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DynaMed Plus

DynaMed Plus is the next-generation clinical reference tool physicians can rely on for fast, easy access to point-of-care decision support. Written by a team of specialized physicians and researchers, content is updated several times daily to include information on the latest evidence-based research, providing practice-changing answers to clinical questions with optimized speed. 

Ebola virus disease

  • Updated 2017 Feb 22 05:37:00 PM: fever, headache, and myalgia common among survivors of Ebola virus disease (Emerg Infect Dis 2017 Jan) view update
  • handling a corpse of an infected person, handling fluids from an infected person, and direct contact with infected persons associated with increased risk of Ebola virus disease among household members of case patients (Emerg Infect Dis 2016 Aug) view update
  • review of immunobiology of Ebola virus infection (Nat Rev Immunol 2017 Jan 23) view update

 

Recommendations Editor

Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS
Deputy Editor

Alan Ehrlich, MD

 

General Information

Description

  • severe viral hemorrhagic fever with mortality rate of 50%-90%(1, 2, 3, 4)
  • endemic in central and sub-Saharan Africa(1, 2, 3, 4)
  • largest outbreak to date occurred in West Africa beginning in 2014, predominantly affecting Guinea, Sierra Leona and Liberia

Also called

  • Ebola virus disease (EVD)
  • Ebola hemorrhage fever (EHF)

Epidemiology

Geographic distribution

  • endemic and epidemic in central Africa, including(1, 2, 3, 6)
    • Gabon
    • Republic of Congo
    • Democratic Republic of Congo
    • Sudan
    • Uganda
  • regions affected in 2014 outbreak included(4, 6)
    • West African countries including
      • Guinea
      • Sierra Leone
      • Liberia
      • Nigeria
      • Senegal
      • Mali
    • other countries outside Africa, including
      • Spain
      • Italy
      • United Kingdom
      • United States
    • map of 2014 Ebola outbreak can be found at Healthmap

Incidence/Prevalence

2014 West Africa outbreak

  • largest outbreak to date occurred in West Africa beginning in 2014, predominantly affecting Guinea, Sierra Leona and Liberia
  • 4 cases confirmed in United States as of October 17, 2014
    • first imported Ebola case reported from Texas on September 30, 2014
    • 2 cases involving transmission to healthcare workers reported on October 12 and October 15, 2014
    • second imported case in a volunteer international aid worker reported from New York City on October 23, 2014
    • Reference - CDC 2014 Ebola Outbreak in West Africa

Democratic Republic of Congo outbreaks

Historic cases

Risk factors

General considerations

  • risk factors include(1, 2, 3, 4)
    • living in or travel to areas with active transmission
    • contact with blood, bodily fluids, or human remains of infected persons, typically affecting
      • healthcare workers
      • family members of infected patients
    • direct handling of bats, rodents, or primates from disease-endemic areas
  • increased incidence of Ebola virus disease reported in household members who had close contact with patients
    • based on cohort study of 173 household members of 27 patients with Ebola virus infection during epidemic in Kikwit, Democratic Republic of Congo in 1995
    • 16% had Ebola virus infection
    • increased incidence of Ebola virus infection in household members associated with
      • exposure to body fluids of ill persons (adjusted rate ratio [RR] 3.6, 95% CI 1.9-6.8)
      • age > 18 years (adjusted RR 4.6, 95% CI 2-10.3)
      • sharing hospital bed (adjusted RR 3.4, 95% CI 1.8-6.2)
    • Reference - J Infect Dis 1999 Feb;179 Suppl 1:S87 full-text
  • household contact and attendance of funerals of patients with Ebola virus disease and work in healthcare settings increase risk of transmission
    • handling a corpse of an infected person, handling fluids from an infected person, and direct contact with infected persons associated with increased risk of Ebola virus disease among household members of case patients
      • based on retrospective cohort study
      • 937 household members of 123 Ebola virus disease survivors in 94 households in Sierra Leone between 2014 and 2015 evaluated
      • 448 household members (48%) had Ebola virus disease, of whom 53% died
      • factors associated with increased risk of Ebola virus exposure in multivariate analysis
        • handling a corpse of someone who died from Ebola virus disease (relative risk [RR] 11.1, 95% CI 4.5-27.4)
        • handling fluids from a patient with Ebola virus disease (RR 8.5, 95% CI 3.5-20.6)
        • direct contact with a patient with Ebola virus disease
          • RR 7.1, 95% CI 3-17.1 for wet contact
          • RR 5.3, 95% CI 2.2-12.9 for dry contact
        • indirect wet contact (RR 4.7, 95% CI 1.5-14.6)
      • aged 5-14 years associated with reduced risk of Ebola virus exposure compared to aged 20-29 years in multivariate analysis
        • RR 0.7, 95% CI 0.5-0.97 for ages 5-9 years
        • RR 0.64, 95% CI 0.45-0.93 for ages 10-14 years
      • Reference - Emerg Infect Dis 2016 Aug;22(8):1403 full-text
    • primary route of transmission in 2014 outbreak appeared to be clustered transmission within social groups in households, at funerals, and in healthcare settings based on analysis of genomic and epidemiologic data (Clin Infect Dis 2015 Apr 1;60(7):1079)
    • 162 (7.9%) of 2,210 cases of laboratory-confirmed or probable Ebola virus disease in persons aged ≥ 15 years in Guinea during 2014 outbreak occurred in healthcare workers (relative risk vs. non-healthcare workers 42.2, 95% CI 36-49.5) (MMWR Morb Mortal Wkly Rep 2015 Oct 2;64(38):1083 full-text)
  • contact with a patient or another healthcare worker with Ebola virus disease associated with increased risk of Ebola virus infection among healthcare workers
    • based on cohort study
    • 600 patients with Ebola virus disease in Kenema District, Sierra Leone during 2014-2015 outbreak evaluated
    • 92 patients (15%) were healthcare workers
    • factors associated with increased risk of Ebola virus infection among healthcare workers
      • contact with a patient with Ebola virus disease
      • contact with another healthcare worker with Ebola virus disease
    • Reference - Clin Infect Dis 2016 Aug 15;63(4):454 full-text
  • contact with bats and consumption of birds associated with increased Ebola virus seroprevalence in Republic of Congo
    • based on prospective cohort study
    • 809 blood donors in Republic of Congo were tested for serum titers of Ebola and Marburg immunoglobulin G antibodies between March and July 2011
    • 9.3% were from rural areas
    • Ebola seroprevalence 2.5% overall, peaking at 4% among persons from rural areas and Pointe Noire
    • factors associated with increased risk of Ebola seroprevalence in multivariate analysis
      • contact with bats (odds ratio [OR] 7.5, 95% CI 2.6-21.7)
      • consumption of birds (OR 2.6, 95% CI 1.1-6.9)
    • Reference - PLoS Negl Trop Dis 2015 Jun;9(6):e0003833 full-text
  • risk of Ebola virus transmission from survivors of Ebola virus disease appears low 6 weeks after clearance of viremia
    • based on cross-sectional study
    • 112 survivors of Ebola virus disease in Sierra Leone between April and June 2015 had body sites and fluid samples tested for Ebola virus RNA by reverse transcriptase polymerase chain reaction (RT-PCR)
    • patient median age 21.5 years
    • time from Ebola treatment unit discharge to sample collection range 42-190 days (median 142 days)
    • 555 specimens were collected, mostly from mouth (18.9%), axilla (18.6%), blood (16.8%), conjunctiva 16.6%), and urine (12.4%)
    • in single semen sample collected, virus detected 114 days after treatment unit discharge
    • all other samples tested negative
    • Reference - Lancet Infect Dis 2016 Sep;16(9):1052, editorial can be found in Lancet Infect Dis 2016 Sep;16(9):987

Centers for Disease Control and Prevention risk stratification

  • Centers for Disease Control and Prevention stratifies risk for the 2014 West Africa epidemic based on degree of exposure
    • high risk exposures include
      • exposure to blood or body fluids of a patient with symptomatic Ebola without appropriate personal protective equipment (PPE)
      • mucous membrane or percutaneous (such as needlestick) exposure to body fluids of patient with symptomatic Ebola infection
      • processing blood or body fluids from a patient with symptomatic Ebola without appropriate PPE or biosafety precautions
      • living in immediate household and providing direct care to patient with symptomatic Ebola
      • direct exposure to human remains in a country with widespread transmission without appropriate PPE
    • exposures with some risk include
      • direct contact with patient with symptomatic Ebola while using appropriate PPE in countries with widespread Ebola transmission
      • close contact (prolonged period of time within about 3 feet [1 meter]) with patient with symptomatic Ebola in household, healthcare facility, or community setting
    • low (but not zero) risk exposures include
      • presence in country with widespread Ebola transmission within previous 21 days without known exposure to patient with Ebola
      • brief direct contact (such as shaking hands) with person in early stages of Ebola without appropriate PPE
      • brief proximity (such as being in same room for brief time) to person with symptomatic Ebola
      • direct contact with patient with symptomatic Ebola while using appropriate PPE in countries without widespread Ebola transmission
      • traveling on aircraft with patient with symptomatic Ebola
      • residence in the same house as an Ebola patient
      • provision of care to an Ebola patient (without known high-risk exposure)
      • casual contact with an Ebola patient
        • defined as being within 3 feet (1 meter) or in same room for prolonged period while not wearing recommended PPE or brief direct contact (such as shaking hands) with an Ebola patient while not wearing PPE
        • brief interactions such as walking by a person or moving through a hospital, do not constitute casual contact
    • no identifiable risk with
      • contact with asymptomatic person who had previous contact with person with Ebola
      • contact with patient with Ebola before development of symptoms
      • presence in country with widespread Ebola transmission over 21 days previously
      • presence in country without widespread Ebola transmission without any other exposures listed above
    • Reference - CDC Epidemiologic Risk Factors to Consider when Evaluating a Person for Exposure to Ebola Virus 2014 Dec 24

Etiology and Pathogenesis

Pathogen

  • Ebolaviruses(1, 2, 3, 6)
    • zoonotic viral pathogens
    • members of Filoviridae family
    • enveloped, nonsegmented, negative-stranded RNA viruses
    • 5 species have been identified
      • Zaire ebolavirus
        • associated with greater virulence
        • circulating in central Africa since 1976, including Republic of Congo, Democratic Republic of Congo, and Gabon
        • 2 novel variants identified in 2014 outbreaks
          • Lomela variant responsible for outbreak in Democratic Republic of Congo
          • Makona variant responsible for outbreaks in Guinea, Liberia, Nigeria, and Sierra Leone
        • References - PLoS Curr 2014 May 2;6 full-text, Viruses 2014 Nov 24;6(11):4760 full-text
      • Sudan ebolavirus, circulating in Sudan, Republic of Congo, and Uganda since 1976
      • Bundibugyo ebolavirus, circulating on borders between Democratic Republic of Congo and Uganda since 2007
      • Tai Forest ebolavirus, only 1 documented human case in 1994
      • Reston ebolavirus, circulating in Philippines but nonpathogenic in humans

Transmission

  • fruit bats are potential reservoirs in endemic settings(1, 2, 3, 6)
    • 3 tree-roosting species, Epomops franqueti, Hypsignathus monstrosus, and Myonycteris torquata, may play role
    • each shown to harbor viral RNA and Ebola virus-specific antibodies
    • found throughout central and sub-Saharan Africa
    • Reference - Science 2014 Apr 11;344(6180):140 full-text
  • disease transmitted to humans likely via(1, 2, 3, 6)
    • direct contact with bats or their excretions or secretions
    • contact with infected end hosts, such as apes or other mammals
  • human-to-human transmission may lead to epidemics(1, 2, 3, 6)
    • epidemics often begin with single introduction from wildlife reservoir
    • infected humans are viremic from about 3 to 16 days
    • transmission to next human host likely requires direct contact with blood, bodily fluid, or remains of an infected patient
    • portal of entry may be mucous membrane, breach in skin, or parenterally, such as with a needlestick
    • all bodily fluids are thought to be infectious
    • Ebola virus may be detected by PCR in saliva, stool, semen, breast milk, tears, nasal blood, and on skin from patients with acute or convalescent infection
      • based on cohort study
      • 54 clinical samples from 26 patients with Ebola virus infection were assessed using viral culture and/or reverse transcription polymerase chain reaction (RT-PCR)
      • viral culture positive in 1 sample each of acute saliva, acute and convalescent breast milk, and convalescent semen
      • RT-PCR positive in 16 samples of acute saliva, acute skin swab, acute and convalescent breast milk, acute stool, acute tears, acute nasal blood, and acute semen
      • Reference - J Infect Dis 2007 Nov 15;196 Suppl 2:S142 full-text
    • fatal case of Ebola virus disease in 9-month-old infant who likely acquired infection via breastfeeding from mother with asymptomatic infection in case report (Clin Infect Dis 2017 Feb 15;64(4):513)
    • detection of Ebola virus by PCR in semen up to 290 days after disease onset reported in 5 survivors of Ebola virus disease (Clin Infect Dis 2016 Jun 15;62(12):1552)
    • about 50% of 5,055 cases of laboratory-confirmed Ebola virus disease in Sierra Leone between May 2014 to January 2015 reported physical contact with a suspected case or any ill person and/or funeral attendance (Clin Infect Dis 2015 Dec 1;61(11):1648)
    • estimated household secondary attack rate 12.5% (95% CI 8.6%-16.3%) based on meta-analysis of 9 studies (Clin Infect Dis 2016 May 15;62(10):1277)
  • incubation period in humans(1, 2, 5, 6)
    • range 1-21 days
    • average 4-10 days
    • estimated 6-12 days in 2014 West Africa outbreak
    • review of incubation period (time from exposure to any symptoms), latent period (time from exposure to wet symptoms), and infectious period can be found in Clin Infect Dis 2015 Oct 1;61(7):1135
  • virus may persist for prolonged periods in immune privileged sites such as the eye or testes after apparent clinical recovery
  • virus has been isolated for up to 82 days from semen, 63 days from aqueous humor, 26 days from urine, and 15 days from breast milk after onset of illness based on systematic review of 12 studies (Epidemiol Infect 2016 Jun;144(8):1652 full-text)
  • stability of Ebola virus
    • virus not thought to be long-lived on environmental surfaces in hospital settings (where cleaning measures are applied), although can theoretically survive up to several days
      • viral RNA not detected on dialysate or high-touch objects such as bedrails or bathroom surfaces during care of 2 patients in United States (presented at IDWeek 2014 Oct)
      • Ebola virus detected in 2 of 33 environmental specimens collected from isolation ward by RT-PCR but not culture, with both positive samples containing visible blood (J Infect Dis 2007 Nov 15;196 Suppl 2:S142 full-text)
      • Ebola virus persisted for several days on surfaces and in fluids under simulated environmental conditions for climate-controlled hospitals and for the climate of West Africa (no cleaning measures performed) (Emerg Infect Dis 2015 Jul;21(7):1243 full-text)
  • no reported transmission during commercial air travel to date (MMWR Morb Mortal Wkly Rep 2015 Jan 30;64(3):63 full-text)

