2021   M – Z

N MalaguttiV Fancello A CarianiF BattistiniC FabbriA Di LaoraG ValpianiC MorottiV IanniniM BorinA RavaniC BianchiniA CiorbaF StomeoS Pelucchi.   Ion concentrations in nasal airway surface liquid: a prediction model for the identification of cystic fibrosis carriersRhinology. 2021 Aug 16.doi: 10.4193/Rhin21.064. Online ahead of print    [Pubmed]
Background: Cystic fibrosis (CF) carriers seem to have a higher risk to develop chronic rhino-sinusitis (CRS), although the full underlying mechanisms are unknown. Ion concentrations in nasal airway surface liquid (ASL) may be influenced by the heterozygosity for CF gene mutation, with possible impacts on the development of CRS.
Methods: A cheap and feasible standardized technique was designed to measure the ion levels in nasal ASL. With this purpose we collected, under basal conditions, samples from the nasal cavity of 165 adults: 14 homozygous for CF, 83 carriers and 68 healthy controls. Sodium (Na) and Chlorine (Cl) concentrations were then evaluated among different groups.
Results: Statistical analysis revealed a significant difference of Na and Cl values between controls and carriers and between controls and homozygotes. Receiver operating characteristic (ROC) curves and derived indicators (Youden’s index and Area Under the Curve, AUC) were used to further evaluate the diagnostic capability of Na and Cl concentrations to differentiate heterozygotes from controls. ROC curves demonstrated that the optimal diagnostic cut-off value of Na is at 124, and the optimal cut-off value of Cl is at 103,2.
Conclusion: ASL sampling can be considered a new diagnostic tool for providing quantitative information on nasal ion composition. According to our findings, Na and Cl concentrations of nasal ASL could represent a useful tool to assess heterozygotes and healthy controls.

Dr L Malgutti is at the ENT and Audiology Unit, Department of Neuroscience and Rehabilitation, University Hospital of Ferrara, Ferrara, Italy

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

Christophe Marguet

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

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

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

ProfessorChristophe Marguet is at theCF Centre, Dept of Paediatrics and Adolescent Medicine, University Hospital Charles Nicolle, CIC INSERM 1404, EA 2656, Rouen University, Rouen, France.

C MartinE BurnetA Ronayette-PreiraP de CarliJ MartinL DelmasB PrieurP-R BurgelPatient perspectives following initiation of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis and advanced lung diseaseRespir Med Res. 2021 May 17;80:100829.doi: 10.1016/j.resmer.2021.100829.Online ahead of print.  [Pubmed]
Backgound:Elexacaftor-tezacaftor-ivacaftor partially restores cystic fibrosis transmembrane conductance regulator function, and has been shown to induce significant clinical improvement in patients with at least one Phe508del allele. Yet little data exist on patient perspectives following elexacaftor-tezacaftor-ivacaftor initiation.
Methods:A mixed methods study was conducted using an online 13-item questionnaire (including 9 closed questions and 4 open questions), submitted from July 10th to August 21th2020 to French patients aged 12 years and older with advanced CF who were treated with elexacaftor-tezacaftor-ivacaftor. Their responses were summarized as numbers (%), and free-text items were analysed using a grounded theory approach.
Results:Of 245 patients who started elexacaftor-tezacaftor-ivacaftor in France, 101 (41%) participated. Median [IQR] age was 35 [28-41] years and duration of elexacaftor-tezacaftor-ivacaftor treatment was 4.3 [3.0-5.6] months. Patients generally reported a rapid impact on respiratory symptoms, sleep quality, general well-being and physical self-esteem, and a reduction in overall treatment burden. The majority of patients contrasted treatment burden, symptom severity, depression and a closed future marked by death or transplantation before elexacaftor-tezacaftor-ivacaftor, to renewed and unexpected physical strength, leading to greater self-confidence, autonomy and long-term planning, after treatment initiation. A small number of patients expressed concerns, mainly regarding changes in body representation and/or the fear of becoming dependent on the treatment.
Conclusion:After initiation of elexacaftor-tezacaftor-ivacaftor, CF patients with advanced disease reported rapid and positive physical, psychological and social effects, which translated into improved quality of life and the formulation of new life goals.

Dr C Martin is at the Université de Paris, Institut Cochin, Inserm U1016, 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.

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

Paul B McCray

Laura Marquez Loza

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

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

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

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

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

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

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

Stacey L MartinianoAlexander ElbertPhillip M FarrellClement L Ren Marci K SontagRunyu WuSusanna A McColley.  Outcomes of infants born during the first 9 years of CF newborn screening in the United States: a retrospective Cystic Fibrosis Foundation Patient Registry cohort study.  Pediatr Pulmonol 2021 Sep 1. doi:10.1002/ppul.25658. Online ahead of print.[Pubmed]

Stacey L Martiniano

Introduction: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis generating study was designed to form the basis of additional analyses and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS.
Methods: We included participants in the CF Foundation Patient Registry born 2010-2018 with age of recorded CF diagnosis 0-365 days old. We compared age of center-reported diagnosis, age at first CF event (defined as earliest sweat test, clinic visit or hospitalization), demographics, and outcomes between 3 cohorts born between 2010-2012, 2013-2015, and 2016-2018.
Results: In 6354 infants, the median age at first CF event decreased from the 1st to the 3rd cohort. Weight-for-age (WFA) was < 10th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was > 0 but height-for-age (HFA) z-score was < 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection was less common in later cohorts. About 1/3 of infants were hospitalized in the first year of life with no changes over time.
Conclusion: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts, but early life nutritional deficits and a high rate of infant hospitalizations persist.

Dr Stacey L Martiniano is pediatric pulmonologist at the University of Colorado Anschutz Medical Center, United States and the Children’s Hospital Colorado, United States

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

J Abram McBride

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

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

Paul McNally,Daryl ButlerYuliya V KarpievitchBarry LinnaneSarath RanganathanStephen M StickGraham L HallAndre SchultzSHIELD CF and ARESTCFIvacaftor and Airway Inflammation in Preschool Children with Cystic Fibrosis. Am J Respir Crit Care Med   2021 Jun 2.doi: 10.1164/rccm.202012-4332LE.Online ahead of print. [Pubmed]

Paul McNally

The authors comment – Notwithstanding certain limitations to our study, our data suggest that in stable preschool  children with CF, ivacaftor does not have a significant beneficial effect on airway infection and inflammation.  Therefore caution should be applied in this group of children before discontinuing, avoiding or delaying the use of the use of traditional treatments that we might typically prescribe such as airway clearance,  mucoactive agents and antibiotics.

