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1. Long term health outcomes in people with diabetes 12 months after hospitalisation with COVID-19 in the UK: a prospective cohort studyResearch in context

Author

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

Subjects
Diabetes, Covid-19, Long Covid, Medicine (General), R5-920
Abstract

Summary: Background: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes. Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions. Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions. Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes. Funding: UK Research and Innovation and National Institute for Health Research. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107).

Published
2025
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2. Long-term impact of COVID-19 hospitalisation among individuals with pre-existing airway diseases in the UK: a multicentre, longitudinal cohort study – PHOSP-COVID

Author

Omer Elneima, John R. Hurst, Carlos Echevarria, Jennifer K. Quint, Samantha Walker, Salman Siddiqui, Petr Novotny, Paul E. Pfeffer, Jeremy S. Brown, Manu Shankar-Hari, Hamish J.C. McAuley, Olivia C. Leavy, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Matthew Richardson, Ruth M. Saunders, Victoria C. Harris, Linzy Houchen-Wolloff, Neil J. Greening, Ewen M. Harrison, Annemarie B. Docherty, Nazir I. Lone, James D. Chalmers, Ling-Pei Ho, Alex Horsley, Michael Marks, Krisnah Poinasamy, Betty Raman, Rachael A. Evans, Louise V. Wain, Aziz Sheikh, Chris E. Brightling, Anthony De Soyza, Liam G. Heaney, J.K. Baillie, N.I. Lone, E. Pairo-Castineira, N. Avramidis, K. Rawlik, S Jones, L. Armstrong, B. Hairsine, H. Henson, C. Kurasz, A. Shaw, L. Shenton, H. Dobson, A. Dell, S. Fairbairn, N. Hawkings, J. Haworth, M. Hoare, V. Lewis, A. Lucey, G. Mallison, H. Nassa, C. Pennington, A. Price, C. Price, A. Storrie, G. Willis, S. Young, K. Poinasamy, S. Walker, I. Jarrold, A. Sanderson, K. Chong-James, C. David, W.Y. James, P. Pfeffer, O. Zongo, A. Martineau, C. Manisty, C. Armour, V. Brown, J. Busby, B. Connolly, T. Craig, S. Drain, L.G. Heaney, B. King, N. Magee, E. Major, D. McAulay, L. McGarvey, J. McGinness, T. Peto, R. Stone, A. Bolger, F. Davies, A. Haggar, J. Lewis, A. Lloyd, R. Manley, E. McIvor, D. Menzies, K. Roberts, W. Saxon, D. Southern, C. Subbe, V. Whitehead, A. Bularga, N.L. Mills, J. Dawson, H. El-Taweel, L. Robinson, L. Brear, K. Regan, D. Saralaya, K. Storton, S. Amoils, A. Bermperi, I. Cruz, K. Dempsey, A. Elmer, J. Fuld, H. Jones, S. Jose, S. Marciniak, M. Parkes, C. Ribeiro, J. Taylor, M. Toshner, L. Watson, J. Worsley, L. Broad, T. Evans, M. Haynes, L. Jones, L. Knibbs, A. McQueen, C. Oliver, K. Paradowski, R. Sabit, J. Williams, I. Jones, L. Milligan, E. Harris, C. Sampson, E. Davies, C. Evenden, A. Hancock, K. Hancock, C. Lynch, M. Rees, L. Roche, N. Stroud, T. Thomas-Woods, S. Heller, T. Chalder, K. Shah, E. Robertson, B. Young, M. Babores, M. Holland, N. Keenan, S. Shashaa, H. Wassall, L. Austin, E. Beranova, T. Cosier, J. Deery, T. Hazelton, H. Ramos, R. Solly, S. Turney, H. Weston, M. Ralser, L. Pearce, S. Pugmire, W. Stoker, A. Wilson, W. McCormick, E. Fraile, J. Ugoji, L. Aguilar Jimenez, G. Arbane, S. Betts, K. Bisnauthsing, A. Dewar, N. Hart, G. Kaltsakas, H. Kerslake, M.M. Magtoto, P. Marino, L.M. Martinez, M. Ostermann, J. Rossdale, T.S. Solano, M. Alvarez Corral, A. Arias, E. Bevan, D. Griffin, J. Martin, J. Owen, S. Payne, A. Prabhu, A. Reed, W. Storrar, N. Williams, C. Wrey Brown, T. Burdett, J. Featherstone, C. Lawson, A. Layton, C. Mills, L. Stephenson, Y. Ellis, P. Atkin, K. Brindle, M.G. Crooks, K. Drury, N. Easom, R. Flockton, L. Holdsworth, A. Richards, D.L. Sykes, S. Thackray-Nocera, C. Wright, S. Coetzee, K. Davies, R. Hughes, R. Loosley, H. McGuinness, A. Mohamed, L. O'Brien, Z. Omar, E. Perkins, J. Phipps, G. Ross, A. Taylor, H. Tench, R. Wolf-Roberts, L. Burden, E. Calvelo, B. Card, C. Carr, E.R. 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Nolan, B. Patel, S. Patel, O. Polgar, P. Shah, S. Singh, J.A. Walsh, M. Gibbons, S. Ahmad, S. Brill, J. Hurst, H. Jarvis, L. Lim, S. Mandal, D. Matila, O. Olaosebikan, C. Singh, C. Laing, H. Baxendale, L. Garner, C. Johnson, J. Mackie, A. Michael, J. Newman, J. Pack, K. Paques, H. Parfrey, J. Parmar, A. Reddy, M. Halling-Brown, P. Dark, N. Diar-Bakerly, D. Evans, E. Hardy, A. Harvey, D. Holgate, S. Knight, N. Mairs, N. Majeed, L. McMorrow, J. Oxton, J. Pendlebury, C. Summersgill, R. Ugwuoke, S. Whittaker, W. Matimba-Mupaya, S. Strong-Sheldrake, P. Chowienczyk, J. Bagshaw, M. Begum, K. Birchall, R. Butcher, H. Carborn, F. Chan, K. Chapman, Y. Cheng, L. Chetham, C. Clark, Z. Coburn, J. Cole, M. Dixon, A. Fairman, J. Finnigan, H. Foot, D. Foote, A. Ford, R. Gregory, K. Harrington, L. Haslam, L. Hesselden, J. Hockridge, A. Holbourn, B. Holroyd-Hind, L. Holt, A. Howell, E. Hurditch, F. Ilyas, C. Jarman, A. Lawrie, J-H. Lee, E. Lee, R. Lenagh, A. Lye, I. Macharia, M. Marshall, A. 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McNarry, K.E. Lewis, M. Coulding, S. Kilroy, J. McCormick, J. McIntosh, V. Turner, J. Vere, A. Butt, H. Savill, S.S. Kon, G. Landers, H. Lota, S. Portukhay, M. Nasseri, A. Daniels, A. Hormis, J. Ingham, L. Zeidan, M. Chablani, L. Osborne, S. Aslani, A. Banerjee, R. Batterham, G. Baxter, R. Bell, A. David, E. Denneny, A.D. Hughes, W. Lilaonitkul, P. Mehta, A. Pakzad, B. Rangelov, B. Williams, J. Willoughby, M. Xu, N. Ahwireng, D. Bang, D. Basire, J.S. Brown, R.C. Chambers, A. Checkley, R. Evans, M. Heightman, T. Hillman, J. Jacob, R. Jastrub, M. Lipman, S. Logan, D. Lomas, M. Merida Morillas, H. Plant, J.C. Porter, K. Roy, E. Wall, T. Treibel, N. Ahmad Haider, C. Atkin, R. Baggott, M. Bates, A. Botkai, A. Casey, B. Cooper, J. Dasgin, C. Dawson, K. Draxlbauer, N. Gautam, J. Hazeldine, T. Hiwot, S. Holden, K. Isaacs, T. Jackson, V. Kamwa, D. Lewis, J.M. Lord, S. Madathil, C. McGhee, K. McGee, A. Neal, A. Newton-Cox, J. Nyaboko, D. Parekh, Z. Peterkin, H. Qureshi, L. Ratcliffe, E. 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Spencer, B. Vinson, M. Ashworth, K. Abel, H. Chinoy, B. Deakin, M. Harvie, C.A. Miller, S. Stanel, P. Barran, D. Trivedi, H. McAllister-Williams, S. Paddick, A. Rostron, J.P. Taylor, D. Baguley, C. Coleman, E. Cox, L. Fabbri, S. Francis, I. Hall, E. Hufton, S. Johnson, F. Khan, P. Kitterick, R. Morriss, N. Selby, L. Wright, C. Antoniades, A. Bates, M. Beggs, K. Bhui, K. Breeze, K.M. Channon, D. Clark, X. Fu, M. Husain, X. Li, E. Lukaschuk, C. McCracken, K. McGlynn, R. Menke, K. Motohashi, T.E. Nichols, G. Ogbole, S. Piechnik, I. Propescu, J. Propescu, A.A. Samat, Z.B. Sanders, L. Sigfrid, M. Webster, L. Kingham, P. Klenerman, H. Lamlum, G. Carson, M. Taquet, L. Finnigan, L.C. Saunders, J.M. Wild, P.C. Calder, N. Huneke, G. Simons, D. Baldwin, S. Bain, L. Daines, E. Bright, P. Crisp, R. Dharmagunawardena, M. Stern, L. Bailey, A. Reddington, A. Wight, A. Ashish, J. Cooper, E. Robinson, A. Broadley, L. Barman, C. Brookes, K. Elliott, L. Griffiths, Z. Guy, K. Howard, D. Ionita, H. Redfearn, C. Sarginson, and A. Turnbull

Subjects
Medicine
Abstract

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Published
2024
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3. Prevalence of physical frailty, including risk factors, up to 1 year after hospitalisation for COVID-19 in the UK: a multicentre, longitudinal cohort studyResearch in context

