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1. Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial

Author

Fish, M., Rynne, J., Jennings, A., Lam, C., Lamikanra, A. A., Ratcliff, J., Cellone-Trevelin, S., Timms, E., Jiriha, J., Tosi, I., Pramanik, R., Simmonds, P., Seth, S., Williams, J., Gordon, A. C., Knight, J., Smith, D. J., Whalley, J., Harrison, D., Rowan, K., Harvala, H., Klenerman, P., Estcourt, L., Menon, D. K., Roberts, D., and Shankar-Hari, M.

Published
2022
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6. Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial

Author

Fish, Matthew, Rynne, Jennifer, Jennings, Aislinn, Lam, C, Lamikanra, A, Ratcliff, J, Cellone-Trevelin, S, Timms, E, Jeriha, Jakob, Tosi, I, Pramanik, R, Simmonds, P, Seth, Sohan, Williams, J, Gordon, A C, Knight, J, Smith, D J, Whalley, J, Harrison, D, Rowan, K, Harvala, H, Klenerman, P, Estcourt, L, Menon, D K, Roberts, D, Shankar-Hari, Manu, NIHR, and National Institute for Health Research

Subjects
Adult, Science & Technology, Convalescent plasma, sub-phenotypes, Critical Illness, Precision medicine, COVID-19, 1103 Clinical Sciences, Critical Care and Intensive Care Medicine, Subphenotypes, Emergency & Critical Care Medicine, 1117 Public Health and Health Services, REMAP-CAP Immunoglobulin Domain UK Investigators, Treatment Outcome, Critical Care Medicine, General & Internal Medicine, convalescent plasma, Humans, Cytokines, Life Sciences & Biomedicine, COVID-19 Serotherapy, Biomarkers
Abstract

Purpose Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . Methods We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . Results Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (− 1, 21) vs 10 (− 1, to 21) in subphenotype-2; 1.5 (− 1, 21) vs 12 (− 1, to 21) in suphenotype-3, and 0 (− 1, 21) vs 0 (− 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). Conclusions We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.

Published
2022

9. Effects of SARS-CoV-2 strain variation on virus neutralisation titres: therapeutic use of convalescent plasma

Author

Nguyen, D, Xiao, J, Simmonds, P, Lamikanra, A, Odon, V, Ratcliff, J, Townsend, A, Roberts, DJ, and Harvala, H

Abstract

We compared neutralising antibody titres of convalescent samples collected before and after the emergence of novel strains of SARS-CoV-2, against the wild-type virus (WT), Alpha (B.1.1.7) and Beta (B.1.351) variants. Plasma collected in 2020 before emergence of variants showed reduced titres against the Alpha variants, and both sets of samples demonstrated significantly reduced titres against Beta. Comparison of microneutralisation titres to those obtained with pseudotype and HAT assays showed a good correlation of titres and effects of strain variation, supporting the use of these simpler assays for assessment of convalescent plasma potency against currently circulating and emerging strains of SARS-CoV-2.

Published
2021

13. Virological and serological characterization of critically ill patients with COVID-19 in the UK: Interactions of viral load, antibody status and B.1.1.7 variant infection

Author

Ratcliff, J, Nguyen, D, Fish, M, Rynne, J, Jennings, A, Williams, S, Al-Beidh, F, Bonsall, D, Evans, A, Golubchik, T, Gordon, AC, Lamikanra, A, Tsang, P, Ciccone, NA, Leuscher, U, Slack, W, Laing, E, Mouncey, PR, Ziyenge, S, Oliveira, M, Ploeg, R, Rowan, KM, Shankar-Hari, M, Roberts, DJ, Menon, DK, Estcourt, L, Simmonds, P, Harvala, H, NIHR, and National Institute for Health Research

Subjects
Male, Critical Illness, Antibodies, Viral, Microbiology, Polymerase Chain Reaction, Major Article, Humans, Serologic Tests, clade B.1.1.7, 11 Medical and Health Sciences, COVID-19 Serotherapy, Aged, SARS-CoV-2, SARS-CoV-2 COVID-19, Immunization, Passive, COVID-19, 06 Biological Sciences, Middle Aged, Viral Load, randomized clinical trial, Antibodies, Neutralizing, United Kingdom, REMAP-CAP Immunoglobulin Domain UK Investigators, Coronavirus, AcademicSubjects/MED00290, Immunoglobulin G, convalescent plasma, Spike Glycoprotein, Coronavirus, RNA, Viral, ELISA, Female, variant of concern
Abstract

Background Convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation for COVID-19 treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial that potentially influence treatment outcomes. Methods SARS-CoV-2 RNA in nasopharyngeal swabs collected pre-treatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. Results Of 1274 subjects, 90% were PCR-positive with viral loads 118-1.7x10 11 IU/ml. Median viral loads were 40-fold higher in those seronegative for IgG antibodies (n=354; 28%) compared to seropositives (n=939; 72%). Frequencies of B.1.1.7 increased from

Published
2021

14. Recommendations for the introduction of metagenomic high-throughput sequencing in clinical virology, part I: Wet lab procedure

Author

Lopez-Labrador, F.X., Brown, J.R., Fischer, N., Harvala, H., Boheemen, S. van, Cinek, O., Sayiner, A., Madsen, T.V., Auvinen, E., Kufner, V., Huber, M., Rodriguez, C., Jonges, M., Honemann, M., Susi, P., Sousa, H., Klapper, P.E., Perez-Cataluna, A., Hernandez, M., Molenkamp, R., Hoek, L. van der, Schuurman, R., Couto, N., Leuzinger, K., Simmonds, P., Beer, M., Hoper, D., Kamminga, S., Feltkamp, M.C.W., Rodriguez-Diaz, J., Keyaerts, E., Nielsen, X.C., Puchhammer-Stockl, E., Kroes, A.C.M., Buesa, J., Breuer, J., Claas, E.C.J., Vries, J.J.C. de, ESCV Network Next-Generation Seque, Virology, Medicum, Eeva Auvinen / Principal Investigator, Biosciences, HUSLAB, Department of Virology, University of Helsinki, and Helsinki University Hospital Area

Subjects
0301 basic medicine, Pathogen detection, Standardization, Computer science, 030106 microbiology, Recommendations, INFLUENZA-A VIRUS, DIAGNOSIS, VALIDATION, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Virology, Wet lab, Viral metagenomics, 030212 general & internal medicine, 11832 Microbiology and virology, Laboratory methods, High-throughput sequencing, Quality assessment, Network on, High-Throughput Nucleotide Sequencing, DNA, EFFICIENT TRANSLATION, Data science, 3. Good health, Infectious Diseases, Metagenomics, Viruses, Next-generation sequencing, 3111 Biomedicine, DEPLETION, MESSENGER-RNA, Clinical virology, PATHOGEN DETECTION
Abstract

Metagenomic high-throughput sequencing (mHTS) is a hypothesis-free, universal pathogen detection technique for determination of the DNA/RNA sequences in a variety of sample types and infectious syndromes. mHTS is still in its early stages of translating into clinical application. To support the development, implementation and standardization of mHTS procedures for virus diagnostics, the European Society for Clinical Virology (ESCV) Network on Next-Generation Sequencing (ENNGS) has been established. The aim of ENNGS is to bring together professionals involved in mHTS for viral diagnostics to share methodologies and experiences, and to develop application recommendations. This manuscript aims to provide practical recommendations for the wet lab procedures necessary for implementation of mHTS for virus diagnostics and to give recommendations for development and validation of laboratory methods, including mHTS quality assurance, control and quality assessment protocols.

