Defining the road map to a UK national lung cancer screening programme.

Lung cancer screening with low-dose CT was recommended by the UK National Screening Committee (UKNSC) in September, 2022, on the basis of data from trials showing a reduction in lung cancer mortality. These trials provide sufficient evidence to show clinical efficacy, but further work is needed to prove deliverability in preparation for a national roll-out of the first major targeted screening programme. The UK has been world leading in addressing logistical issues with lung cancer screening through clinical trials, implementation pilots, and the National Health Service (NHS) England Targeted Lung Health Check Programme. In this Policy Review, we describe the consensus reached by a multiprofessional group of experts in lung cancer screening on the key requirements and priorities for effective implementation of a programme. We summarise the output from a round-table meeting of clinicians, behavioural scientists, stakeholder organisations, and representatives from NHS England, the UKNSC, and the four UK nations. This Policy Review will be an important tool in the ongoing expansion and evolution of an already successful programme, and provides a summary of UK expert opinion for consideration by those organising and delivering lung cancer screenings in other countries.

Pseudomonas aeruginosa population diversity and turnover in cystic fibrosis chronic infections.

RATIONALE: Pseudomonas aeruginosa isolates from chronic cystic fibrosis lung infections display multiple phenotypes indicating extensive population diversity. OBJECTIVES: We aimed to examine how such diversity is distributed within and between patients, and to study the dynamics of single-strain phenotypic diversity in multiple patients through time. METHODS: Sets of 40 P. aeruginosa isolates per sputum samples were analyzed for a series of phenotypic and genotypic characteristics. Population differentiation between patients, between samples within patients, and between isolates within samples was analyzed. MEASUREMENTS AND MAIN RESULTS: We characterized 15 traits for a total of 1,720 isolates of an important and widely disseminated epidemic strain of P. aeruginosa from 10 chronically infected patients with cystic fibrosis multiply sampled during 2009. Overall, 43 sputum samples were analyzed and 398 haplotypes of the Liverpool Epidemic Strain were identified. The majority of phenotypic diversity occurred within patients. Such diversity is highly dynamic, displaying rapid turnover of haplotypes through time. P. aeruginosa populations within each individual sputum sample harbored extensive diversity. Although we observed major changes in the haplotype composition within patients between samples taken at intervals of several months, the compositions varied much less during exacerbation periods, despite the use of intravenous antibiotics. Our data also highlight a correlation between periods of pulmonary exacerbation and the overproduction of pyocyanin, a quorum sensing-controlled virulence factor. CONCLUSIONS: These results significantly advance our understanding of the within-host population biology of P. aeruginosa during infection of patients with cystic fibrosis, and provide in vivo evidence for a link between pyocyanin production and patient morbidity.

Effect of antibiotic treatment on bacteriophage production by a cystic fibrosis epidemic strain of Pseudomonas aeruginosa.

Phage production in response to antibiotics varied among four isolates of a Pseudomonas aeruginosa cystic fibrosis (CF) epidemic strain. Whereas ciprofloxacin induced higher levels of phage production, other CF-relevant antibiotics led to reduced production. We detected free phages directly in CF patient sputum samples by both plaque (40% positive) and PCR (76% positive) assays. Our observations suggest that the choice of antibiotics could influence the number of free phages within the CF lung environment.

Analysis of the baseline performance of five UK lung cancer screening programmes.

