136 results found
Castellani C, De Boeck K, De Wachter E, et al., 2022, ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria., J Cyst Fibros
This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved. The definition of a CFTR-RD remains "a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF". Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD.
Tanner KT, Daniel RM, Bilton D, et al., 2022, Mediation of the total effect of cystic fibrosis-related diabetes on mortality: A UK Cystic Fibrosis Registry cohort study, DIABETIC MEDICINE, Vol: 39, ISSN: 0742-3071
Stanford GE, Jones M, Charman SC, et al., 2022, Clinimetric analysis of outcome measures for airway clearance in people with cystic fibrosis: a systematic review, Therapeutic Advances in Respiratory Disease, Vol: 16, Pages: 1-12, ISSN: 1753-4666
Background:Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy.Objectives:To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF.Design and Methods:A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required.Results:No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified.Discussion and conclusion:This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essenti
Davies J, Hughes D, Rosenthal M, et al., 2022, An invisible threat? Aspergillus positive cultures and co-infecting bacteria in airway sample, Journal of Cystic Fibrosis, ISSN: 1569-1993
BackgroundAspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing.MethodsFrequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010–2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates.ResultsPa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02–1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium.ConclusionsPa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed.
Cameron RA, Office D, Matthews J, et al., 2022, Treatment Preference Among People With Cystic Fibrosis: The Importance of Reducing Treatment Burden., Chest
BACKGROUND: There is a growing consensus that the perspective of the patient should be considered in the evaluation of novel interventions. RESEARCH QUESTION: What treatment outcomes matter to people with cystic fibrosis (CF), and what trade-offs would they make to realize these outcomes? STUDY DESIGN AND METHODS: Adults attending a specialist CF center were invited to complete an online discrete choice experiment (DCE). The DCE required participants to evaluate hypothetical CF treatment profiles, defined by impact on lung function, pulmonary exacerbations, abdominal symptoms, life expectancy, quality of life, inhaled medicine usage, and physiotherapy requirement. Choice data were analyzed, using multinomial logit and latent class models. RESULTS: One hundred and three people with CF completed the survey (median age, 35 years; range, 18-76 years); 52% were female; mean FEV1 % predicted, 69% [SD, 22%]). On average, an improvement in life expectancy by 10 years or more had the greatest impact on treatment preference, followed by a 15% increase in lung function. However, it was shown that people would trade substantial reductions in these key outcomes to reduce treatment time or burden. Preference profiles were not uniform across the sample: three distinct subgroups were identified, each placing markedly different importance on the relative importance of both life expectancy and lung function compared with other attributes. INTERPRETATION: The relative importance of treatment burden to people with CF, compared with life expectancy and lung function, suggests it should be routinely captured in clinical trials as an important secondary outcome measure. When considering the patient perspective, it is important that decision-makers recognize that the values of people with CF are not homogeneous.
Balfour-Lynn IM, Puckey M, Simmonds NJ, et al., 2022, Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 29-34, ISSN: 1526-0542
Simmonds NJ, van der Ent CK, Colombo C, et al., 2022, VOCAL: An observational study of ivacaftor for people with cystic fibrosis and selected non-G551D-CFTR gating mutations., J Cyst Fibros
BACKGROUND: VOCAL was an observational study of the effect of long-term ivacaftor on real-world clinical outcomes and healthcare resource utilization (HCRU) in people with cystic fibrosis (pwCF) in Italy, the Netherlands, and the UK. METHODS: pwCF aged ≥6 years with non-G551D-CFTR gating mutations were eligible. Prospective data were collected up to 48 months after enrollment; retrospective data were collected to ensure that 12 months of pre-ivacaftor data were available. Endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and measures of nutritional status. Pulmonary exacerbation (PEx) rates, HCRU, and respiratory microbiology during ivacaftor treatment were compared with data from the 12-month period before initiation. RESULTS: Seventy-three eligible pwCF were enrolled and received ivacaftor; 65 (89.0%) completed the study (48 [65.8%] completed ≥48 months of ivacaftor). During the first 6 months of ivacaftor, ppFEV1, body mass index (BMI), and BMI-for-age z-score showed least-squares mean absolute improvements of 10.8 percentage points, 0.79 kg/m2, and 0.54, respectively; improvements were maintained through 48 months. Rates of PEx, antibiotic use due to PEx, and hospitalization decreased by >50% during ivacaftor treatment compared with before ivacaftor. The number of respiratory cultures and sputum was lower post-ivacaftor, as was the percentage of pwCF with positive respiratory cultures for 3 of 9 pathogens evaluated (Pseudomonas aeruginosa, Aspergillus fumigatus, Stenotrophomonas maltophilia). Reported safety results were consistent with CF and ivacaftor's known safety profile. CONCLUSIONS: These results demonstrate the positive long-term effectiveness of ivacaftor on clinical outcomes and HCRU in pwCF with non-G551D-CFTR gating mutations in real-world settings.
