1) Ebola Virus Disease is a rare, potentially fatal, disease caused by an infection of an Ebola virus strain. Ebola Virus Disease has also been called Ebola hemorrhagic fever. Four of the 5 identified Ebola virus species cause disease in humans: Ebola virus (Zaire ebolavirus), Sudan virus (Sudan ebolavirus), Tai Forest virus (Tai Forest ebolavirus, formerly Cote d'lvoire ebolavirus), and Bundibugyo virus (Bundibugyo ebolavirus). Reston virus (Reston ebolavirus) is the fifth virus species that has caused disease in nonhuman primates only. Outbreaks of Ebola have developed sporadically in Africa since it was discovered in 1976 near the Ebola River (Centers for Disease Control and Prevention (CDC), 2014; Breman et al, 1997; Le Guenno et al, 1995).
2) The Zaire subtype of Ebola appears most virulent to humans, while the Reston subtype has caused infection, but not disease in 4 humans (CDC, 1990). McCormick et al (1983) reported that fewer than 10 infectious particles of a Zaire strain were lethal for mice, whereas 10,000 infectious particles of a Sudan strain were unable to kill any of the mice (McCormick et al, 1983).
3) Ebola virus is pleomorphic and filamentous, with an average length of 920 nm and average diameter of 80 nm. The virus is a linear, single stranded RNA molecule, enclosed in a helical capsid, and covered by an envelope containing virus-specified glycoprotein spikes (Al-Ahdal, 1995). Ebola virus is structurally similar to Marburg virus, but antigenically different.

1) Johnson et al (1996) have described 3 strains or subtypes of Marburg virus: Ravn (RAV), Musoki (MUS) and Popp (POP) (Johnson et al, 1996).

a) Intensive supportive treatment is the mainstay of therapy. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.

a) Intensive supportive treatment is the mainstay of therapy. Transfusions of fresh frozen plasma/packed red blood cells, and platelets (as needed) for severe thrombocytopenia, bleeding. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Hemodialysis may be necessary in cases of renal failure.

a) PREHOSPITAL: Remove contaminated clothing immediately. Sites exposed to blood/body fluids should be immediately washed with soap and water. FIRST RESPONDERS: Any healthcare personnel should follow strict isolation precautions (ie, includes gloves, gown, mask) and avoid direct contact with blood or bodily fluids of a patient with suspected Ebola or Marburg virus infection.
b) HOSPITAL: Strict barrier techniques and infection control are recommended while treating any patient with confirmed or suspected Ebola or Marburg virus infection.

a) In cases of airway compromise, supportive measures including endotracheal intubation and mechanical ventilation may be necessary.

a) No antidote or vaccine is available for filovirus infections.

a) Hemodialysis is unlikely to be necessary, but may be needed in patients that develop acute renal failure.

a) HOME CRITERIA: Close contacts of filovirus-infected patients should be stringently monitored and asked to report any fever (ie, record temperature twice daily for 3 weeks). Surveillance should be continued for 3 weeks after the date of the last contact.
b) OBSERVATION CRITERIA: Any person who has a history of close physical contact with an infected patient(s) should be put under strict surveillance (ie, obtain temperature twice daily; in the case of a temperature greater than 38.3 degrees C (101 degrees F), hospitalize the patient immediately and place in strict isolation).
c) ADMISSION CRITERIA: All patients with suspected filovirus infections should be admitted to a strict isolation unit that can provide intensive care as needed; the staff should use barrier techniques.
d) CONSULT CRITERIA: Infectious disease staff/intensivists, should manage the care of these patients. All confirmed and suspected cases should be reported immediately through local and State health departments to the Viral Special Pathogens Branch of the Centers for Disease Control (CDC).

a) Failure to diagnose filovirus infection. Failure to appropriately use barriers or personal protective equipments causing further infection and exposure. Failure to recognize shock and hemorrhage.

