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/

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.

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.

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,

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/

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.

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

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.

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.

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.

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.

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.

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.

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 Jain, Claire E Wainwright, Alan 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.

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/
Background: Iron deficiency is highly prevalent in people with cystic fibrosis (PwCF).

Dana P Albon
UVA Health

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.
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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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 Sellers , David N Assis , Shruti M Paranjape , Meghana Sathe , Frank Bodewes , Melissa Bowen , et al. Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations. Hepatology 2024 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.

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/
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

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.

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.

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.

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.

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 Waters , Michelle Shaw, Lucy Perrem, Bradley S Quon. Elizabeth Tullis ⁶, Melinda 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

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.

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.

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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.

 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.