Author

Hamish J.C. McAuley, Rachael A. Evans, Charlotte E. Bolton, Christopher E. Brightling, James D. Chalmers, Annemarie B. Docherty, Omer Elneima, Paul L. Greenhaff, Ayushman Gupta, Victoria C. Harris, Ewen M. Harrison, Ling-Pei Ho, Alex Horsley, Linzy Houchen-Wolloff, Caroline J. Jolley, Olivia C. Leavy, Nazir I. Lone, William D-C Man, Michael Marks, Dhruv Parekh, Krisnah Poinasamy, Jennifer K. Quint, Betty Raman, Matthew Richardson, Ruth M. Saunders, Marco Sereno, Aarti Shikotra, Amisha Singapuri, Sally J. Singh, Michael Steiner, Ai Lyn Tan, Louise V. Wain, Carly Welch, Julie Whitney, Miles D. Witham, Janet Lord, Neil J. Greening, K. Abel, H. Adamali, D. Adeloye, O. Adeyemi, R. Adrego, L.A. Aguilar Jimenez, S. Ahmad, N. Ahmad Haider, R. Ahmed, N. Ahwireng, M. Ainsworth, B. Al-Sheklly, A. Alamoudi, M. Ali, M. Aljaroof, A.M. All, L. Allan, R.J. Allen, L. Allerton, L. Allsop, P. Almeida, D. Altmann, M. Alvarez Corral, S. Amoils, D. Anderson, C. Antoniades, G. Arbane, A. Arias, C. Armour, L. Armstrong, N. Armstrong, D. Arnold, H. Arnold, A. Ashish, A. Ashworth, M. Ashworth, S. Aslani, H. Assefa-Kebede, C. Atkin, P. Atkin, R. Aul, H. Aung, L. Austin, C. Avram, A. Ayoub, M. Babores, R. Baggott, J. Bagshaw, D. Baguley, L. Bailey, J.K. Baillie, S. Bain, M. Bakali, M. Bakau, E. Baldry, D. Baldwin, M. Baldwin, C. Ballard, A. Banerjee, B. Bang, R.E. Barker, L. Barman, S. Barratt, F. Barrett, D. Basire, N. Basu, M. Bates, A. Bates, R. Batterham, H. Baxendale, H. Bayes, M. Beadsworth, P. Beckett, M. Beggs, M. Begum, P. Beirne, D. Bell, R. Bell, K. Bennett, E. Beranova, A. Bermperi, A. Berridge, C. Berry, S. Betts, E. Bevan, K. Bhui, M. Bingham, K. Birchall, L. Bishop, K. Bisnauthsing, J. Blaikely, A. Bloss, A. Bolger, C.E. Bolton, J. Bonnington, A. Botkai, C. Bourne, M. Bourne, K. Bramham, L. Brear, G. Breen, J. Breeze, A. Briggs, E. Bright, C.E. Brightling, S. Brill, K. Brindle, L. Broad, A. Broadley, C. Brookes, M. Broome, A. Brown, J. Brown, J.S. Brown, M. Brown, V. Brown, T. Brugha, N. Brunskill, M. Buch, P. Buckley, A. Bularga, E. Bullmore, L. Burden, T. Burdett, D. Burn, G. Burns, A. Burns, J. Busby, R. Butcher, A. Butt, S. Byrne, P. Cairns, P.C. Calder, E. Calvelo, H. Carborn, B. Card, C. Carr, L. Carr, G. Carson, P. Carter, A. Casey, M. Cassar, J. Cavanagh, M. Chablani, T. Chalder, J.D. Chalmers, R.C. Chambers, F. Chan, K.M. Channon, K. Chapman, A. Charalambou, N. Chaudhuri, A. Checkley, J. Chen, Y. Cheng, L. Chetham, C. Childs, E.R. Chilvers, H. Chinoy, A. Chiribiri, K. Chong-James, G. Choudhury, N. Choudhury, P. Chowienczyk, C. Christie, M. Chrystal, D. Clark, C. Clark, J. Clarke, S. Clohisey, G. Coakley, Z. Coburn, S. Coetzee, J. Cole, C. Coleman, F. Conneh, D. Connell, B. Connolly, L. Connor, A. Cook, B. Cooper, J. Cooper, S. Cooper, D. Copeland, T. Cosier, M. Coulding, C. Coupland, E. Cox, T. Craig, P. Crisp, D. Cristiano, M.G. Crooks, A. Cross, I. Cruz, P. Cullinan, D. Cuthbertson, L. Daines, M. Dalton, P. Daly, A. Daniels, P. Dark, J. 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Wheeler, S. White, V. Whitehead, J. Whitney, S. Whittaker, B. Whittam, V. Whitworth, A. Wight, J. Wild, M. Wilkins, D. Wilkinson, B. Williams, N. Williams, J. Williams, S.A. Williams-Howard, M. Willicombe, G. Willis, J. Willoughby, A. Wilson, D. Wilson, I. Wilson, N. Window, M. Witham, R. Wolf-Roberts, C. Wood, F. Woodhead, J. Woods, D.G. Wootton, J. Wormleighton, J. Worsley, D. Wraith, C. Wrey Brown, C. Wright, L. Wright, S. Wright, J. Wyles, I. Wynter, M. Xu, N. Yasmin, S. Yasmin, T. Yates, K.P. Yip, B. Young, S. Young, A. Young, A.J. Yousuf, A. Zawia, L. Zeidan, B. Zhao, B. Zheng, and O. Zongo

Subjects
COVID-19, Physical frailty, Long-COVID, Fried's frailty phenotype, Hospitalisation, Medicine (General), R5-920
Abstract

Summary: Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.

Published
2023
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4. Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study

Author

Callum Jackson, Iain D Stewart, Tatiana Plekhanova, Peter S Cunningham, Andrew L Hazel, Bashar Al-Sheklly, Raminder Aul, Charlotte E Bolton, Trudie Chalder, James D Chalmers, Nazia Chaudhuri, Annemarie B Docherty, Gavin Donaldson, Charlotte L Edwardson, Omer Elneima, Neil J Greening, Neil A Hanley, Victoria C Harris, Ewen M Harrison, Ling-Pei Ho, Linzy Houchen-Wolloff, Luke S Howard, Caroline J Jolley, Mark G Jones, Olivia C Leavy, Keir E Lewis, Nazir I Lone, Michael Marks, Hamish J C McAuley, Melitta A McNarry, Brijesh V Patel, Karen Piper-Hanley, Krisnah Poinasamy, Betty Raman, Matthew Richardson, Pilar Rivera-Ortega, Sarah L Rowland-Jones, Alex V Rowlands, Ruth M Saunders, Janet T Scott, Marco Sereno, Ajay M Shah, Aarti Shikotra, Amisha Singapuri, Stefan C Stanel, Mathew Thorpe, Daniel G Wootton, Thomas Yates, R Gisli Jenkins, Sally J Singh, William D-C Man, Christopher E Brightling, Louise V Wain, Joanna C Porter, A A Roger Thompson, Alex Horsley, Philip L Molyneaux, Rachael A Evans, Samuel E Jones, Martin K Rutter, John F Blaikley, C Jackson, I D Stewart, T Plekhanova, P S Cunningham, A L Hazel, B Al-Sheklly, R Aul, C E Bolton, T Chalder, J D Chalmers, N Chaudhuri, A B Docherty, G Donaldson, C L Edwardson, O Elneima, N J Greening, N A Hanley, V C Harris, E M Harrison, L-P Ho, L Houchen-Wolloff, L S Howard, C J Jolley, M G Jones, O C Leavy, K E Lewis, N I Lone, M Marks, H J C McAuley, M A McNarry, B Patel, K Piper-Hanley, K Poinasamy, B Raman, M Richardson, P Rivera-Ortega, S L Rowland-Jones, A V Rowlands, R M Saunders, J T Scott, M Sereno, A M Shah, A Shikotra, A Singapuri, S C Stanel, M Thorpe, D G Wootton, T Yates, G Jenkins, S J Singh, W D-C Man, C E Brightling, L V Wain, J C Porter, R Thompson, A Horsley, P L Molyneaux, R A Evans, S E Jones, M K Rutter, J F Blaikley, K Abel, H Adamali, D Adeloye, O Adeyemi, R Adrego, L A Aguilar Jimenez, S Ahmad, N Ahmad Haider, R Ahmed, N Ahwireng, M Ainsworth, A Alamoudi, M Ali, M Aljaroof, AM All, L Allan, R J Allen, 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Wright, S Wright, J Wyles, I Wynter, M Xu, N Yasmin, S Yasmin, K P Yip, B Young, S Young, A Young, A J Yousuf, A Zawia, L Zeidan, B Zhao, B Zheng, O Zongo, Apollo - University of Cambridge Repository, PHOSP-COVID Study Collaborative Group, and Group, PHOSP-COVID Study Collaborative

Subjects
Pulmonary and Respiratory Medicine, PHOSP-COVID Study Collaborative Group
Abstract

Data sharing: The PHOSP-COVID study protocol, consent form, definition, and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online. UK Biobank information can be released once necessary approvals have been obtained. Other data (eg, the R code and protocol) will be made available on reasonable request to the corresponding author. Copyright © 2023 The Author(s). Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council. UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.

Published
2023
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6. SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

Author

Felicity Liew, Shubha Talwar, Andy Cross, Brian J. Willett, Sam Scott, Nicola Logan, Matthew K. Siggins, Dawid Swieboda, Jasmin K. Sidhu, Claudia Efstathiou, Shona C. Moore, Chris Davis, Noura Mohamed, Jose Nunag, Clara King, A.A. Roger Thompson, Sarah L. Rowland-Jones, Annemarie B. Docherty, James D. Chalmers, Ling-Pei Ho, Alexander Horsley, Betty Raman, Krisnah Poinasamy, Michael Marks, Onn Min Kon, Luke Howard, Daniel G. Wootton, Susanna Dunachie, Jennifer K. Quint, Rachael A. Evans, Louise V. Wain, Sara Fontanella, Thushan I. de Silva, Antonia Ho, Ewen Harrison, J. Kenneth Baillie, Malcolm G. Semple, Christopher Brightling, Ryan S. Thwaites, Lance Turtle, Peter J.M. Openshaw, Beatrice Alex, Petros Andrikopoulos, Benjamin Bach, Wendy S. Barclay, Debby Bogaert, Meera Chand, Kanta Chechi, Graham S. Cooke, Ana da Silva Filipe, Thushan de Silva, Gonçalo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christopher A. Green, William Greenhalf, Julian Griffin, Rishi K. Gupta, Ewen M. Harrison, Antonia Y.W. Ho, Karl Holden, Peter W. Horby, Samreen Ijaz, Say Khoo, Paul Klenerman, Andrew Law, Matthew Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, Alexander J. Mentzer, Laura Merson, Alison M Meynert, Mahdad Noursadeghi, Michael Olanipekun, Anthonia Osagie, Massimo Palmarini, Carlo Palmieri, William A. Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Clark D. Russell, Vanessa Sancho-Shimizu, Caroline Sands, Janet T. Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Olivia V. Swann, Zoltan Takats, Panteleimon Takis, Richard S. Tedder, Emma C. Thomson, Lance C.W. Turtle, Maria Zambon, Thomas M. Drake, Cameron J. Fairfield, Stephen R. Knight, Kenneth A. Mclean, Derek Murphy, Lisa Norman, Riinu Pius, Catherine A. Shaw, Marie Connor, Jo Dalton, Carrol Gamble, Michelle Girvan, Sophie Halpin, Janet Harrison, Clare Jackson, James Lee, Laura Marsh, Daniel Plotkin, Stephanie Roberts, Egle Saviciute, Sara Clohisey, Ross Hendry, Susan Knight, Eva Lahnsteiner, Gary Leeming, Lucy Norris, James Scott-Brown, Sarah Tait, Murray Wham, Richard Clark, Audrey Coutts, Lorna Donelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy, Nicola Wrobel, Gail Carson, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. 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Subjects
SARS-CoV-2 variants, Mucosal immunity, Nasal antibody, SDG 3 - Good Health and Well-being, Biochemistry, Genetics and Molecular Biology(all), SARS-CoV-2 immunity, Vaccination, COVID-19, General Medicine, Convalescent, General Biochemistry, Genetics and Molecular Biology
Abstract

