A common eligibility criterion in respiratory clinical trials is a per cent-predicted forced expiratory volume in 1 second (ppFEV1) between 40% and 90%, using the ethnicity-dependent Global Lung Function Initiative (GLI)-2012 spirometry reference equations. International societies now endorse the newer 'race-neutral' GLI-Global equations. We quantify the impact on trial eligibility of switching from GLI-2012 to GLI-Global for the UK Cystic Fibrosis Registry (n=8182). In a future trial with a maximum eligibility threshold of ppFEV1=90%, the changes in ppFEV1 would lead to over 700 people becoming newly ineligible. Urgent review of fixed ppFEV1 thresholds is required, with an initial recommendation to widen the range to 30-95% ppFEV1 when GLI-Global is implemented to ensure equitable access for people of all ethnicities. There is also a wider need to review the use of fixed ppFEV1 spirometry limits for trial eligibility.

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust’s (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients.There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK’s capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

A causal link between gastroesophageal reflux disease (GORD) and respiratory symptoms is unclear. The 2019 CHEST guideline recommends GORD treatment only in the context of clinical symptoms, signs or a positive test. We evaluated the feasibility of 24-hour ambulatory impedance testing as a minimally invasive test to identify GORD contributing to symptoms. Our centre performs flexible bronchoscopy and pH-Multichannel intraluminal impedance (pH-Mii™) probe placement under general anaesthesia as part of the assessment of complex persistent respiratory symptoms. Oesophageal probe placement is confirmed by direct laryngoscopy before x-ray confirmation of probe sensor position. The probe is removed 18-24 hours later, and study analysed using ESPGHAN EURO-PIG standards. 43 children had this combined procedure from Sept 2021 to Feb 2023, 18 (42%) for CF/PCD exacerbations, 11 (26%) for recurrent chest infection, 9 (21%) for recurrent croup and 5 (12%) for persistent x-ray changes. Age distribution was: <1y = 2, 1-5y = 11, 6-12y = 24, >12y = 6 (mean 6.55 + 4.55y)). Testing succeeded in 37/43 (86%). 4 (9%) did not tolerate the probe (ages 1-5 years) and 2 (5%) studies failed for technical reasons. 6/37 were studied while taking proton pump inhibitor (PPI). 12/31 children studied off PPI had pathological reflux (despite no GORD-specific symptoms -'silent GORD') prompting initiation of PPI therapy. Once in situ, pH-Mii is well tolerated, portable and does not require admission. Ambulatory pH-Mii in children undergoing elective flexible bronchoscopy is a key investigation to exclude GORD contributory to persistent respiratory symptoms as it may identify GORD with extraoesophageal manifestations amenable to targeted treatment.

Abstract Introduction Gastroesophageal reflux disease (GERD) is associated with accelerated decline in lung health in children with cystic fibrosis (CF). Thus, antireflux surgery (ARS) is offered to a selected CF cohort with refractory GERD, but outcomes remain poorly investigated. This study aimed to determine the incidence of GERD in children with CF and to evaluate complications and outcomes of ARS. Materials and Methods A systematic literature-based search was conducted using various online databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The number of GERD cases in pediatric CF cohorts who underwent diagnostic investigation(s) was recorded. Data on postoperative complications and outcomes (including symptoms, lung function, and nutritional status) following ARS were analyzed. Results Ten articles (n = 289 patients) met the defined inclusion criteria (51% male; age range, 0.5 month–36 years). The overall incidence of GERD was 46% (range, 19–81%), derived from seven studies (n = 212 patients). Four publications (n = 82 patients) reported on ARS due to uncontrolled GERD. All ARSs were Nissen fundoplication (majority with gastrostomy placement). Major postoperative complications occurred in 15 (18%) patients, two required redo-ARS. Median follow-up time was 2 years (range, 3 months–6 years); 59% showed symptom improvement, and pulmonary exacerbations and decline in lung function were reduced. Nutritional status mainly improved in milder CF cases. There were no deaths related to ARS. Conclusion Approximately half of pediatric CF patients have GERD. Published data for children with CF are limited and heterogeneous in terms of GERD diagnosis and outcomes following ARS. However, ARS has shown to slow the deterioration of lung function in CF.

