Annually, community-acquired pneumonia (CAP) affects millions of individuals worldwide, resulting in more than 200 000 hospital admissions in England alone. CAP is a major cause of morbidity and mortality. Previous studies have explored the causes, risk factors, and the clinical course of CAP in detail. Sepsis and respiratory failure are important well-recognised consequences of progressive infection and have been researched extensively. In this Review, we focus on complications of CAP beyond the natural history of the condition. These sequelae of CAP often have long-term implications for patients and encompass a wide range of physical, functional, and psychosocial impairments, including reduced functional ability and persistent symptoms that adversely affect quality of life. Research on complications after CAP has increased since the COVID-19 pandemic. A growing body of literature informs clinical trials and guides clinical management. We explore the recovery trajectory and discuss updates in the management of post-CAP pleural infection, the established risk of cardiovascular events after CAP, and association of CAP with cognitive impairment and lung cancer. Finally, we conclude that improved long-term data, standardisation, and targeted research are needed to understand, prevent, and manage these outcomes effectively.

Introduction Pleural mesothelioma (PM) is often presaged by benign asbestos-associated pleural inflammation (AAPI), offering a unique window of opportunity for translational research. The PREDICT-Meso International Accelerator Network is leveraging this natural history to perform target identification and develop novel therapies for early-stage or pre-invasive disease. This requires assembly of a unique bioresource of longitudinal human tissue samples spanning the terminal stages of PM evolution, development of preclinical models for drug screening and reliable tools for risk prediction in patients presenting with AAPI.Methods and analysis Mesothelioma Observational study of Risk prediction and Generation of paired benign-meso tissue samples, Including a Nested MRI Substudy (Meso-ORIGINS) is a prospective, multicentre observational study, comprising two arms (A and B), with a nested MRI substudy in arm A. Arm A will recruit 300 AAPI patients and perform 6-monthly surveillance for 2 years. Suspicion of PM evolution will prompt repeat biopsy and banking, delivering a primary objective of ≥38 longitudinal AAPI-PM tissue pairs. This target reflects a projected PM evolution rate of 14% (95% CI 10.5 to 19.2) derived from a prior multicentre feasibility trial. Multiomic risk profiling will be performed in arm A, using blood proteomics, exhaled breath metabolomics and perfusion MRI. Arm B will recruit 300 patients with suspected PM, permitting collection of multiregion pleural biopsies in patients spanning AAPI and PM timepoints for evaluation of anatomical heterogeneity. Where possible, patients in arm B diagnosed with AAPI will be recruited to arm A for 2-year surveillance +/− repeat biopsy in subsequent PM evolution cases. Pleural fluid will be collected in arm B for cell-line generation and diagnostic biomarker evaluation. Exhaled breath will be collected in arm B for diagnostic biomarker evaluation.Ethics and dissemination The study has ethical approval (REC Ref 21/WS/0120). Results will be disseminated via peer-reviewed journals and national/international scientific conferences. Tissues, data and derived omics will be shared via the PREDICT-Meso Research Tissue Bank (REC Ref 21/WS/0011).Trial registration number ISRCTN22929761.

Background Eosinophilic pleural effusion (EPE) is a relatively uncommon condition. The objective of this study was to evaluate the clinical, laboratory and radiological features of EPE in a multicentre cohort of patients. Methods This retrospective study included patients with EPE, defined as pleural fluid in which eosinophils constitute ≥10% of the total nucleated cell count, treated between 2009 and 2021 at eight respiratory centres. Predefined data were collected in the International Multicentre Pleural Research Collaborative (IMPACT) registry. Results The study included 210 patients (144 (68.6%) males), with a median age of 67 years (interquartile range (IQR) 55–78 years). Radiological evaluation showed unilateral effusion in 194 (94.2%) patients. Most EPEs (199; 95.7%) were exudates. The median pleural fluid eosinophil percentage was 23% (IQR 14.8–43.3%). The most common aetiologies were malignancy (n=61, 29%), infection (n=43, 20.5%), heart diseases/cardiac intervention (n=17, 8.1%) or trauma (n=16, 7.6%). In 42 (20%) patients, the cause of EPE remained undetermined. In univariate and multivariable analyses incorporating available clinical and laboratory data, EPE was not a significant predictor of either malignancy or benign disease. Conclusion EPE is a nonspecific diagnostic entity and should not, by itself, be regarded as a relevant factor in clinical decision-making.