Data sharing statement This is an Open Access article under the CC BY 4.0 license The ISARIC4C protocol, data sharing and publication policy are available at https://isaric4c.net. ISARIC4C's Independent Data and Material Access Committee welcomes applications for access to data and materials (https://isaric4c.net). The PHOSP-COVID protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online: https://phosp.org/resource/. Access to these materials can be granted by contacting phosp@leicester.ac.uk and Phospcontracts@leicester.ac.uk. All data used in this study is available within ODAP and accessible under reasonable request. Data access criteria and information about how to request access is available online: https://phosp.org/resource/. If criteria are met and a request is made, access can be gained by signing the eDRIS user agreement. Supplementary data are available online at https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00584-9/fulltext#supplementaryMaterial . Copyright © 2022 The Author(s). 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. This work is supported by the following grants: The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute for Health and Care Research (grant references: MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). Other grants which have supported this work include: the UK Coronavirus Immunology Consortium [funder reference:1257927], the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit (HPRU) in Respiratory Infections at Imperial College London and NIHR HPRU in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, [NIHR award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], Health Data Research UK (HDR UK) [grant code: 2021.0155], Medical Research Council [grant code: MC_UU_12014/12], and NIHR Clinical Research Network for providing infrastructure support for this research. FL is supported by an MRC clinical training fellowship [award MR/W000970/1]. LPH is supported by Oxford NIHR Biomedical Research Centre. AART is supported by a BHF Intermediate Clinical Fellowship (FS/18/13/33281). SLRJ receives support from UKRI, GCRF, Rosetrees Trust, BHIVA, EDCTP, Globvac. JDC has grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed. RAE holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). AH is currently supported by UK Research and Innovation. NIHR and NIHR Manchester BRC. BR receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. SJD is funded by an NIHR Global Research Professorship [NIHR300791]. DW is supported by an NIHR Advanced Fellowship. AH has received support from MRC and the Coronavirus Immunology Consortium (MR/V028448/1). LVW has received support from UKRI, GSK/Asthma + Lung UK and NIHR for this study. MGS has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool. JKB is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1, and MC_PC_20029). PJMO is supported by a NIHR Senior Investigator Award [award 201385]. LT is supported by the Wellcome Trust [clinical career development fellowship grant number 205228/Z/16/Z], the Centre of Excellence in Infectious Diseases Research (CEIDR) and the Alder Hey Charity.

Published
2022
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7. Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls

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Bang Zheng, Giulia Vivaldi, Luke Daines, Olivia C. Leavy, Matthew Richardson, Omer Elneima, Hamish J.C. McAuley, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Ruth M. Saunders, Victoria C. Harris, Linzy Houchen-Wolloff, Neil J. Greening, Paul E. Pfeffer, John R. Hurst, Jeremy S. Brown, Manu Shankar-Hari, Carlos Echevarria, Anthony De Soyza, Ewen M. Harrison, Annemarie B. Docherty, Nazir Lone, Jennifer K. Quint, James D. Chalmers, Ling-Pei Ho, Alex Horsley, Michael Marks, Krishna Poinasamy, Betty Raman, Liam G. Heaney, Louise V. Wain, Rachael A. Evans, Christopher E. Brightling, Adrian Martineau, Aziz Sheikh, K. Abel, H. Adamali, D. Adeloye, O. Adeyemi, R. Adrego, L.A. Aguilar Jimenez, S. Ahmad, N. Ahmad Haider, R. Ahmed, N. Ahwireng, M. Ainsworth, B. Al-Sheklly, A. Alamoudi, M. Ali, M. Aljaroof, A.M. All, L. Allan, R.J. Allen, L. Allerton, L. Allsop, P. Almeida, D. Altmann, M. Alvarez Corral, S. Amoils, D. Anderson, C. Antoniades, G. Arbane, A. Arias, C. Armour, L. Armstrong, N. 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White, V. Whitehead, J. Whitney, S. Whittaker, B. Whittam, V. Whitworth, A. Wight, J. Wild, M. Wilkins, D. Wilkinson, B. Williams, N. Williams, J. Williams, S.A. Williams-Howard, M. Willicombe, G. Willis, J. Willoughby, A. Wilson, D. Wilson, I. Wilson, N. Window, M. Witham, R. Wolf-Roberts, C. Wood, F. Woodhead, J. Woods, D.G. Wootton, J. Wormleighton, J. Worsley, D. Wraith, C. Wrey Brown, C. Wright, L. Wright, S. Wright, J. Wyles, I. Wynter, M. Xu, N. Yasmin, S. Yasmin, T. Yates, K.P. Yip, B. Young, S. Young, A. Young, A.J. Yousuf, A. Zawia, L. Zeidan, B. Zhao, B. Zheng, O. Zongo, and PHOSP-COVID Study Collaborative Group

Subjects
Long COVID, Oncology, Recovery, Health Policy, Dyspnoea, Cohort, Internal Medicine, COVID-19
Abstract

Data sharing statement: PHOSP-COVID: The protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, requests for data access and other relevant study materials are available online at https://www.phosp.org. COVIDENCE UK: De-identified participant data will be made available upon reasonable request to the corresponding author. Supplementary data is available online at: https://www.sciencedirect.com/science/article/pii/S2666776223000546?via%3Dihub#appsec1 . Copyright © 2023 The Author(s). Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings: We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation: Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding: PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders. PHOSP-COVID: This study would not be possible without all the participants who have given their time and support. We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the study at all of the 65 NHS trusts/Health boards and 25 research institutions across the UK, as well as all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland, and Public Health England, and support from the ISARIC Coronavirus Clinical Characterisation Consortium. We thank Kate Holmes at the NIHR Office for Clinical Research Infrastructure (NOCRI) for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well NOCRI for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer's Research UK, Asthma + Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations, and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and Long Covid Support. COVIDENCE UK: We thank all participants of COVIDENCE UK, and the following organisations who supported study recruitment: Asthma UK/British Lung Foundation, the British Heart Foundation, the British Obesity Society, Cancer Research UK, Diabetes UK, Future Publishing, Kidney Care UK, Kidney Wales, Mumsnet, the National Kidney Federation, the National Rheumatoid Arthritis Society, the North West London Health Research Register (DISCOVER), Primary Immunodeficiency UK, the Race Equality Foundation, SWM Health, the Terence Higgins Trust, and Vasculitis UK.

Published
2023
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8. Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study

