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1. The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: A genotypic analysis

Author

Timothy M Walker, Paolo Miotto, Claudio U Köser, Philip W Fowler, Jeff Knaggs, Zamin Iqbal, Martin Hunt, Leonid Chindelevitch, Maha R Farhat, Daniela Maria Cirillo, Iñaki Comas, James Posey, Shaheed V Omar, Timothy EA Peto, Anita Suresh, Swapna Uplekar, Sacha Laurent, Rebecca E Colman, Carl-Michael Nathanson, Matteo Zignol, Ann Sarah Walker, Derrick W Crook, Nazir Ismail, Timothy C Rodwell, A Sarah Walker, Adrie J C Steyn, Ajit Lalvani, Alain Baulard, Alan Christoffels, Alberto Mendoza-Ticona, Alberto Trovato, Alena Skrahina, Alexander S Lachapelle, Alice Brankin, Amy Piatek, Ana Gibertoni Cruz, Anastasia Koch, Andrea Maurizio Cabibbe, Andrea Spitaleri, Angela P Brandao, Angkana Chaiprasert, Anna Barbova, Annelies Van Rie, Arash Ghodousi, Arnold Bainomugisa, Ayan Mandal, Aysha Roohi, Babak Javid, Baoli Zhu, Brice Letcher, Camilla Rodrigues, Camus Nimmo, Carl-Michael NATHANSON, Carla Duncan, Christopher Coulter, Christian Utpatel, Chunfa Liu, Clara Grazian, Clare Kong, Daniel J Wilson, Daniela Matias, Danielle Jorgensen, Danila Zimenkov, Darren Chetty, David AJ Moore, David A Clifton, Dick van Soolingen, Dongxin Liu, Donna Kohlerschmidt, Draurio Barreira, Dumisani Ngcamu, Elias David Santos Lazaro, Ellis Kelly, Emanuele Borroni, Emma Roycroft, Emmanuel Andre, Erik C Böttger, Esther Robinson, Fabrizio Menardo, Flavia F Mendes, Frances B Jamieson, Francesc Coll, George Fu Gao, George W Kasule, Gian Maria Rossolini, Gillian Rodger, E Grace Smith, Graeme Meintjes, Guy Thwaites, Harald Hoffmann, Heidi Albert, Helen Cox, Ian F Laurenson, Irena Arandjelovic, Ivan Barilar, Jaime Robledo, James Millard, James Johnston, Jamie Posey, Jason R Andrews, Jennifer Gardy, Jennifer Guthrie, Jill Taylor, Jim Werngren, John Metcalfe, Jorge Coronel, Joseph Shea, Joshua Carter, Juliana MW Pinhata, Julianne V Kus, Katharina Todt, Kathryn Holt, Kayzad S Nilgiriwala, Kelen T Ghisi, Kerri M Malone, Kiatichai Faksri, Kimberlee A Musser, Lavania Joseph, Leen Rigouts, Lisa Jarrett, Louis Grandjean, Lucilaine Ferrazoli, Mabel Rodrigues, Maha Farhat, Marco Schito, Margaret M Fitzgibbon, Marguerite Massinga Loembé, Maria Wijkander, Marie Ballif, Marie-Sylvianne Rabodoarivelo, Marina Mihalic, Mark WILCOX, Matteo ZIGNOL, Matthias Merker, Matthias Egger, Max O'Donnell, Maxine Caws, Mei-Hua Wu, Michael G Whitfield, Michael Inouye, Mikael Mansjö, Minh Ha Dang Thi, Moses Joloba, SM Mostofa Kamal, Nana Okozi, Nazir ISMAIL, Nerges Mistry, Nhung N Hoang, Niaina Rakotosamimanana, Nicholas I Paton, Paola M V Rancoita, Pascal Lapierre, Patricia J Hall, Patrick Tang, Pauline Claxton, Penelope Wintringer, Peter M Keller, Phan Vuong Khac Thai, Philip Supply, Prapaporn Srilohasin, Prapat Suriyaphol, Priti Rathod, Priti Kambli, Ramona Groenheit, Rick Twee-Hee Ong, Robin M Warren, Robert J Wilkinson, Roland Diel, Rosangela S Oliveira, Rukhsar Khot, Ruwen Jou, Sabira Tahseen, Saheer Gharbia, Samaneh Kouchaki, Sanchi Shah, Sara Plesnik, Sarah G Earle, Sarah Dunstan, Sarah J Hoosdally, Satoshi Mitarai, Sebastien Gagneux, Shen-Yuan Yao, Simon Grandjean Lapierre, Simone Battaglia, Stefan Niemann, Sushil Pandey, Tanya A Halse, Ted Cohen, Teresa Cortes, Therdsak Prammananan, Thomas A Kohl, Nguyen T T Thuong, Tik Ying Teo, Timothy E A Peto, Timothy William, Thomas R Rogers, Utkarsha Surve, Vanessa Mathys, Victoria Furió, Victoria Cook, Srinivasan Vijay, Vincent Escuyer, Viola Dreyer, Vitali Sintchenko, Vonthanak Saphonn, Walter Solano, Wan-Hsuan Lin, Wayne van Gemert, Wencong He, Yang Yang, Yanlin Zhao, Youwen Qin, Yu-Xin Xiao, Zahra Hasan, Zully M Puyen, Iqbal, Zamin [0000-0001-8466-7547], Apollo - University of Cambridge Repository, Bill & Melinda Gates Foundation, Medical Research Council (UK), Wellcome Trust, Unitaid, Comas, Iñaki, National Institute for Health Research, University of Zurich, Walker, Timothy M, Rodwell, Timothy C, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and Comas, Iñaki [0000-0001-5504-9408]

