History – 2020 (Section 1)


Nature Outlook 29th July 2020 is devoted to Cystic fibrosis
The majority of the articles are written by professional scientific writers and clearly summarise a number of topical subjects.

– Cystic fibrosis
Innovative therapies are bringing hope to people with this inherited lung disorder.
Herb Brody is chief supplements editor of Nature
Nature 2020 Jul;583(7818):S1. doi: 10.1038/d41586-020-02105-x. [Pubmed]

Cystic fibrosis drugs target the malformed proteins at the root of the disease
New combinations of molecules put many patients on the path to good health. But those with rarer mutations are, for now, left behind.
Sarah DeWeerdt is a Freelance Science writer and editor                                                                                          Nature. 2020 Jul;583(7818):S2-S4. doi: 10.1038/d41586-020-02106-w.[Pubmed]

 A simple test could extend cystic-fibrosis treatments to those left behind
Sweat-chloride measurements could be used to develop and approve drugs for rare mutations in cystic fibrosis.
Steven M. Rowe professor and Director Cystic Fibrosis Research Center University of Birmingham Alabama
Nature. 2020 Jul;583(7818):S5. doi: 10.1038/d41586-020-02107-9.  [Pubmed]

– In utero intervention to stem the damage of cystic fibrosis
To safeguard organs, therapies must tackle this hereditary disease in the womb.
Elie Dolgin is a freelance science writer, editor and podcaster (abstracted below)
In utero intervention to stem the damage of cystic fibrosis Nature  2020 Jul;583(7818):S6-S7.doi: 10.1038/d41586-020-02108-8. [Pubmed]

Bacteria-eating viruses could provide a route to stability in cystic fibrosis
Phage therapy is broadening the treatment landscape for people with drug-resistant infections.
Elizabeth Svoboda is a writer in San Jose California                                                                                                  Nature. 2020 Jul;583(7818):S8-S9. doi: 10.1038/d41586-020-02109-7. [Pubmed]

 Gene therapy could offer an inclusive cure for cystic fibrosis
After three decades of false starts, gene therapy against the disease is in new clinical trials — and there is even hope of a cure.Roxanne Khamsi is chief news editor of Nature Medicine in New York
Khamsi R. Nature. 2020 Jul;583(7818):S12-S14. doi: 10.1038/d41586-020-02111-z.[Pubmed]

The coronavirus pandemic has forced rapid changes in care protocols for cystic fibrosis
Lockdowns have accelerated the drive towards telemedicine for people with cystic fibrosis — but the system needs critical appraisal.
Jane Davies is Professor paediatrics at Imperial College and Royal Brompton London                                      Nature. 2020 Jul;583(7818):S15. doi: 10.1038/d41586-020-02112-y. [Pubmed]

 Living, breathing proof
A cadre of older patients with cystic fibrosis have defied the life expectancy associated with their illness. They’re inspiring and educating others about surviving with the disease long-term.
Roxanne Khamsi is chief news editor of nature medicine in New York

 How much protein function needs to be restored in cystic fibrosis?
Knowing the percentage of function that is required to eliminate disease symptoms could help to shape treatment in the coming years and ensure sufferers don’t slip through the net.
Benjamin Plackett is a science journalist in London and Middle East                                                                   Nature. 2020 Jul;583(7818):S17. doi: 10.1038/d41586-020-02114-w.[Pubmed]

 Research round-up: Cystic fibrosis
Molecular pathways of inflammation, the cystic fibrosis microbiome and other highlights from clinical trials and laboratory studies.
Liam Drew is a writer covering medicine and biology                                                                                                Nature. 2020 Jul;583(7818):S18-S19. doi: 10.1038/d41586-020-02115-9.[Pubmed]

 Vertex Pharmaceuticals: Humanizing drug discovery
This article reviews the Vertex strategy to discover, develop and manufacture breakthrough medicines for people suffering with serious diseases.
David Altshuler is Executive Vice President, Global Research and Chief Scientific Officer at Vertex Pharmaceuticals                                                                                                                                                       Sponser feature

B L Aalbers R W Hofland I Bronsveld K M de Winter-de Groot H G M Arets A C de Kiviet M M M van Oirschot-van de VenM A KruijswijkS SchotmanS MichelC K van der EntH G M Heijerman.   Females With Cystic Fibrosis Have a Larger Decrease in Sweat Chloride in Response to lumacaftor/ivacaftor Compared to Males.   J Cyst Fibros  2020 May 21;S1569-1993(20)30135-1.  [Pubmed]
A study to explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data.
160 CF patients were identified who had used lumacaftor/ivacaftor (ORKAMBI) for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations.
Results: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy.

The authors concluded that the Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor (ORKAMBI). Sweat chloride response does not correlate with the responses in ppFEV1and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.

Dr B L Aalbers is in the Department of Pulmonology, University Medical Center Utrecht, the Netherlands.

 B L Aalbers K M de Winter-de Groot H G M Arets R W Hofland A C de Kiviet M M M van Oirschot-van de Ven M A Kruijswijk S Schotman S Michel C K van der Ent H G M Heijerman.  Clinical Effect of lumacaftor/ivacaftor in F508del Homozygous CF Patients With FEV 1 ≥ 90% Predicted at Baseline. J Cyst Fibros. 2020 Jul;19(4):654-658.doi: 10.1016/j.jcf.2019.12.015. Epub 2020 Jan 7. [Pubmed]
 Objective: The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor (ORKAMBI) , has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group.   In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously.
Results: They identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later.
Conclusion: Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.

Dr B L Aalbers is in the Department of Pulmonology, University Medical Center Utrecht, the Netherlands.

Albright JC, Houck AP, Pettit RS. Effects of CFTR modulators on pharmacokinetics of tobramycin during acute pulmonary exacerbations in the pediatric cystic fibrosis population [published online ahead of print, 2020 Jun 22]. Pediatr Pulmonol. 2020;10.1002/ppul.24917.
Individuals with cystic fibrosis (CF) require higher dosages of aminoglycosides due to an increased volume of distribution (Vd ) and clearance. Optimal dosing of aminoglycosides in the CF population is essential as repeated exposure to aminoglycosides during acute pulmonary exacerbations increases risk of nephrotoxicity and ototoxicity. To date, no studies have evaluated whether chronic CFTR modulator therapy affects pharmacokinetics of aminoglycoside antibiotics in CF patients. The objective of this study was to determine if the addition of a CFTR modulator affects elimination rate (Ke ) for intravenously administered tobramycin in the pediatric CF population
This retrospective study included patients aged 2 to 18 years with CF receiving chronic therapy with a CFTR modulator. Patients included had an admission both pre- and post-chronic CFTR modulator therapy during which they received therapy with IV tobramycin.

The pharmacokinetic parameters of intravenously administered tobramycin during admission for acute pulmonary exacerbation do not appear to change significantly after initiating chronic therapy with a CFTR modulator. Empiric dose adjustments for patients on CFTR modulators are not recommended. This article is protected by copyright. All rights reserved.

Dr Jared C  Albright is at the Riley Hospital for Children at IU Health, Indianapolis.

Allobawi R, Ghelani DP, Schneider-Futschik EK. Metabolomic Description of Ivacaftor Elevating Polymyxin B Mediated Antibacterial Activity in Cystic Fibrosis Pseudomonas aeruginosa. ACS Pharmacol Transl Sci. 2020;3(3):433-443. Published 2020 Apr 27. doi:10.1021/acsptsci.0c00030 [Pubmed]

Dr Elena Schneider- Futschik

We have demonstrated that ivacaftor displays synergistic antibacterial activity in combination with polymyxin B against polymyxin-resistant Pseudomonas aeruginosa that commonly colonizes the lungs of people with cystic fibrosis (CF). However, the underlying mechanism(s) remain unclear. In the present study, we employed untargeted metabolomics to investigate  synergistic killing mechanism of polymyxin B in combination with ivacaftor against a polymyxin-susceptible P. aeruginosa FADDI-PA111 (polymyxin B MIC = 2 mg/L) and a polymyxin-resistant CF P. aeruginosaFADDI-PA006 (polymyxin B MIC = 8 mg/L). Metabolites were extracted at 3 h after treatments with polymyxin B alone (2 μg/mL for FADDI-PA111 and 4 μg/mL FADDI-PA006 P. aeruginosa), ivacaftor alone (8 μg/mL), and in combination. Polymyxin B monotherapy induced significant perturbations in the glycerophospholipid and fatty acid metabolism pathways against FADDI-PA111 and to a lesser extent in FADDI-PA006. In both strains, treatment with ivacaftor alone induced more pronounced perturbations in glycerophospholipid and fatty acid metabolism pathways than that with polymyxin B alone. This highlights the unique antimicrobial mode of action of ivacaftor. Pathway analysis revealed that in combination treatment, polymyxin B mediated killing is elevated by ivacaftor, largely due to the inhibition of cell envelope biogenesis via suppression of key membrane lipid metabolites (e.g., sn-glycerol 3-phosphate and sn-glycero-3-phosphoethanolamine) as well as perturbations in peptidoglycan and lipopolysaccharide biosynthesis. Furthermore, significant perturbations in the levels of amino sugars and nucleotide sugars, glycolysis, the tricarboxylic acid cycle, and pyrimidine ribonucleotide biogenesis were observed with the combination treatment. These findings provide novel mechanistic information on the synergistic antibacterial activity of polymyxin-ivacaftor combination.

Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia

Margarida D AmaralMargarida C QuaresmaInes Pankonien.What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer?Int J Mol Sci 2020 Apr 29;21(9):E3133.doi: 10.3390/ijms21093133. [Pubmed]

   Margarida Quaresma

         Margarida Amaral

One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial-mesenchymal transition (EMT).
Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches.

From the BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Portugal.

– A very interesting detailed and timely review of this important subject from Margarida Amaral’s laboratory.

Aoyama BCMogayzel PJ.  Ivacaftor for the treatment of cystic fibrosis in children under six years of age. 
Expert Rev Respir Med.
 2020 Mar 17:1-11. doi: 10.1080/17476348.2020.1741352. [Epub ahead of print]  [Pubmed]
The authors reviewed the sentinel studies that lead to the approval of the use of ivacaftor in people with CF age six months and older with at least one CFTR gene mutation that is responsive to ivacaftor based on clinical trial and/or in vitro data. Children with CF have the greatest potential to benefit from CFTR modulator therapy when it is initiated prior to the development of permanent damage; however, challenges remain regarding use of ivacaftor in the youngest pediatric population.                      Ivacaftor is safe and effective CFTR modulator that can be prescribed in children over six months of age with at least one CFTR gene mutation that is responsive to ivacaftor.

From the Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore,

Arnold CABurke APCalomeni EMayer RCRishi ASinghi ADStashek KVoltaggio LTondon R. Brown Bowel Syndrome: A Multi-institutional Case Series. Am J Surg Pathol. 2020 Jan 23. doi: 10.1097/PAS.0000000000001443. [Epub ahead of print][Pubmed]

Christina Arnold

Brown bowel syndrome (BBS) is a rare condition associated with vitamin E deficiency and defined by prominent lipofuscin deposition in the muscularis propria. Eight unique cases of BBS were identified: 5 men and 3 women (mean age=58.6 y). Pertinent comorbidities included bariatric surgery=2, malnourishment=2, Crohn=2, cystic fibrosis=1, alcohol and cocaine abuse=1, and prior small bowel resections=1.
(Details in full summary)
BBS is important to recognize because it is linked with malnutrition, specifically vitamin E deficiency, and it can (rarely) clinically simulate malignancy. The diagnosis is based on the identification of the lipofuscin pigment in the cytoplasm of smooth muscle cells, which is most easily seen in the muscularis propria of the small bowel

Dr Christina A Arnold is in the Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO.

Ashcroft A, Chapman SJ, Mackillop L.  The outcome of pregnancy in women with cystic fibrosis: a UK population based descriptive study.  BJOG. 2020 Jul 19. doi: 10.1111/1471-0528.16423. Online ahead of print. [Pubmed]
All pregnant women with a diagnosis of cystic fibrosis who booked for antenatal care in a UK obstetric unit between March 2015 and February 2017.     There were 71 pregnancies over a two-year period. There was one early miscarriage, four terminations and three sets of twins, resulting in the live birth of 69 infants. There were no maternal deaths. One infant died following spontaneous pre-term birth at 29 weeks gestation. The mean gestation at delivery was 36.2 completed weeks. The mean birthweight centile for gestational age was the 61st centile. We report a positive correlation between both maternal lung function (FEV1) and mean gestation at delivery, and between FEV1 and mean birthweight centile for gestational age.

The authors concluded pregnancy outcomes are generally good in women with cystic fibrosis. Successful pregnancy is possible even in those women with FEV1 <60% predicted although such women have higher chance of preterm delivery and a smaller baby

Dr Anna Ashcroft is at the Oxford University Hospitals NHS Foundation Trust.

Atteih SERaraigh KSBlackman SMCutting GRCollaco JM.   Predictive effects of low birth weight and small for gestational age status on respiratory and nutritional outcomes in cystic fibrosis. 
J Cyst Fibros.
 2020 Feb 12. pii: S1569-1993(20)30048-5. doi: 10.1016/j.jcf.2020.02.003. [Epub ahead of print]  [Pubmed]

Michael Collaco

Prior literature shows that neonates with cystic fibrosis (CF) are more likely to be born low birth weight (LBW, <2500 grams) and/or small for gestational age (SGA, <10thpercentile for weight) than non-CF counterparts. There is limited literature exploring the predictive effects of birth parameters on long-term outcomes.The study population (CF Twin and Sibling Study) was recruited between 2000-2013 (n = 1677). Relationships between FEV1 percent predicted at 6, 12, or 18 years or BMI z-score at 2, 6, 12, or 18 years, and predictor variables (LBW or SGA status) were assessed using adjusted linear regressions.

Mean birth weight was 3.3 ± 0.7 kg (Females: 3.2 ± 0.7kg; males: 3.4 ± 0.7kg) and mean gestational age was 38.4 ± 2.6 weeks, with 10.2% of participants classified as SGA. Predictors of LBW included female sex, pancreatic insufficiency, and prematurity. Predictors of SGA included female sex. After adjustment, LBW was associated with lower BMI at ages 2-12 years and SGA was associated with lower BMI at age 2 years. LBW was associated with lower FEV1 percent predicted only at age 6 years. SGA was not associated with FEV1.

We did not observe higher rates of LBW or SGA in full term infants compared to the general population. We observed associations particularly between LBW and BMI or FEV1, but these associations decreased with age, suggesting that alternate factors contribute to outcomes over time. In lieu of the ability to target growth during gestation, efforts could be considered to optimize infant nutritional status, which may improve later life outcomes.

Dr Samar Atteih is a Third-Year Resident ta Johns Hopkins Children’s Center, Baltimore, MD, USA.

Dr J Michael Collaco is Associate Professor of Pediatrics at Johns Hopkins

I M Balfour-Lynn J A King.  CFTR Modulator Therapies – Effect on Life Expectancy in People With Cystic Fibrosis.  Paediatr Respir Rev   2020 May 26;S1526-0542(20)30081-6. doi: 10.1016/j.prrv.2020.05.002. Online ahead of print. [Pubmed]
CFTR modulators have dramatically changed the clinical course of CF in those fortunate enough to receive them. Inevitably, randomised controlled trials during the development of these drugs are too short to use mortality as an outcome. Evidence for their effect on life expectancy are best gained from real world registry studies specifically looking at mortality, but these are only available for ivacaftor to date. Therefore, indirect evidence must be obtained by looking at outcomes known to affect mortality and seeing the effect of these drugs on those outcomes.

Dr Ian Balfour-Lynn is a consultant paediatrician at the Royal Brompton Hospital, London

Barreda CB, Farrell PM, Laxova A, Eickhoff JC, Braun AT, Coller RJ, Rock MJ.  Newborn screening alone insufficient to improve pulmonary outcomes for cystic fibrosis. J Cyst Fibros. 2020 Jun 13:S1569-1993(20)30731-1. doi: 10.1016/j.jcf.2020.06.002. Online ahead of print.   32546430

        Christina Barreda

The Wisconsin Cystic Fibrosis Neonatal Screening Project was a randomized clinical trial (RCT) revealing that children receiving an early diagnosis of CF via newborn screening (NBS) had improved nutritional outcomes but similar lung disease severity compared to those who presented clinically. Because the evaluations of these subjects by protocol ended in 2012, our objective was to assess long-term pulmonary and mortality outcomes.
Retrospective analysis of the RCT cohort utilized longitudinal outcome measures obtained from the Cystic Fibrosis Foundation Patient Registry (CFFPR). Data included screening assignment, clinical characteristics, percent predicted forced expiratory volume in 1 s (ppFEV1) and mortality. A random intercept model was used to compare the ppFEV1 decline of subjects between the two groups up to age 26 years. Mortality was analyzed using the Kaplan-Meier method.
Of the 145 subjects who consented to the original study, 104 subjects met inclusion criteria and had adequate data in the CFFPR. Of 57 subjects in the screened group and 47 in the control group, the rates of ppFEV1 decline were 1.76%/year (95% CI 1.62 to 1.91%) and 1.43%/year (95% CI 1.26 to 1.60%), respectively (p<0.0002). Pseudomonas aeruginosa acquired before 2 years was partially responsible. There was no difference in mortality between the two groups
Conclusions: NBS alone does not improve pulmonary outcomes in CF, particularly when other risk factors supervene. In an era prior to strict infection control and current therapies, NBS for CF may be associated with worse pulmonary outcomes.

