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2. 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

4. 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

5. 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

6. 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

7. 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

8. 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
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9. 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

10. 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

11. 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

12. 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

13. 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

14. Correction to: Recommendations for the nomenclature of enteroviruses and rhinoviruses (Archives of Virology, (2020), 165, 3, (793-797), 10.1007/s00705-019-04520-6)

Author

Simmonds, P., Gorbalenya, A. E., Harvala, H., Hovi, T., Knowles, N. J., Lindberg, A. M., Oberste, M. S., Palmenberg, A. C., Reuter, G., Skern, T., Tapparel, C., Wolthers, K. C., Woo, P. C. Y., Zell, R., Medical Microbiology and Infection Prevention, and AII - Infectious diseases

Abstract

Unfortunately, one of the affiliations of author “A. E. Gorbalenya” was missed in original version. The affiliation is updated here.

Published
2020

15. Recommendations for the nomenclature of enteroviruses and rhinoviruses

Author

Simmonds, P., Gorbalenya, A. E., Harvala, H., Hovi, T., Knowles, N. J., Lindberg, A. Michael, Oberste, M. S., Palmenberg, A. C., Reuter, G., Skern, T., Tapparel, C., Wolthers, K. C., Woo, P. C. Y., Zell, R., Simmonds, P., Gorbalenya, A. E., Harvala, H., Hovi, T., Knowles, N. J., Lindberg, A. Michael, Oberste, M. S., Palmenberg, A. C., Reuter, G., Skern, T., Tapparel, C., Wolthers, K. C., Woo, P. C. Y., and Zell, R.

Abstract

Enteroviruses (EVs) and rhinoviruses (RVs) are significant pathogens of humans and are the subject of intensive clinical and epidemiological research and public health measures, notably in the eradication of poliovirus and in the investigation and control of emerging pathogenic EV types worldwide. EVs and RVs are highly diverse in their antigenic properties, tissue tropism, disease associations and evolutionary relationships, but the latter often conflict with previously developed biologically defined terms, such as "coxsackieviruses", "polioviruses" and "echoviruses", which were used before their genetic interrelationships were understood. This has created widespread formatting problems and inconsistencies in the nomenclature for EV and RV types and species in the literature and public databases. As members of the International Committee for Taxonomy of Viruses (ICTV) Picornaviridae Study Group, we describe the correct use of taxon names for these viruses and have produced a series of recommendations for the nomenclature of EV and RV types and their abbreviations. We believe their adoption will promote greater clarity and consistency in the terminology used in the scientific and medical literature. The recommendations will additionally provide a useful reference guide for journals, other publications and public databases seeking to use standardised terms for the growing multitude of enteroviruses and rhinoviruses described worldwide., Correction published in: Archives of Virology, DOI 10.1007/s00705-020-04558-x

Published
2020
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18. 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

26. 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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27. 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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28. 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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29. 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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33. 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

34. 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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35. Poliovirus circulation in the WHO European region, 2015-2022: a review of data from WHO's three core poliovirus surveillance systems.

Author

Fischer TK, Johannesen CK, Benschop KSM, Berginc N, Saxentoff EV, Huseynov S, Hagan JE, and Harvala H

