharmacie, centre hospitalier universitaire de Rennes, 35000 Rennes, France.

Sydney Blankenship, Aaron R Landis, Emily Harrison Williams, Jacelyn E Peabody Lever , Bryan Garcia, George Solomon, Stefanie Krick.  What the future holds: cystic fibrosis and aging.  Review  Front Med (Lausanne). 2024 Jan 8:10:1340388. doi: 10.3389/fmed.2023.1340388.  eCollection 2023.    pubmed.ncbi.nlm.nih.gov/38264036/   

Sydney Blankenship
USNews. Health

Cystic fibrosis (CF) is one of the most common genetic diseases with around 70,000 affected patients worldwide. CF is a multisystem disease caused by a mutation in the CF transmembrane conductance regulator gene, which has led to a significant decrease in life expectancy and a marked impairment in the quality of life for people with CF (pwCF). In recent years, the use of highly effective CFTR modulator therapy (HEMT) has led to improved pulmonary function, fewer CF exacerbations, lower symptom burden, and increased weight. This has coincided with an increased life expectancy for pwCF, with mean age of survival being now in the 50s. This being a major breakthrough, which the CF population has hoped for, pwCF are now facing new challenges by growing old with a chronic respiratory disease. In this mini review, we are attempting to summarize the current knowledge of the aging process and its effect on CF disease and its manifestations including new developments, the current research gaps and potential future developments in the field to allow healthy aging for the CF community..

Sydney Blankenship is a Resident Physician in the  Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States.

Frank A J A Bodewes, Alvin Jay Freeman, Alexander Weymann, Dominique Debray, Isabelle Scheers, Henkjan J Verkade , Michael R Narkewic.  Towards a Standardized Classification of the Hepatobiliary Manifestations in Cystic Fibrosis (CFHBI): A Joint ESPGHAN/NASPGHAN Position Paper.  J Pediatr Gastroenterol Nutr. 2024 Jan;78(1):153-165. doi: 10.1097/MPG.0000000000003944.  pubmed.ncbi.nlm.nih.gov/38291686/

Frank A J A Bodewes
AMilner

The broad spectrum of hepatobiliary involvement in cystic fibrosis (CF) has been commonly referred to as cystic fibrosis liver disease (CFLD). However, differences in the definitions of CFLD have led to variations in reported prevalence, incidence rates, and standardized recommendations for diagnosis and therapies. Harmonizing the description of the spectrum of hepatobiliary involvement in all people with CF (pwCF) is deemed essential for providing a reliable account of the natural history, which in turn supports the development of meaningful clinical outcomes in patient care and research. Recognizing this necessity, The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) commissioned and tasked a committee to develop and propose a systematic classification of the CF hepatobiliary manifestations to increase uniformity, accuracy, and comparability for clinical, registry, and research purposes. This report describes the committee’s combined expert position statement on hepatobiliary involvement in CF, which has been endorsed by NASPGHAN and ESPGHAN. We recommend using CFHBI (Cystic Fibrosis Hepato-Biliary Involvement) as the updated term to describe and classify all hepatobiliary manifestations in all pwCF. CFHBI encompasses the current extensive spectrum of phenotypical, clinical, or diagnostic expressions of liver involvement observed in pwCF. We present a schematic categorization of CFHBI, which may also be used to track and classify the changes and development of CFHBI in pwCF over time. The proposed classification for CFHBI is based on expert consensus and has not been validated for clinical practice and research purposes. Achieving validation should be an important aim for future research.

Frank A J A Bodewes is in the Division of Pediatric Gastroenterology/Hepatology, Beatrix Children’s Hospital/University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Naïm Bouazza, Saïk Urien, Frantz Foissac, Laure Choupeaux, Gabrielle Lui, Léo Froelicher Bournaud. Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy. Clin Pharmacokinet. 2024 Mar;63(3):333-342.  doi: 10.1007/s40262-023-01342-3. Epub 2024 Feb 4.  pubmed.ncbi.nlm.nih.gov/38310629/
Background: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols.Objectives and methods: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated.
Results: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment.

Conclusions: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

Naïm Bouazza is at the Université Paris Cité, EA7323, Paris, France; Unité de Recherche Clinique Necker Cochin, AP-HP, Paris, France;  CIC-1419 Inserm, Cochin-Necker, Paris, France.

Rebekah F Brown , Charlotte T CloseMolly G Mailes , Luis J Gonzalez , Danielle M Goetz , Stephanie S Filigno , Rebecca Preslar , Quynh T Tran , Sarah E Hempstead , Paula Lomas , A Whitney Brown , Patrick A Flume ; CFF Care Model Committee. Cystic fibrosis foundation position paper: Redefining the cystic fibrosis care team. Cyst Fibros. 2024 Sep 24:S1569-1993(24)01778-8.doi: 10.1016/j.jcf.2024.09.011. Online ahead of print.pubmed.ncbi.nlm.nih.gov/39327194/

Rebekah F Brown
health.usnews.com

Interdisciplinary teams care for people with cystic fibrosis (pwCF) at specialized treatment centers. These teams have laid the foundation for the cystic fibrosis (CF) care model responsible for gains in health outcomes and quality of life within the CF community. However, the landscape of CF care is transforming, invigorated by new technologies, accessibility of cystic fibrosis transmembrane conductance regulator (CFTR) therapies, and increased utilization of telemedicine. In light of these advances, it is appropriate to re-evaluate the CF care team structure. This position paper offers guidance for the structure of a CF care center designed to meet the evolving needs of the CF community. Fundamental to the proposed center structure is recognition of pwCF and their families as integral members of their care teams, underpinning the necessity for shared decision making, awareness of social determinants of health, and active partnership between all healthcare professionals involved in the care of pwCF.

Rebekah F Brown is in the Department of Pediatrics, Division of Allergy, Immunology and Pulmonary Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Burgel P-R, Southern KW, Addy C, Battezzati A, Berry C, Bouchara J-P, et al. Standards for the care of people with cystic fibrosis (CF); recognising and addressing CF health issues. Journal of Cystic Fibrosis. 2024. DOI:https://doi.org/10.1016/j.jcf.2024.01.005

 Pierre-Régis Burgel, Jean-Louis Paillasseur, Isabelle Durieu, Martine Reynaud-Gaubert, Rebecca Hamidfar, Marlène Murris-Espin, Isabelle Danner-Boucher, Raphaël Chiron, Sylvie Leroy, Benoit Douvry, Dominique Grenet, Laurent Mely, Sophie Ramel  13 , Sylvie Moncouquiol  14 , Espérie Burnet  15 , El Hassane Ouaalaya, Philippe Sogni, Jennifer Da Silva, Clémence Martin.  Multisystemic Effects of Elexacaftor-Tezacaftor-Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease.  Ann Am Thorac Soc. 2024 Apr 5.  doi: 10.1513/AnnalsATS.202312-1065OC. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38579175/

Pierre-Regis Burgel
Institut Cochin

Rationale: Limited data exist on safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease.
Objective: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease.
Methods: A prospective observational study, including all adults, aged 18 years and older, with a percent predicted FEV1 (ppFEV1)≤ 40 who initiated ETI from December 2019 to June 2021 in France was conducted. PwCF were followed until August 8th, 2022.Results: ETI was initiated in 434 pwCF with a median [interquartile range, IQR] ppFEV1=30 [25; 35], including 27 with severe CF liver disease and 183 with diabetes. PwCF were followed for a median [IQR] 587 [396; 728] days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was mostly due to lung transplantation (n=5) or death (n=4). Absolute increase in ppFEV1 by a mean +14.2% (95% CI, 13.1-15.4) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the younger age quartile was almost twice that of the oldest quartile (P<0.001); body mass index <18.5 kg/m2 was found in 38.6% at initiation vs. 11.3% at 12 months (P=0.0001). Increase in serum concentrations of vitamin A and E, but not 25OHD3, was observed. Significant reduction in the % of pwCF using oxygen therapy, non-invasive ventilation, nutritional support, inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of diabetics.

Conclusion: ETI is safe in pwCF and advanced lung disease with multisystem pulmonary and extrapulmonary benefits.

Pierre-Régis Burgel is at the Cochin Hospital, APHP, Respiratory Medicine, Paris,

Pierre-Régis Burgel,  Isabelle Sermet-Gaudelus, Emmanuelle Girodon, Isabelle Durieu, Véronique Houdouin, et al.  French Cystic Fibrosis Reference Network study group. The expanded French compassionate programme for elexacaftor-tezacaftor-ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study. Lancet Respir Med. 2024 Aug 13:S2213-2600(24)00208-X. doi: 10.1016/S2213-2600(24)00208-X. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39151434/
Background: Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response.
Methods: The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France’s 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses
Findings: The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV1 (ppFEV1) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV1 was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor

Interpretation: In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population.

Funding: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.

FranceeAlice Castaldo, Monica Gelzo, Paola Iacotucci, Annalisa Longobardi, Giovanni Taccetti, Vito Terlizzi, Vincenzo Carnovale. One year of treatment with elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis homozygous for the F508del mutation causes a significant increase in liver biochemical indexes.Front Mol Biosci. 2024 Jan 8:10:1327958. doi: 10.3389/fmolb.2023.1327958. eCollection 2023 Free PMC article   pubmed.ncbi.nlm.nih.gov/38259684/

Introduction: Modulators of cystic fibrosis transmembrane conductance regulator mutated protein significantly improved the outcome of patients with cystic fibrosis (CF). We describe 63 patients who were independently followed up in two CF regional centers (i.e., Campania and Tuscany regions).
Methods: All patients were homozygous for the F508del mutation and were treated with lumacaftor/ivacaftor (LI) for 3 years, followed by 1 year of treatment with elexacaftor/tezacaftor/ivacaftor (ETI). We studied the biochemical parameters of liver damage and cholesterol metabolism.
Results: Beyond the improvement of BMI and lung function with LI treatment and even more with ETI, we found that the 3 years of LI treatment significantly improved liver function parameters (total and conjugated bilirubin, ALT, AP, and GGT), while the subsequent ETI treatment caused a significant increase of such parameters. Discussion: We confirm that treatment with LI does not correct hypocholesterolemia, whereas treatment with ETI significantly increases serum cholesterol. Such an increase is likely due to enhanced de novo biosynthesis, as indicated by the significant increase in serum lathosterol, and it is likely that the subsequent liver cholesterol accumulation may contribute to triggering inflammation and worsening liver biochemical indexes. The increase in serum bilirubin and ALT that we observed in approximately 94% and 84% of patients treated with ETI, respectively, suggests further investigation of the impact of ETI therapy on liver function indexes.

Alice Castaldo is in the Dipartimento di Scienze Mediche Traslazionali, Centro Regionale Fibrosi Cistica del Bambino – Pediatria, Università di Napoli Federico II, Naples, Italy.

Martina Cecchetti, Luca Scarallo, Paolo Lionetti , Chee Y Ooi, Vito Terlizzi Impact of highly effective modulator therapy on gastrointestinal symptoms and features in people with cystic fibrosis. Review Paediatr Respir Rev
. 2024 Sep 20:S1526-0542(24)00076-9. doi: 10.1016/j.prrv.2024.07.004. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/39341749/
Highly effective modulator therapy (HEMT), particularly the triple combination elexacaftor-tezacaftor-ivacaftor (ETI), significantly improved clinical outcomes and quality of life in people with Cystic Fibrosis (pwCF). This review analyzes current knowledge on the impact of HEMTs on gastrointestinal (GI) symptoms and features in pwCF. A descriptive review of English literature until February 29, 2024, was conducted using medical databases. Observational studies and clinical trials addressing GI reflux disease (GERD), lower GI symptoms and pancreatic disease were considered. Studies report positive effects of HEMTs on pH levels and bicarbonate secretion as well as improvement on intestinal inflammation. HEMTs also demonstrated positive effects on GERD and lower GI symptoms or conditions CF related such as dysbiosis. Taking ETI during pregnancy could also allow resolution of meconium ileus in fetuses with CF. The best benefits were observed in pancreatic function, potentially delaying CF-related diabetes and recovering pancreatic function in some children on ETI. Larger trials, particularly in pediatric populations, need to confirm these findings and explore long-term effects.

Martina Cecchetti is in the Department of Health Sciences, University of Florence, Florence, Italy; Meyer Children Hospital IRCCS, Florence, Italy.

Emily Chesshyre, Fiona C Warren, Angela C Shore, Jane C Davies, Darius Armstrong-James , Adilia Warris. Long-Term Outcomes of Allergic Bronchopulmonary Aspergillosis and Aspergillus Colonization in Children and Adolescents with Cystic Fibrosis. J Fungi (Basel)
. 2024 Aug 24;10(9):599. doi: 10.3390/jof10090599.  pubmed.ncbi.nlm.nih.gov/39330359/
Observational studies indicate that Aspergillus colonization and allergic bronchopulmonary aspergillosis (ABPA) in people with cystic fibrosis (CF) are associated with poorer lung health and increased disease severity. We performed a longitudinal observational cohort study to analyse long-term outcomes of Aspergillus colonization and ABPA in children with CF. Anonymised UK CF Registry data from 2009 to 2019 for patients aged 8-17 years in 2009-2010 were collected. For the baseline cohort analysis, patients were classified based on the presence of Aspergillus colonization and ABPA in 2009 and/or 2010. For the longitudinal analysis, patients were categorised according to annual Aspergillus colonization and ABPA status. Comparisons made were (1) Aspergillus positive vs. negative; (2) excluding those with ABPA: Aspergillus positive vs. negative; and (3) ABPA positive vs. negative. Primary outcome was percentage predicted FEV1 decline and secondary outcomes included BMI decline, mortality, lung transplant, and IV antibiotic use.
Of the 1675 children, 263 had Aspergillus colonization in the baseline cohort, 260 were diagnosed with ABPA, and 80 had both. Baseline cohort analysis showed significantly lower lung function (p < 0.0001) and increased antibiotic treatment (p < 0.001) in those with Aspergillus colonization and in those with ABPA. Longitudinal analysis showed ABPA was associated with increased decline in lung function (p < 0.00001) and BMI (p < 0.00001). Aspergillus colonization was associated with increased decline in BMI (p = 0.005) but not lung function (p = 0.30). ABPA was associated with increased decline in long-term lung function and BMI in children and young people with CF. Aspergillus colonization was associated with lower lung function at baseline, but no increased rate of decline was observed long-term

Emily Chesshyre is Paediatric Infectious Disease Consultant at the MRC Centre for Medical Mycology, University of Exeter, Exeter EX4 4QD, UK. and Department of Paediatrics, Royal Devon University Healthcare NHS Foundation Trust, Exeter EX2 5DW, UK

Dinu Zinovie Ciobanu , Nara Liessi, Valeria Tomati , Valeria Capurro , Sine Mandrup Bertozzi , Maria Summa, Rosalia Bertorelli, Nicoletta Loberto, Dorina Dobi, Massimo Aureli, Lucilla Nobbio, Tiziano Bandiera, Nicoletta Pedemonte , Rosaria Bassi, Andrea Armirotti. Tezacaftor is a direct inhibitor of sphingolipid delta-4 desaturase enzyme (DEGS). J Cyst Fibros
. 2024 Nov;23(6):1167-1172. doi: 10.1016/j.jcf.2024.05.004. Epub 2024 May 24.
pubmed.ncbi.nlm.nih.gov/38789319/
Background: We recently demonstrated that 48 h exposure of primary human bronchial epithelial (hBE) cells, obtained from both CF (F508del homozygous) and non-CF subjects, to the triple drug combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) results in a CFTR genotype-independent modulation of the de novo synthethic pathway of sphingolipids, with an accumulation of dihydroceramides (dHCer). Since dHCer are converted into ceramides (Cer) by the action of a delta-4 sphingolipid desaturase (DEGS) enzyme, we aimed to better understand this off-target effect of ETI (i.e., not related to CFTR rescue) METHODS: hBE cells, both F508del and wild-type, were cultured to create fully differentiated bronchial epithelia. We analyzed Cer and dHCer using an LC-MS based method previously developed by our lab. DEGS expression levels in differentiated hBE cells lysates were quantified by western blot analysis.
Results: We demonstrated that 1) dHCer accumulate in hBE with time following prolonged ETI exposure, that 2) similar inhibition occurs in wild-type primary human hepatocytes and that 3) this does not result in an alteration of DEGS expression. We then proved that 4) ETI is a direct inhibitor of DEGS, that 5) Tezacaftor is the molecule responsible for this effect, that 6) the inhibition is concentration dependent. Finally, after repeated oral administration of ETI to naïve, non-CF, mice, we observed a slight accumulation of dHCer in the brain.

Conclusions: We believe that further investigations on Tezacaftor should be envisaged, particularly for the use of ETI during pregnancy, breastfeeding and in the early stages of development. DEGS dysfunction and dHCer accumulation causes impairment in the development of the nervous system, due to a derangement in myelin formation and maintenance.

Dinu Zinovie Ciobanu is a PhD student at the Chemistry Facility, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy.

Giuseppe Cimino, Sara Sorrenti, Manuel Murciano,  Paola Galoppi, Fiorentina Ascenzioni, Bruno Botta, Roberto Brunelli ; Sapienza University Working Group on Cystic Fibrosis in Pregnancy.  Use of elexacaftor/tezacaftor/ivacaftor combination in pregnancy.  Review Arch Gynecol Obstet.

Jan;309(1):9-15.  doi: 10.1007/s00404-023-06962-5. Epub 2023 Mar 13.     pubmed.ncbi.nlm.nih.gov/36907900/
Introduction: Management of cystic fibrosis has recently stepped forward with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, although data on potential adverse effects are lacking for many categories of patients, such as pregnant women.
Methods: We report one of the first reports on the outcome of pregnancy in a woman treated with Elexacaftor/Tezacaftor/Ivacaftor during the second and third trimester of pregnancy, showing a significant improvement of respiratory status, compared with the first trimester when the medication was discontinued due to unknown and, therefore, potential teratogenic effects. Also, we performed the review of the existing literature on the topic.
Results: The course of pregnancy was uneventful, with reference to major obstetric complications, and the patient delivered a healthy neonate. These results were similar to those coming from other short series of pregnant women affected by cystic fibrosis and treated with CFTR modulators during pregnancy.
Conclusions: Thus, despite the lack of evidence on the topic, the use of Elexacaftor/Tezacaftor/Ivacaftor in pregnancy seems to be apparently not associated with major adverse events, thus opening optimistic scenarios in terms of management of these patients.

Giuseppe Cimino is at the Cystic Fibrosis Regional Reference Center, A.O.U. Policlinico Umberto I, Rome, Italy and the Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Via del Policlinico, 155, 00161, Rome, Italy.

Cinzia Colombo, Rita Banzi, Chiara Gerardi, Eleonora Allocati, Paola Mosconi , Emanuela Foglia , Lucrezia Ferrario, Francesca Romano, Carlo Castellani; Gruppo Multidisciplinare HTA.  Cystic fibrosis carrier screening: a Health technology assessment  Recenti Prog Med   2024 Jan;115(1):35-39. doi: 10.1701/4169.41644.     pubmed.ncbi.nlm.nih.gov/38169359/

Cinzia Colombo
ResearchGate

This project of Health technology assessment was aimed at defining the impacts of offering a cystic fibrosis (CF) carrier screening to the general population, compared to the current situation, where the test is offered to individuals at high-risk to give birth to a child with CF. Results revealed: i) a lack of robust and updated data; ii) a return on investment up to six years from the screening’s introduction, despite important economic and organizational efforts; iii) a general positive attitude of healthcare professionals, people with CF, families and general population; iv) possible issues related to the social impact.

Cinzia Colombo is a post-doctoral Researcher at the Istituto di Ricerche farmacologiche Mario Negri Irccs, Milano.

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/

Gary Connett
childhealthinternational.org

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.

Luca Cristiani, Flávia Fonseca Fernandes  Year in review 2023 – Back to the future.       J Cyst Fibros. 2024 Mar 1:S1569-1993(24)00022-5. doi: 10.1016/j.jcf.2024.02.007. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38431442/

Flavia Fonseca Fernades Facebook

This review synthesizes articles published in 2023, focusing on the impact of elexacaftor-tezacaftor-ivacaftor (ETI) in cystic fibrosis (CF) care. Real-world data highlights sustained benefTits of ETI across age groups, while challenges like neuropsychological side effects persist. Beyond CFTR modulators, research explores telemedicine and novel therapies. Prioritizing equitable access and addressing unmet needs remain crucial for comprehensive CF management.

Luca Cristiani is in the Department of Pneumology and Cystic Fibrosis Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy.

Flavia Fonseca Fernades (Corresponding author)  is at the Medicine Department, Universidade Federal de Catalao,, Brazil;  Pneumology Unit, Hospital de Base do Distrito Federal, Brasília, Brazil;
Thoracic Diseases Unit, Hospital Regional da Asa Norte, Brasília, Brazi

Valeria Daccò , Andrea Gramegna , Chiara Rosazza , Alessandra Mariani , Arianna Biffi , Chiara Lanfranchi  Laura Zazzeron , Federica Bellante, Francesco Blasi , Gianfranco Alicandro.  Lung clearance index improves in people with cystic fibrosis not achieving a clinical important difference in Forced Expiratory Volume in One Second After  Elexacaftor/Tezacaftor/Ivacaftor Therapy. Observational Study Lung
. 2024 Nov 30;203(1):9. doi: 10.1007/s00408-024-00768-1.   pubmed.ncbi.nlm.nih.gov/39614886/

Valerie Dacco Policlinico di Milano

Purpose: In people with cystic fibrosis (pwCF), elexacaftor/tezacaftor/ivacaftor (ETI) therapy is associated with an average improvement in FEV1 of 10-14%. However, a subset of individuals fails to achieve a clinically meaningful increase in spirometric indicators. In this study, we aimed to assess whether the lung clearance index (LCI2.5), a more sensitive indicator of lung involvement, improves following ETI initiation in this population.
Methods: We conducted a prospective observational study in a specialized CF center in Italy. PwCF performed a spirometry and a multiple breath nitrogen washout test the day they initiated ETI therapy and after 6 and 12 months. They were grouped according to the 12-month change in FEV1 into two groups: Individuals who experienced a change in FEV1 ≥ a minimal clinically important difference (MCID) of 3% and those who did not. Mean changes in LCI2.5 were estimated using generalized estimating equations.
Results: The study included 129 pwCF who initiated ETI at our center (Age Range: 12-36 years). In 20 subjects (15.5%), the FEV1 change was < MCID. These individuals had better baseline pulmonary function than those with FEV1 changes ≥ MCID (Median FEV1: 102.5 vs 87.0%), with the majority (90%) having FEV1 values ≥ 90%. Mean changes in LCI2.5 at 12-month follow-up visit were – 1.44 units (95% CI: – 2.12; – 0.75) in individuals with changes in FEV1 < MCID and – 2.64 units (95% CI: -3.05; -2.23) in those with values ≥ MCID.

Conclusion: LCI2.5 is a useful measure to monitor the effectiveness of ETI in pwCF with normal spirometry and limited FEV1 change following treatment initiation.

Valeria Daccò is at the Mother and Child Department, Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy.

Trevor A Davis, Abra Miller , Christine Hachem, Christopher Velez, Dhiren Patel. The current state of gastrointestinal motility evaluation in cystic fibrosis: a comprehensive literature review.Review Transl Gastroenterol Hepatol. 2023 Dec 6:9:10. doi: 10.21037/tgh-23-59. eCollection 2024.  Free PMC article.  pubmed.ncbi.nlm.nih.gov/38317748/

Trevor Davies Washington University School of Medicine

Background and objective: As life expectancy in cystic fibrosis (CF) has increased over the years, a shift in focus toward extra-pulmonary comorbidities such as gastrointestinal (GI) disease has become a topic of particular importance. Although not well-defined in the current literature, GI dysmotility is thought to significantly contribute to GI symptomatology in the CF population. The objective of this article was to provide a comprehensive review of diagnostic modalities at the disposal of the clinician in the evaluation of patients with CF (pwCF) presenting with GI complaints. Furthermore, we aimed to highlight the available literature regarding utilization of these modalities in CF, in addition to their shortcomings, and emphasize areas within the motility literature where further research is essential.

Methods: A comprehensive review of all available literature in the English language through December 1, 2022 utilizing PubMed was conducted. Our search was limited to GI motility/transit and dysmotility in pwCF. Two researchers independently screened references for applicable articles and extracted pertinent data.

Key content and findings: Several diagnostic imaging and manometry options exist in the evaluation of dysmotility; however, the literature is lacking in high-quality, prospective studies to validate such testing in pwCF. Common symptoms experienced and diagnostic motility tools available based on segment of the GI tract as related to pwCF are explored in the current review. Shortcomings in the current literature are identified and future direction to enhance research efforts within the field of CF-related dysmotility is provided.