Dr Christina B Barreda is a paediatrician in the Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health.

.Sara L Rassoulian Barrett Elizabeth A Holmes Dustin R LongRyan C SheanGilbert E BautistaSumedha RavishankarVikas PedduBrad T CooksonPradeep K SinghAlexander L GreningerStephen J Salipante   Cell Free DNA From Respiratory Pathogens Is Detectable in the Blood Plasma of Cystic Fibrosis Patients. 2020 Apr 23;10(1):6903.doi: 10.1038/s41598-020-63970-0.  [Pubmed]

Stephen Salipante

Sara L Rassoulian Barrett

Diagnostically informative microbial cell-free DNA (cfDNA) can be detected from blood plasma during fulminant infections such as sepsis. However, the potential for DNA from airway pathogens to enter the circulation of cystic fibrosis (CF) patients during chronic infective states has not yet been evaluated.
The authors assessed whether patient blood contained measurable quantities of cfDNA from CF respiratory microorganisms by sequencing plasma from 21 individuals with CF recruited from outpatient clinics and 12 healthy controls. To account for possible contamination with exogenous microbial nucleic acids, statistical significance of microbe-derived read counts from CF patients was determined relative to the healthy control population.
In aggregate, relative abundance of microbial cfDNA was nearly an order of magnitude higher in CF patients than in healthy subjects (p = 8.0×10-3). 15 of 21 (71%) CF patients demonstrated cfDNA from one or more relevant organisms. In contrast, none of the healthy subjects evidenced significant microbial cfDNA for any of the organisms examined. Concordance of cfDNA with standard microbiological culture of contemporaneously collected patient sputum was variable.

The authors consider their findings provide evidence that cfDNA from respiratory pathogens are present in the bloodstream of most CF patients, which could potentially be exploited for the purposes of non-invasive clinical diagnosis.

Sara L Rassoulian Barrett  is in the Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.

Stephen J Salipante  is a pathologist and Assistant professor of Laboratory Medicine in the Department of Laboratory Medicine, University of Washington, Seattle, WA, USA. stevesal@uw.edu.

P BarthP BruijnzeelA WachO Sellier KesslerL HooftmanJ ZimmermannN NaueB HuberI HeimbeckD KappelerW TimmerE Chevalier. Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis J Cyst Fibros 2020 Mar;19(2):299-304.doi:10.1016/j.jcf.2019.08.020. Epub 2019 Sep. [Pubmed]
Background: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF).
Methods: Two studies, one in healthy volunteers (HVs, doses 20 to 960 mg) and one in subjects with CF (doses 80 to 320 mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24 h. In addition, NE activity in CF sputum was measured.
Results: After single doses, POL6014 was safe and well tolerated up to 480 mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmaxbetween 0.2 and 2.5 μM in HVs and between 0.2 and 0.5 μM in subjects with CF. Tmax was reached at approximately 2-3 h. Mean POL6014 levels in CF sputum rapidly reached 1000 μM and were still above 10 μM at 24 h. >1-log reduction of active NE was observed at 3 h after dosing.
Conclusion: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing..

Dr O Sellier Kessler the corresponding author at: Santhera Pharmaceuticals, Hohenrainstrasse 24, 4133

Bartley BL, Gardner KJ, Spina S, Hurley BP, Campeau D, Berra L, Yonker LM, Carroll RW.    High-Dose Inhaled Nitric Oxide as Adjunct Therapy in Cystic Fibrosis Targeting Burkholderia multivorans.   Case Rep Pediatr. 2020 Jun 24;2020:1536714. doi: 10.1155/2020/1536714. eCollection 2020. Free PMC article.[Pubmed]
Background: Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. The gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers.

Conclusions: High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans. Inhaled high-dose NO therapy, utilized as an anti-infective adjunct therapy, improved pathogen antibiotic resistance patterns and clinical outcomes in our patient.    Inhaled high-dose NO therapy, utilized as an anti-infective adjunct therapy, improved pathogen antibiotic resistance patterns and clinical outcomes in our patient. Mechanistic studies in vitro and larger randomized controlled clinical trials are needed to better understand the bactericidal efficacy and biofilm dispersal properties of high-dose NO on Bmultivorans. To our knowledge, this is the first report of high-dose inhaled NO therapy in an individual with CF and pulmonary colonization with Bmultivorans. In follow-up, the patient continues to require frequent courses of antibiotics for pulmonary exacerbations though much less frequent inpatient admissions. During inpatient stays, we continue to offer high-dose inhaled NO therapy as an adjunct therapy to intravenous antibiotics. The patient’s genotype qualifies for the newly available, highly effective, triple combination CFTR modulator, elexacaftor-ivacaftor-tezacaftor (Vertex Pharmaceuticals) [21], which has improved her lung function but has not yet altered her sputum microbiota. Recalcitrant infection with multidrug-resistant pathogens will likely continue to be a major problem in CF despite the advent of CFTR modulators [2223], and high-dose inhaled NO may help those who continue to struggle with difficult to treat respiratory pathogens.

Dr Bethany L Bartley is at the Department of Pediatric Pulmonology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA

Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, Burgel PR, Tullis E, Castaños C, Castellani C, Byrnes CA, Cathcart F, Chotirmall SH, Cosgriff R, Eichler I, Fajac I, Goss CH, Drevinek P, Farrell PM, Gravelle AM, Havermans T, Mayer-Hamblett N, Kashirskaya N, Kerem E, Mathew JL, McKone EF, Naehrlich L, Nasr SZ, Oates GR, O’Neill C, Pypops U, Raraigh KS, Rowe SM, Southern KW, Sivam S, Stephenson AL, Zampoli M, Ratjen F.  The Future of Cystic Fibrosis Care: A Global Perspective. Lancet Respir Med Jan 2020;8(1): 65-124   [Pubmed]

      Felix Ratjen

     Scott Bell

The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available, and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.

Scott Bell and Felix Ratjen coordinated the Commision and reviewed and edited all sections of the paper.

Prof. Scott Bell of the Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.  Previous editor of the JCF.

Prof. Felix Ratjen of the Division of Respiratory Medicine, Department of Paediatrics Translational Research Programme, Hospital for Sick Children, University of Toronto, Toronto, Canada

-This really impressive article by 38 of the world’s experts with 522 references can be unreservedly recommended for anyone who wishes a detailed comprehensive readable review of the subject.

Siân Bentley Jane C Davies Siobhán B Carr Ian M Balfour-Lynn Combination Antifungal Therapy for Scedosporium Species in Cystic Fibrosis. . 2020 Apr 27.doi: 10.1002/ppul.24789. Online ahead of print.  [Pubmed]

       Sian Bentley

A study to evaluate safety and efficacy of oral posaconazole and terbinafine for Lomentospora prolificans and Scedosporium apiospermum in children with cystic fibrosis.  There were five children (four girls), median age 15.0 years; three had S. apiospermum and two had L. prolificans. Treatment duration: median 5 months (range: 5-18 m). In no patient was eradication achieved, with the follow-up range being 6 months to 4 years. Effect on lung function was variable but encouraging. No adverse effects were reported, one child had transient elevation of liver enzymes.
The authors concluded while the combination therapy was well tolerated, it was unsuccessful at eradication

Sian Bentley is Lead Pharmacist, Paediatrics Royal Brompton and Harefield NHS Foundation Trust, London

Bentur L, Gur M, Ashkenazi M, Livnat-Levanon G, Mizrahi M, Tal A, Ghaffari A, Geffen Y, Aviram M, Efrati O.  Pilot study to test inhaled nitric oxide in cystic fibrosis patients with refractory Mycobacterium abscessus lung infection.    J Cyst Fibros. 2020 Mar;19(2):225-231. doi: 10.1016/j.jcf.2019.05.002. Epub 2019 May 23.PMID: [Pubmed]

 Lea Bentur

Background: Airways of Cystic Fibrosis (CF) patients are Nitric Oxide (NO) deficient which may contribute to impaired lung function and infection clearance. Mycobacterium abscessus (M. abscessus) infection prevalence is increasing in CF patients and is associated with increased morbidity and mortality. Here, we assess the safety and efficacy of intermittent inhaled NO (iNO) as adjuvant therapy in CF patients with refractory M. abscessus lung infection.

Methods: A prospective, open-label pilot study of iNO (160 ppm) administered five times/day during hospitalization (14 days), and three times/day during ambulatory treatment (7 days) was conducted. The primary outcome was safety measured by NO-related adverse events (AEs). Secondary outcomes were six-minute walk distance (6MWD), forced expiratory volume in 1 s (FEV1), and M. abscessus burden in airways.
Results: Nine subjects were recruited. INO at 160 ppm was well-tolerated and no iNO-related SAEs were observed during the study. Mean FEV1 and 6WMD were increased relative to baseline during NO treatment. M. abscessus culture conversion was not achieved, but 3/9 patients experienced at least one negative culture during the study. Mean time to positivity in M. abscessus culture, and qPCR analysis showed reductions in sputum bacterial load. The study was not powered to achieve statistical significance in FEV1, 6WMD, and bacterial load.
Conclusions: Intermittent iNO at 160 ppm is well tolerated and safe and led to increases in mean 6MWD and FEV1. INO exhibited potential antibacterial activity against M. abscessus. Further evaluation of secondary endpoints in a larger cohort of CF patients is warranted to demonstrate statistical significance.

Professor Lea Bentur is Director of the Pediatric Pulmonary Institute and CF Center, Ruth Children’s Hospital, Rambam Health Care Campus, POB 9602, Haifa, Israel; Technion-Israel Institute of Technology, Haifa, Israel

Bienvenu T, Lopez M, Girodon E.  Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges.  Genes (Basel). 2020 Jun 4;11(6):E619. doi: 10.3390/genes11060619. Free article. Review.[Pubmed]

Thierry Bienvenu

Identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its numerous variants opened the way to fantastic breakthroughs in diagnosis, research and treatment of cystic fibrosis (CF). The current and future challenges of molecular diagnosis of CF and CFTR-related disorders and of genetic counseling are here reviewed. Technological advances have enabled to make a diagnosis of CF with a sensitivity of 99% by using next generation sequencing in a single step. The detection of heretofore unidentified variants and ethnic-specific variants remains challenging, especially for newborn screening (NBS), CF carrier testing and genotype-guided therapy. Among the criteria for assessing the impact of variants, population genetics data are insufficiently taken into account and the penetrance of CF associated with CFTRvariants remains poorly known. The huge diversity of diagnostic and genetic counseling indications for CFTR studies makes assessment of variant disease-liability critical. This is especially discussed in the perspective of wide genome analyses for NBS and CF carrier screening in the general population, as future challenges.

Dr Thierry Bienvenu is at the Molecular Genetics Laboratory, Cochin Hospital, APHP.Centre-Université de Paris, 75014 Paris, France.

Bieth ENectoux JGirardet AGruchy NMittre HLaurans MGuenet DBrouard JGerard M. Genetic counseling for cystic fibrosis: A basic model with new challenges. Arch Pediatr. 2020 Feb;27 Suppl 1:eS30-eS34. doi: 10.1016/S0929-693X(20)30048-8. [Pubmed]
While the goals of genetic counseling for cystic fibrosis – delivering relevant information on the risk of recurrence and nondirectional support of couples at risk in their reproductive choices – have not changed fundamentally, the practice has evolved considerably in the last decade, growing more complex to face new challenges but also proving more effective. Many factors have contributed to this evolution: technical progress in the exploration of the genome (new generation sequencing) and in reproductive medicine, but also societal developments promoting access to genetic information and the professionalization of genetic counselors in France. The prospect of expanded pre-conception screening of at-risk couples makes genetic counselors major actors not only in medical care centers, but also in modern society by contributing to genetic education among citizens.

Dr Eric Bieth is at Génétique Médicale, CHU Toulouse, France.

Birket SE, Davis JM, Fernandez-Petty CM, et al. Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR [published online ahead of print, 2020 Jun 25]. Am J Respir Crit Care Med. 2020;10.1164/rccm.202002-0369OC. doi:10.1164/rccm.202002-0369O, [Pubmed]

             Susan Birket

Animal models have been highly informative for understanding characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR-/- rat has revealed insights into the airway mucus defect characteristic of CF, but does not replicate a human-relevant CFTR variant. The authors hypothesized that a rat expressing a humanized version of CFTR, harbouring the ivacaftor-sensitive variant G551D, could be used to test the impact of CFTR modulators on pathophysiologic development and correction.

In this study, they describe a humanized-CFTR rat expressing the G551D variant, obtained by zinc finger nuclease editing of a human cDNA super-exon, spanning exon 2-27, with a 5′ insertion site into the rat gene just beyond intron 1. This targeted insertion takes advantage of the endogenous rat promoter, resulting in appropriate expression compared to wild-type.

Measurements and main results: The bioelectric phenotype of the epithelia recapitulates the expected absence of CFTR activity, which was restored with ivacaftor. Large airway defects, including depleted airway surface liquid and periciliary layers, delayed mucus transport rates, and increased mucus viscosity were normalized following administration of ivacaftor. The authors conclude this model is useful to understand mechanisms of disease and the extent of pathology reversal with CFTR modulators.

Dr Susan Birket directs the CF Knockout Rat colony at the University of Alabama at Birmingham, Medicine, Cystic Fibrosis Center, Birmingham, Alabama, United States

Bonhoure ABoudreau VLitvin MColomba JBergeron CMailhot M4Tremblay FLavoie ARabasa-Lhoret R.  Overweight, obesity and significant weight gain in adult patients with cystic fibrosis association with lung function and cardiometabolic risk factors.  Clin Nutr. 2020 Jan 10. pii: S0261-5614(20)30005-4. doi: 10.1016/j.clnu.2019.12.029. [Epub ahead of print] [Pubmed]

Anne Bonhoure

Given therapy improvements, some CF patients are now overweight, obese or present rapid weight gain. However, the impact of being overweight on clinical outcomes (e.g. FEV1 & metabolic complications) remains unknown.
Baseline data from 290 adult CF patients and observational follow-up (3.5 years; n = 158) were collected. BMI categories: underweight (UW < 18.5 kg/m2), normal (NW 18.5-26.9 kg/m2), and overweight/obese (OW ≥ 27 kg/m2). Follow-up data (weight change over time): weight loss (WL>10%), stable (WS), and weight gain (WG>10%). BMI categories and follow-up data were compared to FEV1 and cardiometabolic parameters: glucose tolerance, estimated insulin resistance (IR), blood pressure (BP), and lipid profile.

For BMI categories, 35 patients (12.1%) were UW, 235 (81.0%) NW, and 20 (6.9%) OW. Compared to UW and NW patients, OW patients are older (p < 0.001), had less pancreatic insufficiency (p = 0.009), a higher systolic BP (p = 0.004), higher LDL (p < 0.001), and higher IR (p < 0.001). Compared to UW patients, OW patients had a better FEV1 (p < 0.001). For weight change, WL was observed in 7 patients (4.4%), WS in 134 (84.8%) and WG in 17 patients (10.8%). Compared to WL and WS patients, WG patients had a 5% increase in FEV1 accompanied by higher IR (p = 0.017) and triglycerides (p < 0.001). No differences were observed for glucose tolerance for neither BMI nor weight change.

The authors concluded a higher weight or weight gain over time are associated with a better FEV1 but also some unfavourable cardio-metabolic trends.

Dr A Bonhoure is at the Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Canada; McGill University, Faculty of Medicine, Division of Experimental Medicine, Montréal, Canada.

M Boon J Calvo-Lerma I Claes T HavermansI AsseiceiraA Bulfamante, et al. Use of a Mobile Application for Self-Management of Pancreatic Enzyme Replacement Therapy Is Associated With Improved Gastro-Intestinal Related Quality of Life in Children With Cystic FibrosisJ Cyst Fibros. 2020 Apr 22;S1569-1993(20)30114-4. doi: 10.1016/j.jcf.2020.04.001.Online ahead of print. [Pubmed]

       Mieke Boon

Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency (PI), leading to fat malabsorption, malnutrition, abdominal discomfort and impaired growth. Pancreatic enzyme replacement therapy (PERT) is effective, but evidence based guidelines for dose adjustment are lacking. A mobile app for self-management of PERT was developed in the context of the HORIZON 2020 project MyCyFAPP. It contains an algorithm to calculate individual PERT-doses for optimal fat digestion, based on in vitro and in vivo studies carried out in the same project. In addition, the app includes a symptoms diary, educational material, and it is linked to a web tool allowing health care professionals to evaluate patient’s data and provide feedback.A 6-month open label prospective multicentre interventional clinical trial was performed to assess effects of using the App on gastro-intestinal related quality of life (GI QOL), measured by the CF-PedsQL-GI (shortened, CF specific version of the Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Module).

Results: One hundred and seventy-one patients with CF and PI between 2 and 18 years were recruited at 6 European CF centers. Self-reported CF-PedsQL-GI improved significantly from month 0 (M0) (84.3, 76.4-90.3) to month 6 (M6) (89.4, 80.35-93.5) (p< 0.0001). Similar improvements were reported by parents. Lower baseline CF-PedsQL-GI was associated with a greater improvement at M6 (p < 0.001).
Conclusions: The results suggest that the MyCyFAPP may improve GI QOL for children with CF. This tool may help patients to improve self-management of PERT, especially those with considerable GI symptoms.

