Imperial College London

Dr Kate C. Tatham

Faculty of MedicineDepartment of Surgery & Cancer

Honorary Clinical Senior Lecturer
 
 
 
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k.tatham

 
 
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Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

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Year
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86 results found

RECOVERY Collaborative Group, 2024, Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial, The Lancet Child & Adolescent Health, Vol: 8, Pages: 190-200, ISSN: 2352-4642

BACKGROUND: Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment. METHODS: We did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK. Eligible patients were younger than 18 years and had been admitted to hospital for PIMS-TS. In the first randomisation, patients were randomly assigned (1:1:1) to usual care (no additional treatments), usual care plus methylprednisolone (10mg/kg per day for 3 consecutive days), or usual care plus intravenous immunoglobulin (a single dose of 2 g/kg). If further anti-inflammatory treatment was considered necessary, children aged at least 1 year could be considered for a second randomisation, in which patients were randomly assigned (1:2:2) to usual care, intravenous tocilizumab (12 mg/kg in patients <30 kg; 8mg/kg in patients ≥30 kg, up to a maximum dose of 800 mg), or subcutaneous anakinra (2 mg/kg once per day in patients ≥10 kg). Randomisation was by use of a web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was duration of hospital stay. Analysis was by intention to treat. For treatments assessed in each randomisation, a single Bayesian framework assuming uninformative priors for treatment was used to jointly assess the efficacy of each intervention compared with usual care. The trial was registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between May 18, 2020, and Jan 20, 2022, 237 children with PIM

Journal article

Michael BD, Dunai C, Needham EJ, Tharmaratnam K, Williams R, Huang Y, Boardman SA, Clark JJ, Sharma P, Subramaniam K, Wood GK, Collie C, Digby R, Ren A, Norton E, Leibowitz M, Ebrahimi S, Fower A, Fox H, Tato E, Ellul MA, Sunderland G, Held M, Hetherington C, Egbe FN, Palmos A, Stirrups K, Grundmann A, Chiollaz A-C, Sanchez J-C, Stewart JP, Griffiths M, Solomon T, Breen G, Coles AJ, Kingston N, Bradley JR, Chinnery PF, Cavanagh J, Irani SR, Vincent A, Baillie JK, Openshaw PJ, Semple MG, ISARIC4C Investigators, COVID-CNS Consortium, Taams LS, Menon DKet al., 2023, Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses, Nature Communications, Vol: 14, ISSN: 2041-1723

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

Journal article

RECOVERY Collaborative Group, 2023, Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial, The Lancet Diabetes & Endocrinology, Vol: 11, Pages: 905-914, ISSN: 2213-8587

BACKGROUND: Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic, and haemodynamic effects. The RECOVERY trial aimed to assess its safety and efficacy in patients admitted to hospital with COVID-19. METHODS: In the randomised, controlled, open-label RECOVERY trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. In this analysis, we assess eligible and consenting adults who were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus oral empagliflozin 10 mg once daily for 28 days or until discharge (whichever came first) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. On March 3, 2023 the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on March 7, 2023. The ongoing RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between July 28, 2021 and March 6, 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Primary and secondary outcome data were known for greater than 99% of randomly assigned patients. Overall, 289 (14%) of 2113 patients allocated to empagliflozin and 307 (14%) of 2158 patients allocated to usual care died within 28 days (rate ratio 0·96 [95% CI 0·82-1·13]; p=0·64). There was no evidence of significant differences in duration of hospitalisation (median 8 days for both groups) or the proportion of patients discharged from hospital alive within 28 days (1678 [79%] in the empagliflozin group vs 1677 [78%] in the usual

Journal article

Nelmes E, Edwards L, Jhanji S, Antcliffe D, Tatham Ket al., 2023, Patients with cancer and sepsis trials: an unfairrepresentation?, Clinical Medicine, Vol: 23, Pages: 635-636, ISSN: 1470-2118

Approximately 20% of sepsis cases are thought to occur in patients with cancer. Thus, such patients are an important cohort to be represented and characterised among sepsis trials. However, patients with cancer are commonly excluded from sepsis trials, although the extent to which is unknown. In this opinion article, we discuss our findings that suggest that patients with cancer are being under-represented in sepsis trials, often with an unclear rationale. We question the validity of generalising results from sepsis trials to heterogenous cancer populations and call for wider inclusion of patients with cancer to bridge this knowledge gap in sepsis management.