Paul McNally is Associate Professor of Paediatrics at the at the RCSI, 8863, Paediatrics, Dublin, Ireland and  Children’s Health Ireland, 575376, Respiratory Medicine, Dublin, Ireland; paulmcnally@rcsi.ie

Chadia MekkiAbdel AissatVéronique MirlesseSophie Mayer LacrosniereElsa EcheAnnick Le FlochSandra WhalenCecile Prud’HommeChristelle RemusBenoit FunalotVanina CastaignePascale FanenAlix de BecdelièvrePrenatal Ultrasound Suspicion of Cystic Fibrosis in a Multiethnic Population: Is Extensive CFTRGenotyping Needed?  Genes (Basel) 2021 Apr 29;12(5):670.doi: 10.3390/genes12050670.   Free PMC article. [Pubmed]

Chadia Mekki

In families without a Cystic Fibrosis (CF) history, fetal ultrasound bowel abnormalities can unexpectedly reveal the disease. Isolated or in association, the signs can be fetal bowel hyperechogenicity, intestinal loop dilatation and non-visualization of fetal gallbladder. In these cases, search for CF transmembrane conductance regulator (CFTR) gene mutations is part of the recommended diagnostic practices, with a search for frequent mutations according to ethnicity, and, in case of the triad of signs, with an exhaustive study of the gene. However, the molecular diagnosis remains a challenge in populations without well-known frequent pathogenic variants. We present a multiethnic cohort of 108 pregnancies with fetal bowel abnormalities in which the parents benefited from an exhaustive study of the CFTR gene. We describe the new homozygous p.Cys1410* mutation in a fetus of African origin. We did not observe the most frequent p.Phe508del mutation in our cohort but evidenced variants undetected by our frequent mutations kit. Thanks to the progress of sequencing techniques and despite the difficulties of interpretation occasionally encountered, we discuss the need to carry out a comprehensive CFTR study in all patients in case of fetal bowel abnormalities.

Dr Chadia Mekki is in the Departement de Genetique, DMU Biologie-Pathologie, GH Mondor-Chenevier, AP-HP, F-94010 Creteil, France.

Sylwia Michorowska Ataluren-Promising Therapeutic Premature Termination Codon Readthrough FrontrunnerPharmaceuticals (Basel). 2021 Aug 9;14(8):785.doi: 10.3390/ph14080785. [Pubmed]Free PMC article

Sywia Michorowska

Around 12% of hereditary disease-causing mutations are in-frame nonsense mutations. The expression of genes containing nonsense mutations potentially leads to the production of truncated proteins with residual or virtually no function. However, the translation of transcripts containing premature stop codons resulting in full-length protein expression can be achieved using readthrough agents. Among them, only ataluren was approved in several countries to treat nonsense mutation Duchenne muscular dystrophy (DMD) patients.

This review summarizes ataluren’s journey from its identification, via first in vitro activity experiments, to clinical trials in DMD, cystic fibrosis, and aniridia. Additionally, data on its pharmacokinetics and mechanism of action are presented. The range of diseases with underlying nonsense mutations is described for which ataluren therapy seems to be promising. What is more, experiments in which ataluren did not show its readthrough activity are also included, and reasons for their failures are discussed.

 Dr Sylwia Michorowska is in the Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland.

– The full article is an interesting very detailed review of the development and clinical trials of ataluren, initially known as PTC124, in muscular dystrophy, cystic fibrosis  and various metabolic disorders.

Christina M MingoraPatrick A Flume.Pulmonary Complications in Cystic Fibrosis: past, present and future. Chest 2021 Jun 17;S0012-3692(21)01127-2.doi:0.1016/j.chest.2021.06.017.Online ahead of print.   [Pubmed]

Christina MIngora

Cystic Fibrosis (CF) is an autosomal recessive genetic condition with multi-systemic disease manifestations, the most prominent of which occur in the respiratory system. Despite significant developments in disease understanding and therapeutics, each contributing to improved lung function and survival in persons with CF, several pulmonary complications including pneumothorax, massive hemoptysis, and respiratory failure continue to occur. In this review, we briefly describe each of these complications and their management, as well as discuss how they impact the care and disease trajectory of individuals in whom they occur. Finally, we discuss the evolving role that palliative care and cystic fibrosis transmembrane conductance regular modulator therapies play in the natural disease course and care of persons with CF.

Dr Christina M Mingora is at the Medical University of South Carolina, Charleston, SC.

– This is a clear account of the chest problems which remain a major factor affecting the lives of the majority of people with CF

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

Pedro Mondejar-López

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

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

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

        Renee N Ng

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

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

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

Anne Neerincx

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

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

Yasmeen ObeidatDavinder SinghSaba AlTarawnehJoseph SimmonsAdnan Elghezewi Eva Patton-TackettWesam Frandah.Ascending Cholangitis Caused by Methicillin-Resistant Staphylococcus aureus Species in a Patient With Cystic Fibrosis. Cureus 2021 Aug 10;13(8):e17045 doi: 10.7759/cureus.17045.eCollection 2021 Aug. Free PMC article [Pubmed]

Yasmeen Obeidat

Ascending cholangitis is a bacterial infection of the extra-hepatic biliary system and presents as a life-threatening systemic condition. Increased bacterial loads and biliary obstruction favor bacterial translocation into the vascular and lymphatic systems. Common organisms isolated are Escherichia ColiKlebsiellaEnterococcus species, and Enterobacter speciesMethicillin-resistant Staphylococcus aureus (MRSA) is a rare isolate in ascending cholangitis. We present a case of a 24-year-old patient with cystic fibrosis who presented with epigastric abdominal pain, low-grade fever, jaundice, dark urine, and nausea for two days. Initial workup revealed elevated liver enzymes, hyperbilirubinemia, leukocytosis, and an ultrasound which showed common bile duct dilation to 14 mm with choledocholithiasis. He underwent endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction and bile fluid culture. Cultures grew out MRSA and the patient was treated with appropriate antibiotic therapy. The mainstay of therapy for ascending cholangitis is adequate hydration, antibiotics, and biliary decompression. Early recognition of the offending organism is critical in guiding therapy. Current guidelines focus on the empiric treatment of Gram-negative and anaerobic bacteria. Clinicians should be aware of the possibility of less common pathogens (such as MRSA), especially in a patient who is decompensating despite antibiotic therapy.

Dr Yasmeen Obeidat is a Resident in Internal medicine in the department Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, USA.

