A refresh of the top 10 research priorities in cystic fibrosis.

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.

Real-World Comparison of Bezlotoxumab to Standard of Care Therapy for Prevention of Recurrent Clostridioides difficile Infection in Patients at High Risk for Recurrence.

BACKGROUND: Bezlotoxumab (BEZ) is a monoclonal antibody used to prevent recurrent Clostridioides difficile infection (rCDI). This study investigates BEZ effectiveness in relation to rCDI and patient-specific risk factors in a real-world setting. METHODS: A matched, retrospective cohort study was conducted from 2015 to 2019 to compare BEZ to historical standard of care (SoC) therapy with vancomycin or fidaxomicin. The primary outcome was incidence of 90-day rCDI. Secondary outcomes were incidence of all-cause hospital readmission and all-cause mortality at 90 days, infusion-related reactions, and incidence of heart failure exacerbation. Baseline confounding was addressed using inverse probability of treatment weighting (IPTW). RESULTS: Overall, 107 participants were included (54 BEZ and 53 SoC). Mean number of prior CDI episodes was 2, median number of risk factors for rCDI was 4, and 28% of participants had severe CDI. Incidence of 90-day rCDI was 11% BEZ vs 43% SoC (P = < .001) and 90-day all-cause readmission was 40% BEZ vs 64% SoC (P = .011). In IPTW-adjusted analyses, BEZ was associated with significantly reduced odds of rCDI (odds ratio [OR], 0.14 [95% confidence interval {CI}: .05-.41]) and all-cause readmission (OR, 0.36 [95% CI: .16-.81]). No safety signals were detected with BEZ use. CONCLUSIONS: BEZ is effective for the prevention of rCDI and reduction in all-cause hospital readmission for patients at high risk for recurrence, supporting current guideline recommendations.

Stakeholder Views of the Proposed Introduction of Next Generation Sequencing into the Cystic Fibrosis Screening Protocol in England.

The project aimed to gather, analyse, and compare the views of stakeholders about the proposed UK cystic fibrosis (CF) screening protocol incorporating next generation sequencing (NGS). The study design was based on principles of Q-methodology with a willingness-to-pay exercise. Participants were recruited from 12 CF centres in the UK. The study contained twenty-eight adults who have experience with CF (parents of children with CF (n = 21), including parents of children with CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS)/CF screen positive-inconclusive diagnosis (CFSPID), an uncertain outcome (n = 3), and adults with CF (n = 4)), and nine health professionals involved in caring for children with CF. Parents and health professionals expressed a preference for a sensitive approach to NGS. This was influenced by the importance participants placed on not missing any children with CF via screening and the balance of harm between missing a case of CF compared to picking up more children with an uncertain outcome (CRMS/CFSPID). Given the preference for a sensitive approach, the need for adequate explanations about potential outcomes including uncertainty (CFSPID) at the time of screening was emphasized. More research is needed to inform definitive guidelines for managing children with an uncertain outcome following CF screening.

International Perspectives of Extended Genetic Sequencing When Used as Part of Newborn Screening to Identify Cystic Fibrosis.

There is increasing interest in using extended genetic sequencing (EGS) in newborn screening (NBS) for cystic fibrosis (CF). How this is implemented will change the number of children being given an uncertain outcome of CRMS/CFSPID (cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/CF Screen Positive Inconclusive Diagnosis), probable carrier results, and the number of missed CF diagnoses. An international survey of CF health professionals was used to gather views on two approaches to EGS-specific (may reduce detection of CRMS/CFSID but miss some CF cases) versus sensitive (may increase detection of CRMS/CFSPID but avoid missing more CF cases). Health professionals acknowledged the anxiety caused to parents (and health professionals) from the uncertainty surrounding the prognosis and management of CRMS/CFSPID. However, most preferred the sensitive approach, as overall, identifying more cases of CRMS/CFSPID was viewed as less physically and psychologically damaging than a missed case of CF. The importance of early diagnosis and treatment for CF to ensure better health outcomes and reducing diagnostic odysseys for parents were highlighted. A potential benefit to identifying more children with CRMS/CFSPID included increasing knowledge to obtain a better understanding of how these children should best be managed in the future.