a) Includes other hemorrhagic fevers (eg, Crimean-Congo hemorrhagic fever, Dengue hemorrhagic fever), typhoid fever, meningococcemia, toxic shock syndrome, malaria. Also includes noninfectious causes of bleeding manifestations, (eg, idiopathic or thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acute leukemia, and collagen-vascular diseases).

a) After about a week of illness, mental status changes often occur and include confusion, lack of concentration, memory loss, and delirium (Edmond et al, 1977; Johnson et al, 1996; Sodhi, 1996).
b) Delirium may be persistent throughout the infectious course of illness (Al-Ahdal, 1995; WHO, 1978a). Combativeness and bizarre behavior were commonly seen during a 1976 Ebola outbreak in Sudan (n=183), with abnormal behavior often persisting for several weeks following recovery (WHO, 1978a).

a) An early and common symptom of illness is severe headache and general malaise with chills and fever (Centers for Disease Control and Prevention (CDC), 2014; Geisbert & Jaax, 1998; CDC, 1988; WHO, 1995).

a) It is not unusual for sudden blindness, tinnitus, hearing loss, and dysesthesias to develop in the late phases of filovirus infections (Bwaka et al, 1999; Rollin & Ksiazek, 1998).

a) Beginning the second week of the illness, frank bleeding, which can arise from any part of the gastrointestinal tract and from multiple other sites, is common (Centers for Disease Control and Prevention (CDC), 2014; CDC, 1988; Geisbert & Jaax, 1998; WHO, 1978b; WHO, 1995; Johnson et al, 1996).
b) Gingival bleeding may occur (WHO, 1978b; Baron et al, 1983; Anon, 1996; Johnson et al, 1996).

a) Early in the illness, anorexia, nausea, abdominal pain, vomiting and diarrhea often occur, and may be persistent, resulting in significant fluid losses (Centers for Disease Control and Prevention (CDC), 2014; Leroy et al, 2002; CDC, 1988; Edmond et al, 1977; Geisbert & Jaax, 1998; WHO, 1978b; Al-Ahdal, 1995; Baron et al, 1983; Rollin & Ksiazek, 1998; Bwaka et al, 1999; Formenty et al, 1999).

a) Acute pancreatitis may be part of the pathogenesis of Ebola hemorrhagic fever (WHO, 1978b).

a) Non-icteric hepatitis is included in the pathogenesis of filoviral infections (WHO, 1978b). Serum liver function tests may be markedly elevated. Focal necrosis of the liver has been reported (Formenty et al, 1999; Al-Ahdal, 1995).

a) MONKEYS: Abrupt, marked elevation of hepatic enzymes, including LDH, ALT and AST, were reported in cynomolgus monkeys with Ebola viral infections (Dalgard et al, 1992).

a) MONKEYS: Histopathologic examination of monkeys infected with Ebola Reston virus revealed hepatocellular necrosis ranging from individual cells to clusters multifocally scattered throughout the parenchyma. This appeared to be a common effect in the infected monkeys (Dalgard et al, 1992).

a) MONKEYS: Splenomegaly was the most consistent finding on necropsy in monkeys with known Ebola Reston virus infection. The spleen was often 3 to 4 times normal size (Dalgard et al, 1992).

a) Proteinuria has been reported; it was noted on the fourth day of illness and persisted for about one week (Edmond et al, 1977). Decreased urine output was also noted.
b) Proteinuria was reported as uniformly positive and was used as a major diagnostic criterion in an Ebola hemorrhagic fever outbreak in Zaire in 1976 (WHO, 1978b). Proteinuria was observed in a few patients in a 1976 Ebola outbreak in Sudan (WHO, 1978a).

a) Oliguria and anuria have been reported following filoviral infections (WHO, 1978b). In severe cases renal failure, necessitating hemodialysis, may occur (Johnson et al, 1996).

a) Multifocal petechial hemorrhages have been observed in the renal cortex and pelvis, and urinary bladder at necropsy (Geisbert & Jaax, 1998).