Pathogenesis

  • pathogenesis not clearly defined but hypothetical models propose
    • a wide range of cell types may become infected but dendritic cells, monocytes, and macrophages may be preferred replication sites
    • infected dendritic cells, monocytes, and macrophages
      • overexpress tissue factor potentially resulting in coagulation abnormalities
      • travel via lymphatic system leading to disseminated infection
    • primary target tissues appear to be liver, spleen, and adrenal glands
    • viral replication in target leads to tissue damage and multiorgan dysfunction
      • hepatocellular necrosis may contribute to coagulopathy
      • adrenal necrosis may contribute to vascular instability
    • lymphoid depletion and lymphatic tissue necrosis are also common features of infection
    • mechanism of lymphocytolysis not fully clear but cell loss may lead to immune dysfunction
    • this may be further exacerbated by dysfunction of infected dendritic cells, which appear unable to secrete interferon-alpha, fully mature, and stimulate adaptive response
    • inability to mount an effective immune response may lead to uncontrolled viremia and ultimately death
    • References - (2, 6), Expert Rev Clin Immunol 2014 Jun;10(6):781

Immune response

  • innate immune response
    • infection induces robust expression of inflammatory mediators including(2, 6)
      • type I interferons (IFNs)
      • interleukins (IL-2, IL-6, IL-8, and IL-10)
      • IFN-inducible protein 10
      • monocyte chemoattractant protein 1
      • regulated upon activation normal T-cell expressed and secreted (RANTES)
      • tumor necrosis factor alpha (TNF-alpha)
      • reactive oxygen and nitrogen species
    • innate immune response may also play role in virus pathogenesis, supported by
      • infected monocytes and macrophages secrete high levels of TNF-alpha which is associated with rapid lymphocytolysis
      • uncontrolled secretion of proinflammatory cytokines may be associated with disease severity and poor survival
      • Reference - Expert Rev Clin Immunol 2014 Jun;10(6):781
  • adaptive immune response
    • critical for virus elimination and inhibition
      • neutralizing antibodies can be detected in humans following disease resolution
      • passive transfer of these antibodies protects animal models against lethal infection
      • cytotoxic CD8 T-cell response reported associated with survival in animal models
      • References - (6), Expert Rev Clin Immunol 2014 Jun;10(6):781
    • role of adaptive response not fully clear
      • robust T- and B-cell responses detected during acute phase of Ebola virus infection among survivors
        • plasmablast frequencies of 10%-50% of B-cells reported, compared < 1% in healthy persons
        • activated CD4 T-cell frequencies ranged from 5% to 30%, compared with 1%-2% in healthy persons
        • activated CD8 T-cell frequencies of > 50% reported
      • immune activation may persist following resolution of viremia, particularly in CD8 T-cell compartment
        • suggestive of ongoing antigen stimulation
        • calls into question hypothesized immunosuppressive nature of the virus
      • Reference - Proc Natl Acad Sci U S A 2015 Apr 14;112(15):4719 full-text, editorial can be found in Proc Natl Acad Sci U S A 2015 Apr 14;112(15):4518
  • recovery from Ebola is associated with an antibody response that lasts for at least 10 years(4)
    • unclear if antibody response confers lifelong immunity
    • unclear if antibody response provides protection from different Ebola virus species
  • review of immune evasion in Ebola virus infections can be found in Viral Immunol 2015 Feb;28(1):10

History and Physical

Clinical presentation

General features

  • symptoms typically arise 8-10 days after exposure (range 1-21 days)(4, 6)
  • initial symptoms are nonspecific and may include(1, 2, 3, 6)
    • fever (in about 90% of patients)
    • headache
    • nausea/vomiting
    • diarrhea
    • myalgias
  • rash reported in up to half of patients in first week of infection(3, 4, 6)
    • diffuse, erythematous, and maculopapular
    • may involve face, neck, trunk, and arms
    • desquamation may occur later
  • hemorrhagic signs seen in < 50% of patients after several days of illness, including(1, 2, 3, 6)
    • conjunctival injection
    • petechia
    • ecchymosis
    • bleeding from puncture sites
  • some patients may develop severe illness within 6-16 days after symptom onset, including(2, 3, 6)
    • mucosal hemorrhages (typically from gastrointestinal tract)
    • hypotension
    • shock
    • multiorgan failure
    • neurologic involvement such as headache, confusion, and coma
  • estimated asymptomatic infection rate 27.1% (95% CI 14.5%-39.6%) based on meta-analysis of 7 studies, results limited by significant heterogeneity (Clin Infect Dis 2016 May 15;62(10):1277)

2014 West Africa outbreak

  • clinical features associated with 2014 West Africa outbreak of Ebola virus
    • based on surveillance data from 3,343 confirmed cases and 667 probable cases of Ebola virus infection in Guinea, Liberia, Nigeria, and Sierra Leone
    • affected populations
      • no significant difference between men and women
      • healthcare workers account for 11.1% of all infections
    • mean incubation period 11.4 days, with 95% of cases developing symptoms within 21 days, based on mathematical modeling
    • common symptoms reported between onset of illness and case detection
      • fever in 87.1%
      • fatigue in 76.4%
      • vomiting in 67.6%
      • diarrhea in 65.5%
      • loss of appetite in 64.5%
      • headache in 53.4%
      • abdominal pain in 44.3%
      • joint pain in 39.4%
      • muscle pain in 38.9%
      • chest pain in 37%
      • cough in 29.6%
      • jaundice in 10.4%
      • rash in 5.8%
    • hemorrhagic symptoms uncommon
      • unexplained bleeding reported in 18%
      • blood in stool in 5.7%
      • hematemesis in 3.9%
      • blood from vagina in 3.2% of female patients
      • bloody cough in 2.4%
      • bleeding at injection site in 2.4%
      • bleeding gums in 2.3%
      • bloody nose in 1.9%
      • blood in urine in 1.2%
      • bleeding under skin in 0.6%
      • other bleeding in 1.2%
    • Reference - N Engl J Med 2014 Oct 16;371(16):1481 full-text, commentary can be found in N Engl J Med 2014 Oct 16;371(16):1545 full-text; similar findings found in case series in Guinea (N Engl J Med 2015 Jan;372(1):40, N Engl J Med 2014 Oct 9;371(15):1418 full-text) and Sierra Leone (5)
  • notable clinical signs and symptoms in 2 patients infected in West Africa and cared for in United States included
  • hemorrhagic manifestations appear less common in 2014 West Africa outbreak compared to previous Eastern-Central Africa outbreaks based on meta-analysis of 15 observational studies (BMC Infect Dis 2015 Dec 11;15(1):564 full-text)
  • encephalitis, with detectable virus in cerebrospinal fluid, reported in case series Clin Infect Dis 2015 Nov 15;61(10):1627, Clin Infect Dis 2016 Oct 15;63(8):1076

Clinical features in previous outbreaks

  • Ebola virus disease associated with fever, diarrhea, and vomiting in early phase; subsequent visible hemorrhage observed in less than half of patients
    • based on 2 cohort studies
      • 103 patients (mean age 38 years) with Zaire ebolavirus infection during outbreak in Kikwit, Democratic Republic of Congo in 1995
      • 23 patients (mean age 36 years) with Zaire ebolavirus infection during outbreak in Mosango, Democratic Republic of Congo in 1995
    • early signs and symptoms (typically lasting for < 1 week) included
      • fever in 93%-100%
      • asthenia in 86%-100%
      • diarrhea in 85%-96%
      • nausea in 74%
      • vomiting in 72%-83%
      • abdominal pain in 62%-96%
      • headache in 56%-74%
      • anorexia in 44%-96%
      • arthralgia or myalgia in 22%-55%
      • sore throat, odynophagia, or dysphagia in 48%-56%
      • conjunctival injection in 43%
      • rash in 4%-14%
        • initially on lateral sides of trunk, groin, and axillary spaces and spreading to entire body except face in hours
        • often associated with petechia but not with pruritus
    • subsequent signs and symptoms (after 1 week) included
      • hemorrhagic signs in < 45%, including
        • gum bleeding in 12%-30%
        • melena in 9%-43%
        • bleeding at injection sites in 7%-30%
        • hematemesis in 11%-30%
        • ecchymosis in 26%
        • petechia in 7%-22%
        • hematuria in 9%
        • epistaxis in 2%-4%
      • neurologic symptoms including
        • confusion in 9%
        • delirium in 13%
        • neck stiffness in 4%
      • tachypnea in 25%
      • hearing loss in 6%
      • miscarriage in 3%

History

  • ask about(4, 6)
    • travel to areas with active transmission in the past 21 days
    • specific dates of travel to these areas and precise locations within
    • exposure to anyone with known or suspected Ebola including
      • work in medical facility for which Ebola patients were cared for
      • involvement in burial or funeral participation for Ebola victims
    • handling of bats, rodents, or primates (potential reservoirs for disease)
    • earliest date of symptom onset
    • ill contacts and knowledge of any others who may have been exposed to Ebola

Diagnosis

Making the diagnosis

  • Centers for Disease Control and Prevention (CDC) case definitions
    • persons under investigation for Ebola virus disease include those with BOTH
      • fever (subjective or ≥ 100.4°F or 38.0°C) and an additional symptom such as headache, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage
      • potential exposure within the past 21 days such as
        • contact with blood, bodily fluids, or human remains of a patient known to have or suspected to have Ebola virus disease (EVD)
        • residence in, or travel to, an area with active transmission
        • direct handling of bats, rodents, or primates from disease-endemic areas
  • diagnostic testing options
  • testing is typically performed or coordinated by international or national reference centers or local health departments
  • in United States, testing is performed at CDC, Viral Special Pathogens Branch (VSPB)
  • consider testing for alternative diagnoses, such as malaria or typhoid fever(4, 6)
  • immediately isolate any patient under investigation Ebola virus disease (see Infection Control for more information)

