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

Author

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

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

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

Published
2022

2. Airway soluble CSF1R predicts progression in patients with idiopathic pulmonary fibrosis.

Author

Oldham, JM, Johnson, KW, Albers, GJ, Calamita, E, Mah, J, Ghai, P, Hewitt, RJ, Maher, TM, Molyneaux, PL, Huang, M, Byrne, AJ, Oldham, JM, Johnson, KW, Albers, GJ, Calamita, E, Mah, J, Ghai, P, Hewitt, RJ, Maher, TM, Molyneaux, PL, Huang, M, and Byrne, AJ

Abstract

This study provides the first evidence for a role of airway sCSF1R in IPF https://bit.ly/3KTBrCA.

Published
2023

3. A comparison of long-term outcomes in patients managed with venovenous extracorporeal membrane oxygenation in the first and second waves of the COVID-19 pandemic in the United Kingdom

Author

Garfield, BE, Bianchi, P, Arachchillage, DJ, Caetano, F, Desai, S, Doyle, J, Hernandez Caballero, C, Doyle, A-M, Mehta, S, Law, A, Jaggar, S, Kokosi, M, Molyneaux, PL, Passariello, M, Naja, M, Ridge, C, Alçada, J, Patel, B, Singh, S, and Ledot, S

Abstract

OBJECTIVES: Early studies of venovenous extracorporeal membrane oxygenation (ECMO) in COVID-19 have revealed similar outcomes to historical cohorts. Changes in the disease and treatments have led to differences in the patients supported on venovenous ECMO in the first and second waves. We aimed to compare these two groups in both the acute and follow-up phase. DESIGN: Retrospective single-center cohort study comparing mortality at censoring date (November 30, 2021) and decannulation, patient characteristics, complications and lung function and quality of life (QOL-by European Quality of Life 5 Dimensions 3 Level Version) at first follow-up in patients supported on venovenous ECMO between wave 1 and wave 2 of the COVID-19 pandemic. SETTING: Critical care department of a severe acute respiratory failure service. PATIENTS: Patients supported on ECMO for COVID-19 between wave 1 (March 17, 2020, to August 31, 2020) and wave 2 (January 9, 2020, to May 25, 2021). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three patients were included in our analysis. Survival at censoring date (χ2, 6.35; p = 0.012) and decannulation (90.4% vs 70.0%; p < 0.001) was significantly lower in the second wave, while duration of ECMO run was longer (12.0 d [18.0-30.0 d] vs 29.5 d [15.5-58.3 d]; p = 0.005). Wave 2 patients had longer application of noninvasive ventilation (NIV) prior to ECMO and a higher frequency of barotrauma. Patient age and NIV use were independently associated with increased mortality (odds ratio 1.07 [1.01-1.14]; p = 0.025 and 3.37 [1.12-12.60]; p = 0.043, respectively). QOL and lung function apart from transfer coefficient of carbon monoxide corrected for hemoglobin was similar at follow-up across the waves. CONCLUSIONS: Most patients with COVID-19 supported on ECMO in both waves survived in the short and longer term. At follow-up patients had similar lung function and QOL across the two waves. This suggests that ECMO has an ongoing role in the management of a carefully selected group of patients with COVID-19.

Published
2023

4. Epithelial senescence in idiopathic pulmonary fibrosis is propagated by small extracellular vesicles

Author

Asghar, S, Monkley, S, Smith, DJF, Hewitt, RJ, Grime, K, Murray, LA, Overed-Sayer, CL, and Molyneaux, PL

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that affects 3 million people worldwide. Senescence and small extracellular vesicles (sEVs) have been implicated in the pathogenesis of IPF, although how sEVs promote disease remains unclear. Here, we profile sEVs from bronchial epithelial cells and determine small RNA (smRNA) content. Methods Conditioned media was collected and sEVs were isolated from normal human bronchial epithelial cells (NHBEs) and IPF-diseased human bronchial epithelial cells (DHBEs). Results Increased sEV release from DHBEs compared to NHBEs (n = 4; p Conclusions This data demonstrates that DHBE-derived sEVs transfer senescence to neighbouring healthy cells, promoting the disease state in IPF.

Published
2023

5. Residual lung abnormalities following COVID-19 hospitalization: interim analysis of the UKILD Post-COVID study

Author

Stewart, I, Molyneaux, PL, Fabbri, L, Quint, JK, Walsh, SLF, Weeks, M, and Jenkins, RG

Abstract

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post–COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP–COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP–COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83–155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05–1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00–1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07–1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6–9.5), rising to 11.7% (95% CrI, 10.3–13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19–related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Published
2022

6. S2 Nocturnal hypoxaemia rather than obstructive sleep apnoea is associated with progressive deterioration in quality of life in patients with fibrotic interstitial lung disease

Author

Myall, KJ, primary, West, AG, additional, Martinovic, JL, additional, Lam, JL, additional, Roque, D, additional, Domi, V, additional, Wu, Z, additional, Jackson, DJ, additional, Maher, T, additional, Molyneaux, PL, additional, Suh, ES, additional, and Kent, BD, additional

Published
2022
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8. S109 Genome-wide analysis of longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis

