Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study
Summary
Background
Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19.
Methods
The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded.
Findings
We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives.
Interpretation
In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist.
Funding
National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.
Introduction
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and other severe respiratory viral infections, in which they are associated with increased morbidity and mortality.
- Joseph C
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National and international COVID-19 guidelines vary in their recommendations on empirical antimicrobial therapy—some recommend empirical antimicrobial therapy in severe disease,
Clinical management of COVID-19: living guidance. Jan 25, 2021.
,
- Alhazzani W
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- Arabi YM
- et al.
whereas others do not.
Coronavirus Disease 2019 (COVID-19) Treatment Guidelines.
UK guidelines advise against empirical therapy when lower respiratory tract infection is thought to be due to COVID-19, without specific evidence of bacterial infection.
COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital.
,
Advice to antimicrobial management teams (AMTs) on antimicrobial prescribing in suspected lower respiratory tract infections in the context of the COVID-19 pandemic.
Living systematic reviews and meta-analyses have reported a low prevalence of confirmed bacterial co-infection (8%), but a high proportion of patients with COVID-19 received antimicrobials (pooled prevalence 75%).
- Langford BJ
- So M
- Raybardhan S
- et al.
,
- Langford BJ
- So M
- Raybardhan S
- et al.
The collective implication of these studies is a widespread failure of antimicrobial stewardship with the potential to worsen the global antimicrobial resistance crisis.
Evidence before this study
An understanding of co-infections, secondary infections, and patterns of antimicrobial use in patients with COVID-19 is required to inform optimal empirical antimicrobial management strategies. We searched PubMed on Dec 29, 2020, for studies published in English, using the keywords “COVID-19”, “SARS-CoV-2”, “bacterial infection”, “bacterial pneumonia”, “superinfection”, “co-infection”, “secondary infection”, and “nosocomial infection”. Systematic reviews were included in the search. A low incidence of bacterial respiratory and bloodstream infections has been consistently reported in patients admitted to hospital with COVID-19. This finding is supported by a systematic review and meta-analysis, but individual studies lack granularity in microbiological and clinical details, are retrospective, and report on small cohorts. The timing of infection (co-infection or secondary infection) is often unknown. Reporting of positive results has lacked species-level detail on cultured organisms and exclusion of clinically irrelevant pathogens. PCR-based bacterial diagnosis is associated with higher pathogen detection than culture-based methods. Antimicrobial use in inpatients appears to be high, but studies infrequently report the drug classes used.
Added value of this study
This is a large, multicentre, prospective cohort study reporting microbiological findings and antimicrobial use in patients admitted to hospital with COVID-19 undergoing standardised microbiological investigation of samples submitted by clinical teams (UK Standards for Microbiology Investigations). Microbiologically confirmed bacterial co-infection (≤2 days after admission) and secondary infections (>2 days after admission) were uncommon in patients admitted to hospital with COVID-19, supporting the findings of a meta-analysis of smaller studies. When they did occur, bloodstream and respiratory infections were more likely to be secondary infections and Gram-negative organisms and Staphylococcus aureus were key aetiological agents, adding granularity in microbiological detail. Aetiology was affected by the timing of infection onset (co-infection or secondary infection), critical care admission, and chronic pulmonary disease. We confirmed high inpatient antimicrobial usage, additionally finding evidence of regional variation, frequent use of broad-spectrum empirical therapy for lower respiratory tract infections (β-lactam–β-lactamase inhibitor combinations), and use of carbapenems rather than carbapenem-sparing alternatives.
Implications of all the available evidence
Bacterial co-infections and secondary infections are rare in patients admitted to hospital with COVID-19. Most infections are secondary. Gram-negative organisms and S aureus are important pathogens and should be considered when designing empirical antimicrobial guidelines, but emphasis should be placed on restricting empirical prescribing, especially at hospital admission. The high frequency and nature of inpatient antimicrobial use might have long-term negative consequences for antimicrobial resistance. Specific targets exist for antimicrobial stewardship and should be integrated into COVID-19 patient care pathways.
Most studies to date have been retrospective with small sample sizes, and few have systematically reported the spectrum of bacteria, timing of infection onset, or described the frequency and nature of antimicrobials used to treat them. There is an urgent need to characterise the causes of bacterial infections in patients admitted to hospital with COVID-19 to determine optimal empirical antimicrobial management strategies and identify targets for antimicrobial stewardship interventions.
