The Lancet

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.

During the current COVID-19 pandemic, it has been suggested that BAME background patients may be disproportionately affected compared to White but few detailed data are available. We took advantage of near real-time hospital data access and analysis pipelines to look at the impact of ethnicity in 1200 consecutive patients admitted between 1st March 2020 and 12th May 2020 to Kings College Hospital NHS Trust in London (UK). Our key findings are firstly that BAME patients are significantly younger and have different co-morbidity profiles than White individuals. Secondly, there is no significant independent effect of ethnicity on severe outcomes (death or ITU admission) within 14-days of symptom onset, after adjustment for age, sex and comorbidities.

BackgroundThe optimal antiviral drug for treatment of non-severe influenza remains unclear. To support an update of WHO guidelines on antiviral treatment for influenza, this systematic review compared effects of antiviral drugs for treating non-severe influenza. MethodsWe systematically searched Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomized controlled trials published between database inception and 20 September 2023, comparing direct-acting influenza antiviral drugs, including but not limited to baloxavir, favipiravir, laninamivir, oseltamivir, peramivir, umifenovir, and zanamivir, to placebo, standard care, or another antiviral drug for treating people with non-severe influenza. We performed frequentist network meta-analyses to summarize the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We registered the protocol with PROSPERO, CRD42023456650. FindingsWe identified 11878 records, of which 73 trials with 34332 participants proved eligible. Compared with standard care or placebo, all antiviral drugs have little or no effect on mortality for low-risk patients (risk difference (RD) varied from 0.12 fewer to 0.02 fewer per 1000) and high-risk patients (RD varied from 1.22 fewer to 0.24 fewer per 1000) (all high certainty). All antivirals (no data for peramivir and amantadine) have little or no effect on admission to hospital (RD varied from 2 fewer to 1 more per 1000) for low-risk patients (high certainty). With respect to hospital admission, for high-risk patients, oseltamivir (RD 4 fewer per 1000, 95% CI 10 fewer to 4 more; high certainty) and zanamivir (RD 4 more per 1000, 95% CI 4 fewer to 15 more; high certainty) have little or no effect; baloxavir may reduce risk (RD 16 fewer per 1000, 95% CI 20 fewer to 4 more; low certainty); all other drugs may have little or uncertain effect. For time to alleviation of symptoms, baloxavir probably reduces symptom duration (mean difference (MD) 1.02 days lower, 95% CI 1.41 lower to 0.63 lower; moderate certainty); umifenovir may reduce symptom duration (MD 1.10 days lower, 95% CI 1.57 lower to 0.63 lower; low certainty); oseltamivir probably has no important effect (MD 0.75 days lower, 95% CI 0.93 lower to 0.57 lower, moderate certainty) and other drugs may have no important or little effect. For adverse events related to treatment, baloxavir (RD 32 fewer per 1000, 95% CI 52 fewer to 6 fewer; high certainty) has few or no such events; oseltamivir (RD 28 more per 1000, 95% CI 12 more to 48 more; moderate certainty) probably increases such events; other drugs may have little or no effect, or uncertain effect. InterpretationBaloxavir may reduce the risk of hospital admission for high-risk patients and probably reduces time to alleviation of symptoms, without increasing adverse events related to treatment in patients with non-severe influenza. All other antivirals either probably have little or no effect, or uncertain effects on patient-important outcomes. FundingWHO. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAntiviral drugs may play a role in reducing illness duration, preventing serious complications, and lowering morbidity, particularly in high-risk populations. Previous systematic reviews and network meta-analyses have assessed the effects of antiviral drugs for treating influenza, but none assessed all approved antivirals for influenza or addressed patient-important outcomes of mortality and admission to hospital. The effect of many antiviral drugs for treating patients with non-severe influenza remains uncertain. Added value of this studyThis systematic review and network meta-analysis represents the most comprehensive assessment of the benefits and harms of antivirals in treating patients with non-severe influenza and demonstrates that baloxavir may reduce the risk of admission to hospital for high-risk patients and probably reduces time to alleviation of symptoms, does not increase adverse events related to treatment, but may increase emergence of resistance. Oseltamivir has little or no effect on mortality and admission to hospital, probably has no important effect on time to alleviation of symptoms, and probably increases adverse events related to treatments. Other antivirals probably have little or no effect on mortality and admission to hospital and may have no important effect on time to alleviation of symptoms. Implications of all the available evidenceOur study provides evidence that baloxavir may be superior to standard care or placebo in reducing the risk of admission to hospital for high-risk patients and probably decreases time to alleviation of symptoms with few or no adverse effects. These findings support the use of baloxavir for treatment of high-risk non-severe influenza patients.