Author

Allen, RJ, primary, Oldham, JM, additional, Jenkins, DA, additional, Leavy, OC, additional, Guillen-Guio, B, additional, Melbourne, CA, additional, Ma, SF, additional, Jou, J, additional, Kim, JS, additional, Fahy, WA, additional, Oballa, E, additional, Hubbard, RB, additional, Navaratnam, V, additional, Braybrooke, R, additional, Saini, G, additional, Roach, KM, additional, Tobin, MD, additional, Hirani, N, additional, Whyte, MKB, additional, Kaminski, N, additional, Zhang, Y, additional, Martinez, FJ, additional, Linderholm, AL, additional, Adegunsoye, A, additional, Strek, ME, additional, Maher, TM, additional, Molyneaux, PL, additional, Flores, C, additional, Noth, I, additional, Jenkins, RG, additional, and Wain, LV, additional

Published
2022
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13. CYFRA 21-1 predicts progression in IPF: a prospective longitudinal analysis of the PROFILE cohort

Author

Molyneaux, PL, Fahy, WA, Byrne, AJ, Braybrooke, R, Saunders, P, Toshner, R, Albers, G, Chua, F, Renzoni, EA, Wells, AU, Karkera, Y, Oballa, E, Saini, G, Nicholson, AG, Jenkins, G, Maher, TM, and Action for Pulmonary Fibrosis

Subjects
interstitial lung disease, clinical trials, Respiratory System, biomarkers, epithelium, 11 Medical and Health Sciences
Abstract

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making. RATIONALE: To determine the relationship between serum levels of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the PROFILE study. METHODS: CYFRA 21-1 was identified by immunohistochemistry in samples of human lung. Concentrations of CYFRA 21-1 were measured using an Elisa-based assay in serum, collected at baseline, 1- and 3-months, from 491 individuals with an incident diagnosis of IPF enrolled in the PROFILE study and from 100 control subjects. Study subjects were followed for a minimum of 3 years. MEASUREMENTS AND MAIN RESULTS: CYFRA 21-1 localises to hyperplastic epithelium in IPF lung. CYFRA 21-1 levels were significantly higher in IPF subjects compared to healthy controls in both discovery (n=132) (control 0.96±0.81 ng/mL versus IPF; 2.34±2.15 ng/mL, p < 0.0001) and validation (n=359) (control; 2.21±1.54 ng/mL and IPF; 4.13±2.77 ng/mL, p

Published
2022

14. Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study

Author

Allen, RJ, Oldham, JM, Jenkins, DA, Leavy, OC, Guillen-Guio, B, Melbourne, CA, Ma, S-F, Jou, J, Kim, JS, CleanUP-IPF Investigators of the Pulmonary Trials Cooperative, Fahy, WA, Oballa, E, Hubbard, RB, Navaratnam, V, Braybrooke, R, Saini, G, Roach, KM, Tobin, MD, Hirani, N, Whyte, MKB, Kaminski, N, Zhang, Y, Martinez, FJ, Linderholm, AL, Adegunsoye, A, Strek, ME, Maher, TM, Molyneaux, PL, Flores, C, Noth, I, Gisli Jenkins, R, and Wain, LV

Subjects
Pulmonary and Respiratory Medicine
Abstract

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p

Published
2022

15. CYFRA 21-1 Predicts Progression in Idiopathic Pulmonary Fibrosis: A Prospective Longitudinal Analysis of the PROFILE Cohort.

Author

Molyneaux, PL, Fahy, WA, Byrne, AJ, Braybrooke, R, Saunders, P, Toshner, R, Albers, G, Chua, F, Renzoni, EA, Wells, AU, Karkera, Y, Oballa, E, Saini, G, Nicholson, AG, Jenkins, RG, Maher, TM, Molyneaux, PL, Fahy, WA, Byrne, AJ, Braybrooke, R, Saunders, P, Toshner, R, Albers, G, Chua, F, Renzoni, EA, Wells, AU, Karkera, Y, Oballa, E, Saini, G, Nicholson, AG, Jenkins, RG, and Maher, TM

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making. Objectives: To determine the relationship between serum concentrations of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE) study. Methods: CYFRA 21-1 was identified by immunohistochemistry in samples of human lung obtained at surgery. Concentrations of CYFRA 21-1 were measured using an ELISA-based assay in serum samples collected at baseline, 1 month, and 3 months from 491 individuals with an incident diagnosis of IPF who were enrolled in the PROFILE study and from 100 control subjects at baseline. Study subjects were followed for a minimum of 3 years after their first blood draw. Measurements and Main Results: CYFRA 21-1 localizes to hyperplastic epithelium in IPF lung tissue. Peripheral CYFRA 21-1 concentrations were significantly higher in subjects with IPF than in healthy control subjects in both the discovery (n = 132) (control: 0.96 ± 0.81 ng/ml; vs. IPF: 2.34 ± 2.15 ng/ml; P < 0.0001) and validation (n = 359) (control: 2.21 ± 1.54 ng/ml; and IPF: 4.13 ± 2.77 ng/ml; P < 0.0001) cohorts. Baseline concentrations of CYFRA 21-1 were able to distinguish individuals at risk of 12-month disease progression (C-statistic, 0.70; 95% confidence interval, 0.61-0.79; P < 0.0001) and were predictive of overall mortality (hazard ratio, 1.12 [95% confidence interval, 1.06-1.19] per 1 ng/ml increase in CYFRA 21-1; P = 0.0001). Furthermore, 3-month change in concentrations of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts. Conclusions: CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.