Journal article

Kanai M, Andrews SJ, Cordioli M, Stevens C, Neale BM, Daly M, Ganna A, Pathak GA, Iwasaki A, Karjalainen J, Mehtonen J, Pirinen M, Chwialkowska K, Trankiem A, Balaconis MK, Veerapen K, Wolford BN, Ahmad HF, Andrews S, von Hohenstaufen Puoti KA, Boer C, Boua PR, Butler-Laporte G, Cadilla CL, Chwiałkowska K, Colombo F, Douillard V, Dueker N, Dutta AK, El-Sherbiny YM, Eltoukhy MM, Esmaeeli S, Faucon A, Fave M-J, Cadenas IF, Francescatto M, Francioli L, Franke L, Fuentes M, Durán RG, Cabrero DG, Harry EN, Jansen P, Szentpéteri JL, Kaja E, Kanai M, Kirk C, Kousathanas A, Krieger JE, Patel SK, Lemaçon A, Limou S, Lió P, Marouli E, Marttila MM, Medina-Gómez C, Michaeli Y, Migeotte I, Mondal S, Moreno-Estrada A, Moya L, Nakanishi T, Nasir J, Pasko D, Pearson NM, Pereira AC, Priest J, Prijatelj V, Prokić I, Teumer A, Várnai R, Romero-Gómez M, Roos C, Rosenfeld J, Ruolin L, Schulte EC, Schurmann C, Sedaghati-khayat B, Shaheen D, Shivanathan I, Sipeky C, Sirui Z, Striano P, Tanigawa Y, Remesal AU, Vadgama N, Vallerga CL, van der Laan S, Verdugo RA, Wang QS, Wei Z, Zainulabid UA, Zárate RN, Auton A, Shelton JF, Shastri AJ, Weldon CH, Filshtein-Sonmez T, Coker D, Symons A, Aslibekyan S, OConnell J, Ye C, Hatoum AS, Agrawal A, Bogdan R, Colbert SMC, Thompson WK, Fan CC, Johnson EC, Niazyan L, Davidyants M, Arakelyan A, Avetyan D, Bekbossynova M, Tauekelova A, Tuleutayev M, Sailybayeva A, Ramankulov Y, Zholdybayeva E, Dzharmukhanov J, Kassymbek K, Tsechoeva T, Turebayeva G, Smagulova Z, Muratov T, Khamitov S, Kwong ASF, Timpson NJ, Niemi MEK, Rahmouni S, Guntz J, Beguin Y, Cordioli M, Pigazzini S, Nkambule L, Georges M, Moutschen M, Misset B, Darcis G, Gofflot S, Bouysran Y, Busson A, Peyrassol X, Wilkin F, Pichon B, Smits G, Vandernoot I, Goffard J-C, Tiembe N, Morrison DR, Afilalo J, Mooser V, Richards JB, Rousseau S, Durand M, Butler-Laporte G, Forgetta V, Laurent L, Afrasiabi Z, Bouab M, Tselios C, Xue X, Afilalo M, Oliveira M, St-Cyr J, Boisclair A, Ragoussis J, Auld D, Kaufet al., 2023, A second update on mapping the human genetic architecture of COVID-19, Nature, Vol: 621, Pages: E7-E26, ISSN: 0028-0836

Journal article

Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, Clohisey S, Abellan J, Alex B, Shelton JF, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, Baillie JKet al., 2023, Author Correction: GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 619, Pages: E61-E61, ISSN: 0028-0836

Journal article

Smith S, Edwards L, Wigmore T, Jhanji S, Antcliffe D, Tatham Ket al., 2023, Survival of patients with solid tumors and sepsis admitted to intensive care in a tertiary oncology center: A retrospective analysis, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, GenOMICC Investigators, SCOURGE Consortium, ISARICC Investigators, 23andMe COVID-19 Team, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, Baillie JKet al., 2023, GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 617, Pages: 764-768, ISSN: 0028-0836

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. 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 group3. 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).

