Imperial College London

Peter Openshaw - Professor of Experimental Medicine

Faculty of MedicineNational Heart & Lung Institute

Proconsul, Professor of Experimental Medicine
 
 
 
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Contact

 

+44 (0)20 7594 3854p.openshaw Website

 
 
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Assistant

 

Ms Gale Lewis +44 (0)20 7594 0944

 
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Location

 

353Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

371 results found

Wickenhagen A, Sugrue E, Lytras S, Kuchi S, Noerenberg M, Turnbull ML, Loney C, Herder V, Allan J, Jarmson I, Cameron-Ruiz N, Varjak M, Pinto RM, Lee JY, Iselin L, Palmalux N, Stewart DG, Swingler S, Greenwood EJD, Crozier TWM, Gu Q, Davies EL, Clohisey S, Wang B, Trindade Maranhão Costa F, Freire Santana M, de Lima Ferreira LC, Murphy L, Fawkes A, Meynert A, Grimes G, ISARIC4C Investigators, Da Silva Filho JL, Marti M, Hughes J, Stanton RJ, Wang ECY, Ho A, Davis I, Jarrett RF, Castello A, Robertson DL, Semple MG, Openshaw PJM, Palmarini M, Lehner PJ, Baillie JK, Rihn SJ, Wilson SJet al., 2021, A prenylated dsRNA sensor protects against severe COVID-19., Science, Vol: 374

[Figure: see text].

Journal article

Cuthbertson L, James P, Habibi MS, Thwaites RS, Paras A, Chiu C, Openshaw PJM, Cookson WOC, Moffatt MFet al., 2021, Resilience of the respiratory microbiome in controlled adult RSV challenge study., Eur Respir J

Journal article

Sullivan MK, Lees JS, Drake TM, Docherty AB, Oates G, Hardwick HE, Russell CD, Merson L, Dunning J, Nguyen-Van-Tam JS, Openshaw P, Harrison EM, Baillie JK, ISARIC4C Investigatorset al., 2021, Acute kidney injury in patients hospitalised with COVID-19 from the ISARIC WHO CCP-UK Study: a prospective, multicentre cohort study., Nephrol Dial Transplant

BACKGROUND: Acute kidney injury (AKI) is common in COVID-19. This study investigated adults hospitalised with COVID-19 and hypothesised that risk factors for AKI would include co-morbidities and non-white race. METHODS: A prospective multicentre cohort study was performed using patients admitted to 254 UK hospitals with COVID-19 between January 17th 2020 and December 5th 2020. RESULTS: Of 85,687 patients, 2,198 (2.6%) received acute kidney replacement therapy (KRT). Of 41,294 patients with biochemistry data, 13,000 (31.5%) had biochemical AKI: 8,562 stage 1 (65.9%), 2,609 stage 2 (20.1%) and 1,829 stage 3 (14.1%). The main risk factors for KRT were chronic kidney disease (CKD: Adjusted odds ratio (aOR) 3.41: 95% confidence interval 3.06-3.81), male sex (aOR 2.43: 2.18-2.71) and black race (aOR 2.17: 1.79-2.63). The main risk factors for biochemical AKI were admission respiratory rate >30 breaths per minute (aOR 1.68: 1.56-1.81), CKD (aOR 1.66: 1.57-1.76) and black race (aOR 1.44: 1.28-1.61). There was a gradated rise in the risk of 28-day mortality by increasing severity of AKI: stage 1 aOR 1.58 (1.49-1.67); stage 2 aOR 2.41 (2.20-2.64); stage 3 aOR 3.50 (3.14-3.91); KRT aOR 3.06 (2.75-3.39). AKI rates peaked in April 2020 and the subsequent fall in rates could not be explained by the use of dexamethasone or remdesivir. CONCLUSIONS: AKI is common in adults hospitalised with COVID-19 and it is associated with a heightened risk of mortality. Although the rates of AKI have fallen from the early months of the pandemic, high-risk patients should have their kidney function and fluid status monitored closely.