Dr Mieke Boon is a paediatric pulmonologist in the Department of Pediatrics, Center for Cystic Fibrosis, University Hospital Leuven, Leuven, Belgium.

– This is obviously a major project running from Jan 2015 to end 31 Dec 2018.     My Cystic Fibrosis Application is funded by the European Commission under Grant Agreement number 643806 the overall budget: € 5,087,507,50   The team is composed by 12 European organisations. The multidisciplinary team comprises health institutions, biomedical research centres, IT developers, gaming companies and patients’ representatives.   Since January 2018, around 200 patients from five European countries participated in the clinical trialsuccessfully achieve a new Pancreatic Enzyme Replacement Therapy (PERT) plus make it accessib

Bose SJKrainer GNg DRSSchenkel MShishido HYoon JSHaggie PMSchlierf MSheppard DNSkach WR. Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR. J Cyst Fibros. 2020 Jan 2. pii: S1569-1993(19)30989-0. doi: 10.1016/j.jcf.2019.12.009. [Epub ahead of print] [Pubmed]
The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, they review selectively recent advances in CFTR folding, function and pharmacology. They highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. They discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, they illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators.

The first author of this multinational paper is S J Bose from the School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK

Bressan ARodio DMStangherlin FPuggioni GAmbrosi CArcari GCarattoli AAntonelli GPietropaolo VTrancassini M.  In vitro activity of fosfomycin against mucoid and non-mucoid Pseudomonas aeruginosa strains. 
J Glob Antimicrob Resist.
 2020 Feb 24;20:328-331. doi: 10.1016/j.jgar.2020.02.014. [Epub ahead of print]  Full text [Pubmed]
P. aeruginosa resistance to first line antibiotics limits therapeutic options in CF, but the therapeutic potential of older generation antibiotics, such as fosfomycin is under investigation. Fosfomycin does not belong to any other antibiotic class and acts by inhibiting the biosynthesis of the bacterial cell wall during the initial phases. A major problem for the use of fosfomycin against P. aeruginosa is the absence of a clinical breakpoint, the last one of 32 μg/mL was proposed in 2013 by the CA-SFM (Comité de l’Antibiogramme de la Société Française de Microbiologie).
Sixty-one strains of P. aeruginosa (thirty mucoid and thirty-one non mucoid) were collected from respiratory samples of cystic fibrosis patients. All isolates were identified by MALDI-TOF (Bruker, Bremen, Germany). Fosfomycin MICs against P. aeruginosa were measured using an automated system and confirmed by the gold standard method.
There was no significant difference between mucoid and non-mucoid strains. MIC distribution and susceptibility rates were obtained by agar dilution method and from this data we measured MIC50 and MIC90 which were equal to 32 μg/mL and 64 μg/mL, respectively. From automated method results we measured a very major error (VME), major error (ME) and categorical agreement (CA) which were equal to 0%, 11% and 89%, respectively. Comparing automated and agar dilution methods, a Cohen’s kappa equal to 73% (0.726) was measured.

The  authors concluded their data suggest that fosfomycin has good effect against mucoid and non-mucoid strains of P. aeruginosa and automated systems can be implemented in clinical microbiology laboratories to assess fosfomycin with rapid and reproducible results.

Dr Alessia Brassan is in the Department of Molecular Medicine, “Sapienza” University Rome, Rome, Italy.

Burgel PR, Durieu I, Chiron R, et al. Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function [published online ahead of print, 2020 Jun 23]. J Cyst Fibros. 2020;S1569-1993(20)30752-9. doi:10.1016/j.jcf.2020.06.012  [Pubmed]

Pierre-Regis Burgel

Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) (ORKAMBI) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1s (ppFEV1) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV1.
This study to evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV1<40 or ppFEV1≥90 in comparison with those with ppFEV1 [40-90[. Analysis of data collected during a real world study, which included all patients aged ≥12 years who started LUMA-IVA in 2016 across all 47 French CF centres.
827 patients were classified into 3 subgroups according to ppFEV1 at treatment initiation (ppFEV1<40, n = 121; ppFEV1 [40-90[, n = 609; ppFEV1≥90, n = 97). Treatment discontinuation rate was higher in ppFEV1<40 patients (28.9%) than in those with ppFEV1 [40-90[(16.4%) or ppFEV1≥90 (17.5%). In patients with uninterrupted treatment, significant increase in ppFEV1occurred in the ppFEV1 [40-90[subgroup (+2.9%, P<0.001), and in those ppFEV1<40 (+0.5%, P = 0.03) but not in those with ppFEV1≥90 (P = 0.46).Compared with the year prior to initiation, the number of days of intravenous antibiotics were reduced in all subgroups, although 72% of patients with ppFEV1<40 still experienced at least one exacerbation/year under LUMA-IVA. Comparable increase in body mass index was seen in the three subgroups.

The authors concluded Phe508del homozygous CF patients benefit from LUMA-IVA (ORKAMBI) at all levels of baseline lung function, but the characteristics and magnitude of the response vary depending on ppFEV1 at baseline.

Pierre Regis Burgel is at Université de Paris, Institut Cochin, Paris, France; Respiratory Medicine and National Reference Cystic Fibrosis Reference Center, Cochin Hospital; Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; ERN-Lung CF network.

L CaleyL SmithH WhiteD G PeckhamAverage Rate of Lung Function Decline in Adults With Cystic Fibrosis in the United Kingdom: Data From the UK CF Registry.  J Cyst Fibros  2020 May 4;S1569-1993(20)30121-1. doi: 10.1016/j.jcf.2020.04.008.Online ahead of print.[Pubmed]
Rate of change in lung function is used as a measure of disease progression and a predictor of mortality in individuals with cystic fibrosis (CF). The aim of this study was to determine the national rate of decline in percent predicted Forced Expiratory Volume in 1 second (ppFEV1) in adults in the UK accounting for age, sex and pancreatic status.
Data on ppFEV1 for adults with CF, excluding those post lung transplantation, was extracted from the UK CF registry between 2015 and 2017. Multilevel modelling was conducted to calculate the annual rate of change in ppFEV1 accounting for age, sex and pancreatic status. The overall annual ppFEV1 decline was -1.52% (95% CI: -1.66 to -1.38%) and -0.55% (95% CI: -0.86 to -0.23%) in pancreatic insufficient (PI) and sufficient (PS) adults respectively. In PI individuals, females had a greater rate of decline in ppFEV1. There were differences between age groups. The fastest rate of decline was observed in the 18-28 years group, declining -1.76% (95% CI: -2.06 to -1.46) and -1.61% (95% CI: -1.91 to -1.31) per year in PI females and males respectively. The pattern between the sexes and age categories was more inconsistent in the PS group.

The average annual rates of decline in lung function in adults with CF in the UK are similar to reports from other large international cohorts. Pancreatic status has a marked impact on average rate of decline. Younger adults, especially females, have a faster rate of decline and need close monitoring.

Laura Caley is in the School of Medicine, Clinical Sciences Building, St James’s University Hospital, Leeds, LS9.

 Diego A Calvopina Charlton NobleAnna WeisGunter F HartelLouise E RammFariha BalouchManuel A Fernandez-RojoMiranda A ColemanPeter J LewindonGrant A Ramm. Supersonic shear-wave elastography and APRI for the detection and staging of liver disease in pediatric cystic fibrosis.  J Cyst Fibros. 2020 May;19(3):449-454.doi: 10.1016/j.jcf.2019.06.017. Epub 2019 Jul 11 [Pubmed]

      Grant A Ramm

Background: Current diagnostic methods for the diagnosis of Cystic fibrosis (CF)-associated liver disease (CFLD) are non-specific and assessment of disease progression is difficult prior to the advent of advanced disease with portal hypertension. This study investigated the potential of Supersonic shear-wave elastography (SSWE) to non-invasively detect CFLD and assess hepatic fibrosis severity in children with CF.
Methods: 125 children were enrolled in this study including CFLD (n = 55), CF patients with no evidence of liver disease (CFnoLD = 41) and controls (n = 29). CFLD was diagnosed using clinical, biochemical and imaging best-practice guidelines. Advanced CFLD was established by the presence of portal hypertension and/or macronodular cirrhosis on ultrasound. Liver stiffness measurements (LSM) were acquired using SSWE and diagnostic performance for CFLD detection was evaluated alone or combined with aspartate aminotransferase-to-platelet ratio index (APRI).
Results: Liver stiffness measurements were significantly higher in CFLD (8.1 kPa, IQR = 6.7-11.9) versus CFnoLD (6.2 kPa, IQR = 5.6-7.0; P < 0.0001) and Controls (5.3 kPa, IQR = 4.9-5.8; P < 0.0001). LSM was also increased in CFnoLD versus Controls (P = 0.0192). Receiver Operating Characteristic (ROC) curve analysis demonstrated good diagnostic accuracy for LSM in detecting CFLD using a cut-off = 6.85 kPa with an AUC = 0.79 (Sensitivity = 75%, Specificity = 71%, P < 0.0001). APRI also discriminated CFLD (AUC = 0.74, P = 0.004). Classification and regression tree modelling combining LSM + APRI showed 14.8 times greater odds of accurately predicting CFLD (AUC = 0.84). The diagnostic accuracy of SSWE for discriminating advanced disease was excellent with a cut-off = 9.05 kPa (AUC = 0.95; P < 0.0001).

Conclusions: SSWE-determined LSM shows good diagnostic accuracy in detecting CFLD in children, which was improved when combined with APRI. SSWE alone discriminates advanced CFLD.

Dr Diego A Calvopina is in the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston Australia and a member of the Faculty of Medicine, The University of Queensland, Brisbane

Professor Grant A Ramm, the corresponding author, is Head of the Hepatic Fibrosis Group d Coordinator of the Cell and Molecular Biology Department at QIMR Berghofer.

 Jose Caparrós-Martín, Stephanie FlynnF Jerry ReenDavid F WoodsPatricia Agudelo-RomeroSarath C Ranganathan Stephen M StickFergal O’GaraThe Detection of Bile Acids in the Lungs of Paediatric Cystic Fibrosis Patients Is Associated With Altered Inflammatory PatternsDiagnostics (Basel). 2020 May 6;10(5):E282.doi: 10.3390/diagnostics10050282. [Pubmed]

                Fergal Ogara

Jose Caparros-Martin

Cystic fibrosis respiratory disease starts early in life, with the detection of inflammatory markers and infection evident even before respiratory symptoms arise. Thus, identifying factors that dysregulate immune responsiveness at the earliest stages of the disease will provide novel targets for early therapeutic intervention.
The authors evaluated the clinical significance of bile acid detection in the bronchoalveolar lavage fluid of clinically stable preschool-aged children diagnosed with CF. Results: We applied an unbiased classification strategy to categorize these specimens based on bile acid profiles. We provide clear associations linking the presence of bile acids in the lungs with alterations in the expression of inflammatory markers. Using multiple regression analysis, we also demonstrate that clustering based on bile acid profiles is a meaningful predictor of the progression of structural lung disease.

The authors consider their work has identified a clinically relevant host-derived factor that may participate in shaping early events in the aetiology of CF respiratory disease.

Dr Jose A Caparrós-Martín is a Research Associate with the Human Microbiome Programme, School of Pharmacy and Biomedical Sciences, Curtin University, Perth 6102, Australia and the Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth 6102, Australia.                            He is senior researcher in the Human Microbiome Programme directed by Professor Fergal O’Gara.

Christopher Boyd AGuo SHuang LKerem BOren YSWalker AJHart SL. New approaches to genetic therapies for cystic fibrosis.   J Cyst Fibros. 2020 Jan 13. pii: S1569-1993(19)30992-0. doi: 10.1016/j.jcf.2019.12.012. [Epub ahead of print] [Pubmed]

Christopher Boyd

Gene therapy offers great promise for cystic fibrosis which has never been quite fulfilled due to the challenges of delivering sufficient amounts of the CFTR gene and expression persistence for a sufficient period of time in the lungs to have any effect. Initial trials explored both viral and non-viral vectors but failed to achieve a significant breakthrough. However, in recent years, new opportunities have emerged that exploit our increased knowledge and understanding of the biology of CF and the airway epithelium. New technologies include new viral and non-viral vector approaches to delivery, but also alternative nucleic acid technologies including oligonucleotides and siRNA approaches for gene silencing and gene splicing, described in this review, as presented at the 2019 Annual European CF Society Basic Science meeting (Dubrovnik, Croatia). They also briefly discuss other emerging technologies including mRNA and CRISPR gene editing that are advancing rapidly. The future prospects for genetic therapies for CF are now diverse and more promising probably than any time since the discovery of the CF gene.

From the University of Edinburgh, Centre for Genomic and Experimental Medicine, University of Edinburgh and Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh UK; UK Cystic Fibrosis Gene Therapy Consortium, UK

Calthorpe RJSmith SGathercole KSmyth AR. Using digital technology for home monitoring, adherence and self-management in cystic fibrosis: a state-of-the-art review.
 2020 Jan;75(1):72-77. doi: 10.1136/thoraxjnl-2019-213233. Epub 2019 Oct 8.[Pubmed]

Rebecca Calthorpe

Digital healthcare is a rapidly growing healthcare sector. Its importance has been recognised at both national and international level, with the WHO recently publishing its first global strategy for digital health. The use of digital technology within cystic fibrosis (CF) has also increased. CF is a chronic, life-limiting condition, in which the treatment burden is high and treatment regimens are not static. Digital technologies present an opportunity to support the lives of people with CF. We included 59 articles and protocols in this state-of-the-art review, relating to 48 studies from 1999 until 2019. This provides a comprehensive overview of the expansion and evolution of the use of digital technology. Technology has been used with the aim of increasing accessibility to healthcare, earlier detection of pulmonary exacerbations and objective electronic adherence monitoring. It may also be used to promote adherence and self-management through education, treatment management Apps and social media.

-This is a comprehensive review of the use of technology in various aspects of CF care. The fully referenced Thorax draft of the paper is available on the internet (R J Calthorpe) and is an excellent source of information for anyone looking in depth into this area.

Dr Rebecca J Calthorpe Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK.

Calvo-Lerma JRoca MBoon MColombo Cde Koning BFornés-Ferrer VMasip EGarriga MBulfamante AAsensio-Grau AAndrés Ade Boeck KHulst JRibes-Koninckx C.  Association between faecal pH and fat absorption in children with cystic fibrosis on a controlled diet and enzyme supplements dose. Pediatr Res. 2020 Apr 4. doi: 10.1038/s41390-020-0860-3. [Epub ahead of print [Pubmed]  

Joaquim Calvo-Lerma

Despite treatment with pancreatic enzyme replacement therapy (PERT), patients with cystic fibrosis (CF) can still suffer from fat malabsorption. A cause could be low intestinal pH disabling PERT. The aim of this study was to assess the association between faecal pH (as intestinal pH surrogate) and coefficient of fat absorption (CFA). Additionally, faecal free fatty acids (FFAs) were quantified to determine the amount of digested, but unabsorbed fat.

In a 24-h pilot study, CF patients followed a standardised diet with fixed PERT doses, corresponding to theoretical optimal doses determined by an in vitro digestion model. Study variables were faecal pH, fat and FFA excretion, CFA and transit time. Linear mixed regression models were applied to explore associations.

In 43 patients, median (1st, 3rd quartile) faecal pH and CFA were 6.1% (5.8, 6.4) and 90% (84, 94), and they were positively associated (p < 0.001). An inverse relationship was found between faecal pH and total fat excretion (p < 0.01), as well as total FFA (p = 0.048). Higher faecal pH was associated with longer intestinal transit time (p = 0.049) and the use of proton pump inhibitors (p = 0.009).

The authors concluded although the clinical significance of faecal pH is not fully defined, its usefulness as a surrogate biomarker for intestinal pH should be further explored.  They suggest faecal pH is a physiological parameter that may be related to intestinal pH and may provide important physio-pathological information on CF-related pancreatic insufficiency. Faecal pH is correlated with fat absorption, and this may explain why pancreatic enzyme replacement therapy is not effective in all patients with malabsorption related to CF. Use of proton pump inhibitors is associated to higher values of faecal pH. Faecal pH could be used as a surrogate biomarker to routinely monitor the efficacy of pancreatic enzyme replacement therapy in clinical practice. Strategies to increase intestinal pH in children with cystic fibrosis should be targeted.

J Calvo-Lerma is at the Cystic Fibrosis Unit, Instituto de Investigación Sanitaria La Fe de Valencia, 46026, Valencia, Spain and the Research Institute of Food Engineering for Development, Universitat Politècnica de València, 46022, Valencia, Spain.

– This is an interesting paper and there are figures showing a good correlation of faecal pH with both the coefficient of fat absorption and faecal fat excretion. The authors’ suggestion that faecal pH could be used as a routine monitor of the efficacy of pancreatic replacement therapy seems to be worth exploring – particularly as faecal fat estimations are understandably unpopular and rarely used except for research purposes.

Cares KKlein MThomas REl-Baba M Rectal Prolapse in Children: An Update to Causes, Clinical Presentation, and Management.   J Pediatr Gastroenterol Nutr. 2020 Feb;70(2):243-246. doi: 10.1097/MPG.0000000000002546   [Pubmed]

Rectal Prolapse

A total of 158 patients were diagnosed with rectal prolapse, with mean age of onset being 3 years. Constipation was the leading cause, with straining being the most common complaint. Cystic fibrosis was only diagnosed in 4 patients. Thirty-four patients (22%) required surgical correction.

