2023

Lucy Allen, Lorna Allen, Siobhan B Carr , Gwyneth Davies , Damian Downey , Marie Egan , Julian T Forton , Robert Gray , Charles Haworth  , Alexander Horsley, Alan R Smyth , Kevin W Southern , Jane C Davies. Future therapies for cystic fibrosis. Review Nat Commun. 2023 Feb 8;14(1):693. doi: 10.1038/s41467-023-36244-2.  Free PMC article     pubmed.ncbi.nlm.nih.gov/36755044/

We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.

Dr Lucy Allen is Director of Research and Health Care Data at the Cystic Fibrosis Trust, London, UK.

Meliksah Arslan, Sarah Chalmers, Kelly Rentfrow Janelle M Olson , Vicki Dean , Mark E Wylam , Nadir Demirel. Suicide attempts in adolescents with cystic fibrosis on Elexacaftor/Tezacaftor/Ivacaftor therapy. Case Reports J Cyst Fibros
. 2023 Feb 7;S1569-1993(23)00023-1. doi: 10.1016/j.jcf.2023.01.015. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36759252/

Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a recently approved cystic fibrosis (CF) transmembrane conductance regulator modulator therapy that has shown promising clinical and laboratory improvements on multiple organ systems in people with CF (pwCF). While original clinical trials found little to no effect on depression and anxiety, many post-marketing reports have suggested that ETI may be associated with adverse mental health effects. Here we report on two pwCF with adverse mental health effects shortly after starting ETI. Although many factors such as the burden of living with a chronic disease or widespread effects of the Covid-19 pandemic may have contributed to these events, similar reports have led to mounting concern that ETI may be the cause of such events. Regular mental health screening before the initiation of ETI and monitoring for signs and symptoms of mental diseases afterward should be a routine part of care, given the gravity of possible outcomes.

Meliksah Arslan is at theMarmara University School of Medicine, Istanbul, Turkey.

Mafalda Bacalhau, Filipa C Ferreira , Arthur Kmit , Felipe R Souza , Verônica D da Silva  , André S Pimentel  , Margarida D Amaral  , Camilla D Buarque  , Miquéias Lopes-Pacheco. Identification of novel F508del-CFTR traffic correctors among triazole derivatives. Eur J Pharmacol
. 2023 Jan 5;938:175396. doi: 10.1016/j.ejphar.2022.175396. Epub 2022 Nov 19.    Free article  pubmed.ncbi.nlm.nih.gov/36410419/

The most prevalent cystic fibrosis (CF)-causing mutation – F508del – impairs the folding of CFTR protein, resulting in its defective trafficking and premature degradation. Small molecules termed correctors may rescue F508del-CFTR and therefore constitute promising pharmacotherapies acting on the fundamental cause of the disease. Here, we screened a collection of triazole compounds to identify novel F508del-CFTR correctors. The functional primary screen identified four hit compounds (LSO-18, LSO-24, LSO-28, and LSO-39), which were further validated and demonstrated to rescue F508del-CFTR processing, plasma membrane trafficking, and function. To interrogate their mechanism of action (MoA), we examined their additivity to the clinically approved drugs VX-661 and VX-445, low temperature, and genetic revertants of F508del-CFTR. Rescue of F508del-CFTR processing and function by LSO-18, LSO-24, and LSO-28, but not by LSO-39, was additive to VX-661, whereas LSO-28 and LSO-39, but not LSO-18 nor LSO-24, were additive to VX-445. All compounds under investigation demonstrated additive rescue of F508del-CFTR processing and function to low temperature as well as to rescue by genetic revertants G550E and 4RK. Nevertheless, none of these compounds was able to rescue processing nor function of DD/AA-CFTR, and LSO-39 (similarly to VX-661) exhibited no additivity to genetic revertant R1070W. From these findings, we suggest that LSO-39 (like VX-661) has a putative binding site at the NBD1:ICL4 interface, LSO-18 and LSO-24 seem to share the MoA with VX-445, and LSO-28 appears to act by a different MoA. Altogether, these findings represent an encouraging starting point to further exploit this chemical series for the development of novel CFTR correctors.

Mafalda Bacalhau is at Biosystems& Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisbon, Lisbon, Portugal.

Liron Birimberg-Schwartz , Wan Ip , Claire Bartlett , Julie Avolio , Jeffrey M Beekman , Johanna Rommens, Lisa Strug , Christine E Bear , Theo J Moraes , Tanja Gonska. Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis.Life Sci Alliance
. 2023 Apr 5;6(6):e202201857. doi: 10.26508/lsa.202201857. Print 2023 Jun.  37024122   Free PMC article pubmed.ncbi.nlm.nih.gov/37024122/

Highly effective drugs modulating the defective protein encoded by the CFTR gene have revolutionized cystic fibrosis (CF) therapy. Preclinical drug-testing on human nasal epithelial (HNE) cell cultures and 3-dimensional human intestinal organoids (3D HIO) are used to address patient-specific variation in drug response and to optimize individual treatment for people with CF.
This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE. Furthermore, 2D HIO showed good correlation to clinical outcome markers. A larger measurable CFTR functional range and access to the apical membrane were identified as advantages of 2D HIO over HNE and 3D HIO, respectively. Our study thus expands the utility of 2D intestinal monolayers as a preclinical drug testing tool for CF.

Liron Birimberg-Schwartz is in Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Toronto, Toronto, Canada.and Translational Medicine, The Hospital for Sick Children, Toronto, Canada.

— The subject is reviewed in detail in the Free PMC article

Julie K Bower, Nataliya Volkova, Neil Ahluwalia, Gurvaneet Sahota, Fengjuan Xuan, Anna Chin, Tanya G Weinstock, Josh Ostrenga, Alexander Elbert. Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study. J Cyst Fibros
. 2023 Mar 22;S1569-1993(23)00066-8. doi: 10.1016/j.jcf.2023.03.002. Online ahead of print.  Free article. pubmed.ncbi.nlm.nih.gov/36963986/

Background: Phase 3 clinical trials showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele. To assess long-term effects of ELX/TEZ/IVA under real-world conditions of use, a 5-year observational registry-based study is being conducted. We report interim results from the first 2 years of follow-up.
Methods: The study included people with CF in the US Cystic Fibrosis Foundation Patient Registry (CFFPR) who initiated ELX/TEZ/IVA between October 2019 and December 2020. Pulmonary exacerbations (PEx), percent predicted forced expiratory volume in 1 second (ppFEV1), hospitalizations, bacterial pathogens, body mass index (BMI), CF complications and comorbidities, and liver function tests (LFTs) after treatment initiation were compared with the 5-year pre-treatment period. Death and lung transplantation were assessed relative to 2019 CFFPR data.
Results: 16,116 people with CF were included (mean treatment duration 20.4 months). Among those with 5 years of pre-treatment data, mean PEx/patient/year declined to 0.18 (95% CI: 0.17, 0.19) in Years 1 and 2 post-treatment from 0.86 (95% CI: 0.83, 0.88) in the baseline year (79% reduction), after a continued increase observed pre-treatment. Similarly, a decline in mean hospitalizations/patient/year was observed in Year 1 that was sustained in Year 2 (74% reduction from baseline year). The mean absolute change in ppFEV1 from baseline was +8.2 percentage points (95% CI: 8.0, 8.4) in Year 1 and +8.9 percentage points (95% CI: 8.7, 9.1) in Year 2, after a continued decline observed pre-treatment. Positive bacterial cultures decreased for all evaluated pathogens, and mean BMI increased by 1.6 kg/m2 (95% CI: 1.5, 1.6) by Year 2. No new safety concerns were identified based on evaluation of CF complications, comorbidities, and LFTs. The annualized rates of death (0.47% [95% CI: 0.39, 0.55]) and lung transplantation (0.16% [95% CI: 0.12, 0.22]) were considerably lower than reported in 2019 (1.65% and 1.08%, respectively).

Conclusions: ELX/TEZ/IVA treatment was associated with sustained improvements in lung function, reduced frequency of PEx and all-cause hospitalization, increased BMI, and lower prevalence of positive bacterial cultures. Additionally, there was a 72% lower rate of death and 85% lower rate of lung transplantation relative to the year before ELX/TEZ/IVA availability. These results, from the largest cohort of ELX/TEZ/IVA-treated people to date, extend our understanding of the broad clinical benefits of ELX/TEZ/IVA.

Julie K Bower is  Associate Director of Clinical Epidemiology, Global Patient Safety at Vertex Pharmaceuticals, Boston, MA, United States of America.

Do-Yeon Cho , Jessica W Grayson , Bradford A Woodworth Unified Airway-Cystic Fibrosi Review Otolaryngol Clin North Am
. 2023 Feb;56(1):125-136. doi: 10.1016/j.otc.2022.09.009. Epub 2022 Oct 18. /pubmed.ncbi.nlm.nih.gov/36266104/

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR channel is responsible for the transport of the anions (chloride and bicarbonate) across airway epithelia. Patients with CF have thick mucus, disrupted mucociliary transport, and chronic bacterial infections in the upper and lower airways. In this article, the pathophysiology of CFTR dysfunction and its impact on the united airway are reviewed as well as the treatment strategies for patients with chronic rhinosinusitis-related CF and acquired CFTR dysfunction.

Do-Yeon Cho is in the Dept of Otolaryngology – Head & Neck Surgery, University of Alabama at Birmingham, 1155 Faculty Office Tower 510 20th Street South, Birmingham, AL 35233, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Surgery, Division of Otolaryngology, Veteran Affairs Medical Center, Birmingham, AL, USA.

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. 2023 Mar 13.  doi: 10.1007/s00404-023-06962-5. Online ahead of print. 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.