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.

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

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

Surveillance of acute lower respiratory tract disease (aLRTD) is fundamental for understanding population health burden and healthcare needs. COVID-19 altered the epidemiology of respiratory infections, but post-pandemic aLRTD incidence and severity remain underexplored in the UK. We conducted a prospective cohort study of adults ([&ge;]18 years) admitted to two Bristol hospitals (August 2020-July 2024) with symptoms or a diagnosis of pneumonia, non-pneumonic lower respiratory tract infection (NP-LRTI), or no evidence of LRTI. Of 457,112 hospitalizations, 44,792 (9.8%) were due to aLRTD: 48.2% pneumonia, 35.2% NP-LRTI, and 16.7% no LRTI. Incidence peaked in 2021-22 (14.4/1,000 person-years) due to COVID-19 before stabilizing around 13.6. SARS-CoV-2 pneumonia declined; non-COVID pneumonia remained stable. Mortality risk was lower for NP-LRTI (HR 0.32) and no LRTI (HR 0.43) compared to pneumonia. Older age and comorbidities increased mortality. Non-COVID infections persisted despite interventions, emphasizing the need for surveillance and vaccination in public health planning.

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+.

BackgroundRespiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in older adults that can result in hospitalisations and death. Estimating RSV- associated hospitalisation is critical for planning RSV-related healthcare needs for the ageing population across Europe. MethodsWe gathered national RSV-associated hospitalisation estimates from the REspiratory Syncytial virus Consortium in EUrope (RESCEU) for adults in Denmark, England, Finland, Norway, Netherlands, and Scotland from 2006 to 2017. We extrapolated these estimates to 28 EU countries using nearest-neighbour matching, multiple imputations, and two sets of 10 indicators. ResultsOn average, 158 229 (95%CI: 140 865-175 592) RSV-associated hospitalisations occur annually among adults in the EU (above 18 years); 92% of these hospitalisations occur in adults over 65 years. Among 75-84 years old, the annual average is estimated at 74 519 (95%CI: 69 923-79 115) at a rate of 2.24 (95%CI: 2.10-2.38) per 1000 adults. Among adults aged [&ge;]85 years, the annual average is estimated at 37 904 (95%CI: 32 444-43 363) at a rate of 2.99 (95%CI: 2.56-3.42). ConclusionOur estimates of RSV-associated hospitalisations in older adults are the first analysis integrating available data to provide estimates of the disease burden in this population across the EU. Importantly, for a condition which was considered in the past to be primarily a disease of young children, the average annual hospitalisation estimate in adults was lower but of a similar magnitude to the estimate in young children aged 0-4 years: 158 229 (95%CI: 140 865-175 592) versus 245 244 (95%CI: 224 688 -265 799).

BackgroundThe 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. MethodsPatients 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. FindingsBetween 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. InterpretationIn patients hospitalised with COVID-19, dexamethasone (at a dose of 6mg daily in hypoxic patients), tocilizumab (in hypoxic patients with CRP [&ge;]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. FundingUK 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).

