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.

Face masks are a commonly used public health measure to control the spread of airborne infections, including in school-aged children. However, no trial of their effectiveness has been conducted in school settings to date. We undertook a mixed-method study to explore the feasibility of conducting such a trial. This study followed a multi-phased mixed-methods approach. We first conducted a secondary analysis of qualitative data (39 young people) and five Patient and Public Involvement focus groups (11 young people, three teachers, two parents), to understand the barriers and facilitators relating to engaging with a trial of face masks. Strategies to enhance recruitment and engagement were generated based on this qualitative work. These were refined further in additional PPI focus groups with young people (n = 7). We then conducted a 6-week two-arm parallel cluster-randomised feasibility trial in a local school. Two year groups were cluster-randomised into one of the two arms: (1) school rules group (SR, control), following school policy at the time on the use of face coverings; (2) face-mask group (FM, intervention), wearing standard lightweight surgical masks while in an indoor setting for the duration of the school day. Primary outcomes were recruitment and adherence to trial procedures: completion of surveys capturing frequency of mask-wearing, impact of mask-wearing, mood and compliance with the provision of weekly saliva samples for the detection of viral infections. A total of 93 pupils (29

PURPOSE OF REVIEW:We review recent evidence on the effectiveness of non-antimicrobial adjunctive interventions on the recovery of adults diagnosed with community-acquired pneumonia (CAP). RECENT FINDINGS:Respiratory physiotherapy, early mobilization or tailored exercises may decrease length of stay (LoS), dyspnoea and readmissions, but there is little evidence of an effect on mortality. Nutritional interventions may decrease readmissions and improve 30-day mortality, but there are few studies on the effect of individual micronutrient supplementation. Strategies to improve discharge communications and patient education may decrease readmission rates, improve treatment compliance and patient satisfaction, whereas the implementation of guidelines and care bundles may decrease 30-day mortality but does not appear to affect length of stay or 30-day readmissions. For adjunctive therapeutic interventions, there is evidence that for severe CAP, corticosteroids probably decrease short-term mortality and possibly longer term mortality and LoS. Antiplatelet agents and statins may decrease short-term mortality. SUMMARY:A wide range of adjunctive interventions have been trialled aiming to improve patient outcomes with variable results and considerable heterogeneity between studies and populations. Future studies should involve engagement with patient groups to identify uncertainties and outcomes they consider important, utilize a core set of outcome measures, and assess long-term outcomes.

OBJECTIVES:We aimed to describe the incidence, presentation and clinical outcomes of RSV-associated acute respiratory infection (ARI) in older adults using a new national Hospital-based ARI Sentinel Surveillance (HARISS) system in England, prior to RSV vaccine introduction. METHODS:Adults aged ≥65 years from seven hospitals admitted for ≥24 hours with symptomatic ARI were included. We estimated the hospitalisation rate of RSV-associated ARI compared to influenza-associated ARI and assessed clinical outcomes using Poisson regression and mortality using Cox regression. RESULTS:This study included 2743 adults. During winter 2023/4 the hospitalisation rate for RSV-associated ARI was 58.3 per 100,000, compared to 114.6 per 100,000 for influenza-associated ARI. Hospitalisations increased with age. Exacerbation of chronic illness (lung disease, heart disease, frailty) was a common admission reason in RSV-associated ARI, with a combined incidence of 33.1 per 100,000. Most adults with RSV-associated ARI had at least one comorbidity (81%); a high proportion with immunosuppression (26%). Symptoms and clinical outcomes including mortality were similar between RSV- and influenza-associated ARI; 30-day mortality 10.6% vs 8.7% (adjusted hazard ratio 0.85, 95% confidence interval 0.6-1.2). CONCLUSIONS:In England, RSV infection is a common cause of hospitalisation in older adults. Symptoms and clinical outcomes, including mortality, are comparable to influenza.

