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Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Summary: Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.

Abstract Sepsis results in complex alterations to the immune system. Our understanding of how these alterations in immune responses could help characterize extreme immune phenotypes, identify biomarkers with the ability to stratify patients for therapeutic interventions, surrogates in the causal pathway of clinical end-points, and treatable traits are still rudimentary. A methodologically rigorous, consensus-based approach should enrich sepsis immune subpopulations to increase the probability of successful trials.

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Medical progress is reflected in the advance from broad clinical syndromes to mechanistically coherent diagnoses. By this metric, research in sepsis is far behind other areas of medicine-the word itself conflates multiple different disease mechanisms, whilst excluding noninfectious syndromes (e.g., trauma, pancreatitis) with similar pathogenesis. New technologies, both for deep phenotyping and data analysis, offer the capability to define biological states with extreme depth. Progress is limited by a fundamental problem: observed groupings of patients lacking shared causal mechanisms are very poor predictors of response to treatment. Here, we discuss concrete steps to identify groups of patients reflecting archetypes of disease with shared underlying mechanisms of pathogenesis. Recent evidence demonstrates the role of causal inference from host genetics and randomised clinical trials to inform stratification analyses. Genetic studies can directly illuminate drug targets, but in addition they create a reservoir of statistical power that can be divided many times among potential patient subgroups to test for mechanistic coherence, accelerating discovery of modifiable mechanisms for testing in trials. Novel approaches, such as subgroup identification in-flight in clinical trials, will improve efficiency. Within the next decade, we expect ongoing large-scale collaborative projects to discover and test therapeutically relevant sepsis archetypes., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

The interplay between the immune system, coagulation, and endothelium is critical in regulating the host response to infection. However, in sepsis and other critical illnesses, a dysregulated immune response can lead to excessive alterations in these mechanisms, resulting in coagulopathy, endothelial dysfunction, and multi-organ dysfunction. This review aims to provide a comprehensive analysis of the pathophysiological mechanisms that govern the complex interplay between immune dysfunction, endothelial dysfunction, and coagulation in sepsis. It emphasises clinical significance, evaluation methods, and potential therapeutic interventions. Understanding these mechanisms is essential for developing effective treatments that can modulate the immune response, mitigate thrombosis, restore endothelial function, and ultimately improve patient survival., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: International guidelines recommend IV crystalloid as the primary fluid for sepsis resuscitation, with 5% human albumin solution (HAS) as the second line. However, it is unclear which fluid has superior clinical effectiveness. We conducted a trial to assess the feasibility of delivering a randomized controlled trial comparing balanced crystalloid against 5% HAS as sole early resuscitation fluid in patients with sepsis presenting to hospital., Design: Multicenter, open, parallel-group randomized feasibility trial., Setting: Emergency departments (EDs) in 15 U.K. National Health Service (NHS) hospitals., Patients: Adult patients with sepsis and a National Early Warning Score 2 greater than or equal to five requiring IV fluids withing one hour of randomization., Interventions: IV fluid resuscitation with balanced crystalloid or 5% HAS for the first 6 hours following randomization., Measurements and Main Results: Primary feasibility outcomes were recruitment rate and 30-day mortality. We successfully recruited 301 participants over 12 months. Mean ( sd ) age was 69 years (± 16 yr), and 151 (50%) were male. From 1303 participants screened; 502 participants were potentially eligible and 300 randomized to receive trial intervention with greater than 95% of participants receiving the intervention. The median number of participants per site was 19 (range, 1-63). Thirty-day mortality was 17.9% ( n = 53). Thirty-one participants died (21.1%) within 30 days in the 5% HAS arm, compared with 22 participants (14.8%) in the crystalloid arm (adjusted odds ratio, 1.50; 95% CIs, 0.84-2.83)., Conclusions: Our results suggest it is feasible to recruit critically ill patients to a fluid resuscitation trial in U.K. EDs using 5% HAS as a primary resuscitation fluid. There was lower mortality in the balanced crystalloid arm. Given these findings, a definitive trial is likely to be deliverable, but the point estimates suggest such a trial would be unlikely to demonstrate a significant benefit from using 5% HAS as a primary resuscitation fluid in sepsis., Competing Interests: Dr. Bell is supported by the National Institute of Applied Research Collaboration Northwest London. Dr. Gray’s, Ms. Oatey’s, Dr. Irvine’s, Mr. Kennel’s, Dr. Norrie’s, Dr. Walsh’s, and Dr. Hall’s institutions received funding from the John Moulton Charitable Trust. Dr. Gray, Ms. Grahamslaw, and Dr. Appelboam received support for article research from the John Moulton Charitable Trust. Ms. Oatey disclosed work for hire. Dr. Cafferkey’s institution received funding from the Royal College of Emergency Medicine and the Sepsis FEAT Charity. Dr. Horner’s institution received funding from the National Institute for Health Research (132594). Mr. Skipworth received funding from Helsinn, Faraday Pharmaceuticals, Actimed Therapeutics, and Pfizer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Competing Interests: AB declares that she receives funding from the Wellcome Innovations Flagship Collaboration for Implementation and Training in Critical Care in Asia and Africa (224048/Z/21/Z). MS-H declares that he received a National Institute of Health and Care Research (NIHR) Clinician Scientist Award (NIHR-CS-2016–16–011) between February, 2017, and January, 2023, to study health-care burden among sepsis survivors; is a Director of Research for the Intensive Care Society, member of the Medical Research Council (MRC) and NIHR Efficacy and Mechanism Evaluation Programme (EME), Chair of the EME-NIHR Advanced Fellowship Committee, council member of the International Sepsis Forum; receives funding from the NIHR, Wellcome Trust, and MRC; and has served on advisory boards (either directly or indirectly through the International Sepsis Forum) for Biotest, Endpoint Health, Janssen, Pfizer, Aurobac, GSK, and Santersus, with payments received to the institutional research funds. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health and Social Care.

Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children., (© 2024. The Author(s).)

Molecular changes in lymphocytes following SARS-CoV-2 vaccination are incompletely understood. We hypothesized that studying the molecular (transcriptomic, epigenetic, and T cell receptor (TCR) repertoire) changes in CD4 + T cells following SARS-CoV-2 vaccination could inform protective mechanisms and refinement of future vaccines. We tested this hypothesis by reporting alterations in CD4 + T cell subsets and molecular features of CD4 + naïve and CD4 + central memory (CM) subsets between the unvaccinated and vaccinated groups. Compared with the unvaccinated, the vaccinated had higher HLA-DR expression in CD4 + T subsets, a greater number of differentially expressed genes (DEGs) that overlapped with key differentially accessible regions (DARs) along the chromatin linked to inflammasome activation, translation, regulation (of apoptosis, inflammation), and significant changes in clonal architecture beyond SARS-CoV-2 specificity. Several of these differences were more pronounced in the CD4 + CM subset. Taken together, our observations imply that the COVID-19 vaccine exerts its protective effects via modulation of acute inflammation to SARS-CoV-2 challenge.

