Ebola Virus Disease

Terminology

Clinical Clarification

• Ebola virus disease is a severe, often fatal, viral infection spread by direct contact. It causes fever and gastrointestinal symptoms with progression to capillary leak syndrome, disseminated intravascular coagulation, shock, and multisystem organ failure

• Ebola virus disease is caused by Ebola virus, which is a single-stranded RNA virus that belongs to the Filoviridae family.

• First identified in 1976, it led to a major outbreak in West Africa in 2014 to 2015, and there have been sporadic outbreaks since

Classification

• Person under investigation for Ebola virus disease ^[13]

  • Fever (subjective or measured) or symptoms (eg, severe headache, fatigue, muscle pain, vomiting, diarrhea, abdominal pain, unexplained hemorrhage), and

  • Epidemiologic risk factor within the 21 days before symptom onset

• Confirmed case of Ebola virus disease ^[13]

  • Laboratory-confirmed Ebola virus infection

Diagnosis

Clinical Presentation

History

• Ebola virus disease should be considered in a patient who, in addition to having appropriate clinical features, has also had exposure to the virus either owing to travel or residence in endemic areas of Africa or through direct contact with infected patient ^[13]

• A person is considered exposed if:

  • Patient has lived or traveled in a country with Ebola transmission within the 21 days before illness onset, or ^[8]

  • Patient has had contact with someone with Ebola virus disease within the past 21 days ^[8]

• Determine patient's level of risk on the basis of extent of contact, stage of illness in source (eg, symptomatic or not), use of personal protective equipment, and presence of concurrent widespread infection

  • Important risks for exposures to Ebola virus include:

    • Contact with blood or other body fluids of acutely ill persons with suspected or confirmed Ebola virus disease ^[14]

      • Providing care in any setting (eg, home, clinic, hospital) poses high risk of such contact

    • Contact with objects (such as needles and syringes) contaminated with blood or other body fluids ^[14]

    • Contact with body of person who died of suspected or confirmed Ebola virus disease ^[14]

      • Participation in funeral rituals, including preparation of bodies for burial or touching a corpse at a traditional burial ceremony ^[15]

    • Working in a laboratory where human specimens are handled ^[16]

    • Handling wild animals or carcasses that may be infected with Ebola virus (eg, primates, fruit bats, duikers) ^[14]

    • Contact with semen from a male patient who has recovered from Ebola virus disease (eg, oral, vaginal, or anal sex) ^[14]

• Symptoms

  • Typically appear 2 to 21 days after exposure; mean is 6 to 12 days ^[1]

  • Nonspecific symptoms develop first and last for several days

    • Fever, usually of abrupt onset ^[1]

    • Anorexia ^[1]

    • Weakness

    • Fatigue ^[1]

    • Muscle pain ^[1]

    • Protracted hiccups have been reported ^[1]

  • Gastrointestinal symptoms usually develop approximately 3 to 5 days after onset of nonspecific symptoms, approximately 14 to 16 days post-exposure ^[1]

    • Abdominal pain

    • Diarrhea, which is profuse and watery ^[1]

    • Vomiting ^[1]

    • Decreased or absent urine output due to volume depletion

  • Other symptoms that develop after day 6 may represent complications of hemorrhage caused by disseminated intravascular coagulation, cerebral edema, septic shock, and multiorgan failure

    • Bleeding was reported in approximately 18% of cases, most commonly in the stool (6%), in the 2022 outbreak

      • Other bleeding sites include skin and mucous membranes (eg, hematemesis from upper gastrointestinal tract)

    • Cardiac and respiratory findings such as chest pain, shortness of breath, tachypnea, and dyspnea ^[1]

    • Neurologic findings such as headache, confusion, and seizures ^[1]

    • Ocular findings such as photophobia and vision changes ^[1]

Physical examination

• Fever ^[1]

• Hypotension and tachycardia often present in later stage of disease

• Skin has poor turgor owing to dehydration

• Petechiae, ecchymosis, and oozing from venipuncture or IV line sites

• Conjunctival injection may be seen

• Oral mucous membranes are usually dry

• Diffuse erythematous maculopapular rash of neck, trunk, and arms on days 5 to 7, which eventually desquamates ^[1]

• Lung examination findings may be normal initially; in later stages, they may include rales (due to pulmonary edema) or dullness to percussion (due to pleural effusion)

• Abdominal examination findings may be normal in early stages; as gastrointestinal symptoms develop, abdomen may be distended or tender to palpation

• Pedal edema may be seen with capillary leak syndrome

• Neurologic examination findings may be normal initially

  • If cerebral edema develops, patient may be confused, delirious, or somnolent

Causes and Risk Factors

Causes

• Ebola virus ^[17]

