The Lancet

BACKGROUNDThe interleukin-6 receptor antagonist tocilizumab improves outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). However, the effectiveness of other immune modulating agents is unclear. METHODSWe evaluated four immunomodulatory agents in an ongoing international, multifactorial, adaptive platform trial. Adult participants with COVID-19 were randomized to receive tocilizumab, sarilumab, anakinra, or standard care (control). In addition, a small group (n=21) of participants were randomized to interferon-{beta}1a. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial used a Bayesian statistical model with pre-defined triggers for superiority, equivalence or futility. RESULTSStatistical triggers for equivalence between tocilizumab and sarilumab; and for inferiority of anakinra to the other active interventions were met at a planned adaptive analysis. Of the 2274 critically ill participants enrolled, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (interquartile range [IQR] -1, 16), 9 (IQR -1, 17), 0 (IQR -1, 15) and 0 (IQR -1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted odds ratios were 1.46 (95%CrI 1.13, 1.87), 1.50 (95%CrI 1.13, 2.00), and 0.99 (95%CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared to control. Median adjusted odds ratios for hospital survival were 1.42 (95%CrI 1.05,1.93), 1.51 (95%CrI 1.06, 2.20) and 0.97 (95%CrI 0.66, 1.40) for tocilizumab, sarilumab and anakinra respectively, compared to control, yielding 98.8%, 98.8% and 43.6% posterior probabilities of superiority, respectively, compared to control. All treatments appeared safe. CONCLUSIONSIn patients with severe COVID-19 receiving organ support, tocilizumab and sarilumab are similarly effective at improving survival and reducing duration of organ support. Anakinra is not effective in this population. (ClinicalTrials.gov number: NCT02735707)

ImportanceRecent reports have highlighted an intense influenza activity related to the circulation of the influenza A(H3N2) subclade k variant. There is no data available on the impact of the emergence of H3N2 subclade k on the severity of the 2025-2026 epidemic or on the clinical phenotype of patients requiring admission to the intensive care unit (ICU). ObjectiveTo compare the clinical presentation, hospital mortality and virological characteristics of patients with laboratory-confirmed influenza infection included in French intensive care units during the 2025-2026 epidemic season with those of patients admitted during the 2024-2025 season. We also aimed at measuring the impact of the A(H3N2) subtype on hospital mortality during the 2025-2026 season. DesignProspective, multicenter, observational SEVARVIR cohort study including patients admitted during the 2024-2025 and 2025-2025 influenza seasons. SettingForty-two French ICUs ParticipantsAdult patients with laboratory-confirmed influenza infection Interventionsnone Main Outcomes and MeasuresThe primary outcome measure was in-hospital mortality. ResultsPatients admitted in intensive care units for influenza in 2024-2025 (n=360) and 2025-2026 (n=325) were included in the French nationwide prospective multicentre SEVARVIR study. There was no significant difference in day-28 mortality between the seasons (12.7%, n=45/355 vs 16.5% n=28/170; p=0.28). In the 2025-26 season, 49% had the A(H1N1) subtype and 51% the A(H3N2) subtype (k subclade: 77%). The univariable Cox analysis revealed that patients infected with A(H3N2) viruses were at greater risk of death over time. Multivariable Cox analysis revealed that during the 2025-2026 season, age (adjusted hazard ratio, aHR=1.05 [1.00;1.11]; p=0.046) and the clinical frailty scale (aHR=1.82 [1.26;2.72]; p=0.001) were associated with an increased risk of death. The A(H3N2) subtype was not associated with an increased risk of death (aHR=1.13 [0.32;4.51]; p=0.85). Phylogenetic analyses from our ICU cohort together with 300 contextual sequences from community-acquired influenza cases collected during the same period showed no clustering according to severity. Conclusions and RelevanceThis French national prospective observational study, found that the emergence of the influenza A(H3N2) subclade K was associated with an increased risk of death in univariable but not multivariable analysis, adjusting for host-related factors. Trial RegistrationNCT051625 Key PointsQuestion: What impact did the 2025-26 influenza epidemic and the A(H3N2) variant have on the mortality of patients admitted to intensive care units? Findings: In this prospective, nationwide cohort study of 685 patients admitted to intensive care units with severe influenza during the 2024-25 or 2025-26 seasons, no difference in hospital mortality was observed between the two seasons. Patients infected with the A(H3N2) virus, 77% of which corresponded to clade k, were at higher risk of death in univariable but not in multivariable analysis after adjusting for age and clinical frailty scale. Meaning: Patients in intensive care units with severe A(H3N2) infection during the 2025/2026 season were not at higher risk of death after adjusting for confounding variables.

BackgroundThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. MethodsWe evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility. ResultsTocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] -1, 16), 11 (IQR 0, 16) and 0 (IQR -1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists. ConclusionsIn critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.gov number: NCT02735707)

BACKGROUNDThe evidence for benefit of convalescent plasma for critically ill patients with Covid-19 is inconsistent. We hypothesized that convalescent plasma would improve outcomes for critically ill adult patients with Covid-19. METHODSIn an ongoing adaptive platform trial, critically ill patients with confirmed Covid-19, defined as receiving intensive care-level organ support, were randomized to open-label convalescent plasma or not (i.e., control group). The primary end point was organ support-free days (i.e., days alive and free of ICU-based organ support) up to day 21. The primary analysis was a Bayesian cumulative logistic model with predefined criteria for superiority or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTSThe convalescent plasma intervention was stopped after pre-specified criteria for futility were met. At that time, 1084 participants had been randomized to convalescent plasma and 916 to no convalescent plasma (control). The median organ support-free days were 0 (interquartile range, -1 to 16) for the convalescent plasma group and 3 (interquartile range, -1 to 16) days for the control group. The median adjusted odds ratio (OR) was 0.97 (95% credible interval 0.83 to 1.15) and posterior probability of futility (OR < 1.2) was 99.4% for convalescent plasma compared to control. In-hospital mortality was 37.3% (401/1075) in convalescent plasma group, and 38.4% (347/904) in controls. The observed treatment effects were consistent across primary and secondary outcomes. CONCLUSIONSIn critically ill adults with confirmed Covid-19, treatment with convalescent plasma, did not improve clinical outcomes. Clinicaltrials.gov: NCT02735707

BackgroundTwelve-month mortality in sepsis survivors has not been previously characterized in sub-Saharan Africa. MethodsHospitalized adults with [&ge;] 2 modified systemic inflammatory response syndrome (SIRS) criteria (temperature < 36{degrees}C or > 38{degrees}C, heart rate [&ge;] 90 beats per minute, or respiratory rate [&ge;] 20 breaths per minute) were enrolled at a tertiary care centre from October 2017 to August 2022. Multiple clinical blood and respiratory molecular and antigen assays were used to identify infectious etiologies. Baseline demographics were evaluated for risk of death by 1 month and 12 months using Cox proportional hazards regression. ResultsAmong 435 participants, the median age was 45.0 years (interquartile range [IQR]: 28.0, 60.0) years, 57.6% were female, and 31.7% were living with HIV. Malaria (17.7%) followed by tuberculosis (4.7%), and bacteremia (4.6%) were the most common detected causes of illness. Overall, 49 (11.3%) participants died, and 24 participants died between one month and one year (49.0% of deaths and 5.5% of the cohort). Female participants had a decreased risk of death by 12-months (unadjusted hazard ratio [HR]: 0.37; 95% confidence interval [CI]: 0.21 to 0.66). ConclusionsThe burden of sepsis may be underestimated in sub-Saharan Africa due to limited long-term follow-up.