ABSTRACT Introduction Acute lower respiratory tract disease (aLRTD) is a leading cause of hospitalisation and death, particularly in older adults and adults with comorbidities, with acute lower respiratory tract infection (aLRTI; pneumonia and non-pneumonic LRTI) being a major component. Non-pulmonary complications and functional decline after aLRTI are recognised, but their pathogen-specific burden is poorly described. We aimed to quantify renal, hepatic, thromboembolic and functional complications, and mortality, after aLRTI hospitalisation, by clinical phenotype and pathogen. Methods We conducted a cohort study of adults (≥18 years) admitted with aLRTD to two hospitals in Bristol, UK (01 August 2022–31 July 2024). aLRTD was classified as pneumonia, non-pneumonic LRTI (NP-LRTI) or no diagnosis of aLRTI. Pathogens were identified from standard-of-care and research microbiology. Outcomes were acute kidney injury (AKI), acute liver dysfunction, venous thromboembolism (VTE), in-hospital falls, reduced mobility at discharge, increased care requirements, and 30-day and 1-year mortality. Analyses were descriptive. Results Among 246,797 adult admissions, 21,456 aLRTD hospitalisations were included: 10,239 (47.7%) pneumonia, 7,742 (36.1%) NP-LRTI and 3,475 (16.2%) with no evidence of aLRTI. Of 19,152 tested aLRTD admissions, 8,503 (44.4%) had a positive microbiological/virological test, yielding 9,204 pathogen detections; 1,194 (6.2%) had co-infections, and SARS-CoV-2 was most frequent, with influenza the second most common in pneumonia and NP-LRTI. Pneumonia had greater severity than NP-LRTI and no diagnosis of aLRTI (median length of stay 6 vs 4 vs 4 days; ICU admission 3.4% vs 0.7% vs 0.5%, respectively). Overall, 22.2% developed AKI, 6.1% acute liver dysfunction, 0.6% DVT and 2.4% PE; 1.8% had a fall, 11.5% reduced mobility, and 16.6% required increased care at discharge. 30-day and 1-year mortality were highest for pneumonia (14.0% and 32.0%, respectively). Pathogen-specific analyses showed longer stays and higher complications and mortality rates for SARS-CoV-2 and Streptococcus pneumoniae , and shorter stays with lower complication and mortality rates for influenza and Haemophilus influenzae . Conclusions Non-cardiovascular complications and functional decline after aLRTI were common, particularly in pneumonic and SARS-CoV-2 or pneumococcal disease. These findings support routine surveillance for renal, hepatic, thromboembolic events, early mobilisation and rehabilitation, and consideration of multi-system outcomes when evaluating public health and economic value of vaccines and therapies.

BACKGROUND:Patients with suspected malignant pleural effusions (MPE) are often in need of both a confirmatory diagnosis and symptom control. Therapeutic options include talc pleurodesis via chest drain, poudrage during medical thoracoscopy, or alternatively an indwelling pleural catheter (IPC). Combining the diagnostic and therapeutic efficacy of medical thoracoscopy and poudrage with the ambulatory benefits of an IPC has not been studied within a randomised controlled trial. The aim of the TACTIC trial was to determine whether this approach resulted in a reduced length of hospital stay and improvements in dyspnoea. METHODS:This unblinded, phase 3, randomised controlled trial was undertaken in 11 UK hospitals. Patients with MPE and confirmed malignancy (during medical thoracoscopy or beforehand) received talc poudrage and were randomly assigned by a centralised web-based system to an IPC at the time of medical thoracoscopy or usual care (ie, medical thoracoscopy, poudrage, and admission with large bore tube). Co-primary outcomes were time in hospital (including initial admission for trial procedure and any subsequent readmissions over 4 weeks post procedure) and average breathlessness assessed with visual analogue scale dyspnoea scores, measuring severity of dyspnoea from 0 mm to 100 mm, over a 4-week period. All randomised patients in whom an outcome was available were included in the analysis on a modified intention-to-treat basis. TACTIC was registered with ISRCTN on Aug 8, 2021 (ISRCTN11058680). FINDINGS:Participants were recruited from between Dec 15, 2021, and Jan 3, 2024. 124 participants were randomised: 62 to the intervention and 62 to standard care. Leading diagnoses were pleural mesothelioma (46%), lung cancer (28%), and breast cancer (10%). Co-primary outcome data were available for 102 patients for total length of hospital stay (52 in intervention group vs 50 in standard care group) and 108 patients for breathlessness (57 vs 51). Median time in hospital was 1 day (IQR 1-3, 95% CI 1-2) in the intervention group versus 2 days (IQR 1-3, 95% CI 1-2) in standard care group (p=0·26). Median visual analogue scale dyspnoea scores did not differ between groups: 14·0 mm (IQR 8·8-32·4) in the intervention group versus 19·6 mm (8·1-38·7) in standard care group (p=0·26). Participants in the intervention group required fewer additional invasive pleural procedures by 12 weeks (two [3%] of 60 vs 19 [34%] of 56, p<0·0001) Trial related adverse events rates were similar in both groups (46 [74%] of 62 vs 44 [71%] of 62, p=0·84). Three related serious adverse events were recorded, all occurring in the intervention group. INTERPRETATION:The combination of medical thoracoscopy, poudrage, and IPC did not result in shorter hospital stay but was safe and resulted in similar dyspnoea control compared with standard care. For patients with symptomatic MPE undergoing medical thoracoscopy for pleurodesis who prioritise minimising the length of hospital stay or the need for further invasive pleural procedures, the addition of an IPC alongside poudrage might help to achieve this goal. FUNDING:National Institute of Health Research, Research for Patient Benefit.

