History – 2020 (Section 2)

First author M to Z

Marcus A Mall ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapiesEur Respir J 2020 Jul 30;2000946.doi: 10.1183/13993003.00946-2020.Online ahead of print [Pubmed]

     Marcus A Mall

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are the first approved drugs targeting underlying epithelial ion/fluid transport defects in patients with cystic fibrosis (CF). Current CFTR modulators restore mutant CFTR activity to up to ∼50% of normal CFTR Cl channel function, translating into improvements in percentage predicted FEV1 and other clinical outcomes. In addition, reductions in airway bacterial colonisation are observed; however, patients fail to eradicate bacteria over time and still experience pulmonary exacerbations, and long-term safety of CFTR modulator therapy remains unknown. Currently approved CFTR modulators are predicted to be effective for up to 90% of patients. A mutation-agnostic approach could address the remaining 10% with CFTR mutations unresponsive to CFTR modulator therapy and may act together with CFTR modulator therapy to further improve epithelial ion/fluid transport and clinical outcomes. Together with CFTR and other Cl channels, the epithelial Na+ channel (ENaC) is key to regulating airway surface liquid homeostasis. ENaC activity is limiting for Na+/fluid absorption and remains intact or may even be increased in CF airways, leading to increased Na+/fluid absorption, airway surface dehydration, impaired mucociliary clearance, bacterial infection, inflammation and progressive lung damage – the major cause of CF-related morbidity and mortality. Inhibition of ENaC in the airways is therefore an attractive therapeutic target to counteract airway surface dehydration and downstream consequences in CF lung disease. This review examines ENaC inhibition in CF therapy, and describes a new ENaC inhibitor with potential mutation-agnostic therapeutic benefit, both alone, and in synergy with CFTR modulators.

Professor Marcus Mall is at Department of Pediatric Pulmonology, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin,  Berlin Institute of Health and the  German Center for Lung Research (DZL), associated partner site, Berlin.

Mayer-Hamblett N, van Koningsbruggen-Rietschel S, Nichols DP, VanDevanter DR, Davies JC, Lee T, Durmowicz AG, Ratjen F, Konstan MW, Pearson K, Bell SC, Clancy JP, Taylor-Cousar JL, De Boeck K, Donaldson SH, Downey DG, Flume PA, Drevinek P, Goss CH, Fajac I, Magaret AS, Quon BS, Singleton SM, VanDalfsen JM, Retsch-Bogart GZ.  Building global development strategies for cf therapeutics during a transitional cftr modulator era. J Cyst Fibros. 2020 Jun 7:S1569-1993(20)30161-2. doi:10.1016/j.jcf.2020.05.011. Online ahead of print. [Pubmed]

Nicole Mayer-Hamblett

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Nicole Hamblett is in the University of Washington, Seattle, WA; Seattle Children’s Hospital, Seattle, WA. Electronic address: nicole.hamblett@seattlechildrens.org.

Meeker SMMears KSSangwan NBrittnacher MJWeiss EJTreuting PMTolley NPope CEHager KRVo ATPaik JFrevert CWHayden HSHoffman LRMiller SIHajjar AM CFTR dysregulation drives active selection of the gut microbiome. 
PLoS Pathog.
 2020 Jan 21;16(1):e1008251. doi: 10.1371/journal.ppat.1008251. eCollection  2020 Jan.Free full text [Pubmed]

    Stacy M Meeker

Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear.                                                                                                                   To test the relationships between CFTR dysfunction, microbes, and intestinal health, the authors established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune respo

The authors consider their findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome.

Dr Stacy M Meeker is in the Department of Comparative Medicine, University of Washington, Seattle, WA, United States of America.

McKinzie CJ, Chen L, Ehlert K, et al. Off-label use of intravenous antimicrobials for inhalation in patients with cystic fibrosis. Pediatr Pulmonol. 2019;54 Suppl 3:S27S45. doi:10.1002/ppul.24511  [Pubmed]

Cameron J McKinzie

Management of infections in patients with cystic fibrosis (CF) presents challenges for healthcare providers, including the eradication of initial acquisition, treatment of acute exacerbations, and chronic infection with suppressive therapy. Inhaled antimicrobial therapy for infections in patients with CF has been used in these capacities, often in an effort to achieve optimal concentrations in sputum for antimicrobial efficacy while mitigating potential toxicities associated with systemic therapy. Unfortunately, there are few commercially available products formulated for inhalation, resulting in the off-label use of other formulations, such as intravenous products, administered via nebulization. This review aims to examine the evidence supporting the efficacy of these off-label formulations for management of acute and chronic infections associated with CF, as well as adverse effects associated with their use.

Dr Cameron McKinzie is in the Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, North Carolina.

Munck ABourmaud ABellon GPicq PFarrell PMDPAM Study Group.  Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening.
Pediatr Pulmonol.
Jan 9. doi: 10.1002/ppul.24634. [Epub ahead of print]  [Pubmed]

     Anne Munck

To characterize the phenotypic expression of children with conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive inconclusive diagnosis (CFSPID) designation after positive newborn screening, reassign labelling if applicable and better define these children’s prognosis.
A multicentre cohort with CRMS/CFSPID designation was matched with cystic fibrosis (CF)-diagnosed cohort. Cohorts were prospectively compared on baseline characteristics, cumulative data and when they reached 6 to 7 years at endpoint assessment.
Results – Compared to infants with CF (n = 63), the CRMS/CFSPID cohort (n = 63) had initially lower   immunoreactive trypsinogen (IRT) and sweat chloride (SC) values, delayed visits, less symptoms, and better nutritional status; during follow-up, they had fewer hospitalizations, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus identification, CF comorbidities, and treatment burden. At endpoint assessment, they presented a milder pulmonary phenotype on Brody computed tomography scores (0.0[0.0; 2.0] vs 13[2.0; 31.0]; P < .0001, respectively), Wisconsin and Brasfield chest radiograph scores, pulmonary function tests, and improved nutritional status. Among the inconclusive CF diagnosis cohort, 28 cases (44%) converted to CF diagnosis based on genotype (44%), SC (28%) or both (28%); yet, comparing those with or without final CF diagnosis, we found no differences, possibly related to their young age and mild degree of lung disease. In the total cohort, we found significant associations between Brody scores and IRT, SC values, genotype, Wisconsin and Brasfield score and spirometry.

The authors concluded the matched CRMS/CFSPID and CF cohorts showed differences in outcomes. By a mean age of 7.6 years, a high proportion of the CRMS/CFSPID cohort converted to CF. Our results highlight that monitoring at CF clinics until at least 6 years is needed as well as further studies.

 Dr Anne Munck is at the Service des maladies digestives et respiratoires de l’enfant, CRCM, Hôpital Robert Debré, Paris, France.

-The final practical message of this useful paper is important – these infants should be followed up by experts in CF for a long time.

Aaron C Miller Alejandro P Comellas Douglas B Hornick David A Stoltz Joseph E CavanaughAlicia K GerkeMichael J WelshJoseph ZabnerPhilip M Polgreen. Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions. Proc Natl Acad Sci U S A  . 2020 Jan 21;117(3):1621-1627.doi: 10.1073/pnas.1914912117.Epub 2019 Dec 27.      Free PMC article [Pubmed]

Aaron Miller

Some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions.Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related condition

Dr Aaron Miller is in the Department of Epidemiology, College of Public Health, University of Iowa, Iowa City

Misgault BChatron EReynaud QTouzet SAbely MMelly LDominique STroussier FRonsin-Pradel OGerardin MMankikian JCosson LChiron RBounyar LPorzio MDurieu IWeiss LKessler RKessler L.   Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients.  J Cyst Fibros. 2020 Mar 19. pii: S1569-1993(20)30073-4. doi: 10.1016/j.jcf.2020.03.002. [Epub ahead of print] [Pubmed
To investigate the effects of 1-year lumacaftor-ivacaftor treatment on abnormalities in glucose tolerance (AGT) in Phe508del homozygous cystic fibrosis (CF) patients.   Untreated CF patients with glucose intolerance or newly diagnosed diabetes were included in a prospective, observational study. After 1-year lumacaftor-ivacaftor treatment, AGT were evaluated by using oral glucose tolerance test.

Forty patients participated. 78% of patients had glucose intolerance and 22% diabetes at baseline. After one-year treatment, 50% of patients had normal glucose tolerance, 40% glucose intolerance, and 10% diabetes (p <0.001). The two-hour OGTT glycemia decreased from 171 (153-197) to 139 (117-162) mg/dL (p <0.001). 57.5% (n = 23) of patients improved their glucose tolerance with a significant decrease in both 1-hour (p<0.01) and 2-hour (p<0.001) OGTT glycemia.

The authors concluded improvements in AGT were observed following 1-year lumacaftor-ivacaftor treatment. Larger studies are needed to comprehensively assess CF transmembrane conductance regulator (CFTR) modulators.

Dr B Misgault  is at the Service d’endocrinologie, diabète et nutrition, Hôpitaux Universitaires de Strasbourg, place de l’hôpital, Strasbourg 67091, France

Mithal A, Capilla A, Heinze D, Berical A, Villacorta-Martin C, Vedaie M, Jacob A, Abo K, Szymaniak A, Peasley M, Stuffer A, Mahoney J, Kotton DN, Hawkins F, Mostoslavsky G. Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells.    Nat Commun. 2020 Jan 10;11(1):215. doi: 10.1038/s41467-019-13916-6.    [Pubmed]  Free PMC Article

Gustavo Mostoslavsky

        Aditya Mithal

Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, the authors report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2eGFP iPSC knock-in reporter line to track the emergence of hindgut progenitors, they follow the kinetics of CDX2 expression throughout directed differentiation, enabling the purification of intestinal progenitors and robust generation of mesenchyme-free organoids expressing characteristic markers of small intestinal or  colonic epithelium. They employ HIOs generated in this way to measure CFTR function using cystic fibrosis patient-derived iPSC lines before and after correction of the CFTR mutation, demonstrating their future potential for disease modelling and therapeutic screening applications.

Dr Aditya Mithal is at the Center for Regenerative Medicine of Boston University and Boston Medical Center.

Dr  Gustavo Mostoslavsky is Associate Professor of Medicine and Microbiology Boston University School of Medicine.

Mingione ADei Cas MBonezzi FCaretti APiccoli MAnastasia LGhidoni RParoni RSignorelli P.Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis.  Cell Physiol Biochem. 2020 Jan 31;54(1):110-125. doi: 10.33594/000000208. Free full text   [Pubmed]
Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we describe the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells.

Cystic Fibrosis bronchial epithelia accumulate lipids, exacerbating inflammation. Myriocin administration: i) activates the transcriptions of genes involved in enhancing autophagy-mediated stress clearance; ii) reduces the content of several lipid species and, at the same time, iii) enhances mitochondrial lipid oxidation. Silencing the expression of Sptlc1 reproduces Myriocin induced autophagy and transcriptional activities, demonstrating that the inhibition of sphingolipid synthesis drives a transcriptional program aimed at addressing cell metabolism towards lipid oxidation and at exploiting autophagy mediated clearance of stress. They speculate that regulating sphingolipid de novo synthesis can relieve from chronic inflammation, improving energy supply and anti-oxidant responses, indicating an innovative therapeutic strategy for CF.

From the Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, Italy.

Samuel T MontgomeryDario L FreyMarcus A MallStephen M StickAnthony Kicic AREST CF.  Rhinovirus Infection Is Associated With Airway Epithelial Cell Necrosis and Inflammation via Interleukin-1 in Young Children With Cystic Fibrosis. Front Immunol   2020 Apr 9;11:596.  doi: 10.3389/fimmu.2020.00596. eCollection 2020.[Pubmed]

Samuel T Montgomery

The responses of cystic fibrosis (CF) airway epithelial cells (AEC) to rhinovirus (RV) infection are likely to contribute to early pathobiology of lung disease with increased neutrophilic inflammation and lower apoptosis reported. Necrosis of AEC resulting in airway inflammation driven by IL-1 signalling is a characteristic finding in CF detectable in airways of young children. Being the most common early-life infection, RV-induced epithelial necrosis may contribute to early neutrophilic inflammation in CF via IL-1 signalling. As little is known about IL-1 and biology of CF lung disease, this study assessed cellular and pro-inflammatory responses of CF and non-CF AEC following RV infection, with the hypothesis that RV infection drives epithelial necrosis and IL-1 driven inflammation.

Conclusions: This study found rhinovirus (RV) infection drives necrotic cell death in CF airway epithelial cells (AEC). Furthermore, RV induced IL-1 strongly correlated with necrotic cell death in these cells. As IL-1R signalling drives airway neutrophilia and mucin production, these observations suggest RV infection early in life may exacerbate inflammation and mucin accumulation driving early CF lung disease. Since IL-1R can be targeted therapeutically with IL-1Ra, these data suggest a new anti-inflammatory therapeutic approach targeting downstream effects of IL-1R signalling to mitigate viral-induced, muco-inflammatory triggers of early lung disease.

Dr Samuel T Montgomery is at the Faculty of Health and Medical Sciences, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia.

Morlacchi LC, Rossetti V, Gigli L, Amati F, Rosso L, Aliberti S, Nosotti M, Blasi F. COVID-19 In Lung Transplant Recipients: A Case Series From Milan, Italy. Transpl Infect Dis. 2020 Jun 8:e13356. doi: 10.1111/tid.13356. Online ahead of print. [Pubmed]

        Letzia Morlacchi

Limited data is currently available regarding the course of COVID-19 in lung and solid organ transplant recipients. We hereby present 4 cases of SARS-CoV-2 pneumonia in lung transplant recipients from our centre, set in Milan, Italy. We reduced immunosuppressive regimen in all these patients, typically holding the antiproliferative agent and augmenting steroids; everybody received hydroxychloroquine, initial empiric antibiotic treatment with piperacillin/tazobactam and high dose low molecular weight heparin. Clinical course seemed favourable in three of our patients, but one of them deteriorated after 10 days of hospitalization, probably due to an acute form of graft dysfunction triggered both by COVID19 and a nosocomial bacterial infection, and eventually died. Although short-term prognosis could be considered benign in the majority of our patients, we should carefully monitor these individuals in order to detect early sign of clinical deterioration and graft dysfunction in the next few months.