a) Eighteen days following exposure to Ebola virus from an accidental needle prick, semen was still positive for the virus. The patient recovered (Edmond et al, 1977).
b) A seminal fluid sample, obtained from one patient who was recovering from an Ebola virus infection during the 1995 Ebola hemorrhagic fever outbreak in Kikwit, Democratic Republlic of Congo, was positive for the infectious virus 82 days post-onset of the disease (Rodriguez et al, 1999).

a) Orchitis was occasionally manifested in males during a 1976 Ebola outbreak in Sudan (WHO, 1978a). Unilateral orchitis is reported as a late manifestation of disease in convalescent patients (Bwaka et al, 1999).

a) INCIDENCE: During a 1976 Ebola outbreak in Sudan, 100% of patients (n=183) experienced fever (WHO, 1978a).

a) Beginning the second week of the illness, severe hemorrhagic manifestations are common. Gastrointestinal bleeding, which can arise from any part of the GI tract, is most common, although bleeding may occur from other organ sites, any orifice, mucous membranes, and skin (Centers for Disease Control and Prevention (CDC), 2014; Geisbert & Jaax, 1998; CDC, 1988; WHO, 1978b; Sodhi, 1996). Overt hemorrhagic features may supervene from day 5 onward (Richards et al, 2000). Hemoglobin levels will be decreased during the acute phase of illness during active hemorrhaging. Richards et al (2000) reported a death due to refractory thrombocytopenia and an intracerebral hemorrhage in one patient (Richards et al, 2000).
b) Following viral replication in many organs, focal necrosis occurs in the liver, kidneys, and lymphatics. The blood fails to clot, and main lesions appear in the vascular endothelium and the platelets, resulting in severe bleeding in the liver, mucosa, abdomen, pericardium, and other organs.

a) Disseminated intravascular coagulation (DIC) may occur in the later stages of illness and is usually present in fatal cases. Thrombocytopenia, prolonged prothrombin, and partial thromboplastin times are reported to be consistent with DIC (Geisbert & Jaax, 1998; WHO, 1978b; Johnson et al, 1996; CDC, 1995a; Borio et al, 2002). DIC may lead to micro-thrombi with surrounding tissue infarction (Johnson et al, 1996). Thrombocytopenia may be evident early in the disease; a petechial rash may appear on days 3-10 (Richards et al, 2000).

a) Leukocytosis may occur in filovirus infections (Geisbert & Jaax, 1998; Johnson et al, 1996). White blood cell counts, when measured, were elevated in patients following Ebola viral infections in Sudan in 1976 (WHO, 1978a).

a) Neutrophilia and lymphopenia are striking features of filoviral infections and occur early in the illness (CDC, 1988; Edmond et al, 1977; Takada & Kawaoka, 1998; Sodhi, 1996).

a) GUINEA PIGS: Four days following aerogenic infection with Marburg virus, guinea pigs exhibited leukopenia and hyperthermia as the earliest virological and clinical signs of disease (Lub et al, 1995).

a) Approximately 5 to 7 days after the onset of illness, a transient and morbilliform skin rash, which subsequently desquamates, often appears (WHO, 1978b; Edmond et al, 1977; CDC, 1988; Johnson et al, 1996; Rollin & Ksiazek, 1998; Bwaka et al, 1999; Formenty et al, 1999; Borio et al, 2002). The rash often spreads to all areas of the body and may become confluent.

a) Beginning the second week of the illness, hemorrhagic manifestations appear and include petechiae as well as frank bleeding (Centers for Disease Control and Prevention (CDC), 2014; CDC, 1988; Johnson et al, 1996; Sodhi, 1996; Edmond et al, 1977).