The UK Medicines and Healthcare products Regulatory Agency is considering prescription of e-cigarettes on the National Health Service.1Medicines and Healthcare Products Regulatory AgencyGuidance for licensing electronic cigarettes and other inhaled nicotine-containing products as medicines.https://www.gov.uk/guidance/licensing-procedure-for-electronic-cigarettes-as-medicinesDate: Oct 29, 2021Date accessed: October 29, 2021Google Scholar This consideration heralds the next big revenue stream for big tobacco, whose lobbyists have campaigned for the prescription of e-cigarettes as UK smoking rates dwindle. We absolutely disagree that “doctors, medical leaders and health campaigners welcomed the move”.2Gregory A Regulator paves way for NHS e-cigarette prescriptions in England.https://www.theguardian.com/society/2021/oct/29/regulator-paves-way-for-nhs-e-cigarette-prescriptions-in-englandDate: Oct 29, 2021Date accessed: October 29, 2021Google Scholar The argument underpinning this volte-face (physicians always shunned so-called big pharma's attempts at co-optation in the guise of antismoking collaborations3WHO Convention on Tobacco ControlThe tobacco epidemic has not gone away.https://fctc.who.int/newsroom/news/item/01-11-2021-the-tobacco-epidemic-has-not-gone-awayDate: Nov 1, 2021Date accessed: November 2, 2021Google Scholar) is that e-cigarettes are safer than conventional cigarettes, an assertion that could prove as harmful as the endorsement of tobacco by physicians between 1920 and 1950. It is universally accepted that cigarette smoking is harmful. Big tobacco eventually had to end its exploitation of misguided medical approval to sell cigarettes to a credulous public. Many doctors (and the public) are falling victim to a campaign built on selective reporting and misleading interpretation of scanty, poor-quality data to secure support for replacing one harmful mass addiction with another. The immediate toxic effects of e-cigarettes far outweigh those of conventional cigarettes,4Landman ST Dhaliwal I Mackenzie CA Martinu T Steele A Bosma KJ Life-threatening bronchiolitis related to electronic cigarette use in a Canadian youth.CMAJ. 2019; 191: e1321-31Crossref PubMed Scopus (59) Google Scholar, 5Nair N Hurley M Gates S et al.Life-threatening hypersensitivity pneumonitis secondary to e-cigarettes.Arch Dis Child. 2020; 105: 1114-1116Crossref PubMed Scopus (15) Google Scholar, 6O'Carroll O Sharma K Fabre A Murphy DJ Keane MP McCarthy C Vaping-associated lung injury.Thorax. 2020; 75: 706-707Crossref PubMed Scopus (4) Google Scholar so how can we assert that they are safer in the long term? As with any medicinal product, it is up to the manufacturer to prove that they are safe, not for doctors to prove that they are harmful. There is no robust evidence that e-cigarettes accelerate smoking cessation; e-cigarettes should be properly compared with existing methods of quitting smoking. The single study7Hajek P Phillips-Waller A Przulj D et al.A randomized trial of e-cigarettes versus nicotine-replacement therapy.N Engl J Med. 2019; 380: 629-637Crossref PubMed Scopus (667) Google Scholar cited by Public Health England suggesting the benefit of e-cigarettes showed that, after 1 year, smokers using conventional nicotine replacement had quit smoking, whereas those using e-cigarettes were still using these devices, essentially exchanging one form of nicotine addiction for another, thus guaranteeing continued income for big tobacco. Many e-cigarette users also used tobacco—the dream scenario for manufacturers. The suggestion that e-cigarettes are a benign alternative will encourage smokers aiming to quit to take up vaping in preference to conventional nicotine replacement. Nicotine addiction will therefore not diminish. There is rising use of vaping among children and young people globally. This rise represents a ticking public health time bomb, is a threat to decades of fighting smoking, and is the next big income generator for the tobacco industry. Rather than promote e-cigarettes, policy makers should treat vaping as equivalent to conventional tobacco: plain packaging, prohibition of flavourings and advertising, and inclusion of graphic health warnings. The UK has a proud track record in smoking cessation, which should not be tarnished by tacit promotion of this latest incarnation of an old addiction. The views of Public Health England are contradicted by the rest of the world. WHO, Forum of International Respiratory Societies, American Thoracic Society, European Academy of Paediatrics, and American Academy of Pediatrics have all recognised the dangers of e-cigarettes, resulting in a unanimous call for tougher regulation in line with that applied to conventional cigarettes. We must heed past lessons and prevent the delivery of a repurposed old addiction to an unsuspecting public. Unless they take heed of this warning, Public Health England, fresh from presiding over the biggest public health disaster in UK history, are now about to preside over an even bigger one. JV is a member of the Danish Medical Association Council for Prevention; is an advocate for restrictions in access to tobacco and alternative nicotine products; and is an active member in the European Respiratory Society leadership in promoting advocacy about the dangers of tobacco smoking and nicotine addiction. SB, CN, AB, WL, CP, and ST declare no competing interests. Medicinal licensing of e-cigarettesIn their criticism of the UK Medicines and Healthcare products Regulatory Agency's decision to support the process to develop medicinal licensing of e-cigarettes,1 Sarah Brown and colleagues2 overlook a wealth of evidence suggesting that use of these devices is substantially less harmful than smoking3–5 as well as a Cochrane review6 and actual use data7 showing that, by providing an alternative source of nicotine, e-cigarettes can be an effective aid to support people to quit smoking. Full-Text PDF

