BACKGROUND:The impact of CFTR modulator therapy on host immunity and outcomes in people with Cystic Fibrosis (CF)-related Aspergillus lung disease is poorly defined. We aimed to characterise fungal-relevant clinical outcomes post-CFTR modulators and assess effects on the Aspergillus-dependent Type I/III interferome. METHODS:Biomarkers of Aspergillus-related lung disease (Aspergillus-specific IgE/IgG), anti-fungal and corticosteroid therapy were analysed in a retrospective cohort of people with CF pre and post Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy. Homozygous F508del (CF) and CFTR TALEN-corrected bronchial epithelial cells (BECs) were challenged with Aspergillus conidia and hyphae in the presence or absence of ETI CFTR modulator therapy with bulk RNA transcriptomics and RT-PCR used to analyse Type I/III interferon genes. Effects of exogenous type I and III interferons on CF-neutrophil antifungal effector function was further characterised. FINDINGS:CFTR modulator (ETI) therapy was associated with a significant reduction in Aspergillus biomarkers alongside use of corticosteroid and anti-fungal therapy. In vitro Aspergillus stimulation enriched the Type I/III interferome in CFTR-corrected BECs compared to CF BECs, with ETI therapy partially restoring type I/III interferon gene expression in CF BECs. Administration of exogenous IFNλ1 increased anti-fungal killing in CF neutrophils without increased reactive-oxygen species or neutrophil extracellular trap production. INTERPRETATION:CFTR modulators have led to improved clinical outcomes in CF related Aspergillus-related lung disease potentially due to partial restoration of the host antifungal epithelial type I/III interferon response. Exogenous IFNλ1 further improved antifungal killing capacity of CF-neutrophils presenting a plausible future therapeutic strategy. FUNDING:This study was funded by the Cystic Fibrosis Trust (SRC015).

OBJECTIVE:A comprehensive review of maternal, obstetric and neonatal outcomes in pregnancies in females with cystic fibrosis (fwCF) following the introduction of Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy in a novel, dedicated CF-Maternal Health service. DESIGN:Retrospective data review from a CF-Maternal Health service between September 2020 and February 2025. SETTING:A large adult-CF service in London, UK. POPULATION OR SAMPLE:Pregnant fwCF attending the Royal Brompton Hospital CF Service. METHODS:Review of CF-Maternal Health service data. MAIN OUTCOME MEASURES:Maternal, obstetric and neonatal outcomes. RESULTS:Fifty-three fwCF completed 67 pregnancies, with 69 infants born. There were no stillbirths, neonatal or maternal deaths. ETI-therapy was reported in 81% of pregnancies. In fwCF without CF-Diabetes, 57% developed gestational diabetes. Hospital admission to treat an infective pulmonary exacerbation was required in 31% of pregnancies. Forty-five percent of pregnancies delivered vaginally; 78% of babies were born at term. A major congenital abnormality was diagnosed in 4% of infants. Baseline lung-function correlated positively with birth-weight and gestation at birth. CONCLUSIONS:FwCF have improved maternal, obstetric and neonatal outcomes since the introduction of ETI-therapy, within a dedicated CF-Maternal Health service.

Aminoglycoside antibiotics cause ototoxicity for which baseline audiometric testing is recommended but often not done. Barriers to successful implementation include limited availability of sound-booths and audiologists. An ototoxicity monitoring programme (OMP) was implemented using tablet-based audiometry (TBA) by non-audiologists.A quality improvement project conducted over 1 year (19 April 2021 to 18 April 2022), using Plan Do Study Act (PDSA) cycles, monitored the adherence to the OMP using Shoebox Standard Edition application on iPads. Barriers to adoption were identified to determine potential solutions for improved adherence. Adult respiratory patients (cystic fibrosis (CF), bronchiectasis, non-tuberculosis mycobacteria (NTM) infection) aged 17–82 years receiving >1 day of intravenous aminoglycosides (IVAGs) at a single tertiary-referral hospital were included. Other reported outcomes were patient characteristics, risk factors associated with abnormal hearing and ototoxic shift.73 patients were tested in the OMP (46 received ≥2 hearing tests) giving an overall adherence rate of 69% after 12 months. Patient identification using referral and reporting systems initially improved adherence from 36% to 88% (p=0.03) during PDSA 1. Barriers to successful adherence were staff availability and COVID-19 infection outbreaks (p=0.057). Older age (p<0.001), higher Body Mass Index (p=0.041), non-CF bronchiectasis (p=0.01), non-CF NTM (p=0.028) and higher Hearing Handicap Inventory for Adults scores (p=0.002) were significantly associated with abnormal baseline hearing. 78% with hearing loss were asymptomatic. Ototoxic shift was associated with gentamicin use compared to amikacin/tobramycin (p=0.027). TBA was associated with high usability in patients ≤50 years old.TBA by non-audiologists was feasible and demonstrated good patient usability, permitting screening of patients within 72 hours of starting IVAG and earlier referrals for formal audiometry. Hearing loss and ototoxicity were detected at earlier stages, enabling more rapid decision-making and treatment modification.