Dr Letizia Corrina Morlacchi of the Respiratory Unit and Adult Cystic, Fibrosis Centre, Internal Medicine Dept, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano; and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.

Mroz MS, Harvey BJ. Ursodeoxycholic acid inhibits ENaC and Na/K pump activity to restore airway surface liquid height in cystic fibrosis bronchial epithelial cells. Steroids. 2019;151:108461. doi:10.1016/j.steroids.2019.108461 [Pubmed] 

   Magdalene Mroz

         Brian Harvey

Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that in the airways result in reduced Cl secretion and increased Na+ absorption, airway surface liquid (ASL) dehydration, decreased mucociliary clearance, infection and inflammation leading to lung injury. Cystic fibrosis patients often present with bile acids in the lower airways, however the effects of bile acids on ASL and ion transport in CF airways are not known. Secondary bile acids, such as ursodeoxycholic acid (UDCA), have been shown to modulate immune responses and epithelial ion transport. Here we investigated the effects of UDCA in normal and CF airway epithelial cell models. NuLi-1 (normal genotype) and CuFi-1 (CF genotype, Δ508/Δ508) primary immortalized airway epithelial cells were grown under an air-liquid interface. Electrogenic transepithelial ion transport was measured by short-circuit current (Isc) across cell monolayers mounted in Ussing chambers. We observed that UDCA (500 μM, 60 min, bilateral) decreased the basal Isc and ENaC currents in both NuLi-1 and CuFi-1 cells. UDCA inhibited the amiloride-sensitive ENaC current by 44% in NulI-1 monolayers and by 30% in CuFi-1 cells. Interestingly, UDCA also inhibited currents through the basolateral Na/K pump in both Nuli-1 and CuFi-1 monolayers without alterting the expression of ENaC or Na+/K+-ATPase proteins. The airway surface liquid height is regulated by transpeithelial Na+ absorption (ENaC) and Clsecretion (CFTR) in normal airway but mainly by ENaC activity in CF epithelia when Cl secretion is compromised by CFTR mutations. UDCA increased ASL height by 50% in Nuli-1 and by 40% in CUFI-1 monolayers. In conclusion, we demonstrate a previously unknown effect of UDCA to inhibit ENaC activity and increase ASL height in normal and CF human airway epithelial cells suggesting a therapeutic potential for UDCA in CF lung disease.

Dr Magdalena Mroz is a postdoctoral researcher in the Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI ERC Beaumont Hospital, Dublin 9, Ireland.

Professor Brian J Harvey, Chair of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI ERC Beaumont Hospital, Dublin 9, Ireland; Centro di Estudios Cientificos CECs, Valdivia, Chile.

Munck A, Kerem E, Ellemunter H, Campbell D, Wang LT, Ahluwalia N, Owen CA, Wainwright C.  Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations.   J Cyst Fibros. 2020 Jun 13:S1569-1993(20)30128-4. doi: 10.1016/j.jcf.2020.04.015. Online ahead of print.  [Pubmed]

Anne Munck

Tezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF).
This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro.
Participants were randomized 1:1 to receive tezacaftor/ivacaftor or placebo for 12 weeks. The primary endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) between the tezacaftor/ivacaftor and placebo groups through week 12. Key secondary endpoints included absolute change from baseline in CF Questionnaire-Revised respiratory domain scores and the number of pulmonary exacerbations through week 12 and the absolute change from baseline in body mass index at week 12. A prespecified interim analysis (IA) for futility was conducted when approximately 50% of a planned enrolment of 300 participants reached week 12 of the study.

At the time of the interim analysis 83 participants were randomized to tezacaftor/ivacaftor and 85 to placebo; 165 participants completed treatment. The study failed to demonstrate that tezacaftor/ivacaftor significantly improved ppFEV1 or any of the key secondary endpoints and was terminated for futility. The safety profile and PK parameters of tezacaftor/ivacaftor were similar to those reported in prior studies in participants ≥12 years of age with CF.

Conclusions: Tezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410).

Dr Anne Munck is at the Robert Debré Hospital, Assistance Publique-Hopitaux de Paris, Université Paris Diderot, Paris, France.

Muston HN, Perrem L, Davis MD, Ratjen F, Ren CL. The Remaining Barriers to Normalcy in CF: Advances in Assessment of CF Lung Disease [published online ahead of print, 2020 Jun 26]. Pediatr Pulmonol. 2020;10.1002/ppul.24929.doi:10.1002/ppul.24929    [Pubmed]

Heather Muston

Despite early diagnosis of cystic fibrosis (CF) through newborn screening, a substantial proportion of infants and young children with CF still demonstrate physiologic and structural evidence of lung disease progression, such as obstructive airway disease and bronchiectasis. The growing availability of highly effective CF transmembrane conductance regulatory modulator therapy to the vast majority of people with CF has led to the potential to alter the natural history of CF lung disease, but in order to assess the full impact of these therapies on CF lung disease and to help guide treatment, sensitive measures of early and mild disease are needed. Chest imaging using computed tomography or magnetic resonance imaging is one approach, but technologic barriers and/or concern about exposure to ionizing radiation may limit its use. However, advances in physiologic measurement techniques and exhaled breath analysis offer another option for assessment of CF lung dise

Dr Heather N Muston from the Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Nabi ZTalukdar RVenkata RAslam MShava UReddy DN. Genetic Evaluation of Children with Idiopathic Recurrent Acute Pancreatitis.  Dig Dis Sci. 2020 Jan 3. doi: 10.1007/s10620-019-06026-2. [Epub ahead of print]      [Pubmed]

      Zaheer Nabi

Several genetic risk factors have been identified in adults with idiopathic acute recurrent pancreatitis (IARP). However, the literature regarding the genetics of IARP is sparse in children. In this study, we aimed to analyse the genetic risk factors in children with IARP.
All children (< 18 years) with ARP from January 2015 to May 2018 were prospectively enrolled in the study. Children with a known cause of ARP like obstructive, toxic/metabolic, and autoimmune were excluded from the final analysis. Children with IARP underwent genetic testing for mutations/polymorphisms in genes known to predispose to pancreatitis including cationic trypsinogen protease serine 1 (PRSS1), serine protease inhibitor    Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator gene (CFTR), chymotrypsin C (CTRC), claudin-2 (CLDN2) and cathepsin B (CTSB).
Results: A total of 239 children (116 boys, 10.3 ± 3.7 years) were enrolled during the study period. Of these, 204 (85.35%) children were identified as IARP. The mean age of symptom onset and the number of pancreatitis episodes were 8.3 ± 3.7 years and 3.3 ± 1.8, respectively. A family history of pancreatitis was noted in 4.6% children. Mutations/polymorphisms in at least 1 gene were identified in 89.5% (129/144) children including SPINK1 in 41.9%, PRSS1 (rs10273639) in 58.2%, CTRC in 25.6%, CTSB in 54.9%, CLDN2 in 72.9%, and CFTR in 2.3%. There was no significant incidence of genetic mutations/polymorphisms in IARP with or without pancreas divisum (95.7 vs 88.4%; p = 0.467).
The authors concluded genetic alterations are present in the majority of the children with IARP. The incidence of genetic mutations is similar in children with or without pancreas divisum

Dr Zaheer Nabi is at the Asian Institute of Gastroenterology,  Hyderabad, India

-Interesting that only 2.3% of the mutations were of CFTR

Nash EFMiddleton PGTaylor-Cousar JL. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators – an international survey. J Cyst Fibros. 2020 Mar 6. pii: S1569-1993(20)30067-9. doi: 10.1016/j.jcf.2020.02.018. [Epub ahead of print]  [Pubmed]

        Edward Nash

A survey was sent to lead clinicians of adult CF centres in Europe, the United Kingdom (UK), United States of America (USA), Australia and Israel requesting anonymised data on pregnancy outcomes in women using CFTR modulators before and during pregnancy and lactation. The survey identified 64 pregnancies in 61 women taking IVA (n = 31), LUM/IVA (n = 26) or TEZ/IVA (n = 7), resulting in 60 live births. In 44 pregnancies, CFTR modulators were either continued throughout pregnancy or temporarily stopped and then restarted. Two maternal complications were deemed related to CFTR modulator therapy; cessation of modulator therapy resulted in clinical decline in 9 women prompting resumption of therapy during pregnancy. No modulator-related complications were reported in infants exposed in utero and/or during breastfeeding.

CFTR modulators were reported to be generally well tolerated in pregnancy and breastfeeding, with only 2 maternal complications that were deemed related to CFTR modulator therapy. Women stopping CFTR modulators in pregnancy may experience a decline in clinical status and in the cases identified in this survey, restarting therapy led to a clinical improvement. Current experience remains limited and longer-term prospective follow-up is required to exclude delayed adverse effects.

Dr Edward Nash is a Pulmonologist West Midlands Adult Cystic Fibrosis Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham

New Drug Hailed as Major Breakthrough in Cystic Fibrosis. Am J Med Genet A. 2020 Jan;182(1):8-9. doi: 10.1002/ajmg.a.61420.[Pubmed] My summary as their is no abstract:  No authors are listed for this neat account of the progress in the development of CFTR modulator therapy from the FDA approval of ivacaftor (VX-771) in January 2012 for patients with one copy of the G551D mutation, to Orkambi, the combination of lumacaftor (VX-809) and ivacaftor, for those with 2 copies of the F508del mutation in 2015, to another drug combination of tezacaftor (VX-661) and ivacaftor (Symdeko) in 2018 for those people with at least one F508del mutation.

In 2019 the combination drug Trikafta, combining elexacaftor (VX-445), ivacaftor (Kalydeco) and tezacaftor (VX-661), was approved for patients aged 12 years and over with at least one F508del – a group comprising some 90% of the CF population. Approval was based on two phase III clinical trials (Middleton et al, 2019; Heijerman et al, 2019).  Sadly these drugs are very expensive and funding is and will remain a major problem.

Christabella NgNeele S DellschaftCaroline L HoadLuca MarcianiLu BanAndrew P Prayle Helen L BarrAnke JaudszusJochen G MainzRobin C SpillerPenny GowlandGiles MajorAlan R Smyth  Postprandial changes in gastrointestinal function and transit in cystic fibrosis assessed by Magnetic Resonance Imaging. J Cyst Fibros  2020 Jun 16;S1569-1993(20)30733-5.doi: 10.1016/j.jcf.2020.06.004.Online ahead of print. [Pubmed]

        Christabella Ng

Background: Cystic fibrosis (CF) is a multi-system genetic disorder affecting >72,000 people worldwide. Most CF patients experience gastrointestinal symptoms and can develop complications. However, the mechanisms of CF gut disease are not well understood. We evaluated gut function and transit in CF using magnetic resonance imaging (MRI). We hypothesised oro-caecal transit time (OCTT) is longer in CF; with lower small bowel water content (SBWC).
Methods: Twelve CF patients aged 12-40 years and 12 age and sex-matched controls underwent serial MRIs over 1 day with standardised meals. The primary endpoint was OCTT, assessed by the appearance of a food bolus in the caecum. Other measures included corrected SBWC and corrected colonic volume (both area under the curve, AUC), gastric half-emptying time and gastrointestinal symptoms.
Results: OCTT was longer in CF (CF 330 mins [270, >360] vs. controls 210 mins [173, 315], p = 0.04), with no difference in gastric half-emptying times. Corrected SBWC was higher in CF (CF 62 L.min/m2 [36, 80] vs. controls 34 L.min/m2 [28, 41], p = 0.021); minimal postprandial decrease between T240 and T300 (CF 13 mL/m2 [-13, 57] vs. controls 102 mL/m2 [67, 108], p = 0.002) suggests impaired ileal emptying. Corrected colonic volumes were higher in CF (CF 186 L.min/m2[167, 206] vs. controls 123 L.min/m2 [89, 146], p = 0.012). There were no differences in gastrointestinal symptoms.
Conclusions: MRI provides novel insights into CF pathophysiology. Sub-clinical ileal obstruction may be more prevalent than previously thought. Gastrointestinal MRI shows promise as an investigational tool in CF.

Dr Christabella Ng is CF Research Fellow in Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, UK

Nichols AL, Davies JC, Jones D, Carr SB. Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor. Paediatr Respir Rev. 2020 Apr 14. pii: S1526-0542(20)30073-7. doi: 10.1016/j.prrv.2020.04.003. [Epub ahead of print] Review. [Pubmed]
Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1-5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.

Dr A L Nichols is in the Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

Nichols DPMoss RB. Early Aspergillosis in Cystic Fibrosis and Air Trapping: Guilt by Association? Am J Respir Crit Care Med. 2020 Jan 6. doi: 10.1164/rccm.201912-2309ED. [Epub ahead of print]  [Pubmed]

       Richard Moss

David Nichols

These authors discuss recent work on the significance of Aspergillus in young children and in particular the study of Breuer et. (Am J Respir Crit Care Med [online ahead of print] 20 November 2019) that provides substantial further evidence for relatively high prevalence and potential pathogenicity of early lower airways Aspergillus infection without allergic sensitization. They find the longitudinal patterns of association and a clear dose-response between Aspergillus positive cultures and CT abnormalities are compelling. They are encouraged by reports indicating that effective CFTR modulator drugs significantly reduce Aspergillus positivity in respiratory cultures, and the years ahead may allow us to test the impact of early introduction of these therapies in young children with CF. Despite anticipated advances in care, they consider it is important to continue to wrestle with how best to detect, diagnose, and treat lower airway infections in young children with this disease. An increased appreciation for the role of non-allergic fungal infections appears to be an important part of that discussio

-Wise advice from two experts. Once infection in the airways causes damage the course is relentlesly downwards – the speed of which is dependent on the intensity of treatment.

