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Ebola: The Evolving Catastrophe

3.00 Contact Hours
This course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN), Respiratory Therapist (RT)
This course will be updated or discontinued on or before Monday, April 5, 2021
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
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    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Pamela Downey (MSN, ARNP)

Outcomes

The goal of this course is to prepare healthcare professionals to identify and deal with Ebola. This includes the epidemiology, transmission including risk factors, pathogenesis, clinical manifestations, diagnosis, differential diagnosis, treatment, as well as, prevention strategies used in the treatment of Ebola virus disease (EVD).

Objectives

After completing this course, the participant will be able to meet the following 5 objectives:

  1. Discuss modes of transmission of EVD from human-to-human.
  2. Relate the clinical manifestations of EVD including time of exposure to the Ebola virus, onset of symptomology and laboratory values.
  3. Describe the treatment of patients with suspected or confirmed EVD.
  4. Apply strategies to prevent the spread of the Ebola virus.
  5. List some long-term problems which may persist and/or occur after surviving EVD.

Introduction

Ebola virus disease (EVD) or simply Ebola, also previously known as Ebola hemorrhagic fever (EHF). It is a viral hemorrhagic fever of humans and other primates caused by ebolaviruses.1 Signs and symptoms typically start between two days and three weeks after contracting the virus with a fever, sore throat, muscular pain, and headaches. Vomiting, diarrhea and rash usually follow, along with decreased function of the liver and kidneys.1 At this time, some people begin to bleed both internally and externally.1 The disease has a high risk of death, killing between 25 and 90 % of those infected, with an average of about 50%.1 This is often due to low blood pressure from fluid loss, and typically follows six to sixteen days after symptoms appear.2

Historic Perspective of Ebola Outbreaks

Major or Massive Cases

Major or Massive Cases
DateVirusCasesDeathsFatality RateDescription

Jun–Nov 1976

SUDV28415153%Sudan: Occurred in Nzara (source), Maridi,and Juba (cities in present-day South Sudan). The index cases were workers in a cotton factory. The disease was spread by close contact with an acute case, usually from patients to their nurses. Many medical care personnel were infected.3

Aug 1976

EBOV31828088%

Zaire: Occurred in Yambuku and surrounding areas (present-day Democratic Republic of the Congo). It spread through personal contact and by use of contaminated needles and syringes in hospitals and clinics.4

Aug–Sep 1979

SUDV342265%

Sudan: Occurred in Nzara and Maridi. This was a recurrent outbreak at the same site as the 1976 Sudan epidemic.5

Dec 1994–Feb 1995

EBOV523160%

Gabon: Occurred in Makokou and gold-mining camps deep in the rain forest along the Ivindo River. Until 1995, the outbreak was incorrectly classified as yellow fever.6

May–Jul 1995

EBOV31525481%

Zaire: Occurred in Kikwit and surrounding areas. The outbreak was traced to a patient who worked in a forest adjoining the city. The epidemic spread through families and hospital admissions.7,8

Jan–Apr 1996

EBOV372157%

Gabon: Occurred in the village of Mayibout 2 and neighboring areas. A chimpanzee found dead in the forest was eaten by villagers hunting for food. Nineteen people involved in the butchery of the animal became ill, and other cases occurred in their family members.6

Jul 1996–Mar 1997

EBOV604575%

Gabon: Occurred in the Booué area with transport of patients to Libreville. The index case-patient was a hunter who lived in a forest timber camp. The disease was spread by close contact with infected persons. A dead chimpanzee found in the forest at the time was determined to be infected.6

Oct 2000–Jan 2001

SUDV42522453%

Uganda: Occurred in the Gulu, Masindi, and Mbarara districts of Uganda. The three greatest risks associated with Sudan virus infection were attending funerals of case-patients, having contact with case-patients in one's family, and providing medical care to case-patients without using adequate personal protective measures.9

Oct 2001–Jul 2002

EBOV13510779%

Gabon and Republic of the Congo (RC): Occurred on both sides of the border.This outbreak included the first reported occurrence of Ebola virus disease in the RC.10

Dec 2002–Apr 2003

EBOV14312890%

Republic of the Congo: Occurred in the districts of Mbomo and Kelle in the Cuvette-Ouest Department.11

Nov–Dec 2003

EBOV352983%

Republic of the Congo: Occurred in Mbomo and Mbandza villages, located in Mbomo District in the Cuvette-Ouest Department.12

Apr–Jun 2004

SUDV17741%

 

Sudan: Occurred in Yambio county in Western Equatoria of southern Sudan (present-day South Sudan). This outbreak was concurrent with an outbreak of measles in the same area, and several suspected EVD cases were reclassified later as measles cases.13

 

Aug–Nov 2007

EBOV26418771%

Democratic Republic of the Congo: Occurred in Kasaï-Occidental province. The outbreak was declared over on 20 November. The last confirmed case was on 4 October, and the last death was on 10 October.14

Dec 2007–Jan 2008

BDBV1493725%

Uganda: Occurred in the Bundibugyo District in western Uganda. This was the first identification of the Bundibugyo virus (BDBV).16-17

Dec 2008–Feb 2009

EBOV321445%

Democratic Republic of the Congo: Occurred in the Mweka and Luebo health zones of the Kasaï-Occidental province.18

Jun–Aug 2012

SUDV241771%

Uganda: Occurred in the Kibaale District.19

Jun–Nov 2012

BDBV773647%

Democratic Republic of the Congo: Occurred in the Orientale Province.20,21

Dec 2013–Jan 2016

EBOV28,61,62211,31070–71% (general)23-25
57–59% (among hospitalized patients)26
Widespread: Liberia, Sierrra Leone, Guinea: Limited and local: Nigeria, Mali, US, Senegal, Spain, UK, Italy: This was the most severe Ebola outbreak in recorded history due to both the number of human cases and fatalities. It began in Guéckédou, Guinea, in December 2013 and spread abroad.23,27,28 Flare-ups of the disease continued into 2016,29 and the outbreak was declared over on 9 June 2016.

Aug–Nov 2014

EBOV6630493074%

Democratic Republic of the Congo: Occurred in Équateur province. Outbreak detected 24 August and, as of 28 October 2014, the WHO said that twenty days had passed since the last reported case was discharged and no new contacts were being followed.30,31 Declared over on 15 November 2014.32

May–Jul 2018

EBOV543361%

Democratic Republic of the Congo: On 8 May 2018, the government of the Democratic Republic of the Congo reported two confirmed cases of Ebola infection in the northwestern town of Bikoro.33 On 17 May, a case was confirmed in the city of Mbandaka.34 Health authorities are planning to ring vaccinate with rVSV-ZEBOV, a recently developed experimental Ebola vaccine, to contain the outbreak.34,35 The outbreak is ongoing as of 24 June 2018, in 2014 a different area of equator province was affected 36,37 On July 24, 2018 the outbreak was declared over.38-42

August 2018 – present

EBOV524268ongoing

Democratic Republic of the Congo: On the 1 August 2018, the Democratic Republic of the Congo Ministry of Health declared an outbreak when 4 individuals tested positive for the Ebola virus.43-46 As of 12/4/18, the outbreak is ongoing.47

Minor or Single Cases

Minor or Single Cases
DateVirusHuman CasesDeathsDescription

1976

SUDV or EBOV10

UK: Laboratory infection by accidental stick of contaminated needle.48,49

1977

EBOV11

Zaire: Noted retroactively in the village of Tandala.49-51

1989–1990

RESTV30

Philippines: The Reston virus (RESTV) was first identified when it caused high mortality in crab-eating macaques in a primate research facility responsible for exporting animals to the United States.52 Three workers in the facility developed antibodies to the virus but did not get sick.53

1989

RESTV00

US: RESTV was introduced into quarantine facilities in Virginia and Pennsylvania by monkeys imported from the Philippines. No human cases were reported.54

1990

RESTV40

US: Monkeys imported from the Philippines introduced RESTV into quarantine facilities in Virginia and Texas. Four humans developed antibodies but did not get sick.55

1992

RESTV00

Italy: RESTV was introduced into quarantine facilities in Siena by monkeys imported from the same facility in the Philippines that was the source of the 1989 and 1990 U.S. outbreaks. No human cases resulted.56

1994

TAFV10Cote d’Ivoire: This case was the first and thus far only recognition of Taï Forest virus (TAFV). Approximately one week after conducting necropsies on infected western chimpanzees in Taï National Park, a scientist contracted the virus and developed symptoms similar to those of dengue fever. She was discharged from a

Swiss hospital two weeks later and fully recovered after six weeks.57

1995

TAFV10

Cote d’Ivoire: One person, fleeing the civil war in neighboring Liberia, was identified as an Ebola case in Gozon.58

1996

EBOV21

South Africa: A medical professional traveled from Gabon to Johannesburg, South Africa, in October 1996 after having treated Ebola virus-infected patients. He was hospitalized, and the nurse that took care of him became infected and died.59

1996

RESTV00

US: RESTV was again introduced into a quarantine facility in Texas by monkeys imported from the same facility in the Philippines that was the source of the 1989 and 1990 U.S. outbreaks. No human cases resulted.60

1996

RESTV00

Philippines: RESTV was identified at a monkey export facility in the Philippines. No human cases resulted.61

1996

EBOV11

Russia: Laboratory contamination.62

2004

EBOV11

Russia: Laboratory contamination.63

2008

RESTV60

Philippines: First recognition of RESTV in pigs. Strain very similar to earlier strains. Occurred in November. Six workers from the pig farm and slaughterhouse developed antibodies but did not become sick.64,65

2015

RESTV00

Philippines: On 6 September 2015, the Philippine health secretary reported an outbreak of RESTV in a primate research and breeding facility. Twenty-five workers subsequently tested negative for the virus.66

2017

EBOV84

Democratic Republic of the Congo: On 11 May 2017, the Ministry of Public Health for the Democratic Republic of the Congo notified the WHO of an Ebola outbreak in the Likati health zone (LHZ) in Bas-Uele province, in the northern part of the country. Suspected infections were reported from Nambwa, Mouma, and Ngay. The LHZ borders the Central African Republic, which made this outbreak a moderate risk to the region.67,68

 

2018

EBOV00

Hungary: On April 20 a laboratory accident led to the Ebola virus being exposed to a single worker, though he did not develop symptoms.69,70

Classifications

Each species of the genus Ebolavirus has one member virus, and four of these cause EVD in humans, a type of hemorrhagic fever having a very high case fatality rate. Ebolaviruses were first described after outbreaks of EVD in southern Sudan in June 1976 and in Zaire in August 1976.72,73 The name Ebolavirus is derived from the Ebola River in Zaire (now the Democratic Republic of the Congo), the location of the 1976 outbreak,72 and the taxonomic suffix -virus (denoting a viral genus).73 This genus was introduced in 1998 as the "Ebola-like viruses".74,75 In 2002, the name was changed to Ebolavirus76,77 and in 2010, the genus was emended.73 Ebolaviruses are closely related to marburgviruses.

The Ebola virus is a nonsegmented, negative-sense, single-stranded RNA virus that resembles rhabdoviruses (e.g., rabies) and paramyxoviruses (e.g., measles, mumps) in its genome organization and replication mechanisms. It is a member of the family Filoviridae, taken from the Latin "filum", meaning thread-like, based upon their filamentous structure.

The genus Ebolavirus is a virological taxon included in the family Filoviridae, order Mononegavirales. The members of this genus are called ebolaviruses.73 The six known virus species are named for the region where each was originally identified.

Only the following four species cause disease in humans: Zaire, Sudan, Tai Forest and Bundibugyo.78

Zaire ebolavirus

  • Zaire ebolavirus
    • The Zaire virus, since it was first recognized in 1976, has caused multiple large outbreaks in Central Africa, with mortality rates ranging from 55 to 88%. It was the causative agent of the 2014 - 2016 West African epidemic.

    • Zaire ebolavirus is the type species (reference or example species) for Ebolavirus, has the highest mortality rate of the ebolaviruses, and is responsible for the largest number of outbreaks of the six known species of the genus, including the 1976 Zaire outbreak and the outbreak with the most deaths.

Sudan ebolavirus

  • Sudan ebolavirus
    • The Sudan virus has been associated with a case fatality rate of approximately 50% in four epidemics: two in Sudan in the 1970s, one in Uganda in 2000, and another in Sudan in 2004.

Taï Forest ebolavirus (originally Côte d'Ivoire ebolavirus)

  • Taï Forest ebolavirus (originally Côte d'Ivoire ebolavirus)
    • The Tai Forest virus has only been identified as the cause of illness in one person in the Ivory Coast, and that individual survived.76 The exposure occurred when an ethologist performed a necropsy on a chimpanzee found dead in the Tai Forest, where marked reductions in the great ape population had been observed.

Bundibugyo ebolavirus

  • Bundibugyo ebolavirus
    • The Bundibugyo virus emerged in Uganda in 2007, causing an outbreak of EVD with a lower, case fatality rate (approximately 30%) than is typical for the Zaire and Sudan viruses.79 Another epidemic with a case fatality rate of 22% among confirmed cases occurred in the northeastern Democratic Republic of the Congo in 2012.78 Sequencing has shown that the agent is most closely related to the Tai Forest species.

Reston ebolavirus

The following two species are not known to cause severe disease in humans:

  • Reston ebolavirus
    • The Reston virus, has caused EVD in other primates.79-80

    • The Reston virus, differs markedly from the others, because it is apparently maintained in an animal reservoir in the Philippines and has not been found in Africa. The Ebola Reston virus was discovered when it caused an outbreak of lethal infection in macaques imported into the United States in 1989. Three more outbreaks occurred among nonhuman primates in quarantine facilities in the United States and Europe before the Philippine animal supplier ceased operations. None of the animal caretakers who were exposed to sick animals without protective equipment became ill but several showed evidence of seroconversion consistent with asymptomatic infection.

    • Nothing further was heard of the Reston virus until 2008, when the investigation of an outbreak of disease in pigs in the Philippines unexpectedly revealed that some of the sick animals were infected both by an arterivirus (porcine reproductive and respiratory disease virus) and by Ebola Reston virus. Serologic studies have shown that a small percentage of Philippine pig farmers have IgG antibodies against the agent without ever developing severe symptoms, providing additional evidence that Ebola Reston virus is able to cause mild or asymptomatic infection in humans.

Bombali ebolavirus

  • Bombali ebolavirus
    • This is the most recent species to be named and was isolated from Angolan free-tailed bats in Sierra Leone.81

    • Bombali ebolavirus is a newly discovered strain of Ebolavirus, first reported on 27 July 2018.82 It was discovered by a research team from the U.S. in the western Africa country of Sierra Leone.83-84 The virus was found in the Angolan free-tailed bat and the Little free-tailed bat.85Bombaliebolavirus has the capacity to infect human cells, although it had not yet been shown to be pathogenic.86-87

Epidemiology

Viral Reservoirs

The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate species.88 Three types of fruit bats (Hypsignathus monstrosus, Epomops franqueti and Myonycteris torquata) were found to possibly carry the virus without getting sick.90 As of 2013, whether other animals are involved in its spread is not known.98 Plants, arthropods, rodents, and birds have also been considered possible viral reservoirs.1,91

Bats were known to roost in the cotton factory, in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EVD, only bats became infected.92 The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EVD. In a 2002 – 2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo, 13 fruit bats were found to contain EVD RNA.93 Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh, suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia.94

Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EVD outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys) and one shrew (Sylvisorex ollula) collected from the Central African Republic. However, further research efforts have not confirmed rodents as a reservoir. Traces of EVD were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EVD infection make it unlikely that these species represent a natural reservoir for the virus.

Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic. Index cases of EVD have often been close to recently-deforested lands.95-96

LIFE CYCLES OF THE EBOLA VIRUS
Ebola Life Cycle

Transmission

Epidemics of EVD are generally thought to begin when an individual becomes infected through contact with the tissues or body fluids of an infected animal. Once the patient becomes ill or dies, the virus then spreads to others who come into direct contact with the infected individual’s blood, skin, or other body fluids. Studies in laboratory primates have found that animals can be infected with Ebola virus through droplet inoculation of virus into the mouth or eyes. This suggests that human infection can result from the inadvertent transfer of virus to these sites from contaminated hands.

Prior to the epidemic in West Africa, outbreaks of EVD were typically controlled within a period of a few weeks to a few months. This outcome was generally attributed to the fact that most outbreaks occurred in remote regions with low population density, where residents rarely traveled far from home. However, the West African epidemic showed that EVD can spread rapidly and widely as a result of the extensive movement of infected individuals. The disease is spread by infected individuals who move to densely populated urban areas, the avoidance and/or lack of adequate personal protective equipment, and the absence of dedicated medical isolation centers.97,98

Person-to-Person Transmission

Person-to-person transmission is associated with direct contact with the body fluids of individuals, who are ill with EVD or have died from the infection, in the absence of personal protective equipment (PPE).199-101 Those who provide hands-on medical care or prepare a cadaver for burial are at greatest risk. Examples:

  • In a meta-analysis of Ebola virus transmission among household contacts that included nine studies, the secondary attack rates for those providing nursing care was 47.9% compared with 2.1% for those household members who had direct physical contact but did not provide nursing care.102
  • The ritual washing of Ebola victims at funerals has played a significant role in the spread of infection in past outbreaks and contributed to the epidemic in West Africa. As an example, a single funeral ceremony in late 2014 in Guinea was linked to 85 subsequent cases of EVD.103
  • During the early phase of the West African epidemic, several hundred African doctors and nurses, who performed patient care without appropriate PPE, acquired EVD.
  • A retrospective study of intra-household transmission in the West African epidemic found that the spread of infection was more likely in larger households.103 In addition, more transmissions resulted from older patients and those with severe disease. The estimated secondary attack rate was 18%.

Risk of Transmission through Different Body Fluids

The likelihood of infection depends, in part, upon the type of body fluid to which an individual is exposed and the amount of virus it contains. Transmission is most likely to occur through direct contact of broken skin or unprotected mucous membranes with virus-containing body fluids from a person who has developed signs and symptoms of illness.100, 105

  • Acute infection
    • According to the World Health Organization (WHO), the most infectious body fluids are blood, feces, and vomitus. Infectious virus has also been detected in urine, semen, saliva, aqueous humor, vaginal fluid, and breast milk.106-107 Reverse-transcription polymerase chain reaction (RT-PCR) testing has also identified viral RNA in tears and sweat, suggesting that infectious virus may be present.