Differential diagnosis

  • other febrile illnesses including(2, 4, 6)
    • malaria
    • typhoid fever
    • chikungunya fever
    • viral hepatitis
    • meningococcal disease
    • bacillary dysentery
    • plague
    • leptospirosis
    • anthrax
    • relapsing fever
    • typhus
    • measles
    • bacterial sepsis
    • streptococcal toxic shock syndrome
  • other viral hemorrhagic fevers including
    • other filovirus infections such as Marburg hemorrhagic fever (endemic in central Africa, including Democratic Republic of Congo, Angola, and Kenya)
    • arenavirus infections
      • Lassa fever (endemic in West Africa, including Liberia, Guinea, Sierra Leone, Nigeria, and Central African Republic)
      • New World arenaviruses (endemic in South America) such as
        • Argentine hemorrhagic fever
        • Bolivian hemorrhagic fever
    • flavivirus infections, including
      • yellow fever (endemic in tropical regions of Africa and South America)
      • dengue (endemic in Southeast Asia, Pacific rim tropics and subtropics, Caribbean islands, and subtropical South America, Mexico, Florida, and Texas)
      • Omsk hemorrhagic fever (endemic in Western Siberia)
      • Kyasanur Forest disease virus (endemic in India)
    • bunyavirus infections
      • Crimean-Congo hemorrhagic fever (endemic in the Middle East, southeastern Europe, and western China)
      • Rift Valley fever (endemic in Africa and Arabian Peninsula)
      • Hantavirus cardiopulmonary syndrome (endemic in Americas)
      • hemorrhagic fever with renal syndrome (endemic in Europe and Asia)
      • severe fever with thrombocytopenia syndrome (endemic in China)
    • Reference - Annu Rev Pathol 2013 Jan 24;8:411
  • wide variety of febrile illnesses may present similarly to Ebola virus disease
    • based on retrospective cohort study
    • 91 patients with acute fever or history of fever and ≥ 3 symptoms consistent with Ebola infection who were admitted to an Ebola virus disease treatment unit in Sierra Leone were evaluated
      • all patients tested for Ebola virus using reverse transcriptase-polymerase chain reaction and malaria using rapid diagnostic tests
      • additional tests for other infectious agents performed depending on individual's risk of exposure and clinical examination
    • 38 patients (41.8%) had Ebola virus disease
    • 32 patients had alternative diagnosis including
      • malaria in 13 patients
      • enteric infection in 13 patients (mostly due to diarrheagenic Escherichia coli or Shigella)
      • upper respiratory tract infection in 4 patients (due to coronavirus or influenza A infection)
      • other infections such as lower respiratory tract infection and pharyngitis in 12 patients
    • 9 patients had no identifiable cause
    • 2 patients were international health care workers repatriated to host nation
    • Reference - Clin Infect Dis 2015 Sep 1;61(5):795
  • several febrile and gastrointestinal illnesses common among ill returned travelers and immigrants from countries affected by 2014 Ebola outbreak, including Sierra Leone, Liberia, and Guinea
    • based on GeoSentinel surveillance network data covering 57 clinics in 25 countries
    • 805 ill returned travelers and new immigrants from Sierra Leone, Liberia, or Guinea seen between 2009 and 2014 evaluated
      • 49.2% had systemic febrile illness
      • 19.6% had acute diarrhea
      • 11.7% had other gastrointestinal illness
      • 6.7% had respiratory syndrome
    • most common diagnoses among 770 ill returned travelers
      • malaria in 40.3%
      • acute diarrhea in 12.3%
      • upper respiratory tract infection/influenza-like illness in 4.2%
      • viral syndrome in 3.8%
      • febrile illness of unspecified cause persisting < 3 weeks in 3.1%
    • most common diagnoses among 35 immigrants
      • latent tuberculosis infection in 42.9%
      • dental caries in 31.4%
      • schistosomiasis in 31.4%
      • strongyloidiasis in 17.1%
      • giardiasis in 14.3%
    • Reference - Ann Intern Med 2015 Jun 2;162(11):757

Case definitions

  • Centers for Disease Control and Prevention (CDC) case definitions
    • person under investigation (PUI) - has BOTH
      • signs or symptoms consistent with Ebola infection
        • elevated body temperature or subjective fever
        • other symptoms, including
          • severe headache
          • fatigue
          • muscle pain
          • vomiting
          • diarrhea
          • abdominal pain
          • unexplained hemorrhage
      • epidemiologic risk factor, including
        • travel to country with widespread Ebola disease within previous 21 days
        • contact with person with symptomatic Ebola infection
    • confirmed case - patient meets criteria for PUI and has laboratory-confirmed diagnostic evidence of Ebola
    • References - CDC Case Definition for Ebola Virus Disease (EVD) 2015 Jan 26, CDC Safe Management Practices

Testing overview

  • Ebolaviruses classified as biosafety level 4 agents(2, 4, 6)
  • options for testing include
    • reverse transcriptase-polymerase chain reaction (RT-PCR)
      • primary test for confirming acute infection
      • viremia typically detectable from 3 to 10 days after symptom onset
    • Ebola-specific serologies
      • presence of immunoglobulin M (IgM) on acute phase sample ≥ 2 days of illness onset
      • 4-fold rise in IgG titers in paired acute and convalescent samples considered diagnostic
      • typically used to monitor immune response
    • viral antigen detection
      • may be useful in acute phase
      • diagnostic if performed with RT-PCR
      • first antigen rapid test approved by World Health Organization for emergency evaluation (WHO 2015 Feb 19)
    • viral isolation(4, 6)
  • consider testing for alternative diagnoses, such as malaria or typhoid fever(4, 6)

Blood tests

General laboratory findings

  • routine blood tests may show(2, 4, 6)
    • early leukopenia (as low as 1,000 cells/mcL), particularly with lymphopenia
    • relative neutrophilia with left shift
    • atypical lymphocytosis
    • thrombocytopenia (50,000-100,000 cells/mcL)
    • elevated hepatic aminotransferase levels (aspartate aminotransferase typically > alanine aminotransferase)
    • hyperproteinemia
    • diffuse intravascular coagulopathy
      • prolonged prothrombin and partial thromboplastin times
      • detectable fibrin split products
    • elevated amylase and lipase in cases with pancreatic involvement
  • significant electrolyte losses reported in 2 patients infected in West Africa and cared for in United States, notably
  • elevated creatinine kinase, hepatic transaminases, and acute kidney injury each reported in over half of patients presenting with Ebola virus disease
    • based on cohort study
    • blood samples from 118 patients (mean age 26 years) with confirmed Ebola virus disease in 2014 outbreak were analyzed for general hematologic and biochemical markers
      • clinical presentation at admission
        • 31 patients (26%) presented with early and mild, non-specific features such as pyrexia, weakness, lethargy, myalgia, and arthritis (stage 1)
        • 72 patients (61%) had additional gastrointestinal involvement (stage 2)
        • 12 patients (10%) had additional complicated manifestations such as hemorrhage, shock, neurologic involvement, or signs of organ failure (stage 3)
      • 87% were Ebola-positive at admission on reverse transcriptase-polymerase chain reaction (RT-PCR) assay
    • case fatality rate 34.7% (median time from admission to death 4 days)
    • laboratory findings showed
      • elevated creatinine kinase (> 380 units/L) in 83%
      • severe hepatitis (defined as aspartate transaminase > 525 units/L) in 59%
      • elevated alanine transaminase (> 240 units/L) in 53%
      • acute kidney injury (defined according to risk, injury, failure, loss of function, and end-stage (RIFLE) criteria, > 1.5 × baseline creatinine) in 50%
      • thrombocytopenia (< 150 × 109/L) in 45%
      • granulocytosis (> 7.5 × 109/L) in 42%
      • abnormal serum potassium in 33%
      • elevated C-reactive protein (> 100 mg/L) in 21%
      • elevated hematocrit in 15%
    • factors associated with mortality in multivariate analysis
      • severe acute kidney injury (RIFLE-3, > 3 × baseline creatinine) (odds ratio [OR] 5.84, 95% CI 1.15-29.58)
      • low RT-PCR cycle threshold (< 20 cycles) (OR 6.72, 95% CI 1.5-30.07)
    • Reference - Lancet Infect Dis 2015 Nov;15(11):1292, editorial can be found in Lancet Infect Dis 2015 Nov;15(11):1247
  • rhabdomyolysis (creatine kinase > 1,000 units/L) appears to be more common in patients with confirmed Ebola virus disease, compared to patients with other diagnoses
    • based on cohort study
    • 22 patients with confirmed Ebola virus disease and 16 control patients with other diagnoses had measurement of creatine kinase level at admission
    • comparing patients with v.s without Ebola virus disease
      • creatine kinase > 380 units/L in 81% vs. 25% (p = 0.002)
      • rhabdomyolysis (creatine kinase > 1,000 units/L) in 59% vs. 19% (p = 0.03)
    • Reference - Clin Infect Dis 2016 Jan 1;62(1):19
  • elevations in several inflammatory markers, such as IL-6 and ferritin associated with decreased survival in a small cohort of Ebola virus patients (J Infect Dis 2014 Aug 15;210(4):558)

Reverse transcriptase-polymerase chain reaction (RT-PCR)

  • RT-PCR is main test for confirming acute infection(1, 2, 6)
    • detectable from day 3 up to 6-17 days after illness onset
    • useful for making diagnosis in remote outbreak settings
    • repeat testing within 48 hours in those with initial negative results if diagnosis is still suspected
  • during 2014 outbreak
    • viral RNA reported detectable in several clinical samples including
      • blood
      • urine
      • vomitus
      • stool
      • endotracheal suctioning
      • semen
      • skin
    • no viral RNA detected in dialysate samples or other environmental samples collected from patient rooms
    • Reference - presented at IDWeek 2014 Oct
  • RT-PCR may detect viremia earlier than antigen detection assays in patients with Ebola virus in outbreak settings (level 2 [mid-level] evidence)
    • based on cohort study with test under investigation not performed on all samples
    • blood samples from patients with suspected Ebola virus infection during Uganda outbreak in 2000 were analyzed using RT-PCR and antigen-capture assays
      • of 1,083 samples analyzed by RT-PCR, 246 were positive
      • of 1,771 samples tested by antigen detection, 282 were positive
    • RT-PCR detected viremia 24-48 hours prior to antigen detection
    • viremia detectable from time of symptom onset until day 14 in some patients
    • viral RNA copies ranging from 104 copies/mL to 109 copies/mL
    • Reference - J Virol 2004 Apr;78(8):4330 full-text
  • RT-PCR on capillary blood samples via fingerstick may have high positive predictive value but only moderate sensitivity for diagnosis of Ebola virus disease in outbreak settings compared to venous blood samples (level 2 [mid-level] evidence)
    • based on diagnostic cohort study with blinding not stated
    • 120 paired venous and capillary (via fingerstick) blood samples from 53 patients with suspected Ebola virus disease during 2014 outbreak in Guinea were analyzed for presence of Ebola virus by RT-PCR
    • 63% of venous samples were positive for Ebola virus (reference standard)
    • diagnostic performance of RT-PCR on capillary blood samples
      • sensitivity 86.8%
      • specificity 100%
      • positive predictive value 100%
      • negative predictive value 81.5%
    • Reference - Clin Infect Dis 2015 Sep 1;61(5):669 full-text
  • Ebola viral load at admission > 10 million copies/mL associated with increased risk of mortality
    • based on retrospective cohort study
    • 525 patients with Ebola virus disease in Sierra Leone between June and October 2014 who had evaluable outcome data were reviewed
    • mortality 51%
    • 76% had measurement of Ebola viral load (on whole blood sample)
    • viral load at admission > 10 million copies/mL associated with increased risk of mortality in multivariate analysis (odds ratio 10.8, 95% CI 6.13-19.66)
    • Reference - J Infect Dis 2015 Dec 1;212(11):1752

Antigen detection

  • viral antigen detection(1, 2, 6)
    • used in acute phase and is diagnostic if performed with RT-PCR
    • viral antigens typically detectable from day 3 up to 7-16 days after illness onset
  • ReEBOV Antigen Rapid Test kit
    • approved by World Health Organization for emergency evaluation (WHO 2015 Feb 19)
    • ReEBOV Antigen Rapid Test kit helps diagnose Ebola virus disease (level 1 [likely reliable] evidence)
      • based on diagnostic cohort study
      • 408 field-collected samples (196 plasma and 212 serum) from patients in West Africa with suspected Ebola virus disease during 2013-2016 outbreak were assessed using ReEBOV Antigen Rapid Test kit (serum samples collected predominantly during early stage of outbreak and plasma samples in later stages)
      • prevalence of Ebola virus disease 52.5% overall (61.3% in plasma samples and 42.9% in serum samples) by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) with cycle threshold cutoff < 37 (reference standard)
      • performance of ReEBOV Antigen Rapid Test kit for diagnosis of Ebola virus disease
        • overall
          • sensitivity 91.1%
          • specificity 90.2%
          • positive predictive value 91.1%
          • negative predictive value 90.2%
        • in plasma samples, sensitivity 85.7% and specificity 97.3%
        • in serum samples, sensitivity 94.6% and specificity 80.5%
      • in analysis of 176 plasma samples using qRT-PCR cycle threshold cutoff < 45 as reference standard, ReEBOV Antigen Rapid Test had sensitivity 62.1% and specificity 96.7%
      • Reference - J Infect Dis. 2016 Oct 15;214(suppl 3):S203, analytical validation study can be found in J Infect Dis 2016 Oct 15;214(suppl 3):S210
    • DynaMed commentary -- ReEBOV kit designed for use with either venous or fingerstick samples. Sample sources were not specified in article.
    • ReEBOV Antigen Rapid Test kit on fingerstick samples may help diagnose Ebola virus disease at point-of-care (level 2 [mid-level] evidence)
      • based on validation cohort study without reliable reference standard
      • 105 patients with suspected Ebola virus disease in Sierra Leone evaluated using ReEBOV Antigen Rapid Test kit on fingerstick samples at point-of-care and altona RT-PCR assay on venipuncture plasma samples (reference standard)
      • 26.7% had Ebola virus disease by reference standard
      • performance of ReEBOV Antigen Rapid Test kit on fingerstick samples at point-of-care for diagnosis of Ebola virus disease
        • sensitivity 100%
        • specificity 92.2%
        • positive predictive value 82.4%
        • negative predictive value 100%
      • altona RT-PCR determined to have suboptimal sensitivity under field conditions based on reanalysis of subset of samples using Trombley RT-PCR , although not all samples could be retested
      • similar diagnostic performance reported in laboratory testing of 277 whole blood venipuncture samples by ReEBOV test compared to RT-PCR assay on plasma
      • Reference - Lancet 2015 Aug 29;386(9996):867, editorial can be found in Lancet 2015 Aug 29;386(9996):833

Serologic testing

  • Ebola-specific antibody assays(1, 2, 4, 6)
    • immunoglobulin M (IgM) antibodies
      • may be present on acute phase sample ≥ 2 days of illness onset
      • become undetectable 30-168 days after infection
    • IgG antibodies
      • present within 6-18 days after illness onset
      • 4-fold rise in IgG titers in paired acute and convalescent samples considered diagnostic
    • serologies more often used to monitor immune response than for diagnosis