Journal article

Evans RA, McAuley H, Harrison EM, Shikotra A, Singapuri A, Sereno M, Elneima O, Docherty AB, Lone NI, Leavy OC, Daines L, Baillie JK, Brown JS, Chalder T, De Soyza A, Diar Bakerly N, Easom N, Geddes JR, Greening NJ, Hart N, Heaney LG, Heller S, Howard L, Hurst JR, Jacob J, Jenkins RG, Jolley C, Kerr S, Kon OM, Lewis K, Lord JM, McCann GP, Neubauer S, Openshaw PJM, Parekh D, Pfeffer P, Rahman NM, Raman B, Richardson M, Rowland M, Semple MG, Shah AM, Singh SJ, Sheikh A, Thomas D, Toshner M, Chalmers JD, Ho L-P, Horsley A, Marks M, Poinasamy K, Wain LV, Brightling CE, PHOSP-COVID Collaborative Groupet al., 2021, Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study, The Lancet Respiratory Medicine, Vol: 9, Pages: 1275-1287, ISSN: 2213-2600

BACKGROUND: The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. METHODS: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9-6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40-59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health bur

Journal article

Gu-Lung L, Drysdale SB, Snape MD, O'Connor D, Brown A, MacIntyre-Cockett G, Mellado-Gomez E, de Cesare M, Bonsall D, Ansari MA, Oner D, Aerssens J, Butler C, Bont L, Openshaw P, Martinon-Torres F, Nair H, Bowden R, Golubchik T, Pollard AJet al., 2021, Publisher Correction: Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus, Nature Communications, Vol: 12, Pages: 1-1, ISSN: 2041-1723

Journal article

Hurst EA, Mellanby RJ, Handel I, Griffith DM, Rossi AG, Walsh TS, Shankar-Hari M, Dunning J, Homer NZ, Denham SG, Devine K, Holloway PA, Moore SC, Thwaites RS, Samanta RJ, Summers C, Hardwick HE, Oosthuyzen W, Turtle L, Semple MG, Openshaw PJM, Baillie JK, Russell CDet al., 2021, Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study, BMJ OPEN, Vol: 11, ISSN: 2044-6055

Journal article

Cevik M, Grubaugh ND, Iwasaki A, Openshaw Pet al., 2021, COVID-19 vaccines: Keeping pace with SARS-CoV-2 variants., Cell, Vol: 184, Pages: 5077-5081, ISSN: 0092-8674

As the SARS-CoV-2 pandemic evolves, new variants continue to emerge. Some highly transmissible variants, such as Delta, also raised concerns about the effectiveness provided by current vaccines. Understanding immunological correlates of protection and how laboratory findings correspond to clinical effectiveness is imperative to shape future vaccination strategies.

Journal article

McGinley J, Thwaites R, Brebner W, Greenan-Barrett L, Aerssens J, Öner D, Bont L, Wildenbeest J, Martinón-Torres F, Nair H, Pollard AJ, Openshaw P, Drysdale S, REspiratory Syncytial virus Consortium in EUrope RESCEU Investigatorset al., 2021, A systematic review and meta-analysis of animal studies investigating the relationship between serum antibody, T lymphocytes, and respiratory syncytial virus disease, Journal of Infectious Diseases, ISSN: 0022-1899

BACKGROUND: Respiratory syncytial virus (RSV) infections occur in human populations around the globe, causing disease of variable severity, disproportionately affecting infants and older adults (>65 years of age). Immune responses can be protective but also contribute to disease. Experimental studies in animals enable detailed investigation of immune responses, provide insights into clinical questions, and accelerate the development of passive and active vaccination. We aimed to review the role of antibody and T-cell responses in relation to RSV disease severity in animals. METHODS: Systematic review and meta-analysis of animal studies examining the association between T-cell responses/phenotype or antibody titers and severity of RSV disease. The PubMed, Zoological Record, and Embase databases were screened from January 1980 to May 2018 to identify animal studies of RSV infection that assessed serum antibody titer or T lymphocytes with disease severity as an outcome. Sixty-three studies were included in the final review. RESULTS: RSV-specific antibody appears to protect from disease in mice, but such an effect was less evident in bovine RSV. Strong T-cell, Th1, Th2, Th17, CD4/CD8 responses, and weak Treg responses accompany severe disease in mice. CONCLUSIONS: Murine studies suggest that measures of T-lymphocyte activity (particularly CD4 and CD8 T cells) may be predictive biomarkers of severity. Further inquiry is merited to validate these results and assess relevance as biomarkers for human disease.

