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In 2018 we published the James Lind Alliance (JLA) top 10 priorities for clinical research in cystic fibrosis (CF), chosen jointly by the patient and clinical communities. These priorities have led to new research funding. To establish whether priorities have changed with novel modulator therapies, we undertook an online international update through a series of surveys and a workshop. Patients and clinicians (n=1417) chose the refreshed top 10 from 971 new research questions (suggested by patients and clinicians) and 15 questions from 2018. We are working with the international community to promote research based on these refreshed top 10 priorities., Competing Interests: Competing interests: NJR reports support from Cystic Fibrosis Trust for attending meetings. KC reports consultancy fees for facilitation services with James Lind Alliance and CF Trust. ARS reports a Vertex Pharmaceuticals Investigator Sponsored Study Award (paid to University of Nottingham) and consultancy fees for Viatris Advisory Board (paid to University of Nottingham), a patent (Camara M, Williams P, Barrett D, Halliday N, Knox A, Smyth A, Fogarty A, Barr H, Forrester D. Alkyl quinolones as biomarkers of pseudomonas aeruginosa infection and uses thereof. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Patent Summary for US-2016131648-A1; [cited 2020 Nov. 17]. Available from: https://pubchem.ncbi.nlm.nih.gov/patent/US-2016131648-A1) and participation on the US CF Foundation data safety monitoring board., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Persisting respiratory symptoms in COVID-19 survivors may be related to development of pulmonary fibrosis. We assessed the proportion of chest CT scans and pulmonary function tests consistent with parenchymal lung disease in the follow-up of people hospitalised with COVID-19 and viral pneumonitis., Methods: Systematic review and random effects meta-analysis of proportions using studies of adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza pneumonia and followed up within 12 months. Searches performed in MEDLINE and Embase. Primary outcomes were proportion of radiological sequelae on CT scans; restrictive impairment; impaired gas transfer. Heterogeneity was explored in meta-regression., Results: Ninety-five studies (98.9% observational) were included in qualitative synthesis, 70 were suitable for meta-analysis including 60 SARS-CoV-2 studies with a median follow-up of 3 months. In SARS-CoV-2, the overall estimated proportion of inflammatory sequelae was 50% during follow-up (0.50; 95% CI 0.41 to 0.58; I 2 =95%), fibrotic sequelae were estimated in 29% (0.29; 95% CI 0.22 to 0.37; I 2 =94.1%). Follow-up time was significantly associated with estimates of inflammatory sequelae (-0.036; 95% CI -0.068 to -0.004; p=0.029), associations with fibrotic sequelae did not reach significance (-0.021; 95% CI -0.051 to 0.009; p=0.176). Impaired gas transfer was estimated at 38% of lung function tests (0.38 95% CI 0.32 to 0.44; I 2 =92.1%), which was greater than restrictive impairment (0.17; 95% CI 0.13 to 0.23; I 2 =92.5%), neither were associated with follow-up time (p=0.207; p=0.864)., Discussion: Sequelae consistent with parenchymal lung disease were observed following COVID-19 and other viral pneumonitis. Estimates should be interpreted with caution due to high heterogeneity, differences in study casemix and initial severity., Prospero Registration Number: CRD42020183139., Competing Interests: Competing interests: GJ reports NIHR BRC salaries, studentships, professorship (RP-2017-08-ST2-014)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

This case is an example of a rare cause of a common clinical presentation (persistent lobar collapse with wheeze). We describe patient management from primary care through to a national thoracic referral centre. We highlight the importance of objective testing to support an asthma diagnosis and the need to consider alternative or additional diagnoses if a patient does not respond to treatment or the clinical course is unexpected. We highlight the importance of follow-up X-ray to determine whether atelectasis has resolved, which was significantly delayed in this case due to COVID-19 restrictions. Though rare, an endobronchial tumour should be considered if atelectasis persists and when planning endoscopy for a presumed foreign body, especially if the clinical history and patient factors make a foreign body less likely. Greater awareness of this as a differential may expedite diagnoses for patients in future. We show how virtual, multicentre, multidisciplinary meetings can aid rapid diagnosis, surgical planning and coordination of follow-up across centres., Competing Interests: Competing interests: ARS reports grants and speaker honoraria from Vertex as well as expenses and personal fees from Vertex, outside the submitted work. In addition, ARS has a patent issued 'alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof'. The other authors had no competing interests to declare., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Reducing treatment burden in cystic fibrosis (CF) is the top research priority for patients and clinicians. Difficulty accessing medication is one aspect of treatment burden. We investigated this with an online survey available globally for patients with CF and healthcare professionals. Almost three quarters of patients with CF in our survey report difficulty getting repeat prescriptions on time, and most community pharmacists experience interrupted supplies of CF-specific medications. These barriers affect emotional and physical health of people with CF. Two-thirds of people with CF would like to get all their CF medication from one place, their CF centre., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV 1 ) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV 1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of 'normal' (FEV 1 ≥90% predicted) and 'mild lung disease' (FEV 1 70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled 'Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis', was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted., Competing Interests: Competing interests: TR reports personal fees from Vertex Pharmaceuticals during the conduct of the study; in addition, TR has a patent PCT/AU2016/000079 issued. JCD reports others from Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Galapagos NV, ImevaX GmbH, Nivalis Therapeutics, Inc., ProQR Therapeutics III B.V., Proteostasis Therapeutics, Inc., Raptor Pharmaceuticals, Inc, Vertex Pharmaceuticals (Europe) Limited, Enterprise, Novartis, Pulmocide and Flatley; grants from CF Trust; and others from Teva, outside the submitted work. JSE reports grants from Ionis and the European Commission; personal fees and others from Vertex, during the conduct of the study. MM reports grants from the German Federal Ministry of Education and Research and Einstein Foundation Berlin, during the conduct of the study; personal fees and others from Boehringer Ingelheim and Vertex Pharmaceuticals; personal fees from Arrowhead Pharmaceuticals, Santhera, Galapagos, Sterna Biologicals, Enterprise Therapeutics and Antabio, outside the submitted work. FR reports non-financial support from Vertex during the conduct of the study and acts as a consultant to Vertex Pharmaceuticals, who was the sponsor of this meeting. ARS reports grants from Vertex and personal fees from Novartis, Teva and Vertex, outside the submitted work; and patent issued: 'Alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof'. SS reports a patent licensed to Thirona, and a patent licensed to Resonance Health Ltd and Institutional reimbursement from Vertex Pharmaceuticals (Australia) Pty Ltd. for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth. CEW reports institutional reimbursement from Vertex Pharmaceuticals (Australia) P/L for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth; income on a per patient basis derived from Pharmaceutical Studies - Vertex Pharmaceuticals Inc., and Boehringer-Ingelheim; research grant from Novo Nordisk Pharmaceuticals P/L- CF-IDEA Study; other reimbursements from Vertex Pharmaceuticals P/L honorarium to attend CF International Advisory Board Meeting in February 2014, Vertex Pharmaceuticals P/L honorarium to attend CF Medical Advisory Board Meeting in Adelaide in April 2014, Novartis Pharmaceuticals P/L honorarium to present symposium at National Pediatric Congress in Lebanon in May 2014, European CF Conference in Gothenburg June 2014 Vertex Pharmaceuticals P/L return travel and honorarium for lecture and discussions, North American CF Conference Georgia October 2014 DKBmed, LLC honorarium to present symposium, Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting series in Brisbane and Sydney in April 2015, Vertex Pharmaceuticals P/L honorarium to attend the Vertex Steering Committee Meetings re VX15-770-123 Study in 2014, Vertex Pharmaceuticals P/L honorarium for Vertex Medical Advisory Board- Innovative endpoints in CF in August 2015, The University of Miami honorarium for meeting attendance in 2015, Thorax honorarium for associate editor duties Q3/Q4 2015, BMJ honorarium for work as reviewer, Vertex Pharmaceuticals 2015 Chicago return flight and accommodation as investigator in Lumacaftor study, Vertex Pharmaceuticals 2015–2017 honorarium as speaker at Vertex sponsored educational meeting series in Australia, Vertex Pharmaceuticals 2016 Phoenix return flight and accommodation as investigator in Next Gen study, Vertex Pharmaceuticals December 2016 honoraria as speaker at Vertex sponsored educational meeting in Liverpool, UK DKBmed eCF Review Issue honoraria in January 2017, Vertex Pharmaceuticals–March 2017 honoraria as speaker at TSANZ meeting Vertex Pharmaceuticals Inc. 2014–2018, honorarium for acting as consultant on the Vertex Orkambi 6-11 HTA Advisory Board, the Global Pediatric Advisory Committee, the Global Medical Advisory Board, and the VIA Grants Committee; Gilead Sciences Ltd. honorarium for meeting attendance on CF imaging; Honorarium for In Vivo Academy Limited for webcast meeting attendance at ECFC–2018; Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting at ECFC in Belgrade–2018; Vertex Pharmaceuticals Inc. honorarium to attend Next Gen Early Lifecycle Management Plan–London–2018; Vertex Pharmaceuticals P/L to act as consultant and to render such services in the form of documents, advice, meetings and conferences during the period October 2018; present Vertex Pharmaceuticals P/L to attend the EU Real World Evidence Steering Committee in Amsterdam–2019 Current Board Positions–International Advisory Board Vertex Pharmaceuticals P/L Deputy Editor Thorax /Associate Editor Respirology. PDR reports institutional reimbursement from Vertex Pharmaceuticals (Australia) Pty. Ltd for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19., Methods: Electronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality., Results: 71 studies totalling 22 058 patients were included, 6 were randomised trials. Most studies explored outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 0.83, 95% CI 0.72 to 0.96, I 2 =0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 1.34, 95% CI 1.10 to 1.64, I 2 =98%) and adjusted mortality risk (HR 0.52, 95% CI 0.41 to 0.66, I 2 =76.6%). The mean difference in duration of hospitalisation was 0.36 days (95% CI -0.07 to 0.80, I 2 =93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent., Conclusion: Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings., Prospero