  • Genus Ebolavirus contains various species (eg, Zaire ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, Bundibugyo ebolavirus) that cause human disease

    • Many large outbreaks, including the 2014 to 2015 West African epidemic, have been caused by the Zaire species ^[18]

    • R eston ebolavirus and Bombali ebolavirus species have not been associated with human illness ^[1]

• The origin of the Ebola virus is unclear, but may have a natural animal reservoir, most likely primates or bats ^[1]

• From 1976 to 2022, there were 35 Ebola virus disease outbreaks with 48 primary/index cases

  • Majority of outbreaks were associated with wildlife spillover

  • Resurgence of human-to-human transmission could account for roughly a quarter of outbreaks caused by Ebola virus ^[12]

  • In rare cases, relapsing disease and long-term shedding of virus in semen can lead to transmission ^[19][20]

Risk factors and/or associations

Other risk factors/associations

• For health care workers especially

  • Health care workers are at risk of Ebola virus entry via their own uncovered, broken skin or unprotected mucous membranes through the following actions: ^[14]

    • Touching a patient's body fluids (eg, blood, vomit, feces, saliva, sweat, urine, semen)

      • Transmission is most likely during severe illness; may be caused by microcontamination with body fluids not visible on skin

    • Touching a patient's skin

    • Touching contaminated medical supplies and equipment

    • Touching contaminated environmental surfaces or fomites

  • Similarly, the following events pose risk:

    • Splashes to unprotected mucous membranes

    • Percutaneous exposure to patient's body fluids via needle or other sharp object

    • Procedures that increase environmental contamination with infectious material

• For the public

  • Personal and household contacts are also at risk from Ebola virus entry through uncovered, broken skin or unprotected mucous membranes, either via direct exposure to blood or other body fluids or via contact with contaminated surfaces ^[14]

  • Ebola may also be transmitted by sexual activity via semen

  • Participants in certain burial rituals (those that involve touching the corpse) of a person who died while infected with Ebola virus are at high risk ^[15]

  • Airborne transmission has not been documented in human populations

Diagnostic Procedures

Primary diagnostic tools

• Diagnosis is suggested by history (level of exposure and symptoms) and physical examination (fever or other suggestive findings)

• Laboratory testing (after consultation with local and state health department) confirms infection

  • Indications for testing vary with the worldwide activity of Ebola virus disease ^[13]

  • In the absence of local disease activity, public health officials play a major role in determining the need for testing and implementing where deemed appropriate

  • CDC recommends testing only for persons who meet the criteria for a person under investigation, which includes both of the following: ^[13]

    • Elevated body temperature or subjective fever or symptoms, including severe headache, fatigue, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage, and

    • An epidemiologic risk factor within the 21 days before onset of symptoms as noted above

  • Testing is usually not indicated in persons without symptoms and recognized exposure history

    • Having been in an epidemic area within the last 21 days without other identified exposure presents "little risk" per CDC (eg, never within 1 m of a person with known or suspected Ebola virus disease) ^[14]

    • Nonetheless, any person with such travel history who presents to an emergency department (even if asymptomatic) requires reporting to local or state health department

      • Health department will contact CDC ^[13]

      • Reporting provides data for outbreak control if it becomes necessary

• Key diagnostic tool is real-time reverse transcription polymerase chain reaction to identify viral nucleic acid, which can be detected 3 days after symptom onset ^[1]

• Other blood tests appropriate for evaluation of a severe febrile illness include CBC, coagulation tests, chemistry panel, cultures of blood and other clinically indicated specimens, and, if appropriate for patient's history, malaria tests

• CDC recommends an "identify, isolate, and inform" policy on every patient entering an emergency department in the context of an outbreak of Ebola virus disease ^[8]

  • First identify those in the broad risk category of having lived or traveled in a high-risk region or having had contact with a patient infected with Ebola virus in the past 21 days. Also, quickly identify those patients who have signs or symptoms of possible Ebola virus disease, including fever, headache, fatigue, weakness, abdominal pain, vomiting, diarrhea, or signs of hemorrhage, such as coffee-ground vomit or bloody or black diarrhea

  • Isolate those patients immediately in a separate room with attached private bathroom or covered bedside commode

  • Inform the local and state health department

Laboratory

• Specific diagnostic tests

  • Ebola testing in the United States is performed only at a CDC-affiliated laboratory and is confirmed by CDC ^[3]

  • Consult local and state health department immediately in cases of suspected Ebola virus disease to help determine if testing and identification of contacts is necessary ^[3]

    • These agencies will consult with CDC. No specimens will be accepted without prior consultation ^[3]

  • Complete information about shipping of specimens to CDC is available on CDC website ^[3]