Journal article

Shaw RJ, Abrams ST, Austin J, Taylor JM, Lane S, Dutt T, Downey C, Du M, Turtle L, Baillie JK, Openshaw PJM, Wang G, Semple MG, Toh C-Het al., 2021, Circulating histones play a central role in COVID-19-associated coagulopathy and mortality, Haematologica: the hematology journal, Vol: 106, Pages: 2493-2498, ISSN: 0390-6078

Journal article

Sigfrid L, Drake TM, Pauley E, Jesudason EC, Olliaro P, Lim WS, Gillesen A, Berry C, Lowe DJ, McPeake J, Lone N, Munblit D, Cevik M, Casey A, Bannister P, Russell CD, Goodwin L, Ho A, Turtle L, O'Hara ME, Hastie C, Donohue C, Spencer RG, Donegan C, Gummery A, Harrison J, Hardwick HE, Hastie CE, Carson G, Merson L, Baillie JK, Openshaw P, Harrison EM, Docherty AB, Semple MG, Scott JT, ISARIC4C investigatorset al., 2021, Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol., The Lancet Regional Health - Europe, Vol: 8, Pages: 1-13, ISSN: 2666-7762

Background: This study sought to establish the long-term effects of Covid-19 following hospitalisation. Methods: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). Findings: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. Interpretation: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females. Funding: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation.

Journal article

Marciniak SJ, Farrell J, Rostron A, Smith I, Openshaw PJM, Baillie JK, Docherty A, Semple MGet al., 2021, COVID-19 pneumothorax in the UK: a prospective observational study using the ISARIC WHO clinical characterisation protocol., Eur Respir J, Vol: 58

Journal article

Lin G-L, Drysdale SB, Snape MD, O'Connor D, Brown A, Maclntyre-Cockett G, Mellado-Gomez E, de Cesare M, Bonsall D, Ansari MA, Oner D, Aerssens J, Butler C, Bont L, Openshaw P, Martinon-Torres F, Nair H, Bowden R, Golubchik T, Pollard AJet al., 2021, Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus, Nature Communications, Vol: 12, Pages: 1-11, ISSN: 2041-1723

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.

Journal article

Jacobsen H, Walendy-Gnirss K, Tekin-Bubenheim N, Kouassi NM, Ben-Batalla I, Berenbrok N, Wolff M, dos Reis VP, Zickler M, Scholl L, Gries A, Jania H, Kloetgen A, Duesedau A, Pilnitz-Stolze G, Jeridi A, Yildirim AO, Fuchs H, Gailus-Durner V, Stoeger C, de Angelis MH, Manuylova T, Klingel K, Culley FJ, Behrends J, Loges S, Schneider B, Krauss-Etschmann S, Openshaw P, Gabriel Get al., 2021, Offspring born to influenza A virus infected pregnant mice have increased susceptibility to viral and bacterial infections in early life, NATURE COMMUNICATIONS, Vol: 12

Journal article

Read JM, Green CA, Harrison EM, Docherty AB, Funk S, Harrison J, Girvan M, Hardwick HE, Turtle L, Dunning J, Nguyen-Van-Tam JS, Openshaw PJM, Baillie JK, Semple MGet al., 2021, Hospital-acquired SARS-CoV-2 infection in the UK's first COVID-19 pandemic wave, The Lancet, ISSN: 0140-6736

Journal article

Russell CD, Fairfield CJ, Drake TM, Turtle L, Seaton RA, Wootton DG, Sigfrid L, Harrison EM, Docherty AB, de Silva T, Egan C, Pius R, Hardwick HE, Merson L, Girvan M, Dunning J, Nguyen-Van-Tam JS, Openshaw PJM, Baillie JK, Semple MG, Ho Aet al., 2021, Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study, The Lancet Microbe, Vol: 2, Pages: E354-E365, ISSN: 2666-5247

BackgroundMicrobiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19.MethodsThe International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded.FindingsWe analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli a

Journal article

Yates T, Zaccardi F, Islam N, Razieh C, Gillies CL, Lawson CA, Chudasama Y, Rowlands A, Davies MJ, Docherty AB, Openshaw PJM, Baillie JK, Semple MG, Khunti Ket al., 2021, Obesity, chronic disease, age, and in-hospital mortality in patients with covid-19: analysis of ISARIC clinical characterisation protocol UK cohort, BMC Infectious Diseases, Vol: 21, Pages: 1-9, ISSN: 1471-2334