INTRODUCTION: Low-dose CT (LDCT) screening reduces lung cancer specific mortality. Several countries, including the UK, are evaluating the clinical impact and cost-effectiveness of LDCT screening using the latest evidence. In this paper we report baseline screening performance from five UK-based lung cancer screening programmes. METHODS: Data was collected at baseline from each screening programme. Measures of performance included prevalence of screen detected lung cancer, rate of surveillance imaging for indeterminate findings and surgical resection rates. Screening related harms were assessed by measuring false positive rates, number of invasive tests with associated complications in individuals without lung cancer and benign surgical resection rates. RESULTS: A total of 11,148 individuals had a baseline LDCT scan during the period of analysis (2011 to 2020). Overall, 84.7% (n = 9,440) of baseline LDCT scans were categorised as negative, 11.1% (n = 1,239) as indeterminate and 4.2% (n = 469) as positive. The prevalence of screen detected lung cancer was 2.2%, ranging between 1.8% and 4.4% for individual programmes. The surgical resection rate was 66% (range 46% to 83%) and post-surgical 90-day mortality for those with lung cancer 1.2% (n = 2/165). The false positive rate was 2% (n = 219/10,898) and of those with a positive result, one in two had lung cancer diagnosed (53.3%). An invasive test was required in 0.6% (n = 61/10,898) of screening attendees without lung cancer; there were no associated major complications or deaths. The benign surgical resection rate was 4.6% (n = 8/173), equating to 0.07% of the screened population. DISCUSSION: The performance of UK-based lung cancer screening programmes, delivered within or aligned to the National Health Service, compares favourably to published clinical trial data. Reported harms, including false positive and benign surgical resection rates are low. Ongoing monitoring of screening performance is vital to ensure standards are maintained and harms minimised.

Lung cancer mortality reduction by LDCT screening: UKLS randomised trial results and international meta-analysis.

BACKGROUND: The NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the results of the UKLS trial. METHODS: From October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50-75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence. FINDINGS: 1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1-7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 [95% CI 0.41-1.02]; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76-0.92) from nine eligible trials. INTERPRETATION: The UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups. FUNDING: NIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.

Impact of Pseudomonas aeruginosa genomic instability on the application of typing methods for chronic cystic fibrosis infections.

The Liverpool epidemic strain (LES) of Pseudomonas aeruginosa is widespread among cystic fibrosis (CF) patients in the United Kingdom and has emerged recently in North America. In this study, we report the analysis of 24 "anomalous" CF isolates of P. aeruginosa that produced inconsistent results with regard to either pulsed-field gel electrophoresis (PFGE) or PCR tests for the LES. We used a new typing method, the ArrayTube genotyping system, to determine that of the 24 anomalous isolates tested, 13 were confirmed as the LES. LES isolates could not be clearly distinguished from non-LES isolates by two other commonly used genetic fingerprinting tests, randomly amplified polymorphic DNA (RAPD) analysis and BOX-PCR, and varied considerably in their carriage of LES genomic islands and prophages. The genomic instability of the LES suggests that identification of this emerging transmissible strain could be a challenging task, and it questions whether discrimination is always a desirable feature of bacterial typing methods in the context of chronic CF infections.

Evaluation of a health service adopting proactive approach to reduce high risk of lung cancer: The Liverpool Healthy Lung Programme.

OBJECTIVES: This Liverpool Healthy Lung Programme is a response to high rates of lung cancer and respiratory diseases locally and aims to diagnose lung cancer at an earlier stage by proactive approach to those at high risk of lung cancer. The objective of this study is to evaluate the programme in terms of its likely effect on mortality from lung cancer and its delivery to deprived populations. METHODS: Persons aged 58-75 years, with a history of smoking or a diagnosis of chronic obstructive pulmonary disease (COPD)2 according to general practice records were invited for lung health check in a community health hub setting. A detailed risk assessment and spirometry were performed in eligible patients. Those with a 5% or greater five-year risk of lung cancer were referred for a low dose CT3 scan. RESULTS: A total of 4 566 subjects attended the appointment for risk assessment and 3 591 (79%) consented to data sharing. More than 80% of the patients were in the most deprived quintile of the index of multiple deprivation. Of those attending, 63% underwent spirometry and 43% were recommended for a CT scan. A total of 25 cancers were diagnosed, of which 16 (64%) were stage I. Comparison with the national stage distribution implied that the programme was reducing lung cancer mortality by 22%. CONCLUSIONS: Community based proactive approaches to early diagnosis of lung cancer in health deprived regions are likely to be effective in early detection of lung cancer.