    • Real-time reverse transcription polymerase chain reaction detects viral nucleic acid and is detectable within 3 days after symptom onset ^[1]

      • Consult with CDC for specific instructions on specimen handling

      • In general, submit 4 mL of whole blood preserved with EDTA (preferred); specimens with sodium polyanethol sulfonate, citrate, or clot activator are acceptable

      • Specimens should be immediately stored or transported at 2 to 8 °C or frozen on cold packs

      • Virus is detectable by day 3 of symptoms; result is reported quantitatively (viral load)

      • Negative result for specimen collected less than 72 hours after onset of symptoms does not necessarily exclude Ebola virus infection ^[21]

        • Repeated test is required if patient is still symptomatic after 72 hours

        • Repeated test is not required if symptoms have resolved

      • Negative result for blood specimen collected more than 72 hours after symptom onset excludes Ebola virus infection ^[21]

      • Positive results are considered presumptive until confirmed by CDC

    • Rapid immunoassays have been developed but should only be used for a provisional diagnosis when reverse transcription polymerase chain reaction is not available ^[1][22]

• Routine laboratory testing

  • Obtain testing at first contact and repeat at intervals as guided by clinical status

  • Do not send these specimens to CDC

  • Do not use a pneumatic tube system for sample transport

    • CBC

      • Leukopenia due to lymphopenia initially, followed by increasing neutrophil count with a left shift ^[23]

      • Decreased platelet counts (50,000-100,000 cells/mm³) ^[24]

    • Complete metabolic panel ^[25]

      • Potassium, sodium, magnesium, and calcium levels are commonly low and fluctuate with IV fluid rehydration; however, in some cases potassium is high ^[1]

      • BUN and creatinine levels are often elevated at admission; follow-up to assess hydration status and renal function

    • Prothrombin and partial thromboplastin time ^[24]

      • Either or both may be prolonged, especially with severe disease

    • Fibrin degradation product levels ^[24]

      • May be elevated (consistent with disseminated intravascular coagulation), especially with severe disease

    • Hepatic transaminase levels ^[24]

      • Usually elevated, with AST level greater than ALT

      • Peak at more than 1000 units/L

    • Amylase level ^[24]

      • Usually elevated, reflecting pancreatic inflammation

    • Creatine kinase ^[26]

      • Frequently elevated, indicating skeletal muscle injury, with rhabdomyolysis occurring in more than 50% of cases

    • Blood cultures are done to rule out alternate diagnoses (eg, typhoid fever, meningococcemia)

    • Malaria smear if patient has been in an endemic area ^[23]

Imaging

• Chest radiography is routine; best time to obtain it is after central venous line placement if the latter is necessary

Differential Diagnosis

Most common

• Malaria ^[1]

  • Potentially fatal systemic febrile illness caused by infection of RBCs with any 1 of 5 Plasmodium parasite species transmitted by the bite of certain Anopheles mosquitoes

  • Malaria may initially be clinically indistinguishable from Ebola virus disease

  • Uncomplicated malaria should not present with bleeding diathesis, but complicated malaria can be associated with coagulopathy

  • Differentiate from malaria with thick and thin blood smears or molecular studies

• Typhoid fever

  • Initial symptoms are similar, but onset is slower with typhoid fever and myalgias occur less frequently

  • Typhoid fever is more likely to manifest with early fever and constipation; abdominal pain starts in second week of illness

  • Differentiate with laboratory testing; typhoid fever is most commonly diagnosed with blood and/or bone marrow cultures or, if available, ELISA antigen testing

• Meningococcemia

  • Meningococcemia progresses much more rapidly than Ebola virus disease, with deterioration within 24 hours of symptom onset

  • Purpuric rash may occur in both

  • African meningitis belt is farther north than the endemic areas of Ebola virus infection; however, the 2 areas border each other

  • Differentiate with laboratory testing, including blood and cerebrospinal fluid cultures and polymerase chain reaction for Neisseria meningitidis

• Bacterial sepsis

  • Life-threatening syndrome of organ dysfunction caused by microbial infection in conjunction with a dysregulated host response

  • Presentations may be similar with fever and nonspecific systemic symptoms (eg, myalgia, arthralgia, nausea)

  • History of Ebola virus exposure (geographically or via infected person) is the primary differentiating factor, but such exposure does not exclude bacterial sepsis

  • Differentiate with bacterial cultures of blood and other clinically appropriate specimens

• Dengue fever

  • Febrile illness of varying severity caused by any of several dengue virus serotypes; presentation may be similar to early Ebola virus disease including fever, headache, vomiting, muscle spasm, and skin rash

  • It can also lead to hemorrhagic fever as well as dengue shock syndrome, which are clinically similar to Ebola