Published
2022

16. Therapeutic Targeting of the Respiratory Microbiome.

Author

Chotirmall, SH, Bogaert, D, Chalmers, JD, Cox, MJ, Hansbro, PM, Huang, YJ, Molyneaux, PL, O'Dwyer, DN, Pragman, AA, Rogers, GB, Segal, LN, Dickson, RP, Chotirmall, SH, Bogaert, D, Chalmers, JD, Cox, MJ, Hansbro, PM, Huang, YJ, Molyneaux, PL, O'Dwyer, DN, Pragman, AA, Rogers, GB, Segal, LN, and Dickson, RP

Published
2022

17. Reducing lung function decline in patients with idiopathic pulmonary fibrosis: potential of nintedanib

Author

Woodcock HV, Molyneaux PL, and Maher TM

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Hannah V Woodcock,1,2 Philip L Molyneaux,1,3 Toby M Maher1–31Interstitial Lung Disease Unit, Royal Brompton Hospital, 2Centre for Respiratory Research, University College London, 3National Heart and Lung Institute, Imperial College London, London, UKAbstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with no clear etiology and a paucity of therapeutic options. Nintedanib (previously known as BIBF 1120) is a tyrosine kinase receptor antagonist which inhibits a number of key receptors, including those for platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF). These growth factors are profibrotic and each has been investigated as a potential standalone therapeutic target in IPF. Simultaneous inhibition of these receptors, with an analog of nintedanib, has proved to be effective in experimental animal models of pulmonary fibrosis. This observation, together with extensive safety and pharmacokinetic data from studies of nintedanib in malignancy, paved the way for the clinical development of this drug in IPF. The Phase IIb TOMORROW trial demonstrated that treatment with nintedanib may potentially slow decline in lung function, decrease the frequency of acute exacerbations, and improve quality of life in patients with IPF. While these observations are drawn from a single clinical trial, taken together with the preclinical data they suggest that nintedanib may yet become an important therapeutic option for individuals with IPF. The results of ongoing parallel, international, multicenter Phase III clinical trials are therefore eagerly awaited.Keywords: interstitial lung disease, BIBF 1120, clinical trials, usual interstitial pneumonia, acute exacerbation

Published
2013

18. Interstitial lung damage following COVID-19 hospitalisation: an interim analysis of the UKILD Post-COVID study

Author

Stewart, I, primary, Jacob, J, additional, George, PM, additional, Molyneaux, PL, additional, Porter, JC, additional, Allen, RJ, additional, Baillie, JK, additional, Barratt, SL, additional, Beirne, P, additional, Bianchi, SM, additional, Blaikley, JF, additional, Chalmers, J, additional, Chambers, RC, additional, Chadhuri, N, additional, Coleman, C, additional, Collier, G, additional, Denneny, EK, additional, Docherty, A, additional, Elneima, O, additional, Evans, RA, additional, Fabbri, L, additional, Gibbons, MA, additional, Gleeson, FV, additional, Gooptu, B, additional, Greening, NJ, additional, Guio, B Guillen, additional, Hall, IP, additional, Hanley, NA, additional, Harris, V, additional, Harrison, EM, additional, Heightman, M, additional, Hillman, TE, additional, Horsley, A, additional, Houchen-Wolloff, L, additional, Jarrold, I, additional, Johnson, SR, additional, Jones, MG, additional, Khan, F, additional, Lawson, R, additional, Leavy, OC, additional, Lone, N, additional, Marks, M, additional, McAuley, H, additional, Mehta, P, additional, Omer, E, additional, Parekh, D, additional, Hanley, K Piper, additional, Platé, M, additional, Pearl, J, additional, Poinasamy, K, additional, Quint, JK, additional, Raman, B, additional, Richardson, M, additional, Rivera-Ortega, P, additional, Saunders, LC, additional, Saunders, R, additional, Semple, MG, additional, Sereno, M, additional, Shikotra, A, additional, Simpson, AJ, additional, Singapuri, A, additional, Smith, DJF, additional, Spears, M, additional, Spencer, LG, additional, Stanel, S, additional, Thickett, D, additional, Thompson, AAR, additional, Thorpe, M, additional, Thwaites, R, additional, Walsh, SLF, additional, Walker, S, additional, Weatherley, ND, additional, Weeks, M, additional, Wild, JM, additional, Wootton, DG, additional, Brightling, CE, additional, Ho, LP, additional, Wain, LV, additional, and Jenkins, RG, additional

Published
2022
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19. Lung microbiology and exacerbations in COPD