Acute respiratory distress syndrome (ARDS) is characterized by a dysregulated immune response to infection or injury. This framework has driven long-standing interest in immunomodulatory therapies as treatments for ARDS. In this narrative review, we first define what constitutes a dysregulated immune response in ARDS. In this context, we describe the rationale and available evidence for immunomodulatory therapies studied in randomized controlled trials of ARDS patients to date. Finally, we address factors that have contributed to the failure to develop therapies in the past and highlight current and future developments designed to address them., Competing Interests: Disclosure J E. Millar has no conflicts to disclose. T H. Craven has no conflicts to disclose. M Shankar-Hari is Chief Investigator of trial of GuARDS trial (https://www.isrctn.com/ISRCTN15076735). M Shankar-Hari was supported by the National Institute for Health Research Clinician Scientist Award (CS-2016–16–011; 2017–2023). M Shankar-Hari reported receiving grants from the Chief Scientist Office Scotland, the National Institute for Health and Care Research, United Kingdom (Efficacy and Mechanism Evaluation and Health Technology Assessment programs), the UK Medical Research Council, United Kingdom, Canadian Institute For Health Research, and the Huo Foundation. M Shankar-Hari highlights industry support for TRAITS Research Programme (a Chief Scientists Office, Scotland) funded time critical precision medicine in adult critically ill patients (TRAITS Program) https://traits-trial.ed.ac.uk. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the National Institute for Health Research or the Department of Health and social care., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sepsis pathobiology is complex. Heterogeneity refers to the clinical and biological variation within sepsis cohorts. Sepsis subtypes refer to subpopulations within sepsis cohorts derived based on these observable variations and latent features. The overarching goal of such endeavors is to enable precision immunomodulation. However, we are yet to identify immune endotypes of sepsis to achieve this goal. The sepsis subtyping field is just starting to take shape. The current subtypes in the literature do not have a core set of shared features between studies. Thus, in this narrative review, we reason that there is a need to a priori state the purpose of sepsis subtyping and minimum set of features that would be required to achieve the goal of precision immunomodulation for future sepsis., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown., Methods: Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease ( i.e. , asthma, COPD or bronchiectasis) were compared to the non-airways group., Results: A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p<0.001), had higher burden of anxiety (29.1% versus 22.0%, p=0.002), depression (31.2% versus 24.7%, p=0.006), higher percentage of impaired mobility using short physical performance battery ≤10 (57.4% versus 45.2%, p<0.001) and 27% had a new disability (assessed by the Washington Group Short Set on Functioning) versus 16.6%, p=0.014. HRQoL assessed using EQ-5D-5L Utility Index was lower in the airways group (mean±SD 0.64±0.27 versus 0.73±0.25, p<0.001). Burden of breathlessness, fatigue and cough measured using a study-specific tool was higher in the airways group., Conclusion: Individuals with pre-existing airway diseases hospitalised due to COVID-19 were less likely to feel fully recovered, had lower physiological performance measurements, more burden of symptoms and reduced HRQoL up to 1 year post-hospital discharge., Competing Interests: Conflict of interest: J.R. Hurst has received support to attend meetings, research grants, and personal payment and payment to his employer from pharmaceutical companies that make medicines to treat airways diseases. J.K. Quint reports grants from Industrial Strategy Challenge Fund, the Medical Research Council, Health Data Research, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Asthma+Lung UK and AstraZeneca (AZ), and consulting fees from GSK, Evidera, Chiesi, AZ and Insmed outside the submitted work. P.E. Pfeffer reports grants from NIHR and GSK, Honoraria payments for lectures from AZ, GSK, Sanofi and Chiesi and travel fees from AZ, GSK, Sanofi outside the submitted work. N.J. Greening reports grants from GSK and BioAge, and personal fees and travel grants from Genentech, Roche, Chiesi, AZ, GSK, Pulmonx and Chiesi outside the submitted work. J.D. Chalmers is an associate editor of this journal. A. Horsley reports grants from UKRI, NIHR and NIHR Manchester BRC during the conduct of this study and unenumerated role as the chair of NIHR Translational Research Collaboration. A. Sheikh has served on AZ's thrombotic thrombocytopenic taskforce, and on a number of UK and Scottish Government COVID-19 advisory bodies; all these roles were unremunerated. B. Raman reports grant from BHF Oxford CRE and speaker fees from Axcella Therapeutics. R.A. Evans reports grants from UKRI/MRC, DHSC/NIHR, Wolfson Foundation and Genentec/Roche during the conduct of this study, travel and speaker fees from AZ/Evidera, Boehringer Ingelheim (BI), Moderna and Chiesi, and unremunerated leadership roles in ERS/ATS outside the submitted work. C.E. Brightling declares that their institute was awarded a grant from UKRI/NIHR to complete this work; the author reports grants from GSK, AZ, Sanofi, Regeneron, BI, Chiesi, Novartis, Roche, Genentech, Mologic and 4DPharma; and consultancy fees paid to their institution from GSK, AZ, Sanofi, BI, Chiesi, Novartis, Roche, Genentech, Mologic, 4DPharma and Areteia. A. De Soyza declares receiving personal consulting fees and travel grants from AZ, Bayer, GSK, Chiesi, Novartis, Pfizer, Insmed, Gilead and 30T outside the submitted work. All other authors declare no competing interests., (Copyright ©The authors 2024.)

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. To impact clinical care, identification of subpopulations must do more than differentiate prognosis. It must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway, but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry, and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields.