BACKGROUND:A respiratory syncytial virus (RSV) vaccination programme for older adults using bivalent pre-F vaccine was introduced in England from Sept 1, 2024. Although vaccine effectiveness has been reported against all-cause RSV-associated respiratory hospital admissions, data are scarce on vaccine effectiveness against different presentations of RSV-associated illness, such as exacerbation of chronic illness. METHODS:This multicentre, test-negative, case-control study used data from a national, hospital-based, acute respiratory infection sentinel surveillance (HARISS) system across 14 hospitals in England. Eligibility criteria were vaccine-eligible adults aged 75-79 years admitted to hospital with acute respiratory infection (ARI) for ≥24 h and tested with molecular diagnostic assays within 48 h of admission. Cases were RSV positive, and controls were negative for RSV, influenza, and SARS-CoV-2. Vaccination status and data on sex were obtained from the National Immunisation Information System. The primary outcome was hospital admission due to RSV-associated ARI, which was tested for using nasopharyngeal or combined nose and throat swabs. Clinical data were collected using a structured questionnaire. FINDINGS:Between Oct 1, 2024, and March 31, 2025, 1006 older adults were admitted to hospital with ARI; 173 were RSV positive (cases) and 833 were RSV negative (controls). 526 (52·3%) of 1006 individuals were female and 480 (47·7%) were male. Mean age was 77·8 years (SD 1·4) in individuals who were RSV positive and 77·6 years (SD 1·3) in those who were negative for RSV, influenza, and SARS-CoV-2. Vaccine effectiveness was 82·3% (95% CI 70·6-90·0) against hospitalisation for any RSV-associated ARI and 86·7% (75·4-93·6) in those with severe disease including oxygen supplementation. Vaccine effectiveness was 88·6% (75·6-95·6) among individuals admitted due to lower respiratory tract infection, including pneumonia, 77·4% (42·4-92·8) due to exacerbation of chronic lung disease, and 78·8% (47·8-93·0) due to exacerbation of chronic heart disease, lung disease, and/or frailty. In individuals with immunosuppression, vaccine effectiveness was 72·8% (39·5-89·3). INTERPRETATION:This study provides evidence that the RSV pre-F vaccine is highly effective against RSV-associated hospital admissions, including exacerbations of chronic disease, and in adults with immunosuppression. FUNDING:UK Health Security Agency.

SUMMARYBackgroundSotrovimab is a neutralising monoclonal antibody that has been proposed as a treatment for patients admitted to hospital with COVID-19.MethodsIn this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 pneumonia. In the sotrovimab comparison, eligible and consenting patients were randomly allocated to either usual care alone or usual care plus a single 1g dose of sotrovimab, using web-based unstratified randomisation. Participants were retrospectively categorised according to their baseline serum SARS-CoV-2 nucleocapsid antigen concentration as ‘high-antigen’ or ‘low-antigen’, using the median concentration as a cut-off. The primary outcome was 28-day mortality assessed by intention to treat. Secondary outcomes were time to discharge alive from hospital, and, among those not on invasive ventilation at baseline, progression to invasive ventilation or death. Recruitment closed on 31 March 2024 when funding ended. ISRCTN (50189673) andclinicaltrials.gov(NCT04381936).FindingsFrom 4 January 2022 to 19 March 2024, 1723 patients were recruited to the sotrovimab comparison. 720 (42%) were classified as high-antigen, 717 (42%) as low-antigen, and 286 (17%) had unknown antigen status. Over 80% of patients were vaccinated, over 80% had anti-spike antibodies at randomisation, and almost all were infected with Omicron variants. In the prespecified primary efficacy population of high-antigen patients, 82/355 (23%) allocated sotrovimab versus 106/365 (29%) allocated usual care died within 28 days (rate ratio 0.75; 95% CI 0.56-0.99; p=0.046). In an analysis of all randomised patients (regardless of antigen status), 177/828 (21%) allocated sotrovimab versus 201/895 (22%) allocated usual care died within 28 days (rate ratio 0.95; 95% CI 0.77-1.16; p=0.60).InterpretationIn patients hospitalised with COVID-19, sotrovimab was associated with reduced mortality in the primary analysis population of patients with a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Background:The lack of international consensus on defining and categorising immunosuppression has undermined disease surveillance and patient care, particularly during the COVID-19 pandemic. To address this, a global expert panel was recruited to join the eDElphi STudy to fully defiINe and COVID-risk stratify ImmunosupprESsion (DESTINIES) and develop a COVID risk-stratified digital phenotype for 'adult immunosuppression' (the DESTINIES phenotype). Methods:Panellists were presented with all medical diagnoses and procedures cited in prevailing immunosuppressed definitions; they evaluated their appropriateness for the DESTINIES phenotype and their risks for severe COVID-19 outcomes through anonymous online questionnaires and discussion. Panel agreement with a series of clinical statements were also assessed; statements incorporated longstanding disputes, including variables that could reverse immunosuppression. Each round of data collection informed and refined a draft phenotype until final ratification. This study was active between May and September 2024. Findings:Sixty-four experts from four continents and 12 international agencies completed two rounds of consensus questionnaire, a discussion group and ratifying vote. Panellists identified candidates posing higher (e.g. Transplantation, Primary Immunodeficiency) and lower COVID-19 risk (e.g. Anorexia nervosa, Cerebral spinal fluid leak) but disagreed on the categorisation of others (e.g. Asplenia, Immune-mediated Inflammatory Disease). Consensus was reached on ten clinical statements, notably removing Drug-managed HIV and Cancer remission from consideration as immunosuppressed. The DESTINIES phenotype was ratified with near unanimous support (94%) for implementation in surveillance. Interpretation:Pending validation, the DESTINIES phenotype provides a clinically meaningful, internationally ratified and digitally practical method for identifying and COVID-19 risk-stratifying adult immunosuppressed patients in healthcare data. Funding:This work was funded by the UK Medical Research Council and EMIS Health.