Background Surveillance of acute lower respiratory tract disease (aLRTD) is fundamental for understanding population health burden and healthcare needs. COVID-19 altered respiratory infection epidemiology, but the post-pandemic baseline incidence and severity of aLRTD remain underexplored. We describe the incidence and clinical outcomes of acute lower respiratory tract disease (aLRTD) hospitalisations in adults, stratified by clinical presentation and SARS-CoV-2 status. Methods We conducted a prospective cohort study of adults (>= 18 years) admitted with signs/symptoms or diagnoses of aLRTD to two Bristol acute-care hospitals (1 August 2020-31 July 2024). Patients were classified as having pneumonia (radiological changes or clinician diagnosis, in line with the British Thoracic Society (BTS) and National Institute for Health and Care Excellence (NICE) guidance), non-pneumonic lower respiratory tract infection (NP-LRTI; signs and symptoms of infection without radiological change or pneumonia diagnosis), or no evidence of LRTI (principally chronic respiratory disease exacerbations and heart failure). The primary outcome was incidence of aLRTD, stratified by clinical presentation, age, and SARS-CoV-2 status. Secondary outcomes included 30-day mortality, hospital discharge within 30 days, hospital length of stay, Intensive Care Unit (ICU) admission, ICU length of stay, and 1-year mortality. Population denominators were calculated using General Practitioner (GP) registration data linked to hospital admission patterns. Findings Among 457,112 hospitalisations, 44,766 were attributed to aLRTD (96% with consented data available): 20,639 pneumonia (48.2%), 15,061 NP-LRTI (35.2%), and 7134 no evidence of LRTI (16.7%). Overall, aLRTD incidence peaked in Year 2 (Aug 2021-Jul 2022) at 14.4/1000 person-years, driven primarily by COVID-19 cases, before stabilising around 13.6/1000 in Year 4 (Aug 2023-Jul 2024). SARS-CoV-2 pneumonia decreased from 2.6 in Year 2 to 0.9/1000 in Year 4, while non-COVID pneumonia remained stable (3.6-5.5/1000) between Year 2 and 4. Compared to pneumonia, NP-LRTI (HR 0.32, 95% CI: 0.29-0.35) and no evidence of LRTI (HR 0.43, 95% CI: 0.19-0.97) had lower mortality risk. Age >= 85 years (HR 5.1, 95% CI: 2.8-9.5, compared with 18-64 years) and severe comorbidities (HR 3.4, 95% CI: 2.8-4.1, compared with none) were associated with increased risk of 30-day mortality. Interpretation XXaLRTD incidence and severity remained substantial throughout and after COVID-19, with non-COVID infections maintaining consistent rates despite public health measures. These findings highlight the persistent burden of hospitalisations for aLRTD, measured in incidence and adverse outcomes and the importance of comprehensive aLRTD surveillance for public health planning. Funding AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer. Copyright (c) 2025 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract Background: Pegargiminase (ADI-PEG20)-based chemotherapy quadrupled the overall survival of patients at 3 years (12% versus 3%) with non-epithelioid (biphasic and sarcomatoid) pleural mesothelioma in the randomized placebo-controlled ATOMIC-Meso phase 2-3 trial (AACR 2023, JAMA Oncol 2024). Here, we report a novel genetic biomarker, namely HFE-related hereditary haemochromatosis as a predictor for durable response to arginine deprivation therapy for cancer using pegargiminase. Methods: We scrutinised the Barts patient cohort which recruited 20.9% (n=52/249) of patients enrolled on the ATOMIC-Meso study to identify potential pharmacogenomic factors linked to a prolonged therapeutic response. This led to identification of an index patient with the HFE C282Y variant who completed 2 years of pegargiminase. Common HFE variants (C282Y and H63D) were generated in the MSTO mesothelioma cell line using CRISPR/Cas9-mediated mutagenesis, followed by characterisation of mutant and parental controls relating to in vitro drug sensitivity, apoptosis, single/double strand DNA breaks (SSBs/DSBs), performed RNAseq to dissect the mechanism of drug action, and analyzed in vivo tumorigenesis and ADI-PEG20 efficacy using xenograft murine studies. Results: The index patient was homozygous for C282Y and was diagnosed with sarcomatoid mesothelioma during venesection to manage his iron overload. He was enrolled on ATOMIC-Meso and unexpectedly completed 2 years of pegargiminase with a durable partial response. Only one other patient at the same institution completed 2 years of pegargiminase with a durable partial response and was heterozygous for the HFE H63D variant with a biphasic mesothelioma. Bed-to-benchside studies confirmed increased ADI-PEG20 sensitivity in MSTOH63D+/- compared to parental cells using a 3D tumor spheroid model as evidenced by caspase 3 activation, PARP cleavage, higher Annexin V staining and upregulation of SSBs and DSBs. To understand the mechanism of enhanced cytotoxicity to ADI-PEG20 we performed RNA-Seq in MSTOH63D+/- and MSTOWT cells. This identified regulation of AP-1 signalling and suppression of Bcl-2 specifically in ADI-PEG20 treated MSTOH63D+/-cells by 48hrs. Differential modulation of the Bcl-2 family triggering enhanced apoptosis was confirmed in the MSTOH63D+/- compared to MSTOWT cells. Finally, MSTOH63D+/- tumors displayed earlier sensitivity to ADI-PEG20 monotherapy compared to MSTOWT tumor parental controls (14 days vs. 28 days) using murine xenografts. There was no difference in survival between MSTOH63D+/- and MSTOWT tumors, although there was a statistically significant earlier growth advantage for MSTOWT cells. Conclusions: In the Barts ATOMIC-Meso patient cohort, our data reveal mutant HFE as a novel pharmacogenomic biomarker for enhanced sensitivity and prolonged remission to pegargiminase-based chemotherapy for mesothelioma. Further analyses of durable responders to pegargiminase are ongoing with prospective clinical trials planned using HFE as a selection biomarker. Citation Format: Peter Wojciech Szlosarek, George Field, Iuliia Pavlyk, Matthew Young, Michael Allen, Josephine Carpentier, Riyaz Shah, Nick Maskell, David Houghton, Amanda Johnston, John Bomalaski, Louise Jones, Michael Sheaff. Germline HFE mutations predict for durable response to arginine depletion with pegargiminase-based chemotherapy in pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT139.