Constipation remains the main cause of rectal prolapse. Cystic fibrosis is no longer a common aetiology for rectal prolapse, because of the implementation of newborn screening. Patients with social stressors or atypical behaviour may be at risk for recurrent rectal prolapse.

From the Children’s Research Center, Children’s Hospital of Michigan, Detroit, MI.

Chevalier BHinzpeter A. The influence of CFTR complex alleles on precision therapy of cystic fibrosis. 
J Cyst Fibros.
2020 Mar;19 Suppl 1:S15-S18. doi: 10.1016/j.jcf.2019.12.008. Epub 2019 Dec 26.[Pubmed]      CFTR is an extensively studied gene and multiple sequence variants have been identified, many of which still need to be defined as neutral or disease causing. Complex alleles are defined when at least two variants are identified on the same allele. Each pathogenic variant can affect distinct steps of the CFTR biogenesis. As CFTR modulators are being developed to alleviate specific defects, pathogenic variants need to be characterized to propose adequate treatments. Conversely, cis-variants can affect treatment response when defects are additive or if they alter the binding or efficacy of the modulator. Hence, complex alleles increase the complexity of CFTR variant classification and need to be assigned as neutral, disease causing or modulating treatment efficacy. This review was based on a symposium session presented at the 16th ECFS Basic Science Conference, Dubrovnik, Croatia, 27 to 30 March, 2019.

Both authors from INSERM U1151, Institut Necker Enfants Malades, Paris, France; Université Paris Descartes, Paris, France. Electronic address: benoit.chevalier@inserm.fr.

Brian Cicali Tao LongSarah Kim, Rodrigo Cristofoletti. Assessing the Impact of Cystic Fibrosis on the Antipyretic Response of Ibuprofen in Children: Physiologically-Based Modeling as a Candle in the DarkBr J Clin Pharmacol  2020 Apr 25.doi: 10.1111/bcp.14326. Online ahead of print. [Pubmed]

Rodrigo Cristofoletti

The goal of this study is to present the utility of quantitative modelling for extrapolation of drug safety and efficacy to underrepresented populations in controlled clinical trials. To illustrate this, the stepwise development of an integrated disease/pharmacokinetics/pharmacodynamics model of antipyretic efficacy of ibuprofen in children with cystic fibrosis (CF) is presented along with therapy optimization suggestions.
Published clinical trials, in vitro data and drug physiochemical properties were used to develop an ibuprofen-mediated antipyresis model for febrile children also having CF. Workflow included first developing a mechanistic absorption model using in vitro-in vivo extrapolation followed by physiologically-based pharmacokinetic (PBPK) modeling. The verified PBPK model was then scaled to pediatric patients with CF. Once verified, the PBPK model was linked to an indirect response model of antipyresis for simulation of the overall antipyretic efficacy of ibuprofen in CF children.
Model simulations showed therapeutic inequivalence between healthy children and pediatric patients with CF; Cmax and AUC decreased by 39% (32-46%) and 44% (36-52%), respectively, in patients. Further and in agreement with literature reports, predicted pharmacodynamics time courses suggest a slower onset and faster offset of action in patients compared to healthy children, 30 and 60 minutes, respectively. Exploratory simulations suggest an increase in dosing frequency for CF children as a better therapeutic strategy.

The authors concluded model-informed approaches to leveraging knowledge obtained throughout the life cycle of drug development may play a key role in extrapolating drug efficacy and safety to underrepresented populations.

Dr Rodrigo Cristofoletti is Research Assistant Professor at the Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA

Cipolli M, Fethney J, Waters D, Zanolla L, Meneghelli I, Dutt S, Assael BM, Gaskin KJ.Occurrence, outcomes and predictors of portal hypertension in cystic fibrosis: A longitudinal prospective birth cohort study.  J Cyst Fibros. 2020 May;19(3):455-459. doi: 10.1016/j.jcf.2019.09.016. Epub 2019 Oct 31. [Pubmed]

    Kevin Gaskin

           Marco Cipolli

Background: The reported prevalence of portal hypertension (PH) in Cystic Fibrosis is variable, incidence rates rarely provided and the utility of liver function tests (LFT’s) early in life to predict PH is questionable. The aims were to (1) determine PH prevalence (P) and incidence rate (IR) and combined mortality transplant (MTX) data in PH vs non-PH patients and (2) to assess association of LFTs in early life with liver disease and PH.
(1) A double centre longitudinal cohort study of 577 CF patients diagnosed by newborn screening (NBS) with annual examinations for PH up to 18.5 years of age (max) was performed over 28 years for P, IR, and MTX data; (2) Cox proportional hazard models were used to assess the association of elevated LFTs on 2 or more occasions over 0-6.5 years and PH.
Results: 51/577(8.8%) developed PH with an average IR of near 3/1000 patient years per 5 year interval representing young, mid and late childhood respectively in patients 3-18 years of age. Combined mortality/liver transplant occurred in 12/51 (23.5%) PH and 25/526 (4.8%) non-PH (p < 0.001). Elevated enzymes particularly GGT (HR:5.71, 95% CI 3.11-10.47); ALT/GGT (HR: 5.56, 95% CI 2.82-10.98); and ALP/GGT (HR: 5.74, 95% CI 2.78-11.86) were associated with the onset of PH.
The authors concluded: This birth cohort with annual examination for PH provides an accurate assessment of the prevalence, and IR of PH and MTX of PH vs non-PH. Early elevated LFTs are associated with onset of MBC/PH.

Marco Cipolli is Director of the Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Kevin J Gaskin is Professor at the Department of Gastroenterology/James Fairfax Institute of Paediatric Nutrition, The Children’s Hospital at Westmead, Sydney, Australia

– A study from the Verona CF Centre in Italy and the Children’s Hospital at Westmead CF clinic Australia – the former introduced neonatal CF screening in the mid-Seventies (Gianni Mastella) and the latter from the early Eighties (Bridget Wilcken). This is the first time a CF neonatal cohort has been followed for 18.5 years assessing the occurrence and subsequent evolution of severe liver disease

Coffey MJGarg MHomaira NJaffe AOoi CY. Probiotics for people with cystic fibrosis. Cochrane Database Syst Rev. 2020 Jan 22;1:CD012949. doi: 10.1002/14651858.CD012949.pub2. [Pubmed]

Michael J Coffey

The conclusions of this review were that probiotics significantly reduce faecal calprotectin (a marker of intestinal inflammation) in children and adults with CF, however the clinical implications of this require further investigation. Probiotics may make little or no difference to pulmonary exacerbation rates, however, further evidence is required before firm conclusions can be made. Probiotics are associated with a small number of adverse events including vomiting, diarrhoea and allergic reactions. In children and adults with CF, probiotics may be considered by patients and their healthcare providers. Given the variability of probiotic composition and dosage, further adequately-powered multicentre RCTs of at least 12 months duration are required to best assess the efficacy and safety of probiotics for children and a

Dr Michael Jonathon Coffey is a researcher at the University of New South Wales, School of Women’s and Children’s Health,

Colombo C, Burgel PR, Gartner S, van Konigbruggen-Rietschel S, Noehrlich L, Seet-Gaudelus I, Southern KW. Impact of COVID-19 on people with cystic fibrosis. Lancet Respir Med. 2020;8(5):e35e36. doi:10.1016/S2213-2600(20)30177-6  [Pubmed]   Free PMC article                                                                    

     Carla Colombo

Carla Colombo and colleagues briefly review certain aspects of the coronavirus pandemic as it affects people with CF.  In Lombardy there have been only 10 people with CF out of total of 42,161 infected patients. They usually acquired the infection from family members. Similar experience came from UK, Germany and Spain with no serious impact on their CF disease severity of patients. The ECFS Registry is collecting data. Features of COVID-19 are clearly differentiated from those of cystic fibrosis. Requirement for availability of medication, foods are required for affected patients. No new clinical trials are starting and support is given to subjects with CF on current trials.

The article concludes  “People with cystic fibrosis and their families have invested considerable time and energy to maintain good health and, now, on the cusp of remarkable new therapies to transform their condition, they face a global pandemic, the effect of which is unclear. Early data suggest that most patients with cystic fibrosis are doing an exceptional job avoiding SARS-CoV-19 infection, but they must remain dedicated to this task, as data are gathered from across Europe to better understand factors that affect the severity of COVID-19 in people with cystic fibrosis.

Prof. Carla Colombo is at the Cystic Fibrosis Regional Reference Center, University of Milan and the Department of Pathophysiology and Transplantation, Milan, Italy

Cottrill KA, Farinha CM, McCarty NA. The bidirectional relationship between CFTR and lipids. Commun Biol. 2020;3(1):179. Published 2020 Apr 20. doi:10.1038/s42003-020-0909-1 [Pubmed]

       Kirsten Cottrill

While work to understand this CFTR has resulted in new treatment strategies, it is important to emphasise that CFTR exists within a complex lipid bilayer – a concept largely overlooked when performing structural and functional studies. In this review the authors discuss cellular lipid imbalances in CF, mechanisms by which lipids affect membrane protein activity, and the specific impact of detergents and lipids on CFTR function.

Kirsten A Cottrill is a Graduate Student at the McCarty Lab, Molecular and Systems Pharmacology Program, Emory University, Atlanta, GA, USA.

Danahay HLLilley SFox RCharlton HSabater JButton BMcCarthy CCollingwood SPGosling M. TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis.
Am J Respir Crit Care Med.
 2020 Jan 3. doi: 10.1164/rccm.201908-1641OC. [Epub ahead of print] [Pubmed]

     Henry Donahay

Rationale: Enhancing non-CFTR mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis and other muco-obstructive diseases. Objectives: To determine the effects of TMEM16A potentiation upon epithelial fluid secretion and mucociliary clearance. Methods: The effects of a novel low molecular weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. Measurements & Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca2+-activated Cl- channel activity and anion secretion in human bronchial epithelial cells from cystic fibrosis patients without impacting on calcium signalling. ETX001 rapidly increased fluid secretion and airway surface liquid height in cystic fibrosis human bronchial epithelial cells under both static and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with cystic fibrosis and non-CF muco-obstructive diseases. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/

Dr Henry Danahay is co-founder of Enterprise Therapeutics Ltd, Brighton, head of biology and Hon. Senior Research Fellow University of Sussex

De Boeck K, Lee T, Amaral M, Drevinek P, Elborn JS, Fajac I, Kerem E, Davies JC.  Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders’ consensus view.  J Cyst Fibros. 2020 Jun 8:S1569-1993(20)30162-4. doi: 10.1016/j.jcf.2020.05.012. Online ahead of print.[Pubmed]
CFTR modulators associated with substantial clinical benefit are expected to rapidly improve the baseline condition of people with cystic fibrosis (PWCF) as well as decrease the rate of lung function decline, the occurrence of pulmonary exacerbations and likely even other disease complications. These changes in clinical status of PWCF introduced by clinically effective modulator therapy will have major repercussions on modalities of future CF drug development.
As part of its ‘Strategic Plan to speed up Access to new Drugs’, the European Cystic Fibrosis Society (ECFS) convened a meeting in Brussels on November 27th 2019 with relevant stakeholders (CF researchers and clinicians, patient organization and pharmaceutical company representatives, regulators, health technology assessors; see Acknowledgments for list of attendees) to discuss the future of clinical trials in cystic fibrosis (CF) in the context of HEMT entering the clinical arena. The following is the conclusion of the presentations and discussions. It is hoped that these concepts will be considered in future regulatory guidelines and may provide rationale and support for alternative trial designs.

Department of Paediatrics, University Hospital of Leuven, University of Leuven, Leuven, Belgium. Electronic address: christiane.deboeck@uzleuven.be.

– A distinguished group of authors make an important point in this era of changing treatments and outlooks

Angélique Denis Sandrine Touzet Lamoussa Diabaté Isabelle Durieu Lydie Lemonnier Stéphanie Poupon-BourdyJean Iwaz Quitterie Reynaud Muriel Rabilloud . Quantifying Long-Term Changes in Lung Function and Exacerbations After Initiation of Azithromycin in Cystic Fibrosis.  Ann Am Thorac Soc 2020; 17(2):195-201.  [Pubmed]
 In cystic fibrosis, information on the efficacy of azithromycin past 12 months of treatment is still scarce. The study sought to quantify the changes in lung function and the number of intravenous antibiotic courses (IVACs) after initiation of azithromycin in patients included in the French Cystic Fibrosis Registry.  The study followed 1,065 children and 990 adults from 2 years before to 5 years after long-term azithromycin treatment initiated between 2001 and 2011. Mixed change-point models were used to quantify the changes in the forced expiratory volume (FEV) in 1 second and the yearly number of IVACs.

The authors concluded in children, long-term azithromycin treatment was associated with immediate and sustained beneficial changes in lung function and sustained beneficial changes in the frequency of pulmonary exacerbations. In adults, it was associated with immediate beneficial changes in lung function.

Dr Angelique Denis is at  Hospices Civils de Lyon, Pole Sante Publique and the Universite de Lyon.

Davies GThia LPStocks JBush AHoo AFWade ANguyen TTDBrody ASCalder AKlein NJCarr SBWallis CSuri RPao CSRuiz GBalfour-Lynn IMLondon Cystic Fibrosis Collaboration (LCFC).   Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year.  J Cyst FIBROS 2020 Feb 7. pii: S1569-1993(20)30031-X.doi: 10.1016/j.jcf.2020.01.006. [Epub ahead of print] [Pubmed[]

With the widespread introduction of newborn screening for cystic fibrosis(CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age.
Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs.

65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT =0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT.

The authors concluded that in this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes.

Dr Gwyneth Davies is a Research Associate Respiratory, Critical Care and Anaesthesia section, UCL Great Ormond Street Institute of Child Health (GOS ICH), London,

De Jong E, Garratt LW, Looi K, Lee AHY, Ling KM, Smith ML, Falsafi R, Sutanto EN, Hillas J, Iosifidis T, Martinovich KM, Shaw NC, Montgomery ST, Kicic-Starcevich E, Lannigan FJ, Vijayasekaran S, Hancock REW, Stick SM, Kicic A; WAERP, Arest CF. Ivacaftor or lumacaftor/ivacaftor treatment does not alter the core CF airway epithelial gene response to rhinovirus.   J Cyst Fibros. 2020 Jul 17:S1569-1993(20)30796-7. doi: 10.1016/j.jcf.2020.07.004. Online ahead of print. [Pubmed]

      Emma De Jong

Background: Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection.
Methods: Nineteen CF epithelial cultures (10 homozygous for p.Phe508del as CFTR Class 2, 9 p.Phe508del/p.Gly551Asp as Class 3) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 h. Culture RNA and supernatants were harvested to assess gene and protein expression respectively.
Results: RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated with CFTR modulators and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3 and only 68 genes for Class 2. Changes were predominantly related to regulators of lipid metabolism and inflammation, aspects of epithelial biology known to be dysregulated in CF. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection.

Conclusions: Though long-term clinical data is not yet available, results presented here suggest that first generation CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Future work should investigate the latest triple modulation therapies

Emma de Jong is at Senior Research Officer at the Telethon Kids Institute Respiratory Research Centre, Nedlands, 6009, Western Australia, Australia.

de Vries JM, Green D, Kucera JN, Fabbrini AL, Kidder M, Brown J, Wilsey M. Cystic Fibrosis-Related Pancreatic Cysts Decrease in Size and Number Upon Treatment With Cystic Fibrosis Transmembrane Conductance Regulator Modulators. Pancreas. 2020;49(6):e50-e51. doi:10.1097/MPA.0000000000001567 [Pubmed]

Michael Wilsey

No access to abstract  at time of reviewing – although the title contains the message!

Dr J M de Vries is in the Department of Pediatric Gastroenterology and Nutrition, Johns Hopkins All Children’s Hospital.

Dr. Wilsey specializes in pediatric gastroenterology, hepatology and nutrition in the Department of Medicine. He became chief of the medical staff in January 2020 and is vice chair of the Department of Gastroenterology.

Jordan B Dennis Andrew M Jones Emma A Davies William Welfare Peter J Barry Lisa Collier Andrew Turner Rowland J Bright-Thomas.   Influenza B Outbreak at an Adult Cystic Fibrosis Centre – Clinical Impact and Factors Influencing Spread.  J Cyst Fibros  2020 Jun 19;S1569-1993(20)30124-7. doi: 10.1016/j.jcf.2020.04.011.Online ahead of print. [Pubmed]
An outbreak of Influenza B occurred at a large United Kingdom (UK) regional adult cystic fibrosis (CF) centre in May 2016. This was late in the UK 2015-2016 influenza season and occurred on a specialist ward with strict infection control procedures. This study investigates the spread of influenza, clinical consequences and potential contributing factors.
10 of 21 inpatients developed influenza B between 5th and 12th May 2016, an attack rate of 48%. All those characterised were confirmed as the same strain of influenza B/Victoria-lineage. Influenza infection resulted in a mean FEV1 reduction of 10.5% (SD 11.3, p = 0.012), which persisted at 3 months post infection (p = 0.003). Nine of the affected cases rooms were in close proximity on the ward while patients in the two isolation rooms with enhanced ventilation did not become infected. Ventilation measurements in affected rooms ranged from 1.75 to 2.10 air changes/hour, below national recommendations. Seventy percent of affected inpatients had received the 2015/16 trivalent seasonal influenza vaccine, which did not contain a B/Victoria-lineage influenza B virus.