Treatment

Treatment overview

  • no specific antiviral therapy available
  • treatment approaches used in a limited number of patients have included
    • ZMapp, a cocktail of monoclonal antibodies directed at viral proteins
    • convalescent sera or blood transfusion
    • plasmapheresis
  • aggressive supportive care is typically needed, focused on(2, 3, 6)
    • hemodynamic support
    • correction of electrolyte disturbances
    • blood transfusion
    • reversal of coagulopathy, using fresh frozen plasma and platelet transfusion
    • renal replacement therapy
      • recommendations for safely performing hemodialysis can be found at CDC 2015 Jan 26
    • nutritional support
    • treatment of secondary infections
    • see Sepsis treatment in adults and Sepsis treatment in children for additional information
    • DynaMed commentary -- efficacy of Surviving Sepsis Campaign protocols for more exotic pathogens such as Ebolaviruses not studied
  • infection control
    • immediately isolate any patient under investigation for Ebola who presents to a healthcare setting in a private room, containing a bathroom, with the door closed
    • protocols regarding patient transport to appropriate care facilities may vary by region
    • asymptomatic patients may required quarantine depending on degree of exposure
    • contact local or state health departments when coordinating care
    • Centers for Disease Control and Prevention (CDC) endorses stepwise protocols for use of personal protective equipment (PPE) when caring for patients with Ebola to ensure that no skin is exposed
    • CDC algorithm PDF and guidance on PPE provide additional information
  • case description of care for an Ebola patient in a biocontainment unit in Germany can be found in N Engl J Med 2014 Dec 18;371(25):2394 full-text

Therapeutic approaches

Antiviral therapies

  • no specific antiviral therapy available(1, 2, 3, 6)
  • ribavirin not shown to have effect in vitro or in vivo and is not recommended(1, 2, 3)
  • efficacy of antiviral therapies in humans
    • addition of nucleotide analog favipiravir to supportive therapy associated with prolonged survival in patients with Ebola virus disease (level 2 [mid-level] evidence)
      • based on cohort study
      • 124 patients with Ebola virus disease during 2014 outbreak in Sierra Leone received supportive therapy plus oral favipiravir vs. supportive therapy alone (control)
      • supportive therapy based on World Health Organization (WHO) recommendations included management of dehydration, sepsis, malaria, and other symptoms
      • oral favipiravir dosing 800 mg twice on day 1, 600 mg twice on day 2, followed by at least 5 days of standard therapy (treatment duration 3-11 days)
      • comparing supportive therapy plus favipiravir vs. control
        • survival rate 56.4% vs. 35.3% (p = 0.027, NNT 5)
        • mean survival time 46.9 days vs. 28.9 days (p = 0.049)
        • > 100-fold reduction in viral load in 52.9% vs. 16.7% (p = 0.028)
      • favipiravir treatment also associated with significant improvement in clinical symptoms such as fever, jaundice, and vomiting/nausea
      • among 35 patients who completed study, survival rate 64.8% in 17 patients with favipiravir vs. 27.8% in 18 patients without favipiravir (p = 0.044, NNT 3)
      • Reference - Clin Infect Dis 2016 Nov 15;63(10):1288
    • case series and reports
      • antiviral therapies included in treatment of 3 patients treated in United States in case series
        • brincidofovir given on day 11 and 14 to 42-year-old man who died
        • brincidofovir, convalescent plasma, TKM-Ebola, and ZMapp given between days 3 and 6 to 26-year-old woman who survived
        • brincidofovir and convalescent plasma given between days 5 and 8 to 29-year-old woman who survived
        • Reference - Ann Intern Med 2015 Jul 21;163(2):81
      • TKM-100802 and convalescent plasma given to 2 patients infected with Ebola in West Africa and treated in United States, both of whom survived, in case series (Clin Infect Dis 2015 Aug 15;61(4):496 full-text)
      • brincidofovir and convalescent plasma given to 33-year-old man infected with Ebola in Liberia and treated in United States who survived in case report (Clin Infect Dis 2015 Sep 15;61(6):969 full-text)
      • GS-5734 (broad-spectrum antiviral), ZMapp, and buffy coat transfusion from an Ebola survivor given to an infant with congenital Ebola virus infection who survived in case report (J Infect Dis 2017 Jan 15;215(2):171)
  • artesunate-amodiaquine therapy associated with reduced risk of death in patients with Ebola virus disease compared to artemether-lumefantrine (level 2 [mid-level] evidence)
    • based on cohort study
    • 328 patients with Ebola virus disease in high malaria burden region in Liberia were treated with or without antimalarial therapy
      • 194 patients received artemether-lumefantrine
      • 71 patients received artesunate-amodiaquine due to shortage of artemether-lumefantrine
      • 63 patients did not receive any antimalarial therapy
    • mortality 64.4% in artemether-lumefantrine group vs. 50.7% in artesunate-amodiaquine group vs. 65.1% in no antimalarial group
    • compared to artemether-lumefantrine, artesunate-amodiaquine associated with reduced risk of death
      • overall (adjusted risk ratio [RR] 0.69, 95% CI 0.54-0.89)
      • in patients without malaria (adjusted RR 0.64, 95% CI 0.49-0.85)
    • Reference - N Engl J Med 2016 Jan 7;374(1):23
    • DynaMed commentary-- unclear if aretestunate-amodiaquine associated with reduced mortality (potentially due to anti-Ebola virus activity) or if artemether-lumefantrine associated with increased mortality (potentially due to QT prolongation in the setting of hypokalemia which is common in patients with Ebola virus disease)

Passive immunization

  • approaches attempted in a limited number of patients have included(1, 2, 3, 6)
    • ZMapp, a cocktail of monoclonal antibodies directed at viral proteins
    • convalescent sera and blood transfusions
  • data supporting use of blood transfusion therapy limited and contradictory
    • convalescent plasma transfusions may not be associated with improved survival in patients with Ebola virus disease in Guinea (level 2 [mid-level] evidence)
      • based on cohort study
      • 99 patients with Ebola virus disease received 2 transfusions of 200-250 mL convalescent plasma and 148 control patients were evaluated for risk of death
      • 84 patients treated with convalescent plasma who had survived after day 3 were included in analysis
      • plasma level of Ebola-neutralizing antibodies unknown at time of transfusion
      • at baseline, comparing convalescent plasma group vs. control
        • difficulty swallowing in 18% vs. 9% (p = 0.02)
        • eye redness (both conjunctivitis and conjunctival bleeding) in 40% vs. 20% (p < 0.001)
        • symptom duration > 6 days in 19% vs. 49% (p < 0.001)
      • mortality from day 3 to day 16 after diagnosis 31% in convalescent plasma group vs. 38% in control group (not significant)
      • no convalescent plasma-associated serious adverse effects reported
      • Reference - N Engl J Med 2016 Jan 7;374(1):33
    • convalescent blood transfusions reported to improve survival in patients with Ebola virus disease (level 3 [lacking direct] evidence)
      • based on 2 case series
      • 8 patients with Ebola virus disease during outbreak in Kikwit, Democratic Republic of Congo received convalescent blood transfusions and only 1 died (J Infect Dis 1999 Feb;179 Suppl 1:S18 full-text)
      • 1 patient with Ebola virus disease due to exposure to contaminated needle in England in 1976 received convalescent blood transfusions and survived (Br Med J 1977 Aug 27;2(6086):541 PDF)
    • modeling of Ebola transmission suggests that widespread use of transfusion therapy could substantially reduce mortality in epidemic settings
    • acute respiratory distress syndrome following transfusion of convalescent plasma reported in 44-year-old healthcare worker who contracted Ebola virus disease in Madrid, Spain, in 2014 (Lancet Respir Med 2015 Jul;3(7):554)
    • review of use of convalescent plasma for treatment of Ebola virus disease in resource-limited settings can be found in Clin Infect Dis 2016 Jan 1;62(1):69 full-text
  • monoclonal antibodies
    • ZMapp (combination of MB-003 and ZMab)
      • addition of ZMapp to standard care may not reduce mortality in patients with Ebola virus disease (level 2 [mid-level] evidence)
        • based on randomized trial with inadequate power
        • 72 patients with Ebola virus disease during 2015 outbreak randomized to standard care plus 3 doses of ZMapp (50 mg/kg IV every third day) vs. standard care alone
        • mean time from onset of clinical symptoms to study enrollment 4.2 days
        • prespecified superiority criteria defined as ≥ 97.5% posterior probability on Bayesian analysis
        • patients in Guinea also received oral favipiravir as part of standard care
        • 71 patients included in analysis
        • comparing standard care plus ZMapp vs. standard care alone
          • mortality at 28 days in 22% vs. 37% (posterior probability of superiority of standard care plus ZMapp 91.2%, prespecified superiority criteria not met)
          • serious adverse events in 31% vs. 37% (not significant)
        • Reference - PREVAIL II trial (N Engl J Med 2016 Oct 13;375(15):1448)
        • DynaMed commentary -- authors noted that the timing of ZMapp infusion might miss the 5-day window in which ZMapp associated with higher survival rate in nonhuman primate trials
    • MB-003 or ZMab each reported to show antiviral effects in macaques
      • MB-003 consists of 3 anti-Ebola virus mouse/human chimeric monoclonal antibodies
        • MB-003 prophylaxis may provide protection in macaques exposed to Ebola virus
          • mortality 0% in 2 rhesus macaques receiving MB-003 after 1 hour of virus challenge
          • mortality 33.3% in rhesus macaques receiving MB-003 after 24 or 48 hours of virus challenge vs. 100% in control animals (p < 0.05)
          • little or no viremia and few clinical symptoms observed in 4 surviving macaques
          • Reference - Proc Natl Acad Sci U S A 2012 Oct 30;109(44):18030 full-text
        • MB-003 therapy may improve survival in macaques after detection of symptoms and viremia
          • MB-003 treatment initiated in 7 rhesus macaques after symptom onset and laboratory confirmation of viremia
            • first treatment given by 120 hours after exposure
            • additional doses given about 170 and 250 hours after exposure
          • mortality 57% in 7 rhesus macaques receiving MB-003 vs. 100% in 2 control animals (no p value reported)
          • Reference - Sci Transl Med 2013 Aug 21;5(199):199ra113 full-text
      • ZMab consists of 3 monoclonal antibodies specific for Ebola virus glycoprotein
        • ZMab prophylaxis may provide protection in macaques exposed to Ebola virus
        • ZMab plus interferon-alpha may improve survival in macaques after detection of symptoms and viremia
          • mortality 25% in 4 cynomolgus macaques and 0% in 4 rhesus macaques receiving ZMab plus interferon-alpha after detection of viremia (3 days after virus challenge)
          • 50% mortality in 4 cynomolgus macaques receiving interferon-alpha after 1 day of exposure and ZMab after detection of viremia (4 days after virus challenge)
          • Reference - Sci Transl Med 2013 Oct 16;5(207):207ra143 full-text
    • passive immunotherapies included in treatment of 2 patients treated in United States in case series
      • brincidofovir, convalescent plasma, TKM-Ebola, and ZMapp given between days 3 and 6 to 26-year-old woman who survived
      • brincidofovir and convalescent plasma given between days 5 and 8 to 29-year-old woman who survived
      • Reference - Ann Intern Med 2015 Jul 21;163(2):81
    • human-derived monoclonal antibody mAb114 shown to provide protection in macaques (Science 2016 Mar 18;351(6279):1339)
    • review of monoclonal antibodies targeting Ebola can be found in Sci Rep 2014 Nov 6;4:6881 full-text

Plasmapheresis

  • plasmapheresis used in a small number of patients but is not clearly associated with improved survival(2)
  • lectin affinity plasmapheresis used during successful treatment of 38-year-old man with severe Ebola virus disease in case report (Blood Purif 2014;38(3-4):286)