ABSTRACT Background The 2023 SARS‐CoV‐2 environment differs greatly from the initial outbreak, with new variants and widespread vaccination. Early in the pandemic, blood group A was linked to increased hospitalisation and poor outcomes, but its role now, since the availability of vaccination, is unclear. Methods We analysed data (1 August 2020–31 July 2023) from a prospective cohort of adults hospitalised in Bristol with SARS‐CoV‐2 and known ABO group (n = 3413). Admission date acted as a proxy for viral strain. Regression models assessed length of stay, survival, cardiovascular complications and ICU admission in non‐O groups versus Group O. Results Group A was over‐represented and Group O was under‐represented, compared to the blood donor population, except during Alpha dominance (p < 0.001; Alpha: p = 0.796). ABO group generally did not affect cardiovascular risk. However, during Wild‐Type, Group AB had higher odds of cardiovascular complications (odds ratio [OR] = 3.18, p = 0.060) and intensive care unit [ICU] admission (OR = 4.79, p = 0.013). During Omicron, AB group patients had lower 30‐day survival (HR = 2.09, p = 0.018). Group A was less likely to be discharged during Alpha (HR = 0.85, p = 0.013), while Group B was more likely to be discharged during Omicron (HR = 1.30, p = 0.002). Conclusions ABO groups may still influence hospitalisation risk but appear less relevant to outcomes once admitted, likely reflecting advances in care and vaccination.