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.

Clinical spectrum of Cutibacterium acnes infections: The SAPHO syndrome.

Cutibacterium acnes, previously known as Proprionobacterium, is a commensal Grampositive bacterium of the skin commonly implicated in prosthetic joint infections. However, it has been documented to play a role in other conditions, including SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), a rare autoinflammatory disorder. Diagnosing SAPHO syndrome is cumbersome, as the clinical manifestations are variable and overlap with many inflammatory joint disorders. Herein, we describe a 56-year-old female patient with a presumed diagnosis of longstanding seronegative rheumatoid arthritis and history of C. acnes prosthetic joint infection following revision arthroplasty of the right shoulder. She presented to our clinic with a rash over the upper extremities and trunk and joint symptoms involving the right shoulder. Treatment was initiated with ceftriaxone followed by doxycycline suppressive therapy, with clinical improvement of joint and skin involvement. Symptoms recurred upon brief cessation of antibiotic therapy due to adverse gastrointestinal effects; however, symptoms abated once again upon re-initiation of treatment. Given the patient's cutaneous lesions and longstanding history of arthritis that improved with antimicrobial therapy against C. acnes, the diagnosis of SAPHO syndrome was entertained. The present case demonstrates the clinical challenges of diagnosing SAPHO syndrome and the importance of its consideration on the differential for a patient with osteoarticular and cutaneous features. Additional literature is needed to improve diagnostic criteria and treatment guidelines.

Future therapies for cystic fibrosis.

We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.

Exercise as an Airway Clearance Technique in people with Cystic Fibrosis (ExACT-CF): rationale and study protocol for a randomised pilot trial.

Background: Chest physiotherapy is an established cornerstone of care for people with cystic fibrosis (pwCF), but is often burdensome. Guidelines recommend at least one chest physiotherapy session daily, using various airway clearance techniques (ACTs). Exercise (with huffs and coughs) may offer an alternative ACT, however the willingness of pwCF to be randomised into a trial needs testing. The 'ExACT-CF: Exercise as an Airway Clearance Technique in people with Cystic Fibrosis' trial will test the feasibility of recruiting pwCF to be randomised to continue usual care (chest physiotherapy) or replace it with exercise ACT (ExACT) for 28-days. Secondary aims include determining the short-term clinical impact (and safety) of stopping routine chest physiotherapy and replacing it with ExACT, and effects on physical activity, sleep, mood, quality of life and treatment burden, alongside preliminary health economic measures and acceptability. Methods: Multi-centre, two-arm, randomised (1:1 allocation using minimisation), pilot trial at two sites. Fifty pwCF (≥10 years, FEV 1 >40% predicted, stable on Elexacaftor/Tezacaftor/Ivacaftor (ETI)) will be randomised to an individually-customised ExACT programme (≥once daily aerobic exercise of ≥20-minutes duration at an intensity that elicits deep breathing, with huffs and coughs), or usual care. After baseline assessments, secondary outcomes will be assessed after 28-days, with additional home lung function and exacerbation questionnaires at 7, 14 and 21-days, physical activity and sleep monitoring throughout, and embedded qualitative and health-economic components. Feasibility measures include recruitment, retention, measurement completion, adverse events, interviews exploring the acceptability of trial procedures, and a trial satisfaction questionnaire. Discussion: Co-designed with the UK CF community, the ExACT-CF pilot trial is the first multi-centre RCT to test the feasibility of recruiting pwCF stable on ETI into a trial investigating ExACT. This pilot trial will inform the feasibility, design, management, likely external validity for progression to a main phase randomised controlled trial. Registration: Clinicaltrials.gov ( NCT05482048).