Rationale: Heterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported., Objectives: We investigated whether inflammatory clusters based on cytokine protein abundance were seen in sepsis, and the relationships with previously described transcriptomic subphenotypes., Methods: Hierarchical cluster and latent class analysis were applied to an observational study (UK Genomic Advances in Sepsis (GAinS)) (n=124 patients) and two clinical trial datasets (VANISH, n=155 and LeoPARDS, n=484) in which the plasma protein abundance of 65, 21, 11 circulating cytokines, cytokine receptors and regulators were quantified. Clinical features, outcomes, response to trial treatments and assignment to transcriptomic subphenotypes were compared between inflammatory clusters., Measurements and Main Results: We identified two (UK GAinS, VANISH) or three (LeoPARDS) inflammatory clusters. A group with high levels of pro-inflammatory and anti-inflammatory cytokines was seen that was associated with worse organ dysfunction and survival. No interaction between inflammatory clusters and trial treatment response was found. We found variable overlap of inflammatory clusters and leucocyte transcriptomic subphenotypes., Conclusions: These findings demonstrate that differences in response at the level of cytokine biology show clustering related to severity, but not treatment response, and may provide complementary information to transcriptomic sepsis subphenotypes., Trial Registration Number: ISRCTN20769191, ISRCTN12776039., Competing Interests: Competing interests: ACG reports that he has received speaker fees from Orion Corporation, Orion Pharma and Amomed Pharma. He has consulted for Ferring Pharmaceuticals, Tenax Therapeutics and received grant support from Orion Corporation, Orion Pharma and Tenax Therapeutics with funds paid to his institution. DFMcA reports grants to his institution from the MRC/NIHR EME programme for the conduct of this work. Outside the submitted work, DFMcA reports personal fees for consultancy from Bayer, GSK, Boehringer Ingelheim, Eli Lilly, Novartis and SOBI and for being a member of the data monitoring and ethics committee for Vir Biotechnology and Faron studies and as an educational seminar speaker for GSK. DFMcA has received funding to his institution from the NIHR, MRC, Wellcome Trust, Innovate UK, Northern Ireland Health and Social Care Research and Development Office, Novavax and Randox. In addition, DFMcA is a named inventor on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution. DFMcA was a Director of Research for the Intensive Care Society and is the Director for the MRC/NIHR EME Programme. MS-H is a Director of Research for the Intensive Care Society, Member of the MRC/NIHR EME Programme, UK Representative of the ESICM and on the Board of International Sepsis Forum. MS-H declares that he has done advisory board activity either directly or indirectly through International Sepsis Forum for Biotest, Endpoint Health, Janssen, Pfizer and Santersus, with payments going into the unrestricted institutional research funds. CMO’K reports grants to her institution from the MRC/NIHR EME programme for the conduct of this work. Outside the submitted work, CMO’K reports personal fees for consultancy from INSMED and for committee membership for the California Institute of Regenerative Medicine. Outside of the submitted work, CMO'K has received research funding from MRC, Wellcome Trust, NIHSC R&D and Innovate UK. CMO'K’s spouse has received personal fees for consultancy outside of the submitted work from Bayer, GSK, Boehringer Ingelheim, Eli Lilly, Novartis and SOBI and fees for being a member of the data monitoring and ethics committee for Vir Biotechnology and Faron studies and as an educational seminar speaker for GSK. CMO'K’s spouse is a named inventor on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution. JCK reports a grant to his institution from the Danaher Beacon Programme for work on RNA biomarker point-of-care test development but this did not fund the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objectives: We hypothesized that the immunosuppressive effects associated with antibiotics, sedatives, and catecholamines amplify sepsis-associated immune suppression through mitochondrial dysfunction, and there is a cumulative effect when used in combination. We thus sought to determine the impact of the exemplar drugs ciprofloxacin, propofol, and norepinephrine, used alone and in combination, at clinically relevant concentrations, on the ex vivo functionality of peripheral blood mononuclear cells (PBMCs) drawn from healthy, infected, and septic individuals., Design: In vitro/ex vivo investigation., Setting: University laboratory., Subjects: Healthy volunteers, infected (nonseptic) patients in the emergency department, and septic ICU patients., Interventions: PBMCs were isolated from these subjects and treated with ciprofloxacin (100 µg/mL), propofol (50 µg/mL), norepinephrine (10 µg/mL), or all three drugs combined, with and without lipopolysaccharide (100 ng/mL) for 6 or 24 hours. Comparison was made between study groups and against untreated cells. Measurements were made of cell viability, cytokine production, phagocytosis, human leukocyte antigen-DR (HLA-DR) status, mitochondrial membrane potential, mitochondrial reactive oxygen species production, and oxygen consumption. Gene expression in immune and metabolic pathways was investigated in PBMCs sampled from healthy volunteers coincubated with septic serum., Measurements and Results: Coincubation with each of the drugs reduced cytokine production and phagocytosis in PBMCs isolated from septic patients, and healthy volunteers coincubated with septic serum. No effect was seen on HLA-DR surface expression. No cumulative effects were seen with the drug combination. Sepsis-induced changes in gene expression and mitochondrial functionality were not further affected by addition of any of the drugs., Conclusion: Drugs commonly used in critical care lead to significant immune dysfunction ex vivo and enhance sepsis-associated immunosuppression. Further studies are required to identify underlying mechanisms and potential impact on patient outcomes., Competing Interests: Dr. Melis’ institution received funding from the European Union’s Horizon 2020 research and innovation program (number 676129). Dr. Singer’s institution received funding from Biotest, Roche, and Deltex Medical; they received funding from Volition, Calbiochem, AOP Pharma, Aptarion, Matisse, NewB, Paion, Pfizer, Biomerieux, and Hemotune. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes., Competing Interests: Declaration of interests SC reports personal fees from Pfizer, AstraZeneca, Swedish Orphan Biovitrum (SOBI), GSK, and Merck Sharp & Dohme (MSD). MK reports personal fees from ARTCLINE, Atriva, AOP pharma, Inflammatix, and 4TEEN4; and discloses institutional funding from MediSieve, 4TEEN4, Adrenomed, Spinghotec, Cytosorbents, and Inflammatix. MAW reports personal fees from MSD, Gilead, Pfizer, Shionogi, Eumedica, Coulter, Biotest, Sedana, SOBI, and Böhringer; and patent EPA17198330 “Delta-Like Ligand 1 for diagnosing severe infections”. IM-L reports personal fees from MSD, Pfizer, and Gilead. GL reports personal fees from SOBI. EJG-B discloses institutional funding from Abbott, bioMérieux, InflaRx, Johnson & Johnson, MSD, SOBI, XBiotech, Horizon 2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy”, Horizon 2020 European Grants ImmunoSep and RISCinCOVID, and Horizon Health European Grants EPIC-CROWN-2. MSW has received unrestricted funding from Sartorius and reports personal fees from GRIFOLS, Gilead, and Amomed. MO is president of the European Shock Society and Deputy Editor of Intensive Care Medicine Experimental. JFB-M reports personal fees from GSK, PROFARMA programme, Ministry of Industry Spain, GSK-MODUS programme, and Inflammatix; and patents on the following biomarkers related to management of severe infections: PCT/EP2018/064363 “MMP-8 as a marker for identifying infectious disease”, PCT/EP2018/052499 “Pro-ADM as marker indicating an adverse event”, WO2020030745 “Pro-ADM for prognosing the risk of a medical condition requiring hospitalisation in patients with symptoms of infectious disease”, and EP20383140.9 “In vitro method for predicting mortality in COVID-19 patients” (based on detecting N-antigenaemia of SARS-CoV-2 in plasma). JCS discloses institutional funding from Orion Pharma, Abbott Nutrition International, B Braun Medical, CSEM, Edwards Lifesciences Services, Kenta Biotech, Maquet Critical Care, Omnicare Clinical Research, Nestle, Pierre Fabre Pharma, Pfizer, Bard Medica, Abbott, Anandic Medical Systems, Pan Gas Healthcare, Bracco, Hamilton Medical, Fresenius Kabi, Getinge Group Maquet, Dräger, Teleflex Medical, GSK, MSD, Eli Lilly and Company, Baxter, Astellas, AstraZeneca, CSL Behring, Novartis, Covidien, Philips Medical, Prolong Pharmaceuticals and Nycomed, Phagenesis, and Cytel, outside of the submitted work. JCS is Chair of the Clinical Advisory Board of Hemotune. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as altered homoeostasis with pathological disruption of immune-driven resistance, disease tolerance, resilience, and resolution mechanisms. Our proposal highlights opportunities to identify novel treatment targets and could enable successful immunomodulation in the future., Competing Interests: Declaration of interests MS-H is supported by the UK National Institute for Health and Care Research (NIHR) Clinician Scientist Award (CS-2016-16-011; 2017–2023). MPS's laboratory is supported by the Calouste Gulbenkian Foundation, La Caixa Foundation (HR18-00502), Fundação para a Ciência e a Tecnologia (GlucoInfect, 5723/2014; FEDER029411, FEDER/29411/2017; Infectenergy, PTDC/MED-FSL/4681/2020; MalBil, 2022.02426.PTDC), the Oeiras–European Research Council Frontier Research Incentive Awards, SymbNET Research Grants (H2020-WIDESPREAD-2020-5-952537), and Congento (LISBOA-01-0145-FEDER-022170). MPS is an associate member of the Deutsche Forschungsgemeinschaft (DFG) Balance of the Microverse initiative (EXC 2051; 390713860). MB is principal investigator of the DFG Balance of the Microverse initiative (EXC 2051; 390713860). JCK is supported by the Medical Research Council (MR/V002503/1), a Wellcome Trust Investigator Award (204969/Z/16/Z), and Wellcome Trust grants (090532/Z/09/Z and 203141/Z/16/Z) to the Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, and the NIHR Oxford Biomedical Research Centre. JM reports grants from the Canadian Institutes of Health Research and has served as chair of data and safety monitoring boards for AM Pharma and Adrenomed. CWS reports grants from the US National Institutes of Health National Institute of General Medical Sciences, during the conduct of the study, and personal fees from Inotrem and Beckman Coulter, outside of the submitted work. IBM has received funding or consultancy fees from Abbvie, Amgen, Bristol Myers Squibb, Cabaletta, Causeway, Eli Lilly, Evelo, GSK, Janssen, Moonlake, Novartis, Pfizer, and UCB. TvdP has received grants from the EU's Horizon 2020 research and innovation funding programme (grant agreements: Flagellin Aerosol Therapy in Treatment of Drug-resistant Bacterial Pneumonia, 847786; ImmunoSEP, 847422). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rationale: Sepsis is a frequent cause of ICU admission and mortality. Objectives: To evaluate temporal trends in the presentation and outcomes of patients admitted to the ICU with sepsis and to assess the contribution of changing case mix to outcomes. Methods: We conducted a retrospective cohort study of patients admitted to 261 ICUs in the United Kingdom during 1988-1990 and 1996-2019 with nonsurgical sepsis. Measurements and Main Results: A total of 426,812 patients met study inclusion criteria. The patients had a median (interquartile range) age of 66 (53-75) years, and 55.6% were male. The most common sites of infection were respiratory (60.9%), genitourinary (11.5%), and gastrointestinal (10.3%). Compared with patients in 1988-1990, patients in 2017-2019 were older (median age, 66 vs. 63 yr), were less acutely ill (median Acute Physiology and Chronic Health Evaluation II acute physiology score, 14 vs. 20), and more often had genitourinary sepsis (13.4% vs. 2.0%). Hospital mortality decreased from 54.6% (95% confidence interval [CI], 51.0-58.1%) in 1988-1990 to 32.4% (95% CI, 32.1-32.7%) in 2017-2019, with an adjusted odds ratio of 0.64 (95% CI, 0.54-0.75). The adjusted absolute hospital mortality reduction from 1988-1990 to 2017-2019 was 8.8% (95% CI, 5.6-12.1). Thus, of the observed 22.2-percentage point reduction in hospital mortality, 13.4 percentage points (60% of total reduction) were explained by case mix changes, whereas 8.8 percentage points (40% of total reduction) were not explained by measured factors and may be a result of improvements in ICU management. Conclusions: Over a 30-year period, mortality for ICU admissions with sepsis decreased substantially. Although changes in case mix accounted for the majority of observed mortality reduction, there was an 8.8-percentage point reduction in mortality not explained by case mix.