Background Malignant pleural effusion (MPE) is a condition characterised by excessive fluid build-up in the pleural cavity caused by cancer. Management options focus on drainage of fluid from the pleural cavity with a common aim of minimising symptoms and improving quality of life. Definitive pleural intervention is recommended for most patients with MPE to achieve longer-term symptom control. A patient-centred approach is also emphasised. However, little is known about the patient and carer experiences of MPE management. Therefore, this study sought to examine patient and carer experiences of differing procedural interventions within a trial setting. Methods Patients with MPE and their carers who were taking part in the TACTIC trial in hospitals across the UK were invited to take part in a one-off interview. Thirty-two participants were recruited, and 22 semistructured interviews were conducted. Interview formats were either patient only, carer only or patient and carer dyad interviews. Interviews were audio recorded, transcribed verbatim and analysed using a generalised thematic analysis approach. Results Initial findings demonstrated that patients and carers were generally satisfied with the MPE management and care received. No significant differences in acceptability were found between the two management strategies. Further analysis led to the development of four overarching themes: experiences of MPE beyond the trial, experiences of pain, preferences in MPE care and measuring MPE: rethinking patient relevance. These findings underscore the importance of greater consideration of pain management during MPE care, as well as improved communication and information prior to procedures. Conclusion Patients and carers found the TACTIC combined procedure tolerable and acceptable. Echoing the growing evidence of research in this field, authors emphasise the importance of outcome measure selection in MPE trials and suggest a need for a Core Outcome Set to establish fundamental priorities in MPE management.

Introduction:Comorbid cardiovascular disease has been reported extensively in community COPD populations, but to a lesser degree in acute hospital settings. Shared risk factors and acute infection both increase acute coronary syndrome (ACS) risk. Our objective is to assess a cohort of adults hospitalised for an acute lower respiratory tract infection (aLRTI) to determine whether COPD status is an independent risk factor for ACS. Methods:A prospective observational cohort study of adults aged ≥40 years (n=8496) with community-acquired aLRTI (Bristol, UK) was conducted between 27 July 2020 and 28 November 2022. Cases included physician diagnosis of COPD; controls were aLRTI without COPD. Outcomes included physician-diagnosed ACS occurring within 30 days of admission. Logistic regression models were adjusted for shared cardiovascular risk factors and aLRTI severity. Results:30-day ACS events in patients hospitalised with aLRTI with COPD were 7.59% (190 out of 2502), versus without COPD 6.96% (417 out of 5994) (p=0.3094). Across both groups ACS incidence was 95.1 events per 100 inpatient years. There was no association between COPD and 30-day ACS risk, when adjusting for shared cardiovascular risk factors (OR 1.14, 95% CI 0.93-1.39). However, a diagnosis of COPD increased ACS risk in those without pneumonia versus controls (OR 1.38, 95% CI 1.02-1.87). Markers of infection were associated with increased risk of ACS in both groups (white cell count >10×109 cells·L-1 OR 1.31, 95% CI 1.10-1.56). Pneumonia was associated with the highest risk of ACS (OR 1.49, 95% CI 1.19-1.87 (no COPD); OR 1.46, 95% CI 1.11-1.92 (with COPD)). Conclusions:In this large, real-world cohort of hospitalised adults with aLRTI, 30-day ACS event rates were high at ∼7-13%. A diagnosis of COPD even in the absence of pneumonia increases ACS risk versus our control group without COPD. Markers of infection severity appear to be key drivers of ACS in this population. This highlights the importance of both COPD and infection severity on risk of ACS following hospitalisation with aLRTI.

