History – 2021

A M Akkerman-Nijland J E MöhlmannO W AkkermanH Vd VaartC J MajoorB L RottierJ G M BurgerhofE HakG H KoppelmanD J Touw The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heartExpert Opin Drug Saf 2021 May 25. doi: 10.1080/14740338.2021.1932814.Online ahead of print. [Pubmed]

Anne M Akkerman-Nijland

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation.
Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively.
Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed.

Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

A M Akkerman-Nijland  is at the University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, University of Groningen, Groningen, the Netherlands, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.

Margarida D Amaral  How to determine the mechanism of action of CFTR modulator compounds: A gateway to theranostics. Eur J Med Chem 2021 Jan 15;210:112989.doi: 10.1016/j.ejmech.2020.112989.Epub 2020 Nov 5.  [Pubmed]

The greatest challenge of 21st century biology is to fully understand mechanisms of disease to drive new approaches and medical innovation. Parallel to this is the huge biomedical endeavour of treating people through personalised medicine. Until now all CFTR modulator drugs that have entered clinical trials have been genotype-dependent. An emerging alternative is personalized/precision medicine in CF, i.e., to determine whether rare CFTR mutations respond to existing (or novel) CFTR modulator drugs by pre-assessing them directly on patient’s tissues ex vivo, an approach also now termed theranostics. To administer the right drug to the right person it is essential to understand how drugs work, i.e., to know their mechanism of action (MoA), so as to predict their applicability, not just in certain mutations but also possibly in other diseases that share the same defect/defective pathway. Moreover, an understanding the MoA of a drug before it is tested in clinical trials is the logical path to drug discovery and can increase its chance for success and hence also approval. In conclusion, the most powerful approach to determine the MoA of a compound is to understand the underlying biology. Novel large datasets of intervenients in most biological processes, namely those emerging from the post-genomic era tools, are available and should be used to help in this task.

Dr Margarida D Amaral is at BioISI – Biosystems & Integrative Sciences Institute, Lisboa, Faculty of Sciences, University of Lisboa, Portugal.

Justin D AndersonZhongyu LiuL Victoria OdomLatona KershJennifer S Guimbellot. CFTR Function and Clinical Response to Modulators Parallel Nasal Epithelial Organoid SwellingAm J Physiol Lung Cell Mol Physiol 2021 May 19.doi: 10.1152/ajplung.00639.2020.Online ahead of print. [Pubmed]
Rationale: In vitro biomarkers to assess Cystic Fibrosis Transmembrane Conductance Regulator activity are desirable for precision modulator selection and as a tool for clinical trials.
Objectives: We describe an organoid swelling assay derived from human nasal epithelia using commercially available reagents and equipment and an automated imaging process.
Methods: Cells were collected in nasal brush biopsies, expanded in vitro, and cultured as spherical organoids or as monolayers. Organoids were used in a functional swelling assay with automated measurements and analysis, while monolayers were used for short-circuit current measurements to assess ion channel activity. Clinical data was collected from patients on modulators. Relationships between swelling data and short-circuit current, as well as between swelling data and clinical outcome measures, were assessed.
Main results: The organoid assay measurements correlate with short-circuit current measurements for ion channel activity. The functional organoid assay distinguished individual responses as well as differences between groups. The organoid assay distinguished incremental drug responses to modulator monotherapy with ivacaftor and combination therapy with ivacaftor, tezacaftor, and elexacaftor. The swelling activity paralleled clinical response.
Conclusions: An in vitro biomarker derived from patients’ cells can be used to predict responses to drugs and is likely to be useful as a pre-clinical tool to aid in development of novel treatments, and as a clinical trial outcome measure for a variety of applications, including gene therapy or editing.

Dr Justin D Anderson is at the Gregory Fleming James Cystic Fibrosis Research Center, grid.265892.2University of Alabama at Birmingham, Birmingham, AL, and the Department of Pediatrics, Division of Pulmonary and Sleep Medicine, grid.265892.2University of Alabama at Birmingham, Birmingham, AL, USA.

Nicholas J AntosAdrienne P Savant. Cystic fibrosis year in review 2020: Section 2 pulmonary disease, infections, and inflammation. Pediatr Pulmonol. 2021 May 25.doi: 10.1002/ppul.25459. Online ahead of print. [Pubmed]

Adrienne Savant

Nicholas Antos

The outlook for those with cystic fibrosis (CF) has never been brighter with ever increasing life expectancy and the approval of the highly effective CFTR modulators, such as elexacaftor/tezacaftor/ivacaftor. With that being said, the progressive pulmonary decline and importance of lung health, infection, and inflammation in CF remains.

This review is the second part in a three-part CF Year in Review 2020. Part one focused on the literature related to CFTR modulators while part three will feature the multisystem effects related to CF. This review focuses on articles from Pediatric Pulmonology, including articles from other journals that are of particular interest to clinicians. Herein, we highlight studies published during 2020 related to CF pulmonary disease, infection, treatment, and diagnostics.

Dr Nicholas J Antos is in the Department of Pediatrics, Division of Pulmonary and Sleep Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. & the Department of Pediatric Pulmonology, Children’s Wisconsin, Milwaukee, Wisconsin, USA.

Dr Adrienne P Savant is in the Department of Pediatrics, Children’s Hospital of New Orleans, New Orleans, Louisiana, USA & the Department of Pediatrics, Tulane University, New Orleans, Louisiana, USA.

Bardin E, Pastor A, Semeraro M, Golec A, Hayes K, Chevalier B, Berhal F, Prestat G, Hinzpeter A, Gravier-Pelletier C, Pranke I, Sermet-Gaudelus I.   Modulators of CFTR. Updates on clinical development and future.  Eur J Med Chem. 2021 Mar 5;213:113195.doi: 10.1016/j.ejmech.2021.113195. Epub 2021 Jan 16. [Pubmed]

Emmanuelle Bardin

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR “modulators” have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.

Dr Emmanuelle Bardin is a post-doctoral researcher at the Institut Necker Enfants Malades. INSERM U1151, Paris, France. in 2020 she was awarded a European Cystic Fibrosis Society and Cystic Fibrosis Europe Post-Doctoral Research Fellowship to research into “Novel insights into the impact of CFTR modulators on the response of the cystic fibrosis respiratory epithelium to S. aureus infection”.

 Sarah E BauerMelissa WessonSylwia K OlesClement L Ren.      Outcomes of Repeat Sweat Testing in Cystic Fibrosis Newborn Screen Positive Infants. Pediatr Pulmonol 2021 Jan 29.doi: 10.1002/ppul.25296. Online ahead of print.[Pubmed]

Sarah Bauer

Infants with a positive cystic fibrosis (CF) newborn screen, only one identified CFTR mutation (NBS+/1mut), and an initial intermediate sweat chloride (30-59 mmol/L) should have repeat sweat chloride testing (SCT). However, the outcome of repeat SCT and the relationship between initial sweat Cl and subsequent CF diagnosis have not been reported.   The objective of this study was to analyze the outcomes of repeat SCT and subsequent CF diagnosis in NBS+/1mut infants based on their initial sweat chloride concentration.We retrospectively identified all infants born in Indiana from 2007 through 2017 with NBS+/1mut and initial SCT in the intermediate range. For each infant, we recorded the initial and repeat SCT results and/or a final CF diagnosis.
Results: From 2007 through 2017 there were 2,822 NBS+/1mut infants of which 2,613 (82%) had at least one SCT result. No infants with an initial SCT of 30-39 mmol/L were subsequently diagnosed with CF. Of the 31 infants with an initial SCT of 40-49 mmol/L, only 1 was subsequently diagnosed with CF. In contrast, 61% of those with SCTs of 50-59 mmol/L were later diagnosed with CF.
Conclusion: These results suggest that infants with a positive NBS for CF and 1 CFTR mutation whose initial sweat chloride concentration is 50-59 mmol/L need to be monitored more closely for CF with strong consideration for earlier repeat SCTs and immediate genotyping.

Dr Sarah E Bauer is a Fellow at Pediatrics, Indiana University, Indianapolis, IN, United States.

Katie J Bayfield Tonya A Douglas Tim RosenowJane Carolyn DaviesStuart J ElbornMarcus MallAnthony PaprokiFelix RatjenPeter D SlyAlan Robert SmythStephen StickClaire E WainwrightPaul D Robinson Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis.Thorax. 2021 Apr 29;thoraxjnl-2020-216085.doi: 10.1136/thoraxjnl-2020-216085. Online ahead of print. [Pubmed]    

Tonya Douglas

Katie Bayfield

Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of ‘normal’ (FEV1≥90% predicted) and ‘mild lung disease’ (FEV1 70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques.

The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.   Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups.
Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.
To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled ‘Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis’, was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.

Dr Katie J Bayfield is in the Department of Respiratory Medicine, Children’s Hospital at Westmead, Westmead, New South Wales, Australia.

Dr Tonya A Douglas is Department of Respiratory and Sleep Medicine, Queensland Children’s Hospital, South Brisbane, Queensland, Australia and the Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia.

Marina M BelletMonica BorghiMarilena ParianoGiorgia RengaClaudia StincardiniFiorella D’OnofrioStefano BrancorsiniEnrico GaraciClaudio CostantiniLuigina Romani.  Thymosin alpha 1 exerts beneficial extrapulmonary effects in cystic fibrosis Eur J Med Chem 2021 Jan 1;209:112921.doi: 10.1016/j.ejmech.2020.112921. Epub 2020 Oct 9. [Pubmed]

Marina M Bellet

We have previously demonstrated that thymosin alpha1 (Tα1), a naturally occurring immunomodulatory peptide, displays multi-sided beneficial effects in CF that concur in ameliorating the lung inflammatory pathology. In the present study, by resorting to murine models of gut inflammation with clinical relevance for CF patients, we demonstrate that Tα1 can also have beneficial effects in extrapulmonary pathology. Specifically, Tα1 restored barrier integrity and immune homeostasis in the inflamed gut of CF mice as well as in mice with the metabolic syndrome, a disorder that may arise in CF patients with high caloric intake despite pancreatic sufficiency. The protective effects of Tα1 also extended to pancreas and liver, further emphasizing the beneficial effects of Tα1 in extra-pulmonary complications of CF. By performing wide-ranging multi-organ anti-inflammatory effects, Tα1 could potentially integrate current therapeutic approaches to tackle the complex symptomatology of CF diseas

Marina M Bellet is in the Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.

Amelia BercussonGeorge JarvisAnand Shah CF Fungal Disease in the Age of CFTR ModulatorsMycopathologia   2021 Apr 4.doi: 10.1007/s11046-021-00541-5.Online ahead of print. [Pubmed]
Fungi are increasingly recognised to have a significant role in the progression of lung disease in Cystic fibrosis with Aspergillus fumigatus the most common fungus isolated during respiratory sampling. The emergence of novel CFTR modulators has, however, significantly changed the outlook of disease progression in CF. In this review we discuss what impact novel CFTR modulators will have on fungal lung disease and its management in CF. We discuss how CFTR modulators affect antifungal innate immunity and consider the impact of Ivacaftor on fungal disease in individuals with gating mutations. We further review the increasing complication of drug-drug interactions with concurrent use of azole antifungal medication and highlight key unknowns that require addressing to fully understand the impact of CFTR modulators on fungal disease.

Dr Amelia Bercusson is at the Cystic Fibrosis Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK. Co-authors are from the Royal Brompton in London.

Peder BergMajbritt JeppesenJens Leipziger  Cystic fibrosis in the kidney: new lessons from impaired renal HCO3- excretion. Curr Opin Nephrol Hypertens 2021 Jul 1;30(4):437-443.doi: 10.1097/MNH.0000000000000725. [Pubmed]

Peter Berg

Purpose of review: A key role of cystic fibrosis transmembrane conductance regulator (CFTR) in the kidney has recently been uncovered. This needs to be integrated into the understanding of the developed phenotypes in cystic fibrosis (CF) patients.
Recent findings: In the beta-intercalated cells of the collecting duct , CFTR functions in very similar terms as established in the exocrine pancreatic duct and both CFTR and SLC26A4 (pendrin) orchestrate regulated HCO3- secretion. Like in the pancreas, the hormone secretin is a key agonist to activate renal HCO3- secretion. In mice lacking CFTR or pendrin, acute and chronic base challenges trigger marked metabolic alkalosis because collecting duct base secretion is defective. Also in CF patients, the ability to acutely increase renal HCO3- excretion is markedly reduced.

Summary: The now much enlarged understanding of CFTR in the kidney may permit the measurement of challenged urine HCO3- excretion as a new biomarker for CF. We suggest a new explanation for the electrolyte disorder in CF termed Pseudo-Bartter Syndrome. The hallmark electrolyte disturbance features of this can be well explained by a reduced function of collecting duct Cl-/HCO3- exchange. Eventually, we suggest the diagnostic term distal renal tubular alkalosis to cover those disturbances that causes metabolic alkalosis by a reduced collecting duct base secretion.

Dr Peder Berg is in the Department of Biomedicine, Physiology, Health, Aarhus University, Aarhus, Denmark. For this work he was awarded the Gerd Döring award of the ECFS in 2021

Molly Bozic Christopher H Goss Rabindra M TirouvanziamArthur BainesMargaret KlosterLiebe AntoineDrucy BorowitzSarah Jane SchwarzenbergGROW study group. Oral Glutathione and Growth in Cystic Fibrosis: A Multicenter, Randomized, Placebo-controlled, Double-blind Trial J Pediatr Gastroenterol Nutr 2020 Dec;71(6):771-777.doi: 10.1097/MPG.0000000000002948. [Pubmed]

       Molly Bozic

Objectives: The nutritional status of children with cystic fibrosis (CF) is associated with mortality and morbidity. Intestinal inflammation may contribute to impaired digestion, absorption, and nutrient utilization in patients with CF and oral glutathione may reduce inflammation, promoting improved nutritional status in patients with CF.
Methods: The GROW study was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase II clinical trial in pancreatic insufficient patients with CF between the ages of 2 and 10 years. Patients received reduced glutathione or placebo orally daily for 24 weeks. The primary endpoint was the difference in change in weight-for-age z-scores from baseline through week 24 between treatment groups. Secondary endpoints included other anthropometrics, serum, and fecal inflammatory markers in addition to other clinical outcomes.
Results: Fifty-eight participants completed the study. No significant differences were seen between glutathione (n = 30) and placebo (n = 28) groups in the 6-month change in weight-for-age z-score (-0.08; 95% CI: -0.22 to 0.06; P = 0.25); absolute change in weight (kg) (-0.18; 95% CI: -0.55 to 0.20; P = 0.35); or absolute change in BMI kg/m (-0.06; 95% CI: -0.37 to 0.25; P = 0.69). There were no significant differences in other secondary endpoints. Overall, glutathione was safe and well tolerated.

Conclusions: Oral glutathione supplementation did not impact growth or change serum or fecal inflammatory markers in pancreatic insufficient children with CF when compared with placebo.

 Dr Molly Bozic is Associate Professor of Pediatrics at the Indiana University School of Medicine, Indianapolis, IN.

Kubra M BozkanatNatalie E WestSigrid LadoresKristina MontemayorMaria Gabriela Tupayachi OrtizMindy ChristiansonRaksha Jain Catamenial haemoptysis in females with cystic fibrosis: a case series with review of management strategies. Respirol Case Rep 2021 May 7;9(6):e00755.doi: 10.1002/rcr2.755.eCollection 2021 Jun. [Pubmed]

Kubra Bozkanat

Catamenial haemoptysis, the expectoration of blood during menses, has not been extensively reported in the cystic fibrosis (CF) literature. We describe four cases (age range: 25-34 years) of catamenial haemoptysis across four CF centres in the United States. These cases may represent thoracic endometriosis versus hormonal fluctuations in airway inflammation or infection resulting in bronchial artery bleeding. We identify common and nuanced management strategies including use of pro-coagulants, hormone contraceptives, anti-inflammatories, bronchial artery embolization, and use of the newer cystic fibrosis transmembrane conductance regulator (CFTR) modulators.

Kubra M Bozkanatis a paediatrician in the Department of Pediatrics University of Texas, Southwestern Medical Center, Dallas TX USA.

 Josephine M BryantKaren P BrownSophie BurbaudIsobel Everall Juan M Belardinelli Daniela Rodriguez-Rincon et al. Stepwise pathogenic evolution of Mycobacterium abscessus.   Science 2021 Apr 30;372(6541):eabb8699. doi:10.1126/science.abb8699.  [Pubmed]

Josephine Bryant

Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis, have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones.

Dr Josephine M Bryant is a researcher at the Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC Laboratory of Molecular Biology, Cambridge, UK, and the University of Cambridge Centre for AI in Medicine, Cambridge, UK.

[“saltational”= “a sudden and large mutational change from one generation to the next, potentially causing single-step speciation]

Buqing YiAlexander H DalpkeSébastien Boutin.  Changes in the Cystic Fibrosis Airway Microbiome in Response to CFTR Modulator Therapy.  Front Cell Infect Microbiol 2021 Mar 17;11:548613.doi: 10.3389/fcimb.2021.548613. eCollection 2021.Free PMC article   [Pubmed]

 Buqing Yi

The development of CFTR modulator therapies significantly changed the treatment scheme of people with cystic fibrosis. However, CFTR modulator therapy is still a life-long treatment, which is not able to correct the genetic defect and cure the disease. Therefore, it becomes crucial to understand the effects of such modulation of CFTR function on the airway physiology, especially on airway infections and inflammation that are currently the major life-limiting factors in people with cystic fibrosis. In this context, understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections. Whether and how the newly available therapies affect the airway microbiome is still at the beginning of being deciphered. We present here a brief review summarizing the latest information about microbiome alterations in light of modern cystic fibrosis modulator therapy.

Dr Buqing Yi is at the Medical Faculty, Institute of Medical Microbiology and Virology, Technische Universität Dresden, Dresden, Germany

A CapalboM FabianiS CaroselliM PoliL GirardiC PatassiniF FaveroD CimadomoA VaiarelliC SimonL F RienziF M Ubaldi Clinical validity and utility of preconception expanded carrier screening for the management of reproductive genetic risk in IVF and general population. Hum Reprod 2021 May 22;deab087.doi: 10.1093/humrep/deab087. Online ahead of print.[Pubmed]

   Antonio Capalbo

Study question: What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents?
Summary answer: The high detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population.
What is known already: About 2-4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds    the potential to significantly improve couple’s genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring.
Study design, size, duration: A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples.
Participants/materials, setting, methods: A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making.
Main results and the role of chance: A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby.
Limitations, reasons for caution: The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene-disease associations.

