Imperial College London

Professor Anthony Gordon

Faculty of MedicineDepartment of Surgery & Cancer

Chair in Anaesthesia and Critical Care
 
 
 
//

Contact

 

anthony.gordon

 
 
//

Location

 

ICUQueen Elizabeth the Queen Mother Wing (QEQM)St Mary's Campus

//

Summary

 

Publications

Publication Type
Year
to

188 results found

Ratcliff J, Al-Beidh F, Bibi S, Bonsall D, Costa Clemens SA, Estcourt L, Evans A, Fish M, Folegatti PM, Gordon AC, Jay C, Jennings A, Laing E, Lambe T, MacIntyre-Cockett G, Menon D, Mouncey PR, Nguyen D, Pollard AJ, Ramasamy MN, Roberts DJ, Rowan KM, Rynne J, Shankar-Hari M, Williams S, Harvala H, Golubchik T, Simmonds P, AMPHEUS Project, REMAP-CAP Immunoglobulin Domain UK Investigators, and Oxford COVID-19 Vaccine Trial Groupet al., 2022, Highly Sensitive Lineage Discrimination of SARS-CoV-2 Variants through Allele-Specific Probe PCR., J Clin Microbiol, Vol: 60

Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality. To this aim, an allele-specific probe PCR (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. Individual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. The comparative advantage for ASP-PCR over NGS was most pronounced in samples with cycle threshold (CT) values between 26 and 30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well suited to augment but not replace NGS. The method can differentiate SARS-CoV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer-target base mismatch through altered oligonucleotide chemistry or chemical additives.

Journal article

Phillips R, Cro S, Wheeler G, Bond S, Morris TP, Creanor S, Hewitt C, Love S, Lopes A, Schlackow I, Gamble C, MacLennan G, Habron C, Gordon A, Vergis N, Li T, Qureshi R, Everett C, Holmes J, Kirkham A, Peckitt C, Pirrie S, Ahmed N, Collett L, Cornelius Vet al., 2022, Visualising harms in Randomised Controlled Trial publications: a consensus and recommendations, BMJ: British Medical Journal, ISSN: 0959-535X

Journal article

REMAP-CAP Writing Committee for the REMAP-CAP Investigators, Bradbury CA, Lawler PR, Stanworth SJ, McVerry BJ, McQuilten Z, Higgins AM, Mouncey PR, Al-Beidh F, Rowan KM, Berry LR, Lorenzi E, Zarychanski R, Arabi YM, Annane D, Beane A, van Bentum-Puijk W, Bhimani Z, Bihari S, Bonten MJM, Brunkhorst FM, Buzgau A, Buxton M, Carrier M, Cheng AC, Cove M, Detry MA, Estcourt LJ, Fitzgerald M, Girard TD, Goligher EC, Goossens H, Haniffa R, Hills T, Huang DT, Horvat CM, Hunt BJ, Ichihara N, Lamontagne F, Leavis HL, Linstrum KM, Litton E, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Morpeth SC, Murthy S, Neal MD, Nichol AD, Parke RL, Parker JC, Reyes L, Saito H, Santos MS, Saunders CT, Serpa-Neto A, Seymour CW, Shankar-Hari M, Singh V, Tolppa T, Turgeon AF, Turner AM, van de Veerdonk FL, Green C, Lewis RJ, Angus DC, McArthur CJ, Berry S, Derde LPG, Webb SA, Gordon ACet al., 2022, Effect of antiplatelet therapy on survival and organ support-free days in critically ill patients with COVID-19: a randomized clinical trial., JAMA: Journal of the American Medical Association, ISSN: 0098-7484

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment

Journal article

Fisher BA, Veenith T, Slade D, Gaskell C, Rowland M, Whitehouse T, Scriven J, Parekh D, Balasubramaniam MS, Cooke G, Morley N, Gabriel Z, Wise MP, Porter J, McShane H, Ho L-P, Newsome PN, Rowe A, Sharpe R, Thickett DR, Bion J, Gates S, Richards D, Kearns P, CATALYST investigatorset al., 2022, Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial., The Lancet Respiratory Medicine, Vol: 10, Pages: 255-266, ISSN: 2213-2600

BACKGROUND: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. METHODS: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. FINDINGS: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment-time interactions were -0·09 (95% CI -0·19 to 0·00) for namilumab and 0·06 (-0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with

Journal article

Jones T, Janani L, Gordon A, Al-Beidh F, Antcliffe Det al., 2022, A novel role for cytochrome P450 epoxygenase metabolites in septic shock, Critical Care Explorations, Vol: 4, ISSN: 2639-8028