    • Ebola virus can also be spread through direct contact with the skin of a patient, but the risk of developing infection from this type of exposure is thought to be lower than from exposure to blood or body fluids.100 Virus present on the skin surface might result either from viral replication in dermal and epidermal structures, contamination with blood or other body fluids, or both.

    • The risk of Ebola transmission also depends upon the quantity of virus in the fluid. During the early phase of illness, the amount of virus in the blood may be quite low, but levels then increase rapidly and may exceed 108 RNA copies/mL of serum in severely ill and moribund patients.100 Epidemiologic studies have found that family members were at greatest risk of infection if they had physical contact with sick relatives (or their body fluids) during the later stages of illness or helped to prepare a corpse for burial.104

  • Convalescent period
    • Infectious virus or viral RNA can persist in some body fluids of patients recovering from EVD even after it is no longer detected in blood. For example:
      • Follow-up studies of approximately 40 survivors in the 1995 outbreak in Kikwit, Democratic Republic of the Congo found that viral RNA sequences could be detected by RT-PCR in the semen of male patients for up to three months, and infectious virus was recovered from the semen of one individual 82 days after disease onset.

      • A study of patient samples collected during the outbreak of Ebola Sudan virus disease in Gulu, Uganda in 2000 detected virus in the breast milk of a patient even after the virus was no longer detectable in the bloodstream. Two children who were breastfed by infected mothers died of the disease.

      • During the 2014 - 2016 outbreak in West Africa, infectious virus or viral RNA has been detected from several sites. These include:

        • Urine
          • Ebola virus was cultured from a patient’s urine 26 days after the onset of symptoms, which was 9 days after the plasma RNA level became negative.106

        • Semen
          • In a sample of 93 men who were discharged from an Ebola treatment center, the virus was detected in semen up to nine months after discharge.109 However, the percentage of patients with persistent virus and the level of virus detected in semen decreased over time. In a patient treated in the United States, the concentration of viral RNA in semen during early recovery was 4 logs higher than in blood during peak infection.110 A modeling study from the 2014 - 2016 outbreak suggests the median time to semen RT-PCR negativity is 47 days after symptom onset and the probability of shedding at 18 months is <1%.111

          • Although transmission from persistent virus at these sites is possible, the risk of transmission is not well established.112 As an example, a patient in West Africa who had viral RNA in his semen at least 199 days after symptom onset transmitted Ebola virus to one, but not another, of his sexual contacts.113, 114 The transmission occurred approximately five months after his blood tested negative for Ebola virus.

        • Aqueous humor
          • Ebola virus RNA was detected and infectious virus isolated from the aqueous humor of a patient with uveitis 14 weeks after the onset of Ebola symptoms and 9 weeks after viremia had resolved.107
        • Cerebrospinal fluid
          • A patient who had recovered from EVD developed meningitis approximately 10 months after her initial diagnosis, and infectious virus was recovered from the cerebrospinal fluid.115, 116

Risk of Transmission through Contact with Contaminated Surfaces

Ebola virus may be transmitted though contact with contaminated surfaces and objects. The US Centers for Disease Control and Prevention (CDC) indicates that virus on surfaces may remain infectious from hours to days.117, 116 There are no high-quality data to confirm transmission through exposure to contaminated surfaces117, but it is clear that the potential risk can be greatly reduced or eliminated by proper environmental cleaning.119

Risk of Airborne Transmission

There are no reported cases of Ebola virus being spread from person to person by the respiratory route.100, 208 However, laboratory experiments have shown that Ebola virus released as a small-particle aerosol is infectious for rodents and nonhuman primates.149, 150 Healthcare workers may therefore be at risk of EVD if exposed to aerosols generated during medical procedures.

Nosocomial Transmission

Transmission to healthcare workers may occur when appropriate PPE is not available or is not properly used, especially when caring for a severely ill patient who is not recognized as having EVD.

During the epidemic in West Africa, a large number of doctors and nurses became infected with Ebola virus. In Sierra Leone, the incidence of confirmed cases over a seven-month period was approximately 100-fold higher in healthcare workers than in the general population.122 Several factors accounted for these infections, including:

  • Delayed laboratory diagnosis
  • Inadequate training about safe management of contaminated waste and burial of corpses
  • Incorrect triage and/or failure to recognize patients and corpses with EVD
  • Limited availability of appropriate PPE and hand washing facilities

Medical procedures played a major role in some past Ebola epidemics by amplifying the spread of infection. For example:

  • An iatrogenic point-source outbreak occurred in 1976, when an individual infected with Ebola virus was among the patients treated in a small missionary hospital in Yambuku, Zaire. At this hospital, the medical staff routinely injected all febrile patients with antimalarial medications, employing syringes that were rinsed in the same pan of water, then reused. Virus from the index case was transmitted simultaneously to nearly 100 people, all of whom developed EVD and died.123 Infection then spread to family caregivers, hospital staff, and those who prepared bodies for burial.
  • A different type of iatrogenic amplification occurred in 1995 in Kikwit, Democratic Republic of the Congo, when a patient was hospitalized with abdominal pain and underwent exploratory laparotomy. The entire surgical team became infected, probably through unprotected respiratory exposure to aerosolized blood. Once those persons were hospitalized, the disease spread to hospital staff, patients, and family members through direct physical contact.

Despite these dramatic episodes of nosocomial transmission, other hospital-based experiences have demonstrated a much lower incidence of secondary spread. For example:

  • A patient with unrecognized EVD was treated in a South African hospital in 1998. Only one person became infected among 300 potentially exposed healthcare workers.124
  • A similar observation was made when a patient with an unrecognized infection with Marburgvirus, a closely related filovirus, was treated in a South African hospital in 1975, resulting in the spread of infection to only two people with close physical contact.

Assistance from the international medical community has played an important role in controlling large epidemics in Africa. In the past, intervention strategies focused largely on helping local healthcare workers to identify Ebola patients, transfer them to isolation facilities, provide basic supportive care, monitor all persons who had been in direct contact with cases, and rigorously enforce infection control practices.99 During the West African epidemic, the massive international response made it possible to supplement isolation procedures with more effective supportive care.125

Transmission from Animals

  • Contact with infected animals
    • Human infection with Ebola virus can occur through contact with wild animals (e.g., hunting, butchering, and preparing meat from infected animals).126-127 In Mayibou, Gabon in 1996, for example, a dead chimpanzee found in the forest was butchered and eaten by 19 people, all of whom became severely ill over a short interval. Since that time, several similar episodes have resulted from human contact with infected gorillas or chimpanzees through hunting. To help prevent infection, food products should be properly cooked, since the Ebola virus is inactivated through cooking. In addition, basic hygiene measures (e.g., hand washing and changing clothes and boots after touching the animals) should be followed. Some public health messages in West Africa regarding the consumption of "bush meat" have contained incorrect information and may have been counterproductive.129
  • Exposure to bats
    • Direct transmission of Ebola virus infection from bats to wild primates or humans has not been proven. However, Ebola RNA sequences and antibodies to Ebola virus have been detected in bats captured in Central Africa. Bats have been identified as a direct source of human infection with Marburg virus.

Other Routes of Transmission

Other potential routes of transmission include the following:

  • Accidental infection of workers in any Biosafety-Level-4 (BSL-4) facility where filoviruses are being studied.
  • Use of filoviruses as biological weapons.

To date, there is no evidence that Ebola virus can be transferred from person to person by mosquitoes or other biting arthropods. Past epidemics of EVD in Central Africa would certainly have been larger and more difficult to control if the virus were transmitted by these mechanisms.

Pathogenesis

Because of the difficulty of performing clinical studies under outbreak conditions, almost all data on the pathogenesis of EVD have been obtained from laboratory experiments employing mice, guinea pigs, and nonhuman primates. Case reports and large-scale observational studies of patients in the West African epidemic have provided additional data on pathogenesis. Observations of disease mechanisms from the epidemic have been consistent with findings in animal studies.106,125

Cell Entry and Tissue Damage

After entering the body through mucous membranes, breaks in the skin, or parenterally, Ebola virus infects many different cell types. Macrophages and dendritic cells are probably the first to be infected. Filoviruses replicate readily within these ubiquitous "sentinel" cells, causing their necrosis and releasing large numbers of new viral particles into extracellular fluid.

Rapid systemic spread is aided by virus-induced suppression of type I interferon responses.130 Dissemination to regional lymph nodes results in further rounds of replication, followed by spread through the bloodstream to dendritic cells and fixed and mobile macrophages in the liver, spleen, thymus, and other lymphoid tissues. Necropsies of infected animals have shown that many cell types may be infected, including endothelial cells, fibroblasts, hepatocytes, adrenal cortical cells, and epithelial cells. Lymphocytes and neurons are the only major cell types that remain uninfected. Fatal disease is characterized by multifocal necrosis in tissues such as the liver and spleen.

Gastrointestinal Dysfunction

Patients with EVD commonly suffer from vomiting and diarrhea, which can result in acute volume depletion, hypotension, and shock. It is not clear if such dysfunction in EVD is the result of viral infection of the gastrointestinal tract, or if it is induced by circulating cytokines, or both.

Systemic Inflammatory Response

In addition to causing extensive tissue damage, Ebola virus also produces a systemic inflammatory syndrome by causing the release of cytokines, chemokines, and other proinflammatory mediators from macrophages and other cells.

Infected macrophages produce tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, macrophage chemotactic protein (MCP)-1, and nitric oxide (NO). These and other substances have also been identified in blood samples from Ebola-infected macaques and from acutely ill patients in Africa. Breakdown products of necrotic cells also stimulate the release of the same mediators.

This systemic inflammatory response may play a role in inducing gastrointestinal dysfunction, as well as, the diffuse vascular leak and multiorgan failure that are seen later in the disease course.

Coagulation Defects

The coagulation defects seen in EVD appear to be induced indirectly, through the host inflammatory response. Virus-infected macrophages synthesize cell-surface tissue factor (TF), triggering the extrinsic coagulation pathway. Proinflammatory cytokines also induce macrophages to produce TF. The simultaneous occurrence of these two stimuli helps to explain the rapid development and severity of the coagulopathy in Ebola virus infection.

Additional factors may also play a role in the coagulation defects that are seen with EVD. For example, blood samples from Ebola-infected monkeys contain D-dimers within 24 hours after virus challenge, and D-dimers are also present in the plasma of humans with EVD. In Ebola virus-infected macaques, activated protein C is decreased on day two, but the platelet count does not begin to fall until days three or four after virus challenge, suggesting that activated platelets are adhering to endothelial cells. As the disease progresses, hepatic injury may also cause a decline in plasma levels of certain coagulation factors.

Impairment of Adaptive Immunity

Failure of adaptive immunity through impaired dendritic cell function and lymphocyte apoptosis helps to explain how filoviruses are able to cause a severe, frequently fatal illness. Ebola virus acts both directly and indirectly to disable antigen-specific immune responses. Dendritic cells, which have primary responsibility for the initiation of adaptive immune responses, are a major site of filoviral replication. In vitro studies have shown that infected cells fail to undergo maturation and are unable to present antigens to naive lymphocytes, potentially explaining why patients dying from EVD may not develop antibodies to the virus.

Adaptive immunity is also impaired by the loss of lymphocytes that accompanies lethal Ebola virus infection. Although these cells appear to remain uninfected, they undergo "bystander" apoptosis, presumably induced by inflammatory mediators and/or the loss of support signals from dendritic cells. A similar phenomenon is observed in septic shock. However, one study has shown that, at least in Ebola-infected mice, virus-specific lymphocyte proliferation still occurs despite the surrounding massive apoptosis, but it arrives too late to prevent a fatal outcome. Discovering ways to accelerate and strengthen such responses may prove to be a fruitful area of research.

Clinical Manifestations

During the nearly 40 years between the first recognized Ebola outbreaks in Zaire and Sudan in 1976 and the beginning of the 2014 - 2016 epidemic in West Africa, several publications described the clinical and laboratory features of the disease. That information has since been supplemented by many patient series from Ebola treatment units in West Africa and case reports of patients treated in the United States and in Europe (Table 1):130-133

Table 1
State of IllnessTime Post-Symptom OnsetClinicalLaboratory

Early febrile

Days 1 - 3

Fever

Malaise

Fatigue

Body aches

Leukopenia

Lymphopenia

Thrombocytopenia

Elevated *AST and *ALT

Gastrointestina

Days 3 - 10

Primary:

Epigastric and abdominal pain

Nausea

Vomiting

Diarrhea

Associated:

Persistent fever

Asthenia

Headache

Conjunctival injection

Chest pain

Dysphagia

Odynophagia

Arthralgias

Myalgias

Hiccups

Delirium

Rash

 

Persistently elevated *AST/*ALT and thrombocytopenia

Elevated *BUN and creatinine

Hypokalemia Hypomagnesemia Hyponatremia Hypoalbuminemia

Elevated *PT/*PTT/*INR/fibrin-split products

Leukocytosis (elevated neutrophils and band cells)

 

Shock

Days 7 - 12

Diminished consciousness or coma

Thready pulse

Oliguria

Anuria

Tachypnea

In addition to findings during gastrointestinal stage:

Elevated lactate

Decreased bicarbonate

Other complications

Day 10 and after

Gastrointestinal hemorrhage

Respiratory failure associated with aggressive fluid resuscitation or lung injury

Secondary infections

Neurocognitive abnormalities

Seizures

Syndrome consistent with menigoencephalitis

Findings may overlap with prior stages of illness

Decreased hemoglobin and hematocrit observed with gastrointestinal bleeding

Hypoxemia observed with respiratory failure

Recovery

Days 7 - 12

Resolution of gastrointestinal symptoms

Increased oral intake

Increased energy

Resolution of laboratory abnormalities

Convalescence

Up to 12 months

Arthralgias

Myalgias

Abdominal pain

Fatigue

Persistent neurocognitive abnormalities

Uveitis

Meningitis

Hearing loss

 

*ALT: alanine aminotransferase

*AST: aspartate aminotransferase

*PT: prothrombin time

*PTT: partial thromboplastin time

*INR: international normalized ratio

*BUN: blood urea nitrogen.

Although most features of EVD in the West African epidemic matched earlier descriptions, patients differed in two respects:

  • Major hemorrhage was less common than previously described. Thus, the name of the disease was changed from "Ebola hemorrhagic fever" to "Ebola virus disease (EVD)."
  • Volume losses from vomiting and diarrhea made a greater contribution to severe illness in patients in West Africa than previously recognized.

Before the 2014 - 2016 epidemic, reports of Ebola outbreaks in Africa largely focused on severe and fatal illness, but the spectrum of Ebola virus infection may have also included milder infections that escaped detection.134 One report that reviewed past serosurveys from Central Africa suggested "asymptomatic" Ebola virus infections could occur102, and a subsequent study from the Democratic Republic of the Congo reached a similar conclusion.135 However, such studies have mostly been based on somewhat nonspecific serologic assays and have lacked control groups, preventing any firm conclusions.

Incubation Period

Patients with EVD typically have an abrupt onset of symptoms 6 to 12 days after exposure (range 2 to 21 days).106,109 There is no evidence that infected persons who have not yet developed signs of illness are infectious to others. However, all symptomatic individuals should be assumed to have the virus in the blood and other body fluids, and appropriate safety precautions should be taken.

Signs and Symptoms

  • Initial syndrome
    • Most cases of EVD begin with the abrupt onset of fever and chills, but low-grade fever and malaise may also precede the development of more severe symptoms.133, 138
    • Common signs and symptoms reported from the West African outbreak include:106,136,139
      • Diarrhea
      • Fatigue
      • Fever
      • Headache
      • Loss of appetite
      • Vomiting
      • Reports have also described:89,138
        • Weakness
        • Myalgias
        • A high fever accompanied by relative bradycardia as seen in typhoid fever
  • Rash
    • A diffuse erythematous, nonpruritic maculopapular rash may develop by day 5 to 7 of illness.
    • The rash usually involves the face, neck, trunk, and arms, and can desquamate.
    • It is generally easier to see in light-skinned persons
    • During the outbreak in Sierra Leone, rash was reported as rare.131 It was, however, clearly described in case reports of infected health care workers.138
  • Gastrointestinal
    • Gastrointestinal signs and symptoms are common and usually develop within the first few days of illness. These include:
      • Abdominal pain
      • Nausea
      • Vomiting
      • Watery diarrhea (up to 10 liters per day)
    • During the 2014 - 2016 West African outbreak, vomiting and diarrhea resulted in severe fluid loss, potentially leading to dehydration, hypotension, and shock.106
  • Hemorrhage
    • Case series from the West African epidemic indicate that many patients develop some degree of bleeding during their illness, most commonly manifested as:136, 140
      • Blood in the stool (about 6%)
      • Ecchymoses
      • Mucosal bleeding
      • Oozing from venipuncture sites
      • Petechiae
    • Clinically significant hemorrhage may be seen in the terminal phase of illness and in pregnancy.
  • Neurologic
    • Patients occasionally develop meningoencephalitis, with findings such as:106, 141, 142
      • Altered level of consciousness
      • Gait instability
      • Hyperreflexia
      • Myopathy
      • Seizures
      • Stiff neck
    • These clinical manifestations typically develop around days 8 to 10 of illness.
  • Cardiac
    • Pulse-temperature dissociation with relative bradycardia may be observed during acute illness.
    • In addition, retrosternal chest pain attributed to pericarditis has been reported.
    • Myocarditis has also been described.141
  • Respiratory
    • Tachypnea and shortness of breath may represent hypoxia or hypoventilation due to respiratory muscle fatigue, contributing to impending respiratory failure. This phenomenon was observed in nearly one-third of patients treated in Europe and the United States in the setting of intravenous fluid resuscitation.133
  • Ocular
    • Patients may develop conjunctival injection and/or signs and symptoms of uveitis (e.g., blurred vision, photophobia, blindness) during the acute phase of illness.
    • In addition, uveitis has been documented during convalescence.

Laboratory Findings

Patients with EVD typically develop leukopenia, thrombocytopenia, and serum transaminase elevations, as well as, renal and coagulation abnormalities. Other laboratory findings include a marked decrease in serum albumin, hypoglycemia, and elevated amylase levels (see Table 1 above).