Dr Dave P Nichols is at Seattle Children’s Hospital, 7274, Pediatrics, Seattle, Washington, United States.

Dr Richard Moss is at the Department of Pedaitrics, Stanford University School of Medicine, Palo Alto, California.

Ogbolu CArregui-Fresneda IDaniels THolt RIG. Some young adults with cystic fibrosis-related diabetes may safely stop insulin without any adverse clinical sequelae.  Diabet Med. 2020 Mar 1. doi: 10.1111/dme.14288. [Epub ahead of print]  [Pubmed]

Richard Holt

University Hospital Southampton NHS Foundation Trust hosts the Wessex regional CFRD service. In 2018, there were 45 men and 31 women aged 18–25 years attending the service. Of these, 34 had CRFD, 12 had impaired glucose tolerance and 30 had normal glucose tolerance. Of the 34 with CFRD, 29 were treated with insulin at transition from the paediatric to adult services. The organization of care across our region means that children are seen by paediatric teams at different hospitals prior to transition to adult services in Southampton. We were therefore unable to determine why insulin was initiated as we did not have access to the paediatric records. The remaining five people with CFRD were managing their diabetes with lifestyle modification alone.

Fourteen (53%) of the 26 people treated with insulin at the point of transition stopped taking insulin at a mean ± SD age of 20.6 ± 2.4 years. The mean dose of insulin and the mean HbA1c at insulin cessation were 5.8 ± 1.3 units/day and 38 ± 6 mmol/mol (5.7 ± 0.7%), respectively. There were 1-year post-insulin cessation assessments available for all 14 people; 12 were followed for 2 years and eight had 3-year post-insulin cessation data. There were no differences in sex, gene mutation, baseline BMI or lung function between those who stopped insulin compared with those who continued, but those who stopped insulin were older when CFRD was diagnosed (Table 1). After the insulin was stopped, there was no deterioration in HbA1c (P=0.923) or decrease in body weight (P=0.588; Figs 1a,b). No one needed to re-start insulin. Figure 1c shows a small expected decline in lung function with time, but the rate of decline was unaffected by the decision to stop insulin (P=0.135).

In conclusion, although further work is needed to ascertain who can stop insulin safely in early adulthood, the authors suggest that stopping insulin in selected people with CFRD may be one way to simplify their treatment burden.

From the Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and the Wessex Adult Cystic Fibrosis Service, Southampton, UK.

Richard Holt is Professor in Diabetes and Endocrinology within Medicine at the University of Southampton.

Olivereau LNave VGarcia SPerceval MRabilloud MDurieu IReynaud Q. Adherence to lumacaftor-ivacaftor therapy in patients with cystic fibrosis in France. 
J Cyst Fibros.
 2020 Jan 2. pii: S1569-1993(19)30901-4. doi: 10.1016/j.jcf.2019.09.018. [Epub ahead of print] [Pubmed]
This retrospective study used pharmacy refills data to calculate proportion of days covered (PDC). Adherence was defined as a PDC ≥80%. A logistic regression analysis was conducted to examine factors associated with medication adherence.
Ninety-six patients were included in the final cohort for analysis. The mean PDC was 96%  ± 14 at 6 months, and 91% ± 17 at 12 months. The proportion of adherent patients was 89% and 83% at 6 and 12 months respectively. Age and ppFEV1 were found to affect medication adherence.
Considering the medico-economic impact of CFTR modulator therapy, high adherence rates to lumacaftor-ivacaftor found in this study are encouraging.

Dr L Olivereau is at the Pharmacie Centrale, Hospices Civils de Lyon, F-69230 Saint Genis Laval, France.

Oudraad MCJKuo WRosenow TAndrinopoulou ERStick SMTiddens HAWM Assessment of early lung disease in young children with CF: A comparison between pressure-controlled and free-breathing chest computed tomography.  Pediatr Pulmonol. 2020 Mar 2. doi: 10.1002/ppul.24702. [Epub ahead of print] [Pubmed]

     Merel Oudraad

Chest computed tomography (CT) in children with cystic fibrosis (CF) is sensitive in detecting early airways disease. The pressure-controlled CT-protocol combines a total lung capacity scan (TLC PC-CT) with a near functional residual capacity scan (FRC PC-CT) under general anaesthesia, while another CT-protocol is acquired during free breathing (FB-CT) near functional residual capacity. The aim of this study was to evaluate the sensitivity in detecting airways disease of both protocols in two cohorts.

Routine PC-CTs (Princess Margaret Children’s Hospital) and FB-CTs (Erasmus MC-Sophia Children’s Hospital) were retrospectively collected from CF children aged 2 to 6 years. Total airways disease (%disease), bronchiectasis (%Bx), and low attenuation regions (%LAR) were scored on CTs using the Perth-Rotterdam annotated grid morphometric analysis-CF method. The Wilcoxon signed-rank test was used for differences between TLC and FRC PC-CTs and the Wilcoxon rank-sum test for differences between FRC PC-CTs and FB-CTs.

RESULTS: Fifty patients with PC-CTs (21 male, aged 2.5-5.5 years) and 42 patients with FB-CTs (26 male, aged 2.3-6.8 years) were included. %Disease was higher on TLC PC-CTs compared with FRC PC-CTs (median 4.51 vs 2.49; P < .001). %Disease and %Bx were not significantly different between TLC PC-CTs and FB-CTs (median 4.51% vs 3.75%; P = .143 and 0.52% vs 0.57%; P = .849). %Disease, %Bx, and %LAR were not significantly different between FRC PC-CTs and FB-CTs (median 2.49% vs 3.75%; P = .055, 0.54% vs 0.57%; P = .797, and 2.49% vs 1.53%; P = .448).

The authors consider their data suggest that FRC PC-CTs are less sensitive than TLC PC-CTs and that FB-CTs have similar sensitivity to PC-CTs in detecting lung disease. FB-CTs seem to be a viable alternative for PC-CTs to track CF lung disease in young patients with CF.

Dr Merel C J Oudraad was Student researcher of the Lung Analysis research group Erasmus MC and now Clinical Fellow Emergency Department Royal Infirmary Edinburgh.

Sandra Kwarteng OwusuBrenda M MorrowDebbie WhiteSusan KlugmanAneesa VankerDiane GrayMarco Zampoli Cystic fibrosis in black African children in South Africa: a case control study.  J Cyst Fibros   2020 Jul;19(4):540-545. doi: 10.1016/j.jcf.2019.09.007. Epub 2019 Oct 31.  [Pubmed]  

Sandra Kwarteng Owusu

Background: Cystic fibrosis (CF) is described more commonly in Caucasian populations in whom p.Phe508del is the most common mutation. There is a paucity of data of CF in black African children. The aim of this study was to describe and compare the presentation and outcomes of black African children with CF to those with p.Phe508del genotype.
Methods: A retrospective case-controlled study was conducted from January 2000 – March 2018 of children with CF attending two CF centres in South Africa. Presentation, genotype, nutrition and pulmonary function outcomes of black African children were compared to matched controls with the p.Phe508del mutation.
Results: Thirty-four black African children (cases) with median age of diagnosis (5.5 months, IQR 2.0-15.0) were matched to 34 controls. Among cases, 3120+1G->A CFTR mutation was most commonly identified; homozygous n=22 (64.7%) and heterozygous=7(20.5%). Compared to controls, cases at diagnosis were more malnourished and fewer presented with neonatal bowel obstruction [cases n=2 (5.9%) vs. controls n=10 (29.4%); p = 0.03]. Nutrition and pulmonary function (FEV1 in children ≥ 6 years) outcomes and changes over time from ages 3-16 years were similar in both groups; median FEV1 z-score at age 6,10 and 14 years was -0.9 (±1.5), -1.8 (±2.0) and -1.8 (±1.9) respectively for all patients. Deaths were recorded in three cases (8.8%) and one control (2.9%) (p = 0.6).
Conclusion: Black African children with CF were more malnourished at diagnosis, and fewer presented with neonatal bowel obstruction. Cases and controls had comparable nutritional, pulmonary function and early mortality outcomes.

Dr Sandra Kwarteng Owusu is in the Division of Paediatric Pulmonology, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, South Africa and the Department of Child Health and Paediatrics, Komfo Anokye Teaching Hospital Kumasi, Ghana.

– An interesting comprehensive review of the situation regarding CF in African children

Palmer DJTurner DLNg P A Single “All-in-One” Helper-Dependent Adenovirus to Deliver Donor DNA and CRISPR/Cas9 for Efficient Homology-Directed Repair.  Mol Ther Methods Clin Dev. 2020 Feb 4;17:441-447. doi: 10.1016/j.omtm.2020.01.014. eCollection  2020 Jun 12  Free PMC Article [Pubmed]
In this study, we developed a single helper-dependent adenovirus (HDAd) to deliver all of the components (donor DNA, CRISPR-associated protein 9 [Cas9], and guide RNA [gRNA]) needed to achieve high-efficiency gene targeting and homology-directed repair in transduced cells. We show that these “all-in-one” HDAds are up to 117-fold more efficient at gene targeting than donor HDAds that do not express CRISPR/Cas9 in human induced pluripotent stem cells (iPSCs). The vast majority (>90%) of targeted recombinants had only one allele targeted, and this was accompanied by high-frequency indel formation in the non-targeted allele at the site of Cas9 cleavage. These indels varied in size and nature, and included large deletions of ∼8 kb. The remaining minority of recombinants had both alleles targeted (so-called bi-allelic targeting). These all-in-one HDAds represent an important platform for accomplishing and expanding the utility of homology-directed repair, especially for difficult-to-transfect cells and for in vivo applications.

Donna J Palmer is in the Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.

Papale MParisi GFSpicuzza LLicari ABongiovanni AMulè ERotolo NManti SLeonardi S.  Lung clearance index evaluation in detecting nocturnal hypoxemia in cystic fibrosis patients: Toward a new diagnostic tool. Respir Med. 2020 Apr;164:105906. doi: 10.1016/j.rmed.2020.105906. Epub  2020 Feb 19.   [Pubmed]
Nocturnal hypoxemia adversely affects outcomes in patients with cystic fibrosis (CF). Although an early detection of this abnormality may be desirable, still its predictability remains uncertain. The Lung Clearance Index (LCI) is a measure of lung ventilation distribution obtained from a multiple-breath washout technique (MBW), recently implemented in patients with CF. This study aimed to establish whether the LCI predicts nocturnal hypoxemia in patients with stable CF, with mild to moderate disease, and normal diurnal gas exchange.
31 stable patients (15 males, mean age 17.4 ± 5.2 years) with mild to moderate CF, normoxic when awake, were enrolled. In all patients we performed nocturnal cardio-respiratory polygraphy, lung function measurement, and MBW test to derive LCI values.

LCI was abnormal in most of the patients and inversely correlated with mean nocturnal SpO2 (r = -0.880 p < 0.01). A receiver operating characteristic (ROC) analysis, performed to assess whether LCI predicted nocturnal hypoxemia, revealed a high predictive accuracy of LCI for nocturnal desaturation (AUC = 0.96; Youden index = 0.79). Forced expiratory volume in 1 s (FEV1) was predictive only in patients with more severe airway obstruction, with a moderate degree of accuracy (AUC 0.71).

The authors concluded the LCI showed a high effectiveness in predicting nocturnal hypoxemia in stable patients with CF, particularly when compared with a traditional parameter of lung function such as FEV1.

From the Respiratory Unit, AOU Policlinico-Vittorio Emanuele, Department of Clinical and Experimental Medicine, University of Catania, Via Santa Sofia 78, I-95123, Catania, Italy.

Patel DPopple SClaydon AModha DEGaillard EA. Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease  Med Mycol. 2020 Jan 1;58(1):11-21. doi: 10.1093/mmy/myz0 [Pubmed]

      Erol Gaillard

A prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3-17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels >1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy.

Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.

Dr Erol Gaillard, Senior Lecturer in Child Heath and Honorary Consultant in Paediatric Respiratory Medicine.                           Department of Respiratory Sciences, NIHR Biomedical Research Centre (Respiratory theme) and Institute for Lung Health, University of Leicester, Leicester, United Kingdom and the Department of Paediatric Respiratory Medicine, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom.

Pedemonte NBertozzi FCaci ESorana FDi Fruscia PTomati VFerrera LRodríguez-Gimeno ABerti F2Pesce ESondo EGianotti AScudieri PBandiera TGalietta LJV. Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel. Sci Adv. 2020 Feb 21;6(8):eaay9669. doi: 10.1126/sciadv.aay9669. eCollection  2020 Feb. [Pubmed]  Free PMC Article

Luis Gallietta

Tiziano Bandieri

F508del, the most frequent mutation causing cystic fibrosis (CF), results in mistrafficking and premature degradation of the CFTR chloride channel. Small molecules named correctors may rescue F508del-CFTR and therefore represent promising drugs to target the basic defect in CF. The authors screened a carefully designed chemical library to find F508del-CFTR correctors. The initial active compound resulting from the primary screening underwent extensive chemical optimization.

