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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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Pfeffer, J Phipps, J Pimm, R Pius, H Plant, S Plein, M Plowright, O Polgar, L Poll, J Porter, S Portukhay, N Powell, A Prabhu, J Pratt, A Price, C Price, D Price, L Price, A Prickett, J Propescu, S Prosper, S Pugmire, S Quaid, J Quigley, J Quint, H Qureshi, I N Qureshi, K Radhakrishnan, N M Rahman, M Ralser, A Ramos, H Ramos, J Rangeley, B Rangelov, L Ratcliffe, P Ravencroft, A Reddington, R Reddy, A Reddy, H Redfearn, D Redwood, A Reed, M Rees, T Rees, K Regan, W Reynolds, C Ribeiro, A Richards, E Richardson, K Roberts, E Robertson, E Robinson, L Robinson, L Roche, C Roddis, J Rodger, A Ross, G Ross, J Rossdale, A Rostron, A Rowe, A Rowland, J Rowland, M J Rowland, K Roy, M Roy, I Rudan, R Russell, E Russell, G Saalmink, R Sabit, E K Sage, T Samakomva, N Samani, C Sampson, K Samuel, R Samuel, A Sanderson, E Sapey, D Saralaya, J Sargent, C Sarginson, T Sass, N Sattar, K Saunders, P Saunders, L C Saunders, H Savill, W Saxon, A Sayer, J Schronce, W Schwaeble, K Scott, N Selby, M G 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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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5. 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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Kon, S. Kon, S.S. Kon, S. Koprowska, A. Korszun, I. Koychev, C. Kurasz, P. Kurupati, C. Laing, H. Lamlum, G. Landers, C. Langenberg, D. Lasserson, L. Lavelle-Langham, A. Lawrie, C. Lawson, A. Layton, A. Lea, O.C. Leavy, D. Lee, J-H. Lee, E. Lee, K. Leitch, R. Lenagh, D. Lewis, J. Lewis, K.E. Lewis, V. Lewis, N. Lewis-Burke, X. Li, T. Light, L. Lightstone, W. Lilaonitkul, L. Lim, S. Linford, A. Lingford-Hughes, M. Lipman, K. Liyanage, A. Lloyd, S. Logan, D. Lomas, N.I. Lone, R. Loosley, J.M. Lord, H. Lota, W. Lovegrove, A. Lucey, E. Lukaschuk, A. Lye, C. Lynch, S. MacDonald, G. MacGowan, I. Macharia, J. Mackie, L. Macliver, S. Madathil, G. Madzamba, N. Magee, M.M. Magtoto, N. Mairs, N. Majeed, E. Major, F. Malein, M. Malim, G. Mallison, W.D.-C. Man, S. Mandal, K. Mangion, C. Manisty, R. Manley, K. March, S. Marciniak, P. Marino, M. Mariveles, M. Marks, E. Marouzet, S. Marsh, B. Marshall, M. Marshall, J. Martin, A. Martineau, L.M. Martinez, N. Maskell, D. Matila, W. Matimba-Mupaya, L. Matthews, A. Mbuyisa, S. McAdoo, H. McAllister-Williams, A. McArdle, P. McArdle, D. McAulay, G.P. McCann, H.J.C. drury, J. McCormick, W. McCormick, P. McCourt, L. McGarvey, C. McGee, K. Mcgee, J. McGinness, K. McGlynn, A. McGovern, H. McGuinness, I.B. McInnes, J. McIntosh, E. McIvor, K. McIvor, L. McLeavey, A. McMahon, M.J. McMahon, L. McMorrow, T. Mcnally, M. McNarry, J. McNeill, A. McQueen, H. McShane, C. Mears, C. Megson, S. Megson, P. Mehta, J. Meiring, L. Melling, M. Mencias, D. Menzies, M. Merida Morillas, A. Michael, C. Miller, L. Milligan, C. Mills, N.L. Mills, L. Milner, S. Misra, J. Mitchell, A. Mohamed, N. Mohamed, S. Mohammed, P.L. Molyneaux, W. Monteiro, S. Moriera, A. Morley, L. Morrison, R. Morriss, A. Morrow, A.J. Moss, P. Moss, K. Motohashi, N. Msimanga, E. Mukaetova-Ladinska, U. Munawar, J. Murira, U. Nanda, H. Nassa, M. Nasseri, A. Neal, R. Needham, P. Neill, S. Neubauer, D.E. Newby, H. Newell, T. Newman, A. Newton-Cox, T. Nicholson, D. Nicoll, A. Nikolaidis, C.M. Nolan, M.J. Noonan, C. Norman, P. Novotny, J. Nunag, L. Nwafor, U. Nwanguma, J. Nyaboko, C. O'Brien, K. O'Donnell, D. O'Regan, L. O'Brien, N. Odell, G. Ogg, O. Olaosebikan, C. Oliver, Z. Omar, P.J.M. Openshaw, L. Orriss-Dib, L. Osborne, R. Osbourne, M. Ostermann, C. Overton, J. Owen, J. Oxton, J. Pack, E. Pacpaco, S. Paddick, S. Painter, A. Pakzad, S. Palmer, P. Papineni, K. Paques, K. Paradowski, M. Pareek, D. Parekh, H. Parfrey, C. Pariante, S. Parker, M. Parkes, J. Parmar, S. Patale, B. Patel, M. Patel, S. Patel, D. Pattenadk, M. Pavlides, S. Payne, L. Pearce, J.E. Pearl, D. Peckham, J. Pendlebury, Y. Peng, C. Pennington, I. Peralta, E. Perkins, Z. Peterkin, T. Peto, N. Petousi, J. Petrie, P. Pfeffer, J. Phipps, J. Pimm, K. Piper Hanley, R. Pius, H. Plant, S. Plein, T. Plekhanova, M. Plowright, K. Poinasamy, O. Polgar, L. Poll, J.C. Porter, J. Porter, S. Portukhay, N. Powell, A. Prabhu, J. Pratt, A. Price, C. Price, D. Price, L. Price, A. Prickett, J. Propescu, S. Prosper, S. Pugmire, S. Quaid, J. Quigley, J. Quint, H. Qureshi, I.N. Qureshi, K. Radhakrishnan, N.M. Rahman, M. Ralser, B. Raman, A. Ramos, H. Ramos, J. Rangeley, B. Rangelov, L. Ratcliffe, P. Ravencroft, A. Reddington, R. Reddy, H. Redfearn, D. Redwood, A. Reed, M. Rees, T. Rees, K. Regan, W. Reynolds, C. Ribeiro, A. Richards, E. Richardson, M. Richardson, P. Rivera-Ortega, K. Roberts, E. Robertson, E. Robinson, L. Robinson, L. Roche, C. Roddis, J. Rodger, A. Ross, G. Ross, J. Rossdale, A. Rostron, A. Rowe, A. Rowland, J. Rowland, M.J. Rowland, S.L. Rowland-Jones, K. Roy, M. Roy, I. Rudan, R. Russell, E. Russell, G. Saalmink, R. Sabit, E.K. Sage, T. Samakomva, N. Samani, C. Sampson, K. Samuel, R. Samuel, A. Sanderson, E. Sapey, D. Saralaya, J. Sargant, C. Sarginson, T. Sass, N. Sattar, K. Saunders, R.M. Saunders, P. Saunders, L.C. Saunders, H. Savill, W. Saxon, A. Sayer, J. Schronce, W. Schwaeble, J.T. Scott, K. Scott, N. Selby, M.G. Semple, M. Sereno, T.A. Sewell, A. Shah, K. Shah, P. Shah, M. Shankar-Hari, M. Sharma, C. Sharpe, M. Sharpe, S. Shashaa, A. Shaw, K. Shaw, V. Shaw, A. Sheikh, S. Shelton, L. Shenton, K. Shevket, A. Shikotra, J. Short, S. Siddique, S. Siddiqui, J. Sidebottom, L. Sigfrid, G. Simons, J. Simpson, N. Simpson, A. Singapuri, C. Singh, S. Singh, S.J. Singh, D. Sissons, J. Skeemer, K. Slack, A. Smith, D. Smith, S. Smith, J. Smith, L. Smith, M. Soares, T.S. Solano, R. Solly, A.R. Solstice, T. Soulsby, D. Southern, D. Sowter, M. Spears, L.G. Spencer, F. Speranza, L. Stadon, S. Stanel, N. Steele, M. Steiner, D. Stensel, G. Stephens, L. Stephenson, M. Stern, I. Stewart, R. Stimpson, S. Stockdale, J. Stockley, W. Stoker, R. Stone, W. Storrar, A. Storrie, K. Storton, E. Stringer, S. Strong-Sheldrake, N. Stroud, C. Subbe, C.L. Sudlow, Z. Suleiman, C. Summers, C. Summersgill, D. Sutherland, D.L. Sykes, R. Sykes, N. Talbot, A.L. Tan, L. Tarusan, V. Tavoukjian, A. Taylor, C. Taylor, J. Taylor, A. Te, H. Tedd, C.J. Tee, J. Teixeira, H. Tench, S. Terry, S. Thackray-Nocera, F. Thaivalappil, B. Thamu, D. Thickett, C. Thomas, D.C. Thomas, S. Thomas, A.K. Thomas, T. Thomas-Woods, T. Thompson, A.A.R. Thompson, T. Thornton, M. Thorpe, R.S. Thwaites, J. Tilley, N. Tinker, G.F. Tiongson, M. Tobin, J. Tomlinson, C. Tong, M. Toshner, R. Touyz, K.A. Tripp, E. Tunnicliffe, A. Turnbull, E. Turner, S. Turner, V. Turner, K. Turner, S. Turney, L. Turtle, H. Turton, J. Ugoji, R. Ugwuoke, R. Upthegrove, J. Valabhji, M. Ventura, J. Vere, C. Vickers, B. Vinson, E. Wade, P. Wade, L.V. Wain, T. Wainwright, L.O. Wajero, S. Walder, S. Walker, E. Wall, T. Wallis, S. Walmsley, J.A. Walsh, S. Walsh, L. Warburton, T.J.C. Ward, K. Warwick, H. Wassall, S. Waterson, E. Watson, L. Watson, J. Watson, J. Weir McCall, C. Welch, H. Welch, B. Welsh, S. Wessely, S. West, H. Weston, H. 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, O. Zongo, Investigators, ISARIC4C, group, PHOSP-COVID collaborative, Sigfrid, L, ISARIC4C Investigators, and PHOSP-COVID collaborative group

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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6. Theorizing with Microhistory

Author

Andrew B. Hargadon and R. Daniel Wadhwani

Subjects
Management of Technology and Innovation, Strategy and Management, General Business, Management and Accounting
Abstract

Management and organization studies have long been interested in the social contexts and enduring consequences of individual and collective action. Yet empirically observing both the situated nature of actions and their ultimate consequences remains challenging. In this paper, we describe microhistory as a complementary approach to grounded and longitudinal studies that reconciles situated action in time with its broader consequences over time. Microhistorical research involves the reflexive use of dual temporal frames: a microtemporal frame suited for an empirically grounded study of individuals in time and a macrotemporal frame accounting for processes of continuity and change in social structures over time. We describe the epistemology, method, and form inherent in theorizing with microhistory and consider its potential for management researchers. Microhistory's approach, we recognize, is well-suited to several phenomena that remain elusive to contemporaneous and longitudinal studies. For example, exceptional normal actions, unintended consequences, non-linear and emergent processes, contingent process, and unobserved or inconceivable processes. Finally, we consider how microhistory's reflexive temporality offers management scholars opportunities to situate ourselves and our own theorizing in time and to account for their evolving consequences over time.