Subjects
Microbiology (medical), Model organisms, [SDV]Life Sciences [q-bio], Immunology, Antitubercular Agents, Drug Resistance, Infectious Disease, 610 Medicine & health, Microbial Sensitivity Tests, World Health Organization, Microbiology, 2726 Microbiology (medical), Virology, Seq&Treat Consortium, Human Biology & Physiology, Science & Technology, 10179 Institute of Medical Microbiology, CRyPTIC Consortium, FOS: Clinical medicine, 2404 Microbiology, 2725 Infectious Diseases, Mycobacterium tuberculosis, Infectious Diseases, Mutation, 2406 Virology, 570 Life sciences, biology, Life Sciences & Biomedicine, Ethambutol
Abstract

9 páginas, 4 figuras, 1 tabla., Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes. Funding: UNITAID, Wellcome, MRC, BMGF., Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation

Published
2022

2. The 2021 WHO Catalogue of Mycobacterium Tuberculosis Complex Mutations Associated with Drug Resistance: A New Global Standard for Molecular Diagnostics

Author

Timothy M. Walker, Paolo Miotto, Claudio U. Köser, Philip William Fowler, Jeff Knaggs, Zamin Iqbal, Martin Hunt, Leonid Chindelevitch, Maha Farhat, daniela Cirillo, Iñaki Comas, James E. Posey, Shaheed Vally Omar, Timothy E. A. Peto, Anita Suresh, Swapna Uplekar, Sacha Laurent, Rebecca Colman, Carl-Michael Nathanson, Matteo Zignol, Ann Sarah Walker, The CRyPTIC Consortium, The Seq&Treat Consortium, Derrick W. Crook, Nazir Ismail, and Timothy C. Rodwell

Subjects
History, medicine.medical_specialty, Tuberculosis, Polymers and Plastics, business.industry, Becton dickinson, medicine.disease, Precision medicine, Institutional review board, Industrial and Manufacturing Engineering, Patent application, chemistry.chemical_compound, chemistry, Family medicine, medicine, Business and International Management, Delamanid, Bedaquiline, business, Ethambutol, medicine.drug
Abstract

Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosis . There is currently no WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 M. tuberculosis isolates with paired whole-genome sequencing and phenotypic drug susceptibility data were amassed from 41 countries. Mutations were graded according to their odds ratio and associated false discovery rate corrected p-value, and their positive predictive value for phenotypic resistance. A series of expert rules were applied for final confidence grading of each mutation. Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations’ pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: This first WHO endorsed catalogue of molecular targets for M. tuberculosis drug susceptibility testing provides a global standard for resistance interpretation. It will be expanded as data emerge on phenotypically resistant isolates, including for new and repurposed drugs. Funding: UNITAID, Wellcome, MRC, BMGF. Declaration of Interest: C.U.K. is a consultant Becton Dickinson, the Foundation for Innovative New Diagnostics and the TB Alliance. C.U.K. is collaborating with PZA Innovation and Thermo Fisher Scientific. C.U.K. worked as a consultant for QuantuMDx, the Stop TB Partnership, the World Health Organization (WHO) Global TB Programme and the WHO Regional Office for Europe. C.U.K. gave a paid educational talk for Oxford Immunotec. Hain Lifescience covered C.U.K.’s and accommodation to present at a meeting. C.U.K. is an unpaid advisor to BioVersys and GenoScreen. E.R. is employed by Public Health England and holds an honorary contract with Imperial College London. I.F.L. is Director of the Scottish Mycobacteria Reference Laboratory. S.N. receives funding from German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG)tion EXC 2167. P.S. is a consultant at Genoscreen. T.R. is funded by NIH and DoD and receives salary support from the non-profit organization FIND. T.R. is a cofounder, board member and shareholder of Verus Diagnostics Inc, a company that was founded with the intent of developing diagnostic assays. Verus Diagnostics was not involved in any way with data collection, analysis or publication of the results. T.R. has not received any financial support from Verus Diagnostics. UCSD Conflict of Interest office has reviewed and approved T.R.’s role in Verus Diagnostics Inc. T.R. is a co-inventor of a provisional patent for a TB diagnostic assay (provisional patent #: 63/048.989). T.R. is a co-inventor on a patent associated with the processing of TB sequencing data (European Patent Application No. 14840432.0 & USSN 14/912,918). T.R. has agreed to “donate all present and future interest in and rights to royalties from this patent” to UCSD to ensure that he does not receive any financial benefits from this patent. S.S. is working and holding ESOPs at HaystackAnalytics Pvt. Ltd. (Product: Using whole genome sequencing for drug susceptibility testing for Mycobacterium tuberculosis). G.F.G. is listed as an inventor on patent applications for RBDdimer- based CoV vaccines. No other authors declare a conflict of interest. Ethical Approval: Approval for CRyPTIC study was obtained by Taiwan Centers for Disease Control IRB No. 106209, University of KwaZulu Natal Biomedical Research Ethics Committee (UKZN BREC) (reference BE022/13) and University of Liverpool Central University Research Ethics Committees (reference 2286), Institutional Research Ethics Committee (IREC) of The Foundation for Medical Research, Mumbai (Ref nos. FMR/IEC/TB/01a/2015 and FMR/IEC/TB/01b/2015), Institutional Review Board of P.D. Hinduja Hospital and Medical Research Centre, Mumbai (Ref no. 915-15-CR [MRC]), scientific committee of the Adolfo Lutz Institute (CTC-IAL 47-J / 2017) and in the Ethics Committee (CAAE: 81452517.1.0000.0059) and Ethics Committee review by Universidad Peruana Cayetano Heredia (Lima, Peru) and LSHTM (London, UK).