Dr Giuseppe Cimino is at the 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.

Chelsea S Davis, Anna V Faino, Frankline Onchiri, Ronald L Gibson , Lina Merjaneh, Bonnie W Ramsey, Margaret Rosenfeld, Jonathan D Cogen.    Systemic Corticosteroids in the Management of Pediatric Cystic Fibrosis Pulmonary Exacerbations Ann Am Thorac Soc
. 2023 Jan;20(1):75-82. doi: 10.1513/AnnalsATS.202203-201OC. pubmed.ncbi.nlm.nih.gov/36044723/

Rationale: Pulmonary exacerbation (PEx) events contribute to lung function decline in people with cystic fibrosis (CF). CF Foundation PEx guidelines note that a short course of systemic corticosteroids may offer benefit without contributing to long-term adverse effects. However, insufficient evidence exists to recommend systemic corticosteroids for PEx treatment.
Objectives: To determine if systemic corticosteroids for the treatment of in-hospital pediatric PEx are associated with improved clinical outcomes compared with treatment without systemic corticosteroids.
Methods: We conducted a retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System linked database. People with CF were included if hospitalized for a PEx between 2006 and 2018 and were 6-21 years of age. Time to next PEx was assessed by Cox proportional hazards regression. Lung function outcomes were assessed by linear mixed-effect modeling and generalized estimating equations. To address confounding by indication, inverse probability treatment weighting was used.
Results: A total of 3,471 people with CF contributed 9,787 PEx for analysis. Systemic corticosteroids were used in 15% of all PEx. In our primary analysis, systemic corticosteroids were not associated with better pre- to post-PEx percent predicted forced expiratory volume in 1 second responses (mean difference, -0.36; 95% confidence interval [CI], -1.14, 0.42; P = 0.4) or a higher odds of returning to lung function baseline (odds ratio, 0.97; 95% CI, 0.84-1.12; P = 0.7) but were associated with a reduced chance of future PEx requiring intravenous antibiotics (hazard ratio, 0.91; 95% CI, 0.85-0.96; P = 0.002). When restricting the analysis to one PEx per person, lung function outcomes remained no different among PEx treated with or without systemic corticosteroids, but, in contrast to our primary analysis, the use of systemic corticosteroids was no longer associated with a reduced chance of having a future PEx requiring intravenous antibiotics (hazard ratio, 0.96; 95% CI, 0.86, 1.07; P = 0.42).
Conclusions: Systemic corticosteroid treatment for in-hospital pediatric PEx was not associated with improved lung function outcomes. Prospective trials are needed to better evaluate the risks and benefits of systemic corticosteroid use for PEx treatment in children with CF.

Chelsea S Davis is at the  Division of Pulmonary and Sleep Medicine and Department of Pediatrics, University of Washington, Seattle, Washington.

Stefanie Dillenhoefer , Dorothy Grogono , Ana Morales-Tirado.A year in review (2022): Modulators and COVID19, the story goes on…..  Review  J Cyst Fibros. 2023 Mar 6;S1569-1993(23)00065-6. doi: 10.1016/j.jcf.2023.03.001.  Online ahead of print.    Free PMC article   pubmed.ncbi.nlm.nih.gov/36906393/

In this review the authors state they  have aimed to cover some of the highlights of the cystic fibrosis (CF) literature in 2022, which again has been dominated by the SARS-CoV-2 (COVID-19) pandemic and modulator therapy. They have also explored other themes, such as novel findings in relation to pulmonary exacerbations, early lung disease and emerging areas for people with CF (pwCF).

– The free PMC article, accessed through the above PubMed link, is excellent and covers the main advances during the year.

Dr Stefanie Dillenhoefer is in the  Department of Pediatric Pulmonology, Cystic Fibrosis Center, University Children’s Hospital of Ruhr University Bochum at St. Josef-Hospital, 44791 Bochum, Germany.

J Stuart Elborn , Francesco Blasi , Pierre-Régis Burgel , Daniel Peckham.  Role of inhaled antibiotics in the era of highly effective CFTR modulators. Review  Eur Respir Rev. 2023 Jan 11;32(167):220154.  doi: 10.1183/16000617.0154-2022. Print 2023 Mar 31. Free article pubmed.ncbi.nlm.nih.gov/36631132/

Recurrent and chronic bacterial infections are common in people with cystic fibrosis (CF) and contribute to lung function decline. Antibiotics are the mainstay in the treatment of exacerbations and chronic bacterial infection in CF. Inhaled antibiotics are effective in treating chronic respiratory bacterial infections and eradicating Pseudomonas aeruginosa from the respiratory tract, with limited systemic adverse effects. In the past decade, highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have become a new therapy that partially corrects/opens chloride transport in patients with selected CFTR mutations, restoring mucus hydration and improving mucociliary clearance. The recent triple CFTR modulator combination is approved for ∼80-90% of the CF population and significantly reduces pulmonary exacerbations and improves respiratory symptoms and lung function. CFTR modulators have shifted the focus from symptomatic treatment to personalised/precision medicine by targeting genotype-specific CFTR defects. While these are highly effective, they do not fully normalise lung physiology, stop inflammation or resolve chronic lung damage, such as bronchiectasis. The impact of these new drugs on lung health is likely to change the future management of chronic pulmonary infections in people with CF. This article reviews the role of inhaled antibiotics in the era of CFTR modulators.

Prof. Stuart Elbornis in the  Faculty of Medicine Health and Life Sciences, Queen’s University, Belfast, UK s.elborn@qub.ac.uk.

Bettina S Frauchiger , Kathryn A Ramsey , Jakob Usemann , Elisabeth Kieninger , Carmen Casaulta , Daniel Sirtes , Sophie Yammine , Ben Spycher  , Alexander Moeller , Philipp Latzin.Variability of clinically measured lung clearance index in children with cystic fibrosis. Pediatr Pulmonol
. 2023 Jan;58(1):197-205. doi: 10.1002/ppul.26180. Epub 2022 Nov 2.   pubmed.ncbi.nlm.nih.gov/36251441/

Rationale: The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and physiologically relevant changes in LCI during routine clinical surveillance.
Objectives: To evaluate the long-term variability of LCI and propose a threshold for a physiologically relevant change.
Methods: In children aged 4-18 years with CF, LCI was measured every 3 months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for physiologically relevant changes.
Results: Repeated LCI measurements of acceptable quality (N = 858) were available in 100 patients with CF; for 74 patients, 399 visits at clinical stability were available. The variability of repeated LCI measurements over time expressed as the coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%.

Conclusion: We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered physiologically relevant. These findings will help guide clinical decisions according to LCI changes.

Dr Bettina S Frauchiger is in theDepartment of Pediatrics, Division of Pediatric Respiratory Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Enery Gómez-Montes, Enrique Salcedo Lobato, Alberto Galindo, Diana García Alcázar, Cecilia Villalain, Maria Teresa Moral-Pumarega, Gerardo Bustos Lozano, Carmen Luna-Paredes.    Prenatal cystic fibrosis transmembrane conductance regulator modulator therapy: A promising way to change the impact of cystic fibrosis. Case Reports Fetal Diagn Ther
. 2023 Mar 30. doi: 10.1159/000530261. Online ahead of print.pubmed.ncbi.nlm.nih.gov/36996799/

Introduction: Cystic fibrosis (CF) is a potentially severe disease. The development of new therapies with cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been a great advance in the management of this condition because they improve the function of the faulty CFTR protein rather than palliate its consequences. CFTR modulator therapy improves pancreatic and lung function and, therefore, quality of life, with greater benefits the sooner treatment is started. For this reason, the use of these therapies is being approved for increasingly younger patients. Only two cases of pregnant women taking CFTR modulators therapy with CF fetuses have been reported, suggesting that it could resolve meconium ileus (MI) prenatally, and delay/prevent other consequences of CF.

Case presentation: We report a case of a healthy pregnant patient who underwent CFTR modulator therapy with elexacaftor-tezacaftor-ivacaftor (ETI) in order to treat her fetus with CF (F508del homozygous CFTR mutation) and MI. Ultrasound findings suggestive of MI were observed at 24 weeks. Both parents were tested for CFTR mutations, and both were carriers of the F508del CFTR mutation. The fetus was diagnosed with CF by amniocentesis at 26+2 weeks. Maternal ETI therapy was initiated at 31+1 weeks and no dilated bowel was observed at 39 weeks. There were no signs of bowel obstruction after birth. Maternal ETI treatment was continued during breastfeeding, with normal liver function. Immunoreactive trypsinogen in the newborn was 58.1 ng/mL, sweat chloride test was 80 mmol/l, and fecal elastase on the second day of life was 58 μg/g.

Discussion/conclusion: Prenatal ETI treatment, as well as during breastfeeding, could solve, prevent and/or delay CF complications.

Every Gômez-Montes is at Fetal Medicine Unit, Department of Obstetrics and Gynecology, Research Institute Hospital 12 de Octubre (imas12), Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin (RICORS Network), University Hospital 12 de Octubre, Complutense University, Madrid, Spain

Jennifer L Goralski , Jordana E Hoppe , Marcus A Mall, Susanna A McColley  , Edward McKone  , Bonnie Ramsey  , Jonathan H Rayment , Phil Robinson , Florian Stehling , Jennifer L Taylor-Cousar, Elizabeth Tullis , Neil Ahluwalia, Anna Chin , Chenghao Chu , Mengdi Lu, Tao Niu , Tanya Weinstock , Felix Ratjen , Margaret Rosenfeld  ; VX20-445-111 Study Group.Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2 Through 5 Years with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med. 2023 Mar 15. doi: 10.1164/rccm.202301-0084OC. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/36921081/

Rationale: Elexacaftor/tezacaftor/ivacaftor has been shown to be safe and effective in people with cystic fibrosis (CF) aged ≥6 years with ≥1 F508del-CFTR allele but has not been studied in younger children.
Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of elexacaftor/tezacaftor/ivacaftor in children with CF aged 2 through 5 years.