Published
2022

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

Author

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. 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. Dasgin, A. David, C. 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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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11. 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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Thomas, N Choudhury, Mark J. Tobin, Elizabeta B. Mukaetova-Ladinska, Richard W. Francis, J L Heeney, Shyam Madathil, Ellen Guthrie, S Yasmin, H Turton, M Marks, I Koychev, Melanie J. Davies, John P Greenwood, Daniel Peckham, E Lee, Iain B. McInnes, K Hadley, Charlotte Summers, J Chen, A Prickett, Timothy R Nicholson, K Lewis, A Cross, Jamie Brown, G Ross, H Wheeler, Manu Sharma, Igor Rudan, A Routen, M J Noonan, J Wild, K Jiwa, B. Welsh, Jonathan Pimm, J Kwan, A Lucey, C Favager, K Brindle, Nazir I Lone, Naveed Sattar, C Christie, James E. Mitchell, M Wilkins, C Coupland, T Thornton, Christian P Subbe, Alex Horsley, J Blaikely, G F Toingson, S Walsh, A Lea, Jennifer A. Smith, Margot W. Parkes, M Dixon, Luke Howard, N Majeed, A Hayday, Jack A. Sargeant, Michael Pavlides, K Leitch, J. Pendlebury, Andrew Donaldson, T Peto, Thomas A Jackson, N Rahman, M Gibbons, J Phipps, S Logan, D Wilkinson, J Breeze, D Holgate, R Osbourne, M Hoare, M Malim, Ryan S Thwaites, Stephen R Knight, W Ibrahim, J Rowland, Andrew M. Taylor, B Al-Sheklly, R. Loosley, S Megson, C Summersgill, Z Coburn, R Evans, I Wilson, B Pathmanathan, Jeremy George, A Angyal, S Betts, A Deans, C E Brightling, S Kerr, N Selby, L Price, A Ramos, S N Diwanji, P Kurupati, J S Brown, K Scott, A Sheikh, Krisnah Poinasamy, R Ugwuoke, Teresa Thompson, K Chong-James, Gerry P McCann, John R. Petrie, R Hughes, E. Watson, K McIvor, Trudie Chalder, Melissa Heightman, B Gooptu, H Evans, Thomas Yates, R Ahmed, Nicholas Hart, R Allen, W Schwaeble, J Simpson, Sara Clohisey, Janet M. Lord, R Bell, R Baggott, Clare J Taylor, Keir Lewis, Lynda Connor, F Thaivalappil, Kathryn J Saunders, Lynsey S. 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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12. The role of oral methotrexate as a steroid sparing agent in refractory eosinophilic asthma

Author

Peter Bradding, Ruth H. Green, David Bilocca, Neil Martin, B Hargadon, Andrew J. Wardlaw, Salman Siddiqui, Christopher E. Brightling, Ian D. Pavord, and Anna Murphy

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.drug_class, Eosinophilic asthma, Tertiary Care Centers, 03 medical and health sciences, Deprescriptions, 0302 clinical medicine, exacerbations, Refractory, Adrenal Cortex Hormones, Steroid sparing, Internal medicine, Eosinophilia, medicine, Humans, Adverse effect, Aged, Asthma, Hepatitis, 030201 allergy, refractory eosinophilic asthma, business.industry, Middle Aged, medicine.disease, Research Letters, Methotrexate, Treatment Outcome, 030228 respiratory system, Immunology, airways disease, Corticosteroid, Female, pharmacology, business, Immunosuppressive Agents, medicine.drug
Abstract

The use of oral methotrexate for refractory eosinophilic asthma in a tertiary asthma referral centre, Glenfield Hospital, Leicester, was evaluated between January 2006 and December 2014. The patients ( n = 61) were carefully phenotyped at baseline with markers of airway inflammation. In addition, a structured oral methotrexate proforma was utilized to evaluate response to therapy and adverse events. Oral steroid withdrawal was attempted 3 months after commencing treatment. Several outcomes were evaluated at 12 months, including both efficacy and adverse effects; 15% ( n = 9/61) responded by achieving a decrease in daily oral corticosteroid dose (mean 8.43 (±8.76) mg), although we were unable to identify factors that predicted a treatment response. There were no other significant changes in any other clinical outcome measures. There was a high rate of adverse events (19/61 (31%)), primarily gastrointestinal/hepatitis. Our findings support the use of biological agents in preference to using oral methotrexate as a steroid sparing agent at the first instance. In the event of failure of these agents, oral methotrexate remains a therapeutic option, which can be considered in highly specialist severe asthma centres.

Published
2017
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13. Temporal Assessment of Airway Remodeling in Severe Asthma Using Quantitative Computed Tomography

Author

Ana R. Sousa, Richard P. Marshall, James Entwisle, Vimal Raj, Salman Siddiqui, W Monteiro, Amisha Singapuri, Deepak Subramanian, Ian D. Pavord, Sunil Gupta, B Hargadon, Ruth Hartley, David G. Parr, and Christopher E. Brightling

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Time Factors, Vital Capacity, Critical Care and Intensive Care Medicine, Air trapping, Severity of Illness Index, FEV1/FVC ratio, Forced Expiratory Volume, Internal medicine, Correspondence, medicine, Cluster Analysis, Humans, Asthma, Body surface area, Analysis of Variance, business.industry, Repeated measures design, Airway obstruction, medicine.disease, Surgery, Asthma Control Questionnaire, Cardiology, Airway Remodeling, medicine.symptom, Tomography, X-Ray Computed, Airway, business
Abstract

To the Editor: Heterogeneity in asthma is evident in every aspect of the disease process (1–3). Quantitative computed tomography (QCT) has emerged as a reliable, noninvasive tool for assessment of proximal airway remodeling and air trapping in asthma (4). We have identified three asthma clusters based on QCT indices, using factor and cluster analysis (3). Subjects in clusters 1 and 3, with more severe asthma, had distinct patterns of proximal airway remodeling: cluster 1 showing a dilated right upper lobe apical segmental bronchus (RB1) lumen with wall thickening and cluster 3 had no wall thickening and markedly narrowed lumen. Subjects in cluster 2 had milder asthma, and there was a lack of proximal airway remodeling. It remains elusive whether airway structural changes reflect cause or effect; namely, are they a consequence of asthma and represent different stages of disease progression or the distinct remodeling changes that are fundamental to the pathogenesis of asthma, representing distinct asthma endotypes (5)? Our aim was to assess the temporal pattern of proximal airway remodeling in QCT-derived asthma clusters. Some of the results of this study have been previously reported in the form of an abstract (6). Twenty-two patients with severe asthma of mean (SEM) disease duration 28.6 (4) years, who were in the placebo arm of a previous study (7), were included in the analysis. All 22 patients had undergone two inspiratory thoracic CT scans to image RB1 and further inspiratory and expiratory full thoracic CT scans as part of research studies at our institute (3, 7). All CT scans were performed after administration of long-acting β2-agonist. The mean (range) duration between the first (baseline) and second CT scan was 1.6 (0.9–2.7) years and between the second and third was 2.6 (1.9–3.7) years. QCT-derived asthma clusters were determined on the basis of full thoracic paired inspiratory and expiratory CT scans obtained at time point 3 (3). Only inspiratory scans were used for the current analysis. Informed consent was obtained from all subjects and the studies were approved by the Leicestershire, Northamptonshire, and Rutland Research Ethics Committees. Fully automated software (VIDA Pulmonary Workstation, version 2.0; VIDA Diagnostics, Coralville, IA) was used for quantitative airway morphometry as described previously (3). RB1 wall area (WA)/body surface area (BSA) demonstrated a significant increase over time (mean [SEM]: first CT, 14.3 [0.9]; second CT, 14.7 [0.9]; third CT, 16.5 [1.3] mm2/m2; repeated measure analysis of variance [ANOVA], P = 0.008). No significant change was seen in RB1 lumen area (LA)/BSA (mean [SEM]: first CT, 9.1 [1.0]; second CT, 9.6 [1.0]; third CT, 9.9 [0.9]; repeated measure ANOVA, P = 0.4). There was an increase in RB1 length at the time of the third CT (mean [SEM]: first CT, 11.3 [0.8]; second CT, 11.0 [0.7]; third CT, 13.1 [0.6] mm; repeated measure ANOVA, P

Published
2015
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14. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease

Author

Ruth H. Green, Peter Bradding, S S Birring, Ian D. Pavord, R Siva, Mike A. Berry, D Parker, W Monteiro, B Hargadon, S McKenna, and Christopher E. Brightling

Subjects
Male, Pulmonary and Respiratory Medicine, Sputum Cytology, medicine.medical_specialty, medicine.drug_class, Chronic Obstructive Pulmonary Disease, Anti-Inflammatory Agents, Mometasone furoate, Enzyme-Linked Immunosorbent Assay, Placebo, Leukocyte Count, Pulmonary Disease, Chronic Obstructive, Double-Blind Method, Forced Expiratory Volume, Bronchodilator, Internal medicine, Administration, Inhalation, Eosinophilia, Humans, Medicine, Pregnadienediols, Aged, COPD, Cross-Over Studies, business.industry, Interleukin-8, Respiratory disease, Sputum, respiratory system, medicine.disease, Bronchodilator Agents, Surgery, respiratory tract diseases, Eosinophils, Female, medicine.symptom, business, Mometasone Furoate, medicine.drug
Abstract

BACKGROUND: An association between the sputum eosinophil count and the response to a 2 week course of prednisolone has previously been reported in patients with chronic obstructive pulmonary disease (COPD). Whether the response to inhaled corticosteroids is related to the presence of eosinophilic inflammation is unclear. METHODS: A randomised, double blind, crossover trial of placebo and mometasone furoate (800 microg/day), each given for 6 weeks with a 4 week washout period, was performed in subjects with COPD treated with bronchodilator therapy only. Spirometric tests, symptom scores, chronic respiratory disease questionnaire (CRQ), and induced sputum were performed before and after each treatment phase. RESULTS: Ninety five patients were recruited of which 60 were randomised. Overall there were no treatment associated changes in forced expiratory volume in 1 second (FEV(1)), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV(1) increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV(1) with mometasone compared with placebo in the highest tertile was 0.11 l (95% CI 0.03 to 0.19). This improvement was not associated with a fall in the sputum eosinophil count. CONCLUSIONS: An increased sputum eosinophil count is related to an improvement in post-bronchodilator FEV(1) following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count.