Author

Helen McShane, A Alamoudi, D Parekh, G Burns, R. Gisli Jenkins, Marco Sereno, R Djukanovic, Onn Min Kon, N I Lone, David M. Evans, L Daines, N A Hanley, Z. Omar, William Greenhalf, Nicola Williams, K Storton, Asaf David, T Wallis, E Pacpaco, H McCauley, L. O'Brien, K Hainey, P. Novotny, C Tong, L Ingram, S Gurram, C Avram, C Coleman, Edward T. Bullmore, Richard G. Brown, R Aul, K A Tripp, D. Cristiano, A Michael, Michael C Steiner, Padmasayee Papineni, A Howell, Gail Carson, Peter J. M. Openshaw, Simon Heller, G Madzamba, K Paradowski, S Singh, K Bramham, Teresa Light, David Price, V Shaw, A Yousuf, T Dong, T Hiwot, G Simons, Philip L. Molyneaux, A Ashworth, Ashley C. Brown, N Magee, A L Tan, R A Evans, Mark Toshner, Robert Sykes, W Saxon, S Finney, A Mohamed, P Cairns, Christos P Kotanidis, J D Chalmers, O Adeyemi, L Knibbs, A J Moss, S L Rowland-Jones, O M Kon, L P Ho, A Martineau, B Zhao, M G Crooks, J Meiring, Ewen M Harrison, Louise V. Wain, S Wright, E Robertson, David A. Lomas, H Lamlum, David E. Newby, P Chowdhury, K Mangion, Toby Hillman, E Turner, H McAllister-Williams, S West, J McGinness, B Whittam, T. Gorsuch, K Dempsey, L Mcgarvey, K Poinasamy, K Shevket, Emma Baldry, M Buch, N French, Olivia C. Leavy, Stephen C. J. Parker, H Newell, Louise M. Howard, O. Zongo, P Beirne, C Sharpe, N Mills, C David, M Bayley, Carmine M. Pariante, P Haldar, Z Kausar, A Dipper, I Hall, P McArdle, G Ogg, Rachael A. Evans, A.J. Buttress, M Pareek, Paul E Pfeffer, Denise Anderson, James D. Chalmers, P Kar, Caroline J. Jolley, S Plein, Nigel J. Brunskill, C Oliver, John R. Hurst, Clive Ballard, F Barrett, D Baguley, Nick P. Talbot, N Chaudhuri, A Young, Jonathan P. Busby, H Dobson, K Holmes, Liam G Heaney, Ruth E Barker, Anthony N. Price, David J. Stensel, L Brear, Louise Sigfrid, Marcia Soares, Patrice Carter, J R Hurst, John R. Geddes, Donghyung Lee, L Watson, J M Lord, H Parfrey, N Odell, J Glossop, K. 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Hall, Richard Kevin Stone, Aliki Thomas, L Turtle, H Tedd, L Matthews, J Bambrough, S Stanel, M J McMahon, L Chetham, Enya Daynes, R Hurst, Angela Cook, M Aljaroof, Ling-Pei Ho, Paul Moss, H Arnold, S Fairbairn, Anthony J. Rostron, L Garner, Kyle Harrington, Douglas Grieve, B Connolly, Khalida Ismail, Craig Johnson, E. Russell, T Hussell, S Kon, Claudia Langenberg, E Wall, A Rowland, Miriam Harvey, N Powell, Catherine Pennington, N Armstrong, J C Porter, A Ient, Matthew Hotopf, R Parvin, M Richardson, I Smith, L Lightstone, J. Dasgin, Lynne Armstrong, A Charalambou, J R Geddes, C. Clark, E Gourlay, A Botkai, G Choudhury, J Bonnington, Matthew A. Brown, Paul Dark, S Thackray-Nocera, J Woods, E Stringer, R Free, Aarti Shikotra, J Jacob, P Clift, W Man, Sally J Singh, B King, Nikki Gautam, A Zawia, K McCafferty, L Milligan, S Whittaker, A Elmer, H Chinoy, H Welch, J Haworth, A Shikotra, Matthew J. Rowland, A Singapuri, M McNarry, F. Davies, F Khan, T Mcnally, Alfred A.R. Thompson, A McArdle, V Brown, Helen L. Fisher, M Spears, Peter Jezzard, Morag Henderson, D Thickett, U Munawar, M Broome, Graeme Jones, M. Gummadi, S Marciniak, L Poll, E Calvelo, J Hawkes, D Saralaya, S Walder, Omer Elneima, E M Harrison, C E Bolton, S J Singh, Khalid Shah, S Diver, M Willicombe, M Ainsworth, H Nassa, O C Leavy, D C Thomas, R Upthegrove, C Singh, C Echevarria, Sebastian Edwards, N Lewis-Burke, C Bloomfield, D L Sykes, J Parmar, Sam M. Janes, Simon Wessely, Shaney L Barratt, Judith Clarke, S McAdoo, G MacGowan, Hamish McAuley, L O Wajero, C Dobson, David J. Burn, Daniel Lasserson, Gill Arbane, Matthew Richardson, D McAulay, Rhian M. Touyz, Miles D. Witham, E Major, J Whitney, C J Jolley, Michael Beadsworth, N Goodman, S Walmsley, Daniel F. McAuley, Kath Chapman, Paul Cullinan, Margaret Jones, K P Yip, Nilesh J. Samani, M Bourne, Jeremy S. Brown, A Bloss, Alison M. Lawrie, Timothy Felton, L Bishop, T Sass, Oliver Polgar, M Bakali, N Hawkings, T Chalder, Mujtaba Husain, B Jayaraman, Hannah Bayes, Vicky Kamwa, B Hargadon, Y Peng, C Jolley, D Matila, Clare E. Mackay, J Worsley, R Dharmagunawardena, R Samuel, L Fabbri, R Russell, K Bhui, David W. Clark, S Heller, Anne Dell, J Nyaboko, N Huneke, Michael Marks, L Hesselden, A Greenhalgh, L Broad, M Bakau, Susan P. Walker, Marlies Ostermann, Smitaa Patel, E Fraser, R I Evans, V Whitehead, S Ahmad, C King, B Young, David T Arnold, Paul Klenerman, S Dunn, H McAuley, D Faluyi, B Holroyd-Hind, H Qureshi, E Bradley, Brendan G Cooper, P Shah, L Houchen, Shelley Fletcher, Todd Evans, Andrew Smith, Jill Walsh, Amanda F. Elliott, V Harris, L Holdsworth, A Ford, R Saunders, K Vellore, Jonathan Finch, A McGovern, D Nicoll, A Briggs, J Oxton, G A Davies, Milton Ashworth, T I de Silva, V Lewis, James Stockley, S Byrne, Alison G. Harvey, M Sereno, Marc Lipman, S Terry, A Moss, L. McMorrow, Nick A Maskell, Annemarie B Docherty, R Sabit, J Kenneth Baillie, Jennifer M. Short, Louise Stadon, Aziz Sheikh, S A Williams-Howard, Atul Gupta, D Altmann, J Cavanagh, S Francis, E. Perkins, E McIvor, P Atkin, Julie Williams, D Sutherland, J Rangeley, Derek Bell, J Valabhji, J K Baillie, Isobel D. Stewart, P McCourt, P Rivera-Ortega, N J Greening, Anthony De Soyza, M Dalton, Group, PHOSP-COVID Collaborative, Apollo - University of Cambridge Repository, Baguley, David, National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, and UK Research and Innovation

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Health Status, medicine.medical_treatment, MEDLINE, Comorbidity, Disease, Logistic regression, PHOSP-COVID Collaborative Group, 1117 Public Health and Health Services, Cognition, SDG 3 - Good Health and Well-being, medicine, Humans, Prospective Studies, Prospective cohort study, Aged, Mechanical ventilation, United Kingdom/epidemiology, business.industry, COVID-19, 1103 Clinical Sciences, Articles, Middle Aged, Mental health, United Kingdom, Middle age, Hospitalization, Mental Health, Acute Disease, COVID-19/complications, Female, business, 1199 Other Medical and Health Sciences, Follow-Up Studies
Abstract

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 burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Published
2021
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9. Immunohistochemical evidence of increased neutrophil swarms in Cystic Fibrosis lung removed at transplantation

Author

James Lordan, Malcolm Brodlie, Gareth Parry, Andrew J. Fisher, James P. Garnett, K Jiwa, and Chris Ward

Subjects
Lung, biology, business.industry, medicine.disease, Cystic fibrosis, Transplantation, Immune system, medicine.anatomical_structure, Neutrophil elastase, Diabetes mellitus, Parenchyma, Immunology, biology.protein, medicine, Immunohistochemistry, business
Abstract

Background: Cystic fibrosis (CF) is an inherited disease with significant associated morbidity and mortality. Lung infections and neutrophilic inflammation are associated with disease progression. In particular, Cystic fibrosis-related diabetes (CFRD) is a common comorbidity, associated with an accelerated lung function decline, exacerbations of lung disease, and increased mortality. Animal models of infectious and sterile inflammation have observed organized clusters of neutrophils initiating immune responses, called neutrophil swarming [Immunol Rev. 2016 Sep;273(1):76-93]. Neutrophil swarms have yet to be described in humans to our knowledge. We therefore hypothesised that neutrophil “swarm like aggregates” (swarms), are present in CF. Methods: We used paraffin embedded CF lung parenchyma tissue and HbA1c test data to subdivide groups: 13 CF patients with good glycaemic control and 13 patients who were hyperglycaemic (CFRD ≥ HbA1c 6%). 8 donor lungs not used for transplantation were used for control. Immunohistochemical distribution of neutrophil elastase positive swarms in size categories: single, doublet, small, medium and large were quantified. Results: In CF combined; doublet (p= 0.0011), small (p= 0.0001), medium (p= 0.0160) and large (p= 0.0023) neutrophil swarms were significantly elevated compared to controls. There were no significant differences in any swarm category comparing CF against CFRD. Conclusion: We have shown neutrophil swarm like organizations for the first time in human end stage adult CF. Neutrophil swarms were more prevalent in CF lungs removed at time of transplantation compared to controls and this was independent of CFRD.

Published
2020
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10. M19 A pilot study of endotyping in bronchiectasis

Author

G Jones, V Chew, G Davies, J Davison, K Jiwa, R Davidson, and A De Soyza

Subjects
medicine.medical_specialty, Bronchiectasis, business.industry, medicine.medical_treatment, Interleukin, macromolecular substances, Disease, Eosinophil, medicine.disease, Gastroenterology, Vascular endothelial growth factor, chemistry.chemical_compound, medicine.anatomical_structure, Cytokine, chemistry, Internal medicine, Eosinophilic, medicine, Sputum, medicine.symptom, business
Abstract

Aim Bronchiectasis is increasingly common and has diverse aetiologies. It is commonly viewed as a neutrophilic disease but our prior data has shown some patients are highly eosinophilic. We aimed to extend this by undertaking multikine cytokine analysis. Method 53 patients of varying bronchiectasis severity were recruited in our regional bronchiectasis service. Multiple cytokines (Vascular Endothelial Growth Factor (VEGF), Tissue Necrosis Alpha(TNF-A), Interleukin 4,5,6,10,17 were measured with MSD kits. We counted sputum eosinophil and recorded blood eosinophils from routine FBC. We compared our data against the severity based on the bronchiectasis severity index (BSI) which classifies the disease severity into mild, moderate and severe and compared using ANOVA. Results Of the 53 patients 9 patients had mild BSI severity, 22 were moderate and 22 were severe. Levels of VEGF, TNF-a, Interleukins 4,5,6,10,17, sputum and blood eosinophils were not correlated with the severity of bronchiectasis, all P values of >0.05. These data extend our observations in 110 patients where TNF and VEGF were not correlated with BSI. IL-8 was statically significant but not a pattern that was expected. This may be due to the sample size. Conclusion We saw no statistically significant association between the level of cytokines and eosinophils in both blood and sputum with the severity of bronchiectasis. This may reflect the sample size and larger studies should be conducted. There was a large range for each parameter detected however suggested bronchiectasis is highly heterogenous. Future studies targeting distinct pathways may need to consider enriching for certain endotypes.

Published
2019
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11. M16 Blood and sputum eosinophils, interleukin 5 and bronchiectasis

Author

A De Soyza, G Jones, V Chew, J Davison, K Jiwa, R Davidson, and G Davies

Subjects
Sputum Cytology, Bronchiectasis, business.industry, respiratory system, Eosinophil, medicine.disease, respiratory tract diseases, medicine.anatomical_structure, Immunology, Eosinophil activation, medicine, Eosinophilia, Sputum, medicine.symptom, business, Interleukin 5, Asthma
Abstract

Aim Bronchiectasis is thought to be a neutrophilic lung disease. However, increasingly it is recognised in some patients eosinophils may predominate. We have reported previously a significant minority of patients have eosinophilic predominant sputum cytology even in the absence of known asthma. As IL-5 is a key mediator of eosinophil activation, we aim to study the correlation between IL-5 and eosinophil in both serum and sputum. Method 120 patients were recruited into the study from our regional bronchiectasis service. We report data on the first 51 fully analysed. The level of IL-5 in both serum and sputum were measured with the MSD Kits. Sputum eosinophil were counted and serum eosinophil were recorded from routine FBC. Data which includes IL-5 and eosinophil levels in both serum and sputum were analysed to find a correlation with each measurement. Result Blood and sputum eosinophil showed a good correlation with a coefficient of 0.694. Interestingly no correlation was found for other comparisons with a coefficient of 0.042 between serum and sputum IL-5, 0.349 between serum IL-5 and serum eosinophil and 0.055 between serum IL-5 and sputum IL-5. Conclusion Our data suggest there is a good correlation between sputum and blood eosinophil in bronchiectasis. We could not find a correlation between other markers. This may be due to the heterogeneity of bronchiectasis where only a certain subset of patients are predominantly eosinophilic driven and compartmentalization of inflammation within the lung separating it from systemic compartments. The study sample size is being increased in order to exclude a type 1 error. It is plausible that other cytokines beyond IL-5 contribute to eosinophilia in sputum.