Methods: In this Phase 3, open-label, two-part study (Parts A and B), children weighing <14 kg (on Day 1) received elexacaftor 80 mg once daily, tezacaftor 40 mg once daily, and ivacaftor 60 mg each morning and 59.5 mg each evening; children weighing ≥14 kg received elexacaftor 100 mg once daily, tezacaftor 50 mg once daily, and ivacaftor 75 mg every 12 hours.
Measurements and main results: The primary endpoints for Part A (15-day treatment period) were pharmacokinetics and safety and tolerability. For Part B (24-week treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in Part A confirmed the appropriateness of the Part B dosing regimen. In Part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L [95% confidence interval [CI], -61.3 to -54.6]; n = 69) and LCI2.5 (-0.83 units [95% CI, -1.01 to -0.66]; n = 50) were observed from baseline through Week 24. Mean BMI was within the normal range at baseline and remained stable at Week 24.

Conclusions: In this open label study in children 2 through 5 years of age, elexacaftor/tezacaftor/ivacaftor treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and lung clearance index. Clinical trial registration available at www.

Dr Jennifer L Goralski is at the University of North Carolina at Chapel Hill, North Carolina, United States and is Associate Director of the Adult Cystic Fibrosis Center

Andrea Granados , Christine L Chan, Amir Moheet, Timothy Vigers, Ana María Arbeláez, Katie Larson Ode. The impact of elexacaftor/tezacaftor/ivacaftor on body composition in a small cohort of youth with cystic fibrosis. Pediatr Pulmonol. 2023 Mar 17. doi: 10.1002/ppul.26388. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/36929859

Background: The effects of elexacaftor-tezacaftor-ivacaftor (ETI) on body composition in people with CF (pwCF) are unknown.
Methods: Dual-energy X-ray absorptiometry fat-free mass and fat mass adjusted for height (FMI) as well as oral glucose tolerance test derived measures of insulin secretion and sensitivity were compared before and after ETI initiation in eight pwC
Results: Patients median age: 22 years interquartile range (IQR: 16-28), 87.5% male, median time on ETI:11 months. Weight z-score increased from -0.52 to 0.18 (p = 0.014); FMI increased from 4.12 to 6.29 (p = 0.014). Insulin secretion (C pep iAUC/Gluc iAUC) increased from 8.71 to 14.21 (p = 0.021), insulin resistance (HOMA2 IR) increased from 0.73 to 1.25 (p = 0.014) and insulin sensitivity decreased (Matsuda) 8.88 to 5.58 (p = 0.036).

Conclusions: ETI resulted in increased weight and fat mass. BMI and muscle mass did not change. Both insulin secretion and insulin resistance increased. Longer-term metabolic consequences of ETI need further investigation.

Dr Andrea Granados is a pediatric endocrinologist in the Department of Pedaitrics, the  Nicklaus Children’s Hospital, Miami, Florida USA

Emma L Guenther, Karen S McCoy , Mariah Eisner , Shasha Bai , Christopher J Nemastil , Kimberly J Novak, Terri Johnson, Emily M Stephan. Impact of chronic medication de-escalation in patients with cystic fibrosis taking elexacaftor, tezacaftor, ivacaftor: A retrospective review.J Cyst Fibros
. 2023 Apr 15;S1569-1993(23)00082-6. doi: 10.1016/j.jcf.2023.03.018. Online ahead of print.pubmed.ncbi.nlm.nih.gov/37069044/
Background: This single-center, retrospective study evaluated the effects of de-escalating cystic fibrosis (CF) supportive therapies in patients on elexacaftor/tezacaftor/ivacaftor (ETI). For many with CF, the clinical benefit of ETI exceeds that of supportive therapies. Therefore, we anticipated patients would desire to discontinue many of their supportive therapies, leading to the creation of a de-escalation algorithm. If patients were clinically improved and stable on ETI, CF supportive therapies could be de-escalated quarterly in accordance with the algorithm.
Methods: The primary objective was to assess non-inferiority of supportive therapies de-escalation by comparing the absolute change in percent predicted (ppFEV1) from baseline to month 1 versus the absolute change from baseline to month 12 after initiating ETI with patients serving as their own control. A chart review of patients initiated on ETI from September 2019 through December 2020 was conducted. Inclusion criteria included those six years and older with at least one copy of F508del.
Results: The study included 174 patients. The mean ppFEV1 at baseline, month 1, and month 12 was 67%, 78%, and 87% respectively. The mean difference in absolute change in ppFEV1 from baseline to month 1 compared to baseline to month 12 after the initiation of ETI was 1.53% (95% CI: -0.49 to 3.55)

CONCLUSION: De-escalating supportive therapies for those on ETI was non-inferior to remaining on all supportive therapies. This suggests that medications may be able to be discontinued under the context of a de-escalation algorithm, which may decrease medication burden and cost and increase quality of life.

Emma L Guenther is in the Department of Pharmacy, Nationwide Children’s Hospital, Columbus, OH, USA.

Desireé Gutmann , Gerhard Scheuch , Timon Lehmkühler , Laura-Sabine Herrlich , Anton Landeis , Martin Hutter , Christoph Stephan , Maria Vehreschild , Yascha Khodamoradi , Ann-Kathrin Gossmann , Florian King , Frederik Weis , Maximilian Weiss , Holger F Rabenau , Juergen Graf , Helena Donath , Ralf Schubert , Stefan Zielen. Aerosol measurement identifies SARS-CoV 2 PCR positive adults compared with healthy controls. 2023 Jan 1;216(Pt 1):114417.
doi: 10.1016/j.envres.2022.114417. Epub 2022 Sep 24.  Free PMC article pubmed.ncbi.nlm.nih.gov/36162469/

Background: SARS-CoV-2 is spread primarily through droplets and aerosols. Exhaled aerosols are generated in the upper airways through shear stress and in the lung periphery by ‘reopening of collapsed airways’. Aerosol measuring may detect highly contagious individuals (“super spreaders or super-emitters”) and discriminate between SARS-CoV-2 infected and non-infected individuals. This is the first study comparing exhaled aerosols in SARS-CoV-2 infected individuals and healthy controls.
Design: A prospective observational cohort study in 288 adults, comprising 64 patients testing positive by SARS CoV-2 PCR before enrollment, and 224 healthy adults testing negative (matched control sample) at the University Hospital Frankfurt, Germany, from February to June 2021. Study objective was to evaluate the concentration of exhaled aerosols during physiologic breathing in SARS-CoV-2 PCR-positive and -negative subjects. Secondary outcome measures included correlation of aerosol concentration to SARS-CoV-2 PCR results, change in aerosol concentration due to confounders, and correlation between clinical symptoms and aerosol.
Results: There was a highly significant difference in respiratory aerosol concentrations between SARS-CoV-2 PCR-positive (median 1490.5/L) and -negative subjects (median 252.0/L; p < 0.0001). There were no significant differences due to age, sex, smoking status, or body mass index. ROC analysis showed an AUC of 0.8918.
Conclusions: Measurements of respiratory aerosols were significantly elevated in SARS-CoV-2 positive individuals, which helps to understand the spread and course of respiratory viral infections, as well as the detection of highly infectious individuals.

Dr Desireé Gutmann is in the Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic Fibrosis, University Hospital Frankfurt, Goethe University, 60590, Frankfurt, Germany

J Kirk Harris, Brandie D Wagner , Charles E Robertson, Mark J Stevens, Conor Lingard, Drucy Borowitz , Daniel H Leung , Sonya L Heltshe, Bonnie W Ramsey , Edith T Zemanick. Upper airway microbiota development in infants with cystic fibrosis diagnosed by newborn screen. J Cyst Fibros. 2023 May 1;S1569-1993(23)00121-2. doi: 10.1016/j.jcf.2023.04.017. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/37137746/
Background: Changes in upper airway microbiota may impact early disease manifestations in infants with cystic fibrosis (CF). To investigate early airway microbiota, the microbiota present in the oropharynx of CF infants over the first year of life was assessed along with the relationships between microbiota and growth, antibiotic use and other clinical variables.
Methods: Oropharyngeal (OP) swabs were collected longitudinally between 1 and 12 months of age from infants diagnosed with CF by newborn screen and enrolled in the Baby Observational and Nutrition Study (BONUS). DNA extraction was performed after enzymatic digestion of OP swabs. Total bacterial load was determined by qPCR and community composition assessed using 16S rRNA gene analysis (V1/V2 region). Changes in diversity with age were evaluated using mixed models with cubic B-splines. Associations between clinical variables and bacterial taxa were determined using a canonical correlation analysis.
Results: 1,052 OP swabs collected from 205 infants with CF were analyzed. Most infants (77%) received at least one course of antibiotics during the study and 131 OP swabs were collected while the infant was prescribed an antibiotic. Alpha diversity increased with age and was only marginally impacted by antibiotic use. Community composition was most highly correlated with age and was only moderately correlated with antibiotic exposure, feeding method and weight z-scores. Relative abundance of Streptococcus decreased while Neisseria and other taxa increased over the first year.

Conclusions: Age was more influential on the oropharyngeal microbiota of infants with CF than clinical variables including antibiotics in the first year of life.

— The statistics are heavy going for the non-non-statistitian. Not sure where this study takes us.

Jonathan Kirk Harris is in the Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado, 13123 E. 16th Ave, B-395, Aurora, CO 80045, USA.

