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Background: In patients with coronavirus disease 2019 (COVID-19) requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) 1 year after discharge. Methods: Adults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies (Post-hospitalisation COVID-19 and the International Severe Acute Respiratory and emerging Infection Consortium). HRQoL, assessed by the EuroQol-Five Dimensions-Five Levels utility index (EQ-5D-5L UI), pre-hospital and 1 year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient-reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. Findings: Of the 1888 participants included in the primary analysis, 1149 received corticosteroids. There was no between-group difference in EQ-5D-5L UI at 1 year (mean difference 0.004, 95% CI -0.026-0.034). A similar reduction in EQ-5D-5L UI was seen at 1 year between corticosteroid exposed and nonexposed groups (mean±sd change -0.12±0.22 versus -0.11±0.22). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a cohort of 109 318 patients admitted to hospital with COVID-19, EQ-5D-5L UI at 1 year remained similar between the two groups. Interpretation: Systemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL 1 year after hospital discharge. Treatments to address the persistent reduction in HRQoL are urgently needed.

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BACKGROUND: No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation. METHODS: This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference -1·6% [-2·6% to -0·6%]; p(sup)=0·99; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference -1·4% [-2·3% to -0·4%]; p(sup)>0·99; NNT 71·4; 6 months: -0·5% [-1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up. INTERPRETATION: In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat. FUNDING: UK Research and Innovation and National Institute for Health and Care Research.

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BACKGROUND: The role of ECG in ruling out myocardial complications on cardiac magnetic resonance (CMR) is unclear. We examined the clinical utility of ECG in screening for cardiac abnormalities on CMR among post-hospitalised COVID-19 patients. METHODS: Post-hospitalised patients (n = 212) and age, sex and comorbidity-matched controls (n = 38) underwent CMR and 12­lead ECG in a prospective multicenter follow-up study. Participants were screened for routinely reported ECG abnormalities, including arrhythmia, conduction and R wave abnormalities and ST-T changes (excluding repolarisation intervals). Quantitative repolarisation analyses included corrected QT (QTc), corrected QT dispersion (QTc disp), corrected JT (JTc) and corrected T peak-end (cTPe) intervals. RESULTS: At a median of 5.6 months, patients had a higher burden of ECG abnormalities (72.2% vs controls 42.1%, p = 0.001) and lower LVEF but a comparable cumulative burden of CMR abnormalities than controls. Patients with CMR abnormalities had more ECG abnormalities and longer repolarisation intervals than those with normal CMR and controls (82% vs 69% vs 42%, p < 0.001). Routinely reported ECG abnormalities had poor discriminative ability (area-under-the-receiver-operating curve: AUROC) for abnormal CMR, AUROC 0.56 (95% CI 0.47-0.65), p = 0.185; worse among female than male patients. Adding JTc and QTc disp improved the AUROC to 0.64 (95% CI 0.55-0.74), p = 0.002, the sensitivity of the ECG increased from 81.6% to 98.0%, negative predictive value from 84.7% to 96.3%, negative likelihood ratio from 0.60 to 0.13, and reduced sex-dependence variabilities of ECG diagnostic parameters. CONCLUSION: Post-hospitalised COVID-19 patients have more ECG abnormalities than controls. Normal ECGs, including normal repolarisation intervals, reliably exclude CMR abnormalities in male and female patients.

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BACKGROUND: Management of complicated pleural infections (CPIs) had historically been surgical; however, following the publication of the second multicenter intrapleural sepsis trial (MIST-2), combination tissue plasminogen (tPA) and dornase (DNase) offers a less invasive and effective treatment. Our aim was to assess the quality of life (QOL) and functional ability of patients' recovery from a CPI managed with either intrapleural fibrinolytic therapy (IPFT) or surgery. METHODS: We identified 565 patients managed for a CPI between January 1, 2013 and March 31, 2018. There were 460 patients eligible for contact, attempted through 2 phone calls and one mailer. Two questionnaires were administered: the Short Form 36-Item Health Survey (SF-36) and a functional ability questionnaire. RESULTS: Contact was made in 35% (159/460) of patients, and 57% (90/159) completed the survey. Patients had lower QOL scores compared to average US citizens; those managed with surgery had higher scores in physical functioning (surgery: 80, IPFT: 70, P=0.040) but lower pain scores (surgery: 58, IPFT: 68, P=0.045). Of 52 patients who returned to work, 48% (25) reported an impact on their work effectiveness during recovery, similarly between management strategies (IPFT: 50%, 13/26 vs. surgery: 46%, 12/26; P=0.781). CONCLUSION: Patients with a CPI had a lower QOL compared with average US citizens. Surgically managed patients reported improved physical functioning but worse pain compared with patients managed with IPFT. Patients returned to work within 4 weeks of discharge, and nearly half reported their ability to work effectively was impacted by their recovery. With further research into recovery timelines, patients may be appropriately counselled for expectations.

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The incidence of parapneumonic effusions is higher than previously estimated when thoracic ultrasound is used as a diagnostic tool. TUS may have a role in prognostication and prediction of pleural infection, and this requires further evaluation. https://bit.ly/3UkV7nQ.