Early data indicated that infection with Omicron BA.1 sub-lineage was associated with a lower risk of hospitalisation and severe illness, compared to Delta infection. Recently, the BA.2 sub-lineage has increased in many areas globally. We aimed to assess the severity of BA.2 infections compared to BA.1 in South Africa. We performed data linkages for (i) national COVID-19 case data, (ii) SARS-CoV-2 laboratory test data, and (iii) COVID-19 hospitalisations data, nationally. For cases identified using TaqPath COVID-19 PCR, infections were designated as S-gene target failure (SGTF, proxy for BA.1) or S-gene positive (proxy for BA.2). Disease severity was assessed using multivariable logistic regression models comparing individuals with S-gene positive infection to SGTF-infected individuals diagnosed between 1 December 2021 to 20 January 2022. From week 49 (starting 5 December 2021) through week 4 (ending 29 January 2022), the proportion of S-gene positive infections increased from 3% (931/31,271) to 80% (2,425/3,031). The odds of being admitted to hospital did not differ between individuals with S-gene positive (BA.2 proxy) infection compared to SGTF (BA.1 proxy) infection (adjusted odds ratio (aOR) 0.96, 95% confidence interval (CI) 0.85-1.09). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ for individuals with S-gene positive infection compared to SGTF infection (aOR 0.91, 95%CI 0.68-1.22). These data suggest that while BA.2 may have a competitive advantage over BA.1 in some settings, the clinical profile of illness remains similar.

BackgroundCoronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2, has led to significant global mortality and morbidity. Until now, no treatment has proven to be effective in COVID-19. To explore whether the use of remdesivir, initially an experimental broad-spectrum antiviral, is effective in the treatment of hospitalized patients with COVID-19, we conducted a systematic review and meta-analysis of randomized, placebo-controlled trials investigating its use. MethodsA rapid search of the MEDLINE and EMBASE medical databases was conducted for randomized controlled trials. A systematic approach was used to screen, abstract, and critically appraise the studies. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method was applied to rate the certainty and quality of the evidence reported per study. ResultsTwo RCTs studies were identified (n=1,299). A fixed-effects meta-analysis revealed reductions in mortality (RR=0.69, 0.49 to 0.99), time to clinical improvement (3.95 less days, from 3.86 days less to 4.05 less days), serious adverse events (RR=0.77, 0.63 to 0.94) and all adverse events (RR=0.87, 0.79 to 0.96). ConclusionIn this rapid systematic review, we present pooled evidence from the 2 included RCT studies that reveal that remdesivir has a modest yet significant reduction in mortality and significantly improves the time to recovery, as well as significantly reduced risk in adverse events and serious adverse events. It is more than likely that as an antiviral, remdesivir is not sufficient on its own and may be suitable in combination with other antivirals or treatments such as convalescent plasma. Research is ongoing to clarify and contextual these promising findings.

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.

IntroductionRespiratory Syncytial Virus (RSV) is a major cause of morbidity in older adults. With the emergence of the coronavirus disease 2019 (COVID-19) and the subsequent changes in respiratory viral circulation, it is crucial to reassess RSV-associated healthcare burden in adults. This study assessed RSV-associated healthcare burden in adults in six European countries before and during the COVID-19 pandemic. MethodsWe conducted a retrospective analysis using national hospital admissions data from Denmark, England, Finland, the Netherlands, Scotland, and regional surveillance data from the Valencia region (Spain). We included patients aged [&ge;]18 years hospitalised for respiratory tract infections (RTIs) from 2016 to 2023. We assessed RSV-coded and laboratory-confirmed hospitalisations, intensive care unit (ICU) admissions, in-hospital length of stay (LOS), and mortality. ResultsRSV-associated hospitalisations significantly reduced during the 2020/2021 season across all countries, coinciding with strict COVID-19 preventive measures, but resurged in subsequent seasons. We observed the highest hospitalisation rates in adults aged [&ge;]85 years. RSV-coded hospitalisations were found to underestimate the true burden when compared with laboratory-confirmed cases. Underestimation factors ranged from 1.1 to 4.3 times across countries. No significant differences were observed in LOS or ICU admission rates for RSV-associated hospitalisations compared to RTIs. DiscussionOur findings underscore the complex epidemiology of RSV in older adults. The differences between RSV-coded and laboratory-confirmed cases highlight the critical need for improved surveillance and diagnostic practices to better assess the true burden. Our findings could be vital for guiding public health strategies, particularly with the recent introduction of RSV vaccines for older adults.

BackgroundA global comprehensive assessment of influenza-associated hospitalization and mortality across diverse populations and geographical settings is currently lacking. To support an update of WHO influenza clinical guidelines, this systematic review and meta-analysis evaluated the baseline risks of hospitalization and all-cause mortality in patients with seasonal, pandemic, or zoonotic influenza. MethodsWe systematically searched Medline, Embase, CENTRAL, CINAHL, and Global Health for studies published through 26 October 2023, that reported hospitalization and/or mortality among patients with laboratory-confirmed influenza. Paired reviewers independently identified studies, extracted data, and assessed the risk of bias. We performed inverse variance method fixed effects model meta-analyses to summarize the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We registered the protocol with PROSPERO, CRD42023456645. FindingsOf 30054 records, 355 studies with 18,640,366 patients (mean age 0.1 to 87.9 years) proved eligible. The hospitalization rate was 1.01% (95%CI 1% to 1.01%; moderate certainty) for patients with seasonal or pandemic influenza and 93.72% (95%CI 90.12% to 96.58 %; low certainty) for patients with zoonotic influenza. The all-cause mortality rate was 0.23% (95%CI 0.22% to 0.24%; high certainty) for patients with non-severe seasonal or pandemic influenza, 4.15% (95%CI 4.10% to 4.20%; moderate certainty) for patients with severe seasonal or pandemic influenza, and 38.72% (95%CI 36.79% to 40.66%; moderate certainty) for patients with zoonotic influenza. InterpretationThis review estimated a hospitalization rate of 1.01% for seasonal or pandemic influenza and all-cause mortality rates of 0.23% for non-severe seasonal or pandemic influenza, 4.15% for severe seasonal or pandemic influenza, and 38.72% for severe zoonotic influenza. FundingWorld Health Organization to McMaster University in 2023. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSA comprehensive understanding of influenza-associated hospitalization and mortality rates is essential for guiding effective prevention and control strategies and formulating evidence-based clinical practice guidelines and policies. Previous systematic reviews and meta-analyses have investigated influenza-associated hospitalization and mortality rates, but they have often been limited by their focus on a specific strain of influenza, particular patient subgroups, or individual countries, or by a lack of assessment of the certainty of evidence. A global comprehensive assessment of influenza-associated hospitalization and mortality rates across diverse strains, populations, and geographical settings is currently lacking. Added value of this studyWe found a hospitalization rate of 1.01% for seasonal or pandemic influenza and all-cause mortality rates of 0.23% for non-severe seasonal or pandemic influenza, 4.15% for severe seasonal or pandemic influenza, and 38.72% for zoonotic influenza. Among severe seasonal or pandemic influenza cases, patients aged [&ge;]65 years (8.31%) had a higher all-cause mortality rate than those aged 0-14 years (0.76%) and 15-64 years (6.50%). Implications of all the available evidenceOur study provides a comprehensive assessment of the global evidence regarding hospitalization and mortality rates among influenza patients. Our findings highlight the critical need for distinct clinical and public health strategies tailored to influenza type and severity.

Black and minority ethnic groups were at raised risk of dying from COVID-19 during the first few months of the COVID-19 epidemic in England. We aimed to investigate whether ethnic inequalities in COVID-19 deaths were similar in the more recent "second wave" of the epidemic. Working on behalf of NHS England, we used primary care and linked ONS mortality data within the OpenSAFELY platform. All adults in the database at 1st September 2020 and with at least 1 year of prior follow-up and a record of ethnicity were included. The outcome was COVID-19-related death (death with COVID-19 listed as a cause of death on the death certificate). Follow-up was to 9th November 2020. Hazard ratios for ethnicity were calculated using Cox regression models adjusted for age and sex, and then further adjusted for deprivation. 13,223,154 people were included. During the study period, people of South Asian ethnicity were at higher risk of death due to COVID-19 than white people after adjusting for age and sex (HR = 3.47, 95% CI 2.99-4.03); the association attenuated somewhat on further adjustment for index of multiple deprivation (HR = 2.86, 2.46-3.33, Table 2). In contrast with the first wave of the epidemic, we found little evidence of a raised risk in black or other ethnic groups compared to white (HR for black vs white = 1.28, 0.87-1.88 adjusted for age and sex; and 1.01, 0.69-1.49 further adjusted for deprivation). Our findings suggest that ethnic inequalities in the risk of dying COVID-19-related death have changed between the first and early second wave of the epidemic in England. O_TBL View this table: org.highwire.dtl.DTLVardef@987a5org.highwire.dtl.DTLVardef@1a8a141org.highwire.dtl.DTLVardef@1f2de56org.highwire.dtl.DTLVardef@1e2f9b8org.highwire.dtl.DTLVardef@78bfcc_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 2:C_FLOATNO O_TABLECAPTIONAssociation between ethnicity and COVID-19 death 1st Sept - 9th Nov 2020 C_TABLECAPTION C_TBL

