Although Figure 2 suggests that there are still new cases in each country, the most recent data from the WHO report just 9 total cases in the most recent week ending May 10, 2015.b Liberia is now considered free of Ebola, with no reported cases for >40 days. The difference between Figure 2 and the most recent WHO update likely relates to “reported cases,” shown in Figures 1 and 2, and confirmed cases reported in the most recent WHO Situation Report.
None of the health care workers infected in the United States has died from Ebola virus disease, so it appears that aggressive supportive care can reduce the mortality. However, there is no definitive treatment for patients with Ebola.
Beginning approximately 50 years ago, viral hemorrhagic disease caused by previously unrecognized viruses, Marburg virus and Ebola virus, began to appear. Marburg virus is comprised of 1 species within the genus Marburgvirus. Ebola virus consists of 5 viral species within the genus Ebolavirus. Ebolavirus and Marburgvirus comprise 2 of the 3 genera in the family Filoviridae. The third genus in the Filoviridae family is Cuevavirus, which does not appear to cause human disease. Filoviridae are in the order Mononegavirales (Table 1).6 Viruses within the order Mononegavirales are encapsulated single-stranded, negative-sense (-polarity) RNA viruses. The negative-sense RNA must first be converted to a positive-sense RNA within a cell before the gene frames encoded in the RNA can be read, producing messenger RNA, responsible for the production of viral proteins on ribosomes.
Nine years later, in June 1976, in the Democratic Republic of the Sudan (Sudan), a man who lived in a rural area, but who worked in a factory in the township of Nzara, became febrile, with a headache and chest pain, on June 27, 1976.11 Four days later, he was admitted to the hospital. The next day, he developed bleeding from his nose and mouth, along with bloody diarrhea. The patient died on July 6, but not before infecting several of his factory coworkers and family members. Subsequent analysis of household contacts sleeping in the same room as the infected patient demonstrated that 23% of those who had touched the patient and 81% of those who had nursed the patient contracted the disease.11 Before the epidemic was brought under control, 284 people had become infected, 53% of whom died. Similar to the index case, patients initially had an influenza-like syndrome that included headache, fever, arthralgias, myalgias, diarrhea, vomiting, chest pain, sore throat, and rash. Hemorrhagic complications were observed in almost all the fatal cases and in approximately half of the patients who survived. The overall hemorrhagic complication rate was 71% (Table 2). Leukocytosis was noted in those few patients who had complete blood counts measured, and thrombocytopenia was present in the most severely ill patients. There were 2 limited postmortem examinations that demonstrated focal eosinophilic necrosis in the liver of 1 of the cadavers, tubular necrosis of the kidneys in the other. The most consistent finding in both cases was the depletion of lymphocytes in the lymphatic system, with a complimentary increase in plasma cells.11 Investigators at the WHO isolated 2 species of Ebolavirus from patients’ blood and antibodies to Ebolavirus were detected by immunofluorescence in survivors. The WHO observed that the characteristics of the disease were similar to those that patients had developed in Marburg, Germany, 9 years previously. The epidemic lasted 5 months, from June through November 1976.
On the basis of the available evidence, WHO hypothesized that someone from southwest Sudan who was either acutely ill with the disease, or convalescing from it, and who traveled to northeast Zaire (renamed the Democratic Republic of the Congo on May 16, 1997) to seek medical care was the index case. On the basis of the symptoms, the index patient might have received a parenteral injection of chloroquine. If so, the injection would have contaminated the needle, which might have been used on several more patients, thus spreading the disease. However, this theory was dispelled by the discovery that the epidemic that appeared in southwest Sudan was caused by a virus from a different species (now called Sudan ebolavirus) than the one that caused disease in that appeared in Zaire (now called Zaire ebolavirus).