Background: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS., Methods: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality., Results: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality., Conclusions: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS., Competing Interests: Competing interests: PM and RJS are/were clinical training fellows within the Experimental Medicine Initiative to Explore New Therapies (EMINENT) network and receive project funding unrelated to this article from the Medical Research Council and GlaxoSmithKline. PM also receives co-funding by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. RJS receives co-funding by the Cambridge NIHR Biomedical Research Centre. PM reports consultancy fees from SOBI, UCB, Lilly, AbbVie, Boehringer and EUSA Pharma outside the submitted work. KW reports grants from National Institutes of Health, during the conduct of the study. TM reports PhD studentship funding from the Department for the Economy Northern Ireland. RCC reports grants from the Royal Society and the Academy of Medical Sciences during the conduct of the study; personal fees from BioAge Labs, personal fees from ImmVention Therapeutix, outside the submitted work; In addition, RCC has a patent US 10,538,487 licensed to Inflazome Ltd, a patent PCT/IB2017/053059 licensed to Inflazome Ltd and a patent PCT/EP2017/053498 licensed to Inflazome Ltd. AJB reports received funding from the Northern Ireland Health and Social Care Research and Development office for research outside of the submitted work. MS-H reports grants and other from National Institute for Health Research, during the conduct of the study. MS-H is supported by the NIHR Clinician Scientist Award (CS-2016-16-011). AR reports other from Merck, outside the submitted work. CSC reports grants from NIH R35-HL140026, during the conduct of the study; grants and personal fees from Roche/Genentech, grants and personal fees from Bayer, personal fees from Quark Pharmaceuticals, personal fees from Gen1e Life Sciences, personal fees from Vasomune, grants from Quantum Leap Healthcare Collaborative, outside the submitted work. MAM reports grants from Roche Genentec, personal fees from Novartis, personal fees from Johnson and Johnson, personal fees from Gilead Pharmaceuticals, personal fees from Pliant Therapeutics, outside the submitted work. CS is the Director of the EMINENT research training scheme supporting RJS and PM, and reports research funding to her institution from the Wellcome Trust, the Medical Research Council, the NIHR, GlaxoSmithKline, AstraZeneca and the Cambridge NIHR Biomedical Research Centre, all unrelated to this work. CS also reports personal fees for consultancy from Roche, GlaxoSmithKline and AbbVie. RCC reports grants from UKRI-MRC, NIHR-UCLH BRC and GSK, outside the submitted work. DFMA chairs the NIHR and Medical Research Council funding committee for COVID-19 for therapeutics and vaccines. DFMA reports personal fees from consultancy for ARDS for GlaxoSmithKline, Boehringer Ingelheim, and Bayer; in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK and others, all unrelated to this Correspondence. DFMA also has a patent issued to his institution for a treatment for ARDS. DFMA is a Director of Research for the Intensive Care Society and NIHR Efficacy and Mechanism Evaluation Programme Director. CMOK reports grant funding from the Wellcome Trust, MRC, Innovate UK and NIHSC R&D for unrelated work. CMOK reports fees for consultancy from Insmed and for reviews from the California Institute of Regenerative Medicine (CIRM) unrelated to this work. CMOK’s spouse has received consultancy fees from BI, Bayer and GSK unrelated to this work. All other authors declare no competing interests. The views expressed in this manuscript are those of the authors and not necessarily those of the Medical Research Council (MRC), National Health Service, NIHR or Department of Health and Social Care. This study was supported by the UK EME Programme, an MRC and NIHR partnership (08/99/08 and 16/33/01). The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland, the National Institute for Social Care and Health Research in Wales, and the Health and Social Care (HSC) Research and Development Division, Public Health Agency for Northern Ireland. TM is supported by a PhD studentship from the Department for the Economy Northern Ireland. RCC is supported by an Academy of Medical Sciences Springboard Award (SBF005\1104), a Royal Society Research Grant (RGS\R1\201127), and institutional funding from the Wellcome-Wolfson Institute for Experimental Medicine and Queen’s University Belfast., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Platelet function during inflammation is dependent on activation by endogenous nucleotides. Non-canonical signalling via the P2Y 1 receptor is important for these non-thrombotic functions of platelets. However, apart from ADP, the role of other endogenous nucleotides acting as agonists at P2Y 1 receptors is unknown. This study compared the effects of ADP, Ap3A, NAD + , ADP-ribose, and Up4A on platelet functions contributing to inflammation or haemostasis., Experimental Approach: Platelets obtained from healthy human volunteers were incubated with ADP, Ap3A, NAD + , ADP-ribose, or Up4A, with aggregation and fibrinogen binding measured (examples of function during haemostasis) or before exposure to fMLP to measure platelet chemotaxis (an inflammatory function). In silico molecular docking of these nucleotides to the binding pocket of P2Y 1 receptors was then assessed., Key Results: Platelet aggregation and binding to fibrinogen induced by ADP was not mimicked by NAD + , ADP-ribose, and Up4A. However, these endogenous nucleotides induced P2Y 1 -dependent platelet chemotaxis, an effect that required RhoA and Rac-1 activity, but not canonical PLC activity. Analysis of molecular docking of the P2Y 1 receptor revealed distinct differences of amino acid interactions and depth of fit within the binding pocket for Ap3A, NAD + , ADP-ribose, or Up4A compared with ADP., Conclusion and Implications: Platelet function (aggregation vs motility) can be differentially modulated by biased-agonist activation of P2Y 1 receptors. This may be due to the character of the ligand-binding pocket interaction. This has implications for future therapeutic strategies aimed to suppress platelet activation during inflammation without affecting haemostasis as is the requirement of current ant-platelet drugs., Linked Articles: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear., Methods: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2)., Results: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control., Conclusions: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)., (Copyright © 2023 Massachusetts Medical Society.)