Registration Number: CRD42020176375., Competing Interests: Competing interests: GJ received grants from GlaxoSmithKline, during the conduct of the study, Astra Zeneca, Biogen and Galecto; personal fees from Boehringer Ingelheim, Daewoong, Galapagos, Heptares, Promedior and Roche; non-financial support from NuMedii and Redx; grants and personal fees from Pliant and other supports from Action for Pulmonary Fibrosis, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Digital healthcare is a rapidly growing healthcare sector. Its importance has been recognised at both national and international level, with the WHO recently publishing its first global strategy for digital health. The use of digital technology within cystic fibrosis (CF) has also increased. CF is a chronic, life-limiting condition, in which the treatment burden is high and treatment regimens are not static. Digital technologies present an opportunity to support the lives of people with CF. We included 59 articles and protocols in this state-of-the-art review, relating to 48 studies from 1999 until 2019. This provides a comprehensive overview of the expansion and evolution of the use of digital technology. Technology has been used with the aim of increasing accessibility to healthcare, earlier detection of pulmonary exacerbations and objective electronic adherence monitoring. It may also be used to promote adherence and self-management through education, treatment management Apps and social media., Competing Interests: Competing interests: ARS has provided consultancy for Vertex and holds a current unrestricted research grant from Vertex. He has taken part in clinical trials sponsored by Vertex, Raptor and Insmed. He has given lectures at meetings sponsored by Teva and Vertex., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Cystic fibrosis (CF) is a multisystem disorder. Treatment is complex and evidence for treatment decisions may be absent. Characterising gaps in the research evidence will highlight treatment uncertainties and help prioritise research questions. We systematically identified the evidence gaps for treatment decisions in CF., Methods: We searched for systematic reviews and guidelines on treatment interventions in CF. Two researchers identified eligible reviews with arbitration from a third. Using a structured framework, we extracted and characterised evidence gaps., Results: There were 73 reviews and 21 guidelines that met our inclusion criteria. From these, we identified 148 evidence gaps across a range of treatment areas. We found 111 evidence gaps through systematic reviews and a further 37 from guidelines. The reason for an evidence gap could only be reliably characterised for systematic reviews. In most cases, there was more than one explanation-most commonly few or no trials (97/111 evidence gaps). Other important factors leading to evidence gaps were small sample size (49/111), inadequate duration of follow-up (38/111) or intervention (37/111) and factors relating to outcomes (35/111). Evidence gaps from both systematic reviews and guidelines fell into the following categories: Respiratory (91); Gastrointestinal (20); PhysiotherapyandExercise (16); Musculoskeletal (6); Endocrine (4); Basic defect of CF (8); Psychosocial (2); Ears, Nose and Throat (1)., Conclusions: We have compiled an up-to-date list of treatment uncertainties in CF and the reasons for these uncertainties. These can be used as a resource to aid researchers and funders when planning future trials., Prospero Registration Number: Pre-results; CRD42015030111., Competing Interests: Competing interests: Outside the submitted work: NJR reports non-financial support from Teva. ARS reports personal fees from Vertex, PTC, Roche, TEVA and Gilead. In addition, ARS has a patent Application No. 14737297.3 (in Europe) Biomarkers for Pseudomonas aeruginosa for The University of Nottingham pending and has taken part in clinical trials sponsored by Vertex, Raptor, Insmed, Pharmaxis and Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease, such as cystic fibrosis (CF). Pulmonary disease (PD) caused by NTM has emerged as a major threat to the health of individuals with CF, but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened a panel of 19 experts to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM-PD in individuals with CF. PICO (population, intervention, comparison, outcome) methodology and systematic literature reviews were employed to inform draft recommendations, which were then modified to achieve consensus and subsequently circulated for public consultation within the USA and European CF communities. We have thus generated a series of pragmatic, evidence-based recommendations as an initial step in optimising management for this challenging condition., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered 'good' agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

An 11 year old boy with cystic fibrosis suffered a stroke, producing right sided weakness. Four years previously a totally implantable venous access device (Port-a-Cath) had been inserted. Magnetic resonance angiography revealed a filling defect in the left middle cerebral artery. Transoesophageal echocardiography demonstrated a thrombus attached to the tip of the Port-a-Cath and also the presence of a patent foramen ovale. After an initial period of anticoagulation the defect was closed using a septal occlusion device introduced via a cardiac catheter. The boy's neurological signs completely resolved and he remains free from further thromboembolic episodes. Whilst pulmonary embolism has been described before in relation to a totally implantable venous access device, this is believed to be the first description of a paradoxical embolism in relation to such a device.