Abstract

Background: The Global Polio Eradication Initiative (GPEI) has drastically reduced the global incidence of poliomyelitis since its launch in 1988 thanks to effective vaccines and strong global surveillance systems. However, detections of wild-type as well as vaccine-derived poliovirus (VDPV) still occur, also in the WHO European Region. This study aims to describe the poliovirus detection via the acute flaccid paralysis (AFP), clinical enterovirus, and environmental surveillance systems., Methods: In this study, we review data from annual reports from 2015 to 2022 from the World Health Organization (WHO)'s three core poliovirus surveillance systems in place in the WHO European Region: AFP, clinical enterovirus, and environmental surveillance systems., Findings: A total of 4324 reported samples were found positive for poliovirus: 477 from AFP surveillance, 394 from clinical surveillance and 3453 from environmental surveillance. Of these, 366 were VDPV, 3952 vaccine strains, and 6 were wild-type poliovirus. 709 were identified as type 1, 399 as type 2, and 1944 type 3, while 1272 samples contained more than one type. Temporal and spatial association of positive environmental samples with positive samples from AFP or clinical enterovirus surveillance was found in only eight countries., Interpretation: Analysis of poliovirus-positive samples from AFP, clinical enterovirus, and environmental surveillance revealed that type 3 poliovirus was the most prevalent type detected. Most poliovirus-positive samples were identified as vaccine strains. No information on sequences was available., Funding: This study was funded by WHO Regional Office for Europe and received financial support from the Bill and Melinda Gates Foundation., Competing Interests: TKF is co-founder of ENPEN and declare conference and workshop attendance financed by The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Society of Clinical Virology (ESCV). CKJ and NB are members of ENPEN and declare conference and workshop attendance financed by European Society of Clinical Virology (ESCV). In addition, CKJ reports contracted work with WHO on polio- and non-polio surveillance. KSMB and HH are members of the European non-polio enterovirus network (ENPEN) and have no conflicts of interest to declare. EVS, SH, and JEH are employees of the WHO Regional Office for Europe and have no conflicts of interest to declare., (© 2024 Published by Elsevier Ltd.)

Published
2024
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36. Biochemical rationale for transfusion of high titre COVID-19 convalescent plasma.

Author

Verbrugghe C, Wouters E, Devloo R, Nurmi V, Seghers S, De Bleser D, Harvala H, Compernolle V, and Feys HB

Subjects
Humans, Immunoglobulin A blood, Immunoglobulin A immunology, Viral Load, Male, Female, Middle Aged, Blood Donors, Adult, COVID-19 therapy, COVID-19 immunology, COVID-19 virology, COVID-19 blood, Immunization, Passive, COVID-19 Serotherapy, Antibodies, Viral blood, Antibodies, Viral immunology, SARS-CoV-2 immunology, Immunoglobulin G blood, Immunoglobulin G immunology
Abstract

We aimed to model binding of donor antibodies to virus that infects COVID-19 patients following transfusion of convalescent plasma (CCP). An immunosorbent assay was developed to determine apparent affinity (K d, app ). Antibody binding to virus was modelled using antibody concentration and estimations of viral load. Assay and model were validated using reference antibodies and clinical data of monoclonal antibody therapy. A single K d, app or two resolvable K d, app were found for IgG in 11% or 89% of CCP donations, respectively. For IgA this was 50%-50%. Median IgG K d, app was 0.8nM and 3.6nM for IgA, ranging from 0.1-14.7nM and 0.2-156.0nM respectively. The median concentration of IgG was 44.0nM (range 8.4-269.0nM) and significantly higher than IgA at 2.0nM (range 0.4-11.4nM). The model suggested that a double CCP transfusion (i.e. 500 mL) allows for > 80% binding of antibody to virus provided K d, app was < 1nM and concentration > 150nM. In our cohort from the pre-vaccination era, 4% of donations fulfilled these criteria. Low and mid-range viral loads are found early post exposure, suggesting that convalescent plasma will be most effective then. This study provides a biochemical rationale for selecting high affinity and high antibody concentration CCP transfused early in the disease course., (© 2024. The Author(s).)

Published
2024
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38. Castanet: a pipeline for rapid analysis of targeted multi-pathogen genomic data.