Published
2021

15. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author

Estcourt, L.J., Turgeon, A.F., McQuilten, Z.K., McVerry, B.J., Al-Beidh, F., Annane, D., Arabi, Y.M., Arnold, D.M., Beane, A., Bégin, P., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Birchall, J.E., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Callum, J.L., Chassé, M., Cheng, A.C., Cove, M.E., Daly, J., Derde, L., Detry, M.A., Jong, Menno de, Evans, A., Fergusson, D.A., Fish, M., Fitzgerald, M., Foley, C., Goossens, H., Gordon, A.C., Gosbell, I.B., Green, C., Haniffa, R., Harvala, H., Higgins, A.M., Hills, T.E., Hoad, V.C., Horvat, C., Huang, D.T., Hudson, C.L., Ichihara, N., Laing, E., Lamikanra, A.A., Lamontagne, F., Lawler, P.R., Linstrum, K., Litton, E., Lorenzi, E., MacLennan, S., Marshall, J., McAuley, D.F., McDyer, J.F., McGlothlin, A., McGuinness, S., Miflin, G., Montgomery, S., Mouncey, P.R., Murthy, S., Nichol, A., Parke, R., Parker, J.C., Priddee, N., Purcell, D.F.J., Reyes, L.F., Richardson, P., Robitaille, N., Rowan, K.M., Rynne, J., Saito, H., Santos, M., Saunders, C.T., Neto, A. Serpa, Seymour, C.W., Silversides, J.A., Tinmouth, A.A., Triulzi, D.J., Turner, A.M., Veerdonk, F.L. van de, Walsh, T.S., Wood, E.M., Berry, S., Lewis, R.J., Menon, D.K., McArthur, C., Zarychanski, R., Angus, D.C., Webb, S.A., Roberts, D.J., Shankar-Hari, M., Estcourt, L.J., Turgeon, A.F., McQuilten, Z.K., McVerry, B.J., Al-Beidh, F., Annane, D., Arabi, Y.M., Arnold, D.M., Beane, A., Bégin, P., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Birchall, J.E., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Callum, J.L., Chassé, M., Cheng, A.C., Cove, M.E., Daly, J., Derde, L., Detry, M.A., Jong, Menno de, Evans, A., Fergusson, D.A., Fish, M., Fitzgerald, M., Foley, C., Goossens, H., Gordon, A.C., Gosbell, I.B., Green, C., Haniffa, R., Harvala, H., Higgins, A.M., Hills, T.E., Hoad, V.C., Horvat, C., Huang, D.T., Hudson, C.L., Ichihara, N., Laing, E., Lamikanra, A.A., Lamontagne, F., Lawler, P.R., Linstrum, K., Litton, E., Lorenzi, E., MacLennan, S., Marshall, J., McAuley, D.F., McDyer, J.F., McGlothlin, A., McGuinness, S., Miflin, G., Montgomery, S., Mouncey, P.R., Murthy, S., Nichol, A., Parke, R., Parker, J.C., Priddee, N., Purcell, D.F.J., Reyes, L.F., Richardson, P., Robitaille, N., Rowan, K.M., Rynne, J., Saito, H., Santos, M., Saunders, C.T., Neto, A. Serpa, Seymour, C.W., Silversides, J.A., Tinmouth, A.A., Triulzi, D.J., Turner, A.M., Veerdonk, F.L. van de, Walsh, T.S., Wood, E.M., Berry, S., Lewis, R.J., Menon, D.K., McArthur, C., Zarychanski, R., Angus, D.C., Webb, S.A., Roberts, D.J., and Shankar-Hari, M.

Abstract

Item does not contain fulltext, IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromb

Published
2021

16. Recommendations for the introduction of metagenomic high-throughput sequencing in clinical virology, part I: Wet lab procedure

Author

López-Labrador, F.X. (F. Xavier), Brown, J.R. (Julianne R.), Fischer, N. (Nicole), Harvala, H. (Heli), Boheemen, S. (Sander) van, Cinek, O. (Ondrej), Sayiner, A. (Arzu), Madsen, T.V. (Tina Vasehus), Auvinen, E. (Eeva), Kufner, V. (Verena), Huber, M. (Michael), Rodriguez, C. (Christophe), Jonges, M. (Marcel), Hönemann, M. (Mario), Susi, P. (Petri), Sousa, H. (Hugo), Klapper, P.E. (Paul E.), Pérez-Cataluňa, A. (Alba), Hernandez, M. (Marta), Molenkamp, R. (Richard), der Hoek, L.V. (Lia van), Schuurman, R. (Rob), Couto, N. (Natacha), Leuzinger, K. (Karoline), Simmonds, P. (Peter), Beer, M. (Martin), Höper, D. (Dirk), Kamminga, S. (Sergio), Feltkamp, M.C.W. (Mariet C.W.), Rodríguez-Díaz, J. (Jesús), Keyaerts, E. (Els), Nielsen, X.C. (Xiaohui Chen), Puchhammer-Stöckl, E. (Elisabeth), Kroes, A.C.M. (Aloys), Buesa, J. (Javier), Breuer, J. (Judy), Claas, E.C.J. (Eric), Vries, J.J.C. (Jutte) de, López-Labrador, F.X. (F. Xavier), Brown, J.R. (Julianne R.), Fischer, N. (Nicole), Harvala, H. (Heli), Boheemen, S. (Sander) van, Cinek, O. (Ondrej), Sayiner, A. (Arzu), Madsen, T.V. (Tina Vasehus), Auvinen, E. (Eeva), Kufner, V. (Verena), Huber, M. (Michael), Rodriguez, C. (Christophe), Jonges, M. (Marcel), Hönemann, M. (Mario), Susi, P. (Petri), Sousa, H. (Hugo), Klapper, P.E. (Paul E.), Pérez-Cataluňa, A. (Alba), Hernandez, M. (Marta), Molenkamp, R. (Richard), der Hoek, L.V. (Lia van), Schuurman, R. (Rob), Couto, N. (Natacha), Leuzinger, K. (Karoline), Simmonds, P. (Peter), Beer, M. (Martin), Höper, D. (Dirk), Kamminga, S. (Sergio), Feltkamp, M.C.W. (Mariet C.W.), Rodríguez-Díaz, J. (Jesús), Keyaerts, E. (Els), Nielsen, X.C. (Xiaohui Chen), Puchhammer-Stöckl, E. (Elisabeth), Kroes, A.C.M. (Aloys), Buesa, J. (Javier), Breuer, J. (Judy), Claas, E.C.J. (Eric), and Vries, J.J.C. (Jutte) de

Abstract

Metagenomic high-throughput sequencing (mHTS) is a hypothesis-free, universal pathogen detection technique for determination of the DNA/RNA sequences in a variety of sample types and infectious syndromes. mHTS is still in its early stages of translating into clinical application. To support the development, implementation and standardization of mHTS procedures for virus diagnostics, the European Society for Clinical Virology (ESCV) Network on Next-Generation Sequencing (ENNGS) has been established. The aim of ENNGS is to bring together professionals involved in mHTS for viral diagnostics to share methodologies and experiences, and to develop application recommendations. This manuscript aims to provide practical recommendations for the wet lab procedures necessary for im

Published
2021
Full Text
View/download PDF

17. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients with COVID-19: A Randomized Clinical Trial.