Published
2016

15. Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease

Author

Paul Rugman, B Hargadon, M McCormick, Christopher E. Brightling, A. Lloyd, Paul Newbold, M. Shelley, Vijay Mistry, D Parker, S. Saha, S McKenna, Paul Dodson, Mona Bafadhel, Martin Jenkins, and C Reid

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, Chemokine, Inflammation, Severity of Illness Index, Pulmonary Disease, Chronic Obstructive, Young Adult, Severity of illness, Medicine, Humans, Prospective Studies, Young adult, Asthma, Aged, Aged, 80 and over, COPD, biology, business.industry, Sputum, respiratory system, Middle Aged, medicine.disease, Matrix Metalloproteinases, respiratory tract diseases, Immunology, biology.protein, Cytokines, Female, medicine.symptom, Chemokines, Airway, business, Biomarkers, Follow-Up Studies
Abstract

Background: Asthma and chronic obstructive pulmonary disease (COPD) display features of overlap in airway physiology and airway inflammation. Whether inflammatory phenotypes in airway disease describe similar mediator expression is unknown. Objectives: To explore the relationship of airway inflammation and cytokine and chemokine expression in asthma and COPD. Methods: Subjects with asthma and COPD (n = 54 and n = 49) were studied. Clinical characteristics and sputum were collected at entry into the study. A 2-step sputum processing method was performed for supernatant and cytospin preparation. Meso Scale Discovery and Luminex platforms were used to measure cytokines, chemokines and matrix metalloproteinase levels. Results: Analytes sensitive to dithiothreitol (DTT) that had increased recovery in the 2-step sputum process were IL-1β, 4, 5, 10, 13, IFN-γ, TNFRI, GM-CSF, CCL2, 3, 4, 5, 13 and 17. There was a differential expression in IL-8, TNFRI and TNFRII between asthma and COPD [mean fold difference (95% CI): IL-8, 2.6 (1.3–5.4), p = 0.01; TNFRI, 2.1 (1.3–5.4), p = 0.03; TNFRII, 2.6 (1.2–5.6), p = 0.02]. In neutrophilic and eosinophilic airway inflammation, TNFα, TNFRI, TNFRII, IL-6, IL-8 and IL-5 could differentiate between these phenotypes. However, these phenotypes were unrelated to the diagnosis of asthma or COPD. Conclusion: Recovery of sputum mediators sensitive to DTT can be improved using the described sputum processing technique. Within airway inflammatory sub-phenotypes there is a differential pattern of mediator expression that is independent of disease. Whether these inflammatory phenotypes in asthma and COPD confer distinct pathogeneses, therapeutic responses and clinical phenotypes needs to be further evaluated.

Published
2016
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16. British Society for Allergy and Clinical Immunology Annual Conference 2009 Abstracts

Author

R.E. Edwards, J Agbetile, K Mutalithas, Michelle Bourne, Abbie Fairs, N Neale, Ian D. Pavord, Andrew J. Wardlaw, B Hargadon, Catherine H. Pashley, and W Monteiro

Subjects
Allergy, medicine.diagnostic_test, biology, Clinical immunology, business.industry, Immunology, biology.organism_classification, medicine.disease, Sputum culture, Aspergillus fumigatus, Immunology and Allergy, Medicine, business
Abstract

This paper was published as Clinical and Experimental Allergy, 2009, 39 (12), p. 1937: British Society for Allergy and Clinical Immunology Annual Conference 2009 Abstracts, S2. It is available from http://www3.interscience.wiley.com/journal/122683542/issue. Doi: 10.1111/j.1365-2222.2009.03389.x

Published
2009
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17. Airway function and markers of airway inflammation in patients with treated hypothyroidism

Author

J F Falconer Smith, Ian D. Pavord, D Parker, R B Patel, Surinder S. Birring, B Hargadon, S McKenna, and W Monteiro

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Neutrophils, Cough reflex, Vital Capacity, Gastroenterology, Statistics, Nonparametric, Pulmonary function testing, Leukocyte Count, Hypothyroidism, Forced Expiratory Volume, Wheeze, Internal medicine, Humans, Medicine, Respiratory system, Bronchitis, business.industry, Respiratory disease, Sputum, Middle Aged, medicine.disease, respiratory tract diseases, Cross-Sectional Studies, Dyspnea, Case-Control Studies, Immunology, Airway Biology, Female, Methacholine, medicine.symptom, business, Biomarkers, medicine.drug
Abstract

Background: There is increasing evidence of an association between organ specific autoimmune diseases, particularly autoimmune thyroid disease and respiratory morbidity. A study was undertaken to determine whether patients with autoimmune thyroid disease have objective evidence of airway inflammation and dysfunction. Methods: Twenty six non-smoking women with treated hypothyroidism and 19 non-smoking controls completed a symptom questionnaire and underwent full lung function tests, capsaicin cough reflex sensitivity measurement, methacholine challenge test, and sputum induction over two visits. Results: Symptoms of cough (p = 0.01), dyspnoea (p = 0.01), sputum production (p = 0.004), and wheeze (p = 0.04) were reported more commonly in patients than controls. Patients with hypothyroidism had heightened cough reflex sensitivity compared with controls (geometric mean concentration of capsaicin causing five coughs: 40 v 108 mmol/l; mean difference 1.4 doubling doses; 95% confidence interval of difference 0.4 to 2.5; p = 0.008) and a significantly higher proportion of patients had airway hyperresponsiveness (methacholine provocative concentration (PC20)

Published
2005
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18. P131 Outdoor fungal spore levels, lung function and symptoms in patients with asthma and aspergillus sensitisation

Author

Matthew Richardson, Andrew J. Wardlaw, Sherif Gonem, C Manton, B Hargadon, Michelle Bourne, Catherine H. Pashley, J Agbetile, and K Shah

Subjects
Pulmonary and Respiratory Medicine, Voriconazole, medicine.medical_specialty, biology, business.industry, Aeroallergen, biology.organism_classification, medicine.disease_cause, medicine.disease, Alternaria, respiratory tract diseases, Internal medicine, Cohort, medicine, business, Prospective cohort study, Cladosporium, Asthma, Morning, medicine.drug
Abstract

Background IgE sensitisation to Aspergillus fumigatus is seen in a significant proportion of patients with refractory asthma. The EVITA3 study recently showed that three months’ treatment with voriconazole did not improve asthma-related outcomes in this patient group. It is not known whether daily variations in outdoor fungal spore levels are associated with concomitant fluctuations in symptoms and lung function in patients with Aspergillus-associated asthma. Methods Participants in the EVITA3 study kept daily diaries of peak expiratory flow (PEF) and asthma symptoms during their follow-up period. These diary records were retrospectively analysed together with contemporaneous fungal spore levels measured locally, in those patients (n = 36) who consented to the secondary use of their clinical and research data. Participants also underwent skin-prick tests for Aspergillus, Alternaria, Cladosporium, Penicillium and Botrytis. For each participant, cross-correlation was used to investigate the relationship between PEF and local spore counts of Aspergillus/Penicillium, Alternaria, Cladosporium, Botrytis, Sporobolomyces, Tilletiopsis, and Didymella. Group-level relationships were investigated using linear mixed models for PEF and generalised estimating equations for daily symptom scores, with participants stratified by skin prick test status. The analyses were performed with the exposure and outcome measured on the same day (lag 0), and with the exposure lagged by 1 day with respect to the outcome (lag 1). Results The analysis cohort comprised 20 men and 16 women with a mean (standard deviation) age of 60 (8) years. No significant or consistent relationships were observed between fungal spore counts and either PEF or self-reported symptom scores, regardless of skin prick test status and lag time between exposure and outcome. In a linear mixed model, the effect size of total fungal spore count on morning PEF was negligible (−0.000011, p = 0.343 for lag 0; −0.000002, p = 0.847 for lag 1). Conclusion In this retrospective analysis we found no evidence of a significant link between fungal spore counts and either PEF or symptoms in patients with Aspergillus-associated asthma. Further research is required to confirm this result in a prospective study and to identify whether aeroallergen levels relate to other important asthma outcomes such as exacerbations.

Published
2016
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21. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial

Author

B Hargadon, Ruth H. Green, W Monteiro, Christopher E. Brightling, M. Shelley, Mike A. Berry, R Siva, Ian D. Pavord, D Parker, S McKenna, and Andrew J. Wardlaw

Subjects
Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Anti-asthmatic Agent, law.invention, Pulmonary Disease, Chronic Obstructive, Randomized controlled trial, law, Internal medicine, Eosinophilic, Eosinophilia, medicine, Humans, Anti-Asthmatic Agents, Glucocorticoids, Asthma, Aged, Aged, 80 and over, Inflammation, COPD, Analysis of Variance, business.industry, Nebulizers and Vaporizers, Beclomethasone, Sputum, Eosinophil, Middle Aged, respiratory system, medicine.disease, Surgery, Bronchodilator Agents, Respiratory Function Tests, respiratory tract diseases, medicine.anatomical_structure, Treatment Outcome, Female, medicine.symptom, business
Abstract

Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease (COPD) exacerbations. The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD. A total of 82 patients with COPD were randomised into two groups. One group was treated according to traditional guidelines (British Thoracic Society (BTS) group) and the other (sputum group) was treated with the additional aim of minimising eosinophilic airway inflammation, assessed using the induced sputum eosinophil count. The primary outcome was exacerbations, which were categorised as mild, moderate or severe. The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups, respectively (mean reduction 62%). The majority of this benefit was confined to patients with eosinophilic airway inflammation. There was no difference in the frequency of mild and moderate exacerbations. The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups. Out of 42 patients in the sputum group, 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation. A management strategy that aims to minimise eosinophilic airway inflammation, as well as symptoms, is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease.

Published
2007

22. S7 Airway Pathological Phenotypes and their Clinical Utility in Adult Asthma

Author

Matthew Richardson, Andrew J. Wardlaw, David F. Choy, Liam G Heaney, Emma Doran, Salman Siddiqui, M Shelley, Peter Bradding, Aarti Shikotra, Joseph R. Arron, B Hargadon, and Christopher E. Brightling

Subjects
Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, education.field_of_study, medicine.diagnostic_test, business.industry, Population, Inflammation, Late onset, respiratory system, medicine.disease, respiratory tract diseases, Vascular remodelling in the embryo, Immunology, Biopsy, medicine, medicine.symptom, business, Airway, education, Pathological, Asthma
Abstract

Background Airway remodelling and cellular inflammation are well recognised pathological features of asthma. However the relationship between asthma phenotype, treatment intensity and pathology is poorly understood. Objectives We performed a study of common pathological features in adult asthmatic bronchial biopsies to identify (i) whether discrete ‘pathological phenotypes/subtypes’ exist and (ii) their clinical utility. Methods 202 patients (142 asthma and 60 healthy volunteers) were recruited. Patients underwent bronchoscopy and endobronchial biopsy. Bronchial biopsies were evaluated for eleven common features of asthma pathology. Standard biostatistical analyses including a range of cluster analyses and machine learning were applied to pathological features alone to evaluate our objectives. Results Three distinct immunopathological clusters were identified and characterised by distinct biopsy features of cellular inflammation and remodelling. Specifically, i) late onset severe eosinophilic asthma [cluster 1] with evidence of reticular basement membrane thickening, increased epithelial area and vascular remodelling, ii) milder late onset asthma [cluster 2] with few features of remodelling and iii), an early onset atopic eosinophilic asthma [cluster 3] with features of Th2 high asthma, increased airway smooth muscle (ASM) mass, increased mast cells within the ASM and a mixed granulocytic submucosal inflammation. Pre bronchodilator FEV1 and decline (in a subset) differed across the clusters. Pathological features did not add value to the clinical prediction of asthma. Conclusion We have identified three novel pathological clusters of asthma with differing features of airway remodelling, cellular inflammation and airway function. Asthma may be characterised by variable pathological phenotypes warranting further evaluation in larger population studies.