The increasing life expectancy of people with cystic fibrosis (pwCF), largely driven by advancements in early diagnosis, multidisciplinary care and the recent introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, is likely to herald a shift in the focus of care toward managing the complexities of ageing. This review highlights key challenges and research priorities for addressing the health needs of an ageing CF population. A growing body of evidence underscores the heightened risks of cancers, cardiovascular diseases and changing nutritional and metabolic profiles as pwCF age. CFTR modulators have improved clinical outcomes, but their effects on inflammation, immunity and long-term disease trajectories remain incompletely understood. Nutritional management, particularly the implications of obesity and body composition, poses new challenges, as does the potential accelerated ageing of immune and pulmonary systems in CF. Emerging issues such as menopause in females with CF, lifetime antimicrobial resistance and the interplay between chronic inflammation and ageing further complicate the care landscape. The review emphasises the urgent need for multidisciplinary research programmes that integrate clinical, patient and community perspectives. Leveraging established CF registries, clinical trial networks and collaborations with ageing research frameworks is critical to addressing these challenges. Ultimately, the goal is to ensure that pwCF not only live longer but also experience improved quality of life and holistic wellbeing as they realise the full benefits of therapeutic advances.

Aspergillus fumigatus (Af) is a major mould pathogen found ubiquitously in the air. It commonly infects the airways of people with cystic fibrosis (CF) leading to Aspergillus bronchitis or allergic bronchopulmonary aspergillosis. Resident alveolar macrophages and recruited neutrophils are important first lines of defence for clearance of Af in the lung. However, their contribution to the inflammatory phenotype in CF during Af infection is not well understood. Here, utilising CFTR deficient mice we describe a hyperinflammatory phenotype in both acute and allergic murine models of pulmonary aspergillosis. We show that during aspergillosis, CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in CF, accompanied by impaired fungal control. Utilising CFTR deficient murine cells and primary human CF cells we show that at a cellular level there is increased activation of NFκB and NFAT in response to Af which, as in in vivo models, is associated with increased cell death and reduced fungal control. Taken together, these studies indicate that CFTR deficiency promotes increased activation of inflammatory pathways, the induction of macrophage cell death and reduced fungal control contributing to the hyper-inflammatory of pulmonary aspergillosis phenotypes in CF.

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.

Identifying safe and effective therapies that target the underlying cause of cystic fibrosis remains a key priority for the cystic fibrosis community. CFTR modulators are first-in-class, regulatory-approved therapies that improve the function of the protein encoded by the CFTR gene and are associated with dramatic and sustained clinical benefits. Although approximately 90% of the population with cystic fibrosis could benefit from these therapies based on genetic eligibility, a crucial unmet need remains: developing CFTR-directed therapies for the ultra-rare population with cystic fibrosis who are not candidates for CFTR modulators due to either ineligibility or intolerance. Addressing this unmet need will depend on the clinical advancement of nucleic acid-based therapies (NABTs), a term that includes variant-specific antisense oligonucleotide therapies and variant-agnostic mRNA and DNA-based gene therapies. The clinical development of NABTs for those who are not candidates for or unable to take CFTR modulators is challenged not only by the relatively small target population, which affects feasible trial sizes, but also by unique regulatory requirements for long-term safety follow-up and the potential yet unknown short-term and long-term risks with genetic therapy cross-exposure or re-exposure. This Personal View addresses the proactive planning needed to maximise trial opportunities for the population who are not candidates for CFTR modulators, including considerations for subsequent NABT trial participation following previous NABT exposure.

