Persistence of Ebola virus RNA in seminal fluid (2016)

Ebola and Marburg viruses are closely related filoviruses that are among, if not the most, lethal human pathogens, with case fatality rates up to 90%. Outbreaks have occurred sporadically, mostly in central Africa, since their discovery more than 40 years ago. These outbreaks were small in size and generally well contained until December, 2013, when the largest recorded outbreak of a filovirus began in the west African country of Guinea. The outbreak, caused by the Zaire species of Ebola virus, quickly spread to surrounding Liberia and Sierra Leone and travellers exported the virus to Europe and the USA. The outbreak was declared over in January, 2016, after almost 29 000 cases and more than 11 000 deaths had been reported. The size of the 2013–16 outbreak has resulted in a large population of survivors and there are concerns about the persistence of Ebola virus in these people, especially persistence of Ebola RNA in semen and subsequent implications for transmission and outbreak control. In The Lancet Global Health, Daouda Sissoko and colleagues1Sissoko D Duraffour S Kerber R et al.Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study.Lancet Glob Health. 2016; 5: 80-88Summary Full Text Full Text PDF Scopus (79) Google Scholar provide new insight into the time to clearance of Ebola RNA from seminal fluid. Reports of Ebola or Marburg virus RNA or infectious virus in semen are not new;2Deen GF Knust B Broutet N et al.Ebola RNA persistence in semen of Ebola virus disease survivors—preliminary report.N Engl J Med. 2015; (published online Oct 14.)http://dx.doi.org/10.1056/NEJMoa1511410Google Scholar, 3Mate SE Kugelman JR Nyenswah TG et al.Molecular evidence of sexual transmission of Ebola virus.N Engl J Med. 2015; 373: 2448-2454Crossref PubMed Scopus (308) Google Scholar, 4Martini GA Schmidt HA [Spermatogenic transmission of the “Marburg virus”. (Causes of “Marburg simian disease”)].Klin Wochenschr. 1968; 46 ([in German].): 398-400Crossref PubMed Scopus (72) Google Scholar, 5Rodriguez LL De Roo A Guimard Y et al.Persistence and genetic stability of Ebola virus during the outbreak in Kikwit, Democratic Republic of the Congo, 1995.J Infect Dis. 1999; 179: S170-S176Crossref PubMed Scopus (253) Google Scholar, 6Rowe AK Bertolli J Khan AS et al.Clinical, virologic, and immunologic follow-up of convalescent Ebola hemorrhagic fever patients and their household contacts, Kikwit, Democratic Republic of the Congo. Commission de Lutte contre les Epidemies a Kikwit.J Infect Dis. 1999; 179: S28-S35Crossref PubMed Scopus (313) Google Scholar however, because the cohorts of survivors from previous outbreaks have been so small, little is known about the clearance kinetics of filoviruses in people who survive Ebola virus disease. Sissoko and colleagues were able to follow up a cohort of 26 Ebola survivors from Guinea for a median 197 days after inclusion in the study (255 days after disease onset) and to test 130 semen specimens by real time RT-PCR. Furthermore, Sissoko and colleagues inoculated severe combined immune deficiency (SCID) mice with samples of seminal fluid from eight participants to test for infectivity. Sissoko and colleagues detected Ebola RNA in semen of 19 of the 26 convalescent participants (73%)and isolated infectious Ebola virus in SCID mice from semen of seven of eight participants. Median duration of Ebola virus RNA presence was 158 days, with a maximum of 407 days (at the end of follow up). Using biostatistical modelling, Sissoko and colleagues show that mean clearance rate of Ebola virus RNA in semen is −0·58 log units per month. However, the study also showed that there was substantial variability between survivors in the rate of clearance of Ebola RNA from seminal fluid. That, in some rare cases, survivors continuously shed Ebola RNA for more than 13 months after disease onset is cause for worry and has important implications for public health. The risk of sexual transmission is clearly a concern, yet Sissoko and colleagues note that they were unable to show any definitive correlation between the amount of Ebola RNA and infectivity. Nevertheless, active monitoring of male filovirus survivors for shedding of virus in semen and advice on safe sexual practices are warranted in light of Sissoko and colleagues' findings—especially as there has been a probable case of the sexual transmission of Ebola from a male survivor more than 500 days after disease onset.7Diallo B Sissoko D Loman NJ et al.Resurgence of Ebola virus disease in Guinea linked to a survivor with virus persistence in seminal fluid for more than 500 days.Clin Infect Dis. 2016; (published online Sept 1.)http://dx.doi.org/10.1093/cid/ciw601Crossref PubMed Scopus (145) Google Scholar In addition to raising awareness about the potential for the sexual transmission of filoviruses, Sissoko and colleagues' study raises at least two other very important and related concerns: first, where do filoviruses persist in the body? Further research should address this question. Ebola might persist in immunologically privileged sites such as testes; however, Ebola virus RNA has also been detected in other immunologically privileged sites in humans and non-human primates such as the CNS and eyes,8Larsen T Stevens EL Davis KJ et al.Pathologic findings associated with delayed death in nonhuman primates experimentally infected with Zaire Ebola virus.J Infect Dis. 2007; 196: S323-S328Crossref PubMed Scopus (54) Google Scholar, 9Howlett P Brown C Helderman T et al.Ebola virus disease complicated by late-onset encephalitis and polyarthritis, Sierra Leone.Emerg Infect Dis. 2016; 22: 150-152Crossref PubMed Scopus (60) Google Scholar, 10Mattia JG Vandy MJ Chang JC et al.Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study.Lancet Infect Dis. 2016; 16: 331-338Summary Full Text Full Text PDF PubMed Scopus (118) Google Scholar which has caused serious sequelae in convalescent patients. Second, most of the Ebola survivors in this study received the experimental treatment favipiravir during the acute phase of disease. The favipiravir clinical trial11Sissoko D Laouenan C Folkesson E et al.Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea.PLoS Med. 2016; 13: e1001967Crossref PubMed Scopus (362) Google Scholar failed to show any beneficial effect on survival and, not surprisingly, Sissoko and colleagues noted no evidence that favipiravir prevented persistence of Ebola RNA in semen. This finding raises an important consideration in the development of antivirals against Ebola. Not only are antivirals needed that can rescue infected patients during the acute phase of Ebola virus disease but drugs to eliminate Ebola from immunologically privileged or other sites where the virus persists are also needed. I declare no competing interests. Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling studyTime 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. Full-Text PDF Open Access