Long-term effect of insulin treatment in cystic fibrosis-related diabetes.

BACKGROUND: Although insulin treatment confers short-term benefit in cystic fibrosis-related diabetes (CFRD), few studies have compared its long-term effect on the clinical outcome. OBJECTIVES: In this study, we aimed to investigate the long-term impact of insulin treatment on pulmonary function, nutritional status and hospital admissions in patients with CFRD. METHODS: We reviewed pulmonary function, body mass index (BMI) and hospital admissions 5 years before and 3 years after insulin therapy in 42 adult CFRD patients. RESULTS: Prior to treatment, over a period of 5 years, the annual rate of change in forced expiratory volume in 1 s (FEV(1)) was -3.2%, forced vital capacity (FVC) -2.5%, and BMI -0.07%. At treatment of CFRD (baseline), the mean FEV(1) was 51.6% predicted (range 24-96), FVC 66.4% (range 29-103) and BMI 19.5 (range 15.3-29.5). At 3 months following insulin treatment, there was a significant improvement in all parameters, which was maintained at 1 year for FEV(1) (55.1%; p < 0.002), 2 years for FVC (72.1%; p < 0.01) and at 3 years for BMI (20.4%; p < 0.002). After 3 months, FEV(1) declined at a rate similar to that before treatment (-3.2 vs. -3.1% per year; p = 0.77), such that the mean FEV(1) after treatment returned to pretreatment baseline values at 34 months. There was no difference in the number of hospital admissions with insulin treatment. CONCLUSIONS: Insulin enhances the nutritional state and temporarily improves pulmonary function in CFRD patients, on average delaying the decline in FEV(1) by 34 months.

The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer.

BACKGROUND: Lung cancer kills more people than any other cancer in the UK (5-year survival < 13%). Early diagnosis can save lives. The USA-based National Lung Cancer Screening Trial reported a 20% relative reduction in lung cancer mortality and 6.7% all-cause mortality in low-dose computed tomography (LDCT)-screened subjects. OBJECTIVES: To (1) analyse LDCT lung cancer screening in a high-risk UK population, determine optimum recruitment, screening, reading and care pathway strategies; and (2) assess the psychological consequences and the health-economic implications of screening. DESIGN: A pilot randomised controlled trial comparing intervention with usual care. A population-based risk questionnaire identified individuals who were at high risk of developing lung cancer (≥ 5% over 5 years). SETTING: Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire. PARTICIPANTS: Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres. INTERVENTIONS: A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria. MAIN OUTCOME MEASURES: Population-based recruitment based on risk stratification; management of the trial through web-based database; optimal characteristics of CT scan readers (radiologists vs. radiographers); characterisation of CT-detected nodules utilising volumetric analysis; prevalence of lung cancer at baseline; sociodemographic factors affecting participation; psychosocial measures (cancer distress, anxiety, depression, decision satisfaction); and cost-effectiveness modelling. RESULTS: A total of 247,354 individuals were approached to take part in the trial; 30.7% responded positively to the screening invitation. Recruitment of participants resulted in 2028 in the CT arm and 2027 in the control arm. A total of 1994 participants underwent CT scanning: 42 participants (2.1%) were diagnosed with lung cancer; 36 out of 42 (85.7%) of the screen-detected cancers were identified as stage 1 or 2, and 35 (83.3%) underwent surgical resection as their primary treatment. Lung cancer was more common in the lowest socioeconomic group. Short-term adverse psychosocial consequences were observed in participants who were randomised to the intervention arm and in those who had a major lung abnormality detected, but these differences were modest and temporary. Rollout of screening as a service or design of a full trial would need to address issues of outreach. The health-economic analysis suggests that the intervention could be cost-effective but this needs to be confirmed using data on actual lung cancer mortality. CONCLUSIONS: The UK Lung Cancer Screening (UKLS) pilot was successfully undertaken with 4055 randomised individuals. The data from the UKLS provide evidence that adds to existing data to suggest that lung cancer screening in the UK could potentially be implemented in the 60-75 years age group, selected via the Liverpool Lung Project risk model version 2 and using CT volumetry-based management protocols. FUTURE WORK: The UKLS data will be pooled with the NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek: Dutch-Belgian Randomised Lung Cancer Screening Trial) and other European Union trials in 2017 which will provide European mortality and cost-effectiveness data. For now, there is a clear need for mortality results from other trials and further research to identify optimal methods of implementation and delivery. Strategies for increasing uptake and providing support for underserved groups will be key to implementation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78513845. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 40. See the NIHR Journals Library website for further project information.