BackgroundAlthough age, obesity and pre-existing chronic diseases are established risk factors for COVID-19 outcomes, their interactions have not been well researched.MethodsWe used data from the Clinical Characterisation Protocol UK (CCP-UK) for Severe Emerging Infection developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC). Patients admitted to hospital with COVID-19 from 6th February to 12th October 2020 were included where there was a coded outcome following hospital admission. Obesity was determined by an assessment from a clinician and chronic disease by medical records. Chronic diseases included: chronic cardiac disease, hypertension, chronic kidney disease, chronic pulmonary disease, diabetes and cancer. Mutually exclusive categories of obesity, with or without chronic disease, were created. Associations with in-hospital mortality were examined across sex and age categories.ResultsThe analysis included 27,624 women with 6407 (23.2%) in-hospital deaths and 35,065 men with 10,001 (28.5%) in-hospital deaths. The prevalence of chronic disease in women and men was 66.3 and 68.5%, respectively, while that of obesity was 12.9 and 11.1%, respectively. Association of obesity and chronic disease status varied by age (p < 0.001). Under 50 years of age, obesity and chronic disease were associated with in-hospital mortality within 28 days of admission in a dose-response manner, such that patients with both obesity and chronic disease had the highest risk with a hazard ratio (HR) of in-hospital mortality of 2.99 (95% CI: 2.12, 4.21) in men and 2.16 (1.42, 3.26) in women compared to patients without obesity or chronic disease. Between the ages of 50–69 years, obesity and chronic disease remained associated with in-hospital COVID-19 mortality, but survival in those with obesity was similar to those with and without prevalent chronic disease. Beyond the age of 70 years in men and

Journal article

Drake TM, Riad AM, Fairfield CJ, Egan C, Knight SR, Pius R, Hardwick HE, Norman L, Shaw CA, McLean KA, Thompson AAR, Ho A, Swann OV, Sullivan M, Soares F, Holden KA, Merson L, Plotkin D, Sigfrid L, de Silva TI, Girvan M, Jackson C, Russell CD, Dunning J, Solomon T, Carson G, Olliaro P, Nguyen-Van-Tam JS, Turtle L, Docherty AB, Openshaw PJ, Baillie JK, Harrison EM, Semple MG, ISARIC4C investigatorset al., 2021, Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study, The Lancet, Vol: 398, Pages: 223-237, ISSN: 0140-6736

BACKGROUND: COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK. METHODS: We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities. FINDINGS: Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were

Journal article

Paterson S, Kar S, Ung SK, Gardener Z, Bergstrom E, Ascough S, Kalyan M, Zyla J, Maertzdorf J, Mollenkopf H-J, Weiner J, Jozwik A, Jarvis H, Jha A, Nicholson BP, Veldman T, Woods CW, Mallia P, Kon OM, Kaufmann SHE, Openshaw PJ, Chiu Cet al., 2021, Innate-like gene expression of lung-resident memory CD8+ T-cells during experimental human influenza, American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 826-841, ISSN: 1073-449X

Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T cells recognizing peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection.Objectives: To investigate the kinetics, phenotypes, and function of influenza virus–specific CD8+ resident memory T (Trm) cells in the lower airway and infer the molecular pathways associated with their response to infection in vivo.Methods: Healthy volunteers, aged 18–55, were inoculated intranasally with influenza A/California/4/09(H1N1). Blood, upper airway, and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed by using self-reported diaries, and the nasal viral load was assessed by using quantitative PCR. T-cell responses were analyzed by using a three-color FluoroSpot assay, flow cytometry with MHC I–peptide tetramers, and RNA sequencing, with candidate markers being confirmed by using the immunohistochemistry results for endobronchial biopsy specimens.Measurements and Main Results: After challenge, 57% of participants became infected. Preexisting influenza-specific CD8+ T cells in blood correlated strongly with a reduced viral load, which peaked at Day 3. Influenza-specific CD8+ T cells in BAL fluid were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between preinfection CD8+ T cells in BAL fluid and blood by using RNA sequencing revealed 3,928 differentially expressed genes, including all major Trm-cell markers. However, gene set enrichment analysis of BAL-fluid CD8+ T cells showed primarily innate cell–related pathways and, during infection, included upregulation of innate chemokines (Cxcl1, Cxcl10, and Cxcl16) that were also expressed by CD8+ cells in bronchial tissues.Conclusions: CD8+ Trm cells in the human lung display innate-like gene and protein expression that demonstrates blur