Published
2019
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12. Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during human ex vivo lung perfusion

Author

Lee A. Borthwick, Paul A. Corris, Stephen Clark, Henning Pauli, K Jiwa, Kate Gould, D.M. Karamanou, Simi Ali, Tanveer Butt, Hannah R. Walden, Anders Andreasson, Andrew J. Fisher, Faruk Özalp, John H. Dark, Paul Hill, Nicola Green, and Colin S. Gillespie

Subjects
Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Inflammation, 030204 cardiovascular system & hematology, Lung injury, EVLP, 03 medical and health sciences, chemistry.chemical_compound, A900, 0302 clinical medicine, Lactate dehydrogenase, medicine, Inverse correlation, medicine.diagnostic_test, business.industry, Ex vivo lung perfusion, General Medicine, Oxygenation, Transplantation and Mechanical Circulatory Support, respiratory system, C900, Donor lungs, respiratory tract diseases, Bronchoalveolar lavage, 030228 respiratory system, chemistry, Surgery, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Biomarkers, Lung transplant
Abstract

OBJECTIVES: Availability of donor lungs suitable for transplant falls short of current demand and contributes to waiting list mortality.\ud Ex vivo lung perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant.\ud Identifying robust biomarkers that can stratify donor lungs during EVLP to use or non-use or for specific interventions could further improve its clinical impact.\ud METHODS: In this pilot study, 16 consecutive donor lungs unsuitable for immediate transplant were assessed by EVLP. Key inflammatory mediators and tissue injury markers were measured in serial perfusate samples collected hourly and in bronchoalveolar lavage fluid (BALF) collected before and after EVLP. Levels were compared between donor lungs that met criteria for transplant and those that did not.\ud RESULTS: Seven of the 16 donor lungs (44%) improved during EVLP and were transplanted with uniformly good outcomes. Tissue and vascular injury markers lactate dehydrogenase, HMGB-1 and Syndecan-1 were significantly lower in perfusate from transplanted lungs. A model combining IL-1b and IL-8 concentrations in perfusate could predict final EVLP outcome after 2 h assessment. In addition, perfusate IL-1b concentrations showed an inverse correlation to recipient oxygenation 24 h post-transplant.\ud CONCLUSIONS: This study confirms the feasibility of using inflammation and tissue injury markers in perfusate and BALF to identify donor lungs most likely to improve for successful transplant during clinical EVLP. These results support examining this issue in a larger study.

Published
2016

13. Telomere Dysfunction and Senescence-associated Pathways in Bronchiectasis

Author

Stella Victorelli, Jodie Birch, Elizabeth Moisey, K Jiwa, Dina Rahmatika, Anthony De Soyza, Andrew J. Fisher, João F. Passos, Chris Ward, and Rhys Anderson

Subjects
Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, Gerontology, Senescence, Cellular senescence, Telomere dysfunction, Critical Care and Intensive Care Medicine, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Correspondence, Humans, Medicine, Cellular Senescence, Bronchiectasis, business.industry, Middle Aged, Telomere, medicine.disease, 030104 developmental biology, 030228 respiratory system, Female, business, Cell aging
Published
2016
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14. P9 Genetic variants in bronchiectasis- a proof of concept study

Author

K Jiwa, K Schwarz, J Davison, A De Soyza, and S Ehl

Subjects
education.field_of_study, Bronchiectasis, business.industry, Population, Immune dysregulation, medicine.disease_cause, medicine.disease, Cystic fibrosis, DNA extraction, law.invention, law, Immunology, Multiplex polymerase chain reaction, medicine, education, business, Allele frequency, Polymerase chain reaction
Abstract

Bronchiectasis is a clinical syndrome linked with recurrent infections and dysregulation of airway epithelial defences. Prior data suggesting cystic fibrosis genetic mutations are more common in bronchiectasis but there are few other data in bronchiectasis. Recently familial cases of bronchiectasis have led to the identification of activated PI3 kinase syndrome as a genetic cause and bronchiectasis is a manifestation of a number of related immunodeficiencies. Recently a multisite Bronchiectasis collaborative with biobank (www.bronch.ac.uk) has been developed. Future genetics studies may be conducted from the biobank pending appropriate funding. We studied to investigate the feasibility of using frozen whole blood and have chosen to study PI3kinase and other immune regulatory genes in any suspected aetiology of bronchiectasis. Methods 220 unselected adult patients with bronchiectasis were recruited in Newcastle for a single centre study. Using the BronchUk protocol whole frozen blood from a single centre biobank was then used for DNA extraction from 46 patients randomly selected patients. We used a proprietary kit (Qiagen) and used 3 mls of whole blood. The DNA was then quantified using a nanodrop and then studied using a multiplex PCR approach studying PIK3CD, PIK3R1, STAT1, STAT3, CTLA4 and NFKB1 (using in house primers). Positive and negative controls were included. Results Of the 46 patients studied the mean age was 63.7 years and M:F gender was 18:28 and average FEV1% predicted was CCC%. Good DNA extraction was possible from the archived biobank samples (average 28 ng/ul). All patients yielded DNA suitable for pCR amplification. None of the patients samples demonstrated known pathogenic variants in the investigated genes. The STAT1 c.633+6T>A and the STAT3 c.551–4G>A heterozygote variants detected in one patient each have an allele frequency in the general population that favour classification as a polymorphism. Conclusions We have shown that BronchUK methodology archiving frozen whole blood can be used to test for immune dysregulation genes in biobanked samples. Overall, the frequency of primary immunodeficiencies in unselected patients with bronchiectasis appears to be low. Laregr sample sizes studied with broader gene panels including CFTR are needed Acknowledgements MRC funding to Bronch UK, Unrestricted grant to Prof Ehl from UCB.

Published
2018
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15. S89 Interleukin 8 secretion but not superoxide anion production is different between healthy and bronchiectasis patients neutrophils

Author

Christopher Cole, John Simpson, K Jiwa, A De Soyza, G Davies, G Jones, Jonathan M. Scott, and James D. Chalmers

Subjects
medicine.medical_specialty, Interleukin-8 secretion, business.industry, Superoxide, Phagocytosis, Zymosan, Inflammation, In vitro, chemistry.chemical_compound, Endocrinology, chemistry, Internal medicine, Medicine, Propidium iodide, medicine.symptom, business, Whole blood
Abstract

Introduction Bronchiectasis (BR) is a disease featuring a cycle of airway infection and inflammation, with the latter being driven by recruited neutrophils. Currently limited data is available comparing differences in biological function between healthy and BR patient derived neutrophils. Aim To assess potential differences in peripheral blood neutrophil function between healthy individuals and BR patients. Methods Neutrophils were isolated by gradient separation from whole blood samples from BR patients and healthy volunteers (not age matched). Four aspects of neutrophil biology were assessed in vitro: IL-8 secretion following stimulation with BR relevant stimuli (IL-8 ELISA, R and D systems), 24 hour viability (annexin V and propidium iodide staining), superoxide anion production (superoxide dependent cytochrome C reduction measurement) and phagocytosis rates (microscopic counts of neutrophils that had engulfed two or more zymosan particles). Results Patients included those with BR alone and those with comorbid Rheumatoid arthritis (BROS). In all stimulatory conditions mean IL-8 secretion for healthy neutrophils (n=12) was lower than BR patient derived neutrophils (n=13), with the differences between the two groups being significant for unstimulated neutrophils and neutrophils stimulated by TNF-α, P. aeruginosa Whole cell lysates (WCLs) and H. influenzae WCLs (figure 1). Viability measured at regular 4 hour intervals across a 24 hour period showed a negative correlation in viability for both groups (n=3) but no significant difference in viability at any time point. Superoxide production was similar in both healthy (n=8) and BR (n=13) neutrophils, with 50 nM PMA yielding the highest increase in release for both healthy and BR patients (mean superoxide anion release of 14.2 nM and 14.3 nM respectively). 75.7% (95% CI: 71.5%–79.9%) of healthy neutrophils (n=6) phagocytosed 2 or more zymosan particles, BR patient (n=13) had a phagocytosis rate of 66.4% (95% CI: 64%–68.8%) which was significantly lower (p Conclusion The superoxide production and 24 hour viability shows no difference between healthy and BR patients. Phagocytic ability and IL-8 secretion results suggest BR peripheral blood neutrophils had higher IL-8 secretion. There was a lower phagocytosis rate but this may not have reached a minimally clinically important difference.

Published
2018
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16. S87 Bronchiectasis relevant molecules promote NETosis and citrullination in human peripheral blood neutrophils

Author

John Simpson, A De Soyza, K Jiwa, G Davies, James D. Chalmers, G Jones, Jonathan M. Scott, and Christopher Cole

Subjects
business.industry, Extracellular, Medicine, Citrullination, Stimulation, Neutrophil extracellular traps, Bacterial antigen, business, medicine.disease_cause, Protein citrullination, Microbiology, Autoimmunity, Whole blood
Abstract

Introduction The formation of Neutrophil extracellular traps (NETS) may protect against pathogens but might promote autoimmunity. Bronchiectasis (BR) is a model for autoimmunity with strong links to rheumatoid arthritis. Bacterial antigens may promote NETosis and/or peptidyl arginine deiminase (PAD) enzyme activity leading to protein citrullination. The ability of these bronchiectasis relevant pathogens/molecules to induce NETosis and PAD activity in human derived neutrophils using consistent methodologies has not been assessed. Aims To undertake multi-modal assessment of NETosis rates and PAD activity in healthy peripheral blood neutrophils following stimulation with BR relevant stimuli. Methods Neutrophils were isolated from healthy volunteer whole blood by gradient separation then incubated for 4 hours at 37°C in the presence of PMA (used as a positive NET control) or BR relevant stimuli including: LPS, TNF-α, P. aeruginosa whole cell lysates (WCLs) or H. influenzae WCLs. NETosis rates were assessed in neutrophil samples using two methodologies: Microscopy count of immunofluorescent (IF) stained fixed NETs (n=13) and histone-elastase complex ELISAs of collected supernatants (n=16, semi-quantified using a NET containing biological standard). Supernatant PAD activity was measured using a commercial PAD activity assay from Modiquest Research (n=16). Results IF microscopy counts showed NETosis rates in unstimulated neutrophils of 4% (95% CI: 2.8% to 5.4%). All stimuli (excluding H. influenzae WCLs) caused a significant increase in NETosis, with the highest increase being observed in 50 nM PMA with a mean rate of 53% (95% CI: 46% to 59%) (figure 1). NET ELISAs of supernatants showed significant increase in the NET dependent absorbance for neutrophils stimulated with PMA (p Conclusion Collectively the NETosis assays show PMA, LPS and TNF-α promote NETosis, however IF counts also suggest P. aeruginosa WCLs induced NETosis. Extracellular PAD activity increased following stimulation with several BR relevant stimuli. These data may explain the links between Bronchiectasis and Rheumatoid arthritis through protein citrullination.