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The incidence of non-malignant pleural effusions (NMPE) far outweighs that of malignant pleural effusions (MPE) and is estimated to be at least 3-fold higher. These so called "benign" effusions do not follow a "benign course" in many cases, with mortality rates matching and sometimes exceeding that of MPEs. In addition to the impact on patients, healthcare systems are significantly affected, with recent US epidemiological data demonstrating that 75% of resource allocation for pleural effusion management is spent on NMPEs (excluding empyema). Despite this significant burden of disease, and by existing at the junction of multiple medical specialties, reflecting a heterogenous constellation of medical conditions, NMPEs are rarely the focus of research or the subject of management guidelines. With this ERS Taskforce, we assembled a multi-specialty collaborative across eleven countries and three continents to provide a Statement based on systematic searches of the medical literature to highlight evidence in the management of the following clinical areas: a diagnostic approach to transudative effusions, heart failure, hepatic hydrothorax, end stage renal failure, benign asbestos related pleural effusion, post-surgical effusion and non-specific pleuritis.

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Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies.

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OBJECTIVES: Current guidelines recommend broad-spectrum antibiotics for high-severity community-acquired pneumonia (CAP), potentially contributing to antimicrobial resistance (AMR). We aim to compare outcomes in CAP patients treated with amoxicillin (narrow-spectrum) versus co-amoxiclav (broad-spectrum), to understand if narrow-spectrum antibiotics could be used more widely. METHODS: We analysed electronic health records from adults (≥16 y) admitted to hospital with a primary diagnosis of pneumonia between 01-January-2016 and 30-September-2023 in Oxfordshire, United Kingdom. Patients receiving baseline ([-12 h,+24 h] from admission) amoxicillin or co-amoxiclav were included. The association between 30-day all-cause mortality and baseline antibiotic was examined using propensity score (PS) matching and inverse probability treatment weighting (IPTW) to address confounding by baseline characteristics and disease severity. Subgroup analyses by disease severity and sensitivity analyses with missing covariates imputed were also conducted. RESULTS: Among 16,072 admissions with a primary diagnosis of pneumonia, 9685 received either baseline amoxicillin or co-amoxiclav. There was no evidence of a difference in 30-day mortality between patients receiving initial co-amoxiclav vs. amoxicillin (PS matching: marginal odds ratio 0.97 [0.76-1.27], p = 0.61; IPTW: 1.02 [0.78-1.33], p = 0.87). Results remained similar across stratified analyses of mild, moderate, and severe pneumonia. Results were also similar with missing data imputed. There was also no evidence of an association between 30-day mortality and use of additional macrolides or additional doxycycline. CONCLUSIONS: There was no evidence of co-amoxiclav being advantageous over amoxicillin for treatment of CAP in 30-day mortality at a population-level, regardless of disease severity. Wider use of narrow-spectrum empirical treatment of moderate/severe CAP should be considered to curb potential for AMR.

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Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.

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OBJECTIVE: This study aims to correlate the RAPID score with the 3-month survival and surgical results of patients undergoing lung decortication with stage III pleural empyema. METHODS: This was a retrospective study with the population of patients with pleural empyema who underwent pulmonary decortication between January 2019 and June 2022. Data were collected from the institution's database, and patients were classified as low, medium, and high risk according to the RAPID score. The primary outcome was 3-month mortality. Secondary outcomes were the length of hospital stay, readmission rate, and the need for pleural re-intervention. RESULTS: Of the 34 patients with pleural empyema, according to the RAPID score, patients were stratified into low risk (23.5 %), medium risk (47.1 %), and high risk (29.4 %). The high-risk group had a 3-month mortality of 40 %, while the moderate-risk group had a 6.25 % and the low-risk group had no deaths within 90 days, confirming a good correlation with the RAPID score (p < 0.05). Sensitivity and specificity for the primary outcome in the high-risk score were 80.0 % and 79.3 %, respectively. The secondary outcomes did not reach statistical significance. CONCLUSIONS: In this retrospective series, the RAPID score had a good correlation with 3-month mortality in patients undergoing lung decortication. The morbidity indicators did not reach statistical significance. The present data justifies further studies to explore the capacity of the RAPID score to be used as a selection tool for treatment modality in patients with stage III pleural empyema.

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Connective tissue diseases (CTD) are heterogeneous, immune-mediated inflammatory disorders often presenting with multiorgan involvement. With the advent of high-resolution computed tomography, CTD-related pleuritis-pleural thickening and effusion-is now increasingly recognized early in the disease trajectory. The natural history of CTD-related pleural effusions varies from spontaneous resolution to progressive fibrothorax with ventilatory impairment. Treatment of the underlying CTD is necessary to manage the pleural disease. Depending on the degree of symptom burden and physiological insult, specific treatment of pleural disease can include monitoring, repeated aspirations, systemic anti-inflammatory medication, and surgical decortication.