The authors concluded this influenza B outbreak in CF adults had a high attack rate and a significant clinical impact. Room ventilation and a limited protection from the seasonal influenza vaccine were possible contributory factors.

Jordan B Dennis  is at the Manchester Adult Cystic Fibrosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester.

Elie Dolgin. In utero intervention to stem the damage of cystic fibrosis. Nature  2020 Jul; 583(7818): S6-S7.doi: 10.1038/d41586-020-02108-8. [Pubmed]

Elie Dolgin

There is no abstract with article so the text is summarised as follows –

The author reviews the past and present situation regarding intrauterine treatment of the CF genetic defect now that specific modulator treatments are increasingly available since 2012. Organ damage or maldevelopment occurs in utero to many organs such as the pancreas, liver, male genital tract and others and is present and irreversible after birth. Animal evidence suggests this damage is preventable by antenatal use of appropriate modulators such as ivacaftor. Promising animal research in CF mice along these lines by Janet Larson team 20 years ago using intrauterine gene therapy with viruses encoding for CFTR showed promise. However, the death of an 18-year-old undergoing gene therapy for another unrelated condition in 1999 set progress back years, caused funding to dry up. Also two prominent UK groups failed to reproduce Larson’s findings.
More recently precise techniques for gene editing such as CRISPR allow more precise correction of the genetic defect and have revived interest in the intrauterine approach. The precise gene fixing technology could repair F508del CFTR mutation in mice and human cells. Apparently, treatment during a limited critical period in utero will prevent some prenatal damage.
Also, an antenatal blood test is now available which can identify a number of genetic disease including CF by 10 weeks’ gestation and also identify the exact mutation. Also, identifying the exact mutation would enable the mother to take the specific modulator effective against the foetal mutation. Present experience seems to indicate modulators are safe during pregnancy. Treatment of ferrets with CFTR mutations susceptible to ivacaftor are protected from widespread organ damage before birth.

The importance of having normal CFTR function before birth seems established. John Engelhardt who conducted this research considers “There is this in utero period when it is really important to have CFTR function”. As modulators such as ivacaftor are approved for increasingly young CF infants he considers of foetal treatment “It’s probably coming. It’s a natural progression”.

Dr Elie Dolgin is a science journalist and editor in Somerville Massachusetts

Scott H Donaldson T Danielle SamulskiCaroline LaFaveKirby ZemanJihong WuAaron TrimbleAgathe CeppeWilliam D BennettStephanie D Davis.  A four-week trial of hypertonic saline in children with mild cystic fibrosis lung disease: Effect on mucociliary clearance and clinical outcomes.  J Cyst Fibros  2020 Jul 12;S1569-1993(20)30801-8.doi: 10.1016/j.jcf.2020.07.009.Online ahead of print. [Pubmed]

Scott H Donaldson

Hypertonic saline (HS) is commonly prescribed for children with cystic fibrosis (CF) despite the absence of strong data indicating clinical efficacy in a population with mild lung disease. We hypothesized that HS treatment would result in a sustained improvement in mucociliary clearance (MCC) in children with CF who had minimal lung disease, thus providing evidence for a biologically relevant effect that also may be associated with clinical improvements.
The authors performed a randomized, placebo controlled, double blind study of 6% versus 0.12% sodium chloride, delivered three-times daily with an eFlow nebulizer for 4 weeks. MCC was measured using gamma scintigraphy at baseline, 2-hours after the first study treatment, and ~12-hours after the final dose (at day 28). Spirometry, respiratory symptoms (CFQ-R), and safety were also assessed.
Results: Study treatments were generally well tolerated and safe. HS (6% sodium chloride) resulted in a significant, sustained improvement from baseline in whole lung clearance after 4 weeks of therapy (p = 0.014), despite absence of a prolonged single-dose effect after the initial dose. This sustained change (12 hrs after prior dose) was significantly greater when compared to placebo (0.12% sodium chloride) treatment (p = 0.016). Improvements in spirometry with HS did not reach statistical significance but correlated with MCC changes
Conclusions: The observed sustained improvement in MCC with HS suggests that this treatment may yield health benefits, even in relatively mildly affected children with CF. Highlighting this physiologic finding is important due to the lack of meaningful, validated endpoints in this population.

Dr Scott Donaldson is at the University of North Carolina School of Medicine, Chapel Hill.

Dik J, Saglam M, Tekerlek H, Vardar-Yagli N, Calik-Kutukcu E, Inal-Ince D, Arikan H, Eryilmaz-Polat S, Dogru D.  Visuomotor Reaction Time and Dynamic Balance in Children with CysticFibrosis and Non-Cystic Fibrosis Bronchiectasis: A Case-Control Study.   Pediatr Pulmonol. 2020 Jun 13. doi: 10.1002/ppul.24903. Online ahead of print.[Pubmed]

       Jan Dik

Extrapulmonary involvement such as balance and reaction time is unclear in cystic fibrosis (CF) patients. The aim of this study was to evaluate visuomotor reaction time (VMRT) and dynamic balance in children with CF and non-CF bronchiectasis compared to healthy children.   Demographic and clinical characteristics were recorded. All children were evaluated with pulmonary function test (PFT) using a spirometer, incremental shuttle walk test (ISWT) for exercise capacity, Fitlight TrainerTM for VMRT, and functional reach test (FRT) for dynamic balance.

Fourteen children with CF (10.71±2.94 years, 7 females), 17 children with non-CF bronchiectasis (12.75±2.81 years, 8 females), and 21 healthy children (11.36±3.28 years, 11 females) were included. Children with CF had longer total VMRT (p=0.027), poorer FRT performance (p=0.001), and shorter ISWT distances (p=0.03) compared to the children with non-CF bronchiectasis and controls. Although total VMRT was longest in the CF group, there was no significant difference in mean VMRT among the CF, non-CF bronchiectasis, and control groups (p>0.05).

The authors concluded dynamic balance and VMRT show greater impairment in children with CF than in children with non-CF bronchiectasis compared to healthy controls. Findings suggest that VMRT and dynamic balance should be taken into consideration for assessments and exercise programs in pulmonary rehabilitation. This article is protected by copyright. All rights reserved.

Dr Jan Dik is at Hacettepe University, Faculty of Physical Therapy and Rehabilitation, Ankara, Turkey.

DiMango E, Overdevest J, Keating C, Francis SF, Dansky D, Gudis D.  Effect of highly effective modulator treatment on sinonasal symptoms in cysticfibrosis.  J Cyst Fibros. 2020 Jul 18:S1569-1993(20)30794-3. doi: 10.1016/j.jcf.2020.07.002. Online ahead of print. [Pubmed]

Emily DiMango

Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator for cystic fibrosis (CF) patients homozygous or heterozygous for F508del. Effects of the drug on sinonasal symptoms have not been studied    Adult participants were prospectively evaluated at baseline and after three months of treatment using validated questionnaires assessing sinonasal symptoms (SNOT-22) and CF-related quality of life (CFQ-R).
Results: Forty-three participants completed the study; 23 were taking other CF transmembrane conductance (CFTR) modulators at the time of study participation. There was a significant improvement in mean SNOT-22 from 34.8 (29.4-40, 95% confidence interval) to 24.4 (19.9-29.0) (p = 0.000003) and in the Respiratory domain of the CFQR from 60.6 (57.1-64.1) to 83.3 (79.4-87.2) (p = 0.0000002), both achieving a minimal clinically important difference. Patients previously taking CFTR modulators experienced a greater benefit in sinonasal and respiratory symptoms.

Conclusions: Elexacaftor-tezacaftor-ivacaftor is associated with significant improvement in sinonasal symptoms; previous use of CFTR modulators is associated with greater benefit

Dr Emily DiMango is Professor of Medicine at Columbia University Medical Center; Director, John Edsall-John Wood Asthma Center; Director, Adult Cystic Fibrosis Program

Egan ME.  Emerging Technologies for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Restoration in all People with CF.   Pediatr Pulmonol. 2020 Jul 18. doi: 10.1002/ppul.24965. Online ahead of print.[Pubmed]

          Mary Egan

These therapies optimize the function of the patients’ endogenous mutant Cystic FibrosisTransmembrane Conductance Regulator (CFTR), which results in return of CFTR channel function. 2019 will be remembered as a landmark year for the Cystic Fibrosis (CF) community because it marks the year when effective modulator therapy became available for most CF patients. It is unlikely that this approach will provide a game changing therapy for all. In part because the response to even the most promising modulator therapy is variable and an area of active investigation. Also, there are about 10% of patients with CF who don’t produce a mutant protein to modulate, potentiate or optimize and for these patients such therapies are unlikely to be of significant benefit. Efforts to develop small molecule therapy to promote protein production in patients with nonsense mutations such as PTC124 has proved to be far more challenging than predicted.

There is a need to develop new therapeutic approaches that can work for this patient population. These new therapies will be genetic-based therapies that include ribonucleic acid (RNA) therapies, deoxyribonucleic acid (DNA) therapies and gene editing technologies. Each approach will result in functional CFTR expression in CF affected cells. Ideally, these approaches would require less frequent dosing than effective modulators, which are given daily. For instance, RNA based treatments could be given periodically.

Ultimately, treatment with certain gene-altering treatments could be given once in a lifetime and lead to a permanent cure.  In this review which is based on Plenary 1 from the North American Cystic Fibrosis Conference in 2019 which is based on Plenary 1 from the North American Cystic Fibrosis Conference in 2019 the potential of RNA therapies, gene transfer therapies and gene editing therapies for the treatment of CF are reviewed, 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.

 Dr Marie E Egan is  Professor of Pediatrics (Respiratory) and of Cellular and Molecular Physiology; Director Cystic fibrosis Center and Vice Chair of Research Pediatrics, School of Medicine, Yale University, New Haven, CT, USA.

Elkins MDentice R.  Timing of hypertonic saline inhalation for cystic fibrosis.
Cochrane Database Syst Rev.
 2020 Feb 28;2:CD008816. doi: 10.1002/14651858.CD008816.pub4. [Pubmed]

             Mark Elkins

Inhalation of hypertonic saline improves sputum rheology, accelerates mucociliary clearance and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review.

The authors concluded timing of hypertonic saline inhalation makes little or no difference to lung function (low-certainty evidence). However, inhaling hypertonic saline before or during airway clearance techniques may maximise perceived efficacy and satisfaction. The long-term efficacy of hypertonic saline has only been established for twice-daily inhalations; however, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until evidence comparing these regimens is available.

Dr Mark Elkins is Clinical Associate Professor in the University of Sydney, Sydney Medical School and Senior research physiotherapist at the Royal Prince Albert Hospital, Sydney.

Farrell PMRock MJBaker MW.  The Impact of the CFTR Gene Discovery on Cystic Fibrosis Diagnosis, Counseling, and Preventive Therapy.  Genes 2020 Apr 8;11(4). pii: E401. doi: 10.3390/genes11040401.    Free full text [Pubmed]

      Mei Baker

   Michael Rock

  Philip Farrell

Discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene  was the long-awaited scientific advance that dramatically improved the diagnosis and treatment of cystic fibrosis(CF). The combination of a first-tier biomarker, immunoreactive trypsinogen (IRT), and, if high, DNA analysis for CF-causing variants, has enabled regions where CF is prevalent to screen neonates and achieve diagnoses within 1-2 weeks of birth  when most patients are asymptomatic. In addition, IRT/DNA (CFTR) screening protocols simultaneously contribute important genetic data to determine genotype, prognosticate, and plan preventive therapies such as CFTR modulator selection. As the genomics era proceeds with affordable biotechnologies, the potential added value of whole genome sequencing will probably enhance personalized, precision care that can begin during infancy. Issues remain, however, about the optimal size of CFTR panels in genetically diverse regions and how best to deal with incidental findings. Because prospects for a primary DNA screening test are on the horizon, the debate about detecting heterozygote carriers will likely intensify, especially as we learn more about this relatively common genotype. Perhaps, at that time, concerns about CF heterozygote carrier detection will subside, and it will become recognized as beneficial. We share new perspectives on that issue in this article.

Dr Philip M Farrell is Emeritus Dean & Professor Departments of Pedaitrics and population Health Sciences, University of Wisconsin

Dr Michael J Rock is division Head of Pediatric Pulmonology, Director of the Cystic Fibrosis Center, director of the pediatric pulmonology fellowship and he chairs the CF Newborn Screening Advisory group University of Wisconsin School of Medicine

Dr Mei W Baker is a professor in the Dept of Pediatrics and co-director in the Newborn Screening Laboratory at the University of Wisconsin School of Medicine and Public Health

– The authors state that the era of genetic/genomic medicine has brightened the outlook for all patients with CF and especially children. There is a detailed account of the development of the Wisconsin neonatal CF screening programme.      The Full Free Text can be strongly recommended.

Fawcett LKWidger JHenry GMOoi CY. Case report: Cholecystoduodenostomy for cholestatic liver disease in a premature infant with cystic fibrosis and short gut syndrome. 
BMC Pediatr.
 2019 Mar 11;19(1):78. doi: 10.1186/s12887-019-1443-5.
[Pubmed] Free PMC Article
Cholecystoduodenostomy is a surgical procedure that bypasses the extrahepatic biliary tree and connects the gallbladder directly to the duodenum. This case describes the successful use of this procedure in a novel situation.

A premature (34 weeks gestation) female infant with cystic fibrosis required a laparotomy on day 1 of life due to an intrauterine small bowel perforation. Resection of small bowel and ileostomy formation resulted in short gut syndrome, with 82 cm residual small bowel and intact ileocaecal valve. Post-ileostomy reversal at 2 months old, she developed conjugated hyperbilirubinaemia. Despite conservative management including increased enteral feeding, ursodeoxycholic acid, cholecystostomy drain insertion and flushes, her cholestatic jaundice persisted. A liver biopsy revealed an “obstructive/cholestatic” picture with fibrosis. To avoid further shortening her gut with an hepatoportoenterostomy, cholecystoduodenostomy was performed at 3 months of age with subsequent post-operative improvement and eventual normalisation of her clinical jaundice and liver biochemistry.

This is the first reported case of a cholecystoduodenostomy being used successfully to treat an infant with persistent conjugated hyperbilirubinemia, cystic fibrosis and short gut syndrome. Cholecystoduodenostomy is a treatment option that with further study, may be considered for obstruction of the common bile duct in patients with short gut and/or where a shorter operating time with minimal intervention is preferred.

FitzMaurice TSMcNamara PSNazareth DMcCann CBedi RShaw MWalshaw M.  Utility and validity of dynamic chest radiography in cystic fibrosis(dynamic CF): an observational, non-controlled, non-randomised, single-centre, prospective study.  BMJ Open Respir Res. 2020 Mar;7(1). pii: e000569. doi: 10.1136/bmjresp-2020-000569. Free full text[Pubmed]
Dynamic chest radiography (DCR) uses novel, low-dose radiographic technology to capture images of the thoracic cavity while in motion. Pulmonary function testing is important in cystic fibrosis (CF). The tolerability, rapid acquisition and lower radiation and cost compared with CT imaging may make DCR a useful adjunct to current standards of care.

This is an observational, non-controlled, non-randomised, single-centre, prospective study. This study is conducted at the Liverpool Heart and Chest Hospital (LHCH) adult CF unit. Participants are adults with CF. This study reviews DCR taken during routine CF Annual Review (n=150), validates DCR-derived lung volumes against whole body plethysmography (n=20) and examines DCR at the start and end of pulmonary exacerbations of CF (n=20). The primary objectives of this study are to examine if DCR provides lung function information that correlates with PFT, and lung volumes that correlate whole body plethysmography.

Dr Thomas FitzMaurice is a Clinical Fellow at the Adult CF Unit, Liverpool Heart and Chest Hospital NHS Trust, and the Institute of Translational Medicine, University of Liverpool, Liverpool, UK

Flume PAVanDevanter DR. Leveraging early markers of cystic fibrosis structural lung disease to improve outcomesEur Respir J. 2020 Apr 3;55(4). pii: 2000105. doi: 10.1183/13993003.00105-2020. Print  2020 Apr. [Pubmed]        Comment on the article of Wijker NEVidmar S et al Eur Respir J 2020 Apr 3;55(4):

Patrick Flume

(Précis of the article as there is no abstract) Development of a diagnostic tool for a chronic disease is a necessary first step in a longer process of testing interventions and (hopefully) demonstrating subsequent disease modification. Clarification of temporal associations between early CF lung disease manifestations and subsequent irreversible damage by CT prompts the obvious question of how intervention might be deployed to prevent or delay this process. Prescription of inhaled antipseudomonal antibiotics upon the identification of bacteria, notably Pseudomonas, has become standard of care, but what of the chronic therapies such as hypertonic saline, dornase alfa and macrolides? The data presented by WIJKER et al. suggest that earlier interventions guided by CT and inflammatory marker findings may be warranted.

Beyond hypothesising that “benefit is likely” in a subpopulation, we should feel obliged to study interventions longitudinally in that population to determine if benefit has occurred, and if so to what extent. Children with poor nutritional indices at age 3 years have lower lung function by age 6 years and the trajectory of nutritional status is associated with subsequent pulmonary function, justifying nutritional intervention in young children with poor nutritional indices. Is it time to consider subjecting all our infants with CF to MBW and/or CT imaging to identify those patients showing early signs of progression, or could we be more selective in whom we perform testing?