Background Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection (ARI) in older adults. Vaccines that protect against severe RSV infection are now available. Aim We aimed to describe the incidence, presentation, severity and clinical outcomes of RSV-associated ARI in hospitalised older adults using a new Hospital-based ARI Sentinel Surveillance (HARISS) system in England in the winter prior to RSV vaccine introduction. Methods Adults aged ≥65 years from seven hospitals admitted for ≥24 hours with symptomatic ARI were included. Three groups were identified: RSV positive; influenza positive; negative for RSV, influenza and SARS-CoV-2. We estimated the hospitalisation rate of RSV-associated ARI compared to influenza-associated ARI and assessed clinical outcomes using Poisson regression and mortality using Cox regression across groups. Results This surveillance study included 2743 adults. During the 2023/4 season the hospitalisation rate for RSV-associated ARI was 58.3 per 100,000, compared to 114.6 per 100,000 for influenza-associated ARI. Hospitalisation rates increased with age. Exacerbation of chronic illness including lung disease, heart disease or frailty was a frequent cause of admission in RSV-associated ARI, with a combined incidence of 33.1 per 100,000. The majority of adults with RSV-associated ARI had at least one comorbidity (81%); a high proportion with immunosuppression (26%). Symptoms and clinical outcomes including mortality were similar between RSV- and influenza-associated ARI; 30-day mortality 10.6% vs 8.7% (adjusted hazard ratio 0.85,95% confidence interval 0.6-1.2). Conclusion In England, RSV infection is a common cause of hospitalisation in older adults. Symptoms at presentation, severity and clinical outcomes, including mortality, are comparable to influenza. ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: MZ: is Chair of International Society for Influenza and other Respiratory Virus Diseases (ISIRV) and member of NERVTAG, SAGE, and JCVI expert/working groups. LS: UKHSA funding to LS institution for HARISS. Grants or contracts from NIHR Biomedical Research Centre, NIHR Patient Safety Research Collaborative, HDRUK Driver programme paid to LS institution. LS has a leadership role with the British Association for Lung Research. WSL: UKHSA funding to WSL institution as lead coordinating institution of HARISS. Unrestricted investigator-initiated research funding from Pfizer to WSL institution, for an unrelated multi-centre study in pneumonia in which WSL is the CI. WSL is Deputy Chair of Joint Committee on Vaccination and Immunisation (JCVI) (unpaid). SG: Grant funding from NIHR Birmingham Biomedical Research Centre, NIHR Patient Safety Research Collaborative, HDRUK, NIHR and MRC to affiliated institution (PIONEER Hub in acute care, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham). TC: Grants or contracts from Biomerieux, Inflammatix, SenseBiodetection, NIHR SPCR grant NIHR HTA accelerator grant. Consulting fees from Biomerieux, Abbott, Cepheid, Synairgen, Lumos diagnostics. Payment or honoraria from Janssen (Speaker fees), Biomerieux (Speaker fees), Medscape (Webinar), Alira Health (Manuscript preparation), Sanofi (Manuscript preparation). Support to attend Biomerieux meeting 2024. Participation on data safety monitoring or advisory board for Roche, Shionogi, Roche Diagnostics, GSK, Seqirus, Sanofi. Synairgen research, owner of shares. MD: UKHSA funding to MD institution on a non-profit basis for sample handling for HARISS. The UKHSA Immunisation and Vaccine Preventable Diseases Division undertakes regulatory analyses and post marketing surveillance for vaccine makers, for which cost recovery payments are charged. ### Funding Statement The HARISS surveillance system is funded by UK Health Security Agency (UKHSA) and participating HARISS sites received funding for this surveillance work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This surveillance study was undertaken under Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002 (UK legislation) which allows for collection of data for public health purposes without the requirement for individual informed patient consent. The UK Health Security Agency (UKHSA) Caldicott Advisory Panel and Research Ethics and Governance Group considered this study epidemiological surveillance and granted approval for the study to take place. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Original data are confidential and no additional data available.