Wider implications of the findings: These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF.

Dr A Capalbo is Laboratory Manager  at Igenomix Italy.

Chan BK, Stanley G, Modak M, Koff JL, Turner PE. Bacteriophage therapy for infections in CF.  Pediatr Pulmonol. 2021 Feb;56 Suppl 1: S4-S9. doi: 10.1002/ppul.25190. [Pubmed]

    Benjamin Chan

Pseudomonas aeruginosa and Staphylococcus aureus are bacterial pathogens frequently associated with pulmonary complications and disease progression in cystic fibrosis (CF). However, these bacteria increasingly show resistance to antibiotics, necessitating novel management strategies. One possibility is bacteriophage (phages; bacteria-specific viruses) therapy, where lytic phages are administered to kill target bacterial pathogens. Recent publications of case reports of phage therapy to treat antibiotic-resistant lung infections in CF have garnered significant attention. These cases exemplify the renewed interest in phage therapy, an older concept that is being newly updated to include rigorous collection and analysis of patient data to assess clinical benefit, which will inform the development of clinical trials. As outcomes of these trials become public, the results will be a valuable gauge of the potential usefulness of phage therapy to address the rise in antibiotic-resistant bacterial infections. In addition, we highlight the further need for basic research to accurately predict the different responses of target bacterial pathogens when phages are administered alone, sequentially, or as mixtures (cocktails), and whether within-cocktail interactions among phages hold consequences for the efficacy of phage therapy in patient treatment.

 Dr Benjamin K Chan is research scientist in the Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, USA

Chilvers MA, Davies JC, Milla C, Tian S, Han Z, Cornell AG, Owen CA, Ratjen F. Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study.    Lancet Respir Med. 2021 Jan 28:S2213-2600(20)30517-8. doi: 10.1016/S2213-2600(20)30517-8. Online ahead of print. [Pubmed]

     Mark Chilvers

Background: The safety and efficacy of 24 weeks of lumacaftor-ivacaftor combination therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously shown in two phase 3 studies. Here, we report long-term safety and efficacy data.
Methods: In this phase 3, open-label, multicentre, extension study (study 110), we examined the long-term safety, tolerability, and efficacy of lumacaftor-ivacaftor in children pooled from two phase 3 parent studies (open-label study 011B and randomised, placebo-controlled study 109). The study was conducted at 61 clinics in the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK. Children with cystic fibrosis homozygous for the F508del-CFTR mutation who had received lumacaftor-ivacaftor or placebo in the parent studies were treated with lumacaftor-ivacaftor for up to 96 weeks; those who had received the combination therapy in the parent studies (the treatment-to-treatment group) received up to 120 weeks of treatment in total. Participants aged 6-11 years at the start of the parent study received lumacaftor 200 mg-ivacaftor 250 mg orally once every 12 h; those aged 12 years or older received lumacaftor 400 mg-ivacaftor 250 mg orally once every 12 h. The primary endpoint was safety and tolerability in all children who had received at least one dose of the study drug. Secondary endpoints included change from baseline in lung clearance index 2·5% (LCI2·5), sweat chloride concentration, body-mass index, and Cystic Fibrosis Questionnaire-Revised respiratory domain score. This extension study is registered with ClinicalTrials.gov, NCT02544451, and has been completed.
Findings: The extension study ran from Aug 13, 2015, to Aug 17, 2018. Of 239 children who enrolled in the study and received at least one dose of lumacaftor-ivacaftor, 215 (90%) completed 96 weeks of treatment. Most children (236 [99%] of 239 children) had adverse events that were mild (49 [21%] of 239) or moderate (148 [62%] of 239) in severity, and there was a low rate of adverse events leading to treatment discontinuation. The most frequently reported adverse events were common manifestations or complications of cystic fibrosis, such as cough and pulmonary exacerbation, or were consistent with the known safety profile of lumacaftor-ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor-ivacaftor treatment. Children in the placebo-to-treatment group had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in children treated with lumacaftor-ivacaftor in the parent study were generally maintained in the extension study.
Interpretation: Lumacaftor-ivacaftor therapy in children homozygousi for F508del-CFTR who initiated treatment at age 6-11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks. These data support the long-term use of lumacaftor-ivacaftor to treat children aged 6 years and older who are homozygous for the F508del-CFTR mutation.

Dr Mark Chilvers is Clinical Associate Professor, Division of Respiratory Medicine, Department of Pediatrics, Faculty of Medicine, University of British Columbia

C CimbaloA ToscoV TerlizziA SepeA CastaldoL SalvadoriV Raia. Elevated sweat chloride test: is it always cystic fibrosis? Ital J Pediatr 2021 May 14;47(1):112. doi: 10.1186/s13052-021-01060-1. Free PMC article [Pubmed]
Background: The sweat chloride test (ST) is the gold standard for cystic fibrosis (CF) diagnosis in symptomatic patients, within the newborn screening and in the follow-up of CF patients during molecular therapies. However, false positives have been reported in patients with different diseases. We describe and discuss 4 cases due to different clinical conditions in which we recorded false positive ST, and the test remained altered for a period of varying length.

Cases presentation: Case 1: Eight months old female child suffering from constipation, recurrent vomiting and failure to thrive, family history of recurrent pancreatitis without mutations in the PRSS1 and SPINK1 genes. Both ST and fecal elastase were altered although no CFTR gene mutations were found. Due to rapid clinical deterioration, celiac disease was suspected and diagnosed by laboratory tests and intestinal biopsy. After 2 weeks of gluten-free diet ST and fecal elastase normalized. Case 2: 14 months old male suffering from bilateral renal dysplasia, episodes of metabolic alkalosis, recurrent respiratory infections and recurrent vomiting. The child had more ST positives, but no CFTR mutations were found. During follow-up, he developed sensorineural hearing loss and an atrial septic defect was found. Finally, a diagnosis of Klinefelter was made, but the ST normalized several years later. Case 3 and 4: Two boys with stubborn constipation and fecal occlusion treated with Poly Ethylene Glycol (PEG) with salts showed pathological ST. The test returned normal a few days after stopping treatment.
Conclusions: We hypotesized the possible causes of ST alteration in these conditions: in celiac disease it could be due to a transient dysregulation of the aquaporins, rapidly reversed by the diet; in Klinefelter, it may be due to stable pubertal hypoandrogenism; while, the PEG formulation itself contains salts that can temporarily alter ST.

Dr C Cimbalo  is at the Department of Translational Medical Sciences, Cystic Fibrosis Center, University Federico II, Naples, Italy.

Carla ColomboGianfranco AlicandroMark OliverPeter J LewindonGrant A RammChee Y OoiFederico AlghisiNataliya KashirskayaElena KondratyevaFabiola CortiRita PadoanIrina AsherovaHelen EvansIsabelle de MonestrolBirgitta StrandvikAnders LindbladCF UDCA study group.   Ursodeoxycholic acid and liver disease associated with cystic fibrosis: A multicenter cohort study.  J Cyst Fibros  2021 Apr 1;S1569-1993(21)00090-4.doi: 10.1016/j.jcf.2021.03.014.Online ahead of print.[Pubmed]

    Carla Colombo

Background: The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers. The study aimed at evaluating if the incidence of severe liver disease differs between CF centers routinely prescribing or not prescribing UDCA.
Methods: We carried out a retrospective multicenter cohort study including 1591 CF patients (1192 patients from UDCA-prescribing centers and 399 from non-prescribing centers) born between 1990 and 2007 and followed from birth up to 31 December 2016. We computed the crude cumulative incidence (CCI) of portal hypertension (PH) at the age of 20 years in the two groups and estimated the subdistribution hazard ratio (HR) through a Fine and Gray model.
Results: Over the observation period, 114 patients developed PH: 90 (7.6%) patients followed-up in UDCA prescribing centers and 24 (6.0%) in non-prescribing centers. The CCI of PH at 20 years was 10.1% (95% CI: 7.9-12.3) in UDCA-prescribing and 7.7% (95% CI: 4.6-10.7) in non-prescribing centers. The HR among patients followed in prescribing centers indicated no significant difference in the rate of PH either in the unadjusted model (HR: 1.21, 95% CI: 0.69-2.11) or in the model adjusted for pancreatic insufficiency (HR: 1.28, 95% CI: 0.77-2.12).
Conclusions: CF patients followed-up in UDCA prescribing centers did not show a lower incidence of PH as compared to those followed in centers not prescribing UDCA. These results question the utility of UDCA in reducing the occurrence of severe liver disease in CF.

Professor Carla Colombo is at IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan,

– This is surprising and disappointing. Suggest you read the Liver section in TOPICS where Carla Colombo’s earlier work in 1990 and subsequently is described.

Amy DarukhanavalaFilia Van DesselJannifer HoMegan HansenTed KremerDavid Alfego   Use of hemoglobin A1c to identify dysglycemia in cystic fibrosis. PLoS One 2021 Apr 21;16(4):e0250036.doi: 10.1371/journal.pone.0250036. eCollection 2021  Free article   [Pubmed]   (Please see PubMed for full abstract details)

Amy Darukhanaval

Cystic fibrosis (CF) leads to pancreatic endocrine dysfunction with progressive glycemic disturbance. Approximately 30%-50% of people with CF eventually develop CF-related diabetes (CFRD). Pre-CFRD states progress from indeterminant glycemia (INDET) to impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Screening guidelines recommend inconvenient annual 2-hour oral glucose tolerance tests (OGTTs), beginning at age 10 years. More efficient methods, such as hemoglobin A1C (HbA1c), have been evaluated, but only limited, relatively small studies have evaluated the association between HbA1c and pre-CFRD dysglycemic states.
This study to determine whether HbA1c is an appropriate screening tool for identifying patients with pre-CFRD dysglycemia to minimize the burden of annual OGTTs.
Results: Mean HbA1c was not significantly different between patients with normal glucose tolerance and those in the INDET (p = 0.987), IFG (p = 0.690), and IGT (p = 0.874) groups. Analysis of variance confirmed the lack of association between HbA1c and glycemia, as mean HbA1c was not significantly different amongst the four categories (p = 0.250).
The authors concluded there is increasing awareness of the impact of pre-CFRD states, including reduced pulmonary function and nutritional status. Unfortunately, our results do not support using HbA1c as a screening tool for pre-CFRD dysglycemia, specifically INDET, IFG, and IGT. Further studies are warranted to evaluate more efficient screening methods to reduce the burden of annual OGTTs.

Dr Amy Darukhanavala is a paediatric endocrinologist and Assistant Professor at the Department of Pediatric Endocrinology, University of Massachusetts Medical Center, Worcester, MA, United States of America.

Kavita Dave Rebecca Dobra Sandra Scott Clare Saunders Jess Matthews Nicholas J Simmonds Jane C Davies.   Entering the era of highly effective modulator therapies.   Pediatr Pulmonol 2021 Feb;56 Suppl 1:S79-S89. doi: 10.1002/ppul.24968.      [Pubmed]

Kavita Dave

Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF

Dr Kavita Dave is the UK CF Trust Clinical Fellow at Departments of Cystic Fibrosis and Paediatric Respiratory Medicine, Royal Brompton & Harefield Foundation Trust, London, UK

Jane C DaviesClaire E Wainwright Gregory S SawickiMark N Higgins Daniel Campbell Christopher HarrisPaul PanorchanEric HaseltineSimon TianMargaret RosenfeldIvacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation. Results of a Two-Part Phase 3 Clinical Trial. Am J Respir Crit Care Med   2021 Mar 1;203(5):585-593.doi: 10.1164/rccm.202008-3177OC. [Pubmed]

      Jane Davies

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.
Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.
Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.
Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.
Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.

Further detail abstracted from the full text – This study of CFTR modulation in the first year of life suggests that ivacaftor can be safely administered to infants ≥4 months of age. Our findings are consistent with observations in older children and support treating the underlying cause of CF in children ≥4 months. Ivacaftor has a favourable safety profile; it was well tolerated at both doses tested, with no new safety concerns. Results of this study suggest improvements in CFTR function, no adverse effects on growth, and reductions in lipase concentrations with ivacaftor. Improvements in FE-1 and IRT concentrations (together with lipase data) support the potential of ivacaftor to delay or possibly minimize progressive exocrine pancreatic dysfunction. Studies evaluating a larger number of children for longer periods of time are needed to further test this hypothesis. Studies of pharmacokinetics and safety in younger infants are planned.
Substantial decreases in sweat chloride concentration were seen, which is a measure of CFTR function. Although the sample sizes were small, the mean improvement in sweat chloride concentration of −55.7 (SD, 16.2) mmol/L in these infants aged 4 to <12 months appears comparable with what has been reported in older children
Improvements in concentrations of FE-1, a biomarker of exocrine pancreatic function, were seen from baseline to 24 weeks (mean [SD] increases of 164.7 [151.9] μg/g and 99.8 [138.4] μg/g in ARRIVAL and KIWI, respectively).  Similarly, in the current report, mean (SD) improvement in FE-1 concentrations at Week 24 was 166.0 (140.6) μg/g. Eleven infants had baseline FE-1 concentrations of ≤200 μg/g, indicating pancreatic insufficiency, among whom seven of nine with paired data had regained pancreatic sufficiency at Week 24.
Although the clinical relevance of improvements in biomarkers of pancreatic function is unknown, the combined findings in children aged 4 to <24 months in ARRIVAL and aged 2–5 years in KIWI suggest a possible positive and protective effect of ivacaftor on pancreatic exocrine function early in life.

Jane Davies is a Professor in Paediatric Respirology & Experimental Medicine at the National Heart and Lung Institute and an Honorary Consultant in Paediatric Respiratory Medicine at the Royal Brompton & Harefield NHS Foundation Trust.

Joris R DelangheMarc L De BuyzereMarijn M SpeeckaertGenetic Polymorphisms in the Host and COVID-19 Infection. Adv Exp Med Biol 2021;1318:109-118.doi: 10.1007/978-3-030-63761-3_7.  [Pubmed]

      Joris Delange

The outbreak of the COVID-19 pandemic shows a marked geographical variation in its prevalence and mortality. The question arises if the host genetic variation may (partly) affect the prevalence and mortality of COVID-19. We postulated that the geographical variation of human polymorphisms might partly explain the variable prevalence of the infection. We investigated some candidate genes that have the potential to play a role in the immune defense against COVID-19: complement component 3 (C3), galactoside 2-alpha-L-fucosyltransferase 2 (FUT2), haptoglobin (Hp), vitamin D binding protein (DBP), human homeostatic iron regulator protein (HFE), cystic fibrosis transmembrane conductance regulator (CFTR), and angiotensin-converting enzyme 1 (ACE1). In a univariate approach, ACE1 D/I, C3, CFTR, and HFE polymorphisms correlated significantly with COVID-19 prevalence/mortality, whereas Hp and FUT2 polymorphism did not show any significant correlations. In a multivariate analysis, only ACE1 D/I and C3 polymorphisms were determinants for COVID-19 prevalence/mortality. The other polymorphisms (CFTR, DBP, FUT2, HFE, and Hp) did not correlate with COVID-19 prevalence/mortality. Whereas ACE1 D/I polymorphism shows functional links with ACE2 (which is the receptor for the virus) in COVID-19, C3 can act as a critical step in the virus-induced inflammation. Our findings plead against a bystander role of the polymorphisms as a marker for historical migrations, which comigrate with causal genes involved in COVID-19 infection. Further studies are required to assess the clinical outcome of COVID-19 in C3S and ACE1 D allele carriers and to study the role of C3 and ACE1 D/I polymorphisms in COVID-19 and their potential effects on treatment response.

 Joris R Delanghe is professor in the Department of Diagnostic Sciences, Ghent University, Ghent, Belgium. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Ghent, Belgium

Danila DelfinoGiulia MoriClaudio RivettiAntonella GrigolettoGloria BizzottoCristian CavozziMarco MalatestaDavide CavazziniGianfranco PasutRiccardo Percudani Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease. Biomolecules 2021 Mar 10;11(3):410.doi: 10.3390/biom11030410. Free PMC article [Pubmed]
In cystic fibrosis (CF), the accumulation of viscous lung secretions rich in DNA and actin is a major cause of chronic inflammation and recurrent infections leading to airway obstruction. Mucolytic therapy based on recombinant human DNase1 reduces CF mucus viscosity and promotes airway clearance. However, the marked susceptibility to actin inhibition of this enzyme prompts the research of alternative treatments that could overcome this limitation. Within the human DNase repertoire, DNase1L2 is ideally suited for this purpose because it exhibits metal-dependent endonuclease activity on plasmid DNA in a broad range of pH with acidic optimum and is minimally inhibited by actin. When tested on CF artificial mucus enriched with actin, submicromolar concentrations of DNase1L2 reduces mucus viscosity by 50% in a few seconds. Inspection of superimposed model structures of DNase1 and DNase1L2 highlights differences at the actin-binding interface that justify the increased resistance of DNase1L2 toward actin inhibition. Furthermore, a PEGylated form of the enzyme with preserved enzymatic activity was obtained, showing interesting results in terms of activity. This work represents an effort toward the exploitation of natural DNase variants as promising alternatives to DNase1 for the treatment of CF lung disease.

Dr Danila Delfino is in the Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy.

