Standards for the care of people with cystic fibrosis (CF); Planning for a longer life.

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

Airway and Systemic Immunoglobulin Profiling and Immune Response in Adult Asthma.

INTRODUCTION: Immunoglobulins play a vital role in host immune response and in the pathogenesis of conditions like asthma. Therapeutic agents such as monoclonal antibodies target specific elements of the asthmatic inflammatory cascade. Decisions to utilize these medications are often based on systemic inflammatory profiling without direct insight into the airway inflammatory profile. We sought to investigate the relationship between immunoglobulin and cytokine profiles in the airway and systemic immune compartments of adult asthmatics. METHODS: Blood sampling and bronchoscopy with bronchoalveolar lavage (BAL) were performed in 76 well-defined adult asthmatics. Antibody and cytokine profiles were measured in both BAL and serum using ELISA and quantibody arrays. RESULTS: There was no relationship between BAL and serum levels of IgE. This is of significance in an asthma population. For some analytes, correlation analysis was significant (P < 0.05) indicating representativeness of our cohort and experimental setup in those cases. Nevertheless, the predictive power (r2) of the BAL-to-serum comparisons was mostly low except for TNF-α (r2 = 0.73) when assuming a simple (linear) relationship. CONCLUSION: This study highlights the importance of sample site when investigating the roles of immunoglobulins and cytokines in disease pathogenesis and suggests that both localized and systemic immune responses are at play. The prescription of asthma monoclonal therapy is generally based on systemic evaluation of cytokine and immunoglobulin levels. Our research suggests that this approach may not fully reflect the pathophysiology of the disease and may provide insight into why some patients respond to these targeted therapies while others do not.

Considerations for the use of inhaled antibiotics for Pseudomonas aeruginosa in people with cystic fibrosis receiving CFTR modulator therapy.

The major cause of mortality in people with cystic fibrosis (pwCF) is progressive lung disease characterised by acute and chronic infections, the accumulation of mucus, airway inflammation, structural damage and pulmonary exacerbations. The prevalence of Pseudomonas aeruginosa rises rapidly in the teenage years, and this organism is the most common cause of chronic lung infection in adults with cystic fibrosis (CF). It is associated with an accelerated decline in lung function and premature death. New P. aeruginosa infections are treated with antibiotics to eradicate the organism, while chronic infections require long-term inhaled antibiotic therapy. The prevalence of P. aeruginosa infections has decreased in CF registries since the introduction of CF transmembrane conductance regulator modulators (CFTRm), but clinical observations suggest that chronic P. aeruginosa infections usually persist in patients receiving CFTRm. This indicates that pwCF may still need inhaled antibiotics in the CFTRm era to maintain long-term control of P. aeruginosa infections. Here, we provide an overview of the changing perceptions of P. aeruginosa infection management, including considerations on detection and treatment, the therapy burden associated with inhaled antibiotics and the potential effects of CFTRm on the lung microbiome. We conclude that updated guidance is required on the diagnosis and management of P. aeruginosa infection. In particular, we highlight a need for prospective studies to evaluate the consequences of stopping inhaled antibiotic therapy in pwCF who have chronic P. aeruginosa infection and are receiving CFTRm. This will help inform new guidelines on the use of antibiotics alongside CFTRm.

Standards for the care of people with cystic fibrosis (CF); recognising and addressing CF health issues.

This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey.

Standards for the care of people with cystic fibrosis (CF): A timely and accurate diagnosis.

There is considerable activity with respect to diagnosis in the field of cystic fibrosis (CF). This relates primarily to developments in newborn bloodspot screening (NBS), more extensive gene analysis and improved characterisation of CFTR-related disorder (CFTR-RD). This is particularly pertinent with respect to accessibility to variant-specific therapy (VST), a transformational intervention for people with CF with eligible CFTR gene variants. This advance reinforces the need for a timely and accurate diagnosis. In the future, there is potential for trials to assess effectiveness of variant-specific therapy for CFTR-RD. The guidance in this paper reaffirms previous standards, clarifies a number of issues, and integrates emerging evidence. Timely and accurate diagnosis has never been more important for people with CF.

Biologically Relevant Murine Models of Chronic Pseudomonas aeruginosa Respiratory Infection.