  • Leukopenia
    • Leukopenia usually presents as lymphopenia, followed by an elevated neutrophil count.135 Immature granulocytes and abnormal lymphocytes, including plasmacytoid cells and immunoblasts, may be seen in blood smears.
  • Thrombocytopenia
    • Platelet counts decrease during the acute phase of illness, but generally do not fall below 50,000 to 100,000/microL136 Platelet counts typically reach a nadir around day 6 to 8 of illness.
  • Abnormal hematocrit
    • Patients with EVD may present with an increased or decreased hematocrit. As an example, in one cohort study that evaluated 100 patients, 15 had an increased hematocrit upon presentation and 36 were anemic.
  • Transaminase elevations
    • Because Ebola virus can cause multifocal hepatic necrosis, blood chemistry tests usually demonstrate elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels.131
    • In one study, AST levels correlated with viral load.144
  • Coagulation abnormalities
    • Prothrombin (PT) and partial thromboplastin times (PTT) can be prolonged and fibrin degradation products elevated, consistent with disseminated intravascular coagulation (DIC). These changes are most prominent in severe and fatal cases.
  • Renal abnormalities
    • Proteinuria is a common finding, and renal insufficiency with elevated BUN and creatinine can be seen in both the early and late stages of disease.131
    • Acute kidney injury is exacerbated by excessive fluid loss from diarrhea and vomiting without adequate volume replacement, but may also develop as a result of direct viral-mediated tissue injury in the absence of severe volume loss.
  • Electrolyte abnormalities
    • Patients may develop significant electrolyte disturbances (e.g., hyponatremia, hypokalemia, hyperkalemia, hypomagnesemia, and hypocalcemia) secondary to the gastrointestinal manifestations of the disease. Such individuals may require frequent repletion of electrolytes to prevent cardiac arrhythmias.

Disease Course

Patients who survive EVD typically begin to improve during the second week of illness.136 Fatal disease has been characterized by more severe clinical signs and symptoms early during infection, with progression to multiorgan failure with death typically occurring in the second week.

Some patients develop secondary complications related to their disease and/or the treatments they receive.145,146 These include bacterial sepsis, respiratory failure associated with aggressive fluid resuscitation, and/or lung and kidney injury.

Convalescence

The convalescent period of EVD is prolonged and can persist for more than two years.147 Patients may suffer from weakness, fatigue, insomnia, headache, and failure to regain weight that was lost during illness, resulting in significant disability.140 Other clinical manifestations include:

  • Acute arthralgias, which may result from the formation of antigen-antibody complexes during recovery.
  • Extensive sloughing of skin and hair loss, which may result from virus-induced necrosis of infected sweat glands and other dermal structures.
  • Retro-orbital pain, uveitis, and hearing loss107,147,148

Symptoms can be severe, and in one report of Ebola survivors after the outbreak in Uganda, many patients were unable to resume their previous work activities.149 It has been postulated that a higher Ebola viral load at the time of clinical presentation is associated with the development of symptoms during convalescence, but this awaits confirmation.149,150

Some patients develop clinical manifestations soon after recovery from their initial infection. In a study of 277 Ebola survivors from the West African epidemic who were evaluated after discharge from a treatment center. 76% had arthralgias, 60% had new ocular symptoms (e.g., blurry vision, light sensitivity, itchy eye), 24% had auditory symptoms (e.g., tinnitus, hearing loss), and 18% had uveitis.149 The median time from discharge to onset of clinical manifestations was one to two weeks.

However, others appear to develop late complications of EVD, with manifestations developing months after they have recovered from their initial illness. For example:

  • In one patient, uveitis developed 14 weeks after EVD was initially diagnosed, and the aqueous fluid contained infectious virus.107
  • Another patient who had recovered from EVD developed meningitis 10 months after her initial diagnosis, and infectious virus was recovered in the cerebrospinal fluid.149

Although viral RNA and infectious virus may persist in certain bodily fluids after infection, the importance of persistent virus as it relates to the clinical manifestations during convalescence is unclear.112 In one case report, immune activation was felt to contribute to the development of uveitis.152

Pregnancy

During the outbreak in West Africa, reports suggested that an atypical presentation of EVD may be observed in pregnant women and fetal death may occur even if the mother has recovered. For example:

  • In Liberia, a pregnant woman presented in late pregnancy with mild lower abdominal and back pain, sparse contractions, and premature rupture of membranes, without fever or other signs or symptoms of EVD.153 Blood testing for Ebola virus was performed as part of routine care and returned positive with a high viral load. A vaginal swab tested on day 2 was also positive for Ebola virus. The mother died undelivered from complications related to EVD seven days after admission.
  • In Guinea, two pregnant women presented with EVD and had fetal movement detected upon admission. Both fetuses died even though the mothers’ survived.154 The placenta and fetal blood remained positive for Ebola virus using polymerase chain reaction testing up to seven days after the mothers' serum tested negative for virus.

Consequently, pregnant women should be evaluated for Ebola if they have a possible exposure to Ebola virus and present with nonspecific signs and symptoms of EVD (e.g., abdominal pain) and/or pregnancy complications, such as preterm labor, vaginal bleeding, or premature rupture of membranes.

Diagnosis

Whether EVD is considered in the differential diagnosis of a patient with fever and flu-like symptoms will vary markedly depending upon the circumstances, in particular, whether a recognized Ebola epidemic is currently taking place. In addition, clinicians should remember that the acute onset of a febrile illness in a person who lives in or has recently been to West or Central Africa can result from a variety of local infectious diseases, including malaria, Lassa fever, and Marburg virus disease.

In response to the 2014 - 2016 outbreak, the CDC, the WHO, and other international organizations provided recommendations for the evaluation and management of persons who may have been exposed to Ebola virus.136,155-161 The following outlines key principles that should be used when the diagnosis of EVD is being considered.

General Approach

  • Symptomatic patients
    • Even though there are no approved specific therapies for EVD, it is essential to make the diagnosis as early as possible so that infection control procedures can be implemented to reduce the transmission of the virus, and so supportive measures can be initiated before the development of irreversible shock.
    • Patients who present with signs and symptoms consistent with EVD (fever and/or severe headache, weakness, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage) should be assessed to determine the likelihood of recent exposure to Ebola virus (Table 2). In particular, they should be asked if they traveled to an area with a recognized Ebola epidemic or had contact with a patient with possible EVD disease within the 21 days prior to the onset of symptoms.136,162
Table 2: Ebola Virus Disease Case Definition Box
A person under investigation (PUI) for EVD meets the following criteria:155

1. Signs or symptoms compatible with EVD (subjective fever/elevated body temperature, headache, fatigue, muscle pain, vomiting, diarrhea).

AND

2. An epidemiology risk factor for EVD163 within 21 days of symptom onset (e.g., travel to a country with widespread Ebola virus transmission, proximity to a person with symptomatic EVD).

A confirmed case of EVD requires laboratory-confirmed diagnostic evidence of Ebola virus infection.
  • Infection control precautions should be used for all symptomatic patients who may have been exposed to Ebola virus (i.e., those who have had a high, moderate, or low-risk exposure). Infection control precautions should also be used for patients whose risk of exposure is unclear at the time of their initial presentation until a medical evaluation can be performed.
  • Persons under investigation for EVD should undergo testing for Ebola virus by reverse-transcription polymerase chain reaction (RT-PCR) facilitated by local and state health officials.
  • Persons under investigation for EVD should also be evaluated for other possible febrile diseases, including those that are common in areas where the patient traveled or resided (e.g., malaria, typhoid, influenza).
  • The specific triage system used during the initial assessment of a patient with possible EVD may vary depending on the setting (e.g., emergency department, ambulatory clinic) and the known history of transmission in the community.164-167
    • For example, medical facilities, especially those in areas with widespread Ebola transmission, should designate areas for screening patients.168
  • In addition, the types of PPE that are recommended for health care personnel caring for a patient depend upon the patient's clinical symptoms. The PPE used when caring for patients whose condition is associated with a high risk of direct contact with body fluids (e.g., presence of vomiting, diarrhea, bleeding) are different from those used when evaluating a patient who does not present a hazard due to body fluid exposure.169-171 In all settings, only essential personnel who are trained in proper donning and removal of PPE should interact with the patient.
  • Asymptomatic individuals
    • Asymptomatic individuals who have had a possible exposure to Ebola generally do not require strict isolation precautions. Such patients should be monitored so that they can be isolated if fever or other signs or symptoms occur. However, additional restrictions may be required depending upon the type of exposure.

Determining the Risk of Exposure

The risk of exposure to the Ebola virus helps to guide the evaluation and management of both symptomatic and asymptomatic individuals.

Patients are at risk for EVD if they have had an exposure that occurred within 21 days before the onset of symptoms. However, the level of exposure risk ranges from high, to moderate, to low, or no known identifiable risk. For health care workers, the level of exposure risk increases with the number of patients with known EVD they are caring for. Individuals may also be at risk if they have handled bats or nonhuman primates from endemic areas of Africa.

These following guidelines were put forth by the CDC to identify at-risk individuals during the 2014 - 2016 outbreak in West Africa.163

  • High risk: A high-risk exposure includes any of the following:
    • Percutaneous (e.g., needle stick) or mucous membrane exposure to blood or body fluids (e.g., feces, saliva, sweat, urine, vomit, and semen) of a person with symptomatic EVD.
    • Exposure to the blood or body fluids of a person with symptomatic EVD without appropriate PPE.
    • Processing blood or other body fluids of a person with symptomatic EVD without appropriate PPE or standard biosafety precautions.
    • Direct contact with a dead body without appropriate PPE in an area where a recognized Ebola epidemic is occurring.
    • Having lived in the immediate household and provided direct care to a person with symptomatic EVD.
  • Moderate risk: Some risk of exposure includes any of the following:
    • In areas where a recognized epidemic is occurring:
      • Direct contact while using appropriate PPE with a person with symptomatic EVD (or his/her body fluids).
      • Any direct patient care in other health care settings.
    • Close contact in households, health care facilities, or community settings with a person with symptomatic EVD. Close contact is defined as being within approximately three feet (one meter) of the infected person for a prolonged period of time while not wearing appropriate PPE.
  • Low (but Not Zero) Risk: A low-risk exposure includes any of the following:
    • Having been in a country where a recognized epidemic is occurring within the past 21 days and having no known exposures to Ebola virus.
    • Having brief direct contact (e.g., shaking hands), while not wearing appropriate PPE, with a person with Ebola while the person was in the early stage of disease.
    • Brief proximity, such as being in the same room (but not an Ebola patient care area) for a brief period of time, with a person with symptomatic EVD.
    • Direct contact while using appropriate PPE with a person with symptomatic EVD (or their body fluids) in countries without widespread transmission or cases in urban settings with uncertain control measures.
    • Travel on an aircraft with a person with EVD while the person was symptomatic.
  • No Identifiable Risk: Some exposures or situations have no identifiable risk of infection. These include:
    • Contact with an asymptomatic person who had contact with a person with EVD.
    • Contact with a person with EVD before the person developed symptoms.
    • Having been more than 21 days previously in a country where a recognized epidemic is occurring.
    • Having been in a country with Ebola virus cases, but without widespread transmission or cases in urban settings with uncertain control measures, and not having any other exposure as defined above (e.g., direct contact with a patient with EVD).
    • Having remained on or in the immediate vicinity of an aircraft or ship during the entire time that the conveyance was present in a country where a recognized epidemic is occurring, and having had no direct contact with anyone from the community.

Initial Assessment for EVD

  • Symptomatic Patients with Identifiable Risk
    • Clinical findings that are consistent with EVD include fever and/or severe headache, weakness, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage.136,155 Infection control precautions should be used for all symptomatic patients who have an identifiable risk for EVD. In addition, the hospital infection control program and other appropriate staff should be notified, as well as, local and state health departments.
    • Such patients should be isolated in a single room with a private bathroom and with the door to the hallway closed. All health care workers should use standard, contact, and droplet precautions, as well as. PPE recommended for the care of patients with EVD.
    • In patients who are suspected of having EVD, phlebotomy and laboratory testing should be limited to tests that are essential for diagnosing or ruling out Ebola virus, assessing for an alternative or concurrent infection (e.g., malaria), and/or emergency care.136,162-163 In consultation with local and state health officials, evaluation for other potential causes of their illness may also be indicated, particularly for those individuals whose recent history indicates a low risk of exposure to Ebola virus.172
    • In the United States, certain hospitals have been designated as "Ebola assessment hospitals" and are prepared to evaluate and care for patients with possible EVD until a diagnosis can be confirmed or ruled out.173,174
  • Asymptomatic Individuals with Identifiable Risk
    • Monitoring for symptoms and signs of EVD should be performed for asymptomatic persons who have had an exposure to Ebola virus at any risk level (i.e., high, moderate, or low risk).
    • Such individuals should be monitored for 21 days after the last known exposure and should immediately report the development of fever or other clinical manifestations suggestive of EVD.136 The type of monitoring (e.g., self-monitoring and reporting versus direct observation by a designated health official), as well as, the need for travel restrictions, restricted movement within the community, and/or quarantine, depend in part upon the type of exposure. Specific guidelines for management of asymptomatic individuals with an exposure to Ebola virus are typically dictated by public health authorities.
  • Patients with No Identifiable Risk
    • If after initial evaluation patients are determined to have no identifiable risk for Ebola virus infection, monitoring or diagnostic testing for EVD is not warranted. However, if patients have fever and other signs or symptoms of infection, they should be evaluated for other causes of febrile disease (e.g., malaria, Lassa fever, influenza). Appropriate infection control precautions will depend upon the patient's clinical findings, as well as, the specific pathogens that are being considered.

Laboratory Testing

  • Indications
    • Evaluation of all patients with suspected EVD should be done in conjunction with local and state health departments.136,179 In the United States, certain hospitals may be designated as "Ebola assessment hospitals," which are prepared to evaluate and care for patients with possible EVD until a diagnosis can be confirmed or ruled out.173,174
      • Testing for Ebola virus infection is performed in symptomatic patients with any possible risk of exposure to Ebola virus (high, moderate, or low risk).
      • Testing is not warranted for patients who have an identifiable risk but no signs or symptoms of EVD. These patients should be monitored and tested if they become ill.
      • Testing is not warranted for patients without any identifiable risk of exposure to Ebola virus.
  • Ebola virus is generally detectable in blood samples by RT-PCR within three days after the onset of symptoms. Repeat testing may be needed for patients with symptoms for fewer than three days.176 According to CDC guidelines for discharging a person who is under investigation for EVD, a negative RT-PCR test that is collected ≥72 hours after the onset of symptoms excludes EVD.177
  • Patients who have confirmed EVD should be transferred to specialized Ebola treatment centers.

Diagnostic Tests

  • Diagnostic tests for Ebola virus infection are principally based upon the detection of specific RNA sequences by RT-PCR in blood or other body fluids. Viral antigens can also be detected using immunoassays. In the United States, any presumptive positive Ebola test should be confirmed at the CDC.178
    • Nucleic acid testing
      • RT-PCR tests that detect specific RNA sequences have become the standard method of diagnosing EVD. In spite of genetic diversity and the accumulation of sequence changes,179 RT-PCR testing remained effective through the conclusion of the West African epidemic. However, clinicians should be aware of possible viral RNA sequence differences when attempting to employ these assays in future Ebola outbreaks.
      • Viral RNA is generally detectable in serum by RT-PCR within three days after the onset of symptoms.125,176 Results are available in approximately two to six hours, depending upon the assay that is used.180
        • Repeat testing may be needed for patients with symptoms for fewer than three days.180
        • A negative RT-PCR test that is collected >72 hours after the onset of symptoms rules out EVD.125,180
      • Blood is the preferred specimen for testing. Testing of simultaneously collected blood and saliva specimens has shown that viral RNA levels are much lower in saliva. For example, in a group of 32 patients who were positive by blood testing, fewer than 10% were also detected by oral swab, indicating that saliva should not be used for diagnostic testing.181 However, an oral swab from a cadaver may be useful for postmortem diagnosis because fatally infected patients have high viral titers in body fluids at the time of death.
    • Immunoassays
      • A rapid chromatographic immunoassay (ReEBOV) that detects Ebola virus antigen can provide results within 15 minutes.183 This assay can be useful to support a provisional diagnosis based on clinical exam and exposure history. However, the use of the ReEBOV assay alone could result in inappropriate admissions of uninfected persons to Ebola treatment units or fail to detect patients who are early in the disease course. Evaluation of ReEBOV in a field setting, using banked patient samples, found that the test gave a positive result in about 10% of cases in which EVD had been ruled out by RT-PCR. Additionally, it only detected about 90% of cases that were positive by RT-PCR.183-184 In a laboratory setting, the lower limit of detection of this test in blood samples from infected macaques was 3 x 105genomes/mL.185
      • In November of 2018, the US Food and Drug Administration cleared a second Ebola rapid antigen fingerstick test under an Emergency Use Authorization.186 This test uses a portable battery-operated reader that allows testing to be performed at the point of care outside of the laboratory when more sensitive Ebola virus nucleic acid testing is unavailable. Similar to other antigen-based assays, false-negative results may occur. As such, results must be interpreted in the context of associated clinical and epidemiologic findings.
  • If testing is indicated, the local or state health department should be contacted immediately. Clinicians, nurses, and laboratory workers need to be aware that CDC select agent regulations apply to the handling of patient specimens confirmed to contain infectious Ebola virus.187 Additional details on collection and handling of specimens from patients with suspected EVD can be found in the CDC documents that provide guidance for laboratories and submission information.176,178,189 For clinicians outside the United States, the WHO has also issued guidance for the diagnosis, safe collection, and shipment of samples from patients with suspected EVD.190-192

Differential Diagnosis

When evaluating a patient for possible EVD, it is important to consider alternative and/or concurrent diagnoses, including infectious and noninfectious disorders. In one study that evaluated 770 ill nonimmigrant travelers returning from Guinea, Liberia, and Sierra Leone during a five-year period (September 2009 through August 2014), malaria was the most common diagnosis (40%), followed by acute diarrhea (12%).193

The differential diagnosis depends, in part, upon the individual's symptoms, where they have traveled or resided, if they have had close contact with someone who is ill, their vaccination history, and their age and comorbid conditions.136,140,194-196 Since most patients suspected of possible EVD will have travelled to and/or reside in West or Central Africa, the following disorders should be considered:

  • Influenza
    • Influenza often presents with the abrupt onset of fever, headache, myalgia, and malaise, similar to the presenting signs and symptoms of EVD. However, with influenza, these manifestations are usually accompanied by respiratory signs and symptoms, such as nonproductive cough, sore throat, and nasal discharge, which are not typically part of the Ebola syndrome. Direct fluorescent antibody or other rapid assays are used to diagnose influenza.
  • Lassa Fever
    • Lassa fever is restricted to West Africa, though infected travelers have become ill in countries of Europe, as well as, in the United States. Although symptoms may be mild, approximately 20% of patients develop a severe clinical syndrome that can progress to fatal shock. Transmission to humans occurs primarily through exposure to the aerosolized excretions of local multimammate rats, or in rare cases, through contact with body fluids of infected individuals. Diagnosis is made by RT-PCR testing and/or serology.197
  • Malaria
    • Travelers who develop a febrile illness after returning from West or Central Africa should be evaluated for malaria, which can present with similar findings to EVD and may occur concurrently.136 Microscopic examination of blood smears and/or rapid antigen testing are typically used to diagnose malaria.
  • Marburg Virus Disease
    • Marburg virus causes clinical manifestations similar to EVD. Cases have been identified in Central Africa, but not in West Africa. The diagnosis is typically made by RT-PCR testing.
  • Measles
    • The prodromal phases of measles and EVD are similar and are characterized by fever, malaise, and anorexia. However, in measles, this is followed by conjunctivitis, coryza, and cough, as well as, a characteristic maculopapular, blanching rash that begins on the face. The diagnosis of measles is typically established via antibody or polymerase chain reaction (PCR) testing.
  • Meningococcal Disease
    • Patients infected with Neisseria meningitidis can present with meningitis and/or bacteremia, and certain signs and symptoms (headache, fever) may overlap with those seen in EVD.
  • Travelers' Diarrhea
    • This condition develops during or within 10 days after returning from travel, most commonly from resource-limited regions. Patients typically present with malaise, anorexia, and abdominal cramps, followed by the sudden onset of diarrhea. Nausea, vomiting, and low-grade fever may also occur. When attempting to distinguish between travelers' diarrhea and diarrhea that occurs in EVD, clinicians should note whether the condition appears to be part of a systemic illness or is mostly confined to the gastrointestinal tract. A patient who develops diarrhea in the setting of EVD is likely to have a several-day history of fever, myalgia, fatigue, and other signs of a rapidly progressive systemic disease.
  • Typhoid
    • Typhoid fever is a systemic illness characterized by fever and abdominal pain. The organism responsible for the enteric fever syndrome is Salmonella entericaserotype Typhi (formerly S. typhi). Worldwide, typhoid fever is most prevalent in impoverished areas that are overcrowded, with poor access to sanitation. The diagnosis is typically made through identification of the organism in blood cultures.

