Daouda Sissoko1, Sophie Duraffour2, Romy Kerber3, Jacques Seraphin Kolie4, Abdoul Habib Beavogui4, Alseny-Modet Camara5, Géraldine Colin6, Toni Rieger3, Lisa Oestereich3, Bernadett Pályi7, Stephanie Wurr3, Jeremie Guedj8, Thi Huyen Tram Nguyen8, Rosalind M Eggo9, Conall H Watson9, W John Edmunds9, Joseph Akoi Bore10, Fara Raymond Koundouno10, Mar Cabeza-Cabrerizo2, Lisa L Carter11, Liana Eleni Kafetzopoulou12, Eeva Kuisma13, Janine Michel14, Livia Victoria Patrono2, Natasha Y Rickett15, Katrin Singethan16, Martin Rudolf3, Angelika Lander17, Elisa Pallasch3, Sabrina Bockholt3, Estefanía Rodríguez18, Antonino Di Caro19, Roman Wölfel20, Martin Gabriel2, Céline Gurry21, Pierre Formenty21, Sakoba Keïta22, Denis Malvy1, Miles W Carroll23, Xavier Anglaret6, Stephan Günther24. 1. INSERM U1219, Bordeaux University, Bordeaux, France; Bordeaux University Hospital, Bordeaux, France. 2. The European Mobile Laboratory Consortium, Hamburg, Germany; Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany. 3. Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany; German Centre for Infection Research (DZIF), Partner Site Hamburg, Conakry, Guinea. 4. Centre de Formation et de Recherche en Santé Rurale de Mafèrinyah, Conakry, Guinea. 5. Department of Infectious Diseases, Donka Hospital, Conakry, Guinea. 6. INSERM U1219, Bordeaux University, Bordeaux, France; PAC-CI, ANRS Research Site, Treichville University Hospital, Abidjan, Côte d'Ivoire. 7. National Centre for Epidemiology, Hungarian National Biosafety Laboratory, Budapest, Hungary. 8. INSERM, IAME, UMR 1137 Paris, and Université Paris Diderot, Sorbonne Paris Cité, France. 9. Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK. 10. The European Mobile Laboratory Consortium, Hamburg, Germany; Ministry of Health Guinea, Conakry, Guinea. 11. The European Mobile Laboratory Consortium, Hamburg, Germany; University College London, London, UK. 12. The European Mobile Laboratory Consortium, Hamburg, Germany; Laboratory for Clinical and Epidemiological Virology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium. 13. The European Mobile Laboratory Consortium, Hamburg, Germany; Public Health England, Porton Down, Salisbury, UK. 14. The European Mobile Laboratory Consortium, Hamburg, Germany; Robert Koch Institute, Berlin, Germany. 15. The European Mobile Laboratory Consortium, Hamburg, Germany; Institute of Infection and Global Health, University of Liverpool, Liverpool, UK. 16. The European Mobile Laboratory Consortium, Hamburg, Germany; Institute of Virology, Technische Universität München, Munich, Germany. 17. Robert Koch Institute, Berlin, Germany. 18. German Centre for Infection Research (DZIF), Partner Site Hamburg, Conakry, Guinea; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg. 19. The European Mobile Laboratory Consortium, Hamburg, Germany; National Institute for Infectious Diseases Lazzaro Spallanzani, Rome, Italy. 20. The European Mobile Laboratory Consortium, Hamburg, Germany; Bundeswehr Institute of Microbiology, Munich, Switzerland. 21. WHO, Geneva, Switzerland. 22. Ministry of Health Guinea, Conakry, Guinea. 23. The European Mobile Laboratory Consortium, Hamburg, Germany; Public Health England, Porton Down, Salisbury, UK; University of Southampton, South General Hospital, Southampton, UK. 24. The European Mobile Laboratory Consortium, Hamburg, Germany; Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany; German Centre for Infection Research (DZIF), Partner Site Hamburg, Conakry, Guinea. Electronic address: guenther@bni.uni-hamburg.de.