Conclusions: The influence of CF on GI integrity and motility is far-reaching. Despite improvements in longevity and advancement of pulmonary-specific treatment strategies, further high-quality research targeting the evaluation and management of GI dysmotility in pwCF is needed.

Trevor A Davis is in the Division of Gastroenterology, Department of Pediatrics, Washington University School of Medicine, Saint Louis Children’s Hospital, St. Louis, MO, USA.

Emily Devoy, Dominic Hughes, Asma Falah Alharbi, Jacqueline Francis, Jane C Davies  What is cystic fibrosis screen positive inconclusive diagnosis? And what is it not? Arch Dis Child Educ Pract Ed. 2024 Mar 7:edpract-2023-326767. doi: 10.1136/archdischild-2023-pubmed.ncbi.nlm.nih.gov/38453427/

     Jane Davies

Since screening for cystic fibrosis (CF) was incorporated into the newborn screening program, the number of recognised variants in the CF transmembrane conductance regulator (CFTR) gene has significantly increased. This has led to the discovery of combinations of gene variants with an uncertain prognosis. One outcome is the designation of ‘cystic fibrosis screen positive inconclusive diagnosis’ (CFSPID). While the majority of these children are expected to be unaffected by their CFTR variants, a small proportion have been seen to develop symptoms or increasing sweat chloride levels over time, which may reflect dysfunction of the CFTR protein.As the number of children with CFSPID increases, paediatricians and those working in primary care are more likely to encounter them in their practice. It is important that professionals have an understanding of CFSPID: what it is and, importantly, what it is not (ie, they do not have CF). In this article, we hope to explore this using some example cases, illustrating the ways in which these children may present symptomatically and how to manage them.

Emily Devoy is at the Chelsea and Westminster Hospital NHS Foundation Trust, London, UK

Jane Davies is professor at the Royal Brompton Hospital, London and at Imperial College London, National Heart and Lung Institute, London, UK.

Jane C Davies, Deepika Polineni , A Christopher Boyd, Scott Donaldson, Deborah R Gill, Uta Griesenbach, Stephen C Hyde, Raksha Jain, Gerry McLachlan, Marcus A Mall, Eric Wfw Alton. Lentiviral Gene Therapy for Cystic Fibrosis: A Promising Approach and First-In-Human Trial. Am J Respir Crit Care Med. 2024 Sep 5. doi: 10.1164/rccm.202402-0389CI. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39236265/
Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While cystic fibrosis is a multi-organ disease, the leading causes of morbidity and mortality are related to progressive lung disease. Current understanding of the effects of the broad spectrum of CFTR mutations on CFTR function has allowed for the development of CFTR modulator therapies. Despite the remarkable impact that these therapies have had, there remains a significant proportion of people with cystic fibrosis (estimated at 10-15% of the global cystic fibrosis population) who are genetically ineligible for, or intolerant to, current CFTR-targeting therapies and whose therapeutic needs remain unmet. Inhaled genetic therapies offer the prospect of addressing the unmet pulmonary treatment need in people with cystic fibrosis, with several approaches, including gene addition therapy (the focus of this review), RNA-based therapies, antisense oligonucleotides and gene editing, being explored. Various non-viral and viral vectors have been investigated for cystic fibrosis gene addition therapy for mutation-agnostic restoration of CFTR function in the lungs.
Lentiviral vectors offer the prospect of highly efficient and long-lasting gene expression, and the potential to be safely and, in contrast to other commonly used viral vectors, effectively re-dosed. A third-generation lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) has been developed for the treatment of cystic fibrosis. Promising preclinical results support the progression of this vector carrying a full-length CFTR transgene (BI 3720931) into a first-in-human clinical trial expected to begin in 2024.

Jane Davies is professor at the Royal Brompton Hospital, London and at Imperial College London, National Heart and Lung Institute, London, UK.

— The UK Respiratory Gene Therapy Consortium have been working on gene therapy for CF for the past 25 years. It is to be hoped this most recent product proves to be effective.

E De Wachter, K De Boeck, I Sermet-Gaudelus, N J Simmonds,  A Munck, L Naehrlich, et al; ECFS Diagnostic Network Working Group.  ECFS standards of care on CFTR-related disorders: Towards a comprehensive program for affected individuals.  J Cyst Fibros. 2024 Feb 21:S1569-1993(24)00011-0.  doi: 10.1016/j.jcf.2024.01.012. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38388234/

Elke De Wachter
ResearchGate

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders.

Elke De Wachter is a paediatric pulmonologist at the Cystic Fibrosis Center, Pediatric Pulmonology department, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

E De Wachter, JC Davies, NJ Simmonds, C Castellani, KM de Winter-de Groot, A Munck, M Proesmans, KW Southern and J Barben. Risk of false newborn screening after intra-uterine exposure to ETI Journal of Cystic Fibrosis, 2024-01-01, Volume 23, Issue 1, Pages 176-177, Letter to the editor

(part of letter)     As coordinators and members of the European CF Society (ECFS) Diagnostic Network Working Group (DNWG) and the Neonatal Screening Working Group (NSWG), we would like to draw the attention to the potential effects of ETI therapy in pregnant woman on the outcome of NBS, with regard to the IRT level. Collins et al. have shown that ETI drug concentrations in umbilical cord blood are comparable to maternal serum levels and, as a result, therapeutic concentrations can be assumed to reach the foetus. [4] Should the newborn have CF, the IRT results could be reduced below the screening threshold leading to a false negative screen, as was already reported in one case. [5] A recent study showed decreased IRT levels in newborn carriers exposed to ETI, compared to newborn carriers who were not exposed to ETI. [6] This is likely also to be the case for the small proportion of women receiving Ivacaftor monotherapy, although we are not aware of data on pregnancies in this group.

This situation deserves special attention for all CF specialists who care for pregnant women with CF. Knowledge about the potential impact of ETI on newborn IRT levels should be shared by the CF adult physician caring for the mother with the obstetrician and midwife. For a reliable interpretation of a NBS result, it is of utmost interest to mention on the Guthrie card, taken on the third or fourth day of life, if the mother of the child has taken ETI during pregnancy. This already happens in some countries, for example Belgium and Switzerland, and allows the screening laboratory to process these samples differently, not relying on an initial IRT value. Depending on each country’s NBS strategy, details on which CFTR gene variants would be included in this failsafe measure may vary for dry bloodspot samples from newborn babies who were exposed to ETI in utero. Another option is to refer these children from CF mothers for a sweat test anyway.

Furthermore, data from literature show that ETI is also detectable in breastmilk, albeit at lower levels. [4] This implies that sweat chloride values in breastfed neonates that were exposed in utero to ETI may be falsely lowered and thus should be interpreted with caution and repeated following weaning should diagnostic doubt remain. [ 5 , 7 ]

On behalf of the ECFS Diagnostic Network Working Group (DNWG) and the Neonatal Screening Working Group (NSWG)

Scott H Donaldson , Timothy E Corcoran, Joseph M Pilewski, Peter Mogayzel, Beth L Laube, Evan R Boitet, Elex S Harris, Agathe Ceppe,  Lloyd J Edwards, Kirby Zeman  , Jihong Wu , Charles R Esther Jr, David P Nichols, William D Bennett, Steven M Rowe.   Effect of elexacaftor/tezacaftor/ivacaftor on mucus and mucociliary clearance in cystic fibrosis.  Observational Study.  J Cyst Fibros 2024 Jan;23(1):155-160. doi:10.1016/j.jcf.2023.10.010. Epub 2023 Oct 14.  pubmed.ncbi.nlm.nih.gov/37845149/

Scott Donalson
med.unc.edu

The effects of E/T/I on mucociliary clearance (MCC) and sputum properties are unknown. We, therefore, sought to characterize the effects of E/T/I on in vivo MCC and sputum characteristics hypothesized to impact mucus transport.
Methods: Forty-four participants ≥12 years of age were enrolled into this prospective, observational trial prior to initiation of E/T/I and had baseline measurement of MCC and characterization of induced sputum and exhaled breath condensate (EBC) samples. Study procedures were repeated after 1 month of E/T/I treatment.
Results: Average age was 27.7 years with baseline forced expiratory volume in 1 second (FEV1) of 78.2 % predicted. 52 % of subjects had previously been treated with a 2-drug CFTR modulator combination. The average whole lung MCC rate measured over 60 min (WLAveClr60) significantly improved from baseline to post-E/T/I (14.8 vs. 22.8 %; p = 0.0002), as did other MCC indices. Sputum% solids also improved (modelled mean 3.4 vs. 2.2 %; p<0.0001), whereas non-significant reductions in sputum macrorheology (G’, G”) were observed. No meaningful changes in exhaled breath condensate endpoints (sialic acid:urea ratio, pH) were observed.

Conclusions: E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.

Scott Donaldson is at the Department of Medicine, Univ. North Carolina at Chapel Hill, USA.

Scott H DonaldsonTimothy E CorcoranJoseph M PilewskiBeth L LaubePeter MogayzelAgathe CeppeJihong WuKirby ZemanSteven M RoweDavid P NicholsAlex H GiffordWilliam D Bennett ,Nicole Mayer-HamblettSIMPLIFY MCC. The effect of discontinuing hypertonic saline or dornase alfa on mucociliary clearance in elexacaftor/tezacaftor/ivacaftor treated people with cystic fibrosis: The SIMPLIFY-MCC Stdy.     J Cyst Fibros doi: 10.1016/j.jcf.2024.02.003. Online ahead of print.pubmed.ncbi.nlm.nih.gov/38355350/

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.

Scott Donaldson is at the Department of Medicine and the Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Miri Dotan, Hannah Blau, Amihood Singer , Patrick Stafler , Dario Prais , Malena Cohen-Cymberknoh , et al. The new face of cystic fibrosis in the era of population genetic carrier screening. J Cyst Fibros
. 2024 Jul;23(4):782-787. doi: 10.1016/j.jcf.2023.11.003. Epub 2023 Nov 18. pubmed.ncbi.nlm.nih.gov/37980178/

Miri Dotan
LinkeIn

Background: Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features.
Methods: This was a retrospective national study. Demographic and clinical characteristics of children with CF born in Israel between 2008 and 2018 were obtained from the national CF registry and from patients’ medical records. Data on CF births, preimplantation genetic testing (PGT), pregnancy termination and de-identified data from the PGCS program were collected.
Results: CF births per 100,000 live births decreased from 8.29 in 2008 to 0.54 in 2018 (IRR = 0.84, p < 0.001). The CF pregnancy termination rate did not change (IRR = 1, p= 0.9) while the CF-related PGT rate increased markedly (IRR = 1.33, p < 0.001). One hundred and two children were born with CF between 2008 and 2018 with a median age at diagnosis of 4.8 months, range 0-111 months. Unlike the generally high uptake nationally, 65/102 had not performed PGCS. Even if all had utilized PGCS, only 51 would have been detected by the existing genetic screening panel. Clinically, 34 % of children were pancreatic sufficient compared to 23 % before 2008 (p = 0.04).

Conclusions: Since institution of a nationwide PGCS program, the birth of children with CF decreased markedly. Residual function variants and pancreatic sufficiency were more common. A broader genetic screening panel and increased PGCS utilization may further decrease the birth of children with CF.

Miri Dotan is at the  Kathy and Lee Graub Cystic Fibrosis Center, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Sarah Jane Driscoll, Katie Heinz, Philippa Goddard, Maya Desai , Francis J Gilchrist. Outcome data from 15 years of cystic fibrosis newborn screening in a large UK region. Arch Dis Child. 2024 Mar 19;109(4):292-296. doi: 10.1136/archdischild-2023-325955. https://pubmed.ncbi.nlm.nih.gov/37973197/
Background: The West Midlands Newborn Bloodspot Screening Laboratory is one of 16 in the UK and serves two tertiary paediatric cystic fibrosis (CF) centres (Staffordshire Children’s Hospital at Royal Stoke and Birmingham Children’s Hospital). CF newborn bloodspot screening (NBS) in this region started in November 2006 prior to the UK national roll-out in 2007. It uses an immunoreactive trypsinogen (IRT)/DNA/IRT protocol. We report the outcomes from 15 years of CF screening.
Methods: The West Midlands CF NBS outcomes from 1 November 2006 to 31 October 2021 were reviewed. Clinical data were also obtained for babies referred to the CF centres as ‘CF suspected’.
Results: 1 075 161 babies were screened, with 402 referred as ‘CF suspected’ and 205 identified as CF carriers. Of the ‘CF suspected’ babies, 268 were diagnosed with CF, 33 with CF screen positive, inconclusive diagnosis (CFSPID) and 17 as a CF carrier. Any CF-related diagnosis was excluded in 67. Outcome data were not available for 17, of whom 14 had died. Eighteen children with a negative CF NBS have subsequently been diagnosed with CF, 10 had meconium ileus and 8 were true ‘affected not detected’, presenting with respiratory symptoms or failure to thrive. This gives the West Midlands a CF birth prevalence of 1 in 4012 live births and the NBS protocol a sensitivity of 97.1% and a positive predictive value of 66.7%

Conclusions: This large regional data set has excellent case ascertainment and demonstrates successful performance of the CF NBS protocol, with low numbers identified as CFSPID or CF carriers.

Sarah Jane Discoll is at the Staffordshire Children’s Hospital at Royal Stoke, University Hospital of North Staffordshire NHS Trust, Stoke on Trent, UK. Display options

Stephanie R Duehlmeyer, E Claire Elson, Christopher M Oermann. New Tic Disorder in a Child With Cystic Fibrosis Treated With Elexacaftor/Tezacaftor/Ivacaftor.   J Pediatr Pharmacol Ther
. 2024;29(1):82-84. doi: 10.5863/1551-6776-29.1.82. Epub 2024 Feb 7.      Free PMC article     pubmed.ncbi.nlm.nih.gov/38332957/

Stephanie R Duehlmeyer Children’s Mercy Kansas

The widespread use of highly effective cystic fibrosis transmembrane-conductance regulator -modulator therapy has dramatically altered the lives of individuals with cystic fibrosis. Clinical trials leading to -modulator approval by the US Food and Drug Administration demonstrated improvements in major -outcome measures including pulmonary function, gastrointestinal symptoms, and quality of life. Subsequent clinical experience has confirmed significant improvement across these domains. Adverse effects reported -during clinical trials included headache and dizziness amongst others including upper respiratory infections, abdominal pain, diarrhea, rash, and elevated serum transaminases. Post marketing clinical experience has suggested that there may be additional central nervous system adverse effects resulting from modulator therapy. Reported events after initiation of cystic fibrosis transmembrane-conductance regulator modulator treatment include headaches and increased prevalence of mental health concerns including anxiety and depression.
We report a new tic disorder in a 7-year-old girl with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor.

Stephanie R Duehlmeyer is in the Departments of Pharmacy (SRD, ECE) and Pediatrics (CMO) Children’s Mercy – Kansas City, MO.

J Elson, A Drakeley, C Achilli, N Canham, C Kulke; Royal College of Obstetricians and Gynaecologists  The Use of Expanded Carrier Screening in Reproductive Medicine: Scientific Impact Paper No. 74. Editorial BJOG. 2024 Sep;131(10):e81-e85. doi: 10.1111/1471-0528.17832. Epub 2024 Jun 5.  pubmed.ncbi.nlm.nih.gov/38839259/
Expanded carrier screening (ECS) is a genetic screening test carried out by analysing a blood sample. This screen can be used to detect whether the individual unknowingly carries gene variants associated with common genetic conditions, such as cystic fibrosis, that may be passed on to their children. It is typically performed in reproductive medicine for those who are considering having a family either naturally or via fertility treatment. Many donor sperm and egg banks, particularly in the USA and Europe, also perform blanket ECS testing on all their prospective sperm and egg donors. ECS is not currently routine practice in the UK, but a growing number of patients are requesting it before treatment. All of us carry gene variants of some sort that may cause autosomal recessive disease in their children if their partner or donor also carry a variant in the same gene. An autosomal recessive disease means two copies of an abnormal gene must be present in order for the disease or trait (such as cystic fibrosis or sickle cell disease) to develop. One copy of the variant means the person is a carrier but does not have the condition. Two copies, i.e. from the mother and father, means the child has a 25% chance of having the genetic disease. Carrying a gene variant does not mean that the individual would necessarily have any symptoms of the disease or any features of the condition. Genetic tests for specific conditions are currently available either before or during pregnancy for prospective parents who have a family or personal history of a genetic condition, or for those from ethnic backgrounds where certain conditions – such as haemoglobinopathies (blood disorders) – are common, prompting referral to a clinical genetics department. Expanded carrier screens may test for more than 100 genetic conditions. The list of conditions screened for is called a panel. Common panels are 250 or 600 genes. Not all expanded carrier screens that are available analyse the same genes. Some may test for genes that do not cause serious disease, or cause diseases that occur in later life; others test for genes that cause severe conditions in childhood. There is no agreement as to which panel of genes should be tested for in an ECS. Understanding the screening that is being offered, and the meaning of any results, is complicated and requires support from appropriately trained professionals to best inform the prospective parent or parents.

Alistair J A Duff , Tim W R Lee Reply to Piehler et al.: Depression Symptoms in Patients with Cystic Fibrosis Fluctuate at Baseline and Improve with Elexacaftor/Tezacaftor/Ivacaftor Therapy. Am J Respir Crit Care Med
. 2024 Aug 1;210(3):367. doi: 10.1164/rccm.202404-0852LE https://www.atsjournals.org/doi/10.1164/rccm.202404-0852LE

Full letter and useful references available through the link on this important subject.

Tim W R Lee
leedsth.nhs.uk

Alistair Duff leedsth.nhs.uk

Alistair Duff is in the Dept Paedaitric Psychology, Leeds Teaching Hospitals.                  Tim W R Lee is at the Leeds Centre for Children’s Respiratory Medicine.

Lisa Steen Duus , Maria Dons, Rebekka Faber Thudiu , Susanne Dam Nielsen , Mette F Olsen , Tavs Qvist , et al.    Cardiac Structure and Function in People with Cystic Fibrosis. J Cyst Fibros. 2024 Sep 28:S1569-1993(24)01781-8. doi: 10.1016/j.jcf.2024.09.012. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39343639/

Lisa Steen Duus
ResearchGate

Background: The extent of cardiac involvement in cystic fibrosis (CF) remains to be determined. The remarkable therapeutic advancements with new highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator treatment and subsequent increase in life expectancy substantiates further research. We aimed to explore the prevalence of cardiac alterations in people with CF (pwCF) compared to matched controls and investigate potential cardiovascular risk factors.
Methods: In this cross-sectional study, 104 pwCF underwent clinical and echocardiographic assessment. All participants were matched 1:1 with controls from the general population.
Results: Of 104 pwCF, 44 % were female, mean age was 34 years, and 93 % received CFTR modulator treatment. The prevalence of abnormal cardiac function in pwCF was 44 %, more than double the prevalence in controls. PwCF were found to have smaller left ventricular (LV) dimensions, worse LV diastolic function, and reduced right ventricle (RV) as well as LV systolic function. After multivariable adjustment, LV diastolic function as well as LV and RV systolic function remained poorer in pwCF as compared to controls. Male sex and decreasing FEV1/FVC ratio remained independently associated with abnormal cardiac function in pwCF (male sex: OR 3.94 (1.56; 9.95), p = 0.004 and FEV1/FVC ratio: OR 2.05 per 0.1 unit decrease (1.21; 3.52), p = 0.008, respectively).

Conclusions: Both left- and right-sided cardiac alterations were found in pwCF. After adjustments for risk factors, both RV and LV systolic measures remained altered in pwCF, compared to controls. Male sex and decreasing pulmonary function evaluated by FEV1/FVC-ratio were associated with abnormal cardiac function in pwCF.

Lisa Steen Duus is at the  Non-Invasive Imaging Research Laboratory, Department of Cardiology, Copenhagen University Hospital – Herlev & Gentofte. Hospital, Gentofte Hospitalsvej 8, 2900 Hellerup, University of Copenhagen, Denmark.

Ieuan Evans , Aaron Weimann , Timothy Baird , Charles Haworth , Andres Floto. Mycobacterium abscessus treatment outcomes in cystic fibrosis: A single centre experience. J Cyst Fibros. 2024 Jul 26:S1569-1993(24)00801-4. doi: 10.1016/j.jcf.2024.07.016. Online ahead of print.  https://www.cysticfibrosisjournal.com/article/S1569-1993(24)00801-4/fulltext

Ieuan Evans
LinkedIn

Highlights (full article via link)
Treatment outcomes of Mycobacterium abscessus in cystic fibrosis remain poor.  Raised C-reactive protein is associated with worse M. abscessus treatment outcomes in cystic fibrosis.   Side-effect burden of M. abscessus antibiotic treatment is associated with poor treatment outcomes.  The optimal treatment regimen of Mycobacterium abscessus remains unknown.

Ieuan Evans is at the Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Brisbane, Queensland, Australia; Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.

Valentina Fainardi , Federico Cresta, Claudio Sorio, Paola Melotti , Emanuela Pesce , Michela Deolmi , Francesco Longo , Kleinfelder Karina , Susanna Esposito, Giovanna Pisi. Elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and rare mutations. Pediatr Pulmonol. 2024 Aug 30. doi: 10.1002/ppul.27211. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39212240/

Valentina Fairnardi
ResearchGate

Introduction: The triple combination of elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically improved the outcome of people with Cystic Fibrosis (pwCF) with at least one F508del mutation. However, carriers of rare cystic fibrosis transmembrane conductance regulator (CFTR) variants are not candidates for this innovative treatment.
Methods: In this observational study, we report the results of the compassionate use of ETI in 10 pwCF carriers of rare mutations after 2 months of treatment. Rectal organoids and short-term cultures of nasal epithelium obtained from rectal suction biopsies and nasal brushing were obtained from four subjects.
Results: After 2 months of ETI, all patients (4 males, mean age 30.1 ± 13.3 years) showed a significant increase of FEV1% predicted values [+8.0 (3.5-12.7) %, p < 0.010], body mass index [+0.85 (0-1.22) kg/m2, p < 0.020] and cystic fibrosis questionnaire-revised [+19.5 (6.3-29.2) points, p < 0.009]. A significant decrease of sweat chloride concentration [-11.2 (-1.7 to -34.0) mmol/L, p < 0.020] and exacerbations [-1.5 (-2 to -1), p < 0.008] was also recorded. Overall, 7 out of 10 participants were considered full responders. All patients reported cough disappearance (n = 3) or reduction (n = 7). Long-term oxygen was discontinued in two out of three patients and one also stopped noninvasive ventilation and was removed from the lung transplantation waiting list.

Conclusions: Despite the limited number of cases, our results support the use of CFTR modulators in patients with rare CFTR variants that are not currently approved for ETI in Europe.

Valentina Fainardi is in the Dept of Medicine and Surgery, Cystic Fibrosis Unit, Pediatric Clinic, Parma, Italy.

Isabelle FajacPierre-Régis BurgelClémence Martin. New drugs, new challenges in cystic fibrosis care.  Eur Respir Rev  2024 Sep 25;33(173):240045. doi: 10.1183/16000617.0045-2024.Print 2024 July pubmed.ncbi.nlm.nih.gov/39322262/

Isabelle Fajac
ECFS

Cystic fibrosis (CF) is a genetic disease caused by variants in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel. CFTR dysfunction results in a multi-organ disease with the main clinical features being exocrine pancreatic insufficiency and diffuse bronchiectasis with chronic airway infection leading to respiratory failure and premature death. Over the past decades, major progress has been made by implementing multidisciplinary care, including nutritional support, airway clearance techniques and antibiotics in specialised CF centres. The past decade has further seen the progressive development of oral medications, called CFTR modulators, for which around 80% of people with CF are genetically eligible in Europe. CFTR modulators partially restore ion transport and lead to a rapid and major improvement in clinical manifestations and lung function, presumably resulting in longer survival. CFTR modulators have been game-changing in the care of people with CF.
However, many questions remain unanswered, such as the long-term effects of CFTR modulators, especially when treatment is started very early in life, or the new CF-related disease emerging due to CFTR modulators. Moreover, severe complications of CF, such as diabetes or cirrhosis, are not reversed on CFTR modulators and around 20% of people with CF bear CFTR variants leading to a CFTR protein that is unresponsive to CFTR modulators. Challenges also arise in adapting CF care to a changing disease. In this review article, we highlight the new questions and challenges emerging from this revolution in CF care.

Isabelle Fajac at the Department of Respiratory Medicine and National Cystic Fibrosis Reference Centre, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France isabelle.fajac@u-paris.fr. & Université Paris Cité, Inserm U1016, Institut Cochin, Paris, France.& ERN-LUNG, CF Core Network, Frankfurt, Germany.