Acute renal failure in CF patients chronically infected by the Liverpool epidemic Pseudomonas aeruginosa strain (LES).

Although acute renal failure has been described in children with CF in relation to intravenous aminoglycoside use, there are no reports in the adult CF literature. We describe 8 cases of acute renal failure in adult CF patients, all occurring during the use of intravenous aminoglycosides for the treatment of pulmonary exacerbations with an epidemic multi-resistant Pseudomonas aeruginosa strain. Potential contributory factors are discussed. These cases demonstrate another complication of infection by epidemic Pseudomonas strains in CF, and confirm the need for effective segregation policies to prevent this.

PCR-based detection of a cystic fibrosis epidemic strain of Pseudomonas Aeruginosa.

BACKGROUND: The Liverpool epidemic strain (LES) of Pseudomonas aeruginosa is widespread among patients with cystic fibrosis (CF) in specialist centers around Liverpool and elsewhere in the UK. This study evaluates a new diagnostic PCR assay based on a unique DNA sequence (PS21) of LES, for its identification of colonies directly from sputum. METHODS: One hundred and fifty-eight sputum samples from 92 patients were cultured and P. aeruginosa isolates were typed by PS21 PCR and pulsed-field gel electrophoresis (PFGE). Subsequently, PS21 PCR was performed directly on sputum and the results were compared with culture, PFGE, and PS21 PCR typing. RESULTS: Eighty patients were colonized with P. aeruginosa, 63 by LES (79%). There was 100% concordance between PS21 PCR on colonies and PFGE typing. The sensitivity and specificity of PS21 PCR directly on sputum was 98.2% and 93.6%, respectively. CONCLUSIONS: This study shows that PS21 PCR can be used for simple and rapid screening of LES colonization in CF patients.

A randomized double-blinded placebo-controlled crossover trial of nebulized taurolidine in adult cystic fibrosis patients infected with Burkholderia cepacia.

Burkholderia cepacia is an aggressive pathogen that colonizes cystic fibrosis (CF) patients, causing greatly increased morbidity and mortality. It is resistant to most antibiotics, but sensitive in vitro to a novel agent, taurolidine. This has not previously been used against B. cepacia, nor given in nebulized form. We assessed the effect of nebulized taurolidine on United Kingdom epidemic (ET12) B. cepacia infection in 20 adult CF patients attending our regional adult cystic fibrosis outpatient clinic using a prospective, randomized, double-blinded placebo-controlled crossover trial. Nebulized taurolidine (4 mL 2% solution) or saline (4 mL 0.9% solution) was given twice daily. Each arm lasted 4 weeks, with a 2-week intervening washout period. Sputum B. cepacia colony counts (primary outcome measure), spirometry, and symptoms (secondary outcome measures) were assessed. Eighteen patients completed the study. There was no change in B. cepacia colony counts or spirometry, nor symptom scores. We conclude that, although taurolidine is well tolerated in nebulized form, in this study it had no in vivo anti-B. cepacia activity.

The UK Lung Screen (UKLS): demographic profile of first 88,897 approaches provides recommendations for population screening.

