Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19. The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded. We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives. In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist. National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.

Acute respiratory distress syndrome (ARDS) is a life threatening respiratory failure due to lung injury from a variety of precipitants. Pathologically ARDS is characterised by diffuse alveolar damage, alveolar capillary leakage, and protein rich pulmonary oedema leading to the clinical manifestation of poor lung compliance, severe hypoxaemia, and bilateral infiltrates on chest radiograph. Several aetiological factors associated with the development of ARDS are identified with sepsis, pneumonia, and trauma with multiple transfusions accounting for most cases. Despite the absence of a robust diagnostic definition, extensive epidemiological investigations suggest ARDS remains a significant health burden with substantial morbidity and mortality. Improvements in outcome following ARDS over the past decade are in part due to improved strategies of mechanical ventilation and advanced support of other failing organs. Optimal treatment involves judicious fluid management, protective lung ventilation with low tidal volumes and moderate positive end expiratory pressure, multi-organ support, and treatment where possible of the underlying cause. Moreover, advances in general supportive measures such as appropriate antimicrobial therapy, early enteral nutrition, prophylaxis against venous thromboembolism and gastrointestinal ulceration are likely contributory reasons for the improved outcomes. Although therapies such as corticosteroids, nitric oxide, prostacyclins, exogenous surfactants, ketoconazole and antioxidants have shown promising clinical effects in animal models, these have failed to translate positively in human studies. Most recently, clinical trials with β2 agonists aiding alveolar fluid clearance and immunonutrition with omega-3 fatty acids have also provided disappointing results. Despite these negative studies, mortality seems to be in decline due to advances in overall patient care. Future directions of research are likely to concentrate on identifying potential biomarkers or genetic markers to facilitate diagnosis, with phenotyping of patients to predict outcome and treatment response. Pharmacotherapies remain experimental and recent advances in the modulation of inflammation and novel cellular based therapies, such as mesenchymal stem cells, may reduce lung injury and facilitate repair.

COVID-19 is an acute illness caused by SARS-CoV-2.¹ Among the many treatments studied,² only 2 immunomodulatory drugs, glucocorticoids and IL-6 receptor antagonists,^3,4 have been shown to reduce mortality in hospitalized adults with COVID-19; and critically ill patients have shown greater benefit with glucocorticoids.⁵ Convalescent plasma (blood product containing SARS-CoV-2–specific antibodies) is a biologically plausible antiviral treatment with immunomodulatory properties^6-9 that may offer greater benefit to critically ill patients with COVID-19, in whom multiorgan dysfunction could be driven by the higher prevalence of SARS-CoV-2 RNA in blood, also known as RNAemia, and by progressive host response.^10,11 However, use of convalescent plasma for patients with COVID-19 has either been outside clinical trials, with more than 500 000 patients estimated to have received this treatment in the US by March 2021,¹² or in randomized clinical trials that have not focused on critically ill patients with COVID-19, often without improving clinical outcomes, including in the recently published Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial.^13-15

This systematic review and meta-analysis summarizes the clinical effects of increasing perioperative blood flow using fluids with or without inotropes/vasoactive drugs to explicit defined goals in adults. We included randomized controlled trials of adult patients (aged 16 years or older) undergoing surgery. We included 31 studies of 5292 participants. There was no difference in mortality at the longest follow-up: 282/2615 (10.8%) died in the control group and 238/2677 (8.9%) in the treatment group, RR of 0.89 (95% CI: 0.76–1.05; P=0.18). However, the results were sensitive to analytical methods and withdrawal of studies with methodological limitations. The intervention reduced the rate of three morbidities (renal failure, respiratory failure, and wound infections) but not the rates of arrhythmia, myocardial infarction, congestive cardiac failure, venous thrombosis, and other types of infections. The number of patients with complications was also reduced by the intervention. Hospital length of stay was reduced in the treatment group by 1.16 days. There was no difference in critical care length of stay. The primary analysis of this review showed no difference between groups but this result was sensitive to the method of analysis, withdrawal of studies with methodological limitations, and was dominated by a single large study. Patients receiving this intervention stayed in hospital 1 day less with fewer complications. It is unlikely that the intervention causes harm. The balance of current evidence does not support widespread implementation of this approach to reduce mortality but does suggest that complications and duration of hospital stay are reduced.

Thrombotic events are common in patients hospitalized with COVID-19 and occur in spite of standard thromboprophylaxis, with critically ill patients being at highest risk.^1-7 Thrombotic events have been reported in the venous, arterial, and microvascular circulations and are independently associated with poor outcomes.⁴ Vascular endothelial injury and inflammation activate intravascular coagulation through diverse mediators such as elevated fibrinogen, factor VIII, von Willebrand factor, platelet activation, impaired fibrinolysis, and reduced antithrombin.⁸

Randomized clinical trials in critically ill patients, including those with COVID-19, typically assess short-term outcomes, such as organ failure or 28-day mortality, with fewer published trials assessing whether treatments affect long-term survival and patient-centered outcomes, such as disability and health-related quality of life (HRQoL). Longer-term survival free of major disability with an acceptable HRQoL may be more important to patients than short-term survival.^1,2 The World Health Organization and others have called for additional research on the effect of initial therapeutic interventions on longer-term outcomes.³