Published
2021

4. Community prevalence of SARS-CoV-2 in England from April to November, 2020: results from the ONS Coronavirus Infection Survey

Author

Koen B Pouwels, Thomas House, Emma Pritchard, Julie V Robotham, Paul J Birrell, Andrew Gelman, Karina-Doris Vihta, Nikola Bowers, Ian Boreham, Heledd Thomas, James Lewis, Iain Bell, John I Bell, John N Newton, Jeremy Farrar, Ian Diamond, Pete Benton, Ann Sarah Walker, Koen B. Pouwels, A. Sarah Walker, Derrick Crook, Philippa C. Matthews, Tim Peto, Nicole Stoesser, Alison Howarth, George Doherty, James Kavanagh, Kevin K. Chau, Stephanie B. Hatch, Daniel Ebner, Lucas Martins Ferreira, Thomas Christott, Brian D. Marsden, Wanwisa Dejnirattisai, Juthathip Mongkolsapaya, Sarah Hoosdally, Richard Cornall, David I. Stuart, Gavin Screaton, David Eyre, John Bell, Stuart Cox, Kevin Paddon, Tim James, John N. Newton, Julie V. Robotham, Paul Birrell, Helena Jordan, Tim Sheppard, Graham Athey, Dan Moody, Leigh Curry, Pamela Brereton, Jodie Hay, Harper Vansteenhouse, Alex Lambert, Emma Rourke, Stacey Hawkes, Sarah Henry, James Scruton, Peter Stokes, Tina Thomas, John Allen, Russell Black, Heather Bovill, David Braunholtz, Dominic Brown, Sarah Collyer, Megan Crees, Colin Daglish, Byron Davies, Hannah Donnarumma, Julia Douglas-Mann, Antonio Felton, Hannah Finselbach, Eleanor Fordham, Alberta Ipser, Joe Jenkins, Joel Jones, Katherine Kent, Geeta Kerai, Lina Lloyd, Victoria Masding, Ellie Osborn, Alpi Patel, Elizabeth Pereira, Tristan Pett, Melissa Randall, Donna Reeve, Palvi Shah, Ruth Snook, Ruth Studley, Esther Sutherland, Eliza Swinn, Anna Tudor, Joshua Weston, Shayla Leib, James Tierney, Gabor Farkas, Raf Cobb, Folkert Van Galen, Lewis Compton, James Irving, John Clarke, Rachel Mullis, Lorraine Ireland, Diana Airimitoaie, Charlotte Nash, Danielle Cox, Sarah Fisher, Zoe Moore, James McLean, and Matt Kerby

Subjects
Adult, Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Adolescent, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Population, 01 natural sciences, 03 medical and health sciences, Young Adult, 0302 clinical medicine, COVID-19 Testing, Residence Characteristics, Epidemiology, Pandemic, Credible interval, Prevalence, Medicine, Humans, Public Health Surveillance, 030212 general & internal medicine, Positive test, 0101 mathematics, Young adult, education, Child, Aged, education.field_of_study, business.industry, 010102 general mathematics, Public Health, Environmental and Occupational Health, COVID-19, Articles, Middle Aged, Health Surveys, England, Child, Preschool, Female, business, Demography
Abstract