The second epidemic of Ebola virus disease that occurred in northeast Zaire between September and October of 1976 provided many additional lessons.12 The index case patient developed symptoms and signs of the disease on September 1, 1976, after being treated for malaria with an IM injection of chloroquine. The malarial symptoms abated, but within 5 days, he developed a different set of symptoms and signs, as did several other individuals who received parenteral injections at the same facility, the Yambuku Mission Hospital (YMH) near the Ebola River. After a prodrome of a few days, individuals developed a severe sore throat, a maculopapular rash, abdominal pain, and variable abdominal symptoms (e.g., nausea, dysphagia, diarrhea, and bleeding from several sites including the gastrointestinal tract). Although diagnostic capabilities were limited, nonicteric hepatitis, acute pancreatitis, and disseminated intravascular coagulation (DIC) were diagnosed in several more patients and were considered as part of the clinical manifestations of the disease. As the scope and etiology of the epidemic became apparent, on September 30, 1976, 4 weeks after the index case was diagnosed, the YMH was closed. By then, 11 of the 17 of the hospital staff had contracted the disease and had died. An investigation of the outpatient facilities at the hospital revealed that the syringes and needles used for parenteral injections were apparently not sterilized between patients but, rather, rinsed in a pan of water.12
On October 13 and 14, 3 overseas laboratories isolated from infected individuals a virus morphologically similar to, but immunologically distinct from, the Marburg virus, the causative agent of Marburg hemorrhagic viral fever.12 On October 18, 1976, an international commission formed by Zaire’s Minister of Health convened and developed a plan to search house-to-house in >500 villages in the region to find individuals who had the disease; 55 villages had serologically confirmed cases of Ebola virus disease. The WHO estimated that approximately 5% of individuals who came in contact with an infected patient became infected, but approximately 20% of close contacts, those who slept or lived in the same room as a patient, became infected. Three hundred eighteen cases ultimately were identified, of whom 280 died (88% mortality); men and women of all ages were affected though the greatest incidence was in women 17 to 31 years of age. In these women, there was a correlation between the development of the disease and attendance at the obstetric clinic at YMH where some had received injections. The typical incubation period was 1 week, as was the duration of the disease in the 38 survivors.12
The epidemic was brought under control by closing the YMH and isolating individuals with the disease in their village. In some circumstances, patients were treated in facilities where they were isolated from other patients. Staff providing their care exercised stringent infection control measures. In 1 situation, the 3 staff providing care were themselves quarantined. Health care staff wore high-efficiency respirators, goggles, and disposable clothing. Contaminated materials, such as clothing, utensils, excreta, etc., were either burned or decontaminated by boiling or applying 2% hypochlorite (household bleach is approximately 5% sodium hypochlorite). Cadavers were wrapped in shrouds soaked in formalin or phenol and buried deeply.12
Since the initial discovery of Ebola viruses, there has been extensive work to identify their natural reservoirs. Initially, this work focused on arthropods and terrestrial rodents and their ticks, but extensive investigations found no evidence that these animals carried the virus. Nonhuman primates also can be infected and develop a disease similar to humans with equally high mortality rates; however, they are clearly not a reservoir for the virus because the disease has such high lethality in nonhuman primates. Nevertheless, nonhuman primates can transmit the virus to humans.17 Likewise, dogs and pigs can be infected with Ebola virus, but they do not serve as a host.18 Several people have developed Ebola virus disease after exposure to bats.19 On the basis of that observation, it was demonstrated that fruit bats of the Pteropodidae family are indeed a reservoir for Ebola virus and, as of this writing, bats are the only known reservoir.20
Ebola virus antibodies have been identified in 3 species of bats in Central Africa21 and 4 species in West Africa.22 Using these and other data, Pigott et al.23 estimate that there are 23 countries in West and Central Africa where conditions support or would support colonies of fruit bats that could carry the disease. Transmission of Ebola virus from bats to humans must be uncommon because the potential reservoir of Ebola virus is huge.