Other management

Complications and Prognosis

Complications

Post Ebola virus disease syndromes

  • among survivors of 2014 West Africa outbreak
    • arthralgia and anorexia common among survivors of Ebola virus disease
      • based on cross-sectional study
      • 105 survivors (mean age 38.9 years) of 2014 Ebola outbreak in Guinea were surveyed
      • 31 survivors (29.5%) were healthcare personnel
      • mean duration between hospital discharge and questionnaire survey 103.5 days in 89 patients
      • reported symptoms included
        • pain in
          • joints in 86.7%
          • back in 45.7%
          • chest in 30.7%
          • muscles in 26.7%
        • anorexia with varying severity levels
          • mild (loss of appetite without change in eating habits) in 31.4%
          • moderate (change in oral intake without significant weight loss or malnutrition) in 61.9%
          • severe (significant weight loss or malnutrition) in 4.8%
      • 104 survivors reported level of recovery in functional status
        • mild (10%-30% recovery) in 1.9%
        • moderate (30%-70% recovery) in 50%
        • excellent (80%-100% recovery) in 48.1%
      • factors associated with reduced recovery in functional status in multivariate analysis
        • severity of arthralgia (p = 0.008)
        • severity of anorexia (p = 0.04)
      • Reference - Clin Infect Dis 2015 Oct 1;61(7):1035 full-text
    • musculoskeletal pain, headache, visual problems, and insomnia common among survivors of Ebola virus disease
      • based on cross-sectional study
      • 81 survivors (median age 29 years) of 2014 Ebola outbreak in Kenema District, Sierra Leone were surveyed
      • most commonly reported physical or psychosocial sequelae up to at least 4 months after resolution of acute disease included
        • musculoskeletal pain
          • joint pain in about 80%
          • muscle pain in about 50%
        • headache in about 70%
        • visual problems in about 40%
        • insomnia in about 40%
      • Reference - Clin Infect Dis 2016 Jan 1;62(1):125
    • fever, headache, and myalgia common among survivors of Ebola virus disease
      • based on cohort study
      • 115 survivors (60.9% women) of 2014-2015 Ebola outbreak in Kenema District, Sierra Leone were assessed
      • median clinic attendance was 5 visits, median time from discharge to attendance was 261 days
      • most commonly reported signs and symptoms included
        • fever in 61.7%
        • headache in 63.1%
        • myalgia in 43.3%
      • Reference - Emerg Infect Dis 2017 Jan;23(1):66 full-text
    • arthralgias, ocular symptoms, and auditory symptoms common among Ebola survivors; higher viral loads at time of diagnosis associated with development of ocular abnormalities
      • based on cross-sectional study
      • 277 survivors (median age 29 years) of 2014 Ebola outbreak in Port Loko, Sierra Leone were reviewed
      • mean duration between hospital discharge and first convalescent clinic visit 121 days
      • common symptoms included
        • arthralgia in 76%
        • new ocular symptoms in 60% (ranging from blurry vision in 38% to visual loss in 3%)
        • auditory symptoms in 24%
        • uveitis in 18%
      • higher viral load at diagnosis of acute Ebola virus disease associated with increased risk of
        • uveitis (adjusted odds ratio [OR] 3.33, 95% CI 1.87-5.91, for every 5-point decrease in cycle threshold on real-time reverse transcriptase polymerase chain reaction [RT-PCR] testing)
        • new ocular symptoms or ocular diagnoses (adjusted OR 3.04, 95% CI 1.87-4.94)
      • Reference - Lancet Infect Dis 2016 Mar;16(3):331, editorial can be found in Lancet Infect Dis 2016 Mar;16(3):270
    • arthralgia and anorexia are common post-Ebola virus disease complications; conjunctival injection during acute phase associated with development of uveitis during convalescence
      • based on cohort study
      • 166 survivors (mean age 24.7 years) of 2014 Ebola outbreak in Freetown, Sierra Leone were reviewed
      • mean duration between hospital discharge and first convalescent clinic visit 51.1 days
      • common symptoms included
        • arthralgia in 77.7%
        • fatigue in 69.8%
        • ocular symptoms in 56.7%, with uveitis most common
        • abdominal pain in 54.2%
        • headache in 52.4%
        • anemia in 50%
        • skin disorders in 48.8%
        • back pain in 32.5%
        • alopecia in 31.9%
      • presentation with red/injected eyes during acute phase of Ebola virus disease associated with increased risk of uveitis (adjusted odds ratio 10.4, 95% CI 1.91-57.5)
      • Reference - Clin Infect Dis 2016 Jun 1;62(11):1360 full-text
    • late-onset encephalitis and polyarthritis associated with detectable Ebola virus in cerebrospinal fluid in 30-year-old woman with no known history of Ebola exposure in case report (Emerg Infect Dis 2016 Jan;22(1):150 full-text)
  • among survivors of previous outbreaks
    • long-term sequelae, including memory loss, insomnia, musculoskeletal pain, and hearing loss, may persist for > 2 years after Ebola virus disease
      • based on cohort study
      • 49 probable or confirmed adult survivors of 2007 Bundibugyo Ebola virus outbreak in Uganda and 157 seronegative adult contacts were evaluated about 29 months after outbreak
      • baseline differences comparing survivors vs. uninfected contacts
        • mean age 40 years vs. 33.5 years (p = 0.002)
        • occupation as healthcare worker in 18% vs. 5% (p = 0.03)
      • compared to uninfected contacts, survivors of Bundibugyo Ebola virus outbreak associated with increased risk of
        • ocular disorders including
          • retro-orbital pain (relative risk [RR] 4.3, 95% CI 1.9-9.6)
          • blurred vision (RR 1.9, 95% CI 1.1-3.2)
        • musculoskeletal abnormalities including
          • muscle weakness (RR 3.3, 95% CI 1.1-10.3)
          • stiffness in joints (RR 2.5, 95% CI 1.1-5.4)
          • arthralgia (RR 2, 95% CI 1.1-3.6)
        • hearing loss (RR 2.3, 95% CI 1.2-4.5)
        • difficulty swallowing (RR 2.1, 95% CI 1.1-3.9)
        • difficulty sleeping (RR 1.9, 95% CI 1.3-2.8)
        • fatigue (RR 1.9, 95% CI 1.3-2.8)
      • compared to uninfected contacts, survivors of Bundibugyo Ebola virus outbreak associated with increased prevalence of
        • chronic health issues persisting ≥ 1 year (prevalence ratio [PR] 2.1, 95% CI 1.2-3.6)
        • limitations due to memory loss or confusion (PR 5.8, 95% CI 1.5-22.4)
      • Reference - Lancet Infect Dis 2015 Aug;15(8):905, editorial can be found in Lancet Infect Dis 2015 Aug;15(8):865

Secondary infections

  • convalescence may be prolonged and complicated by secondary infections(2, 3, 4, 6)
  • gram-negative septicemia complicated Ebola virus disease in 36-year-old male
    • based on case report
    • 36-year-old man infected with Ebola virus in Sierra Leone, and was transferred to Hamburg, Germany, during treatment
    • initial symptoms of Ebola included malaise, headache, and myalgias
    • fever developed on day 2 and patient treated empirically for malaria and also with ceftazidime on days 2 through 6
    • abdominal pain, nausea, vomiting, and diarrhea developed on day 7
    • ultrasound consistent with paralytic ileus and bowel wall edema
    • single doses of ciprofloxacin and metronidazole given on day 8
    • patient's condition stabilized on days 10 to 12
    • patient displayed signs of sepsis on day 13
      • initially treated with ceftriaxone
      • therapy switched to meropenem plus vancomycin on day 14 after further deterioration
    • blood cultures revealed gram-negative, multidrug resistant bacterium sensitive to meropenem
    • further speciation not performed per biocontainment unit protocols
    • source presumed to be gastrointestinal translocation
    • patient discharged from hospital on day 40
    • Reference - N Engl J Med 2014 Dec 18;371(25):2394 full-text

Prognosis

  • improvement seen in survivors at about day 6-11 and may correlate with antibody response(1, 2, 6)
  • convalescence may be prolonged, and associated with variety of complications, including secondary bacterial infections, fatigue, musculoskeletal pain, memory loss and hearing loss among survivors
  • mortality during outbreaks
    • ranges from 18% to 90%
    • death is largely due to shock and multiorgan failure, and occurs at about 6-16 days (median 9 days) after infection(2, 6)
    • estimated case fatality rates in humans vary by Ebola virus species(1, 2, 6)
      • 60%-90% for Zaire ebolavirus
      • 40%-60% for Sudan ebolavirus
      • 25% for Bundibugyo ebolavirus
      • unclear for Tai Forest ebolavirus since only 1 human case has been documented
      • 0% for Reston ebolavirus, which is nonpathogenic in humans
    • 2014 West Africa Ebola outbreak
      • reported mortality about 40% in 2015 Ebola outbreak in Guinea, Liberia, Sierra Leone, Nigeria, Senegal, and Mali
      • actual mortality may be about 70% in West Africa outbreak, with older age and hemorrhagic symptoms associated with increased risk of death
        • based on surveillance data from 3,343 confirmed cases and 667 probable cases of Ebola virus infection in Guinea, Liberia, Nigeria, and Sierra Leone
        • mortality 70.8% in cases with definitive recorded clinical outcomes (46% of cases)
        • risk factors for fatal outcome include
          • age ≥ 45 years (odds ratio [OR] 2.47, 95% CI 1.79-3.46)
          • general symptoms
            • coma or unconsciousness (OR 4.59, 95% CI 1.61-19.34)
            • difficulty swallowing (OR 2.22, 95% CI 1.41-3.59)
            • hiccups (OR 2.15, 95% CI 1.27-3.82)
            • conjunctivitis (OR 2.03, 95% CI 1.29-3.29)
            • confusion (OR 2, 95% CI 1.14-3.71)
            • sore throat (OR 1.94, 95% CI 1.13-3.46)
            • cough (OR 1.74, 95% CI 1.18-2.61)
            • difficulty breathing (OR 1.68, 95% CI 1.1-2.63)
            • chest pain (OR 1.53, 95% CI 1.07-2.2)
            • diarrhea (OR 1.42, 95% CI 1.06-1.89)
          • hemorrhagic symptoms
            • bloody nose (OR 8.02, 95% CI 1.54-148.62)
            • bleeding gums (OR 6.69, 95% CI 1.35-121.32)
            • bleeding at injection site (OR 6.51, 95% CI 1.32-118.04)
            • bleeding from vagina (OR 6, 95% CI 1.11-112.4)
            • unexplained bleeding (OR 1.83, 95% CI 1.2-2.9)
        • Reference - N Engl J Med 2014 Oct 16;371(16):1481 full-text, commentary can be found in N Engl J Med 2014 Oct 16;371(16):1545 full-text
      • mortality about 70% in 2014 Ebola outbreak in Sierra Leone, with higher rates in older patients, patients with higher viral load, and longer duration from symptom onset to medical care
        • based on 2 retrospective cohort studies
        • 106 patients with Ebola virus infection in Sierra Leone between May 25 and June 18, 2014 evaluated
          • 87 patients who had known outcome were included in analysis
          • overall mortality 74%
          • increased mortality associated with
            • aged > 45 years (94% vs. 57% in patients aged < 21 years, p = 0.03)
            • higher viral load (94% in patients with 107 copies/mL vs. 33% in patients with < 105 copies/mL, p = 0.003)
          • comparing fatal vs. nonfatal cases
            • mean blood urea nitrogen 36.1 mg/dL vs. 16.9 mg/dL (p = 0.01)
            • mean aspartate aminotransferase 793.1 units/L vs. 229 units/L (p = 0.009)
            • mean creatinine 3.2 mg/dL vs. 1.5 mg/dL (p = 0.05)
          • Reference - N Engl J Med 2014 Nov 27;371(22):2092 full-text
        • 61 patients (median age 28 years, range 1.17-67 years) with Ebola virus disease in Sierra Leone between October 1 and November 14, 2014 evaluated
          • mortality 68.9%
          • increased mortality associated with
            • age > 30 years (87% vs. 57.9% in patients aged ≤ 30 years, p = 0.018)
            • longer duration from symptom onset to clinic visit (6.34 days in patients who died vs. 4.57 days patients who survived, p = 0.0365)
          • Reference - Clin Infect Dis 2015 Aug 15;61(4):491 full-text
      • mortality about 43% in 2014 Ebola outbreak in Guinea, with difficulty breathing, myalgia, and hemorrhage associated with increased risk of death
        • based on 1 prospective cohort study and 1 retrospective cohort study
        • 89 patients (median age 32 years) hospitalized with confirmed Ebola virus disease in Guinea in 2014 were followed until discharge or death
          • mortality 43.8%
          • median time from hospitalization to death 3.5 days
          • symptoms associated with increased mortality in multivariate analysis
            • difficulty breathing (odds ratio [OR] 5.75, 95% CI 1.42-23.17)
            • myalgia (OR 4.04, 95% CI 1.27-12.88)
            • hemorrhage (OR 3.52, 95% CI 1.2-10.36)
          • Reference - Clin Infect Dis 2015 Jun 15;60(12):1821 full-text
        • 80 patients with symptoms of Ebola virus infection in Guinea between March 25 and April 26, 2014 reviewed
          • 37 patients had confirmed infection
          • overall mortality 43%
          • age ≥ 40 years associated with increased mortality risk in multivariate analysis (relative risk 3.49, 95% CI 1.42-8.59)
          • Reference - N Engl J Med 2015 Jan;372(1):40 full-text
      • mortality 18.5% in patients with Ebola virus disease treated in Europe and United States, with higher rates associated with delay from symptom onset to hospitalization
        • total of 27 patients with Ebola virus disease received care in Europe or the United States leading to 5 deaths
        • patients were medically evacuated from West Africa to higher-resource settings in Europe and United States, diagnosed upon returning to Europe or United States following infection in West Africa, or nosocomially infected in Europe or United States
        • median duration between symptom onset and hospitalization 3.5 days in survivors vs. 5 days in patients who died (p = 0.03)
        • Reference - N Engl J Med 2016 Feb 18;374(7):636 full-text
    • mortality 71% in 2014 Ebola outbreak in Democratic Republic of Congo
  • fatal recrudescence from Ebola virus disease reported in 0.7%
    • based on retrospective cohort study
    • 151 survivors of Ebola virus disease in Sierra Leone were followed for mean duration of 10 months after discharge
    • 4 deaths reported within 6 weeks after discharge
    • 1 death fulfilled case definition of late Ebola virus disease recrudescence (mortality 0.7%)
    • 448 household members of survivors also had confirmed or probable Ebola virus disease, including 238 deaths (case fatality rate 53.1%)
    • Reference - BMJ 2016 May 17;353:i2403 full-text

