Interactions between ABCC4/MRP4 and ABCC7/CFTR in Human Airway Epithelial Cells in Lung Health and Disease.

Int J Biochem Cell Biol. 2021 Jan 30;:105936

Authors: Nguyen JP, Kim Y, Cao Q, Hirota JA

Abstract
ATP binding cassette (ABC) transporters are present in all three domains of life - Archaea, Bacteria, and Eukarya. The conserved nature is a testament to the importance of these transporters in regulating endogenous and exogenous substrates required for life to exist. In humans, 49 ABC transporters have been identified to date with broad expression in different lung cell types with multiple transporter family members contributing to lung health and disease. The ABC transporter most commonly known to be linked to lung pathology is ABCC7, also known as cystic fibrosis transmembrane conductance regulator - CFTR. Closely related to the CFTR genomic sequence is ABCC4/multi-drug resistance protein-4. Genomic proximity is shared with physical proximity, with ABCC4 and CFTR physically coupled in cell membrane microenvironments of epithelial cells to orchestrate functional consequences of cyclic-adenosine monophosphate (cAMP)-dependent second messenger signaling and extracellular transport of endogenous and exogenous substrates. The present concise review summarizes the emerging data defining a role of the (ABCC7/CFTR)-ABCC4 macromolecular complex in human airway epithelial cells as a physiologically important pathway capable of impacting endogenous and exogenous mediator transport and ion transport in both lung health and disease.

PMID: 33529712 [PubMed - as supplied by publisher]

From genotype to phenotype: adaptations of Pseudomonas aeruginosa to the cystic fibrosis environment.

Microb Genom. 2021 Feb 02;:

Authors: Camus L, Vandenesch F, Moreau K

Abstract
Pseudomonas aeruginosa is one of the main microbial species colonizing the lungs of cystic fibrosis patients and is responsible for the decline in respiratory function. Despite the hostile pulmonary environment, P. aeruginosa is able to establish chronic infections thanks to its strong adaptive capacity. Various longitudinal studies have attempted to compare the strains of early infection with the adapted strains of chronic infection. Thanks to new '-omics' techniques, convergent genetic mutations, as well as transcriptomic and proteomic dysregulations have been identified. As a consequence of this evolution, the adapted strains of P. aeruginosa have particular phenotypes that promote persistent infection.

PMID: 33529147 [PubMed - as supplied by publisher]

Patterns of azithromycin use in obstructive airway diseases: a real-world observational study.

Intern Med J. 2021 Feb 02;:

Authors: Thomas D, McDonald VM, Simpson JL, Smith A, Gupta S, Majellano E, Gibson PG

Abstract
Background and objective Low-dose long-term azithromycin is recommended in clinical practice guidelines for obstructive airway diseases (OADs), however, an optimal therapeutic regimen is not yet established. This study aimed to understand the patterns of azithromycin use in OADs, characterise the patients who received it, and evaluate its safety and efficacy using real-world data.
METHODS: We audited 91 patients who had received azithromycin for at least 4 weeks for the management of asthma, chronic obstructive pulmonary disease (COPD) or non-cystic fibrosis bronchiectasis.
RESULTS: The mean age was 65±18 years, 60% were female, and 48% were ex-smokers. The majority had asthma (75%) either alone (50%) or in combination with COPD (12%) or bronchiectasis (13%). Most (64%) reported cough or sputum at baseline. The most common treatment regimen was azithromycin 250mg daily (73%) for more than 1 year (57%), with only seven adverse events. There was a significant reduction in the proportions of patients requiring emergency department visits (48% versus 32%; p<0.001) and hospital admissions (35% versus 31%; p<0.001) after starting azithromycin. In 88% of cases, physicians favoured the use of azithromycin.
CONCLUSION: Physicians are currently using low-dose azithromycin for a long duration of more than one year for the management of OADs. The typical case-definition is an older non-smoking adult with persistent asthma, often in combination with another OAD, and presenting with bothersome cough or sputum. Azithromycin was well tolerated and led to reduced healthcare utilisation. Further research is required to establish an optimal dosage regimen of azithromycin in OADs. This article is protected by copyright. All rights reserved.

PMID: 33527647 [PubMed - as supplied by publisher]

Cystic Fibrosis.

