Search

Your search keyword '"Wootton DG"' showing total 4 results
Start Over Author "Wootton DG" Topic sars-cov-2
4 results on '"Wootton DG"'

1. SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination.

Author

Liew F, Talwar S, Cross A, Willett BJ, Scott S, Logan N, Siggins MK, Swieboda D, Sidhu JK, Efstathiou C, Moore SC, Davis C, Mohamed N, Nunag J, King C, Thompson AAR, Rowland-Jones SL, Docherty AB, Chalmers JD, Ho LP, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard L, Wootton DG, Dunachie S, Quint JK, Evans RA, Wain LV, Fontanella S, de Silva TI, Ho A, Harrison E, Baillie JK, Semple MG, Brightling C, Thwaites RS, Turtle L, and Openshaw PJM

Subjects
Adult, Humans, COVID-19 Vaccines, Follow-Up Studies, Vaccination, Hospitalization, Immunoglobulin A, Immunoglobulin G, Antibodies, Viral, Antibodies, Neutralizing, SARS-CoV-2, COVID-19 prevention & control
Abstract

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 study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript., Competing Interests: Declaration of interests FL, ST, AC, BJW, SS, NL, MKS, DS, JKS, CE, SCM, CD, CK, NM, JN, EH, ABD, JKQ, LPH, KP, LH, OMK, SF, TIdS, DGW, RST and JKB have no conflicts of interest. AART receives speaker fees and support to attend meetings from Janssen Pharmaceuticals. SLRJ is on the data safety monitoring board for Bexero trial in HIV + adults in Kenya. JDC is the deputy chief editor of ERS and receives consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer and Zambon. AH is Deputy chair of NIHR Translational Research Collaboration (unpaid role). BR receives honoraria from Axcella therapeutics. SJD is a member of the PITCH Consortium which has received funding from UK Department of Health and Social Care. SJD receives support from UKRI as part of “Investigation of proven vaccine breakthrough by SARS-CoV-2 variants in established UK healthcare worker cohorts: SIREN consortium & PITCH Plus Pathway” (MR/W02067X/1), with contributions from UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK–CIC), the Huo Family Foundation and The National Institute for Health & Care Research (UKRIDHSC COVID-19 Rapid Response Rolling Call, Grant Reference Number COV19-RECPLAS). S.J.D. is a Scientific Advisor to the Scottish Parliament on COVID-19 for which she receives a fee. RAE is co–lead of PHOSP-COVID and receives fees from Astrazenaca/Evidera for consultancy on Long Covid and from Astrazenaca for consultancy on digital health. RAE has received speaker fees from Boehringer in June 2021 and has held a role as European Respiratory Society Assembly 01.02 Pulmonary Rehabilitation secretary. RAE is on the American Thoracic Society Pulmonary Rehabilitation Assembly programme committee. LVW receives funding from Orion pharma and GSK and holds contracts with Genentech and AstraZenaca. LVW has received consulting fees from Galapagos and Boehringer, is on the data advisory board for Galapagos and is Associate Editor for European Respiratory Journal. AH is a member of NIHR Urgent Public Health Group (June 2020–March 2021). MM is an applicant on the PHOSP study funded by NIHR/DHSC. MGS acts as an independent external and non-remunerated member of Pfizer's External Data Monitoring Committee for their mRNA vaccine program(s), is Chair of Infectious Disease Scientific Advisory Board of Integrum Scientific LLC, Greensboro, NC, USA and is director of MedEx Solutions Ltd and majority owner of MedEx Solutions Ltd and minority owner of Integrum Scientific LLC, Greensboro, NC, USA. MGS's institution has been gifted Clinical Trial Investigational Medicinal Product from Chiesi Farmaceutici S.p.A. MGS is a non-renumerated member of HMG UK New Emerging Respiratory Virus Threats Advisory Group (NERVTAG) and has previously been a non-renumerated member of SAGE. CB has received consulting fees and/or grants from GSK, AZ, Genentech, Roche, Novartis, Sanofi, Regeneron, Chiesi, Mologic and 4DPharma. LT has received consulting fees from MHRA and speak fees from Eisai Ltd. LT has a patent pending with ZikaVac. PJMO reports grants from the EU Innovative Medicines Initiative (IMI) 2 Joint Undertaking during the submitted work; grants from UK Medical Research Council, GlaxoSmithKline, Wellcome Trust, EU-IMI, UK, National Institute for Health Research, and UK Research and Innovation-Department for Business, Energy and Industrial Strategy; and personal fees from Pfizer, Janssen, and Seqirus, outside the submitted work., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2023
Full Text
View/download PDF

2. Utility of established prognostic scores in COVID-19 hospital admissions: multicentre prospective evaluation of CURB-65, NEWS2 and qSOFA.