The final compound, ARN23765, showed an extremely high potency in bronchial epithelial cells from F508del homozygous patients, with an EC50 of 38 picomolar, which is more than 5000-fold lower compared to presently available corrector drugs. ARN23765 also showed high efficacy, synergy with other types of correctors, and compatibility with chronic VX-770 potentiator. Besides being a promising drug, particularly suited for drug combinations, ARN23765 represents a high-affinity probe for CFTR structure-function studies.

Corresponding authors are Tiziano Bandiera of D3 PharmaChemistry, Fondazione Istituto Italiano di Tecnologia, Genova, Italy and Luis J V Gallietta of Telethon Institute of Genetics and Medicine (TIGEM) Possuoli and University of Naples.

Perrem L, Ratjen F. Anti-inflammatories and mucociliary clearance therapies in the age of CFTR modulators. Pediatr Pulmonol. 2019;54 Suppl 3:S46S55. doi:10.1002/ppul.24364  [Pubmed]

Lucy Perrem

The combination of CFTR dysfunction, mucus obstruction, and infection drive an exaggerated and dysfunctional inflammatory response, which contributes to irreversible airway destruction and fibrosis. CFTR modulators, an exciting new class of drugs, increase the expression and/or function of CFTR variant protein and improve multiple clinical endpoints, such as lung function, pulmonary exacerbation rates, and nutritional status.
However, these genotype-specific drugs are not universally available, the clinical response is variable, and lung function still declines over time when bronchiectasis is established. Consequently, even in the age of CFTR modulators, we must target other important aspects of the CF airway disease, such as inflammation and mucociliary clearance. This review highlights the mechanisms of inflammation and mucus accumulation in the CF lung and discusses anti-inflammatory and mucociliary clearance agents that are currently in development focusing on compounds for which clinical trial data have recently become available.

Dr Lucy Perrem is in the Division of Respiratory Medicine, The Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada.

Pierre-Régis Burgel Anne Munck Isabelle Durieu Raphaël Chiron Laurent Mely Anne Prevotat  et al, French Cystic Fibrosis Reference Network Study GroupReal-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients With Cystic Fibrosis. Am J Respir Crit Care Med. 2020 Jan 15;201(2):188-197. doi: 10.1164/rccm.201906-1227OC. [Pubmed]

Pierre-Regis Burgel

To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life post approval setting. The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society’s recommendations.
Main findings – Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or non-respiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.

The authors concluded Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Dr Pierre-Régis Burgel is at the Faculty of Medicine, Paris Descartes CPSC.

Leonardo PozoFatimah BelloYamely MendezSalim Surani.  Cystic Fibrosis-Related Diabetes: The Unmet Need.  World J Diabetes 2020 Jun 15;11(6):213-217. doi: 10.4239/wjd.v11.i6.213.[Pubmed]
The prevalence of CF-related diabetes (CFRD) increases exponentially as patients’ age. Clinical care guidelines for CFRD from 2010, recommend insulin as the mainstay of treatment. Many patients with CFRD may not require exogenous insulin due to the heterogeneity of this clinical entity. Maintenance of euglycemia by enhancing endogenous insulin production, secretion and degradation with novel pharmacological therapies like glucagon-like peptide-1 agonist is an option that remains to be fully explored. As such, the scope of this article will focus on our perspective of glucagon-like peptide-1 receptor agonist in the context of CFRD. Other potential options such as sodium-glucose cotransporter-2 and dipeptidyl peptidase 4 inhibitors and their impact on this patient population is limited and further studies are required.

Dr Leonardo Pozo is in the Department of Internal Medicine, University of Texas Rio Grande Valley, Edinburg, United States.

Prentice BJOoi CYVerge CFHameed SWidger J. Glucose abnormalities detected by continuous glucose monitoring are common in young children with Cystic Fibrosis.  J Cyst Fibros. 2020 Feb 25. pii: S1569-1993(20)30057-6. doi: 10.1016/j.jcf.2020.02.009. [Epub ahead of print] [Pubmed]

Bernadette Prentice

It is not yet known whether continuous glucose monitoring (CGM) abnormalities persist in young children with CF. We evaluated longitudinal CGM results for children with CF < 10 years of age. We performed 3-day CGM at baseline, 12 months, and 24 months on 11 CF children (1 female) initially aged mean (SD) 3.8 (2.5) years. CGM analysis included (i) mean sensor glucose (SG), (ii) standard deviation (SD) for SG, (iii) peak SG and (iv)% time spent above a threshold of 7.8 mmol/L. Only three (3/11, 27%) had normal CGM at all time-points. Nearly three quarters of the participants (8/11, 73%) spent more than 4.5 percent time > 7.8 mmol/L at one time-point, five of whom had an elevated percent time on a subsequent test.

Young children with CF have glucose abnormalities detected by CGM that fluctuate over time.

Dr Bernadette Prentice is a respiratory paediatrician in the Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, NSW, Australia.

Lara C Pullen. A New Future for Patients With Cystic Fibrosis. Am J Transplant.  2020 May;20(5):1213-1214.doi: 10.1111/ajt.15893. Free Access

Lara Pullen

The key points in this article are –Recently developed clinical guidelines and an improved transplant referral process are bringing hope to patients in the US with CF;  Canadian systems and practice’s show how the US could produce more favourable pre- and post-transplant results; a newly formulated drug Trikafta (elexacaftor, tezacaftor and ivacaftor) has been shown to improve lung function and delay the need for transplant; the transplant and CF communities are working together to bring about more successful treatment outcomes for patients

Dr Lara Pullen is a medical writer who has covered a wide range of topics.

Rang CKeating DWilson JKotsimbos T. Re-Imagining Cystic Fibrosis Care: Next Generation ThinkingEur Respir J. 2020 Mar 5. pii: 1902443. doi: 10.1183/13993003.02443-2019. [Epub ahead of print][Pubmed]

Tom Kotsimbos

Cystic fibrosis is a common multi-system genetically inherited condition, predominately found in individuals of Caucasian decent. Since the identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, and the subsequent improvement in understanding of CF pathophysiology, significant increases in life-expectancy have followed. Initially this was related to improvements in the management and systems of care for treating the various affected organ systems. These cornerstone treatments are still essential for CF patients born today. However, over the last decade, the major advance has been in therapies that target the resultant genetic defect – the dysfunctional CFTR protein. Small molecule agents that target this dysfunctional protein via a variety of mechanisms have led to lung function improvements, reductions in pulmonary exacerbation rates and increases in weight and quality of life indices. As more patients receive these agents earlier and earlier in life, it is likely that general CF care will increasingly pivot around these specific therapies, although it is also likely that effects other than those identified in the initial trials will be discovered and need to be managed. Despite great excitement for modulator therapies, they are unlikely to be suitable or available for all: whether this is due to a lack of availability for specific CFTR mutations, drug-reactions or the health economic set-up in certain countries. Nevertheless, the CF community must be applauded for its ongoing focus on research and development for this life-limiting disease. With time, personalised individualised therapy would ideally be the mainstay of CF care.

– This is a clear summary of the future changing nature of CF care. As with many other such articles there is no mention of prevention.

Dr Tom Kotsimbos is Associate Professor and Head of Respiratory Medicine Laboratory, AIRMed Department, Central Clinical School, Monash University.

Reynaud QRousset Jablonski CPoupon-Bourdy SDenis ARabilloud MLemonnier LNove-Josserand RDurupt STouzet SDurieu IParticipating Centers of the French Cystic Fibrosis Registry.  Pregnancy outcome in women with cystic fibrosis and poor pulmonary function.  J Cyst Fibros. 2020 Jan;19(1):80-83. doi: 10.1016/j.jcf.2019.06.003. Epub 2019 Jul 1.[Pubmed]

Quitterie Raynaud

A study to investigate how poor pre-gestational pulmonary function influenced pregnancy outcome and clinical status evolution in women with cystic fibrosis.    Pregnancies in women without lung transplantation with a first delivery reported to the French cystic fibrosis registry between 2000 and 2012 were identified. Pregnancy outcomes and clinical trends (body mass index – BMI, and pulmonary function) over a 4-year follow-up in women with poor pre-gestational pulmonary function, defined as forced expiratory volume (FEV1) ≤ 50%, were compared to those in women with FEV1 ˃ 50%.

 A total of 149 women had a first delivery and 36 (24.2%) of these had pre-gestational FEV1 ≤ 50%. There was no significant difference in age or frequency of assisted conception between the 2 groups. The rate of caesarean section was significantly higher in women with FEV1 ≤ 50% (43.7% vs. 21.1%, p = .01). The frequency of preterm birth did not differ significantly between the two groups, but median infant birthweight was significantly lower in women with FEV1 ≤ 50% (2705 g; range: 650-3700 vs. 3044 g; range: 1590-3860, p = .003). Despite significantly lower FEV1 and BMI the year before pregnancy for women with poor pulmonary function, the decline in these parameters during the study period did not differ significantly between the two groups.

Poor pre-gestational pulmonary function in women with cystic fibrosis was associated with a higher rate of caesarean section and a clinically significant impact on fetal growth, but was not associated with more important pulmonary and nutritional decline over the study period.

Dr Quitterie Reynaud is a Sub-Investigator at the Centre de référence Adulte de la Mucoviscidose, Service de médecine interne, Hospices Civils de Lyon and the Universite de Lyon

Geraint B RogersSteven L TaylorLucas R HoffmanLucy D Burr.   The impact of CFTR modulator therapies on CF airway microbiology.   J Cyst Fibros 2020 May;19(3):359-364. doi: 10.1016/j.jcf.2019.07.008.Epub 2019 Aug  [Pubmed]

         Geraint Rodgers

Major historical advances in cystic fibrosis (CF) respiratory clinical care, including mechanical airway clearance and inhaled medications, have aimed to address the consequences of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. In contrast, CFTR modulator therapies instead target the underlying protein defect that leads to CF lung disease. The extent to which these therapies might reduce susceptibility to chronic lung infections remains to be seen. However, by improving airway clearance, reducing the requirement for antibiotics, and in some cases, through direct antimicrobial effects, CFTR modulators are likely to result in substantial changes in CF airway microbiology. These changes could contribute substantially to the clinical benefit associated with modulator therapies, as well as providing an important indicator of treatment efficacy and residual pathophysiology. Indeed, the widespread introduction of modulator therapies might require us to re-consider our models of CF airway microbiolo

Prof Geraint B Rogers is a molecular microbiologist and microbial ecologist. He is the Director, Microbiome Research at SAHMRI, leads a laboratory based within the Flinders University School of Medicine, Adelaide

Tim Rosenow, L Clara MokLidija TurkovicLuke J BerryPeter D SlySarath RanganathanHarm A W M TiddensStephen M Stick  The cumulative effect of inflammation and infection on structural lung disease in early cystic fibrosis.  Eur Respir J  2019 Jul 11;54(1):1801771.doi: 10.1183/13993003.01771-2018. Print 2019 Jul. [Pubmed]

     Tim Rosenow

Introduction: Pulmonary inflammation and infection are important clinical and prognostic markers of lung disease in cystic fibrosis (CF). However, whether in young children they are transient findings or have cumulative, long-term impacts on respiratory health is largely unknown. We aimed to determine whether their repeated detection has a deleterious effect on structural lung disease.
Methods: All patients aged <6 years with annual computed tomography (CT) and bronchoalveolar lavage (BAL) were included. Structural lung disease on CT (%Disease) was determined using the PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) method. The number of times free neutrophil elastase (NE) and infection were detected in BAL were counted, to determine cumulative BAL history. Linear mixed model analysis, accounting for repeat visits and adjusted for age, was used to determine associations.
Results: 265 children (683 scans) were included for analysis, with BAL history comprising 1161 visits. %Disease was significantly associated with the number of prior NE (0.31, 95% CI 0.09-0.54; p=0.007) but not infection (0.23, 95% CI -0.01-0.47; p=0.060) detections. Reference equations were determined.
Conclusions: Pulmonary inflammation in surveillance BAL has a cumulative effect on structural lung disease extent, more so than infection. This provides a strong rationale for therapies aimed at reducing inflammation in young children.

Dr Tim Rosenow is a physicist and senior research fellow at the Telethon Kids Institute, Centre for Child Health Research, University of Western Australia, Subiaco, Australia

Amy L Ryan. Correcting CFTR: New Gene Editing Strategies for Rescuing CFTR Function Ex Vivo. Cell Stem Cell. 2020 Apr 2;26(4):476-478. doi: 10.1016/j.stem.2020.03.012.  [Pubmed]

          Amy Ryan

Gene correction presents one of few options for a cure for all patients with cystic fibrosis. This commentary discusses new applications of CRISPR-based gene editing technology with increased efficiency and specificity to correct the cystic fibrosis transmembrane regulator (CFTR) function in patient-specific primary epithelial cells.

Dr Amy L Ryan is Assistant Professor of Medicine at the Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angles, CA, USA; Department of Stem Cell Biology and Regenerative Medicine, University of Southern California.

Clare Saunders Renee JensenPaul D RobinsonSanja StanojevicMichelle KlingelChristopher ShortJane C DaviesFelix Ratjen  Integrating the multiple breath washout test into international multicentre trials.  J Cyst Fibros   2020 Jul;19(4):602-607.doi: 10.1016/j.jcf.2019.11.006. Epub 2019 Nov 24. [Pubmed]
The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials.
Here the authors describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial.

Dr Clare Saunders is at the Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London.