F Holz , E Can , C Grehn , J Klotsche , B Materne , J Kruppa , T Kallinich , C Schwarz.Manifestation and staging of arthropathy in cystic fibrosis. Defining different stages of cystic fibrosis arthropathy using ultrasound imaging and clinical scoring. J Cyst Fibros. 2023 May 5;S1569-1993(23)00116-9. doi: 10.1016/j.jcf.2023.04.011. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/37150649/

Background: The true prevalence of cystic fibrosis arthropathy (CFA) remains unclear and may be significantly higher than previously reported. In recent studies, joint symptoms have been reported up to 30% of adults with CF. This underlines the importance of CFA as a rising and clinically relevant co-morbidity. A clear definition of CFA is yet missing and its pathogenesis remains unclear. We investigated the clinical manifestation of CFA particularly via ultrasound (US) examination to define and implement a staging for clinical assessment.
Methods: In a prospective cohort study between March 2018 and February 2020 a total of 98 consecutively recruited, adult cystic fibrosis (CF) patients underwent joint-US examination according to a newly developed ultrasound score (US-CFA). A clinical assessment including rheumatological scores (DAS28, HAQ) has been conducted as well as a specially designed questionnaire. Investigation on clinical and microbiological data, as well as a comprehensive laboratory analysis, were carried out. Cluster analysis has been performed to detect patterns defining different CFA stages based on disease activity.
Results: US imaging has shown a considerable incidence of mild to moderate effusion as sign of joint inflammation/(teno-)synovitis. K-means clustering was used to distinguish 3 different stages of CFA based on the intensity of the detected effusion. These stages showed a significant association with disease activity (DAS28, p = 0.0004) as well as with patient-reported symptoms such as total weeks of CFA per year (p = 0.004), acute CFA (p = 0.015), chronic CFA (p = 0.016), disease burden (p = 0.04). Based on the US-CFA, 16% of patients suffered from severe CFA (II), 51% from intermediate CFA (I) and 33% did not present detectable arthritis. Positive serology for Chlamydia trachomatis (IgA, IgG) and Chlamydia trachomatis (IgA, IgG) significantly correlated with the US-CFA.

Conclusions: The results of this study show that a definition and categorization for the clinical manifestation of CFA can be described through US examination, which is able to detect disease activity concordant with the DAS28 as a validated clinical score on arthritis. Defining these stages will lead to a better understanding of the clinical phenotype of the disease and will optimize diagnosis, therapy and research on CFA in the future.

Frederik Holz is in the Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Division of Cystic Fibrosis, Charité – Universitätsmedizin, Berlin, Germany. He received an ECFS Young Investigator Award in 2020 for they work.

Steven Levitte, Yonathan Fuchs, Russell Wise , Zachary M Sellers.   Effects of CFTR modulators on serum biomarkers of liver fibrosis in children with cystic fibrosis. J Hepatol Commun. 2023 Jan 20;7(2):e0010. doi: 10.1097/HC9.0000000000000010. Free article  pubmed.ncbi.nlm.nih.gov/36662672/

The cystic fibrosis (CF) transmembrane conductance regulator corrector/potentiator combinations lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve sweat chloride, pulmonary function, and nutrition. Yet it is unclear whether they may also impact the progression of liver fibrosis, which is a substantial source of morbidity and mortality for patients with CF. We conducted a retrospective, single-center analysis of children and adolescents with CF treated with lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor therapy, focusing on alterations in liver function tests and fibrosis indices using previously-established thresholds that corresponded with increased liver elastography.
In pairwise comparisons of before and during treatment timepoints, we found that those with CF-associated liver involvement experienced significant decreases in gamma-glutamyl transferase, aspartate aminotransferase-to-platelet index, and gamma-glutamyl transferase-to-platelet ratio while on lumacaftor/ivacaftor. These differences were not observed in patients treated with elexacaftor/tezacaftor/ivacaftor, nor were they observed in patients without underlying CF-associated liver disease. These results provide the first evidence that lumacaftor/ivacaftor may improve liver fibrosis in children and adolescents with CF and suggest it may be beneficial in the treatment of CF-associated liver disease

Steven Levitt is in the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, California, USA.

Karen S McCoy , Jill Blind , Terri Johnson, Patti Olson, Laura Raterman , Shasha Bai, Mariah Eisner, Shahid I Sheikh, Stephan Druhan, Cody Young, Kimberly Pasley. Clinical change 2 years from start of elexacaftor-tezacaftor-ivacaftor in severe cystic fibrosis .Pediatr Pulmonol 2023 Jan 17. doi: 10.1002/ppul.26318. Online ahead of print.   hpubmed.ncbi.nlm.nih.gov/36650567/

Rationale: Limited published research is available on the impact of elexacaftor/tezacaftor/ivacaftor (ETI) beyond the initial few months postdrug initiation, especially for those who initiated therapy via individual investigational new drug application. The experiences of patients with cystic fibrosis (CF) experiencing severe lung disease were reviewed for significant improvements in clinical symptoms and quality of life.
Objectives: To examine clinical outcomes 2 years post-ETI in patients with CF and advanced lung disease.
Methods: This single center institutional review board-approved, retrospective chart review assessed clinical markers (percent predicted forced expiratory volume in 1 s, weight, sweat chloride), quality of life and computed tomography scans in patients with advanced lung disease who met criteria for compassionate use/expanded access program due to high risk of death or transplant need within 2 years.
Results: Eighteen identified patients (ages 15-49 years) initiated drug between July and September 2019. Clinical markers indicated that therapy was well tolerated, not discontinued by any participant, and lab values did not indicate medical concern or discontinuation. Monitoring results indicated the safety of modulator therapy as there were no adverse clinical occurrences and all patients presented universal stabilization. There were no deaths and no transplants by the end of the study.

Conclusions: This study focused on patients with CF eligible for modulator therapy and were initiated due to advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition, cough, FEV1 , subjective reports of clinical status, level of activity, and a reduction in burden of treatment.

Karen S McCoy is professor at the Pulmonary and Sleep Medicine Division, Nationwide Children’s Hospital, Columbus, Ohio, USA.

Edward McKone, Kathleen J Ramos, Cecilia Chaparro , Joshua Blatter, Ramsey Hachem, Michael Anstead, Fanny Vlahos  , Abby Thaxton , Sarah Hempstead, Thomas Daniels, Michelle Murray, Amparo Sole , Robin Vos , Erin Tallarico , Albert Faro  8 , Joseph M Pilewski. Position paper: Models of post-transplant care for individuals with cystic fibrosis. 2023 Mar 5;S1569-1993(23)00059-0.  doi: 10.1016/j.jcf.2023.02.011. Online ahead of print.  Free article pubmed.ncbi.nlm.nih.gov/36882349/

There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs. The committee then developed a survey that was distributed internationally to both the clinical and individual with CF/family audiences to determine the strengths, weaknesses, and preferences for various models of transplant care.
Discussion generated two models to accomplish optimal CF care after transplant. The first model incorporates the CF team into care and proposes delineation of responsibilities for the CF and transplant teams. This model is reliant on outstanding communication between the teams, while leveraging the expertise of the CF team for management of the non-pulmonary manifestations of CF. The transplant team manages all aspects of the transplant, including pulmonary concerns and management of immunosuppression.
The second model consolidates care in one center and may be more practical for transplant programs that have expertise managing CF and have access to CF multidisciplinary care team members (e.g., located in the same institution). The best model for each program is influenced by several factors and model selection needs to be decided between the transplant and the CF center and may vary from center to center. In either model, CF lung transplant recipients require a clear delineation of the roles and responsibilities of their providers and mechanisms for effective communication

Professor Edward McKone is at St. Vincent’s University Hospital and University College Dublin School of Medicine, Dublin, Ireland.

Caoimhe McParland, Matthew Nunn, Theodore K Marras, Meredith Chiasson.  Eradication of Mycobacterium abscessus infection in cystic fibrosis with initiation of Elexacaftor/Tezacaftor/Ivacaftor. Case Reports J Cyst Fibros
. 2023 Apr 17;S1569-1993(23)00095-4. doi: 10.1016/j.jcf.2023.03.021. Online ahead of print  pubmed.ncbi.nlm.nih.gov/37076409/
Mycobacterium abscessus is a nontuberculous mycobacterium that is often multi-drug resistant, difficult to eradicate and associated with a rapid decline in lung function in cystic fibrosis (CF). Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a combination CFTR modulator that improves lung function and decreases exacerbations, but limited data exists about its impact on respiratory infections. A 23-year-old male with CF (F508del, unknown) was diagnosed with Mycobacterium abscessus subspecies abscessus infection. He completed 12-weeks of intensive therapy, followed by oral continuation therapy. Antimicrobials were later discontinued for optic neuritis secondary to linezolid. He remained off antimicrobials with persistently positive sputum cultures. He then initiated ETI, and bronchoscopy eight months later suggested eradication of M. abscessus. By modulating CFTR protein function, ETI may improve innate airway defence mechanisms, facilitating the clearance of infections such as M. abscessus. This case highlights the potential positive implications of ETI on the challenging treatment of M. abscessus infections in CF.