a) Severe malaise, extreme weakness with myalgias, and joint pain are commonly noted throughout the course of illness (Centers for Disease Control and Prevention (CDC), 2014; CDC, 1988; Edmond et al, 1977; WHO, 1978b; WHO, 1995; Al-Ahdal, 1995; Rollin & Ksiazek, 1998). Asthenia may persist for several weeks following recovery (Rollin & Ksiazek, 1998). Arthralgia, asymmetrical or symmetrical, occurs. It is sometimes migratory, principally involves the large joints, and is a common late manifestation of disease in convalescent patients (Bwaka et al, 1999; Rowe et al, 1999).
b) CASE REPORT: A woman from Medemba village in Gabon presented to the hospital with symptoms of high fever, asthenia, arthralgia, diarrhea, and vomiting. The patient died 4 days later, with evidence of blood in her feces and mouth. She was the fifth person in her family to develop similar symptoms and subsequently die. The symptoms and inter-family transmission suggested Ebola hemorrhagic fever. Sera from two patients, who had developed similar symptoms and had died after coming into contact with the woman, showed high titers of Ebola virus antigen and contained Ebola virus RNA, confirming the suspected diagnosis of Ebola hemorrhagic fever (Leroy et al, 2002).

a) MONKEYS: Multifocal necrosis of the zona glomerulosa in the adrenal cortex was noted on histopathology examination in monkeys infected with Ebola Reston virus (Dalgard et al, 1992).

a) Asymptomatic, replicative Ebola infection can occur in humans. Seroconversion occurs, however, circulating Ebola antigen is not detected. It is suggested that asymptomatic infections do not result from viral mutations. These individuals exhibit a strong inflammatory response early in the infectious process, as characterized by high circulating concentrations of cytokines and chemokines (Leroy et al, 2000).
b) Due to immunosuppression, superinfections with bacteria or fungus may occur during the course of a filoviral infection. Johnson et al (1996) and Geisbert & Jaax (1998) reported Pseudomonas aeruginosa isolated from the blood of fatal Marburg hemorrhagic fever victims (Johnson et al, 1996; Geisbert & Jaax, 1998), and Edmond et al (1977) reported an extensive candidiasis in throat tissue of an Ebola hemorrhagic fever victim (Edmond et al, 1977).
c) Infections with Klebsiella, E coli and S aureus have also been reported (Geisbert & Jaax, 1998). Secondary bacteremia and sepsis may develop due to damage of the gastrointestinal mucosa.

a) Lymphadenopathy may be seen during the acute phase of filoviral illnesses (Geisbert & Jaax, 1998; Sodhi, 1996).

a) A significant level of immune activation accompanies and potentially contributes to terminal Ebola virus infections. Markedly elevated levels of interferon (IFN)-y, IFN-a, interleukin (IL)-2, IL-10, and tumor necrosis factor-a are associated with fatal Ebola viral infections (Villinger et al, 1999).

a) Edema of the soft palate and pharynx may lead to dysphagia. Cough may be associated with oral/throat lesions. Aphthous-like ulcers may be seen in the oral cavities in some patients (WHO, 1978a).
b) INCIDENCE: Sore throat and cough were reported in 63% and 49% of patients (n=183), respectively, in a 1976 Ebola outbreak in Sudan (WHO, 1978a).

a) Hypotension is commonly seen during the acute stage of illness. Death may ensue as a result of intractable hemorrhagic shock and multiple organ failure (Geisbert & Jaax, 1998; Johnson et al, 1996; Sodhi, 1996) (CDC, 1995).
b) In 3 cases of Ebola infection, hypovolemic shock preceded death (Baron et al, 1983). Death may be due to cardiac failure (Johnson et al, 1996). Clinical shock, in severe cases, may lead to diffuse coagulative necrosis (Johnson et al, 1996).

a) Chest pain is a common symptom of Ebola viral infections, reported in 83% of patients (n=183) in a 1976 Ebola outbreak in Sudan (WHO, 1978a).
b) Chest pain was often associated with dry cough. Basilar rales were commonly noted on chest examination. The incidence of chest pain in Marburg viral infections appears to be less frequent (WHO, 1978a).