Author

Beasley V, Joshi PV, Singanayagam A, Molyneaux PL, Johnston SL, and Mallia P

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Victoria Beasley,2 Priya V Joshi,2 Aran Singanayagam,1,2 Philip L Molyneaux,1,2 Sebastian L Johnston,1,2 Patrick Mallia,1,21National Heart and Lung Institute, Imperial College London, London, UK; 2Imperial College Healthcare NHS Trust, London, UKAbstract: Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory condition in adults and is characterized by progressive airflow limitation that is not fully reversible. The main etiological agents linked with COPD are cigarette smoking and biomass exposure but respiratory infection is believed to play a major role in the pathogenesis of both stable COPD and in acute exacerbations. Acute exacerbations are associated with more rapid decline in lung function and impaired quality of life and are the major causes of morbidity and mortality in COPD. Preventing exacerbations is a major therapeutic goal but currently available treatments for exacerbations are not very effective. Historically, bacteria were considered the main infective cause of exacerbations but with the development of new diagnostic techniques, respiratory viruses are also frequently detected in COPD exacerbations. This article aims to provide a state-of-the art review of current knowledge regarding the role of infection in COPD, highlight the areas of ongoing debate and controversy, and outline emerging technologies and therapies that will influence future diagnostic and therapeutic pathways in COPD.Keywords: COPD, exacerbations, bacteria, viruses

Published
2012

20. Pulmonary Rehabilitation in Idiopathic Pulmonary Fibrosis and COPD: A Propensity-Matched Real-World Study

Author

Nolan, CM, Polgar, O, Schofield, SJ, Patel, S, Barker, RE, Walsh, JA, Ingram, KA, George, PM, Molyneaux, PL, Maher, TM, Man, WD-C, National Institute for Health Research, British Lung Foundation, and Action for Pulmonary Fibrosis

Subjects
Respiratory System, COPD, Idiopathic pulmonary fibrosis, 1103 Clinical Sciences, prognosis, respiratory system, idiopathic pulmonary fibrosis, pulmonary rehabilitation, respiratory tract diseases
Abstract

Supplementary data available at: https://journal.chestnet.org/cms/10.1016/j.chest.2021.10.021/attachment/814ea172-99e4-4122-8fd1-15c25422db75/mmc1.pdf (21MB). Cpyright © 2021 The Author(s). Background: The adherence to and clinical efficacy of pulmonary rehabilitation in idiopathic pulmonary fibrosis (IPF), particularly in comparison with COPD, remains uncertain. The objectives of this real-world study were to compare the responses of patients with IPF with a matched group of patients with COPD undergoing the same supervised, outpatient pulmonary rehabilitation program and to determine whether pulmonary rehabilitation is associated with survival in IPF. Research Question: Do people with IPF improve to the same extent with pulmonary rehabilitation as a matched group of individuals with COPD, and are noncompletion of or nonresponse to pulmonary rehabilitation, or both, associated with 1-year all-cause mortality in IPF? Study Design and Methods: Using propensity score matching, 163 patients with IPF were matched 1:1 with a control group of 163 patients with COPD referred for pulmonary rehabilitation. We compared between-group pulmonary rehabilitation completion rates and response. Survival status in the IPF cohort was recorded over 1 year after pulmonary rehabilitation discharge. Cox proportional hazards regression explored the association between pulmonary rehabilitation status and all-cause mortality. Results: Similar pulmonary rehabilitation completion rates (IPF, 69%; COPD, 63%; P = .24) and improvements in exercise response were observed in both groups with no significant mean between-group differences in incremental shuttle walk test (ISWT) change (mean, 2 m [95% CI, –18 to 22 m]). Pulmonary rehabilitation noncompletion (hazard ratio [HR], 5.62 [95% CI, 2.24-14.08]) and nonresponse (HR, 3.91 [95% CI, 1.54-9.93]) were associated independently with increased 1-year all-cause mortality in IPF. Interpretation: This real-word study demonstrated that patients with IPF have similar completion rates and magnitude of response to pulmonary rehabilitation compared with a matched group of patients with COPD. In IPF, noncompletion of and nonresponse to pulmonary rehabilitation were associated with increased all-cause mortality. These data reinforce the benefits of pulmonary rehabilitation in patients with IPF. National Institute for Health Research Doctoral Research Fellowship [No. 2014-07-089 ] and a Medical Research Council New Investigator Research Grant [No. 98576 ]. T. M. M. is supported by a National Institute for Health Research Clinician Scientist Fellowship [Grant: CS-2013-13-017 ] and is a British Lung Foundation Chair in Respiratory Research [Grant: C17-3 ]. W. D.-C. M. is supported by the National Institute for Health Research and the British Lung Foundation .

