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Virus persistence and recrudescence after Ebola virus disease: what are the risks to healthcare workers?

      The 2013–2016 epidemic of Ebola virus disease (EVD) in West Africa demonstrated stark limitations in knowledge, but also provided an opportunity to enhance understanding of this dangerous and often mysterious disease. Albeit unwelcome, the sheer magnitude of almost 30,000 cases in West Africa provides a much larger sample size from which observations can be made, augmented by the 27 cases seen in advanced medical settings in Europe and the USA where more detailed clinical observation and laboratory analysis were often possible. Perhaps at the top of the list of new and sometimes surprising findings are those that relate to sequelae, delayed virus clearance and recrudescent disease in EVD survivors.
      Prior to reports from the West African outbreak, only two controlled studies of EVD survivors had been published.
      • Rowe A.K.
      • Bertolli J.
      • Khan A.S.
      • 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.
      • Clark D.V.
      • Kibuuka H.
      • Millard M.
      • et al.
      Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study.
      Both highlighted an array of sequelae lasting months to years, including extreme fatigue, anorexia, headache, arthralgia, myalgia, abdominal pain, sleep disturbance, hearing loss and visual disturbances. However, neither study incorporated the detailed microbiological and physical examination (especially ocular, audiometric and mental health examinations) required for a thorough understanding of EVD sequelae and associated pathogenesis. Reports emerging in the wake of the massive outbreak in West Africa corroborate and expand earlier findings. These include the observation of new ocular symptoms in over 60% of EVD survivors, with sight-threatening uveitis in 18.1% of cases, some of whom progress to early cataract formation.
      • Mattia J.G.
      • Chang J.C.
      • Platt D.E.
      • et al.
      Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study.
      • Vetter P.
      • Kaiser L.
      • Schibler M.
      • Ciglenecki I.
      • Bausch D.G.
      Sequelae of Ebola virus disease: the emergency within the emergency.
      Neurological deficits, including seizures, and various skin problems have also been noted.
      • Vetter P.
      • Kaiser L.
      • Schibler M.
      • Ciglenecki I.
      • Bausch D.G.
      Sequelae of Ebola virus disease: the emergency within the emergency.
      Lastly, mental health sequelae are unsurprisingly common in survivors and their family members and communities, including sleep and memory disturbances, anxiety disorders, depression, post-traumatic stress disorder and survivors' guilt.
      The underlying pathogenesis of EVD sequelae is not well understood, but anecdotal observations suggest that at least some sequelae relate to virus persistence for months or even years in selected immunologically protected tissue compartments and fluids. These include the testes/semen; chambers of the eye; central nervous system/cerebrospinal fluid (CSF); and the fetus, placenta and amniotic sac/fluid of women infected during pregnancy (Figure 1).
      • Vetter P.
      • Kaiser L.
      • Schibler M.
      • Ciglenecki I.
      • Bausch D.G.
      Sequelae of Ebola virus disease: the emergency within the emergency.
      In many cases, only molecular evidence of viral RNA by reverse transcriptase polymerase chain reaction (RT-PCR) is available, with no confirmatory cell culture, leaving open the question of whether the findings represent inconsequential residual RNA or infectious virus with continued risk of transmission.
      Figure 1
      Figure 1Virus persistence after the day of disease onset in various body compartments in survivors of Ebola virus disease, as detected by reverse-transcription polymerase chain reaction (RT-PCR, green) and cell culture (blue). Red bars represent the day of the first negative RT-PCR detection in the patient’s blood, when available. Reprinted with permission from Vetter et al.
      • Vetter P.
      • Kaiser L.
      • Schibler M.
      • Ciglenecki I.
      • Bausch D.G.
      Sequelae of Ebola virus disease: the emergency within the emergency.
      Particularly vexing is the possibility of virus persistence during pregnancy. Maternal mortality in pregnant women with EVD is high, and fetal and neonatal mortality is nearly 100%.
      • Nelson J.M.
      • Griese S.E.
      • Goodman A.B.
      • Peacock G.
      Live neonates born to mothers with Ebola virus disease: a review of the literature.
      However, a few cases have been noted in West Africa in which women, possibly with asymptomatic infection or atypically mild disease, have recovered and remained pregnant, only to spontaneously abort a macerated or non-viable fetus in subsequent weeks or months.