Author

Bradley P, Frost F, Tharmaratnam K, and Wootton DG

Subjects
Aged, Aged, 80 and over, COVID-19 epidemiology, COVID-19 virology, Case-Control Studies, Female, Humans, Intensive Care Units statistics & numerical data, Male, Middle Aged, Mortality trends, Organ Dysfunction Scores, Predictive Value of Tests, Prognosis, Prospective Studies, Sepsis mortality, Severity of Illness Index, COVID-19 mortality, Hospitalization statistics & numerical data, SARS-CoV-2 genetics, Sepsis epidemiology
Abstract

Introduction: The COVID-19 pandemic is ongoing, yet, due to the lack of a COVID-19-specific tool, clinicians must use pre-existing illness severity scores for initial prognostication. However, the validity of such scores in COVID-19 is unknown., Methods: The North West Collaborative Organisation for Respiratory Research performed a multicentre prospective evaluation of adult patients admitted to the hospital with confirmed COVID-19 during a 2-week period in April 2020. Clinical variables measured as part of usual care at presentation to the hospital were recorded, including the Confusion, Urea, Respiratory Rate, Blood Pressure and Age Above or Below 65 Years (CURB-65), National Early Warning Score 2 (NEWS2) and Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) scores. The primary outcome of interest was 30-day mortality., Results: Data were collected for 830 people with COVID-19 admitted across seven hospitals. By 30 days, a total of 300 (36.1%) had died and 142 (17.1%) had been in the intensive care unit. All scores underestimated mortality compared with pre-COVID-19 cohorts, and overall prognostic performance was generally poor. Among the 'low-risk' categories (CURB-65 score<2, NEWS2<5 and qSOFA score<2), 30-day mortality was 16.7%, 32.9% and 21.4%, respectively. NEWS2≥5 had a negative predictive value of 98% for early mortality. Multivariable logistic regression identified features of respiratory compromise rather than circulatory collapse as most relevant prognostic variables., Conclusion: In the setting of COVID-19, existing prognostic scores underestimated risk. The design of new prognostic tools should focus on features of respiratory compromise rather than circulatory collapse. We provide a baseline set of variables which are relevant to COVID-19 outcomes and may be used as a basis for developing a bespoke COVID-19 prognostication tool., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Published
2020
Full Text
View/download PDF

3. Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study

Author

Evans, RA, Leavy, OC, Richardson, M, Elneima, O, McCauley, HJC, Shikotra, A, Singapuri, A, Sereno, M, Saunders, RM, Harris, VC, Houchen-Wolloff, L, Aul, R, Beirne, P, Bolton, CE, Brown, JS, Choudhury, G, Diar-Bakerly, N, Easom, N, Echevarria, C, Fuld, J, Hart, N, Hurst, J, Jones, MG, Parekh, D, Pfeffer, P, Rahman, NM, Rowland-Jones, SL, Shah, AM, Wootton, DG, Chalder, T, Davies, MJ, De Soyza, A, Geddes, JR, Greenhalf, W, Greening, NJ, Heaney, LG, Heller, S, Howard, LS, Jacob, J, Jenkins, RG, Lord, JM, Man, WD-C, McCann, GP, Neubauer, S, Openshaw, PJM, Porter, JC, Rowland, MJ, Scott, JT, Semple, MG, Singh, SJ, Thomas, DC, Toshner, M, Lewis, KE, Thwaites, RS, Briggs, A, Docherty, AB, Kerr, S, Lone, NI, Quint, J, Sheikh, A, Thorpe, M, Zheng, B, Chalmers, JD, Ho, LP, Horsley, A, Marks, M, Poinasamy, K, Raman, B, Harrison, EM, Wain, LV, Brightling, CE, Abel, K, Adamali, H, Adeloye, D, Adeyemi, O, Adrego, R, Jimenez, LAA, Ahmad, S, Haider, NA, Ahmed, R, Ahwireng, N, Ainsworth, M, Al-Sheklly, B, Alamoudi, A, Ali, M, Aljaroof, M, All, AM, Allan, L, Allen, RJ, Allerton, L, Allsop, L, Almeida, P, Altmann, D, Corral, MA, Amoils, S, Anderson, D, Antoniades, C, Arbane, G, Arias, A, Armour, C, Armstrong, L, Armstrong, N, Arnold, D, Arnold, H, Ashish, A, Ashworth, A, Ashworth, M, Aslani, S, Assefa-Kebede, H, Atkin, C, Atkin, P, Aung, H, Austin, L, Avram, C, Ayoub, A, Babores, M, Baggott, R, Bagshaw, J, Baguley, D, Bailey, L, Baillie, JK, Bain, S, Bakali, M, Bakau, M, Baldry, E, Baldwin, D, Ballard, C, Banerjee, A, Bang, B, Barker, RE, Barman, L, Barratt, S, Barrett, F, Basire, D, Basu, N, Bates, M, Bates, A, Batterham, R, Baxendale, H, Bayes, H, Beadsworth, M, Beckett, P, Beggs, M, Begum, M, Bell, D, Bell, R, Bennett, K, Beranova, E, Bermperi, A, Berridge, A, Berry, C, Betts, S, Bevan, E, Bhui, K, Bingham, M, Birchall, K, Bishop, L, Bisnauthsing, K, Blaikely, J, Bloss, A, Bolger, A, Bonnington, J, Botkai, A, Bourne, C, Bourne, M, Bramham, K, Brear, L, Breen, G, Breeze, J, Bright, E, Brill, S, Brindle, K, Broad, L, Broadley, A, Brookes, C, Broome, M, Brown, A, Brown, J, Brown, M, Brown, V, Brown, CW, Brugha, T, Brunskill, N, Buch, M, Buckley, P, Bularga, A, Bullmore, E, Burden, L, Burdett, T, Burn, D, Burns, G, Burns, A, Busby, J, Butcher, R, Butt, A, Byrne, S, Cairns, P, Calder, PC, Calvelo, E, Carborn, H, Card, B, Carr, C, Carr, L, Carson, G, Carter, P, Casey, A, Cassar, M, Cavanagh, J, Chablani, M, Chambers, RC, Chan, F, Channon, KM, Chapman, K, Charalambou, A, Chaudhuri, N, Checkley, A, Chen, J, Cheng, Y, Chetham, L, Childs, C, Chilvers, ER, Chinoy, H, Chiribiri, A, Chong-James, K, Choudhury, N, Chowienczyk, P, Christie, C, Chrystal, M, Clark, D, Clark, C, Clarke, J, Clohisey, S, Coakley, G, Coburn, Z, Coetzee, S, Cole, J, Coleman, C, Conneh, F, Connell, D, Connolly, B, Connor, L, Cook, A, Cooper, B, Cooper, J, Cooper, S, Copeland, D, Cosier, T, Coulding