Ideally, we seek demonstration that a therapy can reverse or attenuate abnormal findings of diagnostic tests.  WIJKER et al. have left little doubt that addressing early inflammation in the CF lung will be integral to slowing or stopping CF lung disease progression.  Further, their results suggest that studies of intervention-associated change in atelectasis, airway thickening and/or IL-8 concentrations may be justified in infants with CF. Finally, they have provided the methodology for using CT to evaluate the effects of such interventions on lung disease progression in children. Many if not most subjects in this study were already receiving at least some chronic pulmonary interventions intended to mitigate obstruction and infection. It will be of great interest to observe whether early highly effective modulator therapy (HEMT) intervention will slow the development of structural disease later in life, and it appears that we will now be able to use CT to start these observations at a very early age. It may be that a decade from now, it will be possible to use the CT methodologies described by WIJKER et al to discriminate between those children with CF who enjoyed access to CFTR modulators early in life and those who did not.

Francis JCross DSchultz AArmstrong DNguyen RBranch-Smith C. Developing a smartphone application to support social connectedness and wellbeing in young people with cystic fibrosis.
J Cyst Fibros.
 2020 Jan 6. pii: S1569-1993(19)30991-9. doi: 10.1016/j.jcf.2019.12.011. [Epub ahead of print]  [Pubmed]
Young people with cystic fibrosis (CF) may be at increased risk of social isolation and mental illness. This study aimed to design and evaluate the usability and acceptability of a smartphone application (app) to support the social connectedness and wellbeing of young people living with CF.
Young people with CF aged 12-17 years (N = 22) were recruited from two paediatric hospitals in Australia. Study participants tested the CF app for six weeks before responding to an online survey about the app’s usability and acceptability. A subsample of participants (n = 20) discussed the app’s strengths and weaknesses during 11 online group interviews.
During the six-week testing period, 77% of participants used the app at least once a week and 82% accessed the app from a smartphone. Usability of the CF app was rated high. Most participants agreed the app was easy to use (86%) and felt comfortable using it (96%). Acceptability of the app was moderate. 77% of participants agreed they would recommend the app to others. Recommendations to improve the app’s functionality and acceptability included locating the chatroom within the app rather than redirecting users to a web browser and allowing users to personalise images, wellness tips and videos.

The authors concluded this study tested a highly usable, and moderately acceptable, smartphone app to improve the psychosocial health of young people living with CF. Future research will test the efficacy of the CF app on users’ social connectedness and wellbeing.

Dr Jacinta Francis is at Telethon Kids Institute, The University of Western Australia, Perth, Australia.

Ryosuke FukudaTsukasa Okiyoneda.  Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitylation as a Novel Pharmaceutical Target for Cystic Fibrosis. Pharmaceuticals (Basel)   2020 Apr 22;13(4):E75. doi: 10.3390/ph13040075  Full text [Pubmed]

Tsukasa Okiyoneda

Ryosuke Fukuda

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene decrease the structural stability and function of the CFTR protein, resulting in cystic fibrosis. Recently, the effect of CFTR-targeting combination therapy has dramatically increased, and it is expected that add-on drugs that modulate the CFTR surrounding environment will further enhance their effectiveness. Various interacting proteins have been implicated in the structural stability of CFTR and, among them, molecules involved in CFTR ubiquitylation are promising therapeutic targets as regulators of CFTR degradation. This review focuses on the ubiquitylation mechanism that contributes to the stability of mutant CFTR at the endoplasmic reticulum (ER) and post-ER compartments and discusses the possibility as a pharmacological target for cystic fibrosis (CF).

Ryosuke Fukuda is Research Associate in the Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University,  Japan.

Tsukasa Okiyoneda is Associate Professor, Kwansei Gakuin University

(Ubiquitination: The “kiss of death” process for a protein. In ubiquitination, a protein is inactivated by attaching ubiquitin to it. Ubiquitin is a small molecule. It acts as a tag that signals the protein-transport machinery to ferry the protein to the proteasome for degradation).

Garić D, Dumut DC, Shah J, De Sanctis JB, Radzioch D. The role of essential fatty acids in cystic fibrosis and normalizing effect of fenretinide [published online ahead of print, 2020 May 11]. Cell Mol Life Sci. 2020;10.1007/s00018-020-03530-x. doi:10.1007/s00018-020-03530-x [Pubmed]                                                                      Cystic fibrosis (CF) is the most common autosomal-recessive disease in Caucasians caused by mutations in the CF transmembrane regulator (CFTR) gene. Patients are usually diagnosed in infancy and are burdened with extensive medical treatments throughout their lives. One of the first documented biochemical defects in CF, which predates the cloning of CFTR gene for almost three decades, is an imbalance in the levels of polyunsaturated fatty acids (PUFAs). The principal hallmarks of this imbalance are increased levels of arachidonic acid and decreased levels of docosahexaenoic acids (DHA) in CF. This pro-inflammatory profile of PUFAs is an important component of sterile inflammation in CF, which is known to be detrimental, rather than protective for the patients. Despite decades of intensive research, the mechanistic basis of this phenomenon remains unclear. In this review we summarized the current knowledge on the biochemistry of PUFAs, with a focus on the metabolism of AA and DHA in CF. Finally, a synthetic retinoid called fenretinide (N-(4-hydroxy-phenyl) retinamide) was shown to be able to correct the pro-inflammatory imbalance of PUFAs in CF. Therefore, its pharmacological actions and clinical potential are briefly discussed as well.

Dr Dusan Garic of the Department of Human Genetics, McGill University, Montreal, QC, Canada

Monica GelzoPaola IacotucciMafalda CaputoGustavo CerneraMarika ComegnaVincenzo CarnovaleGaetano CorsoGiuseppe Castaldo.  Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis. J Cyst Fibros   2020 Jun 22;S1569-1993(20)30779-7.doi: 10.1016/j.jcf.2020.06.015.Online ahead of print.  [Pubmed]
 Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor (ORKAMBI) CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508).Aim of this study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508).
Methods: Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin.
Results: Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor (ORKAMBI) treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.
Conclusions: These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor (ORKAMBI) does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.

Monica Geizo is in the Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy; CEINGE – Biotecnologie avanzate, Naples, Italy.

George A, Smith B, Sawicki GS, Goetz DM. Survey of Patients with Cystic Fibrosis and Caregivers Decisions Regarding CFTR Modulators [published online ahead of print, 2020 Jun 26]. Pediatr Pulmonol. 2020;10.1002/ppul.24926. doi:10.1002/ppul.24926   [Pubmed]
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators are a novel approach to CF management that has become more readily available chronic CF therapies for certain populations of patients with CF. A cross-sectional survey of adults with CF and caregivers of pediatric patients with CF was done in two CF Centers to better understand the decision-making process including the potential influence of social media, CF care-teams, and family members on their decision whether to begin a CFTR modulator.
For the 90 participants, the most common influences in the decision to start modulator therapy were the CF providers/care teams (n=63), parents (n=49) and individuals with CF (n=27). The most impactful influence in the decision-making process were providers/care team (n=47) and parents (n=18). Social media was an influence for only 12 respondents, with an overall positive impact. Information from the CF Foundation was an influence for 12 participants and the main influence for 6 participants.

The most common reasons for stopping LUM-IVA were having TEZ-IVA as an option (n=25) and side-effects (n=15). Family and CF clinicians were the two main influences on the decision to initiate modulator therapy. CF clinicians were seen to be the most influential source. Social media had less influence on the decision-making process than expected despite the wide presence of the CF community online.

Dr Ashish George is in the Dept of Pediatrics, University at Buffalo, Buffalo, NY, United States.

Gelzo M, Iacotucci P, Caputo M, et al. Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis [published online ahead of print, 2020 Jun 22]. J Cyst Fibros. 2020;S1569-1993(20)30779-7. [Pubmed]
 Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment
Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.

These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.

From Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy; CEINGE – Biotecnologie avanzate, Naples, Italy.

Gettle LSHarden ABridges MAlbon D.  Prevalence and Risk Factors for Iron Deficiency in Adults With Cystic Fibrosis. Nutr Clin Pract. 2020 Jan 29. doi: 10.1002/ncp.10454. [Epub ahead of print]  [Pubmed]
Iron deficiency is common in cystic fibrosis (CF), but previous prevalence studies often reported results confounded by acute exacerbations. This single-center retrospective study aimed to identify the prevalence of iron deficiency in a stable adult CF population, identify the risk factors associated with iron deficiency, and compare common laboratory indicators of iron status.   Medical charts of 105 patients aged 18-67 were reviewed to determine the prevalence of anaemia. Of these patients, a subgroup of 67 were included.

In this stable CF population, the prevalence of iron deficiency was 41.8% (n = 67), and the prevalence of anaemia was 33.3% (n = 105). Iron deficiency was associated with presence of anemia (P < .001), vitamin A deficiency (P = .012), and moderate (P = .047) and severe lung disease (P = .045) compared with mild lung disease. Transferrin agreed poorly with other iron status indicators.

The authors concluded iron deficiency is common in CF, although prevalence rates can vary widely depending on the laboratory parameters used. They suggest CF centers should consider routine screening for iron deficiency.

From the Department of Nutrition Services, University of Virginia Health System, Charlottesville, Virginia, USA

Geurts MHde Poel EAmatngalim GDOka RMeijers FMKruisselbrink Evan Mourik PBerkers Gde Winter-de Groot KMMichel SMuilwijk DAalbers BLMullenders JBoj SFSuen SWFBrunsveld JEJanssens HMMall MAGraeber SYvan Boxtel Rvan der Ent CKBeekman JMClevers H. CRISPR-Based Adenine Editors Correct Nonsense Mutations in a Cystic Fibrosis Organoid Biobank. 
Cell Stem Cell.
Feb 13. pii: S1934-5909(20)30019-9. doi: 10.1016/j.stem.2020.01.019. [Epub ahead of print][Pubmed]

Maarten Geurts 

Hans Clevers

Adenine base editing (ABE) enables enzymatic conversion from A-T into G-C base pairs. ABE holds promise for clinical application, as it does not depend on the introduction of double-strand breaks, contrary to conventional CRISPR/Cas9-mediated genome engineering. Here, the authors describe a cystic fibrosis (CF) intestinal organoid biobank, representing 664 patients, of which ~20% can theoretically be repaired by ABE. We apply SpCas9-ABE (PAM recognition sequence: NGG) and xCas9-ABE (PAM recognition sequence: NGN) on four selected CF organoid samples. Genetic and functional repair was obtained in all four cases, while whole-genome sequencing (WGS) of corrected lines of two patients did not detect off-target mutations. These observations exemplify the value of large, patient-derived organoid biobanks representing hereditary disease and indicate that ABE may be safely applied in human cells.

Dr Maarten Geurts is a PhD student at the Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, the Netherlands and working in the Clevers Group

Professor Hans Clevers is leader of the Clevers Group and Chief Scientific Officer/Director Research of the Princess Máxima Center for pediatric oncology, Utrecht

Gostelie R, Stegeman I, Berkers G, Bittermann J, Ligtenberg-van der Drift I, Kipshagen PV, de Winter-de Groot K, Speleman L.  The impact of ivacaftor on sinonasal pathology in S1251N-mediated cysticfibrosis patients.   PLoS One. 2020 Jul 20;15(7):e0235638. doi: 10.1371/journal.pone.0235638. eCollection 2020 Free article. [Pubmed]
Eight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated. Ivacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy.  Primary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment.
Results: Computed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor.
Conclusion and relevance: Ivacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation.

Fromm the University Medical Center, Utrecht University, Utrecht, The Netherlands.

Guhr Lee TN, Cholon DM, Quinney NL, Gentzsch M, Esther CR Jr. Accumulation and persistence of ivacaftor in airway epithelia with prolonged treatment.   J Cyst Fibros. 2020 Jun 11:S1569-1993(20)30123-5. doi: 10.1016/j.jcf.2020.04.010. Online ahead of print.[Pubmed]

      Tara Guhr Lee

Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment.
CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with ivacaftor plus lumacaftor or ivacaftor plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting.
During treatment, ivacaftor accumulated in CF-HBEs to a much greater extent than either lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further ivacaftor accumulation, though remained above baseline even after washout.

Conclusions: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches.

Dr Tara Nicole Guhr Lee is a Research Technician in the Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina School of Medicine.

Guimbellot JSRyan KJAnderson JDLiu ZKersh LEsther CRRowe SMAcosta EP.  Variable cellular ivacaftor concentrations in people with cystic fibrosis on modulator therapy.  J Cyst Fibros. 2020 Feb 7. pii: S1569-1993(20)30035-7. doi: 10.1016/j.jcf.2020.01.011. [Epub ahead of print) [Pubmed]

Edward P Acosta

Jennifer S Guimbellot

The development of CFTR modulators has transformed the care of patients with cystic fibrosis(CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. The authors developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients.

While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that ivacaftor concentrations influence the activity and stability of restored CFTR protein.

Dr Jennifer S Guimbellot is a respiratory paediatrician at the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama and the Department of Pediatrics, Division of Pulmonary and Sleep Medicine, UAB, Birmingham, Alabama.,

Professor Edward Acosta is Professor; Director, Division of Clinical Pharmacology and the Antiviral Pharmacology laboratory in the University of Alabama, Birmingham

Hahn A, Burrell A, Ansusinha E, Peng D, Chaney H, Sami I, Perez GF, Koumbourlis AC, McCarter R, Freishtat RJ, Crandall KA, Zemanick ET.   Airway microbial diversity is decreased in young children with cystic fibrosiscompared to healthy controls but improved with CFTR modulation.  Heliyon. 2020 Jun 1;6(6):e04104. doi: 10.1016/j.heliyon.2020.e04104. eCollection 2020 Jun. Free PMC article.  [Pubmed]

           Andrea Hahn

The study objective was to test for differences in the upper airway microbiome of children with CF and healthy controls and age-related differences in children with CF.
Oropharyngeal swabs and clinical data were obtained from 25 children with CF and 50 healthy controls aged ≤6 years. Bacterial DNA was amplified and sequenced for the V4 region of 16S rRNA marker-gene. Alpha diversity was measured using operational taxonomic units (OTUs), Shannon diversity, and the inverse Simpson’s index. Beta diversity was measured using Morisita-Horn and Bray-Curtis and Jaccard distances. General linear models were used for comparison of alpha diversity measures between groups to account for differences in demographics and exposures. Mixed effects general linear models were used for longitudinal comparisons 1)   between children with CF of different ages and 2) between children with CF receiving CF transmembrane conductance regulator (CFTR) modulators, children with CF not receiving CFTR modulators, and healthy controls to adjust for repeated measures per subject.

Children with CF were more likely to have received antibiotics in the prior year than healthy controls (92% vs 24%, p < 0.001). Controlling age, race, ethnicity, length of breastfeeding, and having siblings, children with CF had a lower richness than healthy controls: OTUs 62.1 vs 83, p = 0.022; and trended toward lower diversity: Shannon 2.09 vs 2.35, p = 0.057; inverse Simpson 5.7 vs 6.92, p = 0.118. Staphylococcus, three Rothia OTUs, and two Streptococcus OTUs were more abundant in CF children versus healthy controls (all p < 0.05). Bray-Curtis and Jaccard distances, which reflect overall microbial community composition, were also significantly different (both p = 0.001). In longitudinally collected samples from children with CF, Morisita-Horn trended toward more similarity in those aged 0-2 years compared to those aged 3-6 years (p = 0.070). In children >2 years of age, there was a significant trend in increasing alpha diversity measures between children with CF not receiving CFTR modulators, children with CF receiving CFTR modulators, and healthy controls: OTUs 63.7 vs 74.7 vs 97.6, p < 0.001; Shannon 2.11 vs 2.34 vs 2.56, p < 0.001; inverse Simpson 5.78 vs 7.23 vs 7.96, p < 0.001.

Conclusions: Children with CF have lower bacterial diversity and different composition of organisms compared with healthy controls. This appears to start in early childhood, is possibly related to the use of antibiotics, and may be partially corrected with the use of CFTR modulators.

Dr Andrea Hahn is an infectious disease specialist and investigator in the Division of Infectious Diseases, Children’s National Hospital, Washington, DC, USA.

Harris JKWagner BDZemanick ETRobertson CEStevens MJHeltshe SLRowe SMSagel SD. Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation.  Ann Am Thorac Soc. 2020 Feb;17(2):212-220. doi: 10.1513/AnnalsATS.201907-493OC.[Pubmed]

It remains unclear how improving CFTR function modifies existing airway infection and inflammation.  This study aimed to compare sputum microbiome and markers of inflammation before and after 6 months of ivacaftor treatment. The study included 31 people with CF, ages 10 years and older, with at least one G551D CFTR allele and an forced expiratory volume in 1 second (FEV1) of 40% predicted or greater who were enrolled in the GOAL (G551D Observational) study. Sputum samples were collected either by induction (n = 14) or by spontaneous expectoration (n = 17) before and 6 months after initiation of ivacaftor.  Changes in bacterial community indices by sequencing of 16S rRNA amplicons, total and specific bacterial load, and a panel of proteases, antiproteases, and inflammatory cytokines were determined.

The cohort that spontaneously expectorated sputum had a lower FEV1, a higher proportion with Pseudomonas aeruginosa infection, and higher concentrations of sputum inflammatory markers compared with the cohort that provided sputum by induction, no significant changes in bacterial diversity, specific bacterial pathogens, or markers of inflammation were observed in these subjects. Neither total bacterial load nor presence of Pseudomonas changed significantly between paired samples with ivacaftor treatment. Younger patients experienced more shifts in their microbial communities than older patients.