The current model for humans acquiring Ebola virus is through contact with, or consumption of, bushmeat (from animals hunted for food). Specifically, someone could become infected while handling or preparing bats for consumption. Anyone consuming meat from bats containing live virus could become infected.24 However, any food contaminated by droppings from infected bats or any contact with infected bat droppings also could be a source of infection.25 One man became infected while spelunking in a cave with many bats but without any direct contact with the bats.26 A second mechanism for acquisition of Ebola virus is through infected primates, whether nonhuman or human (Fig. 4).27,28
The index case for the current epidemic is thought to have been a child in Guinea who had contact with a bat. Guinea had not had a previously recognized case of Ebola virus disease and is 1700 miles from Gabon, the closest country in which epidemics of Ebola virus disease had previously occurred. The specific strains of Zaire ebolavirus responsible for the current pandemic appear to have diverged from central African lineages of Zaire ebolavirus around 2004.29
The pandemic began in Guinea in December 2013 and spread through human-to-human contact to several other countries in West Africa. Mechanisms to control Ebola virus disease that had been learned in central African countries (Congo, Sudan, and Gabon) during the previous 4 decades were not put in place where Ebola virus disease was now spreading. These countries in West Africa are among the world’s poorest nations and rank among the highest nations for maternal mortality and the lowest for human development as measured by the WHO and the United Nations.30,31 They have very limited resources to deal with such a challenge. The challenges were increased further by the fact that Ebola virus disease rapidly spread to urban settings, where it was more difficult to quarantine patients and to trace contacts than in the countryside.
The epidemics also were spread because of poverty and ignorance. Several times, local populations, afraid that the disease was spread by health care workers, attacked them32 and in 1 case killed 8 of them.c In addition, families were fearful of efforts to quarantine patients and hid affected family member patients from health care workers. Barriers created by poverty, illiteracy, and distrust impaired efforts to contain the disease.33 Individuals in these communities continued handling symptomatic patients without barrier protection, and if these individuals died, customary funereal practices, which exposed additional persons to the virus, were followed.34 The ease of travel within African countries and the ease of international travel, as indicated by the patient from Liberia who flew to Dallas, Texas, transformed the epidemic into a pandemic that has spread to 3 continents.
Ebola virus is spread via bodily fluids and direct patient contact. Ebola virus disease is not contagious until infected patients become symptomatic. At that time, all body fluids, including blood, urine, emesis, stool and semen, contain the virus.35 A previously healthy individual might contract the disease if given a parenteral injection, as occurred in Zaire during the 1976 epidemic, or through secretions from the patient deposited on mucous membranes in the mouth or nose, on the conjunctiva, or through lacerations or skin abrasions. There has not been a documented human case that has contracted the disease via an aerosol. There are studies that show that nonhuman primates can be infected if Ebola virus is aerosolized by mechanical means and delivered through a nebulizer.36,37 In 1 study, 3 nonhuman primates who were in a biocontainment facility developed Ebola virus disease, even though they had no contact with other animals that had Ebola virus disease.38 The investigators speculated that it could have been through aerosolized particles but could not exclude the fact that oral secretions from an infected animal transmitted Ebola virus to another animal via its conjunctiva, mouth, or nose. However, in a recent report of a study conducted in a biosafety level-4 laboratory and designed to repeat this former study and its results, investigators found no evidence of aerosol transmission between nonhuman primates.39
In previous epidemics, some patients do not recall having direct contact with another patient with the disease.40 This does not exclude the possibility that these individuals could have acquired the virus through contact with tables, chairs, or articles in a patient’s room. Ebola virus has been found in alveoli of infected patients41 (Fig. 5). Despite the lack of scientific evidence, there is justifiable concern about aerosolized Ebola virus transmission.42
The role of the environment in the transmission of Ebola virus disease has not been fully elucidated. Under ideal conditions, Ebola virus remains viable on solid surfaces for several days.43,44 However, in another study in patients’ rooms, no virus was recovered from 33 sites that were not visibly bloody.35 There is no epidemiologic evidence of Ebola virus transmission via either the environment or fomites that could become contaminated during patient care (e.g., bed rails, door knobs, laundry). However, given the apparently low infectious dose, potential of high virus titers in the blood of ill patients, and disease severity, the highest levels of precaution are required. We need not wait for scientific proof that the virus can aerosolize or that fomites can be infective to enact appropriate precautions.45 The risks are too high, and we have limited ability to conduct rigorous studies on Ebola virus and on patients with Ebola virus disease.
