Thorax. 2021 May 11:thoraxjnl-2021-216849. doi: 10.1136/thoraxjnl-2021-216849. Online ahead of print.

ABSTRACT

RATIONALE: A previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results.

OBJECTIVES: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences.

METHODS: We used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics).

RESULTS: We included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK.

CONCLUSIONS: Children with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.

PMID:33975926 | DOI:10.1136/thoraxjnl-2021-216849

Eur J Pharmacol. 2021 May 8:174123. doi: 10.1016/j.ejphar.2021.174123. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a recessive inherited disease caused by mutations affecting anion transport by the epithelial ion channel cystic fibrosis transmembrane conductance regulator (CFTR). The disease is characterized by mucus accumulation in the airways and intestine, but the major cause of mortality in CF is airway mucus accumulation, leading to bacterial colonization, inflammation and respiratory failure. Several drug targets are under evaluation to alleviate airway mucus obstruction in CF and one of these targets is the epithelial sodium channel ENaC. To explore effects of ENaC inhibitors on mucus properties, we used two model systems to investigate mucus characteristics, mucus attachment in mouse ileum and mucus bundle transport in piglet airways. We quantified mucus attachment in explants from CFTR null (CF) mice and tracheobronchial explants from newborn CFTR null (CF) piglets to evaluate effects of ENaC or sodium/hydrogen exchanger (NHE) inhibitors on mucus attachment. ENaC inhibitors detached mucus in the CF mouse ileum, although the ileum lacks ENaC expression. This effect was mimicked by two NHE inhibitors. Airway mucus bundles were immobile in untreated newborn CF piglets but were detached by the therapeutic drug candidate AZD5634 (patent WO 2015140527). These results suggest that the ENaC inhibitor AZD5634 causes detachment of CF mucus in the ileum and airway via NHE inhibition and that drug design should focus on NHE instead of ENaC inhibition.

PMID:33974881 | DOI:10.1016/j.ejphar.2021.174123

Pediatr Pulmonol. 2021 May 11. doi: 10.1002/ppul.25462. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a chronic multisystem disease with manifestations from birth. It involves the entire respiratory system, with increased cough, and recurrent pulmonary infections, and it also leads to intestinal malabsorption, all of which can have an impact on sleep. In this review, we summarize the available literature on the various sleep disturbances in children with CF. Sleep quality and sleep efficiency are often impaired in children with CF. They may be accompanied by symptoms associated with sleep-disordered breathing (SDB), and objective findings such as nocturnal hypoxemia. Importantly, a strong association has been shown between SDB and the severity of lung disease, and some studies have reported a similar association for sleep quality. Further research is needed to better characterize the association of sleep disturbances with respiratory outcomes and the impact of treatment of sleep disorders on pulmonary status in children with CF. This article is protected by copyright. All rights reserved.

PMID:33974362 | DOI:10.1002/ppul.25462

Adv Exp Med Biol. 2021;1318:109-118. doi: 10.1007/978-3-030-63761-3_7.

ABSTRACT

The outbreak of the COVID-19 pandemic shows a marked geographical variation in its prevalence and mortality. The question arises if the host genetic variation may (partly) affect the prevalence and mortality of COVID-19. We postulated that the geographical variation of human polymorphisms might partly explain the variable prevalence of the infection. We investigated some candidate genes that have the potential to play a role in the immune defense against COVID-19: complement component 3 (C3), galactoside 2-alpha-L-fucosyltransferase 2 (FUT2), haptoglobin (Hp), vitamin D binding protein (DBP), human homeostatic iron regulator protein (HFE), cystic fibrosis transmembrane conductance regulator (CFTR), and angiotensin-converting enzyme 1 (ACE1). In a univariate approach, ACE1 D/I, C3, CFTR, and HFE polymorphisms correlated significantly with COVID-19 prevalence/mortality, whereas Hp and FUT2 polymorphism did not show any significant correlations. In a multivariate analysis, only ACE1 D/I and C3 polymorphisms were determinants for COVID-19 prevalence/mortality. The other polymorphisms (CFTR, DBP, FUT2, HFE, and Hp) did not correlate with COVID-19 prevalence/mortality. Whereas ACE1 D/I polymorphism shows functional links with ACE2 (which is the receptor for the virus) in COVID-19, C3 can act as a critical step in the virus-induced inflammation. Our findings plead against a bystander role of the polymorphisms as a marker for historical migrations, which comigrate with causal genes involved in COVID-19 infection. Further studies are required to assess the clinical outcome of COVID-19 in C3S and ACE1 D allele carriers and to study the role of C3 and ACE1 D/I polymorphisms in COVID-19 and their potential effects on treatment response.