Published
2015
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23. Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness

Author

Christopher E. Brightling, N Neale, Ian D. Pavord, D Parker, C Ruse, Ruth H. Green, Ian P. Hall, B Hargadon, and S McKenna

Subjects
Pulmonary and Respiratory Medicine, Budesonide, Adult, Cyclopropanes, Male, medicine.drug_class, Anti-Inflammatory Agents, Acetates, Sulfides, Placebo, Anti-asthmatic Agent, Bronchial Provocation Tests, Drug Administration Schedule, Leukocyte Count, Double-Blind Method, Formoterol Fumarate, Administration, Inhalation, medicine, Humans, Anti-Asthmatic Agents, Glucocorticoids, Montelukast, Methacholine Chloride, Asthma, Aged, Cross-Over Studies, Dose-Response Relationship, Drug, business.industry, Sputum, Middle Aged, medicine.disease, respiratory tract diseases, Eosinophils, Ethanolamines, Anesthesia, Quinolines, Corticosteroid, Methacholine, Drug Therapy, Combination, Formoterol, Bronchial Hyperreactivity, business, Lung Volume Measurements, medicine.drug
Abstract

There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 mug b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 mug b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5-0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7-1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2-2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation.

Published
2006

24. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma

Author

B Hargadon, M. Shelley, Ian D. Pavord, Ruth H. Green, Dominick E. Shaw, Christopher E. Brightling, Alexandra Morgan, Mike A. Berry, Andrew J. Wardlaw, and J L Richter

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, Adolescent, Administration, Oral, Nitric Oxide, Nitric oxide, chemistry.chemical_compound, Leukocyte Count, Adrenal Cortex Hormones, Administration, Inhalation, Medicine, Humans, Asthma, Aged, Lung, medicine.diagnostic_test, Inhalation, Dose-Response Relationship, Drug, business.industry, Respiratory disease, Pneumonia, Eosinophil, Middle Aged, respiratory system, medicine.disease, Respiratory Function Tests, respiratory tract diseases, Pulmonary Alveoli, Bronchoalveolar lavage, medicine.anatomical_structure, chemistry, Immunology, Prednisolone, Female, business, Biomarkers, medicine.drug
Abstract

Recent studies have suggested that alveolar nitric oxide (NO) concentration is a noninvasive test of distal lung inflammation. The current study determined whether alveolar NO concentration can be measured in patients with asthma of varying severity, tested the hypothesis that there is an association between alveolar NO and bronchoalveolar lavage (BAL) eosinophil count and determined whether refractory asthma is characterised by a raised alveolar NO concentration. Finally, the present authors assessed the effect of 2 weeks of prednisolone (30 mg q.d.) on alveolar NO concentration. Alveolar NO concentration was both measurable and repeatable in patients with refractory asthma. A positive correlation was found between alveolar NO concentration and BAL eosinophil count but not with bronchial wash or sputum eosinophil count. Alveolar NO concentration was increased in patients with refractory asthma (7.1 ppb) compared with mild-to-moderate asthma (3.4 ppb) and normal controls (3.4 ppb) and reduced by treatment with prednisolone. In conclusion, these findings support the hypothesis that alveolar nitric oxide is a measure of distal airway inflammation and suggest that distal lung inflammation is present in refractory asthma.

Published
2005

25. Schweizerische Gesellschaft für Pneumologie Société Suisse de Pneumologie

Author

Feng Zhao, Damien Denis, François Vincent, Chang-Gui Wu, P. Zabel, Jean-Marc Naccache, Olivia Freynet, S. McKenna, M. Bafadhel, Argyris Tzouvelekis, Kyoko Otsuka, M. Shelley, M. McCormick, Nikolaos Katirtzoglou, Harry J.M. Groen, Ryo Tachikawa, N. Reiling, V. Mistry, Hiroyuki Ueda, J. Rupp, Vincent Cottin, Charlotte Ringsted, Thomas Rothe, P. Rugman, Katerina M. Antoniou, Hai-Feng Ou-Yang, Jan Willem K. van den Berg, Paul Frost Clementsen, A. Lloyd, Muhammad W. Saif, M. Jenkins, Claus Kroegel, James E. Boers, Rocco Trisolini, Ioannis Dannos, Yukihiro Imai, D. Parker, P. Dodson, Shigeki Nanjo, Marios Froudarakis, Petros Bakakos, Paul Newbold, Vasileia Ntomi, Yves Cohen, Satz Mengensatzproduktion, Michio Hayashi, Dominique Valeyre, Lars Konge, Marcellino Burzi, C. Kugler, Nobuyuki Katakami, C. Reid, Pierre-Yves Brillet, Henrik Arendrup, Aikaterini Pierrakou, B. Hargadon, T. Goldmann, Xin-Yu Ti, D. Drömann, Diane Bouvry, M. Abdullah, Virginie Simon-Blancal, Ayako Sakurai, Reiko Kaji, S. Saha, Christian von Buchwald, Nicolas Naggara, D. Kähler, Keisuke Tomii, C.T. Bolliger, Kazuma Nagata, C. Vock, C.E. Brightling, Jos A. Stigt, K. Dalhoff, E. Vollmer, Kostas N. Syrigos, Maria Chorti, H.P. Hauber, Stavros Anevlavis, Klaus Richter Larsen, Marco Patelli, Demosthenes Bouros, H. Fehrenbach, Xin-Peng Han, Ad H. Oostdijk, Grigorios Stratakos, Druck Reinhardt Druck Basel, and Hilario Nunes

Subjects
Pulmonary and Respiratory Medicine, business.industry, Medicine, business, Humanities
Published
2012
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26. S136 Fungal sputum culture in patients with severe asthma is associated with a reduced post bronchodilator FEV1

Author

Catherine H. Pashley, R.E. Edwards, Michelle Bourne, D Desai, W Monteiro, Abbie Fairs, I D Pavord, Andrew J. Wardlaw, Peter Bradding, Ruth H. Green, J Agbetile, K Mutalithas, C E Brightling, B Hargadon, and J. P. Morley

Subjects
Pulmonary and Respiratory Medicine, Spirometry, Aspergillus, biology, medicine.diagnostic_test, business.industry, medicine.disease, medicine.disease_cause, Immunoglobulin E, biology.organism_classification, respiratory tract diseases, Microbiology, Sputum culture, Aspergillus fumigatus, Allergen, Immunology, medicine, biology.protein, Sputum, medicine.symptom, business, Asthma
Abstract

Introduction and objectives IgE sensitisation to fungal allergens is common in severe asthma, but the clinical relevance of this, and the relationship to airway colonisation with fungi, is not known. Many of the fungi that can grow at body temperature are filamentous moulds from the genera Aspergillus and Pencillium . We report here the relationship between lung function and fungal sputum culture in patients with severe asthma. Methods We recruited 126 patients attending a tertiary referral centre with a diagnosis of asthma and 18 healthy volunteers. 93% of patients were on GINA treatment step 4 or higher. At a single stable visit subjects underwent: spirometry with reversibility to 200 μg salbutamol; sputum fungal culture and a sputum cell differential count; skin prick testing to both common aeroallergens and an extended fungal panel (+ve ≥3 mm); specific IgE to Aspergillus fumigatus by CAP (positive >0.35 kU/l). Fungi were identified by morphology and species identity confirmed by sequencing regions of the nuclear ribosomal operon. Results Patients had a mean age of 56 years (21–84 years); 48% were males with median ICS dose of 800 μg Fluticasone equivalent. 60% were atopic to common aeroallergens, 45% were IgE sensitised to one fungal allergen and 27% to ≥2 fungal allergens. 64% of patients cultured a mould in their sputum, 7% more than one species. This compared with three healthy subjects (17%) culturing any mould (p Aspergillus species were most frequently cultured (n=58) followed by Penicillium species (n=15) and Thermoascus species (n=2), others (n=8). Four fungal genera were cultured from healthy volunteers sputum,- Aspergillus , Penicillium, Coprinus and one other. Post bronchodilator FEV 1 % predicted was 71% in those with a positive fungal culture vs 84% in those who were culture negative, (p Conclusions In addition to IgE fungal sensitisation, sputum culture focused towards detection of moulds is frequently positive and associated with impaired post-bronchodilator FEV1. Colonisation of the airways with mould in asthma could be responsible for the development of fixed airflow obstruction.

Published
2010
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27. P20 The eligibility of patients with difficult asthma for omalizumab since the change to the treatment criteria

Author

A J Burton, Peter Bradding, Ruth H. Green, C E Brightling, I D Pavord, Andrew J. Wardlaw, B Hargadon, and Anna Murphy

Subjects
Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Asthma exacerbations, biology, business.industry, Nice, Omalizumab, medicine.disease, Immunoglobulin E, medicine, biology.protein, Dosing, Difficult asthma, business, Atopic asthma, computer, Asthma, medicine.drug, computer.programming_language
Abstract

Omalizumab is a humanised monoclonal anti-IgE agent which is useful as an add-on therapy for severe atopic asthma. We have previously shown that 13.5% of patients attending our adult difficult asthma clinic were eligible for treatment with omalizumab. There has recently been a change to its prescribing licence with a widening of the eligible range of IgE from 30–700 iu/ml to 30–1500 iu/ml. Other prescribing criteria are (1) weight between 20 and 150 kg, (2) FEV1 80%, 46 patients had negative skin prick tests and a further 2 patients′ weight was outside the range for dosing. 67/510 (13.1%) patients met all the licensing criteria for omalizumab. There has therefore not been any increase in the proportion of eligible patients since the widening of the IgE range. Of these 67, 27 patients had two or more admissions with asthma exacerbations in the previous year. A further 16 patients had one admission but less than 2 A&E attendances. 12 patients required maintenance oral prednisolone but did not have sufficient admissions to meet the NICE prescribing guidelines. In total, 27/510 (5.3%) of patients with difficult-to-treat asthma were eligible for treatment with omalizumab according to NICE guidance. Although omalizumab is a helpful additional therapy for allergy-mediated asthma, its licensing criteria and current NICE guidelines limits its use in the UK to a small proportion of patients with difficult asthma.