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen and the leading cause of infection in patients with cystic fibrosis (CF). The ability of P. aeruginosa to evade host responses and develop into chronic infection causes significant morbidity and mortality. Several mouse models have been developed to study chronic respiratory infections induced by P. aeruginosa, with the bead agar model being the most widely used. However, this model has several limitations, including the requirement for surgical procedures and high mortality rates. Herein, we describe novel and adapted biologically relevant models of chronic lung infection caused by P. aeruginosa. Three methods are described: a clinical isolate infection model, utilising isolates obtained from patients with CF; an incomplete antibiotic clearance model, leading to bacterial bounce-back; and the establishment of chronic infection; and an adapted water bottle chronic infection model. These models circumvent the requirement for a surgical procedure and, importantly, can be induced with clinical isolates of P. aeruginosa and in wild-type mice. We also demonstrate successful induction of chronic infection in the transgenic ßENaC murine model of CF. We envisage that the models described will facilitate the investigations of host and microbial factors, and the efficacy of novel antimicrobials, during chronic P. aeruginosa respiratory infections.

Replacing Plain Radiograph with ultra-low dose CT thorax in cystic fibrosis (CF) in the era of CFTR modulation and its impact on cumulative effective dose.

BACKGROUND: Medical radiation exposure is of increasing concern in patients with cystic fibrosis (PWCF) due to improving life expectancy. We aimed to assess and quantify the cumulative effective dose (CED) in PWCF in the context of CFTR-modulator therapy and the advancement of dose reduction techniques. METHODS: We performed a retrospective observational study in a single University CF centre over a 11-year period. We included PWCF, aged over 18 years who exclusively attended our institution. Relevant clinical data (demographics, transplantation history and modulator status) and radiological data (modality, quantity, and radiation exposure measured as CED) were collected. For those on modulator therapy the quantified imaging and radiation data was dichotomised into pre-and-post therapy periods. RESULTS: The study included 181 patients: 139 on CFTR modulator therapy, 15 transplant recipients and 27 with neither exposure. 82% of patients received <25 mSv over the study period. Mean study duration was 6.9 ± 2.6 years pre-modulation and 4.2 ± 2.6 years post-modulation. Pre-modulation CT contributed 9.6% of total chest imaging (n = 139/1453) and 70.9% of the total CED. Post-modulation CT use increased contributing 42.7% of chest imaging (n = 444/1039) and comprised 75.8% of CED. Annual CED was 1.55 mSv pre and 1.36 mSv post modulation (p = 0.41). Transplant recipients had an annual CED of 64 ± 36.1mSv. CONCLUSION: Chest CT utilisation for PWCF is rising in our institution, replacing chest radiography amidst CFTR-modulation. Despite the increasing use of CT, no significant radiation dose penalty was observed with a reduction in mean annual CED, primarily due to the influence of CT dose reduction strategies.

Individualized approach to elexacaftor/tezacaftor/ivacaftor dosing in cystic fibrosis, in response to self-reported anxiety and neurocognitive adverse events: A case series.

The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1 s (ppFEV1), and a mean difference in sweat chloride of -39.3 mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4-6 weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients' preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12 weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV1 was 80.7% on standard dose, and 83.4% at 12 weeks on reduced dose; sweat chloride was 33.4 and 34 mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24 weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.

Telehealth in Cystic Fibrosis. A systematic review incorporating a novel scoring system and expert weighting to identify a 'top 10 manuscripts' to inform future best practices implementation.

The ongoing development and integration of telehealth within CF care has been accelerated in response to the Covid-19 pandemic, with many centres publishing their experiences. Now, as the restrictions of the pandemic ease, the use of telehealth appears to be waning, with many centres returning to routine traditional face-to-face services. For most, telehealth is not integrated into clinical care models, and there is a lack of guidance on how to integrate such a service into clinical care. The aims of this systematic review were to first identify manuscripts which may inform best CF telehealth practices, and second, to analyse these finding to determine how the CF community may use telehealth to improve care for patients, families, and Multidisciplinary Teams into the future. To achieve this, the PRISMA review methodology was utilised, in combination with a modified novel scoring system that consolidates expert weighting from key CF stakeholders, allowing for the manuscripts to be placed in a hierarchy in accordance with their scientific robustness. From the 39 found manuscripts, the top ten are presented and further analysed. The top ten manuscripts are exemplars of where telehealth is used effectively within CF care at this time, and demonstrate specific use cases of its potential best practices. However, there is a lack of guidance for implementation and clinical decision making, which remains an area for improvement. Thus, it is suggested that further work explores and provides guidance for standardised implementation into CF clinical practice.

