B L AalbersJ E BrunsveldC K van der EntJ C van den EijndenJ M BeekmanH G M Heijerman. Forskolin induced swelling (FIS) assay in intestinal organoids to guide eligibility for compassionate use treatment in a CF patient with a rare genotypeJ Cyst Fibros 2022 Jan 30;S1569-1993(22)00028-5.doi: 10.1016/j.jcf.2022.01.008. Online ahead of print. [Pubmed]

Background: Forskolin-induced swelling of patient-derived organoids has been used to measure patient-specific CFTR function and CFTR modulator response. We present a case where CFTR function assessment in intestinal organoids was decisive for a patients’ acceptance to a compassionate use program.
Case description: A 56 years old female with cystic fibrosis compound heterozygous for F508del and a rare CFTR allele (c.3717+5G>T) experienced rapid clinical deterioration. The forskolin-induced swelling assay on her rectal organoids was used to confirm that the rare mutation is a minimal residual function mutation, and that other CFTR modulators would not likely be effective. Based on these two criteria and her clinical status, she was accepted for compassionate use of elexacaftor/tezacaftor/ivacaftor and showed improvement in all clinical parameters.
Conclusions: This reports describes a first example that intestinal organoids were used to identify a previously unknown CFTR mutation as a minimal function mutation. The individual FIS-based definition of minimal residual function, response to ele/tez/iva and/or lack of response to other CFTR modulating drugs, may thus provide a tool for access to ele/tez/ivatreatment for people with rare genotypes.

B L Aalbers  is in the Department of pulmonology, UMC Utrecht, The Netherlands. Electronic address: b.l.aalbers-2@umcutrecht.nl.

Janice AbbottMargaret A HurleyHelen ChadwickDaniel PeckhamWays of coping and survival in Cystic Fibrosis: a 20-year longitudinal studyJ Cyst Fibros 2022 Apr 20;S1569-1993(22)00100-X. doi: 10.1016/j.jcf.2022.04.011.Online ahead of print. [Pubmed]

       Janice Abbott

Background: The relationship between ways of coping and health outcomes has been a focus of interest for decades. There is increasing recognition that positive psychological functioning can influence health outcomes beneficially. This work investigated the role of coping in predicting survival in CF.
Methods: A longitudinal observational cohort study with a 20-year follow-up period was undertaken. At entry to the study, demographic and clinical variables were recorded, and ways of coping were assessed using the Cystic Fibrosis Coping Scale which measures four distinct ways of coping: optimism, hopefulness, distraction and avoidance. Survival outcome was measured as time in days from the date of recruitment to exit from the study, where exit was either death, loss to follow-up or the end of the follow-up period.
Results: Survival time was modelled using Cox’s proportional hazards model. At baseline, 116 people with CF were recruited. By the census date, 54 people had died (14 men had died during 248,565 person-days of observation and 40 women had died during 358,372 person-days of observation). Optimism was the only way of coping that showed any beneficial effect on survival (RR=0.984, p=0.040) after adjustments for age, gender, ppFEV1 and the three other coping variables measured at baseline.

Conclusion: This work suggests that optimistic coping serves as a prognostic measure of survival in CF beyond key clinical and demographic variables. Ways of coping are modifiable, providing a target for clinical intervention; to improve quality of life and clinical outcomes and potentially increase longevity.

Prof Janice Abbott is Professor of Health Psychoilogy at the School of Psychology, University of Central Lancashire, Preston, PR1 2HE, UK

Dorothea AppeltTeresa FuchsGratiana SteinkampHelmut Ellemunter. Malignancies in patients with cystic fibrosis: a case series J Med Case Rep 2022 Jan 19;16(1):27. doi: 10.1186/s13256-021-03234-1.  [Pubmed]
Background: Previous reports have shown an increased number of colorectal cancers in patients with cystic fibrosis. We assessed the database of our cystic fibrosis centre to identify patients with all kinds of cancer retrospectively. All patients visiting the Cystic Fibrosis Centre Innsbruck between 1995 and 2019 were included

Case presentation: Among 229 patients with cystic fibrosis treated at the Cystic Fibrosis Centre in Innsbruck between 1995 and 2019, 11 subjects were diagnosed with a malignant disease. The median age at diagnosis was 25.2 years (mean 24.3 years). There were four gynaecological malignancies (cervical intraepithelial neoplasia and cervical cancer), two haematological malignancies (acute lymphocytic leukemia), one gastrointestinal malignancy (peritoneal mesothelioma), and four malignancies from other origins (malignant melanoma, neuroblastoma, adrenocortical carcinoma, and thyroid cancer). One malignancy occurred after lung transplantation. There was a strong preponderance of females, with 10 of the 11 cases occurring in women. Six deaths were attributed to cancer.
Conclusions: Most diagnoses were made below 30 years of age, and half of the subjects died from the malignant disease.    Awareness of a possible malignancy is needed in patients with atypical symptoms. Regular screenings for cancer should also be considered, not only for gastrointestinal tumours.

Dr Dorothea Applelt is at the Medical University of Innsbruck, Cystic Fibrosis Centre Innsbruck, 6020, Innsbruck, Austria.

P Aurora, Julie Anne DuncanS LumG DaviesA WadeJ StocksL VivianiE RaywoodC PaoG RuizA BushLondon Cystic Fibrosis Collaboration (LCFC)Early Pseudomonas aeruginosa predicts poorer pulmonary function in preschool children with cystic fibrosis.  J Cyst Fibros  2022 Apr 30;S1569-1993(22)00102-3.doi: 10.1016/j.jcf.2022.04.013.Online ahead of print.[Pubmed]

Paul Aurora

Background: We previously reported relatively normal pulmonary function (2 years of age) and computed tomography (CT, 1 year of age) in cystic fibrosis (CF) newborn screened (NBS) infants. We now report follow up of these children to preschool age.
Methods: 67 NBS children with CF and 41 healthy controls underwent pulmonary function tests in infancy (∼3 months, 1 year and 2 years) and at preschool (3-6 years). Broncho-alveolar lavage (BAL) and CT were undertaken in those with CF at 1 year. Primary outcomes at preschool were lung clearance index (LCI) and forced expired volume (FEV0.75). Risk factors for lung function impairment were identified by regression modelling, emphasising factors that could be identified or measured in the first 2 years of life.
Results: At preschool age children with CF had poorer lung function than controls, mean(95% CI) difference in LCI z-score: 1.47(0.96;1.97) and FEV0.75 z-score -0.54(-0.98; -0.10). Isolation of Pseudomonas aeruginosa before 6 months was a highly significant predictor of raised (abnormal) preschool LCI, associated with a mean (95%CI) increase of 1.69(0.43, 2.95) z-scores, compared to those with no Pseudomonas aeruginosa during the first 2 years of life. Including 2 year LCI and 1 year CT data in the predictive model increased the r2 from 13% to 61%.

Conclusions: Lung function deteriorates after 2 years in NBS children with CF. Isolation of Pseudomonas aeruginosa before 6 months and minor abnormalities of infant lung function tests and CT in infancy are associated with higher preschool LCI.

Paul Aurora is in the Department of Infection, Immunity, Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom; Respiratory Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

H L BarrT BihoueeA M Zwitserloot A year in review: Real world evidence, functional monitoring and emerging therapeutics in 2021J Cyst Fibros 2022 Mar;21(2):191-196.doi: 10.1016/j.jcf.2022.02.014.Epub 2022 Mar 7.   Free PMC article   [Pubmed]

       Helen Barr

This is a comprehensive and  extensively referenced review of significant areas of change and new knowledge during 2021. The Free PMC article is available and strongly recommended.

There are joint first authors. The correspondiing author is Dr Helen Barr consultant respiratory physician at the Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Nottingham Respiratory Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom.

Rosara M BassBabette S Zemel  Virginia A StallingsMary B Leonard Jaime Tsao Andrea KellyBone accrual and structural changes over one year in youth with cystic fibrosisJ Clin Transl Endocrinol 2022 Mar 25;28:100297.doi: 10.1016/j.jcte.2022.100297.eCollection 2022 Jun.[Pubmed]

      Rosara Bass

Background: Pediatric bone accrual governs peak bone mass and strength. Longitudinal studies of bone health in youth with cystic fibrosis (CF) may provide insight into CF-related bone disease (CFBD), a prevalent co-morbidity in adults with CF.
Methods: This one-year longitudinal study of youth with pancreatic insufficient CF, enrolled in a nutrition intervention study [n = 62 (36 M/26F)] 1) examined dual-energy x-ray absorptiometry (DXA)-defined lumbar spine (LS) and total body less head (TBLH) bone accrual and 2) compared their changes in peripheral quantitative computed tomography (pQCT) cortical and trabecular tibial bone density and geometry to those of a healthy reference group [n = 143 (68 M/75F)].Main outcome measures were 1) DXA: lumbar spine areal bone mineral density (LSaBMD) and total body less head bone mineral content (TBLH-BMC), sex- and pubertal status-specific, height velocity (HV)-adjusted or HV and lean body mass velocity (HV-LBMV)-adjusted annualized velocity-Z scores and 2) pQCT: age, sex, pubertal status and, when appropriate, tibial length adjusted Z-scores for bone architecture measures.DXA velocity-Z were compared to expected mean of 0 and correlations with clinical parameters (age, BMI-Z and FEV1%-predicted) tested. Within-subject comparisons of HV-adjusted and LBMV-HV-adjusted DXA velocity-Z were conducted in CF.pQCT Z-scores were compared between the two groups over one year using longitudinal models. Longitudinal relationships between measures of bone health and clinical parameters (age, BMI-Z and FEV1%-predicted) were examined in individuals with CF.
Results: DXA velocity-Z were higher than normal in females (p < 0.05) but not males with CF. HV-adjusted and LBMV-HV-adjusted velocity-Z did not differ for LSaBMD or TBLH-BMC.In males with CF, both HV-adjusted and LBMV-HV-adjusted LSaBMD velocity-Z scores correlated negatively with age (HV rho: -0.35; p = 0.045 and LBMV-HV rho: -0.47; p = 0.0046). In males with CF BMI-Z correlated positively with HV-adjusted LSaBMD velocity-Z (rho: 0.37; p = 0.034), but this relationship did not persist for LBMV-HV (rho: 0.14; p = 0.42). In females with CF, no correlations between LSaBMD velocity-Z scores and age or BMI-Z were found (all p > 0.05). No correlations between LSaBMD velocity-Z scores and FEV1%-predicted were seen in either sex (all p > 0.12). TBLH-BMC velocity Z-scores were not correlated with clinical parameters in either sex (all p > 0.1).At baseline, multiple pQCT parameters were lower in CF (p < 0.05). pQCT Z-scores did not differ between baseline and one-year in either CF or reference group. In a longitudinal model comparing pQCT-Z changes in CF and reference, multiple pQCT-Z outcomes remained lower in CF, but the changes in parameters did not differ in CF vs reference (all p > 0.26). Lower pQCT outcomes in CF were largely restricted to males (CF group*female sex interaction beta coefficients > 0). In this combined longitudinal model, of both CF and reference, BMI-Z was positively associated with pQCT-Z parameters(p < 0.001).Multiple pQCT-Z outcomes positively correlated with both BMI-Z and FEV1%-predicted in males with CF, and with FEV1%-predicted in females with CF (p < 0.05). Age was negatively associated with section modulus (p = 0.001) in males and with cortical density-Z in females (p < 0.001).

Conclusions: With improved longevity, bone health in CF is of increasing importance. On average, bone accrual was preserved in youth with CF, and while deficits in bone geometry and strength were found, these deficits did not worsen over the one-year study. Lower LS bone accrual with increasing age suggests emerging adulthood is a period of vulnerability in CF while the role of LBM in bone health is underscored by the lack of relationship between LBMV-adjusted accrual and BMI. These findings may be useful in targeting screening practices and interventions.