Jamie DuckersBeth LesherTeja ThoratEleanor LucasLisa J McGarryKeval ChandaranaFosca De Iorio. Real-World Outcomes of Ivacaftor Treatment in People with Cystic Fibrosis: A Systematic Review. J Clin Med 2021 Apr 6;10(7):1527.doi: 10.3390/jcm10071527. free PMC article [Pubmed]        

      Jamie Duckers

Cystic fibrosis (CF) is a rare, progressive, multi-organ genetic disease. Ivacaftor, a small-molecule CF transmembrane conductance regulator modulator, was the first medication to treat the underlying cause of CF. Since its approval, real-world clinical experience on the use of ivacaftor has been documented in large registries and smaller studies. Here, we systematically review data from real-world observational studies of ivacaftor treatment in people with CF (pwCF). Searches of MEDLINE and Embase identified 368 publications reporting real-world studies that enrolled six or more pwCF treated with ivacaftor published between January 2012 and September 2019. Overall, 75 publications providing data from 57 unique studies met inclusion criteria and were reviewed. Studies reporting within-group change for pwCF treated with ivacaftor consistently showed improvements in lung function, nutritional parameters, and patient-reported respiratory and sino-nasal symptoms. Benefits were evident as early as 1 month following ivacaftor initiation and were sustained over long-term follow-up. Decreases in pulmonary exacerbations, Pseudomonas aeruginosa prevalence, and healthcare resource utilization also were reported for up to 66 months following ivacaftor initiation. In studies comparing ivacaftor treatment to modulator untreated comparator groups, clinical benefits similarly were reported as were decreases in mortality, organ-transplantation, and CF-related complications. The safety profile of ivacaftor observed in these real-world studies was consistent with the well-established safety profile based on clinical trial data.

Our systematic review of real-world studies shows ivacaftor treatment in pwCF results in highly consistent and sustained clinical benefit in both pulmonary and non-pulmonary outcomes across various geographies, study designs, patient characteristics, and follow-up durations, confirming and expanding upon evidence from clinical trials.

Dr Jamie Duckers is a consultant in the All Wales Adult Cystic Fibrosis Centre University Hospital Llandough Cardiff

Marie E EganEmerging technologies for cystic fibrosis transmembrane conductance regulator restoration in all people with CFPediatr Pulmonol 2021 Feb;56 Suppl 1:S32-S39.doi: 10.1002/ppul.24965.  [Pubmed]

    Marie Egan

Although effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has the potential to change the lives of many patients with cystic fibrosis (CF), it is unlikely that these drugs will be a game changing therapy for all. There are about 10% of patients with CF who don’t produce a mutant protein tomodulate, potentiate, or optimize and for these patients such therapies are unlikely to be of significant benefit. There is a need to develop new therapeutic approaches that can work for this patient population and can advance CF therapies. These new therapies will be genetic-based therapies and each approach will result in functional CFTR protein inpreviously affected CF cells. In this review we will examine the potential of RNA therapies, gene transfer therapies, and gene editing therapies for the treatment of CF as well as the challenges that will need to be faced as we harness the power of these emerging therapies towards a one-time cure.

Marie Egan is Professor of Pediatrics and of Cellular and Molecular Physiology: Director, Cystic Fibrosis Center; Vice Chair for Research Department of Pediatrics, Yale School of Medicine.

Patrick A FlumeElena AmelinaCori L DainesBrett Charlton, Joanna LeadbetterAlessandro Guasconi Moira L Aitken. Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study.  J Cyst Fibros 2021 Mar 11;S1569-1993(21)00046-1.doi: 10.1016/j.jcf.2021.02.011.Online ahead of print. [Pubmed]Free article

Patrick Flume

Background: Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol’s efficacy and safety in adults.
Methods: This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV1) 40-90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV1 averaged over the 26-week treatment period.
Results: Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV1 averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV1averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively.

Conclusions: In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV1) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353.

Dr Patrick Flume is at the Medical University of South Carolina, Charleston, SC, United States.

– In UK, where inhaled mannitol has been available for some years, the use is very modest. Only 5.9% of patients were taking regular mannitol – most were adult patients over 16 years of age.

Deane J, Fouhy F, Ronan NJ, Daly M, Fleming C, Eustace JA, Shanahan F, Flanagan ET, Dupont L, Harrison MJ, Haworth CS, Floto A, Rea MC, Ross RP, Stanton C, Plant BJ.   A multicentre analysis of Clostridium difficile in persons with Cystic Fibrosisdemonstrates that carriage may be transient and highly variable with respect to strain and level: Cystic Fibrosis and Clostridium difficile. J Infect. 2021 Jan 11:S0163-4453(20)30788-X. doi:10.1016/j.jinf.2020.12.027. Online ahead of print [Pubmed]

          Jennifer Deane

Clostridium difficile has been reported to occur in the gastrointestinal tract of 50% of Cystic Fibrosis (CF) subjects, however, clinical C. difficile infection (CDI) is a rare occurrence in this cohort despite the presence of toxigenic and hypervirulent ribotypes. Here, we present the first longitudinal, multicentre analysis of C. difficile prevalence among adult CF subjects.
Faecal samples were collected from adults with CF (selected based on confirmed Pseudomonas aeruginosa pulmonary colonisation) from Ireland, UK and Belgium as part of the CFMATTERS clinical research trial (grant No.603038) and from non-CF controls. Faecal samples were collected on enrolment, at three monthly intervals, during pulmonary exacerbation and three months post exacerbation. C. difficile was isolated from faecal samples by ethanol shocking followed by culturing on cycloserine cefoxitin egg yolk agar. Isolates were characterised in terms of ribotype, toxin type and antibiotic susceptibility to antibiotics routinely used in the treatment of CDI (metronidazole and vancomycin) and those implicated in induction of CDI (ciprofloxacin and moxifloxacin).
Results: Prevalence of C. difficile among CF subjects in the three sites was similar ranging from 47-50% at baseline, while the healthy control cohort had a carriage rate of 7.1%. Including subjects who were positive for C. difficile at any time point there was a higher carriage rate of 71.4%, 66.7% and 63.2% in Ireland, UK, and Belgium, respectively. Ribotyping of 80 isolates from 45 CF persons, over multiple time points revealed 23 distinct ribotypes with two ribotypes (046 and 078) shared by all centres. The proportion of toxigenic isolates varied across the sites, ranging from 66.7% in Ireland to 52.9% in Belgium and 100% in the UK. Antibiotic susceptibility rates to vancomycin, metronidazole, ciprofloxacin and moxifloxacin was 100%, 97.5%, 1.3% and 63.8%, respectively.
Conclusions: This study demonstrates the highest carriage rate of C. difficile to date in a CF cohort. Longitudinal data shows that C. difficile can be a transient inhabitant of the CF gut, changing both in terms of strain and excretion rates

Jennifer Deane is a PhD researcher at Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland; HRB Clinical Research Facility, University College Cork, Cork, Ireland; School of Microbiology, University College Cork, Cork, Ireland.

Amir Reza DjavidAlison E ThompsonAlexandria L IraceElen GusmanKimberly AltmanEmily A DiMangoClaire L Keating.  Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Advanced Cystic Fibrosis Lung DiseaseAnn Am Thorac Soc. 2021 May 17.doi: 10.1513/AnnalsATS.202102-220RL.Online ahead of print.  [Pubmed]

Claire Keating

No text available at time of writing

Dr Amir Reza Djavid is at Columbia University Vagelos College of Physicians and Surgeons, 12294, New York, New York, United States.

Dr Claire Keating Associate Professor of Medicine at Columbia University Medical Center, Associate Director, Gunnar Esaison Adult Cystic Fibrosis and Lung Center is the corresponding author

Helmut EllemunterMarkus DumkeGratiana Steinkamp. Reference Values Matter: Fewer Patients with Malnutrition using American Compared to more Recent German Growth Charts. J Pediatr Gastroenterol Nutr 2021 Feb 24.doi: 10.1097/MPG.0000000000003095.Online ahead of print. [Pubmed]

Helmut Ellemunter

Reference values are important for patient care as well as for comparisons between different centres or countries. We investigated two anthropometric reference datasets, the US Centers for Disease Control (CDC) growth charts and the German Health Interview and Examination Survey for Children and Adolescents Study (KiGGS) percentiles, which were established in Germany between 2003 and 2006. A smaller proportion of children with cystic fibrosis had decreased z-scores <-2 with CDC (5.0% for weight and 3.0% for height) compared to KiGGS (7.4% for weight and 6.3% for height) values (p<0.0001). Median z-scores were higher using the CDC reference data. Thus, the choice of growth reference is important, may influence clinical management and must be considered when comparing outcomes of different institutions.


Dr Helmut Ellemunter is Assistant  Professor at the Cystic Fibrosis Centre at the Medical University of Innsbruck, Department of Child and Adolescent Health, Paediatrics III, Austria.  STAT-UP Statistical Consulting & Services, Munich, Germany Clinical Research and Medical Scientific Writing, Schwerin, Germany.

Nagehan EmiraliogluDilber Ademhan TuralHayriye Hizarcioglu GulsenYasin Maruf ErgenBeste OzsezenBirce Sunman İncinur Saltık TemizelEbru YalcinDeniz DogruUğur OzcelikNural Kiper  Does cystic fibrosis make susceptible to celiac disease? Eur J Pediatr 2021 Mar 25.doi: 10.1007/s00431-021-04011-4. Online ahead of print. [Pubmed]

Nagehan Emiralioglu

The incidence of CD in 515 patients with CF was 1.4%. The median age at the time of CF diagnosis was 2 months (1-6 months). CD was diagnosed in six patients with poor weight gain, fatty stools, and low z score for BMI and one patient with poor weight gain despite a high protein and calorie diet and pancreatic enzyme replacement. The median age of CD diagnosis was 8 years (2-12 years). Except for one patient who was recently diagnosed, the other six patients gained weight and their accompanying symptoms resolved after starting a gluten-free diet.
Conclusion: CD should be investigated in patients with CF in the presence of inadequate weight and/or height gain or poor control of malabsorption symptoms despite appropriate and adequate nutritional and enzyme replacement treatment.
What is Known: • CFTR dysfunction may be a risk factor for CD, due to increased intestinal permeability and intestinal inflammation, pancreatic exocrine insufficiency that results in higher antigen load and increased antibodies against to nutritional antigens such as anti-gliadin IgA antibodies.
• Although coexistence of CF and CD are rare in the same patient; there is still no consensus on when children with CF should be screened for CD.
What is New: • Physicians should consider the investigation of CD in patients with CF, in the presence of inadequate weight and/or height gain or i control of malabsorption symptoms despite appropriate and adequate nutritional and enzyme replacement treatment
• CFTR dysfunction has been emphasized to develop susceptibility to CD, and patients with CF who have persistent gastrointestinal symptoms despite appropriate and adequate nutritional and enzyme replacement treatment should be screened for CD.

Dr Nagehan Emiralioglu is in the Department of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, Ankara, Turkey

Gunter FlemmingUlrich BaumannRichter NicolasVondran FlorianBurkhard TümmlerAnna-Maria DittrichCarsten MüllerMandy VogelPfister Eva-DoreenSurvival Benefits Following Liver Transplantation – A Matched-Pair Analysis in Pediatric Patients with Cystic FibrosisJ Pediatr Gastroenterol Nutr  2021 Jun 1.doi: 10.1097/MPG.0000000000003194.Online ahead of print.  [Pubmed]
Objectives and study: Cystic fibrosis related liver disease (CFLD) with consecutive cirrhosis is the third most common cause of death in CF patients (3). The aim of this study is to identify the potential long-term benefits of liver transplantation (LTx) in a match-control comparison.
Methods: Retrospective single-center data analysis of all pediatric LTx for CFLD between 1998 and 2014. A control group was selected from the local CF patient registry. Data were collected from case report forms and included clinical and laboratory data, lung function tests, the indication for LTx and details of surgical procedures.
Results: At our institution 23 patients with severe CFLD median age 13.8 years (range 8.7-17.4; 16 boys) underwent LTx between 1998 and 2014. In all patients, normalization of hepatic CF manifestations were achieved after LTx. But obviously there was no significant positive influence on nutritional status. Signs of post-transplant liver steatosis were documented by ultrasound in 17 patients. Liver biopsies after LTx were performed in 19 patients, in 42% (n = 8) of these biopsies a fatty degeneration was observed. 5 patients died after LTx, none because of primary hepatic dysfunction (1 due to post-transplant proliferative disorder, 4 due to infection).Analysis of matched control pairs revealed that liver function, anthropometry, pulmonary function and life expectancy of CFLD patients with LTx are comparable to matched CF peers without CFLD.
Conclusion: Isolated LTx normalizes the hepatic manifestation of CF disease. LTx enables children and adolescents with severe CFLD to have a comparable prognosis in terms of growth, life expectancy and lung function as CF patients without advanced liver involvement. Our data clarifies the long-term perspectives of affected patients.

From the Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany Hospital for Children and Adolescents, University of Leipzig, Germany Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany Pediatric Pneumology, Allergology, and Neonatology, Hannover Medical School, Hannover, Germany

Jonathan A FridellMolly A BozicBenjamin J UlrichAndrew J LutzJohn A Powelson.  Pancreas transplantation for Cystic Fibrosis: A Frequently Missed Opportunity. Clin Transplant. 2021 May 25;e14371.doi: 10.1111/ctr.14371. Online ahead of print.  [Pubmed]

Jonathan Fridell

As patients with CF are living longer, extra-pulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency, and CF related diabetes (CFRD). Both of these can be managed through pancreas transplantation. Pancreas transplantation is usually performed in combination with another organ, most often with a kidney transplant for end-stage diabetic nephropathy. In the CF patient population, the two settings where inclusion of a pancreas transplant should be considered would be in combination with a lung transplant for CF pulmonary disease, or in combination with a liver for CF related liver disease with cirrhosis. This report will discuss this topic in detail, including a review of the literature regarding combinations of lung/pancreas and liver/pancreas transplant.

Jonathan A Fridell  is professor of Surgery in the Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

Luke W GarrattOded BreuerCraig J SchofieldSamantha A McLeanDaniel R LauciricaRabindra TirouvanziamBarry S ClementsAnthony KicicSarath RanganathanStephen M Stick, CF.  Changes in airway inflammation with pseudomonas eradication in early cystic fibrosisJ Cyst Fibros 2021 Jan 15;S1569-1993(20)30947-4.doi: 10.1016/j.jcf.2020.12.015.Online ahead of print.   [Pubmed]

       Luke Garratt

The authors aimed to evaluate how neutrophil elastase (NE) activity changes after P. aeruginosa eradication and influences early disease outcomes. They assessed participants in the AREST CF cohort between 2000 and 2018 who had P. aeruginosa cultured from their routine annual bronchoalveolar lavage (BAL) fluid and who underwent eradication treatment and a post eradication BAL. Factors associated with persistent P. aeruginosa infection, persistent neutrophilic inflammation following eradication and worse structural lung disease one-year post-eradication were evaluated.
Results: Eighty-eight episodes (3 months to 6 years old) of P. aeruginosa infection were studied. Eradication was successful in 84.1% of episodes. Median activity of NE was significantly reduced post-eradication from 9.15 to 3.4 nM (p = 0.008) but persisted in 33 subjects. High post-eradication NE levels were associated with an increased risk for P. aeruginosa infection in the next annual visit (odds ratio=1.7, 95% confidence interval 1.1-2.7, p = 0.014). Post-eradication NE levels (difference, 0.8; 95% confidence interval, 0.1-1.5) and baseline bronchiectasis computed tomography (CT) score (difference, 0.4; 95% confidence interval, 0.1-0.8) were the best predictors of bronchiectasis progression within 1 year (backward stepwise linear regression model, R2= 0.608, P<0.001), independent of eradication.
Conclusion: In children with CF, NE activity may persist following successful P. aeruginosa eradication and is significantly associated with bronchiectasis progression. Evaluating strategies to diminish neutrophilic inflammation is essential for improving long-term outcomes.

Dr Luke W Garratt is an airway cell biologist and biomedical scientist at the Wal-yan Respiratory Research Centre, Telethon Kids Institute, University of Western Australia, Nedlands, Australia.

Panagiotis GiannakourasMenelaos KanakisFilia DiamanteaMaria TzetisChrysanthi KoutsandreaDimitrios PapaconstantinouIlias Georgalas.   Ophthalmologic manifestations of adult patients with cystic fibrosisEur J Ophthalmol 2021 Apr 8;11206721211008780. doi: 10.1177/11206721211008780.Online ahead of print. [Pubmed]
Introduction: Cystic fibrosis (CF) is the most common life-shortening recessive genetic disease in Caucasians, affecting primarily the lungs. The objective of our study was to investigate potential ophthalmologic involvement in adult patients with CF.
Methods: Fifty adult patients with cystic fibrosis and 60 age- and sex-matched controls underwent complete ophthalmologic examination including tear-film Break-Up Time (BUT), Macular Thickness, and peripapillary Retinal Nerve Fiber Layer (pRNFL) thickness measurements using Spectral Domain-OCT.
Results: CF patients had significantly lower nasal-inferior pRNFL thickness (median 82 IQR 67-102 vs 92.5 IQR 82-107, p = 0.005) and lower percentage of normal tear Break-Up Time (56.0% vs 96.7%, p = 0.001) than healthy controls. All CF patients with BUT <10 s were diagnosed with blepharitis at the time of our assessement. The subgroup of patients homozygous for the most common CF mutation, F508del, had lower nasal-inferior pRNFL thickness (p = 0.014) and lower percentage of normal tear Break-Up Time (p = 0.001) compared to the control group. Additional findings, present in the CF group only, were punctuate retinal hemorrhages (four patients), vessel tortuosity (four patients), snail-track degeneration, and retinal tufts (two patients without refractive error). There were no significant differences in visual acuity, refractive errors, gonioscopic findings, or intraocular pressure between the groups.
Conclusions: Our study is, to the best of our knowledge, the largest ophthalmologic study of patients with cystic fibrosis. We found that CF patients had significantly decreased inferior-quadrant peripapillary retinal nerve fiber layer thickness and decreased tear-film break-up time compared to controls. We highlight the importance of careful regular ophthalmologic assessment and follow-up of these patients.