Virtual monitoring in CF - the importance of continuous monitoring in a multi-organ chronic condition.

Cystic Fibrosis (CF) is a chronic life-limiting condition that affects multiple organs within the body. Patients must adhere to strict medication regimens, physiotherapy, diet, and attend regular clinic appointments to manage their condition effectively. This necessary but burdensome requirement has prompted investigations into how different digital health technologies can enhance current care by providing the opportunity to virtually monitor patients. This review explores how virtual monitoring has been harnessed for assessment or performance of physiotherapy/exercise, diet/nutrition, symptom monitoring, medication adherence, and wellbeing/mental-health in people with CF. This review will also briefly discuss the potential future of CF virtual monitoring and some common barriers to its current adoption and implementation within CF. Due to the multifaceted nature of CF, it is anticipated that this review will be relevant to not only the CF community, but also those investigating and developing digital health solutions for the management of other chronic diseases.

Lung Health in Farming: A Scoping Review.

OBJECTIVE: Lung disease is now recognized as an associated occupational hazard among farming and agricultural communities, however limited research surrounds lung health knowledge within our farming population. It is clear from this limited lack of knowledge that farming practices, perceptions and ideas relating to lung health are yet to be uncovered. This scoping review was conducted to identify what is known about lung health within farming and agricultural communities globally and to map the available evidence relating to lung health and lung health decline within this population. The objectives of this review were (1) focus on available lung health research from a global perspective specific to farming and agriculture relating to occupational lung exposures and (2) consolidate current knowledge, clearly identifying gaps within the literature. METHODS: This systematic scoping review of the literature is guided by the Joanna Briggs Institute Methodology framework. There were 22 studies eligible for inclusion within the scoping review, providing an up-to-date review of research conducted on lung health and lung disease in farming occupations. RESULTS: Results were grouped into three categories emerging from included studies: (1) focused on the prevalence of respiratory symptoms/disease within farming and agricultural occupations, (2) measurements of dust and particulate matter and correlating these with respiratory conditions, (3) common respiratory conditions linked to a decline in lung health among farming and agricultural occupations. Results identified no study focused on or referred to lung health, lung health knowledge or lung health awareness as an outcome, with all studies focusing on respiratory symptoms, development of lung disease and the common occupational hazards this population are exposed to. CONCLUSION: This scoping review demonstrates the lack of literature to specifically map available evidence relating to lung health and farming occupations. Many respiratory symptoms and conditions can arise directly and indirectly from agricultural environments, however many of these cases could be prevented by lung health knowledge within the farming population. The results of this scoping review will be used to inform knowledge, awareness, education, health promotion and future research within this population.

Single-Use or Disposable Flexible Bronchoscopy in Advanced Bronchoscopy Procedures: Experience in a Quaternary Referral Centre.

BACKGROUND: The development of single-use flexible or disposable bronchoscopes (SUFBs) has accelerated in recent years, with the reduced risk of infectious transmission and reduced need for endoscopy staffing particularly advantageous in the COVID-19 pandemic era. OBJECTIVE: The objective of this study was to assess the performance of a novel single-use bronchoscope in an academic quaternary referral centre with on-site interventional pulmonology programme. METHODS: With ethical approval in a quaternary referral centre, we prospectively collected data on sequential bronchoscopy procedures using The Surgical Company Broncoflex© range of SUFBs. Data collected included demographic, procedural, scope performance, user satisfaction, and complication parameters in a tertiary bronchoscopy service. RESULTS: 139 procedures were performed by five pulmonology faculty from January to July 2021. The majority were carried out for infection (45%) and malignancy (32%). Most were performed in the endoscopy suite and 8% were COVID positive or suspected. Most procedures reported the highest score in satisfaction (85%) with technical limitations reported in 15% (predominately related to scope suction or inadequate image quality) reverting to a reusable scope in 2.8 %. CONCLUSION: In our subset of patients in a bronchoscopy unit, SUFBs are safe, and both routine and advanced bronchoscopy procedures can be performed with high satisfaction reported.