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

Beverley C Millar, Margaret McCafferty, Ciara McCann, Damian O’Neill , Jacqueline C Rendall, John E Moore. Cystic fibrosis: Infection prevention & control recommendations for universities, colleges and institutes of further and higher education – A practical guide.Practice Guideline  Infect Dis Health. 2023 Jan 12;S2468-0451(22)00122-5. doi: 10.1016/j.idh.2022.12.002.  Online ahead of print. pubmed.ncbi.nlm.nih.gov/36641287/

Background: The avoidance of cross-infection remains of critical importance to prevent the transmission of cystic fibrosis (CF)-related microbial pathogens to persons/people with cystic fibrosis (PwCF). To date, there has been a paucity of infection prevention and control (IPC) guidance relating to infection risk at higher educational institutions. With improvements in treatments, more PwCF are now attending universities/colleges and educational institutions now seek CF-specific guidance on IPC from clinical CF teams/centres.
Methods: Real world infection-related questions from university students, educators, university support staff and the CF multidisciplinary team were received and collated from various stakeholders, including individual consultations and focus group sessions with two local universities. Subsequently, evidence-based recommendations were compiled from existing peer-reviewed literature and from cystic fibrosis organisations. Glossaries were constructed relating to clinical, microbiological and educational/pedagogical terminology to aid with the understanding amongst these stakeholder groups.
Results: This review addresses CF-related IPC recommendations across five areas of university/college life, including (i) on campus estate, (ii) teaching (lectures/tutorials/small study group work/group assignments), (iii) laboratory practicals, (iv) field trips/study visits/work placements and (v) residential accommodation and lists practical recommendations to help prevent the transmission of infections to PwCF students.

Conclusions: It is important that the educational institutional environment is safe permitting the PwCF student to enjoy their educational experience and journey through higher education, culminating in achievement of their educational goals, employment and independent living. The guidance presented in this review is intended to equip educational establishments in creating their own bespoke and robust IPC policies relating to PwCF students

Beverley C Millar is a clinical scientist at the Laboratory for Disinfection and Pathogen Elimination Studies, Northern Ireland Public Health Laboratory, Belfast City Hospital, Lisburn Road, Belfast, Northern Ireland, BT9 7AD, UK; School of Medicine, Dentistry and Biomedical Sciences, The Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Co. Londonderry, BT52 1SA, Northern Ireland, UK.

S Naehrig , B Schulte-Hubbert, S Hafkemeyer, J Hammermann, M Dumke, S Sieber; Registry working group of the German CF Registry; L Naehrlich. Chronic inhaled antibiotic therapy in people with cystic fibrosis with Pseudomonas aeruginosa infection in Germany. Pulm Pharmacol Ther. 2023 Mar 30;80:102214. doi:10.1016/j.pupt.2023.102214. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/37003541/

Background: Several clinical guidelines recommend chronic inhaled therapy for pwCF (people with cystic fibrosis) and chronic Pseudomonas aeruginosa infection of the lungs.
Methods: To demonstrate what kind of therapy regimens are used in Germany, we retrospectively analysed chronic inhaled antibiotic therapy within the cohort of the German CF Registry in 2020. For comparison we also analysed the use of inhaled antibiotics in pwCF with intermittent Pseudomonas or without Pseudomonas infection.
Results: A total of 1960 pwCF had chronic P. aeruginosa infection and were retrospectively evaluated. Almost 90% (n = 1751) received at least one inhaled antibiotic. The most commonly used inhaled antibiotic was colistin solution for inhalation (55.2%), followed by aztreonam solution for inhalation (32.6%) and tobramycin solution for Inhalation (30%). Almost 56% of adults and 44% of children alternated two antibiotics for inhalation. In children, alternating colistin + tobramycin was the most often used regimen. In adults, only 23% used colistin + tobramycin; there was a wide range of treatment regimens among adults using two inhaled antibiotics alternately. 2456 pwCF had no Pseudomonas infection, but almost 24% had a chronic inhaled antibiotic therapy, while 56% of 361 pwCF and intermittent chronic Pseudomonas infection had a chronic inhaled antibiotic therapy.

Conclusion: In all three groups the most commonly used inhaled antibiotic was colistin solution for inhalation. Almost 56% of adults and 44% of children with chronic Pseudomonas infection alternated two antibiotics for inhalation. It will be interesting to see how the introduction of the highly effective modulator elexacaftor/tezacaftor/ivacaftor will change the use of inhaled antibiotics.

Dr Susanne Naehrig is at the Hospital of the Ludwig Maximilians University Munich (LMU), Department of Internal Medicine V, Cystic Fibrosis Center for Adults, Munich, Geremany.

Sara Immacolata Orsini, Edoardo Marrani, Ilaria Pagnini, Giovanni Taccetti , Vito Terlizzi , Gabriele Simonini. Concomitant Use of Elexacaftor/Tezacaftor/Ivacaftor and Etanercept in a Cystic Fibrosis Patient with Juvenile Idiopathic Arthritis.   Case Reports  J Clin Med. 2023 Feb 21;12(5):1730.  doi: 10.3390/jcm12051730.  Free PMC article   pubmed.ncbi.nlm.nih.gov/36902517/
Patients with cystic fibrosis often complain of joint manifestations. However, only a few studies have reported the association between cystic fibrosis and juvenile idiopathic arthritis and addressed the therapeutic challenges of these patients. We describe the first paediatric case of a patient affected by cystic fibrosis, Basedow’s disease and juvenile idiopathic arthritis who was contemporarily treated with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and anti-tumor necrosis factor α (anti-TNFα). This report seems to reassure regarding the potential side effects of these associations. Moreover, our experience suggests that anti-TNFα is an effective option in CF patients affected by juvenile idiopathic arthritis, and is even safe for children receiving a triple CFTR modulator.

Sara Immacolata Orsini is in the Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy.

Nikita Padmakumar, Haji Sheeraz Khan. A foetus with cystic fibrosis – To treat or not to treat?  Respir Med Res. 2023 Mar 5;83:101006. doi: 10.1016/j.resmer.2023.101006. Online ahead of print. Free article pubmed.ncbi.nlm.nih.gov/37037055/
Background: Cystic fibrosis (CF) is an autosomal recessive health condition caused by gene mutations causing quantitative and or qualitative defect in the cystic-fibrosis transmembrane conductance regulator (CFTR) protein. CFTR defects lead to abnormal ion transport affecting multiple body systems. In CF thick secretions accumulate causing impairment in the pancreas, whole airways, gut and reproductive organs.
Cftr modulators and pregnancy: CFTR modulators have improved the quantity and quality of life of CF patients. There is limited literature on CFTR modulator use in pregnancy and its impact on foetal health. A recent case report described a child with CF being born with pancreatic sufficiency following in-utero CFTR modulator exposure. We review the potential impact of in-utero exposure to CFTR modulators, focusing on pancreatic function and future fertility of unborn individuals with CF.

Conclusion: CFTR modulator exposure in-utero is a new concept, therefore the consequences on foetal health remain uncertain. Foetal exposure to modulators could prevent pancreatic damage and infertility.

Nikita Padmakumar is in the Department of Paediatrics, Hull University Teaching Hospitals, NHS Trust, Hull HU3 2JZ, UK.

— There is a useful review of the present information on the use of modulators during pregnancy.

Linus Piehler, Ralf Thalemann, Christine Lehmann, Stephanie Thee, Jobst Röhmel, Zulfiya Syunyaeva, Mirjam Stahl, Marcus A Mall, Simon Y GraeberEffects of elexacaftor/tezacaftor/ivacaftor therapy on mental health of patients with cystic fibrosis. Front Pharmacol. 2023 Apr 21;14:1179208. doi: 10.3389/fphar.2023.1179208. eCollection 2023.  pubmed.ncbi.nlm.nih.gov/37153809/#full-view-affiliation-3
Introduction: The CFTR modulator drug elexacaftor/tezacaftor/ivacaftor (ETI) was shown to improve CFTR function and clinical symptoms in patients with cystic fibrosis (CF) with at least one F508del allele. Recently, some case reports suggested potential side effects of ETI on mental health with an increase in depressive symptoms and even suicide attempts in patients with CF. However, the general effects of this triple combination therapy on the mental health status of patients with CF remain largely unknown. Methods: We, therefore, performed a prospective, observational study in a real-life setting and investigated the relationship between initiation of ETI therapy and changes in mental health in adult patients with CF. We assessed Cystic Fibrosis Questionnaire-Revised (CFQ-R), Patient Health Questionnaire-9 (PHQ-9), Beck’s Depression Inventory – Fast Screen (BDI-FS) and Generalized Anxiety Disorder 7-item Scale (GAD-7) at baseline and 8-16 weeks after initiation of ETI. Results: In total, 70 adult patients with CF with at least one F508del allele and a median age of 27.9 years were recruited. After initiation of ETI, the CFQ-R respiratory domain score improved by 27.9 (IQR 5.6 to 47.2; p < 0.001). The PHQ-9 score of depressive symptoms decreased by 1.0 (IQR -3.0 to 0.3; p < 0.05) with an increase of 16.9% in the group with a minimal score after initiation of ETI and a decrease in the groups of mild (-11.3%) or moderate (-5.7%) scores compared to baseline. The BDI-FS score of depressive symptoms decreased from 1.0 (IQR 0.0-2.0) at baseline to 0.0 (IQR 0.0 to 2.0; p < 0.05) after initiation of ETI. The group with a minimal BDI-FS score increased by 8.0% after initiation of ETI, whereas the groups with mild (-4.9%), moderate (-1.6%) or severe (-1.6%) scores decreased compared to baseline. The GAD-7 score of anxiety symptoms did not change after initiation of ETI compared to baseline (0.0; IQR -2.0. to 0.0; p = 0.112). Conclusion: Initiation of ETI improves symptoms of depression in adult patients with CF with at least one F508del allele. However, symptoms of anxiety do not change after short-term therapy with ETI.

Linus Piehler is in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

E de Poel, S Spelier, M C Hagemeijer, P van Mourik, S W F Suen, A M Vonk, J E Brunsveld, G N Ithakisiou, E Kruisselbrink, H Oppelaar , G Berker , K M de Winter de Groot , S Heida-Michel , S R Jans , H van Panhuis , M Bakker , R van der Meer , J Roukema, E Dompeling , E J M Weersink , G H Koppelman , A R Blaazer , J E Muijlwijk-Koezen , C K van der Ent, J M Beekman FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurpsing for rare cystic fibrosis genotypes. J Cyst Fibros
. 2023 May 3;S1569-1993(23)00067-X. doi: 10.1016/j.jcf.2023.03.004. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37147251/
Background: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF.