Author

Estcourt L.J., Turgeon A.F., McQuilten Z.K., McVerry B.J., Al-Beidh F., Annane D., Arabi Y.M., Arnold D.M., Beane A., Begin P., Van Bentum-Puijk W., Berry L.R., Bhimani Z., Birchall J.E., Bonten M.J.M., Bradbury C.A., Brunkhorst F.M., Buxton M., Callum J.L., Chasse M., Cheng A.C., Cove M.E., Daly J., Derde L., Detry M.A., De Jong M., Evans A., Fergusson D.A., Fish M., Fitzgerald M., Foley C., Goossens H., Gordon A.C., Gosbell I.B., Green C., Haniffa R., Harvala H., Higgins A.M., Hills T.E., Hoad V.C., Horvat C., Huang D.T., Hudson C.L., Ichihara N., Laing E., Lamikanra A.A., Lamontagne F., Lawler P.R., Linstrum K., Litton E., Lorenzi E., Maclennan S., Marshall J., McAuley D.F., McDyer J.F., McGlothlin A., McGuinness S., Miflin G., Montgomery S., Mouncey P.R., Murthy S., Nichol A., Parke R., Parker J.C., Priddee N., Purcell D.F.J., Reyes L.F., Richardson P., Robitaille N., Rowan K.M., Rynne J., Saito H., Santos M., Saunders C.T., Serpa Neto A., Seymour C.W., Silversides J.A., Tinmouth A.A., Triulzi D.J., Turner A.M., Van De Veerdonk F., Walsh T.S., Wood E.M., Berry S., Lewis R.J., Menon D.K., McArthur C., Zarychanski R., Angus D.C., Webb S.A., Roberts D.J., Shankar-Hari M., Estcourt L.J., Turgeon A.F., McQuilten Z.K., McVerry B.J., Al-Beidh F., Annane D., Arabi Y.M., Arnold D.M., Beane A., Begin P., Van Bentum-Puijk W., Berry L.R., Bhimani Z., Birchall J.E., Bonten M.J.M., Bradbury C.A., Brunkhorst F.M., Buxton M., Callum J.L., Chasse M., Cheng A.C., Cove M.E., Daly J., Derde L., Detry M.A., De Jong M., Evans A., Fergusson D.A., Fish M., Fitzgerald M., Foley C., Goossens H., Gordon A.C., Gosbell I.B., Green C., Haniffa R., Harvala H., Higgins A.M., Hills T.E., Hoad V.C., Horvat C., Huang D.T., Hudson C.L., Ichihara N., Laing E., Lamikanra A.A., Lamontagne F., Lawler P.R., Linstrum K., Litton E., Lorenzi E., Maclennan S., Marshall J., McAuley D.F., McDyer J.F., McGlothlin A., McGuinness S., Miflin G., Montgomery S., Mouncey P.R., Murthy S., Nichol A., Parke R., Parker J.C., Priddee N., Purcell D.F.J., Reyes L.F., Richardson P., Robitaille N., Rowan K.M., Rynne J., Saito H., Santos M., Saunders C.T., Serpa Neto A., Seymour C.W., Silversides J.A., Tinmouth A.A., Triulzi D.J., Turner A.M., Van De Veerdonk F., Walsh T.S., Wood E.M., Berry S., Lewis R.J., Menon D.K., McArthur C., Zarychanski R., Angus D.C., Webb S.A., Roberts D.J., and Shankar-Hari M.

Abstract

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. Objective(s): To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. Design, Setting, and Participant(s): The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. Intervention(s): The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL +/- 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; veno