ImportanceInformation about the severity of Omicron is scarce. ObjectiveTo report the respective risk of ICU admission in patients hospitalized with Delta and Omicron variants and to compare the characteristics and disease severity of critically ill patients infected with both variants according to vaccination status. DesignAnalysis from the APHP database, called Reality, prospectively recording the following information in consecutive patients admitted in the ICU for COVID-19: age, sex, immunosuppression, vaccination, pneumonia, need for invasive mechanical ventilation, time between symptom onset and ICU admission, and in-ICU mortality. Retrospective analysis on an administrative database, "Systeme dInformation pour le Suivi des Victimes" (SI-VIC), which lists hospitalized COVID-19 patients. Setting39 hospitals in the Paris area from APHP group. ParticipantsPatients hospitalized from December 1, 2021 to January 18, 2022 for COVID-19. Main outcomes and measuresRisk of ICU admission was evaluated in 3761 patients and Omicron cases were compared to Delta cases in the ICU in 888 consecutive patients. ResultsOn January 18, 45% of patients in the ICU and 63.8% of patients in conventional hospital units were infected with the Omicron variant (p < 0.001). The risk of ICU admission with Omicron was reduced by 64% than with Delta (9.3% versus 25.8% of cases, respectively, p < 0.001). In critically ill patients, 400 had the Delta variant, 229 the Omicron variant, 98 had an uninformative variant screening test and 161 did not have information on variant screening test. 747 patients (84.1%) were admitted for pneumonia. Compared to patients infected with Delta, Omicron patients were more vaccinated (p<0.001), even with 3 doses, more immunocompromised (p<0.001), less admitted for pneumonia (p<0.001), especially when vaccinated (62.1% in vaccinated versus 80.7% in unvaccinated, p<0.001), and less invasively ventilated (p=0.02). Similar results were found in the subgroup of pneumonia but Omicron cases were older. Unadjusted in-ICU mortality did not differ between Omicron and Delta cases, neither in the overall population (20.0% versus 27.9%, p = 0.08), nor in patients with pneumonia (31.6% versus 29.7%, respectively) where adjusted in-ICU mortality did not differ according to the variant (HR 1.43 95%CI [0.89;2.29], p=0.14). Conclusion and relevanceCompared to the Delta variant, the Omicron variant is less likely to result in ICU admission and less likely to be associated with pneumonia. However, when patients with the Omicron variant are admitted for pneumonia, the severity seems similar to that of patients with the Delta variant, with more immunocompromised and vaccinated patients and no difference in adjusted in-ICU mortality. Further studies are needed to confirm our results.

IntroductionAccess to Hepatitis C virus (HCV) testing and treatment remains low globally. HCV self-testing (HCVST) may facilitate diagnosis and cure. We analysed treatment uptake and outcomes following a positive HCVST result in three distinct African epidemic contexts. MethodsA multi-country cohort study nested within HCVST implementation programmes in Cameroon, Nigeria, and South Africa (May 2023-May 2024). Adults ([&ge;]18 years) with positive HCVST results were followed through confirmatory testing and care outcomes until last event. Co-primary outcomes were: (i) cascade progression, (treatment initiation and sustained virological response [SVR]); estimated using country-cascades; and (ii) cumulative incidence of disengagement from care, estimated using Bayesian competing-risks survival models. Analyses were conducted separately for South Africa and jointly for Cameroon-Nigeria due to structural differences in service organisation. Covariate associations were estimated as hazard ratios. Disease severity was assessed through fibrosis staging derived from AST-to-platelet ratio index (APRI). Results1,341 participants had positive HCVST results (117 in Cameroon, 226 in Nigeria, 998 in South Africa). Among laboratory confirmed HCV cases, treatment initiation and SVR were highest in Cameroon (Tx 98.6%, 71/72; SVR 96.4%, 53/55), followed by Nigeria (Tx 90.8%, 168/185; SVR 91.8%, 56/62), and low in South Africa (Tx 4.3%, 37/854; SVR 60.6%, 3/5). Crude disengagement was lowest in Nigeria (24.4%; 95% CrI 19.1%-30.3%), followed by Cameroon (52.4%; 95% CrI 44.4%-61.2%), and South Africa (77.9%; 95% CrI 76.2%-79.8%). By 24-weeks, disengagement was lower in specialist hospitals than community sites in Cameroon and Nigeria. In South Africa, the greatest predictor of disengagement was HIV positive status (HR 1.96; 95% CrI 1.71 to 2.23). Viraemia exceeded regional estimates (82.2%, 1102/1341), with liver scarring highest in Cameroon (fibrosis: 8.3%, cirrhosis: 6.9%) and lowest in South Africa (2.9% and 1.6%, respectively). ConclusionHCV self-testing enabled detection of HCV cases, including severe disease, but poorer progression in community settings suggests decentralised treatment pathways require strengthening to realise cure.