Infection Control

Emergency department triage

  • Centers for Disease Control and Prevention (CDC) recommendations for patients presenting to the emergency department with possible Ebola include
    • immediate identification of any patient with possible Ebola
      • take an immediate exposure history upon arrival or prior to arrival when possible
      • ask about residence in or travel to an area with widespread transmission or contact with an infected person within the past 21 days
      • for patients with a relevant exposure, ask about signs or symptoms of Ebola
        • fever (subjective or ≥ 100.4 degrees F or 38 degrees C), headache, weakness, myalgia, vomiting, diarrhea, or abdominal pain
        • hemorrhage, including bleeding gums, blood in urine, coffee ground emesis, or melena
    • immediate isolation of any patient with a relevant exposure and signs or symptoms of Ebola
      • place patient in a private room, containing a bathroom or covered bedside commode, with the door closed
      • receive patients arriving by emergency medical services (EMS) transport in designated area away from other patients, and have process for safe transportation to isolation area
      • limit the number of healthcare workers exposed to the patient to only what is essential for care
      • follow CDC guidance on use of personal protective equipment (PPE), which includes
        • ensuring that no skin is exposed by use of double gloves, surgical hood with a single-use face-shield, impermeable gown supplemented by waterproof aprons and boot covers
        • use of a trained observer to ensure that there is no breach in protocol when PPE is removed
        • guidance for donning and doffing PPE, including videos, can be found at CDC 2014 Oct 29
        • video of Ebola emergency department preparedness available at CDC 2015 Mar 20
      • obtain additional history and perform physical exam and routine diagnostics, which may include placement of peripheral IV and phlebotomy
      • use dedicated equipment for patient evaluation as required for patients on transmission-based precautions
    • notification of hospital infection control program and local health department to coordinate care
    • Reference - CDC Identify, Isolate, Inform: Emergency Department Evaluation and Management for Patients Who Present with Possible Ebola Virus Disease 2015 Dec 29

Healthcare settings

Patient placement

  • immediately isolate any patient presenting with possible Ebola virus disease(4)
    • use a private room, containing a bathroom or covered beside commode, with the door closed
    • log all persons entering the patient's room
    • consider posting personnel at the patient’s door to ensure appropriate and consistent use of PPE by all persons entering the patient room

Personal protective equipment (PPE)

  • personal protective equipment (PPE) use in United States(4)
    • key principles for personal protective equipment (PPE)
      • rigorous and repeated training
        • healthcare workers (HCW) should undergo training on all Ebola-related infection control practices and procedures
        • specifically, donning and doffing of PPE in systemic manner should be practiced repeatedly
        • HCWs should demonstrate competency in these practices prior to providing care for Ebola patients
      • no skin exposure when PPE is worn
        • recommended PPE when caring for patient with confirmed Ebola or unstable patient under investigation includes
          • single-use (disposable) impermeable gown that extends to at least mid-calf or single-use impermeable coveralls without integrated hood with or without integrated socks
          • respiratory protection
            • N95 respirator in combination with single-use surgical hood extending to shoulders and single-use full face shield
            • powered air purifying respirators (PAPRs) with full face shield, helmet, or headpiece
          • single-use examination gloves with extended cuff (two pairs)
          • single-use boot covers that go at least to mid-calf
            • shoe covers acceptable only if used with coverall with integrated socks
            • single-use ankle-high shoe covers worn over boot covers may also be used to facilitate doffing
          • single-use apron covering torso to mid-calf
            • use if patient has vomiting or diarrhea
            • use routinely if facility uses coveralls with exposed, unprotected zipper in front
            • choose apron with neck strap that can be easily broken or untied
        • recommended PPE when caring for patient under investigation who is clinically stable and does not have bleeding, vomiting, or diarrhea includes at least
          • single-use (disposable) fluid-resistant gown extending to at least mid-calf or single-use fluid-resistant coveralls without integrated hood
          • single-use full face shield
          • single-use facemask
          • single-use gloves with extended cuffs (two pairs)
      • supervision by a trained observer
        • onsite Ebola site manager should oversee safe care of patients at all times
        • trained observers should actively observe and supervise donning and doffing of PPE, but should not serve as assistant for doffing PPE
        • facility leadership should maintain culture of worker safety, in which PPE is available and workers are appropriately trained
        • any error in donning or doffing PPE must be identified and addressed in real time
    • use of PPE
      • designated areas should be used for donning and doffing PPE
        • must allow clear separation between clean and partially contaminated areas
        • areas should have signage reminding healthcare workers to
          • designate clean vs. contaminated areas
          • wait for trained observer before removing equipment
          • remove PPE slowly and deliberately in set order
          • disinfect gloved hands between steps of removal process
        • areas should have place for workers to sit that can be easily cleaned and disinfected
        • in doffing area, frequent cleaning of floor and work surfaces critical
      • donning of PPE
        • must be overseen by trained observer
        • must be done in designated order before entry
      • during patient care
        • PPE must remain in place for duration of patient care, and should not be adjusted
        • gloved hands should be frequently disinfected, particularly after handling bodily fluids
        • if partial or total breach occurs, personnel should immediately move to doffing area to assess exposure
      • doffing of PPE
        • must be overseen by trained observer
        • must be removed slowly and deliberately in designated order
        • instructions include use of Environmental Protection Agency (EPA)-registered disinfectant wipe or alcohol-based hand rub
          • to disinfect visibly contaminated PPE
          • to disinfect gloved hands between steps of taking off PPE
      • consider having shower available for workers after doffing of PPE
      • step by step instructions for donning and doffing of PPE can be found at CDC 2015 Nov 17
      • video of Ebola emergency department preparedness available at CDC 2015 Mar 20
      • information on best practices for procuring personal protective equipment for Ebola response can be found at CDC 2016 Jan 5
  • personal protective equipment and interventions to reduce noncompliance/errors in donning and doffing in healthcare staff
    • based on Cochrane review of observational studies and trials with unclear allocation concealment
    • systematic review of 5 randomized trials, 3 nonrandomized controlled studies, and 1 retrospective cohort study evaluating personal protective equipment (PPE) for preventing transmission of highly infectious diseases in healthcare staff
    • 8 studies were simulations, and 1 was retrospective cohort study conducted among healthcare workers exposed to severe acute respiratory syndrome
    • interventions to prevent contamination (simulations using noninfectious markers)
      • comparing powered air purifying respirator attire vs. enhanced respiratory and contact precautions attire (according to 2005 Centers for Disease Control and Prevention [CDC] recommendations) in 1 crossover trial with 50 persons
        • any contamination (fluorescent marker to simulate contamination) in 26% vs. 96% (p < 0.05, NNT 2)
        • noncompliance with donning guideline in 30% vs. 4% (p < 0.05)
        • noncompliance with doffing guideline in 12% vs. 24% (not significant)
      • comparing aprons vs. gowns in 1 crossover trial with 50 persons
        • contamination with marker with individual doffing
          • small patches 16.98 vs. 6.7 (p < 0.05)
          • large patches 1.62 vs. 0.26 (p < 0.05)
        • contamination with marker with CDC-recommended doffing
          • small patches 1.88 vs. 1.26 (not significant)
          • large patches 5 vs. 0.14 (p < 0.05)
      • detection of virus (bacteriophage) on any body part in 28% with doffing with double gloves vs. 78% with doffing with single gloves (p < 0.05, NNT 2) in 1 crossover study with 18 persons
    • interventions to increase compliance or reduce errors in donning or doffing
      • in 1 retrospective cohort study with 795 persons
        • no significant difference in PPE noncompliance comparing active training in PPE use vs. passive training
        • active training in PPE doffing significantly decreased noncompliance with doffing protocol vs. passive training
      • significant reduction in errors in donning or doffing with
        • computer simulation vs. no computer simulation in 1 trial with 50 persons
        • spoken instruction vs. no spoken instruction in 1 study with 120 persons
    • Reference - Cochrane Database Syst Rev 2016 Apr 19;(4):CD011621

Patient care considerations

  • general patient care considerations(4)
    • minimize use of needles and other sharps
    • limit blood draws, procedures, and laboratory testing to only what is essential for care
    • handle all needles and sharps with extreme care and dispose in puncture-proof, sealed containers
  • patient care equipment(4)
    • use dedicated medical equipment (preferably disposable, when possible) for provision of patient care
    • clean and disinfect any nondedicated, nondisposable medical equipment used for patient care according to manufacturer's instructions and hospital policy
  • aerosol-generating procedures (AGPs)(4)
    • avoid aerosol-generating procedures (AGPs), such as intubation or bronchoscopy, when possible
    • use combination of measures to reduce exposures from aerosol-generating procedure
      • prohibit visitors during aerosol-generating procedures
      • limit number of personnel present during procedure
      • isolate patient in an Airborne Infection Isolation Room (negative pressure room)
      • keep doors closed during procedure
      • wear appropriate PPE
  • environmental control(4)
  • duration of precautions determined on case-by-case bases, in conjunction with local, state, and federal health authorities(4)

Patient visitor considerations

  • avoid entry of visitors into the patient's room when possible(4)
  • establish procedures for monitoring managing and training visitors(4)
  • schedule visits when needed and screen visitors for symptoms of Ebola virus infection before entering or upon arrival to the hospital(4)
  • evaluate risk to the health of the visitor and ability to comply with precautions before entry into the patient care area and provide instruction on hand hygiene, limiting surfaces touched, and use of PPE(4)
  • restrict visitor movement to patient care area and immediately adjacent waiting area(4)

Monitoring, isolation and quarantine of potentially exposed persons

Definitions

  • active monitoring(4)
    • state or local public health authority is responsible for regularly communicating with potentially exposed persons
    • includes daily checks to ask about fever and symptoms rather than relying on persons to report symptoms
    • temperature should be taken twice daily
  • direct active monitoring - active monitoring through direct observation by public health authority(4)
  • controlled movement(4)
    • travel by long-distance commercial conveyance not allowed
    • any travel should be by noncommercial conveyance, and allow for uninterrupted active monitoring
    • federal public health travel restrictions may be used to enforce policy
    • use of local public transportation only with approval of local public health authority
  • isolation(4)
    • separation of group or individual reasonably believed to be infected
    • reasonable belief in patients with signs and symptoms of Ebola and reason to believe exposure occurred
  • quarantine - separation of group or individual believed to have been exposed to infectious disease, but is not yet ill(4)

Recommendations by exposure category

  • Centers for Disease Control and Prevention (CDC) recommendations for infection control(4)
    • recommendations vary by exposure risk
    • symptomatic persons in high-, some, or low- (but not zero) risk categories
      • patients should have medication evaluation with appropriate infection control precautions
      • isolation may be considered to ensure compliance
      • federal public health travel restrictions will be issued for persons at high risk, and may be considered for those at some or low risk
      • if patient has diagnosis of disease other than Ebola, conditions outlined for asymptomatic persons in relevant exposure category apply until 21 days after last potential exposure
    • asymptomatic persons at high risk
      • direct active monitoring for 21 days after last potential exposure
      • restricted movement within community
      • no travel on public conveyance
      • noncongregate public activities with 3 foot (1 meter) distance from others may be permitted
      • subject to controlled movement
    • asymptomatic persons at some risk
      • direct active monitoring until 21 days after last potential exposure
      • additional restrictions may be considered by public health authorities based on individual assessment, with factors including
        • intensity of exposure
        • point of time in incubation period (risk substantially declines after 2 weeks)
        • complete absence of symptoms
        • compliance with direct active monitoring
        • ability to immediately recognize and report symptoms, self-isolate, and seek medical care
        • probability that proposed activity poses exposure risk to others
    • asymptomatic persons at low (but not zero) risk
      • direct active monitoring recommended for
        • United States-based healthcare workers caring for patients with symptomatic Ebola while wearing appropriate personal protective equipment (PPE)
        • travelers who sat within 3 feet (1 meter) or person with Ebola on an aircraft
      • active monitoring until 21 days after last potential exposure for all other persons
      • no requirement for separation from others or restriction of movement
      • travel permitted provided persons remain asymptomatic and active (or direct active) monitoring continues
    • persons with no identifiable risk do not need monitoring or restrictions unless indicated by diagnosis of disease other than Ebola
  • Centers for Disease Control and Prevention (CDC) interim United States guidance for monitoring and movement of persons with potential Ebola virus exposure can be found at CDC 2016 Feb 19 PDF

Recommendations for healthcare workers

  • Centers for Disease Control and Prevention (CDC) recommendations for infection control in healthcare settings(4)
    • direct patient contact includes
      • doctors, nurses, physician assistants, and other healthcare staff
      • ambulance personnel
      • burial team members and morticians
      • any other person who enters treatment area
    • in United States
      • healthcare workers caring for patients with Ebola while using appropriate PPE with no breaches in infection control considered at low (but not zero) risk
        • workers should undergo direct active monitoring
        • may continue to work as long as they are asymptomatic
      • healthcare workers caring for patients with Ebola where another worker has been diagnosed with confirmed infection without identified breach in infection control considered at high risk
        • workers subject to restrictions, such as controlled movement until 21 days after last potential exposure
        • similar determination made if breach in infection control identified retrospectively during investigation of confirmed infection in healthcare worker
      • in facilities where unidentified breach in infection control occurs
        • assess infection control practices
        • remediate any identified deficiencies
        • train healthcare workers in appropriate practices
      • if percutaneous or mucocutaneous exposure with blood, body fluids, secretions, or excretions from patient with Ebola occurs
        • immediately stop working and wash affected skin surfaces with soap and water
        • irrigate mucous membranes with copious amounts of eyewash solution or water
      • immediately contact occupational health/supervisor
      • if worker develops symptoms after unprotected exposure
        • immediately stop working or do not report to work
        • notify supervisor
        • seek prompt medical evaluation and testing
        • notify state and local health departments
        • comply with work exclusion until no longer infectious
    • for healthcare workers providing direct care to patients with Ebola in countries with widespread transmission
      • high rate of Ebola infections among healthcare workers in these areas likely due to multiple potential sources of exposure
      • 62 healthcare workers diagnosed with Ebola in Liberia worked in non-Ebola treatment unit facilities, where exposures included
        • settings that may lack
          • adequate chlorine
          • running water
          • cleaning supplies
          • hand washing stations
          • adequate types and supplies of PPE
          • isolation areas
        • caring for patients initially thought to have another disease, but later diagnosed with Ebola, without adequate PPE
        • blood spill onto uncovered skin of phlebotomist
        • care for infected persons at home outside of regular duties
        • assisting infected patients into hospital
        • contact with healthcare workers who developed secondary cases
        • Reference - MMWR Morb Mortal Wkly Rep 2014 Nov 21;63(46):1077 full-text
      • these healthcare workers classified in some risk category, and should be managed per CDC recommendations by exposure category
  • CDC interim guidance for United States residence decontamination for Ebola virus disease and removal of contaminated waste can be found at CDC 2015 Mar 2