Panagiotis Giannakouras  is in the First Department of Ophthalmology, G. Gennimatas General Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Morgan GreenNatalie R LindgrenAlexander G Henderson Johnathan D Keith Ashley M Oden Susan E Birket.  Ivacaftor partially corrects airway inflammation in a humanized G551D rat. Am J Physiol Lung Cell Mol Physiol. 2021 Apr 7.doi: 10.1152/ajplung.00082.2021.Online ahead of print. [Pubmed]

Morgan Green

Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when CFTR activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy. To test this, we used a humanized-CFTR rat expressing the G551D variant that responds to the CFTR modulator ivacaftor. Markers typically found in the CF lung were assessed, including neutrophil influx, small airway histopathology, and inflammatory cytokine concentration. Young hG551D rats did not express inflammatory cytokines at baseline but did upregulate these in response to inflammatory trigger. As the hG551D rats aged, histopathology worsened, accompanied by neutrophil influx into the airway and increasing concentrations of TNF-α, IL-1α, and IL-6 in the airways. Ivacaftor administration reduced concentrations of these cytokines when administered to the rats at baseline but was less effective in the rats that had also received inflammatory stimulus. Therefore, we conclude that administration of ivacaftor resulted in an incomplete resolution of inflammation when rats received an external trigger, suggesting that CFTR activation may not be enough to resolve inflammation in the lungs of patients with CF.

Dr Morgan Green is in the Department of Medicine, University of Alabama at Birmingham, United States

Claudia GrehnA-M DittrichJ WosniokF HolzS HafkemeyerL NaehrlichC SchwarzRegistry working group of the German CF Registry. Risk factors for cystic fibrosis arthropathy: Data from the German cystic fibrosis registry. J Cyst Fibros 2021 May 22;S1569-1993(21)00130-2.doi: 10.1016/j.jcf.2021.05.003.Online ahead of print. [Pubmed]

 Claudia Grehn

Background: Epidemiology and potential risk factors for cystic fibrosis arthropathy (CFA) were studied in a relevant cystic fibrosis (CF) patient cohort.
Methods: Cohort study of patients included in the German CF registry in 2016-2017. Descriptive analysis, exploratory tests and multivariable logistic regression were used to assess prevalence of CFA and associated potential risk factors for adult patients with/without chronic Pseudomonas aeruginosa infection.
Results: 6069 CF patients aged from 0 to 78 years were analysed. CFA was observed in 4.9% of the patients. Prevalence was significantly higher in adult patients (8.4%) compared to patients <18 years (0.7%; p<0.0001). Logistic regression analyses in adult patients (n=3319) showed that CFA was significantly associated with increasing age (OR=1.04; 95% CI: 1.02-1.05; p<0.0001), female gender (OR=2.10; 95%CI:1.52-2.90; p<0.0001), number of hospitalizations (OR=1.24; 95%CI:1.12-1.36; p<0.0001), chronic P. aeruginosa infection (OR=1.83; 95%CI:1.28-2.61; p=0.0009), CF-related diabetes (OR=1.69; 95%CI:1.23-2.33; p=0.0013), pancreatic insufficiency (OR=2.39; 95%CI:1.28-4.46; p=0.0060) and sinusitis/polyps (OR=1.91; 95%CI:1.39-2.62; p<0.0001). In a subgroup analysis of adults without chronic P. aeruginosa infection (n=1550) CFA was also significantly associated with increasing age, female gender, increasing number of hospitalizations, pancreatic insufficiency as well as sinusitis/polyps; antimycotic treatment associated only in this subgroup while association with CF-related diabetes was not significant.

Conclusion: CFA is a frequent and clinically relevant co-morbidity particularly in adult CF patients. CFA is significantly more common in patients with chronic P. aeruginosa colonization but associations with other indicators for a more severe disease course were identified regardless of P. aeruginosa colonization status.

Dr Claudia Grehn is in the Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité – Universitätsmedizin, Berlin, Germany. Electronic address: claudia.grehn@charite.de.

Jing GuoRong HeZhi-Qin Mao. Case Report: White Colored Stool: An Early Sign of Cystic Fibrosis in Infants. Front Pediatr 2021 Apr 14;9:656584. doi: 10.3389/fped.2021.656584.eCollection 2021.Free PMC article [Pubmed]
A 2-month-old male infant presented with white colored stools 1 month after birth. There was no jaundice of the skin, mucous membrane, or sclera; his liver was enlarged (4 cm below the ribs), and his liver function tests showed slightly elevated total bilirubin (TB), direct bilirubin (DB), and total bile acid (TBA). An abdominal doppler ultrasound showed no signs of biliary atresia. Genetic testing revealed a CFTR hemizygous mutation site (c.223C>T) in exon 3 and exon 2-3 heterozygous deletion mutation. The infant’s stool turned yellow after oral administration of pancreatic tablets. Finally, the infant was diagnosed with cystic fibrosis (CF).

Review of literature revealed five children (including the infant in this case study) with CF who presented with white stool. All five children had anaemia, four had oedema and hypoproteinemia, five had changes in stool colour (it was pistachio-green colour in two patients, pale coloured in one, acholic stool in one, and white stool in one), two had cholestasis, one infant had delayed meconium discharge, and three children had delayed growth and hepatomegaly. Two children had an abnormal sweat test, one had a F508del compound heterozygous mutation, and one had three mutation sites (C.214G>G/A, P.A72T; C.650A>A/G, P.E217G, and C.3406G>G/A, P. A1136T), which was a compound heterozygous mutation.

So, CF could be included in the differential diagnosis of infants with white stool. Genetic testing could confirm an early diagnosis of CF. Pancreatic replacement therapy has been shown to be beneficial for improving the digestive function.

Jing Guo is in the Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.

Anna Engell HolmHans Henrik Lawaetz SchultzHelle Krogh JohansenTania PresslerThomas Kromann LundMartin IversenMichael PerchBacterial Re-Colonization Occurs Early after Lung Transplantation in Cystic Fibrosis Patients, J Clin Med 2021 Mar 19;10(6):1275.doi: 10.3390/jcm10061275. Free PMC article  [Pubmed]

Anna Engell Holm

Most cystic fibrosis (CF) patients referred for lung transplantation are chronically infected with Gram-negative opportunistic pathogens. It is well known that chronic infections in CF patients have a significant impact on lung-function decline and survival before transplantation. The rate and timing of re-colonization after transplantation have been described, but the impact on survival after stratification of bacteria is not well elucidated. We did a single-center retrospective analysis of 99 consecutive CF patients who underwent lung transplantation since the beginning of the Copenhagen Lung Transplant program in 1992 until October 2014. Two patients were excluded due to re-transplantation. From the time of CF diagnosis, patients had monthly sputum cultures. After transplantation, CF-patients had bronchoscopy with bronchoalveolar lavage at 2, 4, 6 and 12 weeks and 6, 12, 18 and 24 months after transplantation, as well as sputum samples if relevant. Selected culture results prior to and after transplantation were stored. We focused on colonization with the most frequent bacteria: Pseudomonas aeruginosa (PA), Stenotrophomonas maltophilia(SM), Achromobacter xylosoxidans (AX) and Burkholderia cepacia complex (BCC). Pulsed-field gel electrophoresis (PFGE) was used to identify clonality of bacterial isolates obtained before and after lung transplantation.

Time to re-colonization was defined as the time from transplantation to the first positive culture with the same species. Seventy-three out of 97 (75%) had sufficient culture data for analyses with a median of 7 (1-91) cultures available before and after transplantation.
Median colonization-free survival time was 23 days until the first positive culture after transplantation. After 2 years, 59 patients (81%) were re-colonized, 33 (48.5%) with PA, 7 (10.3%) with SM, 12 (17.6%) with AX, and 7 (10.3%) with BCC. No difference in survival was observed between the patients colonized within the first 2 years and those not colonized. Re-colonization of bacteria in the lower airways occurred at a median of 23 days after transplantation in our cohort. In our patient cohort, survival was not influenced by re-colonization or bacterial species.

Dr Anna Engell Holm is in the Department of Cardiology, Section for Lung Transplantation, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.

Jordana E HoppeMark ChilversFelix RatjenJohn J McNamaraCaroline A OwenSimon TianRachel ZahigianAlexandra G CornellSusanna A McColley. Long-term safety of lumacaftor-ivacaftor in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study. Lancet Respir Med 2021 May 6;S2213-2600(21)00069-2.doi: 10.1016/S2213-2600(21)00069-2. Online ahead of print. [Pubmed]

Jordana Hoppe

[Background: A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study.
Methods: In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor-ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor-ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg-ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg-ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg-ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor-ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor-ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395.
Findings: This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor-ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 -29·6 mmol/L [95% CI -33·7 to -25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI.
Interpretation: Lumacaftor-ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor-ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutatio

Dr Jordana Hoppe, MD, a pediatric pulmonologist with Children’s Hospital Colorado and assistant professor of pediatrics at the University of Colorado School of Medicine on the Anschutz Medical Campus

Dominic A HughesOlga ArchangelidiMatthew CoatesDarius Armstrong-JamesStuart J ElbornSiobhán B CarrJane C Davies. Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study. J Cyst Fibros 2021 May 3;S1569-1993(21)00117-X.doi: 10.1016/j.jcf.2021.04.007.Online ahead of print. [Pubmed]

     Dominic Hughes

Background: Pseudomonas aeruginosa (Pa) and Aspergillus species (Asp) are the most common bacterial and fungal organisms respectively in CF airways. Our aim was to examine impacts of Asp infection and Pa/Asp co-infection using the UK CF Registry.Full details on PubMed.

Conclusions: Co-infection with Pa and Asp was not associated with reduced lung function compared with Pa alone, but was associated with additional use of IV antibiotics. Asp infection itself is associated with several important indicators of disease severity. Longitudinal analyses should explore the impact of co-infection on disease progression.

Dr Dominic A Hughes is a researcher at the National Heart & Lung Institute, Imperial College London, UK; Royal Brompton and Harefield Hospitals, London, UK

Ajay S KasiChoo Phei WeeThomas G KeensDanieli B SalinasAbnormal Lung Clearance Index in Cystic Fibrosis Children with Normal FEV 1 and Single-Breath Nitrogen Washout TestLung 2021 Jan 3.doi: 10.1007/s00408-020-00412-8. Online ahead of print. [Pubmed]

Ajay S Kasi

Single- and multiple-breath washout tests (SBW and MBW) measure ventilation inhomogeneity, but the relationship between them is unclear.
Forty-three subjects with cystic fibrosis (CF) and healthy controls (HC) 8-21 years of age were recruited (CF = 30 and HC = 13) and performed nitrogen MBW, vital capacity SBW, spirometry, and plethysmography. Mean phase III slope from SBW (SIII) and lung clearance index (LCI) were significantly different between CF and HC (p = 0.017 and p < 0.0001, respectively). Based on Pearson correlation, SIII and LCI showed strong correlation (ρ = 0.81, p < 0.0001). Both SIII and LCI significantly correlated with spirometry (all p < 0.05). Among CF subjects with normal FEV1 (≥ 80%; n = 17), 76% (n = 13) had normal SIII but abnormal LCI.
We conclude that LCI can be abnormal despite normal SIII and FEV1 in CF children. Although LCI and SIII showed strong correlation, our results suggest that LCI is a better test to detect ventilation inhomogeneity in CF children with normal FEV1.

Dr Ajay S Kasi is in the Division of Pediatric Pulmonology, Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Duncan E KeeganJohn J Brewington. Nasal Epithelial Cell-Based Models for Individualized Study in Cystic FibrosisInt J Mol Sci 2021 Apr 24;22(9):4448.doi: 10.3390/ijms22094448. Free article [Pubmed]
The emergence of highly effective CFTR modulator therapy has led to significant improvements in health care for most patients with cystic fibrosis (CF). For some, however, these therapies remain inaccessible due to the rarity of their individual CFTR variants, or due to a lack of biologic activity of the available therapies for certain variants. One proposed method of addressing this gap is the use of primary human cell-based models, which allow preclinical therapeutic testing and physiologic assessment of relevant tissue at the individual level. Nasal cells represent one such tissue source and have emerged as a powerful model for individual disease study. The ex vivo culture of nasal cells has evolved over time, and modern nasal cell models are beginning to be utilized to predict patient outcomes. This review will discuss both historical and current state-of-the art use of nasal cells for study in CF, with a particular focus on the use of such models to inform personalized patient care.

Dr Duncan E Keegan is a Pulmonary Fellow in the Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center USA.and the Department of Pediatrics, University of Cincinnati College of Medicine.

Dr John Brewington is a pediatric pulmonologist at Cincinnati-Children’s-Hospital-Medical-Center with an interest in CF and other airway disorders.

Carmen Ribes Koninckx Ester Donat Marc A BenningaIlse J BroekaertFrederic Gottrand, et al.  The Use of Fecal Calprotectin Testing in Paediatric Disorders: A Position Paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee.  J Pediatr Gastroenterol Nutr 2021 Apr 1;72(4):617-640.doi: 10.1097/MPG.0000000000003046. [Pubmed]

Carmen Ribes Koninckx

Objectives: The aim of the study was to review the evidence regarding the clinical use and value of fecal calprotectin (FC) measurements in different gastrointestinal disorders in children.
Methods: A literature search was conducted in the PubMed, MEDLINE, EMBASE, and Cochrane databases until October 31, 2019. Subtopics were identified and each assigned to individual authors.
Results: A total of 28 recommendations were voted on using the nominal voting technique. Recommendations are given related to sampling, measurement methods, and results interpretation. The 14 authors anonymously voted on each recommendation using a 9-point scale (1 strongly disagree to 9 fully agree). Consensus was considered achieved if at least 75% of the authors voted 6, 7, 8, or 9.

Conclusions: Consensus was reached for all recommendations. Limitations for the use of FC in clinical practice include variability in extraction methodology, performance of test kits as well as the need to establish local reference ranges because of the influence of individual factors, such as age, diet, microbiota, and drugs. The main utility of FC measurement at present is in the diagnosis and monitoring of inflammatory bowel disease (IBD) as well as to differentiate it from functional gastrointestinal disorders (FAPDs). FC, however, has neither utility in the diagnosis of infantile colic nor to differentiate between functional and organic constipation. A rise in FC concentration, may alert to the risk of developing necrotizing enterocolitis and help identifying gastrointestinal involvement in children with Henoch-Schönlein purpura. FC measurement is of little value in Cow’s Milk Protein Allergy, coeliac disease (CD), and cystic fibrosis. FC does neither help to distinguish bacterial from viral acute gastroenteritis (AGE), nor to diagnose Helicobacter Pylori infection, small intestinal bacterial overgrowth (SIBO), acute appendicitis (AA), or intestinal polyps.

Dr Carmen Ribes Koninckx is head of the Department of Paediatric Gastroenterology, Hepatology and Nutrition, La Fe University Hospital Valencia, Spain.

– A useful summary of the situations in which estimation of fecal calprotectin may be of use and this appears to be mainly for monitoring of inflammatory bowel disease and differentiating IBD from functional bowel disorders.

Michael W KonstanDavid J PastaDonald R VanDevanterJeffrey S WagenerWayne J MorganScientific Advisory Group and the Investigators and Coordinators of ESCF.  Epidemiologic Study of Cystic Fibrosis: 25 years of observational research. Pediatr Pulmonol 2021 May;56(5):823-836.doi: 10.1002/ppul.25248.Epub 2021 Jan 12. [Pubmed}

Michael Konstan

The Epidemiologic Study of Cystic Fibrosis (ESCF) was a prospective observational study of over 32,000 people with cystic fibrosis (CF) from 250 clinical care sites in North America from 1994 to 2005. Begun as a pharmacovigilance study in connection with the approval of dornase alfa in 1993, ESCF was open to all people with CF treated at any participating site in the United States or Canada. In addition to obtaining safety and effectiveness data on dornase alfa, ESCF collected encounter-based data to characterize the natural history and management of CF with a special focus on lung disease. During the study, 32,178 patients reported at least one encounter, contributing 869,136 encounters, 622,592 pulmonary function tests, 432,896 cultures, and 118,563 pulmonary exacerbations treated with intravenous antibiotics. Although ESCF data collection concluded in 2005, through a collaboration with the U.S. Cystic Fibrosis Foundation Patient Registry, additional follow-up data through 2017 was available for two-thirds of patients. This allowed for updating of CF genotype and survival information. Fifty-six peer-reviewed publications (cited over 3600 times) resulted from this study. In this manuscript we summarize the published ESCF manuscripts in thematic groups with key study findings and brief comments, and speculate on how ESCF findings will inform future data registries and patient care practices.

Dr Michael W Konstan at the Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA and the UH Rainbow Children’s Hospital, Cleveland , Ohio..

Jochen G MainzChristin ArnoldKara WittstockUta-Christina HiplerThomas LehmannCarlos ZagoyaFranziska DucksteinHelmut EllemunterJulia Hentschel.   Ivacaftor Reduces Inflammatory Mediators in Upper Airway Lining Fluid From Cystic Fibrosis Patients With a G551D Mutation: Serial Non-Invasive Home-Based Collection of Upper Airway Lining FluidFront Immunol 2021 May 5;12:642180.doi: 10.3389/fimmu.2021.642180. eCollection 2021.   Free PMC article [Pubmed]

       Jochen Mainz

In cystic fibrosis (CF) therapy, the recent approval of CF-transmembrane conductance regulator (CFTR) channel modulators is considered to be the major breakthrough. However, the current first-line approach based mainly on pulmonary function to measure effects of the novel therapy, tested by forced expiratory volumes in one second (FEV1), provides restricted sensitivity to detect early structural damages. Accordingly, there is a need for new sensitive surrogate parameters. Most interestingly, these should quantify inflammation that precedes a decline of pulmonary function.
We present a novel method assessing inflammatory markers in the upper airways’ epithelial lining fluid (ELF) obtained by nasal lavage (NL). In contrast to broncho-alveolar lavage, ELF sampling by NL is an attractive method due to its limited invasiveness which allows repeated analyses, even performed in a home-based setting. In a longitudinal cohort study (ClinicalTrials.gov, Identifier: NCT02311140), we assessed changes of inflammatory mediators in 259 serially obtained nasal lavages taken up to every second day before and during therapy with ivacaftor from ten CF patients carrying a G551D mutation. Patients were trained to sample NL-fluid at home, to immediately freeze and transfer chilled secretions to centers. Neutrophil Elastase, Interleukins IL-1β, IL-6 and IL-8 in NL were quantified. During 8-12 weeks of ivacaftor-treatment, median values of IL-1β and IL-6 significantly declined 2.29-fold (2.97→1.30 pg/mL), and 1.13-fold (6.48→5.72 pg/mL), respectively. In parallel, sweat tests and pulmonary function improved considerably.