BackgroundThe spread of several SARS-CoV-2 variants of concern (VOC) led to increasing numbers of patients with coronavirus disease 2019 (COVID-19) in German intensive care units (ICU), resulting in capacity shortages and even transfers of COVID-19 ICU patients between federal states in late 2021. Comprehensive evidence on the impact of predominant VOC, in this case Delta and Omicron, on inter-hospital transfers of COVID-19 ICU patients remains scarce. MethodsA retrospective cohort study was conducted from July 01, 2021 until May 31, 2022 using nationwide reimbursement inpatient count data of COVID-19 ICU patients and weekly sequence data of VOC in Germany. A multivariable Poisson regression analysis was performed to estimate incidence rates and incidence rate ratios (IRR) for competing events of transfer, discharge and death, adjusted for VOC infection, age group and sex. For corresponding risk estimation, a multistate model for the clinical trajectory in ICU was applied. ResultsOmicron versus Delta infection yielded estimated adjusted IRR of 1.23 (95% CI, 1.16 - 1.30) for transfer, 2.27 (95% CI, 2.20 - 2.34), for discharge and 0.98 (95% CI, 0.94 - 1.02) for death. For death in ICU, estimated adjusted IRR increased progressively with age up to 4.09 (95% CI, 3.74 - 4.47) for those 90 years and older. COVID-19 ICU patients with Omicron infection were at comparatively higher estimated risk of discharge, whereas the estimated risk of transfer and death were higher for those with Delta infection. ConclusionsInter-hospital transfers and discharges occurred more frequently in COVID-19 ICU patients with Omicron infection than in those with Delta infection, who in turn had a higher estimated risk of death. Age emerges as a relevant determinant for fatal clinical trajectories in COVID-19 ICU patients and imposes close therapeutic care.

BackgroundInitial reports suggest that ethnic minorities may be experiencing more severe coronavirus disease 2019 (COVID19) outcomes. We therefore assessed the association between ethnic composition, income deprivation and COVID19 mortality rates in England. MethodsWe performed a cross-sectional ecological analysis across Englands upper-tier local authorities. We assessed the association between the proportion of the population from Black, Asian and Minority Ethnic (BAME) backgrounds, income deprivation and COVID19 mortality rates using multivariable negative binomial regression, adjusting for population density, proportion of the population aged 50-79 and 80+ years, and the duration of the epidemic in each area. FindingsLocal authorities with a greater proportion of residents from ethnic minority backgrounds had statistically significantly higher COVID19 mortality rates, as did local authorities with a greater proportion of residents experiencing deprivation relating to low income. After adjusting for income deprivation and other covariates, each percentage point increase in the proportion of the population from BAME backgrounds was associated with a 1% increase in the COVID19 mortality rate [IRR=1.01, 95%CI 1.01-1.02]. Each percentage point increase in the proportion of the population experiencing income deprivation was associated with a 2% increase in the COVID19 mortality rate [IRR=1.02, 95%CI 1.01-1.04]. InterpretationThis study provides evidence that both income deprivation and ethnicity are associated with greater COVID19 mortality. To reduce these inequalities, Government needs to target effective control and recovery measures at these disadvantaged communities, proportionate to their greater needs and vulnerabilities, during and following the pandemic. FundingNational Institute of Health Research; Medical Research Council

IntroductionThis study aims to explore the impact of COVID-19 vaccination on critical care by examining associations between vaccination and admission to critical care with COVID-19 during Englands Delta wave, by age group, dose, and over time. MethodsWe used linked routinely-collected data to conduct a population cohort study of patients admitted to adult critical care in England for management of COVID-19 between 1 May and 15 December 2021. Included participants were the whole population of England aged 18 years or over (44.7 million), including 10,141 patients admitted to critical care with COVID-19. The intervention was vaccination with one, two, or a booster/three doses of any COVID-19 vaccine. ResultsCompared with unvaccinated patients, vaccinated patients were older (median 64 years for patients receiving two or more doses versus 50 years for unvaccinated), with higher levels of severe comorbidity (20.3% versus 3.9%) and immunocompromise (15.0% versus 2.3%). Compared with patients who were unvaccinated, those vaccinated with two doses had a relative risk reduction (RRR) of between 90.1% (patients aged 18-29, 95% CI, 86.8% to 92.7%) and 95.9% (patients aged 60-69, 95% CI, 95.5% to 96.2%). Waning was only observed for those aged 70+, for whom the RRR reduced from 97.3% (91.0% to 99.2%) to 86.7% (85.3% to 90.1%) between May and December but increased again to 98.3% (97.6% to 98.8%) with a booster/third dose. ConclusionImportant demographic and clinical differences exist between vaccinated and unvaccinated patients admitted to critical care with COVID-19. While not a causal analysis, our findings are consistent with a substantial and sustained impact of vaccination on reducing admissions to critical care during Englands Delta wave, with evidence of waning predominantly restricted to those aged 70+.