Journal article

Kohns Vasconcelos M, Loens K, Sigfrid L, Iosifidis E, Epalza C, Donà D, Matheeussen V, Papachristou S, Roilides E, Gijon M, Rojo P, Minotti C, Da Dalt L, Islam S, Jarvis J, Syggelou A, Tsolia M, Nyirenda Nyang'wa M, Keers S, Renk H, Gemmel A-L, D'Amore C, Ciofi Degli Atti M, Rodríguez-Tenreiro Sánchez C, Martinón-Torres F, Burokienė S, Goetghebuer T, Spoulou V, Riordan A, Calvo C, Gkentzi D, Hufnagel M, Openshaw PJ, de Jong MD, Koopmans M, Goossens H, Ieven M, Fraaij PLA, Giaquinto C, Bielicki JA, Horby P, Sharland Met al., 2021, Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study, BMJ Open Respiratory Research, Vol: 8, ISSN: 2052-4439

BACKGROUND: Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation. METHODS: 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets. RESULTS: RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including Streptococcus pneumoniae, which was weakly associated with case status, and endemic coronaviruses. CONCLUSION: RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and

Journal article

Siggins MK, Thwaites RS, Openshaw PJM, 2021, Durability of immunity to SARS-CoV-2 and other respiratory viruses: (Trends in microbiology, 29, 648-662, 2021)., Trends in Microbiology, ISSN: 0966-842X

Journal article

Drake TM, Fairfield CJ, Pius R, Knight SR, Norman L, Girvan M, Hardwick HE, Docherty AB, Thwaites RS, Openshaw PJM, Baillie JK, Harrison EM, Semple MG, ISARIC4C Investigatorset al., 2021, Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study, The Lancet Rheumatology, Vol: 3, Pages: e498-e506, ISSN: 2665-9913

Background: Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease. Methods: This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations. Results: Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no si

Journal article

Siggins MK, Thwaites RS, Openshaw PJM, 2021, Durability of immunity to SARS-CoV-2 and other respiratory viruses, Trends in Microbiology, Vol: 29, Pages: 648-662, ISSN: 0966-842X

Even in nonpandemic times, respiratory viruses account for a vast global burden of disease. They remain a major cause of illness and death and they pose a perpetual threat of breaking out into epidemics and pandemics. Many of these respiratory viruses infect repeatedly and appear to induce only narrow transient immunity, but the situation varies from one virus to another. In the absence of effective specific treatments, understanding the role of immunity in protection, disease, and resolution is of paramount importance. These problems have been brought into sharp focus by the coronavirus disease 2019 (COVID-19) pandemic. Here, we summarise what is now known about adaptive immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and draw comparisons with immunity to other respiratory viruses, focusing on the longevity of protective responses.