Imogen Felton, Amy Downes, Idan Bokobza, Ladina Weitnauer, Jane C Davies”Shifting sands in cystic fibrosis”: impacts of CFTR modulators on reproductive health in people with cystic fibrosis and challenges related to in utero exposure. Expert Opin Pharmacother. 2024 Nov 14:1-10. doi: 10.1080/14656566.2024.2426677. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39543810/

Imogen Felton
Facebook

Introduction: Mutation-specific disease modifying drugs such as the triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI), are associated with significant improvements in physical health. Reproductive health and a pursuit of parenthood are of increased relevance; a dramatic increase in childbirth rates for females with CF has already been observed.
Areas covered: Fertility in males and females with CF, and any subsequent impact of CFTR modulator therapy, is reviewed. The potential impacts of maternal use of CFTR modulator drugs on offspring health are considered, as constituent components have been found in fetal circulation in animals and humans, and the implications for maternal continuation or cessation of treatment. Clinical data are reassuring, although cases of lens opacities, and missed CF diagnoses due to false negative newborn screening results have been reported.
Expert opinion: More research and high-quality evidence are needed to characterize maternal, fetal and long-term offspring outcomes following CFTR modulator therapy use during pregnancy and breastfeeding. There is a potential therapeutic impact of targeting CFTR-related organ dysfunction in CF-fetuses via maternal-administration of CFTR modulators. Additionally, any consequences of CFTR-modulation in heterozygote carrier infant warrants urgent and collective consensus regarding ethical and clinical research programs to evaluate this discrete population.

Imogen Felton is a Respiratory Consultant at  the Adult Cystic Fibrosis Centre, Royal Brompton Hospital, Guys and St Thomas’ Hospital NHS Foundation Trust, London, UK; Imperial College London, National Heart & Lung Institute, London;Imperial Biomedical Research Centre, Royal Brompton Hospital, London, UK.

Ian Freckelton Cystic Fibrosis and the Law: The Ramifications of New Treatments. Editorial J Law Med. 2024 Jun;31(2):217-224  pubmed.ncbi.nlm.nih.gov/38963243/

Ian Freckelton

Until the discovery of the gene for cystic fibrosis (CF) in 1989, diagnostic developments were limited, and treatment focused on symptom alleviation. However, following the genetic breakthrough, some 2,000 mutations of the gene have been identified. More recently CF transmembrane conductance regulator modulator triple therapy (CFTRm) has been introduced in the form of triple therapy with ivacaftor, lumacaftor and tezacaftor (ETI), in the United States from 2019, Europe from 2020 and then Australia from 2021. The new treatment option has revolutionised both the quality of life and life expectancy of many persons diagnosed with CF. This editorial reviews major developments in the clinical care that can now be provided to patients, and reflects on the legal and ethical ramifications of the improved situation for many patients in the contexts of medical negligence, damages assessment, family law and criminal law. It also considers the difficult issues of access and equity caused by the limited availability of the triple therapy in low- and middle-income countries.

Ian Freckelton is a Barrister, Castan Chambers, Melbourne, Australia; Professor, Law Faculty, and Professorial Fellow in Psychiatry, University of Melbourne; Honorary Professor of Forensic Medicine, Monash University.

Pierre Gabai,  Etienne Novel-Catin , Quitterie Reynaud , Raphaële Nove-Josserand , Solenne Pelletier , Denis Fouque , Laetitia Koppe , Isabelle Durieu. Kidney effects of triple CFTR modulator therapy in people with cystic fibrosis. Clin Kidney J 2024 Aug 27;17(10):sfae256. doi: 10.1093/ckj/sfae256. eCollection 2024 Oct.  pubmed.ncbi.nlm.nih.gov/39359568/
Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a new cystic fibrosis transmembrane conductance regulator (CFTR) modulator that has transformed the respiratory prognosis of people with cystic fibrosis (pwCF). However, its impact on other organs such as the kidneys, where CFTR is expressed, remains unclear. Since pwCF are risk of both kidney disease and urolithiasis, we aimed to study the potential effects of ETI on renal function, volume status, and risk factors for urolithiasis.
Methods: This prospective, observational, single-center, before-after cohort study, involved adult pwCF eligible for ETI. The changes in plasma and urinary profiles were assessed by comparing renal function (using 2021 CKD-EPIcreatinine and 2021 CKD-EPIcreatinine-cystatin C formulas), volume status (using aldosterone/renin ratio and blood pressure), and risk factors for urolithiasis, at the time of ETI introduction (M0) and 7 months after (M7).
Results: Nineteen pwCF were included. No significant change in renal function was observed between M0 and M7 (2021 CKD-EPIcreatinine: 105.5 ml/min/1.73 m² at M0 vs. 103.3 ml/min/1.73 m² at M7; P = .17). There was a significant reduction in aldosterone level (370.3 pmol/l at M0 vs. 232.4 pmol/l at M7; P = .02) and aldosterone/renin ratio (33.6 at M0 vs. 21.8 at M7; P = .03). Among the risk factors for urolithiasis, a significant reduction in magnesuria level was found (4.6 mmol/d at M0 vs. 3.8 mmol/d at M7; P = .01).

Conclusion: These findings suggest that ETI seem to have no short-term impact on the renal function of adult pwCF and appears to correct secondary hyperaldosteronism due to excessive sweat losses. Further investigations are needed to determine the potential impact of decreased magnesuria observed under ETI therapy on the risk of urolithiasis.

Pierre Gabai is at the  Service de Néphrologie, Hospices Civils de Lyon, Hôpital Lyon Sud, 165 Chemin du Grand Revoyet, Pierre-Bénite, Rhône, France.

Andrea Gramegna, Charlotte Addy , Lorna Allen, Egil Bakkeheim , Catherine Brown, Thomas Daniels , Gwyneth Davies et al. Standards for the care of people with cystic fibrosis (CF); Planning for a longer life. Review J Cyst Fibros. 2024 May;23(3):375-387. doi: 10.1016/j.jcf.2024.05.007. Epub 2024 May 24. pubmed.ncbi.nlm.nih.gov/38789317/
Free article

Andrea Gramegna
University of Milan

This is the final of four papers updating standards for the care of people with CF. That this paper “Planning a longer life” was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a “problem” to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

Andrea Gramegna is in the Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Respiratory Unit; Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy.

Laura S Gold, Ryan N Hansen, Nicole Mayer-Hamblett, David P Nichols 6 Alex H Gifford, Margaret Kloster, Christopher H Goss, Larry KesslerThe cost of simplifying treatments for cystic fibrosis: Implications of the SIMPLIFY trial. J Manag Care Spec Pharm. 2024 Jan;30(1):26-33. doi: 10.18553/jmcp.2024.30.1.26.Free PMC article.  pubmed.ncbi.nlm.nih.gov/38153868

Laura Gold       Researchgate

Background: Dornase alfa and hypertonic saline are mucoactive therapies that can improve respiratory symptoms in people with cystic fibrosis (CF). A recent randomized control trial showed that participants with well-preserved pulmonary function taking elexacaftor + tezacaftor + ivacaftor (ETI) who discontinued dornase alfa or hypertonic saline for 6 weeks had no clinically meaningful decline in lung function. This may prompt discussions with care providers regarding ongoing use of these medications.
Objective: To compare the costs of outpatient medications between people taking ETI who continued or discontinued (1) dornase alfa or (2) hypertonic saline from 2 clinical trials and project cost differences in the US CF population if these 2 medications were used only intermittently for symptom relief instead of chronically.
Methods: The SIMPLIFY study was 2 parallel multicenter trials that randomized participants 1:1 to either continue or discontinue therapy. To estimate costs, we used data from the Merative MarketScan Databases to identify people with CF from 2020 to 2021. Our primary outcomes were differences in costs of outpatient prescription drugs among those who continued vs discontinued dornase alfa and, separately, hypertonic saline. We obtained adjusted differences in median costs. To estimate the annual cost savings if the population of people with CF taking ETI used these medications only intermittently, we multiplied the proportion of people in MarketScan with CF diagnoses who were taking each of these medications by the median cost savings per year and subtracted the cost of “rescue” use.
Results: A total of 392 participants from the dornase alfa trial and 273 from the hypertonic saline trial were included in analyses. The adjusted difference in median medication costs was not significant for the hypertonic saline trial, but we observed a significantly decreased 6-week cost of medications in the dornase alfa trial (adjusted median difference in costs between discontinue and continue of $5,860 (95% CI = $4,870-$6,850); P < 0.0001). We estimated that two-thirds of people with CF use ETI and dornase alfa in the United States; if they discontinued dornase alfa except for intermittent use, the resulting annual savings would be $1.21 billion.

Conclusions: Although the costs of dornase alfa and hypertonic saline are smaller compared with ETI, reduction in use would lead to substantial prescription drug cost savings and reduce the treatment burden. However, individual benefits of these therapies should be considered, and decisions regarding changes in therapy remain an important discussion between people with CF and their providers.

Laura S Gold is in the Department of Radiology, University of Washington, Seattle.

Andrea Gramegna , Massimiliano Ruscica , Gloria Leonardi,  a Carnevale Schianca , Leonardo Terranova, Gianfranco Alicandro, Francesco Blasi.    Cardiometabolic risk factors in adults with cystic fibrosis undergoing elexacaftor/tezacaftor/ivacaftor therapy. J Cyst Fibros. 2024 Dec 6:S1569-1993(24)01844-7. doi: 10.1016/j.jcf.2024.11.009. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39645478/

Andrea Gramegna
www/unimi.it

The introduction of elexacaftor/tezacaftor/ivacaftor (ETI) therapy has further extended life expectancy of adults with cystic fibrosis (awCF), highlighting the need for increased attention to potential long-term health issues. Given the increasing prevalence of cardiovascular diseases in the ageing population and the presence of cardiovascular risk factors associated with CF, understanding the impact of ETI on cardiometabolic risk factors is a crucial clinical concern. The aim of our prospective observational study was to explore early changes in cardiac and metabolic biomarkers after 6 months of ETI therapy. A total of 58 consecutive awCF were enrolled during clinical stability at the Adult CF Center of the Policlinico Hospital in Milan, Italy between January 2021 and June 2022. Blood samples were obtained before ETI initiation and after 6 months, and underwent central processing for an extended panel of cardiometabolic biomarkers. We observed a rise in cholesterol, triglycerides, apolipoprotein-B and adipokine levels, while inflammatory markers decreased. The direct relationship between leptin and adiponectin suggest a disruption in the normal regulatory mechanisms that control these hormones, potentially leading to metabolic imbalances, such as increased risk of obesity and cardiovascular events. The impact of ETI on cardiovascular risk in awCF is heterogeneous and while it improves some risk factors, such as chronic inflammation, it has a worsening effect on lipoproteins. Our findings suggest that the dysregulation of adipokines could be he a potential cause of the metabolic disturbances observed in awCF.

Andrea Gramegna is in Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Respiratory Unit and Cystic Fibrosis Adult Center, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy.

Sonia Graziano , Francesca Boldrini , Gaia Romana Pellicano , Francesco Milo , Fabio Majo , Luca Cristiani , Enza Montemitro , Federico Alghisi , Sergio Bella , Renato Cutrera , Alessandro Giovanni Fiocchi , Alexandra Quittner , Paola Tabarini. Longitudinal Effects of Elexacaftor/Tezacaftor/Ivacaftor: Multidimensional Assessment of Neuropsychological Side Effects and Physical and Mental Health Outcomes in Adolescents and Adults. Chest. 2024 Apr;165(4):800-809. doi: 10.1016/j.chest.2023.10.043. Epub 2023 Nov 3. 37925143 pubmed.ncbi.nlm.nih.gov/37925143/

Sonia Graziano
CFF Conference 2022

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.

Sonia Graziano is at the Psychology Unit, Child & Adolescent Psychiatry Unit, Allergy Division, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy.

Nicole Green, Carson Miller, David Suskind, Marshall Brown, Christopher Pope, Hillary Hayden, Sharon McNamara, Anna Kanter, Laura Nay, Lucas Hoffman, Margaret Rosenfeld. The impact of a whole foods dietary intervention on gastrointestinal symptoms, inflammation, and fecal microbiota in pediatric patients with cystic fibrosis: A pilot study.Clin Nutr
. 2024 Sep 25;43(11):156-163. doi: 10.1016/j.clnu.2024.09.036. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39383549/

Nicole F Green
Seattlechildrens.org

Background: Gastrointestinal (GI) complications are a significant source of morbidity for people with cystic fibrosis (PwCF). Historically, dietary recommendations in CF have focused on calories, typically emphasizing a high fat diet. The changing landscape of CF highlights the need to update this nutritional strategy. There is little research into how the quality of calories consumed by PwCF influences nutritional outcomes, GI symptoms, or likely contributors: intestinal inflammation and GI microbiology. We assessed the feasibility of a whole foods-based diet (WFD) and avoidance of ultra-processed foods, measuring safety/tolerability, adherence, and GI symptoms, as well as fecal measures of inflammation and microbiota among children with CF (CwCF) with GI symptoms.
Methods: Single center, 4-week dietary intervention involving CwCF aged 5-14 years who screened positive on GI symptom questionnaire. Assessments included weight, symptom questionnaires and adverse events (AEs). Stool was analyzed for microbiota (16S rRNA) and calprotectin.
Results: 108 children were pre-screened, 9 enrolled and 8 initiated and completed the study. There were no significant changes in weight and no AEs. PEDS-QL GI identified overall improvement in symptoms. Certain symptom domains (constipation, diarrhea, gas/bloating, stomach pain and hurt) demonstrated significant improvement on the WFD. Of two participants with abnormal fecal calprotectin at enrollment, both exhibited decreased values on WFD. There was no significant change in microbiota diversity.

Conclusion: A WFD diet was feasible and safe in CwCF. There was improvement in GI symptom scores based on both parent and child assessments. Larger studies are needed to further investigate effects on intestinal inflammation and microbiota.

Nicole Green is in the Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Washington School of Medicine, Seattle, WA, USA.

Vikram F Gupta,  Samantha E Halpern, Arya Pontula, Madison K Krischak, John M Reynolds, Jacob A Klapper, Matthew G Hartwig, John C Haney.  Short-term outcomes after third-time lung transplantation: A single institution experience.  J Heart Lung Transplant  2024 May;43(5):771-779.doi: 10.1016/j.healun.2023.12.010.Epub 2023 Dec 21.  pubmed.ncbi.nlm.nih.gov/38141895/
Reoperative lung transplantation (LTx) survival has improved over time such that a growing number of patients may present for third-time LTx (L3Tx). To understand the safety of L3Tx, we evaluated perioperative outcomes and 3-year survival after L3Tx at a high-volume US LTx center.
Methods: This retrospective study included all patients who underwent bilateral L3Tx at our institution. Using an optimal matching technique, a primary LTx (L1Tx) cohort was matched 1:2 and a second-time LTx (L2Tx) cohort 1:1. Recipient, operative, and donor characteristics, perioperative outcomes, and 3-year survival were compared among L1Tx, L2Tx, and L3Tx groups.
Results: Eleven L3Tx, 11 L2Tx, and 22 L1Tx recipients were included. Among L3Tx recipients, median age at transplant was 37 years and most (73%) had cystic fibrosis. L3Tx was performed median 6.0 and 10.6 years after L2Tx and L1Tx, respectively. Compared to L1Tx and L2Tx recipients, L3Tx recipients had greater intraoperative transfusion requirements, a higher incidence of postoperative complications, and a higher rate of unplanned reoperation. Rates of grade 3 primary graft dysfunction at 72 hours, extracorporeal membrane oxygenation at 72 hours, reintubation, and in-hospital mortality were similar among groups. There were no differences in 3-year patient (log-rank p = 0.61) or rejection-free survival (log-rank p = 0.34) after L1Tx, L2Tx, and L3Tx.
Conclusions: At our institution, L3Tx was associated with similar perioperative outcomes and 3-year patient survival compared to L1Tx and L2Tx. L3Tx represents the only safe treatment option for patients with allograft failure after L2Tx; however, further investigation is needed to understand the long-term survival and durability of L3Tx.

Vikram Gupta is at Duke University School of Medicine, Durham, North Carolina.

Salman Haider, Daryl Ramai, Saira Shah, Nayna D Riyat, Marco Spadaccini, Saurabh Chandan, Marcello Maida, Asad Ur Rehman, Monique T Barakat.   Outcomes of ERCP in Patients With Cystic Fibrosis: A Nationwide Inpatient Assessment.  J Clin Gastroenterol. 2024 Mar 28.  doi: 10.1097/MCG.0000000000001993. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38546483/

There is a paucity of data assessing ERCP outcomes in patients with CF.: We identified patients from the Healthcare Cost and Utilization Project (HCUP)-National Inpatient Sample (NIS) between the years 2016 and 2020. Our study group included patients with CF of all ages who underwent an inpatient ERCP. We used ICD10 diagnostic and procedural codes to identify patients, procedures, and complications of the procedure.
Results (please see abstract).
Conclusions: ERCP is a safe procedure in patients with CF with a comparable risk of post-procedural complications and mortality to those who do not have cystic fibrosis. However, patients with CF may experience a higher risk of post-ERCP infections and post-ERCP pneumothorax. Further studies are needed to prospectively evaluate outcomes of ERCP in patients with CF and to determine methods of mitigating adverse events.

Salman Haider is in the Dept. of Internal Medicine , The Brooklyn Hospital Center,  Brooklyn, NY.

Thomas H Hampton, Roxanna Barnaby, Carolyn Roche, Amanda B Nymon, Kiyoshi Ferreira Fukutani, Todd A MacKenzie, Lily A Charpentier, Bruce A Stanton. Gene expression responses of CF airway epithelial cells exposed to elexacaftor/tezacaftor/ivacaftor (ETI) suggest benefits beyond improved CFTR channel function. Am J Physiol Lung Cell Mol Physiol
. 2024 Oct 22. doi: 10.1152/ajplung.00272.2024. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39437760/

Thomas Hampton DartCF

The combination of elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) reverses the primary defect in Cystic Fibrosis (CF) by improving CFTR mediated Cl- and HCO3- secretion by airway epithelial cells (AEC), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, has numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression we exposed primary human AEC to ETI for 48 hours and interrogated the transcriptome by RNA-seq and qPCR. ETI increased CFTR Cl- secretion, and defensin gene expression (DEFB1) an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI decreased MMP10 and MMP12 gene expression, suggesting that ETI may reduce proteolytic induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase (HMOX1). qPCR analysis confirmed DEFB1, HMOX1, MMP10 and MMP12 gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation and MHC Class II antigen presentation.
Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug induced increases in DEFB1, and that ETI may reduce lung damage by reducing MMP10 and MMP12 gene expression. Moreover, pathway analysis also identified several other genes responsible for the ETI induced reduction in inflammation observed in pwCF.

Thomas H Hampton is Senior Research Scientist in the Dept. of Microbiology and Immunology, Dartmouth College, Hanover, NH, United States.

Charles S Haworth , Michal Shteinberg , Kevin Winthrop , Alan Barker, Francesco Blasi, Katerina Dimakou, et al.  PROMIS trial investigators. Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months. Lancet Respir Med
. 2024 Sep 6:S2213-2600(24)00225-X. doi: 10.1016/S2213-2600(24)00225-X. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39270696/

Charles Haworth
author’s photo

Background: Chronic lung infection with Pseudomonas aeruginosa is associated with increased exacerbations and mortality in people with bronchiectasis. The PROMIS-I and PROMIS-II trials investigated the efficacy and safety of 12-months of inhaled colistimethate sodium delivered via the I-neb.
Methods: Two randomised, double-blind, placebo-controlled trials of twice per day colistimethate sodium versus placebo were conducted in patients with bronchiectasis with P aeruginosa and a history of at least two exacerbations requiring oral antibiotics or one requiring intravenous antibiotics in the previous year in hospitals in Argentina, Australia, Belgium, Canada, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Spain, Switzerland, the UK, and the USA. Randomisation was conducted through an interactive web response system and stratified by site and long term use of macrolides. Masking was achieved by providing colistimethate sodium and placebo in identical vials. After random assignment, study visits were scheduled for 1, 3, 6, 9, and 12 months (the end of the treatment period); and telephone calls were scheduled for 7 days after random assignment and 2 weeks after the end of treatment. The primary endpoint was the mean annual exacerbation rate. These trials are registered with EudraCT: number 2015-002743-33 (for PROMIS-I) and 2016-004558-13 (for PROMIS-II), and are now completed.
Findings: 377 patients were randomly assigned in PROMIS-I (177 to colistimethate sodium and 200 to placebo; in the modified intention-to-treat population, 176 were in the colistimethate sodium group and 197 were in the placebo group) between June 6, 2017, and April 8, 2020. The annual exacerbation rate was 0·58 in the colistimethate sodium group versus 0·95 in the placebo group (rate ratio 0·61; 95% CI 0·46-0·82; p=0·0010). 287 patients were randomly assigned in PROMIS-II (152 were assigned to colistimethate sodium and 135 were assigned to placebo, in the modified intention-to-treat population), between Feb 12, 2018, and Oct 22, 2021. PROMIS-II was then prematurely terminated due to the effect of the COVID-19 pandemic. No significant difference was observed in the annual exacerbation rate between the colistimethate sodium and placebo groups (0·89 vs 0·89; rate ratio 1·00; 95% CI 0·75-1·35; p=0·98). No major safety issues were identified. The overall frequency of adverse events was 142 (81%) patients in the colistimethate sodium group versus 159 (81%) patients in the placebo group in PROMIS-I, and 123 (81%) patients versus 104 (77%) patients in PROMIS-II. There were no deaths related to study treatment.

Interpretation: The data from PROMIS-I suggest a clinically important benefit of colistimethate sodium delivered via the I-neb adaptive aerosol delivery system in patients with bronchiectasis and P aeruginosa infection. These results were not replicated in PROMIS-II, which was affected by the COVID-19 pandemic and prematurely terminated.

Charles Haworth is Professor at  Cambridge Centre for Lung Infection, Royal Papworth Hospital and University of Cambridge, Cambridge, UK.

Rachel C Hill, Eden Axler, Shari R Lipner. Digital clubbing in cystic fibrosis: The nails as clues to advanced disease.  J Am Acad Dermatol
. 2024 Nov;91(5):e133-e134. doi: 10.1016/j.jaad.2024.06.075. Epub 2024 Jul 9.
.  pubmed.ncbi.nlm.nih.gov/38992504/           Full text and image via link

Rachel C Hill
Linkedin

In summary (from full text link)  , digital clubbing is an important cutaneous manifestation of CF along with findings discussed by Smith et al. Digital clubbing is also an indicator of disease severity and mortality in patients with CF, and dermatologists may play an important role in using physical examination and/or measurement of the Distal phalangeal depth/interphalangeal depth ratio  to monitor the severity of digital clubbing in this population. Future studies are needed to evaluate other nail-specific findings in patients with CF.

Rachel C Hill  a medical student at Weill Cornell Medical College, New York, New York.

Katelyne Hubeaux , Laetitia Gueganton, Emmanuel Nowak , Baptiste Arnouat , Chantal Belleguic , Isabelle Danner-Boucher  , Julie Mankikian , Annabelle Payet , Thierry Urban , Marion Buyse 1, Sophie Ramel. Prevalence and severity of functional urinary and anorectal disorders and their impact on quality of life in cystic fibrosis. J Cyst Fibros. 2024 May;23(3):579-586. doi: 10.1016/j.jcf.2023.10.011. Epub 2023 Oct 29 pubmed.ncbi.nlm.nih.gov/37907384/
Background: In cystic fibrosis (CF), coughing is associated with a risk of pelvic floor dysfunction. However, data on the prevalence of symptoms (stress urinary incontinence, bladder overactivity, dysuria, and faecal incontinence) are lacking in males and females with CF. The impact of incontinence on adherence to respiratory care has not been studied.
Methods: We conducted a multicentre study in adults with CF followed in the North-West French CF network. Urinary disorders and their severity were assessed using the Urinary Symptom Profile (USP) self-report questionnaire; the impact of urinary disorders on general quality of life was measured using the SF-Qualiveen questionnaire; faecal incontinence was assessed using the Wexner self-report questionnaire; and the CFQ-R14+ questionnaire was used to assess quality of life. A self-administered questionnaire developed for the study assessed the impact of symptoms on respiratory care.
Results: Of the 178 people with CF included, 34 % reported stress urinary incontinence, with a large female predominance (63.5 % of females vs. 7.5 % of males), 65 % bladder overactivity (including 16 % urge incontinence) and 50 % faecal incontinence, also with a female predominance. Neither urinary nor faecal incontinence were related to the severity of the respiratory impairment (FEV1). Quality of life was particularly affected in women. Stress urinary Incontinence symptoms affected respiratory care in both sexes.