Keywords: BMC, Bone mineral content; Bone accrual; Bone health; CF, Cystic Fibrosis; Cystic fibrosis; DXA velocity; DXA, Dual energy x-ray densiometry; FEV1, Forced expiratory volume in one second; HAZ, height-for-age-z-score adjusted; HV, height velocity; LBM, lean body mass; LS, lumbar spine; Peripheral quantitative computed tomography; TBLH, total body less head; Vel-Z, velocity-Z; Z-score; aBMD, areal bone mineral density; pQCT, peripheral quantitative tomography.

Rosara M Bass is in the Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA 19146 USA and the Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19146, USA.

Bethany BatsonBryan ZornGiorgia RadicioniStephanie LivengoodTadahiro KumagaiHong DangAgathe CeppePhillip ClappMichael TunneyStuart ElbornGerry McElvaneyMarianne MuhlebachRichard C BoucherMichael TiemeyerMatthew WolfgangMehmet Kesimer.Cystic Fibrosis Airway Mucus Hyperconcentration Produces a Vicious Cycle of Mucin, Pathogen, and Inflammatory Interactions that Promote Disease Persistence. Am J Respir Cell Mol Biol 2022 Apr 29.doi: 10.1165/rcmb.2021-0359OC. Online ahead of print.     [Pubmed]

Mehmet Kesimer

Bethany Batson

The dynamics describing the vicious cycle characteristic of CF lung disease, initiated by stagnant mucus and perpetuated by infection and inflammation, remain unclear.
Here we determine the effect of the CF airway milieu, with persistent muco-obstruction, resident pathogens, and inflammation, on the mucin quantity/quality that govern lung disease pathogenesis/progression. The concentrations of MUC5AC and MUC5B, were measured and characterized in sputum samples from CF (N=44) and healthy (N=29) subjects with respect to their macromolecular properties, degree of proteolysis, and glycomics diversity. These parameters were related to quantitative microbiome and clinical data.
MUC5AC, and MUC5B concentrations were elevated, 30- and 8-fold respectively, in CF as compared to control sputum. Mucin parameters did not correlate with hypertonic saline, inhaled corticosteroids or antibiotics use. No differences in mucin parameters were detected at baseline vs during exacerbations. Mucin concentrations significantly correlated with the age and sputum human neutrophil elastase (HNE) activity. Although significantly more proteolytic cleavages were detected in CF mucins, their macromolecular properties, e.g., size and molecular weight, were not significantly different than controls likely reflecting the role of S-S bonds in maintaining multimeric structures. No evidence of giant mucin macromolecule reflecting oxidative stress-induced cross-linking was found. Mucin glycomic analysis revealed significantly more sialylated glycans in CF and the total abundance of non-sulfated O-glycans was correlated with the relative abundance of pathogens.
Collectively, the interaction of mucins, pathogens, epithelium, and inflammatory cells promotes proteomic and glycomic changes that reflects a persistent muco-obstructive, infectious, and inflammatory state.

Bethany Batson is in the Kesimer Lab. at the University of North Carolina, Pathology and Laboratory Medicine , Chapel Hill, North Carolina, United States.

Mehmet Kesimer is Professor of Pathology and Laboratory Medicine at the Marsico Lung Institute, Cystic Fibrosis/Pulmonary Research and Treatment Center

Lauryn A BenningerCesar TrilloJorge Lascano.  CFTR modulator use in post lung transplant recipientsJ Heart Lung Transplant 2021 Dec;40(12):1498-1501.doi: 10.1016/j.healun.2021.08.009.Epub 2021 Aug 26. [Pubmed]

    Lauryn Benninger

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy has previously been contraindicated in solid organ transplant recipients. This was due to lack of data and concern for interactions with immunosuppressive drug regimens. However, in post-lung transplant recipients, CFTR modulators may improve extrapulmonary manifestations of cystic fibrosis without impacting graft function or immunosuppressive drug levels. Herein, we present our single center experience with the use of elexacaftor/tezacaftor/ivacaftor, Trikafta, in adult post-lung transplant recipients.

Dr Lauryn A Benninger  is a pulmonologist in the Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida

Crystal    Bourke Sunalene DevadasonWilliam DitchamJulie DepiazziMark L Everard.   Controlled inhalation improves central and peripheral deposition in cystic fibrosis patients with moderate lung disease.   J Paediatr Child Health 2022 Feb 17. doi: 10.1111/jpc.15909. Online ahead of print.   [Pubmed]
Aim: With progressive impairment of lung function, deposition of inhaled drug in the lungs becomes progressively more central, limiting its effectiveness. This pilot study explored the possibility that long slow inhalations might improve delivery of aerosol to the lung periphery in cystic fibrosis patients with moderate lung disease.
Methods: Five subjects aged 12-18 years (mean FEV1 72%; range 63-80%) inhaled a radiolabelled aerosol from a jet nebuliser on two occasions. Two inhalation techniques were compared: breathing tidally from a standard continuous output nebuliser and using long slow inhalations from the AKITA® JET system.

An example of one participant’s gamma scintigraphy images (anterior view) showing significantly decreased deposition in the orogastric regions with long slow inhalations. (a) Standard delivery with tidal breathing. (b) Dosimetric delivery with long slow inhalation

Results: Long slow breaths resulted in much lower oropharyngeal deposition with higher lung doses. Importantly, the peripheral lung increased proportionately. The increased lung dose is attributable to more of the larger inhaled droplets passing into the lower airways. This would be expected to increase the central deposition unless significantly more of the smaller droplets were able to penetrate deeper into the lungs. The data support improved delivery of drug to the distal lung when compared with tidal breathing.

Conclusion: These pilot data suggest that this approach may prove to be clinically relevant in improving the efficacy of inhaled medication in those with moderate-severe lung disease.

Crystal Bourke is in the Physiotherapy Department, Perth Children’s Hospital, Perth, Western Australia, Australia.

Ann ChengOlivia BakerUta Hill. Elexacaftor, tezacaftor and ivacaftor: a case of severe rash and approach to desensitisationBMJ Case Rep 2022 Mar 2;15(3):e247042. doi: 10.1136/bcr-2021-247042. [Pubmed]

          Ann Cheng

We present a case of severe rash following induction of elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA) in a young adult male cystic fibrosis patient. While rash is a commonly reported side effect which resolves in 1-2 weeks with minimal intervention, our patient had presented with fever and widespread rash prompting medication cessation. After a washout period, reintroduction with 1/2 tablet of ELX/TEZ/IVA produced a similar systemic response within 24 hours. Repeat attempt, this time with 1/8 tablet and increasing in increments of an eighth daily, was successful and has allowed our patient to experience the transformative benefits of ELX/TEZ/IVA including improved pulmonary function and reduced episodes of infective exacerbation. This case illustrates one of the most common side effects of ELX/TEZ/IVA triple therapy, and our experience of desensitisation to ELX/TEZ/IVA in a challenging case of rash.

Dr Ann Cheng is NIHR Academic Clinical Fellow in the Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Sheffield, UK.   Also Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK.

Hongbo ChengShenmin YangQingxia MengBo ZhengYidongGuLuyun WangTao SongChunlu XuGaigai WangMutian HanLiyan Shen, Jie Ding, Hong Li, Jun Ouyang, Ding, Hong Li Jun Ouyang.    Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital bilateral absence of vas deferens.  J Assist Reprod Genet  2022 Feb 4.doi: 10.1007/s10815-022-02417-z. Online ahead of print. [Pubmed]

Purpose: Congenital bilateral absence of the vas deferens (CBAVD) is a major cause of obstructive azoospermia and male factor infertility. CBAVD is mainly caused by mutations in the genes encoding CFTR (cystic fibrosis transmembrane conductance regulator) and ADGRG2 (adhesion G protein-coupled receptor G2). This study aimed to describe CFTR and ADGRG2 variations in 46 Chinese CBAVD patients and evaluated sperm retrieval and assisted reproductive technology outcomes.

Methods: The CFTR and ADGRG2 genes were sequenced and analyzed by whole-exome sequencing (WES), and variations were identified by Sanger sequencing. Bioinformatic analysis was performed. We retrospectively reviewed the outcomes of patients undergoing sperm retrieval surgery and intracytoplasmic sperm injection (ICSI).
Results: In total, 35 of 46 (76.09%) patients carried at least one variation in CFTR, but no copy number variants or ADGRG2 variations were found. In addition to the IVS9-5 T allele, there were 27 CFTR variations, of which 4 variations were novel and predicted to be damaging by bioinformatics. Spermatozoa were successfully retrachieved in 46 patients, and 39 of the patients had their own offspring through ICSI.

Conclusion: There are no obvious hotspot CFTR mutations in Chinese CBAVD patients besides the IVS9-5 T allele. Therefore, WES might be the best detection method, and genetic counselling should be different from that provided to Caucasian populations. After proper counselling, all patients can undergo sperm retrieval from their epididymis or testis, and most of them can have their own children through ICSI.

Hongbo Cheng is in the Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu, and the China.Center for Reproduction and Genetics, NHC Key Laboratory of Male Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

Harriet Corvol Sandra de MirandaClémence DehillotteLydie LemonnierRaphael ChironIsabelle Danner-BoucherRebecca HamidfarVéronique HoudouinJulie MaceyChristophe MarguetMarlène Murris-EspinQuitterie ReynaudPhilippe ReixMartine Reynaud GaubertAstrid KemgangPierre-Régis BurgelFrench Cystic Fibrosis Reference Network study group. Cumulative Incidence and Risk Factors for Severe COVID-19 in French People with Cystic FibrosisClin Infect Dis 2022 Apr 27;ciac333.doi: 10.1093/cid/ciac333. Online ahead of print.     [Pubmed]

        Harriet Corvol

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are closely monitored in people with cystic fibrosis (pwCF), with a special emphasis on severe cases. Previous studies used hospitalization rates as proxy for severity
Objective: criteria were applied for defining severity (e.g., respiratory failure and/or death). Data were compared to those from all French pwCF using the French CF Registry.
Results: As of April 30, 2021, 223 pwCF were diagnosed with COVID-19, with higher risks in adults (≥18 years, odds ratio [OR] = 2.52, 95% confidence interval [CI] = 1.82-3.48) and post-transplant individuals (OR = 2.68, 95% CI = 1.98-3.63). Sixty (26.9%) patients were hospitalized, with an increased risk in post-transplant individuals (OR = 4.74, 95% CI = 2.49-9.02). In 34 (15%) cases, COVID-19 was considered severe; 28/60 (46.7%) hospitalizations occurred in patients without objective criteria of severity. Severe cases occurred mostly in adults (85.3%) and post-transplant pwCF (61.8%, OR = 6.02, 95% CI = 2.77-13.06). In non-transplanted pwCF, risk factors for severity included low lung function (median ppFEV1 54.6% vs. 75.1%, OR = 1.04, 95% CI = 1.01-1.08) and CF-associated diabetes (OR = 3.26, 95% CI = 1.02-10.4). While most cases recovered without sequelae (n = 204, 91.5%), 16 (13%) were followed for possible sequelae, and three post-transplant females died.

Conclusions: Severe COVID-19 cases occurred infrequently during the first year of the pandemic in French pwCF. Non-transplanted adults with severe respiratory disease or diabetes and post-transplant individuals were at risk for severe COVID-19. Thus, specific preventive measures should be proposed.

Harriet Corvol is Head of the Pediatric Respiratory Department and Pediatric CF Center, Assistance Publique Hôpitaux de Paris (APHP), Hôpital Trousseau, Paris, France and Professor at the Sorbonne Université, Centre de Recherche Saint-Antoine, Paris, France.