Objectives Patient information sheets (PISs) and informed consent forms (ICFs) are essential tools to communicate and document informed consent for clinical trial participation. These documents need to be easily understandable, especially when used to take informed consent from acutely unwell patients. Health literacy guidance recommends written information should be at a level between reading ages 9–11. We aimed to assess the readability and complexity of PISs/ICFs used for clinical trials of acute therapies during the COVID-19 pandemic.Design Retrospective document analysis.Setting PISs/ICFs used in trials involving pharmaceutical interventions recruiting hospitalised patients with COVID-19 during the first year of the pandemic were sourced from hospitals across the UK.Primary and secondary outcome measures PISs/ICFs were assessed for length, approximate reading time and subsection content. Readability and language complexity were assessed using Flesch-Kincaid Grade Level (FKGL) (range 1–18; higher is more complex), Gunning-Fog (GFOG) (range 1–20; higher is more complex) and Flesch Reading Ease Score (FRES) (range 0–100; below 60 is ‘difficult’ for comprehension).Results 13 documents were analysed with a median length of 5139 words (range 1559–7026), equating to a median reading time of 21.4 min (range 6.5–29.3 min) at 240 words per minute. Median FKGL was 9.8 (9.1–10.8), GFOG 11.8 (10.4–13) and FRES was 54.6 (47.0–58.3). All documents were classified as ‘difficult’ for comprehension and had a reading age of 14 years old or higher.Conclusions All PISs/ICFs analysed contained literary complexity beyond both recommendations and the reading level of many in the UK population. Researchers should seek to improve communications to improve trial volunteer comprehension and recruitment.

BACKGROUND:CT scans are the current gold standard for disease monitoring for Pleural mesothelioma (PM), with radiology reported using the modified RECIST criteria. While mRECIST has its own challenges, attending for CT scans adds time and expense. A blood-based biomarker which tracks disease status could enable more responsive, community-based disease monitoring. This study evaluated the relationship between serial serum mesothelin (SM) levels and disease status. METHODS:Patients with PM were recruited from Assess-Meso, a multi-centre prospective cohort study of patients with mesothelioma, between 28/2/2019 and 31/12/2023. Logistic regression, adjusted for sex, age, histology, performance status, eGFR and treatment, was used to assess the relationship between serial SM and radiological disease status. Prespecified sub-group analyses stratified participants by initial SM and treatment status. RESULTS:156 patients had ≥ 2 SM measurements with paired CT scans. Rising SM was associated with disease progression in the coincident time period (Adj OR 1.11, 95 % CI 1.03-1.19) and the subsequent 6 months (Adj OR 1.13, 1.03-1.23), regardless of initial SM. A 25 % change in SM was the optimal threshold, with a 25 % rise associated with disease progression (Adj OR 2.68 (1.52-4.73)) with sensitivity and specificity of 48.7 % (43.1 %-54.4 %) and 75.7 % (70.8 %-80.5 %) respectively. For patients receiving treatment, falling SM predicted subsequent disease response (Adj OR 1.37, 1.16-1.61). CONCLUSIONS:Serial SM is a reliable response biomarker in PM, regardless of initial value and treatment status. These results support the use of SM in routine clinical care as an adjunct to CT scans, with several benefits over radiological monitoring.

Background:Pleural fluid cell differentiation is recommended as an initial investigation of undiagnosed unilateral pleural effusions along with routine biochemical, microbiological, and cytological analysis. However, the sensitivity and specificity of cell differentiation from initial pleural aspiration remains unknown. As such, this study aimed to establish the value of pleural cell differentiation in the investigation of undiagnosed pleural effusions. Methods:We performed a prospective study of 1,023 patients presenting to a UK tertiary pleural service with an undiagnosed unilateral pleural effusion between December 2008 and December 2016. Twenty-six patients were excluded due to incomplete data and unclear diagnoses, leaving 997 for analysis. Two respiratory consultants confirmed the diagnosis at 12 months. Cell differentiation was defined according to the British Thoracic Society (BTS) guidelines. Results:The median age of the cohort was 73 years [95% confidence interval (CI): 71-74 years]. Of the 997 patients, 532 (53.4%) were found to have a malignant aetiology and 465 (46.7%) were non-malignant. On review of the pleural fluid cytology, 423 were mixed (42.4%) with no predominant cell type, 352 were lymphocytic (35.3%), 95 were neutrophilic (9.5%), 72 were eosinophilic (7.2%), and 55 were blood-stained (5.5%). Of the lymphocytic effusions, 53.7% had malignant aetiology. A lymphocyte predominance had a sensitivity of 35.5% (95% CI: 31.5-39.8%) and specificity of 65.0% (95% CI: 60.4-69.3%) for malignancy. The majority (80%) of neutrophilic effusions had infectious aetiology with a positive likelihood ratio of 20.6 (95% CI: 12.8-33.1), however, 14% of cases (13/95) had a final diagnosis of malignancy. Of the eosinophilic effusions, 43.0% were also of malignant aetiology, with a positive likelihood ratio of 0.66 (95% CI: 0.42-1.04). Conclusions:This study demonstrated that pleural fluid cell differentiation has limited diagnostic value. Although it may guide towards the likely diagnosis, it lacks diagnostic accuracy as a rule-in/out test and should be used cautiously by clinicians.

