Background Breathlessness is a common symptom in Long COVID (LC). Using hyperpolarised xenon MRI ( 129 Xe-MRI), we assessed whether this symptom could be attributed to abnormalities in the alveolar-capillary membrane not detected by standard investigations. We focused on never-hospitalised individuals without an identified cause for breathlessness. Methods In this prospective, multicentre study, we compared 129 Xe-MRI, lung function, exercise capacity, and symptom questionnaires in LC patients with breathlessness (BLC) to those without breathlessness (NBLC) and healthy controls. Primary outcome was whether BLC demonstrated measurable impairments in gas exchange focusing on dissolved-phase 129 Xe-MRI metrics: red-blood cell to membrane ratio (RBC:M) and red-blood cell to gas ratio (RBC:Gas). We also explored associations between symptoms and physiological measures. Results Of 269 participants recruited, 196 were included in the analysis (109 BLC, 43 NBLC, 44 controls), with age and sex well matched across groups. BLC had a significantly longer interval from infection to imaging (median 632 days; p<0·001). No significant differences in global or regional RBC:M or RBC:Gas were observed across groups. BLC showed lower FEV 1 , FVC, TLCO, and KCO z-scores compared to controls, though >90% of values remained within normal range. A subset of BLC participants with low TLCO (14/109) showed reduced 129 Xe-MRI metrics and higher breathlessness scores. Interpretation Most non-hospitalised LC participants exhibited no detectable pulmonary abnormalities, including those with breathlessness. However, approximately 13% of breathless individuals demonstrated minor reductions in TLCO and 129 Xe-MRI gas exchange suggesting a potential pulmonary contribution for symptoms in this subgroup.

INTRODUCTION:In patients with malignant pleural effusions (MPE), pleural fluid reaccumulates at variable rates following therapeutic aspiration. The aim of this study was to identify variables which predict time to next procedure and use them to develop a predictive score. METHODS:This prospective observational cohort study in 10 British hospitals recruited patients with known or suspected malignant effusions undergoing therapeutic aspiration. Follow-up lasted 3 months and assessed time to next clinically indicated pleural procedure. Regression analysis was performed to identify independent variables predicting time to next procedure, and a score derived. Initial validation was done in two external cohorts. MEASUREMENTS AND MAIN RESULTS:241 patients were recruited. Within the derivation cohort (n=180), baseline respiratory rate (R), pleural effusion depth on ultrasound (E) and dyspnoea measured using a visual analogue scale (D) (combined to form the RED score) were independent predictors of time to next procedure. Predictive models provided areas under the receiver operator curve of 0.73 and 0.75. Initial validity testing in two cohorts (n=31, n=57) demonstrated reasonable predictive value. CONCLUSIONS:In patients with MPE, baseline respiratory rate, pleural effusion depth on ultrasound and dyspnoea predict time to next procedure. TRIAL REGISTRATION NUMBER:ISRCTN16567838.

Background:Breathlessness is a common symptom in long COVID (LC). Using hyperpolarised xenon magnetic resonance imaging (129Xe-MRI), we assessed whether this symptom could be attributed to abnormalities in the alveolar-capillary membrane not detected by standard investigations. We focused on never-hospitalised individuals without an identified cause for breathlessness. Methods:In this prospective, multicentre study, we compared 129Xe-MRI, lung function, exercise capacity and symptom questionnaires in LC patients with breathlessness (BLC) to those without breathlessness (NBLC) and healthy controls. Primary outcome was whether BLC demonstrated measurable impairments in gas exchange focusing on dissolved-phase 129Xe-MRI metrics: red blood cell to membrane ratio (RBC:M) and red blood cell to gas ratio (RBC:Gas). We also explored associations between symptoms and physiological measures. Results:Of 269 participants recruited, 196 were included in the analysis (109 BLC, 43 NBLC, 44 controls), with age and sex well matched across groups. BLC had a significantly longer interval from infection to MRI (median 632 days; p<0.001). No significant differences in global or regional RBC:M or RBC:Gas were observed across groups. BLC showed lower forced expiratory volume in 1 s, forced vital capacity, transfer factor of the lung for carbon monoxide (T L CO), and carbon monoxide transfer coefficient (K CO) z-scores compared to controls, though >90% of values remained within normal range. A subset of BLC participants with low T L CO (14 out of 109) showed reduced 129Xe-MRI metrics and higher breathlessness scores. Interpretation:Most nonhospitalised LC participants exhibited no detectable pulmonary abnormalities, including those with breathlessness. However, ∼13% of breathless individuals demonstrated minor reductions in T L CO and 129Xe-MRI gas exchange suggesting a potential pulmonary contribution for symptoms in this subgroup.