Bioterrorism

Ebolavirus is classified as a biosafety level 4 agent, as well as, a Category A bioterrorism agent by the United States CDC and the National Institute of Allergy and Infectious Diseases (NIAID). In the case of a bioterror attack, patients with no history of travel to Central or West Africa or other possible exposure to an infected animal or an Ebola patient would develop EVD and would be seen in doctors' offices or hospital emergency departments. The appearance of multiple patients with a similar, rapidly progressive illness would be especially suggestive of bioterrorism. Any clinician suspecting that such an event is unfolding should report it promptly to local and state health authorities.

Treatment

Approach to Therapy

All health care workers involved in the care of patients with suspected or confirmed EVD should rigorously observe infection control precautions, including the proper use of PPE.

The mainstay of treatment for EVD involves supportive care to maintain adequate organ function (e.g., cardiovascular, respiratory, renal) while the immune system mobilizes an adaptive response to eliminate the infection.174,178,276-281 Whenever possible, such patients should receive care in designated treatment centers and by clinicians trained to care for such patients.173,203,204 Treating patients with EVD requires a multidisciplinary approach prior to, during, and following patient care.205,206 Although care provided to patients in low-resource settings has historically been limited,207 efforts to provide more frequent monitoring and advanced care to patients in West Africa progressed during the 2014 - 2016 epidemic.208

Several experimental antiviral therapies were used to treat patients during the 2014 - 2016 outbreak in West Africa, but their efficacy is unclear, and the availability of these drugs is limited. Consequently, decisions about whether to use antiviral therapy, as well as, the choice of therapy and the timing of administration, should be made in conjunction with public health agencies.

Supportive Care

Fundamental aspects of supportive care involve preventing intravascular volume depletion, correcting profound electrolyte abnormalities, and avoiding the complications of shock.

During the outbreak in West Africa, 27 patients with EVD were treated in the United States or Europe, where they received aggressive supportive care.133 Among those patients, 82% survived. Specific lessons learned from the care of patients with EVD during the outbreak include:136

  • Patients may lose large amounts of fluid through vomiting and diarrhea, requiring rapid volume replacement to prevent shock. Antiemetic and antidiarrheal agents may also be beneficial.201 Careful attention to the volume of fluid losses, as well as, intake will assist with fluid repletion targets.
  • When available, patients will benefit from hemodynamic monitoring and intravenous fluid repletion.131 However, patients in the early phase of illness who respond to oral antiemetic and antidiarrheal therapy may be able to take in sufficient fluids by mouth to prevent or correct dehydration.203
  • Patients may develop significant electrolyte disturbances (e.g., hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia) and may require frequent repletion of electrolytes to prevent cardiac arrhythmias.
  • Intensive nursing may be required in order to respond to the patient's changing clinical situation.

Fluid and Electrolyte Replacement

Patients who experience fluid losses from vomiting and diarrhea may require five or more liters per day of a balanced crystalloid solution. Fluid and electrolyte replacement can be administered orally (e.g., WHO-recommended oral rehydration salts) or intravenously (e.g., 0.9% sodium chloride solution). The approach depends in large part upon the stage of illness and the clinical presentation. For example, in resource-limited settings, oral therapy to prevent or correct dehydration may be suitable for patients in the early phase of illness who respond to oral antiemetic and antidiarrheal therapy.203 However, patients in shock and those who are unable to tolerate or manage self-directed oral replacement therapy will require intravenous fluids.

The approach to fluid and electrolyte replacement will also depend upon the availability of resources:211

  • In resource-limited areas with little or no monitoring and laboratory capacity, qualitative assessments of urine frequency, volume, and color, as well as, evaluation of skin turgor and mucous membranes, may assist in guiding volume replacement in the absence of more accurate measures.
  • In areas with greater resources, careful attention to the volume of fluid losses and intake, as well as, indirect assessments of intravascular volume status (e.g., vascular ultrasound, indwelling catheters for central venous pressure monitoring), will assist with fluid repletion targets. Electrolyte replacement should be guided by plasma values since patients can present with a range of abnormalities. For example, in a cohort study of patients admitted to a hospital in Sierra Leone, 32 of 97 presented with abnormal potassium levels, and the number who had hypokalemia and hyperkalemia were similar (19 versus 13, respectively).
  • In resource-rich areas, clinicians may employ standard supportive measures for critically ill patients in shock, including invasive blood pressure and continuous pulse-oximetry monitoring. Hypotension may sometimes persist despite adequate volume resuscitation, requiring the use of vasopressor infusions such as norepinephrine. Aggressive volume resuscitation may contribute to the development of pulmonary edema and acute lung injury in the setting of shock may necessitate supplemental oxygen therapy (e.g., nasal cannula or face mask).

Respiratory Support

Invasive mechanical ventilation (intubation) may be the best option for patients with progressive respiratory failure.145 When considering the management of such patients with EVD, clinicians should recognize that some types of respiratory support present a hazard of generating infectious aerosols. The use of noninvasive mechanical ventilation or high-flow oxygen therapy (e.g., Vapotherm) is generally not recommended given the potential for continuous aerosol production.

Additional Supportive Measures

Additional supportive measures may be needed depending upon the patient's clinical presentation. These include:

  • Analgesic agents to manage pain (e.g., abdominal, joint, muscle).
  • Antiemetic medications to control nausea and vomiting.
  • Anti-epileptic medications for those with seizures.
  • Antimotility agents (e.g., loperamide) to control diarrhea and decrease fluid and electrolyte losses.203
  • Antipyretic agents (e.g., acetaminophen, paracetamol) to decrease fever associated with EVD. Dose reduction of these agents may be needed for patients with progressive hepatic dysfunction. Nonsteroidal anti-inflammatory agents are generally avoided to help minimize the risk of renal failure, which can contribute to fatal disease.
  • Blood products (e.g., packed red blood cells, platelets, fresh frozen plasma) for patients with coagulopathy and bleeding.
  • Renal replacement therapy to manage severe multifactorial acute kidney injury.213 If dialysis is required, clinicians should refer to the CDC document on how to safely perform acute hemodialysis in patients with EVD.214
  • Total parenteral nutrition support for individuals with poor oral intake who are unable to tolerate a moderate- to high-calorie diet.212

Antimicrobial Therapy

As with other severely ill patients, persons with EVD may require evaluation and/or treatment of other concomitant or possible infections (e.g., malaria).134

In addition, empiric antimicrobial treatment should be administered to patients with clinical evidence of bacterial sepsis, which may be a late complication:134

  • The choice of agent should provide adequate coverage for gram-negative pathogens.202
  • Empiric gram-positive therapy should be added in certain patients, such as those with hospital-acquired pneumonia or indwelling central venous catheters.

In some case series from the Ebola epidemic in West Africa, empiric antimicrobial therapy was given to all patients at the time of initial presentation or to patients who had evidence of gastrointestinal dysfunction, even if clinical evidence of bacterial sepsis was absent.134 However, data to justify this approach are lacking.

Considerations during Pregnancy

EVD is associated with a high risk of fetal death and pregnancy-associated hemorrhage.136

The CDC and the American College of Obstetrics and Gynecology have issued recommendations for the care of pregnant women with EVD.215 However, there are no data to suggest whether cesarean or vaginal delivery is preferred or when the baby should be delivered. Thus, decisions regarding obstetrical care must be made on a case-by-case basis.

Prognostic Factors

Experience from the West African epidemic supports the conclusion that early diagnosis and prompt initiation of care increase the likelihood that a patient with EVD will survive.136, 203 In contrast, patients who have already developed evidence of severe intravascular volume depletion, metabolic abnormalities, and impaired oxygen delivery by the time treatment is initiated are at high risk of death.

Additional demographic, clinical, and laboratory findings from the 2014 - 2016 epidemic that were found to affect prognosis include:

  • Age
    • Younger age was associated with a lower case fatality rate in the outbreak in Sierra Leone.200,298 In one study, the case fatality rate was 57% for patients <21 years old versus 94% for those >45 years of age.136
  • Gastrointestinal disease
    • In a review of 106 patients treated in Sierra Leone, 94% of patients with diarrhea died, compared with 65% without diarrhea.136
  • Gender
    • A study from West Africa comparing the outcome of EVD in men and women found a slightly higher case fatality rate in men. This may have resulted from delays in seeking treatment by some male patients.
  • Viral load
    • Experience from Ebola outbreaks in West Africa, Uganda, and the Democratic Republic of the Congo has shown that patients with high Ebola virus RNA levels in the bloodstream have a higher mortality.136 For example, in a retrospective cohort study that followed 525 patients in Sierra Leone, a viral load ≥10 million copies/mL was a significant predictor of mortality.

Information on prognostic factors for EVD was also obtained during earlier outbreaks. Research based upon blood samples collected during the outbreak of Ebola Sudan virus disease in Gulu, Uganda in 2000, in which approximately 50% of patients survived infection, indicates that certain biomarkers are predictive of disease outcome.217 For example, proinflammatory cytokines have been associated with viremia, hemorrhage, and death, whereas soluble CD40 ligands have been associated with nonfatal outcomes.217 However, the clinical utility of these tests is yet to be determined, and they are not routinely available in clinical practice.

Other host factors may also be associated with clinical outcomes. For example, there was a significant association between HLA-B alleles and survival or death during the outbreak of Ebola Sudan in Gulu, Uganda. In addition, studies of Ebola virus infection in mice have found that different genetic backgrounds are linked with variations in disease severity.219

Recovery and Discharge from the Hospital

Patients who survive EVD typically begin to show signs of clinical improvement during the second week of illness.136 In these patients, viremia also resolves during the second week, in association with the appearance of virus-specific IgM and IgG.

RT-PCR testing is used to help determine when a recovering patient can be discharged from a hospital. According to the WHO, individuals who no longer have signs and symptoms of EVD can be discharged if they have two negative RT-PCR tests on whole blood separated by at least 48 hours.192 A similar protocol was followed in a treatment center in Liberia.203

However, a commentary published during the West African epidemic recommended that, in resource-limited settings, the decision to discharge a convalescent patient should be based upon the absence of symptoms of EVD for 48 hours rather than RT-PCR testing.220 This approach is partly supported by a study that evaluated the presence of infectious virus over time in four patients with EVD.221 Twenty-eight plasma samples were tested by RT-PCR, and isolation of the virus was subsequently attempted. Ebola virus was not isolated from plasma samples if the cycle-threshold value was >35.5 (higher cycle-threshold values indicate lower RNA levels) or if the sample was taken more than 12 days after the onset of symptoms.

Regardless of when an individual is discharged from the hospital, patients should receive information to help minimize the risk of transmission in the community (e.g., counseling on safe sexual practices) since the virus can persist in a variety of body fluids (e.g., urine, semen) for up to several months after the plasma tests negative for Ebola virus by RT-PCR.

Follow-Up Care

Patients should be informed that clinical sequelae (e.g., joint pains, uveitis, meningitis) may develop weeks or months after the initial illness resolves.

The WHO suggests that patients be seen in follow-up two weeks after discharge, monthly for six months, and then every three months to complete one year.222

  • Males should have semen testing during these visits until they test negative for Ebola virus RNA.
  • If fever develops, patients should be tested for Ebola RNA by RT-PCR and be evaluated for other causes of infection (e.g., malaria).
  • Uveitis and meningitis may be suggestive of an Ebola relapse. If meningitis is suspected, a lumbar puncture should be performed (using appropriate PPE), even if the blood tests are negative for Ebola virus RNA.

Ebola virus survivors with ocular findings also require follow-up vision care. In a study of 137 EVD survivors, 50 had ocular findings. Visually significant cataracts were present in 46 patients at a median of 19 months from initial Ebola diagnosis. All patients tested negative for Ebola virus RNA by RT-PCR of ocular fluid, and 34 underwent cataract surgery, resulting in improved visual acuity.223

Investigational Therapies

There are no approved medications for the treatment of EVD or for post-exposure prophylaxis in persons who have been exposed to the virus but have not yet become ill. However, the 2014 - 2016 West African outbreak focused attention on the potential anti-Ebola activity of several drugs developed for other purposes. Additionally, it accelerated the evaluation of experimental therapies that had been developed to treat or prevent Ebola or Marburg virus infection and had demonstrated protective efficacy in laboratory animals.224

During the West African outbreak and subsequent outbreaks in the Democratic Republic of the Congo, several of these therapies were administered alone or in combination to individual patients on a compassionate use basis, and some were administered to cohorts of patients in nonrandomized trials. Only one novel therapy (ZMapp) was tested in a randomized trial, but it failed to recruit a sufficient number of subjects to yield a definitive outcome.216 Because of these limitations, conclusive evidence of efficacy was not achieved for any novel therapy.

The following section summarizes reports of therapies that were given to patients in an outbreak setting and describes novel treatments that have shown efficacy in laboratory animals but have not been given to patients.

  • Experimental therapies given to patients during an outbreak setting include:
    • Favipiravir
      • Favipiravir (T-705, Avigan) is a nucleoside analog that inhibits the replication of a wide range of RNA viruses 225 and was effective in preventing the death of mice and nonhuman primates infected with Ebola virus.226-228 The drug must be given orally, largely limiting its use to patients able to swallow tablets.
      • Two clinical trials of favipiravir were performed during the West African epidemic. The first, a nonrandomized trial performed in several Ebola treatment centers, was unable to detect a significant reduction in mortality or serum viral load when 99 adults and adolescents treated with favipiravir were compared with patients previously treated in the same centers.229 The second, also a retrospective nonrandomized study, compared patients given standard of care plus favipiravir over a 10-day period with those who had received standard of care alone during the preceding three weeks.230 A statistically significant increase in survival rate was seen in the favipiravir cohort (56 versus 35% in controls), but the study had numerous limitations, indicating that definitive proof of benefit would require a randomized controlled trial.
    • Convalescent plasma and whole blood
      • Convalescent plasma and whole blood have been administered to patients with EVD both prior to and during the West African outbreak.231-233 However, there is no evidence that this treatment reduces mortality based upon findings from a nonrandomized trial from Guinea 234 and case series from outbreaks in central Africa.201
    • ZMapp
      • ZMapp, a "cocktail" of three monoclonal antibodies (mAbs) targeting the Ebola virus surface glycoprotein, was shown in laboratory studies to protect rodents and nonhuman primates against Ebola virus infection. Treatment prevented the death of Ebola-infected macaques, even when it was initiated after the animals had developed fever, viremia, and other signs of illness.235 This was the first time treatment had prevented the death of nonhuman primates that had developed signs of EVD.
      • ZMapp was evaluated in a randomized controlled trial involving 71 patients in Liberia, Sierra Leone, Guinea, and the United States.216 Patients received either standard of care or standard of care plus three doses of ZMapp. Although there were fewer deaths in the ZMapp arm (22 versus 37%), the decline in the epidemic reduced patient enrollment so that the result did not meet the prespecified threshold for establishment of efficacy.
    • mAb114
      • In addition to "cocktails" of several mAbs, such as ZMapp, individual mAbs have been evaluated in preclinical animal studies. A single mAb isolated from a survivor of EVD neutralized the virus in vitro and protected 100% of macaques from lethal infection when administered up to five days after virus challenge.236 This agent has been administered to patients in the Ebola outbreak that was reported in the Democratic Republic of the Congo on August 1, 2018.
    • GS-5734
      • The novel nucleotide analogue prodrug GS-5734 was found to be highly efficacious in macaques infected with Ebola virus, even when initiated three days after virus challenge.237 Studies of tissue distribution revealed drug penetration to the testes and central nervous system. The drug was given on a compassionate use basis to a nurse who survived EVD, but she relapsed nine months later with meningoencephalitis.116 Further testing will be needed to determine if the compound is capable of entering "sanctuary sites."
    • Artesunate-amodiaquine
      • Artesunate-amodiaquine, an agent used to treat malaria, was found to have anti-Ebola activity in vitro. A possible in vivo effect of this agent was noted in an Ebola treatment center in Liberia, where patients were routinely treated for malaria. In this center, patients were typically given the anti-malaria drug combination artemether-lumefantrine, except for a 12-day period when supplies ran out, when all patients were instead given artesunate-amodiaquine. A retrospective analysis found that the case-fatality rate during that 12-day period was 50.7%, while before and after it averaged 64.4%.238 However, the authors acknowledged that an unrecognized toxicity of the first drug combination might also explain the observed difference.
  • The following therapies were administered to a few patients early in the West African Ebola epidemic, but their use was then discontinued:
    • TKM-Ebola
      • A preparation of short interfering RNA (siRNA) targeting three different Ebola virus genes (TKM-Ebola) effectively blocked Ebola virus infection in laboratory rodents and nonhuman primates 239 and was given to several patients in the United States.240 However, a Phase I trial was put on hold because of fever in some subjects, and the manufacturer subsequently discontinued production of all siRNA products for filovirus diseases.
    • Brincidofovir
      • A prodrug of cidofovir, brincidofovir (CMX001) is under development for the treatment of cytomegalovirus, adenovirus, and other DNA virus infections. Early in the Ebola epidemic the compound was reported by the manufacturer to have in vitro activity against Ebola virus, and it was given to several patients.241 Further testing, however, showed that the drug had no activity in Ebola-infected mice 242 and its use was discontinued.243
  • The following therapies have shown promising activity against Ebola virus in laboratory animals, but have not been administered to humans:
    • Antisense oligonucleotides (PMOs)
      • Chemically modified nucleic acid analogs, known as phosphorodiamidate morpholino oligomers (PMOs), are being developed for the treatment of a number of medical conditions, including filovirus infections.244 These molecules bind to specific sequences in messenger RNA, preventing translation. Combinations of PMOs were protective in mouse and guinea pig models of Ebola and Marburg virus disease and the use of such molecules targeting Ebola or Marburg virus were reported to be safe in a Phase I trial.245 The antisense molecule AVI-7537 is being developed for the treatment of Ebola virus infection 246 but it was not administered to patients during the West African outbreak.
    • BCX4430
      • The nucleoside analog BCX4430 inhibits viral RNA polymerase function, acting as a nonobligate RNA chain terminator.247 BCX4430 protected mice against lethal Ebola virus challenge, and also protected mice, guinea pigs, and macaques infected with Marburg virus when treatment was administered as late as 48 hours after infection.248 Studies are underway to test the drug against Ebola virus challenge in macaques in preparation for eventual human trials.247

Prevention

Experience from the West African epidemic suggests that several concurrent strategies should be employed to prevent the spread of Ebola virus. During acute illness, strict infection control measures and the proper use of PPE are essential to prevent transmission to health care workers. In addition, individuals who have been exposed to Ebola virus should be monitored so they can be identified quickly if signs and symptoms develop.