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

Samuel T Olatunbosun

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

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

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

Yifat S OrenMichal Irony-Tur SinaiAnita GolecOfra Barchad-AvitzurVenkateshwar MutyamYao LiJeong HongEfrat Ozeri-GalaiAurélie HattonChen LeibsonLiran CarmelJoel ReiterEric J SorscherSteve D WiltonEitan KeremSteven M RoweIsabelle Sermet-GaudelusBatsheva Kerem.  Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation.  J Cyst Fibros2021 Jul 2;S1569-1993(21)01287-X.doi: 10.1016/j.jcf.2021.06.003.Online ahead of print.   [Pubmed]

       Yifat Oren

Background: Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849+10 kb C-to-T splicing mutation in the CFTR gene.
Methods: We have screened, in FRT cells expressing the 3849+10 kb C-to-T splicing mutation, ~30 2′-O-Methyl-modified phosphorothioate ASOs, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The effect of highly potent ASO candidates on the splicing pattern, protein maturation and CFTR function was further analyzed in well differentiated primary human nasal and bronchial epithelial cells, derived from patients carrying at least one 3849+10 kb C-to-T allele.
Results: A highly potent lead ASO, efficiently delivered by free uptake, was able to significantly increase the level of correctly  spliced mRNA and completely restore the CFTR function to wild type levels in cells from a homozygote patient. This ASO led to CFTR function with an average of 43% of wild type levels in cells from various heterozygote patients. Optimized efficiency of the lead ASO was further obtained with 2′-Methoxy Ethyl modification (2’MOE).
Conclusion: The highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development.

Dr Yifat S Oren is in the Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem, Israel; SpliSense Therapeutics, Jerusalem, Givat Ram, Israel.

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

Kate O’Shea

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

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

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

Zheng Pang

Zheng PangQingjun ZhuTraditional Chinese Medicine is an Alternative Therapeutic Option for Treatment of Pseudomonas aeruginosa InfectionsFront Pharmacol 2021 Aug 27;12:737252.doi: 10.3389/fphar.2021.737252.eCollection 2021.Free PMC article [Pubmed]
Pseudomonas aeruginosa is an opportunistic pathogen    causing life-threatening infections in cystic fibrosis patients and immunocompromised individuals, and it is a leading cause of nosocomial infections associated with significant morbidity and mortality. Treatment of P. aeruginosa  is challenging due to the antibiotic resistance to most of the conventional antibiotics. Development of alternative therapeutic options is urgently demanded for the patients who have antibiotic-resistant infections. Traditional Chinese medicine (TCM) has a clinical history of thousands of years for prevention and treatment of infectious diseases in China, taking advantages of improving clinical outcomes, producing less side effects, inhibiting pathogen, and modulating host immunity. Recent research has revealed a variety of natural products derived from TCM showing significant antimicrobial effects on antibiotic-resistant strains of P. aeruginosa alone or combined with antibiotics in vitro or in animal models, suggesting that TCM is a promising complementary and alternative therapeutic approach for treatment of chronic P. aeruginosa infections. This review summarizes the recent findings attempting to dissect the mechanisms of TCM combating P. aeruginosa infections and highlights the molecular targets of TCM on P. aeruginosa and host.

Both the authors are at the Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China. Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China. Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Shandong University of Traditional Chinese Medicine, Jinan, China.

Iona PatersonChris JohnsonGordon MacGregor.Tezacaftor-ivacaftor use in routine care of adults with cystic fibrosis: a medicine use evaluation. Eur J Hosp Pharm    2021 Jun 8;ejhpharm-2020-002676.doi: 10.1136/ejhpharm-2020-002676.Online ahead of print[Pubmed]
This study aimed to assess the impact of tezacaftor-ivacaftor use in routine clinical practice for adults with cystic fibrosis.
Methods:A retrospective observational longitudinal cohort study design was applied to examine the clinical effect of tezacaftor-ivacaftor in routine practice in the West of Scotland Adult Cystic Fibrosis Unit. Adults receiving tezacaftor-ivacaftor for at least 4 weeks were included in this medicine use evaluation. A standardised data form was used to collect patient-level data: demographics, genotype, complications of cystic fibrosis, medicine access process. Fifty-two weeks pre and post tezacaftor-ivacaftor initiation data: lung function, body mass index (BMI), days spent in hospital, days receiving antibiotic treatment for respiratory exacerbations. Anonymised data were collated and analysed using SPSS V.26.
Results:Of 121 potential patients, 45 received treatment with tezacaftor-ivacaftor; median age 30 years (range 17-64) at initiation, 56% were male, 76% were deemed to be homozygote and 41 patients continued treatment for at least 52 weeks. There was no significant change in % predicted FEV1; median difference 0 (IQR -3 to 6). There was a significant improvement in BMI, mean 0.6 kg/m2 (95% CI 0.2 to 1.0), as well as a median 4 (IQR -17 to 0) day reduction in days in hospital and 21 (IQR -42 to 0) day reduction in days receiving antibiotics.
Conclusions:The use of tezacaftor-ivacaftor in routine practice for people with cystic fibrosis was associated with improvements in weight, as well as reducing the number of days people needed to spend in hospital and receive antibiotics.

Iona Paterson is Pharmacist at the Queen Elizabeth University Hospital Campus, Glasgow, UK

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

Molly Payne

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

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

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

Thomas Plante-Bordeneuve

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

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

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

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

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

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

Bernadette Prentice

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

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

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

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

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

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

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

Courtney E PriceGeorge A O’Toole.  The Gut-Lung Axis in Cystic FibrosisJ Bacteriol 2021 Aug 2;JB0031121.doi: 10.1128/JB.00311-21.Online ahead of print.[Pubmed]
Cystic Fibrosis (CF) is a heritable, multi-organ disease that impacts all tissues that normally express CFTR protein. While importance of the airway microbiota has long been recognized, the intestinal microbiota has only recently been recognized as an important player in both intestinal and lung health outcomes for persons with CF (pwCF). Here, we summarize current literature related to the gut-lung axis in CF, with a particular focus on three key ideas: Mechanisms through which microbes influence the gut-lung axis, drivers of microbiota alterations, and the potential for intestinal microbiota remediation.

The authors are at the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover NH 03755, US

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

Genevieve Mailhot

Florence Racine

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

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

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

Anabela S RamalhoEva FürstováAnnelotte M VonkMarc FerranteCatherine VerfaillieLieven DupontMieke BoonMarijke ProesmansJeffrey M Beekman,Ifat SaroukCarlos Vazquez CorderoFrancois VermeulenKris De BoeckBelgian Organoid ProjectCorrection of CFTR function in intestinal organoids to guide treatment of cystic fibrosisEur Respir J 2021 Jan 5;57(1):1902426.doi: 10.1183/13993003.02426-2019. Print 2021 Jan.  [Pubmed]

     Anabela Ramalho

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

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

Sarath C Ranganathan Commentary on: “Evaluating barriers and promotors of telehealth during the COVID-19 pandemic at cystic fibrosis programs to inform new models of CF care”J Cyst Fibros   2021 Sep 2;S1569-1993(21)01367-9. doi: 10.1016/j.jcf.2021.08.026.Online ahead of print  Free PMC article [Pubmed]

Sarath Ranaganathan

An interesting commentary by Sarath Ranganathan commenting on recent USA experience and describing the situation regarding telehealth in Australia.

A full version is available via PubMed with useful additional references.