Published
2021

18. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Author

Axfors C., Janiaud P., Schmitt A.M., van't Hooft J., Smith E.R., Haber N.A., Abayomi A., Abduljalil M., Abdulrahman A., Acosta-Ampudia Y., Aguilar-Guisado M., Al-Beidh F., Alejandria M.M., Alfonso R.N., Ali M., AlQahtani M., AlZamrooni A., Anaya J.-M., Ang M.A.C., Aomar I.F., Argumanis L.E., Averyanov A., Baklaushev V.P., Balionis O., Benfield T., Berry S., Birocco N., Bonifacio L.B., Bowen A.C., Bown A., Cabello-Gutierrez C., Camacho B., Camacho-Ortiz A., Campbell-Lee S., Cao D.H., Cardesa A., Carnate J.M., Castillo G.J.J., Cavallo R., Chowdhury F.R., Chowdhury F.U.H., Ciccone G., Cingolani A., Climacosa F.M.M., Compernolle V., Cortez C.F.N., Costa Neto A., D'Antico S., Daly J., Danielle F., Davis J.S., De Rosa F.G., Denholm J.T., Denkinger C.M., Desmecht D., Diaz-Coronado J.C., Diaz Ponce-Medrano J.A., Donneau A.-F., Dumagay T.E., Dunachie S., Dungog C.C., Erinoso O., Escasa I.M.S., Estcourt L.J., Evans A., Evasan A.L.M., Fareli C.J., Fernandez-Sanchez V., Galassi C., Gallo J.E., Garcia P.J., Garcia P.L., Garcia J.A., Garigliany M., Garza-Gonzalez E., Gauiran D.T.V., Gaviria Garcia P.A., Giron-Gonzalez J.-A., Gomez-Almaguer D., Gordon A.C., Gothot A., Grass Guaqueta J.S., Green C., Grimaldi D., Hammond N.E., Harvala H., Heralde F.M., Herrick J., Higgins A.M., Hills T.E., Hines J., Holm K., Hoque A., Hoste E., Ignacio J.M., Ivanov A.V., Janssen M., Jennings J.H., Jha V., King R.A.N., Kjeldsen-Kragh J., Klenerman P., Kotecha A., Krapp F., Labanca L., Laing E., Landin-Olsson M., Laterre P.-F., Lim L.-L., Lim J., Ljungquist O., Llaca-Diaz J.M., Lopez-Robles C., Lopez-Cardenas S., Lopez-Plaza I., Lucero J.A.C., Lundgren M., Macias J., Maganito S.C., Malundo A.F.G., Manrique R.D., Manzini P.M., Marcos M., Marquez I., Martinez-Marcos F.J., Mata A.M., McArthur C.J., McQuilten Z.K., McVerry B.J., Menon D.K., Meyfroidt G., Mirasol M.A.L., Misset B., Molton J.S., Mondragon A.V., Monsalve D.M., Moradi Choghakabodi P., Morpeth S.C., Mouncey P.R., Moutschen M., Muller-Tidow C., Murphy E., Najdovski T., Nichol A.D., Nielsen H., Novak R.M., O'Sullivan M.V.N., Olalla J., Osibogun A., Osikomaiya B., Oyonarte S., Pardo-Oviedo J.M., Patel M.C., Paterson D.L., Pena-Perez C.A., Perez-Calatayud A.A., Perez-Alba E., Perkina A., Perry N., Pouladzadeh M., Poyato I., Price D.J., Quero A.K.H., Rahman M.M., Rahman M.S., Ramesh M., Ramirez-Santana C., Rasmussen M., Rees M.A., Rego E., Roberts J.A., Roberts D.J., Rodriguez Y., Rodriguez-Bano J., Rogers B.A., Rojas M., Romero A., Rowan K.M., Saccona F., Safdarian M., Santos M.C.M., Sasadeusz J., Scozzari G., Shankar-Hari M., Sharma G., Snelling T., Soto A., Tagayuna P.Y., Tang A., Tatem G., Teofili L., Tong S.Y.C., Turgeon A.F., Veloso J.D., Venkatesh B., Ventura-Enriquez Y., Webb S.A., Wiese L., Wiken C., Wood E.M., Yusubalieva G.M., Zacharowski K., Zarychanski R., Khanna N., Moher D., Goodman S.N., Ioannidis J.P.A., Hemkens L.G., Axfors C., Janiaud P., Schmitt A.M., van't Hooft J., Smith E.R., Haber N.A., Abayomi A., Abduljalil M., Abdulrahman A., Acosta-Ampudia Y., Aguilar-Guisado M., Al-Beidh F., Alejandria M.M., Alfonso R.N., Ali M., AlQahtani M., AlZamrooni A., Anaya J.-M., Ang M.A.C., Aomar I.F., Argumanis L.E., Averyanov A., Baklaushev V.P., Balionis O., Benfield T., Berry S., Birocco N., Bonifacio L.B., Bowen A.C., Bown A., Cabello-Gutierrez C., Camacho B., Camacho-Ortiz A., Campbell-Lee S., Cao D.H., Cardesa A., Carnate J.M., Castillo G.J.J., Cavallo R., Chowdhury F.R., Chowdhury F.U.H., Ciccone G., Cingolani A., Climacosa F.M.M., Compernolle V., Cortez C.F.N., Costa Neto A., D'Antico S., Daly J., Danielle F., Davis J.S., De Rosa F.G., Denholm J.T., Denkinger C.M., Desmecht D., Diaz-Coronado J.C., Diaz Ponce-Medrano J.A., Donneau A.-F., Dumagay T.E., Dunachie S., Dungog C.C., Erinoso O., Escasa I.M.S., Estcourt L.J., Evans A., Evasan A.L.M., Fareli C.J., Fernandez-Sanchez V., Galassi C., Gallo J.E., Garcia P.J., Garcia P.L., Garcia J.A., Garigliany M., Garza-Gonzalez E., Gauiran D.T.V., Gaviria Garcia P.A., Giron-Gonzalez J.-A., Gomez-Almaguer D., Gordon A.C., Gothot A., Grass Guaqueta J.S., Green C., Grimaldi D., Hammond N.E., Harvala H., Heralde F.M., Herrick J., Higgins A.M., Hills T.E., Hines J., Holm K., Hoque A., Hoste E., Ignacio J.M., Ivanov A.V., Janssen M., Jennings J.H., Jha V., King R.A.N., Kjeldsen-Kragh J., Klenerman P., Kotecha A., Krapp F., Labanca L., Laing E., Landin-Olsson M., Laterre P.-F., Lim L.-L., Lim J., Ljungquist O., Llaca-Diaz J.M., Lopez-Robles C., Lopez-Cardenas S., Lopez-Plaza I., Lucero J.A.C., Lundgren M., Macias J., Maganito S.C., Malundo A.F.G., Manrique R.D., Manzini P.M., Marcos M., Marquez I., Martinez-Marcos F.J., Mata A.M., McArthur C.J., McQuilten Z.K., McVerry B.J., Menon D.K., Meyfroidt G., Mirasol M.A.L., Misset B., Molton J.S., Mondragon A.V., Monsalve D.M., Moradi Choghakabodi P., Morpeth S.C., Mouncey P.R., Moutschen M., Muller-Tidow C., Murphy E., Najdovski T., Nichol A.D., Nielsen H., Novak R.M., O'Sullivan M.V.N., Olalla J., Osibogun A., Osikomaiya B., Oyonarte S., Pardo-Oviedo J.M., Patel M.C., Paterson D.L., Pena-Perez C.A., Perez-Calatayud A.A., Perez-Alba E., Perkina A., Perry N., Pouladzadeh M., Poyato I., Price D.J., Quero A.K.H., Rahman M.M., Rahman M.S., Ramesh M., Ramirez-Santana C., Rasmussen M., Rees M.A., Rego E., Roberts J.A., Roberts D.J., Rodriguez Y., Rodriguez-Bano J., Rogers B.A., Rojas M., Romero A., Rowan K.M., Saccona F., Safdarian M., Santos M.C.M., Sasadeusz J., Scozzari G., Shankar-Hari M., Sharma G., Snelling T., Soto A., Tagayuna P.Y., Tang A., Tatem G., Teofili L., Tong S.Y.C., Turgeon A.F., Veloso J.D., Venkatesh B., Ventura-Enriquez Y., Webb S.A., Wiese L., Wiken C., Wood E.M., Yusubalieva G.M., Zacharowski K., Zarychanski R., Khanna N., Moher D., Goodman S.N., Ioannidis J.P.A., and Hemkens L.G.

Abstract

Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Method(s): In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Result(s): A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3