Background Respiratory syncytial virus (RSV) is a virus with two antigenic types, A and B, that cause significant morbidity and mortality in infants globally. A recently developed maternal vaccination based on the prefusion F protein (“RSVpreF”) could have a significant impact on disease burden, if introduced globally. Whether or not the effectiveness of this vaccine is affected by circulating viral genomic variability is currently unknown. Objectives To examine whether the vaccine effectiveness of maternal RSVpreF administration in preventing hospitalisation in infants is affected by RSV type or lineage. Methods We will conduct whole genome sequencing of RSV positive samples from infants hospitalised with acute lower respiratory tract infection (ALRI) in the 2024-2025 winter season, at multiple hospitals in England and Scotland, to calculate the relative vaccine effectiveness (rVE) of maternal RSVpreF vaccination by virus type (RSV-A and RSV-B). rVE will be calculated using a case control logistic regression with adjustment by infant age and admission date; sex, socioeconomic status and hospital location will be included as potential confounders if they are associated with a >3% change in rVE. We will also perform a test negative design to examine the VE for RSV-A and RSV-B separately, using RSV-negative controls from hospitals where cases were admitted. Finally, we will compare viral lineages in vaccinated versus unvaccinated infants. Results and conclusions Our study will identify whether currently circulating RSV genomic variability impacts on rVE. Confirmation of the null hypothesis - that there is no impact of viral genomic variability on rVE – will provide reassurance to policymakers and public health bodies as RSVpreF is rolled out globally. Conversely, an association between RSV type or lineage and decreased vaccine effectiveness will highlight the need for the enhanced comprehensive national and global molecular surveillance of RSV.

Background With higher valency pneumococcal vaccines on the horizon and new adult immunisation strategies under discussion, we aimed to evaluate the contribution of individual pneumococcal serotypes to the burden of pneumococcal community-acquired pneumonia (CAP). Over 10 years, trends in pneumococcal pneumonia epidemiology in adults hospitalised with CAP were assessed. The risk factors and severity associated with serotype 3 were examined. Methods We conducted a prospective cohort study of adults hospitalised with CAP between September 2013 and May 2023. Pneumococcal serotypes were identified using a serotype-specific 24-valent urinary-antigen assay. Trends in the proportion of CAP due to pneumococcus and causative serotypes were compared prepandemic and postpandemic. Risk factors and severity of serotype 3 pneumonia were compared with other serotypes using logistic regression. Results Of 5186 patients with CAP, 2193 (42.2%) had pneumococcal pneumonia. The proportion of CAP due to pneumococcus increased across all ages between 2013 and 2023 (36.4%-66.9%, p<0.001). The proportion due to serotype 3 increased significantly from 13.4% (2013) to 48.8% (2023). Serotype 3 pneumonia in adults was associated with older age (p<0.001), male sex (adjusted OR (aOR) 2.22, 95% CI 1.64 to 3.01) and chronic renal disease (aOR 1.81, 95% CI 1.09 to 3.02). Serotype 3 pneumonia was not observed to be associated with severity, critical care requirement, mortality or readmission. Interpretation Serotype 3 is the predominant serotype in adult pneumococcal CAP and has been increasing despite a mature infant pneumococcal immunisation programme, consistent with a lack of herd protection for this serotype.