Methods: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators.
Results: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy.
Conclusion: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies.

One-sentence summary: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

Dr Ellen de Poel is in the Department of Pediatric Respiratory Medicine, Wilhelmina Children’s Hospital, University Medical Center, Utrecht University, Utrecht, EA 3584, the Netherlands; Regenerative Medicine Utrecht, University Medical Center, Utrecht University, Utrecht, CT 3584, the Netherlands.

Katherine Prochownik, Raksha Jain, Jennifer L Taylor-Cousar, Daniel R Lavage, Olivia M Stransky , Holly N Thomas, Traci M Kazmersi. Menopause in people with cystic fibrosis. Menopause
. 2023 Jan 31. doi: 10.1097/GME.0000000000002155. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36720079/
Objective: This study aimed to describe the menopause experience of people with cystic fibrosis (CF).
Methods: We conducted a computer-based cross-sectional survey of women with CF 25 years or older at 10 US CF centers exploring a range of sexual and reproductive health concerns, including menopause. We used descriptive statistics to analyze results.
Results: Of 460 participants, 5 (3%) were perimenopausal and 34 (7%) were postmenopausal. Of participants perimenopausal or menopausal (n = 39), 97% reported the following menopausal symptoms occurring at least once a week: most commonly early wake-up (83%); stiffness/soreness in joints, neck, or shoulders (65%); and night sweats (65%). Among menopausal participants, the median self-reported age at menopause was 48.5 years (interquartile range, 5.5 y). Thirty percent experienced worsened CF symptoms during menopause, and 42% experienced worsening CF symptoms after menopause. Twenty-four percent of menopausal participants were on estrogen therapy and 15% on estrogen and progesterone therapy. Three-fourths of participants using hormone therapy reported no change in their CF symptoms. One percent of the 460 survey participants reported discussing menopause with their CF provider, despite 19% wanting to discuss this topic with their CF team.

Conclusions: This is the first study to describe menopause symptoms of people with CF. People with CF experience a variety of menopausal symptoms and often report a worsening of their CF symptoms after menopause, suggesting an interplay between female sex hormones and CF. Larger studies are needed comparing the sexual and reproductive health experiences and care needs of people with CF in the menopause transition to the general population.

Katherine Prochownik is in the Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA.

Debanjali Purkayastha, Kyla Agtarap, Kristy Wong, Onella Pereira, Jannie Co, Smita Pakhale, Salmaan Kanji. Drug-drug interactions with CFTR modulator therapy in cystic fibrosis: Focus on Trikafta®/Kaftrio®. J Cyst Fibros. 2023 Jan 16;S1569-1993(23)00004-8. doi: 10.1016/j.jcf.2023.01.005. Online ahead of print.pubmed.ncbi.nlm.nih.gov/36653239/

The combination of CFTR modulators ivacaftor, tezacaftor and elexacaftor (Trikafta®, Kaftrio®) significantly improve outcomes, including survival in a broad range of cystic fibrosis patients. These drugs have complicated metabolic profiles that make the potential for drug interactions an important consideration for prescribers, care providers and patients. Prolonged survival also increases risk of age-related disease and their associated pharmacotherapy, further increasing the risk of drug interactions and the need for increased vigilance amongst care providers. We systematically searched the literature for studies identifying and evaluating pharmacokinetic and pharmacodynamic drug interactions involving the components of Trikafta®/Kaftrio®. We also searched electronic databases of drugs for possible drug interactions based on metabolic profiles. We identified 86 potential drug interactions of which 13 were supported by 14 studies. There is a significant need for research to describe the likelihood, magnitude and clinical impact of the drug interactions proposed here.

Debanjali Purkayastha is a Pharmacy Resident at the University of Waterloo, Kitchener, ON, Canada.

Ido Sadras  , Malena Cohen-Cymberknoh , Eitan Kerem, Benjamin Z Koplewitz , Natalia Simanovsky, Michael Wilschanski, Liron Birimberg-Schwartz, Oded Breuer. Acute pancreatitis in pancreatic-insufficient cystic fibrosis patients treated with CFTR modulators. Case Reports  J Cyst Fibros. 2023 Mar 11;S1569-1993(23)00064-4. doi: 10.1016/j.jcf.2023.02.013.  Online ahead of print   pubmed.ncbi.nlm.nih.gov/36914434/
Cystic fibrosis transmembrane conductance regulator modulator therapy is associated with substantial clinical benefit and improved quality of life in patients with cystic fibrosis (CF). While their effect on lung function has been clearly reported, we are still in the process of unraveling the full impact they have on the pancreas. We present two cases of pancreatic-insufficient CF patients who presented with acute pancreatitis shortly after commencing elexacaftor/tezacaftor/ivacaftor modulator therapy. Both patients were treated with ivacaftor for 5 years prior to elexacaftor/tezacaftor/ivacaftor initiation, but had no previous episodes of acute pancreatitis. We suggest that highly effective modulator combination therapy may restore additional pancreatic acinar activity, resulting in the development of acute pancreatitis in the interim until ductal flow is improved. This report adds to the growing evidence for possible restoration of pancreatic function in patients receiving modulator therapy, and highlights that treatment with elexacaftor/tezacaftor/ivacaftor may be associated with acute pancreatitis until ductal flow is restored, even in pancreatic-insufficient CF patients.

Ido Sadras is at the CF Center, Department of Pediatrics, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

L Schembri, S Warraich, S Bentley, S B Carr, I M Balfour-Lynn. Impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in children with cystic fibrosis. J Cyst Fibros 2023 May 2;S1569-1993(23)00125-X. doi: 10.1016/j.jcf.2023.04.019. Online ahead of print.  https://pubmed.ncbi.nlm.nih.gov/37142523/

Background: Children with cystic fibrosis are at risk of fat-soluble vitamin deficiency. CFTR modulators positively affect nutritional status. This study aimed to assess changes in serum vitamins A, D & E after starting ETI therapy to ensure levels were not abnormally high.
Methods: Retrospective review of annual assessment data over 3½ years, before and after starting ETI in a specialist paediatric CF centre, including vitamin levels.
Results: 54 eligible patients were included, aged 5-15 yrs (median age 11.5). Median time to post measurements was 171 days. Median vitamin A was increased (1.38 to 1.63 µmol/L, p<0.001). Three patients (6%) had high vitamin A post-ETI, compared with none at baseline; and 2 (4%) had low levels compared to 4 (8%) at baseline. No changes in vitamins D&E.

Conclusions: This study found increased vitamin A, sometimes to high levels. We recommend testing levels within 3 months of starting ETI

Laura Schembri is in the Department of Paediatric Dietetics, Royal Brompton Hospital, London, UK.

Mathias Schenkel , Dorna Ravamehr-Lake , Tomasz Czerniak , James P Saenz , Georg Krainer , Michael Schlierf , Charles M Deber. Impact of cholesterol and Lumacaftor on the folding of CFTR helical hairpins. Biochim Biophys Acta Biomembr. 2023 Jan 1;1865(1):184078. doi: 10.1016/j.bbamem.2022.184078. Epub 2022 Oct 22.     pubmed.ncbi.nlm.nih.gov/36279907/

Cystic fibrosis (CF) is caused by mutations in the gene that codes for the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR). Recent advances in CF treatment have included use of small-molecule drugs known as modulators, such as Lumacaftor (VX-809), but their detailed mechanism of action and interplay with the surrounding lipid membranes, including cholesterol, remain largely unknown. To examine these phenomena and guide future modulator development, we prepared a set of wild type (WT) and mutant helical hairpin constructs consisting of CFTR transmembrane (TM) segments 3 and 4 and the intervening extracellular loop (termed TM3/4 hairpins) that represent minimal membrane protein tertiary folding units. These hairpin variants, including CF-phenotypic loop mutants E217G and Q220R, and membrane-buried mutant V232D, were reconstituted into large unilamellar phosphatidylcholine (POPC) vesicles, and into corresponding vesicles containing 70 mol% POPC +30 mol% cholesterol, and studied by single-molecule FRET and circular dichroism experiments. We found that the presence of 30 mol% cholesterol induced an increase in helicity of all TM3/4 hairpins, suggesting an increase in bilayer cross-section and hence an increase in the depth of membrane insertion compared to pure POPC vesicles. Importantly, when we added the corrector VX-809, regardless of the presence or absence of cholesterol, all mutants displayed folding and helicity largely indistinguishable from the WT hairpin. Fluorescence spectroscopy measurements suggest that the corrector alters lipid packing and water accessibility. We propose a model whereby VX-809 shields the protein from the lipid environment in a mutant-independent manner such that the WT scaffold prevails. Such ‘normalization’ to WT conformation is consistent with the action of VX-809 as a protein-folding chaperone.