Pediatr Rev. 2021 Feb;42(2):55-67

Authors: Dickinson KM, Collaco JM

Abstract
Cystic fibrosis (CF) is one of the most commonly diagnosed genetic disorders. Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. Future improvements in health and quality of life for individuals with CF are likely with the recent development of mutation-specific modulator therapies. In this review, we will cover the current understanding of the disease manifestations, diagnosis, and management as well as common complications seen in individuals with CF.

PMID: 33526571 [PubMed - in process]

JCF Year in Review.

J Cyst Fibros. 2021 Jan;20(1):1-2

Authors: Flume PA, Castellani C, Davies J

PMID: 33526211 [PubMed - in process]

Environmental Microbial Contamination during Cystic Fibrosis Group-Based Psychotherapy.

Int J Environ Res Public Health. 2021 Jan 28;18(3):

Authors: Rossitto M, Tabarini P, Tuccio Guarna Assanti V, Montemitro E, Pompilio A, Fiscarelli EV

Abstract
Living with cystic fibrosis (CF) exposes patients to the risk of developing anxiety and depression, with therapeutic compliance reduction, hospitalization increase, and quality of life and health outcomes deterioration. As pulmonary infections represent the major cause of morbidity and mortality in patients with CF, environmental contamination due to droplet dispersion and the potential transmission from environment to such patients should be prevented. Therefore, in-person contact, including group-based psychotherapy, are strongly discouraged. Nevertheless, group sharing of disease-related experiences represents a way to recover the inner resources essential for dealing with a chronic pathology. Keeping in mind the guidelines for infection control, the aim of this study is to evaluate the risk of the dissemination of microorganisms in a restricted environment where patients with CF attend group psychotherapy sessions. Five patients, selected according to their microbiological status, attended 32 group-based psychological/psychoanalytic meetings. Before each session, they were asked to observe the infection control recommendations. Microbiological environmental monitoring (MEM) has been performed to evaluate both air and surface contamination. As reported, a strict observation of standard precautions allows one to avoid environmental contamination by pathogens of the CF respiratory tract. Although infection control guidelines discourage group-based psychological/psychoanalytic interventions, our observations report the feasibility and safety of group psychotherapy when strict precautions are taken.

PMID: 33525434 [PubMed - in process]

Improved survival after lung transplantation for adults requiring preoperative invasive mechanical ventilation: A national cohort study.

J Thorac Cardiovasc Surg. 2020 Nov;160(5):1385-1395.e6

Authors: Hamilton BCS, Dincheva GR, Matthay MA, Hays S, Singer JP, Brzezinski M, Kukreja J

Abstract
OBJECTIVE: Early survival after lung transplantation has improved in the last decade. Mechanically ventilated recipients are known to be at greater risk for early post-transplant mortality. We hypothesized that post-transplant survival in mechanically ventilated recipients has improved over time.
METHODS: Using a national registry, we compared hazard of death at 30 days, 4 and 14 months, 3 and 5 years, and overall for adults on mechanical ventilation who underwent lung or heart-lung transplantation from May 4, 2011, to April 4, 2018 (modern group) with those undergoing transplantation from May 4, 2005, to May 3, 2011 (early group). We quantified the impact of mechanical ventilation on survival using population-attributable fractions. We also compared mechanically ventilated recipients with nonmechanically ventilated recipients.
RESULTS: Mechanically ventilated recipients from the modern group had lower hazard of death than recipients in the early group at all time-points, lowest at 30-days post-transplant (hazard ratio, 0.04; 95% confidence interval, 0.02-0.08). In the modern period, mechanically ventilated recipients had greater hazard of death than nonmechanically ventilated recipients at 30 days' post-transplant (9.53; 4.57-19.86). For mechanically ventilated recipients, the population attributable fraction was lower in the modern group compared to the earlier group (0.6% vs 5.7%).
CONCLUSIONS: While mechanically ventilated recipients remain at high risk, survival in this patient population has improved over time. This may reflect improvements in perioperative recipient management.

PMID: 32252988 [PubMed - indexed for MEDLINE]

Modulators of CFTR. Updates on clinical development and future directions.

Eur J Med Chem. 2021 Jan 16;213:113195

Authors: Bardin E, Pastor A, Semeraro M, Golec A, Hayes K, Chevalier B, Berhal F, Prestat G, Hinzpeter A, Gravier-Pelletier C, Pranke I, Sermet-Gaudelus I

Abstract
Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.