Ebola virus is most commonly transmitted when secretions from an infected patient come in contact with mucosa or conjunctiva or via percutaneous injury (e.g., a laceration or abrasion). There are no human data, but data from cynomologus monkeys show that an IM injection of as few as 10 plaque-forming units (each plaque-forming unit is assumed to represent 1 virion) results in lethal Ebola virus disease within 8 to 12 days of receiving the injection. Increasing the IM dose to 1000 plaque-forming units resulted in death within 5 to 8 days.46,47
Ebola virus replication requires attachment to a cell’s membrane, binding to specific cell receptors, and fusion with the cell’s membrane. The virion’s glycoprotein outer capsule is responsible for the attachment of the virus to the cell (Fig. 6).48,49
Several molecules have been proposed that function either as a receptor on a cell’s surface or as a mediator to facilitate viral entry into a cell, including C-type lectins, tyrosine kinase receptors, β1 integrin receptors, and Niemann Pick C1 proteins.48,50–52 Takada et al.53 have argued that, based on Ebola virus’s pantropism, the virus likely uses several different C-type lectins to gain entry into a variety of cells. Because of the virus’s marked selectivity for specific cells, some of the proposed receptors are unique to those cells (e.g., dendritic cell−specific intercellular adhesion molecule-3-grabbing nonintegrin) or human macrophage galactose- and N-acetylgalactosamine-specific C-type lectin).54–57 There also has been speculation that Ebola virus does not fuse to a cell’s membrane58 but rather activates the cell’s endocytic mechanisms, acting as a “Trojan horse” to gain entry into the cell’s cytoplasm. However, the most recent evidence suggests that the virus fuses to the cell membrane through glycoprotein 2, which can undergo conformational changes between an alpha helix and a beta layer to insert itself into the lipid bilayer that comprises the cell membrane.59
Once Ebola virus gains access to the interior of the cell, viral RNA and 7 proteins including MP, VP35, VP30, glycoprotein, and L are released into the cell’s cytoplasm.10 Glycoprotein makes up the virus’s outer coat and is involved in the binding of virus to cell surface receptors.48 The L protein is an RNA polymerase that translates Ebola virus’s negative-sense RNA into positive-sense messenger RNA from which Ebola virus’s structural proteins are generated.60 In addition, because the RNA is a copy of the negative-sense Ebola virus RNA, it serves as a template for replication of Ebola virus’s RNA. The structural proteins and genomes congregate in the cytoplasm near the cell membrane, where they reassemble into new virions, after which they are released by the cell.58,61
In the final stages of the Ebola virus disease, widespread infection of multiple organs results in a massive release of cytokines (e.g., tumor necrosis factor-α, interleukins, nitric oxide radicals, etc).65,66 The resultant cytokine storm is manifested by systemic capillary leakage, decreased left ventricular filling pressure, hypotension, and shock (Fig. 7). Death occurs as a result of circulatory shock or, more commonly, multisystem organ dysfunction.67 In survivors, the viremia clears over several days. Nonsurvivors have a marked viremia, leukocytosis (primarily neutrophils), thrombocytopenia, lymphocytopenia, and coagulopathy. The latter is due to a number of factors, including a decrease in coagulation factors as a result of the liver damage, thrombocytopenia due to consumption and underproduction in the bone marrow, and a consumptive coagulopathy initiated by the release of tissue factor by infected macrophages.68 The net result is DIC in patients with the heaviest viral loads.