Summary Background Decisions about the continued need for control measures to contain the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rely on accurate and up-to-date information about the number of people testing positive for SARS-CoV-2 and risk factors for testing positive. Existing surveillance systems are generally not based on population samples and are not longitudinal in design. Methods Samples were collected from individuals aged 2 years and older living in private households in England that were randomly selected from address lists and previous Office for National Statistics surveys in repeated cross-sectional household surveys with additional serial sampling and longitudinal follow-up. Participants completed a questionnaire and did nose and throat self-swabs. The percentage of individuals testing positive for SARS-CoV-2 RNA was estimated over time by use of dynamic multilevel regression and poststratification, to account for potential residual non-representativeness. Potential changes in risk factors for testing positive over time were also assessed. The study is registered with the ISRCTN Registry, ISRCTN21086382. Findings Between April 26 and Nov 1, 2020, results were available from 1 191 170 samples from 280 327 individuals; 5231 samples were positive overall, from 3923 individuals. The percentage of people testing positive for SARS-CoV-2 changed substantially over time, with an initial decrease between April 26 and June 28, 2020, from 0·40% (95% credible interval 0·29–0·54) to 0·06% (0·04–0·07), followed by low levels during July and August, 2020, before substantial increases at the end of August, 2020, with percentages testing positive above 1% from the end of October, 2020. Having a patient-facing role and working outside your home were important risk factors for testing positive for SARS-CoV-2 at the end of the first wave (April 26 to June 28, 2020), but not in the second wave (from the end of August to Nov 1, 2020). Age (young adults, particularly those aged 17–24 years) was an important initial driver of increased positivity rates in the second wave. For example, the estimated percentage of individuals testing positive was more than six times higher in those aged 17–24 years than in those aged 70 years or older at the end of September, 2020. A substantial proportion of infections were in individuals not reporting symptoms around their positive test (45–68%, dependent on calendar time. Interpretation Important risk factors for testing positive for SARS-CoV-2 varied substantially between the part of the first wave that was captured by the study (April to June, 2020) and the first part of the second wave of increased positivity rates (end of August to Nov 1, 2020), and a substantial proportion of infections were in individuals not reporting symptoms, indicating that continued monitoring for SARS-CoV-2 in the community will be important for managing the COVID-19 pandemic moving forwards. Funding Department of Health and Social Care.

Published
2021
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5. COVID-19: Rapid antigen detection for SARS-CoV-2 by lateral flow assay: A national systematic evaluation of sensitivity and specificity for mass-testing