This is the first study assessing changes of airway inflammation on a day-to-day basis in CF patients receiving a newly administered CFTR-modulator therapy. It proves a decline of airway inflammation during ivacaftor-therapy.

Dr Jochen G Mainz is Professor at the Cystic Fibrosis Center, Brandenburg Medical School (MHB) University, Klinikum Westbrandenburg, Brandenburg an der Havel,, the CF-Center, Jena University Hospital, Jena and the Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus -Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Cottbus, Brandenburg an der Havel and Potsdam, Germany.

Ida MartinelliAlessandro CiavarellaMaria AbbattistaStefano AlibertiValentina De ZanChristian FolliMauro Panigada  Andrea Gori Andrea ArtoniAnna Maria IerardiGianpaolo Carrafiello  Valter MonzaniGiacomo Grasselli  Francesco Blasi Flora PeyvandiIncreasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19. Intern Emerg Med 2021 Jan 3. doi: 10.1007/s11739-020-02585-9. Online ahead of print. [Pubmed]

Ida Martinelli

We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleedi

Ida Martinelli  is at the A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy

Matthew P Moore Iain L LamontDavid WilliamsSteve PatersonIrena Kukavica-IbruljNicholas P Tucker et al.   Transmission, adaptation and geographical spread of the Pseudomonas aeruginosa Liverpool epidemic strain. Microb Genom 2021 Mar 15.doi: 10.1099/mgen.0.000511. Online ahead of print.[Pubmed] Free article
The Liverpool epidemic strain (LES) is an important transmissible clonal lineage of Pseudomonas aeruginosa that chronically infects the lungs of people with cystic fibrosis (CF). Previous studies have focused on the genomics of the LES in a limited number of isolates, mostly from one CF centre in the UK, and from studies highlighting identification of the LES in Canada.
Here we significantly extend the current LES genome database by genome sequencing 91 isolates from multiple CF centres across the UK, and we describe the comparative genomics of this large collection of LES isolates from the UK and Canada. Phylogenetic analysis revealed that the 145 LES genomes analysed formed a distinct clonal lineage when compared with the wider P. aeruginosa population. Notably, the isolates formed two clades (a group of organisms believed to comprise all the evolutionary descendants of a common ancestor) : one associated with isolates from Canada, and the other associated with UK isolates.
Further analysis of the UK LES isolates revealed clustering by clinic geography. Where isolates clustered closely together, the association was often supported by clinical data linking isolates or patients. When compared with the earliest known isolate, LESB58 (from 1988), many UK LES isolates shared common loss-of-function mutations, such as in genes gltR and fleR. Other loss-of-function mutations identified in previous studies as common adaptations during CF chronic lung infections were also identified in multiple LES isolates. Analysis of the LES accessory genome (including genomic islands and prophages) revealed variations in the carriage of large genomic regions, with some evidence for shared genomic island/prophage complement according to clinic location. Our study reveals divergence and adaptation during the spread of the LES, within the UK and between continents.

Dr Matthew Moore’s present address is Nuffield Department of Health, University of Oxford, UK. Also Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.

Zumi MehtaKhalid M KamalRichard MillerJordan R CovveyVincent GiannettiAdherence to cystic fibrosis transmembrane conductance regulator (CFTR) modulators: analysis of a national specialty pharmacy database, J Drug Assess. 2021 Apr 5;10(1):62-67.doi: 10.1080/21556660.2021.1912352. Free PMC article   [Pubmed]                                 

            Zumi Mehta

Objective: To calculate the medication adherence in patients taking CFTR modulators using a national specialty pharmacy database.
Methods: This retrospective observational cohort study utilized de-identified specialty pharmacy data from September 2017 to August 2018 to assess medication adherence for three CFTR modulators: ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor & ivacaftor. The primary outcome was proportion of days covered (PDC) for each medication, with mean PDC values compared across age groups and insurance characteristics. All analyses were performed using the SAS 9.4 University Edition (SAS Institute, Cary, NC).
Results: A total of 2,548 patients were analyzed, including 1,289 (50.59%) patients on lumacaftor/ivacaftor, 784 (30.77%) on ivacaftor, and 475 (18.64%) on tezacaftor/ivacaftor & ivacaftor. The mean PDC value for all CFTR modulators was above 0.80. Tezacaftor/ivacaftor & ivacaftor had the highest overall PDC of 0.92, while PDC values for both lumacaftor/ivacaftor and ivacaftor were 0.84. Children/adolescents on lumacaftor/ivacaftor (p = 0.0001) and tezacaftor/ivacaftor & ivacaftor (p = 0.001) had significantly higher mean PDC values compared to adults but not for ivacaftor (p = 0.3744). No statistical differences were seen in PDC across insurance characteristics.
Conclusion: To the best of our knowledge, this is the first study to assess the adherence of three CFTR modulators using a large nationwide specialty database. With high acquisition costs of CFTR modulator therapies, there is a need to improve rates of adherence in patients with  CF

Dr Zumi Mehta is graduate student in the Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA.

Joseph MoryousefJustin KwongTeruko KishibeMichael Ordon. Systematic Review of the Prevalence of Kidney Stones in Cystic Fibrosis. J Endourol 2021 Apr 28. doi: 10.1089/end.2021.0151. Online ahead of print.[Pubmed]

Joseph Moryousef

A study to investigate the prevalence of urolithiasis in cystic fibrosis (CF) and to summarize the available clinical features within this unique population. [for full details please see PubMed abstract)
The overall prevalence of stone formation in the CF population was 4.6% (137/2,982). The mean age of diagnosis was 25.1 ± 9.6 and ranged from 0.25 – 47. Ultrasound was the most common imaging modality for kidney stone diagnosis. There was no apparent sex difference, with a female to male ratio of 1:1. Surgical intervention was required in 37.8% (34/90) of cases. Stone recurrence was reported in 42.9% (33/77) of stone formers

Mr Joseph Moryousef  of McGill University, Montreal, Quebec, Ca

Beth L LaubeKathryn A CarsonChristopher M Evans, Melis A Aksit Joseph M CollacoVanessa L RichardsonGail Sharpless, Pamela L ZeitlinGarry R CuttingPeter J Mogayzel. Characterizing mucociliary clearance in young children with cystic fibrosis. Pediatr Res 2021 Mar 22.doi: 10.1038/s41390-021-01453-2. Online ahead of print. [Pubmed]

Beth L Laube

Background: This research characterized mucociliary clearance (MCC) in young children with cystic fibrosis
Methods: Fourteen children (5-7 years old) with CF underwent: two baseline MCC measurements (Visits 1 and 2); one MCC measurement approximately 1 year later (Visit 3); and measurements of lungTwo shirts as well clearance index (LCI), a measure of ventilation inhomogeneity.
Results: Median (range) percent MCC through 60 min (MCC60) was similar on Visits 1 and 2 with 11.0 (0.9-33.7) and 12.8 (2.7-26.8), respectively (p = 0.95), and reproducible (Spearman Rho = 0.69; p = 0.007). Mucociliary clearance did not change significantly over 1 year with median percent MCC60 on Visit 3 [12.8 (3.7-17.6)] similar to Visit 2 (p = 0.58). Lower percent MCC60 on Visit 3 was significantly associated with higher LCI scores on Visit 3 (N = 14; Spearman Rho = -0.56; p = 0.04).
Conclusions: Tests of MCC were reproducible and reliable over a 2-week period and stable over a 1-year period in 5-7-year-old children with CF. Lower MCC values were associated with increased ventilation inhomogeneity. These results suggest that measurements of MCC could be used in short-term clinical trials of interventions designed to modulate MCC and as a new, non-invasive test to evaluate early lung pathology in children with CF.
Impact: This is the first study to characterize mucociliary clearance (MCC) in children with cystic fibrosis (CF) who were 5-7 years old. Measurements of mucociliary clearance were reproducible and reliable over a 2-week period and stable over a 1-year period. Variability in MCC between children was associated with differences in ventilation homogeneity, such that children with lower MCC values had increased ventilation inhomogeneity.
These results suggest that measurements of MCC could be used in short-term clinical trials of interventions designed to modulate MCC and as a new, non-invasive test to evaluate early lung pathology in children with CF.

Dr Beth L Laube is a professor of pediatrics in the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. She is an aerosol scientist.

Thomas W LaudoneLauren GarnerCharissa W Kam Charles R Esther Jr Cameron J McKinzie.  Novel therapies for treatment of resistant and refractory nontuberculous mycobacterial infections in patients with cystic fibrosis. Pediatr Pulmonol 2021 Feb;56 Suppl 1:S55-S68.doi: 10.1002/ppul.24939.[Pubmed]

Respiratory infections caused by non-tuberculous mycobacteria (NTM) are a major cause of morbidity for patients living with cystic fibrosis (CF), as NTM pulmonary disease (NTM-PD) is challenging to both diagnose and eradicate. Despite the lengthy courses of the established regimens recommended by the Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) consensus guidelines, only about 50% to 60% of patients achieve culture conversion, and treatment regimens are often complicated by antibiotic resistance and toxicities. Since publication of the CFF/ECFS guidelines, several new or alternative antibiotic regimens have been described for patients with CF who have NTM-PD. These regimens offer new options for patients who do not clear NTM with standard therapies or cannot utilize the usual regimens due to toxicities or drug-drug interactions.

Thomas W Laudone is Pediatric Clinical Pharmacy Specialist at the University of Maryland Medical Center

Michael A LensinkSarah N BoersVincent A M GulmansKarin R JongsmaAnnelien L Bredenoord.  Mini-gut feelings: perspectives of people with cystic fibrosis on the ethics and governance of organoid biobanking.  Per Med 2021 Apr 7.doi: 10.2217/pme-2020-0161. Online ahead of print. [Pubmed]
Aim: Organoid technology has enormous potential for precision medicine, such as has recently been demonstrated in the field of cystic fibrosis. However, storage and use of organoids has been associated with ethical challenges and there is currently a lack of harmony in regulation and guidelines to govern the rapid emergence of ‘organoid medicine’. Developing sound governance demands incorporation of the perspectives of patients as key stakeholders.
Materials & methods: We conducted 17 semi-structured interviews with people with cystic fibrosis to explore their perspectives on the ethics and governance of organoid biobanking.
Results: We identified three themes: prioritization of research and trust, ambivalent views on commercial involvement and transparency and control.
Conclusion: Our study offers important insights for ethically robust governance of ‘organoid medicine’.

Plain Language Summary
Lay abstract Organoids are living tissues that can be grown in a lab out of stem cells, which can replicate some features of actual organs in the body. They can be used to study diseases or develop drugs, but also to test the effectiveness of therapy for a specific patient (which is called precision medicine). Organoid technology is promising for the treatment of cystic fibrosis. At the same, storing and using organoids raises ethical and practical challenges. In order to ensure that the interests of those who provide the cells are respected, we interviewed people with cystic fibrosis. Their motivation to participate in organoid research was high, but at the same time they wanted to know how their organoids are used. In addition, while they did not feel the need to be directly involved in decisions about how their tissue is used, they valued ongoing communication from biobanks about its activities.

Dr Michael A Lensink is at the Julius Center for Health Sciences & Primary Care, Department of Medical Humanities, University Medical Center Utrecht,

Kelsey LeonhardtElizabeth B AutryRobert J KuhnMark A Wurth CFTR modulator drug desensitization: preserving the hope of long term improvement. Pediatr Pulmonol. 2021 Apr 29.doi: 10.1002/ppul.25437. Online ahead of print. [Pubmed]

Kelsey Leonhardt

The development of modulator therapy has, for the first time, allowed direct targeting of the underlying cause of cystic fibrosis (CF), the cystic fibrosis transmembrane conductance regulator (CFTR). Patients treated with CFTR modulators have improvement in lung function and decreased rates of pulmonary exacerbations. In 2019, elexacaftor/tezacaftor/ivacaftor was approved for use in the United States, opening these therapies to 90% of patients with CF.

Intolerable adverse drug reactions (ADRs) to CFTR modulators results in discontinuation of therapy, which can be devastating to our patients. We describe our approach to two cases, not previously reported, of rash to elexacaftor/tezacaftor/ivacaftor in patients with a previous history of cutaneous adverse reactions to dual modulator therapy that had been addressed by desensitization. Case 1 was able to tolerate elexacaftor/tezacaftor/ivacaftor after desensitization to the triple combination therapy, while in case 2 tolerance was obtained by treating through the reaction. The loss of tolerance in these patients was unexpected, and may be a common finding in patients with history of cutaneous adverse reactions to these drugs. We hope reporting our experience, including our desensitization protocol, may benefit CF patients for whom these drug reactions may be limiting access to powerful disease altering therapies.

Dr Kelsey Leonhardt in Clinical Pharmacist in the Department of Pharmacy Services, University of Kentucky HealthCare, Lexington, Kentucky.

 Marco L LeungSallie McAdoo Deborah Watson Kallyn Stumm Margaret Harr Xiang Wang Christine H ChungFernanda MafraAddie I NesbittHakon HakonarsonAvni Santani  A Transparent Approach to Calculate Detection Rate and Residual Risk for Carrier Screening.   J Mol Diagn 2021 Jan;23(1):91-102. doi: 10.1016/j.jmoldx.2020.10.009.   

           Marco L Leung

Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis of the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature
As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these da

Marco L Leung at the Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania;

Barry Linnane Aaron M WalshCalum J WalshFiona CrispieOrla O’SullivanPaul D CotterMichael McDermottJulie RenwickPaul McNally.  The Lung Microbiome in Young Children with Cystic Fibrosis: A Prospective Cohort Study. Microorganisms 2021 Feb 26;9(3):492.doi: 10.3390/microorganisms9030492. Free article        [Pubmed]

 Julie Renwick

          Barry Linnane

The objective of this study was to thoroughly characterise the lower airway microbiome in pre-school children with CF. Bronchoalveolar lavage (BAL) samples were collected annually from children attending the three clinical centres. Clinical and demographic data were collated on all subjects alongside BAL inflammatory markers.  Data on 292 sequenced BALs from 101 children with CF and 51 without CF show the CF lung microbiome, while broadly similar to that in non-CF children, is distinct. Alpha diversity between the two cohorts was indistinguishable at this early age. The CF diagnosis explained only 1.1% of the variation between the cohort microbiomes.

However, several key genera were significantly differentially abundant between the groups. While the non-CF lung microbiome diversity increased with age, diversity reduced in CF with age. Pseudomonas and Staphylococcus were more abundant with age, while genera such as Streptococcus, Porphyromonas and Veillonella were less abundant with age.

There was a negative correlation between alpha diversity and interleukin-8 and neutrophil elastase in the CF population. Neither current flucloxacillin or azithromycin prophylaxis, nor previous oral or IV antibiotic exposure, was correlated with microbiome diversity. Consecutive annual BAL samples over 5 years from a subgroup of children demonstrated diverse patterns of development in the first years of life.

 Dr Barry Linnane is at the Centre for Interventions in Infection, Inflammation and Immunity (4i) and Graduate Entry Medical School, University of Limerick, Limerick V94 T9PX, Ireland.

Corresponding author is Dr Julie Renwick, Assistant Professor of Clinical Microbiology, School of Medicine, Trinity College, Dublin. She cofounded the Airway Microbiome in Cystic Fibrosis project

– There is a detailed full version available. There are no definite suggestions as to the practical implications of the findings

Anna-May LongIan H JonesMarian KnightJanet McNallyBAPS-CASS Early management of meconium ileus in infants with cystic fibrosis: A prospective population cohort studyJ Pediatr Surg 2021 Feb 24;S0022-3468(21)00181-0.doi: 10.1016/j.jpedsurg.2021.02.047.Online ahead of print. [Pubmed]

            Anna-May Long

Background: Contemporary early outcome data of meconium Ileus (MI) in cystic fibrosis (CF) are lacking on a population level. We describe these and explore factors associated with successful non-operative management.
Methods: A prospective population-cohort study using an established surveillance system (BAPS-CASS) was conducted October 2012-September 2014. Live-born infants with bowel-obstruction from inspissated meconium in the terminal ileum and CF were reported. Data are described as median (interquartile range, IQR).
Results: 56 infants were identified. 14/56(25%) had primary laparotomy (13/23 complicated MI, 1/33 simple), the remainder underwent contrast enema. Twelve, (12/33 (36%) with simple MI) achieved decompression. 8/12 (67%) who decompressed had >1 enema vs 3/20 (15%) with simple MI who had laparotomy after enema. The number of enemas per infant (1-4), contrast agents and their concentration, were highly variable. Enterostomy was formed at 24/44(55%) of laparotomies. In infants with simple MI, time to full enteral feeds was 6 (2-10) days in those decompressing with enema vs 15 (9-19) days with laparotomy after enema. Case fatality was 4% (95% CI 0.4-12%). Two infants, both preterm died, both in the second month after birth.
Conclusions: Infants with simple MI achieving successful enema decompression were more likely to have had repeat enemas than those who proceeded to laparotomy. Successful non-operative management was associated with a shorter time to full feeds. The early management of infants with MI is highly variable and not standardised across the UK and Ireland.

Miss Anna-May Long is a paediatric surgeon in the Department of Paediatric Surgery, Cambridge University Hospitals, Cambridge, United Kingdom; she is taking three years off her surgical training to work at  the National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford

Christophe MarguetVéronique HoudouinIsabelle PinPhilippe Reix  Frédéric HuetMarie MittaineSophie Ramel et al.   Chest physiotherapy enhances detection of Pseudomonas aeruginosa in nonexpectorating children with cystic fibrosis.  ERJ Open Res. 2021 Mar 8;7(1):00513-2020.doi: 10.1183/23120541.00513-2020.eCollection 2021 Jan. Free PMC article   [Pubmed]

Christophe Marguet

This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzaeStaphylococcus aureus and P. aeruginosagrowth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 

300 non-expectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. 

The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in non-expectorating children with CF.

Professor  Christophe Marguet is at the CF Centre, Dept of Paediatrics and Adolescent Medicine, University Hospital Charles Nicolle, CIC INSERM 1404, EA 2656, Rouen University, Rouen, France.