In this prospective, multicentre, cohort study of patients admitted to hospital with COVID-19, we aimed to report the microbiological details of laboratory-confirmed co-infections and secondary infections identified by culture-based diagnostics, assess the effect of COVID-19-related co-infection on in-hospital mortality among patients admitted to critical care, and evaluate the nature of antimicrobial usage.
Methods
Study design and setting
- Docherty AB
- Harrison EM
- Green CA
- et al.
This report of microbiological findings and antimicrobial use from the study has been prepared in accordance with the STROBE statement.
Study participants and data collection
- Harris PA
- Taylor R
- Minor BL
- et al.
The requirement for consent for data collection was waived in view of the public health emergency.
Infection data processing
Microbiological data comprising organism name(s), specimen type, result status, and date of sample were recorded as a combination of dropdown fields and free text in REDCap. Results of superficial microbiology, screening swabs, and serology were excluded because of insufficient clinical information to allow interpretation. Additionally, respiratory viruses other than SARS-CoV-2 were excluded since most laboratories prioritised SARS-CoV-2 over multiplex PCR testing during the first wave of the pandemic. Except for urine samples, staphylococci, other than Staphylococcus aureus and Staphylococcus lugdunensis, were considered clinically insignificant and excluded. Unspecified organisms (including positive microscopy findings with no culture result recorded) and results recorded as mixed growth or contaminant were excluded from all sample types. Corynebacterium sp and Cutibacterium sp were excluded from blood cultures. Candida sp were excluded from respiratory samples.
- Cardoso T
- Almeida M
- Friedman ND
- et al.
A patient could be recorded as having multiple infections, based on different sample types and different timepoints, during their admission.
Antimicrobials prescribed over the course of admission were entered as free text and mapped to drug names found in the UK National Health Service Technology Reference Data Update Distribution system.
Statistical analysis
Categorical variables are summarised as frequencies and percentages. Continuous variables are presented as means and SDs or medians and IQRs, depending on data distribution. Analysis of antimicrobial co-occurrence was done using the Jaccard similarity index and represented visually as heatmaps. p≤0·05 was considered to indicate a statistically significant difference. All statistical analyses were done using R version 3.6.3 using the Tidyverse, finalfit, stringdist, and fuzzyjoin packages.
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
TableBaseline characteristics, management, and outcomes of a cohort of 48 902 patients with COVID-19
Data are n (%) or median (IQR).
We identified 1107 patients with COVID-19-related infections (positive blood, sputum, or deep respiratory cultures) and 1002 patients with unrelated infections (urine, abdominopelvic, or pus or abscess cultures). For microbiologically confirmed COVID-19-related infections where sample timing was known, 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Among patients admitted to critical care, we found no association between patients identified to have a respiratory or bloodstream infection and inpatient mortality on univariable analysis (unadjusted odds ratio 1·02, 95% CI 0·86–1·22; p=0·81).
- Russell CD
- Laurenson IF
- Evans MH
- Mackintosh CL
were less frequently prescribed (co-trimoxazole 1·5%, temocillin 0·3%, and aztreonam 0·2%). Almost half of prescriptions involved WHO AWaRe watch antimicrobials (appendix p 8).
Discussion
In this multicentre, prospective cohort of 48 902 patients admitted to hospital with COVID-19, microbiologically confirmed infections were infrequent (1107 patients). Co-infection at hospital admission was rare and when infections were identified, most were secondary. Gram-negative organisms and S aureus were the most frequently recovered pathogens from respiratory and blood cultures. These findings have implications for empirical therapy, indicating a need to treat Gram-negative bacteria and S aureus empirically until culture results are available. Most patients received antimicrobials, which were commonly broad spectrum. We found geographical heterogeneity in antimicrobial usage, reflecting variations in regional and local practices.
- Langford BJ
- So M
- Raybardhan S
- et al.
Langford and colleagues reported a pooled prevalence of confirmed bacterial infections of 8·0% (95% CI 6·1–9·9), with a higher prevalence of secondary infections (16·0%, 12·4–19·6) than co-infections (4·9%, 2·6–7·1).
- Langford BJ
- So M
- Raybardhan S
- et al.
Although this meta-analysis included more than 6000 patients, most of the included studies were retrospective and small (13 studies had
Standards for microbiology investigations (UK SMI).
from a cohort of nearly 50 000 patients. We restricted analyses to clinically significant results, correlated with the timing of sample collection, and described antimicrobial use over time and by geographical region. The multicentre design of our study improves the generalisability of our findings.