Mélanie Faria da CunhaIwona Pranke Ali SassiChristiane SchreiweisStéphanie MoriceauDragana VidovicAurélie HattonMariane Sylvia CarlonGeordie Creste Farouk BerhalGuillaume PrestatRomain Freund Norbert OdolczykJean Philippe Jais Christine Gravier-PelletierPiotr ZielenkiewiczVincent JullienAlexandre HinzpeterFranck OuryAleksander EdelmanIsabelle Sermet-Gaudelus      Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice. Sci Rep 2022 Apr 12;12(1):6132.doi: 10.1038/s41598-022-09678-9.Free PMC article [Pubmed]

Melanie da Cunha

c407 is a bis-phosphinic acid derivative which corrects CFTR dysfunction in epithelial cells carrying the F508del mutation. This study aimed to investigate c407 in vivo activity in the F508del Cftrtm1Eur murine model of CF. Using nasal potential difference measurement, we showed that in vivo administration of c407 by topical, short-term intraperitoneal and long-term subcutaneous route significantly increased the CFTR dependent chloride (Cl) conductance in F508del Cftrtm1Eur mice. This functional improvement was correlated with a relocalization of F508del-cftr to the apical membrane in nasal epithelial cells. Importantly, c407 long-term administration was well tolerated and in vitro ADME toxicologic studies did not evidence any obvious issue.

Our data provide the first in vivo preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis.

Mélanie Faria da Cunha  is at NSERM U1151, équipe 11, Paris, France and 2Université de Paris, Paris, France.

Kevin J Downes Austyn GrimLaura ShanleyRonald C RubensteinAthena F ZuppaMarc R Gastonguay.  A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis: Assessment of Target Attainment with Extended-Interval Dosing through Simulation. Antimicrob Agents Chemother 2022 Apr 28;e0237721.doi: 10.1128/aac.02377-21.Online ahead of print.   [Pubmed]

Kevin Downes

Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF <5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in >75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of Cmax >25 mg/L and AUC24 of 80-120 mg·h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.

Kevin J Downes  is attending physician at the Division of Infectious, Diseases at the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. and other departments.

Neele DellschaftCaroline HoadLuca MarcianiPenny GowlandRobin Spiller Small bowel water content assessed by MRI in health and disease: a collation of single-centre studiesAliment Pharmacol Ther 2022 Feb;55(3):327-338. doi: 10.1111/apt.16673. Epub 2021 Oct 30.    [Pubmed]

    Neele Dellschaft

Background: New developments in MRI have allowed the non-invasive, accurate measurement of the small bowel water content (SBWC).
Aims: To collate studies measuring SBWC following ingestion of a range of foods in both health and disease to provide data for adequately powering future studies in this area.
Methods: This collation brings together 29 studies including 954 participants (530 healthy, 54 diverticulosis, 255 IBS, 53 functional constipation, 12 cystic fibrosis, 15 Crohn’s disease, 20 coeliac disease, 15 scleroderma) which have been carried out in a single centre using comparable study designs.
Results: Fasting SBWC (mean 82 [SD 65] mL) shows high variability with a small decline with advancing age (healthy volunteers only; individual patient data). Fasting values are increased in untreated coeliac disease (202 [290] mL, P = 0.004). Post-prandial SBWC shows less intra-individual variability than fasting values in healthy volunteers. SBWC is increased by eating, most markedly by high fat meals but also by fibre, both viscous and particulate. Indigestible residue accumulates in late post-prandial period but empties soon after ingestion of a high calorie meal which produces a significant drop (by 50 [52] mL) in healthy volunteers. The associated fall in SBWC is abnormal in people with cystic fibrosis (SBWC reduced by 10 [121] mL, P = 0.002) and in people with irritable bowel syndrome with diarrhoea (SBWC reduced by 17 [43] mL, P = 0.007).
Conclusions: SBWC as assessed by MRI is a valuable biomarker indicating the balance of secretion and absorption in health and disease and the impact of treatments.

Dr Neele Dellschaft is a Research Fellow at the Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.  NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK

Maya DesaiChris HineJoanna L Whitehouse. Keith BrownleeSusan C CharmanPrasad Nagakumar. Who are the 10%? – Non eligibility of cystic fibrosis (CF) patients for highly effective modulator therapies. Respir Med  2022 Aug;199:106878.doi: 10.1016/j.rmed.2022.106878. Epub 2022 May 16. [Pubmed]

      Maya Desai

Background: The availability of mutation-specific cystic fibrosis modulator therapies has the potential to improve the lives of children and adults with cystic fibrosis. The frequency of mutations causing defects in the cystic fibrosis transmembrane conductance regulator (CFTR) function varies between sub-groups in multi-ethnic populations. The profile of patients eligible for CFTR modulator ivacaftor/tezacaftor/elexacaftor (Kaftrio™) therapy based on ethnicity has not been reported in the United Kingdom CF population.
Methods: We conducted a descriptive cross-sectional analysis of patients in the UK CF Registry who had annual review data submissions in 2019. Data analysed included demographic characteristics, spirometry, chronic Pseudomonas status, nutrition, and CF related diabetes status. The genotype data was stratified by whether there was at least one copy of F508del or no copy of F508del as current eligibility for ivacaftor/tezacaftor/elexacaftor, or projected future eligibility, is defined as having at least one copy of F508del mutation.
Results: Data from 9887 patients were reviewed, 46.7% female, mean age 22.5 years. 8.6% (n = 852) patients had no copy of F508del making them ineligible for ivacaftor/tezacaftor/elexacaftor. Overall, 93.4% of patients were of white ethnicity, with a similar proportion of those with at least one F508del being white (95.6%). This was reduced to 70.0% of those with no F508del. The proportion of people of Asian ethnicity was much higher in the no F508del group (19.2% vs 1.2%). Compared with one F508del patients, the no F508del group were older (25.2 years vs 22.2 years, p < 0.001), had higher prevalence of pancreatic sufficiency (39.0% vs 14.9% p < 0.001), lower prevalence of chronic Pseudomonas infection (21.1% vs. 26.6%, p < 0.001), and higher best FEV1from the previous year (proportion with greater than 70% FEV1 predicted, 66.1% vs 63.0%, p = 0.005).

Conclusion: Patients from black, Asian and minority ethnic backgrounds are significantly less likely to be eligible for ivacaftor/tezacaftor/elexacaftor based on the current prescribing policy in the UK. At present this is the most highly effective CF modulator therapy available to treat people with CF. The CF community should urgently address the unmet need for effective targeted therapies for patients without F508del.

Maya Desai is Respiratory Clinical Lead in the Department of Cystic Fibrosis and Respiratory Medicine, Birmingham Women’s and Children’s Hospital, Steelhouse Lane, Birmingham, UK.

Samantha L DurfeySudhakar PipavathAnna LiAnh T VoAnina RatjenSuzanne CarterSarah J MorganMatthew C RadeyBrenda GroganStephen J SalipanteMichael J WelshDavid A StoltzChristopher H Goss Edward F McKone Pradeep K Singh./  Combining Ivacaftor and Intensive Antibiotics Achieves Limited Clearance of Cystic Fibrosis InfectionsmBio 2021 Dec 21;12(6):e0314821. doi: 10.1128/mbio.03148-21.Epub 2021 Dec 14.   Free PMC article    [Pubmed]

Samantha Durfey

Drugs called CFTR modulators improve the physiologic defect underlying cystic fibrosis (CF) and alleviate many disease manifestations. However, studies to date indicate that chronic lung infections that are responsible for most disease-related mortality generally persist.
Here, we investigated whether combining the CFTR modulator ivacaftor with an intensive 3.5-month antibiotic course could clear chronic Pseudomonas aeruginosa or Staphylococcus aureus lung infections in subjects with R117H-CFTR, who are highly ivacaftor-responsive. Ivacaftor alone improved CFTR activity, and lung function and inflammation within 48 h, and reduced P. aeruginosa and S. aureus pathogen density by ∼10-fold within a week. Antibiotics produced an additional ∼10-fold reduction in pathogen density, but this reduction was transient in subjects who remained infected. Only 1/5 P. aeruginosa-infected and 1/7 S. aureus-infected subjects became persistently culture-negative after the combined treatment. Subjects appearing to clear infection did not have particularly favourable baseline lung function or inflammation, pathogen density or antibiotic susceptibility, or bronchiectasis scores on CT scans, but they did have remarkably low sweat chloride values before and after ivacaftor. All persistently P. aeruginosa-positive subjects remained infected by their pre-treatment strain, whereas subjects persistently S. aureus-positive frequently lost and gained strains. This work suggests chronic CF infections may resist eradication despite marked and rapid modulator-induced improvements in lung infection and inflammation parameters and aggressive antibiotic treatment.

IMPORTANCE Recent work shows that people with CF and chronic lung infections generally remain persistently infected after treatment with drugs that target the CF physiological defect (called CFTR modulators). However, changes produced by modulators could increase antibiotic efficacy. We tested the approach of combining modulators and intensive antibiotics in rapid succession and found that while few subjects cleared their infections, combined treatment appeared most effective in subjects with the highest CFTR activity. These findings highlight challenges that remain to improve the health of people with CF.

Dr Samantha L Durfey  is in the Department of Microbiology, University of Washington School of Medicinegrid.471394.c, Seattle, Washington, USA.

Raphael Enaud Eric Frison,Sophie MissonnierAude FischerVictor de LedinghenPaul PerezStéphanie BuiMichael FayonJean-François ChateilThierry Lamireau Cystic fibrosis and noninvasive liver fibrosis assessment methods in children. Pediatr Res 2022 Jan;91(1):223-229.doi: 10.1038/s41390-021-01427-4. Epub 2021 Mar 17. [Pubmed]

      Rapheal Enaud

Background: Noninvasive assessments of liver fibrosis are currently used to evaluate cystic fibrosis (CF)-related liver disease. However, there is scarce data regarding their repeatability and reproducibility, especially in children with CF. The present study aimed to evaluate the repeatability and reproducibility of transient elastography (TE) (FibroScan®) and point shear-wave elastography using virtual touch quantification (pSWE VTQ) in children with CF.
Methods: TE and pSWE VTQ were performed in 56 children with CF by two different operators. Analysis of repeatability and reproducibility was available in 33 patients for TE and 46 patients for pSWE VTQ. Intra- and interobserver agreement were assessed using the intraclass correlation coefficient (ICC) and their 95% confidence interval (CI), and Bland and Altman graphs.
Results: For TE, ICC was 0.91 (0.83-0.95) for intraobserver agreement and 0.92 (95% CI: 0.86-0.96) for interobserver agreement. For pSWE VTQ, ICC was 0.83 (0.72-0.90) for intraobserver agreement and 0.67 (0.48-0.80) for interobserver agreement.
Conclusions: Both technics can be proposed in the follow-up of patients, according to their availability in CF centers.

Impact: This study shows that TE and pSWE VTQ are reliable methods to evaluate liver fibrosis in children with CF. This study shows for the first time that TE and pSWE VTQ are both repeatable and reproducible in children with CF. These data indicate that both TE and pSWE VTQ can be proposed for the follow-up of patients with CF, according to their availability in each CF center.