Conclusion: The prevalence of functional urinary and faecal disorders was high in adults with CF and impacted on quality of life and respiratory care. Therefore, multidisciplinary teams must have knowledge of symptoms, the diagnostic tools and management strategies to provide specific treatment.

Katelyne Hubeaux is at CRCM (Centre de Ressources et de Compétences de la Mucoviscidose), Fondation Ildys, Roscoff, France.

Shijing Jia, Yizhuo Wang, Melissa H Ross, Jonathan B Zuckerman, Susan Murray, MeiLan K Han, Shannon E Cahalan, Blair E Lenhan, Ryan N Best,  Jennifer L Taylor-Cousar, Richard H Simon, Linda J Fitzgeral, Jonathan P Troost, Suman L Sood, Alex H Gifford.     Association between CFTR modulators and changes in iron deficiency markers in cystic fibrosis.  J Cyst Fibros. 2024 Mar 14:S1569-1993(24)00030-4.  doi: 10.1016/j.jcf.2024.03.002. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/38490920/

Shijing Jia
NACFC 2022

Background: Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID.
Methods: In a multicenter retrospective cohort study across 4 United States CF centers 2012-2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 μg/dL (<10.7 μmol/L).
Results: A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3-10.6 %; p < 0.0001) and +34.4 μg/dL serum iron (95 % CI, +26.7-42.1 μg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8-8.0 %; p = 0.0001) and +22.1 μg/dL serum iron (95 % CI, +13.5-30.8 μg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9-14.8 %; p < 0.0001) and +46.0 μg/dL serum iron (95 % CI, +33.3-58.8 μg/dL; p < 0.0001) in males.

Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT).
Conclusions: Iron deficiency remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin).

Shijing Jia is clinical assistant professor in theDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Kamini JainClaire E WainwrightAlan R Smyth.  Bronchoscopy-guided antimicrobial therapy for cystic fibrosis. Cochrane Database Syst Rev. 2024 May 3;5(5):CD009530.doi: 10.1002/14651858.CD009530.pub5. pubmed.ncbi.nlm.nih.gov/38700027/

Kamini Jain
Linkedin

Background:Early diagnosis and treatment of lower respiratory tract infections is the mainstay of management of lung disease in cystic fibrosis (CF). When sputum samples are unavailable, diagnosis relies mainly on cultures from oropharyngeal specimens; however, there are concerns about whether this approach is sensitive enough to identify lower respiratory organisms. Bronchoscopy and related procedures such as bronchoalveolar lavage (BAL) are invasive but allow the collection of lower respiratory specimens from non-sputum producers. Cultures of bronchoscopic specimens provide a higher yield of organisms compared to those from oropharyngeal specimens. Regular use of bronchoscopy and related procedures may increase the accuracy of diagnosis of lower respiratory tract infections and improve the selection of antimicrobials, which may lead to clinical benefits. This is an update of a previous review that was first published in 2013 and was updated in 2016 and in 2018 (More details on PubMed link)

Authors’ conclusions
This review, limited to two well-designed randomised controlled studies, shows no evidence to support the routine use of BAL for the diagnosis and management of pulmonary infection in preschool children with CF compared to the standard practice of providing treatment based on results of oropharyngeal culture and clinical symptoms. No evidence is available for adults


Kamini Jain
is at the Leicester Children’s Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK.

Raksha Jain, Giselle Peng, MinJae Lee, Ashley Keller, Sophia Cosmich , Sarthak Reddy , et al.   Impact of Cystic Fibrosis Transmembrane Conductance Regulator Modulators on Maternal Outcomes During and After Pregnancy.     Chest. 2024 Sep 27:S0012-3692(24)05275-9. doi: 10.1016/j.chest.2024.09.019. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39343292/

Raksha Jain
utswmed.org

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are available to the majority of people with CF in the United States (US); little is known about pregnancy outcomes with modulator use. This retrospective study aims to determine the impact of CFTR modulators on maternal outcomes.
Research question: Does pregnancy differentially impact outcomes in females with CF with and without CFTR modulators?
Study design and methods: We collected data on pregnancies from 2010-2021 from 11 US adult CF centers. We conducted multivariable longitudinal regression analysis to assess whether changes in percent predicted forced expiratory volume in 1 second (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), and Pseudomonas aeruginosa prevalence differed from before, during, and after pregnancy by CFTR modulator use, while adjusting for confounders. We also describe infant outcomes based on maternal modulator use.
Results: Among 307 pregnancies, mean age at conception was 28.5 years (range: 17-42), pre-pregnancy ppFEV1 was 74.2 and BMI was 22.3 kg/m2. One hundred and fourteen pregnancies (37.1%) had CFTR modulator exposure during pregnancy (77 with highly effective modulator therapy [HEMT] and 37 with other modulators). The adjusted mean change in ppFEV1 from pre- to during pregnancy was -2.36 (95%CI: -3.56, -1.16) in the unexposed group and +2.60(95%CI: 0.23, 4.97) in the HEMT group, with no significant change from during to one-year post-pregnancy. There was an overall decline in ppFEV1 from pre- to post-pregnancy in the no modulator group (-2.56; 95%CI:-3.62, -1.49) that was not observed in the HEMT group (1.10; 95%CI: -1.13, 3.34). PEx decreased from pre- to post-pregnancy in the HEMT group and BMI increased from pre- to during pregnancy in all groups but without a significant change post-pregnancy. Missing infant outcome data precluded firm conclusions.

Interpretation: We observed superior pregnancy and post-pregnancy pulmonary outcomes in individuals who used HEMT, including a preservation of ppFEV1, compared with those unexposed to HEMT.

Raksha Jain is professor at the University of Texas Southwestern Medical Center, Dallas, TX

Amber James , Galvin Li , Rhonda List , Kevin Lonabaugh , Aaron D Smith  , Andrew Barros  , Lindsay Somerville  , Dana Albon. Analysis of iron status after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis. Pediatr Pulmonol. 2024 Mar;59(3):669-678. doi: 10.1002/ppul.26805. Epub 2023 Dec 13.  pubmed.ncbi.nlm.nih.gov/38088203/

Amber James
giving.uvahealth.com

Background: Iron deficiency is highly prevalent in people with cystic fibrosis (PwCF)While elexacaftor/tezacaftor/ivacaftor (ETI) has shown remarkable improvements in respiratory symptoms in PwCF, the effect of ETI on iron status remains unknown. This study aims to identify the effect of ETI on iron status in PwCF.Methods: A single-center retrospective cohort study of 127 adult PwCF was conducted to assess the impact of ETI on iron, ferritin, transferrin levels, and percent saturation of transferrin (PSAT). Data were collected from the electronic medical record from January 2017 to September 2022, encompassing 2 years before and after ETI initiation. The primary outcome was serum iron parameters: iron, ferritin, transferrin, and PSAT levels following ETI treatment. Secondary outcomes analyzed iron supplementation. Univariate and multivariate mixed-effects models were used for the analysis of ETI.

Dana P Albon
UVA Health

Results: After adjusting for covariates, following ETI initiation, the mean iron level increased by 20.24 μg/dL (p < .001), ferritin levels were 31.4% (p < .001) higher, PSAT showed a 5.09 percentage point increase (p < .001), and transferrin levels increased by 2.71 mg/dL (p = .439). Patients with and without iron supplementation experienced a significant increase in iron after ETI (p < .001).

Conclusions: ETI is associated with a significant increase in iron, ferritin, and PSAT levels. Patients with and without iron supplementation demonstrated a significant increase in iron. This study shows the benefits of ETI on iron status in PwCF. However, further translational studies are required to understand the impact of ETI on iron absorption and metabolism in PwCF.

Amber James is at the Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Dana Albon is Medical director of the UVA Adult Cystic Fibrosis Clinic,

N Jouret, N Van der Poel, S Verhulst, Mjw Lammers, V Van Rompaey, L Jacquemin, K Van Hoorenbeeck. Aminoglycoside-induced sensorineural hearing loss in pediatric cystic fibrosis patients: A retrospective cohort study.Heliyon. 2024 Jan 26;10(3):e25190. doi: 10.1016/j.heliyon.2024.e25190. eCollection 2024 Feb 15. Free PMC article  pubmed.ncbi.nlm.nih.gov/38333844/

Nathalie Jouret Loop.frontiersin.org

Background: Pulmonary infections by gram-negative organisms are important in cystic fibrosis (CF). Aminoglycosides (AG) are often part of the treatment regimen. However, they are a well-known cause of ototoxicity. Even minimal hearing impairment in children could have a future impact on functional well-being.We aimed to investigate the progression of sensorineural hearing loss (SNHL) over several years in pediatric CF patients, and to identify risk factors, such as the use of AG, including both intravenous (IV) and inhaled AG.
Methods: Retrospective analyses of patient records from children and adolescents followed up at the CF clinic of the Antwerp University Hospital, Belgium, were performed. We collected data on age, sex, pure-tone audiometry, and the use of AG. Descriptive and binary logistic regression analyses, and if indicated generalized estimating equations (GEE) analyses were performed.
Results: Forty pediatric patients were enrolled in the study taking part from 2013 to 2020. Pure-tone audiometry revealed an important rate of SNHL over several years, with a prevalence of 29 % for high-frequency SNHL (i.e. 8 kHz). Increasing age was identified as a significant risk factor for the development of SNHL at 8 kHz if 5 or more IV AG courses (p = 0.01) were reported or when IV AG were combined with inhaled AG (p = 0.002).

Conclusions: Age combined with the use of IV AG (≥5 courses or in combination with inhaled AG) are predictive for developing high-frequency SNHL (i.e. 8 kHz). We suggest routine annual hearing screening (incl. high-frequency thresholds) in CF patients, starting from childhood.

Nathalie Jouret is in the Department of Pediatric Pulmonology, Antwerp University Hospital, Edegem, Belgium.

Oguz Karcioglu, Aytekin Idikut, Ebru Ozturk, Ebru Damadoglu. Outcomes of Modulator Therapy Discontinued After Short-Term Use in Adult Cystic Fibrosis.Pediatr Pulmonol. 2024 Nov 28. doi: 10.1002/ppul.27416. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39607351/

Oguz Karacioglu
avensis.hacettepe.edu.tr

Introduction: Cystic fibrosis transmembrane conductance regulator modulator therapies (CFTR-MT) have altered management, reducing exacerbations and slowing pulmonary function decline. Nevertheless, it is still uncertain if the benefits of CFTR-MTs last when they are stopped. This study aimed to assess pulmonary function changes, and exacerbation rates during and after CFTR-MT use in adult cystic fibrosis patients.
Methods: Between 2018 and 2022, we conducted a study involving adult CF patients who initially used CFTR-MTs but later discontinued them due to reimbursement issues. The study was divided into three phases: predrug (T1), in-drug (T2), and postdrug (T3). We recorded pulmonary function tests, laboratory and culture results, and the number of exacerbations.
Results: The study involved 33 patients, with 28 (84.8%) receiving Elexacaftor/Tezacaftor/Ivacaftor and 5 (15.2%) receiving Ivacaftor. The median treatment and interruption durations were 3.1 (IQR = 2.9-5.7), and 2.5 (IQR = 1.5-4.0) months, respectively. The mean FEV1% was 54.3% (± 26.6), 70.4% (± 27.4), and 60.2% (± 26.5) during T1, T2, and T3, respectively (p < 0.001). The mean FVC% was 65.5% (± 23.9) in T1, increased to 81.5% (± 24.5) in T2, and decreased to 71.6% (± 25.9) in T3 (p < 0.001). The number of Psedomonas aeruginosa, and Aspergillus positive sputum cultures decreased significantly with drug use (T1: 72.7%, 39.4%; T2: 48.5%, 9.1%; T3: 45.5%, 18.2%; p = 0.014, p = 0.004, respectively). The median number of hospitalizations was 1.0 (0-5.0) in T1, 0 (0-0) in T2, and 0 (0-1.0) in T3.
Conclusion: This study revealed that CFTR-MTs are effective even in the short term for adult CF patients, but their beneficial effects quickly diminish after discontinuation. Real-life data obtained as a result of discontinuation of drugs due to reimbursement problems has highlighted the significance of regular and uninterrupted use

Oguz Karcioglu is in the Dept.  of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Claire Keating , Lael M Yonker , François Vermeulen , Dario Prais , Rachel W Linnemann , Aaron Trimble, et al (full authors on Link). Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials. Lancet Respir Med. 2024 Dec 20:S2213-2600(24)00411-9. doi: 10.1016/S2213-2600(24)00411-9. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39756424/   Free article

Claire L Keating doctors.columbia.edu

Background: The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older.

Methods: In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete.
Findings: In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6-38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5-42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI -0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI -0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor-ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]).

Interpretation: Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators.

Claire Keating is at Columbia University Irving Medical Center, New York, NY, USA.

Eitan Kerem, Annalisa Orenti, Arianna Adamoli, Elpis Hatziagorou  , Lutz Naehrlich, Isabelle Sermet-Gaudelus ; and the ECFS Patient Registry Steering Group. Cystic fibrosis in Europe: improved lung function and longevity – reasons for cautious optimism, but challenges remain. Eur Respir J. 2024 Mar 7;63(3):2301241. doi: 10.1183/13993003.01241-2023. Print 2024 Mar. Free PMC article. pubmed.ncbi.nlm.nih.gov/38302155/

Eitan Kerem

Background: Prognosis and disease severity in cystic fibrosis (CF) are linked to declining lung function. To characterise lung function by the number of adults in countries with different levels of Gross National Income (GNI), data from the European Cystic Fibrosis Society Patient Registry were utilised.
Methods: Annual 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.
Results: A consistent improvement in FEV1 % pred and survival was observed among the 47 621 people with CF (pwCF), including subjects with chronic Pseudomonas aeruginosa infection, CFRD and/or undernutrition. Mean values of FEV1 % pred changed from 85% to 94.2% for children and from 63.6% to 74.7% for adults. FEV1 % pred further increased among those carrying the F508del mutation in 2021, when elexacaftor/tezacaftor/ivacaftor 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 lower income countries did not demonstrate a significant annual increase in FEV1 % pred or in the number of adults.
Conclusion: This pan-European analysis demonstrates a consistent improvement in FEV1 % pred, number of adult pwCF and survival over the last decade only in European higher and middle income countries. Urgent action is needed in the lower income countries where such improvement was not observed. The notable improvement observed in pwCF carrying the F508del mutation emphasises the need to develop treatments for all CF mutations.

Eitan Kerem is in the Department of Paediatrics and CF Centre, Hebrew University Medical School, Hadassah Medical Center, Jerusalem, Israel

Comment on the above article –

Edward F McKone Socioeconomic disparities in European cystic fibrosis outcomes: time to close the gap.  ClinicalTrials.gov number, NCT02392234 
Eur Respir J. 2024 Mar 7;63(3):2400328. doi: 10.1183/13993003.00328-2024. Print 2024 Mar.  https://pubmed.ncbi.nlm.nih.gov/38453247/

Edward McKone

Extract  – ” It is now clear from European CF registry studies  that there are disparities in CF outcomes across Europe. It is unclear what the exact reasons are for this. Many socioeconomic factors may contribute to different outcomes in CF , including some that are disease-specific, for example a lack of screening for newborns or access to specialist CF centres and/or therapies, along with more general SES factors, including poorer living and working conditions, lower educational attainment or limited general healthcare resources. Further research is needed to understand which of these are the main contributors to disparities in CF outcomes, and whether targeted interventions, such as improved education about CF, mentorship programmes for newer CF centres, and improved workforce planning and training of staff to work in lower-income country CF units, will improve outcomes for people with CF. Either way, studies like these using registry data to identify disparities in CF outcomes should be used as a powerful tool for healthcare workers, people with CF and policymakers to advocate at European and national level for improvements in CF care across Europe.

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.

Amalia Sophia Magaret biostst.washington.edu

Cohen-Cymberknoh and others recently reported an increased drop in lung health for pregnant women with cystic fibrosis who are having their 3rd pregnancy, compared to earlier pregnancies. FEV1 percent-predicted was reported to decline 7.8 % over the course of later pregnancies relative to a decline of 2.5 % over earlier pregnancies. If causally related to birth order, this difference may affect decisions by prospective mothers. Considerations regarding pregnancy and family size are increasingly relevant as health and life expectancies for women with cystic fibrosis improve with use of disease-modifying treatments.

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.

Claire Kim, Mark Higgins, Lingyun Liu, Nataliya Volkova, Anna Zolin, Lutz Naehrlich ; ECFSPR Study Group. Effectiveness of lumacaftor/ivacaftor initiation in children with cystic fibrosis aged 2 through 5 years on disease progression: Interim results from an ongoing registry-based study. J Cyst Fibros. 2024 Feb 23:S1569-1993(24)00017-1. doi: 10.1016/j.jcf.2024.02.004. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/38402082/

Claire Kim Datalead

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

Claire Kim is Director at Vertex Pharmaceuticals Incorporated, Boston, MA, USA.

Theresa Jane Kolaczkowski , Amanda Bevan, Julian Legg , Jay Self , Mark Allenby.Elevated liver function tests in infants exposed to elexacaftor-tezacaftor-ivacaftor in utero and while breastfeeding – Case Reports J Cyst Fibros. 2024 Oct 17:S1569-1993(24)01793-4. doi: 10.1016/j.jcf.2024.09.025. pubmed.ncbi.nlm.nih.gov/39424519/
Highlights.    We describe a monitoring schedule for infants exposed to ETI via breast milk.  We report 2 cases of mildly elevated liver transaminases in infants exposed to ETI.  Neither child had a cataract.  Mothers should be fully informed before continuing ETI while breastfeeding.

Theresa Jane Kolaczkowski is at the Wessex Adult Cystic Fibrosis Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Aleksandra Kowalik, Emma Roberts, Anna Hedborg Harris, Marie Sund, Sara Wird, Ola Kvist, Lena Hjelte.Clinical outcomes of two infants with cystic fibrosis, including presence of the vas deferens, born to a woman with cystic fibrosis taking CFTR modulators during both pregnancies. Case Reports J Cyst Fibros. 2024 Jun 13:S1569-1993(24)00080-8. doi: 10.1016/j.jcf.2024.06.003. Online ahead of print.  Full text via PubMed link pubmed.ncbi.nlm.nih.gov/38876833/

Aleksandra Kowalik is at the CF Centre, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.

HuiChuan J Lai , Taiya R Bach, Tami Miller , Catherine M McDonald , Karen M Maguiness, Erin E Seffrood, Jessica B Leonard, Philip M Farrell    Breastfeeding, growth, and lung disease in the first 3 years of life in children with cystic fibrosis. J Cyst Fibros. 2024 Jul 16:S1569-1993(24)00791-4. doi: 10.1016/j.jcf.2024.07.006. Online ahead of print.
pubmed.ncbi.nlm.nih.gov/39019722/

HuiChuan J Lai
Univ. Wisconsin

Background: The 2009 cystic fibrosis (CF) infant care guidelines recommend breastmilk as the initial feeding but do not address if/when it should be fortified or supplemented with formula to promote optimal growth and pulmonary health.
Methods: We conducted a prospective multi-center cohort study in breastfed and formula-fed infants that included 172 infants with CF who were born during 2012-17, enrolled after newborn screening at age 1.9 ± 1.0 months, and evaluated growth and lung disease manifestations in the first 3 years of life.
Results: Seventy-two percent of our study cohort was breastfed at birth, but 64 % transitioned to receiving fortified feedings (breastmilk, formula, or a combination) by 6 months of age to reverse the downward trajectory of their growth curves. Fortified feedings accelerated catch-up growth to normal weight-for-age (0.12 ± 0.80 z-score) and near normal height-for-age (-0.13 ± 0.90 z-score) at 3 years of age. Within the fortified group, breastmilk and formula were similarly effective in promoting catch-up growth, but proportionately fewer infants with CF fed predominantly breastmilk (30 %) experienced severe or moderate early-onset lung disease compared to those fed predominantly formula (62 %), p = 0.02.
Conclusions: Most infants with CF require fortified feedings to recuperate from growth faltering and achieve normal growth at 3 years of age. For these infants, the proactive/preventive strategy of fortified breastmilk feedings starting soon after CF diagnosis, an alternative to the reactive/monitoring approach, can minimize the risk of prolonged postnatal growth faltering, accelerate the potential of attaining catch-up growth, and decrease the likelihood of experiencing more severe early-onset lung disease.

HuiChua J Lai  is Professor  in the Department of Nutritional Sciences, University of Wisconsin College of Agriculture and Life Sciences, Madison, WI, USA; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Emma L Ledger , Daniel J Smith, Jing Jie Teh, Michelle E Wood, Page E Whibley , Mark Morrison, Joanna B Goldberg, David W Reid, Timothy J Wells.   Impact of CFTR Modulation on Pseudomonas aeruginosa Infection in People With Cystic Fibrosis. J Infect Dis. 2024 Mar 5:jiae051. doi: 10.1093/infdis/jiae051. Online ahead of print pubmed.ncbi.nlm.nih.gov/38442240/

Emma L Ledger
X-com

P. aeruginosa strains (n = 105) were isolated from the sputum of 11 chronically colonized pwCF at baseline and up to 21 months posttreatment with elexacaftor-tezacaftor-ivacaftor or tezacaftor-ivacaftor. Phenotypic characterization and comparative genomics were performed.
Results: Clonal lineages of P. aeruginosa persisted after therapy, with no evidence of displacement by alternative strains. We identified commonly mutated genes among patient isolates that may be positively selected for in the CFTR-modulated lung. However, classic chronic P. aeruginosa phenotypes such as mucoid morphology were sustained, and isolates remained just as resistant to clinically relevant antibiotics.
Conclusions: Despite the clinical benefits of CFTR modulators, clonal lineages of P. aeruginosa persist that may prove just as difficult to manage in the future, especially in pwCF with advanced lung disease

Emma L Ledger is a PhD candidate at the Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia.

Mi-Sun S Lee, Crystal M North, Irada Choudhuri, Subrata K Biswas, Abby F Fleisch, Afifah Farooque, Diane Bao, Sakila Afroz, Sadia Mow, Nazmul Husain, Fuadul Islam, Md Golam Mostafa, Partha Pratim Biswas, David S Ludwig, Subba R Digumarthy, Christopher Hug, Quazi Quamruzzaman, David C Christiani, Maitreyi Mazumdar. Arsenic exposure is associated with elevated sweat chloride concentration and airflow obstruction among adults in Bangladesh: a cross sectional study. medRxiv[Preprint]. 2024 Sep 26:2024.09.25.24314390. doi: 10.1101/2024.09.25.24  pubmed.ncbi.nlm.nih.gov/39399016/

Arsenic is associated with lung disease and experimental models suggest that arsenic-induced degradation of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) is a mechanism of arsenic toxicity. We examined associations between arsenic exposure, sweat chloride concentration (measure of CFTR function), and pulmonary function among 285 adults in Bangladesh. Participants with sweat chloride ≥ 60 mmol/L had higher arsenic exposures than those with sweat chloride < 60 mmol/L (water: median 77.5 µg/L versus 34.0 µg/L, p = 0.025; toenails: median 4.8 µg/g versus 3.7 µg/g, p = 0.024). In linear regression models, a one-unit µg/g increment in toenail arsenic was associated with a 0.59 mmol/L higher sweat chloride concentration, p < 0.001.
We found that toenail arsenic concentration was associated with increased odds of airway obstruction (OR: 1.97, 95%: 1.06, 3.67, p = 0.03); however, sweat chloride concentration did not mediate this association. Our findings suggest that sweat chloride concentration may be a novel biomarker for arsenic exposure and also that arsenic likely acts on the lung through mechanisms other than CFTR dysfunction.

Tim Lee, Claire Nissenbaum. Improving gastrointestinal health in children and young people with cystic fibrosis. Arch Dis Child. 2024 May 9:archdischild-2024-326900.doi: 10.1136/archdischild-2024-326900. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/38724066/

Tim Lee

This is an editorial – unfortunately no abstract.  Extract  “The landscape of CF care is now once again dramatically changing with the introduction of CFTR modulator drugs.1 These medications act directly to improve the function of the mutant protein and in older children and adults have been shown to significantly improve lung function, body mass index and quality of life, reduce pulmonary exacerbation by up to 78%, as well as reduce sweat chloride to normal or borderline levels. Life expectancy is expected to increase significantly. In the UK, elexacaftor/tezacaftor/ivacaftor triple-combination CFTR modulator is now available from the age of 2 years for those with phe508del and other responsive CFTR mutations and ivacaftor from 1 month of age for those with gating mutations of CFTR. As a result, the predominant and most burdensome symptoms of CF may now be switching back to the GI tract,”

Tim Lee is Director of the Leeds Centre for Children’s Respiratory Medicine, Leeds  Children’s Hospital.