The incubation period for Ebola virus disease is from 2 to 21 days, with shorter incubation periods correlating with exposure to a larger viral load. Viremia correlates with the abrupt onset of symptoms and signs of the disease (Fig. 8). The WHO and the Centers for Disease Control and Prevention have established criteria for making a diagnosis of Ebola virus disease that include the sudden onset of high fever and at least 3 of the following: headache, vomiting, loss of appetite, diarrhea, lethargy, stomach pain, aching muscles or joints, dysphagia, dyspnea, or hiccupping. The diagnosis is only confirmed with positive serology for Ebola virus.
Multiple serologic tests have been used to confirm the diagnosis of Ebola virus disease, with reverse- transcriptase polymerase chain reaction assay,69 antibody-capture enzyme-linked immunosorbent assay,55 and electron microscopy70 being the most widely used. Although these technologies are widely available, because of the associated biohazards, only a few laboratories in the world can safely perform them. These tests are performed in a biosafety level-4 facility because the viruses are highly virulent, could potentially be transmitted via an aerosol, and have a high mortality rate. The equipment used for the testing is not portable, and the tests take time to complete. The WHO has released a request for proposals for a portable device or devices that would not require a biosafety level-4 facility but could test for Ebola virus in <3 hours with a high degree of specificity and selectivity.71 Such a device is necessary not only to more quickly identify individuals requiring isolation but also to identify those individuals with similar symptoms who do not have the disease and whose care is currently being compromised because of concern about possible Ebola virus disease and contagion.
Not only are there no known treatments for Ebola virus disease, but very little is known about the mechanisms by which patients develop shock and DIC. The epidemics that have occurred during the past 4 decades have been in low-income countries with limited health care resources. Most patients do not have simple laboratory tests, such as a complete blood cell count, and more costly tests, such as a coagulation panel or cardiac output measurement, are rare. In addition, tests must be performed in a biosafety level-4 laboratory.
What we know has been learned from past epidemics and studies in nonhuman primates. Treatment is supportive. Dehydration is very common, so rehydration should be attempted with an oral balanced electrolyte solution. If the patient cannot maintain fluid balance because of gastrointestinal illness, IV crystalloid fluids should be administered. Hypoxia is reported to occur with Ebola virus disease,46,47 but during the current epidemic, it is not as common as one might expect (personal [written] communication, Robert Fowler, MDCM, World Health Organization, June, 2014) unless the patient develops multisystem organ dysfunction.
There are no predictors of survival. However, as was observed in the nonhuman primate studies, the greater the viral exposure, the shorter the incubation period, and the greater likelihood of death. Therefore, anyone who develops symptoms within 3 to 5 days of contact with an infected patient will likely have a worse outcome than someone who becomes symptomatic after many days.
Encephalitis has not been reported to occur as a complication with Ebola virus disease. Brain examinations at necropsy have confirmed this finding.41
In other viral hemorrhagic diseases, circulatory collapse is thought to be secondary to capillary leakage, decreasing intravascular volume, left ventricular end-diastolic pressure, and cardiac output.72 Although no specific observations support this recommendation in Ebola virus disease, the impression of clinicians in the field is that the hypotension responds to intravascular volume, unlike vasodilatory shock as seen in sepsis, and hemorrhagic shock as observed in DIC (personal communication: Robert Fowler, MDCM, WHO).
For reasons already discussed, there is little known about the management of DIC in patients with Ebola virus disease. DIC is assumed to be similar to that seen in other conditions, with the same laboratory manifestations. However, no reports from the current pandemic confirm this assumption. The DIC, although of interest, is not the reason patients die per se. Therefore, scarce resources are not being used to further characterize or treat individuals with DIC. To limit the degree of laboratory testing when patients do require transfusion, universal donor blood typically is administered. There has been discussion of the use of tranexamic acid to treat the fibrinolysis, but there are no reports of this having been tried.