BackgroundCoronavirus disease 2019 (COVID-19) mortality is predominantly due to acute respiratory distress syndrome (ARDS). There are currently limited treatment options for ARDS, a life-threatening condition with different etiologies, secondary to inflammation-induced lung injury. Paridiprubart is a monoclonal antibody that inhibits Toll-like Receptor 4 (TLR4), a key player in ARDS pathophysiology. MethodsThis was a prespecified sub-study of a randomized, double-blind, placebo-controlled, Phase 2 trial evaluating the efficacy and safety of paridiprubart in COVID-19 patients with ARDS receiving invasive mechanical ventilation and additional organ support. Efficacy outcomes were 28- and 60-day all-cause mortality, and improvement in COVID-19 severity and ventilation-free days at 28-days post-treatment. ResultsThirteen (13) and twenty (20) patients received paridiprubart and placebo, respectively. The groups were comparable for demographics and baseline parameters, except for higher kidney failure incidence and use of immune modulators and antivirals, and lower corticosteroids use in the paridiprubart group. Mortality at 28-days post-treatment was 7.7% (1/13) in the paridiprubart group versus 40.0% (8/20) for placebo (OR=0.125; 95% CI, 0.013-1.160; P=0.067; P[bootstrap]=0.011). 60-day mortality was 23.1% (3/13) in paridiprubart-treated patients and 45.0% (9/20) in placebo patients (OR=0.367; 95% CI, 0.077-1.749; P=0.208; P[bootstrap]=0.162). Mean survival time was 55.78 days for paridiprubart recipients compared to 41.44 days for placebo patients (HR=0.386; 95% CI, 0.077-1.436; P=0.156; P[bootstrap]=0.083). Although not statistically significant, results for other efficacy measures favored paridiprubart. Incidence of adverse events was similar in both groups. ConclusionsIn COVID-19 patients with ARDS requiring invasive ventilation and organ support, paridiprubart was efficacious in preventing mortality and improving clinical outcomes, with no safety concerns.

BackgroundMolnupiravir and nirmatrelvir-ritonavir (Paxlovid) are oral antivirals that have been proposed as treatments for patients admitted to hospital with COVID-19. MethodsIn 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). FindingsFrom 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. InterpretationIn 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. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health and Care Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z). Trial registrationClinicalTrials.gov NCT04381936 https://clinicaltrials.gov/ct2/show/NCT04381936 ISRCTN50189673 http://www.isrctn.com/ISRCTN50189673

BackgroundREACT-2 Study 5 is a population survey of the prevalence of SARS-CoV-2 antibodies in the community in England. MethodsWe contacted a random sample of the population by sending a letter to named individuals aged 18 or over from the NHS GP registrations list. We then sent respondents a lateral flow immunoassay (LFIA) kit for SARS-CoV-2 antibody self-testing and asked them to perform the test at home and complete a questionnaire, including reporting of their test result. Overall, 161,537 adults completed questionnaires and self-administered LFIA tests for IgG against SARS-CoV-2 between 27 October and 10 November 2020. ResultsThe overall adjusted and weighted prevalence was 5.6% (95% CI 5.4-5.7). This was an increase from 4.4% (4.3-4.5) in round 3 (September), a relative increase of 26.9% (24.0-29.9).The largest increase by age was in the 18 to 24 year old age group, which increased (adjusted and weighted) from 6.7% (6.3-7.2) to 9.9% (9.3-10.4), and in students, (adjusted, unweighted) from 5.9% (4.8-7.1) to 12.1% (10.8-13.5). Prevalence increased most in Yorkshire and The Humber, from 3.4% (3.0-3.8) to 6.3% (5.9-6.8) and the North West from 4.5% (4.2-4.9) to 7.7% (7.2-8.1). In contrast, the prevalence in London was stable, at 9.5% (9.0-9.9) and 9.5% (9.1-10.0) in rounds 3 and 4 respectively. We found the highest prevalence in people of Bangladeshi 15.1% (10.9-20.5), Pakistani 13.9% (11.2-17.2) and African 13.5% (10.7-16.8) ethnicity, and lowest in those of white British ethnicity at 4.2% (4.0-4.3). InterpretationThe second wave of infection in England is apparent in increasing antibody prevalence, particularly in younger people, students, and in the Northern Regions. By late October a large proportion of the population remained susceptible to SARS-CoV-2 infection in England based on naturally acquired immunity from the first and early second wave.