Objectives Oxylipins are oxidative breakdown products of cell membrane fatty acids. Animal models have demonstrated that oxylipins generated by the P450 epoxygenase pathway may be implicated in septic shock pathology. However, these mediators are relatively unexplored in humans with septic shock. We aimed to determine if there were patterns of oxylipins that were associated with 28-day septic shock mortality and organ dysfunction. Design Retrospective analysis of samples collected during the Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock trial.Setting Intensive Care Units in the United KingdomPatients Adults recruited within six hours of onset of septic shock. Interventions Trial interventions were not considered in this analysis.Measurements and Main Results Oxylipin profiling was performed on 404 serum samples from 152 patients using liquid chromatography-mass spectrometry. Non-survivors were found to have higher levels of 14,15-dihydroxyeicosatrienoic acid at baseline (DHET) than survivors (p=0.02). Patients with 14,15-DHET levels above the lower limit of quantification of the assay were more likely to die than patients with levels below this limit (Hazard Ratio 2.3, 95% CI 1.2-4.5). Patients with measurable 14,15-DHET had higher levels of organ dysfunction and fewer renal failure free days than those in whom it was unmeasurable. Considering samples collected over the first week of intensive care stay, measurable levels of DHET species were associated with higher daily SOFA scores which appeared to be accounted for predominantly by the liver component. Measurable 14,15-DHET showed positive correlation with bilirubin (rs=0.38, p<0.001) and lactate (rs=0.27, p=0.001).Conclusions The P450 epoxygenase-derived DHET species of oxylipins were associated with organ, particularly liver, dysfunction in septic shock and 14,15-DHET was associated with septic shock mortality. These results support further investigation into the role of the P450 epoxygena

Journal article

Fallerini C, Picchiotti N, Baldassarri M, Zguro K, Daga S, Fava F, Benetti E, Amitrano S, Bruttini M, Palmieri M, Croci S, Lista M, Beligni G, Valentino F, Meloni I, Tanfoni M, Minnai F, Colombo F, Cabri E, Fratelli M, Gabbi C, Mantovani S, Frullanti E, Gori M, Crawley FP, Butler-Laporte G, Richards B, Zeberg H, Lipcsey M, Hultström M, Ludwig KU, Schulte EC, Pairo-Castineira E, Baillie JK, Schmidt A, Frithiof R, WESWGS Working Group Within the HGI, GenOMICC Consortium, GEN-COVID Multicenter Study, Mari F, Renieri A, Furini Set al., 2022, Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity, Human Genetics, Vol: 141, Pages: 147-173, ISSN: 0340-6717

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

Journal article

ISARIC Clinical Characterisation Group, 2021, The value of open-source clinical science in pandemic response: lessons from ISARIC., Lancet Infectious Diseases, Vol: 21, Pages: 1623-1624, ISSN: 1473-3099

Journal article

Axfors C, Janiaud P, Schmitt AM, Van't Hooft J, Smith ER, Haber NA, Abayomi A, Abduljalil M, Abdulrahman A, Acosta-Ampudia Y, Aguilar-Guisado M, Al-Beidh F, Alejandria MM, Alfonso RN, Ali M, AlQahtani M, AlZamrooni A, Anaya J-M, Ang MAC, Aomar IF, Argumanis LE, Averyanov A, Baklaushev VP, Balionis O, Benfield T, Berry S, Birocco N, Bonifacio LB, Bowen AC, Bown A, Cabello-Gutierrez C, Camacho B, Camacho-Ortiz A, Campbell-Lee S, Cao DH, Cardesa A, Carnate JM, Castillo GJJ, Cavallo R, Chowdhury FR, Chowdhury FUH, Ciccone G, Cingolani A, Climacosa FMM, Compernolle V, Cortez CFN, Neto AC, D'Antico S, Daly J, Danielle F, Davis JS, De Rosa FG, Denholm JT, Denkinger CM, Desmecht D, Diaz-Coronado JC, Diaz Ponce-Medrano JA, Donneau A-F, Dumagay TE, Dunachie S, Dungog CC, Erinoso O, Escasa IMS, Estcourt LJ, Evans A, Evasan ALM, Fareli CJ, Fernandez-Sanchez V, Galassi C, Gallo JE, Garcia PJ, Garcia PL, Garcia JA, Garigliany M, Garza-Gonzalez E, Gauiran DT, Gaviria Garcia PA, Giron-Gonzalez J-A, Gomez-Almaguer D, Gordon AC, Gothot A, Grass Guaqueta JS, Green C, Grimaldi D, Hammond NE, Harvala H, Heralde FM, Herrick J, Higgins AM, Hills TE, Hines J, Holm K, Hoque A, Hoste E, Ignacio JM, Ivanov A, Janssen M, Jennings JH, Jha V, King RAN, Kjeldsen-Kragh J, Klenerman P, Kotecha A, Krapp F, Labanca L, Laing E, Landin-Olsson M, Laterre P-F, Lim L-L, Lim J, Ljungquist O, Llaca-Diaz JM, Lopez-Robles C, Lopez-Cardenas S, Lopez-Plaza I, Lucero JAC, Lundgren M, Macias J, Maganito SC, Malundo AFG, Manrique RD, Manzini PM, Marcos M, Marquez I, Javier Martinez-Marcos F, Mata AM, McArthur CJ, McQuilten ZK, McVerry BJ, Menon DK, Meyfroidt G, Mirasol MAL, Misset B, Molton JS, Mondragon A, Monsalve DM, Choghakabodi PM, Morpeth SC, Mouncey PR, Moutschen M, Muller-Tidow C, Murphy E, Najdovski T, Nichol AD, Nielsen H, Novak RM, O'Sullivan MVN, Olalla J, Osibogun A, Osikomaiya B, Oyonarte S, Pardo-Oviedo JM, Patel MC, Paterson DL, Pena-Perez CA, Perez-Calatayud AA, Perez-Alba E, Perkina A, Perry N Pet al., 2021, Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials, BMC Infectious Diseases, Vol: 21, Pages: 1-23, ISSN: 1471-2334

BackgroundConvalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX).MethodsIn this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence.ResultsA total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpub

Journal article

Ratcliff J, Al-Beidh F, Bibi S, Bonsall D, Costa Clemens SA, Estcourt L, Evans A, Fish M, Folegatti PM, Gordon AC, Jay C, Jennings A, Laing E, Lambe T, MacIntyre-Cockett G, Menon D, Mouncey PR, Nguyen D, Pollard AJ, Ramasamy MN, Roberts DJ, Rowan KM, Rynne J, Shankar-Hari M, Williams S, Harvala H, Golubchik T, Simmonds Pet al., 2021, Highly-Sensitive Lineage Discrimination of SARS-CoV-2 Variants through Allele-Specific Probe Polymerase Chain Reaction

<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>Tools to detect SARS-Coronavirus-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>An allele-specific probe polymerase chain reaction (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Individual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. Comparative advantage for ASP-PCR over NGS was most pronounced in samples with Ct values between 26-30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>ASP-PCR is well-suited to augment but not replace NGS. The method can differentiate SARS-COV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer:target base mismatch through

Journal article

Shah F, Meyer NJ, Angus DC, Awdish R, Azoulay É, Calfee CS, Clermont G, Gordon A, Kwizera A, Leligdowicz A, Marshall JC, Mikacenic C, Sinha P, Venkatesh B, Wong HR, Zampieri FG, Yende Set al., 2021, A research agenda for precision medicine in sepsis and acute respiratory distress syndrome: an official American Thoracic Society research statement, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Background: Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure.Methods: This proposal was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS. Results: Six priority recommendations were developed by the working group: (1) the creation of large richly-phenotyped and harmonized knowledge networks of clinical, imaging, and multi-analyte molecular data for sepsis and ARDS; (2) implementation of novel trial designs including adaptive designs and embedding trial procedures in the electronic health record; (3) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; (4) further development of the tools necessary for the real-time application of precision medicine approaches; (5) working to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic and demographic groups; and (6) securing and maintaining adequate and sustainable funding for precision medicine efforts.Conclusions: Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing delivery of therapies and improving care for pati

Journal article

Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, Arabi YM, Arnold DM, Beane A, Bégin P, van Bentum-Puijk W, Berry LR, Bhimani Z, Birchall JE, Bonten MJM, Bradbury CA, Brunkhorst FM, Buxton M, Callum JL, Chassé M, Cheng AC, Cove ME, Daly J, Derde L, Detry MA, De Jong M, Evans A, Fergusson DA, Fish M, Fitzgerald M, Foley C, Goossens H, Gordon AC, Gosbell IB, Green C, Haniffa R, Harvala H, Higgins AM, Hills TE, Hoad VC, Horvat C, Huang DT, Hudson CL, Ichihara N, Laing E, Lamikanra AA, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, MacLennan S, Marshall J, McAuley DF, McDyer JF, McGlothlin A, McGuinness S, Miflin G, Montgomery S, Mouncey PR, Murthy S, Nichol A, Parke R, Parker JC, Priddee N, Purcell DFJ, Reyes LF, Richardson P, Robitaille N, Rowan KM, Rynne J, Saito H, Santos M, Saunders CT, Serpa Neto A, Seymour CW, Silversides JA, Tinmouth AA, Triulzi DJ, Turner AM, van de Veerdonk F, Walsh TS, Wood EM, Berry S, Lewis RJ, Menon DK, McArthur C, Zarychanski R, Angus DC, Webb SA, Roberts DJ, Shankar-Hari Met al., 2021, Effect of convalescent plasma on organ support-free days in critically Ill patients with COVID-19: a randomized clinical trial., JAMA: Journal of the American Medical Association, Vol: 326, Pages: 1690-1702, ISSN: 0098-7484

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. Objective: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. Interventions: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Or