, M, Coupland, C, Cox, E, Craig, T, Crisp, P, Cristiano, D, Crooks, MG, Cross, A, Cruz, I, Cullinan, P, Cuthbertson, D, Daines, L, Dalton, M, Daly, P, Daniels, A, Dark, P, Dasgin, J, David, A, David, C, Davies, E, Davies, F, Davies, G, Davies, GA, Davies, K, Dawson, J, Daynes, E, Deakin, B, Deans, A, Deas, C, Deery, J, Defres, S, Dell, A, Dempsey, K, Denneny, E, Dennis, J, Dewar, A, Dharmagunawardena, R, Dickens, C, Dipper, A, Diver, S, Diwanji, SN, Dixon, M, Djukanovic, R, Dobson, H, Dobson, SL, Donaldson, A, Dong, T, Dormand, N, Dougherty, A, Dowling, R, Drain, S, Draxlbauer, K, Drury, K, Dulawan, P, Dunleavy, A, Dunn, S, Earley, J, Edwards, S, Edwardson, C, El-Taweel, H, Elliott, A, Elliott, K, Ellis, Y, Elmer, A, Evans, D, Evans, H, Evans, J, Evans, R, Evans, RI, Evans, T, Evenden, C, Evison, L, Fabbri, L, Fairbairn, S, Fairman, A, Fallon, K, Faluyi, D, Favager, C, Fayzan, T, Featherstone, J, Felton, T, Finch, J, Finney, S, Finnigan, J, Finnigan, L, Fisher, H, Fletcher, S, Flockton, R, Flynn, M, Foot, H, Foote, D, Ford, A, Forton, D, Fraile, E, Francis, C, Francis, R, Francis, S, Frankel, A, Fraser, E, Free, R, French, N, Fu, X, Furniss, J, Garner, L, Gautam, N, George, J, George, P, Gibbons, M, Gill, M, Gilmour, L, Gleeson, F, Glossop, J, Glover, S, Goodman, N, Goodwin, C, Gooptu, B, Gordon, H, Gorsuch, T, Greatorex, M, Greenhaff, PL, Greenhalgh, A, Greenwood, J, Gregory, H, Gregory, R, Grieve, D, Griffin, D, Griffiths, L, Guerdette, A-M, Guio, BG, Gummadi, M, Gupta, A, Gurram, S, Guthrie, E, Guy, Z, Henson, HH, Hadley, K, Haggar, A, Hainey, K, Hairsine, B, Haldar, P, Hall, I, Hall, L, Halling-Brown, M, Hamil, R, Hancock, A, Hancock, K, Hanley, NA, Haq, S, Hardwick, HE, Hardy, E, Hardy, T, Hargadon, B, Harrington, K, Harris, E, Harrison, P, Harvey, A, Harvey, M, Harvie, M, Haslam, L, Havinden-Williams, M, Hawkes, J, Hawkings, N, Haworth, J, Hayday, A, Haynes, M, Hazeldine, J, Hazelton, T, Heeley, C, Heeney, JL, Heightman, M, Henderson, M, Hesselden, L, Hewitt, M, Highett, V, Hillman, T, Hiwot, T, Hoare, A, Hoare, M, Hockridge, J, Hogarth, P, Holbourn, A, Holden, S, Holdsworth, L, Holgate, D, Holland, M, Holloway, L, Holmes, K, Holmes, M, Holroyd-Hind, B, Holt, L, Hormis, A, Hosseini, A, Hotopf, M, Howard, K, Howell, A, Hufton, E, Hughes, AD, Hughes, J, Hughes, R, Humphries, A, Huneke, N, Hurditch, E, Husain, M, Hussell, T, Hutchinson, J, Ibrahim, W, Ilyas, F, Ingham, J, Ingram, L, Ionita, D, Isaacs, K, Ismail, K, Jackson, T, James, WY, Jarman, C, Jarrold, I, Jarvis, H, Jastrub, R, Jayaraman, B, Jezzard, P, Jiwa, K, Johnson, C, Johnson, S, Johnston, D, Jolley, CJ, Jones, D, Jones, G, Jones, H, Jones, I, Jones, L, Jones, S, Jose, S, Kabir, T, Kaltsakas, G, Kamwa, V, Kanellakis, N, Kaprowska, S, Kausar, Z, Keenan, N, Kelly, S, Kemp, G, Kerslake, H, Key, AL, Khan, F, Khunti, K, Kilroy, S, King, B, King, C, Kingham, L, Kirk, J, Kitterick, P, Klenerman, P, Knibbs, L, Knight, S, Knighton, A, Kon, O, Kon, S, Kon, SS, Koprowska, S, Korszun, A, Koychev, I, Kurasz, C, Kurupati, P, Laing, C, Lamlum, H, Landers, G, Langenberg, C, Lasserson, D, Lavelle-Langham, L, Lawrie, A, Lawson, C, Layton, A, Lea, A, Lee, D, Lee, J-H, Lee, E, Leitch, K, Lenagh, R, Lewis, D, Lewis, J, Lewis, V, Lewis-Burke, N, Li, X, Light, T, Lightstone, L, Lilaonitkul, W, Lim, L, Linford, S, Lingford-Hughes, A, Lipman, M, Liyanage, K, Lloyd, A, Logan, S, Lomas, D, Loosley, R, Lota, H, Lovegrove, W, Lucey, A, Lukaschuk, E, Lye, A, Lynch, C, MacDonald, S, MacGowan, G, Macharia, I, Mackie, J, Macliver, L, Madathil, S, Madzamba, G, Magee, N, Magtoto, MM, Mairs, N, Majeed, N, Major, E, Malein, F, Malim, M, Mallison, G, Mandal, S, Mangion, K, Manisty, C, Manley, R, March, K, Marciniak, S, Marino, P, Mariveles, M, Marouzet, E, Marsh, S, Marshall, B, Marshall, M, Martin, J, Martineau, A, Martinez, LM, Maskell, N, Matila, D, Matimba-Mupaya, W, Matthews, L, Mbuyisa, A, McAdoo, S, McCall, JW, McAllister-Williams, H, McArdle, A, McArdle, P, McAulay, D, McCormick, J, McCormick, W, McCourt, P, McGarvey, L, McGee, C, Mcgee, K, McGinness, J, McGlynn, K, McGovern, A, McGuinness, H, McInnes, IB, McIntosh, J, McIvor, E, McIvor, K, McLeavey, L, McMahon, A, McMahon, MJ, McMorrow, L, Mcnally, T, McNarry, M, McNeill, J, McQueen, A, McShane, H, Mears, C, Megson, C, Megson, S, Mehta, P, Meiring, J, Melling, L, Mencias, M, Menzies, D, Morillas, MM, Michael, A, Milligan, L, Miller, C, Mills, C, Mills, NL, Milner, L, Misra, S, Mitchell, J, Mohamed, A, Mohamed, N, Mohammed, S, Molyneaux, PL, Monteiro, W, Moriera, S, Morley, A, Morrison, L, Morriss, R, Morrow, A, Moss, AJ, Moss, P, Motohashi, K, Msimanga, N, Mukaetova-Ladinska, E, Munawar, U, Murira, J, Nanda, U, Nassa, H, Nasseri, M, Neal, A, Needham, R, Neill, P, Newell, H, Newman, T, Newton-Cox, A, Nicholson, T, Nicoll, D, Nolan, CM, Noonan, MJ, Norman, C, Novotny, P, Nunag, J, Nwafor, L, Nwanguma, U, Nyaboko, J, O'Donnell, K, O'Brien, C, O'Brien, L, O'Regan, D, Odell, N, Ogg, G, Olaosebikan, O, Oliver, C, Omar, Z, Orriss-Dib, L, Osborne, L, Osbourne, R, Ostermann, M, Overton, C, Owen, J, Oxton, J, Pack, J, Pacpaco, E, Paddick, S, Painter, S, Pakzad, A, Palmer, S, Papineni, P, Paques, K, Paradowski, K, Pareek, M, Parfrey, H, Pariante, C, Parker, S, Parkes, M, Parmar, J, Patale, S, Patel, B, Patel, M, Patel, S, Pattenadk, D, Pavlides, M, Payne, S, Pearce, L, Pearl, JE, Peckham, D, Pendlebury, J, Peng, Y, Pennington, C, Peralta, I, Perkins, E, Peterkin, Z, Peto, T, Petousi, N, Petrie, J, Phipps, J, Pimm, J, Hanley, KP, Pius, R, Plant, H, Plein, S, Plekhanova, T, Plowright, M, Polgar, O, Poll, L, Porter, J, Portukhay, S, Powell, N, Prabhu, A, Pratt, J, Price, A, Price, C, Price, D, Price, L, Prickett, A, Propescu, J, Pugmire, S, Quaid, S, Quigley, J, Qureshi, H, Qureshi, IN, Radhakrishnan, K, Ralser, M, Ramos, A, Ramos, H, Rangeley, J, Rangelov, B, Ratcliffe, L, Ravencroft, P, Reddington, A, Reddy, R, Redfearn, H, Redwood, D, Reed, A, Rees, M, Rees, T, Regan, K, Reynolds, W, Ribeiro, C, Richards, A, Richardson, E, Rivera-Ortega, P, Roberts, K, Robertson, E, Robinson, E, Robinson, L, Roche, L, Roddis, C, Rodger, J, Ross, A, Ross, G, Rossdale, J, Rostron, A, Rowe, A, Rowland, A, Rowland, J, Roy, K, Roy, M, Rudan, I, Russell, R, Russell, E, Saalmink, G, Sabit, R, Sage, EK, Samakomva, T, Samani, N, Sampson, C, Samuel, K, Samuel, R, Sanderson, A, Sapey, E, Saralaya, D, Sargant, J, Sarginson, C, Sass, T, Sattar, N, Saunders, K, Saunders, P, Saunders, LC, Savill, H, Saxon, W, Sayer, A, Schronce, J, Schwaeble, W, Scott, K, Selby, N, Sewell, TA, Shah, K, Shah, P, Shankar-Hari, M, Sharma, M, Sharpe, C, Sharpe, M, Shashaa, S, Shaw, A, Shaw, K, Shaw, V, Shelton, S, Shenton, L, Shevket, K, Short, J, Siddique, S, Siddiqui, S, Sidebottom, J, Sigfrid, L, Simons, G, Simpson, J, Simpson, N, Singh, C, Singh, S, Sissons, D, Skeemer, J, Slack, K, Smith, A, Smith, D, Smith, S, Smith, J, Smith, L, Soares, M, Solano, TS, Solly, R, Solstice, AR, Soulsby, T, Southern, D, Sowter, D, Spears, M, Spencer, LG, Speranza, F, Stadon, L, Stanel, S, Steele, N, Steiner, M, Stensel, D, Stephens, G, Stephenson, L, Stern, M, Stewart, I, Stimpson, R, Stockdale, S, Stockley, J, Stoker, W, Stone, R, Storrar, W, Storrie, A, Storton, K, Stringer, E, Strong-Sheldrake, S, Stroud, N, Subbe, C, Sudlow, CL, Suleiman, Z, Summers, C, Summersgill, C, Sutherland, D, Sykes, DL, Sykes, R, Talbot, N, Tan, AL, Tarusan, L, Tavoukjian, V, Taylor, A, Taylor, C, Taylor, J, Te, A, Tedd, H, Tee, CJ, Teixeira, J, Tench, H, Terry, S, Thackray-Nocera, S, Thaivalappil, F, Thamu, B, Thickett, D, Thomas, C, Thomas, S, Thomas, AK, Thomas-Woods, T, Thompson, T, Thompson, AAR, Thornton, T, Tilley, J, Tinker, N, Tiongson, GF, Tobin, M, Tomlinson, J, Tong, C, Touyz, R, Tripp, KA, Tunnicliffe, E, Turnbull, A, Turner, E, Turner, S, Turner, V, Turner, K, Turney, S, Turtle, L, Turton, H, Ugoji, J, Ugwuoke, R, Upthegrove, R, Valabhji, J, Ventura, M, Vere, J, Vickers, C, Vinson, B, Wade, E, Wade, P, Wainwright, T, Wajero, LO, Walder, S, Walker, S, Wall, E, Wallis, T, Walmsley, S, Walsh, JA, Walsh, S, Warburton, L, Ward, TJC, Warwick, K, Wassall, H, Waterson, S, Watson, E, Watson, L, Watson, J, Welch, C, Welch, H, Welsh, B, Wessely, S, West, S, Weston, H, Wheeler, H, White, S, Whitehead, V, Whitney, J, Whittaker, S, Whittam, B, Whitworth, V, Wight, A, Wild, J, Wilkins, M, Wilkinson, D, Williams, N, Williams, J, Williams-Howard, SA, Willicombe, M, Willis, G, Willoughby, J, Wilson, A, Wilson, D, Wilson, I, Window, N, Witham, M, Wolf-Roberts, R, Wood, C, Woodhead, F, Woods, J, Wormleighton, J, Worsley, J, Wraith, D, Wright, C, Wright, L, Wright, S, Wyles, J, Wynter, I, Xu, M, Yasmin, N, Yasmin, S, Yates, T, Yip, KP, Young, B, Young, S, Young, A, Yousuf, AJ, Zawia, A, Zeidan, L, Zhao, B, Zongo, O, Group, The PHOSP-COVID Collaborative, National Institute for Health Research, and UKRI MRC COVID-19 Rapid Response Call