Background Coronavirus disease-2019 was associated with significant mortality and morbidity in care homes in 2020–1. Repurposed antiviral drugs might reduce morbidity and mortality through reducing viral transmission, infection, replication and inflammation. We aimed to compare the safety and efficacy of potential antiviral drugs in care home residents. Methods We designed a cluster-randomised, open-label, blinded end-point platform trial to test drugs in a postexposure prophylaxis paradigm. Participants aged 65+ years from United Kingdom care homes, with or without nursing, were eligible for participation. Care homes were to be allocated at random by computer to administer 42 days of antiviral agent (ciclesonide or niclosamide) plus standard care versus standard care alone to residents. The primary outcome at 60 days after randomisation comprised the most serious outcome, which was defined as all-cause mortality, all-cause hospitalisation, severe acute respiratory syndrome coronavirus 2 infection or no infection. Analysis would be by intention to treat using ordinal logistic regression. Other outcomes included individual components of the primary outcome, transmission, plus health economic and process evaluation outcomes. The planned sample size was 300 care homes corresponding to 9600 residents. With ~40% of care homes predicted to develop an outbreak during the trial, we needed to recruit 750 homes/24,000 residents. Results We initiated the trial including protocol, approvals, insurance, website, database, data algorithms, intervention selection and training materials. We built a network of principal investigators and staff (91) and care homes (299) to support the trial. However, we never contracted care homes or general practitioners since the trial was stopped in September 2021, as vaccination in care homes had significantly reduced infections. Multiple delays significantly delayed the start date, such as: (1) reduced prioritisation of pandemic trials in 2021; (2) cumbersome mechanisms for choosing the investigational medicinal products; (3) contracting between National Institute for Health and Care Research and the investigational medicinal product manufacturers; (4) publicising the investigational medicinal products; (5) identification of sufficient numbers of care homes; (6) identification and contracting with several thousand general practitioners; (7) limited research nurse availability and (8) identification of adequate insurance to cover care homes for research. Generic challenges included working across the four home nations with their different structures and regulations. Limitations The feasibility of contracting between the sponsor and the principal investigators, general practitioners and care homes; screening, consent and treatment of care home residents; data acquisition and the potential benefit of postexposure prophylaxis were never tested. Conclusions The success of vaccination meant that the role of postexposure prophylaxis of coronavirus disease-2019 in care home residents was not tested. Significant progress was made in developing the infrastructure and expertise necessary for a large-scale clinical trial of investigational medicinal products in United Kingdom care homes. Future work The role of postexposure prophylaxis of coronavirus disease-2019 in care home residents remains undefined. Significant logistical barriers to conducting research in care homes need to be removed urgently before future studies are possible. Further work is required to develop the infrastructure for clinical trials of investigational medicinal products in care homes. Serious consideration should be given to building and then hibernating a pandemic-ready platform trial suitable for care home research. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR133443.

