Asymptomatic Ebola virus infections—myth or reality?
Authors: Jens H Kuhn, Sina Bavari
Journal: The Lancet Infectious Diseases (2017)

Ebola virus captures the imagination of the public and experts alike.1Schell H Outburst! A chilling true story about emerging-virus narratives and pandemic social change.Configurations. 1997; 5: 93-133Crossref PubMed Scopus (48) Google Scholar This fascination is in part due to the overall rare occurrence of typically very few outbreaks of Ebola virus disease (EVD) and extremely high case-fatality rates (mean 41·4%).2Kuhn JH Ebolavirus and marburgvirus infections.in: Kasper DL Fauci AS Hauser SL Longo DL Jameson JL Loscalzo J Harrison's principles of internal medicine. 19th edn. McGraw-Hill Education, Columbus2015: 1323-1329Google Scholar More importantly, the identity of the natural Ebola virus reservoir remains unknown.3Judson SD Fischer R Judson A Munster VJ Ecological contexts of index cases and spillover events of different ebolaviruses.PLoS Pathog. 2016; 12: e1005780Crossref PubMed Scopus (32) Google Scholar This lack of knowledge means that novel Ebola virus introductions into human populations cannot be predicted, let alone be prevented, which adds to the enigma of the virus in the public eye. Unsurprisingly, considerable effort has been spent to hone in on the hiding place of the virus. Animals and plants have been screened for Ebola virus infection; ecological niche modelling has been done to predict endemic zones for the Ebola virus; and human sera have been screened for anti-Ebola virus antibodies to identify human populations at risk of infection and consequently to pinpoint geographical areas of endemicity.3Judson SD Fischer R Judson A Munster VJ Ecological contexts of index cases and spillover events of different ebolaviruses.PLoS Pathog. 2016; 12: e1005780Crossref PubMed Scopus (32) Google Scholar, 4Bower H Glynn JR A systematic review and meta-analysis of seroprevalence surveys of ebolavirus infection.Sci Data. 2017; 4: 160133Crossref PubMed Scopus (38) Google Scholar, 5Kuhn JH Filoviruses. A compendium of 40 years of epidemiological, clinical, and laboratory studies.Arch Virol Suppl. 2008; 20: 13-360Crossref PubMed Google Scholar, 6Pigott DM Millear AI Earl L et al.Updates to the zoonotic niche map of Ebola virus disease in Africa.Elife. 2016; 5: e16412Crossref PubMed Scopus (42) Google Scholar, 7Peterson AT Samy AM Geographic potential of disease caused by Ebola and Marburg viruses in Africa.Acta Trop. 2016; 162: 114-124Crossref PubMed Scopus (21) Google Scholar, 8O'Hearn AE Voorhees MA Fetterer DP et al.Serosurveillance of viral pathogens circulating in West Africa.Virol J. 2016; 13: 163Crossref PubMed Scopus (40) Google Scholar Unfortunately, the results of these approaches often appear contradictory. Thus far, Ebola virus could not be isolated from any screened wild animal or plant, and next-generation sequencing has not yet yielded at least coding-complete Ebola virus genomes in samples from any wild organism. These results suggest an unusual Ebola virus host. Niche modelling suggests that Ebola virus should be widely distributed over equatorial Africa, including countries from which Ebola virus infections have not been reported.3Judson SD Fischer R Judson A Munster VJ Ecological contexts of index cases and spillover events of different ebolaviruses.PLoS Pathog. 2016; 12: e1005780Crossref PubMed Scopus (32) Google Scholar, 6Pigott DM Millear AI Earl L et al.Updates to the zoonotic niche map of Ebola virus disease in Africa.Elife. 2016; 5: e16412Crossref PubMed Scopus (42) Google Scholar, 7Peterson AT Samy AM Geographic potential of disease caused by Ebola and Marburg viruses in Africa.Acta Trop. 2016; 162: 114-124Crossref PubMed Scopus (21) Google Scholar These predictions are puzzling because the high EVD case-fatality rate makes it unlikely that EVD outbreaks have been overlooked repeatedly. The most confusing results, however, stem from a myriad of serosurveys, which revealed anti-Ebola virus antibodies in human beings from all over Africa.4Bower H Glynn JR A systematic review and meta-analysis of seroprevalence surveys of ebolavirus infection.Sci Data. 2017; 4: 160133Crossref PubMed Scopus (38) Google Scholar, 5Kuhn JH Filoviruses. A compendium of 40 years of epidemiological, clinical, and laboratory studies.Arch Virol Suppl. 2008; 20: 13-360Crossref PubMed Google Scholar, 8O'Hearn AE Voorhees MA Fetterer DP et al.Serosurveillance of viral pathogens circulating in West Africa.Virol J. 2016; 13: 163Crossref PubMed Scopus (40) Google Scholar Many of these studies were done during the 1980s and 1990s and varied in quality: different assays were used to detect antibodies (eg, immunofluorescence assay, ELISA, western blot); seemingly arbitrary cutoffs were sometimes used to differentiate negative from positive results; different Ebola virus antigens were used for assay development (eg, whole inactivated virions vs individual viral proteins); sample cohort sizes diverged; and proper controls were or could often not be included. However, the results of many of these studies implied high seroprevalence (often >5%) of anti-Ebola virus antibodies throughout Africa among individuals who did not recall having had an EVD-like illness or contact with a suspect EVD case.4Bower H Glynn JR A systematic review and meta-analysis of seroprevalence surveys of ebolavirus infection.Sci Data. 2017; 4: 160133Crossref PubMed Scopus (38) Google Scholar, 5Kuhn JH Filoviruses. A compendium of 40 years of epidemiological, clinical, and laboratory studies.Arch Virol Suppl. 