Author

Siobhan Campbell, Susan Hopkins, Richard Sedgewick, Kelly Hollier, Wendy Byrne, Ashley Pegg, Scott Nicol, Kimerbley Webster, Suzannah Pegler, Lottie Rawden, Gillian Rodger, Beverley Buck, Richard Clarke, Tom G. Ritter, Sally Hammond, Derrick W. Crook, Sulaksan Panchalingam, Deborah Wright, Victoria Hardy, Kathryn J Saunders, Matthew Catton, Sarah Mckee, Mark Pinkerton, Gloria Calderon, Joanne Waldron, Andrew Harris, Rishab Balaji, Dominic Affron, Penny Carter, Bea Choi, Ian Wickens, Chris D. Turnbull, Elena Hazell, Silvia D'Arcangelo, Tillie Graham, Alex Sienkiewicz, Louise Oliver, Arabella Legard, Freddie Mellor, Rima Colston, Geeta Ghadiali, Ella Baldwin, Stephen W. Wilson, Tim Brooks, Kate Webberley, T Peto, Pam Devall, Jenny Wang, Daniel P. Carter, Elena Turek, Shaolin Chidavaenzi, Gemma Nanson, Kate Allen, James Connolly, Mary-Anne Darby, Caroline Coulson, May Havinden-Williams, Emma Marshall, Mark Driver, Pauline Brown, Beinn Khulusi, Iman Aurfan, Codie Fahey, Zoe Lampshire, Emily A. Protheroe, Antoinette McNulty, Alison Vaughan, T Lockett, Sally-Anne Hurford, Juan Dobaldo Pavon, Rangeni Zinyama, John I. Bell, Toi Neibler, Heena Mistry, Helen Permain, Lorraine Archer, Neil McLeod, Amelia Sterry, Susan Johnston, Alexander Grassam-Rowe, Ruth Johns, Sian Tiley, Olivia Carr, Carly Tibbins, Arro Peace, Christopher H. Logue, Narindar Ghuman, Ellena Badenoch, Carla Bratten, Ashley Price, Patrick Robinson, Sophie Barraclough, Bertie Rowell, Marie Corcoran, Mollie French, Daniel Myers, Emily Eaton, Sophie Moore, Anna Sherkat, Julie Miller, Susan Ridge, Hellen Purnell, Tanzina Chaudary, Juliet Jones, Laura Seeney, Jim Chadwick, Julie Timmins, Sarah Hoosdally, Des Markham, John Vertannes, Sami Tatar, Richard Vipond, Lennard Y. W. Lee, Sara Read, Anita Agasu, Rosaline de Koning, Tegan Gumsley-Read, Ben Holloway, Thomas Knight, Cathy Rowe, Beth Hanney, Herika Willis, Shelha Siddiqui, Aleksander Stawiarski, Kevin K Chau, Ellie Watson, Simon Clark, Babak Afrough, Cara Tomas-Smith, Margaret Broughton-Smith, James O. Robinson, Joy Edwards, Ranoromanana Evans, Thomas Starkey, Anna Gronert, Graham Ellis, Lavanya Sinha, Jane Willcocks, Miriam Avery, Collette Allen, Natasha Ashbridge, Jane Mitchell, Natalie Draper, Anuradha Krishna, Kate Trigg-Hogarth, Bindhu Xavier, Joe Stevens, Leon Peto, Anila Sukumaran, Joseph Gernon, Emma Stanton, Alice Field, Rachel Evans, Vindhya Maripuri, Iftikhar Khan, Justin Liu, Jewel Jones Nwanaforo, Samatha Chilcott, Eloïse Cook, Sharon Kempson, Tom Foord, Lucy Hughes, Vanessa Lucas, Ben Corley, Chris Bridgeman, Grace Westland, David W Eyre, Sally Gordon, Peter Hammond, Kayleigh Collins, Priya Bagga, Gurvinder Gill, Claire Hall, Philippa C Matthews, Dominic Britton, Pauline Derbyshire, Jasmine Gan, Steve Hurdowar, Lloyd Shail, Harry Nuttall, Sheila F Lumley, Becky Evans, Mika Erik Moeser, Dimitris Papoulidis, Lucy Sheppard, Zarina Mirza, Rachel Michel, David Chapman, Kate Ellis, Bassam Hallis, Hannah Fuchs, Jodie Owen, Dawn Clarke, Joanne Henry, Sue Elwell, Rosie Boulton, Vanessa Fenech, Laura Costello, Alison Allanson, Mike Newbury, Prem Perumal, Mary Walters, Angela Bloss, Kate Gilmour, Charles Reynard, Mark A. Ainsworth, Jennifer Smith, Philip Walker, Tim E. A. Peto, Amanda Selassie, Lisa Zeidan, Jane Shallcross, Oliver Topping, Linda Wagstaff, Liam J Peck, Ella Smith, Karen Pearson, Thanh Pham, John Davis, Elizabeth Truelove, Kerry Gibbons, David Tyrrell, David Green, Wendy Osbourne, Anika Goel, Harriet Jackson, Michelle Platton, Daniel Lasserson, Barbara Wilson, Susan Bird, Mark Dolman, Tracy Benford, Joanne Jackman, Marion Evans, Nicole Stoesser, Jackie Sears, Alex Mighiu, Elaine Butcher, Ashley Otter, Akhila Muthuswamy, Tom Fowler, Janet Field, Angela Sweed, Katie Keating-Fedders, Megan Cathrall, Richard Body, Abbie Bown, Gabriella Harker, Richard Clayton, Kim Hicklin, Ant Crook, Sarah Sampson, Sarah Dyas, Cristina Leggio, Hannah Claasen, Rachel Sayers, Louise Woodhead, Carol Beane, Fiona Yelnoorkar, Jake Osbourne, Marina Bishop, Tinashe Kanyowa, Hema Thomas, Ruth Elderfield, H Pickford, Alexandra Rowlands, Patrick Lahert, Kirsten Lee, Ann Sarah Walker, Mark Stockbridge, and Deborah F. McKee

Subjects
VIral antigen detection, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), LFD, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Testing, Population, National evaluation, 01 natural sciences, 03 medical and health sciences, 0302 clinical medicine, Antigen, Lateralflow devices, Lateral flow tests, Medicine, Sampling (medicine), 030212 general & internal medicine, 0101 mathematics, education, Lateral flow, Public health, education.field_of_study, SARS-CoV-2, business.industry, 010102 general mathematics, COVID-19, General Medicine, Coronavirus, United kingdom, Cohort, Emergency medicine, False positive rate, business, Research Paper
Abstract

Background Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Methods LFDs were initially reviewed by a Department of Health and Social Care team, part of the UK government, from which 64 were selected for further evaluation from 1st August to 15th December 2020. Standardised laboratory evaluations, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots were performed (UK COVID-19 testing centres, hospital, schools, armed forces). Findings 4/64 LFDs so far have desirable performance characteristics (orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1–6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20–0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists was 78.8% (156/198, 95% CI 72.4–84.3). Interpretation Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission. Funding Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research.