Journal article

Wu MY, Shepherd STC, Fendler A, Carr EJ, Au L, Harvey R, Dowgier G, Hobbs A, Herman LS, Ragno M, Adams L, Schmitt AM, Tippu Z, Shum B, Farag S, Rogiers A, O'Reilly N, Bawumia P, Smith C, Carlyle E, Edmonds K, Del Rosario L, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Barber T, Hepworth S, Emslie-Henry A, Caulfield-Lynch N, Byrne F, Deng D, Williams B, Brown M, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Popat S, Yousaf N, Jhanji S, Tatham K, Cunningham D, Van As N, Young K, Furness AJS, Pickering L, Beale R, Swanton C, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Howell M, Walker S, Nicholson E, Larkin J, Wall EC, Turajlic Set al., 2023, Sotrovimab restores neutralization against current Omicron subvariants in patients with blood cancer, CANCER CELL, Vol: 41, Pages: 821-823, ISSN: 1535-6108

Journal article

RECOVERY Collaborative Group, 2023, Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial, The Lancet, Vol: 401, Pages: 1499-1507, ISSN: 0140-6736

BACKGROUND: Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation <92% on room air) were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg dexamethasone once daily for 5 days or until discharge if sooner) or usual standard of care alone (which included dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality among all randomised participants. On May 11, 2022, the independent data monitoring committee recommended stopping recruitment of patients receiving no oxygen or simple oxygen only due to safety concerns. We report the results for these participants only. Recruitment of patients receiving ventilatory support is ongoing. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen (eight [1%]) or simple oxygen only (1264 [99%]) were randomly allocated to receive usual care plus higher dose corticosteroids (659 patients) versus usual care alone (613 patients, of whom 87% received low-dose corticosteroids during the follow-up period). Of those randomly assigned, 745 (59%) were in Asia, 512 (40%) in the UK, and 15 (1%) in Africa. 248 (19%) had diabetes and 769 (60%) were male. Overall, 123 (19%) of 659

Journal article

Ng K, Boumelha J, Enfield KSS, Almagro JL, Cha HM, Pich O, Karasaki T, Moore D, Salgado R, Sivakumar M, Young G, Molina-Arcas ML, de Carne Trecesson S, Anastasiou P, Fendler AC, Au L, Shepherd STC, Martinez-Ruiz C, Puttick C, Black JRM, Watkins TBK, Kim H, Shim S, Faulkner N, Attig JA, Veeriah S, Magno NJ, Ward ST, Frankell A, Al Bakir M, Lim E, Hill M, Wilson G, Cook D, Birkbak N, Behrens A, Yousaf N, Popat S, Hackshaw A, TRACERx C, CAPTURE C, Hiley CT, Litchfield K, McGranahan N, Jamal-Hanjani M, Larkin J, Lee S-H, Turajlic S, Swanton C, Downward J, Kassiotis Get al., 2023, Antibodies against endogenous retroviruses promote lung cancer immunotherapy, Nature, Vol: 616, Pages: 563-573, ISSN: 0028-0836

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

Journal article

Goldswain H, Dong X, Penrice-Randal R, Alruwaili M, Shawli GT, Prince T, Williamson MK, Raghwani J, Randle N, Jones B, Donovan-Banfield I, Salguero FJ, Tree JA, Hall Y, Hartley C, Erdmann M, Bazire J, Jearanaiwitayakul T, Semple MG, Openshaw PJM, Baillie JK, ISARIC4C Investigators, Emmett SR, Digard P, Matthews DA, Turtle L, Darby AC, Davidson AD, Carroll MW, Hiscox JAet al., 2023, The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection, Genome Biology, Vol: 24, ISSN: 1474-7596