Dr Raphael Enaud is at the following – Pediatric Hepatology and Gastroenterology Unit, Bordeaux University Hospital, Pellegrin-Enfants Hospital, Bordeaux, France.
Bordeaux University Hospital, Pellegrin-Enfants Hospital, Pediatric Cystic Fibrosis-Center (CRCM), Bordeaux, France.
INSERM, Centre de Recherche Cardio-thoracique de Bordeaux (U1045), University of Bordeaux, Bordeaux, France

O B Esan D K SchlüterR PhillipsR CosgriffS ParanjothyD WilliamsR NormanS B CarrJ DuckersD Taylor-Robinson. Pregnancy rates and outcomes in women with cystic fibrosis in the UK: comparisons with the general population before and after the introduction of disease-modifying treatment, 2003-17BJOG 2022 Apr;129(5):743-751.doi: 10.1111/1471-0528.16957. Epub 2021 Nov 8.  [Pubmed]

     Oluwaseun Esan

Objective: To compare pregnancy rates and outcomes for women with cystic fibrosis in the UK with those of the general population and assess the effect of the introduction of disease-modifying treatment. Design: A population-based longitudinal study, 2003-17.Setting: United Kingdom.
Population: Women aged 15-44 years in the UK cystic fibrosis (CF) Registry compared with women in England and Wales.
Methods: We calculated pregnancy and live-birth rates for the CF population and the general population of England and Wales. For women with CF we compared pregnancy rates before and after ivacaftor was introduced in 2013. We further used CF registry data to assess pregnancy outcomes for mothers with CF, and to assess the relationship between maternal pre-pregnancy lung function and nutritional status and child gestational age.
Main outcome measures: Pregnancy and live-birth rates and child gestational age.
Results: Of 3831 women with CF, 661 reported 818 pregnancies. Compared with the general population, the pregnancy rate was 3.3 times lower in the CF population (23.5 versus 77.7 per 1000 woman-years); the live-birth rate was 3.5 times lower (17.4 versus 61.4 per 1000 woman-years) with 70% of pregnancies in CF women resulting in live births; termination of pregnancy rates were also lower (9% versus 22%). Pregnancy rates increased post-ivacaftor for eligible women with CF, from 29.7 to 45.7 per 1000 woman-years. There was no association between pre-pregnancy lung function/nutrition status and gestational age.

Conclusions: Pregnancy rates in women with CF are about one-third of the rates in the general population with favourable outcomes, and increased for eligible women post-ivacaftor.

Tweetable abstract: Pregnancy rates in women with CF are about a third of the rate in England and Wales with 70% live births. Ivacaftor increases the rate.

Dr O B Esan is a postdoctoral researcher in the Department of Public Health, Policy and Systems, University of Liverpool, Liverpool, UK

Hannah FarleySarah PooleStephen ChapmanWilliam Flight. Diagnosis of cystic fibrosis in adulthood and eligibility for novel CFTR modulator therapyPostgrad Med J 2022 May;98(1159):341-345.doi: 10.1136/postgradmedj-2020 [Pubmed]    

Hannah Farley

Background: Cystic fibrosis (CF) is an autosomal recessive condition that primarily manifests as a chronic respiratory disease. CF is usually diagnosed in early childhood or through newborn screening although in a small but important group, diagnosis is not made until adulthood. Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are now available for most genetic causes of CF highlighting the importance of identifying people with late presentations of CF.
Aim: We aimed to identify the clinical characteristics of people diagnosed with CF in adulthood and their resulting eligibility for novel CFTR modulator therapies.
Methods: Patients diagnosed with CF at age 18 years or older were identified from a patient database. Paper and electronic medical records were reviewed and clinical, microbiological and radiological data at diagnosis were recorded.
Results: Nineteen patients were identified. Median age at diagnosis was 38 years (range: 19-71) and 9 (47%) were female. All patients had a history of chronic respiratory symptoms and 18/19 (94%) had radiological evidence of bronchiectasis. All patients had two pathogenic CFTR mutations identified with 16/19 (84%) compound heterozygotes for the F508del mutation. The majority of patients had a CFTR genotype considered eligible for CFTR modulator therapy (84% and 89% according to European and US licences, respectively).

Conclusions: Adult patients with unexplained chronic bronchiectasis should be thoroughly investigated for CF. A low index of suspicion will help to identify adults with undiagnosed CF who are likely to benefit from CFTR modulator therapy.

Dr Hannah Farley  is at the Medical School, Oxford University, Oxford, UK

Julie De GeyterSabina Gallati-KraemerHong ZhangChristian De Geyter.  Identification and selection of healthy spermatozoa in heterozygous carriers of the Phe508del-variant of the CFTR-gene in assisted reproduction 2022 Feb 3;12(1):1866.doi: 10.1038/s41598-022-05925-1. Free PMC article [Pubmed]

Julie de Geyter

The pathogenic variant Phe508del of the CFTR-gene is the most frequent cause of cystic fibrosis (CF). Whereas male CF-patients are infertile due to bilateral agenesis of the efferent ducts, the fertility status of male heterozygous carriers is uncertain. We aimed at demonstrating the involvement of the CFTR-ion channel during sperm capacitation and to potentially select variant-free spermatozoa in heterozygous carriers of the CFTR-variant using flow cytometry (FC). Using FC and sorting, single cell polymerase chain reaction, immuno-fluorescent staining an experimental study was performed on nine fertile semen donors and three heterozygous infertile men carrying the Phe508del gene variant. Chemical inhibition of CFTR interfered with sperm capacitation. Most viable spermatozoa of heterozygous carriers of the Phe508del variant of the CFTR-gene show immune-fluorescent CFTR. Sperm capacitation in Phe508del carriers was similar to that in healthy semen donors. Distribution of the Phe508del allele in trio data of CF-affected families corresponded to the expected recessive inheritance pattern. Infertility in Phe508del heterozygous men is unlikely to be caused by the pathogenic variant although some contribution cannot be excluded. Normal sperm capacitation in carriers of pathogenic variants of the Phe508del-gene may in part explain the high prevalence of a potentially lethal recessive disorder.

Julie De Geyter is in the Department of Medical Genetics, University Hospital, University of Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland

Prof. Christian De Geyter,is the  Research Group Leader

Thomas S FitzMauriceCaroline McCannDilip NazarethMatthew ShawPaul S McNamaraMartin J WalshawMeasuring the effect of elexacaftor/tezacaftor/ivacaftor combination therapy on the respiratory pump in people with CF using dynamic chest radiographyJ Cyst Fibros 2022 Jan 28;S1569-1993(22)00027-3. doi: 10.1016/j.jcf.2022.01.007.Online ahead of print. [Pubmed]

Thomas S FitzMaurice

Background: The CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) leads to significant improvement in the symptoms and spirometry of people with cystic fibrosis (pwCF), but little evidence exists to understand its effect on respiratory pump function. Dynamic chest radiography (DCR) is a novel cineradiographic tool that identifies and tracks the chest wall and diaphragm throughout the breathing cycle, alongside fluoroscopic images of the chest of diagnostic quality.

Methods: In this observational work, we examined the spirometry and DCR of 24 pwCF before and after starting ELX/TEZ/IVA. DCR automatically tracked the hemidiaphragm midpoints and projected lung area (PLA) during tidal and deep breathing manoeuvres.
Results: ppFEV1 (61±18 to 73±22, P<0.001) and ppFVC (77±16 to 88±15, P<0.001) improved significantly. DCR demonstrated a significant increase in hemidiaphragm excursion on both the right (18±11 to 26±9 mm, P<0.001) and left (21±11 to 31±11 mm, P<0.001) sides, as well as maximum hemidiaphragm speed during inspiration (right 22±14 to 31±11 mm/s, P=0.03; left 28±11 to 37±16 mm/s, P=0.02). PLA at end-expiration was significantly reduced (334±71 to 290±72cm2, P<0.001), with a significant increase in ΔPLA (83±40 to 117±36cm2, P<0.001).
Conclusions: DCR demonstrated significant improvements in hemidiaphragm excursion and ΔPLA in pwCF started on ELX/TEZ/IVA. These changes likely reflect a reduction in air trapping and improved elastic recoil of the chest, and are consistent with improvements seen in spirometry. The changes seen with DCR are physiologically plausible and correlate well with spirometry. DCR warrants further investigation as a tool for assessing the impact of CFTR-modulating therapies.

Dr Thomas S FitzMaurice  is a Fellow in the Adult CF Unit, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK; Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.

Thomas Simon FitzMauriceDilip NazarethKapil IyerMartin WalshawMohamed Al-Aloul Elexacaftor/Tezacaftor/Ivacaftor as a Bridge to Lung Retransplant in a Recipient With Cystic Fibrosis. Exp Clin Transplant 2022 Mar 15.doi: 10.6002/ect.2021.0468.Online ahead of print.  Free article [Pubmed]
The triple-combination cystic fibrosis transmembrane conductance regulator modulator elexacaftor/- tezacaftor/ivacaftor is known to improve lung function and have extrapulmonary benefits in people with cystic fibrosis. However, there is limited evidence for its use in patients with cystic fibrosis after lung transplant, where the donor lung expresses normal levels of the cystic fibrosis transmembrane conductance regulator. We describe the use of elexacaftor/tezacaftor/ivacaftor as a bridge to potential lung retransplant in a 37-year-old man with cystic fibrosis and chronic lung allograft dysfunction. Although forced expiratory volume in 1 second did not improve, the patient had decreased sputum volume, no pulmonary exacerbations of cystic fibrosis, and no longer required continuous antibiotic therapy. Pancreatic function, revised Cystic Fibrosis Questionnaire scores, sinus symptoms, weight, and corticosteroid dependence significantly improved. There were no reported side effects attributable to elexacaftor/tezacaftor/ivacaftor. However, the patient exhibited declined renal function, which had been initially attributed to lability in cyclosporin levels but which were corrected after lithotripsy for renal calculi.

Triple-combination modulators of the cystic fibrosis transmembrane conductance regulator may offer benefits to carefully selected individuals awaiting retransplant, balanced against the risk of worsened immunosuppressant level control.

 Thomas Simon FitzMaurice is a Fellow in  the Adult CF Unit, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom and the Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.

Teresa FuchsDorothea AppeltKatharina NiedermayrHelmut Ellemunter REAL-world clinical effectiveness of ivacaftor therapy in the first 24 months in two infants with cystic fibrosis and different gating mutations-A case report.  Clin Case Rep 2022 Feb 10;10(2):e05364.doi: 10.1002/ccr3.5364.eCollection 2022 Feb    Free PMC article [Pubmed]
This study summarizes efficacy of ivacaftor treatment in 2 infants in a real-world setting. Two infants aged 2 and 11 months were started on ivacaftor off label with parental consent.  A distinct decline of sweat chloride and lung clearance index plus increase in fecal elastase was seen. No side effects occurred.  The results underline the early and sustainable effect in patients started aged less than 12 months and give cause for discussing whether a reduction in standard cystic fibrosis therapy is possible. Further details in the Free PMC article where other studies on young infants are discussed.

Teresa Fuchs is at the Medical University of Innsbruck Cystic Fibrosis Centre Innsbruck Innsbruck Austria

Megan E GabelHongyue WangDaniel GelfondChristine RoachSteven M RoweJohn P ClancyScott D SagelDrucy BorowitzPROSPECT GIFT Sub-study Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Changes in Glucose Breath Test in Cystic Fibrosis Patients Treated with one Month of Lumacaftor/ivacaftorJ Pediatr Gastroenterol Nutr   2022 Apr 20.doi: 10.1097/MPG.0000000000003459.Online ahead of print.[Pubmed]

Megan E Gabel

Background: Alteration of the airway microbiota is a hallmark of cystic fibrosis (CF) pulmonary disease. Dysfunction of cystic fibrosis transmembrane regulator (CFTR) in the intestine also promotes changes in local microbiota such as small intestinal bacterial overgrowth (SIBO), which is common in CF. We evaluated whether therapy with the CFTR modulator combination lumacaftor/ivacaftor (luma/iva) has a beneficial impact on SIBO as measured by breath testing (BT).
Methods: A multicenter longitudinal study of CFTR-dependent disease profiling (NCT02477319) included a prospective evaluation for SIBO by BT. Tidal breath samples were collected after fasting and 15, 30, 45, 60, 90 and 120 minutes after ingestion of glucose, before and one month after subjects initiated luma + iva.
Results: Forty-two subjects enrolled in the sub-study (mean age = 23.3 years; 51% female; 9.5% Latinx); 38 completed a hydrogen BT at both time points, of which 73.7% had a positive BT prior to luma/iva (baseline) and 65.8% had a positive test after luma/iva (p = 0.44); shifts from negative to positive were also seen. Use of azithromycin (63.1%) and inhaled antibiotics (60.5%) were not associated with positive BT. Acid-blocking medications were taken by 73% of those with a negative BT at baseline and by 35% with a positive baseline BT (p = 0.04).