Abstract
BACKGROUND: By January, 2016, all known transmission chains of the Ebola virus disease (EVD) outbreak in west Africa had been stopped. However, there is concern about persistence of Ebola virus in the reproductive tract of men who have survived EVD. We aimed to use biostatistical modelling to describe the dynamics of Ebola virus RNA load in seminal fluid, including clearance parameters. METHODS: In this longitudinal study, we recruited men who had been discharged from three Ebola treatment units in Guinea between January and July, 2015. Participants provided samples of seminal fluid at follow-up every 3-6 weeks, which we tested for Ebola virus RNA using quantitative real-time RT-PCR. Representative specimens from eight participants were then inoculated into immunodeficient mice to test for infectivity. We used a linear mixed-effect model to analyse the dynamics of virus persistence in seminal fluid over time. FINDINGS: We enrolled 26 participants and tested 130 seminal fluid specimens; median follow up was 197 days (IQR 187-209 days) after enrolment, which corresponded to 255 days (228-287) after disease onset. Ebola virus RNA was detected in 86 semen specimens from 19 (73%) participants. Median duration of Ebola virus RNA detection was 158 days after onset (73-181; maximum 407 days at end of follow-up). Mathematical modelling of the quantitative time-series data showed a mean clearance rate of Ebola virus RNA from seminal fluid of -0·58 log units per month, although the clearance kinetic varied greatly between participants. Using our biostatistical model, we predict that 50% and 90% of male survivors clear Ebola virus RNA from seminal fluid at 115 days (90% prediction interval 72-160) and 294 days (212-399) after disease onset, respectively. We also predicted that the number of men positive for Ebola virus RNA in affected countries would decrease from about 50 in January 2016, to fewer than 1 person by July, 2016. Infectious virus was detected in 15 of 26 (58%) specimens tested in mice. INTERPRETATION: Time to clearance of Ebola virus RNA from seminal fluid varies greatly between individuals and could be more than 13 months. Our predictions will assist in decision-making about surveillance and preventive measures in EVD outbreaks. FUNDING: This study was funded by European Union's Horizon 2020 research and innovation programme, Directorate-General for International Cooperation and Development of the European Commission, Institut national de la santé et de la recherche médicale (INSERM), German Research Foundation (DFG), and Innovative Medicines Initiative 2 Joint Undertaking.
BACKGROUND: By January, 2016, all known transmission chains of the Ebola virus disease (EVD) outbreak in west Africa had been stopped. However, there is concern about persistence of Ebola virus in the reproductive tract of men who have survived EVD. We aimed to use biostatistical modelling to describe the dynamics of Ebola virus RNA load in seminal fluid, including clearance parameters. METHODS: In this longitudinal study, we recruited men who had been discharged from three Ebola treatment units in Guinea between January and July, 2015. Participants provided samples of seminal fluid at follow-up every 3-6 weeks, which we tested for Ebola virus RNA using quantitative real-time RT-PCR. Representative specimens from eight participants were then inoculated into immunodeficient mice to test for infectivity. We used a linear mixed-effect model to analyse the dynamics of virus persistence in seminal fluid over time. FINDINGS: We enrolled 26 participants and tested 130 seminal fluid specimens; median follow up was 197 days (IQR 187-209 days) after enrolment, which corresponded to 255 days (228-287) after disease onset. Ebola virus RNA was detected in 86 semen specimens from 19 (73%) participants. Median duration of Ebola virus RNA detection was 158 days after onset (73-181; maximum 407 days at end of follow-up). Mathematical modelling of the quantitative time-series data showed a mean clearance rate of Ebola virus RNA from seminal fluid of -0·58 log units per month, although the clearance kinetic varied greatly between participants. Using our biostatistical model, we predict that 50% and 90% of male survivors clear Ebola virus RNA from seminal fluid at 115 days (90% prediction interval 72-160) and 294 days (212-399) after disease onset, respectively. We also predicted that the number of men positive for Ebola virus RNA in affected countries would decrease from about 50 in January 2016, to fewer than 1 person by July, 2016. Infectious virus was detected in 15 of 26 (58%) specimens tested in mice. INTERPRETATION: Time to clearance of Ebola virus RNA from seminal fluid varies greatly between individuals and could be more than 13 months. Our predictions will assist in decision-making about surveillance and preventive measures in EVD outbreaks. FUNDING: This study was funded by European Union's Horizon 2020 research and innovation programme, Directorate-General for International Cooperation and Development of the European Commission, Institut national de la santé et de la recherche médicale (INSERM), German Research Foundation (DFG), and Innovative Medicines Initiative 2 Joint Undertaking.
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