BackgroundThere is an urgent public health need to evaluate disease severity in adults hospitalised with Delta and Omicron SARS-CoV-2 variant infections. However, limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 infections, and to what extent patient-factors, including vaccination, age, frailty and pre-existing disease, affect variant-dependent disease severity. MethodsA prospective cohort study of adults ([&ge;]18 years of age) hospitalised with acute lower respiratory tract disease at acute care hospitals in Bristol, UK conducted over 10-months. Delta or Omicron SARS-CoV-2 infection was defined by positive SARS-CoV-2 PCR and variant identification or inferred by dominant circulating variant. We constructed adjusted regression analyses to assess disease severity using three different measures: FiO2 >28% (fraction inspired oxygen), World Health Organization (WHO) outcome score >5 (assessing need for ventilatory support), and hospital length of stay (LOS) >3 days following admission for Omicron or Delta infection. FindingsIndependent of other variables, including vaccination, Omicron variant infection in hospitalised adults was associated with lower severity than Delta. Risk reductions were 58%, 67%, and 16% for supplementary oxygen with >28% FiO2 [Relative Risk (RR)=0{middle dot}42 (95%CI: 0{middle dot}34-0{middle dot}52), P<0.001], WHO outcome score >5 [RR=0{middle dot}33 (95%CI: 0{middle dot}21-0{middle dot}50), P<0.001], and to have had a LOS>3 days [RR=0{middle dot}84 (95%CI: 0{middle dot}76-0{middle dot}92), P<0.001]. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. InterpretationWe provide reassuring evidence that Omicron infection results in less serious adverse outcomes than Delta in hospitalised patients. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden and an increased admission rate of older patients with Omicron which counteracts some of the benefit arising from less severe disease. FundingAvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSThe burden of COVID-19 on hospital services is determined by the prevalence and severity of SARS-CoV-2 variants, and modified by individual factors such as age, frailty and vaccination status. Real world data suggest that vaccine effectiveness is lower and may wane faster over time against symptomatic disease with Omicron (B.1.1.529) than with Delta (B.1.617.2) SARS-CoV-2 variant. However, numbers of hospitalisations as a case proportion during the Omicron wave have been considerably lower than previous waves. Several reports have compared the risk of hospitalisation or severe disease based on SARS-CoV-2 variant, some suggesting that Omicron is probably less severe than Delta in vaccinated and unvaccinated individuals. Added value of this studyThis study provides robust data assessing the relative severity of Delta and Omicron SARS-CoV-2 variants in patients admitted to hospital, including the first analysis assessing risk for any positive pressure ventilatory support, as well as risk of supplementary oxygen requirement and extended hospital admission, that may guide resource planning in hospitals. We found evidence that infection with Omicron was associated with a milder clinical course following hospital admission than that caused by Delta and that vaccination was independently associated with lower in-hospital disease severity using these three separate severity measures. Specifically, compared to Delta, Omicron-related hospitalizations were 58%, 67%, and 16% less likely to require high flow oxygen >28% FiO2, positive pressure ventilatory support or more critical care, and to have a hospital stay lasting more than three days, respectively. This study reports the considerable morbidity resulting from Omicron infection, with 18% of Omicron admissions requiring oxygen supplementation FiO2 >28%, 6% requiring positive pressure ventilation, 62% needing hospitalization [&ge;]four days, and 4% in-hospital mortality. In determining the reduced requirement of increased oxygen requirement and total positive pressure requirement, including non-invasive ventilation, this analysis should contribute to future hospital care and service planning assessments. Implications of all the available evidenceThe risk of severe outcomes following SARS-CoV-2 infection is substantially lower for Omicron than for Delta, with greater reductions for more severe disease outcomes. Significant variation in risk occurs with age and vaccination status, with older and unvaccinated individuals remaining at particular risk of adverse outcome. These results highlight the importance of maintaining high levels of vaccine coverage in patient groups at risk of severe disease. The impact of lower severity Omicron-related hospitalization must be balanced against increased transmissibility and overall higher numbers of infections with this variant and there remains a substantial patient and public health burden. The increased admission rate of older patients with Omicron counteracts some of the benefit arising from less severe disease. Despite the risk reduction in high level oxygen supplementation requirement and high dependency care with Omicron compared to earlier variants at the individual level, healthcare systems could still be overwhelmed.