Published
2021

22. P145 Marginal short term lung function changes predict mortality in patients with fibrotic hypersensitivity pneumonitis

Author

Macaluso, C, primary, Boccabella, C, additional, Kokosi, M, additional, Kouranos, V, additional, George, PM, additional, Margaritopoulos, G, additional, Molyneaux, PL, additional, Chua, F, additional, Maher, TM, additional, Jenkins, GR, additional, Desai, S, additional, Devaraj, A, additional, Wells, AU, additional, Renzoni, EA, additional, and Stock, CJW, additional

Published
2021
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24. S63 Genome-wide sex-by-SNP interaction analysis of susceptibility to idiopathic pulmonary fibrosis

Author

Leavy, OC, primary, Allen, RJ, additional, Oldham, JM, additional, Guillen-Guio, B, additional, Stockwell, A, additional, Braybrooke, R, additional, Hubbard, RB, additional, Ma, S, additional, Fingerlin, TE, additional, Kaminski, N, additional, Zhang, Y, additional, Schwartz, DA, additional, Yaspan, B, additional, Maher, TM, additional, Molyneaux, PL, additional, Flores, C, additional, Noth, I, additional, Jenkins, RG, additional, and Wain, LV, additional

Published
2021
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25. P4 Lung cancer screening provides a unique opportunity for early diagnosis and management of interstitial lung diseases

Author

Hewitt, RJ, primary, Bartlett, EC, additional, Ganatra, R, additional, Butt, H, additional, Morjaria, J, additional, Kouranos, V, additional, Chua, F, additional, Kokosi, M, additional, Molyneaux, PL, additional, Desai, SR, additional, Wells, AU, additional, Jenkins, RG, additional, Renzoni, EA, additional, Kemp, S, additional, Devaraj, A, additional, and George, PM, additional

Published
2021
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26. S65 Genome-wide association study of survival times after diagnosis of idiopathic pulmonary fibrosis

Author

Allen, RJ, primary, Oldham, JM, additional, Lorenzo-Salazar, JM, additional, Molyneaux, PL, additional, Ma, SF, additional, Stockwell, A, additional, Joseph, C, additional, Kim, JS, additional, Guillen-Guio, B, additional, Hernandez-Beeftink, T, additional, Kropski, J, additional, Huang, Y, additional, Lee, CT, additional, Adegunsoye, A, additional, Pugashetti, JV, additional, Linderholm, A, additional, Vo, V, additional, Strek, M, additional, Hubbard, R, additional, Hirani, N, additional, Whyte, MKB, additional, Hart, S, additional, Nicholson, A, additional, Parfrey, H, additional, Rassl, D, additional, Wallace, W, additional, Fahy, WA, additional, Valenzi, E, additional, Zhang, Y, additional, Kaminski, N, additional, Wolters, P, additional, Molina-Molina, M, additional, Martinez, FJ, additional, Hall, I, additional, Tobin, MD, additional, Maher, TM, additional, Blackwell, T, additional, Yaspan, B, additional, Jenkins, RG, additional, Flores, C, additional, Wain, LV, additional, and Noth, I, additional

Published
2021
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27. Reply: A role for steroids in COVID-19 associated pneumonitis at six-week follow-up?

Author

Myall, KJ, Molyneaux, PL, West, AG, and Action for Pulmonary Fibrosis

Subjects
Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Respiratory System, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, medicine, Humans, 030212 general & internal medicine, Major complication, Pneumonitis, business.industry, SARS-CoV-2, Interstitial lung disease, COVID-19, 1103 Clinical Sciences, Pneumonia, medicine.disease, Comorbidity, 030228 respiratory system, Cohort, Steroids, business, Follow-Up Studies
Abstract

Myall et al provide a response to the comment of Denneny et al on their paper regarding the role for steroids in COVID-19-associated pneumonitis at six-week follow-up. Given the risk factors for severe COVID-19 pneumonitis, they agree that steroid therapy is not without risk in this group. Individual patient discussion was key, and hence, five patients did not commence steroid treatment after review. It is therefore worth noting that the quoted proportions of patients with comorbidity refers to the whole cohort referred to the interstitial lung disease (ILD) service and not to the treatment group, who had lower rates of comorbidity. All patients had weekly telephone support and diabetes team input as appropriate. As a result, they saw no major complications of treatment.

Published
2021

28. Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Author

Dhindsa, RS, Mattsson, J, Nag, A, Wang, Q, Wain, LV, Allen, R, Wigmore, EM, Ibanez, K, Vitsios, D, Deevi, SVV, Wasilewski, S, Karlsson, M, Lassi, G, Olsson, H, Muthas, D, Monkley, S, Mackay, A, Murray, L, Young, S, Haefliger, C, FinnGen Consortium, Maher, TM, Belvisi, MG, Jenkins, G, Molyneaux, PL, Platt, A, Petrovski, S, Dhindsa, RS, Mattsson, J, Nag, A, Wang, Q, Wain, LV, Allen, R, Wigmore, EM, Ibanez, K, Vitsios, D, Deevi, SVV, Wasilewski, S, Karlsson, M, Lassi, G, Olsson, H, Muthas, D, Monkley, S, Mackay, A, Murray, L, Young, S, Haefliger, C, FinnGen Consortium, Maher, TM, Belvisi, MG, Jenkins, G, Molyneaux, PL, Platt, A, and Petrovski, S

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10-7, odds ratio = 2.87, 95% confidence interval: 2.03-4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10-20), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

Published
2021

29. Bronchoalveolar lavage is safe and well tolerated in individuals with idiopathic pulmonary fibrosis: an analysis of the PROFILE study