Objectives: Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct "high-risk" patients not captured by prior LCA classifications., Design: Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar's test and then tested the correlation between IL-18 and LCA biomarkers using Pearson's exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup., Setting: Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients., Subjects: Six hundred eighty-three patients in SAILS and 511 patients in HARP-2., Interventions: None., Measurements and Main Results: We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17-0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8-6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2-3.8; p = 0.009)., Conclusions: Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts., Competing Interests: Dr. Sinha received funding from the National Heart Lung and Blood Institute as part of the Acute Respiratory Distress Syndrome Network and AstraZeneca ( ClinicalTrials.gov number NCT00979121). Drs. Sinha, Matthay, and Calfee received support for article research from the National Institutes of Health (NIH). Dr. O’Kane’s institution received funding from National Intitute for Health and Care Research (NIHR) Efficacy and Evaluation Mechanism (EME); she received funding from Californian Institute for Regenerative Medicine and Insmed; she disclosed that her spouse has received funding from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lily, Sobi, Vir Biotech, and Faron Pharmaceuticals and disclosed that her spouse holds a patent with Queen’s University (USB962032) and director of the NIHR/Medical Research Council (MRC) EME program and co-director of research for intensive care society of the UK; she received support for article research from the Research Councils UK. Dr. Levitt disclosed the off-label product use of the Experimental use of simvastatin and rosuvastatin for acute respiratory distress syndrome. Dr. Matthay’s institution received funding from Roche-Genentech; received funding from Gilead Therapeutics, Novartis, Quantum Therapeutics, and Johnson and Johnson. Drs. Matthay and Calfee received funding from Gen1Life Science. Dr. Calfee’s institution received funding from the NIH; she received funding from Vasomune, Janssen, Cellenkos, and NGMBio. Dr. McAuley’s institution received funding from the NIHR; he received funding from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis Eli Lilly Vir Biotechnology, Inc SOBI Faron Pharmaceuticals Grants from NIHR, Wellcome Trust, MRC, Innovate UK, NI PHA HSC R&D division, Novavax and Randox; disclosed that his spouse received funding from California Institute for Regenerative Medicine. Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) was supported by the UK EME program, an MRC and NIHR partnership (08/99/08 and 16/33/01). The EME program is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland, the National Institute for Social Care and Health Research in Wales, and the Health and Social Care Research and Development Division, Public Health Agency for Northern Ireland. Dr. Moore was supported by T32 HL129970. Dr. Calfee was supported by R35 HL140026. Dr. Baron was supported by R01 HL112747-01 for the original interleukin-18 analyses. Dr. Shankar-Hari was supported by the NIHR Clinician Scientist Award (CS-2016-16-011). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain., Objective: To determine whether vitamin C improves outcomes for patients with COVID-19., Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents., Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses)., Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility., Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy., Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival., Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Background: Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95)., Methods: ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay., Results: Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70-1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27-1.12; p=0.26), while the OR was 0.31 (80% CI 0.09-1.06) in patents with high baseline serum IL-33/sST2 complex levels., Conclusions: Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies., Competing Interests: Conflict of interest: T. Wilkinson has received grants and fees from AstraZeneca, Bergenbio, Boehringer Ingelheim, Chiesi, GSK, Janssen, Olam, MMH, Synairgen, Union Chimique Belge and Valneva. M. Carroll has received consulting fees from OxDx Ltd and VacciTech Ltd. C. Page has received personal fees from EpiEndo, Eurodrug, Glycosynnovation, Helperby, PrEP Biopharma and Recipharm, and owns stock in Verona Pharma. J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GSK, Gilead Sciences, Insmed and Novartis, has received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Janssen, Novartis and Zambon, and is a member of the Editorial Board of ERJ Open Research. A. De Soyza has received grants and fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Gilead Sciences, GSK and Insmed. S. Siddiqui has received speaker/consultancy fees or research grants from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Novartis and Owlstone Medical. A. Ustianowski has received speaker and/or advisory board fees from AstraZeneca, Gilead Sciences, GSK and Merck/MSD. M.G. Crooks has received grants, fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Pfizer and Philips. A. Horsley has received personal fees from Roche-Genentech and Vertex Pharmaceuticals, and is supported by the NIHR Manchester Biomedical Research Centre. H. Pandya, R. Moate, N. van Zuydam, C. Kell, F. Reid and I.C. Scott are employees of AstraZeneca and may hold stock or stock options in AstraZeneca. G. Griffiths has received funding from Astex, AstraZeneca, BionTech, Bristol Myers Squibb, British Lung Foundation, Cancer Research UK, Celldex, GSK, Heartflow, Janssen-Cilag, NIHR, Novartis, Roche and Unitaid for unrelated academic clinical trials and programme funding, and personal fees from AstraZeneca to deliver continuing professional development training courses. M. Shankar-Hari has received funding from the NIHR, has received a grant from the Chief Scientists Office, Scotland, and reports industry interactions for the TRAITS research programme (www.ed.ac.uk/inflammation-research/clinical-trials/traits-ci-trial). D. Singh has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, Glenmark, Gossamer Bio, GSK, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva Pharmaceuticals, Theravance Biopharma and Verona. L-P. Ho, D. Saralaya, B. Lara, J. Raw, A. Woodcock and B. Mishra have no conflicts of interest to disclose., (Copyright ©The authors 2023.)