      • Vetter P.
      • Kaiser L.
      • Schibler M.
      • Ciglenecki I.
      • Bausch D.G.
      Sequelae of Ebola virus disease: the emergency within the emergency.
      • Bower H.
      • Grass J.E.
      • Veltus E.
      • et al.
      Delivery of an Ebola virus-positive stillborn infant in a rural community health center, Sierra Leone, January 2015.
      Although the maternal blood remained free of virus at the time of delivery, swabs of the fetus, placenta and amniotic fluid have tested RT-PCR positive for Ebola virus in some cases.
      Two cases of prolonged virus persistence associated with recrudescence have been well documented. In the USA, Ebola virus was detected by PCR and cell culture from the aqueous humour of a medically evacuated healthcare worker with severe uveitis 14 weeks after disease onset and nine weeks after clearance from the blood, which remained negative during the episode of uveitis.
      • Varkey J.B.
      • Shantha J.G.
      • Crozier I.
      • et al.
      Persistence of Ebola virus in ocular fluid during convalescence.
      Importantly, viral RNA was not detected in tear film or conjunctival swab specimens, suggesting that the virus remained confined to the intra-ocular compartment. In the UK, Ebola virus was noted by RT-PCR in both the CSF and blood in a medically evacuated healthcare worker who developed severe meningitis with seizures nine months after resolution of acute disease.
      • Jacobs M.
      • Rodger A.
      • Bell D.J.
      • et al.
      Late Ebola virus relapse causing meningoencephalitis: a case report.
      The RNA copy number was lower in the blood than in the CSF, and virus could only be isolated in cell culture from the CSF, leading to the conclusion that the viraemia was due to reseeding of the blood from the central nervous system. No obvious underlying immunosuppressive condition or trigger for virus re-activation could be identified in these cases.
      Fortunately, recrudescent disease and viraemia after EVD appear to be rare. With the exception of sporadic cases of sexual transmission related to persistent virus in the semen, no cases of secondary transmission from survivors have been reported. Furthermore, accumulating evidence does not suggest prolonged shedding in other body fluids, at least in the absence of fever and other acute symptoms.
      • Christie A.
      • Davies-Wayne G.J.
      • Cordier-Lasalle T.
      • et al.
      Possible sexual transmission of Ebola virus – Liberia, 2015.
      • Mate S.E.
      • Kugelman J.R.
      • Nyenswah T.G.
      • et al.
      Molecular evidence of sexual transmission of Ebola virus.
      One theory for the apparent rarity of recrudescent cases is that such cases are the consequence of severe initial EVD, which is directly related to the level of viraemia, with high viraemia seeding the immunoprivileged sites. Indeed, both patients described above had very high viraemia and severe disease requiring intensive care (including, in one case, prolonged mechanical ventilation and haemodialysis). Without the intensive medical care usually afforded to medically evacuated patients in resource-rich countries, such severe disease would usually be fatal in West Africa, leaving few survivors at risk of recrudescence. Alternatively, recrudescent disease in West Africa may simply be undetected or misattributed to malaria or other common causes of febrile disease due to a low index of suspicion and limited diagnostic capacity. Indeed, there are anecdotal reports of recrudescent disease and viraemia in West Africa possibly related to underlying human immunodeficiency virus infection, although this association has not been validated.
      Even if infrequent, the possibility of recrudescent disease and virus shedding obligates the development of appropriate guidelines for the management of EVD survivors that maximize the protection of healthcare workers while offering the highest quality care without precipitation of undue fear and stigma. In the absence of evidence of external virus shedding (excluding virus in the semen) from asymptomatic EVD survivors, standard precautions are recommended for routine clinical examination and care.
      • Green E.
      • Hunt L.
      • Ross J.C.
      • et al.
      Viraemia and Ebola virus secretion in survivors of Ebola virus disease in Sierra Leone: a cross-sectional cohort study.
      In the UK, all EVD survivors should be assigned to a designated infectious disease unit where they will receive routine follow-up and guidance.
      • Harries J.
      • Jacobs M.
      • Davies S.C.
      Ebola survivors: not out of the woods yet.