Author

Molyneaux, PL, Smith, JJ, Saunders, P, Chua, F, Wells, AU, Renzoni, EA, Nicholson, AG, Fahy, WA, Jenkins, RG, Maher, TM, and Action for Pulmonary Fibrosis

Subjects
Aged, 80 and over, Male, Treatment Outcome, Respiratory System, Humans, Female, Middle Aged, Bronchoalveolar Lavage, Idiopathic Pulmonary Fibrosis, 11 Medical and Health Sciences, Aged
Published
2020

30. Proportion of idiopathic pulmonary fibrosis risk explained by known genetic loci

Author

Leavy, OC, Ma, S-F, Molyneaux, PL, Maher, TM, Oldham, JM, Flores, C, Noth, I, Jenkins, RG, Dudbridge, F, Wain, LV, and Allen, RJ

Subjects
respiratory system, respiratory tract diseases
Abstract

Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.

Published
2020

31. Outcome of hospitalisation for COVID-19 in patients with interstitial lung disease: an international multicentre study

Author

Drake, TM, Docherty, AB, Harrison, EM, Quint, JK, Adamali, H, Agnew, S, Babu, S, Barber, CM, Barratt, S, Bendstrup, E, Bianchi, S, Villegas, DC, Chaudhuri, N, Chua, F, Coker, R, Chang, W, Crawshaw, A, Crowley, LE, Dosanjh, D, Fiddler, CA, Forrest, IA, George, P, Gibbons, MA, Groom, K, Haney, S, Hart, SP, Heiden, E, Henry, M, Ho, L-P, Hoyles, RK, Hutchinson, J, Hurley, K, Jones, M, Jones, S, Kokosi, M, Kreuter, M, MacKay, L, Mahendran, S, Margaritopoulos, G, Molina-Molina, M, Molyneaux, PL, O’Brien, A, O’Reilly, K, Packham, A, Parfrey, H, Poletti, V, Porter, J, Renzoni, E, Rivera-Ortega, P, Russell, A-M, Saini, G, Spencer, LG, Stella, GM, Stone, H, Sturney, S, Thickett, D, Thillai, M, Wallis, T, Ward, K, Wells, AU, West, A, Wickremasinghe, M, Woodhead, F, Hearson, G, Howard, L, Baillie, JK, Openshaw, PJM, Semple, MG, Stewart, I, ISARIC4C Investigators, and Jenkins, RG

Subjects
body regions, respiratory system, behavioral disciplines and activities, respiratory tract diseases
Abstract

Rationale: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. Objectives: To assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population. Methods: An international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of

Published
2020

32. consensus recommendations, and research priorities

Author

George, PM, Spagnolo, P, Kreuter, M, Altinisik, G, Bonifazi, M, Martinez, FJ, Molyneaux, PL, Renzoni, EA, Richeldi, L, Tomassetti, S, Valenzuela, C, Vancheri, C, Varone, F, Cottin, V, and Costabel, U

Abstract

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice. C1 [George, Peter M.; Molyneaux, Philip L.; Renzoni, Elisabetta A.] Royal Brompton & Harefield NHS Fdn Trust, Interstitial Lung Dis Unit, London, England. [George, Peter M.; Molyneaux, Philip L.; Renzoni, Elisabetta A.] Imperial Coll London, Natl Heart & Lung Inst, London, England. [Spagnolo, Paolo] Univ Padua, Dept Cardiac Thorac Vasc Sci & Publ Hlth, Padua, Italy. [Kreuter, Michael] Heidelberg Univ, Ctr Interstitial & Rare Lung Dis Pneumol, Thoraxklin, Heidelberg, Germany. [Kreuter, Michael] German Ctr Lung Res, Heidelberg, Germany. [Altinisik, Goksel] Pamukkale Univ, Fac Med, Dept Chest Dis, Denizli, Turkey. [Bonifazi, Martina] Univ Politecn Marche, Azienda Osped Univ Osped Riuniti, Resp Dis Unit, Dept Biomed Sci & Publ Hlth, Ancona, Italy. [Martinez, Fernando J.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Richeldi, Luca] Univ Cattolica Sacro Cuore, Fdn Policlin Univ A Gemelli IRCCS, Rome, Italy. [Tomassetti, Sara] Careggi Univ Hosp, Dept Expt & Clin Med, Florence, Italy. [Valenzuela, Claudia] Hosp Univ La Princesa, Inst Invest Princesa, Madrid, Spain. [Vancheri, Carlo] Univ Catania, Univ Hosp Policlin G Rodol, Reg Referral Ctr Rare Lung Dis, Dept Clin & Expt Med, Catania, Italy. [Varone, Francesco] Fdn Policlin A Gemelli IRCCS, Rome, Italy. [Cottin, Vincent] Hosp Civils Lyon, Louis Pradel Hosp, Natl Reference Coordinating Ctr Rare Pulm Dis, Dept Resp Med, Lyon, France. [Cottin, Vincent] Univ Lyon, Univ Claude Bernard Lyon 1, UMR754, IVPC, Lyon, France. [Costabel, Ulrich] Univ Duisburg Essen, Univ Hosp, Ruhrlandklin, Dept Pneumol, Essen, Germany.