Published
2018
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17. Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients

Author

Marie-Hélène Ruchaud-Sparagano, Stephen E Wright, Michael W. Mather, Stephen Cummings, Janet A. Wilson, Faye A. H. Cooles, Jon Scott, Bernard Verdon, John D. Perry, Andrew Nelson, Jason Powell, Chris Ward, James P. Garnett, A. John Simpson, K Jiwa, and Jeffrey P. Pearson

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, Glottis, Neutrophils, Mucoproteins, Critical Illness, Phagocytosis, B100, Critical Care and Intensive Care Medicine, Microbiology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Colonization, Prospective Studies, Aged, Inflammation, Host (biology), business.industry, Mucin, Mucins, Ventilator-associated pneumonia, 030208 emergency & critical care medicine, C500, Middle Aged, A300, bacterial infections and mycoses, medicine.disease, Respiration, Artificial, Immunity, Innate, respiratory tract diseases, Pneumonia, 030228 respiratory system, Female, business
Abstract

Rationale:\ud Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP.\ud \ud Objectives:\ud To characterize subglottic host defense dysfunction in mechanically ventilated patients in the intensive care unit (ICU). To determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth.\ud \ud Methods:\ud Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 minutes). Isolation and culture of primary subglottic epithelial cells from controls. Laboratory analysis of host innate immune defenses.\ud \ud Measurements and Main Results:\ud Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in ICU was characterized by neutrophilic inflammation, significantly increased pro-inflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic function was reversible upon treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium.\ud \ud Conclusions:\ud Mechanical ventilation in ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil dysfunction and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage.

Published
2018

18. Bronchiectasis disease relevant PAMPs stimulate VEGF and neutrophil elastase release from neutrophils

Author

Jodie Birch, Sonya Carnell, John Simpson, Chris Ward, K Jiwa, Christopher Cole, Katy L.M. Hester, and Anthony De Soyza

Subjects
Bronchiectasis, biology, business.industry, VEGF receptors, Elastase, Disease, medicine.disease, Vascular endothelial growth factor, chemistry.chemical_compound, chemistry, In vivo, Neutrophil elastase, Immunology, biology.protein, Medicine, Airway Remodelling, business
Abstract

Intro: Bronchiectasis (BR) is characterised by airway inflammation and infection. Neutrophils play a key role in the disease and may contribute to airway remodelling via elastase and vascular endothelial growth factor (VEGF) release. Aims: To understand neutrophils roles in bronchiectasis and identify if neovascularisation is present in bronchiectasis airways Methods: We isolated and stimulated peripheral blood neutrophils from healthy volunteers (HV) and BR patients with disease relevant PAMPs (e.g. bacterial lysates, fMLP) for 4 hours, the supernatant was then assessed for VEGF and elastase concentration by ELISA. Endobronchial biopsies from HV and BR airways were stained with anti-CD31 for counts of blood vessels. Sera/sputa from BR patients (n=115) and HV sera (n=26) were assessed for VEGF concentration by ELISA and categorised by patient bronchiectasis severity index score. Results: Neutrophils treated with several stimuli (e.g. LPS, TNF-α) released significantly (p Conclusion: Neutrophils release elastase when stimulated by PAMPs. BR peripheral blood neutrophils behave differently to normal and release greater amounts of VEGF. BR airways show signs of hyper-vascularity consistent with in vivo pro-angiogenic conditions. Sera/sputa VEGF cannot be used to directly predict disease severity.

Published
2017
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19. P033 Nasal epithelial cells as an experimental model in cystic fibrosis

Author

Bernard Verdon, Michael A. Gray, Iram J. Haq, Aaron Gardner, K. Jiwa, Malcolm Brodlie, Chris Ward, and Vinciane Saint-Criq

Subjects
Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Experimental model, business.industry, Pediatrics, Perinatology and Child Health, medicine, medicine.disease, business, Cystic fibrosis
Published
2019
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20. Neutrophil vascular endothelial growth factor (VEGF) as a driving force for angiogenesis in bronchiectasis?

Author

John Simpson, Sonya Carnell, K Jiwa, Anthony De Soyza, Jodie Birch, Katy L.M. Hester, Chris Ward, and Christopher Cole

Subjects
Basement membrane, Pathology, medicine.medical_specialty, Bronchiectasis, biology, Angiogenesis, business.industry, medicine.disease, Vascular endothelial growth factor, chemistry.chemical_compound, Vascularity, medicine.anatomical_structure, Vascular endothelial growth factor C, chemistry, medicine, biology.protein, medicine.symptom, Antibody, business, Blood vessel
Abstract

Intro: Bronchiectasis (BR) is a neutrophilic airway inflammation and infection syndrome. VEGF is a plausible stimulant of a pro-angiogenic airway environment supporting neutrophil accumulation but is not well described in BR. Aims: 1) Evaluate BR airways for indications of increased angiogenesis, 2) Determine if neutrophils are a potential source of VEGF in vitro. 3) Assess if sera and sputa VEGF levels could act as a valid biomarker for BR patient severity. Methods: Healthy and BR endobronchial biopsies were stained with anti-CD31 antibody, allowing blood vessel counting (blinded). Peripheral blood neutrophils from healthy volunteers and BR patients were stimulated (e.g. with TNF-α or bacterial PAMPS) for 4 hours, VEGF quantified by ELISA. Finally, an ELISA was used to determine VEGF levels in sera and sputa from BR patients (n=115), categorised by Bronchiectasis severity index (BSI) and sera from controls (n=26). Results: BR endobronchial biopsies had significantly more blood vessels/mm basement membrane than healthy (p Conclusion: BR airways had increased vascularity consistent with a pro-angiogenic milieu. Our in vitro data supports that stimulated normal neutrophils are a source of VEGF. Our data however suggests that sera and sputa VEGF cannot be used as a predictor for disease severity. Further longitudinal studies may help define the role of VEGF in exacerbations and disease severity.

Published
2016
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21. EPS1.04 Use of ex vivo paediatric primary nasal epithelial cultures to investigate TMEM16A as a potential therapeutic target in children with cystic fibrosis

Author

Vinciane Saint-Criq, Michael A. Gray, K. Jiwa, Bernard Verdon, Chris Ward, Aaron Gardner, Iram J. Haq, and Malcolm Brodlie

Subjects
Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Primary (chemistry), business.industry, Pediatrics, Perinatology and Child Health, medicine, medicine.disease, business, Cystic fibrosis, Ex vivo
Published
2018
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22. S46 Neutrophil vascular endothelial growth factor (VEGF) as a driving force for angiogenesis in bronchiectasis?

Author

Sonya Carnell, Chris Ward, K Jiwa, Jodie Birch, J Simpson, Christopher Cole, De, Soyza, Ads, and Klm Hester

Subjects
Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Bronchiectasis, Lung, biology, business.industry, Angiogenesis, medicine.medical_treatment, Inflammation, medicine.disease, Vascular endothelial growth factor, chemistry.chemical_compound, medicine.anatomical_structure, Cytokine, Vascular endothelial growth factor C, chemistry, biology.protein, Medicine, medicine.symptom, Antibody, business
Abstract

Introduction Bronchiectasis (BR) in a pulmonary disease thought to involve a characteristic dilation of the bronchi resulting from a cycle of airway infection and inflammation. This inflammation is believed to be driven by neutrophils, which are present in the BR lung in high number. Vascular endothelial growth factor (VEGF) is a pro-angiogenic cytokine that may be upregulated in BR and could contribute towards creating a pro-angiogenic airway environment by supporting neutrophil migration into the airway tissue, however this has yet to be shown. Aims 1) Examine the BR airway for any indications of increased angiogenesis, 2) Assess the ability of neutrophils to secrete VEGF upon stimulation in vitro, 3) Evaluate sera/sputa samples VEGF concentration to determine if VEGF could act as a biomarker for BR severity. Methods Healthy volunteer (HV) and BR endobronchial biopsies were stained with a HRP conjugated anti-CD31 antibody, allowing blood vessels to be counted in a blinded manner. Peripheral blood neutrophils isolated from HV were stimulated (e.g. with TNF-α or bacterial PAMPs) for 4 hours, VEGF levels in supernatants were then quantified using ELISA. A VEGF ELISA was also used to determine VEGF concentration in sera and sputa samples from BR patients (n = 115), categorised by bronchiectasis severity index (BSI) scores and sera samples from HV controls (n = 26) Results Endobronchial biopsies from BR airways had a significantly (p Conclusion The increased presence of vascular tissue seen in BR could indicate a pro-angiogenic airway environment in BR. The in vitro data collected also show that a variety of stimulants can initiate secretion of VEGF by neutrophils. However, our data does not suggest that VEGF levels in sera or sputa can be used to predict disease severity.