Published
2021

19. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Author

Axfors, C, Janiaud, P, Schmitt, AM, Van't Hooft, J, Smith, ER, Haber, NA, Abayomi, A, Abduljalil, M, Abdulrahman, A, Acosta-Ampudia, Y, Aguilar-Guisado, M, Al-Beidh, F, Alejandria, MM, Alfonso, RN, Ali, M, AlQahtani, M, AlZamrooni, A, Anaya, J-M, Ang, MAC, Aomar, IF, Argumanis, LE, Averyanov, A, Baklaushev, VP, Balionis, O, Benfield, T, Berry, S, Birocco, N, Bonifacio, LB, Bowen, AC, Bown, A, Cabello-Gutierrez, C, Camacho, B, Camacho-Ortiz, A, Campbell-Lee, S, Cao, DH, Cardesa, A, Carnate, JM, Castillo, GJJ, Cavallo, R, Chowdhury, FR, Chowdhury, FUH, Ciccone, G, Cingolani, A, Climacosa, FMM, Compernolle, V, Cortez, CFN, Neto, AC, D'Antico, S, Daly, J, Danielle, F, Davis, JS, De Rosa, FG, Denholm, JT, Denkinger, CM, Desmecht, D, Diaz-Coronado, JC, Diaz Ponce-Medrano, JA, Donneau, A-F, Dumagay, TE, Dunachie, S, Dungog, CC, Erinoso, O, Escasa, IMS, Estcourt, LJ, Evans, A, Evasan, ALM, Fareli, CJ, Fernandez-Sanchez, V, Galassi, C, Gallo, JE, Garcia, PJ, Garcia, PL, Garcia, JA, Garigliany, M, Garza-Gonzalez, E, Gauiran, DT, Gaviria Garcia, PA, Giron-Gonzalez, J-A, Gomez-Almaguer, D, Gordon, AC, Gothot, A, Grass Guaqueta, JS, Green, C, Grimaldi, D, Hammond, NE, Harvala, H, Heralde, FM, Herrick, J, Higgins, AM, Hills, TE, Hines, J, Holm, K, Hoque, A, Hoste, E, Ignacio, JM, Ivanov, A, Janssen, M, Jennings, JH, Jha, V, King, RAN, Kjeldsen-Kragh, J, Klenerman, P, Kotecha, A, Krapp, F, Labanca, L, Laing, E, Landin-Olsson, M, Laterre, P-F, Lim, L-L, Lim, J, Ljungquist, O, Llaca-Diaz, JM, Lopez-Robles, C, Lopez-Cardenas, S, Lopez-Plaza, I, Lucero, JAC, Lundgren, M, Macias, J, Maganito, SC, Malundo, AFG, Manrique, RD, Manzini, PM, Marcos, M, Marquez, I, Javier Martinez-Marcos, F, Mata, AM, McArthur, CJ, McQuilten, ZK, McVerry, BJ, Menon, DK, Meyfroidt, G, Mirasol, MAL, Misset, B, Molton, JS, Mondragon, A, Monsalve, DM, Choghakabodi, PM, Morpeth, SC, Mouncey, PR, Moutschen, M, Muller-Tidow, C, Murphy, E, Najdovski, T, Nichol, AD, Nielsen, H, Novak, RM, O'Sullivan, MVN, Olalla, J, Osibogun, A, Osikomaiya, B, Oyonarte, S, Pardo-Oviedo, JM, Patel, MC, Paterson, DL, Pena-Perez, CA, Perez-Calatayud, AA, Perez-Alba, E, Perkina, A, Perry, N, Pouladzadeh, M, Poyato, I, Price, DJ, Quero, AKH, Rahman, MM, Rahman, MS, Ramesh, M, Ramirez-Santana, C, Rasmussen, M, Rees, MA, Rego, E, Roberts, JA, Roberts, DJ, Rodriguez, Y, Rodriguez-Bano, J, Rogers, BA, Rojas, M, Romero, A, Rowan, KM, Saccona, F, Safdarian, M, Santos, MCM, Sasadeusz, J, Scozzari, G, Shankar-Hari, M, Sharma, G, Snelling, T, Soto, A, Tagayuna, PY, Tang, A, Tatem, G, Teofili, L, Tong, SYC, Turgeon, AF, Veloso, JD, Venkatesh, B, Ventura-Enriquez, Y, Webb, SA, Wiese, L, Wiken, C, Wood, EM, Yusubalieva, GM, Zacharowski, K, Zarychanski, R, Khanna, N, Moher, D, Goodman, SN, Ioannidis, JPA, Hemkens, LG, Axfors, C, Janiaud, P, Schmitt, AM, Van't Hooft, J, Smith, ER, Haber, NA, Abayomi, A, Abduljalil, M, Abdulrahman, A, Acosta-Ampudia, Y, Aguilar-Guisado, M, Al-Beidh, F, Alejandria, MM, Alfonso, RN, Ali, M, AlQahtani, M, AlZamrooni, A, Anaya, J-M, Ang, MAC, Aomar, IF, Argumanis, LE, Averyanov, A, Baklaushev, VP, Balionis, O, Benfield, T, Berry, S, Birocco, N, Bonifacio, LB, Bowen, AC, Bown, A, Cabello-Gutierrez, C, Camacho, B, Camacho-Ortiz, A, Campbell-Lee, S, Cao, DH, Cardesa, A, Carnate, JM, Castillo, GJJ, Cavallo, R, Chowdhury, FR, Chowdhury, FUH, Ciccone, G, Cingolani, A, Climacosa, FMM, Compernolle, V, Cortez, CFN, Neto, AC, D'Antico, S, Daly, J, Danielle, F, Davis, JS, De Rosa, FG, Denholm, JT, Denkinger, CM, Desmecht, D, Diaz-Coronado, JC, Diaz Ponce-Medrano, JA, Donneau, A-F, Dumagay, TE, Dunachie, S, Dungog, CC, Erinoso, O, Escasa, IMS, Estcourt, LJ, Evans, A, Evasan, ALM, Fareli, CJ, Fernandez-Sanchez, V, Galassi, C, Gallo, JE, Garcia, PJ, Garcia, PL, Garcia, JA, Garigliany, M, Garza-Gonzalez, E, Gauiran, DT, Gaviria Garcia, PA, Giron-Gonzalez, J-A, Gomez-Almaguer, D, Gordon, AC, Gothot, A, Grass Guaqueta, JS, Green, C, Grimaldi, D, Hammond, NE, Harvala, H, Heralde, FM, Herrick, J, Higgins, AM, Hills, TE, Hines, J, Holm, K, Hoque, A, Hoste, E, Ignacio, JM, Ivanov, A, Janssen, M, Jennings, JH, Jha, V, King, RAN, Kjeldsen-Kragh, J, Klenerman, P, Kotecha, A, Krapp, F, Labanca, L, Laing, E, Landin-Olsson, M, Laterre, P-F, Lim, L-L, Lim, J, Ljungquist, O, Llaca-Diaz, JM, Lopez-Robles, C, Lopez-Cardenas, S, Lopez-Plaza, I, Lucero, JAC, Lundgren, M, Macias, J, Maganito, SC, Malundo, AFG, Manrique, RD, Manzini, PM, Marcos, M, Marquez, I, Javier Martinez-Marcos, F, Mata, AM, McArthur, CJ, McQuilten, ZK, McVerry, BJ, Menon, DK, Meyfroidt, G, Mirasol, MAL, Misset, B, Molton, JS, Mondragon, A, Monsalve, DM, Choghakabodi, PM, Morpeth, SC, Mouncey, PR, Moutschen, M, Muller-Tidow, C, Murphy, E, Najdovski, T, Nichol, AD, Nielsen, H, Novak, RM, O'Sullivan, MVN, Olalla, J, Osibogun, A, Osikomaiya, B, Oyonarte, S, Pardo-Oviedo, JM, Patel, MC, Paterson, DL, Pena-Perez, CA, Perez-Calatayud, AA, Perez-Alba, E, Perkina, A, Perry, N, Pouladzadeh, M, Poyato, I, Price, DJ, Quero, AKH, Rahman, MM, Rahman, MS, Ramesh, M, Ramirez-Santana, C, Rasmussen, M, Rees, MA, Rego, E, Roberts, JA, Roberts, DJ, Rodriguez, Y, Rodriguez-Bano, J, Rogers, BA, Rojas, M, Romero, A, Rowan, KM, Saccona, F, Safdarian, M, Santos, MCM, Sasadeusz, J, Scozzari, G, Shankar-Hari, M, Sharma, G, Snelling, T, Soto, A, Tagayuna, PY, Tang, A, Tatem, G, Teofili, L, Tong, SYC, Turgeon, AF, Veloso, JD, Venkatesh, B, Ventura-Enriquez, Y, Webb, SA, Wiese, L, Wiken, C, Wood, EM, Yusubalieva, GM, Zacharowski, K, Zarychanski, R, Khanna, N, Moher, D, Goodman, SN, Ioannidis, JPA, and Hemkens, LG