UNLABELLED: The UK Lung Cancer Screening trial (UKLS) aims to evaluate low-dose computed tomography (LDCT) lung cancer population screening in the United Kingdom. In UKLS, a large population sample ages 50 to 75 years is approached with a questionnaire to determine lung cancer risk. Those with an estimated risk of at least 5% of developing lung cancer in the next 5 years (using the Liverpool Lung project risk model) are invited to participate in the trial. Here, we present demographic, risk, and response rate data from the first 88,897 individuals approached. Of note, 23,794 individuals (26.8% of all approached) responded positively to the initial questionnaire; 12% of these were high risk. Higher socioeconomic status correlated positively with response, but inversely with risk (P < 0.001). The 50- to 55-year age group was least likely to participate, and at lowest cancer risk. Only 5% of clinic attendees were ages ≤60 years (compared with 47% of all 88,897 approached); this has implications for cost effectiveness. Among positive responders, there were more ex-smokers than expected from population figures (40% vs. 33%), and fewer current smokers (14% vs. 17.5%). Of note, 32.7% of current smokers and 18.4% of ex-smokers were designated as high risk. Overall, 1,452 of 23,794 positive responders (6.1%) were deemed high risk and attended a recruitment clinic. UKLS is the first LDCT population screening trial, selecting high-risk subjects using a validated individual risk prediction model. KEY FINDINGS: (i) better recruitment from ex- rather than current smokers, (ii) few clinic attendees ages early 50s, and (iii) representative number of socioeconomically deprived people recruited, despite lower response rates.

Health-related quality of life in Cystic Fibrosis patients infected with transmissible Pseudomonas aeruginosa strains: cohort study.

OBJECTIVES: To assess the impact on health-related quality of life (HRQoL) in adult cystic fibrosis (CF) patients of chronic infection with the Liverpool Epidemic Strain (LES) of Pseudomonas aeruginosa (Psa). DESIGN: Cohort study. PARTICIPANTS: Adult CF patients attending a single CF centre. SETTING: Outpatient clinic. MAIN OUTCOME MEASURES: HRQoL measures of adult CF patients chronically infected with LES and Psa strains measured by CFQ-UK. RESULTS: Patients infected by transmissible Psa strains had worse physical functioning, respiratory symptoms, treatment burden, vitality, role, health perception and emotion than those with unique Psa strains (P < 0.01), and significantly poorer physical functioning, respiratory symptoms, treatment burden, body image, weight, role, and emotion than those without any Psa infection (P < 0.05). Furthermore, in a matched cohort of 39 patients, those with LES infection reported significantly worse physical functioning, treatment burden, respiratory symptoms and health perception than those with unique Psa infection (P < 0.02). CONCLUSION: Chronic infection with transmissible Psa strains, particularly LES, confers a worse quality of life in adult CF patients. Coupled with the established poorer clinical outcome, this reinforces the need to prevent the spread of such strains in CF community.

Increasing resistance of the Liverpool Epidemic Strain (LES) of Pseudomonas aeruginosa (Psa) to antibiotics in cystic fibrosis (CF)--a cause for concern?

BACKGROUND: Transmissible Pseudomonas aeruginosa (Psa) strains such as the Liverpool Epidemic Strain (LES) are now widespread throughout UK CF clinics: their susceptibility to antibiotics is therefore important. To study this, we compared antibiogram patterns of Psa strains in our CF clinic over 5 years, looking at differences in resistance patterns between strains and changes to these over time. METHODS: The antibiograms of sputum samples between 2004 and 2008 from patients attending our centre were included. We compared Psa isolate antibiotic resistance (to six anti-pseudomonal antibiotics) patterns for patients infected with LES with those infected with other Psa strains, both in the total population in 2004 (125 patients) and 2008 (166 patients) and also longitudinally from annual review samples 2004 to 2008 in matched and unmatched patient groups. RESULTS: LES exhibited significantly more resistant isolates in 2004 (p<0.0001). There was an increase in antibiotic resistance in both LES and other Psa strains over time (p<0.001). Cox proportional hazards analysis of both unmatched (n=125) and matched (n=56) patients in 2004 revealed that LES infected patients were more likely to develop antibiotic resistant isolates over time (hazard ratio 8.1, p<0.001). Fewer LES isolates were classed as fully sensitive in both matched and unmatched groups at the end of study period (p<0.001). CONCLUSION: This study shows a worrying trend in antibiotic resistance in the Psa isolates amongst patients chronically infected with LES. This highlights the need to prevent cross infection through segregation and also the need to develop new strategies to treat these organisms.