Published
2016
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23. Treating Donor Lung Inflammation by Blocking Interleukin-1Β - An In Vitro Therapy Testing Platform for Ex Vivo Lung Perfusion

Author

Stephen Clark, Anders Andreasson, Simi Ali, K Jiwa, Faruk Özalp, P. Henderson, H. Pauli, Tanveer Butt, Lee A. Borthwick, Colin S. Gillespie, Andrew J. Fisher, D.M. Karamanou, Paul A. Corris, and J.H. Dark

Subjects
Pulmonary and Respiratory Medicine, Transplantation, Lung, business.industry, Blocking (radio), Interleukin 1 family, Ex vivo lung perfusion, Inflammation, In vitro, medicine.anatomical_structure, Cancer research, Medicine, Surgery, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Published
2016
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24. S84 Sputum neutrophils but not Interleukin-8 (IL-8) or Interleukin 17 (IL-17) correlate with the Bronchiectasis Severity Index (BSI)

Author

A Peel, K Jiwa, S Carnell, J Davison, S Koustas, De, Soyza, A, Jonathan M. Scott, and AJ Simpson

Subjects
Pulmonary and Respiratory Medicine, Chemokine, Lung, Bronchiectasis, biology, business.industry, medicine.medical_treatment, medicine.disease, Cytokine, medicine.anatomical_structure, Immunology, biology.protein, Medicine, Biomarker (medicine), Sputum, Interleukin 8, Interleukin 17, medicine.symptom, business
Abstract

Background Bronchiectasis is a progressive neutrophilic inflammatory lung disease associated with abnormal local cytokine release with possible systemic overspill. Early data suggests that interleukin-17 (IL-17) could be involved in the enhanced infiltration of neutrophils in the lungs, via the induction of IL-8 release, and has emerged as a possible biomarker for other chronic neutrophilic lung diseases. Aims to investigate the potential use of IL-17 and IL-8 as biomarkers of disease severity in bronchiectasis by utilising a multidimensional clinical severity scoring system, the Bronchiectasis Severity Index (BSI). correlate sputum neutrophils and pathogen status with serum or sputum IL-17 and IL-8 levels. Methods Spontaneous sputa and sera were collected from stable adult bronchiectasis patients attending a specialist clinic. We quantified both IL-17 and IL -8 concentrations in the pulmonary compartment (sputum) and the systemic compartment (serum) of 119 stable bronchiectasis patients and 26 healthy volunteers. Sputum neutrophils were conducted using standard methods. Results The mean patient age was 65 years, with 24% in mild BSI, 39% moderate BSI and 46% (43% idiopathic, 24% post infectious). IL-17 in the sputum of bronchiectasis patients was found to be two-fold greater than in serum suggesting “local” release (10 pg/ml vs 5 pg/ml). Statistical analysis revealed a significant correlation between these two variables, suggesting a “spillover” of cytokines from the lungs (p However, there was no significant difference in serum IL-17 levels between bronchiectasis and healthy subjects (0 ± 2 pg/ml). In addition, no significant correlation was found between IL-8 and IL-17 levels in the sputum of patients. Sputum IL-17 levels were found to have a significant negative correlation with BSI severity scoring, but this was not reproduced when individual BSI parameters were analysed. IL-8 similarly performed poorly in correlating with BSI. In contrast more severe BSI scores were significantly associated with higher% neutrophils in sputa (p = 0.045). Conclusions The clinical utility of IL-17 and IL-8 as biomarkers for the prediction of disease severity in bronchiectasis patients appears poor. These data may also suggest targeting these chemokines are of limited value. Focus in bronchiectasis may need shifted from neutrophil chemokines to factors that inhibit apoptosis and/or promote neutrophil persistence in the airway.

Published
2015
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25. S65 Large and small airway epithelial cell senescence present in COPD and bronchiectasis?

Author

Jodie Birch, Paul A. Corris, K Jiwa, GE Johnson, Andrew J. Fisher, João F. Passos, Chris Ward, John J. Taylor, Robert H. Anderson, and A De Soyza

Subjects
Pulmonary and Respiratory Medicine, Senescence, COPD, Pathology, medicine.medical_specialty, Lung, Bronchiectasis, business.industry, Inflammation, respiratory system, medicine.disease, respiratory tract diseases, Telomere, Pathogenesis, medicine.anatomical_structure, Immunology, medicine, Respiratory epithelium, medicine.symptom, business
Abstract

Introduction and Objectives Accelerated lung ageing has been implicated in the pathogenesis of COPD and therefore targeting cellular senescence may have therapeutic benefit. COPD is increasingly felt to have significant sub-phenotypes with large and small airway involvement. The airway epithelium likely endures the majority of potentially senescence-inducing insults. However, data on airway epithelial cell (AEC) senescence in COPD is limited and comparisons between large and small airways are lacking. Furthermore, the role of infection in COPD-associated senescence is unclear. To date, senescence in bronchiectasis has not been investigated as a model for infection-induced senescence. We sought to determine AEC expression of senescence-associated markers in COPD and bronchiectasis and to compare large and small airways. Methods Lung explant tissue from our transplant programme from COPD (n = 19) and bronchiectasis (n = 14) with resection tissue from smokers without lung disease (control) (n = 11) was stained for senescence-associated markers by immunohistochemistry. Staining was quantified semi-quantitatively. Fluorescence in situ hybridisation (FISH) was used to investigate telomere length and possible co-localisation with DNA damage-associated proteins. ![Abstract S65 Figure 1.][1] Abstract S65 Figure 1. Expression of Ki67 (A), SIRT1 (B), p16 (C) and γH2AX (D) in large AECs and small AECs (E, F, G and H, respectively). Results are expressed as mean ± SEM. Statistics: Kruskal-Wallis and Mann-Whitney U test. * p < 0.05, ** p < 0.01, \***| p < 0.001. Results In large AECs, expression of the proliferation marker ki67 and the anti-ageing protein sirtuin 1 (SIRT1) was decreased in COPD as compared to bronchiectasis and controls. There was no difference in expression of the cell-cycle inhibitor p16 and the DNA damage associated foci ?H2AX between the three groups. In small AECs, SIRT1 was decreased in COPD compared to controls and p16 and ?H2AX were increased. Here, ki67 expression did not differ between groups. In bronchiectasis, there was no significant change in senescence marker expression compared to controls, with the exception of decreased SIRT1 in large AECs. Marker expression was not significantly correlated with FEV1 or smoking history. Preliminary work suggests potential co-localisation of ?H2AX at telomeres with ongoing analysis underway. Conclusions Differential expression of senescence-associated markers between large and small airways in COPD may reflect the distinct patterns of inflammation and functional impairment occurring in the two airway compartments. There is some evidence suggesting a role for senescence in bronchiectasis, though this is less clear than for COPD. Further markers need to be investigated. [1]: pending:yes

Published
2013
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26. P112 Deeper phenotyping of non CF bronchiectasis through sputum differential counts: Abstract P112 Table 1

Author

A De Soyza, Jodie Birch, J Davison, Andrew J. Fisher, R Wake, K Jiwa, A Cranson, G Johnson, T Small, and B Hood

Subjects
Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, Bronchiectasis, medicine.diagnostic_test, business.industry, Eosinophil, medicine.disease, respiratory tract diseases, Atopy, medicine.anatomical_structure, Internal medicine, Immunology, medicine, Sputum, medicine.symptom, business, Complication, Asthma, Cohort study
Abstract

Introduction and Objectives Non CF Bronchiectasis has diverse aetiologies. This includes idiopathic, systemic disease related and as a complication of asthma. Such diversity may be important in determining therapeutic strategies (personalised medicines) and may also be an important consideration in clinical trial design. This is increasingly relevant when neutrophil targeting or eosinophil targeted therapies are being developed. We hypothesised that patients could be phenotyped by sputum cytospins irrespective of suspected aetiology or disease severity. Methods Patients underwent a standardised clinical phenotyping protocol including HRCT chest (Anwar et al 2013). Baseline therapy was recorded. Spontaneous sputa were collected in stable state and spirometry was undertaken according to guidelines. Sputum cell counts were calculated using standard methods with data expressed as medians and ranges. Results Fifty three patients’ data are reported. The M:F ratio was 1:1.4. The mean FEV1 predicted was 62%, mean FEV1/VC ratio was 64%. Forty three (83%) were on inhaled corticosteroids and 24.5% had a historical diagnosis of asthma and /or ABPA. The predominant cell in sputa was neutrophils, median 94 (range 23–100%), macrophages were the 2nd most prevalent cell type median 2.6 (range 0–75%). Eosinophils showed a skewed distribution with median of 0.2 with a range of 0–24.8%. Four patients had sputum eosinophilia >3%. Of these, only 2 had a history of asthma and / or ABPA being diagnosed. Despite historical diagnoses of asthma and / or ABPA in 13 patients the eosinophil percentage was not statistically different to “non asthmatics”. (P = 0.59 Chi Sq test) This group included features of ABPA in 2 patients and significant atopy in another. Conclusions Non CF bronchiectasis patients usually have sputum neutrophil dominance. Sputum eosinophilia is rare ( References Anwar GA, et al. 2013 Phenotyping adults with non-cystic fibrosis bronchiectasis: A prospective observational cohort study. Respir Med . Jul;107(7):1001–7. doi: 10.1016/j.rmed.2013.04.013. Epub 2013 May 11.

Published
2013
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27. Long COVID and cardiovascular disease: a prospective cohort study

Author

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

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Published
2024
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28. Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19.

Author

Milross L, Hunter B, McDonald D, Merces G, Thomson A, Hilkens CMU, Wills J, Rees P, Jiwa K, Cooper N, Majo J, Ashwin H, Duncan CJA, Kaye PM, Bayraktar OA, Filby A, and Fisher AJ

Subjects
Humans, Young Adult, Adult, Middle Aged, Aged, Aged, 80 and over, Endothelial Cells, SARS-CoV-2, Lung pathology, COVID-19 pathology, Lung Injury pathology
Abstract

Background: Lung damage in severe COVID-19 is highly heterogeneous however studies with dedicated spatial distinction of discrete temporal phases of diffuse alveolar damage (DAD) and alternate lung injury patterns are lacking. Existing studies have also not accounted for progressive airspace obliteration in cellularity estimates. We used an imaging mass cytometry (IMC) analysis with an airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease., Methods: Lung tissue was obtained at post-mortem from severe COVID-19 deaths. Pathologist-selected regions of interest (ROIs) were chosen by light microscopy representing the patho-evolutionary spectrum of DAD and alternate disease phenotypes were selected for comparison. Architecturally normal SARS-CoV-2-positive lung tissue and tissue from SARS-CoV-2-negative donors served as controls. ROIs were stained for 40 cellular protein markers and ablated using IMC before segmented cells were classified. Cell populations corrected by ROI airspace and their spatial relationships were compared across lung injury patterns., Findings: Forty patients (32M:8F, age: 22-98), 345 ROIs and >900k single cells were analysed. DAD progression was marked by airspace obliteration and significant increases in mononuclear phagocytes (MnPs), T and B lymphocytes and significant decreases in alveolar epithelial and endothelial cells. Neutrophil populations proved stable overall although several interferon-responding subsets demonstrated expansion. Spatial analysis revealed immune cell interactions occur prior to microscopically appreciable tissue injury., Interpretation: The immunopathogenesis of severe DAD in COVID-19 lung disease is characterised by sustained increases in MnPs and lymphocytes with key interactions occurring even prior to lung injury is established., Funding: UK Research and Innovation/Medical Research Council through the UK Coronavirus Immunology Consortium, Barbour Foundation, General Sir John Monash Foundation, Newcastle University, JGW Patterson Foundation, Wellcome Trust., Competing Interests: Declaration of interests L Milross was supported by a General Sir John Monash Scholarship awarded by the General Sir John Monash Foundation and a Vice-Chancellor's Global Scholarship from Newcastle University in support of a Master of Research in Immunobiology at Newcastle University. A Thomson was supported by funding from the JGW Patterson Foundation. C. J. A. Duncan was supported by a Wellcome Clinical Research Career Development Fellowship (211153/Z/18/Z)., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2024
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29. miRNA Expression in Fibroblastic Foci within Idiopathic Pulmonary Fibrosis Lungs Reveals Novel Disease-Relevant Pathways.