 Schwensen HFMoser CPerch MPressler THøiby N. Pseudomonas aeruginosa antibody response in cystic fibrosis decreases rapidly following lung transplantation.  J Cyst Fibros. 2020 Feb 7. pii: S1569-1993(20)30044-8. doi: 10.1016/j.jcf.2020.01.012. [Epub ahead of print] [Pubmed]
Specific Pseudomonas aeruginosa (PA) precipitating immunoglobulin G antibodies in serum are correlated with PA biofilm infection and are used as diagnostic and prognostic markers in cystic fibrosis (CF). The aim of this study was to examine the change of PA antibody response in CF patients after bilateral sequential lung transplantation (LTx).

PA antibodies and airway bacteriology were retrospectively evaluated in 20 chronically infected CF patients, who underwent LTx between 2001 and 2016 at Rigshospitalet, Copenhagen. Yearly precipitin counts from one year before LTx and up to five years after LTx were compared. Monthly airway cultures were examined in the five-year period after LTx. In addition, crossed immunoelectrophoresis (CIE) were analysed for each patient for antigenic similarities from time of infection, pre-LTx and post-LTx.

Results: All patients experienced a significant drop in PA antibodies from one year pre-LTx to one year post-LTx (p < 0.0001). The PA antibody level did not differ between those, who became re-infected immediately after LTx, and those, who did not. No patients regained the high pre-LTx precipitin levels in the following five years. The antigenic specificities of the sera post-LTx were in each patient similar to the antigenic specificities at the beginning of infection indicating a decades long memory of their immune response like an “immunological fingerprint”.

The authors concluded that after LTx a significant and continuous reduction in PA antibodies was observed. The reduction was independent of immediate reinfection after LTx. A novel three-factor explanatory model is presented.

From the Department of Clinical Microbiology, Rigshospitalet (Copenhagen University Hospital), Denmark.

Niels Hoiby receives the ECFS Award 2012

Niels Hoiby (L) – 25 years a Professor

Professor Niels Hoiby. the late Dr Christian Koch and their colleagues in Copenhagen have been one of the major influences, well ahead of their time, in recognising the significance of P. aeruginosa infection (1973 Hoiby N, Axelsen NH. Identification and quantitation of precipitins against Pseudomonas aeruginosa in patients with cystic fibrosis by means of crossed immunoelectrophoresis with intermediate gel. Acta Path Microbiol Scand 1973; 81:298-308. [PubMed]) and introducing more aggressive treatment both for chronic infection  (1983 Szaff M, Hoiby N, Flensborg EW. Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection. Acta Paediatr Scand 1983; 72; 651-657.[PubMed]) and early infection  (1991 Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosa infection in cystic fibrosis by early treatment. Lancet 1991; 338:725-726.[ PubMed]. All these papers are abstracted in the appropriate year section of this history

Niels Hoiby and his colleagues in Copenhagen have been one of the major influences, well ahead of their time, in recognising the significance of P. aeruginosa infection and introducing more aggressive treatment both for chronic and early infection.  No one has made a more significant contribution to the treatment of CF than Niels and his colleagues at the Rigshospitalet in Copenhagen. Certainly they were a major influence on us at the Leeds Regional CF Centre in the Eighties. It was great privilege to be invited to speak at Niels’s celebration of 25 years as Professor at the University in Copenhagen.

Patricia ScottKyle AndersonMekhla SinghaniaRobert Cormier. Cystic Fibrosis, CFTR, and Colorectal Cancer. Int J Mol Sci.2020 Apr 21;21(8):E2891. doi: 10.3390/ijms21082891.[Pubmed]

     Patricia Scott

Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new CF colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients.

The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US) who are heterozygous carriers of CFTR gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where downregulation of CFTR is associated with poor survival. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/β-catenin signaling and disruption of intestinal stem cell homeostasis and intestinal barrier integrity, as well as intestinal dysbiosis, immune cell infiltration, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers.

Dr Patricia Scott is Assistant Professor in the Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA.

Shaw MOppelaar MCJensen RStanojevic SDavis SDRetsch-Bogart GRatjen FA.   The utility of moment ratios and abbreviated endpoints of the multiple breath washout test in preschool children with cystic fibrosis. Pediatr Pulmonol. 2020 Jan 3. doi: 10.1002/ppul.24618. [Epub ahead of print] [Pubmed]
The multiple breath washout (MBW) test may be most useful in tracking disease progression over time to inform treatment decisions. In the clinical setting, alternative outcomes, which can be obtained quickly and easily, may facilitate interpretation of clinically relevant changes in lung function.
In this secondary analysis of data from 78 cystic fibrosis (CF) and 72 healthy control (HC) subjects between the ages of 2.6 and 5.9 years, MBW was performed at enrolment, 1, 3, 6, 9, and 12 months, as well as during symptomatic visits using the Exhalyzer D (EcoMedics AG, Duernten, Switzerland). The lung clearance index, LCI2.5, was compared to moment ratios (M1/M0 and M2 /M0 ) at the standard cutoff (1/40th of starting tracer gas concentration) as well as LCI5 and moment ratios at 1/20th of the starting concentration (M1 /M0 at LCI5 , and M2 /M0 at LCI5 ).
All outcomes were able to distinguish between health and disease. LCI5 reduced testing time by 40% and increased feasibility by more than 10%. The limits of biological reproducibility in healthy children were similar between LCI2.5 (15%), LCI5 (12%), M1 /M0 at LCI2.5 (14%), and M1 /M0 at LCI5 (12%), but markedly larger for M2 /M0 at LCI2.5 (30%) and M2/M0 at LCI5 (25%). Each outcome deteriorated significantly with worsening pulmonary symptoms, the magnitude of deterioration was greatest for M2 /M0 .

The authors concluded that in preschool children with CF, LCI5 was more feasible to obtain and track disease progression. The second moment ratio was most sensitive to pulmonary symptoms, but had the greatest variability both within and between subjects.

Dr M Shaw is at the Translational Medicine Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

-LCI seems to be established as an effective non-invasive generally applicable way of monitoring respiratory function in pre-school children – filling a long present need.

Shaw M, Khan U, Clancy JP, Donaldson SH, Sagel SD, Rowe SM, Ratjen F; PROSPECT Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network.  Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: Results from the prospect study.   J Cyst Fibros. 2020 Jun 6:S1569-1993(20)30160-0. doi: 10.1016/j.jcf.2020.05.010. Online ahead of print. [Pubmed]
The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV1% predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population.

Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.

Shteinberg MTaylor-Cousar JL. Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease.  Eur Respir Rev. 2020 Mar 20;29(155). pii: 190112. doi: 10.1183/16000617.0112-2019. Print  2020 Mar 31. Free full text [Pubmed]

Michal Shteinberg

Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug-drug interactions, are discussed.

Dr Michal Shteinberg is heading the bronchiectasis and adult CF service in the Pulmonology institute and CF Center, Carmel medical Center, Haifa, Israel and a Clinical Assistant Professor in the Faculty of medicine at the Technion, Israel Institute of Technology.

Professor Stuart Elborn comments on this article as follows –

Elborn JS. Modulator treatment for people with cystic fibrosis: moving in the right direction. Eur Respir Rev. 2020 Mar 20;29(155). pii: 200051. doi: 10.1183/16000617.0051-2020. Print  2020 Mar 31.   Free full text [Pubmed]

Stuart Elborn

Stuart Elborn in this issue of the European Respiratory Review, describes Shteinberg and Taylor-Cousar’s article as providing a very useful review of the current state of play in Europe for CFTR modulators

There is a benefit from these therapies even in individuals with severely reduced FEV1 who are excluded from the trials in follow-up clinical studies, and people with CF benefit from a significant reduction in pulmonary exacerbations.                                                                                                                The adverse events and drug/drug interactions are comprehensively covered in the article by Shteinberg and Taylor-Cousar.  Drug/drug interactions are also important in this group of drugs as they interact with a number of hepatic enzymes important in drug metabolism. These are particularly relevant for antibacterial and antifungal agents, which are often used in people with CF.

Elborn suggests the delivery of healthcare services for people with CF is likely to evolve over the next decade with a wide implementation of highly effective modulator treatment. It is important for respiratory clinical teams and the wider group of specialists in the multidisciplinary team to understand how these drugs are used, the side-effects and potential for drug interactions. The article by Shteinberg and Taylor-Cousar provides a very useful summary of the current position.

Full texts of both these above articles are available and are excellent.

Siegel MJFreeman AJYe WPalermo JJMolleston JPParanjape SMStoll JLeung DMasand PKarmazyn BHarned RLing SCNavarro OMKarnsakul WAlazraki ASchwarzenberg SJSeidel FGTowbin AAlonso EMNicholas JLMurray KFOtto RKSherker AHMagee JCNarkewicz MRCFLD Network.  Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.  J Pediatr. 2020 Feb 11. pii: S0022-3476(19)31712-3. doi: 10.1016/j.jpeds.2019.12.033. [Epub ahead of print] [Pubmed]

Marilyn Siegel

To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease.  Planned 4-year interim analysis of a 9-year multi-center, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease.

The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern).

The authors’ main conclusion was that research liver research ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.

Dr Marilyn J Siegel is Professor of Radiology and Pediatric Radiology at the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO.

S SimonC BauninJ VialE MasL RoditisM MicheletM Mittaine. Computed Tomography in Children With Cystic Fibrosis: The Role of an Expiratory Protocol.  Rev Mal Respir  2020 Apr 22;S0761-8425(20)30102-9. doi: 10.1016/j.rmr.2020.03.004.Online ahead of print.    [Article in French] [Pubmed]
Chest computed tomography (CT) is essential to monitor lung disease in children with cystic fibrosis, but it involves recurrent exposure to ionizing radiation. The aim of this study was to compare the current complete CT protocol (volumetric end-inspiratory plus sequential expiratory acquisition) to a sequential expiratory acquisition protocol alone in terms of image analysis and ionizing radiation dose.

The authors showed an expiratory chest CT protocol was accurate in diagnosing early signs of CF disease and permitted significant reduction of radiation dose. This protocol would allow spacing out of complete CT scanning with its higher radiation dose and should be considered for the monitoring of lung disease severity in children with CF.

Dr S Simon is at the Service d’imagerie médicale, hôpital des enfants, CHU de Toulouse, Toulouse, France.

Singh HCoffey MJOoi CY. Cystic Fibrosis-related Liver Disease is Associated With Increased Disease Burden and Endocrine Comorbidities. J Pediatr Gastroenterol Nutr. 2020 Mar 5. doi: 10.1097/MPG.0000000000002694. [Epub ahead of print]  [Pubmed]
Cystic fibrosis-related liver disease (CFLD) is the leading non-pulmonary cause of mortality in cystic fibrosis (CF). The authors evaluated and compared the burden of disease and non-respiratory comorbidities of those with severe CFLD and those without (no CFLD).    A retrospective nationwide (Australia) longitudinal review (from 1998 to 2016) of severe CFLD patients compared with no CFLD controls (matched 1 : 1 for age, genotype, pancreatic insufficiency, and center).

One hundred sixty-six patients with severe CFLD and 166 with no CFLD were identified. Forced expiratory volume in 1 second percentage of predicted (FEV1%) was significantly lower in CFLD than no CFLD across all ages. Median (IQR) hospitalizations per patient per year were higher in CFLD than noCFLD for: respiratory indications; gastrointestinal indications); and other indications. In the CFLD cohort, there was increased use of nasogastric and gastrostomy nutritional supplementation Additionally, the CFLD cohort had a higher frequency of bone diseases, osteopenia  and osteoporosis, as well as CF-related diabetes.

The authors demonstrated patients with severe CFLD have greater disease burden, with significantly higher number of hospitalizations (both respiratory and non-respiratory indications), nutritional interventions, and are at higher risk of CF-related bone disease and diabetes.

Dr H Singh is in the Department of Gastroenterology, Sydney Children’s Hospital, Randwick.

Smyth RL. New drug treatments for cystic fibrosis. BMJ. 2020 Jan 20;368:m118. doi: 10.1136/bmj.m11 [Pubmed]

Rosiland Smyth

The present situation regarding the new CFTR modulators is neatly summarised by Prof. Ros Smyth in this BMJ article. As some readers may not have access to the full text, I have summarised some of the key points and added the key references –
Mutations that result in CFTR being expressed on the cell surface but incorrectly regulated, such as G551D, were the most straightforward targets. Ivacaftor, a potentiator, increases the time that the CFTR chloride channel remains open. In a phase III randomised placebo controlled trial, ivacaftor improved forced expiratory volume in one second (FEV1) by 11% as well as respiratory symptoms and weight gain without substantial adverse effects (Ramsey et al 2011). The trial recruited 161 patients and was completed in 19 months despite the small pool of just 2000 people worldwide with the G551D mutation. Ivacaftor was licensed in Europe in 2012.
Ivacaftor is effective for only 4-5% of patients with cystic fibrosis. Many more patients have the F508del mutation, which causes misfolding of CFTR protein so that it remains trapped in the cell’s endoplasmic reticulum. Any CFTR that does reach the cell surface is unable to activate normally. Although potentiators can enhance activation at the cell surface, dealing with the trapped protein requires agents that correct the misfolding (correctors).
In 2015, a trial of Orkambi, a drug combining the corrector lumacaftor with the potentiator ivacaftor, showed improvements in weight gain and respiratory exacerbations among patients who were homozygous for F508del, but the modest 3% increase in FEV1 relative to placebo was associated with transient dyspnoea and abnormal liver function (Wainwright et al, 2015)
Subsequent trials of a different corrector, tezacaftor, combined with ivacaftor showed similar improvements in FEV1 to Orkambi but with fewer side effects (Taylor-Cousar et al, 2017; Rowe SM et al, 2017)
In 2018, tezacaftor-ivacaftor (Symkevi) was licensed in the US and Europe for patients with F508del (either homozygous or F508del plus an allele with another mutation associated with residual CFTR function), representing around 50% of patients worldwide (Davies JC et al, 2018; Keating D et al, 2018).
Although 90% of people with cystic fibrosis have at least one copy of the F508del mutation, around 30% also have other minimal function mutations that are unresponsive to current CFTR modulators. This led to the development of next generation correctors and trials of “triple therapy” combining two correctors and a potentiator.
In 2019, phase III trials of elexacaftor-ivacaftor-tezacaftor in patients with F508del reported greater than 10% improvements in FEV1 compared with placebo and substantial reductions in respiratory exacerbations (Heijerman et al, 2019; Middleton et al, 2019).