PMID: 33524685 [PubMed - as supplied by publisher]

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and penicillins latest update.

Pediatr Pulmonol. 2021 Feb 01;:

Authors: Epps QJ, Epps KL, Zobell JT

PMID: 33524241 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway.

PLoS One. 2021;16(2):e0246050

Authors: Coates MS, Alton EWFW, Rapeport GW, Davies JC, Ito K

Abstract
Pseudomonas aeruginosa (Pa) infection is a major cause of airway inflammation in immunocompromised and cystic fibrosis (CF) patients. Mitogen-activated protein (MAP) and tyrosine kinases are integral to inflammatory responses and are therefore potential targets for novel anti-inflammatory therapies. We have determined the involvement of specific kinases in Pa-induced inflammation. The effects of kinase inhibitors against p38MAPK, MEK 1/2, JNK 1/2, Syk or c-Src, a combination of a p38MAPK with Syk inhibitor, or a novel narrow spectrum kinase inhibitor (NSKI), were evaluated against the release of the proinflammatory cytokine/chemokine, IL-6 and CXCL8 from BEAS-2B and CFBE41o- epithelial cells by Pa. Effects of a Syk inhibitor against phosphorylation of the MAPKs were also evaluated. IL-6 and CXCL8 release by Pa were significantly inhibited by p38MAPK and Syk inhibitors (p<0.05). Phosphorylation of HSP27, but not ERK or JNK, was significantly inhibited by Syk kinase inhibition. A combination of p38MAPK and Syk inhibitors showed synergy against IL-6 and CXCL8 induction and an NSKI completely inhibited IL-6 and CXCL8 at low concentrations. Pa-induced inflammation is dependent on p38MAPK primarily, and Syk partially, which is upstream of p38MAPK. The NSKI suggests that inhibiting specific combinations of kinases is a potent potential therapy for Pa-induced inflammation.

PMID: 33524056 [PubMed - as supplied by publisher]

Implementation of Specialist Palliative Care and Outcomes for Hospitalized Patients with Dementia.

J Am Geriatr Soc. 2021 Feb 01;:

Authors: Lackraj D, Kavalieratos D, Murali KP, Lu Y, Hua M

Abstract
BACKGROUND: In patients with serious illness, use of specialist palliative care may result in improved quality of life, patient and caregiver satisfaction and advance care planning, as well as lower health care utilization. However, evidence of efficacy is limited for patients with dementia, particularly in the setting of an acute hospitalization.
OBJECTIVE: To determine whether implementation of hospital-based specialist palliative care was associated with differences in treatment intensity outcomes for hospitalized patients with dementia.
DESIGN: Retrospective cohort study.
SETTING: Fifty-one hospitals in New York State that either did or did not implement a palliative care program between 2008 and 2014. Hospitals that consistently had a palliative care program during the study period were excluded.
PARTICIPANTS: Hospitalized patients with dementia.
MEASUREMENTS: The primary outcome of this study was discharge to hospice from an acute hospitalization. Secondary outcomes included hospital length of stay, use of mechanical ventilation and dialysis, and days in intensive care. Difference-in-difference analyses were performed using multilevel regression to assess the association between implementing a palliative care program and outcomes, while adjusting for patient and hospital characteristics and time trends.
RESULTS: During the study period, 82,118 patients with dementia (mean (SD) age, 83.04 (10.04), 51,170 (62.21%) female) underwent an acute hospitalization, of which 41,227 (50.27%) received care in hospitals that implemented a palliative care program. In comparison to patients who received care in hospitals without palliative care, patients with dementia who received care in hospitals after the implementation of palliative care were more 35% likely to be discharged to hospice (adjusted odds ratio (aOR) = 1.35 (1.19-1.51), P < .001). No meaningful differences in secondary outcomes were observed.
CONCLUSION: Implementation of a specialist palliative care program was associated with an increase in discharge to hospice following acute hospitalization in patients with dementia.

PMID: 33523466 [PubMed - as supplied by publisher]

Azithromycin and Tobramycin Therapy in Cystic Fibrosis Pulmonary Exacerbations: Less Is More?

Ann Am Thorac Soc. 2021 Feb;18(2):213-215

Authors: Thornton C, Chin M, Somayaji R

PMID: 33522874 [PubMed - as supplied by publisher]

Social Inequities and Cystic Fibrosis Outcomes: We Can Do Better.