Abstract

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% o

Published
2021

20. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Author

Axfors, C., Janiaud, P., Schmitt, A. M., van't Hooft, J., Smith, E. R., Haber, N. A., Abayomi, A., Abduljalil, M., Abdulrahman, A., Acosta-Ampudia, Y., Aguilar-Guisado, M., Al-Beidh, F., Alejandria, M. M., Alfonso, R. N., Ali, M., Alqahtani, M., Alzamrooni, A., Anaya, J. -M., Ang, M. A. C., Aomar, I. F., Argumanis, L. E., Averyanov, A., Baklaushev, V. P., Balionis, O., Benfield, T., Berry, S., Birocco, N., Bonifacio, L. B., Bowen, A. C., Bown, A., Cabello-Gutierrez, C., Camacho, B., Camacho-Ortiz, A., Campbell-Lee, S., Cao, D. H., Cardesa, A., Carnate, J. M., Castillo, G. J. J., Cavallo, R., Chowdhury, F. R., Chowdhury, F. U. H., Ciccone, G., Cingolani, Antonella, Climacosa, F. M. M., Compernolle, V., Cortez, C. F. N., Costa Neto, A., D'Antico, S., Daly, J., Danielle, F., Davis, J. S., De Rosa, F. G., Denholm, J. T., Denkinger, C. M., Desmecht, D., Diaz-Coronado, J. C., Diaz Ponce-Medrano, J. A., Donneau, A. -F., Dumagay, T. E., Dunachie, S., Dungog, C. C., Erinoso, O., Escasa, I. M. S., Estcourt, L. J., Evans, A., Evasan, A. L. M., Fareli, C. J., Fernandez-Sanchez, V., Galassi, C., Gallo, J. E., Garcia, P. J., Garcia, P. L., Garcia, J. A., Garigliany, M., Garza-Gonzalez, E., Gauiran, D. T. V., Gaviria Garcia, P. A., Giron-Gonzalez, J. -A., Gomez-Almaguer, D., Gordon, A. C., Gothot, A., Grass Guaqueta, J. S., Green, C., Grimaldi, D., Hammond, N. E., Harvala, H., Heralde, F. M., Herrick, J., Higgins, A. M., Hills, T. E., Hines, J., Holm, K., Hoque, A., Hoste, E., Ignacio, J. M., Ivanov, A. V., Janssen, M., Jennings, J. H., Jha, V., King, R. A. N., Kjeldsen-Kragh, J., Klenerman, P., Kotecha, A., Krapp, F., Labanca, L., Laing, E., Landin-Olsson, M., Laterre, P. -F., Lim, L. -L., Lim, J., Ljungquist, O., Llaca-Diaz, J. M., Lopez-Robles, C., Lopez-Cardenas, S., Lopez-Plaza, I., Lucero, J. A. C., Lundgren, M., Macias, J., Maganito, S. C., Malundo, A. F. G., Manrique, R. D., Manzini, P. M., Marcos, M., Marquez, I., Martinez-Marcos, F. J., Mata, A. M., Mcarthur, C. J., Mcquilten, Z. K., Mcverry, B. J., Menon, D. K., Meyfroidt, G., Mirasol, M. A. L., Misset, B., Molton, J. S., Mondragon, A. V., Monsalve, D. M., Moradi Choghakabodi, P., Morpeth, S. C., Mouncey, P. R., Moutschen, M., Muller-Tidow, C., Murphy, E., Najdovski, T., Nichol, A. D., Nielsen, H., Novak, R. M., O'Sullivan, M. V. N., Olalla, J., Osibogun, A., Osikomaiya, B., Oyonarte, S., Pardo-Oviedo, J. M., Patel, M. C., Paterson, D. L., Pena-Perez, C. A., Perez-Calatayud, A. A., Perez-Alba, E., Perkina, A., Perry, N., Pouladzadeh, M., Poyato, I., Price, D. J., Quero, A. K. H., Rahman, M. M., Rahman, M. S., Ramesh, M., Ramirez-Santana, C., Rasmussen, M., Rees, M. A., Rego, E., Roberts, J. A., Roberts, D. J., Rodriguez, Y., Rodriguez-Bano, J., Rogers, B. A., Rojas, M., Romero, A., Rowan, K. M., Saccona, F., Safdarian, M., Santos, M. C. M., Sasadeusz, J., Scozzari, G., Shankar-Hari, M., Sharma, G., Snelling, T., Soto, A., Tagayuna, P. Y., Tang, A., Tatem, G., Teofili, Luciana, Tong, S. Y. C., Turgeon, A. F., Veloso, J. D., Venkatesh, B., Ventura-Enriquez, Y., Webb, S. A., Wiese, L., Wiken, C., Wood, E. M., Yusubalieva, G. M., Zacharowski, K., Zarychanski, R., Khanna, N., Moher, D., Goodman, S. N., Ioannidis, J. P. A., Hemkens, L. G., Cingolani A. (ORCID:0000-0002-3793-2755), Teofili L. (ORCID:0000-0002-7214-1561), Axfors, C., Janiaud, P., Schmitt, A. M., van't Hooft, J., Smith, E. R., Haber, N. A., Abayomi, A., Abduljalil, M., Abdulrahman, A., Acosta-Ampudia, Y., Aguilar-Guisado, M., Al-Beidh, F., Alejandria, M. M., Alfonso, R. N., Ali, M., Alqahtani, M., Alzamrooni, A., Anaya, J. -M., Ang, M. A. C., Aomar, I. F., Argumanis, L. E., Averyanov, A., Baklaushev, V. P., Balionis, O., Benfield, T., Berry, S., Birocco, N., Bonifacio, L. B., Bowen, A. C., Bown, A., Cabello-Gutierrez, C., Camacho, B., Camacho-Ortiz, A., Campbell-Lee, S., Cao, D. H., Cardesa, A., Carnate, J. M., Castillo, G. J. J., Cavallo, R., Chowdhury, F. R., Chowdhury, F. U. H., Ciccone, G., Cingolani, Antonella, Climacosa, F. M. M., Compernolle, V., Cortez, C. F. N., Costa Neto, A., D'Antico, S., Daly, J., Danielle, F., Davis, J. S., De Rosa, F. G., Denholm, J. T., Denkinger, C. M., Desmecht, D., Diaz-Coronado, J. C., Diaz Ponce-Medrano, J. A., Donneau, A. -F., Dumagay, T. E., Dunachie, S., Dungog, C. C., Erinoso, O., Escasa, I. M. S., Estcourt, L. J., Evans, A., Evasan, A. L. M., Fareli, C. J., Fernandez-Sanchez, V., Galassi, C., Gallo, J. E., Garcia, P. J., Garcia, P. L., Garcia, J. A., Garigliany, M., Garza-Gonzalez, E., Gauiran, D. T. V., Gaviria Garcia, P. A., Giron-Gonzalez, J. -A., Gomez-Almaguer, D., Gordon, A. C., Gothot, A., Grass Guaqueta, J. S., Green, C., Grimaldi, D., Hammond, N. E., Harvala, H., Heralde, F. M., Herrick, J., Higgins, A. M., Hills, T. E., Hines, J., Holm, K., Hoque, A., Hoste, E., Ignacio, J. M., Ivanov, A. V., Janssen, M., Jennings, J. H., Jha, V., King, R. A. N., Kjeldsen-Kragh, J., Klenerman, P., Kotecha, A., Krapp, F., Labanca, L., Laing, E., Landin-Olsson, M., Laterre, P. -F., Lim, L. -L., Lim, J., Ljungquist, O., Llaca-Diaz, J. M., Lopez-Robles, C., Lopez-Cardenas, S., Lopez-Plaza, I., Lucero, J. A. C., Lundgren, M., Macias, J., Maganito, S. C., Malundo, A. F. G., Manrique, R. D., Manzini, P. M., Marcos, M., Marquez, I., Martinez-Marcos, F. J., Mata, A. M., Mcarthur, C. J., Mcquilten, Z. K., Mcverry, B. J., Menon, D. K., Meyfroidt, G., Mirasol, M. A. L., Misset, B., Molton, J. S., Mondragon, A. V., Monsalve, D. M., Moradi Choghakabodi, P., Morpeth, S. C., Mouncey, P. R., Moutschen, M., Muller-Tidow, C., Murphy, E., Najdovski, T., Nichol, A. D., Nielsen, H., Novak, R. M., O'Sullivan, M. V. N., Olalla, J., Osibogun, A., Osikomaiya, B., Oyonarte, S., Pardo-Oviedo, J. M., Patel, M. C., Paterson, D. L., Pena-Perez, C. A., Perez-Calatayud, A. A., Perez-Alba, E., Perkina, A., Perry, N., Pouladzadeh, M., Poyato, I., Price, D. J., Quero, A. K. H., Rahman, M. M., Rahman, M. S., Ramesh, M., Ramirez-Santana, C., Rasmussen, M., Rees, M. A., Rego, E., Roberts, J. A., Roberts, D. J., Rodriguez, Y., Rodriguez-Bano, J., Rogers, B. A., Rojas, M., Romero, A., Rowan, K. M., Saccona, F., Safdarian, M., Santos, M. C. M., Sasadeusz, J., Scozzari, G., Shankar-Hari, M., Sharma, G., Snelling, T., Soto, A., Tagayuna, P. Y., Tang, A., Tatem, G., Teofili, Luciana, Tong, S. Y. C., Turgeon, A. F., Veloso, J. D., Venkatesh, B., Ventura-Enriquez, Y., Webb, S. A., Wiese, L., Wiken, C., Wood, E. M., Yusubalieva, G. M., Zacharowski, K., Zarychanski, R., Khanna, N., Moher, D., Goodman, S. N., Ioannidis, J. P. A., Hemkens, L. G., Cingolani A. (ORCID:0000-0002-3793-2755), and Teofili L. (ORCID:0000-0002-7214-1561)