Claire Nissenbaum is a paediatrician at Sheffield Children’s Hospital, Sheffield UK.

Danni Li , Martin Donnelley , David Parsons , Mark D Habgood , Elena K Schneider-Futschik.   Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy. Br J Pharmacol. 2024 Aug;181(15):2413-2428. doi: 10.1111/bph.16417. Epub 2024 May 21. pubmed.ncbi.nlm.nih.gov/38770951/

Danni Li
LinkedIn

Background and purpose: Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated.
Experimental approach: Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg-1·day-1 elexacaftor + 3.5 mg·kg-1·day-1 tezacaftor + 25 mg·kg-1·day-1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed
Key results: No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development.

Conclusion and implication: Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.

Danni Li PhD  is a research pharmacologist in the  Department of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia.

— With all the serious problems relating to intrauterine drug exposure over the years, the authors’ comment that cortical neuronal development requires future follow up studies seems appropriate.

Cathy Liu, Taiya R Bach, Philip M Farrell, Derek Pavelec, Nicholas J Antos , Michael J Rock , Fadi Asfour , Michelle Howenstine, Jonathan M Gaffin, Lai HJ.   Impact of acid blocker therapy on growth, gut microbiome, and lung disease in young children with cystic fibrosis. J Pediatr Gastroenterol Nutr
. 2024 Oct 28. doi: 10.1002/jpn3.12389. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39465618/

Cathy Liu
nacfc

Objective: Acid blocker therapy (ABT) has become common in cystic fibrosis (CF), despite insufficient evidence for benefits and studies showing potentially negative effects. We examined associations between ABT usage and growth, gut microbiome (GM), and early-onset lung disease in young children with CF.
Methods: One hundred forty-five infants with CF born during 2012-2017, diagnosed through newborn screening by age 3 months and followed to 36 months of age at six CF centers were evaluated. Longitudinal data on growth, pancreatic functional status, pulmonary symptoms, and acid blocker medications were prospectively collected. Early-onset lung disease severity was evaluated by a clinical scoring system. GM composition was assessed by 16S rRNA methodology.
Results: ABT use before age 3 years was frequent, with 81 (56%) of patients on H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI), and higher among pancreatic insufficient (60%) versus pancreatic sufficient (26%) children. H2RA was commonly prescribed in infancy before transitioning to PPI. Growth improvements were not significantly greater, while GM α-diversity at 3 years of age was significantly lower and early-onset lung disease more severe, in persistent ABT users compared to nonusers of ABT.

Conclusion: In our cohort of young children with CF, early and persistent ABT use was not associated with significant growth benefits and instead showed associations with reduced GM diversity and negative effects on early-onset lung disease. Consequentially, there is a critical need for systematic evaluation and comprehensive risk-benefit analysis of ABT to ensure proper guidelines for children with CF.

Cathy Liu is a third year medical student in the Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA

Daniel Lupas , Frank Y Chou , Mohammad Abdullah Al Hakani , Ishita Kuthiala , Arjuna Srikrishnaraj , Xuan Li , Naomi Potter , Bradley S Quon.    The clrd year medical student inical effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) for people with CF without a F508del variant: A systematic review and meta-analysis.  J Cyst Fibros. 2024 Sep;23(5):950-958.doi: 10.1016/j.jcf.2024.07.012.Epub 2024 Jul 23. pubmed.ncbi.nlm.nih.gov/39048464/
Background: Access to elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (PwCF) without a F508del variant is limited due to lack of clinical data supporting efficacy.
Methods: In this systematic review and meta-analysis, we examined patient-level data from studies reporting the clinical response to ETI for PwCF with non-F508del CFTR variants. We searched electronic data sources including Embase, MEDLINE, and CENTRAL from January 1st, 2019 to May 14th, 2024.
Findings: Our search results identified 4,795 studies and 20 met the eligibility criteria. 120 of 164 (73 %) individuals had a positive clinical response to ETI, defined by a sweat chloride (SwCl) decrease of ≥10 mmol/L or percent-predicted FEV1 (ppFEV1) improvement of ≥5 %. 51 unique ETI-responsive variants were represented across these 120 individuals and 27 of these variants (53 %) have not been previously approved by the U.S. FDA. For variants with at least 10 individuals treated with ETI to date, a consistent positive clinical response was observed for N1303K and G85E. For N1303K (n = 48), the median increase in ppFEV1 was 16 % (IQR: 8 %, 29 %), with a median decrease in SwCl of -9 (IQR: -4, -22) mmol/L. For G85E (n = 16), the median increase in ppFEV1 was 13.5 % (IQR: 8 %, 19 %) with a median decrease in SwCl of -46 (IQR: -39, -66) mmol/L.
Conclusion: Additional ETI-responsive variants were identified following a comprehensive review of ETI clinical use in PwCF without F508del. This data can be used by the CF community in efforts to expand the labelled indications or to help advocate for off-label ETI reimbursement.

Daniel Lupas is at the Schulich School of Medicine, Western University, London, Ontario, Canada.

Jill Maggs, Gregory S Sawicki, Callie Bacon, Emma McWilliams, Dana Yablon, Benjamin Ertman, et. Qualitative understanding of experiences of people with cystic fibrosis in a treatment discontinuation trial: The QUEST study. Contemp Clin Trials
. 2024 Nov 16:107752. doi: 10.1016/j.cct.2024.107752. Online ahead of print.pubmed.ncbi.nlm.nih.gov/39557157/

Jill Maggs
C F  Conference 2022

Background: As people with cystic fibrosis (pwCF) live longer due to the breakthrough drug elexacaftor-tezacaftor-ivacaftor (ETI), they have questioned whether other CF therapies could be safely discontinued. SIMPLIFY was the first prospective, randomized trial to evaluate non-inferiority of discontinuing versus continuing two therapies. The QUEST (Qualitative Understanding of Experiences in the SIMPLIFY Trial) study was conducted to understand experiences of pwCF enrolled in SIMPLIFY, including why they joined, perceptions of randomization, decision-making around study withdrawal, and considerations for future discontinuation studies.
Methods: QUEST enrolled SIMPLIFY participants 14 years or older stable on ETI and caregivers of the 14-17 year-olds. Interviews were audio-recorded, transcribed, and coded. A phenomenological approach was used to inductively develop codes with no a priori hypotheses; identified themes were then organized around current research and recruitment literature.
Results: 114 interviews were completed (68 adults, 23 teenagers, and 23 caregivers). Among pwCF, median age was 27.8 years, 49 % were female and 80 % had participated in research before SIMPLIFY. Five themes were identified: ((Gul and Ali, 2010 [1]) Experience with SIMPLIFY randomization, CFF Patient Registry Annual Data Report [Internet] (2017) [2] Trust, CFF Patient Registry Annual Data Report [Internet] (2022) [3] Altruism, Goss et al. (2008) [4] Perceived personal benefits, and (Goss et al., 2002 [5]) Perceived risks and protocol burden.

Conclusion: QUEST findings highlight how a long-standing culture of research and thoughtful protocol design contributed to SIMPLIFY’s successful recruitment and retention. This included understanding the importance of remaining in the trial despite not being randomized to their preferred treatment assignment. Using patient-centered approaches to select research questions, design a protocol to minimize participant barriers, and frame recruitment materials messaging contribute to successful research participation.

Jill Maggs  Community Member, former STRC Steering Committee Member, c/o Cystic Fibrosis Foundation

Jochen G Mainz , Karen Lester , Basil Elnazir , Michael Williamson , Ed McKone , Des Cox , Barry Linnane , Carlos Zagoya , Franziska Duckstein, Anton Barucha , Jane C Davies, Paul McNally; RECOVER Study Group
Reduction in abdominal symptoms (CFAbd-Score), faecal M2-pyruvate-kinase and Calprotectin over one year of treatment with Elexacaftor-Tezacaftor-Ivacaftor in people with CF aged ≥12 years – The RECOVER study   J Cyst Fibros. 2024 May;23(3):474-480. doi: 10.1016/j.jcf.2023.10.001. Epub 2023 Oct 7. pubmed.ncbi.nlm.nih.gov/37806792/

Jochen G Mainz
ResearchGate

Background: RECOVER is a multicentre post-approval study of Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pwCF in Ireland and the UK. The CFAbd-Score is the first validated CF-specific patient reported outcome measure (PROM) focusing on gastrointestinal symptoms; it comprises 28 items in 5 domains. In a preliminary study, we previously reported reductions in abdominal symptoms (AS) in pwCF after 26 weeks of ETI-therapy using the CFAbd-Score.
Aim: to assess changes in AS in a second, large cohort and explore novel GI-biomarkers of gut inflammation and cell-proliferation in pwCF over one year of ETI-therapy.
Methods: Participants were recruited as part of the RECOVER study at 8 sites (Ireland&UK). The CFAbd-Score was administered prior to ETI-initiation, and subsequently at 1,2,6 and 12 months on treatment. Faecal M2-pyruvate kinase (M2-PK) and calprotectin (FC) were quantified in samples collected at baseline, 1 and 6 months.
Results: 108 CFAbd-Scores and 73 stool samples were collected at baseline. After 12 months of ETI-therapy, total CFAbd-Scores had significantly declined (15.0±1.4→9.8±1.2pts/p<0.001), and so had all its five domains of “pain” (16.9±2.0pts→9.9±1.8pts/p<0.01), “GERD” (14.4±1.8→9.9±1.6/p<0.05), “disorders of bowel movements” (19.2±1.4→14.1±1.5/p<0.01), “appetite” (7.0±1.1→4.6±1.2/p<0.01) and “impaired-QoL” (13.3±1.9→7.5±1.5/p<0.001). Levels of M2-PK and FC significantly decreased during ETI-therapy.

Discussion: In-depth analysis of AS with the CFAbd-Score reveals a statistically significant, clinically relevant and sustained improvement with ETI. We attribute this to high sensitivity of the implemented CF-specific PROM, developed and validated following FDA-guidelines. Furthermore, for the first time during ETI-therapy a significant decline in faecal M2-PK, a marker of inflammation and cell-proliferation, was found, in parallel to FC.

Jochen G Mainz is at the Brandenburg Medical School (MHB) University. Klinikum Westbrandenburg, Brandenburg an der Havel, Germany.

Richard D Maradiaga, Mitchell L Ramsey, Stephen E Kirkby, Lindsay A Sobotka.  The Role of Cystic Fibrosis Transmembrane Conductance Regulator Modulators After Liver Transplantation in Persons With Cystic Fibrosis. Case Reports ACG Case Rep J. 2024 Jan 16;11(1):e01261. doi: 10.14309/crj.0000000000001261. eCollection 2024 Jan.Free PMC article  pubmed.ncbi.nlm.nih.gov/38234978

Despite advances in treatment for cystic fibrosis (CF), liver disease remains a major contributor to morbidity and mortality for persons with CF. Therefore, liver transplantation may be considered in end-stage CF-related liver disease. We present a young patient with CF who underwent solo liver transplantation and has successfully restarted on elexacaftor/tezacaftor/ivacaftor without significant pulmonary or hepatic complications after transplant.

Richard D Maradiaga  is an internist in the Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.

Nicole Mayer-Hamblett, Alex H Gifford, Margaret Kloster, Renee Russell, Andrew T Braun, Ronald L Gibson  et al. Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa After Elexacaftor/Tezacaftor/Ivacaftor in Cystic FibrosisAnn Am Thorac Soc
. 2024 Jul 23. doi: 10.1513/AnnalsATS.202404-366OC. Online ahead of print.pubmed.ncbi.nlm.nih.gov/39041864/

Nicole Mayer-Hamblett
Seattle Children’s

Objective To evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA.
Conclusions SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared to those who remained on both therapies. These data continue to inform a new era of post-modulator care of pwCF.

Nicole Mayer-Hamblett is at the University of Washington, Pediatrics, Seattle, Washington, United States. and  Seattle Children’s Research Institute, Seattle, Washington, United States.

Paul McNally, Alvin Singh, Susanna A McColley, Jane C Davies, Mark Higgins, Meng Liu, Jennifer Lu, Violeta Rodriguez-Romero, Judy L Shih, Margaret Rosenfeld  6 ; VX15-770-124 Study Group.  Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis.   J Cyst Fibros https://onlinelibrary.wiley.com/doi/10.1002/lary.31447. 2024 Apr 4:S1569-1993(24)00042-0.  doi: 10.1016/j.jcf.2024.03.012. Online ahead of print. Free article    pubmed.ncbi.nlm.nih.gov/38580563/

Paul McNally
RCSI

Background: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF.
Methods: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. Results: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed.

Conclusions: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Paul McNally is at the RCSI University of Medicine and Health Sciences and Children’s Health, Dublin

Caoimhe McParland, Matthew Nunn, Theodore K Marras, Meredith Chiasson. Eradication of Mycobacterium abscessus infection in cystic fibrosis with initiation of Elexacaftor/Tezacaftor/Ivacaftor. J Cyst Fibros. 2024 Jan;23(1):38-40. doi: 10.1016/j.jcf.2023.03.021. Epub 2023 Apr 17.   pubmed.ncbi.nlm.nih.gov/37076409/
Mycobacterium abscessus is a nontuberculous mycobacterium that is often multi-drug resistant, difficult to eradicate and associated with a rapid decline in lung function in cystic fibrosis (CF). Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a combination CFTR modulator that improves lung function and decreases exacerbations, but limited data exists about its impact on respiratory infections. A 23-year-old male with CF (F508del, unknown) was diagnosed with Mycobacterium abscessus subspecies abscessus infection. He completed 12-weeks of intensive therapy, followed by oral continuation therapy. Antimicrobials were later discontinued for optic neuritis secondary to linezolid. He remained off antimicrobials with persistently positive sputum cultures. He then initiated ETI, and bronchoscopy eight months later suggested eradication of M. abscessus. By modulating CFTR protein function, ETI may improve innate airway defence mechanisms, facilitating the clearance of infections such as M. abscessus. This case highlights the potential positive implications of ETI on the challenging treatment of M. abscessus infections in CF.

Caoimhe McParland is Professor in the Dept of Medicine,  Dalhousie University, Halifax, NS, Canada.

Angela Metcalf , Stacey L Martiniano, Scott D Sagel , Michael V Zaretsky, Edith T Zemanick , Jordana E Hoppe.  Outcomes of prenatal use of elexacaftor/tezacaftor/ivacaftor in carrier mothers to treat meconium ileus in fetuses with cystic fibrosis. J Cyst Fibros. 2024 Dec 6:S1569-1993(24)01843-5. doi: 10.1016/j.jcf.2024.11.011. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39645477/

Angela Metcalfe
Doximetry

As cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies including elexacaftor/tezacaftor/ivacaftor (ETI) have become widely used in eligible patients with cystic fibrosis (CF), the use of these medications in pregnant people has become a critical area of investigation. Since these medications appear generally safe to both mother and fetus when taken by pregnant people with CF, interest has pivoted to the use of ETI in CF carrier mothers to decrease morbidity and mortality from meconium ileus (MI) in fetuses with cystic fibrosis.
Here we discuss three infants at our institution with ultrasound findings of MI who were exposed to prenatal ETI through CF carrier mothers for the purposes of treating MI and lowering risk of intestinal complications from this severe manifestation of CF. These cases differ in the timing of ETI initiation, severity of outcome, and accessibility of this off-label medication use to families depending on their insurance. All infants and mothers tolerated the medication well without significant side effects. One infant had complete MI resolution, one had persistent MI at birth with easy clearance with minimally invasive therapies, and one had persistent MI requiring jejunostomy. The infant with the most severe outcome had the shortest duration of ETI exposure and may have been able to receive this medication sooner had a referral to a CF center been made. These cases highlight the potentially life-altering effects of prenatal ETI use and the need for awareness of this clinical situation among fetal care providers.

Dr Angela Metcalfe is in the Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado, Aurora, CO, United States. Electronic address: angela.metcalf@childrenscolorado.org.

Noelia Rodriguez Mier, Virginie Antoons, Senne Cuyx , Anabela Santo Ramalho , Mieke Boon , Marijke Proesmans , Djalila Mekahli, François Vermeulen. Pseudo-Bartter syndrome: A CFTR-related disorder?  Case Reports J Cyst Fibros. 2024 Oct 31:S1569-1993(24)01799-5. doi: 10.1016/j.jcf.2024.10.007. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39482189/
This case report presents a 14-month-old boy with a history of cystic fibrosis (CF) carrier status, diagnosed following a positive newborn screening for CF (CF-NBS), who developed symptoms suggestive of Pseudo-Bartter syndrome (PBS). Despite initial evaluations not meeting CF diagnostic criteria, subsequent investigations revealed an intermediate sweat chloride concentration, a second CFTR mutation, and CFTR dysfunction through rectal organoid morphology analysis (ROMA) consistent with CFTR-related disorder (CFTR-RD). This case raises important considerations regarding the diagnosis and management of CFTR-RD. PBS can be considered as a rare presentation of CFTR-RD and can occur in children with sweat chloride below the CF range. Functional testing of CFTR by ROMA enabled a more accurate diagnosis. Despite the negative work-up after CF-NBS, this infant developed CFTR-RD, but this should not be considered as a screen failure. Follow-up of children with CFTR-RD at a CF centre is preferred, because of the risk of developing CF.

Noelia Rodriguez Mie is at the Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven, Belgium; Department of Development and Regeneration, Woman and Child Unit, CF Research Lab, KU Leuven, Leuven, Belgium.

Reza V MilanoKayla Morneault-GillHebat Y KamalJodie A BarkinChristina Baldwin Chadwick. Pancreatitis in cystic fibrosis: Presentation, medical and surgical management, and the impact of modulator therapies  Pediatr Pulmonol. 2024 Sep:59 Suppl 1:S53-S60. doi: 10.1002/ppul.26958.Epub 2024 Mar 19. onlinelibrary.wiley.com/doi/10.1002/ppul.26958
Patients with Cystic Fibrosis (CF) are at increased risk of acute (AP) and chronic (CP) pancreatitis, and their complications. The extent of remaining healthy pancreatic parenchyma determines the risk of developing future episodes of pancreatitis, as well as pancreatic exocrine or endocrine insufficiency. Pancreatitis may be the presenting symptom of CF, and genetic testing is especially important in pediatrics. AP and recurrent AP are managed with intravenous fluid hydration and pain control, in addition to early refeeding and treatment of complications. With the use of modulator therapy in CF, pancreatic function may be restored to some extent. CP related pain is managed with analgesics and neuromodulators, with surgery if indicated in specific situations including TPIAT as a possible type of surgical intervention. Long-term sequelae of CP in patients with CF include exocrine pancreatic insufficiency treated with pancreatic enzyme replacement therapy, fat-soluble vitamin deficiencies and associated metabolic complications such as bone disease/osteoporosis, pancreatogenic diabetes, and less commonly, pancreatic cancer. We review the presentation and etiologies of pancreatitis in CF patients as well as the management of AP and CP primarily in children.

Reza V Milano is in the Dept of Medicine, Division of Digestive Health and Liver Diseases, University of Miami, Leonard M. Miller School of Medicine, Miami, Florida, USA.

Aaron C Miller, Logan M Harris, Kevin L Winthrop, Joseph E Cavanaugh, Mahmoud H Abou Alaiwa, Douglas B Hornick, David A Stoltz, Philip M Polgreen.   Cystic Fibrosis Carrier States Are Associated With More Severe Cases of Bronchiectasis.    Open Forum Infect Dis. 2024 Jan 17;11(2):ofae024.  doi: 10.1093/ofid/ofae024. eCollection 2024 Feb pubmed.ncbi.nlm.nih.gov/38390464/

   Aaron Miller

Background: People with cystic fibrosis (CF) are at increased risk for bronchiectasis, and several reports suggest that CF carriers may also be at higher risk for developing bronchiectasis. The purpose of this study was to determine if CF carriers are at risk for more severe courses or complications of bronchiectasis.
Methods: Using MarketScan data (2001-2021), we built a cohort consisting of 105 CF carriers with bronchiectasis and 300 083 controls with bronchiectasis but without a CF carrier diagnosis. We evaluated if CF carriers were more likely to be hospitalized for bronchiectasis. In addition, we examined if CF carriers were more likely to be infected with Pseudomonas aeruginosa or nontuberculous mycobacteria (NTM) or to have filled more antibiotic prescriptions. We considered regression models for incident and rate outcomes that controlled for age, sex, smoking status, and comorbidities.
Results: The odds of hospitalization were almost 2.4 times higher (95% CI, 1.116-5.255) for CF carriers with bronchiectasis when compared with non-CF carriers with bronchiectasis. The estimated odds of being diagnosed with a Pseudomonas infection for CF carriers vs noncarriers was about 4.2 times higher (95% CI, 2.417-7.551) and 5.4 times higher (95% CI, 3.398-8.804) for being diagnosed with NTM. The rate of distinct antibiotic fill dates was estimated to be 2 times higher for carriers as compared with controls (95% CI, 1.735-2.333), and the rate ratio for the total number of days of antibiotics supplied was estimated as 2.8 (95% CI, 2.290-3.442).

Conclusions: CF carriers with bronchiectasis required more hospitalizations and more frequent administration of antibiotics as compared with noncarriers. Given that CF carriers were also more likely to be diagnosed with Pseudomonas and NTM infections, CF carriers with bronchiectasis may have a phenotype more resembling CF-related bronchiectasis than non-CF bronchiectasis.

Aaron C Miller is in the Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.

Jessa E Miller, Eugene Oh, Aastha Khatiwada, Stephen M Humphries, Alexandra Wilson, Eszter K Vladar, David A Lynch, Jennifer L Taylor-Cousar, Daniel M Beswick.   Two-Year Impact of Highly Effective Modulator Therapy on Olfactory Dysfunction. Laryngoscope 2024 apr 22 doi: 10.1002/lary.31447.Online ahead of print.  pubmed.ncbi.nlm.nih.gov/38647113/

     Jessa E Millar

Conclusion: Olfactory dysfunction  in adults with CF did not improve in a clinically relevant manner after 2 years of ETI. Further study into mechanisms of olfactory loss in PwCF and the impact of early intervention on preventing or improving OD is warranted.

Jessa E Millar is in the Department of Otolaryngology-Head and Neck Surgery, University of California, Los Angeles, Los Angeles, California, U.S.A.

Lisa Morrison, Zoe Louise Saynor, Alison Kirk, Lisa McCann. Revolutionizing Care: Unleashing the Potential of Digital Health Technology in Physiotherapy Management for People With Cystic Fibrosis. JMIR Rehabil Assist Technol. 2024 Jul 15:11:e55718. doi: 10.2196/55718. pubmed.ncbi.nlm.nih.gov/39012075/

      Lisa Morrison
         wosacf.org

This viewpoint paper explores the dynamic intersection of physiotherapy and digital health technologies (DHTs) in enhancing the care of people with cystic fibrosis (CF), in the context of advancements such as highly effective modulator therapies that are enhancing life expectancy and altering physiotherapy needs. The role of DHTs, including telehealth, surveillance, home monitoring, and activity promotion, has expanded, becoming crucial in overcoming geographical barriers and accelerated by the recent pandemic. Physiotherapy, integral to CF care since 1946, has shifted toward patient-centered approaches, emphasizing exercise training and a physically active lifestyle. The reduction in inpatient admissions due to highly effective modulator therapies has led to increased home care and online or electronic consultations, and DHTs have revolutionized service delivery, offering flexibility, self-management, and personalized care options; however, there is a need to comprehensively understand user experiences from both people with CF and physiotherapists. This paper highlights the essential exploration of user experiences to facilitate clinician adaptation to the digital requirements of modern clinical management, ensuring equitable care in the “future hospitals” arena. Identifying research gaps, this paper emphasizes the need for a thorough evaluation of DHT use in CF physiotherapy education, training, and self-monitoring, as well as the experiences of people with CF with online or electronic consultations, self-monitoring, and remote interventions. Online group exercise platforms address historical challenges relating to infection control but necessitate comprehensive evaluations of user experiences and preferences. Future-proofing DHTs within the physiotherapy management of CF demands a shift toward full integration, considering stakeholder opinions and addressing barriers. While DHTs have the potential to extend physiotherapy beyond the hospital, this paper stresses the importance of understanding user experiences, addressing digital poverty, and working toward more equitable health care access. A flexible approach in the “future hospital” is advocated, emphasizing the need for a nuanced understanding of user preferences and experiences to optimize the integration of DHTs in CF care.

Lisa Morrison is Principal Physiotherapist at the West of Scotland Adult Cystic Fibrosis Unit, Queen Elizabeth University Hospital, Glasgow, United Kingdom and the Department of Computer and Information Sciences, University of Strathclyde, Glasgow, United Kingdom.

Nadia Nathan, Guillaume Thouvenin, Béatrice Dubern, Harriet Corvol.Elexacaftor/tezacaftor/ivacaftor can rescue pancreatic function in F508del homozygous children.Pediatr Pulmonol. 2024 Mar;59(3):788-790. doi: 10.1002/ppul.26794. Epub 2023 Dec 13.pubmed.ncbi.nlm.nih.gov/38088210/

Nadia Nathan Linkedin

No abstract available

Nadia Nathan is Professor at Service de Pneumologie Pédiatrique, Centre de Référence des Maladies Respiratoires Rares RespiRare, ssistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau, ASorbonne Université, Paris, France. and the Laboratory of Childhood Genetic Diseases, Inserm UMR_S933, Sorbonne Université, Paris, France.

Christabella Ng , Neele S Dellschaft, Caroline Hoad , Luca Marciani , Robin Spiller , Colin Crooks , Trevor Hill , Alex Menys , Jochen G Mainz , Helen Barr , Penny A Gowland , Giles Major , Alan R Smyth. A randomised crossover trial of tezacaftor-ivacaftor (SYMDEKO) for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study. NIHR Open Res. 2024 Mar 19:3:65. doi: 10.3310/nihropenres.13510.2. eCollection 2023.   pubmed.ncbi.nlm.nih.gov/39139270/

Christabella Ng
X.com

(Shortened summary)    We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI.   We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events.
Conclusions: Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators.

Christabella Ng is at  NIHR Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK. and the Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham, England, UK.

Inès Nidegger, Julie Macey, Marine Ferey, Allison Singier, Marie Tournier, Justine Perino, Francesco Salvo. Suicidal behaviour and CFTR modulators: A case series and WHO database disproportionality analysisCyst Fibros
. 2024 Oct 14:S1569-1993(24)01788-0. doi: 10.1016/j.jcf.2024.09.020. Online ahead of print.  
pubmed.ncbi.nlm.nih.gov/39406576/

Ines Nidegger Linkedin

Background: A highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database.
Methods: First, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) “Suicide/Self-injury” and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect.
Results: Four cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt.

Conclusions: ETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation.

Inès  Nideegger  is at ECHU de Bordeaux, Service de Pharmacologie Médicale, Centre Régional de Pharmacovigilance de Bordeaux, F-33000 Bordeaux.e

Sirish K Palle, Daniel H Leung. Advanced cystic fibrosis liver disease: Endovascular, endoscopic, radiologic, and surgical considerations. Review Pediatr Pulmonol. 2024 Sep:59 Suppl 1:S115-S122. doi: 10.1002/ppul.27174. https://onlinelibrary.wiley.com/doi/10.1002/ppul.27174

Sirish Palle
ouhealth.com

Up to 90% of people with CF (pwCF) will have some form of hepatobiliary involvement. This manuscript aims to explore the different endovascular, endoscopic, radiological and surgical procedures available to diagnose and manage the most severe form of CF hepatobiliary involvement (CFHBI) known as advanced cystic fibrosis liver disease (aCFLD), seen in 10% of pwCF. These procedures and interventions include liver biopsy, hepatic venous pressure gradient measurement, gastrostomy tube placement to optimize nutrition, paracentesis, endoscopic variceal control of bleeding and portosystemic shunting before liver transplantation. By utilizing advanced diagnostic or surgical techniques, healthcare professionals of pwCF can more effectively manage patients with CFHBI and aCFLD and potentially improve patient outcomes.

Sirish K Palle is in the Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Julie Park , Anna Walsh  , Sue Kerr  , Clare Woodland  , Suzanne Southward  , Mark Deakin , Senthil Senniappan  , Rebecca Thursfield Improvements in Glucose Regulation in Children and Young People with Cystic Fibrosis-Related Diabetes following Initiation of Elexacaftor/Tezacaftor/Ivacaftor.Case Reports Horm Res Paediatr. 2024;97(1):94-98. doi: 10.1159/000530571. Epub 2023 Apr 11.   pubmed.ncbi.nlm.nih.gov/37040724/

Julie Park
ResearchGate

Introduction: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are increasingly used in children and young people with cystic fibrosis (CF). Data in adults show there may be an impact on glycaemic control in those with CF-related diabetes (CFRD). Paediatric data are rare. Case Series/Presentation: Children aged >12 years with CFRD, who were eligible for elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) were commenced on treatment. Glucose monitoring via the FreeStyle Libre system was commenced prior to, immediately after, and several months after commencing ELX/TEZ/IVA. Glycaemic control, shown by time in range (3-10 mmol/L), percentage of time spent hypoglycaemic (<3 mmol/L), and percentage of time spent hyperglycaemic (>10 mmol/L) on Insulin doses were recorded. Following ELX/TEZ/IVA, four of seven children stopped insulin, two required substantially reduced doses of insulin, one showed no response. Glycaemic control remained similar on lower doses or no insulin. Hypoglycaemia was detected in those not requiring insulin.

Conclusion: ELX/TEZ/IVA has a positive impact on glycaemic control and insulin requirements in children with CFRD. Close monitoring is required when commencing treatment. Children with CFRD need counselling regarding possible reductions in insulin requirement and re-education regarding symptoms, signs, and management of hypoglycaemia.

Julie Park is in the Department of Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK and the University of Liverpool, Liverpool, UK

Kimberly Pasley , Mary Lynn Dell, Anne May. Diagnosis and treatment of ADHD in pediatric patients during the first year of elexacaftor/tezacaftor/ivacaftor.  Cystic fibrosis referencesPediatr Pulmonol
. 2024 Sep 6. doi: 10.1002/ppul.27246. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39239907/
Background: With elexacaftor/tezacaftor/ivacaftor (ETI), children with cystic fibrosis (CwCF) are living healthier lives with a focus on typical developmental issues such as attention deficit/hyperactivity disorder (ADHD). This paper characterizes CwCF with ADHD within the first year of ETI treatment.
Methods: This retrospective, observational analysis examines a subgroup of CwCF participating in a longitudinal study obtaining prospective data regarding the impact of ETI on mental health. All participants started on ETI were offered enrollment, with rolling enrollment as younger children became eligible. Clinical data regarding CF symptoms, mental health diagnoses, medications, changes in mental health symptoms and BMI were collected via chart review.
Results: Before ETI, ADHD diagnoses were identified in 21 children; an additional 3 were diagnosed within the first year. Eleven children were treated with ADHD medication at ETI initiation; nine children did not use ADHD medication during the study period. In the 1-year follow-up, four children started ADHD medication. Of the 11 who started ETI on ADHD medication, five increased doses, three changed medications and/or decreased dose, and one discontinued medication. Two children experienced no changes to their treatment.

Conclusion: Most CwCF on ADHD medication underwent changes in dosing and/or medication after ETI initiation. Several children were diagnosed with ADHD after starting ETI. The role of ETI in these recent diagnoses and treatment plans is unclear. Given the prevalence of pediatric ADHD diagnoses and the medication changes that were needed by this population, additional research is warranted to clarify the relationship between ETI and ADHD in CwCF.

Kimberley Pasley is a clinical psychologist in the Division of Pulmonary and Sleep Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA.

Nidhi Patel, Maria Ansar, Anh Pham, Kelly Thomsen, Cameron J McKinzie, Deepika Polineni, Charles R Esther Jr, Rebekah F Brown.Gilbert’s syndrome leads to elevated bilirubin after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis. Pediatr Pulmonol. 2024 Jan 5. doi: 10.1002/ppul.26831. Online ahead of print.pubmed.ncbi.nlm.nih.gov/38179880/

Nidhil Patel blog-college.ku.edu

Nine people with cystic fibrosis (pwCF) were found to have isolated elevations in serum total bilirubin after starting elexacaftor/tezacaftor/ivacaftor (ETI) that were associated with Gilbert’s Syndrome. In longitudinal examination, total bilirubin levels increased substantially after initiation of ETI without elevations in liver transaminases in those with this syndrome. Because elevated bilirubin levels in Gilbert’s Syndrome are benign, ETI was able to be continued in these individuals. Genetic testing for this relatively common syndrome should be strongly considered for pwCF experiencing isolated hyperbilirubinemia after starting ETI, since appropriate diagnosis may help pwCF avoid unnecessary interruption in this therapy with significant health benefits in CF.

Nidhi Patel is at the Division of Pulmonary Disease, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.

Tanvi Patel , Kimberly McBennett, Senthilkumar Sankararaman, Teresa Schindler, Krithika Sundaram, Nori Mercuri Minich,  Sindhoosha Malay, Katherine Kutney. Impact of elexacaftor/tezacaftor/ivacaftor on lipid and fat-soluble vitamin levels and association with body mass index.  Pediatr Pulmonol. 2024 Mar;59(3):734-742.  doi: 10.1002/ppul.26823.  Epub 2024 Jan 5.   pubmed.ncbi.nlm.nih.gov/38179878/

Tanvi Patel
LinkedIn

Introduction: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve gastrointestinal absorption of nutrients and may result in changes in body mass index (BMI), serum lipids, and fat-soluble vitamin levels. We hypothesized that serum lipids and vitamin levels would increase with CFTR modulator therapy and that greater increase in lipids and vitamin levels would be related to greater increase in BMI.
Methods: A retrospective study was performed to evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) on nutritional parameters, serum lipids, and fat-soluble vitamin levels. Pre-ETI values (<2 years prior) and post-ETI values (>1 month after) were compared. Linear regression was used to evaluate whether change in BMI is associated with the change in lipid and/or vitamin levels and whether modulator duration is associated with the degree of rise in lipid and/or vitamin levels.
Results: Adults and adolescents with CF (n = 137) were evaluated before and 31-300 days after starting ETI. Median BMI (adults 21.9 vs. 23.5 kg/m2 ; adolescents 48 vs. 63 percentile) increased after initiation of ETI. Total cholesterol (126 vs. 154 mg/dL), low-density lipoprotein cholesterol (63 vs. 78 mg/dL), non-high-density lipoprotein cholesterol (84 vs. 102 mg/dL), and high density lipoprotein cholesterol (43 vs. 49 mg/dL) increased after ETI, while triglycerides and very low density lipoprotein did not change. Median values for vitamin D (34.5 vs. 38.0 ng/mL) and vitamin A (40.1 vs. 47.9 µg/dL) increased, while vitamin E did not change significantly. There was no significant correlation between BMI change or duration of modulator therapy with vitamin levels or lipid changes.

Conclusion: After initiation of ETI therapy, serum lipids increased in our population, but most values remained within the normal range. Vitamins A and D levels increased post-ETI and no changes were noted in vitamin E. No significant correlation between the degree of BMI change and the magnitude of increase in lipids or vitamin levels was found.

Tanvi Patel is an MD candidate at Case Western Reserve University School of Medicine, Cleveland, Ohio, USA and Loyola University School of Medicine, Maywood, Illinois, USA.

Anna Evans Phillips , Jefferson N Brownell  , Alyssa Tindall , Bridget Dowd Kiernan , Dhiren Patel , Daniel Gelfond, Virginia A Stallings.   Proton-Pump Inhibitors and Fat Absorption in Cystic Fibrosis and Pancreatic Insufficiency: A Randomized Crossover Pilot Trial. Dig Dis Sci. 2024 Nov 13. doi: 10.1007/s10620-024-08728-8. Online ahead of print.pubmed.ncbi.nlm.nih.gov/39537890

Ann Evans Phillips champ.pitt.edu

Background: Dietary fat malabsorption contributes to poor nutritional status in patients with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI). Prescribing gastric acid-reducing agents such as proton-pump inhibitors (PPI) as an adjunct to pancreatic enzyme replacement therapy (PERT) to improve dietary fat absorption has been accepted in clinical practice despite limited evidence.
Aims: This was a pilot randomized, double-blind, placebo-controlled crossover trial of subjects aged 12 and older with CF and EPI assessed on placebo and omeprazole to determine if PPI improved the efficacy of PERT as indicated by measures of dietary fat absorption.
Methods: Fat malabsorption via stool coefficient of fat absorption (CFA) and malabsorption blood test (MBT), gastrointestinal pH (wireless motility capsule [WMC]), and quality of life (QOL) were assessed after 14 days on both placebo or PPI (omeprazole).
Results: Total 19 subjects enrolled, 13 were randomized, and 9 provided paired results on placebo and PPI. The 3 subject results for CFA were as follows: 1 increased, 1 decreased, and 1 was within the reference range in both tests for fat absorption. For 9 MBT subjects, 7 decreased and 2 increased fat absorption. For the 4 WMC studies, no change in transit times, nor in pH profiles were noted. No differences were seen in the domains of the two QOL questionnaires comparing placebo and PPI.
Conclusions: These limited descriptive pilot study results in participants with CF and EPI on PERT evaluated by stool, blood, and QOL tests did not suggest improvement in fat absorption attributable to PPI.

Anna Evans Phillips is Assistant Professor of medicine in the Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

—  This result is interesting in view of the high percentage of children on prioton pump inhibitors in the USA.

Charlotte O PiochNiklas ZiegahnChristine AllombaLeonie M BusackAlexandra N SchnorrApolline TosoliniBent R FuhlrottStyliani ZagklaTill OthmerZulfiya SyunyaevaSimon Y Graeber2Mehrak YoosefiStephanie TheeEva SteinkeJobst RöhmelMarcus A MallMirjam Stahl      Elexacaftor/tezacaftor/ivacaftor improves nasal nitric oxide in patients with cystic fibrosis.   J Cyst Fibros. 2024 Sep;23(5):863-869. doi: 10.1016/j.jcf.2024.03.003. Epub 2024 Mar 19.   pubmed.ncbi.nlm.nih.gov/38508948/

Background: In health, nitric oxide (NO) shows high concentrations in the upper airways, while nasal NO (nNO) is significantly lower in patients with sinonasal inflammation, such as people with cystic fibrosis (PwCF). In PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI; PwCF-ETI), clinical improvement of sinonasal symptoms and inflammation was observed. We therefore hypothesised that ETI may increase nNO in PwCF.
Methods: 25 PwCF-ETI underwent nNO measurement at baseline and after 3 to 24 months of ETI treatment. NNO was measured using velum closure (VC) techniques in cooperative patients and tidal breathing (TB) for all patients. As controls, 7 CF patients not eligible for ETI (PwCF-non ETI) and 32 healthy controls (HC) were also repeatedly investigated.

Results: In PwCF-ETI, sinonasal symptoms, lung function parameters and sweat chloride levels improved from baseline to follow-up whereas there was no change in PwCF-non ETI and HC. NNO increased from a median (IQR) value at baseline to follow-up from 348.2 (274.4) ppb to 779.6 (364.7) ppb for VC (P < 0.001) and from 198.2 (107.0) ppb to 408.3 (236.1) ppb for TB (P < 0.001). At follow-up, PwCF-ETI reached nNO values in the normal range. In PwCF-non ETI as well as HC, nNO did not change between baseline and follow-up.

Conclusions: In PwCF-ETI, the nNO values significantly increased after several months of ETI treatment in comparison to baseline and reached values in the normal range. This suggests that nNO is a potential non-invasive biomarker to examine sinonasal inflammatory disease in PwCF and supports the observation of clinical improvement in these patients.

Charlotte O Pioch is in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Hannah E Protich , Jean P Molleston, Molly Bozic, Rebecca S Pettit Elexacaftor/Tezacaftor/Ivacaftor use in Pediatric Cystic Fibrosis Patients with Advanced Liver Disease. J Cyst Fibros
. 2024 Apr 4:S1569-1993(24)00040-7. doi: 10.1016/j.jcf.2024.03.011. Online ahead of print.
pubmed.ncbi.nlm.nih.gov/38580564/

Hannah Protich
LinkedIn

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD.
Methods: This retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI.
Results: Eleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported -15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range -0.5-3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD.

Conclusion: ETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.

Hannah E Protich is in the Dept. of Pharmacy, Riley Hospital for Children at IU Health, 705 Riley Hospital Drive, Simon Family Tower W6111, Indianapolis, IN, USA.

Tavs Qvist, Bibi Uhre Nielsen, Hanne Vebert Olesen, Inger Hee Mabuza Mathiesen, Daniel Faurholt-Jepsen,et al.Close monitoring and early intervention: management principles for cystic fibrosis in Denmark. Review APMIS
. 2024 Apr;132(4):223-235. doi: 10.1111/apm.13375. Epub 2024 Jan 24.

https://pubmed.ncbi.nlm.nih.gov/38267398/

Tavs Qvist               eMedEvents

Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs.

Tavs Qvist is an infectious disease physician and researcher at the Cystic Fibrosis Center Copenhagen, Department of Infectious Diseases, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark.

Bonnie Ramsey, Christoph U Correll, David R DeMaso, Edward McKone, Elizabeth Tullis, Jennifer L Taylor-Cousar, Chenghao Chu, Nataliya Volkova, Neil Ahluwalia, David Waltz, Simon Tian, Marcus A Mall. Elexacaftor/Tezacaftor/Ivacaftor Treatment and Depression-related EventReview Am J Respir Crit Care Med. 2024 Feb 1;209(3):299-306. doi: 10.1164/rccm.202308-1525OC.   Free PMC article   pubmed.ncbi.nlm.nih.gov/37890129/

Bonnie Ramsey University of Washington

Full abstract via PubMed link.

Conclusions: Our review of data from clinical trials, postmarketing reports, an ongoing registry-based ELX/TEZ/IVA postauthorization safety study, and peer-reviewed literature suggests that depression symptoms and depression-related events reported in pwCF treated with ELX/TEZ/IVA are generally consistent with background epidemiology of these events in the CF population and do not suggest a causal relationship with ELX/TEZ/IVA treatment.

Bonnie Ramsey is at Seattle Children’s Research Institute and Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.

Felix Ratjen. The future of cystic fibrosis: A global perspective. Review Pediatr Pulmonol. 2024 Oct 17. doi: 10.1002/ppul.27337. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39417643/
The severity of lung disease as well as other disease manifestations have dramatically improved in those patients with cystic fibrosis (CF) that both have mutations responsive to small molecule- based therapies with CF transmembrane regulator (CFTR) modulators and do have access to these drugs. Unfortunately, these medications are not available to many patients with CF across the globe with access largely limited to high income countries. For those eligible to CFTR modulators new questions have arisen regarding the ongoing need for other medications addressing CF lung disease as well current care models with tight monitoring. This article aims to summarize how CF care may change in the future making a plea to expand the availability of highly effective medications to every child with CF that could benefit from treatment.

Felix Ratjen at the Department of Pediatrics, Division of Respiratory Medicine, Ontario, Canada; Translational Medicine Program, Research Institute, Hospital for Sick Children, Ontario, Canada; University of Toronto, Ontario, Canada.

Gregory A Ratti, Hannah Smith , Sasan Mirfakhraee , Joan Reisch , Leah Cohen  , Raksha Jain , James D Finklea. Development of metabolic syndrome in people with Cystic Fibrosis one year after exposure to elexacaftor-tezacaftor-ivacaftor. J Cyst Fibros. 2024 Oct 16:S1569-1993(24)01790-9. doi: 10.1016/j.jcf.2024.09.022. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/39419654/

Gregory Ratti
utswmed.org

Background: The constellation of hypertension, truncal obesity, impaired fasting glucose, low high-density lipoprotein, and hypertriglyceridemia is known as metabolic syndrome (MetSyn) and is associated with cardiovascular and other diseases. Elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) is associated with weight gain but effects on cardiovascular risk are unknown. This study sought to investigate ETI exposure and risk for development of MetSyn in pwCF.
Methods: A prospective cohort study including pwCF ≥ 18 years old exposed to ETI was performed. All data for calculating MetSyn was collected from the electronic medical record at initiation and 1 year ± 3 months after starting ETI. A total of 152 pwCF exposed to ETI and 34 pwCF never exposed to CF transmembrane conductance regulator modulators were included in the analysis. Changes to hypertension classification was also examined over this period.
Results: After 1 year of ETI there was an increase in MetSyn from 13 to 30 pwCF, p < 0.0001. No new cases of MetSyn were seen in the group not exposed to ETI. After 1 year of ETI, more people met criteria for class 1 (BP 130-139/90-99 mm Hg) or class 2 hypertension (BP ≥140/≥90 mm Hg) regardless of prior modulator exposure, p < 0.0001.

Conclusions: Exposure to ETI for 1 year resulted in an increased number of cases of MetSyn. There was an increased incidence of hypertension associated with ETI exposure. Additional studies are needed to further examine this trend and to determine if these changes will translate to cardiovascular complications over time.

Gregory A Ratti is Assistant Professor in the Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, TX, USA.

Philippe Reix. The day after. Rethinking the Cystic Fibrosis model of care and structure of the CF team in the era of triple combination therapy. J Cyst Fibros. 2024 Sep 21:S1569-1993(24)01784-3.doi: 10.1016/j.jcf.2024.09.016. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39327196/

Phiippe Reix
abbe.univ-lyon

In Dr Dorothy Andersen’s report in the late 1940s, cystic fibrosis (CF) was a pediatric disease with a limited life expectancy [1]. Children with CF exhibited severe respiratory and digestive symptoms that, with limited treatment options, usually leads to death before five year of age. Since then, significant progress has been made thanks to the organization of care and the availability of pharmacological treatments for CF in both North America and Europe [2]. This progress has been accompanied by a sustained increase in life expectancy in those regions of the world [3,4]. The availability of CFTR modulator (CFTRm), and particularly the current triple combination, known as ETI (for elexacaftor, tezacaftor, ivacaftor) has been another important step for many people with CF (pwCF) in improving their health status. Like other diseases before (such as HIV with anti-retroviral agents), ETI has changed the lives of many pwCF and helped reduce the treatment burden for a vast majority of them [5–7]. Data are still lacking on long-term medical benefits, but for now it appears that ETI has given CF a new face to CF from a “life-threatening genetic disease” to a “chronic stabilized disease”. This is accompanied by new needs and missions for pwCF and health providers. ETI is available for a majority of pwCF, including those with one F508del mutation and others [8]. It has dramatically decreased the number of pulmonary exacerbations, hospitalizations and the need for intravenous antibiotics which is one the most obvious change in the care of pWCF reported by providers from both sides of the Atlantic ocean. pwCF under ETI will live longer and healthier. Because of these changes, isn’t it thus time to revise the way we are following pwCF (the model of care) and the way, we, as health providers, work with them (the structure of the CF team)?

Philippe Reix is at Centre de ressources et de compétences pour la mucoviscidose. Hôpital Femme Mère Enfants. Hospices Civils de Lyon. Bron. France et UMR5558. Equipe EMET. Villeurbanne. France.

Mollie Riley , Michele Arigliani , Gwyneth Davies, Paul Aurora. Looking beyond LCI: Multiple breath washout phase III slope derived indices and their application in chronic respiratory disease in children. Review
Pediatr Pulmonol. 2024 Jul 19. doi: 10.1002/ppul.27177. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/39031489/

    Mollie Riley
    Google Scholar

The multiple breath washout (MBW) test is widely reported in the context of Lung Clearance Index (LCI). LCI reflects global ventilation inhomogeneity but does not provide information regarding the localization of disease along the respiratory tree. The MBW-derived normalized phase III slope (SnIII) indices (Scond and Sacin), instead, can distinguish between convective-dependent and diffusion-convection-dependent ventilation inhomogeneity considered to occur within the conductive and acinar airways, respectively. In cystic fibrosis, Scond tends to become abnormal even earlier than LCI and spirometry. The value of Scond and Sacin in clinical practice has been recently explored in other respiratory conditions, including asthma, primary ciliary dyskinesia, bronchopulmonary dysplasia, bronchiolitis obliterans, and sickle cell disease. In this narrative review we offer an overview on the theoretical background, potentialities, and limitations of SnIII analysis in children, including challenges and feasibility aspects. Moreover, we summarize current evidence on the use of SnIII-derived indices across different groups of pediatric chronic respiratory disease and we highlight the gaps in knowledge that need to be addressed in future studies.

Mollie Riley is in the Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health (UCL GOS ICH), London, UK. and the Heart and Lung Directorate, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

Erica A Roesch, Abdelkader Rahmaoui, Robert A Lazarus, Michael W Konstan. The continuing need for dornase alfa for extracellular airway DNA hydrolysis in the era of CFTR modulators. Review Expert Rev Respir Med
. 2024 Aug 30:1-16. doi: 10.1080/17476348.2024.2394694. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39176450/ Full text available

Erica Roesch
uhhosniversity.org

Introduction: The availability of cystic fibrosis transmembrane conductance regulator (CFTR) modulators opens the possibility of discontinuing some chronic pulmonary therapies to decrease cystic fibrosis (CF) treatment burden. However, CFTR modulators may not adequately address neutrophilic inflammation, which contributes to a self-perpetual cycle of viscous CF sputum, airway obstruction, inflammation, and lung function decline.
Areas covered: This review discusses the emerging role of neutrophil extracellular traps in CF and its role in CF sputum viscosity, airway obstruction, and inflammation, based on a literature search of PubMed (1990-present). We summarize clinical trials and real-world studies that support the efficacy of dornase alfa (Pulmozyme) in improving lung function and reducing pulmonary exacerbation in people with CF (PwCF), and we discuss the potential role of dornase alfa in reducing airway inflammation. We also examine the findings of short-term trials evaluating the discontinuation of mucoactive therapy in PwCF receiving CFTR modulators.
Expert opinion: Long-term studies are needed to assess the impact of discontinuing mucoactive therapy in PwCF who are clinically stable while receiving CFTR modulatory therapy. Treatment decisions should take into account the severity of underlying lung disease. People with advanced CF will likely require ongoing mucoactive therapy.