Seth A ReasonerKyle T EnriquezBenjamin AbelsonSteven ScaglioneBennett SchneierMichael G O’ConnorGerald Van HornMaria HadjifrangiskouUrinary tract infections in cystic fibrosis patients.  J Cyst Fibros 2021 Jul 27;S1569-1993(21)01303-5.doi: 10.1016/j.jcf.2021.07.005.Online ahead of print. [Pubmed]

Seth Reasoner

Improved understanding of non-respiratory infections in cystic fibrosis (CF) patients will be vital to sustaining the increased life span of these patients. To date, there has not been a published report of urinary tract infections (UTIs) in CF patients. We performed a retrospective chart review at a major academic medical center during 2010-2020 to determine the features of UTIs in 826 CF patients. We identified 108 UTI episodes during this period. Diabetes, distal intestinal obstruction syndrome (DIOS), and nephrolithiasis were correlated with increased risk of UTIs. UTIs in CF patients were less likely to be caused by Gram-negative rods compared to non-CF patients and more likely to be caused by Enterococcus faecalis. The unique features of UTIs in CF patients highlight the importance of investigating non-respiratory infections to ensure appropriate treatment.

Seth A Reasoner is at the Division of Molecular Pathogenesis, Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.

Philippe ReixAurélie TatopoulosIulia IoanMuriel Le BourgeoisStéphanie BuiMarie Luce ChoukrounKatia Bessaci-KabouyaMichele GerardinPlamen BokovJennifer Da SilvaJean-Louis PaillasseurPierre Regis BurgelFrench Cystic Fibrosis Reference Network study groupReal-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis. J Cyst Fibros 2021 Jun 25;S1569-1993(21)01286-8.doi: 10.1016/j.jcf.2021.06.002.Online ahead of print. [Pubmed]
Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0].

At both M6 and M12, non statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients.
In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.

Dr Philippe Reix is at the Cystic Fibrosis Center, Hospices Civils de Lyon, Lyon, France; UMR 5558 CNRS Equipe EMET Université Claude Bernard Lyon 1 Lyon, France.

Margaret RosenfeldAnna V FainoFrankline OnchiriMelis A AksitScott M BlackmanElizabeth E BlueJoseph M CollacoWilliam W GordonRhonda G PaceKaren S RaraighYi-Hui ZhouGarry R CuttingMichael R KnowlesMichael J BamshadRonald L Gibson. Comparing encounter-based and annualized chronic pseudomonas infection definitions in cystic fibrosisJ Cyst Fibros  2021 Aug 12;S1569-1993(21)01339-4.doi: 10.1016/j.jcf.2021.07.020.Online ahead of print. [Pubmed]

Margaret Rosenfield

Chronic Pseudomonas aeruginosa (Pa) infection is associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no gold standard definition of chronic Pa infection in CF. We compared chronic Pa definitions using encounter-based versus annualized data in the Early Pseudomonas Infection Control (EPIC) Observational study cohort, and subsequently compared annualized chronic Pa definitions across a range of U.S. cohorts spanning decades of CF care. We found that an annualized chronic Pa definition requiring at least 1 Pa+ culture in 3 of 4 consecutive years (“Green 3/4”) resulted in chronic Pa metrics similar to established encounter-based modified Leeds criteria definitions, including a similar age at and proportion who fulfilled chronic Pa criteria, and a similar proportion with sustained Pa infection after meeting the chronic Pa definition. The Green 3/4 chronic Pa definition will be valuable for longitudinal analyses in cohorts with limited culture frequency.

Dr Margaret Rosenfield is in the Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. 

Scott D SagelUmer KhanSonya L HeltsheJohn P ClancyDrucy BorowitzDaniel GelfondScott H DonaldsonAntoinette MoranFelix RatjenJill M VanDalfsenSteven M Rowe.Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical TrialAnn Am Thorac Soc 2021 Jan;18(1):75-83.doi: 10.1513/AnnalsATS.202002-144OC. [Pubmed]

         Scott Segal

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

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

Lisa SaimanJuyan J ZhouKushal S ShahXiaotong JiangWilliam StoudemireMichael R KosorokMarianne S Muhlebach CF IP&C Study GroupBarriers implementing infection prevention and control experienced by healthcare workers, people with CF and parents. J Cyst Fibros 2021 Sep 11;S1569-1993(21)01307-2. doi: 10.1016/j.jcf.2021.07.009.Online ahead of print. [Pubmed]

     Lisa Saiman

Background: Barriers to implementing infection prevention and control (IP&C) practices may be experienced by healthcare workers (HCWs) caring for people with CF (PwCF), PwCF, and their families. We hypothesized that these stakeholders from CF centers with early adoption of the updated 2013 IP&C guideline would experience fewer barriers implementing selected recommendations compared to stakeholders from CF centers with delayed adoption.
Methods: In 2018-2019 we surveyed HCWs and PwCF/parents from 25 CF centers to identify knowledge, attitude, and practice barriers. Each center recruited five HCWs with different occupations. Pediatric centers recruited five parents of children <18 years old and five young adults 18-21 years old. Adult centers recruited 10 adults ≥18 years old. We determined respondents’ knowledge scores, the proportion who agreed with or perceived health benefits from recommendations, and reported adherence to recommendations.
Results: Knowledge scores, perception of health benefits, and adherence to selected practices were similar among participants from centers with early vs. delayed adoption, yet generally lower for inpatient nurses. IP&C practitioners were less likely to perceive health benefits from PwCF wearing masks and HCWs wearing gowns and gloves. Among HCWs, 57% educated >75% of PwCF/parents about IP&C and 43% advised >75% of PwCF/parents to avoid socializing with other PwCF. Among PwCF/parents, 69%, 53%, and 56% reported discussions with their care teams about performing hand hygiene, avoiding socialization, or the 2013 IP&C guideline, respectively.
Conclusions: Our findings suggest opportunities for targeted education for specific HCW occupations and for PwCF and their families.

Dr Lisa Saiman is in the Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Infection Prevention & Control, New York-Presbyterian Hospital, New York, NY, 10032, USA.

Donatello SalvatoreCarmela ColangeloMichele D’AndriaGiovanni MarsicovetereDomenica PassarellaElexacaftor/tezacaftor/ivacaftor as rescue therapy in a patient with the cystic fibrosis genotype F508DELG1244EClin Case Rep 2021 Aug 25;9(8):e04713.doi: 10.1002/ccr3.4713.eCollection 2021 Aug.       OPEN access for full case reports   [Pubmed]

Donatello Salvatore

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane regulator (CFTR) modulator. It is known to be efficacious in stable patients with severe pneumopathy, but there are few data concerning its effectiveness during acute exacerbations. We here describe its use in a woman with CF and respiratory failure.
A 50-year old woman with severe CF who eventually went into respiratory failure. Our patient had an F/G genotype and had been previously treated with ivacaftor but, after an initial improvement, experienced rapid disease progression (as has been previously described in ivacaftor-treated adults with G mutations), possibly aggravated by Bcc colonization. During her subsequent hospitalization, she did not improve significantly until ETI was administered, and, as all her other treatments remained unchanged, this suggests it played a role in her recovery. Furthermore, her lung disease continued to improve after she was discharged: There was no recurrence of PEx, no need for antibiotics, and her lung function and ABG parameters improved.