Journal article

Whittaker C, Watson O, Alvarez-Moreno C, Angkasekwinai N, Boonyasiri A, Triana LC, Chanda D, Charoenpong L, Chayakulkeeree M, Cooke G, Croda J, Cucunubá ZM, Djaafara A, Estofolete CF, Grillet M-E, Faria N, Costa SF, Forero-Peña DA, Gibb DM, Gordon A, Hamers RL, Hamlet A, Irawany V, Jitmuang A, Keurueangkul N, Kimani TN, Lampo M, Levin A, Lopardo G, Mustafa R, Nayagam AS, Ngamprasertchai T, Njeri NIH, Nogueira ML, Ortiz-Prado E, Perroud Jr MW, Phillips AN, Promsin P, Qavi A, Rodger AJ, Sabino EC, Sangkaew S, Sari D, Sirijatuphat R, Sposito AC, Srisangthong P, Thompson H, Udwadia Z, Valderrama-Beltrán S, Winskill P, Ghani A, Walker P, Hallett Tet al., 2021, Understanding the Potential Impact of Different Drug Properties On SARS-CoV-2 Transmission and Disease Burden: A Modelling Analysis, Clinical Infectious Diseases, ISSN: 1058-4838

BackgroundThe public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear.MethodsUsing a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care.ResultsThe impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics.ConclusionsAdvances in the treatment of COVID-19 to date have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Journal article

Gordon AC, Angus DC, Derde LPG, 2021, Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. Reply., N Engl J Med, Vol: 385, Pages: 1147-1149

Journal article

Godolphin PJ, Fisher DJ, Berry LR, Derde LPG, Diaz JV, Gordon AC, Lorenzi E, Marshall JC, Murthy S, Shankar-Hari M, Sterne JAC, Tierney JF, Vale CLet al., 2021, Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalized patients with COVID-19: A network meta-analysis

<jats:p>Objective: To estimate pairwise associations between administration of tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and non-invasive or mechanical ventilation, based on all available direct and indirect evidence.Methods: Eligible trials randomized hospitalized patients with COVID-19 that compared either interleukin-6 receptor antagonist with usual care or placebo in a recent prospective meta-analysis (27 trials, 10930 patients) or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomization. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomization were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence. Results: One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0.82 [0.71-0.95, P=0.008]] and sarilumab [0.80 [0.61-1.04, P=0.09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1.03 [95%CI 0.81-1.32, P=0.80]. The P value for the global test for inconsistency was 0.28.Conclusion: Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.</jats:p>

Journal article

The REMAP-CAP, ACTIV-4a, and ATTACC Investigators, 2021, Therapeutic anticoagulation with heparin in critically Ill patients with Covid-19, New England Journal of Medicine, Vol: 385, Pages: 777-789, ISSN: 0028-4793

BACKGROUNDThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.METHODSIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.RESULTSThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support–free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.CONCLUSIONSIn critically ill patients with Covid-19, an initial strategy of therapeu

Journal article

The ATTACC, ACTIV-4a, and REMAP-CAP Investigators, 2021, Therapeutic anticoagulation with heparin in noncritically Ill patients with Covid-19, New England Journal of Medicine, Vol: 385, Pages: 790-802, ISSN: 0028-4793

BACKGROUNDThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.METHODSIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.RESULTSThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic

Journal article

Festor P, Habil I, Jia Y, Gordon A, Faisal A, Komorowski Met al., 2021, Levels of Autonomy & Safety Assurance forAI-based Clinical Decision Systems, WAISE 2021 : 4th International Workshop on Artificial Intelligence Safety Engineering

Conference paper

Ratcliff J, Nguyen D, Fish M, Rynne J, Jennings A, Williams S, Al-Beidh F, Bonsall D, Evans A, Golubchik T, Gordon AC, Lamikanra A, Tsang P, Ciccone NA, Leuscher U, Slack W, Laing E, Mouncey PR, Ziyenge S, Oliveira M, Ploeg R, Rowan KM, Shankar-Hari M, Roberts DJ, Menon DK, Estcourt L, Simmonds P, Harvala Het al., 2021, Virological and serological characterization of critically ill patients with COVID-19 in the UK: Interactions of viral load, antibody status and B.1.1.7 variant infection., Journal of Infectious Diseases, Vol: 224, Pages: 595-605, ISSN: 0022-1899

BACKGROUND: Convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation for COVID-19 treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial that potentially influence treatment outcomes. METHODS: SARS-CoV-2 RNA in nasopharyngeal swabs collected pre-treatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. RESULTS: Of 1274 subjects, 90% were PCR-positive with viral loads 118-1.7x10 11 IU/ml. Median viral loads were 40-fold higher in those seronegative for IgG antibodies (n=354; 28%) compared to seropositives (n=939; 72%). Frequencies of B.1.1.7 increased from <1% in early November, 2020 to 82% of subjects in January 2021. Seronegative individuals with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians 5.8x10 6 and 2.0 x10 5 IU/ml respectively; p=2x10 -15). However, viral load distributions were elevated in both seronegative and seropositive subjects infected with B.1.1.7 (4.0x10 6 and 1.6x10 6 IU/ml respectively). CONCLUSIONS: High viral loads in seropositive B.1.1.7-infected subjects and resistance to seroconversion indicate less effective clearance by innate and adaptive immune responses. SARS-CoV-2 strain, viral loads and antibody status define subgroups for analysis of treatment efficacy.