Cystic fibrosis (CF) is the UK's most common inherited genetic condition and affects > 10,500 people. CF causes problems with the movement of salt and water in the body, resulting in sticky mucus building up, mostly in the lungs and gut. Thick mucus in the airways leads to repeated infections which can damage the lungs. Chest physiotherapy is routinely prescribed to keep pwCF healthy, by loosening and clearing sticky, thick mucus from the airways. However, many find it time-consuming and burdensome. People with CF (pwCF) have asked if doing exercise could have the same effect for clearing mucus. Surveys show that many pwCF have occasionally replaced chest physiotherapy with exercise for airway clearance. We also showed that many pwCF, their families, physiotherapists and doctors in the UK consider that hard exercise with huffs and coughs may be able to clear mucus from the airways. We now need to know if they would be willing to take part in research that asks some to stop chest physiotherapy and do intense exercise with huffs and coughs instead. We will study 50 pwCF (> 10 years old) for 28 days. We will ask half to continue their usual care, and half to stop chest physiotherapy and do exercise that gets them breathing deeply (with huffs and coughs) instead. We will see if people are willing to start and continue with such a study and what they think of the processes. We will also see how stopping chest physiotherapy and replacing it with exercise affects measurements of their lung function. Within the study we will talk with pwCF and members of their CF team to understand their experiences. This information will tell us whether a larger study can answer whether certain forms of exercise can safely be used as an alternative to chest physiotherapy.

Effectiveness of Bezlotoxumab for Prevention of Recurrent Clostridioides difficile Infection Among Transplant Recipients.

BACKGROUND: Bezlotoxumab significantly reduces the incidence of recurrent Clostridioides difficile infection (CDI); however, limited data are available in solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients. METHODS: We conducted a single-center retrospective analysis comparing recurrent CDI in SOT and HCT recipients receiving standard of care alone (oral vancomycin, fidaxomicin, or metronidazole) or bezlotoxumab plus standard of care. The primary outcome was 90-day incidence of recurrent CDI, and secondary outcomes included 90-day hospital readmission, mortality, and incidence of heart failure exacerbation. RESULTS: Overall, 94 patients received bezlotoxumab plus standard of care (n = 38) or standard of care alone (n = 56). The mean age was 53 years; patients had a median of 3 prior Clostridioides difficile episodes and 4 risk factors for recurrent infection. Most patients were SOT recipients (76%), with median time to index CDI occurring 2.7 years after transplantation. Ninety-day recurrent CDI occurred in 16% (6/38) in the bezlotoxumab cohort compared to 29% (16/56) in the standard of care cohort (P = .13). Multivariable regression revealed that bezlotoxumab was associated with significantly lower odds of 90-day recurrent CDI (odds ratio, 0.28 [95% confidence interval, .08-.91]). There were no differences in secondary outcomes, and no heart failure exacerbations were observed. CONCLUSIONS: In a cohort of primarily SOT recipients, bezlotoxumab was well tolerated and associated with lower odds of recurrent CDI at 90 days. Larger, prospective trials are needed to confirm these findings among SOT and HCT populations.

How can we relieve gastrointestinal symptoms in people with cystic fibrosis? An international qualitative survey.

INTRODUCTION: Relieving gastrointestinal (GI) symptoms was identified as a 'top ten' priority by our James Lind Alliance Priority Setting Partnership in cystic fibrosis (CF). We conducted an online survey to find out more about the effect of GI symptoms in CF. METHODS: We co-produced an online survey distributed to the CF community via web-based platforms. The survey consisted of open and closed questions designed to help us learn more about the effects of GI symptoms for people with CF (pwCF). We analysed the data using descriptive statistics and thematic analysis. We promoted the survey via social media and web-based platforms which allowed respondents from any country to take part. Our participants came from the CF community, including: adults and children with CF, parents and close family of pwCF and healthcare professionals (HCPs) working with pwCF. RESULTS: There were 276 respondents: 90 (33%) pwCF, 79 (29%) family, 107 (39%) HCPs. The most commonly reported symptoms by lay respondents were stomach cramps/pain, bloating and a 'combination of symptoms'. The top three symptoms that HCPs said were reported to them were reduced appetite, bloating and constipation. Almost all (94% (85/90)) HCPs thought medications helped to relieve GI symptoms but only 58% (82/141) of lay respondents agreed. CONCLUSIONS: Our survey has shown that GI symptoms among our participants are prevalent and intrude on daily lives of pwCF. There is a need for well-designed clinical studies to provide better evidence for management of GI symptoms and complications.