- Klein EY
- Monteforte B
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and are predominantly caused by S pneumoniae or S aureus.
- Klein EY
- Monteforte B
- Gupta A
- et al.
Other studies of patients with COVID-19 have identified S aureus as a frequent cause of infection, including bacteraemia. We were unable to definitively determine the sources of bacteraemia in our study. However, in a case series of S aureus bacteraemia in 41 patients with COVID-19, most cases of bacteraemia were of unknown origin (69%), followed by pneumonia (19%), then vascular causes, including vascular access devices (7·1%).
- Cusumano JA
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Exclusion of coagulase-negative staphylococci from our analysis might have led to the under-ascertainment of central line-associated bloodstream infections.
- Langford BJ
- So M
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Elevated C-reactive protein and radiological pulmonary infiltrates are often used to differentiate bacterial from viral causes in community-acquired pneumonia. However, both of these findings are commonly present in patients with COVID-19.
- Luo X
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,
In a Scottish survey, C-reactive protein levels of at least 100 mg/L and chronic obstructive pulmonary disease or chronic lung disease were positively associated with antimicrobial prescribing.
- Seaton RA
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- Cooper L
- et al.
Combined with high morbidity and mortality, the absence of effective therapeutic options for COVID-19 during the study period, and clinical uncertainty during acute illness, high rates of antimicrobial prescription are unsurprising. Nevertheless, the infrequency of confirmed co-infection supports restrictive empirical antimicrobial usage. Antimicrobials should be restricted to individuals with atypical features of COVID-19, such as purulent sputum or lobar pneumonia, or evidence of distinct non-respiratory co-infection. Blood and sputum cultures before empirical antimicrobial treatment and incorporating trends in inflammatory markers into decision making could also support judicious antimicrobial use. The absence of an elevated white cell count at baseline and antimicrobial-associated C-reactive protein reduction can exclude co-infection in around 50% of patients with COVID-19.
- Mason CY
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- Richardson CJ
- et al.
Procalcitonin might be an additional decision-making adjunct, using a threshold of 0·25 ng/mL or less to identify patients with a reduced likelihood of bacterial infection.
- Williams EJ
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- et al.
Regular review of drug charts with discontinuation of antimicrobials if co-infection is deemed unlikely, supported by negative microbiological investigations, are also key to minimise unnecessary antimicrobial exposure. When antimicrobials are required, the choice of antimicrobial should be tailored to likely pathogens and local resistance patterns, with treatment duration limited to 5 days if lower respiratory tract infection is suspected.
COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital.
,
Advice to antimicrobial management teams (AMTs) on antimicrobial prescribing in suspected lower respiratory tract infections in the context of the COVID-19 pandemic.
,
- Sieswerda E
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Co-prescription of glycopeptides and ciprofloxacin was identified, which we postulate is a signature of prescribing in response to penicillin allergy labels. Many patients can be de-labelled without the need for penicillin challenges, associated with reduced broad-spectrum antimicrobial use, and this strategy should be encouraged in patients admitted to hospital with COVID-19 in advance of a potential need for antimicrobials.
- Chua KYL
- Vogrin S
- Bury S
- et al.
Furthermore, we identified frequent use of broad-spectrum empirical therapy (β-lactam–β-lactamase inhibitors) for lower respiratory tract infections, empirical escalation from piperacillin–tazobactam to carbapenems in critical care, and preferential use of carbapenems over carbapenem-sparing alternatives. These findings all represent tractable targets for antimicrobial stewardship.
- Neto AGM
- Lo KB
- Wattoo A
- et al.
co-infection and secondary infection were not associated with inpatient mortality among patients admitted to critical care in our study. Evaluation of the association between co-infection and outcome using observational data is complex. First, a greater proportion of deaths within the study occurred early during the hospital stay; therefore, these patients had less time to undergo microbiological investigations or to acquire a secondary infection. Conversely, any observed association could be driven by prolonged treatment in hospital because of more severe disease or slower recovery—co-infection or secondary infection might simply be a marker of this. Additionally, more thorough investigations might be done in patients who appear likely to have a favourable prognosis with adequate treatment, and such patients might be younger with fewer comorbidities.