BACKGROUND: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. RESULTS: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. CONCLUSIONS: These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

Journal article

Richards T, Miles LF, Clevenger B, Keegan A, Abeysiri S, Rao Baikady R, Besser MW, Browne JP, Klein AA, Macdougall IC, Murphy GJ, Anker SD, Dahly D, PREVENTT trial collaboratorset al., 2023, The association between iron deficiency and outcomes: a secondary analysis of the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial., Anaesthesia, Vol: 78, Pages: 320-329

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30 μg.l-1 ; functional iron deficiency as ferritin 30-100 μg.l-1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9 g.l-1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8 g.l-1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p = 

Journal article

Siggins MK, Davies K, Fellows R, Thwaites RS, Baillie JK, Semple MG, Openshaw PJM, Zelek WM, Harris CL, Morgan BP, ISARIC4C Investigatorset al., 2023, Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19, Immunology, Vol: 168, Pages: 473-492, ISSN: 0019-2805

Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in an COVID-19 to date, a comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalised COVID-19 patients collected across the hospitalisation period as part of the UK ISARIC4C study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to heathy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention.

Journal article

Tabah A, Buetti N, Staiquly Q, Ruckly S, Akova M, Aslan AT, Leone M, Conway Morris A, Bassetti M, Arvaniti K, Lipman J, Ferrer R, Qiu H, Paiva J-A, Povoa P, De Bus L, De Waele J, Zand F, Gurjar M, Alsisi A, Abidi K, Bracht H, Hayashi Y, Jeon K, Elhadi M, Barbier F, Timsit J-F, EUROBACT-2 Study Group, ESICM, ESCMID ESGCIP and the OUTCOMEREA Networket al., 2023, Epidemiology and outcomes of hospital-acquired bloodstream infections in intensive care unit patients: the EUROBACT-2 international cohort study, Intensive Care Medicine, Vol: 49, Pages: 178-190, ISSN: 0342-4642

PURPOSE: In the critically ill, hospital-acquired bloodstream infections (HA-BSI) are associated with significant mortality. Granular data are required for optimizing management, and developing guidelines and clinical trials. METHODS: We carried out a prospective international cohort study of adult patients (≥ 18 years of age) with HA-BSI treated in intensive care units (ICUs) between June 2019 and February 2021. RESULTS: 2600 patients from 333 ICUs in 52 countries were included. 78% HA-BSI were ICU-acquired. Median Sequential Organ Failure Assessment (SOFA) score was 8 [IQR 5; 11] at HA-BSI diagnosis. Most frequent sources of infection included pneumonia (26.7%) and intravascular catheters (26.4%). Most frequent pathogens were Gram-negative bacteria (59.0%), predominantly Klebsiella spp. (27.9%), Acinetobacter spp. (20.3%), Escherichia coli (15.8%), and Pseudomonas spp. (14.3%). Carbapenem resistance was present in 37.8%, 84.6%, 7.4%, and 33.2%, respectively. Difficult-to-treat resistance (DTR) was present in 23.5% and pan-drug resistance in 1.5%. Antimicrobial therapy was deemed adequate within 24 h for 51.5%. Antimicrobial resistance was associated with longer delays to adequate antimicrobial therapy. Source control was needed in 52.5% but not achieved in 18.2%. Mortality was 37.1%, and only 16.1% had been discharged alive from hospital by day-28. CONCLUSIONS: HA-BSI was frequently caused by Gram-negative, carbapenem-resistant and DTR pathogens. Antimicrobial resistance led to delays in adequate antimicrobial therapy. Mortality was high, and at day-28 only a minority of the patients were discharged alive from the hospital. Prevention of antimicrobial resistance and focusing on adequate antimicrobial therapy and source control are important to optimize patient management and outcomes.