Real-World clinical outcomes of asthma patients switched from reslizumab to mepolizumab or benralizumab.

Introduction: Approximately 3%-10% of asthma patients will remain uncontrolled despite maximum, optimal conventional therapy. Treatment of severe refractory asthma often involves the use of targeted biological therapy. Randomised controlled trials have shown improvements in clinical parameters with these treatments but real-world data is lacking. Methods: The clinical parameters, frequency of exacerbations, number of hospital admissions, asthma control questionnaire score (ACQ), forced expiratory volume in one second (FEV1) and maintenance oral corticosteroid (OCS) dose of twenty asthma patients switched from reslizumab to benralizumab or mepolizumab at 1 year prior and 6 months after switching were compared, with adjustments for time. Results: The mean frequency of exacerbations (0.35 v 0.3) and the mean ACQ were essentially unchanged (1.6 v 1.5) following the switch. The number of hospital admissions was one in the 6 months post switch compared to one in 1-year pre switch. 25% of patients were on maintenance OCS before and after switching but one patient required an increased dose post switch resulting in an increase in the mean maintenance OCS dose (1.6 mg to 2.4 mg). The mean FEV1 was unchanged (80% v 77.9%) six months post switching. Regarding asthma control (n = 19), 47.4% were controlled pre and post switch (ACQ < 1.5), 36.8% remained uncontrolled despite switching, 10.5% improved control while 5.3% disimproved. Conclusion: We present real-world clinical outcomes of asthma patients switched from reslizumab to either benralizumab or mepolizumab without a loss of clinical effectiveness in the majority.

Telehealth and virtual health monitoring in cystic fibrosis.

PURPOSE OF REVIEW: At many institutions, the Covid-19 pandemic made it necessary to rapidly change the way services are provided to patients, including those with cystic fibrosis (CF). The purpose of this review is to explore the past, present and future of telehealth and virtual monitoring in CF and to highlight certain challenges/considerations in developing such services. RECENT FINDINGS: The Covid-19 pandemic has proven that telehealth and virtual monitoring are a feasible means for safely providing services to CF patients when traditional care is not possible. However, both telehealth and virtual monitoring can also provide further support in the future in a post-covid era through a hybrid-model incorporating traditional care, remote data collection and sophisticated platforms to manage and share data with CF teams. SUMMARY: We provide a detailed overview of telehealth and virtual monitoring including examples of how paediatric and adult CF services adapted to the need for rapid change. Such services have proven popular with people with CF meaning that co-design with stakeholders will likely improve systems further. In the future, telehealth and virtual monitoring will become more sophisticated by harnessing increasingly powerful technologies such as artificial intelligence, connected monitoring devices and wearables. In this review, we harmonise definitions and terminologies before highlighting considerations and limitations for the future of telehealth and virtual monitoring in CF.

Computed tomography in cystic fibrosis lung disease: a focus on radiation exposure.

Thoracic computed tomography (CT) is the imaging reference method in the diagnosis, assessment and management of lung disease. In the setting of cystic fibrosis (CF), CT demonstrates increased sensitivity compared with pulmonary function tests and chest radiography, and findings correlate with clinical outcomes. Better understanding of the aetiology of CF lung disease indicates that even asymptomatic infants with CF can have irreversible pulmonary pathology. Surveillance and early diagnosis of lung disease in CF are important to preserve lung parenchyma and to optimise long-term outcomes. CF is associated with increased cumulative radiation exposure due to the requirement for repeated imaging from a young age. Radiation dose optimisation, important for the safe use of CT in children with CF, is best achieved in a team environment where paediatric radiologists work closely with paediatric respiratory physicians, physicists and radiography technicians to achieve the best patient outcomes. Despite the radiation doses incurred, CT remains a vital imaging tool in children with CF. Radiologists with special interests in CT dose optimisation and respiratory disease are key to the appropriate use of CT in paediatric imaging. Paediatric radiologists strive to minimise radiation dose to children whilst providing the best possible assessment of lung disease.