PMID:33973175 | DOI:10.1007/978-3-030-63761-3_7

Thorax. 2021 May 10:thoraxjnl-2021-217095. doi: 10.1136/thoraxjnl-2021-217095. Online ahead of print.

NO ABSTRACT

PMID:33972453 | DOI:10.1136/thoraxjnl-2021-217095

Redox Biol. 2021 Apr 30;43:101998. doi: 10.1016/j.redox.2021.101998. Online ahead of print.

ABSTRACT

Lipopolysaccharide (LPS) serves as the interface between gram-negative bacteria (GNB) and the innate immune response in respiratory epithelial cells (REC). Herein, we describe a novel biological role of LPS that permits GNB to persist in the respiratory tract through inducing CFTR and mucociliary dysfunction. LPS reduced cystic fibrosis transmembrane conductance regulater (CFTR)-mediated short-circuit current in mammalian REC in Ussing chambers and nearly abrogated CFTR single channel activity (defined as forskolin-activated Cl- currents) in patch clamp studies, effects of which were blocked with toll-like receptor (TLR)-4 inhibitor. Unitary conductance and single-channel amplitude of CFTR were unaffected, but open probability and number of active channels were markedly decreased. LPS increased cytoplasmic and mitochondrial reactive oxygen species resulting in CFTR carbonylation. All effects of exposure were eliminated when reduced glutathione was added in the medium along with LPS. Functional microanatomy parameters, including mucociliary transport, in human sinonasal epithelial cells in vitro were also decreased, but restored with co-incubation with glutathione or TLR-4 inhibitor. In vivo measurements, following application of LPS in the nasal cavities showed significant decreases in transepithelial Cl- secretion as measured by nasal potential difference (NPD) - an effect that was nullified with glutathione and TLR-4 inhibitor. These data provide definitive evidence that LPS-generated reactive intermediates downregulate CFTR function in vitro and in vivo which results in cystic fibrosis-type disease. Findings have implications for therapeutic approaches intent on stimulating Cl- secretion and/or reducing oxidative stress to decrease the sequelae of GNB airway colonization and infection.

PMID:33971543 | DOI:10.1016/j.redox.2021.101998

Purinergic Signal. 2021 May 10. doi: 10.1007/s11302-021-09771-0. Online ahead of print.

ABSTRACT

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593-596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251-262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.

PMID:33970408 | DOI:10.1007/s11302-021-09771-0

FEMS Microbiol Rev. 2021 May 10:fuab026. doi: 10.1093/femsre/fuab026. Online ahead of print.

ABSTRACT

Antimicrobial resistance (AMR) has become a global medical priority that needs urgent resolution. Pseudomonas aeruginosa is a versatile, adaptable bacterial species with widespread environmental occurrence, strong medical relevance, a diverse set of virulence genes and a multitude of intrinsic and possibly acquired antibiotic resistance traits. P. aeruginosa causes a wide variety of infections and has an epidemic-clonal population structure. Several of its dominant global clones have collected a wide variety of resistance genes rendering them multi-drug resistant (MDR) and particularly threatening groups of vulnerable individuals including surgical patients, immunocompromised patients, Caucasians suffering from cystic fibrosis (CF) and more. AMR and MDR especially are particularly problematic in P. aeruginosa significantly complicating successful antibiotic treatment. In addition, antimicrobial susceptibility testing (AST) of P. aeruginosa can be cumbersome due to its slow growth or the massive production of exopolysaccharides and other extracellular compounds. For that reason, phenotypic AST is progressively challenged by genotypic methods using whole genome sequences (WGS) and large-scale phenotype databases as a framework of reference. We here summarize the state of affairs and the quality level of WGS-based AST for P. aeruginosa mostly from clinical origin.