Author

Sabater L, Gossart JB, Hernandez I, Rico D, Blanchard A, Borthwick LA, Fisher AJ, Majo J, Jiwa K, Collins A, Abbate G, Oakley F, Mann DA, and Mann J

Subjects
Humans, Lung pathology, Fibroblasts metabolism, MicroRNAs genetics, MicroRNAs metabolism, Idiopathic Pulmonary Fibrosis metabolism
Abstract

miRNAs are 22 nucleotides long and belong to a class of noncoding RNAs that plays an important role in regulating gene expression at a post-transcriptional level. Studies show aberrant levels of miRNAs to be associated with profibrotic processes in idiopathic pulmonary fibrosis (IPF). However, most of these studies used whole IPF tissue or in vitro monocultures in which fibrosis was artificially induced. The current study used laser microdissection to collect fibroblastic foci (FF), the key pathologic lesion in IPF, isolated miRNAs, and compared their expression levels with those found in whole IPF lung tissue and/or in vitro cultured fibroblast from IPF or normal lungs. Sequencing libraries were generated, and data generated were bioinformatically analyzed. A total of 18 miRNAs were significantly overexpressed in FF tissue when compared with whole IPF tissue. Of those, 15 were unique to FF. Comparison of FF with cultured IPF fibroblasts also revealed differences in miRNA composition that impacted several signaling pathways. The miRNA composition of FF is both overlapping and distinct from that of whole IPF tissue or cultured IPF fibroblasts and highlights the importance of characterizing FF biology as a phenotypically and functionally discrete tissue microenvironment., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Published
2023
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30. Co-creation to Develop Interventions to Facilitate Deep Reflection for Dental Students.

Author

Campbell F, Hassoon N, Jiwa K, Ridsdill-Smith J, Smith A, Wilson H, Jack K, and Rogers H

Subjects
Humans, Motivation, Delivery of Health Care, Emotions, Students, Dental psychology, Learning
Abstract

Background: Deep reflective practice is important in healthcare education to allow students to explore emotions associated with the learning experience, access deeper learning and develop their personal and professional identity. Previous research demonstrated that the current methods of reflective practice using logbooks at the end of a clinical session to facilitate reflection within this setting were viewed as suboptimal by staff and student users. To address this problem co-creation, or a 'students as partners' approach, was used to develop and implement a comprehensive intervention to facilitate deep reflection for undergraduate dental students. This included the production of educational resources, and development of an online safe space to reflect., Approach: In this paper we discuss the process of using co-creation with undergraduate dental students as a research methodology to successfully produce curricular change with respect to reflective practice by involving the voice and experience of student partners. These student partners were part of a team that included researchers and teaching staff and worked with other stakeholders within the institution within a wider team., Evaluation: This paper demonstrates the positive benefits of using co-creation with undergraduate dental students for students such as increased confidence, developing professional and personal skills and impacting meaningful change., Reflection: For researchers and educators, the process gave motivation and enjoyment in curricular development to address pedagogical problems and ensured that the developed intervention was sustainable and appropriate. The paper discusses benefits and challenges of co-creation to develop curricular change. This co-creation approach is recommended for solving similar problems in healthcare education., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

Published
2023
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31. Stepwise pathogenic evolution of Mycobacterium abscessus .

Author

Bryant JM, Brown KP, Burbaud S, Everall I, Belardinelli JM, Rodriguez-Rincon D, Grogono DM, Peterson CM, Verma D, Evans IE, Ruis C, Weimann A, Arora D, Malhotra S, Bannerman B, Passemar C, Templeton K, MacGregor G, Jiwa K, Fisher AJ, Blundell TL, Ordway DJ, Jackson M, Parkhill J, and Floto RA

Subjects
Communicable Diseases, Emerging transmission, Datasets as Topic, Epigenesis, Genetic, Gene Transfer, Horizontal, Genome, Bacterial, Humans, Mutation, Mycobacterium Infections, Nontuberculous transmission, Pneumonia, Bacterial transmission, Virulence genetics, Communicable Diseases, Emerging microbiology, Evolution, Molecular, Genetic Fitness, Lung microbiology, Mycobacterium Infections, Nontuberculous microbiology, Mycobacterium abscessus genetics, Mycobacterium abscessus pathogenicity, Pneumonia, Bacterial microbiology
Abstract

Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis , have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2021
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32. Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients.

Author

Powell J, Garnett JP, Mather MW, Cooles FAH, Nelson A, Verdon B, Scott J, Jiwa K, Ruchaud-Sparagano MH, Cummings SP, Perry JD, Wright SE, Wilson JA, Pearson J, Ward C, and Simpson AJ

Subjects
Adult, Aged, Critical Illness, Female, Glottis immunology, Glottis physiopathology, Humans, Immunity, Innate immunology, Male, Middle Aged, Prospective Studies, Young Adult, Inflammation immunology, Inflammation physiopathology, Mucins immunology, Neutrophils immunology, Respiration, Artificial adverse effects
Abstract

Rationale: Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP., Objectives: To characterize subglottic host defense dysfunction in mechanically ventilated patients in the ICU; to determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth., Methods: Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 min); isolation and culture of primary subglottic epithelial cells from control patients; laboratory analysis of host innate immune defenses., Measurements and Main Results: Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in the ICU was characterized by neutrophilic inflammation, significantly increased proinflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic impairment was reversible on treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium., Conclusions: Mechanical ventilation in the ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil function and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage.

Published
2018
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33. The role of interleukin-1β as a predictive biomarker and potential therapeutic target during clinical ex vivo lung perfusion.

Author

Andreasson ASI, Borthwick LA, Gillespie C, Jiwa K, Scott J, Henderson P, Mayes J, Romano R, Roman M, Ali S, Fildes JE, Marczin N, Dark JH, and Fisher AJ

Subjects
Adult, Biomarkers metabolism, Cohort Studies, Extracorporeal Circulation methods, Female, Graft Rejection, Graft Survival, Humans, Male, Middle Aged, Odds Ratio, Pilot Projects, Predictive Value of Tests, Prospective Studies, Risk Factors, Interleukin-1beta metabolism, Lung Transplantation methods, Organ Preservation methods, Perfusion methods, Tissue Donors
Abstract

Background: Extended criteria donor lungs deemed unsuitable for immediate transplantation can be reconditioned using ex vivo lung perfusion (EVLP). Objective identification of which donor lungs can be successfully reconditioned and will function well post-operatively has not been established. This study assessed the predictive value of markers of inflammation and tissue injury in donor lungs undergoing EVLP as part of the DEVELOP-UK study., Methods: Longitudinal samples of perfusate, bronchoalveolar lavage, and tissue from 42 human donor lungs undergoing clinical EVLP assessments were analyzed for markers of inflammation and tissue injury. Levels were compared according to EVLP success and post-transplant outcomes. Neutrophil adhesion to human pulmonary microvascular endothelial cells (HPMECs) conditioned with perfusates from EVLP assessments was investigated on a microfluidic platform., Results: The most effective markers to differentiate between in-hospital survival and non-survival post-transplant were perfusate interleukin (IL)-1β (area under the curve = 1.00, p = 0.002) and tumor necrosis factor-α (area under the curve = 0.95, p = 0.006) after 30 minutes of EVLP. IL-1β levels in perfusate correlated with upregulation of intracellular adhesion molecule-1 in donor lung vasculature (R 2 = 0.68, p < 0.001) and to a lesser degree upregulation of intracellular adhesion molecule-1 (R 2 = 0.30, p = 0.001) and E-selectin (R 2 = 0.29, p = 0.001) in conditioned HPMECs and neutrophil adhesion to conditioned HPMECs (R 2 = 0.33, p < 0.001). Neutralization of IL-1β in perfusate effectively inhibited neutrophil adhesion to conditioned HPMECs (91% reduction, p = 0.002)., Conclusions: Donor lungs develop a detectable and discriminatory pro-inflammatory signature in perfusate during EVLP. Blocking the IL-1β pathway during EVLP may reduce endothelial activation and subsequent neutrophil adhesion on reperfusion; this requires further investigation in vivo., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2017
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34. Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during human ex vivo lung perfusion.

Author

Andreasson AS, Karamanou DM, Gillespie CS, Özalp F, Butt T, Hill P, Jiwa K, Walden HR, Green NJ, Borthwick LA, Clark SC, Pauli H, Gould KF, Corris PA, Ali S, Dark JH, and Fisher AJ

Subjects
Adolescent, Adult, Feasibility Studies, Female, Humans, Male, Middle Aged, Organ Preservation Solutions chemistry, Perfusion methods, Pilot Projects, Prognosis, Tissue and Organ Procurement methods, Treatment Outcome, Young Adult, Biomarkers metabolism, Bronchoalveolar Lavage Fluid chemistry, Inflammation Mediators metabolism, Lung Transplantation methods, Organ Preservation methods
Abstract

Objectives: Availability of donor lungs suitable for transplant falls short of current demand and contributes to waiting list mortality. Ex vivo lung perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant. Identifying robust biomarkers that can stratify donor lungs during EVLP to use or non-use or for specific interventions could further improve its clinical impact., Methods: In this pilot study, 16 consecutive donor lungs unsuitable for immediate transplant were assessed by EVLP. Key inflammatory mediators and tissue injury markers were measured in serial perfusate samples collected hourly and in bronchoalveolar lavage fluid (BALF) collected before and after EVLP. Levels were compared between donor lungs that met criteria for transplant and those that did not., Results: Seven of the 16 donor lungs (44%) improved during EVLP and were transplanted with uniformly good outcomes. Tissue and vascular injury markers lactate dehydrogenase, HMGB-1 and Syndecan-1 were significantly lower in perfusate from transplanted lungs. A model combining IL-1β and IL-8 concentrations in perfusate could predict final EVLP outcome after 2 h assessment. In addition, perfusate IL-1β concentrations showed an inverse correlation to recipient oxygenation 24 h post-transplant., Conclusions: This study confirms the feasibility of using inflammation and tissue injury markers in perfusate and BALF to identify donor lungs most likely to improve for successful transplant during clinical EVLP. These results support examining this issue in a larger study., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Published
2017
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