The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial evaluated the effects of sixteen potential treatments for patients hospitalised with COVID-19. Dexamethasone (at a dose of 6mg daily), tocilizumab, baricitinib, and the monoclonal antibodies casirivimab-imdevimab and sotrovimab were shown to reduce 28-day mortality in all or specific groups of patients. Here we report the long-term efficacy and safety of all sixteen therapies. Patients hospitalised with COVID-19 were potentially eligible to join this randomised, controlled, open-label, platform trial. Participants were randomly allocated to receive each trial treatment, or not, on top of usual care. Analyses were by intention to treat comparing each treatment with its own usual care control group. The pre-specified primary long-term follow-up outcome was 6-month all-cause mortality, presented as mortality rate ratios adjusted for baseline age and ventilation status. The key safety outcomes were major non-COVID infection and non-COVID death at 6 months. ISRCTN50189673 and NCT04381936 . Between 19 March 2020 and 19 March 2024, 48,402 patients were included in RECOVERY COVID-19 treatment comparisons. For each of the treatments previously demonstrated to be effective at 28 days, the early mortality benefit was preserved up to 6 months. Among 6425 patients in the dexamethasone (6mg daily) comparison, 6-month mortality was 34.3% vs 44.4% in the invasive mechanical ventilation group (rate ratio [RR] 0.68; 95% confidence interval [CI] 0.55–0.85; p=0.0006); 27.7% vs 29.2% in the oxygen or non-invasive ventilation group (RR 0.87; 95% CI 0.77–0.99; p=0.034); and 26.1% vs 22.5% in the no oxygen group (RR 1.10; 95% CI 0.89–1.36; p=0.39); test for trend p=0.0024. Among 4116 patients in the tocilizumab comparison, 34.3% vs 38.9% died within 6 months (RR 0.87; 95% CI 0.79–0.96; p=0.0077). Among 8156 patients in the baricitinib comparison, 15.7% vs. 16.6% died (RR 0.89; 95% CI 0.80–0.99; p=0.032). Among 3153 anti-SARS-CoV-2 serum antibody negative patients (the primary analysis population) in the casirivimab-imdevimab comparison, 29.3% vs. 34.7% died (RR 0.87; 95% CI 0.77–0.98; p=0.024). Among 720 patients with high serum nucleocapsid antigen concentration (the primary analysis population) in the sotrovimab comparison, 33.0% vs. 38.6% died (RR 0.78; 95% CI 0.61–1.00; p=0.050). In line with the 28-day results, aspirin, azithromycin, colchicine, convalescent plasma, dimethyl fumarate, empagliflozin, lopinavir-ritonavir, molnupiravir, and nirmatrelvir-ritonavir did not reduce 6-month mortality. Mortality at 6 months was higher with hydroxychloroquine therapy (33.3% vs. 30.2%; RR 1.14; 95% CI 1.02–1.27; p=0.018) and, among hypoxic patients not requiring ventilatory support, with higher dose dexamethasone (initial dose 20mg daily, 22.0% vs. 17.6%, RR 1.34; 95% CI 1.04–1.72; p=0.021). Allocation to dexamethasone 6mg once daily resulted in a small increase in major non-COVID infection within 6 months compared with usual care (21.4% vs. 19.1%; absolute difference 2.2%; 95% CI 0.2–4.5%). We found no evidence that any other treatments increased the risk of major non-COVID infection. In patients hospitalised with COVID-19, dexamethasone (at a dose of 6mg daily in hypoxic patients), tocilizumab (in hypoxic patients with CRP ≥75 mg/L), baricitinib, casirivimab-imdevimab (in seronegative patients), and sotrovimab (in high antigen patients) reduced 6-month mortality. Dexamethasone at a dose of 6mg daily was associated with an increase in major non-COVID infection but there was no evidence of other later emerging harms. Other treatments tested in RECOVERY did not reduce 6-month mortality. UK Research and Innovation (Medical Research Council) and National Institute for Health and Care Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

Background Respiratory syncytial virus (RSV) is a virus with two antigenic types, A and B, that cause significant morbidity and mortality in infants globally. A recently developed maternal vaccination based on the prefusion F protein (“RSVpreF”) could have a significant impact on disease burden, if introduced globally. Whether or not the effectiveness of this vaccine is affected by circulating viral genomic variability is currently unknown. Objectives To examine whether the vaccine effectiveness of maternal RSVpreF administration in preventing hospitalisation in infants is affected by RSV type or lineage. Methods We will conduct whole genome sequencing of RSV positive samples from infants hospitalised with acute lower respiratory tract infection (ALRI) in the 2024-2025 winter season, at multiple hospitals in England and Scotland, to calculate the relative vaccine effectiveness (rVE) of maternal RSVpreF vaccination by virus type (RSV-A and RSV-B). rVE will be calculated using a case control logistic regression with adjustment by infant age and admission date; sex, socioeconomic status and hospital location will be included as potential confounders if they are associated with a >3% change in rVE. We will also perform a test negative design to examine the VE for RSV-A and RSV-B separately, using RSV-negative controls from hospitals where cases were admitted. Finally, we will compare viral lineages in vaccinated versus unvaccinated infants. Results and conclusions Our study will identify whether currently circulating RSV genomic variability impacts on rVE. Confirmation of the null hypothesis - that there is no impact of viral genomic variability on rVE – will provide reassurance to policymakers and public health bodies as RSVpreF is rolled out globally. Conversely, an association between RSV type or lineage and decreased vaccine effectiveness will highlight the need for the enhanced comprehensive national and global molecular surveillance of RSV.