Archangelidi O, Cullinan P, Simmonds NJ, et al., 2022, Incidence and risk factors of cancer in individuals with cystic fibrosis in the UK; a case-control study., Journal of Cystic Fibrosis, Vol: 21, Pages: 302-308, ISSN: 1569-1993
To assess cancer incidence in the UK cystic fibrosis (CF) population and determine the associated risk factors, we undertook a nested case-control study of patients with CF, registered with the UK CF Registry. Each case with a first reported cancer between 1999 and 2017 was matched with up to 4 controls: by age (±2-years) and year of cancer diagnosis. Conditional logistic regressions were adjusted for sex, lung function (FEV1%), CF related diabetes (CFRD), F508del status, transplant status, DIOS, gastro-oesophageal reflux disease, meconium ileus, Pseudomonas aeruginosa infection, pancreatic insufficiency, proton pump inhibitor (PPI) use, IV antibiotic days and BMI. Results: From 12,886 registered patients, 146 (1.1%) cases of malignancy were identified with 14.3% of cases occurring post solid organ transplant. Site of primary cancer was available for 98 patients: 22% were gastro-intestinal in origin (77% lower, 23% upper GI), 13% skin, 13% breast and 11% lymphomas/leukaemia. In univariable analysis, transplantation increased the odds of reporting any cancer by 2.46 times (95%CI: 1.3-4.6). CFRD also increased the odds of reporting any cancer (OR 2.35; CI: 1.37-4.0) and PPI use (OR 2.0; CI 1.28-3.19). In the multivariable models significant associations with CFRD and transplant remained, while PA infection, PPI use and being overweight showed increased, but statistically insignificant risks. The incidence of GI cancer was strongly associated with CFRD (OR=4.04; 1.47-11.1). Conclusions: We observed a high incidence of lower GI cancers in our cohort which was significantly affected by the presence of CFRD. Screening for gastrointestinal cancers could benefit patients at higher risk.
Cirilli N, Southern KW, Barben J, et al., 2022, Standards of care guidance for sweat testing; phase two of the ECFS quality improvement programme, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 434-441, ISSN: 1569-1993
Simmonds NJ, van der Ent K, Colombo C, et al., 2021, OBSERVATIONAL STUDY OF IVACAFTOR IN PEOPLE WITH CYSTIC FIBROSIS AND SELECTED NON-G551D GATING MUTATIONS: FINAL RESULTS FROM VOCAL, Publisher: BMJ PUBLISHING GROUP, Pages: A40-A41, ISSN: 0040-6376
Castellani C, Simmonds NJ, Colombo C, et al., 2021, RESPIRATORY MICROBIOLOGY OUTCOMES FROM AN OBSERVATIONAL STUDY OF IVACAFTOR IN PEOPLE WITH CYSTIC FIBROSIS AND NON-G551D GATING MUTATIONS (VOCAL), Publisher: BMJ PUBLISHING GROUP, Pages: A41-A41, ISSN: 0040-6376
Dobra R, Davies G, Pike K, et al., 2021, Optimising equity of access: how should we allocate slots to the most competitive trials in Cystic Fibrosis (CF)?, Journal of Cystic Fibrosis, Vol: 20, Pages: 978-985, ISSN: 1569-1993
Background:Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients’ engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes.Methods:We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis.Results:We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation.Conclusions:Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory.