Published
2021

6. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Author

Guy E Thwaites, Matthew Scarborough, Alexander Szubert, Emmanuel Nsutebu, Robert Tilley, Julia Greig, Sarah A Wyllie, Peter Wilson, Cressida Auckland, Janet Cairns, Denise Ward, Pankaj Lal, Achyut Guleri, Neil Jenkins, Julian Sutton, Martin Wiselka, Gonzalez-Ruiz Armando, Clive Graham, Paul R Chadwick, Gavin Barlow, N Claire Gordon, Bernadette Young, Sarah Meisner, Paul McWhinney, David A Price, David Harvey, Deepa Nayar, Dakshika Jeyaratnam, Tim Planche, Jane Minton, Fleur Hudson, Susan Hopkins, John Williams, M Estee Török, Martin J Llewelyn, Jonathan D Edgeworth, A Sarah Walker, Musa Kamfose, Ana de Veciana, Nicola Claire Gordon, Leon Peto, Gemma Pill, Tiphanie Clarke, Laura Watson, Dai Griffiths, Ali Vaughn, Luke Anson, Elian Liu, Sanuki Perera, Lydia Rylance-Knight, Carmen Cantell, Ruth Moroney, Guy Thwaites, Karen Bisnauthsing, Antonio Querol-Rubiera, Charlotte Gibbs, Amita Patel, Carolyn Hemsley, Anna L Goodman, Duncan Wyncoll, Jason Biswas, Jennifer Fitzpatrick, Lizzie Roberts, James Millard, Neil Stone, Angela Cape, Lisa Hurley, Chi Kai Tam, Marie-Claire Hoyle, Kate Maitland, Leona Trainor, Helen Reynolds, Jennifer Harrison, Jim Anson, Joseph Lewis, Jonathan Folb, Lynsey Goodwin, Nicholas Beeching, Sarah Dyas, Helen Winslow, Elizabeth Foote, Paul Roberts, Pavithra Natarajan, Alex Chrdle, Manuel Fenech, Hannah Allsop, Rachel Austin-Hutchison, Louise Barrett, Karen Brookes, Leanne Carwithen, Andrew Conbeer, Richard Cunningham, Charlotte Eglinton, Rosie Fok, Hannah Gott, Shona Hughes, Lewis Jones, Maggie Kalita, Angela King, Linda March, Mike Marner, Tracey Mynes, Aiden Plant, Suzanne Price, Judy Sercombe, Alison Stolton, Mark Wallis, Marie-Claire West, Jackie Westcott, Claire Williams, Rob Wosley, Leona Yabsley, Laura Butland, Julie Sorrell, Tamara Mitchell, Abiola Alli, James Meiring, Boingotlo Masake, Carlene Rowson, Lynne Smart, Laura Makey, Sarah Moll, Jane Cunningham, Kim Ryalls, Kathryn Birchall, Janet Middle, Yvonne Jackson, Diane Swift, Joby Cole, Bala Subramanian, Faith Okhuoya, Maria Edwards, Cheryl Bailey, Rebecca Warren, Gayti Islam, Michael Ankcorn, Sarah Birchall, Paul Jones, John Humphries, Stephen Booth, Cariad Evan, Sarah Wyllie, Andrew Flatt, Lenka Strakova, Maria Hayes, Stacey Valentine, Clare James, Mary Wands, Nicolas Cortes, Nisa Khan, Robert Porter, Zoe Martin, Keith Yip, Helen Preedy, Helen Chesterfield, Tracey Dobson, Colin Walker, Martin Llewelyn, Angela Dunne, Laura Latter, Alison Porges, James Price, John Paul, Laura Behar, Louise Robinson, Amy Murray, Tenessa Sargent, Carrie Ridley, Laura Ortiz-Ruiz de Gordoa, Deborah Gilliam, Carole McPherson, Simon Matthews, Emma Foreman, Rajesh Jarghese, Alisha Beddoe, Sebastien Martin, Sephora Shaw, Dominika Wlazly, Maggie Cole, Abraham Gihawi, Kevin Cole, M Estée Török, Theodore Gouliouris, Luke Bedford, Rebecca B Saunderson, Ilias Mariolis, Rachel Bousfield, Isobel Ramsay, Daniel Greaves, Sani Aliyu, Kim Cox, Lois Mlemba, Lynne Whitehead, Naval Vyse, Mark Bolton, Pauline Lambert, David Chadwick, Kirsty Baillie, Martyn Cain, Richard Bellamy, Jason Wong, Jane Thompson, Helen Vassallo, Agnieszka Skotnicka, Andrea Boyce, Anthony Donnelly, Graham FitzGerald, Victoria Dean, Kristian Warnes, Anna Reyes, Saadia Rahman, Lillian Tsang, Joanne Williams, Stephen Morris-Jones, Elen Witness, Orla Brady, Elizabeth Woodford, Teresa Pettifer, Angela McCadden, Ben Marks, Sophie Collier, Damien Mack, Simon Warren, Colin Brown, Adrian Lyons, Sara Taiyari, Stephen Mepham, Anna Sweeney, Li-An Brown, Alison Potter, Jess