Published
2010
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28. S132 Airway dysfunction and inflammation in pool and non-pool based elite endurance athletes

Author

Ian D. Pavord, W Monteiro, Martin R. Lindley, Neil R.W. Martin, and B Hargadon

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, biology, Athletes, medicine.drug_class, business.industry, Eosinophil, medicine.disease, biology.organism_classification, Gastroenterology, medicine.anatomical_structure, Internal medicine, Hyperventilation, Eosinophilic, Exhaled nitric oxide, medicine, Physical therapy, Corticosteroid, medicine.symptom, Airway, business, Asthma
Abstract

Introduction Previous studies have suggested that eosinophilic airway inflammation is common in elite swimmers; the chemical pool environment often blamed. We set out to address this question in a cross-sectional study of 109 international athletes from a variety of sporting backgrounds. Methods All had symptoms suggesting exercise-induced asthma and were either inhaled corticosteroid naive or withdrew these for >4 weeks. β 2 -agonists, exercise and caffeine were withheld for 8 h prior to testing. Symptoms were assessed using the Juniper ACQ, airways dysfunction using the eucapnic voluntary hyperventilation (EVH) test and airways inflammation using exhaled nitric oxide (FE NO ) and induced sputum eosinophil % (eos). Athletes were classed as pool based if they exercised in an indoor pool environment for >5 h per week, and non-pool based if they exercised in a pool for Results Demographic details were similar. Mean (±SEM) % fall in FEV 1 post EVH was 18.96±1.701 (n=47) in pool and 11.39±1.249 (n=62) in non-pool athletes (mean difference 7.569; 95% CI 3.480 to 11.66; p=0.0004), 76% of pool and 39% of non-pool athletes had a positive test (>10% fall). The geometric mean (log SD) eos (pool 2.667 (0.797)), non-pool 3.060 (0.867), p=0.802), and FE NO (pool 25.05 (1.570), non-pool 28.06 (1.475) ppb, p=0.914) was no different between groups; 14.9% of pool and 12.9% of non-pool athletes had eos >3%. % fall in FEV1 had good correlation with log eos (r=0.551, p NO and log eos correlated strongly (r=0.644, p NO of >47 being most predictive of eos>3% (AUC 0.912, p Conclusions Individual athletes with symptoms vary markedly in the levels of airways dysfunction and inflammation expressed. There is more airway dysfunction in pool athletes but not more eosinophilic airways inflammation suggesting that the pool environment if anything predisposes to airways dysfunction. Exhaled nitric oxide is a promising non-invasive means of assessing eosinophilic airways inflammation in all elite athletes.

Published
2010
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29. S90 Effectiveness of Voriconazole In the Treatment of Aspergillus fumigatus Associated Asthma

Author

Abbie Fairs, Andrew J. Wardlaw, Michelle Bourne, Ian D. Pavord, Pranabashis Haldar, C Broad, Peter Bradding, D Desai, Ruth H. Green, Catherine H. Pashley, J. P. Morley, B Hargadon, J Agbetile, and Christopher E. Brightling

Subjects
Pulmonary and Respiratory Medicine, Voriconazole, medicine.medical_specialty, Intention-to-treat analysis, biology, business.industry, biology.organism_classification, medicine.disease, Placebo, Immunoglobulin E, Aspergillus fumigatus, Surgery, Quality of life, Internal medicine, medicine, biology.protein, Sputum, medicine.symptom, business, Asthma, medicine.drug
Abstract

Background IgE sensitisation to Aspergillus fumigatus and a positive sputum fungal culture are common in refractory asthma. It is not clear whether these patients would benefit from anti-fungal treatment. Objectives To determine if a three-month course of voriconazole improved asthma related outcomes in people with asthma who are IgE sensitised to A. fumigatus. Methods Asthmatics IgE sensitised to A fumigatus with a history of at least two severe exacerbations in the previous twelve months were treated for three months with voriconazole two hundred milligrams twice daily, followed by observation for nine months, in a double blind, placebo controlled, randomised design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the twelve months of the study. Results 65 patients were randomised. 59 patients started treatment (32 voriconazole and 27 placebo) and were included in an intention to treat analysis. 56 patients took the full three months of medication. There was no significant difference in the number of severe exacerbations between the voriconazole and placebo groups (1.25 vs 1.52/patient/year; mean difference 0.27; 95% CI 0.24 to 0.31) respectively, quality of life (change in AQLQ 0.44 vs 0.35, mean difference between groups 0.08; 95% CI 0.07–0.09), or in any of our secondary outcome measures between the two groups. Conclusion We were unable to show a beneficial effect of three months treatment with voriconazole in people with moderate to severe asthma who were IgE sensitised to A fumigatus on either the rate of severe exacerbations, quality of life or other markers of asthma control. References Fairs A, Agbetile J, Hargadon B, Bourne M, Monteiro WR, Brightling CE, et al . IgE sensitisation to Aspergillus fumigatus is associated with reduced lung function in asthma. Am J Respir Crit Care Med . 2010;182(11):1362–8.

Published
2013
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30. Front & Back Matter

Author

M. Bafadhel, Nobuyuki Katakami, P. Zabel, M. McCormick, T. Goldmann, Diane Bouvry, N. Reiling, Jos A. Stigt, K. Dalhoff, Keisuke Tomii, Michio Hayashi, Damien Denis, C.T. Bolliger, François Vincent, D. Kähler, Kyoko Otsuka, Vasileia Ntomi, C. Kugler, Pierre-Yves Brillet, Ryo Tachikawa, Yves Cohen, Klaus Richter Larsen, Marcellino Burzi, Muhammad W. Saif, Lars Konge, Virginie Simon-Blancal, M. Jenkins, Chang-Gui Wu, Feng Zhao, A. Lloyd, D. Parker, Harry J.M. Groen, Katerina M. Antoniou, Charlotte Ringsted, S. Saha, Claus Kroegel, Yukihiro Imai, Nikolaos Katirtzoglou, Thomas Rothe, Petros Bakakos, Paul Newbold, P. Rugman, Hai-Feng Ou-Yang, C.E. Brightling, Marios Froudarakis, Ioannis Dannos, Ad H. Oostdijk, Marco Patelli, Demosthenes Bouros, Kazuma Nagata, Jean-Marc Naccache, Olivia Freynet, Dominique Valeyre, S. McKenna, J. Rupp, Vincent Cottin, Maria Chorti, V. Mistry, C. Reid, D. Drömann, M. Abdullah, M. Shelley, Satz Mengensatzproduktion, James E. Boers, Hilario Nunes, Druck Reinhardt Druck Basel, Argyris Tzouvelekis, Jan Willem K. van den Berg, Paul Frost Clementsen, Stavros Anevlavis, Aikaterini Pierrakou, Hiroyuki Ueda, Kostas N. Syrigos, Grigorios Stratakos, Xin-Peng Han, Henrik Arendrup, B. Hargadon, Reiko Kaji, Shigeki Nanjo, Nicolas Naggara, C. Vock, E. Vollmer, Christian von Buchwald, H.P. Hauber, H. Fehrenbach, P. Dodson, Rocco Trisolini, Xin-Yu Ti, and Ayako Sakurai

Subjects
Pulmonary and Respiratory Medicine, Optics, business.industry, Medicine, business, Front (military)
Published
2012
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31. P17 Self-reported physical activity levels and attitudes towards a structured exercise programme in adults with difficult asthma

Author

R Carter, Andrew J. Wardlaw, SJ Singh, B Hargadon, I D Pavord, C E Brightling, Amisha Singapuri, D Desai, M Shelley, Peter Bradding, and Ruth H. Green

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Physical activity, Asthma symptoms, Exercise capacity, medicine.disease, Exercise programme, Deconditioning, Physical therapy, Medicine, Difficult asthma, business, Body mass index, Asthma
Abstract

Background Patients with difficult-to-treat asthma often have dyspnoea which limits their physical activity. This may lead to progressive deconditioning which may further hamper exercise capacity. We aimed to assess current levels of activity, perceptions of current fitness and interest in a structured exercise programme in patients attending the Glenfield Hospital Difficult Asthma Clinic. Method Patients completed the General Practice Physical Activity Questionnaire which provides a simple Physical Activity Index (PAI) and answered structured questions about their satisfaction with current fitness and their interest in participating in an exercise programme. They were also asked to rate their current fitness compared to peers of the same age on a 100 mm visual analogue score. Responses were compared to demographic details and markers of asthma severity and control. Results Sixty patients participated (37 female, mean (SD) age 53(13)). Only 15/60 (25%) was classified as ‘active’ by the PAI. There were no significant differences in age, gender, body mass index or Juniper asthma control scores between those patients who were active compared to the remaining group but active patients had less severe airflow obstruction (post-bronchodilator FEV 1 83.7(16.5)% predicted vs 68.7(21.8), p=0.04) and better self-reported fitness scores (55.3(27.4) vs 36.7(23.0), p=0.013). There was a statistically significant inverse correlation between fitness scores and Juniper asthma control scores (r = −0.5, p 1 . 65% of patients reported that they had stopped exercising due to their asthma symptoms and 86.7% of patients wanted to be fitter. 71.7% were interested in participating in an exercise programme. Of these 13 (30%) preferred a hospital setting with the remainder preferring a community scheme or an independent programme with support from healthcare professionals. Conclusion Many patients with difficult asthma reported concerns about their current fitness and most were not exercising at the recommended level. There appears to be a demand for the development of a community-based structured exercise programme and further work is needed to determine whether this would improve asthma related outcomes for this group of patients.

Published
2010
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32. S44 Increased expression of immunoreactive thymic stromal lymphopoetin in severe asthma

Author

Lawren Wu, Peter Bradding, C E Brightling, Cary D. Austin, Joseph R. Arron, J Bennett, Aarti Shikotra, David F. Choy, M Shelley, and B Hargadon

Subjects
Pulmonary and Respiratory Medicine, Pathophysiology of asthma, Pathology, medicine.medical_specialty, Lamina propria, Stromal cell, biology, business.industry, medicine.medical_treatment, Tryptase, Inflammation, medicine.disease, respiratory tract diseases, Cytokine, medicine.anatomical_structure, Immunology, biology.protein, Medicine, Respiratory epithelium, medicine.symptom, business, Asthma
Abstract

Background Thymic stromal lymphopoetin (TSLP) is a cytokine implicated in the pathophysiology of asthma through two pathways: a TSLP-OX40L-T cell axis and a TSLP-mast cell axis. Whether these pathways operate in human asthma is unknown. Aims To investigate whether mucosal TSLP protein expression relates to asthma severity, and distinct immunological pathways. Methods GMA-embedded bronchial biopsies from healthy subjects (n=12) and patients with mild (BTS step 1, n=8), moderate (BTS steps 2 and 3, n=12) and severe (BTS steps 4 and 5, n=16) asthma were immunostained for TSLP, OX40, OX40L, CD83, IL-13, and inflammatory cell markers. Extent of immunostaining was correlated with clinical data. Results Specific TSLP immunoreactivity was evident in both the airway epithelium and lamina propria of both healthy and asthmatic subjects. TSLP immunoreactivity was not present in airway smooth muscle. TSLP epithelial expression was significantly elevated in asthma as a whole compared to healthy controls (p=0.0005), particularly in mild and severe disease. The number of TSLP+ cells in the lamina propria was elevated in patients with severe asthma relative to other groups (p=0.0058). Co-localisation studies in 6 severe asthmatic subjects showed that 5% of TSLP+ cells in the lamina propria were CD68+ macrophages and 20% were tryptase+ mast cells. There were significant inverse correlations between TSLP counts in both the asthmatic bronchial lamina propria and epithelium with the FEV 1 /FVC ratio (r s =−0.53, p=0.002 and r s =−0.40, p=0.037). Immunostaining for OX40, OX40L and CD83 in the airways was sparse, with no difference between asthmatic patients and normal control subjects. IL-13 staining was increased in non-epithelial cells within the airway epithelium in severe asthma (p=0.033). Conclusions TSLP expression is elevated in severe asthma despite high dose corticosteroid therapy. Although we did not detect activity of the TSLP-OX40L-T cell pathway within asthmatic bronchial mucosa, it is possible that this pathway operates in secondary lymphoid organs such as draining lymph nodes. The close approximation of airway stroma and mast cells suggests that the TSLP-mast cell axis, in which TSLP and IL-13 operate in a positive regulatory loop, is active in asthmatic bronchial mucosa and may be important in maintaining chronic airway inflammation.