Long coronavirus disease (COVID) is a heterogeneous clinical condition of uncertain etiology triggered by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we used ultrasensitive approaches to profile the immune system and the plasma proteome in healthy convalescent individuals and individuals with long COVID, spanning geographically independent cohorts from Sweden and the United Kingdom. Symptomatic disease was not consistently associated with quantitative differences in immune cell lineage composition or antiviral T cell immunity. Healthy convalescent individuals nonetheless exhibited higher titers of neutralizing antibodies against SARS-CoV-2 than individuals with long COVID, and extensive phenotypic analyses revealed a subtle increase in the expression of some co-inhibitory receptors, most notably PD-1 and TIM-3, among SARS-CoV-2 nonspike-specific CD8+ T cells in individuals with long COVID. We further identified a shared plasma biomarker signature of disease linking breathlessness with apoptotic inflammatory networks centered on various proteins, including CCL3, CD40, IKBKG, IL-18 and IRAK1, and dysregulated pathways associated with cell cycle progression, lung injury and platelet activation, which could potentially inform the diagnosis and treatment of long COVID.

Background: Long COVID (LC) is a multisystem clinical syndrome with functional disability and compromised overall health. Information on LC clinical severity types is emerging in cross-sectional studies. This study explored the pattern and consistency of long COVID (LC) clinical severity types over time in a prospective sample. Methods: Participants with LC completed the condition-specific outcome measure C19-YRSm (Yorkshire Rehabilitation Scale modified version) at two assessment time points. A cluster analysis for clinical severity types was undertaken at both time points using the k-means partition method. Results: The study included cross-sectional data for 759 patients with a mean age of 46.8 years (SD = 12.7), 69.4% females, and a duration of symptoms of 360 days (IQR 217 to 703 days). The cluster analysis at first assessment revealed three distinct clinical severity type clusters: mild (n = 96), moderate (n = 422), and severe (n = 241). Longitudinal data on 356 patients revealed that the pattern of three clinical severity types remained consistent over time between the two assessments, with 51% of patients switching clinical severity types between the assessments. Conclusions: This study is the first of its kind to demonstrate that the pattern of three clinical severity types is consistent over time, with patients also switching between severity types, indicating the fluctuating nature of LC.

Background:Symptom fluctuations within and between individuals with long COVID are widely reported, but the extent to which severity varies following different types of activity and levels of exertion, and the timing of symptoms and recovery, have not previously been quantified. We aimed to characterise timing, severity, and nature of symptom fluctuations in response to effortful physical, social and cognitive activities, using Ecological Momentary Assessments. Methods:We recorded activity, effort, and severity of 8 core symptoms every 3 h for up to 24 days, in cohorts from both clinic and community settings. Symptom severities were jointly modelled using autoregressive and moving average processes. Findings:Consent was received from 376 participants providing ≥1 week's measurements (273 clinic-based, 103 community-based). Severity of all symptoms was elevated 30 min after all categories of activity. Increased effort was associated with increased symptom severity. Fatigue severity scores increased by 1.8/10 (95% CI: 1.6-1.9) following the highest physical exertions and by 1.5 (1.4-1.7) following cognitive efforts. There was evidence of only mild delayed fatigue 3 h (0.3, 0.2-0.5) or one day later (0.2, 0.0- 0.5). Fatigue severity increased as the day progressed (1.4, 1.0-1.7), and cognitive dysfunction was 0.2 lower at weekends (0.1-0.3). Interpretation:Cognitive, social, self-care and physical activities all triggered increased severity across every symptom, consistent with associated common pathways as potential therapeutic targets. Clear patterns of symptom fluctuations emerged that support more targeted self-management. Funding:National Institute for Health and Care Research.

The protracted form of COVID-19 known as 'long covid' was first described in 2020. Its symptoms, course and prognosis vary widely; some patients have a multi-system, disabling and prolonged illness. In 2021, ring-fenced funding was provided to establish 90 long covid clinics in England; some clinics were also established in Scotland and Wales. The NIHR-funded LOCOMOTION project implemented a UK-wide quality improvement collaborative involving ten of these clinics, which ran from 2021 to 2023. At regular online meetings held approximately 8-weekly, participants prioritised topics, discussed research evidence and guidelines, and presented exemplar case histories and clinic audits. A patient advisory group also held a priority-setting exercise, participated in quality meetings and undertook a service evaluation audit. The goal of successive quality improvement cycles aimed at changing practice to align with evidence was sometimes hard to achieve because definitive evidence did not yet exist in this new condition; many patients had comorbidities; and clinics were practically constrained in various ways. Nevertheless, much progress was made and a series of 'best practice' guides was produced, covering general assessment and management; breathing difficulties; orthostatic tachycardia and other autonomic symptoms; fatigue and cognitive impairment; and vocational rehabilitation. This paper summarises key findings with the frontline clinician in mind.