Abstract

Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of

Published
2021

21. Recommendations for the introduction of metagenomic high-throughput sequencing in clinical virology, part I: Wet lab procedure

Author

López-Labrador, FX, Brown, JR, Fischer, N, Harvala, H, van Boheemen, Sander, Cinek, O, Sayiner, A, Madsen, TV, Auvinen, E, Kufner, V, Huber, M, Rodriguez, C, Jonges, M, Hönemann, M, Susi, P, Sousa, H, Klapper, PE, Pérez-Catalu?a, A, Hernandez, M, Molenkamp, Richard, der Hoek, LV, Schuurman, R (Rob), Couto, N, Leuzinger, K, Simmonds, P, Beer, M, Höper, D, Kamminga, S, Feltkamp, MCW, Rodríguez-Díaz, J, Keyaerts, E, Nielsen, XC, Puchhammer-Stöckl, E, Kroes, AC, Buesa, J, Breuer, J, Claas, ECJ, de Vries, J, López-Labrador, FX, Brown, JR, Fischer, N, Harvala, H, van Boheemen, Sander, Cinek, O, Sayiner, A, Madsen, TV, Auvinen, E, Kufner, V, Huber, M, Rodriguez, C, Jonges, M, Hönemann, M, Susi, P, Sousa, H, Klapper, PE, Pérez-Catalu?a, A, Hernandez, M, Molenkamp, Richard, der Hoek, LV, Schuurman, R (Rob), Couto, N, Leuzinger, K, Simmonds, P, Beer, M, Höper, D, Kamminga, S, Feltkamp, MCW, Rodríguez-Díaz, J, Keyaerts, E, Nielsen, XC, Puchhammer-Stöckl, E, Kroes, AC, Buesa, J, Breuer, J, Claas, ECJ, and de Vries, J

Abstract

Metagenomic high-throughput sequencing (mHTS) is a hypothesis-free, universal pathogen detection technique for determination of the DNA/RNA sequences in a variety of sample types and infectious syndromes. mHTS is still in its early stages of translating into clinical application. To support the development, implementation and standardization of mHTS procedures for virus diagnostics, the European Society for Clinical Virology (ESCV) Network on Next-Generation Sequencing (ENNGS) has been established. The aim of ENNGS is to bring together professionals involved in mHTS for viral diagnostics to share methodologies and experiences, and to develop application recommendations. This manuscript aims to provide practical recommendations for the wet lab procedures necessary for implementation of mHTS for virus diagnostics and to give recommendations for development and validation of laboratory methods, including mHTS quality assurance, control and quality assessment protocols.

Published
2021

24. A European multicentre evaluation of detection and typing methods for human enteroviruses and parechoviruses using RNA transcripts

Author

Hayes, A., primary, Nguyen, D., additional, Andersson, M., additional, Antón, A., additional, Bailly, J.‐L., additional, Beard, S., additional, Benschop, K. S. M., additional, Berginc, N., additional, Blomqvist, S., additional, Cunningham, E., additional, Davis, D., additional, Dembinski, J. L., additional, Diedrich, S., additional, Dudman, S. G., additional, Dyrdak, R., additional, Eltringham, G. J. A., additional, Gonzales‐Goggia, S., additional, Gunson, R., additional, Howson‐Wells, H. C., additional, Jääskeläinen, A. J., additional, López‐Labrador, F. X., additional, Maier, M., additional, Majumdar, M., additional, Midgley, S., additional, Mirand, A., additional, Morley, U., additional, Nordbø, S. A., additional, Oikarinen, S., additional, Osman, H., additional, Papa, A., additional, Pellegrinelli, L., additional, Piralla, A., additional, Rabella, N., additional, Richter, J., additional, Smith, M., additional, Söderlund Strand, A., additional, Templeton, K., additional, Vipond, B., additional, Vuorinen, T., additional, Williams, C., additional, Wollants, E., additional, Zakikhany, K., additional, Fischer, T. K., additional, Harvala, H., additional, and Simmonds, P., additional

Published
2020
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27. Variability and pathogenicity of hepatitis E virus genotype 3 variants

Author

Smith, DB, Ijaz, S, Tedder, RS, Hogema, B, Zaaijer, HL, Izopet, J, Bradley-Stewart, A, Gunson, R, Harvala, H, Kokki, I, and Simrrionds, P

Subjects
TRANSMISSION, viruses, Molecular Sequence Data, RECOMBINATION, CLASSIFICATION, FAMILY HEPEVIRIDAE, Virology, Germany, 07 Agricultural and Veterinary Sciences, INFECTION, Hepatitis E virus, Humans, PHYLOGENETIC ANALYSIS, Phylogeny, 11 Medical and Health Sciences, Netherlands, Science & Technology, Virulence, virus diseases, Genetic Variation, 06 Biological Sciences, Hepatitis E, Biotechnology & Applied Microbiology, Scotland, GENETIC-VARIABILITY, FULMINANT-HEPATITIS, DISEASE SEVERITY, France, Life Sciences & Biomedicine, GERMAN BLOOD-DONORS
Abstract

Infection with hepatitis E virus (HEV) can be clinically inapparent or produce symptoms and signs of hepatitis of varying severity and occasional fatality. This variability in clinical outcomes may reflect differences in host susceptibility or the presence of virally encoded determinants of pathogenicity. Analysis of complete genome sequences supports the division of HEV genotype 3 (HEV-3) variants into three major clades: 3ra comprising HEV isolates from rabbits, and 3efg and 3abchij comprising the corresponding named subtypes derived from humans and pigs. Using this framework, we investigated associations between viral genetic variability of HEV-3 in symptomatic and asymptomatic infections by comparing HEV-3 subgenomic sequences previously obtained from blood donors with those from patients presenting with hepatitis in the UK (54 blood donors, 148 hepatitis patients), the Netherlands (38 blood donors, 119 hepatitis patients), France (24 blood donors, 55 hepatitis patients) and Germany (14 blood donors, 36 hepatitis patients). In none of these countries was evidence found for a significant association between virus variants and patient group (P>0.05 Fisher's exact test). Furthermore, within a group of 123 patients in Scotland with clinically apparent HEV infections, we found no evidence for an association between variants of HEV-3 and disease severity or alanine aminotransferase level. The lack of detectable virally encoded determinants of disease outcomes in HEV-3 infection implies a more important role for host factors in its clinical phenotype.