      Should the patient become unwell, consultation with the designated infectious disease unit and the Rare and Imported Fever Service at Public Health England should be undertaken immediately to assess risk, arrange laboratory testing for EVD, and advise on appropriate infection prevention and control measures, including appropriate handling of biological samples.
      • World Health Organization
      Interim infection prevention and control guidance for care of patients with suspected or confirmed filovirus haemorrhagic fever in health-care settings, with focus on Ebola.
      When in doubt, or in emergencies when expert guidance is not yet available, EVD survivors presenting with acute febrile or meningo-encephalitic syndromes should be placed in isolation, and EVD infection prevention and control precautions should be applied, including the wearing of full personal protective equipment.
      • World Health Organization
      Interim infection prevention and control guidance for care of patients with suspected or confirmed filovirus haemorrhagic fever in health-care settings, with focus on Ebola.
      • World Health Organization
      Personal protective equipment in the context of filovirus disease outbreak response.
      This applies, but is not limited to, when attending to deliveries of women who were infected with Ebola virus while pregnant; performing emergency surgical procedures; attending to penetrating trauma that involves the eye, male genitourinary tract, brain and spinal cord, or female breast; aliquotting specimens or performing centrifugation. Special attention should be given to appropriate waste, sharps and linen management, as well as strict adherence to environmental cleaning and decontamination protocols of re-usable medical equipment. Blood, tissue and organ donation from EVD survivors is currently prohibited in the UK, and should be deferred until further data are available on the precise duration of infectious virus in the various body compartments and potential triggers of virus re-activation. Should exposure to Ebola virus be suspected, various options for postexposure prophylaxis exist, but must be considered experimental in the absence of systematically collected efficacy or safety data.
      • Jacobs M.
      • Aarons E.
      • Bhagani S.
      • et al.
      Post-exposure prophylaxis against Ebola virus disease with experimental antiviral agents: a case-series of health-care workers.
      The estimated 10,000+ EVD survivors from the West Africa outbreak present a moral imperative to provide the required medical care, as well as an opportunity to collect the evidence necessary to inform future guidelines for effective and safe medical care of this vulnerable group.
      • Vetter P.
      • Kaiser L.
      • Schibler M.
      • Ciglenecki I.
      • Bausch D.G.
      Sequelae of Ebola virus disease: the emergency within the emergency.
      The World Health Organization has published interim guidelines for clinical care of EVD survivors.
      • World Health Organization
      Clinical care for survivors of Ebola virus disease. Interim guidance.
      Acquiring the necessary scientific evidence must start with heightened, yet non-stigmatizing, surveillance and testing to document the duration of virus persistence in each body compartment or fluid, and the nature and frequency of recrudescent disease and secondary transmission. Understanding the relationship between viral infectivity and detection of RNA by RT-PCR, a technique now widely available in the field during outbreaks, will be key to determining its practical utility in risk estimation. Full genome sequencing of Ebola viruses identified during acute infection and recrudescence may help to shed light on the mechanisms of these events, especially the possibility of escape mutants.
      • Blackley D.J.
      • Lindblade K.A.
      • Kateh F.
      • et al.
      Rapid intervention to reduce Ebola transmission in a remote village – Gbarpolu County, Liberia, 2014.
      Basic science research will also be needed to identify the implicated cellular reservoirs and immune mechanisms of virus persistence. Clinical research is also needed to identify the best strategies to alleviate symptoms and eliminate virus in survivors. Various West African studies planned or currently underway promise to yield a wealth of new information, including the PREVAIL III study detailing sequelae and viral persistence in a five-year controlled cohort of more than 1500 Liberian EVD survivors.
      • National Institutes of Health
      Study of Ebola survivors opens in Liberia.
      Meanwhile, prudence rather than panic is in order in the clinical management of EVD survivors.

      Acknowledgements

      The authors wish to thank Dr Michael Jacobs and Dr Ian Crozier for their advice and review of the paper.

      Conflict of interest statement

      None declared.

      Funding source

      NM receives funding from the Wellcome Trust .

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