Journal article

Bloom CI, Drake TM, Docherty AB, Lipworth BJ, Johnston SL, Nguyen-Van-Tam JS, Carson G, Dunning J, Harrison EM, Baillie JK, Semple MG, Cullinan P, Openshaw PJM, Alex B, Bach B, Barclay WS, Bogaert D, Chand M, Cooke GS, Filipe AD, Fletcher T, Green CA, Harrison EM, Hiscox JA, Ho AY, Horby PW, Ijaz S, Khoo S, Klenerman P, Law A, Lim WS, Mentzer AJ, Merson L, Meynert AM, Noursadeghi M, Moore SC, Palmarini M, Paxton WA, Pollakis G, Price N, Rambaut A, Robertson DL, Russell CD, Sancho-Shimizu V, Scott JT, Silva TD, Sigfrid L, Solomon T, Sriskandan S, Stuart D, Summers C, Tedder RS, Thomson EC, Thompson AAR, Thwaites RS, Turtle LCW, Zambon M, Hardwick H, Donohue C, Lyons R, Griffiths F, Oosthuyzen W, Norman L, Pius R, Fairfield CJ, Knight SR, Mclean KA, Murphy D, Shaw CA, Dalton J, Girvan M, Saviciute E, Roberts S, Harrison J, Marsh L, Connor M, Halpin S, Jackson C, Gamble C, Leeming G, Law A, Wham M, Clohisey S, Hendry R, Scott-Brown J, Greenhalf W, Shaw V, McDonald S, Keating S, Ahmed KA, Armstrong JA, Ashworth M, Asiimwe IG, Bakshi S, Barlow SL, Booth L, Brennan B, Bullock K, Catterall BWA, Clark JJ, Clarke EA, Cole S, Cooper L, Cox H, Davis C, Dincarslan O, Dunn C, Dyer P, Elliott A, Evans A, Finch L, Fisher LWS, Foster T, Garcia-Dorival I, Greenhalf W, Gunning P, Hartley C, Jensen RL, Jones CB, Jones TR, Khandaker S, King K, Kiy RT, Koukorava C, Lake A, Lant S, Latawiec D, Lavelle-Langham L, Lefteri D, Lett L, Livoti LA, Mancini M, McDonald S, McEvoy L, McLauchlan J, Metelmann S, Miah NS, Middleton J, Mitchell J, Moore SC, Murphy EG, Penrice-Randal R, Pilgrim J, Prince T, Reynolds W, Ridley PM, Sales D, Shaw VE, Shears RK, Small B, Subramaniam KS, Szemiel A, Taggart A, Tanianis-Hughes J, Thomas J, Trochu E, Tonder LV, Wilcock E, Zhang JE, Flaherty L, Maziere N, Cass E, Carracedo AD, Carlucci N, Holmes A, Massey H, Adeniji K, Agranoff D, Agwuh K, Ail D, Alegria A, Angus B, Ashish A, Atkinson D, Bari S, Barlow G, Barnass S, Barrett N, Bassford C, Baxter D, Beadsworth Met al., 2021, Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK, The Lancet Respiratory Medicine, Vol: 9, Pages: 699-711, ISSN: 2213-2600

BackgroundStudies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use.MethodsWe analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age (<16 years, 16–49 years, and ≥50 years). In-hospital mortality was measured by use of multilevel Cox proportional hazards, adjusting for demographics, comorbidities, and medications (inhaled corticosteroids, short-acting β-agonists [SABAs], and long-acting β-agonists [LABAs]). Patients with asthma who were taking an inhaled corticosteroid plus LABA plus another maintenance asthma medication were considered to have severe asthma.Findings75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16–49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16–49 years: adjusted odds ratio [OR] 1·20 [95% CI

Journal article

ISARIC Clinical Characterisation Group, 2021, COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study, Infection: journal of infectious disease, Vol: 49, Pages: 899-905, ISSN: 0300-8126

BACKGROUND: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. METHODS: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. RESULTS: 'Typical' symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. INTERPRETATION: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

Journal article

Arch BN, Kovacs D, Scott JT, Jones AP, Harrison EM, Rosala-Hallas A, Gamble CG, Openshaw PJM, Baillie JK, Semple MGet al., 2021, Evaluation of the effectiveness of remdesivir in treating severe COVID-19 using data from the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, national cohort study

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Remdesivir was given UK early-access approval for use in COVID-19 in people aged 12 years and older on 26<jats:sup>th</jats:sup> May 2020 on the basis of unmet clinical need. Evidence on the side effects, complications of therapy and effectiveness of this therapy is lacking or conflicting.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Adults with severe COVID-19 treated with remdesivir were compared with propensity-score matched controls, identified from the ISARIC WHO Clinical Characterisation Protocol study of UK hospitalised patients with COVID-19. Remdesivir patients were matched to controls according to baseline underlying 14-day mortality risk. The effect of remdesivir on short-term outcomes was investigated (primary outcome: 14-day mortality). Effect sizes were estimated and adjusted for potential confounders using multivariable modelling.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>1,549 patients given remdesivir and 4,964 matched controls were identified satisfying inclusion and exclusion criteria. The balance diagnostic threshold was achieved. Patients had symptoms for a median of 6 days prior to baseline; 62% were male, with mean (SD) age 63.1 (15.6) years, and 80% categorised as ‘White’ ethnicity. Fourteen-day mortality was not statistically significantly associated with treatment (9.3 % remdesivir vs. 11.9% controls, odds-ratio 0.80, [95% CI 0.60-1.07], p=0.116, adjusted for age, sex, number of key comorbidities, dexamethasone use, and diagnosis of viral pneumonia.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Treatment with remdesivir was not associated with a reduction in mortality in our primary endpoint at 14 days.</jats:p>