2008; 20: 13-360Crossref PubMed Google Scholar Plausible explanations for these discrepant serosurvey results are: the serosurveys are artifacts due to cross-reaction of Ebola virus antigens with non-anti-Ebola virus antibodies; the detected antibodies stem from contact with undiscovered, non-pathogenic filoviruses that are endemic in Africa and that are closely related to Ebola virus; or Ebola virus causes widespread subclinical infection in human beings. The last hypothesis has gained popularity, although actual evidence of subclinical Ebola virus infection is sparse9Leroy EM Baize S Debre P Lansoud-Soukate J Mavoungou E Early immune responses accompanying human asymptomatic Ebola infections.Clin Exp Immunol. 2001; 124: 453-460Crossref PubMed Scopus (128) Google Scholar, 10Leroy EM Baize S Volchkov VE et al.Human asymptomatic Ebola infection and strong inflammatory response.Lancet. 2000; 355: 2210-2215Summary Full Text Full Text PDF PubMed Scopus (343) Google Scholar and still debated. Recent studies indicate that Ebola virus can persist in some EVD survivors and replicate in immunoprivileged sites in the absence of clinical signs.11Chughtai AA Barnes M Macintyre CR Persistence of Ebola virus in various body fluids during convalescence: evidence and implications for disease transmission and control.Epidemiol Infect. 2016; 144: 1652-1660Crossref PubMed Scopus (64) Google Scholar, 12MacDermott NE Bausch DG Virus persistence and recrudescence after Ebola virus disease: what are the risks to healthcare workers?.J Hosp Infect. 2016; 94: 113-115Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar Notably, though, such replication has never been convincingly demonstrated in people who did not have previous EVD. In The Lancet Infectious Diseases, Judith Glynn and colleagues13Glynn JR Bower H Johnson S et al.Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virus.Lancet Infect Dis. 2017; (published online Feb 27.)http://dx.doi.org/10.1016/S1473-3099(17)30111-1PubMed Google Scholar present a carefully conducted, well-controlled serosurvey to take a fresh look at the possibility of subclinical EVD exposure and infection. During the recent large EVD outbreak (over 28000 cases) in western Africa, Sierra Leonean household contacts of people with proven EVD were screened for IgG anti-Ebola virus antibodies using a newly developed, non-invasive oral fluid capture assay with high specificity and sensitivity. Seroprevalence among household contacts who did not experience clinical signs indicative of EVD was only 2·6%. This value suggests that asymptomatic Ebola virus infections occur rarely, even when individuals have direct contact to individuals infected with Ebola virus. This result is in line with the observation that individuals infected with Ebola virus typically experience grave and frequently lethal disease, and cast further doubt on results of previous serosurveys. Although a single study such as that of Glynn and colleagues13Glynn JR Bower H Johnson S et al.Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virus.Lancet Infect Dis. 2017; (published online Feb 27.)http://dx.doi.org/10.1016/S1473-3099(17)30111-1PubMed Google Scholar does not suffice to come to wide-sweeping conclusions about the possibility and frequency of subclinical individuals infected with Ebola virus infections, their results certainly indicate that such infections are not a typical or widespread phenomenon. The biggest threat to human populations therefore remains another introduction of Ebola virus from its natural host—and not transmission from an apparently healthy person infected with Ebola virus. Because Glynn and colleagues established an assay based on oral swabs rather than blood draws, future surveillance of EVD patient contacts could be more easily achieved. More intriguingly, oral swab-based assays might be used to do new geographically broad serosurveys to confirm or refute previously determined anti-Ebola virus seroprevalences, to identify and study truly asymptomatically infected people, and to better define the ecological niche of Ebola virus. We declare no competing interests. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, the US Department of Defense, the US Department of the Army, or the institutions and companies affiliated with the authors. This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under contract number HHSN272200700016I. JHK is an employee of Tunnell Government Services, Inc, a subcontractor to Battelle Memorial Institute. Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virusThis new highly specific and sensitive assay showed asymptomatic infection with Ebola virus was uncommon despite high exposure. The low prevalence suggests asymptomatic infection contributes little to herd immunity in Ebola, and even if infectious, would account for few transmissions. Full-Text PDF Open Access