Mandiza, Maxine Hough, Sue Williams, Caroline Renton, Fiona Walters, Maria Nadolski, Andree Evans, Polly Tarrant, Katherine Curley, Sophie Whiteley, Julia Halpin, Melanie Hutchings, Shirley Todd, Christop Lohan, Tamika Chapter, Emma Folland, Alaric Colville, Katy Marden, Marina Morgan, Rob Porter, Mel Baxter, Sarah Rippon, Muge Cevik, Judith Chapman, Tim Kemp, Rachel Vincent, Dave Osborne, Tracey Platt, James Calderwood, Bernadette Cook, Caroline Bedford, Leanne Galloway-Browne, Nadine Abberley, Kelly Attack, Joanna Allen, Melanie Harrison, Sarah Stevenson, Carol Brooks, Paula Harlow, Jordan Ewing, Shirley Cooper, Roderick Balancio-Tolentino, Laura O'Neil, Rebecca Tagney, Daniela Shackcloth, James Fellows, Ruth Millett, Jo Studham, Cherrelle de Souza, Geoffrey Howell, Hezron Greaves, Ella Foncel, Rahul Kurup, Jack Briggs, Melody Smith, Cristina Suarez, Giordana Sorrentino, Antonia Scobie, Angela Houston, Fozia Ahmad, Aodhan Breathnach, Rakhee Chahuan, Katie Wilkins, Natalia Waddington, Rashmi Sharma, Peter Flegg, Veenu Kollipara, Mazhar Alam, Andrew Potter, Stacey Donaldson, Charlote Armer, Julie Frudd, Manju Joy, Asha Mathews, Stephen K Glass, Ayodele Ajayi, Amanda Fife, Saba Qaiser, Sharon Sheehan, Sergio Muñoz-Villaverde, Noah Yogo, Ines De Abreu, Gaynor Notcheva, Joanna Flanagan, Cordelia Watson, Efisia Sais, Adetunji Adedayo, Vicky Chu, Georgina Shaw, Michelle A Graver, Rebecca Palmer, Donna Palmer, Senait Haile, Joanne Gordon, Kirandip Mandar, Weronika Szypura, Josephine Marange, Vusumuzi Shabangu, Katy Moore, Jill Lyons, Melinda Munang, Mirriam Sangombe, Ed Moran, Abid Hussain, Adam Lewszuk, Sally Batham, Kate Ellis, Leila Bahadur, Helena White, Manish Pareek, Amandip Sahota, Stephen Coleman, Hilary Pateman, Atul Kotecha, Christopher Sim, Andrew Rosser, Jill Deane, Richard Nendick, Catherine Aldridge, Anne Clarke, Michelle Wood, Adele Marshall, Lynsey Stephenson, Tracy Matheson-Smith, John Sloss, Kathryn Potts, Joanne Malkin, Lemonia Ftika, Veena Raviprakash, Ahalya Malachira, Miranda Kean, Kristine Criste, Kirsty Gladas, Caroline Andrews, Clare Hutchison, Ellen Adams, Janet Andrews, Belinda Romans, Nicola Ridley, Melanie Ekani, Julie Mitchell, Nicola Smith, Tristan Clark, Sarah Glover, Robert Reed, Tat Yam, Holly Burton, Rasha Said, Amy Janvier, Reni Jacob, Chris Smalley, Alison Fair, Susan Lord, Kate Ripalda, Helen Wooldridge, Luis Cotter, Gus Cardoso, Elaine Strachan, Gagan Kaler, Adam Mohamoodally, Emma Lawrence, Zoe Prime, Rachel Abrahams, David Ashley Price, Lesley Rigden, Laura Shewan, Katherine Cullen, Ingrid Emmerson, Karen Martin, Hesther Wilson, Charley Higham, Kathryn Louise Taylor, Edmund Ong, Bijal Patel, Helena Bond, Janine Gradwell, John Widdrington, Sarah Thornthwaite, Scott Prentice, Una Poultney, Hannah Crowther, Helen Fairlamb, Emily Hetherington, Chris Brewer, Suryabrata Banerjee, Clare Hamson, Anna McSkeane, Paula Sharratt, Joanne Thorpe, Sue Kimachia, Helen Wilson, Benjamin Jeffs, Leslie Masters, Jonathan Wilson, Judith Platt, Lisa Burgess, Paul Chadwick, Adam Jeans, Claire Keatley, Amanda Moran, Zoe Swann, Katherine Pagett, Alex Peel, Jason Howard, Kate Maloney, Avril Masdin, Louise Wright, Samantha Crossman, Vicki Lowthorpe, Emma Moore, Peter Moss, Angela Parkin, Adam Wolstencroft, Bev Warner, Clare Tarbotton, Alison Eyre, Anne Anderson, Tina Burdett, Amy Driffill, Ann Sarah Walker, Alex Szubert, Helen Webb, Charlotte Russell, Brooke Jackson, Damilola Otiko, Chiara Borg, Lindsey Masters, Zaheer Islam, Carlos Díaz-Montaña, Debbie Johnson, Apollo - University of Cambridge Repository, and University of St Andrews. School of Medicine