Dr Donatello Salvatore is Director of the Cystic Fibrosis Centre – Hospital San Carlo Potenza Italy.

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

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

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

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

Meghana Sathe

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

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

Meghana SathePreeti B SharmaAdrienne P Savant.Year in review 2020: Nutrition and gastrointestinal disease in cystic fibrosisPediatr Pulmonol. 2021 Jul 26.doi: 10.1002/ppul.25587. Online ahead of print.  [Pubmed]
The multisystemic manifestations of cystic fibrosis (CF) involve all parts of the gastrointestinal (GI) system, including the pancreas, intestine, and liver. As providers who care for people with CF, knowledge of the manifestations, treatment, and research related to nutrition and GI disease are important. This review is the last instalment of the CF year in review 2020 series, focusing on nutritional, GI, and hepatobiliary articles from Pediatric Pulmonology and other journals of particular interest to clinicians..

– A useful review of the many contributions in these areas during the year. Summarised by the authors in the article as follows – “The lessons from 2020 for nutrition include 1) reminders to assess pancreatic status via genotype/phenotype correlation; 2) apps can help optimize PERT dosing 3) a new nutritional supplement can aid fat malabsorption 4) Nutritional deficiencies are common 5) obesity is not uncommon and associated with a plateau effect on FEV1. The intestinal microbiome is altered early in life with specific environmental tobacco smoke exposure and antibiotics, leading to more pathogenic bacteria while no microbial alterations are seen with acid blocking agents.  The low length was shown to be associated with differences in the intestinal microbiome, allowing for the possibility of intestinal microbiome treatment to improve growth. Liver disease can be assessed with biomarkers and images with GGT being a key biomarker. Ultrasound findings of a heterogenous liver were nine times more likely to predict progression to nodular disease. Liver stiffness measurements have the ability to define the degree of fibrosis.”

Meghana Sathe  is in the Division Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Texas Southwestern and Children’s Health, Dallas, Texas.

Martina Scano

Martina ScanoAlberto BenetolloLeonardo NogaraMichela BondìFrancesco Dalla BarbaMichela SoardiSandra FurlanEylem Emek AkyurekPaola CaccinMarcello CarottiRoberta SacchettoBert Blaauw Dorianna Sandonà     CFTR corrector C17 is effective in muscular dystrophy, in vivo proof of concept in LGMDR3. Hum Mol Genet 2021 Sep 9;ddab260.doi: 10.1093/hmg/ddab260. Online ahead of print.[Pubmed]
Limb-girdle muscular dystrophy 3 (LGMDR3) is caused by mutations in the SGCA gene coding for α-sarcoglycan (SG). Together with β- γ- and δ-SG, α-SG forms a tetramer embedded in the dystrophin associated protein complex (DAPC) crucial for protecting the sarcolemma from mechanical stresses elicited by muscle contraction. Most LGMDR3 cases are due to missense mutations, which result in non-properly folded, even though potentially functional α-SG. These mutants are prematurely discarded by the cell quality control. Lacking one subunit, the SG-complex is disrupted. The resulting loss of function leads to sarcolemma instability, muscle fiber damage and progressive limb muscle weakness. LGMDR3 is severely disabling and, unfortunately, still incurable. Here we propose the use of small molecules, belonging to the class of cystic fibrosis transmembrane regulator (CFTR) correctors, for recovering mutants of α-SG defective in folding and trafficking. Specifically, CFTR corrector C17 successfully rerouted the SG-complex containing the human R98H-α-SG to the sarcolemma of hind-limb muscles of a novel LGMDR3 murine model. Notably, the muscle force of the treated model animals was fully recovered. To our knowledge, this is the first time that a compound designated for cystic fibrosis (CF) is successfully tested in a muscular dystrophy and may represent a novel paradigm of treatment for LGMDR3 as well as different other indications in which a potentially functional protein is prematurely discarded as folding-defective. Furthermore, the use of small molecules for recovering the endogenous mutated SG has an evident advantage over complex procedures such as gene or cell transfer.

Martina Scano is a PhD student in the Department of Biomedical Sciences, University of Padova, Italy.

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

Daniela Schlüter

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

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

Prutha H ShahJun Hee LeeDhairya J SalviRizwan RabbaniDivya R GaviniPousette Hamid. Cardiovascular System Involvement in Cystic FibrosisCureus 2021 Jul 29;13(7):e16723.doi: 10.7759/cureus.16723.eCollection 2021 Jul.  Free PMC article
[Pubmed]
Cystic fibrosis (CF) is an autosomal recessive disease primarily affecting the respiratory system and gastrointestinal system. The life expectancy of patients with CF has significantly improved due to medical advancement and the effective use of screening techniques. However, new challenges have emerged. Particularly those involving cardiovascular pathology. This study aims to provide a better understanding of the different mechanisms that cause cardiovascular complications in patients with CF, which would help find an efficient treatment that not only prolongs survival but also improves their quality of life.

This study extensively reviews different theories such as right ventricular hypertrophy due to lung pathology, ventricular interdependence, the association of nutritional deficiencies and severe cystic fibrosis transmembrane conductance regulator (CFTR) genotypes with myocardial fibrosis, effects of hypoxia, recurrent infections, and systemic inflammation of the heart and blood vessels that explain the direct or indirect involvement of the cardiovascular system in CF. For this review, 258 articles were retrieved from PubMed and Google Scholar. Out of which, a total of 12 high-quality articles were selected using appropriate quality assessment tools and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The result of this study suggests that early detection of cardiovascular dysfunction can improve the survival rate of the patient. Furthermore, this study could aid future researchers in the exploration of various best screening modality techniques for the early detection of cardiovascular dysfunction.

Prutha H Shah is in the department of Internal Medicine, Pediatrics, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA.