PMID:33970247 | DOI:10.1093/femsre/fuab026

J Drug Assess. 2021 Apr 5;10(1):62-67. doi: 10.1080/21556660.2021.1912352.

ABSTRACT

BACKGROUND: There have been significant advances in Cystic Fibrosis (CF) treatment, with the introduction of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators. Adherence is an important goal for CF management, as nonadherence is linked to poor health outcomes.

OBJECTIVE: To calculate the medication adherence in patients taking CFTR modulators using a national specialty pharmacy database.

METHODS: This retrospective observational cohort study utilized de-identified specialty pharmacy data from September 2017 to August 2018 to assess medication adherence for three CFTR modulators: ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor & ivacaftor. The primary outcome was proportion of days covered (PDC) for each medication, with mean PDC values compared across age groups and insurance characteristics. All analyses were performed using the SAS 9.4 University Edition (SAS Institute, Cary, NC).

RESULTS: A total of 2,548 patients were analyzed, including 1,289 (50.59%) patients on lumacaftor/ivacaftor, 784 (30.77%) on ivacaftor, and 475 (18.64%) on tezacaftor/ivacaftor & ivacaftor. The mean PDC value for all CFTR modulators was above 0.80. Tezacaftor/ivacaftor & ivacaftor had the highest overall PDC of 0.92, while PDC values for both lumacaftor/ivacaftor and ivacaftor were 0.84. Children/adolescents on lumacaftor/ivacaftor (p = 0.0001) and tezacaftor/ivacaftor & ivacaftor (p = 0.001) had significantly higher mean PDC values compared to adults but not for ivacaftor (p = 0.3744). No statistical differences were seen in PDC across insurance characteristics.

CONCLUSION: To the best of our knowledge, this is the first study to assess the adherence of three CFTR modulators using a large nationwide specialty database. With high acquisition costs of CFTR modulator therapies, there is a need to improve rates of adherence in patients with CF.

PMID:33968464 | PMC:PMC8078929 | DOI:10.1080/21556660.2021.1912352

Front Microbiol. 2021 Apr 23;12:603151. doi: 10.3389/fmicb.2021.603151. eCollection 2021.

ABSTRACT

Pseudomonas aeruginosa forms biofilms in the lungs of chronically infected cystic fibrosis patients, which are tolerant to both the treatment of antibiotics and the host immune system. Normally, antibiotics are less effective against bacteria growing in biofilms; azithromycin has shown a potent efficacy in cystic fibrosis patients chronically infected with P. aeruginosa and improved their lung function. The present study was conducted to evaluate the effect of azithromycin on P. aeruginosa biofilm. We show that azithromycin exhibited a potent activity against P. aeruginosa biofilm, and microscopic observation revealed that azithromycin substantially inhibited the formation of solid surface biofilms. Interestingly, we observed that azithromycin restricted P. aeruginosa biofilm formation by inhibiting the expression of pel genes, which has been previously shown to play an essential role in bacterial attachment to solid-surface biofilm. In a rat model of chronic P. aeruginosa lung infection, we show that azithromycin treatment resulted in the suppression of quorum sensing-regulated virulence factors, significantly improving the clearance of P. aeruginosa biofilms compared to that in the placebo control. We conclude that azithromycin attenuates P. aeruginosa biofilm formation, impairs its ability to produce extracellular biofilm matrix, and increases its sensitivity to the immune system, which may explain the clinical efficacy of azithromycin in cystic fibrosis patients.

PMID:33967970 | PMC:PMC8102702 | DOI:10.3389/fmicb.2021.603151

Front Physiol. 2021 Apr 23;12:653177. doi: 10.3389/fphys.2021.653177. eCollection 2021.