Patients who have recovered from EVD may continue to have infectious virus in urine, vaginal secretions, and breast milk during early recovery when the virus is no longer present in the blood. Long-term persistence of Ebola virus in semen, ocular fluid, and cerebrospinal fluid may also occur and is related to the "immune privilege" of these sites. Certain precautions should be taken to reduce the risk of transmission during convalescence, as described below.

Infection Control Precautions during Acute Illness

General Approach

  • When caring for patients with confirmed or suspected acute EVD, health care personnel should follow infection prevention and control recommendations from the CDC and the WHO.249-250 These guidelines provide control measures needed to manage patients who are known or suspected to be infected with Ebola virus or other highly pathogenic agents.
  • Infection control recommendations for patients who present with acute infection include:
    • Correct use of appropriate PPE
    • If possible, aerosol-generating procedures should be avoided. However, if they must be performed, patients should be placed in an airborne infection isolation room.251
    • Isolation of hospitalized patients with known or suspected EVD
    • Proper hand hygiene
    • Use of standard, contact, and droplet precautions

Personal Protective Equipment (PPE)

  • The type of PPE used, and its careful placement (donning) and removal (doffing), are critical to preventing nosocomial transmission of Ebola virus. During the 2014 - 2016 epidemic, several patients were cared for in the United States. The staff at Emory University used full body suits and powered air-purifying respirators (PAPR) to help staff work for extended periods, decrease the physical discomfort of working in multi-component PPE, and avoid difficulties like fogged face shields.199 The donning and doffing of PPE was always observed by another staff member.
  • The CDC and the WHO have issued detailed guidelines on the use of PPE for managing patients with suspected or confirmed EVD. The type of PPE depends in part upon the patient's clinical presentation (e.g., presence or absence of diarrhea, vomiting, bleeding). Clinicians should refer to these guidelines when caring for patients. The CDC has also released a video that demonstrates donning and doffing of PPE.
  • Highlights from these guidelines include the following:
    • Rigorous and repeated training of health care workers in correct donning and doffing of PPE. In addition, health care workers should demonstrate competency in performing Ebola-related infection control practices and procedures.
    • PPE should cover all clothing and skin, and completely protect mucous membranes. Such PPE includes double gloves, boot covers, fluid-resistant gowns or coveralls, single-use disposable hoods that cover the head and neck, single-use disposable full face shields, and PAPR or N95 respirators. Additional measures, such as waterproof aprons, may also be required depending upon the patient's symptoms. The combination of PPE used should be determined by the health care facility providing care.
    • Health care workers should perform frequent disinfection of gloved hands using an alcohol-based hand rub, particularly after touching body fluids. In addition, they should immediately disinfect any visibly contaminated PPE using approved disinfectant wipes.
    • A trained monitor should actively observe and supervise each worker donning and doffing PPE. Monitors should not serve as an assistant for taking off PPE.
  • The use of the recommended PPE for health care workers caring for patients with Ebola for extended periods of time can potentially result in heat-related illness, which was of particular concern in West Africa.252 Recommendations to help prevent such complications include: staying well hydrated, working short shifts until the health care worker can adjust to the heat, taking time to rest and cool down, and watching for signs of heat-related illness.

Pregnancy

  • Health care workers who are pregnant should not provide care for patients with EVD. In addition to the increased maternal and fetal risks of EVD during pregnancy, PPE may not be well suited for pregnant health care workers.

Labor and Delivery

  • Strict infection control precautions must be used when caring for pregnant patients with EVD. This should include PPE that is recommended for providers who are at high risk of exposure to bodily fluids. These precautions should be used even if the mother has recovered from infection, since data suggest that the fetus of a mother who survived EVD while pregnant may continue to harbor virus and be infectious.153

Environmental Infection Control

  • If a patient with suspected or confirmed EVD is being cared for in a health care setting, specific precautions should be taken to reduce the potential risk of virus transmission through contact with contaminated surfaces. This includes frequent cleaning of the floor in the doffing area (i.e., where PPE is removed).
  • In a study that surveyed Ebola treatment centers in Sierra Leone, viral RNA was frequently detected on materials that had been in direct contact with patients.253 For example, Ebola virus RNA was detected on four of six gloves tested, despite lack of visible soiling. However, viral RNA was no longer detected after gloves were rinsed with chlorine solution.
  • The CDC has provided guidance for medical waste management, as well as, specific recommendations for environmental infection control in hospitals, health care settings in West Africa, and laboratories.

Infection Control Precautions during Convalescence

  • Patients who have recovered from EVD and have been discharged from the hospital may present for medical care during the convalescent period.
  • Interim guidance for the management of survivors of EVD have been issued by the CDC and the WHO.112 The types of infection control precautions that should be used depend upon the patient's signs and symptoms.
  • For most survivors who have recovered and been discharged after their acute illness, only standard precautions are needed when clinical evaluation and care are performed. According to the CDC, there is no evidence that survivors of EVD pose any special risk to health care personnel when this care involves contact with intact skin, sweat, tears, conjunctivae, saliva, and cerumen. Additionally, persons who have fully recovered from EVD and are not febrile do not pose a risk of Ebola virus exposure through phlebotomy since such patients are not viremic.
  • However, for patients who present during convalescence with late stage manifestations of Ebola disease, such as acute neurological or ocular symptoms, infection control practices recommended for evaluating persons under investigation for EVD should be used until testing for Ebola virus is negative.
  • Infection control precautions used for invasive procedures require special consideration if there is potential contact with body fluids from immunologically protected sites (e.g., semen, spinal or intraocular fluid). Such patients should be managed in consultation with local health departments and/or the CDC to determine appropriate PPE based upon a risk assessment of the potential exposure during the procedure.
  • When a woman becomes pregnant after clearing Ebola virus from her blood, only standard PPE is recommended during delivery since the fetus is presumed not to be infected. In addition, the CDC suggests that no special precautions are needed for patients who require spinal anesthesia, as long as the mother does not have neurologic symptoms suggestive of persistent disease.112

Additional Considerations

  • Sexual transmission
    • Several cases of EVD that occurred during the late phase of the 2014 - 2016 outbreak were attributed to sexual transmission, with supportive epidemiologic and molecular evidence. The CDC and WHO therefore suggest that patients with EVD refrain from sexual activity (oral, anal, vaginal) and that condoms should be used if abstinence is not possible. In addition, hand hygiene is recommended following contact with semen.
    • It is not known when unprotected sexual activity can be safely resumed. For men, the WHO has suggested that the semen be tested for Ebola virus by RT-PCR three months after the onset of disease. Further recommendations are as follows:
      • For those men who test negative, the test should be repeated with an interval of one week between tests. Sexual activity can be resumed if their semen has tested negative for Ebola virus twice by RT-PCR.
      • For those men who test positive for Ebola virus at three months, testing should be repeated every month until their semen tests negative. The test should then be repeated with an interval of one week between tests. Sexual activity can be resumed if the semen has tested negative for Ebola virus twice by RT-PCR.
      • The WHO recommends that if semen testing is unavailable, men should practice safe sex for at least 12 months dating from the onset of illness.
    • Studies evaluating the persistence of Ebola virus have detected viral RNA in vaginal fluids for up to 33 days and in semen for up to two years after the onset of EVD.
      • The persistence of Ebola virus in semen was illustrated in a cross-sectional study in which semen was obtained from 93 men who had previous EVD.109 Among the nine patients who were evaluated two to three months after infection, all tested positive for Ebola virus in the semen using RT-PCR. In addition, 26 of the 40 men who were evaluated 4 to 6 months after infection, and 11 of the 43 men who were evaluated 7 to 9 months after infection had Ebola virus detected in the semen. In later studies, the virus was found to persist in the semen of survivors for a median of 115 days. An outbreak in Guinea was linked to a male survivor with onset of illness more than 500 days before.254 In a study of 137 male survivors, 11 (8%) had RNA-positive semen two years after EVD onset.224
  • Breastfeeding and infant care
    • Ebola virus has been isolated from breast milk and can be transmitted through close contact of an infected mother with her children. The CDC recommends that mothers who are under investigation for EVD, have confirmed infection, or have recently recovered should avoid breastfeeding.255
    • Where available, testing of breast milk can guide when it is safe for mothers who have survived EVD to resume breastfeeding. If Ebola virus RNA is detected, the breast milk should be retested every 48 hours until two consecutive negative results are obtained.
    • In resource-limited settings, the risk of virus transmission during breastfeeding must be weighed against the risk of the infant becoming malnourished or developing diarrheal or respiratory disease or other infections if safe alternative options for feeding are not available.
  • Monitoring and travel restrictions
    • Persons who have had a possible exposure to Ebola virus should be monitored for signs and symptoms of disease. Monitoring should continue for 21 days after the last known exposure. The development of fever and/or other clinical manifestations suggestive of EVD should be reported immediately.
    • During the West African epidemic, the CDC and WHO provided information about restrictions on travel and transport of asymptomatic persons who had been exposed to Ebola virus.
  • Vaccination
    • No approved vaccines are available to prevent the spread of Ebola virus.36 However, as a result of the epidemic in West Africa, accelerated paths were developed for vaccine testing and introduction into field use.256 During two Ebola outbreaks that were reported in the Democratic Republic of the Congo in 2018, health care workers and close contacts of patients were vaccinated using a vesicular stomatitis virus-Zaire Ebola (VSV-Ebola) virus vaccine.
    • Prior to the epidemic in West Africa, a number of experimental vaccines had successfully protected nonhuman primates against an otherwise lethal Ebola virus challenge. These included a DNA vaccine followed by a recombinant human adenovirus type 5 (Ad5) vector encoding the Ebola Zaire and Sudan surface glycoproteins (GP), the recombinant Ad5 vaccine alone, a virus-like particle vaccine, a recombinant vesicular stomatitis virus (VSV) vector encoding Ebola surface GP, and a chimpanzee-adenovirus type 3 vaccine (ChAd3) encoding Ebola virus GP.257 At the time the epidemic was recognized in 2014, the only vaccines that had been evaluated in humans were a multidose DNA vaccine and the recombinant Ad5 vaccine, which had both proven safe and immunogenic in Phase I trials.258 However, because recombinant Ad5 vaccines may be ineffective in persons with prior immunity to the adenovirus vector, the ChAd3 vaccine was believed to be more promising for human use.
    • A WHO expert panel that convened in September 2014 identified both the ChAd3 and VSV vaccines as the most advanced candidates for use in the West African outbreak, principally because both promised to be protective after a single inoculation.231 Both vaccines were evaluated in healthy volunteers during the epidemic, as were an Ad26.ZEBOV vaccine and a recombinant vaccinia Ankara (MVA) vaccine encoding the Ebola glycoprotein (MVA-BN-Filo), and they were all found to be immunogenic.259 A six-month safety study found that the VSV vaccine was generally well tolerated, supporting its use for persons at risk of EVD.260 Additional studies have confirmed these results. For example, a phase I randomized trial in Gabon found that an adult dose of 20 million plaque-forming units (PFU) was safe and immunogenic.261 A subsequent study in European and African adults found that all who received a single dose of 10 to 50 million PFU were still seropositive at two years.262
    • The VSV vaccine was the only specific countermeasure proven to have protective efficacy against Ebola virus during the West African epidemic. In a large trial of ring vaccination in Guinea, the VSV vaccine was safe and effective in inducing rapid immunity against Ebola virus.263 When a new case of EVD was diagnosed, surveillance teams identified all close contacts of the patient and all contacts of those contacts. Each of these clusters was then randomized to receive the VSV vaccine either immediately or after 21 days: 3,528 subjects were randomized and 3,512 were vaccinated (2,014 in the immediate arm and 1,498 in the delayed arm). To exclude individuals who were already infected with Ebola virus at entry into the study, only patients who developed disease ≥10 days after randomization were included in the analysis. Among immediately vaccinated individuals, no EVD was seen after day 10, while there were 16 new cases among those assigned to delayed vaccination, indicating a clear benefit of immediate vaccination. In addition, no recipient developed EVD more than six days after vaccination in either group. One febrile illness was the only serious side effect attributed to vaccination.
    • The recombinant VSV vaccine may also have a role in preventing disease and death when administered promptly after an exposure. This was demonstrated in two laboratory studies in macaques, the first employing challenge with the Zaire Ebola virus, and the second employing the West African Makona strain.264 Cross-protection by inoculation of a VSV-Marburg vaccine was observed in one of the studies, suggesting that innate immune responses to the vaccine may play an important role in protection. During the 2014 - 2016 West African outbreak, the VSV vaccine was administered as post-exposure prophylaxis on a compassionate use basis to close contacts of a patient with EVD, as well as, to two health care workers who sustained a percutaneous injury with a needle that had come in contact with a contaminated glove. All recipients remained well.265
  • Public health response
    • The epidemic in West Africa demonstrated that an effective public health response requires effective communications between government authorities, medical professionals, and the local populace to explain the need for monitoring, sample collection and testing, and isolation and other infection control measures, and to explain the potential benefits of treatment. Preventive interventions also include educating and supporting affected communities to modify long-standing funeral practices and to avoid contact with bush meat and bats. Anthropologists and others with specialized knowledge of local cultures should therefore be included as members of response teams.
    • Several measures were implemented to help contain the 2014 - 2016 outbreak. These included: 266-272
      • The WHO declaring the Ebola outbreak a Public Health Emergency of Concern. This mandated countries to develop national preparedness capacities, including the duty to report significant events, conduct surveillance and contact tracing, as well as, exercise public health powers while balancing human rights and international trade.
      • The United Nations (UN) created a special mission to help contain the outbreak. This is the first time that the UN created a mission for a public health emergency.
      • In the United States, public health authorities monitored health care workers who cared for patients with EVD and travelers who arrived from areas with widespread transmission.
      • Community care centers were established in parts of West Africa to isolate patients who were awaiting Ebola diagnostic test results and to provide basic care (e.g., oral rehydration) to patients who had confirmed EVD pending transfer to Ebola treatment units.
      • The spread of Ebola virus was successfully limited in areas where there were adequate resources and an effective public health response.

Case Study

Scenario/Situation/Patient Description

Sister Marie Jones and Sister Anna Cortez arrive at an Urgent Care Center adjacent to a community hospital. Both c/o fever, abdominal pain, lack of appetite, myalgias and arthralgias. They wait in the waiting room until called for triage by the registered nurse. Both sisters insist upon being triaged at the same time by the RN. Both sisters returned from mission work 10 days ago after spending the last six months traveling to outlying areas around the capital city of Kinshasa in the Democratic Republic of the Congo. Their job was to try to identify suspected cases of EVD, arranging transport to the nearest healthcare facility if necessary, and educating villagers in the prevention of the spread of EVD. Both sisters related that other sisters in the convent in which they reside here in the United States have similar symptoms but not as severe as themselves.

Interventions/Strategies

The registered nurse phones the Urgent Care Center main desk to relate the information she has obtained to an Urgent Care MD. She requests that he gown up, wear double gloves and a mask before he enters the triage room. He concurs. He enters the triage room to continue to assess the two sisters.

Meantime, the triage RN, since she has been inadvertently exposed to the suspected Ebola virus uses her cell phone to contact the Hospital Infection Control professionals/resources. After being informed of the ongoing situation, the Infection Control Professional immediately closes down the Urgent Care Center for the time being diverting arriving patients to the Hospital Emergency Room. She follows protocol which usually includes informing administration, the local and state health departments. All patients who were exposed to the two sisters were asked to be patient and remain in the waiting room for the time being. All patients who were in the other examination rooms in the Urgent Care Center were either discharged to home or transported to the main emergency room.

Discussion of Outcomes

A hazmat/public health team arrives at the Urgent Care Center to assess the other waiting room patients and admission secretaries as PUIs. Another hazmat/public health team visits the convent where the two sisters reside to evaluate the other sisters as PUIs, as well as, any other contacts they may have had.