Dave K, Dunk R, Madge S, et al., 2021, Could a 2-year mortality prediction model have prevented deaths from respiratory failure: a single UK centre experience, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Castellani C, Simmonds NJ, Colombo C, et al., 2021, Respiratory microbiology outcomes from an observational study of ivacaftor in people with cystic fibrosis and non-G551D gating mutations (VOCAL), European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Simmonds N, Van Der Ent K, Colombo C, et al., 2021, Observational study of ivacaftor in people with cystic fibrosis and selected non-G551D gating mutations: final results from VOCAL, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Van Koningsbruggen-Rietschel S, Dunlevy F, Bulteel V, et al., 2021, Protecting clinical trials in cystic fibrosis during the SARS-CoV-2 pandemic: risks and mitigation measures, TRIALS, Vol: 22
Dave K, Gerovasili V, Simmonds NJ, et al., 2021, The Changing Face of Lung Transplant Waiting Lists in the Era of CFTR Modulators, Publisher: ELSEVIER SCIENCE INC, Pages: S368-S368, ISSN: 1053-2498
Kazani S, Rowlands DJ, Bottoli I, et al., 2021, Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251), JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 250-256, ISSN: 1569-1993
Cuthbertson L, Felton I, James P, et al., 2021, The fungal airway microbiome in cystic fibrosis and non-cystic fibrosis bronchiectasis, Journal of Cystic Fibrosis, Vol: 20, Pages: 295-302, ISSN: 1569-1993
BackgroundThe prevalence of fungal disease in cystic fibrosis (CF) and non-CF bronchiectasis is increasing and the clinical spectrum is widening. Poor sensitivity and a lack of standard diagnostic criteria renders interpretation of culture results challenging. In order to develop effective management strategies, a more accurate and comprehensive understanding of the airways fungal microbiome is required. The study aimed to use DNA sequences from sputum to assess the load and diversity of fungi in adults with CF and non-CF bronchiectasis.MethodsNext generation sequencing of the ITS2 region was used to examine fungal community composition (n = 176) by disease and underlying clinical subgroups including allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, non-tuberculous mycobacteria, and fungal bronchitis. Patients with no known active fungal disease were included as disease controls.ResultsITS2 sequencing greatly increased the detection of fungi from sputum. In patients with CF fungal diversity was lower, while burden was higher than those with non-CF bronchiectasis. The most common operational taxonomic unit (OTU) in patients with CF was Candida parapsilosis (20.4%), whereas in non-CF bronchiectasis sputum Candida albicans (21.8%) was most common. CF patients with overt fungal bronchitis were dominated by Aspergillus spp., Exophiala spp., Candida parapsilosis or Scedosporium spp.ConclusionThis study provides a framework to more accurately characterize the extended spectrum of fungal airways diseases in adult suppurative lung diseases.
Davies J, Dobra R, Huband K, et al., 2021, Strengthening clinical trial pharmacovigilance: simple interventions improve communication over serious adverse events, Journal of Clinical Trials
Hughes DA, Cuthbertson L, Price H, et al., 2021, PSEUDOMONAS AERUGINOSA IMPAIRS GROWTH OF ASPERGILLUS FROM CF AIRWAY SAMPLES, Publisher: BMJ PUBLISHING GROUP, Pages: A159-A159, ISSN: 0040-6376
Dave K, Dobra R, Scott S, et al., 2021, Entering the era of highly effective modulator therapies, PEDIATRIC PULMONOLOGY, Vol: 56, Pages: S79-S89, ISSN: 8755-6863
Simmonds NJ, 2021, Introducing the Adult Cystic Fibrosis Series An Exciting Time of Change, But New Challenges Lie Ahead, CHEST, Vol: 159, Pages: 3-4, ISSN: 0012-3692
Stanford GE, Dave K, Simmonds NJ, 2021, Pulmonary Exacerbations in Adults With Cystic Fibrosis A Grown-up Issue in a Changing Cystic Fibrosis Landscape, CHEST, Vol: 159, Pages: 93-102, ISSN: 0012-3692
Savi D, Graziano L, Giordani B, et al., 2020, New strategies of physical activity assessment in cystic fibrosis: a pilot study, BMC PULMONARY MEDICINE, Vol: 20, ISSN: 1471-2466
Stanford G, Davies JC, Usmani O, et al., 2020, Investigating outcome measures for assessing airway clearance techniques in adults with cystic fibrosis: protocol of a single-centre randomised controlled crossover trial, BMJ Open Respiratory Research, Vol: 7, ISSN: 2052-4439
INTRODUCTION: Airway clearance techniques (ACTs) are a gold standard of cystic fibrosis management; however, the majority of research evidence for their efficacy is of low standard; often attributed to the lack of sensitivity from outcome measures (OMs) used historically. This randomised controlled trial (RCT) investigates these standard OMs (sputum weight, forced expiratory volume in 1 s) and new OMs (electrical impedance tomography (EIT), multiple breath washout (MBW) and impulse oscillometry (IOS)) to determine the most useful measures of ACT. METHODS AND ANALYSIS: This is a single-centre RCT with crossover design. Participants perform MBW, IOS and spirometry, and then are randomised to either rest or supervised ACT lasting 30-60 min. MBW, IOS and spirometry are repeated immediately afterwards. EIT and sputum are collected during rest/ACT. On a separate day, the OMs are performed with the other intervention. Primary endpoint is difference in change in OMs before and after ACT/rest. Sample size was calculated with 80% power and significance of 5% for each OM (target n=64). ETHICS AND DISSEMINATION: Ethics approval was gained from the London-Chelsea Research Ethics Committee (reference 16/LO/0995, project ID 154635). Dissemination will involve scientific conference presentation and publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ISRCTN11220163 and NCT02721498.