Our study has several limitations. Retrospectively assigning clinical significance to culture results can be challenging and is further restricted in this study, as clinical findings that would contribute to diagnosis of bacterial infection were not collected at the time of microbiological sampling. The absence of clinical correlation limits interpretation of the microbiological findings—eg, isolation of E coli from sputum could represent true infection but alternative explanations include airway colonisation or altered (post-antimicrobial) flora, particularly in patients with chronic lung disease. We were unable to differentiate colonisation from new infection for patients with chronic lung disease, as previous microbiology results were not available.
Less than 20% of our cohort had microbiological investigations recorded, which is lower than reported for community-acquired pneumonia in a recent UK-wide audit (sputum and blood cultures were done in 23·6% of patients and 58·6% of patients, respectively).
National Audit Report: Adult Community Acquired Pneumonia Audit 2018/19.
Low rates of microbiological sampling in patients with COVID-19 have been reported elsewhere.
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- et al.
Under-ascertainment of true bacterial infection might also be due to antimicrobial receipt before sampling, as well as low sensitivity of culture-based diagnostics. We excluded serological investigations for fungi or atypical bacteria, and urinary antigen tests for pneumococci and Legionella sp, as these were inconsistently recorded and the galactomannan assay cross-reacts with β-lactams.
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We also lacked the data required to address the recently proposed case definition for COVID-19-associated pulmonary aspergillosis.
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Furthermore, we were unable to characterise respiratory viral or Mycoplasma pneumoniae co-infections, as most UK laboratories discontinued routine multiplex respiratory virus PCR testing during the study period. Therefore, we might have missed fungal or atypical bacterial co-infection identified by serum or urinary antigen tests alone, and other respiratory pathogen infections usually diagnosed by PCR.
MRSA bacteraemia: annual data.
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,
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Prospective studies with standardised and comprehensive microbiological sampling before antimicrobial treatment are needed to characterise co-infections and secondary infections in patients with COVID-19. Tractable targets for antimicrobial stewardship interventions exist and should be prioritised.
Contributors
AH, CDR, LT, PJMO, JKB, and MGS conceived the study. CJF, TMD, CE, AH, CDR, LT, RP, LM, ABD, and EMH curated the data. CJF and TMD did the formal analysis. PJMO, JKB, and MGS acquired the funding. AH, CJF, CDR, TMD, LT, RAS, DGW, EMH, ABD, PJMO, JKB, and MGS did the investigation. HEH, MG, AH, CDR, and LM were project administrators. CJF, TMD, and EMH visualised the data. AH and MGS supervised the study. AH and CDR wrote the original draft of the manuscript. AH, CDR, LT, CJF, TMD, RAS, DGW, LS, EMH, ABD, TIdS JD, JSN-V-T, PJMO, JKB, and MGS reviewed and edited the manuscript. EMH, MGS, and JKB validated the study data. CJF, TMD, JKB, MGS, and EMH had access to the raw data. The corresponding author had full access to all the data and final responsibility for the decision to submit for publication.
ISARIC4C investigators
Consortium lead investigator: J Kenneth Baillie. Chief Investigator: Malcolm G Semple. Co-lead investigator: Peter J M Openshaw. ISARIC clinical coordinator: Gail Carson. Co-investigator: Beatrice Alex, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Annemarie B Docherty, Jake Dunning, Ana da Silva Filipe, Tom Fletcher, Christoper A Green, Ewen M Harrison, Julian A Hiscox, Antonia Ying Wai Ho, Peter W Horby, Samreen Ijaz, Saye Khoo, Paul Klenerman, Andrew Law, Wei Shen Lim, Alexander J Mentzer, Laura Merson, Alison M Meynert, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Clark D Russell, Vanessa Sancho-Shimizu, Janet T Scott, Thushan de Silva, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, Emma C Thomson, A A Roger Thompson, Ryan S Thwaites, Lance C W Turtle, Rishi K Gupta, Maria Zambon. Project manager: Hayley E Hardwick, Chloe Donohue, Ruth Lyons, Fiona Griffiths, Wilna Oosthuyzen. Data analyst: Lisa Norman, Riinu Pius, Thomas M Drake, Cameron J Fairfield, Stephen R Knight, Kenneth A Mclean, Derek Murphy, Catherine A Shaw. Data and information system manager: Jo Dalton, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble. Data integration and presentation: Gary Leeming, Andrew Law, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown. Material management: William Greenhalf, Victoria Shaw, Sara McDonald. Patient engagement: Seán Keating. Outbreak laboratory staff and volunteers: Katie A Ahmed, Jane A Armstrong, Milton Ashworth, Innocent G Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Benjamin WA Catterall, Jordan J Clark, Emily A Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis W S Fisher, Terry Foster, Isabel Garcia-Dorival, William Greenhalf, Philip Gunning, Catherine Hartley, Rebecca L Jensen, Christopher B Jones, Trevor R Jones, Shadia Khandaker, Katharine King, Robyn T Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Mancini, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S Miah, Joanna Middleton, Joyce Mitchell, Shona C Moore, Ellen G Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P Matthew Ridley, Debby Sales, Victoria E Shaw, Rebecca K Shears, Benjamin Small, Krishanthi S Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J Eunice Zhang, Lisa Flaherty, Nicole Maziere, Emily Cass, Alejandra Doce Carracedo, Nicola Carlucci, Anthony Holmes, Hannah Massey. Edinburgh laboratory staff and volunteers: Lee Murphy, Nicola Wrobel, Sarah McCafferty, Kirstie Morrice, Alan MacLean. Local principal investigators: Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L Aldera, Ana Alegria, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Nicola Best, Pieter Bothma, David Chadwick, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, David Chadwick, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Samir Dervisevic, Phil Donnison, Sam Douthwaite, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Sanjeev Garg, Atul Garg, Effrossyni Gkrania-Klotsas, Jo Godden, Arthur Goldsmith, Clive Graham, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Mariyam Mirfenderesky, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Megan Nagel, Thapas Nagarajan, Mark Nelson, Matthew K O’Shea, Igor Otahal, Marlies Ostermann, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Brendan Ryan, Taranprit Saluja, Aarti Shah, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jeremy Sizer, Manu Shankar-Hari, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Andrew Ustianowski, Nick Vallotton, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Padmasayee Papineni, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Sarah Cole, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wootton, Andrew Workman, Bryan Yates, Peter Young.
Data sharing
Declaration of interests
All authors declare support from the NIHR, the Medical Research Council (MRC), the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, the NIHR HPRU in Respiratory Infections at Imperial College London, the NIHR Biomedical Research Centre (BRC) at Imperial College London, and the NIHR Clinical Research Network, for the submitted work. ABD reports grants from the UK Department of Health and Social Care (DHSC), during the conduct of the study, and grants from Wellcome Trust, outside the submitted work. PJMO reports personal fees from consultancies (GlaxoSmithKline, Janssen, Bavarian Nordic, Pfizer, and Cepheid) and from the European Respiratory Society, grants from MRC, MRC Global Challenge Research Fund, the EU, NIHR BRC, MRC–GlaxoSmithKline, Wellcome Trust, NIHR (HPRU in Respiratory Infection), and is an NIHR senior investigator outside the submitted work. PJMO’s role as President of the British Society for Immunology was unpaid but travel and accommodation at some meetings was provided by the Society. JKB reports grants from MRC. MGS reports grants from DHSC, NIHR UK, MRC, HPRU in Emerging and Zoonotic Infections, and University of Liverpool, during the conduct of the study, and is chair of the scientific advisory board and a minority share holder at Integrum Scientific, outside the submitted work.
Acknowledgments
This work used data provided by patients and collected by the NHS as part of patient care and support. We are extremely grateful to the 2648 front-line NHS clinical and research staff and volunteer medical students who collected these data in challenging circumstances, and the generosity of the participants and their families for their individual contributions in these difficult times. We also acknowledge the support of Jeremy J Farrar (Wellcome Trust) and Nahoko Shindo (WHO). This work is supported by grants from the NIHR (award CO-CIN-01), the MRC (grant MC_PC_19059), and by the NIHR HPRU in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with the Liverpool School of Tropical Medicine and the University of Oxford (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Wellcome Trust and the UK Department for International Development ( 215091/Z/18/Z ), Bill & Melinda Gates Foundation ( OPP1209135 ), Liverpool Experimental Cancer Medicine Centre ( grant reference C18616/A25153 ), NIHR BRC at Imperial College London (IS-BRC-1215-20013), EU Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE; FP7 project 602525), and NIHR Clinical Research Network. LT is supported by a Wellcome Trust fellowship ( 205228/Z/16/Z ). PJMO is supported by a NIHR Senior Investigator Award (award 201385). This research was funded in whole, or in part, by the Wellcome Trust. The views expressed are those of the authors and not necessarily those of the UK DHSC, the UK Department for International Development, NIHR, MRC, Wellcome Trust, or PHE.
Supplementary Material
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© 2021 The Author(s). Published by Elsevier Ltd.