Author

Mayne R, Secret S, Geoghegan C, Trebes A, Kean K, Reid K, Lin GL, Ansari MA, de Cesare M, Bonsall D, Elliott I, Piazza P, Brown A, Bray J, Knight JC, Harvala H, Breuer J, Simmonds P, Bowden RJ, and Golubchik T

Subjects
Genomics methods, High-Throughput Nucleotide Sequencing methods, Humans, Sequence Analysis, DNA methods, Metagenomics methods, Software
Abstract

Motivation: Target enrichment strategies generate genomic data from multiple pathogens in a single process, greatly improving sensitivity over metagenomic sequencing and enabling cost-effective, high-throughput surveillance and clinical applications. However, uptake by research and clinical laboratories is constrained by an absence of computational tools that are specifically designed for the analysis of multi-pathogen enrichment sequence data. Here we present an analysis pipeline, Castanet, for use with multi-pathogen enrichment sequencing data. Castanet is designed to work with short-read data produced by existing targeted enrichment strategies, but can be readily deployed on any BAM file generated by another methodology. Also included are an optional graphical interface and installer script., Results: In addition to genome reconstruction, Castanet reports method-specific metrics that enable quantification of capture efficiency, estimation of pathogen load, differentiation of low-level positives from contamination, and assessment of sequencing quality. Castanet can be used as a traditional end-to-end pipeline for consensus generation, but its strength lies in the ability to process a flexible, pre-defined set of pathogens of interest directly from multi-pathogen enrichment experiments. In our tests, Castanet consensus sequences were accurate reconstructions of reference sequences, including in instances where multiple strains of the same pathogen were present. Castanet performs effectively on standard computers and can process the entire output of a 96-sample enrichment sequencing run (50M reads) using a single batch process command, in $<$2 h., Availability and Implementation: Source code freely available under GPL-3 license at https://github.com/MultipathogenGenomics/castanet, implemented in Python 3.10 and supported in Ubuntu Linux 22.04. The data underlying this article are available in Europe Nucleotide Archives, at https://www.ebi.ac.uk/ena/browser/view/PRJEB77004., (© The Author(s) 2024. Published by Oxford University Press.)

Published
2024
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39. Changes in Phenotypic and Molecular Features of Naïve and Central Memory T Helper Cell Subsets following SARS-CoV-2 Vaccination.

Author

Mosavie M, Rynne J, Fish M, Smith P, Jennings A, Singh S, Millar J, Harvala H, Mora A, Kaloyirou F, Griffiths A, Hopkins V, Washington C, Estcourt LJ, Roberts D, and Shankar-Hari M

Abstract

Molecular changes in lymphocytes following SARS-CoV-2 vaccination are incompletely understood. We hypothesized that studying the molecular (transcriptomic, epigenetic, and T cell receptor (TCR) repertoire) changes in CD4 + T cells following SARS-CoV-2 vaccination could inform protective mechanisms and refinement of future vaccines. We tested this hypothesis by reporting alterations in CD4 + T cell subsets and molecular features of CD4 + naïve and CD4 + central memory (CM) subsets between the unvaccinated and vaccinated groups. Compared with the unvaccinated, the vaccinated had higher HLA-DR expression in CD4 + T subsets, a greater number of differentially expressed genes (DEGs) that overlapped with key differentially accessible regions (DARs) along the chromatin linked to inflammasome activation, translation, regulation (of apoptosis, inflammation), and significant changes in clonal architecture beyond SARS-CoV-2 specificity. Several of these differences were more pronounced in the CD4 + CM subset. Taken together, our observations imply that the COVID-19 vaccine exerts its protective effects via modulation of acute inflammation to SARS-CoV-2 challenge.

Published
2024
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40. Evaluating metagenomics and targeted approaches for diagnosis and surveillance of viruses.

Author

Buddle S, Forrest L, Akinsuyi N, Martin Bernal LM, Brooks T, Venturini C, Miller C, Brown JR, Storey N, Atkinson L, Best T, Roy S, Goldsworthy S, Castellano S, Simmonds P, Harvala H, Golubchik T, Williams R, Breuer J, Morfopoulou S, and Torres Montaguth OE

Subjects
Humans, High-Throughput Nucleotide Sequencing methods, Virus Diseases diagnosis, Virus Diseases virology, Metagenome, Sensitivity and Specificity, Metagenomics methods, Viruses genetics, Viruses isolation & purification
Abstract