ABSTRACT

The role of inflammation in airway epithelial cells and its regulation are important in several respiratory diseases. When disease is present, the barrier between the pulmonary circulation and the airway epithelium is damaged, allowing serum proteins to enter the airways. We identified that human glycated albumin (GA) is a molecule in human serum that triggers an inflammatory response in human airway epithelial cultures. We observed that single-donor human serum induced IL-8 secretion from primary human airway epithelial cells and from a cystic fibrosis airway cell line (CF1-16) in a dose-dependent manner. IL-8 secretion from airway epithelial cells was time dependent and rapidly increased in the first 4 h of incubation. Stimulation with GA promoted epithelial cells to secrete IL-8, and this increase was blocked by the anti-GA antibody. The IL-8 secretion induced by serum GA was 10-50-fold more potent than TNFα or LPS stimulation. GA also has a functional effect on airway epithelial cells in vitro, increasing ciliary beat frequency. Our results demonstrate that the serum molecule GA is pro-inflammatory and triggers host defense responses including increases in IL-8 secretion and ciliary beat frequency in the human airway epithelium. Although the binding site of GA has not yet been described, it is possible that GA could bind to the receptor for advanced glycated end products (RAGE), known to be expressed in the airway epithelium; however, further experiments are needed to identify the mechanism involved. We highlight a possible role for GA in airway inflammation.

PMID:33967824 | PMC:PMC8102681 | DOI:10.3389/fphys.2021.653177

Front Pharmacol. 2021 Apr 21;12:648203. doi: 10.3389/fphar.2021.648203. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is a rare genetic disease that affects several organs, but lung disease is the major cause of morbidity and mortality. The gene responsible for CF, the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, has been discovered in 1989. Since then, gene therapy i.e., defective gene replacement by a functional one, remained the ultimate goal but unfortunately, it has not yet been achieved. However, patients care and symptomatic treatments considerably increased CF patients' life expectancy ranging from 5 years old in the 1960s to 40 today. In the last decade, research works on CFTR protein structure and activity led to the development of new drugs which, by readdressing CFTR to the plasma membrane (correctors) or by enhancing its transport activity (potentiators), allow, alone or in combination, an improvement of CF patients' lung function and quality of life. While expected, it is not yet known whether taking these drugs from an early age and for years will improve the quality of life of CF patients in the long term and further increase their life expectancy. Besides, these molecules are not available (specific variants of CFTR) or accessible (national health policies) for all patients and there is still no curative treatment. Another alternative that could benefit from new technologies, such as gene therapy, is therefore still attractive, although it is not yet offered to patients. Faced with the development of new CFTR correctors and potentiators, the question arises as to whether there is still a place for gene therapy and this is discussed in this perspective.

PMID:33967785 | PMC:PMC8097140 | DOI:10.3389/fphar.2021.648203

Respir Res. 2021 May 8;22(1):142. doi: 10.1186/s12931-021-01734-8.

ABSTRACT

BACKGROUND: We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels.

METHODS: Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels.

RESULTS: In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups.

CONCLUSION: In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases.

TRIAL REGISTRATION: Clinicaltrials.gov NCT00683722.

PMID:33964910 | PMC:PMC8106850 | DOI:10.1186/s12931-021-01734-8

Orv Hetil. 2021 May 9;162(19):760-765. doi: 10.1556/650.2021.32060.