The treatment of Ebola virus disease has been hampered because Ebola virus encodes 2 glycoproteins, the first is a membrane glycoprotein present in the viral membrane that mediates viral attachment and entry into host cells and the second is a secreted, nonstructural glycoprotein. The latter elicits host non-neutralizing antibodies that cross react with glycoprotein and therefore may prevent effective neutralization of the virus.73
Many people have survived Ebola virus disease. Their convalescent serum has been administered to others who were acutely ill with Ebola virus disease with anecdotal success.74 Convalescent serum therapy is more likely to be used in high-income countries where patients with Ebola virus disease have received care.
Another promising therapy is with monoclonal antibodies. These have been shown to reverse infection in nonhuman primates and to cure infected animals after symptoms and circulating Ebola virus are present.75 A combination of monoclonal antibodies (ZMapp), derived from 2 previous experiments, rescued 100% of rhesus macaques when given 5 days postchallenge, even in the presence of advanced disease.76 As of November 2014, ZMapp has been administered to 7 patients with the disease on a case-by-case basis under a compassionate use protocol, and additional studies of it and several other treatments and vaccines are under way.77
Other therapies are being investigated to treat Ebola virus disease, including the inhibition of membrane fusion by the virus (T-20 Enfuvirtide), transcription/replication inhibitors, nucleoside analogs, antisense oligonucleotides, small-interfering RNAs, maturation inhibitors to include furin inhibitors and budding inhibitors, and modulation of the cytokine storm by a variety of cytokine inhibitors.67
The current Ebola virus disease pandemic has lasted longer, affected more individuals, killed more patients, and created more social havoc than all previous Ebola virus disease epidemics combined. However, to put the current pandemic in context, viral hemorrhagic fevers in toto affect >100 million and kill 60,000 annually.78 Ebola virus disease has caused so much disruption because so little is known about it because of its high mortality and because of its clinical manifestations. However, the current pandemic has not occurred because Ebola virus has mutated but, rather, because a lack of information (avoidance of bats and infected nonhuman primates), inadequate public health practices (protocols for isolation and implementations of quarantines and unsafe burial practices), ease of travel, insufficient infection control (the nurse in Spain who contracted Ebola virus disease was reported in the media to have “touched” her face with her gloved hand after caring for a patient with Ebola virus disease), and poor health care education (not following established protocols for donning and removing PPE). On the basis of past experience, it is likely that 1 year from now nothing will have changed. However, on the basis of what we have learned, we as anesthesiologists should take the necessary steps now to better prepare and educate ourselves so that we can protect our families from the sequelae of such events and provide effective treatment for those to whom we will provide care during this and subsequent epidemics.
a Available at: http://www.cdc.gov/vhf/ebola/csv/graph1-cumulative-reported-cases-all.xlsx. Accessed May 16, 2015.
b Available at: http://apps.who.int/ebola/en/current-situation/ebola-situation-report-13-may-2015. Accessed May 16, 2015.
c Samb S, Felix B, Pomeroy R, Wills K. Eight bodies found after attack on Guinea Ebola education team. Thomson Reuters, 2014. Available at: http://www.reuters.com/article/2014/09/18/us-health-ebbola-guinea-idUSKBN0HD2JE20140918.
d Verbatim caption. Available at: http://phil.cdc.gov/phil/details.asp?pid=10816. Accessed May 16, 2015.
e Verbatim caption. Available at: http://www.cdc.gov/vhf/ebola/resources/virus-ecology.html. Accessed May 16, 2015.
f Verbatim caption. Available at: http://www.icm.jhu.edu/news/index.php?pageid=20. Accessed May 16, 2015.
g Available at: http://www.cdc.gov/vhf/ebola/ppt/ebola-101-cdc-slides-for-us-health care-workers.pptx. Accessed May 16, 2015.
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