Mathias Schenkel is atCUBE – Center for Molecular Bioengineering, TU Dresden, Tatzberg 41, 01307 Dresden, Germany

Katharina Schütz , Simon Grewendorf, Julia Kontsendorn  , Jan Fuge , Christine Happle, Isa Rudolf, Christian Dopfer , Ludwig Sedlacek, Gesine Hansen, Sibylle Junge, Anna-Maria Dittrich. Comparison of Three Eradication Treatment Protocols for Pseudomonas Aeruginosa in Children and Adolescents with Cystic Fibrosis Observational Study Klin Padiatr. 2023 Mar;235(2):75-83. doi: 10.1055/a-1996-0074. Epub 2023 Feb 9. pubmed.ncbi.nlm.nih.gov/36758577/
Background: Pseudomonas aeruginosa (Pa) continues to affect disease progression in cystic fibrosis (CF). However, the best eradication regimen remains unclear. This work compares three different antibiotic eradication regimens in pediatric CF: an administration according to a standard-operating procedure (SOP) order vs. administration outside of this order (ooSOP).
Methods: This observational study includes all CF patients<18 years who received one of three Pa eradication treatments in the past eight years at our center: 1) inhaled high-dose tobramycin (Hi-TOBI), 2) inhaled colistin+oral ciprofloxacin (COL/Cip), 3) inhaled low-dose tobramycin+4 intravenous 14-day Pa active antibiotic treatments (lo-Tobra/IV). We compared eradication rates of the three treatment regimens performed according to the SOP-based order vs. ooSOP. Logistic regression analysis was performed to identify risk factors for eradication failure.
Results: Performed according to SOP order, Hi-TOBI showed the greatest efficacy, followed by lo-Tobra/IV and finally COL/Cip, while ooSOP lo-Tobra/IV was most successful, followed by COL/Cip and Hi-TOBI. Previous Pa-infections and Pa-therapies along with age at CF diagnosis were risk factors for eradication failure.

Conclusion: Antibiotic treatment in SOP-based pre-defined order leads to significantly better eradication rates than individual modifications of the order of administration. A short course of inhalational high-dose Tobramycin is most successful at the first attempt. Prolonged antibiotic therapy seems to improve eradication after failed initial attempts.

Katharina Schütz is in Paediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany and Excellence Cluster RESIST – Resolving Infection Susceptibility, Hannover Medical School, Hannover, Germany.

Janis Kay Shute. Heparin, Low Molecular Weight Heparin, and Non-Anticoagulant Derivatives for the Treatment of Inflammatory Lung Disease.Review Pharmaceuticals (Basel). 2023 Apr 13;16(4):584. doi: 10.3390/ph16040584. Free PMC article   pubmed.ncbi.nlm.nih.gov/37111341/

Unfractionated heparin has multiple pharmacological activities beyond anticoagulation. These anti-inflammatory, anti-microbial, and mucoactive activities are shared in part by low molecular weight and non-anticoagulant heparin derivatives. Anti-inflammatory activities include inhibition of chemokine activity and cytokine synthesis, inhibitory effects on the mechanisms of adhesion and diapedesis involved in neutrophil recruitment, inhibition of heparanase activity, inhibition of the proteases of the coagulation and complement cascades, inhibition of neutrophil elastase activity, neutralisation of toxic basic histones, and inhibition of HMGB1 activity.
This review considers the potential for heparin and its derivatives to treat inflammatory lung disease, including COVID-19, ALI, ARDS, cystic fibrosis, asthma, and COPD via the inhaled route.

The Free article provides an extensive review of heparin including mention of the previous trials in CF. Heparin is not used in CF at present.  Janis Shute suggests “The variable clinical trial results may reflect the considerable variability in measurements of inflammatory mediators in sputum from CF subjects, and may have resulted in the different findings in the early uncontrolled studies. Further dose-ranging, placebo-controlled studies are therefore needed”.

Professor Janis Shute is Professor of Respiratory Physiology at the School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2UP, UK.

Kevin W Southern, Carlo Castellani, Elise Lammertyn, Alan Smyth, Donald VanDevanter, Silke van Koningsbruggen-Rietschel and 36 authors.   Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis. J Cyst Fibros. 2023 Jan;22(1):17-30.  doi: 10.1016/j.jcf.2022.10.002.  Epub 2022 Oct 28.  Free article    pubmed.ncbi.nlm.nih.gov/36916675/

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy.
We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy.

1	For individuals with clinical features consistent with CF, disease-causing variants of the CFTRgene are those characterized as “CF-causing” or “varying clinical consequences” by an established and validated program (for example, CFTR2 or CFTR-France).
2	Individuals under consideration for CFTR modulator use should have molecular diagnostic testing of the CFTR gene that includes, at minimum, the most frequent variants known to be CF-causing in their population of origin. Further analysis may include exonic regions, intron-exon junctions, and presence of copy number variants, in the case of incomplete genotype after initial molecular testing.
3	CFTR gene variants should be considered of uncertain clinical significance in the absence of epidemiological or laboratory evidence. These variants should undergo further evaluation to determine their pathogenic or benign status and potential responsiveness to VST.
4	PwCF aged six years and older, with one or two F508del variants, should have daily treatment with triple modulator therapy (elexacaftor-tezacaftor-ivacaftor).
5	PwCF and at least one responsive non-F508del variant should be considered for mono (ivacaftor), dual (tezacaftor-ivacaftor) or triple CFTR modulator therapy (elexacaftor-tezacaftor-ivacaftor).
6	Children with CF with eligible CFTR gene variants should be offered treatment with ivacaftor from 4 months of age.
7	Children with CF who are homozygous for the F508del variant, aged 2–5 years, should be offered treatment with dual modulator therapy (Lumacaftor-ivacaftor).
8	Parent/carers of pre-school children with CF should be aware of the efficacy data and safety profile of VST before treatment start.
9	Before initiating treatment, pwCF and their families should have a detailed discussion with the CF team, outlining the impact of taking CFTR modulator therapy, backed up with written information.
10	Before starting CFTR modulator therapy, a detailed drug history should be obtained and cross checked with prescribing information about potential drug interactions.
11	Patients should be followed up at least every 3 months after initiating CFTR modulator therapy to monitor progress and screen for side effects.
12	CF teams should monitor adherence to CFTR modulator therapy, for example, by using pharmacy dispensing data.
13	Before commencing and once established on a VST, pwCF, in partnership with the physiotherapy team, may need to adapt and optimise their airway clearance technique and sinus treatments.
14	For pwCF starting a VST, the management of CFRD should be reviewed and adapted on an individual basis, considering clinical and nutritional status.
15	PwCF on VST should continue to receive regular monitoring of nutritional status and dietary intake, according to changing energy requirements.
16	Frequency of support of nutritional assessment should be individualized, depending on age, clinical status and CFTR modulator therapy.
17	CF teams should be familiar with the wide-ranging psychological impact of VST and prepare, advise and support pwCF and their caregivers as required, involving the CF psychologist when indicated.
18	Symptoms of depression and anxiety should be assessed pre-VST and no later than 3 months after starting.
19	Prior to initiating VST in women with CF, contraception and fertility should be reassessed, and appropriate counselling provided.
20	The decision to use VST during pregnancy should weigh the risk to maternal health in the event of withholding therapy and the lack of data regarding safety to the foetus.
21	Women treated with VST planning to breastfeed should be informed regarding lack of data on safety during breastfeeding.
22	PwCF and CFTR gene variant(s) with unclear response to modulator therapy should be offered referral to a centre with capacity for ex vivo testing of CFTR response, to potentially establish an individualized treatment plan, including with modulator therapies.
23	All pwCF with non-responsive CFTR gene variants should continue to receive high-quality CF-specialist multi-disciplinary care at a specialist or accredited CF centre.
24	It is important that pwCF and non-responsive CFTR gene variants are informed of clinical trials and supported to participate in trials.
25	For pwCF after solid organ transplant, VST should be considered for eligible patients after discussion of the potential risks and benefits between the patient, the CF team, and the transplant team.
26	For patients with a diagnosis of CFTR-related disorder, there is no evidence to support the use of VST outside of clinical trials.
27	For infants with an unclear diagnosis following newborn screening for CF (CRMS/CFSPID), the use of VST is not indicated.
28	For new high-cost CF therapies, a robust health technology assessment should evaluate the impact on pwCF and society.
29	Evidence used to inform reimbursement decisions using public money should be transparent and available to the public.
30	The CF community should advocate globally for equitable access to new therapies with proven efficacy for all pwCF.

–  In this rapidly changing area of CF treatment this is a clear article with agreed consensus guidance on the use of the new modulators. The full article is available via the above PubMed link; it is excellent and throughly recommended.

Mirjam Stahl , Jobst Roehmel, Monika Eichinger , Felix Doellinger , Lutz Naehrlich , Matthias V Kopp , Anna-Maria Dittrich , Christopher Lee, Olaf Sommerburg , Simon Tian , Tu Xu , Pan Wu, Aniket Joshi, Partha Ray , Margaret E Duncan , Mark O Wielpütz, Marcus A Mall    Effects of Lumacaftor/Ivacaftor on Cystic Fibrosis Disease Progression in Children 2 through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2 Placebo-controlled Clinical Trial. Ann Am Thorac Soc
. 2023 Mar 21. doi: 10.1513/AnnalsATS.202208-684OC. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36943405/

Rationale: Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index2.5 (LCI2.5), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment.

Objective: To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI).
Methods: This phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). We report results from Part 1. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the MRI global chest score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics.

Results: Fifty-one children were enrolled and received LUM/IVA (n=35) or placebo (n=16). For the change in MRI global chest score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference <0; higher score indicating greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI2.5, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA.

Conclusions: This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years. Clinical trial registered with ClinicalTrials.gov (NCT03625466).

Mirjam Stahl is at the Charité Universitätsmedizin Berlin – Campus Virchow-Klinikum, 72217, Department of Pediatric Pulmonology, Immunology and Critical Care Medicine, Berlin, Germany; German Center for Lung Research (DZL), Berlin, Germany; Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.