a) Two patients with Ebola hemorrhagic fever died with terminal tachycardia (WHO, 1978b).

a) ECG tracings suggestive of myocarditis and pericarditis have been described in patients with filovirus diseases (WHO, 1978a).

a) Blood-tinged pleural effusions and hemorrhagic lungs and tracheobronchial tree have been reported on autopsy following filoviral illnesses (Geisbert & Jaax, 1998; Johnson et al, 1996). Focal necrosis is widely seen in the lungs (Sodhi, 1996).

a) Hiccup and tachypnea may occur in severe cases and are usually precursors of death (Rollin & Ksiazek, 1998). Hiccups were reported in 15% of Ebola viral cases (n=66) in a Kikwit (area of Zaire) outbreak (CDC, 1995b). A high frequency (25%) of hyperventilation was reported as a terminal event, probably reflecting underlying metabolic abnormalities rather than cardiac or lung involvement (Bwaka et al, 1999).

a) GUINEA PIGS: Following aerogenic infection with Marburg virus, primary viral multiplication occurred in the lungs and was reported at the initial stage of infection. Bronchopulmonary washings revealed the presence of virus 2 to 3 days after the infection (Lub et al, 1995).

a) MONKEYS: Patchy interstitial pneumonia was noted on histopathology examination of monkeys infected with Ebola Reston virus (Dalgard et al, 1992).

a) Intensive supportive treatment is the mainstay of therapy. No antidote or vaccine is available for filovirus infections. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.

a) Intensive supportive treatment is the mainstay of therapy. No antidote or vaccine is available for filovirus infections. Transfusions of fresh frozen plasma/packed red blood cells, and platelets (as needed) for severe thrombocytopenia, bleeding. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Hemodialysis may be necessary in cases of renal failure.

a) Contaminated environmental surfaces or inanimate objects should be cleansed and disinfected using standard procedures with EPA registered hospital disinfectant or a 1:100 dilution of household bleach (CDC, 1995).