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

        Zhuqing Shi

A recent study reported associations of CF carriers with risk for cancers of digestive organs and pancreatic cancer. In the current study, we assessed associations of CFTR F508del carriers with the risk for 54 types of cancers in the UK Biobank, a large population-based study.
In Caucasians, compared to the carrier rate of 3.15% (12 357/392274) in noncancer subjects, the rate was significantly higher in cancer patients overall (2621/79619 = 3.29%), especially in patients with colorectal cancer (247/6667 = 3.70%), cancers of gallbladder and biliary tract (21/351 = 5.98%), thyroid cancer (30/665 = 4.51%) and unspecified non-Hodgkin’s lymphoma (74/1805 = 4.10%), all P ≤ .05. In contrast, the carrier rate in patients with cancers of lung and bronchus was significantly lower (89/3463 = 2.57%), P = .05.
The association of CFTR F508del carriers with these types of cancer remained significant after adjusting for respective cancer-specific risk factors. For pancreatic cancer, although a higher carrier rate (38/1004 = 3.78%) was found in patients with this cancer, the difference was not statistically significant (P = .26). This null association was unlikely due to lack of statistical power; the large sample size of our study had >80% power, at a significance level of .05, to detect an association of >1.5-fold increased rPeople with Cystic fibrosis (pwCF) have experienced increased survival and wellbeing in recent decades, such that more than half of those living with CF are adults. Consequently, sexual and reproductive health is increasingly important for pwCF as many are considering parenthood. Most men and some women with CF (wwCF) will have reduced fertility, which in both sexes is multifactorial. However, unplanned pregnancies in women are not rare, and contraception and its interaction with CF complications need to be addressed by the CF team. Reduced fertility may be overcome in most pwCF through use of assisted reproductive technologies; however, the risk of having offspring with CF must be considered. Most wwCF will have normal pregnancies, but premature birth is common especially in the setting of reduced lung function and CF related diabetes (CFRD); optimization of treatment is recommended during pregnancy planning. Parenting imposes an increased burden on pwCF, with the challenges of caring for the newborn, postpartum physiologic changes and maintaining CF treatments. Most drugs used to treat CF are considered safe in pregnancy and lactation, but exceptions need to be acknowledged, including the limited data regarding safety of CF transmembrane conductance regulator (CFTR) modulators during conception, pregnancy, and lactation. As most pwCF are eligible for highly effective CFTR modulators, fertility, contraception, and pregnancy in people with CF is changing. Prospective studies regarding these issues in people treated with CFTR modulators are paramount to provide evidence-based guidance for management in the current era of CF care.

Zhuqing Sh is at the Center for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois, USA.

Michal ShteinbergJennifer L Taylor-CousarIsabelle DurieuMalena Cohen-Cymberknoh“Fertility and Pregnancy in Cystic fibrosis”. Chest 2021 Jul 17;S0012-3692(21)01352-0.doi: 10.1016/j.chest.2021.07.024.Online ahead of print.[Pubmed]

Michal Shteinberg

People with Cystic fibrosis (pwCF) have experienced increased survival and wellbeing in recent decades, such that more than half of those living with CF are adults. Consequently, sexual and reproductive health is increasingly important for pwCF as many are considering parenthood. Most men and some women with CF (wwCF) will have reduced fertility, which in both sexes is multifactorial. However, unplanned pregnancies in women are not rare, and contraception and its interaction with CF complications need to be addressed by the CF team. Reduced fertility may be overcome in most pwCF through use of assisted reproductive technologies; however, the risk of having offspring with CF must be considered. Most wwCF will have normal pregnancies, but premature birth is common especially in the setting of reduced lung function and CF related diabetes (CFRD); optimization of treatment is recommended during pregnancy planning. Parenting imposes an increased burden on pwCF, with the challenges of caring for the newborn, postpartum physiologic changes and maintaining CF treatments. Most drugs used to treat CF are considered safe in pregnancy and lactation, but exceptions need to be acknowledged, including the limited data regarding safety of CF transmembrane conductance regulator (CFTR) modulators during conception, pregnancy, and lactation. As most pwCF are eligible for highly effective CFTR modulators, fertility, contraception, and pregnancy in people with CF is changing. Prospective studies regarding these issues in people treated with CFTR modulators are paramount to provide evidence-based guidance for management in the current era of CF care.

Michal Shteinberg is managing director, the Pulmonology Institute and CF Center, Carmel Medical Center and the Technion- Israel institute of technolog

Megan SmithKevin J RyanHector GutierrezLuz Helena Gutierrez SanchezJanaina Nogueira AndersonEdward P AcostaKim W Benner, Jennifer S Guimbellot  Ivacaftor-elexacaftor-tezacaftor and tacrolimus combination in cystic fibrosisJ Cyst Fibros 2021 Jun 12;S1569-1993(21)00159-4.doi: 10.1016/j.jcf.2021.05.008. Online ahead of print.[Pubmed]

 Jennifer Guimbellot

The CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) is a genetic mutation-targeted treatment in cystic fibrosis that results in profound improvements in clinical outcomes. Each of the compounds are substrates of CYP3A4/5, the cytochrome P450 enzyme family for which tacrolimus is also a substrate.
The use of these compounds in an individual with a solid organ transplant has not been previously studied and there is potential for a drug interaction. In this report, we describe a pediatric liver transplant recipient with clinical decline related to cystic fibrosis who improved substantially with ETI, without significant impact on the systemic exposure of either ETI or tacrolimus.

Megan Smith is at the McWhorter School of Pharmacy, Samford University, Birmingham, AL.

Corresponding author is Dr Jennifer Guimbellot is a pediatric pulmonologist and Assistant Professor in the Department of Pediatric Pulmonology and Sleep Medicine, University of Alabama.

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

Olaf Sommerburg

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

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

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

Giulia Spoletini

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

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

Mirjam StahlEva Steinke , Simon Y GraeberCornelia JoachimChristoph SeitzHans-Ulrich KauczorMonika EichingerSusanne HämmerlingOlaf SommerburgMark O WielpützMarcus A Mall. Magnetic Resonance Imaging Detects Progression of Lung Disease and Impact of Newborn Screening in Preschool Children with Cystic FibrosisAm J Respir Crit Care Med. 2021 Jul 20., oi: 10.1164/rccm.202102-0278OC.Online ahead of print. [Pubmed]

    Mirjam Stahl

Rationale: Previous cross-sectional studies demonstrated that chest magnetic resonance imaging (MRI) is sensitive to detect early lung disease in infants and preschool children with cystic fibrosis (CF) without radiation exposure. However, the ability of MRI to detect progression of lung disease and the impact of early diagnosis in preschool children with CF remains unknown.
Objectives: To investigate the potential of MRI to detect progression of early lung disease and impact of early diagnosis by CF newborn screening (NBS) in preschool children with CF.
Methods: Annual MRI was performed from diagnosis over four years in a cohort of 96 preschool children with CF (age 0-4 yr) that were concurrently diagnosed based on NBS (n=28) or clinical symptoms (n=68). MRI scans were evaluated using a dedicated morphofunctional score and the relationship between longitudinal MRI scores and respiratory symptoms, pulmonary exacerbations, upper airway microbiology and mode of diagnosis were determined.
Measurements and main results: The MRI global score increased in the total cohort of children with CF during preschool years (P<0.001) which was associated with cough, pulmonary exacerbations (P<0.0001), and detection of Staphylococcus aureus and Haemophilus influenzae (P<0.05). MRI-defined abnormalities in lung morphology, especially airway wall thickening/bronchiectasis, were lower in NBS compared to clinically diagnosed children with CF throughout the observation period (P<0.01).
Conclusions: MRI detected progression of early lung disease and benefits of early diagnosis by NBS in preschool children with CF. These findings support MRI as sensitive outcome measure for diagnostic monitoring and early intervention trials in preschool children with CF.