Journal article

Arabi Y, Gordon A, Derde L, Nichol A, Murthy S, Al-Beidh F, Annane D, Al Swaidan L, Beane A, Beasley R, Berry L, Bhimani Z, Bonten M, Bradbury C, Brunkhorst F, Buxton M, Buzgau A, Cheng A, De Jong M, Detry M, Duffy E, Estcourt L, Fitzgerald M, Fowler R, Girard T, Goligher E, Goossens H, Haniffa R, Higgins A, Hills T, Horvat C, Huang D, King A, Lamontagne F, Lawler P, Lewis R, Linstrum K, Litton E, Lorenzi E, Malakouti S, McAuley D, McGlothlin A, Mcguinness S, McVerry B, Montgomery S, Morpeth S, Mouncey P, Orr K, Parke R, Parker J, Patanwala A, Rowan K, Santos M, Saunders C, Seymour C, Shankar-Hari M, Tong S, Turgeon A, Turner A, Van de Veerdonk FL, Zarychanski R, Green C, Berry S, Marshall J, McArthur C, Angus D, Webb Set al., 2021, Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized control trial, Intensive Care Medicine, Vol: 47, Pages: 867-886, ISSN: 0342-4642

Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19) Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir, and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ-support free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR >1 is favorable. Results: We randomized 694 patients to receive lopinavir-ritonavir (n=255), hydroxychloroquine (n=50), combination therapy (n=27) or control (n=362). The median (IQR) organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (–1 to 15), 0 (–1 to 9) and –1 (–1 to 7), respectively, compared to 6 (–1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥99.0%), and high probabilities of harm (98.0%, 99.9% and >99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.Trial registration Clinicaltrials.gov identifier: NCT02735707

Journal article

Shankar-Hari M, Santhakumaran S, Prevost AT, Ward JK, Marshall T, Bradley C, Calfee CS, Delucchi KL, Sinha P, Matthay MA, Hackett J, McDowell C, Laffey JG, Gordon A, OKane CM, McAuley DFet al., 2021, Defining phenotypes and treatment effect heterogeneity to inform acute respiratory distress syndrome and sepsis trials: secondary analyses of three RCTs, Efficacy and Mechanism Evaluation, Vol: 8, Pages: 1-104, ISSN: 2050-4365

BackgroundSepsis and acute respiratory distress syndrome are two heterogeneous acute illnesses with high risk of death and for which there are many ‘statistically negative’ randomised controlled trials. We hypothesised that negative randomised controlled trials occur because of between-participant differences in response to treatment, illness manifestation (phenotype) and risk of outcomes (heterogeneity).ObjectivesTo assess (1) heterogeneity of treatment effect, which tests whether or not treatment effect varies with a patient’s pre-randomisation risk of outcome; and (2) whether or not subphenotypes explain the treatment response differences in sepsis and acute respiratory distress syndrome demonstrated in randomised controlled trials.Study populationWe performed secondary analysis of two randomised controlled trials in patients with sepsis [i.e. the Vasopressin vs Noradrenaline as Initial Therapy in Septic Shock (VANISH) trial and the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial] and one acute respiratory distress syndrome multicentre randomised controlled trial [i.e. the Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial], conducted in the UK. The VANISH trial is a 2 × 2 factorial randomised controlled trial of vasopressin (Pressyn AR®; Ferring Pharmaceuticals, Saint-Prex, Switzerland) and hydrocortisone sodium phosphate (hereafter referred to as hydrocortisone) (EfcortesolTM; Amdipharm plc, St Helier, Jersey) compared with placebo. The LeoPARDS trial is a two-arm-parallel-group randomised controlled trial of levosimendan (Simdax®; Orion Pharma, Espoo, Finland) compared with placebo. The HARP-2 trial is a parallel-group randomised controlled trial of simvastatin compared with placebo.MethodsTo test for heterogeneity of the effect on 28-day mortality of vasopressin, hydrocortisone and levosimendan in

Journal article

Newcombe V, McAuley D, Coats T, Dark P, Gordon A, Harris S, Menon D, Price S, Puthucheary Z, Singer Met al., 2021, The future of acute and emergency care, Future Healthcare Journal, Vol: 8, Pages: e230-e236, ISSN: 2055-3331

The events of the past year have brought into sharp focus the importance of research into acute and emergency care towards improving patient outcomes. With this in mind we present short perspectives from experts in different acute fields as to what research area could make a big difference to healthcare within the next 5-10 years. A consistent theme is improved patient stratification and characterisation to facilitate precision medicine becoming a reality (Figure 1). Breakthroughs in diagnostics, stratification, data analytics and treatments have the potential to lead to many exciting innovations over the next few years which in turn will translate into better patient care.