Background: Metagenomics is a powerful approach for the detection of unknown and novel pathogens. Workflows based on Illumina short-read sequencing are becoming established in diagnostic laboratories. However, high sequencing depth requirements, long turnaround times, and limited sensitivity hinder broader adoption. We investigated whether we could overcome these limitations using protocols based on untargeted sequencing with Oxford Nanopore Technologies (ONT), which offers real-time data acquisition and analysis, or a targeted panel approach, which allows the selective sequencing of known pathogens and could improve sensitivity., Methods: We evaluated detection of viruses with readily available untargeted metagenomic workflows using Illumina and ONT, and an Illumina-based enrichment approach using the Twist Bioscience Comprehensive Viral Research Panel (CVRP), which targets 3153 viruses. We tested samples consisting of a dilution series of a six-virus mock community in a human DNA/RNA background, designed to resemble clinical specimens with low microbial abundance and high host content. Protocols were designed to retain the host transcriptome, since this could help confirm the absence of infectious agents. We further compared the performance of commonly used taxonomic classifiers., Results: Capture with the Twist CVRP increased sensitivity by at least 10-100-fold over untargeted sequencing, making it suitable for the detection of low viral loads (60 genome copies per ml (gc/ml)), but additional methods may be needed in a diagnostic setting to detect untargeted organisms. While untargeted ONT had good sensitivity at high viral loads (60,000 gc/ml), at lower viral loads (600-6000 gc/ml), longer and more costly sequencing runs would be required to achieve sensitivities comparable to the untargeted Illumina protocol. Untargeted ONT provided better specificity than untargeted Illumina sequencing. However, the application of robust thresholds standardized results between taxonomic classifiers. Host gene expression analysis is optimal with untargeted Illumina sequencing but possible with both the CVRP and ONT., Conclusions: Metagenomics has the potential to become standard-of-care in diagnostics and is a powerful tool for the discovery of emerging pathogens. Untargeted Illumina and ONT metagenomics and capture with the Twist CVRP have different advantages with respect to sensitivity, specificity, turnaround time and cost, and the optimal method will depend on the clinical context., (© 2024. The Author(s).)

Published
2024
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41. Why is polio still a concern, also in Europe?

Author

Fischer TK, Johannesen CK, Berginc N, Bailly JL, Benschop K, and Harvala H

Abstract

Competing Interests: None of the authors have worked in the poliovaccine producing industry or have stocks in poliovaccine companies.

Published
2024
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42. Parechovirus A Circulation and Testing Capacities in Europe, 2015-2021.

Author

Bubba L, Broberg EK, Fischer TK, Simmonds P, and Harvala H

Subjects
Child, Infant, Newborn, Humans, Child, Preschool, Retrospective Studies, Europe epidemiology, Disease Outbreaks, Laboratories, Parechovirus genetics
Abstract

Parechovirus infections usually affect neonates and young children; manifestations vary from asymptomatic to life-threatening. We describe laboratory capacity in Europe for assessing parechovirus circulation, seasonality, and epidemiology. We used retrospective anonymized data collected from parechovirus infection case-patients identified in Europe during January 2015-December 2021. Of 21 laboratories from 18 countries that participated in the study, 16 (76%) laboratories with parechovirus detection capacity reported 1,845 positive samples; 12/16 (75%) with typing capability successfully identified 517 samples. Parechovirus A3 was the most common type (n = 278), followed by A1 (153), A6 (50), A4 (13), A5 (22), and A14 (1). Clinical data from 1,269 participants highlighted correlation of types A3, A4, and A5 with severe disease in neonates. We observed a wide capacity in Europe to detect, type, and analyze parechovirus data. To enhance surveillance and response for PeV outbreaks, sharing typing protocols and data on parechovirus-positive cases should be encouraged.

Published
2024
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43. Wastewater Surveillance in Europe for Non-Polio Enteroviruses and Beyond.