Background: Molnupiravir and nirmatrelvir-ritonavir (Paxlovid) are oral antivirals that have been proposed as treatments for patients admitted to hospital with COVID-19. Methods: In this randomised, controlled, open-label, adaptive platform trial, several potential treatments for patients hospitalised with COVID-19 pneumonia were evaluated. Molnupiravir and nirmatrelvir-ritonavir were assessed in separate comparisons in RECOVERY, both of which are reported here. Eligible and consenting adults could join the molnupiravir comparison, the nirmatrelvir-ritonavir comparison, or both. For each comparison, participants were randomly allocated in a 1:1 ratio to the relevant antiviral (five days of molnupiravir 800mg twice daily or nirmatrelvir-ritonavir 300mg/100mg twice daily) or to usual care without the relevant antiviral drug, using web-based unstratified randomisation with allocation concealment. The primary outcome was 28-day mortality, and secondary outcomes were time to discharge alive from hospital, and among those not on invasive ventilation at baseline, progression to invasive ventilation or death. Analysis was by intention-to-treat. Both comparisons were stopped by the investigators because of low recruitment. ISRCTN (50189673) and clinicaltrials.gov ([NCT04381936][1]). Findings: From 24 January 2022 to 24 May 2023, 923 patients were recruited to the molnupiravir comparison (445 allocated molnupiravir and 478 allocated usual care), and from 31 March 2022 to 24 May 2023, 137 patients were recruited to the nirmatrelvir-ritonavir comparison (68 allocated nirmatrelvir-ritonavir and 69 allocated usual care). More than three-quarters of the patients in both comparisons were vaccinated and had anti-spike antibodies at randomisation, and more than two-thirds were receiving other SARS-CoV-2 antivirals (including remdesivir or sotrovimab). In the molnupiravir comparison, 74 (17%) patients allocated to molnupiravir and 79 (17%) patients allocated usual care died within 28 days (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.68-1.28; p=0.66). In the nirmatrelvir-ritonavir comparison, 13 (19%) patients allocated nirmatrelvir-ritonavir and 13 (19%) patients allocated usual care died within 28 days (HR 1.02; 95% CI 0.47-2.23; p=0.96). In neither comparison was there evidence of a significant difference in the duration of hospitalisation or the proportion of patients progressing to invasive ventilation or death. Interpretation: In adults hospitalised with COVID-19, neither molnupiravir nor nirmatrelvir-ritonavir were associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death although these comparisons had limited statistical power due to low recruitment.### Competing Interest StatementThe authors have declared no competing interest.### Clinical TrialNCT04381936, ISRCTN50189673### Funding StatementThe RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation (UKRI) and NIHR (MC\_PC\_19056), the Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator, and by core funding provided by the NIHR Oxford Biomedical Research Centre, the Wellcome Trust, the Bill and Melinda Gates Foundation, the Foreign, Commonwealth and Development Office, Health Data Research UK, the Medical Research Council, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approval was given by the Cambridge East Research Ethics Committee (UK), the Ethical Review Board of the Nepal Health Research Council (Nepal), and the Ethics Committee of the Faculty of Medicine, University of Indonesia (Indonesia)I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe protocol, consent form, statistical analysis plan, definition & derivation of clinical characteristics & outcomes, training materials, regulatory documents, and other relevant study materials are available online at www.recoverytrial.net. As described in the protocol, the Trial Steering Committee will facilitate the use of the study data and approval will not be unreasonably withheld. Deidentified participant data will be made available to bona fide researchers registered with an appropriate institution within 3 months of publication. However, the Steering Committee will need to be satisfied that any proposed publication is of high quality, honours the commitments made to the study participants in the consent documentation and ethical approvals, and is compliant with relevant legal and regulatory requirements (e.g. relating to data protection and privacy). The Steering Committee will have the right to review and comment on any draft manuscripts prior to publication. Data will be made available in line with the policy and procedures described at: https://www.ndph.ox.ac.uk/data-access. Those wishing to request access should complete the form at https://www.ndph.ox.ac.uk/files/about/data\_access\_enquiry\_form\_13\_6\_2019.docx and e-mailed to: data.access@ndph.ox.ac.uk [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04381936&atom=%2Fmedrxiv%2Fearly%2F2024%2F05%2F24%2F2024.05.23.24307731.atom