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) In the West Africa Ebola outbreak of 2014, the use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease was evaluated as a matter of immediate priority. Some Ebola treatment centers have administered this empiric treatment (World Health Organization (WHO), 2014).
b) There are several novel therapies being considered to treat Ebola virus disease (World Health Organization (WHO), 2014).
c) In a case of accidental injection of Ebola virus (from an infected guinea pig) in a laboratory worker, Edmond et al (1977) described treatment with interferon (3 million units IM every 12 hours for 14 days) which was started 20 hours after the onset of the patient's illness. Convalescent serum, from patients recovering from filovirus infection, was given 47 hours after onset of illness, as a 4 hour infusion. On the first and second day of illness, viral concentrations in the blood were at peak levels. Viral concentrations dropped after the start of interferon and serotherapy and remained low until the viremia disappeared on the ninth day of illness. This patient had a relatively mild course of illness and an absence hemorrhage (Edmond et al, 1977). The value of this therapy cannot be accurately assessed without further experiences (Mupapa et al, 1999). Sadek et al (1999) reported no statistical evidence of survival benefit following transfusions of convalescent serum (Sadek et al, 1999).
d) An immunoglobulin to Ebola virus infection has been formed from hyperimmune equine blood sera. The immunoglobulin has been given to monkeys infected intramuscularly with doses of 110 to 29 LD50 Ebola virus and shown to offer protection up to 100%. The immunoglobulin has not been tested in humans (Borisevich et al, 1995) but has shown some activity in suppressing viremia and delaying disease onset and death in non-human primates.
e) Wimer (2002) has suggested that intravenous administration of plant mitogens (particularly PHA) may be able to inhibit Ebola virus glycoprotein effects, that cause vascular cellular damage, as well as interacting with T lymphocytes to stimulate the entire immune system, thereby supporting myelopoiesis and lymphopoiesis, in the event of bioweaponry/bioterrorist assaults (Wimer, 2002).
f) Research and construction of IgG Fab anti-Ebola antibodies is occurring, but is currently in the early phases of development and animal trials (Breman et al, 1997). Non-human primates and guinea pigs will be used to test the immunologic interventions.
g) Development and animal testing of an anti-Ebola vaccine is being investigated (Breman et al, 1997).
h) A study was conducted to evaluate the effects of an anti-Ebola vaccine on non-human primates that was previously successful in protecting mice and guinea pigs from an Ebola viral infection. The vaccine strategies that were used included one of four antigens: RNA replicon particles derived from an attenuated strain of Venezuelan equine encephalitis virus expressing the Ebola virus (EBOV) glycoprotein and nucleoprotein, the recombinant Vaccinia virus expressing EBOV glycoprotein, liposomes containing lipid A and inactivated EBOV, or a concentrated and inactivated whole-virion preparation. All of the primates involved in the study (n=26), including 4 primates that were not given one of the vaccine strategies, were challenged with a Zaire subtype of EBOV, which was isolated from a human patient in 1995. Twenty-five of the 26 primates died within 11 days post-challenge. The one primate that did survive the challenge received the inactivated virion antigen and did not become ill during the study. The primate's neutralizing antibody titers were greater than 320 at day 26 post-challenge and then decreased to 80 at days 26, 61, 99, and 902 post-challenge. The results of this study show that the vaccine strategies, which were successful in protecting rodents from EBOV, are not effective in protecting non-human primates from EBOV. It is suggested that this inconsistency in vaccine efficacy may be due to differences in disease pathology between rodents and primates (Geisbert et al, 2002).
i) A study, involving rhesus macaque monkeys, was conducted to determine the efficacy of a recombinant nematode anticoagulant protein (an inhibitor of factor VIIa/tissue factor) in alleviating effects of Ebola virus infection and subsequently prolonging survival time. The recombinant protein (rNAPc2) was administered to the monkeys either 10 minutes (n=6) or 24 hours (n=3) after a high-dose subcutaneous administration of the Zaire subtype Ebola virus. Three of the monkeys were untreated Ebola virus-positive controls. In the 24-hour group, 1 of the 3 monkeys survived the challenge and remained healthy for at least 1 year. The other two monkeys died within 14 days post-challenge. In the 10-minute group, 2 of the 6 monkeys survived and remained healthy at least 9 months post-challenge. The other four monkeys died within 14 days post-challenge (Geisbert et al, 2003).

1) Treatment with interferon (3 million units IM every 12 hours for 14 days) was started 20 hours after the onset of illness. Convalescent serum was given 47 hours after onset of illness. Between the fourth and seventh day of his illness, symptoms were at their height. Severe weakness, profuse watery diarrhea, persistent vomiting, albuminuria, and a confluent rash covering most of his body developed. Sore throat, with Candidiasis, occurred and was treated. His urinary output dropped to its lowest level, despite adequate fluid replacement. His general condition began to improve after approximately 10 days of illness, with fever subsiding and rash improving. A slow recovery ensued over a 10 week period.
2) On the first and second day of illness, viral concentrations in the blood were at peak levels. Viral concentrations dropped after the start of interferon and serotherapy and remained low until the viremia disappeared on the ninth day of illness (Edmond et al, 1977).

1) Tissue samples sent to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) were evaluated and found to be positive for Marburg virus. Necropsy examination showed extensive petechial and purpuric hemorrhage in the skin, conjunctiva, and gastrointestinal mucosa. Hemorrhage of the lungs and tracheobronchial tree were noted. Pleural, pericardial, and peritoneal effusions were bloody. The epicardium, renal cortex and pelvis, and urinary bladder were observed to have multifocal petechial hemorrhages. No hemorrhage was noted in the liver, spleen, pancreas, or adrenals.

a) The highest Ebola viral concentrations have been reported in the blood, with lower levels present in throat washings and urine (WHO, 1978a; WHO, 1978b; Johnson et al, 1995).