Mirjam Stahl is at the Charité Universitätsmedizin Berlin, 14903, Department of Pediatric Pulmonology, Immunology and Critical Care Medicine, Berlin, Germany.German Center for Lung Research (DZL), associated partner site, Berlin, Germany.University of Heidelberg, Department of Translational Pulmonology, Heidelberg, Germany.German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg (TLRC), Heidelberg, Germany.

Julian StashowerPatrick CarrVirginia MillerBarrett ZlotoffNovel reaction to new cystic fibrosis medication TrikaftaClin Case Rep2021 May 4;9(5):e04116.doi: 10.1002/ccr3.4116.eCollection 2021 May.  [Pubmed]Free PMC article

Legs of patient

Julian Stashower

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

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

Anne L StephensonKathleen J RamosJenna SykesXiayi MaSanja StanojevicBradley S QuonBruce C MarshallKristofer PetrenJoshua S OstrengaAliza K FinkAlbert FaroAlexander ElbertCecilia ChaparroChristopher H Goss. Bridging the survival gap in cystic fibrosis: An investigation of lung transplant outcomes in Canada and the United States. J Heart Lung Transplant. 2021 Mar;40(3):201-209.doi: 10.1016/j.healun.2020.12.001.Epub 2020 Dec 7. [Pubmed]

Anne Stephenson

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

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

Birgitta Strandvik

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

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

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

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

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

Giovanni Taccetti

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

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

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

Jennifer Taylor-Cousar

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

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

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

Vidhu ThakerBen CarterMelissa Putman.  Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database Syst Rev 2021 Aug 23;8:CD008901.doi: 10.1002/14651858.CD008901.pub5.      [Pubmed]

Vidhu Thaker

Objectives: To evaluate the effectiveness and safety of rhGH therapy in improving lung function, quality of life and clinical status of children and young adults with CF.
Authors’ conclusions: When compared with no treatment, rhGH therapy is effective in improving the intermediate outcomes in height, weight and lean body mass. Some measures of pulmonary function showed moderate improvement, but no consistent benefit was seen across all trials. The significant change in blood glucose levels, although not causing diabetes, emphasizes the need for careful monitoring of this adverse effect with therapy in a population predisposed to CF-related diabetes. No significant changes in quality of life, clinical status or side-effects were observed in this review due to the small number of participants. Long-term, well-designed randomised controlled trials of rhGH in individuals with CF are required prior to routine clinical use of rhGH in CF.

Dr Vidhu Thaker  is in the Division of Molecular Genetics and Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.

– It seems unlikely human growth hormone therapy will ever come into “routine clinical use” for people with cystic fibrosis. It should be noted treatment costs between $10,000 and $60,000 per year. Some previous references are detailed after the PubMed entry.

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

    Teja Thorat

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

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

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

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

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

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

     Vito Terlizzi

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

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

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

Christina Thornton

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

Dr Christina Thornton is a Respiratory Fellow at Alberta Health Services

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

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

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

                Davide Treggiari

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

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

Sarah J UllrichMollie Freedman-WeissSamantha AhleHanna K MandlAlexandra S Piotrowski-DaspitKatherine RobertsNicholas YungNathan MaasselTory Bauer-PisaniAdele S RicciardiMarie E EganPeter M GlazerW Mark SaltzmanDavid H StitelmanNanoparticles for delivery of agents to fetal lungs. Acta Biomater. 2021 Mar 15;123:346-353.doi: 10.1016/j.actbio.2021.01.024.Epub 2021 Jan 21.Full text available    [Pubmed]

     Sarah Ullrich

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

Renske van der MeerErik B WilmsHarry G M Heijerman. CFTR Modulators: Does One Dose Fit All?  J Pers Med     2021 May 24;11(6):458.doi: 10.3390/jpm11060458. [Pubmed]

Renske van der Meer

For many people with cystic fibrosis (pwCF), CFTR modulators will be the cornerstone of their treatment. These modulators show robust treatment effects at group level in pwCF with specific mutations. The individual effect however, is variable. In this review we will explain reasons for reconsideration of dosing regimens of CFTR modulating therapy in order to improve treatment response and prevent side effects. Since the effect of a drug depends on pharmacodynamics and pharmacokinetics, pharmacodynamics and pharmacokinetic properties of CFTR modulators will be discussed. Pharmacokinetic-pharmacodynamic relationships will be used to gain insight in dosage response and exposure response relationships. To understand the cause of variation in drug exposure, pharmacokinetic properties that may change due to CF disease will be explained. We show that with current insight, there are conceivable situations that give reason for reconsideration of dosing regimens, however many questions need to be unravelled.

Dr Renske van der Meer is in the Department of Pulmonology, Haga Teaching Hospital, Els Borst-Eilersplein 275, 2545 AA The Hague, The Netherlands

(The Journal of Personalized Medicine is an open access journal)

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

Guido Veit

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

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

Amber VuPaul B McCray , Jr  New Directions in Pulmonary Gene Therapy. Hum Gene Ther 2020 Sep;31(17-18):921-939.doi 10.1089/hum.2020.166.  [Pubmed]

Amber Vu

The lung has long been a target for gene therapy, yet efficient delivery and phenotypic disease correction has remained challenging. Although there have been significant advancements in gene therapies of other organs, including the development of several ex vivo therapies, in vivo therapeutics of the lung have been slower to transition to the clinic. Within the past few years, the field has witnessed an explosion in the development of new gene addition and gene editing strategies for the treatment of monogenic disorders.                                                          In this review, we will summarize current developments in gene therapy for cystic fibrosis, alpha-1 antitrypsin deficiency, and surfactant protein deficiencies. We will explore the different gene addition and gene editing strategies under investigation and review the challenges of delivery to the lung.

 Dr Amba Vu is a post doctoral scholar at the Stead Family Department of Pediatrics, Center for Gene Therapy, The University of Iowa, Iowa City, Iowa, USA.

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

        Connie Yang

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

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

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

       Sibel Yavuz

Sibel YavuzFerhat C PişkinCemil OktayGökhan Tümgör. Assessment of hepatic involvement by two-dimensional shear wave elastography in paediatric patients with cystic fibrosis. J Paediatr Child Health. 2021 Sep 14.doi: 10.1111/jpc.15741. Online ahead of print. [Pubmed]
Aim: This study aimed to investigate parenchymal changes in the liver in paediatric patients with cystic fibrosis (CF) and to analyse diagnostic performance of two-dimensional shear wave elastography (2D-SWE) for the detection of hepatic involvement.
Methods: Patients with CF treated and followed at our centre were evaluated prospectively. All patients underwent liver tissue stiffness (TS) measurements by 2D-SWE, in addition to routine clinical assessments, laboratory work-up and abdominal ultrasound imaging. Data from patients with CF were compared with healthy control subjects.