Ann Am Thorac Soc. 2021 Feb;18(2):215-217

Authors: Oates GR, Schechter MS

PMID: 33522873 [PubMed - as supplied by publisher]

Fibers in pediatric functional gastrointestinal disorders. practical considerations from clinical cases.

Expert Rev Gastroenterol Hepatol. 2021 Jan 31;:

Authors: Romano C, Pallio S, Cucinotta U, Accorsi P, Dipasquale V

Abstract
INTRODUCTION: Functional gastrointestinal disorders (FGIDs) are common in children and incur high direct and indirect social costs. Partially hydrolyzed guar gum (PHGG) is a natural and water-soluble dietary fiber that is derived from guar gum. It has been proposed as complementary therapy in pediatric FGIDs, especially in chronic functional constipation and irritable bowel syndrome.
AREAS COVERED: By focusing on four clinical cases, this article illustrates the use of PHGG fiber as sole supplement ingredient or as a formula component in orally- and tube-fed children suffering from malnutrition due to FGIDs, with or without special medical conditions such as neurological disability. The formula used was a whey peptide-based nutritionally complete formula containing PHGG as a source of soluble dietary fiber. It was offered under medical supervision and after full consideration of all feeding options.
EXPERT OPINION: Implementing appropriate feeding behaviors, adapted to age and potential comorbidities, is an essential requisite for therapeutic management of FGIDs. The use of a PHGG supplement or a nutritionally complete formula containing PHGG as a source of soluble dietary fiber can be helpful to manage pediatric FGIDs.

PMID: 33522316 [PubMed - as supplied by publisher]

Intravital Imaging of Pulmonary Immune Response in Inflammation and Infection.

Front Cell Dev Biol. 2020;8:620471

Authors: Alizadeh-Tabrizi N, Hall S, Lehmann C

Abstract
Intravital microscopy (IVM) is a unique imaging method providing insights in cellular functions and interactions in real-time, without the need for tissue extraction from the body. IVM of the lungs has specific challenges such as restricted organ accessibility, respiratory movements, and limited penetration depth. Various surgical approaches and microscopic setups have been adapted in order to overcome these challenges. Among others, these include the development of suction stabilized lung windows and the use of more advanced optical techniques. Consequently, lung IVM has uncovered mechanisms of leukocyte recruitment and function in several models of pulmonary inflammation and infection. This review focuses on bacterial pneumonia, aspiration pneumonia, sepsis-induced acute lung Injury, and cystic fibrosis, as examples of lung inflammation and infection. In addition, critical details of intravital imaging techniques of the lungs are discussed.

PMID: 33520993 [PubMed]

How Clinically Efficient Is Lumacaftor/Ivacaftor for Cystic Fibrosis Patients? An Updated Literature Review.

Cureus. 2020 Dec 24;12(12):e12251

Authors: Perveen S, Chaudhry MR, AlBabtain S, Amreen S, Brar SK, Zeb M, Khan S

Abstract
Cystic fibrosis (CF) is an autosomal recessive illness caused by the defective cystic fibrosis transmembrane conductance regulator (CFTR) gene. These patients suffer from repeated chronic sinuses and lung infections, resulting in frequent hospital admissions and antibiotic (Abx) courses. These are the major contributing factors responsible for a low health-related quality of life (HRQoL) and increasing the disease burden. The introduction and approval of CFTR modulators-lumacaftor (LUM) and ivacaftor (IVA) in 2015 by the US Food and Drug Administration (FDA) reduced the mortality and morbidity rates associated with the disease. In 2018, the FDA approved these drugs from age two and five years with two copies of F5806 del. This literature review aims to present the studies centered on the clinical effects of LUM/IVA. We searched for the relevant articles, from 2016 to 2020, in PubMed Central (PMC), Google Scholars, and Journal of Cystic Fibrosis. LUM/IVA has a broader range of effects. They showed marked improvement in the reduction of pulmonary exacerbations (PEx), Hospitalization rates, Abx use, and modification in forced expiratory volume in one second (FEV1) status of pre-existing severe lung disease. Now, there is a need for an initiative to conduct more clinical trials and studies in the future to assess and evaluate the long-term clinical benefits and safety of LUM/IVA therapy in all age groups.