Journal article

COVID-19 Host Genetics Initiative, 2021, Mapping the human genetic architecture of COVID-19, Nature, Vol: 600, Pages: 472-477, ISSN: 0028-0836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Journal article

Domingo P, Mur I, Mateo GM, Gutierrez MDM, Pomar V, de Benito N, Corbacho N, Herrera S, Millan L, Muñoz J, Malouf J, Molas ME, Asensi V, Horcajada JP, Estrada V, Gutierrez F, Torres F, Perez-Molina JA, Fortun J, Villar LM, Hohenthal U, Marttila H, Vuorinen T, Nordberg M, Valtonen M, Frigault MJ, Mansour MK, Patel NJ, Fernandes A, Harvey L, Foulkes AS, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Shrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Lampa J, Nowak P, Vesterbacka JC, Rasmuson J, Skorup P, Janols H, Niward KF, Chatzidionysiou K, Asgeirsson H, Parke Å, Blennow O, Svensson A-K, Aleman S, Sönnerborg A, Henter J-I, Horne AC, Al-Beidh F, Angus D, Annane D, Arabi Y, Beane A, Berry S, Bhimani Z, Bonten M, Bradbury C, Brunkhorst F, Buxton M, Cheng A, Cove M, De Jong M, Derde L, Estcourt L, Goossens H, Gordon A, Green C, Haniffa R, Ichihara N, Lamontagne F, Lawler P, Litton E, Marshall J, McArthur C, McAuley D, McGuinness S, McVerry B, Montgommery S, Mouncey P, Murthy S, Nichol A, Parke R, Parker J, Reyes F, Rowan K, Saito H, Santos M, Seymour C, Shankar-Hari M, Turgeon A, Turner A, van Bentum-Puijk W, van de Veerdonk F, Webb S, Zarychanski R, Baillie JK, Beasley R, Cooper N, Fowler R, Galea J, Hills T, King A, Morpeth S, Netea M, Ogungbenro K, Pettila V, Tong S, Uyeki T, Youngstein T, Higgins A, Lorenzi E, Berry L, Salama C, Rosas IO, Ruiz-Antorán B, Muñez Rubio E, Ramos Martínez A, Campos Esteban J, Avendaño Solá C, Pizov R, Sanz Sanz J, Abad-Santos F, Bautista-Hernández A, García-Fraile L, Barrios A, Gutiérrez Liarte Á, Alonso Pérez T, Rodríguez-García SC, Mejía-Abril G, Prieto JC, Leon R, VEIGA VC, SCHEINBERG P, FARIAS DLC, PRATS JG, CAVALCANTI AB, MACHADO FR, ROSA RG, BERWANGER O, AZEVEDO LCP, LOPES RD, DOURADO LK, CASTRO CG, ZAMPIERI FG, AVEZUM A, LISBOA TC, ROJAS SSO, COELHO JC, LEITE RT, CARVALHO JC, ANDRADE LEC, SANDES AR, PINTÃO MCT, SANTOS SV, ALMEIDA TML, COSTA AN, GEBARA OCE, FREITAS FGR, PACHECO ES, MACHADO DJB, MARTINet al., 2021, Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19, JAMA, ISSN: 0098-7484

Importance Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.Objective To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.Data Sources Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.Study Selection Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.Data Extraction and Synthesis In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.Main Outcomes and Measures The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.Results A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL

Journal article

Derde LPG, 2021, Effectiveness of Tocilizumab, Sarilumab, and Anakinra for critically ill patients with COVID-19 The REMAP-CAP COVID-19 Immune Modulation Therapy Domain Randomized Clinical Trial

<jats:title>Abstract</jats:title><jats:sec><jats:title>BACKGROUND</jats:title><jats:p>The interleukin-6 receptor antagonist tocilizumab improves outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). However, the effectiveness of other immune modulating agents is unclear.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>We evaluated four immunomodulatory agents in an ongoing international, multifactorial, adaptive platform trial. Adult participants with COVID-19 were randomized to receive tocilizumab, sarilumab, anakinra, or standard care (control). In addition, a small group (n=21) of participants were randomized to interferon-β1a. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial used a Bayesian statistical model with pre-defined triggers for superiority, equivalence or futility.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Statistical triggers for equivalence between tocilizumab and sarilumab; and for inferiority of anakinra to the other active interventions were met at a planned adaptive analysis. Of the 2274 critically ill participants enrolled, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (interquartile range [IQR] –1, 16), 9 (IQR –1, 17), 0 (IQR –1, 15) and 0 (IQR –1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted odds ratios were 1.46 (95%CrI 1.13, 1.87), 1.50 (95%CrI 1.13, 2.00), and 0.99 (95%CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared to control. Median adjusted odds ratios for hospital survival were 1.42 (95%CrI 1.05,1.93), 1.51 (95%CrI 1.06, 2.2