Conclusion: We found a high rate of positive hydrogen breath tests in individuals with CF, confirming that SIBO is common. One month of luma/iva did not significantly change the proportion of those with positive breath hydrogen measurements.

Megan E Gabel is a pediatric gastroenterologist in the Department of Pediatrics, University of Rochester School of Medicine, Rochester NY.

Gary J Galante Defining and Treating Cystic Fibrosis Liver Disease: Some Things Old and Some Things NewJ Cyst Fibros 2022 Mar;21(2):199-201. doi: 10.1016/j.jcf.2022.03.004. [Pubmed]

Gary J Galante

This is a review of the present situation regarding liver involvement. The authors conclude “that although we may not have significant advancement in the prevention of CFLD and its progression to clinically significant outcomes, it is undoubtedly an exciting time in therapeutics with the advent and widespread use of CFTR modulators. While hepatotoxicity remains a concern and surveillance on treatment is prudent given the potential for idiosyncratic reactions and drug-drug interactions, significant liver injury is rare and generally resolves with medication discontinuation. Moreover, early and consistent use could theoretically prevent or limit CFLD, supported by some clinical data. As is generally the case for therapeutic studies in CFLD, more prospective well-designed studies are needed to examine clinically significant outcomes over the long-term. However, there is reason for cautious optimism with novel CFTR modulators, on the background of improving survival in CFLD reflective of ongoing improvements in overall CF care”

 Gary J Galante is a gastroenterologist and Clinical Assistant Professor in the Department of Pediatrics, Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, Canada.

Cristina de Manuel GómezAna Cecilia Morales PalaciosOlga de la Serna BlázquezPablo Vicente Morillo CarneroMaría Elena Pérez ArenasSonia Milkova IvanovaMarta Ruiz de Valbuena MaizEthmoidal mucocele causing proptosis in a pediatric patient with cystic fibrosis: A case report.   J Cyst Fibros 2022 Mar 1;S1569-1993(22)00048-0.doi: 10.1016/j.jcf.2022.02.016. Online ahead of print. 35246383 [Pubmed]

In cystic fibrosis (CF) patients, Ear Nose Throat (ENT) pathology is often undiagnosed despite its high prevalence and its possible life-threatening complications. We present the case of an ethmoidal mucocele leading to ocular manifestations in a 2-year-old girl with cystic fibrosis with no previous serious complications. She progressively developed non-axial proptosis, limitation of the adduction and exotropia of her left eye. Paranasal sinus magnetic resonance image (MRI) showed a left ethmoidal mucocele causing displacement of the ocular globe, compression of the medial rectus and the optic nerve. Eye fundus revealed disc edema and diffuse vascular congestion. Endoscopic sinus surgery was performed to remove the mass. The mucocele was drained and the discharge was sent for microbiology assessment. Escherichia coli (E. coli) was found in the culture and treated with cefotaxime and dexamethasone with complete resolution of non-axial proptosis and disc edema.

Cristina de Manuel Gómez is in the Pediatric Pulmonology and Cystic Fibrosis Unit, Hospital Universitario La Paz, Madrid.

Jiafen GongGengming HeCheng WangClaire BartlettNaim PanjwaniScott Mastromatteo and 34 co-authors from Canada.Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung diseaseNPJ Genom Med 2022 Apr 8;7(1):28.doi: 10.1038/s41525-022-00299-9.   Free article [Pubmed]

     Jiafen Gong

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10-44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

Dr Jiafen Gong is a biostatistician with the Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

Giulia GorrieriFederico ZaraPaolo ScudieriSLC26A9 as a Potential Modifier and Therapeutic Target in Cystic Fibrosis Lung DiseaseBiomolecules  2022 Jan 25;12(2):202.doi: 10.3390/biom12020202. Free article   [Pubmed]

      Giulia Gorrieri

SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins involved in ion transport mechanisms. On the basis of different preliminary findings, including the phenotype of SlC26A9-deficient mice and its possible role as a gene modifier of the human phenotype and treatment response, SLC26A9 has emerged as one of the most interesting alternative targets for the treatment of cystic fibrosis (CF). However, despite relevant clues, some open issues and controversies remain. The lack of specific pharmacological modulators, the elusive expression reported in the airways, and its complex relationships with CFTR and the CF phenotype prevent us from conclusively understanding the contribution of SLC26A9 in human lung physiology and its real potential as a therapeutic target in CF.

In this review, we summarized the various studies dealing with SLC26A9 expression, molecular structure, and function as an anion channel or transporter; its interaction and functional relationships with CFTR; and its role as a gene modifier and tried to reconcile them in order to highlight the current understanding and the gap in knowledge regarding the contribution of SLC26A9 to human lung physiology and CF disease and treatment.

Giulia Gorrieri  is a PhD student in the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, 16132 Genoa, Italy. Medical Genetics Unit, IRCSS Giannina Gaslini Institute, 16147 Genoa, Italy

Simon Y GraeberDiane M RenzMirjam StahlSophia T PallenbergOlaf Sommerburg Lutz Naehrlichand 16 others. Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Patients with Cystic Fibrosis and One or Two F508del Alleles. Am J Respir Crit Care Med  2022 May 10.doi: 10.1164/rccm.202201-0219OC. Online ahead of print. [Pubmed]

Simon Graeber

Rationale: We recently demonstrated that triple combination CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves CFTR function in airway and intestinal epithelia to 40 to 50% of normal in patients with cystic fibrosis (CF) with one or two F508del alleles. In previous studies, this improvement of CFTR function was shown to improve clinical outcomes, however, effects on the lung clearance index (LCI) determined by multiple breath washout and abnormalities in lung morphology and perfusion detected by magnetic resonance imaging (MRI) have not been studied.

Objectives: To examine the effect of ELX/TEZ/IVA on LCI and lung MRI scores in patients with CF and one or two F508del alleles aged 12 years and older.
Methods: This prospective, observational, multicenter, post-approval study assessed LCI and lung MRI scores before and 8-16 weeks after initiation of ELX/TEZ/IVA.
Measurements and main results: A total of 91 patients with CF including 45 heterozygous for F508del and a minimal function mutation (MF) and 46 homozygous for F508del were enrolled in this study. Treatment with ELX/TEZ/IVA improved LCI in F508del/MF (-2.4;IQR, -3.7 – -1.1;P<0.001) and F508del homozygous (-1.4;IQR, -2.4 – -0.4;P<0.001) patients. Further, ELX/TEZ/IVA improved the MRI global score in F508del/MF (-6.0;IQR, -11.0 – -1.3;P<0.001) and F508del homozygous (-6.5;IQR, -11.0 – -1.3;P<0.001) patients.

Conclusions: Our data demonstrate that improvement of CFTR function by ELX/TEZ/IVA improves lung ventilation and abnormalities in lung morphology including airway mucus plugging and wall thickening in adolescent and adult patients with CF and one or two F508del alleles in a real-world, post-approval setting.

Simon Y Graeber is at the Charité Universitätsmedizin Berlin, 14903, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Berlin, Germany, the Berlin Institute of Health at Charité, 522475, Berlin, Germany and the German Center for Lung Research, 542891, associated partner site, Berlin, Germany

Barbara R GrubbAlessandra Livraghi-Butrico Animal models of cystic fibrosis in the era of highly effective modulator therapiesCurr Opin Pharmacol 2022 Jun;64:102235. doi: 10.1016/j.coph.2022.102235.Epub 2022 May 13.  [Pubmed]

Alessandra Livraghi-Butrico.

Barbara Grubb

Few human genetic diseases can rely on the availability of as many and as diverse animal models as cystic fibrosis (CF), a multiorgan syndrome caused by functional absence of cystic fibrosis transmembrane regulator (CFTR). The recent development of highly effective CFTR modulator drug therapies simultaneously highlighted the remarkable clinical improvement achievable with these treatments, the lack of therapeutic alternatives for non-responders, and the need to understand the kinetics of disease upon early life/chronic treatment. These advances have rekindled efforts to leverage animal models to address critical knowledge gaps in CF. This article provides a concise overview of the areas of interests for therapeutic intervention in the current CF landscape, focusing on the contributions of in vivo models to understand CF pathogenesis, identify therapeutic windows, and develop novel therapies for all CFTR mutations.

Both authors are at the Marsico Lung Institute, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.

Marta GueriniGiorgia CondròValeria FriuliLauretta MaggiPaola Perugini . N-acetylcysteine (NAC) and Its Role in Clinical Practice Management of Cystic Fibrosis (CF): A ReviewPharmaceuticals (Basel 2022 Feb 11;15(2):217. doi: 10.3390/ph15020217.  Free PMC article [Pubmed]

       Marta Guerini

N-acetylcysteine is the acetylated form of the amino acid L-cysteine and a precursor to glutathione (GSH). It has been known for a long time as a powerful antioxidant and as an antidote for paracetamol overdose. However, other activities related to this molecule have been discovered over the years, making it a promising drug for diseases such as cystic fibrosis (CF). Its antioxidant activity plays a key role in CF airway inflammation and redox imbalance. Furthermore, this molecule appears to play an important role in the prevention and eradication of biofilms resulting from CF airway infections, in particular that of Pseudomonas aeruginosa.
The aim of this review is to provide an overview of CF and the role that NAC could play in preventing and eliminating biofilms, as a modulator of inflammation and as an antioxidant, restoring the redox balance within the airways in CF patients. To do this, NAC can act alone, but it can also be used as an adjuvant molecule to known drugs (antibiotics/anti-inflammatories) to increase their activity.

Dr Marta Guerini is in the Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy

Jonathan GuoAnna GarrattAndrew Hill.  Worldwide rates of diagnosis and effective treatment for cystic fibrosisJ Cyst Fibros 2022 Feb 3;S1569-1993(22)00031-5.doi: 10.1016/j.jcf.2022.01.009.Online ahead of print. [Pubmed]

Jonathan Guo

Background: Time has seen management for Cystic Fibrosis (CF) advance drastically, most recently in the development of the disease-modifying triple combination therapy ivacaftor/tezacaftor/elexacaftor. There is currently limited evidence regarding both the global epidemiology of CF and access to this transformative therapy – and therefore where needs are not being met. Therefore, this study aims to define gaps in access to CF treatment.

Methods: Patient data were extracted from established CF registries. Where these were not available, literature searches were conducted alongside an international survey of 51 CF experts to determine the diagnosed patient population. National CF prevalence estimates were combined with registry data on estimated population coverage, to extrapolate the total estimated number of undiagnosed patients. Estimates of ivacaftor/tezacaftor/elexacaftor treatment coverage were extracted from publicly available sales summaries and pricing data.

Results: 162,428 [144,606-186,620] people are estimated to be living with CF across 94 countries. Of these, an estimated 105,352 (65%) are diagnosed, with 19,516 (12%) receiving triple combination therapy. We estimated 57,076 patients with undiagnosed CF. Owing to a paucity of high-quality data, estimates of undiagnosed CF in low- and middle-income countries are highly uncertain. Patient registries were available in 45 countries, and used to identify 90% of the estimated diagnosed population.

Conclusions: A significant CF patient burden exists in countries where disease-modifying drugs are unavailable, and final figures are likely underestimates. This analysis shows the potential to improve rates of diagnosis and treatment for CF, so a higher percentage of patients receive the most effective triple combination treatment.