Author

Bubba L, Benschop KSM, Blomqvist S, Duizer E, Martin J, Shaw AG, Bailly JL, Rasmussen LD, Baicus A, Fischer TK, and Harvala H

Abstract

Wastewater surveillance (WWS) was developed in the early 1960s for the detection of poliovirus (PV) circulation in the population. It has been used to monitor several pathogens, including non-polio enteroviruses (NPEVs), which are increasingly recognised as causes of morbidity in children. However, when applying WWS to a new pathogen, it is important to consider the purpose of such a study as well as the suitability of the chosen methodology. With this purpose, the European Non-Polio Enterovirus Network (ENPEN) organised an expert webinar to discuss its history, methods, and applications; its evolution from a culture-based method to molecular detection; and future implementation of next generation sequencing (NGS). The first simulation experiments with PV calculated that a 400 mL sewage sample is sufficient for the detection of viral particles if 1:10,000 people excrete poliovirus in a population of 700,000 people. If the method is applied correctly, several NPEV types are detected. Despite culture-based methods remaining the gold standard for WWS, direct methods followed by molecular-based and sequence-based assays have been developed, not only for enterovirus but for several pathogens. Along with case-based sentinel and/or syndromic surveillance, WWS for NPEV and other pathogens represents an inexpensive, flexible, anonymised, reliable, population-based tool for monitoring outbreaks and the (re)emergence of these virus types/strains within the general population.

Published
2023
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44. Investigating Blood Donors With Postdonation Respiratory Tract Symptoms During the Wild-Type, Delta, and Omicron Waves of the Coronavirus Disease 2019 Pandemic in England.

Author

Gates S, Ijaz S, Baklan H, Washington C, Brailsford S, Zambon M, and Harvala H

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been shown to be detectable in blood from infected individuals. Though RNAemia frequencies are typically low, the presence of potentially infectious virus potentially poses a transmission risk during blood transfusion., Methods: Archived plasma samples were collected from blood donors who later reported possible SARS-CoV-2 infection with the wild-type strain, Delta variant, or Omicron variant. This was based on either symptom onset or a positive test within 2 weeks from their donation. Donations were tested for SARS-CoV-2 RNA, and information on symptoms and testing results were gathered during postdonation interview., Results: Of 518 archived plasma samples tested, 19 (3.7%) were found to have detectable levels of SARS-CoV-2 RNA. SARS-CoV-2 RNA was detected in donors who donated during the Delta (10/141 [7.1%]) and Omicron (9/162 [5.6%]) waves. SARS-CoV-2 RNA was not detected in donors who donated during the wild-type wave (0/215). Seventeen of 19 RNAemic donors reported symptom onset or a positive test within 2 days of donating. SARS-CoV-2 RNA was detected in asymptomatic or presymptomatic blood donors., Conclusions: Despite RNAemia being correlated with SARS-CoV-2 disease severity, RNAemia was detected in asymptomatic or presymptomatic blood donors., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Published
2023
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45. Changes in transmission of Enterovirus D68 (EV-D68) in England inferred from seroprevalence data.

Author

Pons-Salort M, Lambert B, Kamau E, Pebody R, Harvala H, Simmonds P, and Grassly NC

Subjects
Humans, Seroepidemiologic Studies, Disease Outbreaks, England epidemiology, Enterovirus D, Human, Neuromuscular Diseases, Enterovirus Infections epidemiology
Abstract

The factors leading to the global emergence of Enterovirus D68 (EV-D68) in 2014 as a cause of acute flaccid myelitis (AFM) in children are unknown. To investigate potential changes in virus transmissibility or population susceptibility, we measured the seroprevalence of EV-D68-specific neutralising antibodies in serum samples collected in England in 2006, 2011, and 2017. Using catalytic mathematical models, we estimate an approximately 50% increase in the annual probability of infection over the 10-year study period, coinciding with the emergence of clade B around 2009. Despite such increase in transmission, seroprevalence data suggest that the virus was already widely circulating before the AFM outbreaks and the increase of infections by age cannot explain the observed number of AFM cases. Therefore, the acquisition of or an increase in neuropathogenicity would be additionally required to explain the emergence of outbreaks of AFM. Our results provide evidence that changes in enterovirus phenotypes cause major changes in disease epidemiology., Competing Interests: MP, BL, EK, RP, HH, PS, NG No competing interests declared, (© 2023, Pons-Salort et al.)