Strengths and Weaknesses

All suspected PUIs in the Urgent Care Center and convent were immediately isolated to prevent possible spread of suspected EVD. Federal, state and local healthcare agencies were immediately notified and responded in a timely manner. Levels of risk assessment were ongoing.

Since Ebola is rare in the US, staff may not know infection control protocols and small facilities have limited infection control resources.

Summary and Recommendations

The family Filoviridae contains three genera, Ebolavirus and Marburgvirus, which cause severe disease in humans, and Cuevavirus, which has only been detected as viral RNA in bats in Spain.

The Zaire species of Ebola virus, the causative agent of the 2014 -2016 West African epidemic, is among the most virulent human pathogens known. The case fatality rate in past outbreaks in Central Africa reached 80 to 90%, but the overall fatality rate in West Africa was approximately 40%.

In the past, Ebola virus was classified as a "hemorrhagic fever virus." However, that term is no longer used, because only a small percentage of patients actually develop significant bleeding, and it usually occurs in the terminal phase of illness.

Until the 2014 - 2016 epidemic in West Africa, all outbreaks of EVD had occurred in Central Africa or the Sudan.

The West African epidemic was the largest filovirus outbreak on record. It started in the nation of Guinea in late 2013 and was confirmed by the WHO in March 2014. The countries with widespread transmission included Guinea, Liberia, and Sierra Leone. EVD occurred in hundreds of healthcare personnel who were infected while caring for patients.

A number of patients with EVD (e.g., doctors and nurses infected in West Africa, returning travelers from the region) were treated in hospitals in the United States and Europe.

The reservoir host of Ebola virus is unknown. Evidence is accumulating that various bat species may serve as a source of infection for both humans and wild primates.

Person-to-person transmission is associated with direct contact with body fluids from patients with EVD or from cadavers of deceased patients. Transmission to healthcare workers may occur when appropriate PPE is not available or is not properly used, especially when caring for a severely ill patient.

Infectious virus and/or viral RNA can persist for weeks to months in certain bodily fluids of convalescent patients. Examples include: semen, urine, and breast milk. However, the risk of transmission from persistent virus at these sites is not well established.

Human infection with Ebola virus can also occur through contact with wild animals (e.g., hunting, butchering, and preparing meat from infected animals).

Almost all data on the pathogenesis of EVD have been obtained from laboratory experiments employing mice, guinea pigs, and nonhuman primates. Case reports and large-scale observational studies of patients in the West African epidemic have provided additional data on pathogenesis that have been consistent with findings in animal studies.

The incubation period of EVD is typically 6 to 12 days, but can range from 2 to 21 days.

Patients with EVD usually have an abrupt onset of nonspecific signs and symptoms such as fever, malaise, headache, and myalgias. As the illness progresses, vomiting and diarrhea may develop, often leading to significant fluid loss. Patients with worsening disease display hypotension and electrolyte imbalances leading to shock and multiorgan failure, sometimes accompanied by hemorrhage.

Whether EVD is considered in the differential diagnosis of a patient with fever and flu-like symptoms will vary markedly depending upon the circumstances especially when a recognized Ebola epidemic is currently ongoing. For patients with clinical findings consistent with the disease (i.e., fever and/or severe headache, weakness, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage), healthcare personnel should obtain a careful history to determine if the patient has had a possible exposure to Ebola virus within 21 days prior to the onset of symptoms.

All patients who have or are suspected of having EVD should be promptly isolated. Infection control precautions should be initiated and include hand hygiene, standard, contact, and droplet precautions, as well as, the correct use of appropriate PPE.

Hospital infection control staff, as well as, the local or state health department, should be contacted immediately.

Monitoring for signs and symptoms of EVD should be performed for asymptomatic individuals who have had an exposure to Ebola virus at any risk level (i.e., high, moderate, or low risk).

Medical evaluation of symptomatic patients with a history of exposure generally includes testing for Ebola virus and other likely pathogens. Whether laboratory testing for Ebola virus should be performed depends, in part, upon the relative likelihood that a patient was exposed to the virus and the presence of compatible clinical symptoms and/or laboratory findings.

Diagnostic tests for EVD are principally based upon the detection of specific RNA sequences by RT-PCR testing in blood or other body fluids. Ebola virus is generally detectable in blood samples within three days after the onset of symptoms. Repeat testing may be needed for patients with symptoms for fewer than three days duration.

The differential diagnosis will vary markedly with the clinical and epidemiologic circumstances. For example, travelers returning from West or Central Africa should be evaluated for illnesses commonly seen in those areas, such as malaria etc.

Because of its virulence and high infectivity, Ebola virus is classified as a Category A bioterror agent.

Effective treatment of EVD requires aggressive supportive care to correct volume losses from vomiting and diarrhea, correct electrolyte abnormalities, and prevent shock. Patients may also require evaluation and/or treatment of concomitant infections. Several investigational antiviral therapies were used to treat patients during the 2014 - 2016 outbreak in West Africa, but their efficacy is unclear, and the availability of these drugs is limited.

EVD is associated with a high risk for fetal death and pregnancy-associated hemorrhage. There are no data to suggest whether cesarean or vaginal delivery is preferred or when the baby should be delivered. As a consequence, decisions regarding obstetrical care must be made on a case-by-case basis.

Early diagnosis and prompt initiation of care increase the likelihood that a patient with EVD will survive. Patients who survive EVD typically show signs of clinical improvement during the second week of illness. After discharge from the hospital, patients should be monitored for at least one year.

To prevent transmission of Ebola virus, healthcare personnel should follow infection prevention and control recommendations from the CDC and the WHO:

  • When caring for a patient with acute illness, precautions should include: isolation of hospitalized patients with known or suspected EVD, hand hygiene, the use of standard, contact, and droplet precautions, and the correct use of appropriate PPE.
  • For most survivors, only standard precautions are needed when clinical evaluation and care are performed. However, additional precautions are needed for those who present with late stage manifestations of EVD, such as acute neurological or ocular symptoms.
  • Additional strategies to prevent the spread of EVD include careful monitoring of individuals after a possible virus exposure, educating patients on how to reduce the risk of transmission through sexual contact or breastfeeding, and potentially vaccinating high-risk populations.