Purpose: To determine its cumulative incidence, identify the risk factors associated with Major Adverse Cardiovascular Events (MACE) development, and its impact clinical outcomes., Materials and Methods: This multinational, multicentre, prospective cohort study from the ISARIC database. We used bivariate and multivariate logistic regressions to explore the risk factors related to MACE development and determine its impact on 28-day and 90-day mortality., Results: 49,479 patients were included. Most were male 63.5% (31,441/49,479) and from high-income countries (84.4% [42,774/49,479]); however, >6000 patients were registered in low-and-middle-income countries. MACE cumulative incidence during their hospital stay was 17.8% (8829/49,479). The main risk factors independently associated with the development of MACE were older age, chronic kidney disease or cardiovascular disease, smoking history, and requirement of vasopressors or invasive mechanical ventilation at admission. The overall 28-day and 90-day mortality were higher among patients who developed MACE than those who did not (63.1% [5573/8829] vs. 35.6% [14,487/40,650] p < 0.001; 69.9% [6169/8829] vs. 37.8% [15,372/40,650] p < 0.001, respectively). After adjusting for confounders, MACE remained independently associated with higher 28-day and 90-day mortality (Odds Ratio [95% CI], 1.36 [1.33-1.39];1.47 [1.43-1.50], respectively)., Conclusions: Patients with severe COVID-19 frequently develop MACE, which is independently associated with worse clinical outcomes., Competing Interests: Declaration of Competing Interest Srinivas Murthy declares receiving salary support from the Health Research Foundation and Innovative Medicines Canada Chair in Pandemic Preparedness Research. Ignacio Martin-Loeches declared lectures for Gilead, Thermofisher, MSD; advisory board participation for Fresenius Kabi, Advanz Pharma, Gilead, Accelerate, and Merck; and consulting fees for Gilead outside of the submitted work. These sponsors have not involvement in this manuscript. All the other authors do not have conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Efficiency of randomised clinical trials of acute respiratory distress syndrome (ARDS) depends on the fraction of deaths attributable to ARDS (AF ARDS ) to which interventions are targeted. Estimates of AF ARDS in subpopulations of ARDS could improve design of ARDS trials., Methods: We performed a matched case-control study using the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE cohort. Primary outcome was intensive care unit mortality. We used nearest neighbour propensity score matching without replacement to match ARDS to non-ARDS populations. We derived two separate AF ARDS estimates by matching patients with ARDS to patients with non-acute hypoxaemic respiratory failure (non-AHRF) and to patients with AHRF with unilateral infiltrates only (AHRF-UL). We also estimated AF ARDS in subgroups based on severity of hypoxaemia, number of lung quadrants involved and hyperinflammatory versus hypoinflammatory phenotypes. Additionally, we derived AF AHRF estimates by matching patients with AHRF to non-AHRF controls, and AF AHRF-UL estimates by matching patients with AHRF-UL to non-AHRF controls., Results: Estimated AF ARDS was 20.9% (95% CI 10.5% to 31.4%) when compared with AHRF-UL controls and 38.0% (95% CI 34.4% to 41.6%) compared with non-AHRF controls. Within subgroups, estimates for AF ARDS compared with AHRF-UL controls were highest in patients with severe hypoxaemia (41.1% (95% CI 25.2% to 57.1%)), in those with four quadrant involvement on chest radiography (28.9% (95% CI 13.4% to 44.3%)) and in the hyperinflammatory subphenotype (26.8% (95% CI 6.9% to 46.7%)). Estimated AF AHRF was 33.8% (95% CI 30.5% to 37.1%) compared with non-AHRF controls. Estimated AF AHRF-UL was 21.3% (95% CI 312.8% to 29.7%) compared with non-AHRF controls., Conclusions: Overall AF ARDS mean values were between 20.9% and 38.0%, with higher AF ARDS seen with severe hypoxaemia, four quadrant involvement on chest radiography and hyperinflammatory ARDS., Competing Interests: Competing interests: CS is funded by UKRI (MR/S035753/1 and MR/X005070/1) and the National Institute for Health and Care Research (NIHR133788). Work in her research group is supported by GlaxoSmithKline, the Wellcome Trust and the Cambridge NIHR Biomedical Research Centre, and she has received consultancy fees from AbbVie, Sanofi and GlaxoSmithKline. CSC is funded by National Institutes of Health R35-HL140026 and reports grant funding from Roche-Genentech and Quantum Leap Healthcare collaborative, in addition to the National Institutes of Health, and consulting fees from Vasomune, Gen1e Life Sciences, Cellenkos and Janssen. EF reports personal fees from ALung Technologies, Aerogen, Baxter, GE Healthcare, Inspira and Vasomune outside the submitted work. JGL is funded by a Future Research Leaders Award (16-FRL-3845) from Science Foundation Ireland and reports receiving consulting fees from Baxter and from GlaxoSmithKline. RS reports no conflicts. MS-H is funded by a clinician scientist fellowship from the National Institute for Health Research (CS-2016-16-011) and reports receiving grants from the NIHR, MRC, EME, HTA, Huo Foundation and highlights industry support for TRAITS research programme (a Chief Scientists Office, Scotland funded time critical precision medicine in adult critically ill patients (TRAITS Programme))., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