Journal article

Liew F, Talwar S, Cross A, Willett B, Scott S, Logan N, Siggins M, Swieboda D, Sidhu J, Efstathiou C, Moore S, Davis C, Mohamed N, Nunag J, King C, Thompson AAR, Rowland-Jones S, Docherty A, Chalmers J, Ho L-P, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard L, Wootton D, Dunachie S, Quint J, Evans R, Wain L, Fontanella S, de Silva T, Ho A, Harrison E, Baillie JK, Semple MG, Brightling C, Thwaites R, Turtle L, Openshaw Pet al., 2023, SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination, EBioMedicine, Vol: 87, Pages: 1-14, ISSN: 2352-3964

Background:Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.Methods:In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.Findings:Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination.Interpretation:The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.Funding:This

Journal article

Pop O-T, Geng A, Flint E, Singanayagam A, Ercan C, Possamai L, Patel VC, Kuenzler P, Meier M-A, Soysal S, Hruz P, Kollmar O, Tatham KC, Ward JK, Müllhaupt B, Weber A, Wendon J, Niess JH, Heim M, Semela D, Weston C, Antoniades CG, Terracciano LM, Triantafyllou E, Brenig RG, Bernsmeier Cet al., 2023, AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells, Cellular and Molecular Gastroenterology and Hepatology, Vol: 16, Pages: 17-37, ISSN: 2352-345X

BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14+HLA-DR+AXL+) and acute-on-chronic liver failure (CD14+MERTK+). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced TNF-α/IL-6 production and T cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment- but not interstitial lung-, and tissue-resident synovial lining macrophages. We assessed AXL expression on tissue macrophages in patients with cirrhosis. METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n=22), chronic liver disease (n=8), non-cirrhotic portal hypertension (n=4) and healthy controls (n=4). Phenotype and function of isolated primary human liver macrophages were characterised by flow cytometry (cirrhosis, n=11; control, n=14) ex vivo. Also, AXL expression was assessed on peritoneal- (n=29) and gut macrophages (n=16) from cirrhotic patients. Regulation of AXL expression was analysed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells and GAS6 in co-culture experiments. RESULTS: AXL was expressed on resident (CD68+) but not tissue-infiltrating (MAC387+) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68+AXL+ cells significantly decreased with cirrhosis progression: (Healthy 90.2%; Child Pugh A 76.1%; B 64.5%; C 18.7%, all p<0.05) and negatively correlated with MELD and CRP (all p<0.05). AXL-expressing hepatic macrophages were CD68highHLA-DRhighCD16highCD206high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients, but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, pote

Journal article

Komorowski M, Green A, Tatham KC, Seymour C, Antcliffe Det al., 2022, Sepsis biomarkers and diagnostic tools with a focus on machine learning., EBioMedicine, Vol: 86, Pages: 1-10, ISSN: 2352-3964

Over the last years, there have been advances in the use of data-driven techniques to improve the definition, early recognition, subtypes characterisation, prognostication and treatment personalisation of sepsis. Some of those involve the discovery or evaluation of biomarkers or digital signatures of sepsis or sepsis sub-phenotypes. It is hoped that their identification may improve timeliness and accuracy of diagnosis, suggest physiological pathways and therapeutic targets, inform targeted recruitment into clinical trials, and optimise clinical management. Given the complexities of the sepsis response, panels of biomarkers or models combining biomarkers and clinical data are necessary, as well as specific data analysis methods, which broadly fall under the scope of machine learning. This narrative review gives a brief overview of the main machine learning techniques (mainly in the realms of supervised and unsupervised methods) and published applications that have been used to create sepsis diagnostic tools and identify biomarkers.