Other considerations

Postexposure prophylaxis

  • favipiravir with or without monoclonal antibodies targeting an Ebola virus glycoprotein reported to prevent Ebola virus infection in healthcare workers at intermediate or high risk (level 3 [lacking direct] evidence)
    • based on case series
    • 4 healthcare workers who had needlestick injuries while working in Ebola treatment unit (classified as intermediate- or high-risk exposure) received oral favipiravir for 10 days and followed for 42 days
      • treatment initiated 6-10 hours after potential exposure
      • loading doses 2,400 mg, 2,400 mg, and 1,200 mg every 8 hours on day 1, followed by maintenance dose 1,200 mg twice daily
    • 2 patients also treated with 2 IV doses of monoclonal antibodies to Ebola virus glycoprotein
      • 1 patient received ZMAb on day 2 after exposure (total dose 50 mg/kg) and then MIL77 on day 5 (total dose 50 mg/kg)
      • 1 patient received MIL77 on days 2 and 5 after exposure (total 50 mg/kg per dose)
    • no patient developed Ebola virus disease
    • no serious adverse effects reported
    • Reference - Lancet Infect Dis 2015 Nov;15(11):1300, editorial can be found in Lancet Infect Dis 2015 Nov;15(11):1248
  • self-limited symptoms without Ebola virus disease reported in 6 persons who received rVSV-ZEBOV or TKM-100802 for postexposure prophylaxis after occupational exposure to Zaire ebolavirus in West Africa between September 2014 and April 2015 (Clin Infect Dis 2016 Aug 1;63(3):376)

Immunization

  • no licensed vaccine is available
  • vesicular stomatitis virus-vectored Ebola vaccine
    • vesicular stomatitis virus-vectored Zaire Ebola vaccine appears to prevent transmission of Ebola virus disease (level 2 [mid-level] evidence)
      • based on cluster-randomized trial with low adherence
      • 98 clusters containing 9,096 persons in Guinea were randomized to immediate vaccination with VSV-ZEBOV vs. delayed vaccination (21 days after randomization)
        • clusters were generated using a ring vaccination strategy, and consisted of contacts and contacts-of-contacts of patients with newly confirmed Ebola virus disease
        • vaccination was 1 dose of 2 × 107 plaque-forming units intramuscularly
      • 6,328 persons met eligibility criteria for vaccination (age ≥ 18 years, not pregnant, breastfeeding, or severely ill), of whom 66% had scheduled vaccination
      • comparing immediate vaccination vs. delayed vaccination, Ebola virus disease with symptom onset ≥ 10 days after randomization occurred in
        • 0 persons (0%) vs. 16 persons (0.5%) in per-protocol analysis (p = 0.0045)
        • 7 persons (0.2%) vs. 16 persons (0.5%) in intention-to-treat analysis (not significant)
      • 19 additional clusters with 2,745 contacts and contacts of contacts identified
        • 1,677 were immediately vaccinated (including 194 children)
        • no cases of Ebola virus disease with symptom onset ≥ 10 days after study entry occurred among vaccinated persons
      • in analysis of all 117 clusters
        • 0 persons with immediate vaccination developed Ebola virus disease vs. 23 persons in delayed vaccination clusters or in immediate clusters who were never vaccinated (p = 0.0033)
        • estimated vaccine efficacy 100% (95% CI 79.3%-100%)
      • 3,149 of 5,837 persons who received vaccine reported ≥ 1 adverse event within 14 days of vaccination
        • 87.5% classified as mild, with headache, fatigue, and muscle pain most common
        • 80 serious adverse events occurred
          • 2 determined to be related to vaccination (1 febrile reaction, 1 anaphylaxis) and 1 possibly related (influenza-like illness)
          • all patients recovered without sequelae
      • Reference - Lancet 2017 Feb 4;389(10068):505 full-text; previous publication of interim trial results can be found Lancet 2015 Aug 29;386(9996):857 full-text (free registration required for full-text), commentary can be found at Lancet 2015 Aug 29;386(9996):831
      • DynaMed commentary -- ring vaccination refers to a strategy in which direct contacts and/or contacts of contacts of patients with diagnosed disease are identified and vaccinated
    • vesicular stomatitis virus-vectored Zaire Ebola vaccine may induce sustained immune response for up to 6 months but has high rate of transient, mild-to-moderate adverse events (level 2 [mid-level] evidence)
      • based on analysis of phase 1 study data collected in 3 cohort studies and 1 quasi-randomized randomized trial
      • 158 healthy adults were either given escalating doses of vesicular stomatitis virus-vectored Zaire Ebola vaccine or randomized to vaccine vs. placebo and followed for 6 months
        • 20 adults in Hamburg, Germany received 3 million or 20 million plaque-forming (PF) units
        • 39 adults in Lambaréné, Gabon received 300,000 or 3 million PF units
        • 40 adults in Kilifi, Kenya received 3 million or 20 million PF units
        • 59 adults in Geneva, Switzerland either received 10 million PF units or were randomized to 10 million or 50 million PF units vs. placebo
      • at 6-month follow-up, 100% of vaccinated persons had geometric mean titer of neutralizing antibodies > 8
      • 92% reported ≥ 1 adverse event within 2 weeks, mostly mild-to-moderate and transient with median onset and median duration of 1 day, including
        • fever in 30%
        • arthritis observed in the second week of vaccination
          • affecting up to 4 joints in 22% of 51 persons in Geneva, with pain persisting for median duration of 8 days
          • self-limiting cases in 2 (3%) of 60 persons in all other locations
      • no serious vaccine-associated adverse events reported
      • Reference - N Engl J Med 2016 Apr 28;374(17):1647 full-text
    • low dose of vesicular stomatitis virus-vectored Zaire Ebola vaccine associated with reduced immune response compared to high dose of vaccine (level 3 [lacking direct] evidence) and may not reduce risk adverse events (level 2 [mid-level] evidence)
      • based on interim analysis of quasi-randomized trial
      • 115 healthy participants were either given vesicular stomatitis virus-vectored Zaire Ebola vaccine or randomized to vaccine vs. placebo and followed for 28 days
        • during phase 1
          • 19 participants had high-dose vaccine of 1 x 107 plaque-forming units (pfus) during run-in
          • 16 participants randomized to high-dose vaccine 1 x 107 pfus
          • 16 participants randomized to high-dose vaccine of 5 x 107 pfus
          • 8 participants randomized to placebo
        • during phase 2 (dose lowered due to reported viral arthritides)
          • 13 participants had low-dose vaccine of 3 x 105 pfus
          • 38 participants randomized to low-dose vaccine of 3 x 105 pfus
          • 5 participants randomized to placebo
      • comparing low-dose vaccine vs. high-dose vaccines
        • immune response
          • geometric mean glycoprotein-binding antibody titer 344.5 vs. 1,064 (p < 0.0001)
          • geometric mean neutralizing antibody titer 35.1 vs. 127 (p < 0.0001)
        • adverse events
          • detectable viremia in 20% vs. 90% (p < 0.0001)
          • viral oligoarthritis in 22% vs. 25% (no p value reported)
          • in patients with arthritis, maculopapular and/or vesicular dermatitis developed in 7 of 13 patients vs. 3 of 11 patients (no p value reported)
          • grade 3 adverse events, defined as those preventing daily activity, reported by 14% vs. 22% (not significant)
      • no serious adverse events reported
      • Reference - Lancet Infect Dis 2015 Oct;15(10):1156, editorial can be found in Lancet Infect Dis 2015 Oct;15(10):1117
    • vesicular stomatitis virus-vectored Ebola vaccine reported to induce immune response in patient with high-risk exposure to Ebola virus (level 3 [lacking direct] evidence)
      • based on case report
      • 44-year-old physician working in Ebola treatment unit in Sierra Leone had vesicular stomatitis virus-vectored Ebola vaccine 43 hours after needlestick
      • patient developed fever and moderate-to-severe symptoms 12 hours after vaccination which diminished over 3-4 days
      • antibodies and T cells active against vaccine components detected 1 day after vaccination, but no evidence of viral infection detected
      • Reference - JAMA 2015 Mar 24-31;313(12):1249, editorial can be found in JAMA 2015 Mar 24-31;313(12):1221
  • Ebola virus and Marburg virus glycoprotein DNA vaccines induce immune response when given alone or together (level 3 [lacking direct] evidence)
    • based on randomized trial without clinical outcomes
    • 108 healthy volunteers received intramuscular injections at weeks 0, 4, and 8
      • during part 1, 72 patients were randomized to Ebola virus vaccine only (encoding Zaire and Sudan glycoproteins) vs. Marburg virus vaccine only (encoding Marburg virus glycoprotein) vs. placebo
      • during part 2, 36 patients were randomized to Ebola virus vaccine plus Marburg virus vaccine vs. placebo
    • antibody and T-cell response measured 4 weeks after third vaccination
    • in patients given Ebola virus vaccine alone
      • 57% had antibody response to Zaire glycoprotein and 63% had T-cell response
      • 50% had antibody response to Sudan glycoprotein and 43% had T-cell response
    • in patients given Marburg virus vaccine alone, 31% had antibody response and 52% had T-cell response
    • no significant difference in antibody or T-cell response if vaccines given alone or together
    • no significant differences in local or systemic adverse effects among groups
    • Reference - Lancet 2015 Apr 18;385(9977):1545
    • similar results reported in earlier phase 1 trial with 20 patients (J Infect Dis 2015 Feb 15;211(4):549)
  • adenovirus-vectored Ebola vaccine
    • adenovirus-vectored Ebola vaccine appears safe and immunogenic, although immunogenicity appears to decline over time (level 3 [lacking direct] evidence)
      • based on randomized trial without clinical outcomes
      • 500 healthy adults aged 18-50 years without history of Ebola virus infection or previous Ebola vaccination with any vaccine formulation randomized to
        • high-dose adenovirus type-5 vector-based Ebola vaccine (1.6 × 1011 viral particles)
        • low-dose adenovirus type-5 vector-based Ebola vaccine (8 × 1010 viral particles)
        • placebo
      • no significant differences in rates of overall solicited adverse reactions within 7 days (43%-53%), although placebo associated with lower rate of solicited injection-site adverse reactions within 7 days vs. either vaccine formulation (14% vs. 25%-26%, p = 0.0169)
      • 3 serious adverse events occurred in high-dose vaccine group (malaria, gastroenteritis, and fatal asthma episodes), but none determined to be related to vaccine
      • immunogenicity of vaccine formulations at days 14, 28, and 168
          High-dose VaccineLow-dose Vaccine Placebo
        Geometric mean titre at day 14*1,728.41,2516.2
        Geometric mean titre at day 28*2,043.11,471.86.8
        Geometric mean titre at day 168*254.2223.36
        * p < 0.001 across groups.
      • Reference - Lancet 2017 Feb 11;389(10069):621
    • primary immunization with adenovirus-vectored Ebola vaccine and boosting with modified vaccinia Ankara vector-based vaccine may induce sustained immune response up to 8 months and does not appear to be associated with any severe adverse events (level 3 [lacking direct] evidence)
      • based on analysis of small randomized trial without clinical outcomes and case series
      • 87 healthy adults (median age 38.5 years) were either given active Ebola vaccines or randomized to active vaccines vs. placebo and followed for 8 months
        • 15 adults received adenovirus type-26 vectored vaccine (expressing Ebola glycoprotein), then a boost dose of modified vaccinia Ankara vector-based vaccine (expressing glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein) 14 days later
        • 60 adults randomized to receive active vaccines were given 1 of 2 Ebola vaccines and then a boost dose with the other either 28 or 56 days later
      • 28 days after primary immunization, detectable levels of Ebola-specific immunoglobulin G (IgG) observed in
        • 97% of 29 patients randomized to adenovirus-vectored vaccine
        • 23% of 30 patients randomized to vaccinia Ankara-vectored vaccine
      • after boost dose
        • 100% of vaccinated patients had detectable Ebola-specific IgG at 21 days post boost and at 8-month follow-up
        • ≥ 86% of patients who were randomized to receive active vaccines had Ebola-specific T-cell response at 7 days post boost
      • fever reported in 9% of patients who received adenovirus-vectored vaccine and 0% of those who received vaccinia Ankara-vectored vaccine
      • no vaccine-related serious adverse events reported
      • Reference - JAMA 2016 Apr 19;315(15):1610
      • consistent findings at 1 year
        • based on 1-year follow-up of 64 persons receiving active vaccines (85.3%) in randomized trial and case series above
          • 100% of vaccinated patients had detectable Ebola-specific IgG
          • ≥ 69% of patients receiving MVA-BN-Filo followed by Ad26.ZEBOV booster had Ebola-specific T-cell response
          • ≥ 60% of patients receiving Ad26.ZEBOV first followed by MVA-BN-Filo booster had Ebola-specific T-cell response
          • no serious adverse events reported 240-360 days post vaccination
        • Reference - JAMA 2017 Mar 14;317(10):1075
    • adenovirus-vectored Ebola vaccine may induce immune response within 14 days (level 3 [lacking direct] evidence)
      • based on randomized trial without clinical outcomes
      • 120 healthy adults were randomized to high dose of adenovirus type-5 vector-based Ebola vaccine (expressing 2014 epidemic strain glycoprotein) vs. low dose of vaccine vs. placebo and followed for 28 days
        Comparing High Dose Vaccine vs. Low Dose Vaccine vs. Placebo:
         High Dose Vaccine Low Dose Vaccine Placebo p Value
        Responders at 14 days 100%93%0%p < 0.0001
        Responders at 28 days100%95%0%p < 0.0001
        Any solicited adverse reaction90%68%48%p = 0.0002
        Grade 2 fever18%0%3%p = 0.006
        Mild pain at injection site73%35%20%p < 0.0001
        Mild redness at injection site35%20%13%p = 0.05
      • T-cell response peaked at day 14 in both low-dose and high-dose vaccine groups
      • no significant differences in other adverse reactions or laboratory tests among groups
      • no serious adverse events reported
      • Reference - Lancet 2015 Jun 6;385(9984):2272
  • chimpanzee adenovirus type 3 vector Ebola vaccine
    • chimpanzee adenovirus type 3 vector Ebola vaccine may induce immune response and boosting with modified vaccinia Ankara vector Ebola vaccine may induce long-lasting protective immunity (level 2 [mid-level] evidence)
      • based on small randomized trial
      • adults randomized to escalating doses of single intramuscular injection of chimpanzee adenovirus type 3 vector Ebola vaccine (ChAd3-EBO-Z) expressing Zaire Ebola virus glycoprotein
        • 91 adults in Mali randomized to 1 × 1010 viral particle units (pu) vs. 2.5 × 1010 pu vs. 5 × 1010 pu vs. 1 × 1011 pu
        • 20 adults in United States randomized to 1 × 1010 vs. 1 × 1011 pu
      • 82.9%-100% had positive serologic response by day 28 after primary ChAd3-EBO-Z dose
      • for boosting, 52 Malians randomized to modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo, 2 × 108 plaque-forming units) vs. saline placebo
        • these adults represented all 4 doses of primary ChAd3-EBO-Z vaccine
        • duration from primary immunization to boosting ranged 79-111 days
      • comparing MVA-BN-Filo boost group vs. saline boost group, positive serologic response detected in
        • 100% vs. 87.5% by day 7
        • 100% vs. 83.3% by day 28
      • reported adverse effects included injection-site pain or tenderness, fever, fatigue, and headache
      • no serious adverse effects reported with either vaccine
      • Reference - Lancet Infect Dis 2016 Jan;16(1):31 full-text
    • a second small randomized trial describing similar immune response in 60 adults in United Kingdom randomized to escalating doses of ChAd3-EBO-Z (of which, 30 received MVA-BN-Filo boost) can be found in N Engl J Med 2016 Apr 28;374(17):1635 full-text
    • chimpanzee adenovirus type 3 vector Ebola vaccine reported safe and immunogenic in 20 healthy adults in case series (N Engl J Med 2017 Mar 9;376(10):928 full-text)
  • inactivated rabies virus-based polyvalent filovirus vaccine reported to induce high antibody titers and 100% protection against lethal Ebola virus challenge in nonhuman primates (J Infect Dis 2015 Oct 1;212 Suppl 2:S414)
  • other candidates