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, Adolescent, PHOSP-COVID Collaborative Group, 1117 Public Health and Health Services, Post-Acute COVID-19 Syndrome, SDG 3 - Good Health and Well-being, Humans, Longitudinal Studies, Obesity, Prospective Studies, long COVID, Retrospective Studies, Inflammation, SARS-CoV-2, COVID-19, 1103 Clinical Sciences, Middle Aged, prospective observational study, United Kingdom, Hospitalization, Quality of Life, Female, 1199 Other Medical and Health Sciences
Abstract

Background No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing. Findings 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46–0·99]), obesity (0·50 [0·34–0·74]) and invasive mechanical ventilation (0·42 [0·23–0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74–1·00]), at 5 months (0·74 [0·64–0·88]) to 1 year (0·75 [0·62–0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials. Funding UK Research and Innovation and National Institute for Health Research.

Published
2022
Full Text
View/download PDF

4. A prenylated dsRNA sensor protects against severe COVID-19

Author

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, 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, SJ, ISARIC4C Investigators, Carson, G, Alex, B, Bach, B, Barclay, WS, Bogaert, D, Chand, M, Cooke, GS, Docherty, AB, Dunning, J, da Silva Filipe, A, Fletcher, T, Green, CA, Harrison, EM, Ho, AYW, Horby, PW, Ijaz, S, Khoo, S, Klenerman, P, Law, A, Lim, WS, Mentzer, AJ, Merson, L, Meynert, AM, Noursadeghi, M, Moore, SC, Paxton, WA, Pollakis, G, Price, N, Rambaut, A, 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, Gupta, RK, Palmieri, C, Swann, OV, Zambon, M, Dumas, M-E, Griffin, JL, Takats, Z, Chechi, K, Andrikopoulos, P, Osagie, A, Olanipekun, M, Liggi, S, Lewis, MR, Dos Santos Correia, G, Sands, CJ, Takis, P, Maslen, L, Hardwick, H, Donohue, C, Griffiths, F, Oosthuyzen, W, Donegan, C, Spencer, RG, Norman, L, Pius, R, Drake, TM, 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, Plotkin, D, Lee, J, Leeming, G, Wham, M, Hendry, R, Scott-Brown, J, Greenhalf, W, Shaw, V, McDonald, SE, 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, 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, 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, van Tonder, L, Wilcock, E, Zhang, JE, Flaherty, L, Maziere, N, Cass, E, Carracedo, AD, Carlucci, N, Holmes, A, Massey, H, Wrobel, N, McCafferty, S, Morrice, K, MacLean, A, Adeniji, K, Agranoff, D, Agwuh, K, Ail, D, Aldera, EL, Alegria, A, Allen, S, Angus, B, Ashish, A, Atkinson, D, Bari, S, Barlow, G, Barnass, S, Barrett, N, Bassford, C, Basude, S, Baxter, D, Beadsworth, M, Bernatoniene, J, Berridge, J, Berry, C, Best, N, Bothma, P, Chadwick, D, Brittain-Long, R, Bulteel, N, Burden, T, Burtenshaw, A, Caruth, V, Chambler, D, Chee, N, Child, J, Chukkambotla, S, Clark, T, Collini, P, Cosgrove, C, Cupitt, J, Cutino-Moguel, M-T, Dark, P, Dawson, C, Dervisevic, S, Donnison, P, Douthwaite, S, Drummond, A, DuRand, I, Dushianthan, A, Dyer, T, Evans, C, Eziefula, C, Fegan, C, Finn, A, Fullerton, D, Garg, S, Garg, A, Gkrania-Klotsas, E, Godden, J, Goldsmith, A, Graham, C, Hardy, E, Hartshorn, S, Harvey, D, Havalda, P, Hawcutt, DB, Hobrok, M, Hodgson, L, Hormis, A, Jacobs, M, Jain, S, Jennings, P, Kaliappan, A, Kasipandian, V, Kegg, S, Kelsey, M, Kendall, J, Kerrison, C, Kerslake, I, Koch, O, Koduri, G, Koshy, G, Laha, S, Laird, S, Larkin, S, Leiner, T, Lillie, P, Limb, J, Linnett, V, Little, J, Lyttle, M, MacMahon, M, MacNaughton, E, Mankregod, R, Masson, H, Matovu, E, McCullough, K, McEwen, R, Meda, M, Mills, G, Minton, J, Mirfenderesky, M, Mohandas, K, Mok, Q, Moon, J, Moore, E, Morgan, P, Morris, C, Mortimore, K, Moses, S, Mpenge, M, Mulla, R, Murphy, M, Nagel, M, Nagarajan, T, Nelson, M, Norris, L, O'Shea, MK, Otahal, I, Ostermann, M, Pais, M, Panchatsharam, S, Papakonstantinou, D, Paraiso, H, Patel, B, Pattison, N, Pepperell, J, Peters, M, Phull, M, Pintus, S, Singh Pooni, J, Planche, T, Post, F, Price, D, Prout, R, Rae, N, Reschreiter, H, Reynolds, T, Richardson, N, Roberts, M, Roberts, D, Rose, A, Rousseau, G, Ruge, B, Ryan, B, Saluja, T, Schmid, ML, Shah, A, Shanmuga, P, Sharma, A, Shawcross, A, Sizer, J, Shankar-Hari, M, Smith, R, Snelson, C, Spittle, N, Staines, N, Stambach, T, Stewart, R, Subudhi, P, Szakmany, T, Tatham, K, Thompson, C, Thompson, R, Tridente, A, Tupper-Carey, D, Twagira, M, Vallotton, N, Vancheeswaran, R, Vincent-Smith, L, Visuvanathan, S, Vuylsteke, A, Waddy, S, Wake, R, Walden, A, Welters, I, Whitehouse, T, Whittaker, P, Whittington, A, Papineni, P, Wijesinghe, M, Williams, M, Wilson, L, Winchester, S, Wiselka, M, Wolverson, A, Wootton, DG, Workman, A, Yates, B, Young, P, Division of Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK, Imperial College London - National Heart and Lung Institute, Centre National de la Recherche Scientifique (CNRS), MRC - University of Glasgow Centre for Virus Research, University of Kent [Canterbury], University of Glasgow, National Institute for Health Research, UK Research and Innovation, UKRI MRC COVID-19 Rapid Response Call, Mentzer, AJ, Investigators, ISARIC4C, Lee, J, and Angus, B