Objectives We aimed to determine the prevalence of and risk factors for nasopharyngeal and oral pneumococcal carriage in adults with community-acquired pneumonia (CAP), and the relationship between carried and disease-causing serotypes. Methods Between 2016 and 2018, nasopharyngeal swabs, oral-fluid, and urine were collected from hospitalised adults recruited into a prospective cohort study of CAP. Pneumococcal carriage was detected by semi-quantitative real-time PCR of direct and culture-enriched nasopharyngeal swabs and culture-enriched oral-fluid. LytA and piaB positive/indeterminate samples underwent semi-quantitative serotype/serogroup-specific real-time-PCR. Serotypes in urine were identified using a 24-valent serotype-specific urinary-antigen assay. Results We included 465 CAP patients. Nasopharyngeal carriage was detected in 34/103 (33.0%) swabbed pneumococcal pneumonia patients and oral carriage in 18/155 (12%) of sampled pneumococcal pneumonia patients. Concordance between nasopharyngeal/urine serotypes and oral/urine serotypes was 70.6% and 50% respectively. Serotypes 3 (26%, 22.2%), 8 (19.7%, 19.4%), non-typeable (11.6%, 13.9%) and 19A/F (7.5%, 8.3%) were most prevalent in urine and nasopharyngeal swabs respectively, with non-typeable (35%) and 15A/F (17%) most prevalent in oral-fluid. Pneumococcal carriage was significantly associated with pneumococcal pneumonia (nasopharyngeal adjusted odds ratio [aOR] 8.1, 95% confidence interval [CI] 3.8-17.2; oral aOR 5.5, 95% CI 2.1-13.3). All-cause CAP patients ≥65 years had lower odds of nasopharyngeal carriage (aOR 0.47, 95% CI 0.24-0.91) and current smokers had higher odds of oral carriage (aOR 2.69, 95% CI 1.10-6.60). Conclusions The association between nasopharyngeal carriage and pneumococcal CAP was strong. Adult carriage and disease from serotypes 8 and 19A may support direct protection of adults with PCV vaccines.

Objectives: About 60% of antibiotic prescribing in primary care is for respiratory tract infections (RTIs), some of which is likely unnecessary. There is limited evidence on the association between reduced antibiotic prescribing and adverse events. We aimed to identify associations between practice-level prescribing rates for RTIs in general practice, and patient-level adverse outcomes. Methods: We included 1471 English General Practitioner (GP) practices, linked to hospital admissions in England, from the Clinical Practice Research Datalink for 2005 to 2019. Outcomes were hospitalisations, RTIrelated re-consultations and additional antibiotic prescriptions, adjusted for practice level case-mix prescribing. Results: Prescribing rates for practices falling within the lowest and highest prescribing quintiles were 52 and 139 prescriptions per 1000 RTI-related consultations. Patients from practices in the lowest prescribing quintile did not have significantly higher risk of hospitalisation, adjusted odds ratio 099 (95% CI 096 to 102). Re-consultations within 30 days were significantly higher for the lowest prescribing practices, adjusted odds ratio 1209 (1206 to 1212). Additional antibiotic prescriptions and subsequent prescriptions upon re-consultation were significantly lower for the lowest prescribing practices, adjusted odds ratio 0317 (0314 to 0321) and 0706 (0699 to 0712), respectively. Conclusions: Our results contribute to evidence on the safety of reduced antibiotic prescribing for RTIs in primary care. Results suggest that for the majority of practices, further reductions in RTI-related antibiotic prescribing should be possible without an increase in hospitalisation for pneumonia. Crown Copyright (c) 2024 Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Nottingham University Hospitals NHS Trust, University of Nottingham, Respiratory Medicine Department, Nottingham, UK Correspondence to Wei Shen Lim, Consultant Respiratory Physician & Honorary Professor of Respiratory Medicine, Nottingham University Hospitals NHS Trust, University of Nottingham, Respiratory Medicine Department, Nottingham NG5 1PB, UK. E-mail: [email protected]

A 34 year old woman with pulmonary tuberculosis started first-line anti-tuberculosis therapy comprising rifampicin, isoniazid, pyrazinamide, and ethambutol. Two weeks into treatment, she complained of nausea and dark discoloration of urine. Liver enzymes and bilirubin (normal at baseline) were raised, with levels of bilirubin three times above the upper limit of normal, alanine aminotransferase four times above, and alkaline phosphatase two times above. A diagnosis of anti-tuberculosis drug-induced liver injury (DILI) was made, and all her anti-tuberculosis drugs were stopped. Over a period of 10 days, her DILI related symptoms resolved and liverfunction tests normalised. Ethambutol and isoniazid were then restarted, followed three days later by the addition of rifampicin and, a further three days later, pyrazinamide. No recurrence of DILI was encountered, and the patient completed anti-tuberculosis therapy successfully.