  • Transmission, however, is through a vector/mosquito (ie, Aedes aegypti)

  • Diagnosis is established via cell cultures, nucleic acid detection by polymerase chain reaction, or serologic testing

• Influenza

  • Acute, seasonally epidemic, highly contagious, and febrile respiratory illness caused by infection with influenza virus

  • Presentation varies from mild to severe

  • Symptoms include fever, rhinorrhea, sore throat, muscle pain, headache, and fatigue

  • Can cause pneumonia and acute respiratory distress syndrome

  • Diagnosed with rapid diagnostic tests, using molecular assays for definitive diagnosis

• Marburg virus infection

  • Causes a viral hemorrhagic fever syndrome

  • Disease onset is with constitutional symptoms including high-grade fever as well as gastrointestinal symptoms; rash can occur during this phase

  • This is followed by prostration, dyspnea, edema, conjunctival injection, viral exanthema, and central nervous system symptoms

  • Diagnosed with antibody-capture ELISA, antigen-capture detection tests, reverse transcriptase polymerase chain reaction assay, or cell culture

Treatment

Goals

• Provide supportive care to enable the patient's own immune system to eradicate the infection ^[1]

• Administer therapeutic options

  • Ansuvimab and atoltivimab–maftivimab–odesivimab-ebgn are FDA- approved monoclonal antibodies for adult and pediatric patients with Ebola caused by Zaire ebolavirus ^[1][27]

Disposition

Admission criteria

All patients with confirmed Ebola virus infection should be admitted to an appropriate facility, ideally in a hospital with staff experienced with providing care for patients with Ebola virus disease; a dedicated biocontainment unit is preferred

All patients considered to be persons under investigation for Ebola virus disease should be hospitalized under isolation in an appropriate facility until infection is either confirmed or ruled out

Criteria for ICU admission

• All patients with confirmed Ebola virus disease should receive care directed by infectious disease and critical care physicians in an isolation room or unit containing dedicated equipment necessary for provision of intensive care

Recommendations for specialist referral

• Infectious disease and critical care specialists should manage the patient's care, with additional specialty input as clinically indicated

Treatment Options

Because of the lethal nature of the infection and the high viral loads characteristic of severe infection, stringent infection control and use of personal protective measures are essential and an integral part of patient management

• Minimize the number of personnel exposed to the patient ^[9]

• All personnel should wear full personal protective equipment after receiving full training on its use, including donning and doffing ^[2]

  • Donning and doffing procedures must be witnessed ^[2]

  • There are 2 levels of personal protective equipment, as follows:

    • For patients suspected to have Ebola who appear stable; do not have active bleeding, vomiting, or copious diarrhea; and will not need invasive or aerosol-generating procedures, health care workers should wear, at a minimum, the following: ^[11]

      • Single-use fluid-resistant gown that extends to at least mid-calf or single-use fluid-resistant coveralls without integrated hood

      • Single-use full face shield

      • Single-use facemask

      • 2 pairs of single-use gloves; at a minimum, outer gloves should have extended cuffs

    • For patients with ^[2]

      • Confirmed Ebola virus disease OR

      • Suspected to have Ebola virus disease and clinically unstable with active bleeding, vomiting, or copious diarrhea OR

      • Suspected to have Ebola virus disease and require invasive or aerosol-generating procedures

        • Health care workers should wear full personal protective equipment that fully covers skin and clothing and prevents any exposure of the eyes, nose, and mouth including:

          • Single-use impermeable gown extending to at least mid-calf, or single-use impermeable coverall

          • Powered air-purifying respirator or single-use N95 respirator with single-use surgical hood extending to shoulders and single-use full face shield

          • 2 pairs of single-use gloves; at a minimum, outer gloves should have extended cuffs

          • Single-use boot covers

          • Single-use apron

• Use dedicated rooms and equipment only for patients with Ebola virus disease, preferably in a single room with door closed and private bathroom ^[1][9]

  • If aerosol-generating procedure is anticipated, patient should be placed in airborne infection isolation room

• Dedicated biocontainment unit is preferred (available at the University of Nebraska, NIH Clinical Center, and several other institutions)

• Hand hygiene should be performed using an alcohol-based hand rub or soap and water ^[1][28]

Supportive measures ^[25]

• For patients who are not severely ill (early stages) and who are not vomiting, oral fluids (eg, oral rehydration solution) are preferred ^[29]

  • Antiemetics (eg, ondansetron) can be administered for nausea and vomiting ^[1]

  • Antidiarrheal agents can help reduce volume loss from gastrointestinal tract ^[1]

  • Acetaminophen can be used to treat fever ^[1]

  • NSAIDs including aspirin should be avoided in most cases due to the risk of Ebola-associated renal failure ^[1]