Published
2023
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46. Accelerated waning of the humoral response to COVID-19 vaccines in obesity.

Author

van der Klaauw AA, Horner EC, Pereyra-Gerber P, Agrawal U, Foster WS, Spencer S, Vergese B, Smith M, Henning E, Ramsay ID, Smith JA, Guillaume SM, Sharpe HJ, Hay IM, Thompson S, Innocentin S, Booth LH, Robertson C, McCowan C, Kerr S, Mulroney TE, O'Reilly MJ, Gurugama TP, Gurugama LP, Rust MA, Ferreira A, Ebrahimi S, Ceron-Gutierrez L, Scotucci J, Kronsteiner B, Dunachie SJ, Klenerman P, Park AJ, Rubino F, Lamikanra AA, Stark H, Kingston N, Estcourt L, Harvala H, Roberts DJ, Doffinger R, Linterman MA, Matheson NJ, Sheikh A, Farooqi IS, and Thaventhiran JED

Subjects
Humans, COVID-19 Vaccines, Longitudinal Studies, Prospective Studies, SARS-CoV-2, Obesity epidemiology, Antibodies, Neutralizing, Antibodies, Viral, Vaccination, Obesity, Morbid, COVID-19 epidemiology, COVID-19 prevention & control
Abstract

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m 2 ) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60-1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5-24.9 kg/m 2 ). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies., (© 2023. The Author(s).)

Published
2023
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47. Early, very high-titre convalescent plasma therapy in clinically vulnerable individuals with mild COVID-19 (COVIC-19): protocol for a randomised, open-label trial.

Author

Desmarets M, Hoffmann S, Vauchy C, Rijnders BJA, Toussirot E, Durrbach A, Körper S, Schrezenmeier E, van der Schoot CE, Harvala H, Brunotte G, Appl T, Seifried E, Tiberghien P, Bradshaw D, Roberts DJ, Estcourt LJ, and Schrezenmeier H

Subjects
Humans, Aged, SARS-CoV-2, COVID-19 Serotherapy, Hospitalization, Immunization, Passive methods, Treatment Outcome, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, COVID-19 therapy
Abstract

Introduction: COVID-19 convalescent plasma (CCP) is a possible treatment option for COVID-19. A comprehensive number of clinical trials on CCP efficacy have already been conducted. However, many aspects of CCP treatment still require investigations: in particular (1) Optimisation of the CCP product, (2) Identification of the patient population in need and most likely to benefit from this treatment approach, (3) Timing of administration and (4) CCP efficacy across viral variants in vivo. We aimed to test whether high-titre CCP, administered early, is efficacious in preventing hospitalisation or death in high-risk patients., Methods and Analysis: COVIC-19 is a multicentre, randomised, open-label, adaptive superiority phase III trial comparing CCP with very high neutralising antibody titre administered within 7 days of symptom onset plus standard of care versus standard of care alone. We will enrol patients in two cohorts of vulnerable patients [(1) elderly 70+ years, or younger with comorbidities; (2) immunocompromised patients]. Up to 1020 participants will be enrolled in each cohort (at least 340 with a sample size re-estimation after reaching 102 patients). The primary endpoint is the proportion of participants with (1) Hospitalisation due to progressive COVID-19, or (2) Who died by day 28 after randomisation. Principal analysis will follow the intention-to-treat principle., Ethics and Dissemination: Ethical approval has been granted by the University of Ulm ethics committee (#41/22) (lead ethics committee for Germany), Comité de protection des personnes Sud-Est I (CPP Sud-Est I) (#2022-A01307-36) (ethics committee for France), and ErasmusMC ethics committee (#MEC-2022-0365) (ethics committee for the Netherlands). Signed informed consent will be obtained from all included patients. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings., Trial Registration: Clinical Trials.gov (NCT05271929), EudraCT (2021-006621-22)., Competing Interests: Competing interests: PT is an employee of Établissement Français du Sang, the blood establishment responsible for blood collection, qualification and supply in France. HS, SH, SK, TA and ES are employees of the German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen (or its affiliates), the establishment responsible for blood collection, qualification and supply in Baden-Württemberg and Hesse, Germany. CEV, is an employee of Sanquin, the establishment responsible for blood collection, qualification and supply in the Netherlands. The authors declare no other competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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48. Undeclared pre-exposure or post-exposure prophylaxis (PrEP/PEP) use among syphilis-positive blood donors, England, 2020 to 2021.