BackgroundRespiratory 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. AimWe 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. MethodsAdults aged [&ge;]65 years from seven hospitals admitted for [&ge;]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. ResultsThis 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). ConclusionIn 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.

ObjectiveUse of prone positioning increased among mechanically ventilated patients during the COVID-19 pandemic, but it is unknown whether implementation of this life-saving intervention was sustained. Thus, we aimed to evaluate peri-pandemic trends in proning use. DesignWe conducted a retrospective cohort study of proning use among mechanically ventilated adults, with proning rates compared across pre-pandemic (1/2018-2/2020), pandemic (3/2020-2/2022), and post-pandemic (3/2022-12/2024) periods. Setting37 North American hospitals PatientsMechanically ventilated patients with persistent moderate-to-severe hypoxemia (PaO2/FiO2 [&le;]150 mmHg, FiO2 [&ge;]0.6, and positive end-expiratory pressure [&ge;]5 cmH2O). InterventionProning within 12 hours of meeting study hypoxemia criteria. Measurements and Main ResultsAmong 5,760 proning-eligible patients, 1,737 (30.2%) received proning: 8.0% pre-pandemic, 44.6% pandemic, and 19.9% post-pandemic. The adjusted odds ratio (OR) for proning during pandemic versus pre-pandemic periods was 8.25 (95% Confidence Interval (CI): 6.35-10.70) and pandemic versus post-pandemic, 2.76 (95% CI: 1.83-4.17). Proning varied widely by hospital and was quantified with the median odds ratio (median change in odds of proning an identical patient admitted at a lower versus higher proning hospital) of 2.54 (95% Credible Interval (CrI): 1.75-4.58) pre-pandemic, 2.33 (95% CrI: 1.92-3.04) pandemic, and 2.58 (95% CrI: 1.99-3.73) post-pandemic. Pandemic-period patients with SARS-CoV2 were proned more than those without (OR: 4.55, [95% CI: 3.85-5.56]), but pandemic-period patients without SARS-CoV2 were still proned more than pre-pandemic (OR: 3.87, [95% CI: 2.92-5.13]) or post-pandemic patients (OR: 1.37, [95% CI: 1.03-1.83]). ConclusionsIn a North American cohort of proning-eligible patients, proning increased during the pandemic and then declined. Interventions that improve implementation of this life-saving treatment are urgently needed.

BackgroundThe 2019 novel coronavirus (SARS-CoV-2) is reported to result in both respiratory and non-respiratory severe health outcomes, but quantitative assessment of the risk - while adjusting for underlying risk driven by comorbidities - is not yet established. MethodsA retrospective observational study using electronic health records of 9,344,021 individuals across the U.S. with at-least 1 year of clinical history and followed up throughout 2020. Results131,329 individuals were associated with SARS-CoV-2 infection by January 6, 2021 in three distinct surges. While the age and number of preexisting conditions had decreased throughout the pandemic, the characteristics of those who experienced severe health events did not. During the second surge, between June 7 and November 18, 2020, 425,988 individuals in the base cohort were admitted to emergency rooms or hospitals. Among them, 15,486 were detected with SAR-CoV-2 within few days of admission. Significant adjusted odds ratios were observed between SARS-CoV-2 infection and the following severe health events: respiratory (4.38, 95% confidence interval 4.16- 4.62), bacterial pneumonia (3.25, 2.76-3.83), sepsis (1.71, 1.53-1.91), renal (1.69, 1.57-1.83), hematologic/immune (1.32, 1.20-1.45), neurological (1.23, 1.09-1.38). ConclusionsSARS-CoV-2 infection among hospitalized patients is associated with non-negligible increased risk of severe events including multiple non-respiratory ones. These associations, which complement recent studies, are persistent even after accounting for sources of selection and confounding bias, increasing the confidence they are not spurious.