Published
2010
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33. P176 Evaluating the role of triamcinolone in a difficult asthma service

Author

Peter Bradding, Ruth H. Green, R Carter, Andrew J. Wardlaw, J Agbetile, I D Pavord, B Hargadon, and Anna Murphy

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Triamcinolone acetonide, business.industry, Eosinophil, medicine.disease, medicine.anatomical_structure, Asthma Control Questionnaire, Internal medicine, Anesthesia, Exhaled nitric oxide, Prednisolone, medicine, Sputum, medicine.symptom, business, Adverse effect, medicine.drug, Asthma
Abstract

Introduction and Objectives 10% of patients with asthma have disease that is refractory to conventional therapy. Two important factors in this group of patients are non-adherence to prescribed treatment and steroid insensitive airway inflammation. We report on our experience using intramuscular (IM) triamcinolone to evaluate such patients. Methods We identified 28 patients who were on BTS step 5 treatment for asthma and at risk of fatal or near fatal events, who were given IM triamcinolone in the Glenfield difficult asthma clinic. The primary reason for administration of IM triamcinolone was to evaluate whether these patients had evidence of steroid insensitivity or were potentially non adherent. Adherence was assessed objectively prior to commencing triamcinolone. Juniper asthma control questionnaire (JACQ), fraction of exhaled nitric oxide (FeNO), blood eosinophils, sputum eosinophils, FEV 1 (pre bronchodilator) were measured at baseline and whilst on triamcinolone. Results Triamcinolone was administered monthly at a dose of 40–80 mg for a median (range) course of 4 (1–19) months. Patient demographics were: 75% (21) female, mean age 40 y, mean BMI 29.1, median dose of ICS (BDP equivalent) 2000 mcg, median dose of maintenance prednisolone 20 mg, 29% (8) had previously been ventilated. Adherence was objectively assessed in 93% (26) with non-adherence demonstrated in 77% (20), either by prescription refill check or drug assays. Significant improvements were seen whilst on triamcinolone in the mean JACQ score from 3.66 to 2.52 (p=0.0003), geometric mean FeNO from 52.3 ppb to 17.8 ppb (p=0.0034), mean blood eosinophils from 0.59×10 9 /l to 0.22×10 9 /l (p=0.0032), geometric mean sputum eosinophil count from 12.93% to 1.24% (p 1 from 54% to 67% predicted (p=0.0003). Of 28 patients receiving IM triamcinolone, 68% (19) showed significant improvement in 2 or more disease markers, 7% (2) showed improvement in 1 disease marker, 18% (5) had an equivocal response and 7% (2) demonstrated no response to parenteral steroid. No significant adverse events were reported. Conclusions This study shows that IM triamcinolone is a useful tool that may identify non-adherence in difficult-to-control asthmatic patients prescribed maintenance oral corticosteroids. Absolute steroid resistance is uncommon in this group.

Published
2010
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34. S133 Eosinophilic airway inflammation is associated with FEV1 decline in severe asthma

Author

B Hargadon, J Agbetile, Andrew J. Wardlaw, D Desai, Salman Siddiqui, Peter Bradding, Ruth H. Green, I D Pavord, and C E Brightling

Subjects
Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, medicine.diagnostic_test, Cross-sectional study, business.industry, respiratory system, Random effects model, medicine.disease, respiratory tract diseases, Internal medicine, Cohort, Immunology, Eosinophilic, medicine, Sputum, medicine.symptom, Age of onset, business, Asthma
Abstract

Background Severe asthma is a multidimensional disease, with recent evidence supporting the notion that eosinophilic airway inflammation (EAI) is an important driver for exacerbations. In addition EAI has been shown to be associated with airflow limitation in cross sectional studies. However, it remains to be established whether EAI may drive FEV 1 decline. Methods The severe asthma registry at Glenfield hospital, Leicester, was screened for patients with a physician diagnosis of asthma and at least 5 years of longitudinal data recording sputum eosinophils, pre- and post-bronchodilator spirometry, inhaled corticosteroid usage as well as standard demographic indices during stable scheduled follow-up visits. Linear mixed effects models were used to investigate the effect of log sputum eosinophils as a time varying covariate on decline of post bronchodilator FEV 1 . Models were iteratively compared and refined using standard information criteria. Other fixed effects in the final model were, time and the interaction terms for time * log sputum eosinophils and time *daily dose of inhaled corticosteroids and pack years smoked. Individual variations in the slopes and intercepts of time and time*log sputum eosinophils were considered by adding them iteratively as random effects. A first-order autoregressive correlation structure was used to model covariance of random effects. Results 92 patients, 46% male with severe asthma were identified from a registry cohort of 686 between 2000 and 2009. The mean (sem) age was 54(12.9) years and age of onset 23 (2.1) years. The mean (range) duration of follow-up and number of visits were 6 years (4.6–10.5), 2.7/year. We found a significant interaction between sputum eosinophils, time and post bronchodilator FEV 1 . Indicating a net decline (95% CI) of −16.8 mls(25.8–7.8 mls) /annum/log unit increase in sputum eosinophils (F(1, 43.4); p Conclusion Eosinophilic airway inflammation is associated with a significant decline in FEV 1 in severe asthma.

Published
2010
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35. Sputum eosinophilia in idiopathic pulmonary fibrosis.

Author

S. S. Birring, D. Parker, S. McKenna, B. Hargadon, C. E. Brightling, I. D. Pavord, and P. Bradding

Subjects
EOSINOPHIL disorders, REFLEX testing, DISEASES, AIR pollution
Abstract

Abstract. Objectives and Design: Cough is a common symptom in idiopathic pulmonary fibrosis that is difficult to treat and has a major impact on quality of life. We tested the hypothesis that the cough and increased cough reflex sensitivity seen in patients with idiopathic pulmonary fibrosis may be due to airway inflammation in a prospective, cross-sectional study. [ABSTRACT FROM AUTHOR]

Published
2005

36. 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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37. The effects of inhaled corticosteroids on healthy airways.

Author

Marchi E, Hinks TSC, Richardson M, Khalfaoui L, Symon FA, Rajasekar P, Clifford R, Hargadon B, Austin CD, MacIsaac JL, Kobor MS, Siddiqui S, Mar JS, Arron JR, Choy DF, and Bradding P

Subjects
Humans, Adult, Male, Administration, Inhalation, Female, Young Adult, Middle Aged, DNA Methylation drug effects, Gene Expression Regulation drug effects, Respiratory Mucosa metabolism, Respiratory Mucosa immunology, Respiratory Mucosa drug effects, Fluticasone administration & dosage, Fluticasone pharmacology, Adrenal Cortex Hormones administration & dosage, Healthy Volunteers
Abstract

Background: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined., Objectives: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness., Methods: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics., Results: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV 1 , microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS., Conclusions: In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Published
2024
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38. Visualization of exhaled breath metabolites reveals distinct diagnostic signatures for acute cardiorespiratory breathlessness.

Author

Ibrahim W, Wilde MJ, Cordell RL, Richardson M, Salman D, Free RC, Zhao B, Singapuri A, Hargadon B, Gaillard EA, Suzuki T, Ng LL, Coats T, Thomas P, Monks PS, Brightling CE, Greening NJ, Siddiqui S, Munton R, Le Quesne J, Goodall AH, Pandya HC, Reynolds JC, Clokie MRJ, Samani NJ, Barer MR, and Shaw JA

Subjects
Humans, Breath Tests, Acute Disease, Dyspnea diagnosis, Biomarkers metabolism, Volatile Organic Compounds analysis, Asthma diagnosis, Heart Failure diagnosis
Abstract

Acute cardiorespiratory breathlessness accounts for one in eight of all emergency hospitalizations. Early, noninvasive diagnostic testing is a clinical priority that allows rapid triage and treatment. Here, we sought to find and replicate diagnostic breath volatile organic compound (VOC) biomarkers of acute cardiorespiratory disease and understand breath metabolite network enrichment in acute disease, with a view to gaining mechanistic insight of breath biochemical derangements. We collected and analyzed exhaled breath samples from 277 participants presenting acute cardiorespiratory exacerbations and aged-matched healthy volunteers. Topological data analysis phenotypes differentiated acute disease from health and acute cardiorespiratory exacerbation subtypes (acute heart failure, acute asthma, acute chronic obstructive pulmonary disease, and community-acquired pneumonia). A multibiomarker score (101 breath biomarkers) demonstrated good diagnostic sensitivity and specificity (≥80%) in both discovery and replication sets and was associated with all-cause mortality at 2 years. In addition, VOC biomarker scores differentiated metabolic subgroups of cardiorespiratory exacerbation. Louvain clustering of VOCs coupled with metabolite enrichment and similarity assessment revealed highly specific enrichment patterns in all acute disease subgroups, for example, selective enrichment of correlated C5-7 hydrocarbons and C3-5 carbonyls in heart failure and selective depletion of correlated aldehydes in acute asthma. This study identified breath VOCs that differentiate acute cardiorespiratory exacerbations and associated subtypes and metabolic clusters of disease-associated VOCs.

Published
2022
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39. Airway remodelling rather than cellular infiltration characterizes both type2 cytokine biomarker-high and -low severe asthma.

Author

Khalfaoui L, Symon FA, Couillard S, Hargadon B, Chaudhuri R, Bicknell S, Mansur AH, Shrimanker R, Hinks TSC, Pavord ID, Fowler SJ, Brown V, McGarvey LP, Heaney LG, Austin CD, Howarth PH, Arron JR, Choy DF, and Bradding P

Subjects
Airway Remodeling, Biomarkers, Cytokines analysis, Eosinophils metabolism, Humans, Inflammation pathology, Interleukin-4, Interleukin-5 analysis, Sputum, Asthma metabolism, Eosinophilia pathology
Abstract

Background: The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type 2 (T2) cytokine biology, which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood., Objectives: To explore airway pathology in T2 biomarker-high and -low severe asthma., Methods: T2 biomarker-high severe asthma (T2-high, n = 17) was compared with biomarker-intermediate (T2-intermediate, n = 21) and biomarker-low (T2-low, n = 20) severe asthma and healthy controls (n = 28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD 2 and LTE 4 measurements., Results: Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodelling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared with health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5 and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD 2 and LTE 4 , were increased in T2-high and T2-intermediate asthma compared with healthy controls., Conclusions: Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodelling persists and may be important for residual disease expression beyond eosinophilic exacerbations. Registered at ClincialTrials.gov: NCT02883530., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Published
2022
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40. Diagnosis of COVID-19 by exhaled breath analysis using gas chromatography-mass spectrometry.