ABSTRACT

Összefoglaló. A cystás fibrosis az egyik leggyakoribb veleszületett genetikai rendellenesség, előfordulása Magyarországon 1:4000. Az érintett szervekben a mirigyek által termelt nyák emelkedett viszkozitása krónikus gyulladáshoz vezet. A progressziót a pulmonalis folyamat határozza meg, súlyos esetben a tüdőtranszplantáció az egyetlen megoldás. A betegek instabil állapota és a hosszú várólista miatt a megfelelő előkészítés kihívásokkal teli, a műtét sokszor sikertelen. A szerzők egy eset segítségével ismertetik a személyre szabott, pozitív nyomású légzésterápia szerepét a transzplantációra való előkészítésben cystás fibrosisban. A 13 éves serdülőt csecsemőkorában történt jobb tüdőcsúcs-reszekciót, majd verejtékvizsgálatot és genetikai tipizálást követően 8 hónapos korától gondoztuk a Heim Pál Országos Gyermekgyógyászati Intézetben cystás fibrosissal. Fokozatosan romló klinikai állapota miatt 11 éves korától otthoni oxigénterápiát igényelt, 13 éves korára tüdőtranszplantáció vált szükségessé. A transzplantációig a légzési munka könnyítése érdekében noninvazív lélegeztetést kezdtünk, melyet a beteg nem tolerált. A rapidan romló általános állapot és légzésfunkció, az inhalatív és szisztémás kezelés ellenére is fennálló folyamatos oxigénigény és jelentős nehézlégzés javítása céljából személyre szabott, pozitív nyomású légzésterápia beállítása történt. Ennek eredményeként 4 vízcentiméteres nyomáson 1 liter/perc oxigén adása mellett a teljes alvásidő 100%-a 90% fölötti oxigénszaturációval telt. A kezelést a gyermek jól tűrte, éjszakái nyugodtabban teltek, általános állapota és légzésfunkciója javult, majd sikeres tüdőtranszplantáción esett át. A személyre szabott, pozitív nyomású légzésterápia javítja a cystás fibrosisban szenvedő gyermekek általános állapotát és légzésfunkcióját, ezáltal megkönnyíti a beteg tüdőtranszplantáció előtti felkészülését, és növeli a műtét sikerességének esélyét. Orv Hetil. 2021; 162(19): 760-765. Summary. Cystic fibrosis is one of the most common hereditary genetic disorders, the appearance rate of which in the Hungarian population is 1:4000. The increased viscosity of mucus leads to chronic inflammation in the affected organs. The pulmonary manifestation defines the progression, in severe cases lung transplantation is needed. Unstable health condition can make the preparation for surgery difficult and unsuccessful. The role of personalised positive airway pressure therapy prior to lung transplantation in cystic fibrosis is presented through a case report. The 13-year-old child was treated at Heim Pál National Pediatric Institute from the age of 8 months with cystic fibrosis after pulmonary lobectomy, followed by sweat chlorid- and genetic testing. The significant impairment of his general condition required oxygen therapy from the age of 11 years and lung transplantation at the age of 13 years. Until lung transplantation, to relieve the respiratory distress, noninvasive ventilation was started, without success. Considering the rapid progression and persistent need for oxygen - despite inhalation and systemic treatment - personalised positive airway pressure therapy was indicated. At the pressure of 4 cmH2O and an oxygen flow rate of 1 l/min, oxygen saturation was higher than 90% during 100% of the total sleep time. Improvement was registered in both general condition and respiratory function, followed by a successful lung transplantation. In patients with cystic fibrosis, personalized positive airway pressure therapy improves respiratory function, general condition and elevates the success rate of lung transplantation. Orv Hetil. 2021; 162(19): 760-765.

PMID:33965910 | DOI:10.1556/650.2021.32060

J Glob Antimicrob Resist. 2021 May 6:S2213-7165(21)00101-6. doi: 10.1016/j.jgar.2021.04.004. Online ahead of print.

ABSTRACT

OBJECTIVES: The Genus Burkholderia comprises rod shaped, non-spore forming, obligately aerobic, gram negative bacteria. They are found across diverse ecological niches. Burkholderia contaminans, an emerging pathogen associated with cystic fibrosis, is frequently isolated from the contaminated medical devices in hospital settings. The objective is to understand genomic characteristics, antibiotic resistance profile and virulence determinants of B. contaminans strain SBC01isolated from the right eye of a patient hit by a cow's tail.

METHODS: Hybrid sequence of the study isolate was generated by using Illumina Hiseq and Oxford Nanopore Technology platforms. Unicycler was used for assembling the hybrid genomic sequence. Draft genome was annotated using the NCBI Prokaryotic Genome Annotation Pipeline. Antibiotic Susceptibility Testing (AST) of the bacterial isolate was performed by VITEK-2. Antimicrobial resistance (AMR) and virulence genes were identified using validated bioinformatics tools.

RESULTS: The assembled genome size is 8,841,722 bp, with a G+C content of 66.33% distributed in 19 contigs. The strain SBC01 was found to possess several antibiotic resistance and efflux pump genes. The isolate was susceptible to tetracyclines, meropenem and ceftazidime. Many genes encoding potential virulence factors were identified.

CONCLUSION: Burkholderia contaminans SBC01 belonging to sequence type ST482 is a multi-drug resistant strain containing diverse resistance genes revealing the risks associated with infections of new Burkholderia spp. The large G+C rich genome has myriad of virulence factors highlighting its pathogenic potential. Thus, while providing insights into AMR and virulence potential of this uncommon species, the present analysis will aid in understanding the evolution and speciation in Burkholderia genus.