– Ramsey BW, Davies  J, McElvaney  NG, et al., VX08-770-102 Study Group.  A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-72. doi:10.1056/NEJMoa1105185 [Pubmed]  –Wainwright CE, Elborn JS, Ramsey  BW, et al., TRAFFIC Study Group, TRANSPORT Study Group. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.     N Engl J Med2015;373:2231.doi:10.1056/NEJMoa1409547  [Pubmed]
– Taylor-Cousar  JL, Munck  A, McKone  EF, et al.  Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med2017;377:2013-23. doi:10.1056/NEJMoa1709846 [Pubmed]
– Rowe  SM, Daines  C, Ringshausen  FC, et al.  Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med2017;377:2024-35. doi:10.1056/NEJMoa1709847 [Pubmed]
– Davies JC, Moskowitz SM, Brown  C, et al., VX16-659-101 Study Group.  VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med2018; 379:1599-611. doi:10.1056/NEJMoa1807119 pmid [Pubmed
– Keating D, Marigowda  G, Burr  L, et al., VX16-445-001 Study Group.  VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med2018; 379:1612-20. doi:10.1056/NEJMoa1807120 pmidL [Pubmed]
– Heijerman HGM, McKone EF, Downey  DG, et al., VX17-445-103 Trial Group.  Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet2019; 394:1940-8. doi:10.1016/S0140-6736(19)32597-8 [Pubmed]
– Middleton PG, Mall  MA, Dřevínek  P, et al., VX17-445-102 Study Group.  Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381:1809-19. doi:10.1056/NEJMoa1908639     [Pubmed]

Ranjani Somayaji Yvonne C W Yau Elizabeth TullisJohn J LiPumaFelix RatjenValerie Waters.  Clinical Outcomes Associated with Burkholderia cepacia Complex Infection in Patients with Cystic FibrosisAnn Am Thorac Soc 2020 Jul 17.doi: 10.1513/AnnalsATS.202003-204OC.Online ahead of print  [Pubmed]

         Ranjani Somsyaji

Little is known in contemporary CF cohorts about the outcomes following new Burkholderia species infections.
Objectives: Evaluate the changing epidemiology and clinical outcomes associated with Burkholderia species infections in persons with cystic fibrosis.
Methods: A cohort study of children and adults with CF was conducted from 1997 – 2018 in Toronto, Canada. Patients were characterised as having no history of Burkholderia species infection and those who were culture-positive for Burkholderia spp. for the first time in this time frame, categorized by species (B. gladioli, B. cenocepacia, B. multivorans or other) and strain (B. cenocepacia ET-12). Cox models were used to estimate risk of death or transplantation. Mixed effects models were used to assess impact of Burkholderia species on odds of pulmonary exacerbations (PEx) and effect on lung function (FEV1% predicted).
Results: A total of 1196 patients were followed over 20 years; 88 patients (7.4%) had ≥ 1 culture positive for Burkholderia species. Patients with ET-12 infection had a median time to death of 1.95 years compared to 5.30-6.72 years for those with other Burkholderia infections. ET-12 infection was associated with a greater risk of death or transplantation compared to patients with no history of Burkholderia infection in a univariate model (HR 3.92, 95% CI 2.25 – 6.81) but was no longer significant after adjusting for confounders. PEx were more common in those with Burkholderia infections and remained significant in the ET-12 group after adjusting for confounders (OR 2.96 (1.17 – 7.53)). No differences were noted in baseline FEV1% or the rate of FEV1% decline between the groups with and without Burkholderia species infection.

Conclusion: With the exception of ET-12, acquisition of Burkholderia species infection did not appear to worsen clinical outcomes compared to those with no history of infection. Given this, prognosis, management and clinical trial inclusion protocols may need to be re-evaluated for persons with Burkholderia infection.

Dr Ranjani Somayaji is at the University of Calgary, Calgary, Alberta, Canada

Ranjani Somayaji Dave NicholsScott C Bell    Cystic fibrosis – Ten promising therapeutic approaches in the current era of care. Expert Opin Investig Drugs. 2020 Aug 3.doi: 10.1080/13543784.2020.1805733.Online ahead of print. [Pubmed]
 Introduction: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems. Research and innovations in novel therapeutic agents and health care delivery have resulted in dramatic improvements in quality of life and survival for people with CF. Despite this, significant disease burden persists for many and this is compounded by disparities in treatment access and care which globally necessitates further work to improve outcomes. Because of the advent of a numerous therapies which includes gene-targeted modulators in parallel with specialized care delivery models, innovative efforts continue.
Areas covered: In this review, the authors discuss the available data on investigational agents in clinical development and currently available treatments for CF. They also evaluate approaches to care delivery, consider treatment gaps and propose future directions for advancement.
Expert opinion: Since the discovery of the CF gene, CFTR modulators have provided a hallmark of success, even though it was thought not previously possible. This has led to reinvigorated efforts and innovations in treatment approaches and care delivery. Numerous challenges remain because of genetic and phenotypic heterogeneity, access issues, and therapeutic costs, but the collaborative approach between stakeholders for continued innovation fuels optimism.

Dr Ranjani Somayaji is Assistant Professor in the University of Calgary, Departments of Medicine | Microbiology, Immunology and Infectious Disease | Community Health Sciences. Institutional affiliations: Snyder Institute for Chronic Diseases | O’Brien Institute for Public Health

Virginia A StallingsAlyssa M TindallMaria R Mascarenhas Asim MaqboolJoan I Schall. Improved Residual Fat Malabsorption and Growth in Children With Cystic Fibrosis Treated With a Novel Oral Structured Lipid Supplement: A Randomized Controlled Trial. PLoS One    2020 May 8;15(5):e0232685.doi: 10.1371/journal.pone.0232685. eCollection 2020.[Pubmed]                                       

Virginia Stallings

In the primary analysis of a 12-month double-blind randomized active placebo-controlled trial, treatment of children with cystic fibrosis (CF) and pancreatic insufficiency (PI) with a readily absorbable structured lipid (Encala™, Envara Health, Wayne, PA) was safe, well-tolerated and improved dietary fat absorption (stool coefficient of fat absorption [CFA]), growth, and plasma fatty acids (FA).     [Full details in PubMed abstract above]                           Findings:  Subjects with CF, PI and more severe fat malabsorption experienced greater improvements in CFA, FA and growth after three months of Encala™ treatment. Encala™ was safe, well-tolerated and efficacious in patients with CF and PI with residual fat malabsorption and improved dietary energy absorption, weight gain and FA status in this at-risk grou

Dr Virginla Stallings is in the Division of Gastroenterology, Hepatology and Nutrition and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia.

Stapleton PJ, Izydorcyzk C, Clark S, Blanchard A, Wang PW, Yau Y, Waters V, Guttman DS.  Pseudomonas aeruginosa strain sharing in early infection among children with cystic fibrosis.   Clin Infect Dis. 2020 Jun 16:ciaa788. doi: 10.1093/cid/ciaa788. Online ahead of print.[Pubmed]

     Patrick Stapleton

The authors previously identified Pseudomonas aeruginosa isolates with characteristics typical of chronic infection in some early infections in children with Cystic Fibrosis (CF), suggesting these isolates may have been acquired from other patients. Their objective was to define the extent of P. aeruginosa strain sharing in early CF infections and its impact on antibiotic eradication treatment failure rates.                  They performed whole genome sequencing on isolates from early pediatric CF pulmonary infections and from comparator groups in the same hospital: chronic CF infection, sink drains, sterile site infections and asymptomatic carriage. Univariate logistic   regression was used to assess factors associated with treatment failure.
In this retrospective observational study, 1,029 isolates were sequenced. The CF clones Strain B and Clone C were present. In 70 CF patients with early infections, 14 shared strains infected 29 (41%) patients over five years; 16% (n=14) of infections had mixed-strains. In the 70 children, approximately one third of shared strain infections were likely due to patient-to-patient transmission. Mixed-strain infections were associated with strain sharing (odds ratio 8.50; 95% confidence interval 2.2 – 33.4, P = 0.002). Strain sharing was not associated with antibiotic eradication treatment failure; however, nosocomial strain transmission was associated with establishment of chronic infection in a CF sibling pair.

The authors concluded that although early P. aeruginosa CF infection is thought to reflect acquisition of diverse strains from community reservoirs, they identified frequent early CF strain sharing which was associated with the presence of mixed-strains and instances of possible patient-to-patient transmission.

Dr Patrick J Stapleton is Fellow in Microbiology in the Department of Laboratory Medicine and Pathobiology, University of Toronto,  Canada. Subsequently Consultant Microbiologist at the UL Hospitals in the midwest of Ireland.

Stockwell REWood MEBallard EMoore VWainwright CEBell SC Current infection control practices used in Australian and New Zealand cystic fibrosis centers. BMC Pulm Med.  2020 Jan 17;20(1):16. doi: 10.1186/s12890-020-1052-y. [Pubmed] 
The 2013 update of the Infection Prevention and Control (IP&C) Guideline outlined recommendations to prevent the spread of CF respiratory pathogens. The authors aimed to investigate the current infection control practices used in Australian and New Zealand (NZ) CF centers.
Two online surveys were distributed to Australian and NZ CF centers regarding the uptake of selected IP&C recommendations. One survey was distributed to all the Medical Directors and Lead CF Nurses and the second survey was distributed to all the Lead CF Physiotherapists.
The response rate was 60% (60/100) for medical/nursing and 58% (14/24) for physiotherapy. Over 90% (55/60) of CF centers followed CF-specific infection control guidelines and consistent infection control practices were seen in most CF centers; 76% (41/54) had implemented segregation strategies for ambulatory care and no CF centers housed people with CF in shared inpatient accommodation. However, the application of contact precautions (wearing gloves and apron/gown) by healthcare professionals when reviewing a CF person was variable between CF center respondents but was most often used when seeing CF persons with MRSA infection in both ambulatory care and hospital admission (20/50, 40% and 42/45, 93% of CF centers, respectively). Mask wearing by people with CF was implemented into 61% (36/59) of centers. Hospital rooms were cleaned daily in 79% (37/47) of CF centers and the ambulatory care consult rooms were always cleaned between consults (49/49, 100%) and at the end of the clinic session (51/51, 100%); however the staff member tasked with cleaning changed with 37% (18/49) of CF centers responding that CF multidisciplinary team (MDT) members cleaned between patients whereas at the end of the clinic session, only 12% (6/51) of the CF MDT cleaned the consult room.

Overall, Australian and NZ CF centers have adopted many recommendations from the IP&C. Although, the application of contact precautions was inconsistent and had overall a low level of adoption in CF centers. In ~ 25% of centers, mixed waiting areas occurred in the ambulatory care. Given the variability of responses, additional work is required to achieve greater consistency between centers.

-These results are really surprising in view of the experience of serious cross infection with P. aeruginosa even with some fstalities, reported from this region

Dr Rebecca E Stockwell is with the Lung Bacteria Group, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.

Tang YYan ZEngelhardt JF.  Viral Vectors, Animal Models, and Cellular Targets for Gene Therapy of Cystic Fibrosis Lung Disease.  Hum Gene Ther. 2020 Mar 5. doi: 10.1089/hum.2020.013. [Epub ahead of print]  [Pubmed]

Yinghua (Edward) Tang

After more than two decades since clinical trials tested the first use of recombinant adeno-associated virus (rAAV) to treat cystic fibrosis (CF) lung disease, gene therapy for this disorder has undergone a tremendous resurgence. Fueling this enthusiasm has been an enhanced understanding of rAAV transduction biology and cellular processes that limit transduction of airway epithelia, the development of new rAAV serotypes and other vector systems with high level tropism for airway epithelial cells, an improved understanding of CF lung pathogenesis and the cellular targets for gene therapy, and the development of new animal models that reproduce the human CF disease phenotype. These advances have created a preclinical path for both assessing the efficacy of gene therapies in the CF lung and interrogating the target cell types in the lung required for complementation of the CF disease state. Lessons learned from early gene therapy attempts with rAAV in the CF lung have guided thinking for the testing of next generation vector systems. Although unknown questions still remain regarding the cellular targets in the lung that are required or sufficient to complement CF lung disease, the field is now well positioned to tackle these challenges. This review will highlight the role next-generation CF animal models are playing in the preclinical development of gene therapies for CF lung disease and the knowledge gaps in disease pathophysiology these models are attempting to fill.

Dr Yinghua (Edward) Tang is at the University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, United States.