Author

Ibrahim W, Cordell RL, Wilde MJ, Richardson M, Carr L, Sundari Devi Dasi A, Hargadon B, Free RC, Monks PS, Brightling CE, Greening NJ, and Siddiqui S

Abstract

Background: The ongoing coronavirus disease 2019 (COVID-19) pandemic has claimed over two and a half million lives worldwide so far. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is perceived to be seasonally recurrent, and a rapid noninvasive biomarker to accurately diagnose patients early on in their disease course will be necessary to meet the operational demands for COVID-19 control in the coming years., Objective: The aim of this study was to evaluate the role of exhaled breath volatile biomarkers in identifying patients with suspected or confirmed COVID-19 infection, based on their underlying PCR status and clinical probability., Methods: A prospective, real-world, observational study was carried out, recruiting adult patients with suspected or confirmed COVID-19 infection. Breath samples were collected using a standard breath collection bag, modified with appropriate filters to comply with local infection control recommendations, and samples were analysed using gas chromatography-mass spectrometry (TD-GC-MS)., Results: 81 patients were recruited between April 29 and July 10, 2020, of whom 52 out of 81 (64%) tested positive for COVID-19 by reverse transcription-polymerase chain reaction (RT-PCR). A regression analysis identified a set of seven exhaled breath features (benzaldehyde, 1-propanol, 3,6-methylundecane, camphene, beta-cubebene, iodobenzene and an unidentified compound) that separated PCR-positive patients with an area under the curve (AUC): 0.836, sensitivity: 68%, specificity: 85%., Conclusions: GC-MS-detected exhaled breath biomarkers were able to identify PCR-positive COVID-19 patients. External replication of these compounds is warranted to validate these results., Competing Interests: Conflict of interest: W. Ibrahim has nothing to disclose. Conflict of interest: R.L. Cordell has nothing to disclose. Conflict of interest: M.J. Wilde has nothing to disclose. Conflict of interest: M. Richardson has nothing to disclose. Conflict of interest: L. Carr has nothing to disclose. Conflict of interest: A. Sundari Devi Dasi has nothing to disclose. Conflict of interest: B. Hargadon has nothing to disclose. Conflict of interest: R.C. Free has nothing to disclose. Conflict of interest: P.S. Monks has nothing to disclose. Conflict of interest: C.E Brightling has nothing to disclose. Conflict of interest: N.J. Greening has nothing to disclose. Conflict of interest: S. Siddiqui has nothing to disclose., (Copyright ©The authors 2021.)

Published
2021
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41. Volatile organic compounds in a headspace sampling system and asthmatics sputum samples.

Author

Peltrini R, Cordell RL, Ibrahim W, Wilde MJ, Salman D, Singapuri A, Hargadon B, Brightling CE, Thomas CLP, Monks PS, and Siddiqui S

Subjects
Breath Tests, Gas Chromatography-Mass Spectrometry methods, Humans, Sputum chemistry, Asthma diagnosis, Volatile Organic Compounds analysis
Abstract

The headspace of a biological sample contains exogenous volatile organic compounds (VOCs) present within the sampling environment which represent the background signal. This study aimed to characterise the background signal generated from a headspace sampling system in a clinical site, to evaluate intra- and inter-day variation of background VOC and to understand the impact of a sample itself upon commonly reported background VOC using sputum headspace samples from severe asthmatics. The headspace, in absence of a biological sample, was collected hourly from 11am to 3pm within a day (time of clinical samples acquisition), and from Monday to Friday in a week, and analysed by thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Chemometric analysis identified 1120 features, 37 of which were present in at least the 80% of all the samples. The analyses of intra- and inter-day background variations were performed on 13 of the most abundant features, ubiquitously present in headspace samples. The concentration ratios relative to background were reported for the selected abundant VOC in 36 asthmatic sputum samples, acquired from 36 stable severe asthma patients recruited at Glenfield Hospital, Leicester, UK. The results identified no significant intra- or inter-day variations in compounds levels and no systematic bias of z -scores, with the exclusion of benzothiazole, whose abundance increased linearly between 11am and 3pm with a maximal intra-day fold change of 2.13. Many of the identified background features are reported in literature as components of headspace of biological samples and are considered potential biomarkers for several diseases. The selected background features were identified in headspace of all severe asthma sputum samples, albeit with varying levels of enrichment relative to background. Our observations support the need to consider the background signal derived from the headspace sampling system when developing and validating headspace biomarker signatures using clinical samples., (Creative Commons Attribution license.)

Published
2021
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42. A Feasibility Study of a Randomized Controlled Trial of Asthma-Tailored Pulmonary Rehabilitation Compared with Usual Care in Adults with Severe Asthma.

Author

Majd S, Apps L, Chantrell S, Hudson N, Eglington E, Hargadon B, Murphy A, Singh SJ, Bradding P, Green RH, and Evans RA

Subjects
Adult, Aged, Exercise, Feasibility Studies, Female, Humans, Middle Aged, Vital Capacity, Asthma epidemiology, Quality of Life
Abstract

Background: Currently, the acceptability and efficacy of pulmonary rehabilitation for adults with severe asthma is unknown., Objective: To investigate the feasibility of performing a randomized controlled trial of asthma-tailored pulmonary rehabilitation (AT-PR) versus usual care (UC)., Methods: Adults with severe asthma were recruited and randomized 2:1 to AT-PR and UC. The primary outcomes were recruitment, retention, and serious adverse event rates. Secondary outcome measures included those for a future trial assessing the feasibility of collecting data. Assessments were performed at baseline, 12 weeks, and 9 months including measures of physical performance, health-related quality of life, and asthma control. A recruitment rate of 30% was estimated with 95% CI of ±7%, a retention rate of 75% ± 14% if we recruited 40 patients to AT-PR, and a serious adverse event rate of 2.5%., Results: Sixty-one (26%) of 238 eligible patients were recruited (38 women; mean age, 54 ± 13 years; body mass index, 32 ± 7 kg/m 2 ; FEV 1 , 1.9 ± 0.7 L; FEV 1 /forced vital capacity, 69% ± 11%). Fifty-one patients were randomized to AT-PR (n = 34) and UC (n = 17). The retention rate was 62% for the AT-PR group and 53% for the UC group, with a serious adverse event rate of 3.3% related to the study visits. Overall collection of the outcome measures was feasible. The results of the AT-PR group were suggestive of improvements in exercise performance, health-related quality of life, and asthma control, but the UC group results were either unchanged or worsened., Conclusions: Both recruitment and retention rates were within the a priori estimated 95% CI. Our results indicate that AT-PR may be efficacious for adults with severe asthma but any future intervention and trial design would need further modifications to improve acceptability and retention rate., (Copyright © 2020. Published by Elsevier Inc.)

Published
2020
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43. Lung Computational Models and the Role of the Small Airways in Asthma.

Author

Foy BH, Soares M, Bordas R, Richardson M, Bell A, Singapuri A, Hargadon B, Brightling C, Burrowes K, Kay D, Owers-Bradley J, and Siddiqui S

Subjects
Adult, Aged, Female, Forced Expiratory Volume, Humans, Male, Middle Aged, Models, Anatomic, Respiratory Function Tests methods, Spirometry methods, Airway Remodeling physiology, Asthma diagnosis, Asthma physiopathology, Asthma therapy, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Disease, Chronic Obstructive therapy
Abstract

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique-derived resistance at 5 Hz (R5) - resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date. Objectives: To validate the use of forced oscillation R5 - R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma. Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 - R20 ( n  = 31). The computational models were coupled with regression models in an asthmatic cohort ( n  = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials ( n  = 137). Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 - R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 - R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%. Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 - R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.

Published
2019
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45. Severe exacerbations in moderate-to-severe asthmatics are associated with increased pro-inflammatory and type 1 mediators in sputum and serum.

Author

Ghebre MA, Pang PH, Desai D, Hargadon B, Newby C, Woods J, Rapley L, Cohen SE, Herath A, Gaillard EA, May RD, and Brightling CE

Subjects
Area Under Curve, Biomarkers metabolism, Child, Disease Progression, Female, Humans, Inflammation, Male, Middle Aged, ROC Curve, Severity of Illness Index, Sputum immunology, Sputum metabolism, Asthma immunology, Asthma metabolism, Cytokines metabolism, Receptors, Interleukin-6 metabolism, Receptors, Tumor Necrosis Factor, Type II metabolism
Abstract

Background: Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events., Methods: We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children., Results: The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1β, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve [AUC]) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 [95% CI: 0.71 to 0.99] and 0.80 [0.64 to 0.96] respectively)., Conclusions: Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children.

Published
2019
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46. Assessment of breath volatile organic compounds in acute cardiorespiratory breathlessness: a protocol describing a prospective real-world observational study.

Author

Ibrahim W, Wilde M, Cordell R, Salman D, Ruszkiewicz D, Bryant L, Richardson M, Free RC, Zhao B, Yousuf A, White C, Russell R, Jones S, Patel B, Awal A, Phillips R, Fowkes G, McNally T, Foxon C, Bhatt H, Peltrini R, Singapuri A, Hargadon B, Suzuki T, Ng LL, Gaillard E, Beardsmore C, Ryanna K, Pandya H, Coates T, Monks PS, Greening N, Brightling CE, Thomas P, and Siddiqui S

Subjects
Acute Disease, Adult, Breath Tests, Data Collection, Diagnosis, Differential, Exhalation, Gas Chromatography-Mass Spectrometry, Humans, Prospective Studies, Respiratory Tract Diseases diagnosis, Sample Size, Sputum, Cardiovascular Diseases diagnosis, Dyspnea diagnosis, Multicenter Studies as Topic methods, Observational Studies as Topic methods, Volatile Organic Compounds analysis
Abstract

Introduction: Patients presenting with acute undifferentiated breathlessness are commonly encountered in admissions units across the UK. Existing blood biomarkers have clinical utility in distinguishing patients with single organ pathologies but have poor discriminatory power in multifactorial presentations. Evaluation of volatile organic compounds (VOCs) in exhaled breath offers the potential to develop biomarkers of disease states that underpin acute cardiorespiratory breathlessness, owing to their proximity to the cardiorespiratory system. To date, there has been no systematic evaluation of VOC in acute cardiorespiratory breathlessness. The proposed study will seek to use both offline and online VOC technologies to evaluate the predictive value of VOC in identifying common conditions that present with acute cardiorespiratory breathlessness., Methods and Analysis: A prospective real-world observational study carried out across three acute admissions units within Leicestershire. Participants with self-reported acute breathlessness, with a confirmed primary diagnosis of either acute heart failure, community-acquired pneumonia and acute exacerbation of asthma or chronic obstructive pulmonary disease will be recruited within 24 hours of admission. Additionally, school-age children admitted with severe asthma will be evaluated. All participants will undergo breath sampling on admission and on recovery following discharge. A range of online technologies including: proton transfer reaction mass spectrometry, gas chromatography ion mobility spectrometry, atmospheric pressure chemical ionisation-mass spectrometry and offline technologies including gas chromatography mass spectroscopy and comprehensive two-dimensional gas chromatography-mass spectrometry will be used for VOC discovery and replication. For offline technologies, a standardised CE-marked breath sampling device (ReCIVA) will be used. All recruited participants will be characterised using existing blood biomarkers including C reactive protein, brain-derived natriuretic peptide, troponin-I and blood eosinophil levels and further evaluated using a range of standardised questionnaires, lung function testing, sputum cell counts and other diagnostic tests pertinent to acute disease., Ethics and Dissemination: The National Research Ethics Service Committee East Midlands has approved the study protocol (REC number: 16/LO/1747). Integrated Research Approval System (IRAS) 198921. Findings will be presented at academic conferences and published in peer-reviewed scientific journals. Dissemination will be facilitated via a partnership with the East Midlands Academic Health Sciences Network and via interaction with all UK-funded Medical Research Council and Engineering and Physical Sciences Research Council molecular pathology nodes., Trial Registration Number: NCT03672994., Competing Interests: Competing interests: SS has performed advisory services for Owlstone Medical., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Published
2019
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47. Exacerbations of severe asthma in patients treated with mepolizumab.