The authors concluded 6 months of ivacaftor treatment were not associated with significant changes in airway microbial communities or measures of inflammation. These data suggest that concomitant antimicrobial and anti-inflammatory treatments will still be needed to manage airway disease in patients with CF treated with highly effective CFTR modulator therapy, especially in older patients with more advanced disease.

-These findings are not unexpected as the situation in the airways will have passed from the uninfected CFTR state to the chronic progressive inflammatory phase where restoration of CFTR will not affected the progression of the damaging chronic inflammation.

Hayden HSEng APope CEBrittnacher MJVo ATWeiss EJHager KRMartin BDLeung DH5Heltshe SLBorenstein EMiller SIHoffman LRFecal dysbiosis in infants with cystic fibrosis is associated with early linear growth failure.  Nat Med. 2020 Jan 20. doi: 10.1038/s41591-019-0714-x. [Epub ahead of print] [Pubmed]
Most infants with cystic fibrosis (CF) have pancreatic exocrine insufficiency that results in nutrient malabsorption and requires oral pancreatic enzyme replacement. Newborn screening for CF has enabled earlier diagnosis, nutritional intervention and enzyme replacement for these infants, allowing most infants with CF to achieve their weight goals by 12 months of age. Nevertheless, most infants with CF continue to have poor linear growth during their first year of life. Although this early linear growth failure is associated with worse long-term respiratory function and survival, the determinants of body length in infants with CF have not been defined. Several characteristics of the CF gastrointestinal (GI) tract, including inflammation, maldigestion and malabsorption, may promote intestinal dysbiosis. As GI microbiome activities are known to affect endocrine functions, the intestinal microbiome of infants with CF may also impact growth.

The authors identified an early, progressive fecal dysbiosis that distinguished infants with CF and low length from infants with CF and normal length. This dysbiosis included altered abundances of taxa that perform functions that are important for GI health, nutrient harvest and growth hormone signalling, including decreased abundance of Bacteroidetes and increased abundance of Proteobacteria. Thus, the GI microbiota represent a potential therapeutic target for the correction of low linear growth in infants with CF.

Dr Hilary S Hayden is in the Department of Microbiology, University of Washington, Seattle, WA, USA

 Hernandez-Nieto CAlkon-Meadows TLee JCacchione TIyune-Cojab EGarza-Galvan MLuna-Rojas MCopperman ABSandler B Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population.  Prenat Diagn. 2020 Jan 31. doi: 10.1002/pd.5656. [Epub ahead of print]  [Pubmed]

Dr Carlos Hernandez-Nieto

Genetic carrier screening has the potential to identify couples at risk of having a child affected with an autosomal recessive or X-linked disorder. However, the current prevalence of carrier status for these conditions in developing countries is not well defined. This study assesses the prevalence of carrier status of selected genetic conditions utilizing an expanded, pan-ethnic genetic carrier screening panel (ECS) in a large population of Mexican patients.
A retrospective chart review of all patients tested with a single ECS panel at an international infertility centre from 2012-2018 were included, the prevalence of positive carrier status in a Mexican population was evaluated.
805 individuals were analysed with ECS testing for 283 genetic conditions. 352 carriers (43.7%) were identified with 503 pathogenic variants in 145 different genes. Seventeen of the 391 participating couples (4.34%) were identified as being at-risk couples. The most prevalent alleles found were associated with alpha-thalassemia, cystic fibrosis, GJB2 non-syndromic hearing loss, biotinidase deficiency, and familial Mediterranean fever.

Based on the prevalence and severity of Mendelian disorders, the authors recommend that couples, who wish to conceive regardless of their ethnicity background, explore carrier screening and genetic counselling prior to reproductive medical treatment.

Dr Carlos Alberto Hernández Nieto is Reproductive Endocrinologist at Reproductive Medicine Associates of New York, New York, United States and Mexico, Mexico City, Mexico

Katherine B HisertTimothy P Birkland. Kelly Q SchoenfeltMatthew E LongBrenda GroganSuzanne CarterW Conrad LilesEdward F McKoneLev BeckerAnne M Manicone. Ivacaftor Decreases Monocyte Sensitivity to Interferon-γ in People with Cystic Fibrosis. ERJ Open Res 2020 Apr 19;6(2):00318-2019.doi: 10.1183/23120541.00318-2019.eCollection 2020 Apr.[Pubmed]   (http://bit.ly/2TeI6LG)     Free article

 Katherine Hisert

This study demonstrates that initiation of the CFTR modulator ivacaftor in people with cystic fibrosis and susceptible CFTR mutations causes an acute reduction in blood monocyte sensitivity to the key proinflammatory cytokine IFN-γ   ……..”Studies examining individuals before and after initiation of CFTR modulators have revealed novel functions of CFTR and shown that CFTR modulators do not reverse all disease manifestations [35]. Thus, knowledge of the post-modulator cystic fibrosis disease state is crucial for understanding what continued therapies will be needed for people with cystic fibrosis and what new challenges may arise”…….

Dr Katherine Hisert is in the Dept of Medicine, University of Washington, Seattle, WA, USA

Christine Højte Marianne Hørby JørgensenFlemming JensenTerese L KatzensteinMarianne SkovExtended Screening for Cystic Fibrosis Related Liver Disease Including Elastography Inchildren and Adolescents. Pediatr Gastroenterol Nutr   2020 Jul 28. J doi: 10.1097/MPG.0000000000002872.Online ahead of print. [Pubmed]
Objectives: Advances in treatment of cystic fibrosis (CF) have increased survival and thereby prevalence of patients with liver disease, making chronic liver disease one of the major complications of CF. We describe the prevalence of liver fibrosis, portal hypertension, and liver decompensation by extended screening for cystic fibrosis related liver disease (CFLD) including ultrasound, elastography, and an extended panel of biochemical markers.
Methods: A cross sectional study of CFLD in all pediatric CF patients (1-18 years) from the Copenhagen CF Center. Screening for liver disease included physical examination, biochemical analysis, Vibration-Controlled Transient Elastography (FibroScan), conventional ultrasound, and Real-Time Shear Wave elastography (SWE). Patients were scored according to Williams’ ultrasound scoring scale (WUSS) within six months.
Results: A total of 84 consecutive patients (male sex 46.4%, median age 10.4 years) were included. Eight patients (9.5%) had both ≥ two abnormal results of sonographic methods and ≥ two abnormal biochemical results and were in this study categorized as having manifest CFLD. Manifest CFLD patients were significantly older and had a higher mean value of APRI, but no differences in gender, z-height, z-weight, z-BMI, FEV1% or mean value of bilirubin or albumin were found.
Conclusions: In total eight patients (9.5%) in this pediatric CF population were categorized as having CFLD according to both biochemical and sonographic tests. Consistency was found among the results of FibroScan and SWE. We suggest WUSS and either FibroScan or SWE, combined with GGT as diagnostic markers for CFLD.

From the Copenhagen Cystic Fibrosis Center, Rigshospitalet.

Horati HJanssens HMMargaroli CVeltman MStolarczyk MKilgore MBChou JPeng LTiddens HAMWChandler JDTirouvanziam RScholte BJ.  Airway profile of bioactive lipids predicts early progression of lung disease in cystic fibrosis. 2020 Feb 10. pii: S1569-1993(20)30034-5. doi: 10.1016/j.jcf.2020.01.010. [Epub ahead of print]  [Pubmed]

Hamid N Horati

      Bob Scholte

Previously, these authors showed that abnormal levels of bioactive lipids in bronchoalveolar lavage fluid (BALF) from infants with cystic fibrosis (CF) correlated with early structural lung damage.  To extend these studies, BALF bioactive lipid measurement by mass spectrometry and chest computed tomography (CT, combined with the sensitive PRAGMA-CF scoring method) were performed longitudinally at 2-year intervals in a new cohort of CF children (n = 21, aged 1-5 yrs).

Results: PRAGMA-CF, neutrophil elastase activity, and myeloperoxidase correlated with BALF lysolipids and isoprostanes, markers of oxidative stress, as well as prostaglandin E2 and combined ceramide precursors (Spearman’s Rho > 0.5; P < 0.01 for all). Multiple protein agonists of inflammation and tissue remodeling, measured by Olink protein array, correlated positively (r = 0.44-0.79, p < 0.05) with PRAGMA-CF scores and bioactive lipid levels. Notably, levels of lysolipids, prostaglandin E2 and isoprostanes at first BALF predicted the evolution of PRAGMA-CF scores 2 years later. In wild-type differentiated primary bronchial epithelial cells, and in CFTR-inducible iCFBE cells, treatment with a lysolipid receptor agonist (VPC3114) enhanced shedding of pro-inflammatory and pro-fibrotic proteins.

The authors concluded their findings suggest that bioactive lipids in BALF correlate with and possibly predict structural lung disease in CF children, which supports their use as biomarkers of disease progression and treatment efficacy. Furthermore, our data suggest a causative role of airway lysolipids and oxidative stress in the progression of early CF lung disease, unveiling potential therapeutic targets.

Dr H Horati  is Paediatric Resident n the Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC-Sophia Children’s Hospital, University Hospital Rotterdam, the Netherlands

Dr B J Bob Scholte is group leader and assistant professor (Gene therapy, experimental therapy of lung disease) at Erasmus MC Rotterdam since 1986, presently associated with the Pediatric Pulmonology department, and the Cell biology department (Biomedical Sciences Theme).

– The early detection of bronchial infection is an important area of research if such infection is to be identified before irreversible tissue damage occurs – often at a very early age.

Jarosz-Griffiths HHScambler TWong CH Lara-Reyna SHolbrook JMartinon FSavic SWhitaker PEtherington CSpoletini GClifton I6Mehta AMcDermott MFPeckham D. Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis.  Elife. 2020 Mar 2;9. pii: e54556. doi: 10.7554/eLife.54556.[Pubmed]  Free full text

Thomas E Scambler

Heledd Jarosz-Griffiths

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA.

This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

Co-authors – Dr Heledd H Jarosz-Griffiths is in Leeds Institute of Medical Research at St James’s and the Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, United Kingdom.
Dr Thomas Scambler of the Institute of Medical Research at St James’s, University of Leeds and the Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, United Kingdom.

Comments from the journal Editors, (Jos WM van der Meer and Siroon Bekkering, Radboud University, Netherlands) – “the paper convincingly shows the auto-inflammatory characteristics of CF, and its dependence on NLRP3. The underlying mechanisms have been thoroughly studied. With that, the paper is innovative and provides insights that will be clinically relevant, especially as it will probably have consequences for new treatment modalities”.

Lead authors (Dr Thomas Scambler and Dr Heledd Jarosz-Griffiths, St James’ University Hospital) comment “Blocking the sodium channel (ENaC) in combination with therapies targeting chemical cytokines (IL-18 and IL-1b) which are over-produced in CF is a potential strategy to reduce inflammation in CF, and may help combat the onset of secondary diseases such as diabetes and joint disease.”

Kapnadak SGDimango EHadjiliadis DHempstead SETallarico EPilewski JMFaro AAlbright JBenden CBlair SDellon EPGochenour DMichelson PMoshiree BNeuringer IRiedy CSchindler TSinger LGYoung DVignola LZukosky JSimon RH  Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease.  
J Cyst Fibros.
 2020 Feb 27. pii: S1569-1993(20)30064-3. doi: 10.1016/j.jcf.2020.02.015. [Epub ahead of print]  Free full text [Pubmed]

Siddhartha Kapnadak

The CF Foundation assembled a multidisciplinary expert panel consisting of three workgroups: Pulmonary management; Management of comorbid conditions; Symptom management and psychosocial issues. Topics were excluded if the management considerations did not differ in ACFLD from in the overall CF population or if already addressed in other published guidelines. Recommendations were based on a systematic literature review combined with expert opinion when appropriate.

The committee formulated twenty-three recommendation statements specific to ACFLD that address the definition of ACFLD, pulmonary and intensive care unit management, management of selected comorbidities, symptom control, and psychosocial issues.

These recommendations are intended to be paired with previously published management guidelines for the overall CF population, with the objective of reducing practice variability and improving overall care, quality of life, and survival in those with ACFLD.

Dr Siddhartha G Kapnadak is Assistant Professor Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.

Kessels SJMCarter DEllery BNewton SMerlin TL. Prenatal genetic testing for cystic fibrosis: a systematic review of clinical effectiveness and an ethics review.
Genet Med.
Feb;22(2):258-267. doi: 10.1038/s41436-019-0641-8. Epub 2019 Aug 30  [Pubmed]
The authors aimed to assess the clinical value of prenatal testing for cystic fibrosis (CF) and whether ethical considerations would affect endpoint selection.  To determine effectiveness, they conducted a systematic literature review whose protocol outlined search strategies across eight databases, study inclusion criteria, and prespecified literature screening, data extraction, and synthesis processes. They conducted a scoping search on ethical considerations.
The genetic test showed good diagnostic performance. A change in clinical management was observed: termination of pregnancy (TOP) occurred in most cases where two pathogenic variants were identified in a fetus of carrier parents (158/167; 94.6%). The TOP rate was lower in pregnancies where CF was diagnosed after fetal echogenic bowel detection (~65%). TOP and caring for a child with CF were both associated with poor short-term parental psychological outcomes. Ethical analyses indicated that informed decisions should have been the main endpoint, rather than CF-affected births prevented.

The authors conclude CF testing leads to fewer CF-affected births. It is difficult to assess whether this means the test is valuable, since patients may not value termination of pregnancy primarily in terms of maternal or fetal health outcomes, psychological or otherwise. The value of testing should arguably be measured in terms of improving patient autonomy rather than health.

Adelaide Health Technology Assessment (AHTA), School of Public Health, The University of Adelaide, Adelaide, SA, Australia.

Kessler L. Can lumacaftor-ivacaftor reverse glucose-tolerance abnormalities in cystic fibrosis? J Cyst Fibros. 2020 May 5. pii: S1569-1993(20)30126-0. doi: 10.1016/j.jcf.2020.04.013. [Epub ahead of print] [Pubmed]

     Laurence Kessler

We are thankful to Manfred Ballmann and his colleagues for their interest in our recently published article [1]. By analyzing the effect of one year of lumacaftor–ivacaftor treatment on metabolic status in 40 cystic fibrosis patients affected by early glucose tolerance abnormalities, we observed an improvement in glucose tolerance, together with favourable changes in weight and pulmonary function. Furthermore, both one- and two-hour glycemia decreased in the subgroup, with improved oral glucose tolerance test (OGTT) categories. In their correspondence, Manfred Ballmann et al. propose that the effects of lumacaftor–ivacaftor should be interpreted with caution, due to the selected study population and natural history of glucose-tolerance abnormalities in cystic fibrosis.

The study population was composed of patients with either initial impaired glucose tolerance (IGT) or newly diagnosed cystic fibrosis-related diabetes (CFRD), since the moderate functional alteration of beta cells is still potentially reversible at this stage of the disease. We agree with Manfred Ballmann because, in our study, we did not consider the potential worsening of glucose tolerance in subjects with NGT after treatment. However, at this stage of CFRD, very early structural alterations of islets can be observed in the pancreata of CF patients. As such, CFRD suggests that the CFTR modulator is of low interest at this stage of the disease. Bogdani et al. [

2] have evaluated the morphology of tissue from very young CF children (<4 years of age), as well as adult patients with CF and CFRD. The relative number of beta cells in young CF tissue was reduced by 50% or more, when compared to age-matched controls. Furthermore, young CF tissue displayed significantly smaller insulin-positive areas. CFRD pancreata exhibited greater islet injury, with further reduction in islet density and a decreased relative number of beta cells. Together, these results strongly suggest that an early deficiency in beta-cell number in CF may contribute to the development of glucose intolerance in the young CF population and, later in life, to CFRD.

Although our analysis could not exclude any impact of the natural disease history, various longitudinal studies have reported spontaneous improvements in glucose tolerance in CF patients, as well as improvements in patients’ nutritional status and respiratory function. This is due to the natural disease history. To illustrate this point, Manfred Ballmann cited data from the Scheuing study [3], which observed substantial variability in glucose-tolerance abnormalities in CF, as a large cohort of 1128 CF patients benefited from 4643 OGTT over 9 years. Scheuing reported regression from CFRD to NGT in 21.7% of cases, which is comparable with our study data (22.2%, including 31 patients with IGT and 9 with CFRD). Interestingly, when we analyze Scheuing’s [3] data for patients with IGT, 40.1% of patients returned to NGT and 14.6% altered their glucose tolerance and developed a CFRD. Conversely, in our study, 58% of patients returned to NGT and no patients presented with diabetes. Obviously, analysis of these data should consider the limited number of patients involved in our study.

In comparison with other types of diabetes, CFRD is characterized by very particular abnormalities of glucose tolerance. Early postprandial hyperglycemia is indicated by one-hour glucose values at OGTT and by continuous glucose measurement, which may impact lung function and nutritional status for several years prior to the development of diabetes. Recently, research has highlighted a decrease in the incretin effect, together with the role of a CFTR chloride-channel defect, in terms of both beta-cell function and also in alpha cells. This facilitates better understanding of these particular glucose-tolerance abnormalities, as impaired suppressibility of the glucagon release has been reported in CF patients, after an OGTT that possibly contributes to the development of glucose intolerance [4]. From our perspective, it is impossible for our study to exclude the influence of the lumacaftor–ivacaftor on the improvement of glucose tolerance.

