History – 2020 (Section 1)

SECTION 1 (FIRST AUTHOR  A TO L)

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.

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

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.

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.

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.

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.

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.
Thorax.
 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.

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.

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 adults with CF.

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

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

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,

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.

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

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.

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.
 2020 
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

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

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

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.
 2020 
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.

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

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

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)

Miquelas Lopez-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 CF.

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