Background: With the widespread introduction of newborn screening for cystic fibrosis (CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age. Methods: Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs. Results: 65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT=0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT. Conclusions: In this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes. (C) 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Lung clearance index (LCI) in the early years was associated with LCI during adolescence in children with cystic fibrosis. Pre-school LCI may help to identify children in whom treatment could be intensified.https://bit.ly/2yKyMbM

INTRODUCTION: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has been shown to improve the nutritional status and lung function of cystic fibrosis patients with the G551D mutation in clinical trials. The objective of this study was to describe the real-world progress of children receiving ivacaftor. METHODS: We describe the real-world progress of four children with cystic fibrosis and the F508del/G551D genotype comparing data during ivacaftor treatment with baseline and with the year before commencing treatment. RESULTS: Our sample comprised 4 children aged between 6 and 14 years and including one with a recent diagnosis of CF and other with persistent Mycobacterium abscessus (M. abscessus) and recurrent allergic bronchopulmonary aspergillosis. The baseline FEV1 was 58.5% to 81.8% of the predicted value, and ivacaftor was taken for a mean 24 months (range, 12-30 months). All patients experienced a significant and sustained improvement in lung function. Compared to baseline, the weight z-score improved by 1.53 points, and the BMI z-score by 1.6 points. Compared to the year before starting ivacaftor, the frequency of Pseudomonas aeruginosa (P. aeruginosa) isolates decreased (-0.4/patient/year), as did the number of respiratory exacerbations (-1.8/patient/year). The weight-adjusted dose of lipase per kilogram decreased progressively in all patients. In 1 patient, a previously persistent M. abscessus infection and recurrent allergic bronchopulmonary aspergillosis resolved during treatment. CONCLUSIONS: Children with cystic fibrosis and the F508del/G551D genotype receiving treatment with ivacaftor experienced a real-world improvement in lung function, nutritional status, respiratory exacerbations, isolation of P. aeruginosa, and dose of pancreatic enzymes. Copyright (c) 2018. Publicado por Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction: Cystic Fibrosis (CF) requires multiple pharmaceutical treatments, elevating the risk of medication errors (ME), which may compromise patient safety. This study aimed to improve the quality of discharge prescriptions (DPs) using indicators following admissions for IV antibiotics in pediatric CF patients. Methods: This project involved a longitudinal observational retrospective descriptive study followed by a longitudinal quasi-experimental prospective phase between January 2013 and December 2016 in CF patients admitted to a London Children’s Hospital. The CF pharmacist reviewed DPs. Six rights of medication administration were defined (6R): dose, drug, frequency, duration of treatment, pharmaceutical form, and route of administration. We classified ME according to 6R, including subtype of error: committed/omitted. We calculated quality indicators by dividing the number of each correct parameter defined by 6R by number of DPs. Retrospective results were used prospectively to describe and implement improvement strategies and safety actions. Results: The retrospective study phase included 42 CF children (100 hospital admissions and 1,343 drugs). The prospective phase included thirty-five children (55 admissions and 822 drugs). The total number of ME identified was 148 (78 committed; 70 omitted) in retrospective phase and 135 (19 committed; 116 omitted) in prospective phase. Quality indicators for drug and dose showed significant improvement after implementing safety strategies. The global quality indicator increased from 22% (retrospective) to 41.82% (prospective), but we did not achieve the previously defined quality standard value (50%). Conclusions: A retrospective review of DP by a CF Pharmacist identified failures in DP quality. Implementing improvement strategies improved prescribing. Integrating pharmacist within multidisciplinary team improves DP reducing errors.