PMID: 33520477 [PubMed]

Within-Host Microevolution of Pseudomonas aeruginosa Urinary Isolates: A Seven-Patient Longitudinal Genomic and Phenotypic Study.

Front Microbiol. 2020;11:611246

Authors: Cottalorda A, Leoz M, Dahyot S, Gravey F, Grand M, Froidure T, Aujoulat F, Le Hello S, Jumas-Bilak E, Pestel-Caron M

Abstract
Background: Pseudomonas aeruginosa is responsible for up to 10% of healthcare associated urinary tract infections (UTI), which can be difficult to treat and can lead to bacterial persistence. While numerous whole genome sequencing (WGS) analyses have explored within-host genomic adaptation and microevolution of P. aeruginosa during cystic fibrosis (CF) infections, little is known about P. aeruginosa adaptation to the urinary tract.
Results: Whole genome sequencing was performed on 108 P. aeruginosa urinary isolates, representing up to five isolates collected from 2 to 5 successive urine samples from seven patients hospitalized in a French hospital over 48-488 days. Clone type single nucleotide polymorphisms (ctSNPs) analysis revealed that each patient was colonized by a single clone type (<6000 SNPs between two isolates) at a given time and over time. However, 0-126 SNPs/genome/year were detected over time. Furthermore, large genomic deletions (1-5% of the genome) were identified in late isolates from three patients. For 2 of them, a convergent deletion of 70 genes was observed. Genomic adaptation (SNPs and deletion) occurred preferentially in genes encoding transcriptional regulators, two-component systems, and carbon compound catabolism. This genomic adaptation was significantly associated with a reduced fitness, particularly in artificial urine medium, but no strict correlation was identified between genomic adaptation and biofilm formation.
Conclusion: This study provides the first insight into P. aeruginosa within-host evolution in the urinary tract. It was driven by mutational mechanisms and genomic deletions and could lead to phenotypic changes in terms of fitness and biofilm production. Further metabolomic and phenotypic analyses are needed to describe in-depth genotype-phenotype associations in this complex and dynamic host-environment.

PMID: 33519766 [PubMed]

Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study.

Respir Res. 2021 Feb 01;22(1):30

Authors: Galdi F, Pedone C, McGee CA, George M, Rice AB, Hussain SS, Vijaykumar K, Boitet ER, Tearney GJ, McGrath JA, Brown AR, Rowe SM, Incalzi RA, Garantziotis S

Abstract
BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) carry significant morbidity and mortality. AECOPD treatment remains limited. High molecular weight hyaluronan (HMW-HA) is a glycosaminoglycan sugar, which is a physiological constituent of the lung extracellular matrix and has notable anti-inflammatory and hydrating properties.
RESEARCH QUESTION: We hypothesized that inhaled HMW-HA will improve outcomes in AECOPD.
METHODS: We conducted a single center, randomized, placebo-controlled, double-blind study to investigate the effect of inhaled HMW-HA in patients with severe AECOPD necessitating non-invasive positive-pressure ventilation (NIPPV). Primary endpoint was time until liberation from NIPPV.
RESULTS: Out of 44 screened patients, 41 were included in the study (21 for placebo and 20 for HMW-HA). Patients treated with HMW-HA had significantly shorter duration of NIPPV. HMW-HA treated patients also had lower measured peak airway pressures on the ventilator and lower systemic inflammation markers after liberation from NIPPV. In vitro testing showed that HMW-HA significantly improved mucociliary transport in air-liquid interface cultures of primary bronchial cells from COPD patients and healthy primary cells exposed to cigarette smoke extract.
INTERPRETATION: Inhaled HMW-HA shortens the duration of respiratory failure and need for non-invasive ventilation in patients with AECOPD. Beneficial effects of HMW-HA on mucociliary clearance and inflammation may account for some of the effects (NCT02674880, www.clinicaltrials.gov ).

PMID: 33517896 [PubMed - in process]

The O2-independent pathway of ubiquinone biosynthesis is essential for denitrification in Pseudomonas aeruginosa.