However, our study suggests that the CFTR modulator plays a positive role at the very early stage of glucose-tolerance abnormalities in CF, without being able to demonstrate whether this is a direct effect that targets CFTR, the consequence of an improvement in nutritional and respiratory status, or both. Currently, there is an overall lack of large studies that explore treatments for CFRD. As such, there is a need for more analysis of metabolic parameters in randomized studies that evaluate more effective CFTR modulators (e.g., the new triple-combination CFTR modulator [5].

  1. Misgault, B., et al., Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cystic Fibrosis.https://doi.org/10.1016/j.jcf.2020.03.002. (Abstract included in section 2020B of cysticfibrosis.online)
  2. Bogdani M.et alStructural abnormalities in islets from very young children with cystic fibrosis may contribute to cystic fibrosis-related diabetes  2017; 7: 17231https://doi.org/10.1038/s41598-017-17404-z
  3. Scheuing N.et al.High variability in oral glucose tolerance among 1,128 patients with cystic fibrosis: a multicenter screening study.PLoS ONE. 2014; 9e112578
  4. Edlund A.et al.CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells.Sci Rep. 2017; 7: 90https://doi.org/10.1038/s41598-017-00098-8
  5. Middleton P.G.et al.Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019; 381: 1809-1819      32387043

Laurence Kessler is Professor of Endocrinology and Diabetology at Strasbourg University Hospitals, France

Kirchhoff L, Dittmer S, Weisner AK, Buer J, Rath PM, Steinmann J. Antibiofilm activity of antifungal drugs, including the novel drug olorofim, against Lomentospora prolificans. J Antimicrob Chemother. 2020 May 9:dkaa157. doi:10.1093/jac/dkaa157. Epub ahead of print.[Pubmed]
Patients with immunodeficiency or cystic fibrosis frequently suffer from respiratory fungal infections. In particular, biofilm-associated fungi cause refractory infection manifestations, linked to increased resistance to anti-infective agents. One emerging filamentous fungus is Lomentospora prolificans. Here, the biofilm-formation capabilities of L. prolificans isolates were investigated and the susceptibility of biofilms to various antifungal agents was analysed.  The most promising antibiofilm effects were detected with voriconazole and olorofim. 

The authors believe this is the first study demonstrating the antibiofilm potential of olorofim against the human pathogenic fungus L. prolificans. 

Lisa Kirchhoff is at the Institute of Medical Microbiology, University Hospital Essen Germany.

Konstan MWVanDevanter DRRowe SMWilschanski MKerem ESermet-Gaudelus IDiMango EMelotti PMcIntosh JDe Boeck KACT CF Study Group.  Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF). 
J Cyst Fibros.
 2020 Jan 23. pii: S1569-1993(20)30030-8. doi: 10.1016/j.jcf.2020.01.007. [Epub ahead of print] [Pubmed]

Michael Konstan

Ataluren was developed for potential treatment of nonsense-mutation cystic fibrosis (CF). A previous phase 3 ataluren study failed to meet its primary efficacy endpoint, but post-hoc analyses suggested that aminoglycosides may have interfered with ataluren’s action. Thus, this subsequent trial (NCT02139306) was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation CF not receiving aminoglycosides.
Eligible subjects with nonsense-mutation CF (aged ≥6 years; percent predicted (pp) FEV1 ≥40 and ≤90) from 75 sites in 16 countries were randomly assigned in double-blinded fashion to receive oral ataluren or matching placebo thrice daily for 48 weeks. The primary endpoint was absolute change in average ppFEV1 from baseline to the average of Weeks 40 and 48.

279 subjects were enrolled; 138 subjects in the ataluren arm and 136 in the placebo arm were evaluable for efficacy. Absolute ppFEV1 change from baseline did not differ significantly between the ataluren and placebo groups at Week 40 (-0.8 vs -1.8) or Week 48 (-1.7 vs -2.4). Average ppFEV1 treatment difference from baseline to Weeks 40 and 48 was 0.6 (95% CI -1.3, 2.5; p = 0.54). Pulmonary exacerbation rate per 48 weeks was not significantly different (ataluren 0.95 vs placebo 1.13; rate ratio p = 0.40). Safety was similar between groups. No life-threatening adverse events or deaths were reported.

Neither ppFEV1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive.

– Disappointing result when earlier work seemed so promising.

Dr Michael Konstan is the Gertrude Lee Chandler Tucker Professor of Pediatrics, Department of Pediatrics, School of Medicine, Case Western Reserve University

Kopp BT, Fitch J, Jaramillo L, Shrestha CL, Robledo-Avila F, Zhang S, Palacios S, Woodley F, Hayes D Jr, Partida-Sanchez S, Ramilo O, White P, Mejias A.  Whole-blood transcriptomic responses to lumacaftor/ivacaftor therapy in cystic fibrosis.  J Cyst Fibros. 2020 Mar;19(2):245-254. doi: 10.1016/j.jcf.2019.08.021. Epub 2019 Aug 29.[Pubmed]

Benjamin Kopp

Background: Cystic fibrosis (CF) remains without a definitive cure. Novel therapeutics targeting the causative defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are in clinical use. Lumacaftor/ivacaftor is a CFTR modulator approved for patients homozygous for the CFTR variant p.Phe508del, but there are wide variations in treatment responses preventing prediction of patient responses. We aimed to determine changes in gene expression related to treatment initiation and response.
Methods: Whole-blood transcriptomics was performed using RNA-Seq in 20 patients with CF pre- and 6 months post-lumacaftor/ivacaftor (drug) initiation and 20 non-CF healthy controls. Correlation of gene expression with clinical variables was performed by stratification via clinical responses.

Results: We identified 491 genes that were differentially expressed in CF patients (pre-drug) compared with non-CF controls and 36 genes when comparing pre-drug to post-drug profiles. Both pre- and post-drug CF profiles were associated with marked overexpression of inflammation-related genes and apoptosis genes, and significant under-expression of T cell and NK cell-related genes compared to non-CF. CF patients post-drug demonstrated normalized protein synthesis expression, and decreased expression of cell-death genes compared to pre-drug profiles, irrespective of clinical response. However, CF clinical responders demonstrated changes in eIF2 signaling, oxidative phosphorylation, IL-17 signaling, and mitochondrial function compared to non-responders. Top overexpressed genes (MMP9 and SOCS3) that decreased post-drug were validated by qRT-PCR. Functional assays demonstrated that CF monocytes normalized calcium (increases MMP9 expression) concentrations post-drug.

Conclusions: Transcriptomics revealed differentially regulated pathways in CF patients at baseline compared to non-CF, and in clinical responders to lumacaftor/ivacaftor.

Dr Benjamin T Kopp is in the Division of Pulmonary Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; Center for Microbial Pathogenesis, Nationwide Children’s Hospital, Columbus, OH, USA.

Laselva O, Bartlett C, Popa A, Ouyang H, Gunawardena TNA, Gonska T, Moraes TJ, Bear CE. Emerging preclinical modulators developed for F508del-CFTR have the potential to be effective for ORKAMBI resistant processing mutants.  J Cyst Fibros   2020 Jul 30;S1569-1993(20)30807-9. doi: 10.1016/j.jcf.2020.07.015.Online ahead of print. [Pubmed]

     Onofrio Laselva

F508del is prototypical of Class 2 CFTR mutations associated with protein misprocessing and reduced function. Corrector compounds like lumacaftor partially rescue the processing defect of F508del-CFTR whereas potentiators like ivacaftor, enhance its channel activity once trafficked to the cell surface. We asked if emerging modulators developed for F508del-CFTR can rescue Class 2 mutations previously shown to be poorly responsive to lumacaftor and ivacaftor.
Methods: Rescue of mutant CFTRs by the correctors: AC1, AC2-1 or AC2-2 and the potentiator, AP2, was studied in HEK-293 cells and in primary human nasal epithelial (HNE) cultures, using a membrane potential assay and Ussing chamber, respectively.
Results: In HEK-293 cells, we found that a particular combination of corrector molecules (AC1 plus AC2-1) and a potentiator (AP2) was effective in rescuing both the misprocessing and reduced function of M1101K and G85E respectively. These findings were recapitulated in patient-derived nasal cultures, although another corrector combination, AC1 plus AC2-2 also improved misprocessing in these primary tissues. Interestingly, while this corrector combination only led to a modest increase in the abundance of mature N1303K-CFTR it did enable its functional expression in the presence of the potentiator, AP2, in part, because the nominal corrector, AC2-2 also exhibits potentiator activity.
Conclusions: Strategic combinations of novel modulators can potentially rescue Class 2 mutants thought to be relatively unresponsive to lumacaftor and ivacaftor.

Dr Onofrio Laselva is with the Programme in Molecular Medicine, Hospital for Sick Children, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.

Low DWilson DAFlume PA. Screening practices for nontuberculous mycobacteria at us cystic fibrosis centers.  J Cyst Fibros. 2020 Mar 13. pii: S1569-1993(20)30060-6. doi: 10.1016/j.jcf.2020.02.013. [Epub ahead of print]  [Pubmed]
Current guidelines recommend at least once yearly screening for nontuberculous mycobacteria (NTM) in Cystic Fibrosis (CF), however screening practices remain widely variable. This study evaluates current practices among United States CF centers with specific focus on clinical predictive factors for NTM screening.

Between 2010 AND 2014 NTM screening practices varied widely among United States CF centers with many centers testing only on clinical changes. With higher rates of testing shown as successful in identifying more patients with NTM, routine screening should be emphasized in CF care going forward.

From the Department of Medicine, University of Colorado, Denver, CO, United States.

Järvholm SEricson PGilljam M. Patient acceptance and outcome of mental health screening in Swedish adults with cystic fibrosis.  Qual Life Res. 2020 Jan 9. doi: 10.1007/s11136-020-02417-5. [Epub ahead of print]  [Pubmed]

    Stina Jarvholm

Anxiety and depression are common among adults with cystic fibrosis (CF), and the International Committee on Mental Health in CF (ICMH) recommends annual screening for mental health problems. We implemented screening according to the recently published guidelines and assessed the results from the first year, as well as the patients’ attitude to annual screening METHODS: Adult patients attending Gothenburg CF-center from Feb 2015 to Dec 2016 completed the GAD-7 (anxiety) and PHQ-9 (depression) forms at the time of their annual review. In addition, questions regarding the screening process and instruments used were asked.

All invited patients (n = 100, 52% males, 2% lung transplanted), with a median age of 28 years (range 18-65), agreed to participate. In general (83%), the patients were positive to screening on an annual basis. No significant differences in total GAD-7 and PHQ-9 scores were found when comparing men and women. Patients younger than 30 years of age reported more symptoms of anxiety compared to older patients (p = 0.02). There were 21 (21%) patients with scores > 10 for GAD-7 and/or PHQ-9 indicating at least moderate anxiety or depression. Scores > 10 were reported by 15 patients on GAD-7, 15 patients on PHQ-9, and 9 patients reported scores above 10 on both measures.

The authors concluded the patients considered annual check-ups for mental health issues important. Although the screening results are reassuring, the group is heterogenic and the suggest younger individuals should be given extra attention. They suggest follow-up over longer time should provide more robust data.

Dr Stina Jarvholm is a psychologist in the Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gröna stråket 9, 413 45, Gothenburg

Lavi EGileles-Hillel AZangen D. Somatic growth in cystic fibrosis.   Curr Opin Endocrinol Diabetes Obes. 2020 Feb;27(1):38-46. doi: 10.1097/MED.0000000000000522.  [Pubmed]

     Alex Gileles-Hillel

David Zangen

Cystic fibrosis (CF) is commonly associated with compromised growth especially in severe cases when the pulmonary function (PFT) deteriorates. As growth optimization is an important aspect of CF management, this review will summarize the current knowledge on the prevalence of growth failure in CF patients, and focus on the mechanisms leading to poor growth, on the association of poor linear growth with reduced PFT and on recombinant human growth hormone (rhGH) therapy in CF patients.

Despite the improvement in CF care in the last 2 decades, compromised linear growth is still quite prevalent. The pathophysiology of growth failure in CF is multifactorial. Malnutrition due to decreased energy intake increased energy expenditure and malabsorption of ingested nutrients secondary to pancreatic insufficiency, all probably play a major role in growth restriction. In addition, chronic inflammation characteristic of CF may contribute to growth failure via alteration in the GH-insulin-like growth factor 1 signaling and other changes in the growth plate. rhGH and new CFTR modulators may improve some growth parameters.

Beyond optimizing nutrition and malabsorption, and controlling chronic inflammation, children with CF may benefit from the anabolic effects of rhGH therapy to improve their anthropometric parameters. Whether this translates into better PFT and improved long-term outcomes is yet to be determined.

Prof David Zangen is Head of the Division of Pediatric Endocrinology and Juvenile Diabetes Unit, Pediatric Endocrinology Unit.        Dr Alex Gileles-Hillel  a member of the Pediatric Pulmonology and CF Unit, Department of Pediatrics.  The Wohl Institute for Translational Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

– There is a considerable research on the use of growth hormone in children with CF

Lipman M, Cleverley J, Fardon T, Musaddaq B, Peckham D, van der Laan R, Whitaker P, White J.  Current and future management of non-tuberculous mycobacterial pulmonary disease (NTM-PD) in the UK.   BMJ Open Respir Res. 2020 Jun;7(1):e000591. doi: 10.1136/bmjresp-2020-000591. [Pubmed]

Marc Lipman

A rising number of non-tuberculous mycobacterial (NTM) isolates are being identified in UK clinical practice. There are many uncertainties around the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD), including its epidemiology, diagnosis, treatment and prevention. Regional variations in how patients with NTM-PD are managed reflects the lack of standardised pathways in the UK. Service optimisation and multidisciplinary working can improve the quality of care for patients with NTM-PD, including (1) better identification of patients at risk of NTM-PD and modification of risk factors where applicable; (2) standardisation of reference laboratory testing to offer clinicians access to accurate and prompt information on NTM species and drug sensitivities; (3) development of recognised specialist NTM nursing care; (4) standardisation of NTM-PD imaging strategies for monitoring of treatment and disease progression; (5) establishment of a hub-and-spoke model of care, including clear referral and management pathways, dedicated NTM-PD multidisciplinary teams, and long-term patient follow-up; (6) formation of clinical networks to link experts who manage diseases associated with NTM; (7) enabling patients to access relevant support groups that can provide information and support for their condition; and (8) development of NTM research groups to allow patient participation in clinical trials and to facilitate professional education.

Professor Marc Lipman is at the Centre for Respiratory Medicine, Royal Free Hospital & the Division of Medicine, University College London.

Lopeman RCHarrison JRathbone DLDesai MLambert PACox JAG.  Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus.  Sci Rep. 2020 Jan 27;10(1):928. doi: 10.1038/s41598-020-57844-8.   [Pubmed] Free PMC Article

Rose Lopeman

Infections caused by Mycobacterium abscessus are increasing in prevalence in cystic fibrosispatients. This opportunistic pathogen’s intrinsic resistance to most antibiotics has perpetuated an urgent demand for new, more effective therapeutic interventions. Here they report a prospective advance in the treatment of M. abscessus infection; increasing the susceptibility of the organism to amoxicillin, by repurposing the β-lactamase inhibitor, relebactam, in combination with the front line M. abscessus drug imipenem. They establish by multiple in vitro methods that this combination works synergistically to inhibit M. abscessus. They also show the direct competitive inhibition of the M. abscessus β-lactamase, BlaMab, using a novel assay, which is validated kinetically using the nitrocefin reporter assay and in silico binding studies. Furthermore, they reverse the susceptibility by overexpressing BlaMab in M. abscessus, demonstrating relebactam-BlaMab target engagement. Finally, they highlight the in vitro efficacy of this combination against a panel of M. abscessus clinical isolates, revealing the therapeutic potential of the amoxicillin-imipenem-relebactam combination

Rose Lopeman is at Department of Medical Sciences Aston University

Lopes-Pacheco M.  CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine, Front Pharmacol.  2020 Feb 21;10:1662. doi: 10.3389/fphar.2019.01662. eCollection 2019. [Pubmed]  (Full version on internet)

Miquela Lopes-Pacheco

Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients’ lives with short- and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with C

Dr Miqueias Lopes-Pacheco is at Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.

– This is a very detailed extensively referenced account of the present situation concerning modulators. The full text is available and can be recommended.

Lusman SS, Borowitz D, Marshall BC, Narkewicz MR, Gonska T, Grand RJ, Simon RH, Mascarenhas MR, Schwarzenberg SJ, Freedman SD.  DIGEST: Developing innovative gastroenterology specialty training.    J Cyst Fibros. 2020 Jul 28:S1569-1993(20)30805-5. doi: 10.1016/j.jcf.2020.07.012. Online ahead of print. Free PMC article.[Pubmed]

    Sarah Lusman

Individuals with cystic fibrosis (CF) now have an increased life expectancy, due to advances in care provided by a multidisciplinary team. The care model has expanded over time to include multiple subspecialties. The Cystic Fibrosis Foundation conducted a survey of Care Center Directors and identified a need for pediatric and adult gastroenterologists with expertise in the diagnosis and treatment of intestinal, pancreatic and hepatic complications of CF. To address this need, the Developing Innovative GastroEnterology Specialty Training (DIGEST) program was created. The development, implementation, and early results of this training program are reported herein.

Dr Sarah Shrager Lusman is a paediatric gastroenterologist at the  Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States