Guidelines and Resources

Guidelines

International guidelines

  • World Health Organization (WHO)
    • interim guidance on clinical care for survivors of Ebola virus disease can be found at WHO 2016 Apr 11 PDF
    • rapid advice guideline on personal protective equipment in the context of filovirus disease outbreak response can be found at WHO 2014 Oct PDF
    • interim guidance for use of convalescent blood transfusions as empirical treatment during Ebola outbreaks can be found at WHO 2014 Sep PDF
    • interim manual - Ebola and Marburg virus disease epidemics: preparedness, alert, control, and evaluation can be found at WHO 2014 Aug PDF or PDF [French]
    • interim infection control recommendations for care of patients with suspected or confirmed filovirus (Ebola, Marburg) hemorrhagic fever can be found at WHO 2014 Aug PDF
    • guideline on drawing blood: best practices in phlebotomy can be found at WHO 2010 PDF, PDF [French], PDF [Portuguese], or PDF [Chinese]
    • World Health Organization (WHO) pocket guide for clinical management of viral hemorrhagic fever can be found at WHO 2016 PDF

United States guidelines

  • Centers for Disease Control and Prevention (CDC)
    • interim guidance for United States hospital preparedness for patients with possible or confirmed Ebola virus disease: a framework for a tiered approach can be found at CDC 2015 Aug 28
    • interim guidance for preparing frontline health care facilities for patients with possible Ebola virus disease can be found at CDC 2015 Aug 28
    • interim guidance for preparing Ebola assessment hospitals can be found at CDC 2015 Aug 28
    • interim United States guidance for monitoring and movement of persons with potential Ebola virus exposure can be found at CDC 2016 Feb 19 PDF
    • guidance on personal protective equipment to be used by healthcare workers during management of patients with Ebola virus disease in United States hospitals, including procedures for putting on (donning) and removing (doffing) can be found at CDC 2015 Nov 17
    • guidance on screening and caring for pregnant women with Ebola virus disease for healthcare workers in United States hospitals can be found at CDC 2015 Dec 29
    • infection prevention and control recommendations for hospitalized patients with known or suspected Ebola hemorrhagic fever in United States hospitals can be found at CDC 2015 Sep 3
    • recommendations on safely performing acute hemodialysis in patients with Ebola virus disease in United States hospitals can be found at CDC 2015 Jan 26
    • guidance on safe handling of human remains of Ebola patients in United States hospitals and mortuaries can be found at CDC 2015 Feb 11
    • information on Ebola medical waste management can be found at CDC 2015 Feb 12
    • interim guidance on specimen collection, transport, testing, and submission for patients with suspected infection with Ebola virus disease can be found at CDC 2015 Feb 5
    • interim guidance on compliance with select agent regulations for laboratories handling patient specimens that are known or suspected to contain Ebola virus can be found at CDC 2015 Oct 14
    • guidance on air medical transport for patients with Ebola virus disease can be found at CDC 2015 Jan 27
    • interim guidance on emergency medical services systems and 911 public safety answering points for management of patients with known or suspected Ebola virus disease in United States can be found at CDC 2015 Dec 29
    • flow chart illustrating contact tracing for Ebola outbreak control can be found at CDC 2015 Sep 25 PDF
  • expert guideline on radiology preparedness in Ebola virus disease: guidelines and challenges for disinfection of medical imaging equipment for protection of staff and patients can be found in Radiology 2015 May;275(2):538
  • Institute of Medicine (IOM) workshop recommendations on research priorities to inform public health and medical practice for Ebola virus disease can be found at IOM 2014 Nov 14

Canadian guidelines

  • Society of Obstetricians and Gynaecologists of Canada (SOGC) committee opinion on management of a pregnant woman exposed or infected with Ebola virus disease in Canada can be found in J Obstet Gynaecol Can 2015 Feb;37(2):182 PDF

European guidelines

  • Direção-Geral da Saúde guideline on ebola virus disease: general procedures can be found at DGS 2015 [Portuguese]

Australian and New Zealand guidelines

  • New South Wales Health (NSWH) contingency plan for viral haemorrhagic fevers can be found at NSWH 2016 Jan PDF
  • Communicable Diseases Network Australia (CDNA) national guideline for public health units on Ebolavirus can be found at CDNA 2015 Jun 26

African guidelines

  • National Institute for Communicable Diseases (NICD) guidelines for specialized laboratory investigation of suspected Ebola virus disease in South Africa can be found in NICD 2014 Aug 19 PDF
  • practical guidelines on the management of Ebola infected patients in the field can be found in Med Trop (Mars) 2004;64(2):199 [French]

Review articles

Additional resources

Centers for Disease Control and Prevention (CDC)

  • Centers for Disease Control and Prevention (CDC) - any suspected cases of viral hemorrhagic fever occurring in patients residing in or requiring evacuation to the United States should be reported immediately to the CDC Viral Special Pathogens Branch at 404-639-1115 or the CDC Emergency Operations Center at 770-488-7100 after hours

United States

  • information for healthcare providers and the public can be found at CDC 2016 Jun 22
    • considerations for United States healthcare facilities to ensure adequate supplies of personal protective equipment (PPE) for Ebola preparedness can be found at CDC 2016 Jan 5
    • Ebola virus disease information for clinicians in United States healthcare settings can be found at CDC 2016 Feb 22
    • case definition for Ebola virus disease can be found at CDC 2015 Jan 26
    • epidemiologic risk factors to consider when evaluating a person for exposure to Ebola virus can be found at CDC 2015 Aug 28
    • infographic: is it flu or Ebola? can be found at CDC 2015 May 4 PDF
    • fact sheet on monitoring symptoms and controlling movement to stop spread of Ebola can be found at CDC 2016 Feb 19
    • resources for parents, schools, and pediatric healthcare professionals can be found at CDC 2016 Feb 18
    • interim guidance for United States residence decontamination for Ebola virus disease and removal of contaminated waste can be found at CDC 2015 Mar 2
  • instructions for sending sample can be found at CDC Viral Special Pathogens Branch (VSPB) website
  • CDC VSPB specimen submission form PDF
  • information for travelers can be found at CDC 2016 Feb 19
  • phone lines for state and local health departments monitored 24 hours a day, 7 days a week

West Africa

  • information for general healthcare settings in West Africa on
    • 4 keys to infection control can be found at CDC 2014 Dec 19
    • managing patient flow during triage, isolation, and care of patients with confirmed or suspected Ebola can be found at CDC 2014 Dec 3
    • case definitions for evaluating suspected Ebola patients can be found at CDC 2015 Feb 10
    • personal protective equipment (PPE) recommended for low resource settings can be found at CDC 2015 Apr 25
    • drawing blood safely when caring for patients with confirmed or suspected Ebola can be found at CDC 2015 Jan 28
    • safely cleaning and disinfecting areas used by patients with confirmed or suspected Ebola can be found at CDC 2015 Feb 10
    • managing Ebola patients, their families, and the community safely and compassionately can be found at CDC 2014 Dec 3
    • mixing and using chlorine solutions can be found at CDC 2015 Feb 27
    • hand hygiene can be found at CDC 2014 Nov 13
  • communication resources for West African audiences can be found at CDC 2016 Mar 30
  • information on CDC safety training course for healthcare workers going to West Africa in response to the 2014 Ebola outbreak can be found at CDC 2015 Aug 17
  • interim recommendations for cleaning houses safely in West Africa Ebola-affected areas after persons with symptoms of Ebola are transferred to Ebola treatment units or community care centers can be found at CDC 2014 Dec 2
  • additional continuously updated information on the Ebola virus disease 2014 West Africa outbreak can be found at CDC 2016 Apr 14

World Health Organization (WHO)

  • information for healthcare providers can be found at WHO 2016 Jun 9
  • statement on the Meeting of the International Health Regulations Emergency Committee regarding 2014 Ebola outbreak in West Africa can be found at WHO 2014 Aug 8

Infectious Diseases Society of America (IDSA)

  • statement on involuntary quarantine of healthcare workers returning from Ebola-affected countries can be found at IDSA 2014 Oct 27
  • Ebola guidance can be found at IDSA 2014 Aug 21

Other resources

Patient Information

  • handout for travelers from World Health Organization (WHO)
  • information from Centers for Disease Control and Prevention (CDC)
    • for travelers from CDC
    • for people working and living abroad from CDC
    • handout for airline personnel from CDC
    • handout for West Africans living in the United States from CDC PDF
  • FDA warns consumers about fraudulent products sold online claiming to prevent or treat Ebola virus (FDA Press Release 2014 Aug 14)

ICD-9/ICD-10 Codes

ICD-9 codes

  • 065.8 other specified arthropod-borne hemorrhagic fever
  • 078.89 other specified diseases due to viruses

ICD-10 codes

  • A98.4 Ebola virus disease

References

General references used

DynaMed editorial process

  • DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
  • All editorial team members and reviewers have declared that they have no financial or other competing interests related to this topic, unless otherwise indicated.
  • DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster University and F1000.

Special acknowledgements

  • Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS (Director of Bahrain Branch of the United Kingdom Cochrane Center, The Cochrane Collaboration; Awali, Bahrain)
  • Alan Ehrlich, MD (Executive Editor; Clinical Associate Professor of Family Medicine, University of Massachusetts Medical School; Massachusetts, United States)
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