Background Cystic fibrosis (CF) is a chronic condition that requires complex and long-term treatments. While substantial research has explored treatment burden associated with CF; its impact remains complex to quantify. This review aims to identify the different methods used in the literature to measure treatment burden in people with CF (pwCF). Method Five databases were searched for interventional and observational studies that focused primarily on treatment burden. The studies were presented using narrative synthesis structured around the perspective of treatment burden (subjective vs. objective). Results This review synthesised 17 articles, which utilised subjective and objective measures separately or collectively. Twelve studies used subjective treatment burden measures (CF-specific and generic scales), while 14 studies used objective measures (treatment time, volume and complexity, and cost). Eight studies investigated treatment burden reported by proxy on behalf of children with CF. The most used measures were treatment time (9/17) and CF questionnaire-revised (CFQ-R) treatment burden subscale (6/17). Older age and lower lung function were associated with greater burden, treatment time, and complexity. Caregivers/parents reported worse treatment burden compared to children with CF (6-13 y/o) when completing the same measure. Conclusion No single measure used in the reviewed studies fully the multidimensional nature of treatment burden and summarised it in a single score. Given the rapidly evolving landscape of CF care a pragmatic approach to capture a broader array of treatment burden dimensions may be to routinely complement subjective measures with objective measures.

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.

Background:Although recent advancements in the treatment of cystic fibrosis (CF) have improved survival, reducing high levels of treatment burden remains a priority issue for many people with cystic fibrosis (pwCF). However, economic evaluations of novel interventions may fail to capture their impact on treatment burden due to a lack of suitable outcome measures. This study aimed to estimate health state utilities (HSUs) for changes in treatment burden associated with different CF treatments. Research Question:What value do pwCF place on changes in treatment burden associated with IV antibiotic treatment of pulmonary exacerbations, use of inhaled medicines, and physiotherapy? Study Design and Methods:Adults attending a specialist CF center were invited to participate in a web-based time trade-off interview. Participants valued their own health and five health state vignettes describing varying levels of intensity of physiotherapy, use of inhaled medicines, and IV antibiotic treatment. HSUs for additional instances of each treatment type were estimated using mixed effect linear regression models. Results:Fifty one pwCF completed the interview (median age, 30 years; range, 19-66); 53% were female; mean FEV1 % predicted was 65% (SD, 20%). Mean utility scores for own health were very similar between the EQ-5D index value (0.81; SD, 0.20) and the time trade-off value (0.82; SD, 0.20); however, limited concordance was observed at the individual level. Adjusted utility decrements associated with treatment burden were -0.037 (SE, 0.008) for an additional annual IV antibiotic treatment, -0.029 (SE, 0.014) for an additional daily physiotherapy session, and -0.019 (SE, 0.013) for an additional daily inhaled medicine. Interpretation:In this study, increasing treatment burden was associated with decreasing HSU values. The utility decrements associated with treatment burden changes suggest meaningful differences in health-related quality of life for pwCF. These findings align with existing literature on the impact of treatment burden on health-related quality of life, and highlight the importance of considering treatment burden in economic evaluations of interventions in CF.

