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).
After completing this course, the participant will be able to meet the following 5 objectives:
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
|SUDV||284||151||53%||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|
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
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
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
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
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
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
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
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
Republic of the Congo: Occurred in the districts of Mbomo and Kelle in the Cuvette-Ouest Department.11
Republic of the Congo: Occurred in Mbomo and Mbandza villages, located in Mbomo District in the Cuvette-Ouest Department.12
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
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
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
Democratic Republic of the Congo: Occurred in the Mweka and Luebo health zones of the Kasaï-Occidental province.18
Uganda: Occurred in the Kibaale District.19
Democratic Republic of the Congo: Occurred in the Orientale Province.20,21
Dec 2013–Jan 2016
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.|
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
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
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
|SUDV or EBOV||1||0|
UK: Laboratory infection by accidental stick of contaminated needle.48,49
Zaire: Noted retroactively in the village of Tandala.49-51
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
US: RESTV was introduced into quarantine facilities in Virginia and Pennsylvania by monkeys imported from the Philippines. No human cases were reported.54
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
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
|TAFV||1||0||Cote 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
Cote d’Ivoire: One person, fleeing the civil war in neighboring Liberia, was identified as an Ebola case in Gozon.58
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
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
Philippines: RESTV was identified at a monkey export facility in the Philippines. No human cases resulted.61
Russia: Laboratory contamination.62
Russia: Laboratory contamination.63
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
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
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
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
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
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.
The following two species are not known to cause severe disease in humans:
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.
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
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
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 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:
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
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
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:
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
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.
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
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
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.
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:
Medical procedures played a major role in some past Ebola epidemics by amplifying the spread of infection. For example:
Despite these dramatic episodes of nosocomial transmission, other hospital-based experiences have demonstrated a much lower incidence of secondary spread. For example:
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
Other potential routes of transmission include the following:
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.
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
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.
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.
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.
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.
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.
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
|State of Illness||Time Post-Symptom Onset||Clinical||Laboratory|
|Days 1 - 3|
Elevated *AST and *ALT
|Days 3 - 10|
Epigastric and abdominal pain
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)
|Days 7 - 12|
Diminished consciousness or coma
In addition to findings during gastrointestinal stage:
|Day 10 and after|
Respiratory failure associated with aggressive fluid resuscitation or lung injury
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
|Days 7 - 12|
Resolution of gastrointestinal symptoms
Increased oral intake
Resolution of laboratory abnormalities
|Up to 12 months|
Persistent neurocognitive abnormalities
*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:
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.
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.
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).
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.
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:
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:
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
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:
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.
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.
|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).
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.|
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
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:
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.
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.
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 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-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).
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 may be needed depending upon the patient's clinical presentation. These include:
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
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.
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.
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:
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
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.
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
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
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.
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.
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.
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.
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.
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.
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: