2024

2024

                              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/

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/

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.

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/   

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/

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.

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/

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,

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.

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. 2024 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/

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.

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/

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

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/

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/

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.

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/

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.

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/

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.

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

 2024

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

Alice 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.

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/

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

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/

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.