Laura I Marquez Loza Ashley L CooneyQian DongChristoph O RandakStefano RivellaPatrick L SinnPaul B McCray Jr.  Increased CFTR expression and function from an optimized lentiviral vector for cystic fibrosis gene therapy.  Mol Ther Methods Clin Dev 2021 Feb 27;21:94-106.doi: 10.1016/j.omtm.2021.02.020.eCollection 2021 Jun 11. Free PMC article [Pubmed]

Paul B McCray

Laura Marquez Loza

Despite significant advances in cystic fibrosis (CF) treatments, a one-time treatment for this life-shortening disease remains elusive. Stable complementation of the disease-causing mutation with a normal copy of the CF transmembrane conductance regulator (CFTR) gene fulfills that goal. Integrating lentiviral vectors are well suited for this purpose, but widespread airway transduction in humans is limited by achievable titers and delivery barriers. Since airway epithelial cells are interconnected through gap junctions, small numbers of cells expressing supraphysiologic levels of CFTR could support sufficient channel function to rescue CF phenotypes.
Here, we investigated promoter choice and CFTR codon optimization (coCFTR) as strategies to regulate CFTRexpression. We evaluated two promoters-phosphoglycerate kinase (PGK) and elongation factor 1-α (EF1α)-that have been safely used in clinical trials. We also compared the wild-type human CFTRsequence to three alternative coCFTR sequences generated by different algorithms. With the use of the CFTR-mediated anion current in primary human CF airway epithelia to quantify channel expression and function, we determined that EF1α produced greater currents than PGK and identified a coCFTR sequence that conferred significantly increased functional CFTR expression. Optimized promoter and CFTR sequences advance lentiviral vectors toward CF gene therapy clinical trials.

Dr Laura I Marquez Loza is at the Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA 52242, USA and the Pappajohn Biomedical Institute and the Center for Gene Therapy, The University of Iowa, Iowa City, IA 52242, USA

 Dr Paul b McCray is Professor of Pediatrics – Pulmonary Medicine and Professor of Microbiology and Immunology

Martin Y NgHong LiMikel D GhelfiYale E GoldmanBarry S CoopermanAtaluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms.   Proc Natl Acad Sci U S A  2021 Jan 12;118(2):e2020599118.doi: 10.1073/pnas.2020599118.  Free article   [Pubmed]

During protein synthesis, nonsense mutations, resulting in premature stop codons (PSCs), produce truncated, inactive protein products. Such defective gene products give rise to many diseases, including cystic fibrosis, Duchenne muscular dystrophy (DMD), and some cancers.
Small molecule nonsense suppressors, known as TRIDs (translational read-through-inducing drugs), stimulate stop codon read-through. The best characterized TRIDs are ataluren, which has been approved by the European Medicines Agency for the treatment of DMD, and G418, a structurally dissimilar aminoglycoside. Previously, we applied a highly purified in vitro eukaryotic translation system to demonstrate that both aminoglycosides like G418 and more hydrophobic molecules like ataluren stimulate read-through by direct interaction with the cell’s protein synthesis machinery.

Our results suggested that they might do so by different mechanisms. Here, we pursue this suggestion through a more-detailed investigation of ataluren and G418 effects on read-through. We find that ataluren stimulation of read-through derives exclusively from its ability to inhibit release factor activity. In contrast, G418 increases functional near-cognate tRNA mispairing with a PSC, resulting from binding to its tight site on the ribosome, with little if any effect on release factor activity. The low toxicity of ataluren suggests that development of new TRIDs exclusively directed toward inhibiting termination should be a priority in combatting PSC diseases. Our results also provide rate measurements of some of the elementary steps during the eukaryotic translation elongation cycle, allowing us to determine how these rates are modified when cognate tRNA is replaced by near cognate tRNA ± TRIDs.

Martin Y Ng is at the Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104.

J Abram McBride Taylor P Kohn Daniel J Mazur Larry I Lipshultz , R Matthew Cowar.  Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis disease versus congenital bilateral absence of the vas deferens.  Asian J Androl  Mar-Apr 2021;23(2):140-145.doi: 10.4103/aja.aja_48_20. Free article   [Pubmed]

J Abram McBride

Authors sought to compare gene alterations, sperm retrieval rates, and intracytoplasmic sperm injection (ICSI) outcomes among men with cystic fibrosis (CF) disease and congenital bilateral absence of the vas deferens (CBAVD) only. Those men CF demonstrated lower sperm quality, greater difficulty with sperm retrieval, and worse ICSI outcomes compared with CBAVD-only patients. Homozygous delta F508 CFTR mutations appear to significantly impair spermatogenesis and sperm function.     (More details in Pubmed abstract and in Free article)

Dr J Abram McBride is at the Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA

Pedro Mondéjar-LópezAlexander HorsleyFelix RatjenSilvia Bertolo,  Helene de VicenteÒscar Asensio de la Cruz.  A multimodal approach to detect and monitor early lung disease in cystic fibrosis. Expert Rev Respir Med. 2021 Apr 12;1-12.doi: 10.1080/17476348.2021.1908131.Online ahead of print.[Pubmed]

Pedro Mondejar-López

Introduction: In the early stages, lung involvement in cystic fibrosis (CF) can be silent, with disease progression occurring in the absence of clinical symptoms. Irreversible airway damage is present in the early stages of disease; however, reliable biomarkers of early damage due to inflammation and infection that are universally applicable in day-to-day patient management have yet to be identified.
Areas covered: At present, the main methods of detecting and monitoring early lung disease in CF are the lung clearance index (LCI), computed tomography (CT), and magnetic resonance imaging (MRI). LCI can be used to detect patients who may require more intense monitoring, identify exacerbations, and monitor responses to new interventions. High-resolution CT detects structural alterations in the lungs of CF patients with the best resolution of current imaging techniques. MRI is a radiation-free imaging alternative that provides both morphological and functional information. The role of MRI for short-term follow-up and pulmonary exacerbations is currently being investigated.
Expert opinion: The roles of LCI and MRI are expected to expand considerably over the next few years. Meanwhile, closer collaboration between pulmonology and radiology specialties is an important goal toward improving care and optimizing outcomes in young patients with CF.

Dr Pedro Mondéjar-López is Pediatric Pulmonologist at the Pediatric Pulmonology and Cystic Fibrosis Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain.

Renee N NgAnna S TaiBarbara J ChangStephen M StickAnthony Kicic    Overcoming Challenges to Make Bacteriophage Therapy Standard Clinical Treatment Practice for Cystic Fibrosis. Front Microbiol 2021 Jan 11;11:593988.doi: 10.3389/fmicb.2020.593988.eCollection 2020. Free PMC article   [Pubmed]

        Renee N Ng

Individuals with cystic fibrosis (CF) are given antimicrobials as prophylaxis against bacterial lung infection, which contributes to the growing emergence of multidrug resistant (MDR) pathogens isolated. Pathogens such as Pseudomonas aeruginosa that are commonly isolated from individuals with CF are armed with an arsenal of protective and virulence mechanisms, complicating eradication and treatment strategies. While translation of phage therapy into standard care for CF has been explored, challenges such as the lack of an appropriate animal model demonstrating safety in vivo exist. In this review, we have discussed and provided some insights in the use of primary airway epithelial cells to represent the mucoenvironment of the CF lungs to demonstrate safety and efficacy of phage therapy. The combination of phage therapy and antimicrobials is gaining attention and has the potential to delay the onset of MDR infections. It is evident that efforts to translate phage therapy into standard clinical practice have gained traction in the past 5 years. Ultimately, collaboration, transparency in data publications and standardized policies are needed for clinical translation.

Renee N Ng is a PhD Candidate at the School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia

Anne H NeerincxKatrine WhitesonJoann L PhanPaul BrinkmanMahmoud I Abdel-AzizEls J M WeersinkJosje AltenburgChristof J MajoorAnke H Maitland-van der ZeeLieuwe D J Bos.  Lumacaftor/ivacaftor changes the lung microbiome and metabolome in cystic fibrosis patients. ERJ Open Res 2021 Apr 19;7(2):00731-2020.doi: 10.1183/23120541.00731-2020.eCollection 2021 Apr.  Free PMC article [Pubmed]      (please see PubMed abstract for more detail)

Anne Neerincx

Targeted cystic fibrosis (CF) therapy with lumacaftor/ivacaftor partly restores chloride channel function and improves epithelial fluid transport in the airways. Consequently, changes may occur in the microbiome, which is adapted to CF lungs
A study to investigate the effects of lumacaftor/ivacaftor on respiratory microbial composition and microbial metabolic activity by repeatedly sampling the lower respiratory tract.
Findings – After starting CF transmembrane conductance regulator (CFTR) modulating treatment in CF patients with a homozygous Phe508del mutation, a temporary and moderate change in the lung microbiome is observed, which is mainly characterised by a reduction in the relative abundance of Pseudomonas aeruginosa.

Dr  Anne H Neerincx is a Postdoctoral Researcher in the Dept of Respiratory Medicine, Amsterdam UMC – Location AMC, University of Amsterdam, Amsterdam, the Netherlands.

Samuel T Olatunbosun. Chronic incretin-based therapy in cystic fibrosis-related diabetes: A tale of 3 patients treated with sitagliptin for over 5 years. J Cyst Fibros. 2021 Mar 2;S1569-1993(21)00040-0.doi: 10.1016/j.jcf.2021.02.005. Online ahead of print. [Pubmed]

Samuel T Olatunbosun

Cystic fibrosis-related diabetes (CFRD) affects 40-50% of adult patients with cystic fibrosis. Insulin therapy is recommended but there are therapeutic challenges, particularly risk of hypoglycemia and aversion of some patients to injectables. An oral incretin-based therapy using a DPP-4i (dipeptidyl peptidase-4 inhibitor), may be a reasonable option, especially in the early stage of the disease. The effect of chronic incretin-based therapy on CFRD is unknown. Here is a report of 3 cases of CFRD patients treated with sitagliptin and the response to therapy over a period of 5-10 years. An effective glycemic control was demonstrated in all the patients, at least during the first 5 years of sitagliptin treatment, and the benefit persisted for a decade in two of them. The secondary failure of the DPP-4i occurred in a CFRD patient with a phenotype resembling type 2 diabetes. A DPP-4i may have an important role in the management of CFRD

Dr Samuel T Olatunbosun. Uniformed Services, University of the Health Sciences & Department of Endocrinology, David Grant Medical Center, California

– Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. It is taken by mouth. It is also available in the fixed-dose combination medication sitagliptin/metformin (Janumet, Janumet XR).

Kate M O’Shea Orla M O’CarrollCatherine CarrollBrenda GroganAnna ConnollyLynda O’ShaughnessyTrevor T NicholsonCharles G GallagherEdward F McKone.   Efficacy of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung diseaseEur Respir J. 2021 Feb 25;57(2):2003079.doi: 10.1183/13993003.03079-2020. Print 2021 Feb. [Pubmed]

Kate O’Shea

No abstract but the following abstract form the article – This study shows that ELX/TEZ/IVA improves multiple outcome measures in a small cohort of 14 patients with advanced CF lung disease attending a single centre and that these improvements are similar to those seen in patients with milder disease.
Follow-up measurement dates varied with mean repeat FEV1 at 26.4±4.2 days, mean BMI at 62±35 days and mean SwCl at 64±84 days after ELX/TEZ/IVA initiation. After treatment with ELX/TEX/IVA, FEV1 improved (27.3±7.3% pred versus 36.3±16.5% pred; p<0.0001). BMI also improved (20.7±3.6 versus 22.1±3.4 kg·m−2; p<0.0001). Sweat chloride results were only available for 11 patients, mainly due to insufficient sweat volume despite multiple attempts, but also revealed significant improvement (104.9±15.04 versus 53.6±23.3 mmol·L−1; p<0.0001). Infective exacerbations requiring hospitalisation reduced in frequency (0.28±0.17 exacerbations per month in 12 months prior versus 0.04±0.07 exacerbations per month during follow-up period of 4.9 months; p<0.001)
Most significant were the reduction in requirement for intravenous antibiotic therapy as well as improvements in lung function and sweat chloride. These results were seen in both patients exposed to previous modulator therapies and in those who were CFTR modulator-naïve. There were few significant adverse events. This therapy is expected to improve the disease trajectory for many CF patients with at least one Phe508del mutation and this expectation should also apply to those groups with more advanced disease.

 Kate M O’Shea is studying at the School of Medicine University College Dublin

Dr Orla M O’Carroll is a Respiratory Specialist Registrar in the Department of Respiratory medicine St Vincent’s University Hospital, Dublin

Molly R PayneAnne-Bine SkytteJoyce C Harper The use of expanded carrier screening of gamete donorsHum Reprod. 2021 Apr 11;deab067.doi: 10.1093/humrep/deab067. Online ahead of print. [Pubmed]

Molly Payne

Study question: What are the sperm and egg donor rejection rates after expanded carrier screening (ECS)?
Summary answer: Using an ECS panel looking at 46/47 genes, 17.6% of donors were rejected.
What is known already: The use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available.
Study design, size, duration: A review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS.
Participants/materials, setting, methods: Data on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data.
Main results and the role of chance: A total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155).
Limitations, reasons for caution: Panel information was found on company websites and may not have been accurate.
Wider implications of the findings: This study highlights the need for consistent EU regulations and guidelines that allow genetic matching of gamete donors to their recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial; however, this would not be viable without matching of donors and recipients.

Molly Payne is Genetic Technologist at Royal Devon and Exeter NHS Trust   Exeter, England,

Thomas Planté-BordeneuveSilvia Berardis Pierre BastinDamien GrusonLaurence HenriSophie Gohy  Vitamin D intoxication in patients with cystic fibrosis: report of a single-center cohort.. Sci Rep 2021 Apr 8;11(1):7719. doi: 10.1038/s41598-021-87099-w. [Pubmed]

Thomas Plante-Bordeneuve

Vitamin D toxicity is associated with accidental overdoses due to manufacturing or intake errors and its secondary hypercalcemia can result in severe morbidity. Although patients with cystic fibrosis are potentially at increased risk for this intoxication as prescription of vitamin D preparations is a common practice in this population, the frequency of such events is currently unknown. We performed a retrospective analysis of all the files of cystic fibrosis patients followed at the Cliniques universitaires Saint-Luc over a 10-year period, recording 25(OH)- and 1,25(OH)2vitamin D levels as well as demographic data, lung function tests, Pseudomonas aeruginosa infection and results from pharmacological analysis of magistral liposoluble vitamins preparations. A total of 244 patients were included in the study. 13 patients (5%) had serum vitamin D levels corresponding to vitamin D overdose. Patients who had experienced an overdose were more likely to be F508del homozygous or suffer from exocrine pancreatic insufficiency. 2 patients developed significant hypercalcemia necessitating monitoring and hospitalization. Errors in the preparation of magistral liposoluble vitamin pills were identified in several intoxicated patients. Retrospective assessment of the dosing errors with the local pharmacists showed that trituration and dosing errors were their most frequent causes

Dr Thomas Planté-Bordeneuve is in the Department of Pneumology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.

– Valuable study for although the literature on vitamin D and CF is now vast little attention has been given to overdosing which appears to be no rarity according the the experience reported here.

Mordechai PollakMichelle ShawDavid WilsonMelinda SolomonFelix RatjenHartmut Grasemann.   Bronchodilator responsiveness in cystic fibrosis children treated for pulmonary exacerbations. Pediatr Pulmonol 2021 Apr 8.doi: 10.1002/ppul.25409. Online ahead of print.[Pubmed]
Background: Cystic fibrosis (CF) pulmonary exacerbations (PEx) are associated with a significant drop in pulmonary function. The clinical value of measuring bronchodilator (BD) responsiveness during treatment for PEx to monitor or predict recovery of lung function is unclear.
Methods: A retrospective analysis of spirometry with BD response testing obtained during hospital admissions for PEx in pediatric CF patients. Repeated events were included for patients with BD testing during multiple admissions.
Results: Two hundred forty-nine spirometries with BD testing in 102 patients were completed around Day 7 (Days 4-10) of hospital admission for treatment of CF PEx. Median (IQR) forced expiratory volume in 1 s (FEV1 ) was 70.6% predicted (58.1, 84.6) before the PEx event (best FEV1in 6 months before admission), 54.4% (41.5, 66.9) at admission, 62.3% (48.4, 74.7) around Day 7 of admission and 67.1% predicted (53.8, 78.2) at the end of treatment. BD response around Day 7 correlated poorly with FEV1 before PEx (r = -.16, p = .02) and did not correlate with recovery to baseline FEV1 at end of treatment (r = .08, p = .22). Only 23/249 (9%) individual tests had a BD response in FEV1 of ≥12% and 200 ml. BD response was not related to age or severity of lung disease and led to an immediate change in clinical management in only four cases.
Conclusions: Significant BD response in CF patients treated for PEx is rare, shows poor correlation with baseline pulmonary function and does not correlate with the recovery of FEV1 with treatment. These data suggest that routine testing for BD response is not indicated during PEx.

Dr Mordechai Pollak  is in the Division of Respiratory Medicine, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

Bernadette J Prentice Adam JaffeShihab HameedCharles F VergeShafagh WatersJohn Widger  Cystic fibrosis-related diabetes and lung disease: an update. Eur Respir Rev. 2021 Feb 16;30(159):200293.doi: 10.1183/16000617.0293-2020.Print 2021 Mar 31.    Free article  [Pubmed]

Bernadette Prentice

The development of cystic fibrosis-related diabetes (CFRD) often leads to poorer outcomes in patients with cystic fibrosis including increases in pulmonary exacerbations, poorer lung function and early mortality. This review highlights the many factors contributing to the clinical decline seen in patients diagnosed with CFRD, highlighting the important role of nutrition, the direct effect of hyperglycaemia on the lungs, the immunomodulatory effects of high glucose levels and the potential role of genetic modifiers in CFRD.

Bernadette J Prentice is a Paediatric Respiratory Physician at the Dept of Respiratory Medicine, Sydney Children’s Hospital, and School of Women’s and Children’s Health, University of New South Wales, Sydney, Randwick, Australia.

– A clear detailed fully referenced excellent review of the present situation regarding CF related diabetes by a respiratory paediatrician and her colleagues. The full article is recommended.