Taylor-Cousar JLEvans TACutting GRSharma N. Potentially lethal cystic fibrosis gene variant in the orangutan. Am J Primatol. 2020 Jan 22:e23097. doi: 10.1002/ajp.23097. [Epub ahead of print   [Pubmed]

Jennifer Taylor-Cousar

A syndrome of chronic upper and lower airway disease leading to increased morbidity and mortality occurs primarily in captive orangutans. Similarities in symptoms to the inherited human respiratory disease, cystic fibrosis, led the authors to hypothesize that orangutan respiratory disease is a result of variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. They identified the nonsense variant, c.484A>T (p.Lys162X), in heterozygosity in an unaffected orangutan. Analysis of the pedigree of this orangutan confirmed that both his sire and deceased fetus also harboured the c.484A>T allele. An expression minigene harbouring c.484A>T produced no full-length CFTR protein in HEK293 cells. Finally, the c.484A>T CFTR messenger RNA abundance was severely reduced in primary nasal epithelial cells of the orangutan indicating that c.484A>T (p.Lys162X) is potentially lethal. Genetic screening of the captive orangutan population could be used to prevent transmission of this potentially lethal variant, and thus aid in the conservation of this critically endangered species

Taylor SLLeong LEXIvey KLWesselingh SGrimwood KWainwright CERogers GBAustralasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group. Total bacterial load, inflammation, and structural lung disease in paediatric cystic fibrosis.  J Cyst Fibros. 2020 Mar 18. pii: S1569-1993(20)30079-5. doi: 10.1016/j.jcf.2020.03.008. [Epub ahead of print] [Pubmed]
Cystic fibrosis (CF) is characterised by reduced airway clearance, microbial accumulation, inflammation, and lung function decline. Certain bacterial species may contribute disproportionately to worsening lung disease. However, the relative importance of these microorganisms compared to the absolute abundance of all bacteria is uncertain. The authors aimed to identify the characteristics of lower airway microbiology that best reflect CF airway inflammation and disease in children.

Analysis was performed on bronchoalveolar lavage (BAL) fluid from 78 participants of the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial, aged 4.5-5.5 years. Universal bacterial quantitative PCR (qPCR), species-specific qPCR, and 16S rRNA gene sequencing were performed on DNA extracts to determine total bacterial load, species-specific load and taxa relative abundance. Quantification of pre-specified pathogens was performed by culture-based methods. Bacteriological data were related to neutrophil counts, interleukin-8, lung function, and two computed-tomography based measures, CF-CT (as the primary measure) and PRAGMA.
Of all bacteriological measures assessed, total bacterial load determined by qPCR correlated most strongly with structural disease (CF-CT total score, rs=0.30, P=0.0095). Specifically, total bacterial load correlated with bronchiectasis, airway wall thickening, mucus plugging and parenchymal disease sub-scores. In contrast, culture-based quantification, microbiota-derived measures, and pathogen-specific qPCR-based quantification were weakly associated with total CF-CT. Regression analyses supported correlation findings, with total bacterial load explaining the greatest variance in total CF-CT (R2=0.097, P=0.0061). Correlations with PRAGMA score were comparable to CF-CT total score.

the authors concluded within the ACFBAL trial, culture-independent quantification of total bacteria provided the most clinically informative bacteriological measure in 5-year-old CF patients.

Steven Taylor is at the SAHMRI Microbiome Research Laboratory, Flinders University College of Medicine and Public Health, Adelaide, SA, Australia; Microbiome and Host Health, South Australia Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia

Tétard C, Mittaine M, Bui S, Beaufils F, Maumus P, Fayon M, Burgel PR, Lamireau T, Delhaes L, Mas E, Enaud R. Reduced Intestinal Inflammation with Lumacaftor/Ivacaftor in Adolescents with Cystic Fibrosis.  J Pediatr Gastroenterol Nutr. 2020 Jul 30. doi: 10.1097/MPG.0000000000002864. Online ahead of print. [Pubmed]
A chronic intestinal inflammation may occur in patients with cystic fibrosis (CF), while no therapeutic management is proposed. While Lumacaftor/Ivacaftor is well-known to modulate the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in lungs, no data are available on the impact of this treatment on CF intestinal disorders. The authors therefore investigated the evolution of intestinal inflammation after initiation of Lumacaftor/Ivacaftor in CF adolescents (median of follow-up: 336 days (IQR: 278;435)). Median fecal calprotectin concentrations decreased significantly after Lumacaftor/Ivacaftor initiation (102 μg/g (IQR: 69;210)) compared to the baseline (713 μg/g (IQR:148;852), p = 0.001).

To their knowledge, this study showed for the first time that CF-related intestinal inflammation is improved by Lumacaftor/Ivacaftor treatment.

From Centre Hospitalier Universitaire de Bordeaux, CHU Bordeaux, CRCM Pédiatrique, Bordeaux, France.

Koliarne TongDaniel BarkerMegan FranceLucy BurrHugh GrevilleSimone VisserPeter MiddletonClaire WainwrightDouglas DorahyPeter Wark.  Lumacaftor/ivacaftor reduces exacerbations in adults homozygous for Phe508del mutation with severe lung disease.  J Cyst Fibros   2020 May;19(3):415-420.doi: 10.1016/j.jcf.2019.12.006. Epub 2019 Dec 15.[Pubmed]

Peter Wark

       Koliarne Tong

Background: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 < 40 would reduce the rate of pulmonary exacerbations.
Methods: This was a case control study performed on patients > 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events.
Results: Data was collected from 7 Australian CF centres on 105 patients; 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI; 0.306 – 0.676), p < 0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common; chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%.
Conclusions: Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent and resulted in a very high discontinuation rate.

Dr Koliarne Tong is Staff Specialist in Respiratory and Sleep at the Adult Cystic Fibrosis Centre, John Hunter Hospital, Australia.

Professor Peter Wark, the corresponding author, a senior staff specialist in Respiratory and Sleep Medicine at John Hunter Hospital, Newcastle and a conjoint Professor with the University of Newcastle

Turkovic LCaudri DRosenow TBreurer OMurray CTiddens HAWMRamanauskas FRanganathan SCHall GLStick SMAREST CF. Structural determinants of long term functional outcomes in young children with cystic fibrosis.  Eur Respir J. 2020 Mar 5. pii: 1900748. doi: 10.1183/13993003.00748-2019. [Epub ahead of print] [Pubmed]          

Lidijat Turkovic

Accelerated lung function decline in individuals with cystic fibrosis (CF) starts in adolescence with respiratory complications being the most common cause of death in later life. Factors contributing to lung function decline are not well understood, in particular its relationship with structural lung disease in early childhood. Detection and management of structural lung disease could be an important step in improving outcomes in CF patients.
Annual chest computed tomography (CT) scans were available from 2005 to 2016 as a part of AREST CF cohort for children aged 3-months to 6-years. Annual spirometry measurements were available for 89.77% of the cohort (n=167 children at age 5-6 years) from ages 5 to 15 years through outpatient clinics at Perth Children’s Hospital and The Royal Children’s Hospital in Melbourne. (n=697 measurements, age 9.3 (2.1) years).
Findings:  Children with a total CT score at 5-6 years above the median were more likely to have abnormal FEV1 (aHR 2.67 (1.06, 6.72) p=0.037) during the next 10 years compared to those below the median chest CT score. The extent of all structural abnormalities except bronchial wall thickening were associated with lower FEV1 Z scores. Mucus plugging and trapped air were the most predictive sub-score (adjusted mean change -0.17 (-0.26, -0.07) p<0.001 and -0.09 (-0.14, -0.04) p<0.001 respectively).

The authors observe that this study shows that chest CT identifies children at an early age who have adverse long-term outcomes. The prevention of structural lung damage should be a goal of early intervention and can be usefully assessed with chest CT. In an era of therapeutics that might alter disease trajectories, chest CT could provide an early readout of likely long-term success.

Dr Lidijat Turkovic was at Telethon Kids Institute, Perth, Australia and now Principal Biostatistician, IQVIA Human Data Science Company, Melbourne, Australia

– This excellent long-term data from AREST CF study provides further hard evidence that what happens in very early childhood determines the situation many years later.  Once damage occurs progress is downhill even though considerably slowed by treatment during childhood.

van Heusden CButton BAnderson WHCeppe AMorton LCO’Neal WKDang HAlexis NEDonaldson SStephan HBoucher RCLazarowski ER.  Inhibition of ATP hydrolysis restores airway surface liquid production in cystic fibrosis airway epithelia.
Am J Physiol Lung Cell Mol Physiol.
 2020 Feb 1;318(2):L356-L365. doi: 10.1152/ajplung.00449.2019. Epub 2019 Dec 4[Pubmed]
Airway surface dehydration is a pathological feature of cystic fibrosis (CF) lung disease. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated Cl channel controlled in part by the adenosine A2B receptor. An alternative CFTR-independent mechanism of fluid secretion is regulated by ATP via the P2Y2 receptor (P2Y2R) that activates Ca2+-regulated Cl channels (CaCC/TMEM16) and inhibits Na+ absorption. However, due to rapid ATP hydrolysis, steady-state ATP levels in CF airway surface liquid (ASL) are inadequate to maintain P2Y2R-mediated fluid secretion. Therefore, inhibiting airway epithelial ecto-ATPases to increase ASL ATP levels constitutes a strategy to restore airway surface hydration in CF.
Using [γ32P]ATP as radiotracer, we assessed the effect of a series of ATPase inhibitory compounds on the stability of physiologically occurring ATP concentrations. We identified the polyoxometalate [Co4(H2O)2(PW9O34)2]10- (POM-5) as the most potent and effective ecto-ATPase inhibitor in CF airway epithelial cells. POM-5 caused long-lasting inhibition of ATP hydrolysis in airway epithelia, which was reversible upon removal of the inhibitor. Importantly, POM-5 markedly enhanced steady-state levels of released ATP, promoting increased ASL volume in CF cell surfaces.
These results provide proof of concept for ecto-ATPase inhibitors as therapeutic agents to restore hydration of CF airway surfaces. As a test of this notion, cell-free sputum supernatants from CF subjects were studied and found to have abnormally elevated ATPase activity, which was markedly inhibited by POM-5.

Dr C van Heusden of the Marsico Lung Institute/UNC CF Research Center, University of North Carolina, Chapel Hill, North Carolina.

Silke van Koningsbruggen-RietschelKatja ConrathRainald Fischer Sivagurunathan SutharsanAxel KempaWolfgang GleiberCarsten SchwarzAndreas HectorNancy Van OsselaerArian PanoSam CorveleynDieudonné BwirireEva SantermansKarine MullerSusan BellaireOlivier Van de Steen . GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN). J Cyst Fibros. 2020 Mar;19(2):292-298. doi: 10.1016/j.jcf.2019.09.006. Epub 2019 Oct 5.[Pubmed]

Silke van Koningsbruggen

Background: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy.
Methods: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics.
Results: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected.
Conclusions: GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination.

Dr Silke van Koningsbruggen-Rietschel is a Pediatric Pulmonologist and Director of the CF Clinical Research Center at the Cystic Fibrosis Center, Children’s Hospital, University of Cologne, Faculty of Medicine and University Hospital Cologne, Germany.

Guido Veit Dillon F Da FonteRadu G AvramescuAiswarya PremchandarMiklos BagdanyHaijin XuDennis BensingerDaniel StubbaBoris SchmidtElias MatoukGergely L Lukacs.  Mutation-specific dual potentiators maximize rescue of CFTR gating mutants. J Cyst Fibros   2020 Mar;19(2):236-244.doi: 10.1016/j.jcf.2019.10.011. Epub 2019 Oct 31. [Pubmed]

     Guido Veit

The potentiator ivacaftor (VX-770) has been approved for therapy of 38 cystic fibrosis (CF) mutations (∼10% of the patient population) associated with a gating defect of the CF transmembrane conductance regulator (CFTR). Despite the success of VX-770 treatment of patients carrying at least one allele of the most common gating mutation G551D-CFTR, some lung function decline and P. aeruginosa colonization persist. This study aims at identifying potentiator combinations that can considerably enhance the limited channel activity of a panel of CFTR gating mutants over monotherapy.
The functional response of 13 CFTR mutants to single potentiators or systematic potentiator combinations was determined in the human bronchial epithelial cell line CFBE41o- and a subset of them was confirmed in primary human nasal epithelia (HNE).
Results: In six out of thirteen CFTR missense mutants the fractional plasma membrane (PM) activity, a surrogate measure of CFTR channel gating, reached only ∼10-50% of WT channel activity upon VX-770 treatment, indicating incomplete gating correction. Combinatorial potentiator profiling and cluster analysis of mutant responses to 24 diverse investigational potentiators identified several compound pairs that improved the gating activity of R352Q-, S549R-, S549N-, G551D-, and G1244E-CFTR to ∼70-120% of the WT. Similarly, the potentiator combinations were able to confer WT-like function to G551D-CFTR in patient-derived human nasal epithelia.
Conclusion: This study suggests that half of CF patients with missense mutations approved for VX-770 administration, could benefit from the development of dual potentiator therapy.

Christian VoldbyKent GreenThomas KongstadAstrid Madsen RingRikke Mulvad SandvikMarianne SkovFrederik BuchvaldTacjana PresslerKim Gjerum Nielsen.   Lung clearance index-triggered intervention in children with cystic fibrosis – A randomised pilot study. J Cyst Fibros    2020 Jun 20;S1569-1993(20)30755-4. doi: 10.1016/j.jcf.2020.06.010.Online ahead of print. [Pubmed]

      Kim Gjerum Nielsen

Using increase in the lung clearance index (LCI) as a trigger for bronchoalveolar lavage (BAL) and associated antimicrobial treatment might benefit clinical outcomes in children with cystic fibrosis (CF).
Methods: A 2-year, longitudinal, interventional, randomized, controlled pilot study with quarterly visits in 5-18 years old children with CF. LCI and z-scores for the forced expired volume in 1 s (zFEV1) and body mass index (zBMI) were obtained at every visit, CF Questionnaire-revised (CFQ-R) yearly and BAL and chest computed tomography at first and last visit. Children in the intervention group had BAL performed if LCI increased >1 unit from a fixed baseline value established at first visit. If the      presence of a pathogen was documented in the BAL fluid, treatment was initiated/altered accordingly.
Results: Twenty-nine children with CF were randomized to the control (n = 14) and intervention group (n = 15). The median (interquartile range) number of BAL procedures per child was 2.5 (2.0; 3.0) and 6.0 (4.0; 7.0) in the control and intervention group, respectively. There was no significant difference between groups in slope for the primary outcome LCI; difference was 0.21 (95% confidence interval: -0.45; 0.88) units/year. Likewise, there was no significant difference between groups in slope for the secondary outcomes zFEV1, zBMI, CFQ-R respiratory symptom score and the proportion of total disease and trapped air on chest computed tomography.
Conclusions: LCI-triggered BAL and associated antimicrobial treatment did not benefit clinical outcomes in a small cohort of closely monitored school-age children with CF.