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References

  1. World Health Organization. Ebola Virus Disease. 12 February 2018.
  2. Ruzek, edited by Sunit K. Singh, Daniel (2014). Viral hemorrhagic fevers. Boca Raton: CRC Press, Taylor & Francis Group. p. 444 (Visit Source).
  3. WHO/International Study Team. Ebola Hemorrhagic Fever in Sudan, 1976. Bull World Health Organ. 56 (2): 247–70, 1978 (Visit Source).
  4. Bull World Health Organ. Ebola haemorrhagic fever in Zaire, 1976. 56 (2):271–93. 1978.
  5. Baron RC, McCormick B, Zubeir OA (1983).Ebola virus disease in southern Sudan: hospital dissemination and intrafamilial spread. (PDF). Bulletin of the World Health Organization. 61 (6):997–1003.
  6. Georges AJ, Leroy EM, Renaut AA, et al. 1999. Ebola Hemorrhagic Fever Outbreaks in Gabon, 1994-1997: Epidemiologic and Health Control Issues. Journal of Infectious Diseases. 179: S65–S75.
  7. Khan AS, Tshioko FK, Heymann, DL, Le Guenno B, et al. 1999. The Reemergence of Ebola Hemorrhagic Fever, Democratic Republic of the Congo, 1995. Journal of Infectious Diseases. 179: S76–S86.
  8. Roels TH, Bloom AS, Buffington J, et al. 1999. Ebola Hemorrhagic Fever, Kikwit, Democratic Republic of Congo, 1995. Journal of Infectious Diseases. 179: S92–7.
  9. Okware SI, Omaswa FG, Zaramba S, et al. 2002. An outbreak of Ebola in Uganda. Tropical Medicine & International Health. 7 (12): 1068–1075.
  10. Outbreaks of Ebola haemorrhagic fever, Congo and Gabon, October 2001-July 2002. Releve Epidemiologique Hebdomadaire. Canada Communicable Disease Report. 29 (15): 223–228.
  11. Formenty P, Libama F, Epelboin A, et al. 2003. Outbreak of Ebola hemorrhagic fever in the Republic of the Congo, 2003: a new strategy? Revue du Corps de Santé Colonial (in French). 63 (3): 291–295.
  12. World Health Organization. Ebola haemorrhagic fever in the Republic of the Congo-Update 6. 6 January 2004.
  13. Outbreak of Ebola haemorrhagic fever in Yambio, south Sudan, April-June 2004. Weekly Epidemiological Record. 80 (43): 370–375. 2005.
  14. Outbreak news. Ebola virus haemorrhagic fever, Democratic Republic of the Congo-Update. Weekly Epidemiological Record. 82(40): 345–346. 2007.
  15. Towner JS, Sealy TK, Khristova ML, et al. (2008). Basler, Christopher F., ed. Newly Discovered Ebola Virus Associated with Hemorrhagic Fever Outbreak in Uganda. PLoS Pathogens. 4 (11): e1000212.
  16. Uganda: Deadly Ebola Outbreak Confirmed. UN News Service. November 30, 2007. Accessed December 13, 2018.
  17. World Health Organization. End of Ebola outbreak in Uganda. (Press release). 20 February 2008. Retrieved December 20, 2018.
  18. World Health Organization. Global Alert and Response (17 February 2009). End of Ebola outbreak in the Democratic Republic of the Congo. Disease Outbreak News. Geneva, Switzerland. Accessed December 2, 2018.
  19. World Health Organization (4 October 2012). End of Ebola outbreak in Uganda. Geneva, Switzerland. Accessed December 2, 2018.
  20. Centers for Disease Control and Prevention (Division of High-Consequence Pathogens and Pathology; Viral Special Pathogens Branch). Outbreaks Chronology Ebola Virus Disease. National Center for Emerging and Zoonotic Infectious Diseases. 20 October 2016 [Last updated 14 April 2016]. Accessed on December 13, 2018.
  21. Centers for Disease Control and Prevention Outbreak Postings. Centers for Disease Control. Accessed December 14, 2018.
  22. World Health Organization. Ebola data and statistics. Accessed December 4, 2018.
  23. WHO Ebola Response Team (23 September 2014). Ebola Virus Disease in West Africa-The First Nine Months of the Epidemic and Forward Projections. New England Journal of Medicine. 371 (16): 1481–1495.
  24. World Health Organization. Case Fatality Rate for ebolavirus. Ebola data and statistics. 2015. Archived from the original on 29 August 2014. Accessed December 15, 2018 (Visit Source).
  25. Ebola response roadmap - Situation report - 31 December 2014 (PDF). 31 December 2014. Accessed December 20, 2018. The reported case fatality rate in the three intense transmission countries among all cases for whom a definitive outcome is known is 71 percent (Visit Source).
  26. World Health Organization. Ebola Situation report. Ebola data and statistics. January 12, 2015. Accessed December 15, 2018… Is between 57% and 59% in the 3 intense-transmission countries, with no detectable improvement since the onset of the epidemic (Visit Source).
  27. Tracing Ebola's Breakout to an African 2-Year-Old. New York Times. 9 August 2014. Accessed December 19, 2018 (Visit Source).
  28. Toll in West Africa Ebola Epidemic Reaches 2,630, Says WHO. Fox News. FOX News Network, 18 September 2014. Web. 19 September 2014 (Visit Source).
  29. World Health Organization. WHO Director-General addresses the Executive Board. Accessed December 15, 2018 (Visit Source).
  30. World Health Organization. Ebola Response Roadmap Situation Report Update (PDF). 29 October 2014. Accessed December 15, 2018 (Visit Source).
  31. UN Office for the Coordination of Humanitarian Affairs. Update on the Ebola virus disease in DRC, No. 5, 30 August 2014. Accessed December 15, 2018 (Visit Source).
  32. Congo declares its Ebola outbreak over. Reuters. 15 November 2014. Accessed December 15, 2018 (Visit Source).
  33. Congo health ministry confirms 2 Ebola cases in new outbreak. ABC News. Accessed December 15, 2018 (Visit Source).
  34. World Health Organization. Ebola Virus Disease: Democratic Republic of the Congo: External Situation Report 3 (PDF). Reliefweb. 18 May 2018. Accessed December 15, 2018 (Visit Source).
  35. Ebola Erupts Again in Africa, Only Now There's a Vaccine. The New York Times. 2018-05-11. ISSN 0362-4331.Accessed December 15, 2018 (Visit Source).
  36. Democratic Republic of Congo: Ebola Virus Disease - External Situation Report 13. ReliefWeb. Accessed December 16, 2018 (Visit Source).
  37. Centers for Disease Control and Prevention. 2018 Democratic Republic of the Congo, Bikoro | Democratic Republic of Congo | Ebola (Ebola Virus Disease) |. 29 May 2018. Accessed December 16, 2018 (Visit Source).
  38. Democratic Republic of Congo: Ebola Virus Disease - External Situation Report 15. ReliefWeb. Accessed December 2, 2018 (Visit Source).
  39. EBOLA RDC - Evolution de la riposte de l'épidémie d'Ebola au Vendredi 13 juillet 2018. us13.campaign-archive.com. Accessed December 5, 2018 (Visit Source)
  40. Media Advisory: Expected end of Ebola outbreak. ReliefWeb. Accessed December 5, 2018 (Visit Source).
  41. World Health Organization. Ebola outbreak in DRC ends: WHO calls for international efforts to stop other deadly outbreaks in the country. Accessed December 15, 2018 (Visit Source).
  42. Ebola virus disease – Democratic Republic of the Congo: Disease outbreak news, 25 July 2018. ReliefWeb. Accessed December 15, 2018 (Visit Source).
  43. Editorial, Reuters. Congo declares new Ebola outbreak in eastern province. U.S. Accessed December 15, 2018 (Visit Source).
  44. Congo announces 4 new Ebola cases in North Kivu province. Washington Post. Accessed December 15, 2018 (Visit Source).
  45. World Health Organization. Cluster of presumptive Ebola cases in North Kivu in the Democratic Republic of the Congo. Accessed December 15, 2018 (Visit Source).
  46. The Democratic Republic of the Congo: Ebola Virus Disease Outbreak – Epidemiological Situation DG ECHO Daily Map | 03/08/2018. ReliefWeb. Accessed December 15, 2018 (Visit Source).
  47. EBOLA RDC - Evolution de la riposte contre l'épidémie d'Ebola dans les provinces du Nord Kivu et de l'Ituri au Mardi 4 décembre 2018. us13.campaign-archive.com. Accessed December 15, 2018 (Visit Source).
  48. Emond RTD, Evans B, Bowen ETW, et al. 1977. A case of Ebola virus infection (PDF). British Medical Journal. 2(6081): 541–544 (Visit Source).
  49. Centers for Disease Control and Prevention. Outbreaks Chronology: Ebola Virus Disease. 14 April 2016. Accessed December 15, 2018 (Visit Source).
  50. Heymann DL, Weisfeld JSI, Webb PA, et al. 1980. Ebola hemorrhagic fever: Tandala, Zaire, 1977-1978. Journal of Infectious Diseases. 142 (3): 372–376.
  51. World Health Organization. Ebola Virus Disease. N.p., n.d. Web. 19 September 2014.
  52. Hayes CG, Burans JP, Ksiazek TG, et al.1992. Outbreak of fatal illness among captive macaques in the Philippines caused by an Ebola-related filovirus. The American Journal of Tropical Medicine and Hygiene. 46 (6): 664–671.
  53. Miranda ME, White ME, Dayrit MM, et al. 1991. Seroepidemiological study of filovirus related to Ebola in the Philippines (Submitted manuscript). Lancet. 337(8738): 425–426 (Visit Source).
  54. Jahrling PB, Geisbert TW, Dalgard DW, et al. 1990. Preliminary report: isolation of Ebola virus from monkeys imported to USA. Lancet. 335(8688): 502–505.
  55. Centers for Disease Control and Prevention 1990. Update: filovirus infection in animal handlers. MMWR. Morbidity and Mortality Weekly Report. 39(13): 221.
  56. World Health Organization.Viral haemorrhagic fever in imported monkeys (Visit Source).Weekly Epidemiological Record. 1992;67(24):183
  57. Le Guenno B, Formenty P, Wyers M, et al. 1995. Isolation and partial characterisation of a new strain of Ebola virus. Lancet. 345 (8960): 1271–1274.
  58. Chippaux J. P. 2014. Outbreaks of Ebola virus disease in Africa: the beginnings of a tragic saga. Journal of Venomous Animals and Toxins Including Tropical Diseases. 20 (1): 44 (Visit Source).
  59. Ebola haemorrhagic fever - South Africa (PDF). Weekly Epidemiological Record. 71 (47): 353–360. 22 November 1996 (Visit Source).
  60. Rollin PE, Williams RJ, Bressler DS, et al. 1999. Ebola (Subtype Reston) Virus among Quarantined Nonhuman Primates Recently Imported from the Philippines to the United States. The Journal of Infectious Diseases. 179: S108–14.
  61. Miranda ME, Ksiazek TG, Retuya TJ, et al. 1999. Epidemiology of Ebola (Subtype Reston) Virus in the Philippines, 1996. The Journal of Infectious Diseases. 179: S115–S119.
  62. Borisevich IV, Markin VA, Firsova IV, et al. 2006. Hemorrhagic (Marburg, Ebola, Lassa, and Bolivian) fevers: Epidemiology, clinical pictures, and treatment. Voprosy Virusologi. 51 (5): 8–16.
  63. Akinfeyeva LA, Aksyonova OI, Vasilyevich IV, et al. A case of Ebola hemorrhagic fever. Infektsionnye Bolezni (Moscow). 2005;3(1):85–88.
  64. Barrette R, Metwally S, Rowland J, et al. 2009. Discovery of swine as a host for the Reston ebolavirus. Science. 325(5937): 204–206.
  65. Outbreak news. Ebola Reston in pigs and humans, Philippines. Weekly Epidemiological Record / Health Section of the Secretariat of the League of Nations. 84 (7): 49–50. 2009.
  66. Philippine monkeys infected with Ebola not lethal to humans. 6 September 2015. Accessed December 15, 2018 (Visit Source).
  67. World Health Organization. External Situation Report 1 (PDF). Regional Office for Africa. Ebola Virus Disease − Democratic Republic of the Congo. 15 May 2017. Accessed December 15, 2018 (Visit Source).
  68. World Health Organization. External Situation Report 25" (PDF). Regional Office for Africa. Ebola Virus Disease − Democratic Republic of the Congo. 22 June 2017. Accessed December 15, 2018 (Visit Source).
  69. World News, Reuters (20 April 2018). Hungarian lab worker isolated after exposure to Ebola virus. IN. Reuters. Accessed December 15, 2018 (Visit Source).
  70. News, Tampa Bay Times (20 April 2018). UN health agency: Hungarian scientist exposed to Ebola. Accessed December 15, 2018 (Visit Source).
  71. Kalra S, Kelkar D, Galwankar SC, et al. The emergence of Ebola as a global health security threat: From 'lessons learned' to coordinated multilateral containment efforts. J Global Infect Dis [serial online] 2014 [cited 2015 Mar 1]; 6:164–77.
  72. Pringle CR. 1998. Virus taxonomy-San Diego 1998. Archives of Virology. 143 (7): 1449–59.
  73. Bray M, Chertow D. Filoviruses. In: Richman DD, Whitley RJ, Hayden FG., eds Clinical Virology. 4th ed. ASM Press, 2017.
  74. WHO Ebola Response Team, Aylward B, Barboza P, et al. Ebola virus disease in West Africa--the first 9 months of the epidemic and forward projections. N Engl J Med 2014; 371:1481 (Visit Source).
  75. World Health Organization. Global Alert and Response. Ebola virus disease (Visit Source).
  76. Formenty P, Hatz C, Le Guenno B, et al. Human infection due to Ebola virus, subtype Côte d'Ivoire: clinical and biologic presentation. J Infect Dis 1999; 179 Suppl 1:S48 (Visit Source).
  77. Wamala JF, Lukwago L, Malimbo M, et al. Ebola hemorrhagic fever associated with novel virus strain, Uganda, 2007-2008. Emerg Infect Dis 2010; 16:1087 (Visit Source).
  78. Kratz T, Roddy P, Tshomba Oloma A, et al. Ebola Virus Disease Outbreak in Isiro, Democratic Republic of the Congo, 2012: Signs and Symptoms, Management and Outcomes. PLoS One 2015; 10:e0129333 (Visit Source).
  79. Spickler, Anna. "Ebolavirus and Marburgvirus Infections" (PDF) (Visit Source).
  80. Centers for Disease Control and Prevention. About Ebola Virus Disease. Accessed December 3, 2018 (Visit Source).
  81. New Ebola species is reported for first time in a decade - STAT. statnews.com. 27 July 2018. Accessed December 24, 2018 (Visit Source).
  82. Ministry of Health Sierra Leone (PDF). Accessed December 20, 2018 (Visit Source).
  83. New Ebola species is reported for first time in a decade - STAT. statnews.com. 27 July 2018. Accessed December 24, 2018 (Visit Source).
  84. New Ebola virus strain found in Sierra Leone. reliefweb.int. Accessed December 24, 2018 (Visit Source).
  85. Rosenbaum, Leah (27 July 2018). A new Ebola species has been found in bats in Sierra Leone. Science News. Accessed December 24, 2018 (Visit Source).
  86. New Ebola virus found in Sierra Leone, govt says. punchng.com. Accessed December 24, 2018 (Visit Source).
  87. Scientists in West Africa are warning that a new strain of Ebola could infect humans. Newsweek. 28 July 2018. Accessed December 24, 2018 (Visit Source).
  88. Chowell G, Nishiura H (October 2014). Transmission dynamics and control of Ebola virus disease (EVD): a review. BMC Med. 12(1): 196 (Visit Source).
  89. Weingartl HM, Nfon C, Kobinger G (May 2013). Review of Ebola virus infections in domestic animals. Dev Biol. Developments in Biologicals. 135. pp. 211–18 (Visit Source).
  90. Laupland KB, Valiquette L (May 2014). Ebola virus disease. Can J Infect Dis Med Microbiol. 25 (3): 128–29.
  91. Sharma N, Cappell MS (September 2015). Gastrointestinal and Hepatic Manifestations of Ebola Virus Infection. Digestive Diseases and Sciences (Review). 60 (9): 2590–603.
  92. Swanepoel R, Leman PA, Burt FJ, et al. October 1996. Experimental inoculation of plants and animals with Ebola virus. Emerg. Infect. Dis. 2 (4): 321–25 (Visit Source).
  93. Leroy EM, Kumulungui B, Pourrut X, et al. December 2005. Fruit bats as reservoirs of Ebola virus. Nature. 438 (7068): 575–76.
  94. Olival KJ, Islam A, Yu M, et al. February 2013. Ebola virus antibodies in fruit bats, Bangladesh. Emerg. Infect. Dis. 19 (2): 270–73 (Visit Source).
  95. Did deforestation cause the Ebola outbreak? New Internationalist. 10 April 2018. Accessed December 15, 2918 (Visit Source).
  96. Olivero J, Fa JE, Real R, eta al. October 2017. Recent loss of closed forests is associated with Ebola virus disease outbreaks. Scientific Reports. 7 (1): 14291 (Visit Source).
  97. World Health Organization. Ebola situation in Liberia: non-conventional interventions needed. Accessed on December 16, 2018 (Visit Source).
  98. World Health Organization: Ebola response roadmap situation report:17 October 2014. Accessed on December 16, 2018 (Visit Source).
  99. Green A. Ebola emergency meeting establishes new control centre. Lancet 2014; 384:118 (Visit Source).
  100. Centers for Disease Control and Prevention. Review of human-to-human transmission of Ebola virus. Accessed on December 16, 2018 (Visit Source).
  101. Reichler MR, Bangura J, Bruden D, et al. Household Transmission of Ebola Virus: Risks and Preventive Factors, Freetown, Sierra Leone, 2015. J Infect Dis 2018; 218:757 (Visit Source).
  102. Dean NE, Halloran ME, Yang Y, Longini IM. Transmissibility and Pathogenicity of Ebola Virus: A Systematic Review and Meta-analysis of Household Secondary Attack Rate and Asymptomatic Infection. Clin Infect Dis 2016; 62:1277 (Visit Source).
  103. Victory KR, Coronado F, Ifono SO, et al. Ebola transmission linked to a single traditional funeral ceremony - Kissidougou, Guinea, December, 2014-January 2015. MMWR Morb Mortal Wkly Rep 2015; 64:386 (Visit Source).
  104. Glynn JR, Bower H, Johnson S, et al. Variability in Intrahousehold Transmission of Ebola Virus, and Estimation of the Household Secondary Attack Rate. J Infect Dis 2018; 217:232 (Visit Source).
  105. Centers for Disease Control and Prevention. Ebola virus disease: transmission. Accessed on December 16, 2018 (Visit Source).
  106. Kreuels B, Wichmann D, Emmerich P, et al. A case of severe Ebola virus infection complicated by gram-negative septicemia. N Engl J Med 2014; 371:2394 (Visit Source).
  107. Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola Virus in Ocular Fluid during Convalescence. N Engl J Med 2015; 372:2423 (Visit Source).
  108. Nordenstedt H, Bah EI, de la Vega MA, et al. Ebola Virus in Breast Milk in an Ebola Virus-Positive Mother with Twin Babies, Guinea, 2015. Emerg Infect Dis 2016; 22:759 (Visit Source).
  109. Deen GF, Knust B, Broutet N, et al. Ebola RNA Persistence in Semen of Ebola Virus Disease Survivors - Preliminary Report. N Engl J Med 2015 (Visit Source).
  110. Barnes KG, Kindrachuk J, Lin AE, et al. Evidence of Ebola Virus Replication and High Concentration in Semen of a Patient During Recovery. Clin Infect Dis 2017; 65:1400 (Visit Source).
  111. Subtil F, Delaunay C, Keita AK, et al. Dynamics of Ebola RNA persistence in semen: report from the Postebogui cohort in Guinea. Clin Infect Dis 2017 (Visit Source).
  112. Centers for Disease Control and Prevention. Interim guidance for management of survivors of Ebola virus disease in U.S. healthcare settings. Accessed on December 17, 2018 (Visit Source).
  113. Christie A, Davies-Wayne GJ, Cordier-Lassalle T, et al. Possible sexual transmission of Ebola virus - Liberia, 2015. MMWR Morb Mortal Wkly Rep 2015; 64:479 (Visit Source).
  114. Mate SE, Kugelman JR, Nyenswah TG, et al. Molecular Evidence of Sexual Transmission of Ebola Virus. N Engl J Med 2015; 373:2448 (Visit Source).
  115. World Health Organization. Ebola situation report-21 October 2015. Accessed on December 18, 2018 (Visit Source).
  116. Jacobs M, Rodger A, Bell DJ, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet 2016; 388:498 (Visit Source).
  117. Centers for Disease Control and Prevention. Interim guidance for environmental infection control in hospitals for Ebola virus. Accessed on December 18, 2018 (Visit Source).
  118. Centers for Disease Control and Prevention. Q&As on Transmission. Accessed on December 16, 2018 (Visit Source).
  119. World Health Organization. What we know about transmission of the Ebola virus among humans. Accessed on December 16, 2018 (Visit Source).
  120. World Health Organization. Barriers to rapid containment of the Ebola outbreak. Accessed on December 16, 2018 (Visit Source).
  121. Zumbrun EE, Abdeltawab NF, Bloomfield HA, et al. Development of a murine model for aerosolized ebolavirus infection using a panel of recombinant inbred mice. Viruses 2012; 4:3468 (Visit Source).
  122. Kilmarx PH, Clarke KR, Dietz PM, et al. Ebola virus disease in health care workers--Sierra Leone, 2014. MMWR Morb Mortal Wkly Rep 2014; 63:1168 (Visit Source).
  123. Breman JG, Piot P, Johnson KM, et al. The epidemiology of Ebola haemorrhagic fever in Zaire, 1978. In: Pattyn S, ed. Ebola Virus Haemorrhagic Fever, Elsevier/North-Holland, Amsterdam 1978. p.85.
  124. Gradon J. An outbreak of Ebola virus: lessons for everyday activities in the intensive care unit. Crit Care Med 2000; 28:284 (Visit Source).
  125. Chertow DS, Kleine C, Edwards JK, et al. Ebola virus disease in West Africa--clinical manifestations and management. N Engl J Med 2014; 371:2054 (Visit Source).
  126. Centers for Disease Control and Prevention. Health advisory network 367: CDC Ebola Response Update #3. Accessed on December 15, 2018 (Visit Source).
  127. Centers for Disease Control and Prevention. Facts about bushmeat and Ebola. Accessed on December 15, 2018 (Visit Source).
  128. World Health Organization.Global Alert and Response. Information note: Ebola and Food Safety. Accessed December 15, 2018 (Visit Source).
  129. Bonwitt J, Dawson M, Kandeh M, et al. Unintended consequences of the 'bushmeat ban' in West Africa during the 2013-2016 Ebola virus disease epidemic. Soc Sci Med 2018; 200:166 (Visit Source).
  130. Basler CF. Molecular pathogenesis of viral hemorrhagic fever. Semin Immunopathol 2017; 39:551 (Visit Source).
  131. Schieffelin JS, Shaffer JG, Goba A, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med 2014; 371:2092 (Visit Source).
  132. Bah EI, Lamah MC, Fletcher T, et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N Engl J Med 2015; 372:40 (Visit Source).
  133. Uyeki TM, Mehta AK, Davey RT Jr, et al. Clinical Management of Ebola Virus Disease in the United States and Europe. N Engl J Med 2016; 374:636 (Visit Source).
  134. Bellan SE, Pulliam JR, Dushoff J, Meyers LA. Ebola control: effect of asymptomatic infection and acquired immunity. Lancet 2014; 384:1499 (Visit Source).
  135. Mulangu S, Alfonso VH, Hoff NA, et al. Serologic Evidence of Ebolavirus Infection in a Population With No History of Outbreaks in the Democratic Republic of the Congo. J Infect Dis 2018; 217:529 (Visit Source).
  136. Centers for Disease Control and Prevention. Ebola virus disease information for clinicians in U.S. healthcare settings Accessed on December 16, 2018 (Visit Source).
  137. World Health Organization. Travel and transport risk assessment: Recommendations for public health authorities and transport sector. Accessed on December 15, 2018 (Visit Source).
  138. Parra JM, Salmerón OJ, Velasco M. The first case of Ebola virus disease acquired outside Africa. N Engl J Med 2014; 371:2439 (Visit Source).
  139. Ansumana R, Jacobsen KH, Sahr F, et al. Ebola in Freetown area, Sierra Leone--a case study of 581 patients. N Engl J Med 2015; 372:587 (Visit Source).
  140. Jamieson DJ, Uyeki TM, Callaghan WM, et al. What obstetrician-gynecologists should know about Ebola: a perspective from the Centers for Disease Control and Prevention. Obstet Gynecol 2014; 124:1005 (Visit Source).
  141. Chertow DS, Nath A, Suffredini AF, et al. Severe Meningoencephalitis in a Case of Ebola Virus Disease: A Case Report. Ann Intern Med 2016; 165:301 (Visit Source).
  142. de Greslan T, Billhot M, Rousseau C, et al. Ebola Virus-Related Encephalitis. Clin Infect Dis 2016; 63:1076 (Visit Source).
  143. Chertow DS, Childs RW, Arai AE, Davey RT Jr. Cardiac MRI Findings Suggest Myocarditis in Severe Ebola Virus Disease. JACC Cardiovasc Imaging 2016 (Visit Source).
  144. Janvier F, Foissaud V, Cotte J, et al. Monitoring of Prognostic Laboratory Markers in Ebola Virus Disease. J Infect Dis 2016; 213:1049 (Visit Source).