Journal article

Whittaker C, Watson OJ, Alvarez-Moreno C, Angkasekwinai N, Boonyasiri A, Triana LC, Chanda D, Charoenpong L, Chayakulkeeree M, Cooke GS, Croda J, Cucunubá ZM, Djaafara BA, Estofolete CF, Grillet ME, Faria NR, Costa SF, Forero-Peña DA, Gibb DM, Gordon AC, Hamers RL, Hamlet A, Irawany V, Jitmuang A, Keurueangkul N, Kimani TN, Lampo M, Levin AS, Lopardo G, Mustafa R, Nayagam S, Ngamprasertchai T, Hannah Njeri NI, Nogueira ML, Ortiz-Prado E, Perroud MW, Phillips AN, Promsin P, Qavi A, Rodger AJ, Sabino EC, Sangkaew S, Sari D, Sirijatuphat R, Sposito AC, Srisangthong P, Thompson HA, Udwadia Z, Valderrama-Beltrán S, Winskill P, Ghani AC, Walker PGT, Hallett TBet al., 2021, Understanding the Potential Impact of Different Drug Properties On SARS-CoV-2 Transmission and Disease Burden: A Modelling Analysis

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear.</jats:p></jats:sec><jats:sec><jats:title>Methods and Findings</jats:title><jats:p>We develop a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care to explore the potential public-health impact of a range of different potential therapeutics, under a range of different scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) drug efficacy in the absence of supportive care. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. We find the impact of drugs like dexamethasone (which are delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>There is a global asymmetry in who is likely to benefit from advances in the treatment of

Journal article

Estcourt LJ, 2021, Convalescent Plasma in Critically ill Patients with COVID-19

<jats:p>BACKGROUND The evidence for benefit of convalescent plasma for critically ill patients with Covid–19 is inconsistent. We hypothesized that convalescent plasma would improve outcomes for critically ill adult patients with Covid–19.METHODS In an ongoing adaptive platform trial, critically ill patients with confirmed Covid–19, defined as receiving intensive care–level organ support, were randomized to open–label convalescent plasma or not (i.e., control group). The primary end point was organ support–free days (i.e., days alive and free of ICU–based organ support) up to day 21. The primary analysis was a Bayesian cumulative logistic model with predefined criteria for superiority or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both.RESULTS The convalescent plasma intervention was stopped after pre–specified criteria for futility were met. At that time, 1084 participants had been randomized to convalescent plasma and 916 to no convalescent plasma (control). The median organ support-free days were 0 (interquartile range, −1 to 16) for the convalescent plasma group and 3 (interquartile range, −1 to 16) days for the control group. The median adjusted odds ratio (OR) was 0.97 (95% credible interval 0.83 to 1.15) and posterior probability of futility (OR &lt; 1.2) was 99.4% for convalescent plasma compared to control. In-hospital mortality was 37.3% (401/1075) in convalescent plasma group, and 38.4% (347/904) in controls. The observed treatment effects were consistent across primary and secondary outcomes.CONCLUSIONS In critically ill adults with confirmed Covid-19, treatment with convalescent plasma, did not improve clinical outcomes.Clinicaltrials.gov: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02735707">NCT02735707</jats:ext-link><

Journal article

Billot L, Cuthbertson B, Gordon A, Al-Beidh F, Correa M, Davis J, Finfer S, Glass P, Goodman F, Hammond N, Iredell J, Miller J, Murthy S, Rose L, Seppelt I, Taylor C, Young P, Myburgh J, The SuDDICU Investigatorset al., 2021, Protocol summary and statistical analysis plan for the Selective Decontamination of the Digestive Tract in Intensive Care Units cross-over, cluster randomised controlled trial. (SuDDICU), Critical Care and Resuscitation, ISSN: 1441-2772