Dr Christian Voldby is at the CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Professor Kim G Nielsen at the  CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet Copenhagen, Denmark.

Wang Y, Zhao J, Cai Y, Ballard HJ. Cystic Fibrosis Transmembrane Conductance Regulator-dependent bicarbonate entry controls rat cardiomyocyte ATP release via pannexin1 through mitochondrial signalling and caspase activation. Acta Physiol (Oxf). 2020 May 9. doi: 10.1111/apha.13495. Epub ahead of print. [Pubmed]
Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in the heart, but its function there is unclear. CFTR regulates an ATP release pore in many tissues, but the identity and regulatory mechanism of the pore are unknown. The authors investigated the role of CFTR in ATP release from primary cardiomyocytes and ventricular wall in vivo.
They found that during simulated ischaemia, CFTR-dependent bicarbonate entry stimulated ATP and cytochrome c release from mitochondria; in the cytoplasm, cytochrome c activated caspase 3, which in turn activated Panx1, and ATP was released through the opened Panx1 channel.

Dr Y Wang is at the School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.

Waterer GLord JHofmann TJouhikainen T.  A Phase I, dose-escalating study of safety and pharmacokinetics of inhaled dry powder vancomycin (AeroVanc) in volunteers and patients with cystic fibrosis: a new approach to therapy for methicillin-resistant Staphylococcus aureus.
Antimicrob Agents Chemother.
 2020 Jan 21. pii: AAC.01776-19. doi: 10.1128/AAC.01776-19. [Epub ahead of print]  [Pubmed]

Grant Waterer

Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administration of vancomycin would overcome these limitations, the authors developed a dry powder formulation suitable for inhalation (AeroVanc).

They report a Phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability of AeroVanc. In conclusion, AeroVanc was well tolerated and achieved high levels in sputum with a mean systemic absorption of 49%, making it a potential therapeutic strategy for respiratory infection with MRSA.

Dr Grant Waterer is Professor of Medicine, University of Western Australia is a respiratory physician at Royal Perth Hospital and is a professor of medicine at the University of Western Australia and professor of medicine at Northwestern University, Chicago, USA.

Weber AG, Chau AS, Egeblad M, Barnes BJ, Janowitz T.  Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: A case series.  medRxiv. 2020 May 15:2020.05.13.20087734. doi: 10.1101/2020.05.13.20087734. Preprint. Free PMC article.[Pubmed]

Andrew Weber

Following nebulized in-line administration of dornase alfa with albuterol, the fraction of inspired oxygen requirements was reduced for all five patients. All patients remain alive and two patients have been discharged from the intensive care unit. No drug associated toxicities were identified.
The results presented in this case series suggest that dornase alfa will be well-tolerated by critically ill patients with COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and two have recently been registered ( NCT04359654 and NCT04355364 ). With this case series, we hope to contribute to the development of management approaches for critically ill patients with COVID-19.

Dr Andrew G Weber of the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Northwell Health, NY.

Wijker NEVidmar SGrimwood KSly PDByrnes CACarlin JBCooper PJRobertson CFMassie RJKemner van de Corput MPCCheney JTiddens HAWMWainwright CEAustralasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) and Follow-up of the ACFBAL (CF-FAB) study groups.Early markers of cystic fibrosis structural lung disease: follow-up of the ACFBAL cohort. Eur Respir J. 2020 Apr 3;55(4). pii: 1901694. doi: 10.1183/13993003.01694-2019. Print 2020 Apr. [Pubmed]

 Suzanna Vidmar

Naomi Wijker

Little is known about early predictors of later cystic fibrosis (CF) structural lung disease. This study examined early predictors of progressive structural lung abnormalities in children who completed the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial at age 5-years and participated in an observational follow-up study (CF-FAB).  Eight Australian and New Zealand CF centres participated in CF-FAB and provided follow-up chest computed-tomography (CT) scans for children who had completed the ACFBAL study with baseline scans at age 5-years. CT scans were annotated using PRAGMA-CF scoring. Ordinal regression analysis and linear regression were used to investigate associations between PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) outcomes at follow-up and variables measured during the ACFBAL study.

99 out of 157 ACFBAL children (mean±sd age 13±1.5 years) participated in the CF-FAB study. The probability of bronchiectasis at follow-up increased with airway disease severity on the baseline CT scan. In multiple regression (retaining factors at p<0.05) the extent of bronchiectasis at follow-up was associated with baseline atelectasis (OR 7.2, 95% CI 2.4-22; p≤ 0.001), bronchoalveolar lavage (BAL) log2 interleukin (IL)-8 (OR 1.2, 95% CI 1.05-1.5; p=0.010) and body mass index z-score (OR 0.49, 95% CI 0.24-1.00; p=0.05) at age 5 years. Percentage trapped air at follow-up was associated with BAL log2 IL-8 (coefficient 1.3, 95% CI 0.57-2.1; p<0.001) at age 5 years.

The study established that the extent of airway disease, atelectasis, airway inflammation and poor nutritional status in early childhood are risk factors for progressive structural lung disease in adolescence.

Dr Naomi E Wijker of the Departments of Pulmonology and Allergology, Erasmus Medical Center Sophia Children’s Hospital, Rotterdam, The Netherlands  & Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Dr Suzanna Vidmar is Senior Research Officer in the Clinical Epidemiology and Biostatistics Unit, Murdoch Children’s Research Institute, Melbourne, Australia & the Dept of Paediatrics, University of Melbourne, Melbourne, Australia.

Jennifer YanAjay KevatElena MartinezNicky TeeseKareena JohnsonSarath RanganathanJo HarrisonJohn MassieAndrew Daley. Investigating transmission of Mycobacterium abscessus amongst children in an Australian cystic fibrosis centre. J Cyst Fibros  2020 Mar;19(2):219-224. doi: 10.1016/j.jcf.2019.02.011. Epub 2019 Mar 8. [Pubmed]

     Jennifer Yan

Mycobacterium abscessus is an emerging pathogen in cystic fibrosis (CF) lung disease. Hospital transmission of M. abscessus has been described. This paper details the investigation into possible cross-transmission of M. abscessus locally at our paediatric hospital CF centre, and the subsequent infection control response. Whole genome sequencing (WGS) of M. abscessus respiratory isolates with epidemiological linkage analysis using hospital electronic medical records was carried out.
Results: 6.7% (22/328) of CF patients had M. abscessus isolated from respiratory specimens. WGS revealed a cluster of three patients with genomically related isolates that differed by <7 single nucleotide polymorphisms (SNPs), suggesting a shared recent ancestor and probable cross-transmission. Epidemiological investigation revealed multiple potential crossovers between patients with genomically similar M. abscessus isolates.

The authors concluded cross-infection of NTM occurs in CF hospital patients. Hospital infection control practices should be upgraded to reflect this. Consensus is needed between centres.

Dr Jennifer Yan is in the Department of Microbiology & Department of Infection Prevention and Control, Royal Children’s Hospital, Victoria, Australia.

Yeung JCMachuca TNChaparro CCypel MStephenson ALSolomon MSaito TBinnie MChow CWGrasemann HPierre AFYasufuku Kde Perrot MDonahoe LLTikkanen JMartinu TWaddell TKTullis ESinger LGKeshavjee S.  Lung transplantation for cystic fibrosis.
J Heart Lung Transplant.
 2020 Feb 20. pii: S1053-2498(20)31404-2. doi: 10.1016/j.healun.2020.02.010. [Epub ahead of print] [Pubmed]

Jonathan Yeung

The contribution of lung transplantation to the treatment of patients with end-stage cystic fibrosis (CF) has been debated. The authors  aimed to describe achievable outcomes from high-volume CF and lung transplant programs. This study reports on the largest single-center experience of lung transplantation for adult and pediatric patients with CF. It also highlights the evolution of practice and outcomes over time.  A retrospective analysis of the prospectively collected Toronto Lung Transplant database was carried out. Post-transplant survival in CF was calculated using the Kaplan-Meier method and analyzed with log-rank tests.
From 1983 to 2016, a total of 1,885 transplants were performed at our institution, where 364 (19.3%) were CF recipients and another 39 (2.1%) were CF re-transplants. The mean age at first transplant was 29.5 ± 9.7 years where 56.6% were males and 91.5% were adults. Pre-transplantation, 88 patients (24.2%) were Burkholderia cepacia complex (BCC)-positive, 143 (39.3%) had diabetes mellitus, and the mean forced expiratory volume in one second was 26.0 ± 7.2%, as predicted at listing. The 1-, 5-, and 10-year probabilities of survival in adults who were BCC-negative were 94%, 70%, and 53%, respectively. Pediatric, BCC-positive, and re-transplant recipients had worse survival than adult patients who were BCC-negative. Strategies to improve the donor pool did not affect survival but possibly reduced waitlist mortality. For the entire cohort, the most common causes of death after lung transplant were infection and chronic lung allograft dysfunction.

The authors consider lung transplantation for CF provides excellent short- and long-term outcomes. These results strongly support lung transplantation as the standard of care for patients with CF having advanced lung disease.

Dr Jonathan Yeung, Thoracic surgeon and members of the Toronto Lung Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada; Division of Thoracic Surgery, Toronto General Hospital, Toronto, Ontario, Canada.

Zhang DLi SWang NTan HYZhang ZFeng Y. The Cross-Talk Between Gut Microbiota and Lungs in Common Lung Diseases. 
Front Microbiol.
 2020 Feb 25;11:301. doi: 10.3389/fmicb.2020.00301. eCollection  2020. Free PMC Article [Pubmed]
Emerging findings indicate there is a vital cross-talk between gut microbiota and the lungs, which is known as gut-lung axis. The gut disturbances in lung diseases including allergy, asthma, chronic obstructive pulmonary disease, cystic fibrosis and lung cancer were observed by extensive studies. Investigating how gut microbiota impact other distant organs is of great interest in recent years. Although it has not been fully understood whether the disturbance is the cause or effect of lung diseases, alterations in the gut microbial species and metabolites have been linked to changes in immune responses and inflammation as well as the disease development in the lungs. In this article, we systemically review the role and mechanisms underlying the changes in the constituent of gut microbiota and metabolites in lung diseases. In particular, the roles of gut-lung axis in mediating immune responses and reshaping inflammation are highlighted. Furthermore, we discuss the potential of strategies to manipulate the gut microbiota and metabolites as the therapeutic approach for lung diseases.

D Zhang  is at the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Zofia N Zysman-ColmanMarissa J KilbergVictor S HarrisonAlessandra ChesiStruan F A Grant Jonathan MitchellSaba SheikhDenis HadjiliadisMichael R RickelsRonald C RubensteinAndrea KellyGenetic Potential and Height Velocity During Childhood and Adolescence Do Not Fully Account for Shorter Stature in Cystic Fibrosis. Pediatr Res 2020 May 9.doi: 10.1038/s41390-020-0940-4. Online ahead of print.  32386398   Pubmed]

Zofia N Zysman-Colman

Despite improved health, shorter stature is common in cystic fibrosis (CF). The authors aimed to describe height velocity (HV) and contribution of height-related genetic variants to height (HT) in CF.  Methods: HV cohort: standard deviation scores (-Z) for HT, mid-parental height-adjusted HT (MPAH), and HV were generated using our Pediatric Center’s CF Foundation registry data. HV-Z was compared with population means at each age (5-17 y), the relationship of HV-Z with HT-Z assessed, and HT-Z compared with MPAH-Z. GRS cohort: HT genetic risk-Z (HT-GRS-Z) were determined for pancreatic exocrine sufficient (PS) and insufficient (PI) youth and adults from our CF center and their relationships with HT-Z assessed.
Results: HV cohort: average HV-Z was normal across ages in our cohort but was 1.5× lower (p < 0.01) for each SD decrease in HT-Z. MPAH-Z was lower than HT-Z (p < 0.001). GRS cohort: HT-GRS-Z more strongly correlated with HT-Z and better explained height variance in PS (rho = 0.42; R2= 0.25) vs. PI (rho = 0.27; R2 = 0.11).
Conclusions: Despite shorter stature compared with peers and mid-parental height, youth with CF generally have normal linear growth in mid- and late childhood. PI tempered the heritability of height. These results suggest that, in CF, final height is determined early in life in CF and genetic potential is attenuated by other factors.

The authors comment this manuscript is a clinical study: Children with CF remain shorter than their healthy peers despite advances in care.  Our study demonstrates that children with CF have persistent shorter stature from an early age and fail to reach their genetic potential despite height velocities comparable to those of average maturing healthy peers and similar enrichment in known height increasing single-nucleotide polymorphisms (SNPs).  Genetic risk scores better explained variability in pancreatic sufficient than in pancreatic insufficient individuals, suggesting that other modifying factors are in play for pancreatic insufficient individuals with CF. Given the CF Foundation’s recommendation to target not only normal body mass index, but normal height percentiles as well, this study adds valuable insight to this discussion.

Zofia N Zysman-Colman is in the Division of Pulmonary Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.

Section 2