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BACKGROUND: Lung ultrasound (LUS) is increasingly used as an extension of physical examination, informing clinical diagnosis, and decision making. There is particular interest in the assessment of patients with pulmonary congestion and extravascular lung water, although gaps remain in the evidence base underpinning this practice as a result of the limited evaluation of its inter-rater reliability and comparison with more established radiologic tests. METHODS: 30 patients undergoing haemodialysis were prospectively recruited to an observational cohort study (NCT01949402). Patients underwent standardised LUS assessment before, during and after haemodialysis; their total LUS B-line score was generated, alongside a binary label of whether appearances were consistent with an interstitial syndrome. LUS video clips were recorded and independently scored by two blinded expert clinician sonographers. Low-dose non-contrast thoracic CT, pre- and post dialysis, was used as a "gold standard" radiologic comparison. RESULTS: LUS detected a progressive reduction in B-line scores in almost all patients undergoing haemodialysis, correlating with the volume of fluid removed once individuals with no or minimal B-lines upon pre-dialysis examination were discounted. When comparing CT scans pre- and post dialysis, radiologic evidence of the change in fluid status was only identified in a single patient. CONCLUSIONS: This is the first study to demonstrate that LUS detects changes in extravascular lung water caused by changing fluid status during haemodialysis using a blinded outcome assessment and that LUS appears to be more sensitive than CT for this purpose. Further research is needed to better understand the role of LUS in this and similar patient populations, with the aim of improving clinical care and outcomes.

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Introduction: Rates of mortality and re-admission after a hospitalised exacerbation of COPD are high and resistant to change. COPD guidelines do not give practical advice about the optimal selection of inhaled drugs and device in this situation. We hypothesised that a failure to optimise inhaled drug and drug delivery prior to discharge from hospital after an exacerbation would be associated with a modifiable increased risk of re-admission and death. We designed a study to 1) develop a practical inhaler selection tool to use at the point of hospital discharge and 2) implement this tool to understand the potential impact on modifying inhaler prescriptions, clinical outcomes, acceptability to clinicians and patients, and the feasibility of delivering a definitive trial to demonstrate potential benefit. Methods: We iteratively developed an inhaler selection tool for use prior to discharge following a hospitalised exacerbation of COPD using surveys with multiprofessional clinicians and a focus group of people living with COPD. We surveyed clinicians to understand their views on the minimum clinically important difference (MCID) for death and re-admission following a hospitalised exacerbation of COPD. We conducted a mixed-methods implementation feasibility study using the tool at discharge, and collated 30- and 90-day follow-up data including death and re-admissions. Additionally, we observed the tool being used and interviewed clinicians and patients about use of the tool in this setting. Results: We completed the design of an inhaler selection tool through two rounds of consultations with 94 multiprofessional clinicians, and a focus group of four expert patients. Regarding MCIDs, there was majority consensus for the following reductions from baseline being the MCID: 30-day readmissions 5-10%, 90-day readmissions 10-20%, 30-day mortality 5-10% and 90-day mortality 5-10%. 118 patients were assessed for eligibility and 26 had the tool applied. A change in inhaled medication was recommended in nine (35%) out of 26. Re-admission or death at 30 days was seen in 33% of the switch group and 35% of the no-switch group. Re-admission or death at 90 days was seen in 56% of the switch group and 41% of the no-switch group. Satisfaction with inhalers was generally high, and switching was associated with a small increase in the Feeling of Satisfaction with Inhaler questionnaire of 3 out of 50 points. Delivery of a definitive study would be challenging. Conclusion: We completed a mixed-methods study to design and implement a tool to aid optimisation of inhaled pharmacotherapy prior to discharge following a hospitalised exacerbation of COPD. This was not associated with fewer re-admissions, but was well received and one-third of people were eligible for a change in inhalers.

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Lung cancer is the leading cause of cancer mortality in the world. It greatly affects the patients' quality of life, and is thus a challenge for the daily practice in respiratory medicine. Advances in the genetic knowledge of thoracic tumours' mutational landscape, and the development of targeted therapies and immune checkpoint inhibitors, have led to a paradigm shift in the treatment of lung cancer and pleural mesothelioma. During the 2023 European Respiratory Society Congress in Milan, Italy, experts from all over the world presented their high-quality research and reviewed best clinical practices. Lung cancer screening, management of early stages of lung cancer, application of artificial intelligence and biomarkers were discussed and they will be summarised here.

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Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031.

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BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over 6 months. DESIGN AND SETTING: An economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK NHS and personal social services perspective and a 6-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base-case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] = 445 to 453) and higher mean QALYs of 0.0055 (95% CI = 0.0044 to 0.0067) than usual care (mean incremental cost per QALY of £81 190). Sensitivity and subgroup analyses showed similar results, except for those aged ≥75 years, with a 55% probability of being cost-effective at a £30 000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15 000 per QALY threshold. CONCLUSION: At the current cost of £513 per course, molnupiravir is unlikely to be cost-effective relative to usual care over a 6-month time horizon among mainly vaccinated patients with COVID-19 at increased risk of adverse outcomes, except those aged ≥75 years.

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