Resumen: Introducción: Ivacaftor es un potenciador de la proteína reguladora de la conductancia transmembrana de la fibrosis quística (CFTR) que ha demostrado en ensayos clínicos mejoría del estado nutricional y la función pulmonar de pacientes con fibrosis quística con mutación G551D. El objetivo de este estudio es describir la evolución en la vida real de niños tratados con ivacaftor. Métodos: Se describe la evolución en vida real de 4 niños con fibrosis quística con genotipo F508del/G551D comparando los datos durante el tratamiento con ivacaftor respecto a la situación basal y al año previo al tratamiento. Resultados: Se analizan 4 niños de entre 6 y 14 años, incluyendo uno con diagnóstico reciente de fibrosis quística y otro con infección persistente por Mycobacterium abscessus (M. abscessus) y aspergilosis broncopulmonar alérgica (ABPA) recurrente. El volumen espiratorio forzado en el primer segundo (FEV1) basal fue del 58,5-81,8% del predicho y recibieron ivacaftor 24 meses de media (rango 12-30 meses). Todos los pacientes tuvieron una mejoría significativa y mantenida de la función pulmonar. Respecto a la situación basal, el z-score del peso mejoró 1,53 puntos y el z-score del índice de masa corporal (IMC) 1,6 puntos. Comparado con el año previo al tratamiento con ivacaftor, disminuyeron la frecuencia de aislamientos de Pseudomonas aeruginosa (P. aeruginosa) (−0,4/paciente/año) y el número de exacerbaciones respiratorias (−1,8/paciente/año). La dosis de lipasa ajustada por kilo disminuyó progresivamente en todos los pacientes. Un paciente resolvió durante el tratamiento la infección por M. abscessus y la ABPA. Conclusiones: Los niños con fibrosis quística y mutación F508del/G551D tratados con ivacaftor mostraron en la vida real mejoría de la función pulmonar, el estado nutricional, las exacerbaciones respiratorias, los aislamientos de P. aeruginosa y la dosis de enzimas pancreáticas. Abstract: Introduction: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has been shown to improve the nutritional status and lung function of cystic fibrosis patients with the G551D mutation in clinical trials. The objective of this study was to describe the real-world progress of children receiving ivacaftor. Methods: We describe the real-world progress of four children with cystic fibrosis and the F508del/G551D genotype comparing data during ivacaftor treatment with baseline and with the year before commencing treatment. Results: Our sample comprised 4 children aged between 6 and 14 years and including one with a recent diagnosis of CF and other with persistent Mycobacterium abscessus (M. abscessus) and recurrent allergic bronchopulmonary aspergillosis. The baseline FEV1 was 58.5% to 81.8% of the predicted value, and ivacaftor was taken for a mean 24 months (range, 12-30 months). All patients experienced a significant and sustained improvement in lung function. Compared to baseline, the weight z-score improved by 1.53 points, and the BMI z-score by 1.6 points. Compared to the year before starting ivacaftor, the frequency of Pseudomonas aeruginosa (P. aeruginosa) isolates decreased (−0.4/patient/year), as did the number of respiratory exacerbations (−1.8/patient/year). The weight-adjusted dose of lipase per kilogram decreased progressively in all patients. In 1 patient, a previously persistent M. abscessus infection and recurrent allergic bronchopulmonary aspergillosis resolved during treatment. Conclusions: Children with cystic fibrosis and the F508del/G551D genotype receiving treatment with ivacaftor experienced a real-world improvement in lung function, nutritional status, respiratory exacerbations, isolation of P. aeruginosa, and dose of pancreatic enzymes.