Author

Maddox V, Reynolds C, Amara A, Else L, Brailsford SR, Khoo S, and Harvala H

Subjects
Humans, Male, Post-Exposure Prophylaxis, Blood Donors, England, Homosexuality, Male, HIV Infections prevention & control, Syphilis epidemiology, Syphilis prevention & control, Pre-Exposure Prophylaxis
Abstract

An individualised blood donor selection policy was implemented in the United Kingdom from summer 2021. We have investigated the impact of this policy by comparing the extent of undeclared use of HIV pre-exposure or post-exposure prophylaxis (PrEP/PEP) before and after this change. The rate of PrEP usage in syphilis-positive male blood donors has not changed since individualised donor assessment was implemented but provides continuing evidence of undisclosed PrEP use which may be associated with current or past higher-risk sexual behaviours.

Published
2023
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49. Fulminant Transfusion-Associated Hepatitis E Virus Infection Despite Screening, England, 2016-2020.

Author

Harvala H, Reynolds C, Brailsford S, and Davison K

Subjects
Blood Donors, Blood Transfusion, Humans, Mass Screening methods, RNA, Viral genetics, Hepatitis E diagnosis, Hepatitis E epidemiology, Hepatitis E virus genetics
Abstract

In England, all blood donations are screened in pools of 24 by nucleic acid test (NAT) for hepatitis E virus (HEV) RNA. During 2016-2020, this screening successfully identified and intercepted 1,727 RNA-positive donations. However, review of previous donations from infected platelet donors identified 9 donations in which HEV RNA detection was missed, of which 2 resulted in confirmed transmission: 1 infection resolved with ribavirin treatment, and 1 proceeded to fatal multiorgan failure within a month from infection. Residual risk calculations predict that over the 5-year study period, HEV RNA detection was missed by minipool NAT in 12-23 platelet and 177-354 whole-blood donations, but transmission risk remains undetermined. Although screening has been able to largely eliminate infectious HEV from the blood supply in England, missed detection of low levels of HEV RNA in donated blood can lead to a severe, even fulminant, infection in recipients and could be prevented by more sensitive screening.

Published
2022
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50. Highly Sensitive Lineage Discrimination of SARS-CoV-2 Variants through Allele-Specific Probe PCR.

Author

Ratcliff J, Al-Beidh F, Bibi S, Bonsall D, Costa Clemens SA, Estcourt L, Evans A, Fish M, Folegatti PM, Gordon AC, Jay C, Jennings A, Laing E, Lambe T, MacIntyre-Cockett G, Menon D, Mouncey PR, Nguyen D, Pollard AJ, Ramasamy MN, Roberts DJ, Rowan KM, Rynne J, Shankar-Hari M, Williams S, Harvala H, Golubchik T, and Simmonds P

Subjects
Alleles, Humans, Polymerase Chain Reaction, COVID-19 diagnosis, SARS-CoV-2 genetics
Abstract

Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality. To this aim, an allele-specific probe PCR (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. Individual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. The comparative advantage for ASP-PCR over NGS was most pronounced in samples with cycle threshold ( C T ) values between 26 and 30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well suited to augment but not replace NGS. The method can differentiate SARS-CoV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer-target base mismatch through altered oligonucleotide chemistry or chemical additives.

Published
2022
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