Journal article

Vink E, Davis C, MacLean A, Pascall D, McDonald SE, Gunson R, Hardwick HE, Oosthuyzen W, Openshaw PJM, Baillie JK, Semple MG, Ho Aet al., 2022, Viral coinfections in hospitalized Coronavirus disease 2019 patients recruited to the international severe acute respiratory and emerging infections consortium WHO clinical characterisation protocol UK study, Open Forum Infectious Diseases, Vol: 9, Pages: 1-10, ISSN: 2328-8957

BackgroundWe conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity.MethodsMultiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge.ResultsA coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity.ConclusionsViral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward.

Journal article

Fendler A, Shepherd STC, Au L, Wu M, Harvey R, Wilkinson KA, Schmitt AM, Tippu Z, Shum B, Farag S, Rogiers A, Carlyle E, Edmonds K, Del Rosario L, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Barber T, Emslie-Henry A, Caulfield-Lynch N, Byrne F, Deng D, Kjaer S, Song O-R, Queval CJ, Kavanagh C, Wall EC, Carr EJ, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Shea RL, Gardner G, Murray D, Popat S, Yousaf N, Jhanji S, Tatham K, Cunningham D, Van As N, Young K, Furness AJS, Pickering L, Beale R, Swanton C, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Howell M, Nicholson E, Walker S, Wilkinson RJ, Larkin J, Turajlic Set al., 2022, Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer, Cell Reports Medicine, Vol: 3, ISSN: 2666-3791

Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.

Journal article

RECOVERY Collaborative Group, 2022, Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis., The Lancet, Vol: 400, Pages: 359-368, ISSN: 0140-6736

BACKGROUND: We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1-2 inhibitor, for the treatment of patients admitted to hospital with COVID-19. METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936) and is ongoing. FINDINGS: Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77-0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45-0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed t

Journal article

Närhi F, Moonesinghe SR, Shenkin SD, Drake TM, Mulholland RH, Donegan C, Dunning J, Fairfield CJ, Girvan M, Hardwick HE, Ho A, Leeming G, Nguyen-Van-Tam JS, Pius R, Russell CD, Shaw CA, Spencer RG, Turtle L, Openshaw PJM, Baillie JK, Harrison EM, Semple MG, Docherty AB, ISARIC4C investigatorset al., 2022, Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study., The Lancet Digital Health, Vol: 4, Pages: e220-e234, ISSN: 2589-7500

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70-0·89], p=0·0001, for 70-79 years; 0·52 [0·46-0·58], p<0·0001, for >80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75-80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant wom

Journal article

Kousathanas A, Pairo-Castineira E, Rawlik K, Stuckey A, Odhams CA, Walker S, Russell CD, Malinauskas T, Wu Y, Millar J, Shen X, Elliott KS, Griffiths F, Oosthuyzen W, Morrice K, Keating S, Wang B, Rhodes D, Klaric L, Zechner M, Parkinson N, Siddiq A, Goddard P, Donovan S, Maslove D, Nichol A, Semple MG, Zainy T, Maleady-Crowe F, Todd L, Salehi S, Knight J, Elgar G, Chan G, Arumugam P, Patch C, Rendon A, Bentley D, Kingsley C, Kosmicki JA, Horowitz JE, Baras A, Abecasis GR, Ferreira MAR, Justice A, Mirshahi T, Oetjens M, Rader DJ, Ritchie MD, Verma A, Fowler TA, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Elliott P, Walsh T, Tenesa A, GenOMICC Investigators, 23andMe, Covid-19 Human Genetics Initiative, Fawkes A, Murphy L, Rowan K, Ponting CP, Vitart V, Wilson JF, Yang J, Bretherick AD, Scott RH, Hendry SC, Moutsianas L, Law A, Caulfield MJ, Baillie JKet al., 2022, Whole genome sequencing reveals host factors underlying critical Covid-19, Nature, Vol: 607, Pages: 97-103, ISSN: 0028-0836

Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2-4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing in 7,491 critically-ill cases compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical Covid-19. We identify 16 new independent associations, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5, CD209) and coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of Covid-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication, or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.