Dr Jonathan Guo is in the Faculty of Medicine, Imperial College London, United Kingdom.

Leo HanMackenzie RobertsAddie LuoShuhao Wei Ov D SlaydenKelvin D Macdonald.  Functional Evaluation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in the EndocervixBiol Reprod 2022 May 9;ioac090. doi: 10.1093/biolre/ioac090. Online ahead of print. [Pubmed]

         Leo Han

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is an apical membrane chloride/bicarbonate ion channel in epithelial cells. Mutations in CFTR cause cystic fibrosis (CF), a disease characterized by thickened mucus secretions and is associated with subfertility and infertility. CFTR function has been well characterized in vitro and in vivo in airway and other epithelia studies. However, little is known about CFTR function in the cervix in health and its contribution to cyclic regulation of fertility from endocervical mucus changes. Contributing to this research gap is the lack of information on effect of sex steroid hormones on CFTR expression in cervix epithelial cells across the menstrual cycle. Herein we demonstrate hormonal regulation of CFTR expression in endocervical cells both in vitro and in vivo, and that conditionally reprogrammed endocervical epithelial cells can be used to interrogate CFTR ion channel function. CFTR activity was demonstrated in vitro using electrophysiology methods and functionally inhibited with the CFTR-specific inhibitors inh-172 and GlyH-101. We also report that CFTR expression is increased by estradiol in the macaque cervix both in vitro and in vivo in Rhesus macaques treated with artificial menstrual cycles. Estrogen upregulation of CFTR is blocked in vivo by co-treatment with progesterone. Our findings provide the most comprehensive evidence to date that steroid hormones drive changes in CFTR expression. These data are integral to understanding the role of CFTR as a fertility regulator in the endocervix. Summary: CFTR is hormonally regulated and functional in the macaque endocervix.

Leo Han is Assistant Professor of Obstetrics and Gynecology, School of MedicineAffiliate Assistant Professor, Oregon National Primate Research Center

Caitlyn Harvey, Sinead WeldonStuart ElbornDamian G DowneyClifford Taggart.  The Effect of CFTR Modulators on Airway Infection in Cystic Fibrosis. Int J Mol Sci 2022 Mar 23;23(7):3513.doi: 10.3390/ijms23073513.  [Pubmed]

The advent of Cystic fibrosis transmembrane receptor (CFTR) modulators in 2012 was a critical event in the history of cystic fibrosis (CF) treatment. Unlike traditional therapies that target downstream effects of CFTR dysfunction, CFTR modulators aim to correct the underlying defect at the protein level. These genotype-specific therapies are now available for an increasing number of CF patients, transforming the way we view the condition from a life-limiting disease to one that can be effectively managed.

Several studies have demonstrated the vast improvement CFTR modulators have on normalization of sweat chloride, CFTR function, clinical endpoints, and frequency of pulmonary exacerbation. However, their impact on other aspects of the disease, such as pathogenic burden and airway infection, remain under explored. Frequent airway infections as a result of increased susceptibility and impaired innate immune response are a serious problem within CF, often leading to accelerated decline in lung function and disease progression.

Current evidence suggests that CFTR modulators are unable to eradicate pathogenic organisms in those with already established lung disease. However, this may not be the case for those with relatively low levels of disease progression and conserved microbial diversity, such as young patients. Furthermore, it remains unknown whether the restorative effects exerted by CFTR modulators extend to immune cells, such as phagocytes, which have the potential to modulate the response of people with CF (pwCF) to infection. Throughout this review, we look at the potential impact of CFTR modulators on airway infection in CF and their ability to shape impaired pulmonary defences to pathogens.

Dr Caitlyn Harvey is in the Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7BL, UK.

Eunjin HongLisa M AlmondP S ChungA Peter RaoPaul M Beringer   PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19Clin Pharmacol Ther 2022 Mar 16.doi: 10.1002/cpt.2585. Online ahead of print. [Pubmed]

      Eunjin Hong

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDI). However, CF population is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.
CYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators. When ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited.

Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with delayed resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of ETI administered concomitantly with nirmatrelvir/ritonavir in people with CF that will likely decrease the impact of the drug interaction.

Eunjin Hong is a graduate student the Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, USA.

Alex R HorsleyJohn BelcherKatie BayfieldBrooke BiancoSteve CunninghamCatherine Fullwood Andrew JonesAnna ShawcrossJaclyn A SmithAnirban MaitraFrancis J Gilchrist. Longitudinal assessment of lung clearance index to monitor disease progression in children and adults with cystic fibrosisThorax 2022 Apr;77(4):357-363.doi: 10.1136/thoraxjnl-2021-216928. Epub 2021 Jul 22. Free PMC article     [Pubmed]

       Alex Horsley

Background: Lung clearance index (LCI) is a valuable research tool in cystic fibrosis (CF) but clinical application has been limited by technical challenges and uncertainty about how to interpret longitudinal change. In order to help inform clinical practice, this study aimed to assess feasibility, repeatability and longitudinal LCI change in children and adults with CF with predominantly mild baseline disease.
Methods: Prospective, 3-year, multicentre, observational study of repeated LCI measurement at time of clinical review in patients with CF >5 years, delivered using a rapid wash-in system
112 patients completed at least one LCI assessment and 98 (90%) were still under follow-up at study end. The median (IQR) age was 14.7 (8.6-22.2) years and the mean (SD) FEV1z-score was -1.2 (1.3). Of 81 subjects with normal FEV1 (>-2 z-scores), 63% had raised LCI (indicating worse lung function). For repeat stable measurements within 6 months, the mean (limits of agreement) change in LCI was 0.9% (-18.8% to 20.7%). A latent class growth model analysis identified four discrete clusters with high accuracy, differentiated by baseline LCI and FEV1. Baseline LCI was the strongest factor associated with longitudinal change. The median total test time was under 19 min.
Most patients with CF with well-preserved lung function show stable LCI over time. Cluster behaviours can be identified and baseline LCI is a risk factor for future progression. These results support the use of LCI in clinical practice in identifying patients at risk of lung function decline.

 Dr Alex Horsley is in the Division of Infection, Immunity and Respiratory Medicine, The University of Manchester Faculty of Biology, Medicine and Health, Manchester, UK and the Manchester Adult Cystic Fibrosis Centre, Manchester University NHS Foundation Trust, Manchester, UK.

Taylor A Imburgia Michelle L KussinA Review of Extended and Continuous Infusion Beta-Lactams in Pediatric PatientsJ Pediatr Pharmacol Ther 2022;27(3):214-227.doi: 10.5863/1551-6776-27.3.214.Epub 2022 Mar 21.   [Pubmed]

   Taylor Imburgia

Intravenous beta-lactam antibiotics are the most prescribed antibiotic class in US hospitalized patients of all ages; therefore, optimizing their dosing is crucial. Bactericidal killing is best predicted by the time in which beta-lactam drug concentrations are maintained above the organism’s minimum inhibitory concentration (MIC), rather than achievement of a high peak concentration. As such, administration of beta-lactam antibiotics via extended or continuous infusions over a minimum of 3 hours, rather than standard infusions over approximately 30 minutes, has been associated with improved achievement of pharmacodynamic targets and improved clinical outcomes in adult medical literature.
This review summarizes the pediatric medical literature. Applicable studies include pharmacodynamic models, case series, retrospective analyses, and prospective studies on the use of extended infusion and continuous infusion penicillins, cephalosporins, carbapenems, and monobactams in neonates, infants, children, and adolescents. Specialized patient populations with unique pharmacokinetics and high-risk infections (neonates, critically ill, febrile neutropenia, cystic fibrosis) are also reviewed.

While more studies are needed to confirm prospective clinical outcomes, the current body of evidence suggests extended and continuous infusions of beta-lactam antibiotics are well tolerated in children and improve achievement of pharmacokinetic pharmacodynamic targets with similar or superior clinical outcomes, particularly in infections associated with high MICs.

Dr Taylor A Imburgia is Pediatric Pharmacy Specialist in the Department of Pharmacy (TAI), WVU Medicine Children’s, Morgantown, WV.

Melissa HiteWolfgang B GaertnerBryan GarciaPatrick FlumeJohnstone P Maxwell 4thVirgilio V GeorgeThomas Curran. Abdominal Surgical Procedures in Adult Patients with Cystic Fibrosis: What are the Risks? Dis Colon Rectum 2022 Jan 12. doi: 10.1097/DCR.0000000000002162. Online ahead of print [Pubmed]

Melissa Hite

Background: With advances in medical care, patients with cystic fibrosis are more commonly living into adulthood yet there are limited data describing the need for gastrointestinal surgery and its outcomes in adult cystic fibrosis patients.
Objective: We aim to use a national administrative database to evaluate trends in abdominal gastrointestinal surgery and associated postoperative outcomes among adult cystic fibrosis patients.
Design: This was a national retrospective cohort study.
Setting: A national all payor administrative database from 2000-2014 was used.
Patients: Patients included all adult (age ≥18) patients with cystic fibrosis undergoing abdominal gastrointestinal surgery.
Main outcome measures: The primary outcome was trend over time in number of surgical admissions. Secondary outcomes included morbidity and mortality by procedure type.
Results: We identified 3,075 admissions for abdominal surgery of which 28% were elective. Major GI surgical procedures increased over the study period (p<0.01) while appendectomy and cholecystectomy did not demonstrate a clear trend (p=0.90). The most common procedure performed was cholecystectomy (n=1,280; 42%). The most common major surgery was segmental colectomy (n=535; 18%). Obstruction was the most common surgical indication (n=780; 26%). For major surgery, in-hospital mortality was 6%, morbidity 37% and mean length of stay 15.9 days (SE 1.2).
Limitations: The study is limited by a lack of granular physiologic and clinical data within the administrative data source.
Conclusions: Major surgical admissions for adult patients with cystic fibrosis are increasing with the majority being non-elective. Major surgery is associated with significant morbidity, mortality and prolonged length of hospital stay. These findings may inform perioperative risk for adult patients with cystic fibrosis in need of gastrointestinal surgery. See Video Abstract at http://links.lww.com/DCR/B850.

Dr Melissa Hite is Surgical Fellow in the Division of Colon and Rectal Surgery, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina

Eva JaspersIne Van DijckIlse Hoffman, Noël Knops  Xavier StéphennePeter WittersMarijke Proesmans. Cystic fibrosis and alpha-1 antitrypsin deficiency: case report and review of literature. BMC Pediatr  2022 May 3;22(1):247. doi: 10.1186/s12887-022-03290-6.  [Pubmed]

   Eva Jaspers

Background: This case report describes a child born with both cystic fibrosis (CF) and alpha-1 antitrypsin deficiency (A1ATD). Both are autosomal recessive inherited diseases, mainly affecting the lungs and the liver. The combination of both diseases together is rare and may lead to a fulminant disease with limited life span. To the best of our knowledge, no case has been reported of a patient born with both diseases.

Case presentation: After an uneventful pregnancy, a male baby was born with meconium ileus. The suspected diagnosis of CF was confirmed based on the sweat test and genetic analysis. The child developed persisting cholestasis, too severe to be likely caused by CF alone and indicating an associated problem. The diagnosis of A1ATD was established based on clinical suspicion (persisting cholestasis), decreased serum alpha-1 antitrypsin and genetic analysis. Supportive therapy was started, however the boy evolved to rapidly progressive liver disease leading to liver failure which necessitated an infant liver transplantation.

Conclusions: This case illustrates the complexity of care in case of two severe inherited diseases as well as post solid organ transplant care.

Dr Eva Jaspers  is Associate Professor at the University Hospital Leuven, Herestraat 49, 3001, Leuven, Belgium.