BackgroundPrescribers have an increasing range of inhaled antimicrobial formulations to choose from when prescribing both eradication and chronic suppression regimens in cystic fibrosis (CF). This study aimed to investigate the decision-making process behind prescribing of inhaled antimicrobials for Pseudomonas aeruginosa infections.MethodsA questionnaire was developed using Microsoft Forms and then forwarded to 57 Principal Investigators (PIs), at each of the CF centres within the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). Data collection occurred between November 2021 and February 2022.ResultsThe response rate was 90 % (n = 51/57 PIs), with at least 50 % of CF centers in each of the 17 countries represented in the ECFS-CTN. Physicians used a median of eight factors in their decision-making process with delivery formulations (92.2 %), adherence history (84.3 %), and antibiotic side-effect profile (76.5 %) often selected. Nebulised tobramycin or colistin were frequently selected as the inhaled antimicrobial in first-line eradication (n = 45, 88.2 %) and chronic suppression regimens (n = 42, 82.4 %). Combination regimens were more often chosen in eradication (first-line: n = 35, 68.6 %, second-line: n = 34, 66.7 %) and later chronic suppression regimens (third-line: n = 27, 52.9 %) than monotherapy. For pwCF also prescribed CFTR modulator therapies, most PIs did not alter inhaled antimicrobial regimens (n = 40, 78.4 %), with few pwCF (n = 18, 35.3 %) or PIs (n = 10, 19.6 %) deciding to stop inhaled antimicrobials.ConclusionsThe inhaled antimicrobial prescribing decision-making process is multifactorial. Nebulised tobramycin or colistin are often used in initial eradication and chronic suppression regimens. To date, CFTR modulator therapy has had a limited impact on the prescribing of inhaled antimicrobial regimens.

Aspergillus fumigatus (Af) is a major mould pathogen found ubiquitously in the air. It commonly infects the airways of people with cystic fibrosis (CF) leading to Aspergillus bronchitis or allergic bronchopulmonary aspergillosis. Resident alveolar macrophages and recruited neutrophils are important first lines of defence for clearance of Af in the lung. However, their contribution to the inflammatory phenotype in CF during Af infection is not well understood. Here, utilising CFTR deficient mice we describe a hyperinflammatory phenotype in both acute and allergic murine models of pulmonary aspergillosis. We show that during aspergillosis, CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in CF, accompanied by impaired fungal control. Utilising CFTR deficient murine cells and primary human CF cells we show that at a cellular level there is increased activation of NFκB and NFAT in response to Af which, as in in vivo models, is associated with increased cell death and reduced fungal control. Taken together, these studies indicate that CFTR deficiency promotes increased activation of inflammatory pathways, the induction of macrophage cell death and reduced fungal control contributing to the hyper-inflammatory of pulmonary aspergillosis phenotypes in CF. ### Competing Interest Statement The authors have declared no competing interest.

Background: The EQ-5D is the recommended measure to capture health-related quality of life (HRQoL), recognised for use in health technology appraisal bodies. In order to assess whether it is appropriate to use the EQ-5D for making decisions about the cost-utility of treatments in cystic fibrosis (CF), this study assesses the performance of the EQ-5D-5L in adults and adolescents with CF. Method: This was a cross-sectional observational survey study of patients with CF attending a single large CF centre. Participants were asked to complete a survey that included two HRQoL measures; the EQ-5D-5L and CF Quality of Life (CFQoL) questionnaires. Results: Among 213 participants, the median EQ-5D-5L index score was 0.76 (IQR 0.66 - 0.84) and the visual analogue (EQ-VAS) was 70 (60 - 80). Both the EQ-5D index and EQ-VAS discriminated between disease severity based on lung function (p = 0.01 and p <0.01, respectively) and pulmonary exacerbation (p = 0.02 and p < 0.01, respectively); however, EQ-VAS differentiated between more lung function severity groups compared to EQ-5D index. The EQ-5D-5L demonstrated convergent validity as its dimensions, index score, and EQ-VAS had significant correlations with most CFQoL domains. Though, EQ-VAS significantly predicted more domains of CFQoL (4 domains) compared to EQ-5D index (only 1 domain). Conclusion: The generic EQ-5D-5L performed adequately in discriminating between CF disease severity, and its index score and EQ-VAS had moderate correlations with CFQoL. However, using a complementary condition-specific measure alongside the EQ-5D-5L can provide better insight of HRQoL in CF and benefit the process of cost-utility analysis. (c) 2024 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

•Pseudomonas/Aspergillus co-positive cultures are less common than expected in CF airway samples.•Increasing Pseudomonas culture density is associated with decreasing Aspergillus frequency.•Af-sequencing positive, culture negative samples were more common with Pseudomonas present.•Interpretation of negative Aspergillus culture in Pa-positive samples should be cautious.