Published
2015

38. The Association of Recombination Events in the Founding and Emergence of Subgenogroup Evolutionary Lineages of Human Enterovirus 71

Author

McWilliam Leitch, E. C., primary, Cabrerizo, M., additional, Cardosa, J., additional, Harvala, H., additional, Ivanova, O. E., additional, Koike, S., additional, Kroes, A. C. M., additional, Lukashev, A., additional, Perera, D., additional, Roivainen, M., additional, Susi, P., additional, Trallero, G., additional, Evans, D. J., additional, and Simmonds, P., additional

Published
2012
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41. Evolutionary Dynamics and Temporal/Geographical Correlates of Recombination in the Human Enterovirus Echovirus Types 9, 11, and 30

Author

McWilliam Leitch, E. C., primary, Cabrerizo, M., additional, Cardosa, J., additional, Harvala, H., additional, Ivanova, O. E., additional, Kroes, A. C. M., additional, Lukashev, A., additional, Muir, P., additional, Odoom, J., additional, Roivainen, M., additional, Susi, P., additional, Trallero, G., additional, Evans, D. J., additional, and Simmonds, P., additional

Published
2010
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42. The emergence of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus amongst hospitalised immunocompromised patients in Scotland, November-December, 2009

Author

Harvala, H, primary, Gunson, R, additional, Simmonds, P, additional, Hardie, A, additional, Bennett, S, additional, Scott, F, additional, Roddie, H, additional, McKnight, J, additional, Walsh, T, additional, Rowney, D, additional, Clark, A, additional, Bremner, J, additional, Aitken, C, additional, and Templeton, K, additional

Published
2010
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43. Recombination dynamics of human parechoviruses: investigation of type-specific differences in frequency and epidemiological correlates

Author

Calvert, J., primary, Chieochansin, T., additional, Benschop, K. S., additional, Leitch, E. C. M., additional, Drexler, J. F., additional, Grywna, K., additional, da Costa Ribeiro, H., additional, Drosten, C., additional, Harvala, H., additional, Poovorawan, Y., additional, Wolthers, K. C., additional, and Simmonds, P., additional

Published
2010
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49. Characterisation of emergent and emerging human-infective RNA viruses

Author

Ratcliff, J, Simmonds, P, Smith, A, and Harvala, H

Subjects
Virology
Abstract

Improved understanding of the early adaptation of zoonotic, human-infective RNA viruses and the genetic factors leading to spillover will inform public health approaches attempting to limit the morbidity and mortality associated with these events. In this thesis, I use clinical microbiological methods to characterize the intra-host replicative and evolutionary dynamics of SARS-CoV-2 and bioinformatic approaches to investigate genetic factors associated with spillover of arboviruses. Chapter one broadly reviews the field of virology. Chapter two reviews the apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) family of proteins, focusing on their emergence, diversification, and function, and summarizes the bioinformatic and functional evidence of their role in SARS-CoV-2 evolution. Chapter three details the methods underlying the subsequent results chapters. Chapter four describes the development and validation of single nucleotide polymorphism-based genotyping assays for identifying variants of concern in COVID-19 clinical samples. Their performance is compared to next-generation sequencing, demonstrating the superiority of the genotyping assays at a wide range of viral loads. Chapter five uses amplification data generated from two COVID-19 clinical trials to explore factors associated with viral load and within-patient viral load dynamics, uses a novel polymerase chain reaction approach to quantify subgenomic RNA transcripts, and investigates the emergence and spread of the Alpha variant in the United Kingdom and the Zeta, Gamma, and Delta variants in Brazil. Chapter six investigates the interaction between SARS-CoV-2 virological features and COVID-19 clinical outcomes leveraging patients admitted to intensive care within the REMAP-CAP convalescent plasma clinical trial. The null results in this chapter support severe COVID-19 pathology being primarily immune-mediated. Chapter seven quantitatively tests the hypothesis that convalescent plasma treatment was responsible for the emergence of SARS-CoV-2 variants of concern using an intensively sampled cohort within the REMAP-CAP convalescent plasma trial. Using a variety of approaches, no evidence in support of convalescent plasma therapy as a general driver of immune-escape substitutions was found. Chapter eight probes the genetic factors associated with human-human transmissibility of arboviruses, finding strong evidence for the role of CpG suppression in the host optimization of flaviviruses. The strong genetic barriers to spillover enable more focused surveillance of this informal classification of viruses.

Published
2023

50. Evolutionary Dynamics and Temporal/Geographical Correlates of Recombination in the Human Enterovirus Echovirus Types 9, 11, and 30.

Author

Leitch, E. C. McWilliam, Cabrerizo, M., Cardosa, J., Harvala, H., Ivanova, O. E., Kroes, A. C. M., Lukashev, A., Muir, P., Odoom, J., Roivainen, M., Susi, P., Trallero, G., Evans, D. J., and Simmonds, P.

Subjects
*ENTEROVIRUSES, *GENETIC research, *GENETIC polymorphisms, *EPIDEMIOLOGY, *MONTE Carlo method
Abstract

The relationship between virus evolution and recombination in species B human enteroviruses was investigated through large-scale genetic analysis of echovirus type 9 (E9) and E11 isolates (n = 85 and 116) from 16 European, African, and Asian countries between 1995 and 2008. Cluster 1 E9 isolates and genotype D5 and A E11 isolates showed evidence of frequent recombination between the VP1 and 3Dpol regions, the latter falling into 23 (E9) and 43 (E11) clades interspersed phylogenetically with 46 3Dpol clades of E30 and with those of other species B serotypes. Remarkably, only 2 of the 112 3Dpol clades were shared by more than one serotype (E11 and E30), demonstrating an extremely large and genetically heterogeneous recombination pool of species B nonstructural-region variants. The likelihood of recombination increased with geographical separation and time, and both were correlated with VP1 divergence, whose substitution rates allowed recombination half-lives of 1.3, 9.8, and 3.1 years, respectively, for E9, E11, and E30 to be calculated. These marked differences in recombination dynamics matched epidemiological patterns of periodic epidemic cycles of 2 to 3 (E9) and 5 to 6 (E30) years and the longer-term endemic pattern of E11 infections. Phylotemporal analysis using a Bayesian Markov chain Monte Carlo method, which placed recombination events within the evolutionary reconstruction of VP1, showed a close relationship with VP1 lineage expansion, with defined recombination events that correlated with their epidemiological periodicity. Whether recombination events contribute directly to changes in transmissibility that drive epidemic behavior or occur stochastically during periodic population bottlenecks is an unresolved issue vital to future understanding of enterovirus molecular epidemiology and pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2010
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