Published
2020

33. Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities

Author

George, PM, Spagnolo, P, Kreuter, M, Altinisik, G, Bonifazi, M, Martinez, FJ, Molyneaux, PL, Renzoni, EA, Richeldi, L, Tomassetti, S, Valenzuela, C, Vancheri, C, Varone, F, Cottin, V, Costabel, U, Erice ILD working group, The Jon Moulton Charity Trust, and Action for Pulmonary Fibrosis

Subjects
Pulmonary and Respiratory Medicine, Lung Diseases, medicine.medical_specialty, Biomedical Research, Pulmonary Fibrosis, Erice ILD working group, Medizin, Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO, Multidisciplinary team, 1117 Public Health and Health Services, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Fibrosis, Pulmonary fibrosis, Medicine, Humans, 030212 general & internal medicine, Intensive care medicine, Lung, business.industry, Research, Interstitial lung disease, 1103 Clinical Sciences, respiratory system, medicine.disease, respiratory tract diseases, Clinical Practice, medicine.anatomical_structure, Disease Progression, Lung Diseases, Interstitial, 030228 respiratory system, Position paper, business, Interstitial, 1199 Other Medical and Health Sciences
Abstract

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice.

Published
2020

35. Utility of nuclear grading system in epithelioid malignant pleural mesothelioma in biopsy-heavy setting

Author

Zhang, YZ, Brambilla, C, Molyneaux, PL, Rice, A, Robertus, JL, Jordan, S, Lim, E, Lang-Lazdunski, L, Begum, S, Dusmet, M, Anikin, V, Beddow, E, Finch, J, Asadi, N, Popat, S, Cookson, WOC, Moffatt, MF, Nicholson, AG, and Action for Pulmonary Fibrosis

Subjects
OUTCOMES, Science & Technology, PROGNOSIS, CELL FEATURES REPORT, SURGERY, INTERNATIONAL-ASSOCIATION, nuclear grade, 1103 Clinical Sciences, GUIDELINES, DIAGNOSIS, CANCER, mesothelioma, Pathology, SURVIVAL, biopsy, Life Sciences & Biomedicine, PNEUMONECTOMY
Abstract

Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P

Published
2019

36. Right ventricle to left ventricle ratio at CTPA predicts mortality in interstitial lung disease

Author

Bax, S, Jacob, J, Ahmed, R, Bredy, C, Dimopoulos, K, Kempny, A, Kokosi, M, Kier, G, Renzoni, E, Molyneaux, PL, Chua, F, Kouranos, V, George, P, McCabe, C, Wilde, M, Devaraj, A, Wells, A, Wort, SJ, and Price, LC

Subjects
interstitial lung disease, pulmonary hypertension, Respiratory System, 1103 Clinical Sciences, right ventricle, CT scan pulmonary
Abstract

INTRODUCTION: Patients with interstitial lung disease (ILD) may develop pulmonary hypertension (PH), often disproportionate to ILD severity. Right ventricle to left ventricle diameter ratio (RV:LV) measured at CT pulmonary angiography (CTPA), has been shown to provide valuable information in pulmonary arterial hypertension patients and to predict death or deterioration in acute pulmonary embolism. METHODS: Demographics, ILD subtype, echocardiography and detailed CTPA measurements were collected in consecutive patients undergoing both CTPA and right heart catheterisation (RHC) at the Royal Brompton Hospital between 2005 and 2015. Fibrosis severity was formally scored using CT criteria. RV:LV ratio at CTPA was evaluated by three different methods. Cox-proportional hazard analysis was used to assess the relation of CTPA-derived parameters to predict death or lung transplantation. RESULTS: 92 patients were included: 64% male, mean age 65±11 years, with FVC 57±20% (predicted), TLCOc 22±8% (predicted) and KCOc 51±17% (predicted). PH was confirmed at RHC in 78%. Of all CTPA-derived measures, an RV:LV ratio ≥1.0 strongly predicted mortality or transplantation at univariate analysis (HR 3.26, 95%CI:1.49-7.13, p=0.003), whereas invasive haemodynamic data did not. The RV:LV ratio remained an independent predictor at multivariate analysis (HR: 3.19, CI:1.44-7.10, p=0.004), adjusting for an ILD diagnosis of IPF and CT derived ILD severity. CONCLUSION: An increased RV:LV ratio measured at CTPA provides a simple, non-invasive method of risk stratification in patients with suspected ILD-PH. This should prompt closer follow up, more aggressive treatment and consideration of lung transplantation.