Subjects
0301 basic medicine, Male, Placebo-controlled study, Administration, Oral, Bacteremia, Community-acquired Infections/drug therapy, Administration, intravenous, Rifampin/administration & dosage, law.invention, Randomized controlled trial, law, Treatment Failure, Middle aged, Cross Infection, QR Microbiology, General Medicine, Middle Aged, Staphylococcal Infections, 16. Peace & justice, 3. Good health, Community-Acquired Infections, Staphylococcal infections/drug therapy, Antibiotics, antitubercular/administration & dosage, Cross infection/drug therapy, Administration, Intravenous, Female, Rifampin, medicine.drug, RM, medicine.medical_specialty, Double-blind method, 030106 microbiology, NDAS, Placebo, Staphylococcal infections, Drug Administration Schedule, 03 medical and health sciences, Double-Blind Method, Bacteremia/drug therapy, Internal medicine, medicine, Humans, Adverse effect, Antibiotics, Antitubercular, Aged, Intention-to-treat analysis, business.industry, Administration, oral, Drug administration schedule, medicine.disease, R1, RM Therapeutics. Pharmacology, QR, Treatment failure, Flucloxacillin, business, Rifampicin
Abstract

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FUNDING: UK National Institute for Health Research Health Technology Assessment.

Published
2018

7. A whole-genome sequencing approach to targeting Mycobacterium tuberculosis outbreak management

Author

Camilla L. C. Ip, Daniel J. Wilson, Jason T. Evans, Ruth H. Harrell, Timothy M Walker, David A. Harris, Georgia Kapatai, Derrick W. Crook, Peter M Hawkey, Philip Monk, E Grace Smith, Tim E. A. Peto, David W Eyre, Rory Bowden, Martin J Dedicoat, Ann Sarah Walker, and Julian Parkhill

Subjects
medicine.medical_specialty, Tuberculosis, Public health, Outbreak, Context (language use), General Medicine, Disease, Biology, medicine.disease, biology.organism_classification, Bioinformatics, Mycobacterium tuberculosis, Epidemiology, medicine, Genotyping, Demography
Abstract

Background Epidemiological investigations into Mycobacterium tuberculosis outbreaks use 24-locus genotyping (MIRU-VNTR typing). Where no epidemiological link can be found between patients, the importance of shared genotypes remains unclear. This issue is especially problematic and time-consuming when tracing contacts within some social groups at high tuberculosis risk, in which unwillingness to volunteer information is common. We investigated whether whole-genome sequencing (WGS) could delineate outbreaks with greater resolution than MIRU-VNTR typing has done. Methods We sequenced 390 M tuberculosis isolates from 254 patients from the UK Midlands (1994–2011) using Illumina technology (appendix). We estimated the expected genomic diversity between isolates within a transmission chain by measuring pairwise nucleotide differences between genomes within hosts (79 individuals with pulmonary and extrapulmonary disease, or multiple pulmonary episodes) and between hosts within 25 household outbreaks (63 individuals). We then investigated 11 MIRU-VNTR-based community clusters (168 patients, 157 transmission events) to assess whether WGS could delineate outbreaks more effectively. For each cluster we reconstructed the most plausible transmission chain based on epidemiological data collected by tuberculosis nurses, pairwise nucleotide distances, and times of diagnosis, and compared the genomic diversity across these constructed links with that within individuals and within household outbreaks. Findings 109 (96%) of 114 isolates were within five SNPs of another isolate taken from the same individual or from an individual in the same household outbreak. On the basis of longitudinal isolates from individuals or households, we estimated an evolutionary rate of 0·5 SNPs per genome per year, consistent with a maximum of five SNPs between related isolates 3 years or less apart. Using a greater than five SNP threshold to assess 11 MIRU-VNTR-based community clusters, we found that none of 69 epidemiologically related pairs of MIRU-VNTR-matched cases plausibly related by transmission, two of 13 possibly related pairs, and 13 of 75 pairs with no known epidemiological relation were separated by more than five SNPs (p Interpretation WGS can delineate tuberculosis outbreaks with greater resolution than has previously been possible. These findings offer public health teams the potential to limit outbreak investigations to patients who are likely to be linked by recent transmission, irrespective of whether it has been possible to identify epidemiological links, and to save resources where they are not, even in the context of matched MIRU-VNTR genotypes. Uniquely, WGS also provides information about the genetic structure of outbreak clusters, thereby providing the potential to direct public health resources towards individuals most likely to have infected the largest number of secondary cases. As a consequence, the Health Protection Agency is considering introduction of WGS technology for routine tuberculosis public health practice in England. Funding NIHR Oxford Biomedical Research Centre and the UKCRC Modernising Medical Microbiology Consortium (UKCRC Translational Infection Research Initiative supported by MRC, Biotechnology and Biological Sciences Research Council, and NIHR on behalf of the Department of Health [grant G0800778] and the Wellcome Trust [087646/Z/08/Z]).

Published
2012

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