Newborn screening and extensive genetic analysis has led to the recognition of a cohort of infants with an equivocal diagnosis of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) disease. This paper reviews the comprehensive approach required for diagnosis of Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) and uses an illustrative case with p.Asp1152His (D1152H) mutation to examine the varying clinical phenotype seen amongst CFSPID patients. Whilst infants are well at diagnosis, uncertainties about cystic fibrosis (CF) disease progression indicate the importance of monitoring and early specialist involvement. However, over-medicalisation can cause significant psychosocial impact on patients’ and families. The complexities underlying the surveillance and long-term management of patients with CFSPID are explored.

Lung infections with Mycobacterium abscessus , a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.

Lung infections with Mycobacterium abscessus, a species of multidrug resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF) where they accelerate inflammatory lung damage leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.

The success of whole-exome sequencing to identify mutations causing single-gene disorders has been well documented. In contrast whole-exome sequencing has so far had limited success in the identification of variants causing more complex phenotypes that seem unlikely to be due to the disruption of a single gene. We describe a family where two male offspring of healthy first cousin parents present a complex phenotype consisting of peripheral neuropathy and bronchiectasis that has not been described previously in the literature. Due to the fact that both children had the same problems in the context of parental consanguinity we hypothesised illness resulted from either X-linked or autosomal recessive inheritance. Through the use of whole-exome sequencing we were able to simplify this complex phenotype and identified a causative mutation (p.R1070*) in the gene periaxin (PRX), a gene previously shown to cause peripheral neuropathy (Dejerine–Sottas syndrome) when this mutation is present. For the bronchiectasis phenotype we were unable to identify a causal single mutation or compound heterozygote, reflecting the heterogeneous nature of this phenotype. In conclusion, in this study we show that whole-exome sequencing has the power to disentangle complex phenotypes through the identification of causative genetic mutations for distinct clinical disorders that were previously masked.

Background: Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) leads to a negative impact in disease evolution and enforces therapeutic programs for controlling and eradication of this infection. Objectives: The assessment of tobramycin inhaled therapy in patients with CF associated with P. aeruginosa chronic lung infection. Methods: The study includes 15 patients with CF associated with chronic airway infection with P. aeruginosa. CF diagnosis was confirmed through positive sweat test and genetic testing of the CFTR mutations. The patients’ average age was 14.86±5.6 years (8−25 years). Tobramycin aerosol therapy (TOBI 300mg/5ml) was performed in an alternating program (300mg ×2, 28 days 4−6 cycles). Respiratory FVC and FEV1 indices were used for lung function monitoring. Results: Before starting tobramycin treatment, all the patients showed decreased spirometric indices: FVC (63.66±1.64%) and FEV1 (59.8±1.46%). After 12 months of treatment, these indices improved to FVC 67.23±1.11%, FEV1 62.95±2.33%. Inhaled tobramycin treatment also determined a suppression of P. aeruginosa infection in patients with CF. P. aeruginosa titres were 103−108 (mean titre 6.31±0.11) before the treatment and decreased with 1−3 titres in 46.7% of cases. P. aeruginosa infection was completely eradicated in 13.3% of cases. Conclusion: Tobramycin aerosol therapy helps to control and eradicate P. aeruginosa lung infection and improves respiratory function by increasing FVC and FEV1 spirometric indices.