PMID:33965629 | DOI:10.1016/j.jgar.2021.04.004

Chest. 2021 May;159(5):1693-1695. doi: 10.1016/j.chest.2021.01.043.

NO ABSTRACT

PMID:33965120 | DOI:10.1016/j.chest.2021.01.043

Lancet Respir Med. 2021 May 6:S2213-2600(21)00176-4. doi: 10.1016/S2213-2600(21)00176-4. Online ahead of print.

NO ABSTRACT

PMID:33965001 | DOI:10.1016/S2213-2600(21)00176-4

Lancet Respir Med. 2021 May 6:S2213-2600(21)00069-2. doi: 10.1016/S2213-2600(21)00069-2. Online ahead of print.

ABSTRACT

BACKGROUND: A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study.

METHODS: In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor-ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor-ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg-ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg-ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg-ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor-ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor-ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395.

FINDINGS: This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor-ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 -29·6 mmol/L [95% CI -33·7 to -25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI.

INTERPRETATION: Lumacaftor-ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor-ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutation.

FUNDING: Vertex Pharmaceuticals Incorporated.

PMID:33965000 | DOI:10.1016/S2213-2600(21)00069-2

BMC Med Imaging. 2021 May 8;21(1):79. doi: 10.1186/s12880-021-00608-1.

ABSTRACT

BACKGROUND: Functional lung MRI techniques are usually associated with time-consuming post-processing, where manual lung segmentation represents the most cumbersome part. The aim of this study was to investigate whether deep learning-based segmentation of lung images which were scanned by a fast UTE sequence exploiting the stack-of-spirals trajectory can provide sufficiently good accuracy for the calculation of functional parameters.

METHODS: In this study, lung images were acquired in 20 patients suffering from cystic fibrosis (CF) and 33 healthy volunteers, by a fast UTE sequence with a stack-of-spirals trajectory and a minimum echo-time of 0.05 ms. A convolutional neural network was then trained for semantic lung segmentation using 17,713 2D coronal slices, each paired with a label obtained from manual segmentation. Subsequently, the network was applied to 4920 independent 2D test images and results were compared to a manual segmentation using the Sørensen-Dice similarity coefficient (DSC) and the Hausdorff distance (HD). Obtained lung volumes and fractional ventilation values calculated from both segmentations were compared using Pearson's correlation coefficient and Bland Altman analysis. To investigate generalizability to patients outside the CF collective, in particular to those exhibiting larger consolidations inside the lung, the network was additionally applied to UTE images from four patients with pneumonia and one with lung cancer.

RESULTS: The overall DSC for lung tissue was 0.967 ± 0.076 (mean ± standard deviation) and HD was 4.1 ± 4.4 mm. Lung volumes derived from manual and deep learning based segmentations as well as values for fractional ventilation exhibited a high overall correlation (Pearson's correlation coefficent = 0.99 and 1.00). For the additional cohort with unseen pathologies / consolidations, mean DSC was 0.930 ± 0.083, HD = 12.9 ± 16.2 mm and the mean difference in lung volume was 0.032 ± 0.048 L.

CONCLUSIONS: Deep learning-based image segmentation in stack-of-spirals based lung MRI allows for accurate estimation of lung volumes and fractional ventilation values and promises to replace the time-consuming step of manual image segmentation in the future.

PMID:33964892 | DOI:10.1186/s12880-021-00608-1

J Physiol. 2021 May 7. doi: 10.1113/JP281285. Online ahead of print.

ABSTRACT

This review summarizes the newly discovered molecular mechanism of secretin-stimulated urine HCO3 - excretion and the role of CFTR in renal HCO3 - excretion. The secretin receptor is functionally expressed in the basolateral membrane of the HCO3 - -secreting beta-intercalated cells of the collecting duct. Here it activates a fast and efficient secretion of HCO3 - into the urine serving to normalize metabolic alkalosis. The ability to acutely increase renal base excretion is entirely dependent on functional pendrin (SLC26A4) and CFTR, and both proteins localize to the apical membrane of the beta-intercalated cells. In cystic fibrosis (CF) mice and also in CF patients, this function is absent or markedly reduced. We discuss that the alkaline tide, namely the transient urine alkalinity after a meal, has now received a clear physiological explanation. This article is protected by copyright. All rights reserved.

PMID:33963548 | DOI:10.1113/JP281285