Erica A Roesch is in the Dept of Pediatrics, Rainbow Babies and Children’s Hospital and Case Western Reserve University, Cleveland, OH, USA.

Maryam Sahibqran, Gordon MacGregor , Louise Thomson, Patrick McCrossan , Anne Devenny, Ross J Langley    E-Cigarettes and Cystic Fibrosis-Current Perceptions and Future Directions. Pediatr Pulmonol. 2024 Nov 15:e27406. doi: 10.1002/ppul.27406. Online ahead of print.    https://pubmed.ncbi.nlm.nih.gov/39545636/

To the Editor precedes the article also contains full references .   The rise in availability and use of electronic-cigarettes (E-cigarettes) in children and adults (1, 2] is causing concern amongst healthcare professionals. Evidence of acute lung injury secondary to E-cigarettes is increasing (3] and there is a serious risk that cystic fibrosis (CF) patients become attracted to/use E-cigarettes and become directly exposed to the harm- ful chemicals contained in them [3]. Children and adults with CF may also be exposed to second-hand vapor from the  increasing use of E-cigarettes in the community (1, 2).
Long-term  data on the impact of E-cigarettes is as yet unavailable (3] and little is currently known about the extent of E-cigarette use in the CF community. Our study has identified current E-cigarette use trends amongst our CF population and allowed us to get a valuable insight into patient perspectives on this topic. It is crucial to utilize this data to enable us to tackle E-cigarette rise, address the risks, and
direct resources at cessation programmes and education. There is a need to develop E-cigarette cessation strategies to ensure a future that is both smoke and vape free.

Maryam Sahibqran is in the Dept of Paediatric Respiratory & Sleep Medicine, Royal Hospital for Children, Glasgow, UK.

Pavithra Saikumar , Marisa Sadauskas , Sophia Izhar , Baha Moshiree, Dhiren Patel. Constipation and DIOS: Diagnosis, differential diagnosis, and management. Review Pediatr Pulmonol. 2024 Sep:59 Suppl 1:S81-S90. doi: 10.1002/ppul.27104  https://onlinelibrary.wiley.com/doi/10.1002/ppul.27104

Pavithra Saikumar
Doximetry

Cystic Fibrosis (CF) is a complex disorder that requires multidisciplinary expertise for effective management. The GALAXY study estimated the prevalence of constipation to be about 25% among People with Cystic Fibrosis (PwCF), identifying it as one of the common gastrointestinal (GI) symptoms within this patient population. Quality of Life (QoL) assessments uncovered high patient dissatisfaction, highlighting the imperative need for enhanced treatment strategies. Similarly, Distal Intestinal Obstruction Syndrome (DIOS) is a unique condition exclusive to PwCF that, if left undiagnosed, can lead to considerable morbidity and mortality. Given the broad spectrum of differential diagnoses for abdominal pain, including constipation and DIOS, it is paramount for healthcare providers to possess a clear understanding of these conditions. This paper aims to delineate various differentials for abdominal pain while elucidating the pathogenesis, diagnostic criteria, and treatment options for managing constipation and DIOS in PwCF.

Pavithra Saikumar is a paediatrician in the Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cardinal Glennon Children’s Medical Center, Saint Louis University School of Medicine, St. Louis, Missouri, USA.

Michael S Schechter , Joshua S Ostrenga , Elizabeth A Cromwell , Clement L Ren  , Aliza K Fink , D B Sanders , Wayne J Morgan. Treatment of small as well as large declines in lung function enhances recovery to baseline in people with CF.   Pediatr Pulmonol
. 2024 Jul 12. doi: 10.1002/ppul.27176. Online ahead of print.
38995116

Michael Schechter, Children’s Hospital Richmond

Background: The benefit of antibiotic treatment of acute drops in FEV1 percent predicted (FEV1pp) has been clearly established, but data from the early 2000s showed inconsistent treatment. Further, there is no empirical evidence for what magnitude of drop is clinically significant.
Methods: We used data from the CF Foundation Patient Registry (CFFPR) from 2016 to 2019 to determine the association between treatment (any IV antibiotics, only oral or newly prescribed inhaled antibiotics, or no antibiotic therapy) following a decline of ≥5% from baseline FEV1pp and return to 100% baseline FEV1pp days using multivariable logistic regression including an interaction between the magnitude of decline and treatment category.
Results: Overall, 16,495 PWCF had a decline: 16.5% were treated with IV antibiotics, 25.0% non-IV antibiotics, and 58.5% received no antibiotics. Antibiotic treatment was more likely for those with lower lung function, history of a positive PA culture, older age and larger FEV1 decline (p < 0.001). Treatment with IV antibiotics or oral/inhaled antibiotics was associated with a higher odds of recovery to baseline compared to no treatment across all levels of decline, including declines of 5%-10%.

Conclusions: A large proportion of acute drops in FEV1pp continue to be untreated, especially in younger patients and those with higher baseline lung function. Acute drops as small as 5% predicted are less likely to be recovered if antibiotic treatment is not prescribed. These findings suggest the need for more aggressive antimicrobial treatment of acute drops in FEV1, including those of a magnitude previously believed to be associated with self-recovery

Dr Michael Schechter is Professor at the .Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, Virginia, USA.

Elena K Schneider-Futschik, Yimin Zhu, Danni Li, Mark D Habgood, Bao N Nguyen , Ines Pankonien, Margarida D Amaral, Laura E Downie, Holly R Chinnery. The role of CFTR in the eye, and the effect of early highly effective modulator treatment for cystic fibrosis on eye health. Review Prog Retin Eye Res 2024 Sep 6:103:101299. doi: 10.1016/j.preteyeres.2024.101299. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39245300/

Elena K. Schneider-Futschik Linkedin

Cystic fibrosis transmembrane conductance regulator (CFTR) is a protein that plays a crucial role in various human organs, including the respiratory and digestive systems. Dysfunctional CFTR is the key variant of the lethal genetic disorder, cystic fibrosis (CF). In the past decade, highly effective CFTR modulator therapies, including elexacaftor-tezacaftor-ivacaftor, have revolutionised CF management by correcting the underlying molecular defect to improve patient outcomes and life expectancy. Despite demonstrating multiorgan efficacy, clinical studies have largely overlooked the potential for ocular disturbances with CFTR modulator therapy, with the exception of a few case studies reporting the presence of crystalline lens pathologies in young children on CFTR modulators, and in breastfed infants born to individuals who were on CFTR modulator treatment during pregnancy. CFTR is present in multiple tissues during embryonic development, including the eye, and its expression can be influenced by genetic and environmental factors. This review summarises the role of CFTR in the eye, and the potential impact of CFTR on eye function and vision later in life. This information provides a framework for understanding the use and possible effects of CFTR-modulating therapeutics in the context of eye health, including the potential to leverage the eye for non-invasive and accessible diagnostic and monitoring capabilities in patients with CF.

Elena K Schneider-Futschik is in the Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.

Gabrielle Schwartzman , Barrett J Zlotoff , Alejandro A Gru , Darren J Guffey. Cystic fibrosis dermatitis arthritis syndrome: A series of four cases.Case Reports Pediatr Dermatol. 2024 Aug 8. doi: 10.1111/pde.15727. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39117496/

Full text with excellent images via the Pubmed link above

Gabrielle Schwartzman
LinkedIn

Dermatologic manifestations of cystic fibrosis (CF) include nutrient deficiency dermatoses, vasculitis, transient reactive papulotranslucent acrokeratodema, digital clubbing, and increased rates of atopy and drug reactions.
Few cases of a characteristic eruption in patients with episodic arthritis of CF have been described with prior reports primarily occurring outside of the dermatology literature.
We report four cases consistent with this presentation to add to the literature and propose a new and unifying name to recognize this entity as cystic fibrosis dermatitis arthritis syndrome (CF-DAS). Clinical suspicion should remain high in young female patients with cystic fibrosis presenting with episodic joint pain and rash, independent of pulmonary exacerbations.

Gabrielle Schwartzman is in the  Dept. of Dermatology, University of Virginia, Charlottesville, Virginia, USA.

Stanley Sciortino, Steve Graham, Tracey Bishop. Diagnostic Transitions of Cystic Fibrosis and Related Metabolic Syndrome Compared After 12 Years of Newborn Screening in California. J Pediatr. 2024 Sep 2:114287. doi: 10.1016/j.jpeds.2024.114287. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/39233118/Objective: To compare the long-term diagnostic transitions for cystic fibrosis (CF) and CF-Related Metabolic Syndrome (CRMS) side-by-side during follow-up since the onset of newborn screening in California.
Study design: Using real-world data, we conducted a retrospective cohort study to compare long-term observations of CRMS and CF in California and the diagnostic transitions from one to the other using clinical and diagnostic metrics. The California Genetic Disease Screening Program (GDSP) newborn screening for CF employs an immunoreactive trypsinogen tier-1 laboratory test, followed by molecular testing. This approach captures CF and CRMS, a diagnosis of “watchful waiting” among infants at risk for CF but with signs and symptoms that may emerge outside the screening window. Waiting entails periodic diagnostic reviews that can continue for many years; GDSP routinely conducts five years of follow-up for each child identified with a disorder. We utilized categorial logistic regression to compare the transitions with CRMS.
Results: After screening 5,944,700 newborns between July 2007 and July 2019, 694 CF cases and 1,258 CRMS cases were identified. Of the 1,258 CRMS cases, 66 (5.2%, 95% CI=3.9%,6.4%) transitioned from CRMS to CF (CRMS2CF) at a mean age of 3.3 years (median=2.9 years). CRMS2CF cases had longer follow-up periods and were more likely later to develop positive sweat chloride and fecal elastase test results after 6 months of life than other CRMS cases.

Conclusion: These results suggest that children who have a CRMS2CF transition are more likely to develop positive biochemical markers than other CRMS patients and have few clinical indications during the first five years of follow-up.

Stanley Sciortino is Chief Program Development and Evaluation Section at California Department of Public Health.  Genetic Disease Screening Program, Center for Family Health, California Dept. of Public Health, Richmond, CA.

Javier Segovia-Cubero , Lorena Ruiz-Bautista, Luis Maiz-Carro, Rosa M Girón-Moreno, M Concepción Prados-Sánchez, M Teresa Martínez-Martínez  et al.   The cardiomyopathy of cystic fibrosis: a modern form of Keshan disease.  Front Cardiovasc Med. 2024 Feb 1:11:1285223.  doi: 10.3389/fcvm.2024.1285223. eCollection 2024.  pubmed.ncbi.nlm.nih.gov/38361580/

Javier Segovia-Cubero
ResearchGate

Introduction: We conducted a study to determine the prevalence of structural heart disease in patients with CF, the characteristics of a cardiomyopathy not previously described in this population, and its possible relationship with nutritional deficiencies in CF.
Methods: We studied 3 CMP CF patients referred for heart-lung transplantation and a prospective series of 120 adult CF patients. All patients underwent a clinical examination, blood tests including levels of vitamins and trace elements, and echocardiography with evaluation of myocardial strain. Cardiac magnetic resonance imaging (CMR) was performed in patients with CMP and in a control group. Histopathological study was performed on hearts obtained in transplant or necropsy.
Results: We found a prevalence of 10% (CI 4.6%-15.4%) of left ventricular (LV) dysfunction in the prospective cohort. Myocardial strain parameters were already altered in CF patients with otherwise normal hearts. Histopathological examination of 4 hearts from CF CMP patients showed a unique histological pattern of multifocal myocardial fibrosis similar to Keshan disease. Four of the five CF CMP patients undergoing CMR showed late gadolinium uptake, with a characteristic patchy pattern in 3 cases (p < 0.001 vs. CF controls). Selenium deficiency (Se < 60 µg/L) was associated with more severe LV dysfunction, higher prevalence of CF CMP, higher NTproBNP levels, and more severe pulmonary and digestive involvement.

Conclusion: 10% of adults with CF showed significant cardiac involvement, with histological and imaging features resembling Keshan disease. Selenium deficiency was associated with the presence and severity of LV dysfunction in these patients.

Javier Segovia-Cubero is in the Cardiolology Dept., Hospital Universitario Puerta de Hierro, Madrid, Spain.and the Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.

Nicholas Simmonds

Simmonds NJ, Southern KW, De Wachter E, De Boeck K, Bodewes F, Mainz JG, Middleton PG, Schwarz C, Vloeberghs V, Wilschanski M, Bourrat E, Chalmers JD, Ooi CY, Debray D, Downey DG, Eschenhagen P, Girodon E, Hickman G, Koitschev A, Nazareth D, Nick JA, Peckham D, VanDevanter D, Raynal C, Scheers I, Waller MD, Sermet-Gaudelus I, Castellani C; ECFS Diagnostic Network Working Group.     ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.J Cyst Fibros. 2024 Mar 19:S1569-1993(24)00037-7. doi: 10.1016/j.jcf.2024.03.008. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38508949/
This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). .  This paper covers the individual disorders, including the established conditions – congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis – and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

Keywords:ABPA; Aquagenic palmoplantar keratoderma; Aquagenic wrinkling; Bronchiestasis; CFTR; CFTR-related disorder; Congenital absence of the vas deferens; Cystic fibrosis; Genetics; Intestinal current measurement; Nasal potential difference; Pancreatitis; Rhinosinusitis; Sclerosing cholangitis; Sweat test.

Zachary M SellersDavid N AssisShruti M ParanjapeMeghana SatheFrank BodewesMelissa Bowen, et al. Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations. Hepatology2024 May 1;79(5):1220-1238.doi: 10.1097/HEP.0000000000000646.Epub 2023 Oct 26. pubmed.ncbi.nlm.nih.gov/37934656/

Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. A committee of hepatologists, gastroenterologists, pulmonologists, pharmacists, nurses, dietitians, individuals with CF, and the parents of a child with CF devised “population, intervention, comparison, and outcome” questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each population, intervention, comparison, and outcome question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to the formulation of final recommendations. Thirty-one population, intervention, comparison, and outcome questions were assembled, 6401 manuscripts were title screened for relevance, with 1053 manuscripts undergoing detailed full-text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring, and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment.

Zachary M Sellers is in t he Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, California, USA.

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 Cmax range according to the pharmacokinetic data in the manufacturer’s product characteristics. Pulmonary function largely remained stable without pulmonary exacerbations requiring intravenous antibiotic treatment.

Conclusion: This observational report shows the most extensive dataset for ETI concentrations during pregnancy. Individualized dose adjustments could help to resolve adverse side effects while continuing CFTR therapy. Specific populations, such as pregnant women, might benefit from a TDM. However, future research with more pharmacokinetic data from pregnant pwCF is needed.

Christina Shad is at the Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Germany.

James A M Shaw.   Editorial: Cystic fibrosis-related diabetes.Front Endocrinol (Lausanne). 2024 Jul 26:15:1464440. doi: 10.3389/fendo.2024.1464440. eCollection 2024   pubmed.ncbi.nlm.nih.gov/?term=James+A+M+Shaw&sort=date&size=100

       James A M Shaw

There is helpful Free PMC article via the PubMed link. Number of relevant articles on the subject are reviewed.

James A M Shaw is Professor  in the Translational and Clinical Research Institute, The Medical School, Framlington Place, Newcastle University, Newcastle-upon-Tyne, United Kingdom.

Ugo Sorrentino, Massimo Menegazzo  , Ilaria Gabbiato , Davide Calosci , Carlo Federico Zambon, Daniela Zuccarello. Challenges of Preimplantation Genetic Counselling in the Context of Cystic Fibrosis and Other CFTR-Related Disorders: A Monocentric Experience in a Cohort of 92 Couples. Genes (Basel). 2024 Jul 18;15(7):937. doi: 10.3390/genes15070937. pubmed.ncbi.nlm.nih.gov/39062716/

Ugo Sorrentino
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Cystic fibrosis is a highly prevalent genetic disorder caused by biallelic pathogenic variants in the CFTR gene, causing an altered function of the exocrine glands and a subsequent spectrum of hypofunctional and degenerative manifestations. The increasing availability of carrier screening programmes, the enhanced life expectancy of patients due to improved treatment and care strategies and the development of more precise and affordable molecular diagnostic tools have prompted a rise in demand of prenatal diagnosis procedures for at-risk couples, including Preimplantation Genetic Testing (PGT). However, challenges remain: heterogeneity among screening programmes, nuances of variant interpretation and availability of novel treatments demand a considerate and knowledgeable approach to genetic counselling. In this work, we retrospectively evaluated the molecular data of 92 unselected couples who received a diagnosis of CFTR-related status and were referred to the genetics clinic at the University Hospital of Padua for genetic counselling on eligibility for PGT. A total of 50 couples were considered eligible for the procedure based on risk of transmitting biallelic pathogenic variants. We report and discuss our experience with this case series in the context of the Italian medical care system and present an overview of the most relevant issues regarding genetic counselling for PGT in CFTR-related disorders.

Ugo Sorrentino is in the  Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, 35128 Padova, Italy.

Kevin W Southern, Charlotte Addy,  Scott C Bell, Amanda Bevan, Urzula Borawska, Catherine Brown et al.  Standards for the care of people with cystic fibrosis; establishing and maintaining health.  Review  J Cyst Fibros. 2024 Jan;23(1):12-28.  doi: 10.1016/j.jcf.2023.12.002. Epub 2023 Dec 21. DOI:38129255 10.1016/j.jcf.2023.12.002 Free article pubmed.ncbi.nlm.nih.gov/38129255/

Kevin Southern

This is the second 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 establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy.

Kevin Southern is Professor in the Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK

Sacha Spelier, Karin de Winter-de Groot, Natascha Keijzer-Nieuwenhuijze, Yves Liem, Kors van der Ent, Jeffrey Beekman, Lieke S Kamphuis. Organoid-guided synergistic treatment of minimal function CFTR mutations with CFTR modulators, roflumilast and simvastatin: a personalised approach. Eur Respir J. 2024 Jan 25;63(1):2300770. doi: 10.1183/13993003.00770-2023. Print 2024 Jan. 37857424    pubmed.ncbi.nlm.nih.gov/37857424/   Free PMC article
This study describes how preclinical research has guided a successful personalised clinical treatment regimen in a person with minimal function CFTR, upon a synergistic treatment regimen consisting of CFTR modulators, simvastatin and roflumilast https://bit.ly/3rDTHZL

Sacha Spellier is at the Department of Pediatric Respiratory Medicine, Wilhelmina Children’s Hospital, University Medical Center, Utrecht University, Utrecht, The Netherlands.& Regenerative Medicine Utrecht, University Medical Center, Utrecht University, Utrecht, The Netherlands.

Mirjam Stahl , Martha Dohna , Simon Y Graeber , Olaf Sommerburg , Diane M Renz, Sophia T Pallenberg et al. , Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Children with Cystic Fibrosis and One or Two F508del Alleles. Respir J 2024 Jun 20:2400004. doi: 10.1183/13993003.00004-2024. pubmed.ncbi.nlm.nih.gov/38901883/

Mirjam Stahl
Euro Resp Soc

The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children with CF and one or two F508del alleles aged 6 to 11 years.
Methods: This prospective, observational, multicenter, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and three months after initiation of ETI.
Results: A total of 107 children with CF including 40 heterozygous for F508del and a minimal function mutation (F/MF) and 67 homozygous for F508del (F/F) were enrolled in this study. Treatment with ETI improved the LCI in F/MF children (-1.0; IQR, -2.0 to -0.1; p<0.01) and F/F children (-0.8; IQR, -1.9 to -0.2; p<0.001) from 3 months onwards. Further, ETI improved the MRI global score in F/MF (-4.0; IQR, -9.0 to 0.0; p<0.01) and F/F children (-3.5; IQR, -7.3 to -0.8; p<0.001).
Conclusions: ETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least one F508del alleles 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.

Mirjam Stahl is in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Mirjam Stahl, Jobst Roehmel, Monika Eichinger, Felix Doellinger, Lutz Naehrlich, Matthias V Kopp, Anna-Maria Dittrich, Olaf Sommerburg, Partha Ray, Anita Maniktala, Tu Xu, Sarah Conner, Aniket Joshi, Molly Mascia, Mark O Wielpütz, Marcus A Mall.     Long-Term Impact of Lumacaftor/Ivacaftor Treatment on Cystic Fibrosis Disease Progression in Children 2 Through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2, Open-Label Clinical Trial. Ann Am Thorac Soc. 2024 Aug 22. doi: 10.1513/AnnalsATS.202402-201OC. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39173175/    

Rationale: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age.
Objective: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2 through 5 years.
Methods: This phase 2 trial had two parts: Part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2 through 5 years (previously reported) was followed by a 48-week open-label treatment period where all children received LUM/IVA (Part 2; reported here). Endpoints assessed in Part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z-scores at week 96; lung clearance index (LCI2.5) through week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at week 96; sweat chloride, serum levels of immunoreactive trypsinogen, fecal elastase-1 levels, and fecal calprotectin through week 96; and number of pulmonary exacerbations (PEx), time-to-first PEx, and number of CF-related hospitalizations.
Results: Forty-nine children received ≥1 dose of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group); mean exposure 47.1 (SD, 5.2) weeks. The mean absolute change in MRI global score (negative value = improvement) from baseline at Week 96 was -2.7 (SD 7.0; 95% CI, -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI2.5, sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events (AEs) considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment due to AEs (distal intestinal obstruction syndrome [n=1] and alanine aminotransferase increase [n=1]).

Conclusion: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age.

Mirjam Stahl is at Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine, Berlin, Germany. The German Center for Lung Research (DZL), associated partner site, Berlin, Germany.
The Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.

Michelle M Szabo  , Sarah E Foushee, Chelsey M McPheeters, Adrian R O’Hagan , Allan M Ramirez, Emily A O’Reilly.  Impact of elexacaftor/tezacaftor/ivacaftor on respiratory colonization in an adult cystic fibrosis clinic. Am J Med Sci. 2024 Feb 7:S0002-9629(24)01059-0. doi: 10.1016/j.amjms.2024.02.001. Online ahead of print.pubmed.ncbi.nlm.nih.gov/38336262/

Michelle M Szabo ULHealth

Background: Little research has been completed on the correlation between cystic fibrosis (CF) modulator therapy and its effect on respiratory cultures in CF patients. This study evaluated the effect of elexacaftor/tezacaftor/ivacaftor (ETI) on respiratory colonization with Pseudomonas aeruginosa.
Methods: This single center, IRB approved, retrospective chart review compared patient data two years immediately prior to ETI initiation with patient data two years post-initiation from January 2017-December 2022. Patients were included in the study if they were at least 18 years old with a diagnosis of CF and had at least one month of ETI dispensed, at least one sputum culture obtained, and were currently on ETI. Those who had not been seen since ETI initiation or received a bilateral lung transplant were excluded. The primary outcome was rate of patients with respiratory colonization post-ETI. Colonization was defined as two or more positive P. aeruginosa cultures in a 12-month period. Decolonization was defined as three consecutive negative P. aeruginosa cultures after previous colonization. Key secondary outcomes included average time to discontinuation of mucolytic therapy and relative risk of pulmonary exacerbation.
Results: A significant reduction (p<0.001) in colonization with P. aeruginosa was observed with 49 patients in the pre-ETI group compared to 25 in the post-ETI group meeting the definition of colonization (n=79). Average time to discontinuation of mucolytic therapy was 14 months (p=0.002). Relative risk of pulmonary exacerbation was 4.80 (p<0.001).
Conclusions: ETI use resulted in reduced colonization with P. aeruginosa, discontinuation of mucolytic therapy, and decreased frequency of pulmonary exacerbation.

Michelle M Szabo is  PGY-2 Ambulatory Care Pharmacy Resident, UofL Health-UofL Hospital, Louisville, KY, USA.