Published
2019

38. Modelling Forced Vital Capacity in Idiopathic Pulmonary Fibrosis: Optimising Trial Design

Author

Santermans, E, Ford, P, Kreuter, M, Verbruggen, N, Meyvisch, P, Wuyts, WA, Brown, KK, Lederer, DJ, Byrne, AJ, Molyneaux, PL, Sivananthan, A, Moor, Karen, Maher, TM, Wijsenbeek - Lourens, Marlies, Santermans, E, Ford, P, Kreuter, M, Verbruggen, N, Meyvisch, P, Wuyts, WA, Brown, KK, Lederer, DJ, Byrne, AJ, Molyneaux, PL, Sivananthan, A, Moor, Karen, Maher, TM, and Wijsenbeek - Lourens, Marlies

Published
2019

40. T1 Meta-analysis of idiopathic pulmonary fibrosis genome-wide analyses identifies three novel genetic signals associated with disease susceptibility

Author

Allen, RJ, primary, Guillen-Guio, B, additional, Oldham, JM, additional, Ma, SF, additional, Dressen, A, additional, Paynton, ML, additional, Kraven, LM, additional, Obeidat, M, additional, Li, X, additional, Braybrooke, R, additional, Fingerlin, TE, additional, Hall, IP, additional, Sayers, I, additional, Tobin, MD, additional, Maher, TM, additional, Schwartz, DA, additional, Yaspan, BL, additional, Molyneaux, PL, additional, Flores, C, additional, Noth, I, additional, Jenkins, RG, additional, and Wain, LV, additional

Published
2019
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41. S69 Verification of genetic associations with scleroderma associated interstitial lung disease

Author

Stock, CJW, primary, DeLauretis, A, additional, Visca, D, additional, Daccord, C, additional, Kokosi, M, additional, Kouranos, V, additional, Margaritopoulos, G, additional, George, PM, additional, Molyneaux, PL, additional, Chua, F, additional, Maher, TM, additional, Abraham, DJ, additional, Denton, CP, additional, Ong, V, additional, Wells, AU, additional, and Renzoni, EA, additional

Published
2019
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44. S47 Impact of number of sampling sites and specimen dimension on the performance of nuclear grade and growth patterns in predicting survival in epithelioid malignant pleural mesothelioma: a single institution review of 614 cases

Author

Zhang, YZ, primary, Brambilla, C, additional, Molyneaux, PL, additional, Rice, A, additional, Robertus, JL, additional, Jordan, S, additional, Lim, E, additional, Lang-Lazdunski, L, additional, Begum, S, additional, Dusmet, M, additional, Anikin, V, additional, Beddow, E, additional, Finch, J, additional, Asadi, N, additional, Popat, S, additional, Cookson, WOC, additional, Moffatt, MF, additional, and Nicholson, AG, additional

Published
2019
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45. S86 Serum biomarkers in SSc-ILD: association with presence, severity and prognosis

Author

Stock, CJW, primary, Visca, D, additional, DeLauretis, A, additional, Daccord, C, additional, Kokosi, M, additional, Alfieri, V, additional, Kouranos, V, additional, Margaritopoulos, G, additional, George, PM, additional, Molyneaux, PL, additional, Chua, F, additional, Maher, TM, additional, Ong, V, additional, Abraham, DJ, additional, Denton, CP, additional, Wells, AU, additional, and Renzoni, EA, additional

Published
2019
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48. S143 Serum CYFRA 21–1 as a prognostic marker in scleroderma-associated interstitial lung disease

Author

Stock, CJW, primary, Hoyles, R, additional, D’accord, C, additional, Kokosi, M, additional, Alfieri, V, additional, Campochiaro, C, additional, Donovan, J, additional, Mori, L, additional, Maher, TM, additional, Kouranos, V, additional, Margaritopoulos, G, additional, George, PM, additional, Molyneaux, PL, additional, Chua, F, additional, Abraham, DJ, additional, Ong, V, additional, Denton, CP, additional, Wells, AU, additional, and Renzoni, EA, additional

Published
2018
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50. Role of airway glucose in bacterial infections in chronic obstructive pulmonary disease

Author

Tregoning, JS, Mallia, P, Webber, J, Gill, SK, Trujillo-Torralbo, Calderazzo, MA, Finney, L, Bakhsoliani, E, Farne, H, Singanayagam, A, Footitt, J, Hewitt, R, Kebadze, Aniscenko, J, Padmanaban, V, Molyneaux, PL, Adcock, Barnes, PJ, Ito, K, Elkin, SL, Kon, OM, Cookson, WO, MOffatt, MF, Johnston, SL, Imperial Health Charity, Wellcome Trust, Imperial College Healthcare NHS Trust, British Medical Association, Medical Research Council (MRC), National Institute for Health Research, Asthma UK, and Dunhill Medical Trust

Subjects
Male, Allergy, INCREASES, METFORMIN, Immunology, PATHOGENESIS, Respiratory System, RHINOVIRUS INFECTION, airway inflammation, Pulmonary Disease, Chronic Obstructive, HYPERGLYCEMIA, COPD, FIBROSIS, Humans, Pseudomonas Infections, glucose, Respiratory Tract Infections, Aged, Science & Technology, Picornaviridae Infections, Chronic obstructive pulmonary disease, Smoking, bacterial infection, Sputum, BLOOD-GLUCOSE, Middle Aged, Viral Load, Nasal Lavage Fluid, TRANSPORT, Bacterial Load, respiratory tract diseases, EXACERBATIONS, 1107 Immunology, Female, viral infection, Life Sciences & Biomedicine, Bronchoalveolar Lavage Fluid
Abstract

Background Patients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear. Objectives The aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection. Methods We measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined. Results Sputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro. Conclusions Airway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prevention or treatment of bacterial infection in patients with COPD.

Published
2017

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