Hughes D, Cuthbertson L, Price H, et al., 2020, PSEUDOMONAS AERUGINOSA IMPAIRS GROWTH OF ASPERGILLUS FROM CF AIRWAY SAMPLES, Publisher: WILEY, Pages: S153-S153, ISSN: 8755-6863
van der Ent K, Simmonds NJ, Colombo C, et al., 2020, AN OBSERVATIONAL STUDY OF IVACAFTOR IN PEOPLE WITH CYSTIC FIBROSIS AND SELECTED NON-G551D GATING MUTATIONS: OUTCOMES FROM THE THIRD INTERIM ANALYSIS OF THE VOCAL STUDY, Publisher: WILEY, Pages: S220-S220, ISSN: 8755-6863
Silva GF, Simmonds NJ, Roth Dalcin PDT, 2020, Clinical characteristics and outcomes in adult cystic fibrosis patients with severe lung disease in Porto Alegre, southern Brazil, BMC Pulmonary Medicine, Vol: 20, Pages: 1-8, ISSN: 1471-2466
BackgroundAdvanced lung disease in adult cystic fibrosis (CF) drives most clinical care requirements. The aim was to evaluate outcome (time to death while in the study) in a cohort of adult CF patients with severe lung disease, and to determine the association among baseline patient characteristics and outcome.MethodsA retrospective cohort study was performed and clinical records between 2000 and 2015 were reviewed. Severe lung disease was defined as forced expiratory volume in the first second (FEV1) < 30% of predicted. Outcomes of all patients, including their date of death or transplantation, were determined till January 1st, 2016. Clinical data were recorded at the entry date.ResultsAmong 39 subjects included in the study, 20 (51.3%) died, 16 (41.0%) underwent bilateral lung transplantation, and 3 were alive at the end of the study period. Two variables were independently associated with death: body mass index (BMI ≥ 18.5 kg/m2) (HR = 0.78, 95% CI = 0.64–0.96 and p = 0.017) and use of tobramycin inhalation therapy (HR = 3.82, 95% CI = 1.38–10.6 and p = 0.010). Median survival was 37 (95% CI = 16.4–57.6) months. The best cut-off point for BMI was 18.5 kg/m2. Median survival in patients with BMI < 18.5 kg/m2 was 36 months (95% CI = 18.7–53.3).ConclusionMedian survival of CF subjects with FEV1 < 30% was 37 months. BMI and tobramycin inhalation therapy were independently associated with death. Median survival in patients with BMI < 18.5 kg/m2 was significantly lower than in patients with BMI ≥ 18.5 kg/m2. The association of tobramycin inhalation with death was interpreted as confounding by severity (use was reserved for advanced lung disease).
Vijayasingam A, Frost E, Wilkins J, et al., 2020, Tablet and web-based audiometry to screen for hearing loss in adults with cystic fibrosis, Thorax, Vol: 75, Pages: 632-639, ISSN: 0040-6376
INTRODUCTION: Individuals with chronic lung disease (eg, cystic fibrosis (CF)) often receive antimicrobial therapy including aminoglycosides resulting in ototoxicity. Extended high-frequency audiometry has increased sensitivity for ototoxicity detection, but diagnostic audiometry in a sound-booth is costly, time-consuming and requires a trained audiologist. This cross-sectional study analysed tablet-based audiometry (Shoebox MD) performed by non-audiologists in an outpatient setting, alongside home web-based audiometry (3D Tune-In) to screen for hearing loss in adults with CF. METHODS: Hearing was analysed in 126 CF adults using validated questionnaires, a web self-hearing test (0.5 to 4 kHz), tablet (0.25 to 12 kHz) and sound-booth audiometry (0.25 to 12 kHz). A threshold of ≥25 dB hearing loss at ≥1 audiometric frequency was considered abnormal. Demographics and mitochondrial DNA sequencing were used to analyse risk factors, and accuracy and usability of hearing tests determined. RESULTS: Prevalence of hearing loss within any frequency band tested was 48%. Multivariate analysis showed age (OR 1.127; (95% CI: 1.07 to 1.18; p value<0.0001) per year older) and total intravenous antibiotic days over 10 years (OR 1.006; (95% CI: 1.002 to 1.010; p value=0.004) per further intravenous day) were significantly associated with increased risk of hearing loss. Tablet audiometry had good usability, was 93% sensitive, 88% specific with 94% negative predictive value to screen for hearing loss compared with web self-test audiometry and questionnaires which had poor sensitivity (17% and 13%, respectively). Intraclass correlation (ICC) of tablet versus sound-booth audiometry showed high correlation (ICC >0.9) at all frequencies ≥4 kHz. CONCLUSIONS: Adults with CF have a high prevalence of drug-related hearing loss and tablet-based audiometry can be a practical, accurate screening tool within integrated ototoxicity monitoring programmes for early detection.
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