Freerk PrenzelUta CeglarekInes AdamsJutta HammermannUlrike IssaGerhild LohseJochen G Mainz Jochen MeisterDana SpittelKarin ThossMandy VogelFranziska Duckstein Constance HennJulia Hentschel.  Audit of sweat chloride testing reveals analytical error.  Clin Chem Lab Med 2021 Apr 7.doi: 10.1515/cclm-2020-1661. Online ahead of print. [Pubmed]
Objectives: Sweat chloride testing (SCT) is the mainstay for the diagnosis of cystic fibrosis (CF) and biomarker in the evaluation of CFTR-modifying drugs. To be a reliable and valid tool, analytical variance (CVA) must be minimized. However, external quality assessments have revealed significant deviations in routine clinical practice. Our goal was to identify and quantify technical errors through proficiency testing and simulations.
Methods: Chloride concentrations of three blinded samples (each as triplicates) were measured in 9 CF centers using a chloridometer in a routine setting. Technical errors were simulated and quantified in a series of measurements. We compared imprecision and bias before and after a counseling session by evaluating coefficients of variation (CV), adherence to tolerance limits, and inter-rater variability coefficients.
Results: Pipetting errors resulting in changes in sample volume were identified as the main source of error with deviations up to 41%. After the counseling session, the overall CVA decreased from 7.6 to 5.2%, the pass rate increased from 67 to 92%, and the inter-rater variability diminished. Significant deviations continued to be observed in individual centers.

Conclusions: Prevention of technical errors in SCT decreases imprecision and bias. Quality assurance programs must be established in all CF centers, including staff training, standard operating procedures, and proficiency testing.

Dr Freerk Prenzel is in the Department of Pediatrics, University of Leipzig Medical Center, Leipzig, Germany.

– A very relevant study as the effect on the sweat electrolytes of the new modulator drugs is one important factor in judging their effect.

Florence RacineAzadeh ShohoudiValérie BoudreauCécile Q T NguyenMarie-Hélène DenisKatherine DesjardinsQuitterie ReynaudRémi Rabasa-LhoretGeneviève Mailhot.  Glycated Hemoglobin as a First-line Screening Test for Cystic Fibrosis‒Related Diabetes and Impaired Glucose Tolerance in Children With Cystic Fibrosis: A Validation StudyCan J Diabetes 2021 Mar 26;S1499-2671(21)00079-4.doi: 10.1016/j.jcjd.2021.03.005.Online ahead of print.[Pubmed]

Genevieve Mailhot

Florence Racine

Objectives: Our aims in this study were to document the screening rate for cystic fibrosis‒related diabetes (CFRD) in children followed at a cystic fibrosis (CF) clinic in Canada and to evaluate the accuracy of various glycated hemoglobin (A1C) cutoffs to screen for CFRD and impaired glucose tolerance (IGT) in a pediatric CF population.
Methods: The CFRD screening rate was calculated over a follow-up period of up to 8 years among children who attended the CF clinic between 1993 and 2018. Test performance of A1C at various thresholds ranging from 5.5% to 6.2% was compared with the oral glucose tolerance test (OGTT) as the reference method. Children with CF aged ≥10 years with an OGTT performed within 120 days of A1C measurement were included in the analysis.
Results: The overall CFRD screening rate was 53.0%. A total of 256 children were included for the A1C performance analysis, of whom 8.6% had an OGTT-confirmed CFRD diagnosis. An A1C threshold of 5.8% demonstrated an optimal balance between sensitivity (90.9%) and specificity (60.7%) for CFRD screening, leading to a potential reduction of 56.3% of the annual required OGTTs. A1C demonstrated poor accuracy for identifying children with IGT.
Conclusions: An A1C threshold ≥5.8% allows for identification of children requiring further CFRD investigations, which may reduce the clinical burden of children with CF without compromising the ability of early CFRD diagnosis.

Dr Florence Racine is at the Montreal Clinical Research Institute, Montréal, Québec, Canada; Research Centre, CHU Sainte-Justine, Montréal, Québec, Canada; Department of Nutrition, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada

Dr Genevieve Mailhot is Associate Professor Department of Nutrition, University of Montreal

Anabela S Ramalho Eva Fürstová Annelotte M Vonk Marc FerranteCatherine VerfaillieLieven Dupont Mieke Boon Marijke Proesmans Jeffrey M Beekman, Ifat SaroukCarlos Vazquez CorderoFrancois VermeulenKris De Boeck Belgian Organoid ProjectCorrection of CFTR function in intestinal organoids to guide treatment of cystic fibrosisEur Respir J 2021 Jan 5;57(1):1902426.doi: 10.1183/13993003.02426-2019. Print 2021 Jan.  [Pubmed]

     Anabela Ramalho

Given the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF). To study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data.
Intestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature.
Across 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit.
Measurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.

Dr Anabela Santo Ramalho is in Dept of Development and Regeneration, Woman and Child Unit, CF Research Lab, KU Leuven, Leuven, Belgium.

Scott D Sagel Umer Khan Sonya L Heltshe John P Clancy Drucy BorowitzDaniel GelfondScott H DonaldsonAntoinette MoranFelix RatjenJill M VanDalfsenSteven M RoweClinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical TrialAnn Am Thorac Soc 2021 Jan;18(1):75-83.doi: 10.1513/AnnalsATS.202002-144OC. [Pubmed]

         Scott Segal

To evaluate the effectiveness of LUM/IVA in children (6 yr or more) and adults (more than 18 yr) in a postapproval setting.  A total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV1) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV1 was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m2P < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3; P < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and Pseudomonas aeruginosa infection status with treatment.
Conclusions: In this real-world multicentre cohort of children and adults, LUM/IVA treatment was associated with significant improvements in growth and reductions in sweat chloride without statistically significant or clinically meaningful changes in lung function, hospitalization rates, or P. aeruginosa infection. (NCT02477319).

Dr Scott D Sagel is Professor Pediatrics and Pulmonary Medicine at the Department of Pediatrics, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Afsoon SepahzadDeborah J Morris-Rosendahl, JaneDavies.  Cystic Fibrosis Lung Disease Modifiers and Their Relevance in the New Era of Precision Medicine.   Genes (Basel) 2021 Apr 13;12(4):562.doi: 10.3390/genes12040562. Free PMC article[Pubmed]
Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTRthat are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies.

This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.

Dr Afsoon Sepahzad is in the Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield Hospitals, London SW3 6NP, UK.

Meghana N SatheDhiren PatelArchie StoneEric First  Evaluation of the Effectiveness of In-line Immobilized Lipase Cartridge in Enterally Fed Patients With Cystic Fibrosis. J Pediatr Gastroenterol Nutr  2021 Jan 1;72(1):18-23.doi: 10.1097/MPG.0000000000002984.  [Pubmed]

Meghana Sathe

An immobilized lipase cartridge (ILC) for extracorporeal digestion of enteral feedings was developed. The sponsor provided it to patients via a structured program, which we evaluated to assess the effectiveness of the ILC on nutritional status.
Inclusion criteria were met by 100 patients (age = 0–45 years). Over 12 months of use in patients >2 years of age (n = 93), there were significant improvements seen in height and weight z-scores with improvement trend seen in BMI. The frequency of achieving the 50th percentile increased steadily for weight and BMI from baseline to 12 months but not for height.
Conclusions: This evaluation of a program to assist patient access to ILC demonstrates that better growth is possible over standard of care. The association of ILC use with significant improvements in anthropometric parameters over a 12-month period in people with CF demonstrates the effectiveness of ILC as rational enzyme therapy during enteral feediA total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV1) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV1 was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m2P < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3; P < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and Pseudomonas aeruginosa infection status with treatm

Dr Meghana N Sathe is a paediatric gastroenterologist at the University of Texas Southwestern and Children’s Health Dallas, Dallas, TX.

Daniela K SchlüterJosh S OstrengaSiobhán B Carr Aliza K FinkAlbert FaroRhonda D SzczesniakRuth H KeoghSusan C CharmanBruce C MarshallChristopher H GossDavid Taylor-Robinson. Lung function in children with cystic fibrosis in the USA and UK: a comparative longitudinal analysis of national registry data. Thorax 2021 May 11;thoraxjnl-2021-216849. doi: 10.1136/thoraxjnl-2021-216849.Online ahead of print.  [Pubmed]

Daniela Schlüter

Rationale: A previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results.
Conclusions: Children with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.

Daniela K Schlüter is a lecturer in Public Health Data Science in the Department of Public Health, Policy and Systems, University of Liverpool, Liverpool, UK

Zhuqing ShiJun WeiRong NaW Kyle ResurreccionS Lilly ZhengPeter J HulickBrian T Helfand Mark S Talamonti Jianfeng XuCystic fibrosis F508del carriers and cancer risk: Results from the UK BiobankInt J Cancer. 2021 Apr 1;148(7):1658-1664.doi: 10.1002/ijc.33431. Epub 2020 Dec 18. [Pubmed]

        Zhuqing Shi

A recent study reported associations of CF carriers with risk for cancers of digestive organs and pancreatic cancer. In the current study, we assessed associations of CFTR F508del carriers with the risk for 54 types of cancers in the UK Biobank, a large population-based study.
In Caucasians, compared to the carrier rate of 3.15% (12 357/392274) in noncancer subjects, the rate was significantly higher in cancer patients overall (2621/79619 = 3.29%), especially in patients with colorectal cancer (247/6667 = 3.70%), cancers of gallbladder and biliary tract (21/351 = 5.98%), thyroid cancer (30/665 = 4.51%) and unspecified non-Hodgkin’s lymphoma (74/1805 = 4.10%), all P ≤ .05. In contrast, the carrier rate in patients with cancers of lung and bronchus was significantly lower (89/3463 = 2.57%), P = .05.
The association of CFTR F508del carriers with these types of cancer remained significant after adjusting for respective cancer-specific risk factors. For pancreatic cancer, although a higher carrier rate (38/1004 = 3.78%) was found in patients with this cancer, the difference was not statistically significant (P = .26). This null association was unlikely due to lack of statistical power; the large sample size of our study had >80% power, at a significance level of .05, to detect an association of >1.5-fold increased ri

In conclusion, the identified associations of CFTR F508del carriers with multiple types of cancer may have potential biological and clinical implications if confirmed in independent study populations.

Dr Zhuqing Shi is with the Program for Personalized Cancer Care, NorthShore University Health System, Evanston, Illinois, USA.

Olaf Sommerburg Susanne Hämmerling S Philipp SchneiderJürgen OkunClaus-Dieter LanghansPatricia Leutz-SchmidtMark O WielpützWerner SiemsSimon Y GräberMarcus A MallMirjam Stahl.  CFTR Modulator Therapy with Lumacaftor/Ivacaftor Alters Plasma Concentrations of Lipid-Soluble Vitamins A and E in Patients with Cystic Fibrosis. Antioxidants (Basel) 2021 Mar 19;10(3):483.doi: 10.3390/antiox10030483.    Free PMC article [Pubmed]

Olaf Sommerburg

Previous studies showed that CFTR modulator therapy with lumacaftor-ivacaftor (LUM/IVA) in Phe508del-homozygous patients with CF results in improvement of pulmonary disease and thriving. However, the effects of LUM/IVA on plasma concentration of the lipid soluble vitamins A and E remain unknown.
Methods: Data from annual follow-up examinations of patients with CF were obtained to assess clinical outcomes including pulmonary function status, body mass index (BMI), and clinical chemistry as well as fat-soluble vitamins in Phe508del-homozygous CF patients before initiation and during LUM/IVA therapy.
Results: Patients with CF receiving LUM/IVA improved substantially, including improvement in pulmonary inflammation, associated with a decrease in blood immunoglobulin G (IgG) from 9.4 to 8.2 g/L after two years (p < 0.001). During the same time, plasma vitamin A increased significantly from 1.2 to 1.6 µmol/L (p < 0.05), however, levels above the upper limit of normal were not detected in any of the patients. In contrast, plasma vitamin E as vitamin E/cholesterol ratio decreased moderately over the same time from 6.2 to 5.5 µmol/L (p < 0.01).
Conclusions: CFTR modulator therapy with LUM/IVA alters concentrations of vitamins A and vitamin E in plasma. The increase of vitamin A must be monitored critically to avoid hypervitaminosis A in patients with CF.

Dr Olaf Sommerburg is head of the Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Member of the German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg (TLRC), 69120 Heidelberg, Germany.

Giulia SpoletiniKim Pollard Ruth WatsonMichael J DarbyAnnette JohnstoneChristine EtheringtonPaul WhitakerIan J CliftonDaniel G PeckhamNoninvasive Ventilation in Cystic Fibrosis: Clinical Indications and Outcomes in a Large UK Adult Cystic Fibrosis Center. Respir Care  2021 Mar;66(3):466-474.doi: 10.4187/respcare.07862. Epub 2020 Sep 8. [Pubmed]

Giulia Spoletini

Background: Noninvasive ventilation (NIV) is routinely used to treat patients with cystic fibrosis and respiratory failure. However, evidence on its use is limited, with no data on its role in disease progression and outcomes. The aim of this study was to assess the indications of NIV use and to describe the outcomes associated with NIV in adults with cystic fibrosis in a large adult tertiary center.
Methods: A retrospective analysis of data captured prospectively on the unit electronic patient records was performed. All patients with cystic fibrosis who received NIV over a 10-y period were included in the study. A priori, 2 groups were identified based on length of follow-up, with 2 subgroups identified based on duration of NIV treatment.
Results: NIV was initiated on 64 occasions. The duration of follow-up was categorized as > 6 months or < 6 months in 31 (48.4%) and 33 (51.6%) occasions, respectively. The most common indications for starting NIV were chronic (48.5%) and acute (32.8%) hypercapnic respiratory failure. Among those with a follow-up > 6 months, subjects who stopped using NIV early showed a steady median (interquartile range) decline in FEV1 (pre-NIV: -0.04 [-0.35 to 0.03] L/y vs post-NIV: -0.07 [-0.35 to 0.01] L/y, P = .51), while among those who continued using it had an improvement in the rate of decline (pre-NIV: -0.25 [-0.52 to -0.02] L/y vs post-NIV: -0.07 [-0.13 to 0.16] L/y, P = .006). No differences in intravenous antibiotic requirement or pulmonary exacerbations were noted with the use of NIV. Pneumothorax and massive hemoptysis occurred independently in 4 cases.
Conclusions: NIV is being used in cystic fibrosis as adjunct therapy for the management of advanced lung disease in a similar fashion to other chronic respiratory conditions. Adherence to NIV treatment can stabilize lung function but does not reduce pulmonary exacerbations or intravenous antibiotic requirement.

Dr Giulia Spoletini Consultant in Respiratory and Adult CF Medicine at the Leeds Regional Adult Cystic Fibrosis Centre, St James’s University Hospital, Leeds Teaching Hospital NHS Trust and the Leeds Institute of Medical Research, University of Leeds, Leeds, UK.

Julian StashowerPatrick CarrVirginia MillerBarrett ZlotoffNovel reaction to new cystic fibrosis medication TrikaftaClin Case Rep 2021 May 4;9(5):e04116.doi: 10.1002/ccr3.4116.eCollection 2021 May.  [Pubmed]      Free PMC article

Legs of patient

Julian Stashower

The authors describe a novel case of an urticaria multiforme-type drug reaction to the new cystic fibrosis medication Trikafta (elexacaftor + tezacaftor + ivacaftor). Equipped with this information, clinicians may be more prepared to counsel and treat patients if they experience similar symptoms after beginning Trikafta.

Dr Julian Stashower is at the University of  Virginia School of Medicine, Charlottesville USA

Anne L StephensonKathleen J RamosJenna SykesXiayi Ma Sanja Stanojevic Bradley S Quon Bruce C Marshall Kristofer Petren Joshua S Ostrenga Aliza K Fink Albert Faro Alexander Elbert Cecilia Chaparro Christopher H Goss.    Bridging the survival gap in cystic fibrosis: An investigation of lung transplant outcomes in Canada and the United States. J Heart Lung Transplant. 2021 Mar;40(3):201-209.doi: 10.1016/j.healun.2020.12.001.Epub 2020 Dec 7. [Pubmed]

Anne Stephenson

Background: Previous literature in cystic fibrosis (CF) has shown a 10-year survival gap between Canada and the United States (US). We hypothesized that differential access to and survival after lung transplantation may contribute to the observed gap. The objectives of this study were to compare CF transplant outcomes between Canada and the US and estimate the potential contribution of transplantation to the survival gap.
Methods: Data from the Canadian CF Registry and the US Cystic Fibrosis Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. The probability of surviving after transplantation between 2005 and 2016 was calculated using the Kaplan‒Meier method. Survival by insurance status at the time of transplantation and transplant center volume in the US were compared with those in Canada using Cox proportional hazard models. Simulations were used to estimate the contribution of transplantation to the survival gap.
Results: Between 2005 and 2016, there were 2,653 patients in the US and 470 in Canada who underwent lung transplantation for CF. The 1-, 3-, and 5-year survival rates were 88.3%, 71.8%, and 60.3%, respectively, in the US compared with 90.5%, 79.9%, and 69.7%, respectively, in Canada. Patients in the US were also more likely to die on the waitlist (p < 0.01) than patients in Canada. If the proportion of who underwent transplantation and post-transplant survival in the US were to increase to those observed in Canada, we estimate that the survival gap would decrease from 10.8 years to 7.5 years.
Conclusions: Differences in waitlist mortality and post-transplant survival can explain up to a third of the survival gap observed between the US and Canada

Birgitta Strandvik. Is the ENaC Dysregulation in CF an Effect of Protein-Lipid Interaction in the Membranes?  Int J Mol Sci 2021 Mar 8;22(5):2739.doi: 10.3390/ijms22052739.  Free PMC article [Pubmed]

Birgitta Strandvik

While approximately 2000 mutations have been discovered in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), only a small amount (about 10%) is associated with clinical cystic fibrosis (CF) disease. The discovery of the association between CFTR and the hyperactive epithelial sodium channel (ENaC) has raised the question of the influence of ENaC on the clinical CF phenotype. ENaC disturbance contributes to the pathological secretion, and overexpression of one ENaC subunit, the β-unit, can give a CF-like phenotype in mice with normal acting CFTR. The development of ENaC channel modulators is now in progress. Both CFTR and ENaC are located in the cell membrane and are influenced by its lipid configuration. Recent studies have emphasized the importance of the interaction of lipids and these proteins in the membranes. Linoleic acid deficiency is the most prevailing lipid abnormality in CF, and linoleic acid is an important constituent of membranes. The influence on sodium excretion by linoleic acid supplementation indicates that lipid-protein interaction is of importance for the clinical pathophysiology in CF. Further studies of this association can imply a simple clinical adjuvant in CF therapy

Dr Birgitta Strandvik is Professor Emerita at the University of Gothenburg and affiliated researcher at the Department of Biosciences and Nutrition, Karolinska Institutet NEO, 14183 Stockholm, Sweden.  She is author or co-author of  253 (122 on CF) publications, the first in 1968, and she has been a leading figure in paediatric gastroenterology and cystic fibrosis for over fifty years.