BackgroundNorovirus causes substantial burden to healthcare systems. England experienced high activity in recent seasons alongside a shift in the dominant genotype from GII.4 to GII.17. It remains unclear whether this increased burden reflects changes in severity or other transmission mechanisms associated with the strain replacement. MethodsIndividual-level testing and mortality data in England from 2022/23-2024/25 seasons were linked from national surveillance systems. Piece-wise exponential additive mixed models estimated all-cause case-fatality risk (CFR) for death within 28 days of a positive test, adjusting for age, location, primary or secondary care case identification and temporal effects. Additional analysis tested the effect of the death linkage threshold. ResultsCFR did not differ significantly between GII.4 and GII.17, but increased markedly with age and was substantially higher for cases detected in secondary versus primary care. At the 2024/25 season peak, the CFR for the average cohort case (age 75) was 8.01% (95% CI: 6.88-9.33%) for cases identified in secondary care compared with 1.18% (95% CI: 0.61-2.25%) for primary care, likely driven by different case mixes and unmeasured confounding between patients managed in these settings. InterpretationWe found no evidence that the newly dominant GII.17 genotype had higher CFR than GII.4 among test-positive cases. The increased burden is therefore more consistent with changes in transmissibility, population immunity, or testing dynamics than increased genotype-specific severity. Norovirus remains a major public health threat, and understanding genotype switching supports enhanced surveillance, expanded genotyping, routine clinical data linkage and advanced modelling to inform control strategies.

BackgroundA new variant of SARS-CoV-2, B.1.1.7/VOC202012/01, was identified in the UK in December-2020. Direct estimates of its potential to enhance transmission are limited. MethodsNose and throat swabs from 28-September-2020 to 2-January-2021 in the UKs nationally representative surveillance study were tested by RT-PCR for three genes (N, S and ORF1ab). Those positive only on ORF1ab+N, S-gene target failures (SGTF), are compatible with B.1.1.7/VOC202012/01. We investigated cycle threshold (Ct) values (a proxy for viral load), percentage of positives, population positivity and growth rates in SGTF vs non-SGTF positives. Results15,166(0.98%) of 1,553,687 swabs were PCR-positive, 8,545(56%) with three genes detected and 3,531(23%) SGTF. SGTF comprised an increasing, and triple-gene positives a decreasing, percentage of infections from late-November in most UK regions/countries, e.g. from 15% to 38% to 81% over 1.5 months in London. SGTF Ct values correspondingly declined substantially to similar levels to triple-gene positives. Population-level SGTF positivity remained low (<0.25%) in all regions/countries until late-November, when marked increases with and without self-reported symptoms occurred in southern England (to 1.5-3%), despite stable rates of non-SGTF cases. SGTF positivity rates increased on average 6% more rapidly than rates of non-SGTF positives (95% CI 4-9%) supporting addition rather than replacement with B.1.1.7/VOC202012/01. Excess growth rates for SGTF vs non-SGTF positives were similar in those up to high school age (5% (1-8%)) and older individuals (6% (4-9%)). ConclusionsDirect population-representative estimates show that the B.1.1.7/VOC202012/01 SARS-CoV-2 variant leads to higher infection rates, but does not seem particularly adapted to any age group.

ObjectiveTo determine if Tocilizumab treatment in patients hospitalized with laboratory confirmed SARS-CoV-2 infection and subsequent COVID-19 disease provides short-term survival benefit. DesignCase-control, observational study that includes an observation period from arrival to discharge or inpatient death. Both Cox proportional hazards and average treatment effects models were used to determine survival and treatment benefits. SettingThree Cone Health acute care hospitals including one COVID dedicated facility. PatientsPatients admitted with confirmed SARS-CoV-2 from March 16, 2020 through April 22, 2020. ExposureTocilizumab dosed at either 400 mg fixed dose or 8 mg/kg weight-based dose with maximum single dose of 800mg. Measurements and Main ResultsOverall, 86 patients were admitted during the observation period with confirmed COVID-19 disease. Of these, 21 received Tocilizumab during the hospital stay. Both the Cox model and treatment effects models showed short-term survival benefit. There was an associated 75% reduction in the risk of inpatient death when treated (HR 0.25; 95% CI 0.07-0.90) in the Cox model. This association was confirmed in the treatment effects model where we found a 52.7% reduced risk of dying while hospitalized compared to those not treated (RR 0.472; 95% CI 0.449-0.497). In both models, we show short-term survival benefit in patients with severe COVID-19 illness.