Kazani S, Rowlands DJ, Bottoli I, Milojevic J, Alcantara J, Jones I, Kulmatycki K, Machineni S, Mostovy L, Nicholls I, Nick JA, Rowe SM, Simmonds NJ, Vegesna R, Verheijen J, Danahay H, Gosling M, Ayalavajjala PS, Salman M, Strieter R.  Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251).  J Cyst Fibros. 20(2):250-256, 2021 03.  Free article [Pubmed]
Background: This is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.
Methods: Safety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level.
Results: Class IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.

Conclusions: Icenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations. (ClinicalTrials.gov: NCT02190604).

Dr Shamsah Kazani is at Novartis Institutes for BioMedical Research, Cambridge, MA, United States; Novartis Institutes for BioMedical Research, Basel, Switzerland.

Rebecca KeyteSophia KauserMichail MantziosHelen Egan. The psychological implications and health risks of cystic fibrosis pre- and post- CFTR modulator therapyChronic Illn 2022 May 3;17423953221099042.doi: 10.1177/17423953221099042.Online ahead of print.[Pubmed]

Rebecca Keyte

Objectives: Cystic Fibrosis (CF) care is entering a period of personalised medicine with the emergence of CF transmembrane conductance regulator (CFTR) modulator therapies. Anecdotally individuals are reporting life-changing effects of modulator therapies, proposing an important area of study.
Methods: Twenty adult participants (males: 8, age range: 22-51 years, average FEV1: 53.45%) were recruited via social media to participate in a semi-structured interview; 17 participants were currently taking Elexacaftor/Tezacaftor/Ivacaftor (Kaftrio).
Results: An appreciation of a “normal life” post-modulator therapy is paramount, with improvements in symptoms and quality-of-life bringing a more urgent imperative for the provision of effective support to encourage positive health and lifestyle choices.

Discussion: In this new era of CF care, there remains many challenges present for the CF community, with participants suggesting that proactive psychological support is required along with proactive awareness regarding health risk behaviours for the current and future CF generations.

Rebecca Keyte  is in the Department of Psychology, School of Social Sciences, 34651 Birmingham City University, Birmingham, UK.

Elisabeth KieningerCorin WillersKatrin RöthlisbergerSophie YammineOrso PusterlaGrzegorz BaumanEnno StranzingerOliver BieriPhilipp LatzinCarmen Casaulta. Effect of Salbutamol on Lung Ventilation in Children with Cystic Fibrosis: Comprehensive Assessment Using Spirometry, Multiple-Breath Washout, and Functional Lung Magnetic Resonance Imaging. Respiration 2022;101(3):281-290. doi: 10.1159/000519751. Epub 2021 Nov 22.  [Pubmed]

Dr Elisabeth Kieninger

Background: Inhalation therapy is one of the cornerstones of the daily treatment regimen in patients with cystic fibrosis (CF). Recommendations regarding the addition of bronchodilators, especially salbutamol are conflicting due to the lack of evidence. New diagnostic measures such as multiple-breath washout (MBW) and functional magnetic resonance imaging (MRI) have the potential to reveal new insights into bronchodilator effects in patients with CF.
Objective: The objective of the study was to comprehensively assess the functional response to nebulized inhalation with salbutamol in children with CF.
Methods: Thirty children aged 6-18 years with stable CF performed pulmonary function tests, MBW, and matrix pencil-MRI before and after standardized nebulized inhalation of salbutamol.
Results: Lung clearance index decreased (improved) by -0.24 turnover (95% confidence interval [CI]: -0.53 to 0.06; p = 0.111). Percentage of the lung volume with impaired fractional ventilation and relative perfusion decreased (improved) by -0.79% (CI: -1.99 to 0.42; p = 0.194) and -1.31% (CI: -2.28 to -0.35; p = 0.009), respectively. Forced expiratory volume (FEV1) increased (improved) by 0.41 z-score (CI: 0.24-0.58; p < 0.0001). We could not identify specific clinical factors associated with a more pronounced effect of salbutamol.

Conclusions: There is a positive short-term effect of bronchodilator inhalation on FEV1 in patients with CF, which is independent of ventilation inhomogeneity. Heterogeneous response between patients suggests that for prediction of a therapeutic effect this should be tested by spirometry in every patient individually.

Elisabeth Kieninger is a Fellow in the Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Insa KortenElisabeth KieningerLinn KruegerMarina BulloChrista E FlückPhilipp LatzinCarmen CasaultaClaudia Boettcher  Short-Term Effects of Elexacaftor/Tezacaftor/Ivacaftor Combination on Glucose Tolerance in Young People With Cystic Fibrosis-An Observational Pilot Study.  Front Pediatr 2022 Apr 21;10:852551.doi: 10.3389/fped.2022.852551. eCollection 2022. [Pubmed]

Insa Korten

The effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on glucose tolerance and/or cystic-fibrosis-related diabetes (CFRD) is not well understood. We performed an observational study on the short-term effects of ELX/TEZ/IVA on glucose tolerance.
Methods: Sixteen adolescents with CF performed oral glucose tolerance tests (OGTT) before and 4-6 weeks after initiating ELX/TEZ/IVA therapy. A continuous glucose monitoring (CGM) system was used 3 days before until 7 days after starting ELX/TEZ/IVA treatment.
Results: OGTT categories improved after initiating ELX/TEZ/IVA therapy (p = 0.02). Glucose levels of OGTT improved at 60, 90, and 120 min (p < 0.05), whereas fasting glucose and CGM measures did not change.

Conclusion: Shortly after initiating ELX/TEZ/IVA therapy, glucose tolerance measured by OGTT improved in people with CF. This pilot study indicates that ELX/TEZ/IVA treatment has beneficial effects on the endocrine pancreatic function and might prevent or at least postpone future CFRD.

Insa Korten is in the Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Pradeep Kota  Sustained inhibition of ENaC in CF: Potential RNA-based therapies for mutation-agnostic treatmentCurr Opin Pharmacol 2022 Apr 25;64:102209.doi: 10.1016/j.coph.2022.102209.Online ahead of print.[Pubmed]

Pradeep Kota

Disruption of the equilibrium between ion secretion and absorption processes by the airway epithelium is central to many muco-obstructive lung diseases including cystic fibrosis (CF). Besides correction of defective folding and function of CFTR, inhibition of amiloride-sensitive epithelia sodium channels (ENaC) has emerged as a bona fide therapeutic strategy to improve mucociliary clearance in patients with CF. The short half-life of amiloride-based ENaC blockers and hyperosmotic therapies have led to the development of novel RNA-based interventions for targeted and sustained reduction of ENaC expression and function in preclinical models of CF. This review summarizes the recent advances in RNA therapeutics targeting ENaC for mutation-agnostic treatment of CF.

Pradeep Kota is a Research Associate at the Cystic Fibrosis Research and Treatment Center, University of North Carolina at Chapel Hill, NC 27599, USA.

Vaclav KouckyArnost KomarekPetr PohunekRepeatability of lung clearance index in infants with cystic fibrosis and recurrent wheezePediatr Pulmonol 2022 Apr 13.doi: 10.1002/ppul.25921. Online ahead of print. [Pubmed]

Vaclav Koucky

Objectives: To describe the short- and medium-term repeatability of lung clearance index (LCI2.5) in infants and calculate the number of patients needed to enrol in a study (N) using LCI2.5 as a primary outcome.
Methods: An 8-month follow-up observational study was employed for assessing short-term [coefficient of repeatability (CR) and intraclass correlation (ICC)] and medium-term repeatability (Bland-Altman method) of LCI2.5 in infants with cystic fibrosis (CF) or recurrent wheeze (RW) measured by the nitrogen multiple-breath washout test (N2 -MBW). Using these variability data, the N to reach 90% test power at the level of statistical significance (0.05) was calculated.
Results: Forty infants with CF and 21 with RW were enrolled. Initial N2 -MBW testing was successful in 33 and 17 patients, respectively. Follow-up data were available for 23 and 11 infants, respectively. Short-term repeatability of LCI2.5 was high (CR = 1.10 and 1.04 in CF and RW patients, respectively; ICC = 0.88 and 0.83 in CF and RW patients, respectively). The between-subject standard deviation was <13% of the actual LCI2.5 value. In clinically stable patients, LCI2.5did not significantly change during the 8-month follow-up. Mean LCI2.5 change was -0.08 (1% of baseline) in CF and -0.05 (0.6%) in RW, with 95% limits of agreement being (-1.70; 1.53) in CF and (-1.51; 1.40) in RW patients. N = 23 infants if both intra-group differences of LCI2.5 and minimal difference to be detected would be 2.0.

Conclusion: N2 -MBW may be a reproducible tool with reasonable test power to detect differences in infant studies. This article is protected by copyright. All rights reserved.

Dr Vaclav Koucky is a paediatric pulmonologist in the Department of Paediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

Cecilia KristenssonAnnika ÅstrandScott DonaldsonRon GoldwaterRaolat AbdulaiNaimish PatelPhilip GardinerUlrika TehlerAnne-Kristina MercierMarita OlssonEva ErsdalJukka MäenpääTobias BramerAnna MalmgrenWilliam BennettChristina KeenAZD5634, an inhaled ENaC inhibitor, in healthy subjects and patients with cystic fibrosisJ Cyst Fibros  2022 Feb 26;S1569-1993(22)00042-X. doi: 10.1016/j.jcf.2022.02.010.Online ahead of print.   [Pubmed]


Background: Epithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibrosis (CF); however, data are limited. We report the outcomes of a Phase I (NCT02679729) and a Phase Ib (NCT02950805) study of AZD5634, a novel inhaled ENaC inhibitor.
Methods: A Phase I, first-in-human, single-blind, placebo-controlled, single ascending dose, sequential dose group study assessed the safety, tolerability, and pharmacokinetics of AZD5634 in healthy subjects (n=53) in part A following inhaled doses up to 1700 µg, and, in part B, following administration of single inhaled (1700 µg) and intravenous (65 µg) doses. A Phase Ib, randomized, double-blind, placebo-controlled, single-dose, 2-way cross-over study assessed the effects of a single dose (600 µg) of inhaled AZD5634 on mucociliary clearance (MCC), pharmacokinetics and safety and tolerability in patients with CF (n=11). Nasal potential difference (NPD) was assessed as an in situ target engagement exploratory biomarker.

Results: Absolute bioavailability of AZD5634 after inhalation was approximately 3%, indicating minimal distribution into the systemic circulation. Urinary excretion was a minor elimination pathway. Administration of inhaled AZD5634 did not improve MCC in CF patients, but AZD5634 inhibited ENaC in the nasal epithelium, as measured by NPD. AZD5634 was safe and well tolerated in both studies.
Conclusions: AZD5634 showed favourable pharmacokinetics and safety in healthy subjects and patients with CF. However, despite achieving target engagement, proof of mechanism was not achieved after a single dose in patients with CF. Further evaluation into multiple dose studies is warranted to explore its therapeutic potential.

Dr Cecilia Kristensson Clinical Programme Director with Early Respiratory & Immunology Early Clinical Development, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Mutsuka KuriharaKosuke IshizukaMasatomi Ikusaka. Aquagenic wrinkling of the palmsAm J Med 2022 Mar 13;S0002-9343(22)00185-1.doi: 10.1016/j.amjmed.2022.02.026. Online ahead of print.[Pubmed}

A 47‐year‐old Japanese woman presented with blanching and whitening of both palms after bathing and washing dishes for the past 20 years. It is induced by immersion of hands in water for about 5 minutes. She did not report any pain or itching. Her medical history and medications were unremarkable. A five-minute water immersion test induced wrinkling of the palms. Also known as aquagenic keratoderma, a rare dermatosis characterized by hyper-wrinkling of the palms with white papules induced by water immersion. The disease is usually asymptomatic; however, patients sometimes present with painful and pruritic sensations. This condition was first reported by Prof. Bob Elliott in 1974 in a patient with cystic fibrosis, and it has been suggested to be linked to cystic fibrosis and marasmus to date.   Our patient was not related to any of the aetiologies and was considered to be idiopathic.