BACKGROUND:Pleural infection is associated with marked local and systemic inflammation leading to significant morbidity. It may be possible to therapeutically augment this response and interleukin-6 is a key signalling cascade in inflammatory pathologies. METHODS:We performed a prospective observational study recruiting patients with pleural effusions secondary to infection and measured interleukin-6 in matched pleural fluid and serum (n = 76). We subsequently performed a large-scale, two sample Mendelian Randomisation study (1601 cases and 830,709 controls), using genetic variation at IL6R to proxy the effect of interleukin-6 inhibition on pleural infection and overcome confounding inherent in observational analyses. FINDINGS:Pleural interleukin-6 levels in infection were 5000-fold higher than matched serum levels (median 72,752 pg/ml vs. 15 pg/ml). Pleural interleukin-6 predicted systemic inflammation (neutrophil count, C- reactive protein), correlated with clinical markers of disease severity (effusion size, pH, glucose), and was strongly associated with length of hospital stay. In Mendelian randomisation analyses, interleukin-6 inhibition was predicted to have a large protective effect on the incidence of infection (OR 0.23; 95% CI 0.14-0.39 per standard deviation decrease in C- reactive protein). The effect size was larger than that seen in COVID-19 and coronary artery disease, where interleukin-6 inhibition has been successful in trials. INTERPRETATION:Multiple lines of evidence suggest pleural interleukin-6 drives pathology in pleural infection. Targeting interleukin-6 may hold promise and should be considered in randomised trials. FUNDING:This study has been funded by the National Institutes of Health and Care Research Bristol Biomedical Research Centre.

Rationale Respiratory tract infections are transmitted in part by infectious aerosol. Developing a greater understanding of how clinical and demographic factors affect aerosol generation could help to identify airborne infection ‘superspreaders’.Objectives To measure respiratory aerosol from a diverse clinical population, exploring the impact of demographics, physiological factors and disease status.Methods We recruited people with chronic lung disease, respiratory infection and healthy volunteers. We sampled aerosol from an enclosed circuit to exclude background non-respiratory aerosol, uniquely enabling bedside measurements of respiratory aerosol generation from an unwell population, while participants performed simple manoeuvres such as speaking and coughing.Measurements and main results Across 128 participants, we detected lower aerosol generation among patients with a lung disease during a forced expiratory manoeuvre. This is likely to be related to differences in forced exhalation rather than demographic or clinical status. We observed a 500-fold variation in peak aerosol production when coughing. There was an association between aerosol generation and higher body mass index during coughing, but not with other clinical or demographic factors, and most of the variation remained unexplained.Conclusions Our measurement of respiratory aerosol generation from patients with lung disease and infection is comparable with those published previously for healthy subjects. The amount of aerosol generation across the studied population was most closely linked with expiratory flow. While we observed variation in respiratory aerosol generation between participants in a clinical environment, there was no meaningful impact of demographics or respiratory disease on aerosol generation.

The burden of Respiratory Syncytial Virus (RSV) infection in adults is of interest in the context of recently-licensed vaccines. However, burden estimates are affected by test error associated with the testing platform, and number and type of samples tested. We conducted a prospective cohort study of adults with acute lower respiratory tract disease (aLRTD) hospitalised in Bristol, UK, from April 2022–March 2023. RSV was detected by RT-PCR both by routine standard-of-care (SOC) testing, and by testing of additional nasopharyngeal swabs, saliva and sputum samples from a patient subset. Latent class analysis was used to quantify and adjust for test error rates, including effects of multiple testing. RSV test-positivity rates are reported, and after adjustment for test error, are used to calculate adult population incidence/1000 person-years. 6906/11445 aLRTD cases (60