Subjects
2',5'-Oligoadenylate Synthetase/genetics, L PATHWAY, viruses, SINGLE-NUCLEOTIDE POLYMORPHISM, RNASE-L, RNA, Viral/chemistry, RNA, Double-Stranded/chemistry, Virus Replication, Severity of Illness Index, COVID-19/enzymology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chiroptera, Sense (molecular biology), 2',5'-Oligoadenylate Synthetase, MESH: COVID-19, MESH: Animals, MESH: Interferons, ENZYME-ACTIVITY, MESH: 2',5'-Oligoadenylate Synthetase, Endoribonucleases/metabolism, 0303 health sciences, MESH: Protein Prenylation, Multidisciplinary, I INTERFERON, Coronaviridae/enzymology, MESH: Polymorphism, Single Nucleotide, 030302 biochemistry & molecular biology, MESH: Chiroptera, CORONAVIRUS REPLICATION, 3. Good health, Cell biology, Multidisciplinary Sciences, Isoenzymes, RNA silencing, VIRUS NS1 PROTEIN, MESH: RNA, Viral, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Isoenzymes, Science & Technology - Other Topics, RNA, Viral, MESH: 5' Untranslated Regions, [SDV.IMM]Life Sciences [q-bio]/Immunology, SARS-CORONAVIRUS, Gene isoform, MESH: Endoribonucleases, Retroelements, RNase P, Coronaviridae, General Science & Technology, Protein Prenylation, Biology, Polymorphism, Single Nucleotide, Chiroptera/genetics, 03 medical and health sciences, MESH: RNA, Double-Stranded, MESH: Retroelements, SARS-CoV-2/genetics, MESH: Severity of Illness Index, Endoribonucleases, Animals, Humans, MESH: SARS-CoV-2, Interferons/immunology, Gene, ISARIC4C Investigators, 030304 developmental biology, RNA, Double-Stranded, Science & Technology, MESH: Humans, ACCEPTOR SITE, Phosphoric Diester Hydrolases, SARS-CoV-2, fungi, MESH: Virus Replication, RNA, COVID-19, Phosphoric Diester Hydrolases/genetics, Viral replication, A549 Cells, Protein prenylation, SPLICE-SITE POLYMORPHISM, Interferons, MESH: A549 Cells, 5' Untranslated Regions, MESH: Phosphoric Diester Hydrolases, Isoenzymes/genetics, MESH: Coronaviridae
Abstract

International audience; INTRODUCTIONInterferons (IFNs) are cytokines that are rapidly deployed in response to invading pathogens. By initiating a signaling cascade that stimulates the expression of hundreds of genes, IFNs create an antiviral state in host cells. Because IFNs heavily influence COVID-19 outcomes, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication can be inhibited by the antiviral state, it is important to understand how the individual antiviral effectors encoded by IFN-stimulated genes (ISGs) inhibit SARS-CoV-2.RATIONALEWe hypothesized that IFN-stimulated antiviral effectors can inhibit SARS-CoV-2, and that variation at the loci encoding these defenses underlies why some people are more susceptible to severe COVID-19.RESULTSWe used arrayed ISG expression screening to reveal that 2′-5′-oligoadenylate synthetase 1 (OAS1) consistently inhibited SARS-CoV-2 in different contexts. Using CRISPR-Cas9, we found that endogenous OAS1 makes a substantial contribution to the antiviral state by recognizing short stretches of double-stranded RNA (dsRNA) and activating RNase L. We globally mapped where OAS1 binds to SARS-CoV-2 viral RNAs and found that OAS1 binding is remarkably specific, with two conserved stem loops in the SARS-CoV-2 5′-untranslated region (UTR) constituting the principal viral target.OAS1 expression was readily detectable at the sites of infection in individuals who died of COVID-19, and specific OAS1 alleles are known to be associated with altered susceptibility to infection and severe disease. It had previously been reported that alleles containing a common splice-acceptor single nucleotide polymorphism in OAS1 (Rs10774671) were associated with less severe COVID-19. We determined that people with at least one allele with a G at this position could express a prenylated form of OAS1 (p46), whereas other individuals could not. Using a series of mutants, we found that C-terminal prenylation was necessary for OAS1 to initiate a block to SARS-CoV-2. Furthermore, confocal microscopy revealed that prenylation targeted OAS1 to perinuclear structures rich in viral dsRNA, whereas non-prenylated OAS1 was diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication.The realization that prenylation is essential for OAS1-mediated sensing of SARS-CoV-2 allowed us to examine the transcriptome of infected patients and investigate whether there was a link between the expression of prenylated OAS1 and SARS-CoV-2 disease progression. Analysis of the OAS1 transcripts from 499 hospitalized COVID-19 patients revealed that expressing prenylated OAS1 was associated with protection from severe COVID-19.Because prenylated OAS1 was so important in human cases, we wanted to determine whether horseshoe bats, the likely source of SARS-CoV-2, possessed the same defense. When we examined the genomic region where the prenylation signal should reside, retrotransposition of a long terminal repeat sequence had ablated this signal, preventing the expression of prenylated anti-CoV OAS1 in these bats.CONCLUSIONC-terminal prenylation targets OAS1 to intracellular sites rich in viral dsRNA, which are likely the SARS-CoV-2 replicative organelles. Once in the right place, OAS1 binds to dsRNA structures in the SARS-CoV-2 5′-UTR and initiates a potent block to SARS-CoV-2 replication. Thus, the correct targeting of OAS1 and the subsequent inhibition of SARS-CoV-2 likely underpins the genetic association of alleles containing a G at Rs10774671 with reduced susceptibility to infection and severe disease in COVID-19. Moreover, the conspicuous absence of this antiviral defense in horseshoe bats potentially explains why SARS-CoV-2 is so sensitive to this defense in humans.

Published
2021
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results