High-density lipoprotein (HDL) levels are reduced in patients with coronavirus disease 2019 (COVID-19), and the extent of this reduction is associated with poor clinical outcomes. While lipoproteins are known to play a key role during the life cycle of the hepatitis C virus, their influence on coronavirus (CoV) infections is poorly understood. In this study, we utilize cross-linking mass spectrometry (XL-MS) to determine circulating protein interactors of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoprotein. XL-MS of plasma isolated from patients with COVID-19 uncovered HDL protein interaction networks, dominated by acute-phase serum amyloid proteins, whereby serum amyloid A2 was shown to bind to apolipoprotein (Apo) D. XL-MS on isolated HDL confirmed ApoD to interact with SARS-CoV-2 spike but not SARS-CoV-1 spike. Other direct interactions of SARS-CoV-2 spike upon HDL included ApoA1 and ApoC3. The interaction between ApoD and spike was further validated in cells using immunoprecipitation-MS, which uncovered a novel interaction between both ApoD and spike with membrane-associated progesterone receptor component 1. Mechanistically, XL-MS coupled with data-driven structural modeling determined that ApoD may interact within the receptor-binding domain of the spike. However, ApoD overexpression in multiple cell-based assays had no effect upon viral replication or infectivity. Thus, SARS-CoV-2 spike can bind to apolipoproteins on HDL, but these interactions do not appear to alter infectivity., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Key underlying pathological mechanisms contributing to sepsis are hemostatic dysfunction and overwhelming inflammation. Platelet aggregation is required for hemostasis, and platelets are also separately involved in inflammatory responses that require different functional attributes. Nevertheless, P2Y receptor activation of platelets is required for this dichotomy of function. The aim of this study was to elucidate whether P2YR-dependent hemostatic and inflammatory functions were altered in platelets isolated from sepsis patients, compared with patients with mild sterile inflammation. Platelets from patients undergoing elective cardiac surgery (20 patients, 3 female) or experiencing sepsis after community-acquired pneumonia (10 patients, 4 female) were obtained through the IMMunE dysfunction and Recovery from SEpsis-related critical illness in adults (IMMERSE) Observational Clinical Trial. In vitro aggregation and chemotaxis assays were performed with platelets after stimulation with ADP and compared with platelets isolated from healthy control subjects (7 donors, 5 female). Cardiac surgery and sepsis both induced a robust inflammatory response with increases in circulating neutrophil counts with a trend toward decreased circulating platelet counts being observed. The ability of platelets to aggregate in response to ex vivo ADP stimulation was preserved in all groups. However, platelets isolated from patients with sepsis lost the ability to undergo chemotaxis toward N -formylmethionyl-leucyl-phenylalanine, and this suppression was evident at admission through to and including discharge from hospital. Our results suggest that P2Y 1 -dependent inflammatory function in platelets is lost in patients with sepsis resulting from community-acquired pneumonia. Further studies will need to be undertaken to determine whether this is due to localized recruitment to the lungs of a platelet responsive population or loss of function as a result of dysregulation of the immune response., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Rationale: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in coronavirus disease (COVID-19)-related acute respiratory distress syndrome (ARDS). Objectives: We investigated the safety and efficacy of ORBCEL-C (CD362 [cluster of differentiation 362]-enriched, umbilical cord-derived MSCs) in COVID-19-related ARDS. Methods: In this multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial (NCT03042143), patients with moderate to severe COVID-19-related ARDS were randomized to receive ORBCEL-C (400 million cells) or placebo (Plasma-Lyte 148). The primary safety and efficacy outcomes were the incidence of serious adverse events and oxygenation index at Day 7, respectively. Secondary outcomes included respiratory compliance, driving pressure, Pa O 2 :Fi O 2 ratio, and Sequential Organ Failure Assessment score. Clinical outcomes relating to duration of ventilation, lengths of ICU and hospital stays, and mortality were collected. Long-term follow-up included diagnosis of interstitial lung disease at 1 year and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at Days 0, 4, and 7. Measurements and Main Results: Sixty participants were recruited (final analysis: n  = 30 received ORBCEL-C, n  = 29 received placebo; 1 participant in the placebo group withdrew consent). Six serious adverse events occurred in the ORBCEL-C group and three in the placebo group (risk ratio, 2.9 [95% confidence interval, 0.6-13.2]; P  = 0.25). Day 7 mean (SD) oxygenation index did not differ (ORBCEL-C, 98.3 [57.2] cm H 2 O/kPa; placebo, 96.6 [67.3] cm H 2 O/kPa). There were no differences in secondary surrogate outcomes or in mortality at Day 28, Day 90, 1 year, or 2 years. There was no difference in the prevalence of interstitial lung disease at 1 year or significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. Conclusion: ORBCEL-C MSCs were safe in subjects with moderate to severe COVID-19-related ARDS but did not improve surrogates of pulmonary organ dysfunction.

Individuals with SARS-CoV-2 infection can develop symptoms that persist well beyond the acute phase of COVID-19 or emerge after the acute phase, lasting for weeks or months after the initial acute illness. The post-acute sequelae of COVID-19, which include physical, cognitive, and mental health impairments, are known collectively as long COVID or post-COVID-19 condition. The substantial burden of this multisystem condition is felt at individual, health-care system, and socioeconomic levels, on an unprecedented scale. Survivors of COVID-19-related critical illness are at risk of the well known sequelae of acute respiratory distress syndrome, sepsis, and chronic critical illness, and these multidimensional morbidities might be difficult to differentiate from the specific effects of SARS-CoV-2 and COVID-19. We provide an overview of the manifestations of post-COVID-19 condition after critical illness in adults. We explore the effects on various organ systems, describe potential pathophysiological mechanisms, and consider the challenges of providing clinical care and support for survivors of critical illness with multisystem manifestations. Research is needed to reduce the incidence of post-acute sequelae of COVID-19-related critical illness and to optimise therapeutic and rehabilitative care and support for patients., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Sepsis causes significant morbidity and mortality worldwide. Resuscitation is a cornerstone of management. This review covers five areas of evolving practice in the management of early sepsis-induced hypoperfusion: fluid resuscitation volume, timing of vasopressor initiation, resuscitation targets, route of vasopressor administration, and use of invasive blood pressure monitoring. For each topic, we review the seminal evidence, discuss the evolution of practice over time, and highlight questions for additional research. Intravenous fluids are a core component of early sepsis resuscitation. However, with growing concerns about the harms of fluid, practice is evolving toward smaller-volume resuscitation, which is often paired with earlier vasopressor initiation. Large trials of fluid-restrictive, vasopressor-early strategies are providing more information about the safety and potential benefit of these approaches. Lowering blood pressure targets is a means to prevent fluid overload and reduce exposure to vasopressors; mean arterial pressure targets of 60-65 mm Hg appear to be safe, at least in older patients. With the trend toward earlier vasopressor initiation, the need for central administration of vasopressors has been questioned, and peripheral vasopressor use is increasing, although it is not universally accepted. Similarly, although guidelines suggest the use of invasive blood pressure monitoring with arterial catheters in patients receiving vasopressors, blood pressure cuffs are less invasive and often sufficient. Overall, the management of early sepsis-induced hypoperfusion is evolving toward fluid-sparing and less-invasive strategies. However, many questions remain, and additional data are needed to further optimize our approach to resuscitation.

Background: In this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity., Methods: Hospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF)., Results: One hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex., Conclusion: Low dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered., Trial Registration: The trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021., (© 2023. The Author(s).)

Aims: The incidence of in hospital cardiac arrest (IHCA) varies throughout the day. This study aimed to report the variation in incidence of IHCA, presenting rhythm and outcome based on the hour in which IHCA occurred., Methods: We conducted a retrospective analysis of the National Cardiac Arrest Audit (NCAA) including patients who suffered an IHCA from 1st April 2011 to 31st December 2019. We then linked the NCAA and intensive care Case Mix Programme databases to explore the effect of time of IHCA on hospital survival in the subgroup of patients admitted to intensive care following IHCA., Results: We identified 115,690 eligible patients in the NCAA database. Pulseless electrical activity was the commonest presenting rhythm (54.8%). 66,885 patients died in the immediate post resuscitation period. Overall, hospital survival in the NCAA cohort was 21.3%. We identified 13,858 patients with linked ICU admissions in the Case Mix Programme database; 37.0% survived to hospital discharge. The incidence of IHCA peaked at 06.00. Rates of return of spontaneous circulation, survival to hospital discharge and good neurological outcome were lowest between 05.00 and 07.00. Among those admitted to ICU, no clear diurnal variation in hospital survival was seen in the unadjusted or adjusted analysis. This pattern was consistent across all presenting rhythms., Conclusions: We observed higher rates of IHCA, and poorer outcomes at night. However, in those admitted to ICU, this variation was absent. This suggests patient factors and processes of care issues contribute to the variation in IHCA seen throughout the day., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A)., (© 2023. The Author(s).)

Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea., Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up., Findings: We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01-1.03), male (1.54, 1.16-2.04), neither obese nor severely obese (1.82, 1.06-3.13 and 4.19, 2.14-8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09-2.22) or cardiovascular disease (1.33, 1.00-1.79), and shorter hospital admission (1.01 per day, 1.00-1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission)., Interpretation: Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19., Funding: PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care.COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders., Competing Interests: Aziz Sheikh received research grant to Institution from the National Institute of Health and Care Research (NIHR); participated in AstraZeneca's Thrombotic Thrombocytopenic TaskForce (unremunerated); served as an adviser to UK and Scottish Government COVID bodies (unremunerated). LGH received project grant funding to Institution from MedImmune, Novartis UK, Roche/Genentech and GlaxoSmithKline (GSK); payment for lectures from AstraZeneca, Novartis, Roche/Genentech, Sanofi, Circassia, GSK, Chiesi, Teva; travel funding from AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim, Teva and GSK; attended advisory boards/lectures of Novartis, Roche/Genentech, GSK, Evelo Biosciences, Teva, Theravance and Vectura. ADS received grants unrelated to the current work from AstraZeneca, Bayer, GSK, Pfizer, Novartis; consulting fees from AstraZeneca, GSK, Insmed and Bayer; travel support from Chiesi, AstraZeneca and GSK; attended advisory board of Insmed. AH received funding from UK Research and Innovation, National Institute of Health Research, NIHR Manchester BRC; chair NIHR Translational Research Collaboration (unpaid). JDC received funding from AstraZeneca, Genentech, Gilead Sciences, GSK, Insmed, Grifols, Novartis, Boehringer Ingelheim; consulting fees from Astrazeneca, Chiesi, GSK, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio, Zambon. RAE received funding from NIHR, UKRI, Wolfson Foundation; consulting fees from AstraZeneca; payment for lecture from Boeringher; support for attending meetings from Chiesi; served as ERS Group 01.02 Pulmonary Rehabilitation Secretary (unpaid). AM received funding to Institution from Barts Charity, Pharma Nord, Fischer Family Foundation, DSM Nutritional Products, The Exilarch's Foundation, The Karl R Pfleger Foundation, The AIM Foundation, Synergy Biologics, Cytoplan Ltd, UK NIHR Clinical Research Network, Health Data Research UK BREATHE Hub, UK Research and Innovation Industrial Strategy Challenge Fund, Thornton & Ross, Warburtons, Matthew Isaacs (personal donation), Barbara Boucher (personal donation), Hyphens Pharma. Amisha Singapuri received funding to Institution from UKRI and NIHR. BR received funding from BHF Oxford CRE Transition Intermediate Clinical Research Fellowship; payment for lecture from Axcella Therapeutics. CEB received funding to Institution from MRC, NIHR, Leicester NIHR BRC, GSK, AstraZeneca, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma, Mologic; consulting fees to institution from GSK, AstraZeneca, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma, Mologic. MS received funding to Institution from UKRI-MRC and DHSC-NIHR. LVW received funding from UK Research and Innovation, GSK/Asthma + Lung UK, NIHR, Orion Pharma, GSK, Genentech, AstraZeneca; consulting fees to institution from Galapagos, Boehringer Ingelheim; travel support from Genentech; attended Advisory Board for Galapagos; served as Associate Editor for European Respiratory Journal. PEP received funding from NIHR. JKQ received funding to Institution from MRC, HDR UK, GSK, BI, asthma + lung UK, AstraZeneca; consulting fees from GSK, AstraZeneca, Insmed. MM received funding from the PHOSP Covid grant. Other authors declare no conflict of interests., (© 2023 The Author(s).)

The currently recommended dose of dexamethasone for patients with severe or critical COVID-19 is 6 mg per day (mg/d) regardless of patient features and variation. However, patients with severe or critical COVID-19 are heterogenous in many ways (e.g., age, weight, comorbidities, disease severity, and immune features). Thus, it is conceivable that a standardized dosing protocol may not be optimal. We assessed treatment effect heterogeneity in the COVID STEROID 2 trial, which compared 6 mg/d to 12 mg/d, using a causal inference framework with Bayesian Additive Regression Trees, a flexible modeling method that detects interactive effects and nonlinear relationships among multiple patient characteristics simultaneously. We found that 12 mg/d of dexamethasone, relative to 6 mg/d, was probably associated with better long-term outcomes (days alive without life support and mortality after 90 days) among the entire trial population (i.e., no signals of harm), and probably more beneficial among those without diabetes mellitus, that were older, were not using IL-6 inhibitors at baseline, weighed less, or had higher level respiratory support at baseline. This adds more evidence supporting the use of 12 mg/d in practice for most patients not receiving other immunosuppressants and that additional study of dosing could potentially optimize clinical outcomes., (© 2023. The Author(s).)

Around one-third of patients diagnosed with COVID-19 develop a severe illness that requires admission to the Intensive Care Unit (ICU). In clinical practice, clinicians have learned that patients admitted to the ICU due to severe COVID-19 frequently develop ventilator-associated lower respiratory tract infections (VA-LRTI). This study aims to describe the clinical characteristics, the factors associated with VA-LRTI, and its impact on clinical outcomes in patients with severe COVID-19. This was a multicentre, observational cohort study conducted in ten countries in Latin America and Europe. We included patients with confirmed rtPCR for SARS-CoV-2 requiring ICU admission and endotracheal intubation. Only patients with a microbiological and clinical diagnosis of VA-LRTI were included. Multivariate Logistic regression analyses and Random Forest were conducted to determine the risk factors for VA-LRTI and its clinical impact in patients with severe COVID-19. In our study cohort of 3287 patients, VA-LRTI was diagnosed in 28.8% [948/3287]. The cumulative incidence of ventilator-associated pneumonia (VAP) was 18.6% [610/3287], followed by ventilator-associated tracheobronchitis (VAT) 10.3% [338/3287]. A total of 1252 bacteria species were isolated. The most frequently isolated pathogens were Pseudomonas aeruginosa (21.2% [266/1252]), followed by Klebsiella pneumoniae (19.1% [239/1252]) and Staphylococcus aureus (15.5% [194/1,252]). The factors independently associated with the development of VA-LRTI were prolonged stay under invasive mechanical ventilation, AKI during ICU stay, and the number of comorbidities. Regarding the clinical impact of VA-LRTI, patients with VAP had an increased risk of hospital mortality (OR [95% CI] of 1.81 [1.40-2.34]), while VAT was not associated with increased hospital mortality (OR [95% CI] of 1.34 [0.98-1.83]). VA-LRTI, often with difficult-to-treat bacteria, is frequent in patients admitted to the ICU due to severe COVID-19 and is associated with worse clinical outcomes, including higher mortality. Identifying risk factors for VA-LRTI might allow the early patient diagnosis to improve clinical outcomes.Trial registration: This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable., (© 2023. The Author(s).)