History – 2021

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.

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

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.

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.

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

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]
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

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.

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.

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.

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.

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

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

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.

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.

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..

 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.

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, 

 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

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

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

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.

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. 

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.

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.

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.

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.

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

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Section 2