• For severely ill patients, the above therapeutics can be used; additionally:

  • Administer aggressive IV fluids to maintain hydration

    • Adjust fluid input based on careful monitoring of fluid output, accounting for urinary, emetic, and fecal losses; consider rectal tube owing to copious amounts of stool to be excreted

    • Balanced crystalloids are recommended ^[1]

    • Large volumes of fluid (as much as 5 L per day) may be necessary ^[1]

  • Consider central venous catheter placement for administration of fluids and electrolytes, and to facilitate phlebotomy

  • Electrolyte repletion (most commonly sodium, potassium, magnesium, and calcium) is essential ^[1]

• Patients with significant blood loss may require transfusion of blood or platelets ^[25]

• Give supplemental oxygen to maintain adequate oxygenation; use mechanical ventilation for respiratory failure ^[25]

  • Use supplemental oxygen cautiously and with target oxygen saturations of less than 94% owing to a potentially elevated mortality risk with more intensive administration ^[30]

  • Try to minimize aerosol-generating procedures such as high-flow nasal cannula and noninvasive positive pressure ventilation if possible ^[1]

  • Some patients may require invasive mechanical ventilation

• Administer vasopressors to maintain blood pressure, if needed ^[1]

  • No data regarding specific first line agents in patients with Ebola virus infection; norepinephrine is the drug of choice for septic shock in general and has been recommended in the setting of Ebola virus disease

  • Epinephrine may be added as a second line agent

• For patients who are unable to eat, enteral nutrition via tube is preferred to parenteral nutrition

• Treat concurrent medical conditions and coinfections ^[1]

• Continuous renal replacement therapy may be required (preferable to peritoneal dialysis owing to lesser infection risk) ^[1][18]

• Anti-epileptic therapy should be administered to patients with seizures

Monoclonal antibodies atoltivimab–maftivimab–odesivimab and ansuvimab are FDA-approved treatments for adult and pediatric patients with Ebola virus disease caused by Zaire ebolavirus ^[4][31]

• Atoltivimab–maftivimab–odesivimab was the first FDA-approved treatment for patients with Ebola virus disease in October 2020; ansuvimab received approval in December 2020

• Both ansuvimab and atoltivimab–maftivimab–odesivimab separately reduce mortality compared with ZMapp (triple monoclonal antibody cocktail), remdesivir, or standard care in patients with Ebola virus disease ^[27]

A number of alternative therapies including products derived from blood of convalescent survivors, monoclonal antibodies, and novel antiviral agents have been investigated but evidence is limited ^[32][33]

• Contact CDC Ebola Clinical Team by calling 770-488-7100 (CDC's Emergency Operations Center) for additional information on use of experimental therapy ^[34]

Drug therapy

• Antiviral monoclonal antibodies

  • Ansuvimab

    • Ansuvimab Solution for injection; Neonates: 50 mg/kg/dose IV as a single dose.

    • Ansuvimab Solution for injection; Infants, Children, and Adolescents: 50 mg/kg/dose IV as a single dose.

    • Ansuvimab Solution for injection; Adults: 50 mg/kg/dose IV as a single dose.

  • Atoltivimab–maftivimab–odesivimab

    • Atoltivimab, Maftivimab, Odesivimab Solution for injection; Neonates: 50 mg/kg/dose atoltivimab; 50 mg/kg/dose maftivimab; 50 mg/kg/dose odesivimab IV as a single dose.

    • Atoltivimab, Maftivimab, Odesivimab Solution for injection; Infants, Children, and Adolescents: 50 mg/kg/dose atoltivimab; 50 mg/kg/dose maftivimab; 50 mg/kg/dose odesivimab IV as a single dose.

    • Atoltivimab, Maftivimab, Odesivimab Solution for injection; Adults: 50 mg/kg/dose atoltivimab; 50 mg/kg/dose maftivimab; 50 mg/kg/dose odesivimab IV as a single dose.

• Antiemetics

  • Serotonin receptor antagonist

    • Ondansetron

      • Oral

        • Ondansetron Hydrochloride Oral solution; Children and Adolescents: 0.15 mg/kg/dose (Max: 8 mg/dose) PO every 12 hours as needed.

        • Ondansetron Hydrochloride Oral tablet; Adults: 8 mg PO every 12 hours as needed.

      • IV

        • Ondansetron Hydrochloride Solution for injection; Children and Adolescents weighing less than 40 kg: 0.15 mg/kg/dose IV every 12 hours as needed or 0.1 mg/kg/dose IV as a single dose.

        • Ondansetron Hydrochloride Solution for injection; Children and Adolescents weighing 40 kg or more: 0.15 mg/kg/dose (Max: 8 mg/dose) IV every 12 hours as needed or 4 mg IV as a single dose.