Background: NHLC patients typically have no structural cause on chest CT to explain their symptoms. Aims: EXPLAIN is a multi-centre, prospective, observational, cohort study comparing Lung Function Tests (LFT), dyspnoea scores and hyperpolarised 129Xe MRI in dyspnoeic and non-dyspnoeic NHLC patients and asymptomatic post-COVID controls. Here, we present the LFT interim analysis of 116 participants. Methods: NHLC patients were recruited from post-COVID clinics. Participants with significant smoking history and cardiorespiratory diseases were excluded from the study. The median time from infection was 463, 235, and 202 days in dyspnoeic NHLC patients, non-dyspnoeic NHLC patients and controls respectively. Results: All participants had normal or near-normal chest CT. At least 89% of participants were Caucasians in each group (p=0.5). Although within normal limits, FVC (101 vs 109%predicted, p=0.007) and DLCO (94 vs 102%predicted, p=0.013) were significantly lower in the breathless group compared with the control group. Conclusion: Preliminary data suggests unexplained lower FVC %predicted and DLCO %predicted seen in NHLC breathless patients with no associated CT abnormalities beyond a year of mild COVID-19 infection compared with fully recovered controls. We aim to use 129Xe MRI to elucidate the underlying mechanisms contributing to these observed differences.

Introduction: Gas exchange (TLCO ) is age and sex dependent. It is possible to image regional gas transfer with dissolved 129Xe (Xe-MRI) but clinical studies to date have used small reference cohorts with contrasting demographics. Aim: Characterise age, sex and lung volume dependence of Xe-MRI gas transfer metrics in a group of healthy volunteers. Methods: 62 subjects with no history of chronic lung disease were assessed with 129Xe-MRI using a 4 echo time 3D radial sequence and a dose of xenon titrated according to subject height and inhaled from a lung volume of FRC. The imaging was repeated in 33 subjects at TLC. Regional maps of fractions of dissolved xenon in blood (RBC), membrane (M) and airspace (GAS) were produced at the isotropic resolution of 1.25 cm and global average ratio of RBC/M, RBC/GAS and M/GAS were computed. Results: 26 Males and 36 Females with a mean age of 43 y (range: 20-69 y) were scanned. Age (p=0.0006) and sex (p<0.0001) were significant predictors for RBC/M and a linear regression showed higher values and steeper decline in males: RBC/M (M) = -0.00362*Age + 0.60 (p=0.01, r=-0.5); RBC/M (F) = -0.00169*Age + 0.44 (p=0.02, r=-0.39). Only age was a significant predictor for RBC/GAS and age and sex were not significant predictors for M/GAS. RBC/M, M/GAS and RBC/GAS were significantly lower at TLC than at FRC with an average 9%, 30% and 35% decrease, respectively. Conclusions: The age and sex dependence of 129Xe RBC/M concurs with GLI predicted equations for TLCO and demonstrate that these factors must be considered when reporting Xe-MRI metrics. Doses and breathing manoeuvres should be controlled due to the strong dependence of Xe-MRI metrics upon lung inflation.

Introduction Malignant pleural effusions (MPE) are associated with poor prognosis, with a median survival of 6 months. However, there is a wide variation in survival. Predicting prognosis is important in determining treatment. In heart failure and idiopathic pulmonary disease, breathlessness is associated with poor prognosis. Objective To determine whether breathlessness following pleural drainage is associated with survival in patients with MPE. Methods A post-hoc analysis of patients in the TIME2 (chest drain and pleurodesis versus indwelling pleural catheter in patients with MPE, JAMA 2012; 307: 2383–9) and TIME3 (intrapleural fibrinolytics versus placebo in patients with non-draining MPE, AJRCCM 2018; 197: 502–508) randomised trials. In both studies, average breathlessness over the last 24 hours was measured using the validated 100 mm visual analogue scale (VASD). Minimal important difference is 19 mm. Subjects assessed their breathlessness at baseline and, following drainage, completed a daily diary for 42 (TIME2) or 28 (TIME3) days. Survival was measured in days from randomisation to death. Follow up was for 1 year. Cox regression was used to identify associations between breathlessness and survival. Responders were defined as patients with a reduction in mean post-drainage VASD of ³19 mm. Results The study included 177 patients. Mean baseline VASD was 50 mm (SD 27). Median survival was 83 days (IQR 33–288). There was no significant association between baseline VASD and survival (p=0.563). The association between mean post-drainage VASD and survival was highly significant (hazard ratio per 1 mm increase in mean VASD 1.02, 95% CI 1.01 to 1.03; p<0.001). The difference in survival between responders and non-responders was highly significant (log rank test p<0.001). Conclusion In these patients, there was a significant association between mean post-drainage VASD and survival. Patients who did not respond symptomatically to pleural fluid drainage had a worse survival than those who did. A limitation of this study is that it was a retrospective analysis of patients enrolled into two clinical trials, so results may not apply to all patients with MPE. Further research into the association between breathlessness and survival is needed.

