title: Late Ebola virus relapse causing meningoencephalitis: a case report.
abstract: BACKGROUND
  There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13.2).
  
  
  METHODS
  A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach.
  
  
  RESULTS
  On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23.7) than plasma (31.3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus.
  
  
  CONCLUSIONS
  Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern.
  
  
  BACKGROUND
  Royal Free London NHS Foundation Trust.
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK. Electronic address: michael.jacobs@ucl.ac.uk.
authors.forename: Michael
authors.initials: M
authors.lastname: Jacobs
authors.affiliation: Research Department of Infection and Population Health, University College London, London, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Rodger
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bell
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhagani
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Cropley
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Filipe
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gifford
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Hopkins
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Department of Radiology, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Farrah
authors.initials: F
authors.lastname: Jabeen
authors.affiliation: Regional Virus Laboratory Specialist Virology Centre, Edinburgh Royal Infirmary, Edinburgh, UK.
authors.forename: Ingolfur
authors.initials: I
authors.lastname: Johannessen
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Drosos
authors.initials: D
authors.lastname: Karageorgopoulos
authors.affiliation: Virus Reference Department, National Infection Service, Public Health England, Colindale, UK.
authors.forename: Angie
authors.initials: A
authors.lastname: Lackenby
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lester
authors.affiliation: Department of Neurology, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Rebecca S N
authors.initials: RS
authors.lastname: Liu
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: Alisdair
authors.initials: A
authors.lastname: MacConnachie
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Tabitha
authors.initials: T
authors.lastname: Mahungu
authors.affiliation: Division of Surgery, University College London, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.affiliation: Department of Pharmacy, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Neal
authors.initials: N
authors.lastname: Marshall
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Mepham
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Orton
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Palmarini
authors.affiliation: High Containment Microbiology Department, National Infection Service, Public Health England, Colindale, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Patel
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Perry
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: S Erica
authors.initials: SE
authors.lastname: Peters
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Porter
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ritchie
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Ritchie
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Seaton
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Vattipally B
authors.initials: VB
authors.lastname: Sreenu
authors.affiliation: Regional Virus Laboratory Specialist Virology Centre, Edinburgh Royal Infirmary, Edinburgh, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Templeton
authors.affiliation: Department of Infection, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Warren
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Gavin S
authors.initials: GS
authors.lastname: Wilkie
authors.affiliation: Virus Reference Department, National Infection Service, Public Health England, Colindale, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Zambon
authors.affiliation: High Containment Microbiology Department, National Infection Service, Public Health England, Colindale, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Gopal
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Thomson
mesh_terms: D000208:Acute Disease; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives; D000328:Adult; D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D003389:Cranial Nerve Diseases / Q000821:virology; D004196:Disease Outbreaks; D015507:Drugs, Investigational / Q000627:therapeutic use; D029043:Ebolavirus / Q000235:genetics / Q000302:isolation & purification*; D005260:Female; D016679:Genome, Viral; D019142:Hemorrhagic Fever, Ebola / Q000175:diagnosis* / Q000188:drug therapy; D006801:Humans; D008590:Meningoencephalitis / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000821:virology*; D009726:Nurses; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid / Q000302:isolation & purification; D011843:Radiculopathy / Q000821:virology; D012008:Recurrence; D012265:Ribonucleotides / Q000627:therapeutic use*; D012606:Scotland; D012807:Sierra Leone; D019562:Viral Load / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D015507:Drugs, Investigational; D012367:RNA, Viral; D012265:Ribonucleotides; C000606551:remdesivir; D000249:Adenosine Monophosphate; D000409:Alanine