Journal article

Fendler A, Shepherd STC, Au L, Wu M, Harvey R, Schmitt AM, Tippu Z, Shum B, Farag S, Rogiers A, Carlyle E, Edmonds K, Del Rosario L, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Barber T, Emslie-Henry A, Caulfield-Lynch N, Byrne F, Deng D, Kjaer S, Song O-R, Queval C, Kavanagh C, Wall EC, Carr EJ, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Shea RL, Gardner G, Murray D, Yousaf N, Jhanji S, Tatham K, Cunningham D, Van As N, Young K, Furness AJS, Pickering L, Beale R, Swanton C, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Howell M, Nicholson E, Walker S, Larkin J, Turajlic S, CAPTURE consortiumet al., 2022, Omicron neutralising antibodies after third COVID-19 vaccine dose in patients with cancer., Lancet, Vol: 399, Pages: 905-907

Journal article

RECOVERY Collaborative Group, 2022, Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial, The Lancet, Vol: 399, Pages: 665-676, ISSN: 0140-6736

BACKGROUND: Casirivimab and imdevimab are non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells. We aimed to evaluate the efficacy and safety of casirivimab and imdevimab administered in combination in patients admitted to hospital with COVID-19. METHODS: RECOVERY is a randomised, controlled, open-label platform trial comparing several possible treatments with usual care in patients admitted to hospital with COVID-19. 127 UK hospitals took part in the evaluation of casirivimab and imdevimab. Eligible participants were any patients aged at least 12 years admitted to hospital with clinically suspected or laboratory-confirmed SARS-CoV-2 infection. Participants were randomly assigned (1:1) to either usual standard of care alone or usual care plus casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion. Investigators and data assessors were masked to analyses of the outcome data during the trial. The primary outcome was 28-day all-cause mortality assessed by intention to treat, first only in patients without detectable antibodies to SARS-CoV-2 infection at randomisation (ie, those who were seronegative) and then in the overall population. Safety was assessed in all participants who received casirivimab and imdevimab. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between Sept 18, 2020, and May 22, 2021, 9785 patients enrolled in RECOVERY were eligible for casirivimab and imdevimab, of which 4839 were randomly assigned to casirivimab and imdevimab plus usual care and 4946 to usual care alone. 3153 (32%) of 9785 patients were seronegative, 5272 (54%) were seropositive, and 1360 (14%) had unknown baseline antibody status. 812 (8%) patients were known to have received at least one dose of a SARS-CoV-2 vaccine. In the primary efficacy population of seronegative patients, 396 (2

Journal article

Dejnirattisai W, Huo J, Zhou D, Zahradník J, Supasa P, Liu C, Duyvesteyn HME, Ginn HM, Mentzer AJ, Tuekprakhon A, Nutalai R, Wang B, Dijokaite A, Khan S, Avinoam O, Bahar M, Skelly D, Adele S, Johnson SA, Amini A, Ritter TG, Mason C, Dold C, Pan D, Assadi S, Bellass A, Omo-Dare N, Koeckerling D, Flaxman A, Jenkin D, Aley PK, Voysey M, Costa Clemens SA, Naveca FG, Nascimento V, Nascimento F, Fernandes da Costa C, Resende PC, Pauvolid-Correa A, Siqueira MM, Baillie V, Serafin N, Kwatra G, Da Silva K, Madhi SA, Nunes MC, Malik T, Openshaw PJM, Baillie JK, Semple MG, Townsend AR, Huang K-YA, Tan TK, Carroll MW, Klenerman P, Barnes E, Dunachie SJ, Constantinides B, Webster H, Crook D, Pollard AJ, Lambe T, OPTIC Consortium, ISARIC4C Consortium, Paterson NG, Williams MA, Hall DR, Fry EE, Mongkolsapaya J, Ren J, Schreiber G, Stuart DI, Screaton GRet al., 2022, SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses, Cell, Vol: 185, Pages: 467-484.e15, ISSN: 0092-8674