Self-care and cystic fibrosis: a review of research with adults.

The issue of self-care is becoming increasingly central to both policy and practice in health and social care in the community. It is imperative therefore that research in this important area is drawn together and presented coherently so as to ensure that change can be informed by evidence and implemented sensitively. As cystic fibrosis (CF) has until recently been regarded as a paediatric condition, there is relatively little research that focuses on the self-care of adults. Although not entirely uncritical of traditional biomedicine, these studies focus on individual patient deficits and are directed primarily at facilitating their 'compliance'. After discussing some important methodological, evidential and theoretical limitations of this research, other recent CF literature will be considered that suggests the possibility of developing a 'social model' for self-care research. The proposed model is more pluralistic and less prescriptive than its predecessors and the resulting 'types' of self-care indicate that both old and new, mainstream and marginal discourses should co-exist. Indeed, recognising the legitimacy of distinct varieties of self-care not only guards against unwarranted moralising and pathologising but may also enable self-care support to be negotiated and tailored more appropriately.

Empyema due to a highly transmissible Pseudomonas aeruginosa strain in an adult cystic fibrosis patient.

Chronic pulmonary infection with Pseudomonas aeruginosa occurs in up to 85 % of individuals with cystic fibrosis (CF) by the time they reach adulthood, and is the major cause of morbidity and mortality: nearly all patients die from progressive respiratory failure due to repeated pulmonary exacerbations. However, despite the predilection of this organism for the lungs of CF people, infection of the pleura is much less common and is not well described in the CF population. We describe what is believed to be the first case of pleural empyema due to a particularly pathogenic transmissible strain of P. aeruginosa (the Liverpool epidemic strain) in an adult CF patient.

Fluctuations in phenotypes and genotypes within populations of Pseudomonas aeruginosa in the cystic fibrosis lung during pulmonary exacerbations.

Chronic respiratory infection by Pseudomonas aeruginosa contributes significantly to the morbidity and mortality associated with cystic fibrosis (CF). Using a series of phenotypic and genotypic tests on collections of 40 isolates per sputum sample, we analysed fluctuations within sputum populations of the P. aeruginosa Liverpool epidemic strain (LES) during pulmonary exacerbations. For each of three patients, three sequential sputum samples were analysed: (1) on presentation with exacerbation at the Regional Adult Cystic Fibrosis Unit, Liverpool; (2) a few days into intravenous antibiotic treatment; (3) when the patient had recovered. Fluctuations were observed in morphotype distribution, the production of virulence-associated quorum-sensing-dependent exoproducts (the phenazine compound pyocyanin and the elastase LasA), antibiotic susceptibility profiles and levels of auxotrophy. PCR assays were used to screen isolates for the presence of novel regions of the LES genome (islands and prophages) and to detect free phages. In one patient there was an increase in the prevalence of the LESGI-5 genomic island during the sampling period from 10 to 97.5 % carriage. LES phages 2-4 were detected in either the majority or all sputum samples tested, indicating widespread phage activity during the sampling period. The results of this study are indicative that significant fluctuations occur within P. aeruginosa populations during short periods of pulmonary exacerbation and intravenous antibiotic therapy.