        • Ondansetron Hydrochloride Solution for injection; Adults: 4 mg IV every 8 hours as needed.

  • First-generation antipsychotic

    • Haloperidol

      • IV and subcutaneous

        • Note: haloperidol lactate injection is not FDA approved for IV administration. Cases of QT interval prolongation and torsades de pointes have occurred, including fatalities, during IV use. ECG monitoring is recommended during IV administration

        • Haloperidol Lactate Solution for injection; Children and Adolescents: 0.25 to 0.5 mg IV/subcutaneously every 8 hours as needed.

        • Haloperidol Lactate Solution for injection; Adults: 1 mg IV/subcutaneously every 8 hours as needed.

      • Oral

        • Haloperidol Lactate Oral solution; Children and Adolescents: 0.25 to 0.5 mg PO every 8 hours as needed.

        • Haloperidol Oral tablet; Adults: 1 mg PO every 8 hours as needed.

  • Phenothiazine

    • Promethazine

      • Promethazine Hydrochloride Oral solution; Children and Adolescents 2 to 17 years: 0.25 to 1 mg/kg/dose (Max: 25 mg/dose) PO every 4 to 6 hours as needed.

      • Promethazine Hydrochloride Oral tablet; Adults: 12.5 to 25 mg PO every 4 to 6 hours as needed.

  • Prokinetic agent

    • Metoclopramide

      • IV or subcutaneous

        • Metoclopramide Hydrochloride Solution for injection; Children and Adolescents: 0.1 mg/kg/dose (Max: 10 mg/dose) IV/subcutaneously every 6 hours as needed.

        • Metoclopramide Hydrochloride Solution for injection; Adults: 10 mg IV/subcutaneously every 6 hours as needed.

      • Oral

        • Metoclopramide Hydrochloride Oral syrup; Children and Adolescents: 0.1 mg/kg/dose (Max: 10 mg/dose) PO every 6 hours as needed.

        • Metoclopramide Hydrochloride Oral tablet; Adults: 10 mg PO every 6 hours as needed.

• Vasopressors

  • Norepinephrine

    • Norepinephrine Bitartrate Solution for injection; Infants†, Children†, and Adolescents†: 0.1 mcg/kg/minute continuous IV infusion, initially. Titrate dose as needed based on clinical response. Usual Max: 2 mcg/kg/minute.

    • Norepinephrine Bitartrate Solution for injection; Adults: 0.1 mcg/kg/minute (weight-based) or 8 to 12 mcg/minute (flat-dose) continuous IV infusion, initially. Titrate dose by 0.02 mcg/kg/minute (or more in emergency cases) every 2 to 5 minutes based on clinical response. Usual dose: 0.05 to 0.4 mcg/kg/minute (weight-based) or 2 to 4 mcg/minute (flat-dose). Infusion rates up to 3.3 mcg/kg/minute have been used.

  • Epinephrine

    • Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate dose as needed based on clinical response.

    • Epinephrine Hydrochloride Solution for injection; Adults: 0.01 to 2 mcg/kg/minute continuous IV infusion. Titrate dose by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes based on clinical response. Use ideal body weight as the weight parameter for dosing.

Nondrug and supportive care

IV fluids to maintain hydration and electrolyte balance ^[25][29]

• Lactated Ringer solution may be the fluid of choice

Electrolyte repletion of potassium, magnesium, and phosphate ^[25]

Supplemental oxygen to maintain adequate oxygenation; mechanical ventilation for respiratory failure ^[25]

Transfusion of blood and platelets as needed (for hemoglobin level less than 7 g/mL or overt bleeding, respectively) ^[25]

Treatment of concurrent medical conditions and coinfections ^[1]

Renal replacement therapy may be required ^[18]

Nutrition ^[25]

• Quickly begin enteral nutrition (preferred, if tolerated) or total parenteral nutrition

Procedures

Central venous line placement

General explanation

• Placement of indwelling IV catheter, usually in internal jugular vein or subclavian vein

Indication ^[25]

• To facilitate large-volume fluid replacement

• To allow repeated blood draws without repeated venipuncture

Contraindications

• Usually none, in cases of suspected or confirmed Ebola virus infection

Complications

• Bleeding

• Pneumothorax

Comorbidities

• Coinfection with other infectious or parasitic diseases endemic in the patient's area of residence may complicate management

Special populations

• Pregnant patients, in particular, have high mortality and high risk of miscarriage and stillbirth ^[30]

• Pediatric patients ^[19]

  • The overall incidence of Ebola virus infections is lower in children compared with adults, but pediatric mortality is high, with the youngest children having the highest case fatality rates