What effective ways of motivation, support and technologies help people with cystic fibrosis improve and sustain adherence to treatment?

INTRODUCTION: "What effective ways of motivation, support and technologies help people with cystic fibrosis improve and sustain adherence to treatment?" was identified as one of the James Lind Alliance Priority Setting Partnership's top 10 research questions in cystic fibrosis (CF). Using electronic questionnaires, we aimed to gain a deeper understanding of this research priority. METHOD: The work was led by the steering group representative of the UK CF community consisting of patients, carers and healthcare professionals (HCPs). Electronic questionnaires were completed over a 4-week period and promoted via online forums such as Twitter, the UK CF Trust and US CF Foundation websites and via professional networks. Analysis of the closed questions was completed using Microsoft Excel, with keyword analysis and the final thematic analysis completed using NVivo software. RESULTS: There were 313 respondents; 176/313 (56%) were from people with CF and their families. HCPs comprised of 10 professional groups accounting for 137/313 (44%) of respondents, with global involvement of participants with the majority from the UK. Common themes identified as impacting on adherence included: having no time, treatment burden, competing life demands, fatigue and the patient's general health. Having a routine was identified as the most frequently used motivational strategy, valued by both the patient and professional community. However, some strategies were valued more by HCPs than used in practice by patients; these included the use of short-term goal setting and technology use. CONCLUSION: Adherence to treatment is crucial, however it is often suboptimal and strategies valued by HCPs to promote adherence are not always shared by patients. To promote adherence clinicians and researchers should be mindful that in a condition where treatment burden and time pressures are considerable, any interventions should focus on simplifying care and reducing treatment burden.

Overview of Cutaneous Mycobacterial Infections.

PURPOSE OF REVIEW: Mycobacterial infections may affect any human organ and produce disseminated disease in immunocompromised individuals. Their most common clinical presentations include pulmonary, cutaneous (skin and soft tissues), and disseminated forms. The skin and soft tissues are frequent targets of affection by mycobacterial pathogens manifesting as localized or diffuse disease. RECENT FINDINGS: Overall, infections due to Mycobacterium leprae, Mycobacterium ulcerans, and Mycobacterium tuberculosis are the most frequently recognized mycobacterial pathogens involving the skin and soft tissues. Additionally, all mycobacterial species of the nontuberculous group may also produce cutaneous disease. Of these, the most commonly identified organisms causing localized infections of the skin and subcutaneous tissues are the rapidly growing species (Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus complex), Mycobacterium marinum, and M. ulcerans. Since the skin and soft tissues are important protective barriers for environmental pathogens, their disruption often represents the portal of entry of nontuberculous environmental mycobacteria (soil, natural water systems, engineered water networks, etc.). Additionally, some mycobacterial diseases affecting cutaneous structures occur after exposure to infected animals or their products (i.e., Mycobacterium bovis). Mycobacterial infections of the skin and soft tissues may manifest with a broad range of clinical phenotypes such as cellulitis, single or multiple abscesses, subacute or chronic nodular lesions, macules, superficial lymphadenitis, plaques, nonhealing ulcers, necrotic plaques, verrucous lesions, and many other dermatologic manifestations. SUMMARY: Geography and environmental exposure play an important role in the epidemiology of cutaneous mycobacterial infections. Mycobacterial infection of the skin and subcutaneous tissue is an important cause of human suffering in terms of morbidity, deformity, dysfunction, and stigma. The diagnosis of cutaneous mycobacterial infections is challenging requiring a low threshold of clinical suspicion for obtaining skin biopsies of cutaneous lesions for acid-fast staining and cultures, and molecular probe assays to detect the presence of mycobacterial pathogens. The choice of antibacterial therapy combinations and length of therapy for cutaneous mycobacterial infections is species-specific.