BackgroundWe evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19. MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0{middle dot}87; 95% CI 0{middle dot}77-0{middle dot}98; p=0{middle dot}026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes. InterpretationIn patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

The re-emergence of the high pathogenicity avian influenza virus (HPAIV) subtype H5N1 in the United Kingdom in 2021-2022 has caused unprecedented epizootic events in wild birds and poultry. During the summer of 2022 there was a shift in virus transmission dynamics resulting in increased HPAIV infection in seabirds and consequently a profound impact on seabird populations. To understand the pathological impact of HPAIV in seabirds, we have evaluated the virus distribution and associated pathological changes in the tissues of great skua (Stercorarius skua, n=8), long tailed skua (Stercorarius longicaudus, n=1), European herring gull (Larus argentatus, n=5), and black-headed gull (Chroicocephalus ridibundus, n=4). Grossly there was gizzard ulceration in one great skua and pancreatic necrosis in four herring gulls, which were confirmed for virus infection in situ by immunohistochemistry. Microscopical analysis revealed neuro-, pneumo-, lymphoidand cardiotropism of HPAIV H5N1, with the most common virus-associated pathological changes being pancreatic and splenic necrosis. Examination of the reproductive tract of the great skua revealed HPAIV-associated oophoritis and salpingitis, and virus replication within the oviductal epithelium. Across the birds, epitheliotropism was evident in the intestine, nasal turbinate, and trachea. This was, in contrast, not observed in the 2021 summer mortality event in great skuas and may be significant for the disease epidemiology observed in 2022. The emergence of HPAIV in seabirds, particularly during summer 2022, has challenged the dogma of HPAIV dynamics, posing a significant threat to wild bird life with potential implications to the reproductive performance of seabirds of conservation importance.

BackgroundDuring pandemics, early outpatient treatments reduce the health system burden. Randomized controlled trials (RCTs) in COVID-19 outpatients have tested therapeutic agents, but no RCT or systematic review has been conducted comparing the efficacy of the main outpatient treatment classes to each other. We aimed in this systematic review of outpatient RCTs in COVID-19 to compare hospitalisation rate reductions with four classes of treatment: convalescent plasma, monoclonal antibodies, small molecule antivirals and repurposed drugs. MethodsWe conducted a systematic review and meta-analysis of all COVID-19 outpatient RCTs that included the endpoint of progression to hospitalisation. We assembled, from multiple published and preprint databases, participant characteristics, hospitalisations, resolution of symptoms and mortality from January 2020 to May 21, 2023. The risk of bias from COVID-NMA was incorporated into the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We measured heterogeneity with I2. Meta-analysis by a random or fixed effect model dependent on significant heterogeneity (I2 >50%) was performed. The protocol was registered in PROSPERO, CRD42022369181. FindingsThe search identified 281 studies of which 54 RCTs for 30 diverse interventions were included in the final analysis. These trials, performed largely in unvaccinated cohorts during pre-Omicron waves, focused on populations with at least one COVID-19 hospitalisation risk factor. Grouping by class, monoclonal antibodies (OR=0.31 [95% CI=0.24-0.40]) had highest efficacy, followed by COVID-19 convalescent plasma (CCP) (OR=0.69 [95% CI=0.53 to 0.90]) and small molecule antivirals (OR=0.78 [95% CI=0.48-1.33]) for hospital reduction. Repurposed drugs (OR=0.82 [95% CI-0.72-0.93]) had lower efficacy. InterpretationInasmuch as omicron sublineages (XBB and BQ.1.1) are now resistant to monoclonal antibodies, oral antivirals are the preferred treatment in outpatients where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised. FundingUS Department of Defense and National Institute of Health Research in context Evidence before this studyWe systematically searched the published and preprint data bases for outpatient randomized clinical trials of treatment of COVID-19 disease with hospitalisation as an endpoint. Previous systematic reviews and meta-analyses have confined the reviews to specific classes such as convalescent plasma, monoclonal antibodies, small molecule antivirals or repurposed drugs. Few comparisons have been made between these therapeutic classes. The trials took place both in the pre-vaccination and the vaccination era, spanning periods with dominance of different COVID variants. We sought to compare efficacy between the four classes of treatments listed above when used in outpatient COVID-19 patients as shown in randomized, placebo-controlled trials. Added value of this studyThis systematic review and meta-analysis brings together trials that assessed hospitalisation rates in diverse COVID-19 outpatient populations varying in age and comorbidities, permitting us to assess the efficacy of interventions both within and across therapeutic classes. While heterogeneity exists within and between these intervention classes, the meta-analysis can be placed in context of trial diverse populations over variant time periods of the pandemic. At present most of the world population has either had COVID-19 or been vaccinated with a high seropositivity rate, indicating that future placebo-controlled trials will be limited because of the sample sizes required to document hospitalisation outcomes. Implications of all the available evidenceNumerous diverse therapeutic tools need to be ready for a resilient response to changing SARS-CoV-2 variants in both immunocompetent and immunocompromised COVID-19 outpatient populations. To date few head-to-head randomized controlled trials (RCTs) has compared treatment options for COVID-19 outpatients, making comparisons and treatment choices difficult. This systematic review compares outcomes among RCTs of outpatient therapy for COVID-19, taking into account time between onset of symptoms and treatment administration. We found that small-chemical antivirals, convalescent plasma and monoclonal antibodies had comparable efficacy between classes and amongst interventions within the four classes. Monoclonals have lost efficacy with viral mutation, and chemical antivirals have contraindications and adverse events, while intravenous interventions like convalescent plasma or remdesivir remain resilient options for the immunocompromised, and, in the case of CCP, in resource constrained settings with limited availability of oral drugs.