  145. Wolf T, Kann G, Becker S, et al. Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care. Lancet 2015; 385:1428 (Visit Source).
  146. West TE, von Saint André-von Arnim A. Clinical presentation and management of severe Ebola virus disease. Ann Am Thorac Soc 2014; 11:1341 (Visit Source).
  147. Clark DV, Kibuuka H, Millard M, et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect Dis 2015; 15:905 (Visit Source).
  148. Jagadesh S, Sevalie S, Fatoma R, et al. Disability Among Ebola Survivors and Their Close Contacts in Sierra Leone: A Retrospective Case-Controlled Cohort Study. Clin Infect Dis 2018; 66:131 (Visit Source).
  149. Mattia JG, Vandy MJ, Chang JC, et al. Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. Lancet Infect Dis 2016; 16:331 (Visit Source).
  150. Scott JT, Sesay FR, Massaquoi TA, et al. Post-Ebola Syndrome, Sierra Leone. Emerg Infect Dis 2016; 22:641 (Visit Source).
  151. Jacobs M, Rodger A, Bell DJ, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet 2016; 388:498 (Visit Source).
  152. Chancellor JR, Padmanabhan SP, Greenough TC, et al. Uveitis and Systemic Inflammatory Markers in Convalescent Phase of Ebola Virus Disease. Emerg Infect Dis 2016; 22:295 (Visit Source).
  153. Akerlund E, Prescott J, Tampellini L. Shedding of Ebola Virus in an Asymptomatic Pregnant Woman. N Engl J Med 2015; 372:2467 (Visit Source).
  154. Baggi FM, Taybi A, Kurth A, et al. Management of pregnant women infected with Ebola virus in a treatment centre in Guinea, June 2014. Euro Surveill 2014; 19 (Visit Source).
  155. Centers for Disease Control and Prevention. Case Definition for Ebola Virus Disease (EVD). Accessed on December 16, 2018 (Visit Source).
  156. World Health Organization: Travel and transport risk assessment: interim guidance for public health authorities and the transport sector. Accessed on December 15, 2018 (Visit Source).
  157. World Health Organization. Ebola and Marburg virus disease epidemics: preparedness, alert, control, and evaluation. Accessed on December 17, 2018 (Visit Source).
  158. World Health Organization. Case definition recommendations for Ebola or Marburg Virus Diseases. Accessed on December 16, 2018 (Visit Source).
  159. Public Health Agency of Canada. Ebola clinical care guidelines: A guide for clinicians in Canada. Accessed on December 15, 2018 (Visit Source).
  160. European Centre for Disease Prevention and Control. Critical aspects of the safe use of personal protective equipment. Accessed on December 18, 2018 (Visit Source).
  161. World Health Organization. Implementation and management of contact tracing for Ebola virus disease. Accessed December 18, 2018 (Visit Source).
  162. Centers for Disease Control and Prevention. Ebola virus disease: algorithm for evaluation of the returned traveler. Accessed on December 18, 2018 (Visit Source).
  163. Centers for Disease Control and Prevention. Epidemiologic risk factors to consider when evaluating a person for exposure to Ebola virus. Accessed on December 16, 2018 (Visit Source).
  164. Wu HM, Fairley JK, Steinberg J, Kozarsky P. The potential Ebola-infected patient in the ambulatory care setting: preparing for the worst without compromising care. Ann Intern Med 2015; 162:66 (Visit Source).
  165. Centers for Disease Control and Prevention. Determining risk of Ebola transmission in healthcare and community settings. Accessed on December 14, 2018 (Visit Source).
  166. Isakov A, Jamison A, Miles W, Ribner B. Safe management of patients with serious communicable diseases: recent experience with Ebola virus. Ann Intern Med 2014; 161:829 (Visit Source).
  167. Cummings KJ, Choi MJ, Esswein EJ, et al. Addressing Infection Prevention and Control in the First U.S. Community Hospital to Care for Patients With Ebola Virus Disease: Context for National Recommendations and Future Strategies. Ann Intern Med 2016 (Visit Source).
  168. Centers for Disease Control and Prevention. Questions and answers: infection control in general healthcare settings in countries with widespread Ebola Transmission. Accessed on December 17, 2018 (Visit Source).
  169. Centers for Disease Control and Prevention. Identify, isolate, and inform: emergency department evaluation and management for patients who present with possible Ebola virus. Accessed on December 17, 2018 (Visit Source).
  170. Centers for Disease Control and Prevention. Guidance on personal protective equipment (PPE) to be used by healthcare workers during management of patients with confirmed Ebola or persons under investigation (PUIs) for Ebola who are clinically unstable or have bleeding, vomiting, or diarrhea in U.S. Hospitals, including procedures for donning and doffing PPE. Accessed on December 15, 2018 (Visit Source).
  171. Centers for Disease Control and Prevention. For US healthcare settings: donning and doffing personal protective equipment (PPE) for evaluating persons under investigation (PUIs) for Ebola who are clinically stable and do not have bleeding, vomiting, or diarrhea. Accessed on December 16, 2018 (Visit Source).
  172. Centers for Disease Control and Prevention. Assessment of persons under investigation having low (but not zero) risk of exposure to Ebola. Accessed on December 15, 2018 (Visit Source).
  173. United States Centers for Disease Control and Prevention. Interim guidance for U.S. hospital preparedness for patients with possible or confirmed Ebola virus disease: a framework for a tiered approach. Accessed on December 16, 2018 (Visit Source).
  174. United States Centers for Disease Control. Hospital Preparedness: A Tiered Approach. Accessed on December 16, 2018 (Visit Source).
  175. Centers for Disease Control and Prevention. Ebola update: updated CDC guidance monitoring symptoms and controlling movement to stop spread of Ebola. Accessed on December 16, 2018 (Visit Source).
  176. Centers for Disease Control and Prevention. Interim guidance for specimen collection, transport, testing, and submission for patients with suspected infection with Ebola virus disease. Accessed on December 16, 2018 (Visit Source).
  177. Considerations for discharging persons under investigation (PUI) for Ebola virus disease. Accessed on December 17, 2018 (Visit Source).
  178. Centers for Disease Control and Prevention. Guidance for U.S. laboratories for managing and testing routine clinical specimens when there is a concern about Ebola virus disease. Accessed on December 16, 2018 (Visit Source).
  179. Gire SK, Goba A, Andersen KG, et al. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Accessed on December 16, 2018 (Visit Source).
  180. Su S, Wong G, Qiu X, et al. Diagnostic strategies for Ebola virus detection. Lancet Infect Dis 2016; 16:294 (Visit Source).
  181. Erickson BR, Sealy TK, Flietstra T, et al. Ebola Virus Disease Diagnostics, Sierra Leone: Analysis of Real-time Reverse Transcription-Polymerase Chain Reaction Values for Clinical Blood and Oral Swab Specimens. J Infect Dis 2016; 214:S258 (Visit Source).
  182. World Health Organization. First antigen rapid test for Ebola through emergency assessment and eligible for procurement. Accessed on December 16, 2018 (Visit Source).
  183. Boisen ML, Cross RW, Hartnett JN, et al. Field Validation of the ReEBOV Antigen Rapid Test for Point-of-Care Diagnosis of Ebola Virus Infection. J Infect Dis 2016; 214:S203 (Visit Source).
  184. Broadhurst MJ, Kelly JD, Miller A, et al. ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study. Lancet 2015; 386:867 (Visit Source).
  185. Cross RW, Boisen ML, Millett MM, et al. Analytical Validation of the ReEBOV Antigen Rapid Test for Point-of-Care Diagnosis of Ebola Virus Infection. J Infect Dis 2016; 214:S210 (Visit Source).
  186. FDA authorizes emergency use of first Ebola fingerstick test with portable reader. Accessed on December 16, 2018 (Visit Source).
  187. Centers for Disease Control and Prevention. Interim guidance regarding compliance with select agent regulations for laboratories.
  188. Handling patient specimens that are known or suspected to contain Ebola virus. Accessed on December 16, 2018 (Visit Source).
  189. Centers for Disease Control and Prevention. Specimen Submission Information. Accessed on December 16, 2018 (Visit Source).
  190. World Health Organization. How to safely collect blood samples from persons suspected to be infected with highly infectious blood-borne pathogens (e.g. Ebola). Accessed December 18, 2018 (Visit Source).
  191. World Health Organization. In-Country shipment: How to safely ship human blood samples from suspected Ebola cases within a country by road, rail and sea. Accessed December 18, 2018 (Visit Source).
  192. World Health Organization. Laboratory guidance for the diagnosis of Ebola virus disease, interim recommendations. Accessed on December 18, 2018 (Visit Source).
  193. Boggild AK, Esposito DH, Kozarsky PE, et al. Differential diagnosis of illness in travelers arriving from Sierra Leone, Liberia, or Guinea: a cross-sectional study from the GeoSentinel Surveillance Network. Ann Intern Med 2015; 162:757 (Visit Source).
  194. Peacock G, Uyeki TM, Rasmussen SA. Ebola virus disease and children: what pediatric health care professionals need to know. JAMA Pediatr 2014; 168:1087 (Visit Source).
  195. Centers for Disease Control and Prevention. Interim recommendations for Influenza vaccination and post-exposure hemoprophylaxis to prevent Influenza virus. Infection in People Being Actively Monitored for Potential Ebola Virus Exposure. Accessed on December 18, 2018 (Visit Source).
  196. Takahashi S, Metcalf CJ, Ferrari MJ, et al. Reduced vaccination and the risk of measles and other childhood infections post-Ebola. Science 2015; 347:1240 (Visit Source).
  197. The Centers for Disease Control and Prevention. Lassa fever. Accessed on December 18, 2018 (Visit Source).
  198. World Health Organization. Clinical management of patients with viral haemorrhagic fever: A pocket guide for the front-line health worker. Accessed on December 17, 2018 (Visit Source).
  199. Ribner BS. Treating patients with Ebola virus infections in the US: lessons learned. Presented at IDWeek, October 8, 2014. Philadelphia PA.
  200. Fowler RA, Fletcher T, Fischer WA 2nd, et al. Caring for critically ill patients with ebola virus disease. Perspectives from West Africa. Am J Respir Crit Care Med 2014; 190:733 (Visit Source).
  201. Kreuels B, Wichmann D, Emmerich P, et al. A case of severe Ebola virus infection complicated by gram-negative septicemia. N Engl J Med 2014; 371:2394 (Visit Source).
  202. Lamontagne F, Clément C, Fletcher T, et al. Doing today's work superbly well--treating Ebola with current tools. N Engl J Med 2014; 371:1565 (Visit Source).
  203. Kortepeter MG, Kwon EH, Hewlett AL, et al. Containment Care Units for Managing Patients With Highly Hazardous Infectious Diseases: A Concept Whose Time Has Come. J Infect Dis 2016; 214:S137 (Visit Source).
  204. Herstein JJ, Biddinger PD, Kraft CS, et al. Current Capabilities and Capacity of Ebola Treatment Centers in the United States. Infect Control Hosp Epidemiol 2016; 37:313 (Visit Source).
  205. Decker BK, Sevransky JE, Barrett K, et al. Preparing for critical care services to patients with Ebola. Ann Intern Med 2014; 161:831 (Visit Source).
  206. Garibaldi BT, Chertow DS. High-Containment Pathogen Preparation in the Intensive Care Unit. Infect Dis Clin North Am 2017; 31:561 (Visit Source).
  207. Sprecher A, Van Herp M, Rollin PE. Clinical Management of Ebola Virus Disease Patients in Low-Resource Settings. Curr Top Microbiol Immunol 2017; 411:93 (Visit Source).
  208. Dickson SJ, Clay KA, Adam M, et al. Enhanced case management can be delivered for patients with EVD in Africa: Experience from a UK military Ebola treatment centre in Sierra Leone. J Infect 2018; 76:383 (Visit Source).
  209. Lamontagne F, Fowler RA, Adhikari NK, et al. Evidence-based guidelines for supportive care of patients with Ebola virus disease. Lancet 2018; 391:700 (Visit Source).
  210. Chertow DS, Uyeki TM, DuPont HL. Loperamide therapy for voluminous diarrhea in Ebola virus disease. J Infect Dis 2015; 211:1036 (Visit Source).
  211. Perner A, Fowler RA, Bellomo R, Roberts I. Ebola care and research protocols. Intensive Care Med 2015; 41:111 (Visit Source).
  212. Johnson DW, Sullivan JN, Piquette CA, et al. Lessons learned: critical care management of patients with Ebola in the United States. Crit Care Med 2015; 43:1157 (Visit Source).
  213. Connor MJ Jr, Kraft C, Mehta AK, et al. Successful delivery of RRT in Ebola virus disease. J Am Soc Nephrol 2015; 26:31 (Visit Source).
  214. Centers for Disease Control and Prevention. Recommendations for safely performing acute hemodialysis in patients with Ebola virus disease in U.S. hospitals. Accessed on December 16, 2018 (Visit Source).
  215. The American College of Obstetricians and Gynecologists. Practice advisory: care of obstetric patients during an Ebola virus outbreak. Accessed on December 16, 2018 (Visit Source).
  216. PREVAIL II Writing Group, Multi-National PREVAIL II Study Team, Davey RT Jr, et al. A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med 2016; 375:1448 (Visit Source).
  217. McElroy AK, Erickson BR, Flietstra TD, et al. Ebola hemorrhagic Fever: novel biomarker correlates of clinical outcome. J Infect Dis 2014; 210:558 (Visit Source).
  218. McElroy AK, Erickson BR, Flietstra TD, et al. Biomarker correlates of survival in pediatric patients with Ebola virus disease. Emerg Infect Dis 2014; 20:1683 (Visit Source).
  219. Rasmussen AL, Okumura A, Ferris MT, et al. Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance. Science 2014; 346:987 (Visit Source).
  220. O'Dempsey T, Khan SH, Bausch DG. Rethinking the discharge policy for Ebola convalescents in an accelerating epidemic. Am J Trop Med Hyg 2015; 92:238 (Visit Source).
  221. Spengler JR, McElroy AK, Harmon JR, et al. Relationship Between Ebola Virus Real-Time Quantitative Polymerase Chain Reaction-Based Threshold Cycle Value and Virus Isolation From Human Plasma. J Infect Dis 2015; 212 Suppl 2:S346 (Visit Source).
  222. World Health Organization. Clinical care for survivors of Ebola virus disease. Accessed on December 16, 2018 (Visit Source).
  223. Shantha JG, Mattia JG, Goba A, et al. Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) Study: Reverse Transcription-Polymerase Chain Reaction and Cataract Surgery Outcomes of Ebola Survivors in Sierra Leone. EBioMedicine 2018; 30:217 (Visit Source).
  224. Fischer WA 2nd, Vetter P, Bausch DG, et al. Ebola virus disease: an update on post-exposure prophylaxis. Lancet Infect Dis 2018; 18:e183 (Visit Source).
  225. Furuta Y, Gowen BB, Takahashi K, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 2013; 100:446 (Visit Source).
  226. Oestereich L, Lüdtke A, Wurr S, et al. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res 2014; 105:17 (Visit Source).
  227. Smither SJ, Eastaugh LS, Steward JA, et al. Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antiviral Res 2014; 104:153 (Visit Source).
  228. Bixler SL, Bocan TM, Wells J, et al. Efficacy of favipiravir (T-705) in nonhuman primates infected with Ebola virus or Marburg virus. Antiviral Res 2018; 151:97 (Visit Source).
  229. Sissoko D, Laouenan C, Folkesson E, et al. Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLoS Med 2016; 13:e1001967 (Visit Source).
  230. Bai CQ, Mu JS, Kargbo D, et al. Clinical and Virological Characteristics of Ebola Virus Disease Patients Treated With Favipiravir (T-705)-Sierra Leone, 2014. Clin Infect Dis 2016; 63:1288 (Visit Source).
  231. World Health Organization. Statement on the WHO consultation on potential Ebola therapies and vaccines. Accessed on December 16, 2018 (Visit Source).
  232. World Health Organization. Experimental therapies: growing interest in the use of whole blood or plasma from recovered Ebola patients (convalescent therapies). Accessed on December 16, 2018 (Visit Source).
  233. World Health Organization. Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion, as an empirical treatment during outbreaks. Accessed on December 16, 2018 (Visit Source).
  234. Van Griensven J, Edwards T, de Lamballerie X, et al. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. N Engl J Med 2016; 374:33 (Visit Source).
  235. Qiu X, Wong G, Audet J, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 2014; 514:47 (Visit Source).
  236. Corti D, Misasi J, Mulangu S, et al. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science 2016; 351:1339 (Visit Source).
  237. Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016; 531:381 (Visit Source).
  238. Gignoux E, Azman AS, de Smet M, et al. Effect of Artesunate-Amodiaquine on Mortality Related to Ebola Virus Disease. N Engl J Med 2016; 374:23 (Visit Source).
  239. Thi EP, Mire CE, Lee AC, et al. Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates. Nature 2015; 521:362 (Visit Source).
  240. Wong KK, Davey RT Jr, Hewlett AL, et al. Use of Postexposure Prophylaxis After Occupational Exposure to Zaire ebolavirus. Clin Infect Dis 2016; 63:376 (Visit Source).
  241. Florescu DF, Kalil AC, Hewlett AL, et al. Administration of Brincidofovir and Convalescent Plasma in a Patient with Ebola Virus Disease. Clin Infect Dis 2015; 61:969 (Visit Source).
  242. McMullan LK, Flint M, Dyall J, et al. The lipid moiety of brincidofovir is required for in vitro antiviral activity against Ebola virus. Antiviral Res 2016; 125:71 (Visit Source).
  243. Dunning J, Kennedy SB, Antierens A, et al. Experimental Treatment of Ebola Virus Disease with Brincidofovir. PLoS One 2016; 11:e0162199 (Visit Source).
  244. Warren TK, Shurtleff AC, Bavari S. Advanced morpholino oligomers: a novel approach to antiviral therapy. Antiviral Res 2012; 94:80 (Visit Source).
  245. Heald AE, Iversen PL, Saoud JB, et al. Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against ebola virus and marburg virus: results of two single-ascending-dose studies. Antimicrob Agents Chemother 2014; 58:6639 (Visit Source).
  246. Sarepta Therapeutics. http://www.sarepta.com/. Accessed on December 23, 2018 (Visit Source).
  247. Taylor R, Kotian P, Warren T, et al. BCX4430 - A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease. J Infect Public Health 2016; 9:220 (Visit Source).
  248. Warren TK, Wells J, Panchal RG, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature 2014; 508:402 (Visit Source).
  249. Centers for Disease Control and Prevention. Infection prevention and control recommendations for hospitalized patients with known or suspected Ebola hemorrhagic fever in U.S. hospitals. Accessed on December 16, 2018 (Visit Source).
  250. World Health Organization. Interim Infection Prevention and Control Guidance for Care of Patients with Suspected or Confirmed Filovirus Haemorrhagic Fever in Health-Care Settings. With Focus on Ebola. Accessed on December 16, 2018 (Visit Source).
  251. Centers for Disease Control and Prevention. Safe management of patients with Ebola virus disease (EVD) in U.S. hospitals. Accessed on December 16, 2018 (Visit Source).
  252. Centers for Disease Control and Prevention. Interim guidance for healthcare workers providing care in West African countries affected by the Ebola outbreak: limiting heat burden while wearing personal protective equipment. Accessed on December 16, 2018 (Visit Source).
  253. Poliquin PG, Vogt F, Kasztura M, et al. Environmental Contamination and Persistence of Ebola Virus RNA in an Ebola Treatment Center. J Infect Dis 2016; 214:S145 (Visit Source).
  254. Diallo B, Sissoko D, Loman NJ, et al. Resurgence of Ebola Virus Disease in Guinea Linked to a Survivor With Virus Persistence in Seminal Fluid for More Than 500 Days. Clin Infect Dis 2016; 63:1353 (Visit Source).
  255. Centers for Disease Control and Prevention. Recommendations for breastfeeding/infant feeding in the context of Ebola. Accessed on December 17, 2018 (Visit Source).
  256. Levine MM, Tapia M, Hill AV, Sow SO. How the current West African Ebola virus disease epidemic is altering views on the need for vaccines and is galvanizing a global effort to field-test leading candidate vaccines. J Infect Dis 2015; 211:504 (Visit Source).
  257. Stanley DA, Honko AN, Asiedu C, et al. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nat Med 2014; 20:1126 (Visit Source).
  258. Sarwar UN, Costner P, Enama ME, et al. Safety and immunogenicity of DNA vaccines encoding Ebolavirus and Marburgvirus wild-type glycoproteins in a phase I clinical trial. J Infect Dis 2015; 211:549 (Visit Source).
  259. Ledgerwood JE, DeZure AD, Stanley DA, et al. Chimpanzee Adenovirus Vector Ebola Vaccine. N Engl J Med 2017; 376:928 (Visit Source).
  260. Halperin SA, Arribas JR, Rupp R, et al. Six-Month Safety Data of Recombinant Vesicular Stomatitis Virus-Zaire Ebola Virus Envelope Glycoprotein Vaccine in a Phase 3 Double-Blind, Placebo-Controlled Randomized Study in Healthy Adults. J Infect Dis 2017; 215:1789 (Visit Source).
  261. Agnandji ST, Fernandes JF, Bache EB, et al. Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial. PLoS Med 2017; 14:e1002402 (Visit Source).
  262. Huttner A, Agnandji ST, Combescure C, et al. Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study. Lancet Infect Dis 2018; 18:738 (Visit Source).
  263. Henao-Restrepo AM, Longini IM, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomized trial. Lancet 2015; 386:857 (Visit Source).
  264. Marzi A, Hanley PW, Haddock E, et al. Efficacy of Vesicular Stomatitis Virus-Ebola Virus Postexposure Treatment in Rhesus Macaques Infected With Ebola Virus Makona. J Infect Dis 2016; 214:S360 (Visit Source).
  265. Cnops L, Gerard M, Vandenberg O, et al. Risk of Misinterpretation of Ebola Virus PCR Results After rVSV ZEBOV-GP Vaccination. Clin Infect Dis 2015; 60:1725 (Visit Source).
  266. World Health Organization. Statement on the meeting of the International Health Regulations Emergency Committee regarding the 2014 Ebola outbreak in West Africa. Accessed on December 16, 2018 (Visit Source).
  267. World Health Organization. Statement on the second meeting of the International Health Regulations Emergency Committee regarding the 2014 Ebola outbreak in West Africa. Accessed on December 16, 2018 (Visit Source).
  268. Gostin LO, Lucey D, Phelan A. The Ebola epidemic: a global health emergency. JAMA 2014; 312:1095 (Visit Source).
  269. Briand S, Bertherat E, Cox P, et al. The international Ebola emergency. N Engl J Med 2014; 371:1180 (Visit Source).
  270. World Health Organizations. WHO welcomes decision to establish United Nations Mission for Ebola Emergency Response. Accessed on December 16, 2018 (Visit Source).
  271. Centers for Disease Control and Prevention. CDC announces active post-arrival monitoring for travelers from impacted countries. Accessed on December 16, 2018 (Visit Source).
  272. Washington ML, Meltzer ML, Centers for Disease Control and Prevention (CDC). Effectiveness of Ebola treatment units and community care centers -Liberia, September 23-October 31, 2014. MMWR Morb Mortal Wkly Rep 2015; 64:67 (Visit Source).