Carmen Streibel, Corin C Willers , Orso Pusterla , Grzegorz Bauman, Enno Stranzinger, Ben Brabandt , Oliver Bieri, Marion Curdy, Marina Bullo, Bettina Sarah Frauchiger , Insa Korten, Linn Krüger, Carmen Casaulta, Felix Ratjen, Philipp Latzin, Elisabeth Kieninger.  Effects of elexacaftor/tezacaftor/ivacaftor therapy in children with cystic fibrosis – a comprehensive assessment using lung clearance index, spirometry, and functional and structural lung MRI .  J Cyst Fibros. 2023 Jan 10;S1569-1993(22)01432-1.  doi: 10.1016/j.jcf.2022.12.012. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36635199/

 Background: With improvement in supportive therapies and the introduction of cystic fibrosis transmembrane conductance regulator (CFTR)-modulator treatment in patients with cystic fibrosis (CF), milder disease courses are expected. Therefore, sensitive parameters are needed to monitor disease course and effects of CFTR-modulators. Functional lung MRI using matrix-pencil decomposition (MP-MRI) is a promising tool for assessing ventilation and perfusion quantitatively. This study aimed to assess the treatment effect of elexacaftor/tezacaftor/ivacaftor combination regimen (ELX/TEZ/IVA) on measures of structural and functional lung abnormalities.
Methods: 24 children with CF underwent lung function tests (multiple breath washout, spirometry), functional and structural MRI twice (one year apart) before and once after at least two weeks (mean 4.7 ± 2.6 months) on ELX/TEZ/IVA. Main outcomes were changes (Δ) upon ELX/TEZ/IVA in lung function, defect percentage of ventilation (VDP) and perfusion (QDP), defect distribution index of ventilation and perfusion (DDIV, DDIQ), and Eichinger score. Statistical analyses were performed using paired t-tests and multilevel regression models with bootstrapping.
Results: We observed a significant improvement in lung function, structural and functional MRI parameters upon ELX/TEZ/IVA treatment (mean; 95%-CI): ΔLCI2.5 (TO) -0.84 (-1.62 to -0.06); ΔFEV1 (z-score) 1.05 (0.56 to 1.55); ΔVDP (% of impairment) -6.00 (-8.44 to -3.55); ΔQDP (% of impairment) -3.90 (-5.90 to -1.90); ΔDDIV -1.38 (-2.22 to -0.53); ΔDDIQ -0.31 (-0.73 to 0.12); ΔEichinger score -3.89 (-5.05 to -2.72).

Conclusions: Besides lung function tests, functional and structural MRI is a suitable tool to monitor treatment response of ELX/TEZ/IVA therapy, and seems promising as outcome marker in the future.

Carmen Streibel is in the Dept of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland.Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Daniel H Tewkesbury, Varinder Athwal, Rowland J Bright-Thomas, Andrew M Jones, Peter J Barry Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on liver tests at a large single adult cystic fibrosis centre. J Cyst Fibros. 2023 Jan 18;S1569-1993(23)00008-5. doi: 10.1016/j.jcf.2023.01.007. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36669962/
Background: Elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking.
Methods: Patients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD.
Results: 255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy.

Conclusions: E/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD.

Daniel H Tewkesbury is at the Manchester University NHS Foundation Trust, Manchester, UK; Division of Immunology, Immunity to Infection & Respiratory Medicine, University of Manchester, Manchester, UK.

Burhard Tummler.Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor-Ivercaftor.  Front Pharmacol. 2023 Mar 21;14:1158207. doi: 10.3389/fphar.2023.1158207. eCollection 2023.     pubmed.ncbi.nlm.nih.gov/37025483/    Free PMC article

Triple combination therapy with the CFTR modulators elexacaftor (ELX), tezacaftor (TEZ) and ivacaftor (IVA) has been qualified as a game changer in cystic fibrosis (CF). We provide an overview of the body of literature on ELX/TEZ/IVA published between November 2019 and February 2023 after approval by the regulators. Recombinant ELX/TEZ/IVA-bound Phe508del CFTR exhibits a wild type conformation in vitro, but in patient’s tissue a CFTR glyoisoform is synthesized that is distinct from the wild type and Phe508del isoforms. ELX/TEZ/IVA therapy improved the quality of life of people with CF in the real-life setting irrespective of their anthropometry and lung function at baseline. ELX/TEZ/IVA improved sinonasal and abdominal disease, lung function and morphology, airway microbiology and the basic defect of impaired epithelial chloride and bicarbonate transport. Pregnancy rates were increasing in women with CF. Side effects of mental status changes deserve particular attention in the future.

Prof. Burkhard Tümmler is at the Dept. of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany and the Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover, Germany.

— This is a comprehensive review of the post approved studies on published work up to the present. The free article is recommended.

theses drugsClaire Wainwright, Susanna A McColley, Paul McNally , Michael Powers, Felix Ratjen , Jonathan H Rayment , George Retsch-Bogart , Erica Roesch  , Neil Ahluwalia , Anna Chin , Chenghao Chu, Mengdi Lu, Prema Menon, David Waltz 11, Tanya Weinstock, Laura Zelazoski, Jane C Davies; VX19-445-107 Study Group. Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged ≥6 Years with Cystic Fibrosis and At Least One F508del Allele: A Phase 3, Open-Label Clinical Trial. Am J Respir Crit Care Med
. 2023 May 8. doi: 10.1164/rccm.202301-0021OC. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/37154609/  

Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6 through 11 years with cystic fibrosis and ≥1 F508del-CFTR allele.
Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial.

Methods: In this phase 3, two-part (Part A and Part B), open-label extension study, children aged ≥6 years with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours while children weighing ≥30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of Part A of this extension study is reported here.
Measurements and main results: Sixty-four children (F/MF genotypes, n=36; F/F genotype, n=28) were enrolled and received ≥1 dose of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of cystic fibrosis disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, mean ppFEV1 increased (11.2 [95% CI 8.3, 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI 65.9, -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI 11.4, 15.1] points), and LCI2.5 decreased (-2.00 [95% CI -2.45, -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in ppFEV1 was 0.51 (95% CI -0.73, 1.75) percentage points per year.

Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ≥6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registration available at www.                     Clinicaltrials: gov, ID: NCT04183790.

Prof. Claire Wainwright is at the Royal Children’s Hospital, Respiratory Medicine, Brisbane, Queensland, Australia

J Westhoff, S Barth, L Naehrlich.  Drug desensitization to lumacaftor/ivacaftor: A fast lane to drug tolerance. Case Reports J Cyst Fibros
. 2023 Apr 10;S1569-1993(23)00079-6. doi: 10.1016/j.jcf.2023.03.015. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37045685/
We present the case of a girl (now 11 years and 9 months old) with cystic fibrosis (F508del homozygote), who developed pruritic rash and urticaria six days after the first dose of the CFTR modulators lumacaftor/ivacaftor. The treatment was paused and had to be interrupted due to an immediate recurrence of the urticarial rash after rechallenge. We developed a drug desensitization protocol, aligned to protocols used for desensitization against oral antibiotics. In contrast to other published protocols, it was performed by rapidly increasing the dose of lumacaftor/ivacaftor granulate at 15 min intervals. The medication was continued without interruption, the rash did not reappear during follow-up of two years. This drug desensitization protocol provides a potential new therapeutic option for patients with drug hypersensitivity reactions to CFTR modulators, especially when there are no alternative treatments. Lumacaftor/ivacaftor is available as granulate, doses can be titrated during desensitization and used for long-term treatment.

Julia Westoff is in the Department of Pediatrics, Pediatric Pulmonology, Justus-Liebig-University Giessen, Germany.

Qingtian Wu, Xiubin Liang  Xia Hou, Zhenfeng Song, Mohamad Bouhamdan, Yining Qiu , Yui Koike , Carthic Rajagopalan, Hong-Guang Wei, Hong Jiang, Gerry Hish, Jifeng Zhang, Y Eugene Chen, Jian-Ping Jin, Jie Xu , Kezhong Zhang, Fei Sun. Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes. PNAS Nexus
. 2022 Dec 23;2(1):pgac306. doi: 10.1093/pnasnexus/pgac306. eCollection 2023 Jan. 36712930 
Free PMC article  pubmed.ncbi.nlm.nih.gov/36712930/

Erratum in  Correction to: Volume 2 Issue 1 of PNAS Nexus.  PNAS Nexus. 2023 Jan 27;2(1):pgad016. doi: 10.1093/pnasnexus/pgad016. eCollection 2023 Jan.  pubmed.ncbi.nlm.nih.gov/36744020/

Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting multiple organs. Approximately 30% CF patients develop CF-related liver disease (CFLD), which is the third most common cause of morbidity and mortality of CF. CFLD is progressive, and many of the severe forms eventually need liver transplantation. The mechanistic studies and therapeutic interventions to CFLD are unfortunately very limited. Utilizing the CRISPR/Cas9 technology, we recently generated CF rabbits by introducing mutations to the rabbit CF transmembrane conductance regulator (CFTR) gene. Here we report the liver phenotypes and mechanistic insights into the liver pathogenesis in these animals. CF rabbits develop spontaneous hepatobiliary lesions and abnormal biliary secretion accompanied with altered bile acid profiles. They exhibit nonalcoholic steatohepatitis (NASH)-like phenotypes, characterized by hepatic inflammation, steatosis, and fibrosis, as well as altered lipid profiles and diminished glycogen storage. Mechanistically, our data reveal that multiple stress-induced metabolic regulators involved in hepatic lipid homeostasis were up-regulated in the livers of CF-rabbits, and that endoplasmic reticulum (ER) stress response mediated through IRE1α-XBP1 axis as well as NF-κB- and JNK-mediated inflammatory responses prevail in CF rabbit livers.
These findings show that CF rabbits manifest many CFLD-like phenotypes and suggest targeting hepatic ER stress and inflammatory pathways for potential CFLD treatment

Qingtian Wu is in the Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.