Introduction TIME3, a randomised controlled trial of intrapleural urokinase versus placebo for patients with non-draining malignant pleural effusion (MPE), demonstrated that these patients appear to be a distinct subgroup of patients with a poor prognosis (median survival 58 days). The aim of this study was to identify patient and fluid characteristics associated with this subgroup, to enable further understanding of why patients with non-draining effusion may have poor prognosis. Methods Baseline demographics and pleural fluid (PF) characteristics of patients enrolled in TIME3 were compared to patients enrolled in TIME2,2 a randomised controlled trial of indwelling pleural catheter versus chest drain and pleurodesis for patients with recurrent MPE. Demographic characteristics compared were: age, sex, histological type of cancer and ECOG performance status (PS). Pleural fluid characteristics compared were: total protein, glucose, cytology (positive or negative), pH, lactate dehydrogenase (LDH) and presence of septations on ultrasound. These characteristics were compared using t test for linear variables and chi squared for categorical variables. Results The median survival was 58 days (IQR 27–123) in TIME3 versus 187 days (IQR 48–358) in TIME2. Patients with non-draining effusions had a significantly higher PF LDH (mean 1900 (SD 3100) versus 660 (SD 840), p<0.001) and CRP (mean 117 (SD 80) versus 62 (SD 55), p<0.001). Patients in TIME3 were on average 4 years older (mean 71 years in TIME3 versus 67 in TIME2, p=0.01) and less likely to be cytology positive (24% versus 51%, p=0.021). Conclusion Non draining MPEs have a higher LDH than those without. There was a large difference in mortality between groups, but despite this no identifiable differences in baseline ECOG, PS or tumour type, despite these variables being associated with a poor prognosis in unselected cohorts of patients with MPE.1 We postulate that survival in MPE may be associated with septations and the intrapleural inflammatory milieu. Further study of the association between PF LDH, septations and survival is warranted. References Clive, A. O. Predicting survival in malignant pleural effusion: Development and validation of the LENT prognostic score. Thorax2014;69(12):1098–104. Davies HE, M. E. TIME2 randomised controlled trial. Journal of the American Medical Association2012;2383–9.

Introduction Malignant pleural effusions (MPE) cause disabling symptoms often relieved by thoracentesis. Indwelling pleural catheter (IPC) insertion and talc pleurodesis (TP) are equally effective treatments1 yet; current BTS guidelines suggest talc pleurodesis as the preferred method of fluid control2 IPCs may reduce hospital bed-days and minimise the need for repeated pleural intervention.3 Aim To compare the impact of IPC and TP on length of hospital stay (LOS) and need subsequent pleural intervention. Complication frequency and survival rates were also measured. Methods Retrospective review of Pleural clinic and electronic case note records of all MPE patients at our institution requiring TP or IPC insertion over an 18 month period (01/05/15–01/11/16). Results A total of 73 procedures (46 TP, 27 IPCs) were carried out on 71 patients. Mean LOS was shorter in the IPC group (0.85 (0–7) days) than with TP (7.65 (2–36) days). 11 patients (24%) required further pleural intervention following TP (2 had repeat TP, 8 had an IPC and one patient underwent therapeutic pleural aspiration). One patient in the IPC group had a second procedure (2nd IPC placed – a patient with cognitive impairment cut his tube). There were no hospitalisations as a consequence of complications in the IPC patients; 2 patients required antibiotics for drain site cellulitis (7%). In the TP group, 3 drains fell out (7%); one patient had a pneumothorax. 52 patients (73%) had died at follow-up (until January 2017). Median (IQR) survival after IPC insertion was 62 (24–146) compared with 74 (23–153) days. Conclusions Our findings support first-line use of IPC in patients with a symptomatic MPE. IPCs resulted in shorter LOS and reduced the need for subsequent ipsilateral pleural drainage. All patients necessitating definitive intervention for a symptomatic MPE should be offered the choice between IPC and TP. References Davies, et al. JAMA 2012;307(22):2383–9. BTS Pleural Diseases Guidelines. 2010. Fysh, et al. BMJ Open 2014;4(11).