Dr Mutsuka Kurihara is in the Department of General Medicine, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba pref. Japan.

HuiChuan J LaiLyanne H ChinSangita MuraliTaiya BachDanielle SanderPhilip M FarrellFIRST Study Group. Vitamins A, D, E status as related to supplementation and lung disease markers in young children with cystic fibrosis. Pediatr Pulmonol 2022 Jan 11.doi: 10.1002/ppul.25825. Online ahead of print.[Pubmed]

HuiChuan J Lai

Background: The variable response to fat-soluble vitamin supplementation in young children with CF, and factors contributing to this variability, remain under-investigated.
Objective: To determine if recommended supplement doses normalize serum vitamin A (retinol), D (25-hydroxy-vitamin D, 25OHD) and E (α-tocopherol), and identify factors predictive of achieving sufficiency, in children with CF in the first 3 years of life.
Design: We studied 144 infants born during 2012-2017 and diagnosed with CF through newborn screening. Serum retinol, 25OHD, α-tocopherol and plasma cytokines interleukin(IL)-6, IL-8, IL10 and tumor necrosis factor (TNF)-α were measured in early infancy and yearly thereafter. Vitamin supplement intakes and respiratory microbiology were assessed every 1-2 months in infancy and quarterly thereafter.
Results: The prevalence of vitamin D insufficiency (<30 ng/mL) at all ages combined was significantly higher (22%) compared to vitamin A (<200 ng/mL, 3%) and vitamin E (<5 µg/mL, 5%). All children were vitamin A sufficient by age 2 years. Vitamin E insufficiency was rare. Only 42% were early responders of vitamin D and 17% remain insufficient despite high supplement intakes. IL-6 was positively correlated, while IL-8, IL-10 and TNF-α were negatively correlated, with retinol and 25OHD. Multiple regression analysis revealed that supplement dose, season, α-tocopherol, pancreatic insufficiency, respiratory infections and IL-10 were significant predictors of 25OHD.

Conclusion: Diagnosis through newborn screening coupled with supplementation normalized serum retinol and α -tocopherol in almost all infants with CF by age 3 years. However, response to vitamin D supplements in young children with CF occurred later and variably despite early and sustained supplementation.

HuiChuan J Lai  is Professor Nutritional Sciences , Pediatrics and Population Health Sciences in the Departments of Nutritional Sciences and the Department of Pediatrics University of Wisconsin-Madison, Madison, Wisconsin, USA.

Beth L LaubeKathryn A CarsonChristopher M EvansMelis A AksitJoseph M CollacoVanessa L RichardsonGail SharplessPamela L ZeitlinGarry R CuttingPeter J Mogayzel. Characterizing mucociliary clearance in young children with cystic fibrosisPediatr Res 2022 Feb;91(3):612-620.doi: 10.1038/s41390-021-01453-2. Epub 2021 Mar 22.   Free PMC article   [Pubmed]

      Bethe Laube

Background: This research characterized mucociliary clearance (MCC) in young children with cystic fibrosis (CF).
Methods: Fourteen children (5-7 years old) with CF underwent: two baseline MCC measurements (Visits 1 and 2); one MCC measurement approximately 1 year later (Visit 3); and measurements of lung clearance index (LCI), a measure of ventilation inhomogeneity.
Results: Median (range) percent MCC through 60 min (MCC60) was similar on Visits 1 and 2 with 11.0 (0.9-33.7) and 12.8 (2.7-26.8), respectively (p = 0.95), and reproducible (Spearman Rho = 0.69; p = 0.007). Mucociliary clearance did not change significantly over 1 year with median percent MCC60 on Visit 3 [12.8 (3.7-17.6)] similar to Visit 2 (p = 0.58). Lower percent MCC60 on Visit 3 was significantly associated with higher LCI scores on Visit 3 (N = 14; Spearman Rho = -0.56; p = 0.04).

Conclusions: Tests of MCC were reproducible and reliable over a 2-week period and stable over a 1-year period in 5-7-year-old children with CF. Lower MCC values were associated with increased ventilation inhomogeneity. These results suggest that measurements of MCC could be used in short-term clinical trials of interventions designed to modulate MCC and as a new, non-invasive test to evaluate early lung pathology in children with CF.

Impact: This is the first study to characterize mucociliary clearance (MCC) in children with cystic fibrosis (CF) who were 5-7 years old. Measurements of mucociliary clearance were reproducible and reliable over a 2-week period and stable over a 1-year period. Variability in MCC between children was associated with differences in ventilation homogeneity, such that children with lower MCC values had increased ventilation inhomogeneity.
These results suggest that measurements of MCC could be used in short-term clinical trials of interventions designed to modulate MCC and as a new, non-invasive test to evaluate early lung pathology in children with CF.

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

Delphine LeyDominique Turck. Digestive outcomes in Cystic fibrosis.  Best Pract Res Clin Gastroenterol Feb-Mar 2022;56-57:101788.doi: 10.1016/j.bpg.2022.101788. Epub 2022 Feb 24.[Pubmed]

Delphine Ley

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disease in Caucasians, affecting the respiratory tract, but also the pancreas, gut, and hepatobiliary tract. CF is caused by variants in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Prognosis of CF has markedly improved over the last 20 years because of the management in CF centers and recent introduction of CFTR modulators, aimed at correcting the defective CFTR protein. There are nowadays more CF adults than children, with a predicted median survival age of around 50 years in high-income countries. Around 85% of CF patients have pancreatic insufficiency present at birth. Gastroesophageal reflux disease (GERD) is more frequent in CF patients, but its role on decline in lung health is controversial. Distal small bowel obstruction syndrome (DIOS) caused by meconium-like stool plugs occurs at any age after the neonatal period, affecting up to 15-20% of CF patients. Because of increased life expectancy, most CF patients are expected to live to their fifties or beyond, when cancer is more frequent. In addition, CF is associated with a higher risk for GI malignancy as compared with the general population. Colorectal cancer represents the most significant risk, and colonoscopy-based screening is recommended from 40 years of age onwards. Other digestive outcomes in CF reviewed in this paper include meconium ileus, Clostridium difficile infection, intussusception, acute appendicitis, small intestinal bacterial overgrowth, appendiceal mucocele and rectal prolapse. Every CF Center should comprise a gastroenterologist with expertise in the care of CF patients.

Delphine Ley  is at the Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE – Institute for Translational Research in Inflammation, F-59000, Lille, France; Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Jeanne de Flandre Children’s Hospital, CHU Lille, F-59000, Lille, France

Jessica S Little Rebekah M DedrickKrista G FreemanMadison CristinzianoBailey E SmithConstance A BensonTulip A JhaveriLindsey R BadenDaniel A SolomonGraham F Hatfull Bacteriophage treatment of disseminated cutaneous Mycobacterium chelonae infection. Nat Commun  2022 May 3;13(1):2313.doi: 10.1038/s41467-022-29689-4. [Pubmed]

     Jessica Little

Mycobacterium chelonae is a rare cause of chronic disseminated cutaneous infections in immunocompromised patients. Multidrug-resistant M. chelonae infections present a challenge for treatment, and prolonged antimicrobial courses lead to significant toxicities and further antimicrobial resistance. We report a case of refractory cutaneous disseminated M. chelonae infection in a patient with seronegative arthritis on immunotherapy with tofacitinib that was treated with combination antimicrobial, surgical, and single     bacteriophage therapy with excellent clinical response. The patient developed neutralizing antibodies against the bacteriophage but continues to have stable improvement of disease with negative biopsies and no evidence of bacterial resistance to the phage.

Jessica S Little  is Infectious Disease Fellow in the Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, The  Harvard Medical School, Boston, MA, USA. and the the Dana-Farber Cancer Institute, Boston, MA, USA

Jia Liu Allison P BergYiting WangWalailak JantarajitKaty J SutcliffeEdward B StevensLishuang CaoMarko J PregelDavid N Sheppard A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR.  J Pharmacol 2022 Apr;179(7):1319-1337. doi: 10.1111 Br /bph.15709. Epub 2022 Jan 21.[Pubmed]
Background and purpose: 
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators are small molecules developed to treat the genetic disease cystic fibrosis (CF). They interact directly with CFTR Cl channels at the plasma membrane to enhance channel gating. Here, we investigate the action of a new CFTR potentiator, CP-628006 with a distinct chemical structure.
Experimental approach: Using electrophysiological assays with CFTR-expressing heterologous cells and CF patient-derived human bronchial epithelial (hBE) cells, we compared the effects of CP-628006 with the marketed CFTR potentiator ivacaftor.
Key results: CP-628006 efficaciously potentiated CFTR function in epithelia from cultured hBE cells. Its effects on the predominant CFTR variant F508del-CFTR were larger than those with the gating variant G551D-CFTR. In excised inside-out membrane patches, CP-628006 potentiated wild-type, F508del-CFTR, and G551D-CFTR by increasing the frequency and duration of channel openings. CP-628006 increased the affinity and efficacy of F508del-CFTR gating by ATP. In these respects, CP-628006 behaved like ivacaftor. CP-628006 also demonstrated notable differences with ivacaftor. Its potency and efficacy were lower than those of ivacaftor. CP-628006 conferred ATP-dependent gating on G551D-CFTR, whereas the action of ivacaftor was ATP-independent. For G551D-CFTR, but not F508del-CFTR, the action of CP-628006 plus ivacaftor was greater than ivacaftor alone. CP-628006 delayed, but did not prevent, the deactivation of F508del-CFTR at the plasma membrane, whereas ivacaftor accentuated F508del-CFTR deactivation.

Conclusions and implications: CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.

Jia Liu  is at the Neuroscience and Pain Research Unit, Pfizer Inc., Cambridge, UK and Senior Research Assistant at the School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.

Liu-Yi Lu Ni PanZe-Han HuangJing-Song WangYong-Bo TangHong-Shuo SunHui HanHan-Yan YangJun-Zhen ZhuYong-Yuan GuanBin ZhangDong-Zhi LiGuan-Lei Wang CFTR suppresses neointimal formation through attenuating proliferation and migration of aortic smooth muscle cellsJ Cardiovasc Pharmaco 2022 Mar 9.doi: 10.1097/FJC.0000000000001257.Online ahead of print   [Pubmed]
Cystic fibrosis transmembrane conductance regulator (CFTR) plays important roles in arterial functions and the cells fate. To further understand its function in vascular remodeling, we examined whether CFTR directly regulates platelet-derived growth factor-BB(PDGF-BB)-stimulated vascular smooth muscle cells(VSMCs) proliferation and migration, as well as the balloon injury-induced neointimal formation. The CFTR adenoviral gene delivery was used to evaluate the effects of CFTR on neointimal formation in a rat model of carotid artery balloon injury. The roles of CFTR in PDGF-BB-stimulated VSMCs proliferation and migration was detected by MTT assay, wound healing assay, trsnswell chamber method, western blot and qPCR. We found that CFTR expression was declined in injured rat carotid arteries, while adenoviral overexpression of CFTR in vivo attenuated neointimal formation in carotid arteries. CFTR overexpression inhibited PDGF-BB-induced VSMCs proliferation and migration whereas CFTR silencing caused the opposite results. Mechanistically, CFTR suppressed the phosphorylation of PDGFRβ, SGK1, JNK, p38 and ERK induced by PDGF-BB, as well as the increased mRNA expression of MMP9 and MMP2 induced by PDGF-BB.

In conclusion, our results indicated that CFTR may attenuate neointimal formation by suppressing PDGF-BB-induced activation of SGK1 and the JNK/p38/ERK signaling pathway.

Liu-Yi Lu is in the  Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, Guangzhou, 510080, China. and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

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