  • Data from the 2014-2016 Ebola outbreak in West Africa shows that children may have shorter incubation periods than adults, and 20% of infected children have no fever at presentation

  • Respiratory symptoms are more common and central nervous system manifestations less common in children than in adults

  • Factors associated with pediatric Ebola deaths in the 2014-2016 outbreak include age younger than 5 years, bleeding at any time during hospitalization, and high Ebola viral load

  • At least 2 fatal cases associated with breastfeeding have been reported, so infants should not breastfeed if mother has Ebola; mothers who are symptomatic for Ebola should be isolated from their infants ^[19]

Monitoring

• Carefully monitor fluid intake and output, accounting for urinary, emetic, and fecal measured losses; consider rectal tube owing to copious amounts of stool to be excreted ^[25]

• Monitor telemetry, blood pressure, and oxygen saturation in critically ill patients ^[25]

  • Watch for prolonged QT interval

  • End-tidal CO₂ monitoring, in conjunction with oxygen saturation, may reduce the need for invasive arterial blood gas monitoring in ventilated patients ^[25]

• Closely monitor renal function, hemoglobin or hematocrit values, electrolyte levels, anion gap, blood glucose level, and lactate level ^[30]

• Confirm virologic cure in surviving patients ^[18]

  • Repeat reverse transcription polymerase chain reaction when patient becomes asymptomatic; 2 negative results at least 24 hours apart are required before a patient is discharged from hospital ^[25]

• Survivors of Ebola virus disease with new or recurrent neurologic or ocular symptoms should be evaluated for complications of potential virus persistence ^[35]

Complications and Prognosis

Complications

• Disseminated intravascular coagulation

• Shock

• Multiorgan failure

• Death

Prognosis

• A meta-analyses of 23 Ebola virus disease outbreaks reported a weighted case fatality rate of 65%, with the Zaire variant having the highest case fatality rate of 75% ^[1]

• Pregnant patients, in particular, have high mortality and high risk of miscarriage and stillbirth ^[30]

• In patients who do not survive, early symptoms are more severe and death occurs between days 6 and 16 of illness ^[1]

• In patients who recover, symptoms tend to be less severe and begin to improve on day 6 of illness ^[1]

• Prevalence of depression and post-traumatic stress disorder symptoms among survivors is extremely high ^[36]

• Patients who survive often have a prolonged convalescence ^[1]

  • Sequelae include extreme fatigue, persistent arthralgia and myalgia, arthritis, vision complaints, and deafness for as long as 2 or more years after the initial infection ^[1][5][30]

  • The majority of patients continue to have symptoms 5 years after acute infection ^[5]

  • Additionally, although believed to be a rare event, prolonged persistence and reactivation of disease in immune-privileged sites such as the eye, testicles, or central nervous system is possible ^[19][35]

• After recovery from Ebola virus disease, the immune response may last for 10 years or more, but the existence of lifelong immunity is uncertain

Screening and Prevention

Screening

According to WHO, in geographic areas where Ebola virus is circulating, all persons (patients, visitors, health care workers) should be screened using a no-touch technique at the first point of contact with any health care facility to enable early recognition of suspected cases and rapid implementation of source control measures ^[37]

Screening tests

• Screening consists of a series of questions about possible exposure to Ebola virus disease:

  • Determine whether either of the following is true: ^[8]

    • Patient has lived or traveled in a country with Ebola virus transmission within the 21 days before illness onset, or

    • Patient has had contact with someone infected with Ebola virus disease within the past 21 days

Prevention

• For travelers to areas of Ebola outbreaks ^[38]

  • Avoid contact with body fluids, items that have come into contact with an infected person, and participation in funeral or burial rites that require touching the body

  • Avoid medical facilities where patients with Ebola are being treated

  • Avoid contact with bats and nonhuman primates

  • Monitor health status and body temperature for 21 days after return; seek medical care if fever or other symptoms of illness develop

• For household contacts ^[38]

  • Avoid contact with body fluids, items that have come into contact with an infected person, and participation in funeral or burial rites that require touching the body

• For sexual partners of a male patient who has recovered from Ebola virus disease ^[38]

  • Virus may be sexually transmitted via semen more than a year after clinical recovery ^[18]

  • Advise male patients who have survived Ebola virus disease to abstain from sexual intercourse or use condoms for at least 3 months, and for a subsequent period guided by semen testing for presence of Ebola virus ^[18]

• For health care workers who may be exposed to patients with Ebola virus disease

  • Strict infection control measures must be implemented promptly as soon as infection with Ebola virus is suspected

    • If patient has been exposed and has had symptoms, do the following: ^[9]

      • Isolate patient in a private room with attached private bathroom or covered bedside commode; close door to hallway

      • Limit access to the room and keep a log documenting all entries to the room; only essential personnel should interact with patient