J Biol Chem. 2020 Jul 03;295(27):9021-9032

Authors: Vo CD, Michaud J, Elsen S, Faivre B, Bouveret E, Barras F, Fontecave M, Pierrel F, Lombard M, Pelosi L

Abstract
Many proteobacteria, such as Escherichia coli, contain two main types of quinones: benzoquinones, represented by ubiquinone (UQ) and naphthoquinones, such as menaquinone (MK), and dimethyl-menaquinone (DMK). MK and DMK function predominantly in anaerobic respiratory chains, whereas UQ is the major electron carrier in the reduction of dioxygen. However, this division of labor is probably not very strict. Indeed, a pathway that produces UQ under anaerobic conditions in an UbiU-, UbiV-, and UbiT-dependent manner has been discovered recently in E. coli. Its physiological relevance is not yet understood, because MK and DMK are also present in E. coli. Here, we established that UQ9 is the major quinone of Pseudomonas aeruginosa and is required for growth under anaerobic respiration (i.e. denitrification). We demonstrate that the ORFs PA3911, PA3912, and PA3913, which are homologs of the E. coli ubiT, ubiV, and ubiU genes, respectively, are essential for UQ9 biosynthesis and, thus, for denitrification in P. aeruginosa. These three genes here are called ubiTPa, ubiVPa, and ubiUPa. We show that UbiVPa accommodates an iron-sulfur [4Fe-4S] cluster. Moreover, we report that UbiUPa and UbiTPa can bind UQ and that the isoprenoid tail of UQ is the structural determinant required for recognition by these two Ubi proteins. Since the denitrification metabolism of P. aeruginosa is believed to be important for the pathogenicity of this bacterium in individuals with cystic fibrosis, our results highlight that the O2-independent UQ biosynthetic pathway may represent a target for antibiotics development to manage P. aeruginosa infections.

PMID: 33516498 [PubMed - in process]

Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study.

Lancet Respir Med. 2021 Jan 28;:

Authors: Chilvers MA, Davies JC, Milla C, Tian S, Han Z, Cornell AG, Owen CA, Ratjen F

Abstract
BACKGROUND: The safety and efficacy of 24 weeks of lumacaftor-ivacaftor combination therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously shown in two phase 3 studies. Here, we report long-term safety and efficacy data.
METHODS: In this phase 3, open-label, multicentre, extension study (study 110), we examined the long-term safety, tolerability, and efficacy of lumacaftor-ivacaftor in children pooled from two phase 3 parent studies (open-label study 011B and randomised, placebo-controlled study 109). The study was conducted at 61 clinics in the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK. Children with cystic fibrosis homozygous for the F508del-CFTR mutation who had received lumacaftor-ivacaftor or placebo in the parent studies were treated with lumacaftor-ivacaftor for up to 96 weeks; those who had received the combination therapy in the parent studies (the treatment-to-treatment group) received up to 120 weeks of treatment in total. Participants aged 6-11 years at the start of the parent study received lumacaftor 200 mg-ivacaftor 250 mg orally once every 12 h; those aged 12 years or older received lumacaftor 400 mg-ivacaftor 250 mg orally once every 12 h. The primary endpoint was safety and tolerability in all children who had received at least one dose of the study drug. Secondary endpoints included change from baseline in lung clearance index 2·5% (LCI2·5), sweat chloride concentration, body-mass index, and Cystic Fibrosis Questionnaire-Revised respiratory domain score. This extension study is registered with ClinicalTrials.gov, NCT02544451, and has been completed.
FINDINGS: The extension study ran from Aug 13, 2015, to Aug 17, 2018. Of 239 children who enrolled in the study and received at least one dose of lumacaftor-ivacaftor, 215 (90%) completed 96 weeks of treatment. Most children (236 [99%] of 239 children) had adverse events that were mild (49 [21%] of 239) or moderate (148 [62%] of 239) in severity, and there was a low rate of adverse events leading to treatment discontinuation. The most frequently reported adverse events were common manifestations or complications of cystic fibrosis, such as cough and pulmonary exacerbation, or were consistent with the known safety profile of lumacaftor-ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor-ivacaftor treatment. Children in the placebo-to-treatment group had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in children treated with lumacaftor-ivacaftor in the parent study were generally maintained in the extension study.
INTERPRETATION: Lumacaftor-ivacaftor therapy in children homozygous for F508del-CFTR who initiated treatment at age 6-11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks. These data support the long-term use of lumacaftor-ivacaftor to treat children aged 6 years and older who are homozygous for the F508del-CFTR mutation.
FUNDING: Vertex Pharmaceuticals Incorporated.

PMID: 33516285 [PubMed - as supplied by publisher]