Author

Shrimanker R, Pavord ID, Yancey S, Heaney LG, Green RH, Bradding P, Hargadon B, Brightling CE, Wardlaw AJ, and Haldar P

Subjects
Asthma diagnosis, Double-Blind Method, Humans, Treatment Outcome, Anti-Asthmatic Agents administration & dosage, Antibodies, Monoclonal, Humanized administration & dosage, Asthma drug therapy, Disease Progression
Abstract

Competing Interests: Conflict of interest: R. Shrimanker has nothing to disclose. Conflict of interest: I.D. Pavord reports receiving speaker's honoraria, travel expenses and honoraria for attending advisory boards from AstraZeneca, GSK, Boehringer Ingelheim and Teva, a research grant, speaker's honoraria, travel expenses and honoraria for attending advisory boards from Chiesi, honoraria for attending advisory boards from Sanofi/Regeneron, speaker's honoraria from Circassia and Mundipharma, honoraria for attending advisory boards from Merck, Novartis, Knopp and Roche/Genentech, a research grant and honoraria for attending advisory boards from Afferent, outside the submitted work. Conflict of interest: S. Yancey is an employee of GSK and holds stock in that company. Conflict of interest: L.G. Heaney reports reports that Vitalograph Ltd provided INCA inhaler technology as part of the MRC-funded RASP-UK programme and Aerocrine AB provided FeNO machines at reduced cost as part of that programme. He took part in advisory boards and gave lectures at meetings supported by GSK, Respivert, MSD, Nycomed, Boehringer Ingelheim, Teva, Vectura, Novartis and AstraZeneca, during the conduct of the study. He received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, GSK and Napp Pharmaceuticals, and received lecture and advisory board fees from Novartis, Roche Genentech Inc., Sanofi, GSK, Amgen, AstraZeneca and Aerocrine, outside the submitted work. Conflict of interest: R.H. Green reports receiving educational speaker fees from AstraZeneca and Novartis, outside the submitted work. Conflict of interest: P. Bradding reports receiving non-financial support (provision of the study drug) from GSK during the conduct of the study. Conflict of interest: B. Hargadon has nothing to disclose. Conflict of interest: C.E. Brightling reports receiving grants from GSK and the NIHR, during the conduct of the study; grants and personal fees from AZ/MedImmune, grants and personal fees from GSK, Boehringer Ingelheim, Chiesi, Novartis and Roche/Genentech, personal fees from Glenmark, Gilead and Teva, Sanofi, Regeneron, 4DPharma, PreP and Mologic, paid to his institution, outside the submitted work. Conflict of interest: A.J. Wardlaw reports receiving grants from GSK during the conduct of the study, and grants from Pulmocide, and personal fees from GSK, AstraZeneca/MedImmune, Teva and GfK, outside the submitted work. Conflict of interest: P. Haldar has nothing to disclose.

Published
2018
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48. Airway pathological heterogeneity in asthma: Visualization of disease microclusters using topological data analysis.

Author

Siddiqui S, Shikotra A, Richardson M, Doran E, Choy D, Bell A, Austin CD, Eastham-Anderson J, Hargadon B, Arron JR, Wardlaw A, Brightling CE, Heaney LG, and Bradding P

Subjects
Adult, Airway Remodeling, Asthma genetics, Bronchi metabolism, Cluster Analysis, Cohort Studies, Female, Gene Expression, Humans, Male, Middle Aged, Phenotype, Asthma pathology, Bronchi pathology
Abstract

Background: Asthma is a complex chronic disease underpinned by pathological changes within the airway wall. How variations in structural airway pathology and cellular inflammation contribute to the expression and severity of asthma are poorly understood., Objectives: Therefore we evaluated pathological heterogeneity using topological data analysis (TDA) with the aim of visualizing disease clusters and microclusters., Methods: A discovery population of 202 adult patients (142 asthmatic patients and 60 healthy subjects) and an external replication population (59 patients with severe asthma) were evaluated. Pathology and gene expression were examined in bronchial biopsy samples. TDA was applied by using pathological variables alone to create pathology-driven visual networks., Results: In the discovery cohort TDA identified 4 groups/networks with multiple microclusters/regions of interest that were masked by group-level statistics. Specifically, TDA group 1 consisted of a high proportion of healthy subjects, with a microcluster representing a topological continuum connecting healthy subjects to patients with mild-to-moderate asthma. Three additional TDA groups with moderate-to-severe asthma (Airway Smooth Muscle High , Reticular Basement Membrane High , and Remodeling Low groups) were identified and contained numerous microclusters with varying pathological and clinical features. Mutually exclusive T H 2 and T H 17 tissue gene expression signatures were identified in all pathological groups. Discovery and external replication applied to the severe asthma subgroup identified only highly similar "pathological data shapes" through analyses of persistent homology., Conclusions: We have identified and replicated novel pathological phenotypes of asthma using TDA. Our methodology is applicable to other complex chronic diseases., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Published
2018
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49. Responsiveness to oral prednisolone in severe asthma is related to the degree of eosinophilic airway inflammation.

Author

Sousa AR, Marshall RP, Warnock LC, Bolton S, Hastie A, Symon F, Hargadon B, Marshall H, Richardson M, Brightling CE, Haldar P, Milone R, Chalk P, Williamson R, Panettieri R Jr, Knowles R, Bleecker ER, and Wardlaw AJ

Subjects
Administration, Oral, Adrenal Cortex Hormones administration & dosage, Adult, Asthma diagnosis, Biomarkers, Cohort Studies, Cytokines blood, Cytokines metabolism, Eosinophils metabolism, Eosinophils pathology, Exhalation, Female, Humans, Male, Middle Aged, Nitric Oxide metabolism, Respiratory Function Tests, Severity of Illness Index, Treatment Outcome, Young Adult, Anti-Asthmatic Agents administration & dosage, Asthma drug therapy, Asthma etiology, Eosinophils immunology, Prednisolone administration & dosage
Abstract

Background: Patients with severe asthma appear relatively corticosteroid resistant. Corticosteroid responsiveness is closely related to the degree of eosinophilic airway inflammation. The extent to which eosinophilic airway inflammation in severe asthma responds to treatment with systemic corticosteroids is not clear., Objective: To relate the physiological and inflammatory response to systemic corticosteroids in asthma to disease severity and the baseline extent of eosinophilic inflammation., Methods: Patients with mild/moderate and severe asthma were investigated before and after 2 weeks of oral prednisolone (Clintrials.gov NCT00331058 and NCT00327197). We pooled the results from two studies with common protocols. The US study contained two independent centres and the UK one independent centre. The effect of oral corticosteroids on FEV 1 , Pc20, airway inflammation and serum cytokines was investigated. Baseline measurements were compared with healthy subjects., Results: Thirty-two mild/moderate asthmatics, 50 severe asthmatics and 35 healthy subjects took part. At baseline, both groups of asthmatics had a lower FEV 1 and Pc20 and increased eosinophilic inflammation compared to healthy subjects. The severe group had a lower FEV 1 and more eosinophilic inflammation compared to mild/moderate asthmatics. Oral prednisolone caused a similar degree of suppression of eosinophilic inflammation in all compartments in both groups of asthmatics. There were small improvements in FEV 1 and Pc20 for both mild/ moderate and severe asthmatics with a correlation between the baseline eosinophilic inflammation and the change in FEV 1 . There was a ~50% reduction in the serum concentration of CXCL10 (IP-10), CCL22 (MDC), CCL17 (TARC), CCL-2 (MCP-1) and CCL-13 (MCP-4) in both asthma groups after oral corticosteroids., Conclusions and Clinical Relevance: Disease severity does not influence the response to systemic corticosteroids. The study does not therefore support the concept that severe asthma is associated with corticosteroid resistance. Only baseline eosinophilic inflammation was associated with the physiological response to corticosteroids, confirming the importance of measuring eosinophilic inflammation to guide corticosteroid use., (© 2017 John Wiley & Sons Ltd.)

Published
2017
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50. A CEACAM6-High Airway Neutrophil Phenotype and CEACAM6-High Epithelial Cells Are Features of Severe Asthma.

Author

Shikotra A, Choy DF, Siddiqui S, Arthur G, Nagarkar DR, Jia G, Wright AK, Ohri CM, Doran E, Butler CA, Hargadon B, Abbas AR, Jackman J, Wu LC, Heaney LG, Arron JR, and Bradding P

Subjects
Adult, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Fluorescent Antibody Technique, GPI-Linked Proteins immunology, Gene Expression Profiling, Humans, Immunohistochemistry, Male, Middle Aged, Phenotype, Polymerase Chain Reaction, Transcriptome, Antigens, CD immunology, Asthma immunology, Cell Adhesion Molecules immunology, Epithelial Cells immunology, Neutrophils immunology, Respiratory Mucosa immunology
Abstract

Severe asthma represents a major unmet clinical need; understanding the pathophysiology is essential for the development of new therapies. Using microarray analysis, we previously found three immunological clusters in asthma: Th2-high, Th17-high, and Th2/17-low. Although new therapies are emerging for Th2-high disease, identifying molecular pathways in Th2-low disease remains an important goal. Further interrogation of our previously described microarray dataset revealed upregulation of gene expression for carcinoembryonic Ag cell adhesion molecule (CEACAM) family members in the bronchi of patients with severe asthma. Our aim was therefore to explore the distribution and cellular localization of CEACAM6 using immunohistochemistry on bronchial biopsy tissue obtained from patients with mild-to-severe asthma and healthy control subjects. Human bronchial epithelial cells were used to investigate cytokine and corticosteroid in vitro regulation of CEACAM6 gene expression. CEACAM6 protein expression in bronchial biopsies was increased in airway epithelial cells and lamina propria inflammatory cells in severe asthma compared with healthy control subjects. CEACAM6 in the lamina propria was localized to neutrophils predominantly. Neutrophil density in the bronchial mucosa was similar across health and the spectrum of asthma severity, but the percentage of neutrophils expressing CEACAM6 was significantly increased in severe asthma, suggesting the presence of an altered neutrophil phenotype. CEACAM6 gene expression in cultured epithelial cells was upregulated by wounding and neutrophil elastase. In summary, CEACAM6 expression is increased in severe asthma and primarily associated with airway epithelial cells and tissue neutrophils. CEACAM6 may contribute to the pathology of treatment-resistant asthma via neutrophil and airway epithelial cell-dependent pathways., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Published
2017
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