Dimitri StylemansChantal DarquenneDaniël SchuermansSylvia VerbanckEef Vanderhelst. Peripheral lung effect of elexacaftor/tezacaftor/ivacaftor in adult cystic fibrosisJ Cyst Fibros 2021 Apr 6;S1569-1993(21)00098-9.doi: 10.1016/j.jcf.2021.03.016.Online ahead of print. [Pubmed]
Despite being an important patient group, adult cystic fibrosis patients with an FEV1 below 40%predicted have been excluded from clinical trials with elexacaftor/tezacaftor/ivacaftor. We conducted a real-life 3 months follow-up study in 14 adult CF patients (median FEV134%predicted) demonstrating significant treatment effects in terms of FEV1 (an increase of 12%predicted at 4 weeks, remaining stable thereafter). Corresponding decreases in lung clearance index LCI (by 31%predicted, down from baseline 247%predicted) and ventilation heterogeneity in the acinar compartment (Sacin) (by 411%predicted, down from baseline 798%predicted) suggest a distinct peripheral lung effect. One patient had intermittent treatment interruptions because of drug-induced liver injury. Our real-life data confirm that treatment with elexacaftor/tezacaftor/ivacaftor is effective in severely obstructive patients, and this is the first study to show time evolution of ventilation distribution improvement, pointing to the peripheral lung as the main site of treatment effect.

Dr Dimitri Stylemans is a pneumonologist in the Respiratory Division, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium

Giovanni TaccettiMichela FrancalanciGiovanna PizzamiglioBarbara MessoreVincenzo CarnovaleGiuseppe CiminoMarco Cipolli.   Cystic Fibrosis: Recent Insights into Inhaled Antibiotic Treatment and Future Perspectives. Antibiotics (Basel) 2021 Mar 22;10(3):338.doi: 10.3390/antibiotics10030338  Free PMC article [Pubmed]

Giovanni Taccetti

Although new inhaled antibiotics have profoundly improved respiratory diseases in cystic fibrosis (CF) patients, lung infections are still the leading cause of death. Inhaled antibiotics, i.e., colistin, tobramycin, aztreonam lysine and levofloxacin, are used as maintenance treatment for CF patients after the development of chronic Pseudomonas aeruginosa (P. aeruginosa) infection. Their use offers advantages over systemic therapy since a relatively high concentration of the drug is delivered directly to the lung, thus, enhancing the pharmacokinetic/pharmacodynamic parameters and decreasing toxicity. Notably, alternating treatment with inhaled antibiotics represents an important strategy for improving patient outcomes. The prevalence of CF patients receiving continuous inhaled antibiotic regimens with different combinations of the anti-P. aeruginosaantibiotic class has been increasing over time. Moreover, these antimicrobial agents are also used for preventing acute pulmonary exacerbations in CF. In this review, the efficacy and safety of the currently available inhaled antibiotics for lung infection treatment in CF patients are discussed, with a particular focus on strategies for eradicating P. aeruginosa and other pathogens. Moreover, the effects of long-term inhaled antibiotic therapy for chronic P. aeruginosa infection and for the prevention of pulmonary exacerbations is reviewed. Finally, how the mucus environment and microbial community richness can influence the efficacy of aerosolized antimicrobial agents is discussed.

Professor Giovanni Taccetti is at the Cystic Fibrosis Center, Anna Meyer Children’s University Hospital, Firenze, Italy

Jennifer L Taylor-CousarR Jain Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation. J Cyst Fibros. 2021 Mar 21;S1569-1993(21)00055-2.doi: 10.1016/j.jcf.2021.03.006.Online ahead of print.  [Pubmed]

Jennifer Taylor-Cousar

There is currently no data in the literature regarding use of Elexacaftor-tezacaftor-ivacaftor (ETI) in pregnant women. Thus, the decision to continue therapy during pregnancy (with the associated unknown fetal impact) versus discontinuing therapy (with the known risk of maternal health decline) is challenging.
Methods: CF Center staff completed an anonymous questionnaire regarding pregnancy and infant outcomes for women who used ETI during pregnancy and/or lactation.
Results: Of 45 ETI-exposed pregnancies reported to date, complications in 2 mothers and in 3 infants (2 born to mothers with poorly controlled diabetes) were rated by clinicians as unknown (possible) or suspected relatedness to ETI use. Two women terminated unplanned pregnancies. Miscarriage rates were consistent with that known in the general U.S.
Population: Five of the six women who discontinued ETI out of concern for unknown foetal risk restarted because of clinical deterioration. No infant cataracts were reported though only two infants were formally evaluated.
Conclusions: In the context of the known increased rate of complications in women with CF and their infants, data from this retrospective survey is reassuring for women who choose to continue ETI during pregnancy. However, a large, multi-centre prospective study is needed to assess impact of use of ETI in pregnancy.

Dr Jennifer L Taylor-Cousar  is in the Departments of Medicine and Pediatrics, National Jewish Health, 1400 Jackson Street; J318, Denver, CO 80206.

– Evidence accumulating that there seems to be no serious consequences of taking ETI during pregnancy.

Teja ThoratLisa J McGarryKrutika Jariwala-ParikhBrendan LimoneMachaon BonafedeKeval ChandaranaMichael W Konstan. Long-Term Impact of Ivacaftor on Healthcare Resource Utilization Among People with Cystic Fibrosis in the United States.  Pulm Ther 2021 Apr 28.doi: 10.1007/s41030-021-00154-9. Online ahead of print.[Pubmed]

    Teja Thorat

Introduction: Ivacaftor was first approved in 2012 for the treatment of a select population of individuals with cystic fibrosis (CF), a rare, life-shortening genetic disease. Reductions in healthcare resource utilization (HCRU) associated with ivacaftor have been observed during limited follow-up and for selected outcomes in real-world studies. This study aimed to further describe the long-term impact of ivacaftor treatment on multiple measures of HCRU among people with CF (pwCF).

Methods: This retrospective study used US commercial and Medicaid claims data from 2011-2018. We included pwCF ≥ 6 years of age with ≥ 1 claim for ivacaftor and 12 months of continuous health plan enrollment before ivacaftor initiation (“pre-ivacaftor” period) who also had 36 months of continuous enrolment and persistent ivacaftor use (i.e., no gap ≥ 90 days between refills) following initiation (“post-ivacaftor” period). We compared comorbidities occurring pre-ivacaftor versus the last 12 months post-ivacaftor. HCRU outcomes included medication use, inpatient admissions, and outpatient office visits. We compared medication use pre-ivacaftor versus the last 12 months post-ivacaftor and inpatient admissions and outpatient office visits pre-ivacaftor versus the post-ivacaftor period annualized across 36 months.

Results: Seventy-nine pwCF met all criteria, including persistent ivacaftor use during the post-ivacaftor period. Ivacaftor treatment was associated with a significant reduction in pneumonia prevalence (10.1% vs. 26.6%; p < 0.001) and significantly fewer mean [SD] antibiotics claims (8.0 [7.3] vs. 12.3 [11.1]; p < 0.001) in the last 12 months post-ivacaftor versus pre-ivacaftor. In comparing the 36-month post-ivacaftor period to the pre-ivacaftor period, we also observed fewer mean [SD] annual inpatient admissions (0.2 [0.4] vs. 0.4 [0.7]), CF-related inpatient admissions (0.1 [0.2] vs. 0.2 [0.5]), and outpatient office visits (8.8 [4.9] vs. 9.9 [5.4]) (all, p < 0.05).

Conclusion: Long-term ivacaftor treatment reduced the health care resource utilisation (HCRU), consistent with trends observed in prior real-world studies. Our results support the sustained, long-term value of ivacaftor treatment in reducing CF burden.

Teja Thorat is a scientist who is Associate Director Health Economics and Outcomes Research at Vertex Pharmaceuticals Incorporated, Boston, MA. USA

Vito TerlizziLaura ClautAntonella ToscoCarla ColomboValeria Raia Benedetta Fabrizzi et al. A survey of the prevalence, management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS/CFSPID) in six Italian centres. J Cyst Fibros 2021 Apr 18;S1569-1993(21)00097-7. doi: 10.1016/j.jcf.2021.03.015.Online ahead of print. [Pubmed]

     Vito Terlizzi

Objective: We evaluated the prevalence, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene profile, clinical data, management and outcome for infants with a CFTR-related metabolic syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) designation from six Italian centres.
Methods: All newborn bloodspot screening (NBS) positive infants born from January 2011 to August 2018 with a CF diagnosis or a CRMS/CFSPID designation were enrolled. Data on sweat testing, genetics, clinical course and management were collected.
Results: We enrolled 257 CF patientsand 336 infants with a CRMS/CFSPID designation (CF: CRMS/CFSPID ratio of 1:1.30).Blood immuno-reactive trypsinogen (IRT) was significantly lower in CRMS/CFSPID infants and the F508del variant accounted for only 20% of alleles. Children with CRMS/CFSPID showed a milder clinical course, pancreatic sufficiency compared to CF infants. Varied practice across centres was identified regarding sweat testing, chest radiograph (8-100%) and salt supplementation (11-90%). Eighteen (5.3%) CRMS/CFSPID infants converted or were reclassified to diagnosis of CF. Four infants (1.3%) developed a clinical feature consistent with a CFTR-related disorder (1.2%). Twenty-seven were re-classified as healthy carriers (8.0%) and 16 as healthy infants (4.8%).
Conclusions: We have identified considerable variability in the evaluation and management of infants with an inconclusive diagnosis following NBS across six Italian centres. CRMS/CFSPID is more regularly seen in this population compared to countries with higher prevalence of F508del.Conversion to a CF diagnosis was recorded in 18 (5.3%) of CRMS/CFSPID infants and in 16 was as a result of increasing sweat chloride concentration.

Dr Vito Terlizzi is at the Cystic Fibrosis Regional Reference Center, Department of Paediatric Medicine, Anna Meyer Children’s University, Florence, Italy.

Christina ThorntonRanjani SomayajiMichael ParkinsMark G SwainKathleen J RamosChristopher H GossAbdel A Shaheen. Characteristics and Outcomes of Children With Cystic Fibrosis Hospitalized With Cirrhosis in the United States.  Am J Gastroenterol 2021 Apr 29.doi: 10.14309/ajg.0000000000001275. Online ahead of print. 33927124

Christina Thornton

A population-based cohort study of hospitalizations among children with CF using the 2016 Kid’s Inpatient Database.    In total, 9,615 admissions were analyzed. Diagnosis of cirrhosis was present in 509 (5.3%) and was significantly associated with increased mortality, length of stay, and hospital charges compared with those without cirrhosis. Hepatic encephalopathy was significantly associated with death in children with cirrhosis.
The authors suggest future interventions should be designed to support children with CF who have cirrhosis to improve clinical outcomes.

Dr Christina Thornton is a Respiratory Fellow at Alberta Health Services

Amanda TraylorDenee DiPilla-GeorgePornchai Tirakitsoontorn. An Unusual Presentation of Chest Pain in a Patient With Cystic Fibrosis: A Case Report.  Pediatr Phys Ther 2021 Apr 1;33(2):E99-E102.doi: 10.1097/PEP.0000000000000790. [Pubmed]
This case report describes the identification and treatment of costochondritis with suspected neural entrapment in a 14-year-old individual diagnosed with cystic fibrosis.   The individual discussed in this report had resolution of his chest pain with additional improvement in pulmonary function test results.
Statement of conclusion and recommendations for clinical practice: This case supports the need for musculoskeletal and neuromuscular screening and intervention for patients with cystic fibrosis. The success of the intervention suggests that when traditional approaches to treatment of costochondritis fail, use of myofascial release at the accessory muscles of breathing could be beneficial.

From the Departments of Rehabilitation (Drs Traylor and DiPilla-George) and Pulmonology (Dr Tirakitsoontorn), CHOC Children’s Hospital of Orange County, Orange, California.

Davide TreggiariGloria TridelloLaura MeninAntonella BorrusoEmily PintaniPatrizia IansaMarco CipolliPaola Melotti.  ROLE OF SWEAT ION RATIOS IN DIAGNOSING CYSTIC FIBROSIS. Pediatr Pulmonol 2021 Apr 6  doi: 10.1002/ppul.25395. Online ahead of print.  [Pubmed

                Davide Treggiari

Sweat chloride (Cl ) concentration is the gold standard for diagnosing cystic fibrosis (CF). This is however, challenging among patients with borderline values. Previous studies have reported that the sweat Cl /Na+ ratio may be useful for diagnosing CF; however, little is known about Cl /K+ and (Cl +Na+ )/K+ ratios. This study aimed to retrospectively define the most appropriate outcome of the sweat test. Samples of sweat were collected using the Gibson and Cooke method. Cl , Na+ , and K+ were further quantified in 2084 participants-1283 CF and 801 non-CF-based on clinical diagnosis. Among those with borderline sweat Cl values (n=502), 34.8% had CF. In the receiver operating characteristic curve analysis, the area under the curve was calculated to evaluate the diagnostic value of the ion ratios. In the overall population, all the ratios significantly discriminated CF from non-CF, whereas in the borderline group, only Cl /Na+ significantly discriminated CF and non-CF subjects, regardless of age.

Dr Davide Treggiari is a postdoctoral researcher at the Centro Fibrosi Cistica, Azienda Ospedaliera Universitaria Integrata, Piazzale A. Stefani, 1-37126, Verona, Italy.

Sarah J Ullrich Mollie Freedman-WeissSamantha AhleHanna K MandlAlexandra S Piotrowski-DaspitKatherine RobertsNicholas YungNathan MaasselTory Bauer-Pisani Adele S Ricciardi  Marie E EganPeter M Glazer W Mark Saltzman David H Stitelman Nanoparticles for delivery of agents to fetal lungs. Acta Biomater. 2021 Mar 15;123:346-353.doi: 10.1016/j.actbio.2021.01.024. Epub 2021 Jan 21. Full text available    [Pubmed]

     Sarah Ullrich

Fetal treatment of congenital lung disease, such as cystic fibrosis, surfactant protein syndromes, and congenital diaphragmatic hernia, has been made possible by improvements in prenatal diagnostic and interventional technology. Delivery of therapeutic agents to fetal lungs in nanoparticles improves cellular uptake. The efficacy and safety of nanoparticle-based fetal lung therapy depends on targeting of necessary cell populations. This study aimed to determine the relative distribution of nanoparticles of a variety of compositions and sizes in the lungs of fetal mice delivered through intravenous and intra-amniotic routes. Intravenous delivery of particles was more effective than intra-amniotic delivery for epithelial, endothelial and hematopoietic cells in the fetal lung. The most effective targeting of lung tissue was with 250nm Poly-Amine-co-Ester (PACE) particles accumulating in 50% and 44% of epithelial and endothelial cells. This study demonstrated that route of delivery and particle composition impacts relative cellular uptake in fetal lung, which will inform future studies in particle-based fetal therapy.

Guido VeitChristian VaccarinGergely L Lukacs.  Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR. J Cyst Fibros 2021 Mar 25;S1569-1993(21)00087-4.doi: 10.1016/j.jcf.2021.03.011.Online ahead of print.  [Pubmed]

Guido Veit

Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by ~24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants

Dr Guido Veit is a Research Associate in the Department of Physiology, McGill University, Montréal, Canada. His main research interest: Epithelial biology with focus on the interplay between extracellular events (cytokines, extracellular matrix) and cellular responses (transmembrane proteins, signalling, transcriptional activation)

Connie YangMark Montgomery.  Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev 2021 Mar 18;3:CD001127.doi: 10.1002/14651858.CD001127.pub5.   [Pubmed]

        Connie Yang

Background: This is an update of a previously published review.(Full summary via PubMed abstract link)
Authors’ conclusions: There is evidence to show that, compared with placebo, therapy with dornase alfa may improve lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer, probably due to treatment. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.

Dr Connie Yang is Investigator and Paediatric Respirologist and Assoociate Professor in the Department of Pediatrics, Division of Respiratory Medicine, BC Children’s Hospital, Vancouver, Canada.

– It would be of interest to ask CF patients their opinion. The number taking regular Dornase Alpha would not support this guarded assessment. The proportion of people with CF who are taking is still increasing each year.

Edith T ZemanickJennifer L Taylor-CousarJane DaviesRonald L GibsonMarcus A MallEdward F McKone et al, A Phase 3 Open-Label Study of ELX/TEZ/IVA in Children 6 Through 11 Years of Age With CF and at Least One F508del Allele.  Am J Respir Crit Care Med 2021 Mar 18. doi: 10.1164/rccm.202102-0509OC.Online ahead of print.  [Pubmed]

Edith Zermanick

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients aged 12 years and older with cystic fibrosis and at least one F508del-CFTR allele, but has not been evaluated in children <12 years of age.
Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes.
Methods: In this 24-week open-label Phase 3 study, children (N=66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours) while children weighing ≥30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours).
Measurements and main results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most common reported adverse events (AEs) included cough, headache, and pyrexia; in most of the children who had AEs, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the ppFEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period compared to the pre-treatment baseline.

Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. 

Dr Edith T Zemanick is Associate Professor at the Colorado Anschutz Medical Campus and Children’s Hospital Colorado, Department of Pediatrics, Aurora, Colorado, United States


Section 2