Results: This study included 39 patients with CF and 37 healthy controls. Patients had a mean body weight of 29.9 (16.6-55) kg, mean age of 9 (5-17) years, mean height of 130 (107-172) cm and a mean body mass index of 16.1 (12.8-21.4) kg/m2 . Average SWE values of the liver were 1.02 (0.70-1.60) m/s in patients with CF (n = 39) and 0.89 (0.60-1.35) m/s in healthy controls (n = 37). Cystic fibrosis patients had significantly increased tissue stiffness by liver elastography compared to controls (P = 0.005).
Conclusion: Parenchymal liver changes may occur early in cystic fibrosis, which cannot be detected by conventional ultrasonography but may be demonstrated by 2D-SWE. Based on this cross-sectional study, 2D-SWE may be a promising, simple and non-invasive modality for objective monitoring of patients with cystic fibrosis who require lifelong follow-up, by providing numerical data for tissue stiffness early in the disease.

Dr Sibel Yavuz  is in the Department of Pediatric Gastroenterology, Cukurova University Medical Faculty, Adana, Turkey.

Nicholas K YungNathan L MaasselSarah J UllrichAdele S RicciardiDavid H StitelmanA narrative review of in utero gene therapy: advances, challenges, and future considerationsTransl Pediatr 2021 May;10(5):1486-1496.doi: 10.21037/tp-20-89   Free PMC article    [Pubmed]

Nicholas K Yung

The field of in utero gene therapy (IUGT) represents a crossroad of technologic advancements and medical ethical boundaries. Several strategies have been developed for IUGT focusing on either modifying endogenous genes, replacing missing genes, or modifying gene transcription products. The list of candidate diseases such as hemoglobinopathies, cystic fibrosis, lysosomal storage disorders continues to grow with new strategies being developed as our understanding of their respective underlying molecular pathogenesis increases. Treatment in utero has several distinct advantages to postnatal treatment. Biologic and physiologic phenomena enable the delivery of a higher effective dose, generation of immune tolerance, and the prevention of phenotypic onset for genetic diseases. Therapeutic technology for IUGT including CRISPR-Cas9 systems, zinc finger nucleases (ZFN), and peptide nucleic acids (PNAs) has already shown promise in animal models and early postnatal clinical trials. While the ability to detect fetal diagnoses has dramatically improved with developments in ultrasound and next-generation sequencing, treatment options remain experimental, with several translational gaps remaining prior to implementation in the clinical realm. Complicating this issue, the potential diseases targeted by this approach are often debilitating and would otherwise prove fatal if not treated in some manner. The leap from small animals to large animals, and subsequently, to humans will require further vigorous testing of safety and efficacy.

Dr Nicholas K Yung is in the Department of General Surgery, Yale University, he New Haven, CT, USA.

Marco ZampoliJanine VerstraeteMarlize FrauendorfReshma KassanjeeLesley WorkmanBrenda M MorrowHeather J ZarCystic fibrosis in South Africa: spectrum of disease and determinants of outcomeERJ Open Res 2021 Aug 2;7(3):00856-2020.doi: 10.1183/23120541.00856-2020.eCollection 2021 Jul. 34350279     Free PMC article

Marco Zampoli

Introduction:Little is known about cystic fibrosis (CF) in low- to middle-income settings. This study aimed to describe the spectrum and outcomes of CF in South Africa (SA) from the recently established SA CF registry (SACFR).
Methods:Demographic, diagnosis and clinical data were extracted from the SACFR. Cross-sectional univariable and multivariable regression analysis of best forced expiratory volume in 1 s (FEV1; age≥6 years) and nutrition (all ages) in 2018 was conducted to investigate factors associated with severe lung disease (SLD; FEV1 ≤3.0 z-score) and undernutrition.
Results:By December 2018, ancestry of 447 individuals included in the SACFR was Caucasian (315; 70%), mixed (87; 19%) and black African (41; 9%). Median diagnosis age was 7.6 months (IQR 2.7-37.1). Genotype was p.Phe508del homozygous (220; 49%); p.Phe508del heterozygous (144; 32%) and neither p.Phe508del or unknown Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) variant in 83 (19%); the second most frequent CFTR variant was 3120+1G>A, common in black Africans. Median age of patients in 2018 was 14.7 years (IQR 7.4-24.4). SLD was independently associated with chronic methicillin-resistant Staphylococcus aureus (MRSA) (adjusted odds ratio( aOR) 16.75; 95% CI 1.74-161.50), undernutrition (aOR 5.20; 95% CI 2.23-12.13) and age (aOR 2.23 per 10 years; 95% CI 1.50-3.31). Undernutrition was associated in univariable analysis with low weight at diagnosis, non-Caucasian ancestry, chronic P. aeruginosa infection and lower socioeconomic status.
Conclusion:Interventions targeting MRSA infection and nutrition are needed to improve CF outcomes in SA. Most people with CF in SA are eligible for highly effective CFTR modulator therapy.

Dr Marco Zampoli is a paediatric pulmonologist in the Dept. of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.

South African MRC Unit for Child and Adolescent Health, University of Cape Town, Cape Town, South Africa.

Keyan ZareiDavid K MeyerholzDavid A StoltzEarly intrahepatic duct defects in a cystic fibrosis porcine modelPhysiol Rep. 2021 Jul;9(14):e14978.doi: 10.14814/phy2.14978.[Pubmed]

   Keyan Zarei

Hepatobiliary disease causes significant morbidity and mortality in people with cystic fibrosis (CF), yet this problem remains understudied. Previous studies in the newborn CF pig demonstrated decreased bile flow into the small intestine and a microgallbladder with increased luminal mucus and fluid secretion defects. In this study, we examined the intrahepatic bile ducts of the newborn CF pig. We assessed whether our findings from the gallbladder are present elsewhere in the porcine biliary tract and if CF pig cholangiocytes have fluid secretion defects. Immunohistochemistry demonstrated apical CFTR expression in non-CF pig intrahepatic bile ducts of a variety of sizes; CF pig intrahepatic bile ducts lacked CFTR expression. Assessment of serum markers did not reveal significant signs of hepatobiliary disease except for an elevation in direct bilirubin. Quantitative histology demonstrated that CF pigs had smaller bile ducts that more frequently contained luminal mucus. CF intrahepatic cholangiocyte organoids were smaller and lacked cAMP-mediated fluid secretion. Together these data suggest that cholangiocyte fluid secretion is decreased in the CF pig, contributing to structural changes in bile ducts and decreased biliary flow.

Keyan Zarei is a graduate student in the Stolz lab in Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine and the Department of Biomedical Engineering, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

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

Edith Zermanick

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

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

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

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