Journal article

Leclerc QJ, Fuller NM, Keogh RH, Diaz-Ordaz K, Sekula R, Semple MG, ISARIC4C Investigators, CMMID COVID-19 Working Group, Atkins KE, Procter SR, Knight GMet al., 2021, Importance of patient bed pathways and length of stay differences in predicting COVID-19 hospital bed occupancy in England., BMC Health Services Research, Vol: 21, Pages: 1-15, ISSN: 1472-6963

BACKGROUND: Predicting bed occupancy for hospitalised patients with COVID-19 requires understanding of length of stay (LoS) in particular bed types. LoS can vary depending on the patient's "bed pathway" - the sequence of transfers of individual patients between bed types during a hospital stay. In this study, we characterise these pathways, and their impact on predicted hospital bed occupancy. METHODS: We obtained data from University College Hospital (UCH) and the ISARIC4C COVID-19 Clinical Information Network (CO-CIN) on hospitalised patients with COVID-19 who required care in general ward or critical care (CC) beds to determine possible bed pathways and LoS. We developed a discrete-time model to examine the implications of using either bed pathways or only average LoS by bed type to forecast bed occupancy. We compared model-predicted bed occupancy to publicly available bed occupancy data on COVID-19 in England between March and August 2020. RESULTS: In both the UCH and CO-CIN datasets, 82% of hospitalised patients with COVID-19 only received care in general ward beds. We identified four other bed pathways, present in both datasets: "Ward, CC, Ward", "Ward, CC", "CC" and "CC, Ward". Mean LoS varied by bed type, pathway, and dataset, between 1.78 and 13.53 days. For UCH, we found that using bed pathways improved the accuracy of bed occupancy predictions, while only using an average LoS for each bed type underestimated true bed occupancy. However, using the CO-CIN LoS dataset we were not able to replicate past data on bed occupancy in England, suggesting regional LoS heterogeneities. CONCLUSIONS: We identified five bed pathways, with substantial variation in LoS by bed type, pathway, and geography. This might be caused by local differences in patient characteristics, clinical care strategies, or resource availability, and suggests that national LoS averages may not be appropriate for local forecasts of bed occ

Journal article

Salimi V, Viegas M, Trento A, Agoti CN, Anderson LJ, Avadhanula V, Bahl J, Bont L, Brister JR, Cane PA, Galiano M, Graham BS, Hatcher EL, Hellferscee O, Henke DM, Hirve S, Jackson S, Keyaerts E, Kragten-Tabatabaie L, Lindstrom S, Nauwelaers I, Nokes DJ, Openshaw PJ, Peret TC, Piedra PA, Ramaekers K, Rector A, Trovão NS, von Gottberg A, Zambon M, Zhang W, Williams TC, Barr IG, Buchholz UJet al., 2021, Proposal fo human respiratory syncytial virus nomenclature below the species level., Emerging Infectious Diseases, Vol: 27, Pages: 1-9, ISSN: 1080-6040

Human respiratory syncytial virus (HRSV) is the leading viral cause of serious pediatric respiratory disease, and lifelong reinfections are common. Its 2 major subgroups, A and B, exhibit some antigenic variability, enabling HRSV to circulate annually. Globally, research has increased the number of HRSV genomic sequences available. To ensure accurate molecular epidemiology analyses, we propose a uniform nomenclature for HRSV-positive samples and isolates, and HRSV sequences, namely: HRSV/subgroup identifier/geographic identifier/unique sequence identifier/year of sampling. We also propose a template for submitting associated metadata. Universal nomenclature would help researchers retrieve and analyze sequence data to better understand the evolution of this virus.

Journal article

Docherty AB, Mulholland RH, Lone NI, Cheyne CP, De Angelis D, Diaz-Ordaz K, Donegan C, Drake TM, Dunning J, Funk S, García-Fiñana M, Girvan M, Hardwick HE, Harrison J, Ho A, Hughes DM, Keogh RH, Kirwan PD, Leeming G, Nguyen Van-Tam JS, Pius R, Russell CD, Spencer RG, Tom BD, Turtle L, Openshaw PJ, Baillie JK, Harrison EM, Semple MG, ISARIC4C Investigatorset al., 2021, Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK, The Lancet Respiratory Medicine, Vol: 9, Pages: 773-785, ISSN: 2213-2600

BACKGROUND: Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital. METHODS: In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260. FINDINGS: Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8-32·7) in March 9 to April 26, 2020, to 16·4% (15·0-17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in