Background:There is uncertainty whether the use of Selective Decontamination of the Digestive Tract (SDD) improves outcomes in ventilated patients in Intensive Care Units (ICUs) and whether SDD is associated with the development of antibiotic resistance. Objectives:To describe the study protocol and statistical analysis plan for the Selective Decontamination of the Digestive Tract in ICUs (SuDDICU) trial.Design, setting and participants:SuDDICU is an international, cross-over, cluster-randomised-controlled trial of mechanically ventilated patients in ICUs using two 12-month trial periods. Participating ICUs will implement either SDD plus standard care or standard care for each period. The SuDDICU drug intervention is an oral paste and gastric suspension of three antibiotics combined with a 4-day course of intravenous antibiotics. An observational ecological assessment will be conducted during the interventional periods and 5 surveillance periods. The trial will be conducted in 19 ICUs in Australia and 10 ICUs in Canada and the UK that will recruit 15000-17000 patients. Recruitment commenced in Australia in 2017. Outcomes:The primary outcome is all-cause hospital mortality. Secondary outcomes include duration of ventilation, ICU and hospital stay, the incidence of new antibiotic resistant organisms during the index ICU admission, changes in antibiotic resistant organism rates, incidence of new Clostridioides difficile infections and total antibiotic usage.Results and conclusions:SuDDICU will determine whether the use of SDD plus standard care is associated with a reduction in hospital mortality in ventilated ICU patients compared to standard care alone and will quantify the impact of the use of SDD on the development of antibiotic resistance. Trial registration:The trial is registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12615000411549) and on ClinicalTrials.gov Registry (NCT02389036).

Journal article

Axfors C, Schmitt AM, Janiaud P, Van't Hooft J, Abd-Elsalam S, Abdo EF, Abella BS, Akram J, Amaravadi RK, Angus DC, Arabi YM, Azhar S, Baden LR, Baker AW, Belkhir L, Benfield T, Berrevoets MAH, Chen C-P, Chen T-C, Cheng S-H, Cheng C-Y, Chung W-S, Cohen YZ, Cowan LN, Dalgard O, de Almeida E Val FF, de Lacerda MVG, de Melo GC, Derde L, Dubee V, Elfakir A, Gordon AC, Hernandez-Cardenas CM, Hills T, Hoepelman AIM, Huang Y-W, Igau B, Jin R, Jurado-Camacho F, Khan KS, Kremsner PG, Kreuels B, Kuo C-Y, Le T, Lin Y-C, Lin W-P, Lin T-H, Lyngbakken MN, McArthur C, McVerry BJ, Meza-Meneses P, Monteiro WM, Morpeth SC, Mourad A, Mulligan MJ, Murthy S, Naggie S, Narayanasamy S, Nichol A, Novack LA, O'Brien SM, Okeke NL, Perez L, Perez-Padilla R, Perrin L, Remigio-Luna A, Rivera-Martinez NE, Rockhold FW, Rodriguez-Llamazares S, Rolfe R, Rosa R, Røsjø H, Sampaio VS, Seto TB, Shahzad M, Soliman S, Stout JE, Thirion-Romero I, Troxel AB, Tseng T-Y, Turner NA, Ulrich RJ, Walsh SR, Webb SA, Weehuizen JM, Velinova M, Wong H-L, Wrenn R, Zampieri FG, Zhong W, Moher D, Goodman SN, Ioannidis JPA, Hemkens LGet al., 2021, Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials., Nature Communications, Vol: 12, Pages: 1-2, ISSN: 2041-1723

Journal article

Patel BV, Haar S, Handslip R, Auepanwiriyakul C, Lee TM-L, Patel S, Harston JA, Hosking-Jervis F, Kelly D, Sanderson B, Borgatta B, Tatham K, Welters I, Camporota L, Gordon AC, Komorowski M, Antcliffe D, Prowle JR, Puthucheary Z, Faisal AAet al., 2021, Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom, Intensive Care Medicine, Vol: 47, Pages: 549-565, ISSN: 0342-4642

PurposeThe trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions.MethodsWe included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU).ResultsData for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P < 0.001; median PaO2/FiO2 on the day of death was 12.3(8.9–18.4) kPa] and non-response to proning (69.5% vs.31.1%; P < 0.001). Two ML models using weeklong data demonstrated an increased predictive accuracy for mortality compared to admission data (74.5% and 76.3% vs 60%, respectively). XAI models highlighted the increasing importance, over the first week, of PaO2/FiO2 in predicting mortality. Prone positioning improved oxygenation only in 45% of patients. A higher peak pressure (OR 1.42[1.06–1.91]; P < 0.05), raised respiratory component (OR 1.71[ 1.17–2.5]; P < 0.01) and cardiovascular component (OR 1.36 [1.04–1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33 [0.99–1.79

Journal article

DeMerle KM, Angus DC, Baillie JK, Brant E, Calfee CS, Carcillo J, Chang C-CH, Dickson R, Evans I, Gordon AC, Kennedy J, Knight JC, Lindsell CJ, Liu V, Marshall JC, Randolph AG, Scicluna BP, Shankar-Hari M, Shapiro NI, Sweeney TE, Talisa VB, Tang B, Thompson BT, Tsalik EL, van der Poll T, van Vught LA, Wong HR, Yende S, Zhao H, Seymour CWet al., 2021, Sepsis subclasses: a framework for development and interpretation, Critical Care Medicine, Vol: 49, Pages: 748-759, ISSN: 0090-3493

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00402077&limit=30&person=true