BackgroundA COVID-19 hospital guideline was implemented across all acute hospitals in Wales in March 2020, and data was collected across the first 3 Waves of the pandemic. We aimed to observe trends in mortality with a focus on ward-based outcomes. MethodsRetrospective case-note review of data for adults admitted to hospital with community acquired COVID-19 between March 2020 and December 2021 Results5887 cases were analysed. Overall mortality from COVID-19 fell from 31.5% in Wave 1 to 22.6% in Wave 2 to 18.8% in Wave 3 (p<0.01). Ward mortality for patients on oxygen fell from 34.6% in Wave 1 to 19.5% in Wave 2 (p<0.01) to 14.3% in Wave 3 (p=0.03). For those managed with CPAP/HFNO on wards, the mortality reduced from 58.9% in Wave 1 to 45.6% in Wave 2 (p=0.05) and further to 42.6% in Wave 3 (p=0.03). The mortality for patients managed with CPAP/HFNO on ICU reduced from 43.8% in Wave 1 to 24.7% in Wave 2 (p=0.12) and further to 20.4% in Wave 3 (p=0.03). Patients receiving CPAP/HFNO on the wards were on average 11 years older and more co-morbid than those on ICU. In Wave 3, 77% of hospital admissions with COVID-19 were unvaccinated with mortality rates of 20.5% compared to 4.8% mortality in those who had received three vaccines (p<0.01). ConclusionsThere were successive reductions in mortality in inpatients over the 3 Waves reflecting new treatments and better management of complications. The impact of vaccines on outcomes of hospitalised patients was notable in Wave 3. Key Messages What is the key question?What are the outcomes from COVID-19 pneumonitis managed on respiratory wards and how have they changed over successive waves of the pandemic? What is the bottom line?Significant improvements in mortality over time were noted in patients requiring oxygen, CPAP or HFNO. Patients managed with these modalities in ICU had lower mortality rates than those on wards, but they were younger and less co-morbid. In wave 3 patients were largely unvaccinated with higher mortality rates than those who were fully vaccinated. Why read on?This is a national study including all acute hospitals in Wales over three waves of the pandemic from March 2020 to December 2021. It is the first paper to demonstrate at a national level the outcomes of ward management of COVID pneumonitis over successive waves.