Journal article

Ogbe A, Kronsteiner B, Skelly DT, Pace M, Brown A, Adland E, Adair K, Akhter HD, Ali M, Ali S-E, Angyal A, Ansari MA, Arancibia-Carcamo CV, Brown H, Chinnakannan S, Conlon C, de Lara C, de Silva T, Dold C, Dong T, Donnison T, Eyre D, Flaxman A, Fletcher H, Gardner J, Grist JT, Hackstein C-P, Jaruthamsophon K, Jeffery K, Lambe T, Lee L, Li W, Lim N, Matthews PC, Mentzer AJ, Moore SC, Naisbitt DJ, Ogese M, Ogg G, Openshaw P, Pirmohamed M, Pollard AJ, Ramamurthy N, Rongkard P, Rowland-Jones S, Sampson O, Screaton G, Sette A, Stafford L, Thompson C, Thomson PJ, Thwaites R, Vieira V, Weiskopf D, Zacharopoulou P, Chalk J, Kerr G, Phalora P, Csala A, Jones M, Robinson N, Brown R, Hutchings C, Provine N, Ratcliff J, Amini A, Borak M, Dimitriadis S, Fordwoh T, Horsington B, Johnson S, Morrow J, Warren Y, Wells C, Turtle L, Klenerman P, Goulder P, Frater J, Barnes E, Dunachie Set al., 2021, T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses, Nature Communications, Vol: 12, Pages: 1-14, ISSN: 2041-1723

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.

Journal article

Gupta RK, Harrison EM, Ho A, Docherty AB, Knight SR, van Smeden M, Abubakar I, Lipman M, Quartagno M, 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, Scott-Brown J, Shaw CA, Sheikh A, Solomon T, Sudlow C, Swann OV, Turtle L, Openshaw PJM, Baillie JK, Semple MG, Noursadeghi M, Baillie JK, Semple MG, Openshaw PJM, Carson G, Alex B, Bach B, Barclay WS, Bogaert D, Chand M, Cooke GS, Docherty AB, Dunning J, Filipe ADS, Fletcher T, Green CA, Harrison EM, Hiscox JA, Ho AYW, Horby PW, Ijaz S, Khoo S, Klenerman P, Law A, Lim WS, Mentzer AJ, Merson L, Meynert AM, Noursadeghi M, Moore SC, Palmarini M, Paxton WA, Pollakis G, Price N, Rambaut A, Robertson DL, Russell CD, Sancho-Shimizu V, Scott JT, de Silva T, Sigfrid L, Solomon T, Sriskandan S, Stuart D, Summers C, Tedder RS, Thomson EC, Thompson AAR, Thwaites RS, Turtle LCW, Zambon M, Hardwick H, Donohue C, Lyons R, Griffiths F, Oosthuyzen W, Norman L, Pius R, Drake TM, Fairfield CJ, Knight S, Mclean KA, Murphy D, Shaw CA, Dalton J, Lee J, Plotkin D, Girvan M, Mullaney S, Petersen C, Saviciute E, Roberts S, Harrison J, Marsh L, Connor M, Halpin S, Jackson C, Gamble C, Leeming G, Law A, Wham M, Clohisey S, Hendry R, Scott-Brown J, Greenhalf W, Shaw V, McDonald S, Keating S, Ahmed KA, Armstrong JA, Ashworth M, Asiimwe IG, Bakshi S, Barlow SL, Booth L, Brennan B, Bullock K, Catterall BWA, Clark JJ, Clarke EA, Cole S, Cooper L, Cox H, Davis C, Dincarslan O, Dunn C, Dyer P, Elliott A, Evans A, Finch L, Fisher LWS, Foster T, Garcia-Dorival I, Greenhalf W, Gunning P, Hartley C, Ho A, Jensen RL, Jones CB, Jones TR, Khandaker S, King K, Kiy RT, Koukorava C, Lake A, Lant S, Latawiec D, Lavelle-Langham L, Lefteri D, Lett L, Livoti LA, Mancini M, McDonald S, McEvoy L, McLauchlan J, Metelmann S, Miah NS, Middleton J, Mitchell J, Moore SC, Murphy EG, Penrice-Randalet al., 2021, Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study, The Lancet Respiratory Medicine, Vol: 9, Pages: 349-359, ISSN: 2213-2600

BackgroundPrognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.MethodsWe developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).Findings74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [–0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than

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