Extended-culture and culture-independent molecular analysis of the airway microbiota in cystic fibrosis following CFTR modulation with ivacaftor.

BACKGROUND: Treatment with Ivacaftor provides a significant clinical benefit in people with cystic fibrosis (PWCF) with the class III G551D-CFTR mutation. This study determined the effect of CFTR modulation with ivacaftor on the lung microbiota in PWCF. METHODS: Using both extended-culture and culture-independent molecular methods, we analysed the lower airway microbiota of 14 PWCF, prior to commencing ivacaftor treatment and at the last available visit within the following year. We determined total bacterial and Pseudomonas aeruginosa densities by both culture and qPCR, assessed ecological parameters and community structure and compared these with biomarkers of inflammation and clinical outcomes. RESULTS: Significant improvement in FEV1, BMI, sweat chloride and levels of circulating inflammatory biomarkers were observed POST-ivacaftor treatment. Extended-culture demonstrated a higher density of strict anaerobic bacteria (p = 0.024), richness (p = 1.59*10-4) and diversity (p = 0.003) POST-treatment. No significant difference in fold change was observed by qPCR for either total bacterial 16S rRNA copy number or P. aeruginosa density for oprL copy number with treatment. Culture-independent (MiSeq) analysis revealed a significant increase in richness (p = 0.03) and a trend towards increased diversity (p = 0.07). Moreover, improvement in lung function, richness and diversity displayed an inverse correlation with the main markers of inflammation (p < 0.05). CONCLUSIONS: Following treatment with ivacaftor, significant improvements in clinical parameters were seen. Despite modest changes in overall microbial community composition, there was a shift towards a bacterial ecology associated with less severe CF lung disease. Furthermore, a significant correlation was observed between richness and diversity and levels of circulating inflammatory markers.

A multicentre analysis of Clostridium difficile in persons with Cystic Fibrosis demonstrates that carriage may be transient and highly variable with respect to strain and level.

PURPOSE: Clostridium difficile has been reported to occur in the gastrointestinal tract of 50% of Cystic Fibrosis (CF) subjects, however, clinical C. difficile infection (CDI) is a rare occurrence in this cohort despite the presence of toxigenic and hypervirulent ribotypes. Here, we present the first longitudinal, multicentre analysis of C. difficile prevalence among adult CF subjects. METHODOLOGY: Faecal samples were collected from adults with CF (selected based on confirmed Pseudomonas aeruginosa pulmonary colonisation) from Ireland, UK and Belgium as part of the CFMATTERS clinical research trial (grant No. 603038) and from non-CF controls. Faecal samples were collected on enrolment, at three monthly intervals, during pulmonary exacerbation and three months post exacerbation. C. difficile was isolated from faecal samples by ethanol shocking followed by culturing on cycloserine cefoxitin egg yolk agar. Isolates were characterised in terms of ribotype, toxin type and antibiotic susceptibility to antibiotics routinely used in the treatment of CDI (metronidazole and vancomycin) and those implicated in induction of CDI (ciprofloxacin and moxifloxacin). RESULTS: Prevalence of C. difficile among CF subjects in the three sites was similar ranging from 47% to 50% at baseline, while the healthy control cohort had a carriage rate of 7.1%. Including subjects who were positive for C. difficile at any time point there was a higher carriage rate of 71.4%, 66.7% and 63.2% in Ireland, UK, and Belgium, respectively. Ribotyping of 80 isolates from 45 CF persons, over multiple time points revealed 23 distinct ribotypes with two ribotypes (046 and 078) shared by all centres. The proportion of toxigenic isolates varied across the sites, ranging from 66.7% in Ireland to 52.9% in Belgium and 100% in the UK. Antibiotic susceptibility rates to vancomycin, metronidazole, ciprofloxacin and moxifloxacin was 100%, 97.5%, 1.3% and 63.8%, respectively. CONCLUSIONS: This study demonstrates the highest carriage rate of C. difficile to date in a CF cohort. Longitudinal data show that C. difficile can be a transient inhabitant of the CF gut, changing both in terms of strain and excretion rates.