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

Journal article

Keeling MJ, Dyson L, Guyver-Fletcher G, Holmes A, Semple MG, Tildesley MJ, Hill EMet al., 2022, Fitting to the UK COVID-19 outbreak, short-term forecasts and estimating the reproductive number, Statistical Methods in Medical Research, ISSN: 0962-2802

The COVID-19 pandemic has brought to the fore the need for policy makers to receive timely and ongoing scientific guidance in response to this recently emerged human infectious disease. Fitting mathematical models of infectious disease transmission to the available epidemiological data provide a key statistical tool for understanding the many quantities of interest that are not explicit in the underlying epidemiological data streams. Of these, the effective reproduction number, R, has taken on special significance in terms of the general understanding of whether the epidemic is under control (R<1). Unfortunately, none of the epidemiological data streams are designed for modelling, hence assimilating information from multiple (often changing) sources of data is a major challenge that is particularly stark in novel disease outbreaks. Here, focusing on the dynamics of the first wave (March–June 2020), we present in some detail the inference scheme employed for calibrating the Warwick COVID-19 model to the available public health data streams, which span hospitalisations, critical care occupancy, mortality and serological testing. We then perform computational simulations, making use of the acquired parameter posterior distributions, to assess how the accuracy of short-term predictions varied over the time course of the outbreak. To conclude, we compare how refinements to data streams and model structure impact estimates of epidemiological measures, including the estimated growth rate and daily incidence.

Journal article

RECOVERY Collaborative Group, 2022, Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial, The Lancet, Vol: 399, Pages: 143-151, ISSN: 0140-6736

BACKGROUND: Aspirin has been proposed as a treatment for COVID-19 on the basis of its anti-thrombotic properties. We aimed to evaluate the efficacy and safety of aspirin in patients admitted to hospital with COVID-19. METHODS: In this randomised, controlled, open-label, platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. The trial took place at 177 hospitals in the UK, two hospitals in Indonesia, and two hospitals in Nepal. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care plus 150 mg aspirin once per day until discharge or usual standard of care alone using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28 day mortality. All analyses were done by intention to treat. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between Nov 1, 2020, and March 21, 2021, 14 892 (66%) of 22 560 patients enrolled into the RECOVERY trial were eligible to be randomly allocated to aspirin. 7351 patients were randomly allocated (1:1) to receive aspirin and 7541 patients to receive usual care alone. Overall, 1222 (17%) of 7351 patients allocated to aspirin and 1299 (17%) of 7541 patients allocated to usual care died within 28 days (rate ratio 0·96, 95% CI 0·89-1·04; p=0·35). Consistent results were seen in all prespecified subgroups of patients. Patients allocated to aspirin had a slightly shorter duration of hospitalisation (median 8 days, IQR 5 to >28, vs 9 days, IQR 5 to >28) and a higher proportion were discharged from hospital alive within 28 days (75% vs 74%; rate ratio 1·06, 95% CI 1·02-1·10; p=0·0062). Among patients not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (2

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

Knight SR, Gupta RK, Ho A, Pius R, Buchan I, Carson G, Drake TM, Dunning J, Fairfield CJ, Gamble C, Green CA, Halpin S, Hardwick HE, Holden KA, Horby PW, Jackson C, Mclean KA, Merson L, Nguyen-Van-Tam JS, Norman L, Olliaro PL, Pritchard MG, Russell CD, Shaw CA, Sheikh A, Solomon T, Sudlow C, Swann O, Turtle LCW, Openshaw PJM, Baillie JK, Docherty A, Semple MG, Noursadeghi M, Harrison EMet al., 2021, Prospective validation of the 4C prognostic models for adults hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol, Thorax, Vol: 77, Pages: 1-10, ISSN: 0040-6376

Purpose To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19.Methods Prospective observational cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups.Results 76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, –0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions.Conclusion Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making.Trial registration number ISRCTN66726260.

Journal article

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