Corrado Tagliati, Daniele Veri , Andrea Pietra , Giuseppe Lanni , Davide Battista , Marco Fogante  , Giulio Argalia , Cecilia Lanza , Stefano Pantano , Francesca Collini , Maria Di Sabatino , Pietro Ripani. Gallbladder sludge and microlithiasis disappearance in a cystic fibrosis patient 1 year after triple combination therapy initiation. Clin Case Rep
. 2024 Oct 17;12(10):e9481. doi: 10.1002/ccr3.9481. eCollection 2024 Oct.  pubmed.ncbi.nlm.nih.gov/39430919/

Gallstones, microlithiasis, gallbladder sludge, and micro-gallbladder are frequently reported in cystic fibrosis patients, and modulators could modify gallbladder disease, probably reducing biliary secretions viscosity.
Part of Full text link:   A 23‐year‐old man with F508del/G85E genotype showed a huge amount of gallbladder sludge and microlithiasis in a small gallbladder under ursodeoxycholic acid treatment. However, 1 year after ETI treatment initiation gallbladder disease disappeared on ultrasound examination, and to the best of our knowledge this is the first case reported in literature . During this first year of treatment, the patient showed mild increase of direct bilirubin and transaminase without biliary symptoms. Moreover, during modulators treatment this patient showed lung and sinus involvement reduction, forced expiratory volume in the first second improvement and forced vital capacity amelioration

Corrado Tagliati is in the Department of Radiology AST Pesaro Urbino Pesaro Italy.

Daniel H Tewkesbury Louise R Pollard  Heather D Green Alexander Horsley Dervla Kenna Andrew M Jones .When is Burkholderia cepacia complex truly eradicated in adults with cystic fibrosis? A 20-year follow up study.  J Cyst Fibros. 2024 Jan;23(1):87-90.doi: 10.1016/j.jcf.2023.09.016. Epub 2023 Sep 28.pubmed.ncbi.nlm.nih.gov/37775444/

Daniel Tewkesbury 2022 NCFC conference

Background: Burkholderia cepacia complex (BCC) infection in cystic fibrosis (CF) is associated with increased morbidity and mortality. Current UK guidance recommends segregation of people with CF according to infection status. To date there is no universally agreed consensus on the number of negative samples or time interval since last isolation of BCC for eradication to be deemed successful.
Methods: All cases of new BCC isolation at Manchester Adult Cystic Fibrosis Centre were followed-up between May 2002-May 2022. The number of subsequent positive and negative sputum samples for BCC were recorded, as well as eradication treatment received. Eradication was deemed successful if there were ≥3 negative sputum samples and no further positive sputum samples for the same species and strain ≥12 months until the end of follow-up.
Results: Of 46 new BCC isolation, 25 were successfully eradicated and 21 resulted in chronic infection. 5 (16.7%) cases with exclusively negative sputum samples 6-12 months after initial isolation had subsequent samples that were culture-positive for BCC and 3 (10.7%) cases with exclusively negative sputum samples after 12-24 months had subsequent culture-positive samples. Cases where BCC was eradicated had a greater median number of days of eradication treatment (42, IQR 21-63) compared to those in whom BCC isolation resulted in chronic infection (28, IQR 14-42), p = 0.04.

Conclusions: A cautious approach to segregation should be maintained after new isolation of BCC in CF, as some individuals with ≥3 negative samples 12-24 months after initial isolation had subsequent sputum samples culture-positive for BCC.

Daniel Tewkesbury is at Manchester University NHS Foundation Trust, Manchester, United Kingdom; University of Manchester, Manchester, United Kingdom.

Pascal Trouvé , Aude Saint Pierre , Claude Férec. Cystic Fibrosis: A Journey through Time and Hope. Review Int J Mol Sci
. 2024 Sep 4;25(17):9599. doi: 10.3390/ijms  pubmed.ncbi.nlm.nih.gov/39273547/

Pascal Trouve
Linkedin

Just over thirty years is the span of a generation. It is also the time that has passed since the discovery of the gene responsible for cystic fibrosis. Today, it is safe to say that this discovery has revolutionized our understanding, research perspectives, and management of this disease, which was, thirty years ago, a pediatric condition with a grim prognosis. The aim of this review is to present the advances that science and medicine have brought to our understanding of the pathophysiology of the disease and its management, which in many ways, epitomizes modern molecular genetic research. Since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, modeling the CFTR protein, deciphering its function as an ion channel, and identifying its molecular partners have led to numerous therapeutic advances. The most significant advancement in this field has been the discovery of protein modulators that can target its membrane localization and chloride channel activity. However, further progress is needed to ensure that all patients can benefit from a therapy tailored to their mutations, with the primary challenge being the development of treatments for mutations leading to a complete absence of the protein. The present review delves into the history of the multifaceted world of CF, covering main historical facts, current landscape, clinical management, emerging therapies, patient perspectives, and the importance of ongoing research, bridging science and medicine in the fight against the disease.

Pascal Trouve is at the University of Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France.

Don S Urquhart , Heather Dowle, Kellie Moffat, Jody Forster, Steve Cunningham, Kenneth A Macleod.   Lung clearance index (LCI2.5 ) changes after initiation of Elexacaftor/Tezacaftor/Ivacaftor in children with cystic fibrosis aged between 6 and 11 years: The “real-world” differs from trial data. Pediatr Pulmonol. 2024 Feb 28. doi: 10.1002/ppul.26938. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/38415920/

Don S Urquhart Healio.com

Background: Elexacaftor in combination with Tezacaftor and Ivacaftor (ETI) became licensed in the United Kingdom in early 2022 for children aged 6-11 years with cystic fibrosis (CF) and an eligible mutation. Many in this age group have excellent prior lung health making quantitative measurement of benefit challenging. Clinical trials purport that lung clearance index (LCI2.5 ) measurement is most suitable for this purpose.
Objectives: This study aimed to understand the clinical utility of LCI2.5 in detecting change after commencing ETI in the real world.
Patient selection/methods: Baseline anthropometric data were collected along with spirometry (forced expiratory volume in 1 s [FEV1 ], forced vital capacityFV and LCI2.5 measures in children aged 6-11 years with CF before starting ETI. Measures were repeated after a mean (range) of 8.2 (7-14) months of ETI treatment. The primary endpoint was a change in LCI2.5 , with secondary endpoints including change in FEV1 and change in body mass index (BMI) also reported.
Results: Twelve children were studied (seven male, mean age 9.5 years at baseline). Our study population had a mean (SD) LCI2.5 of 7.01 (1.14) and FEV1 of 96 (13) %predicted at baseline. Mean (95% confidence interval) changes in LCI2.5 [-0.7 (-1.4, 0), p = .06] and BMI [+0.7 (+0.1, +1.3), p = .03] were observed, along with changes in FEV1 of +3.1 (-1.9, +8.1) %predicted.
Conclusions: Real-world changes in LCI2.5 (-0.7) are different to those reported in clinical trials (-2.29). Lower baseline LCI2.5 as a result of prior modulator exposure, high baseline lung health, and new LCI2.5 software analyses all contribute to lower LCI2.5 values being recorded in the real world of children with CF.

Don S Urquhart is in the Department of Paediatric Respiratory and Sleep Medicine, Royal Hospital for Children and Young People,and the Department of Child Life and Health, Edinburgh Bioquarter, University of Edinburgh, Edinburgh, UK.

Dilara Fatma Kocacik Uygun, Mehmet Akif Kaya, Betül Bankoglu, Abdurrahman Erdem Basaran, Ayşen Bingol. Successful Desensitization With ELX/TEZ/IVA. J Pediatr Pharmacol Ther. 2024 Oct;29(5):539-543. doi: 10.5863/1551-6776-29.5.539. Epub 2024 Oct 14. Full test in link with images.    pubmed.ncbi.nlm.nih.gov/39411414/

Dilara Fatma Kocacik Uygun WinAlly

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was given US Food and Drug Administration approval based on its therapeutic benefits to treat patients with cystic fibrosis (CF) who had at least 1 allele of the CF transmembrane conductance regulator (CFTR) with phenylalanine deleted at position 508 (F508del). The increase in genotyping studies has increased the frequency of use of CFTR modulators; however, severe allergic reactions to CFTR modulators have also been described. It is critical to avoid the offending medication and select alternative treatments while dealing with drug allergies. Drug desensitization may be taken into consideration in situations where there is no other option. This article describes home desensitization treatment for a patient with CF who developed a maculopapular rash following CFTR modulator medication. There are currently no alternative drugs for CFTR modulators, which are crucial for patients with CF, and limited experience is available with allergic reactions to these drugs. It is important to establish desensitization protocols in order to control drug reactions to CFTR modulators, which are vital for individuals with CF.

Dilara Fatma Kocacik Uygun Pediatric Allergy-Immunology Department (DFKU, MAK, AB), Akdeniz University School of Medicine, Pediatric Pulmonology Department (BB, AEB), Akdeniz University School of Medicine, Antalya, Turkey.

Renske van der Meer, Erik B Wilms , Margot N Eggermont, Helena M Paalvast, Matthijs van Luin, Richard C J M van Rossen, Harry G M Heijerman.  Elexacaftor/tezacaftor/ivacaftor in liver or kidney transplanted people with cystic fibrosis using tacrolimus, a drug-drug interaction study.  J Cyst Fibros. 2024 Jan 29:S1569-1993(24)00007-9.  doi: 10.1016/j.jcf.2024.01.008. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/38290918/

Renske van der Meer
LinkedIn

Background: The use of elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis (pwCF) after solid organ transplantation is controversial because of potential drug-drug interactions (DDI) with tacrolimus. We aimed to improve insight into the safety and clinical benefits of co-administration of ETI and tacrolimus in liver or kidney transplanted adult pwCF.: In 5 pwCF, tacrolimus concentrations were monitored during 2 weeks before and 4 weeks after starting ETI treatment. Trough levels, area under the curve (AUC) and clinical effect of ETI were investigated. During the study (6 weeks in total) adverse events were monitored.
Results: The DDI between tacrolimus and ETI resulted in an increased exposure of tacrolimus in all subjects, the dose adjusted AUC0-24h was 1.79 (median) times higher at the end of the study. Five dose adjustments were performed in 4 subjects in order to attain tacrolimus target range. No adverse events were reported and all subjects showed clinical improvement during ETI treatment.

Conclusion: The clinical value of ETI treatment in kidney and liver transplanted pwCF is clear. The use of ETI may increase tacrolimus levels moderately. Therefore, we recommend close monitoring of tacrolimus trough levels in patients who start ETI.

Renske van der Meer is in the Department of Pulmonology and Adult CF Centre, Haga Hospital, Els Borst-Eilersplein 275, The Hague 2545 AA, The Netherlands.

Sanaz Vaziri , Meghan E McGarry, Chiung-Yu Huang, Addison A Cuneo , Shaina M Willen, Kensho Iwanaga , Fatima Neemuchwala , Elizabeth R Gibb , Marilynn Chan , Ngoc P Ly. Time to be blunt: Substance use in cystic fibrosis. Pediatr Pulmonol. 2024 Apr;59(4):1015-1027. doi: 10.1002/ppul.26880. Epub 2024 Jan 22.    pubmed.ncbi.nlm.nih.gov/38251844

Sanaz Vasiri
LinkedIn

Background: As the population of people with cystic fibrosis (pwCF) continues to age, attention is shifting towards addressing the unique challenges teenagers and adults face, including substance use. Changing attitudes and legality regarding marijuana and cannabidiol (CBD) may influence their use among pwCF, but data on the rate of use, reasons for use, and administration methods are lacking.
Objective: Investigate marijuana, CBD, e-cigarette, and cigarette usage among pwCF and explore differences in demographics, disease severity, and cystic fibrosis transmembrane receptor (CFTR) modulator use between recent users and nonusers.
Methods: This cross-sectional study used a one-time electronic survey to assess marijuana, CBD, e-cigarette, and cigarette use in pwCF aged >13 years. Demographic and clinical characteristics were compared between recent users and nonusers. The association between recent substance use and CFTR modulator use was analyzed using logistic regressions.
Results: Among 226 participants, 29% used marijuana, 22% used CBD, 27% used e-cigarettes, and 22% used cigarettes in the last 12 months. Users of all substances were more likely to be college-educated or aged 29-39 years than nonusers. E-cigarette users were 2.9 times more likely to use CFTR modulators (95% confidence interval [95% CI]: 0.98-11.00, p = .08) and marijuana users were 2.5 times more likely to use CFTR modulators compared to nonusers, adjusted for confounders. CBD, e-cigarettes, and cigarettes users were more likely to have an abnormal mental health screen compared to nonusers. A high proportion of never-users of marijuana and CBD expressed interest in using.
Conclusion: Substance use is more prevalent among pwCF than previously reported and needs to be addressed by healthcare providers.

Sanaz Vasiri is in the Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.

Steffie E M Vonk, Rianne Lub, Els J M Weersink, Ulrich Beuers, Ron A A Mathôt, E Marleen Kemper, Josje Altenburg 4 ; Amsterdam Mucociliary Clearance Disease Research Group. Stepwise Introduction of Elexacaftor-Tezacaftor-Ivacaftor in Patients With Cystic Fibrosis and Liver Cirrhosis Child-Pugh A or B Using Clinical and Therapeutic Drug Monitoring: A Case Series. Clin Ther. 2024 Feb;46(2):154-158. doi:10.1016/j.clinthera.2023.11.003. Epub 2023 Dec 1 Free article           .pubmed.ncbi.nlm.nih.gov/38042631

Steffie Vonk Hyphenprojects.nl

Purpose: Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and affecting multiple organs, including the lungs and liver. Almost 90% of people affected carry at least 1 Phe508del CFTR mutation. Medical treatment with the CFTR-modulating drug elexacaftor-tezacaftor-ivacaftor (ETI) has been proven to be efficacious in carriers of at least 1 Phe508del CFTR mutation. Use of ETI in patients with CF (pwCF) and liver cirrhosis is still controversial. Therefore, stepwise introduction of ETI in pwCF and liver cirrhosis Child-Pugh A or B was evaluated using clinical and therapeutic drug monitoring.
Methods: Seven consecutive pwCF received ETI. Four dosing steps were defined, at each of which the patients underwent clinical examination, routine blood tests, and therapeutic drug monitoring. Exposure of elexacaftor, tezacaftor, and ivacaftor was assessed by means of determination of AUC.
Findings: ETI was successfully introduced and maintained in all pwCF. In those with Child-Pugh B cirrhosis (n = 2), diminishment of the dose as recommended by the label resulted in AUC values that were lower than the mean AUC values in pwCF without hepatic impairment, as reported previously.
Implications: Despite the limitations of this small case series, stepwise elevation of ETI dose did not induce clinical adverse effects or increases in serum liver test results under strict clinical follow-up and therapeutic drug monitoring, and may allow tolerable introduction of this therapy in pwCF and cirrhosis Child-Pugh A and possibly B.

Steffie E M Vonk is in the Dept of Pharmacy and Clinical Pharmacology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Steffie E M Vonk, Josje Altenburg, Ron A A Mathôt, E Marleen Kemper; Amsterdam Mucociliary Clearance Disease (AMCD) Research Group.  Correlation between trough concentration and AUC for elexacaftor, tezacaftor and ivacaftor. J Cyst Fibros. 2024 Mar 16:S1569-1993(24)00038-9.  doi: 10.1016/j.jcf.2024.03.010. Online ahead of print   Free article pubmed.ncbi.nlm.nih.gov/38494378/
Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (Cmin) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured Cmin concentration and AUC was evaluated. Serial plasma samples, including Cmin, were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between Cmin and AUC0-24h was found, with Pearson’s r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of Cmin levels.

Steffie E M Vonk is at  Amsterdam UMC location University of Amsterdam, Department of Hospital Pharmacy & Clinical Pharmacology, Meibergdreef 9, Amsterdam, the Netherlands

Valerie WatersMichelle Shaw,Lucy Perrem,Bradley S Quon.Elizabeth TullisMelinda Solomon, et al.  PIPE Study Investigators.   A randomized trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.Eur Respir J 2024 May 2:2302278. doi: 10.1183/13993003.02278-2023. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/38697648/

Valerie Waters
sickkids.ca

Background:Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations (PExs) in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 second (ppFEV1) in CF PExs not responding to antibiotic therapy.Methods:This was a randomized, double-blind, placebo-controlled trial in pwCF treated with intravenous (IV) antibiotics for a PEx. At Day 7, those who had not returned to >90% baseline ppFEV1 were randomized to adjuvant prednisone 1 mg·kg-1 twice daily (max 60 mg/day) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline ppFEV1 at Day 14 of IV antibiotic therapy.Results:173 subjects were enrolled, with 76 randomized. 50% of subjects in the prednisone group recovered baseline FEV1 on Day 14 compared to 39% of subjects in the placebo group for a difference of 11% (95% CI -11, 34%, p=0.34). The mean (sd) change in ppFEV1 from Day 7 to Day 14 was 6.8% predicted (8.8) in the prednisone group and 4.6% (6.9) in the placebo group (mean difference 2.2% predicted 95% CI -1.5, 5.9%, p=0.24). Time to subsequent exacerbation was not prolonged in prednisone treated subjects (HR 0.83, 95% CI 0.45, 1.53; p=0.54)
.Conclusions:This study failed to detect a difference in ppFEV1 recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of IV antibiotic therapy for PExs.

Valerie Waters is Professor in the Division of Infectious Diseases, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada & Translational Medicine, Hospital for Sick Children, University of Toronto, Toronto, Canada.

Alexander Yule , Christabella Ng  , Arantxa Recto , Florence Lockwood , Neele S Dellschaft  , Caroline  Hoad,  et al.  A longitudinal study assessing the impact of elexacaftor/tezacaftor/ivacaftor on gut transit and function in people with cystic fibrosis using magnetic resonance imaging (MRI). Observational Study J Cyst Fibros. 2024 Sep;23(5):984-990. doi: 10.1016/j.jcf.2024.08.001. Epub 2024 Sep 5.  pubmed.ncbi.nlm.nih.gov/39242338/

Alexander Yule CFF  photo

Background: Gastrointestinal (GI) symptoms in cystic fibrosis (CF) are common and disruptive. The effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the GI tract is not fully understood. The aim was to use magnetic resonance imaging (MRI) to determine if elexacaftor/tezacaftor/ivacaftor (ETI) changed GI function and transit.
Methods: This was an 18 month prospective, longitudinal, observational study. We enrolled 24 people with CF aged 12 years or older to undergo MRI scans before starting ETI and 3, 6, and 18 months after starting ETI. The primary outcome measure was change in oro-caecal transit time (OCTT) at 6 and 18 months. Secondary outcome measures included change in small bowel water content (SBWC), change in the reduction in small bowel water content following a meal (DeltaSBWC) and change in total colonic volume (TCV).
Results: A total of 21 participants completed MRI scans at 6 months and 11 completed at 18 months. After 18 months of ETI, median OCTT significantly reduced, from >360 min [IQR 240->360] to 240 min [IQR 180-300] (p = 0.02, Wilcoxon signed-rank). Both SBWC and DeltaSBWC increased after starting ETI. TCV reduced significantly after 18 months (p = 0.005, Friedman).

Conclusions: Our findings suggest an improvement in small bowel transit, small bowel response to food and a reduction in colonic volume after starting ETI. These effects may relate to CFTR activation in the small bowel. To our knowledge this is the first study to show a physiological change in GI transit and function in response to CFTR modulator use through imaging studies.

Alexander Yule is in the Academic Unit of Lifespan & Population Health, School of Medicine, University of Nottingham, Nottingham, UK; NIHR Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.

Michael Wilschanski, Anne Munck, Estefania Carrion, Marco Cipolli, Sarah Collins , Carla Colombo, Dimitri Declercq, Elpis Hatziagorou 8 , Jessie Hulst , Daina Kalnins, Christina N Katsagoni, Jochen G Mainz, Carmen Ribes-Koninckx, Chris Smith, Thomas Smith, Stephanie Van Biervliet, Michael Chourdakis. ESPEN-ESPGHAN-ECFS guideline on nutrition care for cystic fibrosis. Clin Nutr. 2024 Feb;43(2):413-445. doi: 10.1016/j.clnu.2023.12.017. Epub 2023 Dec 27. pubmed.ncbi.nlm.nih.gov/38169175/

Michael Wilschanski.

Full version via PubMed Link

Background: Nutritional status is paramount in Cystic Fibrosis (CF) and is directly correlated with morbidity and mortality. The first ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with CF were published in 2016. An update to these guidelines is presented.
Methods: The study was developed by an international multidisciplinary working group in accordance with officially accepted standards. Literature since 2016 was reviewed, PICO questions were discussed and the GRADE system was utilized. Statements were discussed and submitted for on-line voting by the Working Group and by all ESPEN members.
Results: The Working Group updated the nutritional guidelines including assessment and management at all ages. Supplementation of vitamins and pancreatic enzymes remains largely the same. There are expanded chapters on pregnancy, CF-related liver disease, and CF-related diabetes, bone disease, nutritional and mineral supplements, and probiotics. There are new chapters on nutrition with highly effective modulator therapies and nutrition after organ transplantation.

Michael Wilschanski is Professor in the  Gastroenterology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Jeffrey J Wine. Calibrating sweat chloride levels to CFTR activity via ETI effects on CF subjects with one or two F508DEL mutations. J Cyst Fibros
. 2024 Oct 14:S1569-1993(24)01712-0. doi: 10.1016/j.jcf.2024.09.004. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39406575/

Jeffrey J Wine
Stanford University

Background: It is difficult to determine CFTR activity following highly effective CFTR modulator therapies (HEMT). The sweat gland provides two biomarkers of CFTR activity: a linear readout via the β-sweat rate and a logarithmic readout via sweat chloride concentration (SCC). In prior work, different logarithmic functions were generated to calibrate SCC with the percent of healthy control CFTR activity (HCCFTR). Two functions, A and B, were fit to SCC means from healthy controls set = 100 % and CF carriers measured as 50 % HCCFTR. A and B differ in the % HCCFTR activity assigned to SCC for minimal function mutations = 0.01 % for A and 1 % for B.
Methods: Here, the functions are evaluated based on retrospective analysis of three multi-center studies of CF subjects with one or two F508del mutations treated with Elexacaftor/Tezacaftor/Ivacaftor (ETI). Predictions of the percent HCCFTR activity for one vs two mutations were compared for the two functions. The expectation is that after ETI treatment, subjects with two responsive mutations will have 2-fold higher HCCFTR activity than subjects with only one. The hypothesis is that the SCCHCCFTR function that most closely fits that expectation provides the more accurate prediction of CFTR activity.
Results: In two separate comparisons, function B most accurately predicted a 2-fold (1.9, 2.3-fold) higher level of HCCFTR activity in subjects on ETI with two vs. one responsive mutation. Function A predicted a 4, 5.5-fold higher level.

Conclusions: Function B predicts that 60 mmol/L SCC, the cutoff for a CF diagnosis, is associated with 10 % HCCFTR activity. Comparing HEMT effects on subjects with one or two mutations provides an additional tool for calibrating SCC to CFTR activity.

Jeffrey J Wine is at the  Cystic Fibrosis Research Laboratory, Department of Psychology, Human Biology and (by courtesy) Pediatrics, Stanford University, Room 210, Bldg. 420, Jane Stanford Way, Stanford, CA 94305-2130, USA.

Andrea Zbinden, Helena M B Seth-Smith, Vanessa Beltrami , Stefano Mancini , Sara Droz , Urs Bürgi , David Melillo , Mace M Schuurmans , Bernhard Schwizer , Iris Schmid , Carmen Casaulta , Jürg Barben, Nicolas J Mueller , Frank Imkamp. Burkholderia cenocepacia ST-250 in cystic fibrosis patients in Switzerland: Genomic investigation of transmission routes.   Diagn Microbiol Infect Dis. 2024 Aug 7;110(2):116429. doi:10.1016/j.diagmicrobio.2024.116429. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/39116652/   Free article

Andrea Zbinden
linkedIn

This report describes the characterization of Burkholderia cenocepacia isolates belonging to sequence type (ST)-250, detected in eight patients with cystic fibrosis (CF) in Switzerland. We retrospectively analyzed 18 isolates of B. cenocepacia ST-250 isolated between 2003 and 2015 by whole-genome sequencing and evaluated clinical and epidemiological data. Single nucleotide polymorphism analysis of the B.°cenocepacia ST-250 lineage showed that the isolates from all patients cluster tightly, suggesting that this cluster has a recent common ancestor. Epidemiological investigations showed that six out of eight patients acquired B.°cenocepacia ST-250 in the years 2001-2006, where participation in CF summer camps was common. Two patients were siblings. Genomic relatedness of the B. cenocepacia ST-250 isolates supported transmission by close contact, however, a common source or nosocomial routes cannot be excluded. With respect to the fatal outcome in six patients, our study shows the importance of infection control measurements in CF patients with B.°cenocepacia.

Andrea Zbinden  is at the Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland.

— A useful reminder of the danger of cross infection at summer camps and the serious nature of infection with this organism.