      • Wear personal protective equipment; such protection should be worn by anyone entering the room

        • Review full guidance on selecting, donning, and doffing personal protective equipment, available on CDC website ^[2]

          • Proper donning is essential to ensure maximum coverage and to reduce contamination when doffing

          • Doffing has been identified as a risk for exposure to contaminated clothing; proper technique is essential to reduce risk

          • An independent trained observer should be present to detect breaches

        • If patient has confirmed or suspected Ebola and has active bleeding, vomiting, or diarrhea or needs any invasive or aerosol-generating procedures, full personal protective equipment for a hospital setting should be worn ^[2]

          • Single-use impermeable gown that extends to at least mid-calf or single-use coverall

          • Powered air-purifying respirator or N95 respirator with with single-use surgical hood extending to shoulders and single-use full face shield or goggles worn under the head and neck covering

          • 2 pairs of gloves; outer gloves should have extended cuff ^[28]

          • Single-use boot covers that extend to mid-calf

          • Single-use apron

        • If patient with suspected Ebola virus disease is clinically stable; does not have bleeding, vomiting, or diarrhea; and does not need any invasive or aerosol-generating procedures, full equipment or, at a minimum, the following should be worn: ^[11]

          • Single-use fluid-resistant gown that extends to at least mid-calf or single-use fluid-resistant coveralls without integrated hood ^[28]

          • Single-use full face shield

          • Single-use facemask

          • 2 pairs of gloves; outer gloves should have extended cuff

        • WHO has issued similar guidance ^[37]

          • Specifies that nitrile gloves are preferred over latex

          • States that if a distance of 1 meter can be maintained, personal protective equipment is not required, but medical scrubs and closed-toe shoes should be worn

          • While conducting screening, medical provider should wear:

            • A medical mask in combination with eye protection

            • A fluid-resistant gown

            • 1 pair of gloves

          • While conducting triage for a patient with suspected or confirmed Ebola virus disease, medical provider should wear:

            • A medical mask in combination with eye protection (a face shield or goggles)

            • A fluid-resistant coverall

            • 2 pairs of gloves

          • While in contact with patients who have Ebola virus disease, medical provider should wear:

            • A medical mask in combination with eye protection

            • A head and neck covering if a gown is being used instead of a coverall

            • 2 pairs of gloves

            • Either a disposable or reusable apron to cover the coverall (or gown, if used)

          • Cleaners/hygienists and mortuary/burial workers should wear the same personal protective equipment recommended for other health care workers, with the following exceptions: ^[28]

            • The outer pair of gloves should be heavy duty (utility) gloves

            • Aprons should be heavy duty

            • Shoes should be waterproof boots

        • Immediately notify health department (and hospital infection control program, if applicable) of any patient seeking care who has lived in or traveled to areas of active Ebola virus transmission within 21 days of illness, even if they are afebrile and do not have overt Ebola virus disease symptoms ^[8]

          • Health department will contact CDC ^[13]

• Heavily soiled linens resulting from care of patients with Ebola disease should be safely disposed of (eg, incinerated) ^[37]

• For most survivors of Ebola virus disease, only standard precautions are needed when clinical evaluation and care are performed ^[35]

  • Additional precautions are recommended when specific procedures are performed that could result in exposure to certain body fluids and tissues (eg, invasive ophthalmologic procedures or obtaining and handling cerebral spinal fluid)

• There are 2 approved vaccine regimens to protect against Ebola virus disease

  • Ebola Zaire Vaccine, Live (Ervebo)

    • Live attenuated vaccine approved for individuals aged 12 months and older ^[6][7][38]

      • Meets WHO standards for quality, safety, and efficacy and is approved for use in Europe, the United States, and several countries in Africa

      • Dose

        • Ebola Zaire Vaccine, Live Suspension for injection; Children and Adolescents: 1 mL IM as a single dose.

        • Ebola Zaire Vaccine, Live Suspension for injection; Adults: 1 mL IM as a single dose. May administer a second dose at least 6 months after the first dose for those who are at a potential occupational risk for exposure.

      • Duration of protection is unknown; safety and efficacy in infants (younger than 12 months) is also unknown ^[7]

      • A booster dose is available at least 6 months after the single dose under an expanded access investigational new drug program, with eligibility assessed on an individual basis ^[39]

    • This live attenuated vaccine uses vesicular stomatitis virus that has been genetically engineered to express a protein from Zaire ebolavirus; it has been found safe and protective against only the Zaire ebolavirus species ^[1][6]

      • Since the vaccine contains live vesicular stomatitis virus, it is possible that this virus (not the Ebola virus) may be transmitted to others; recipients should: ^[39]

        • Use effective barrier methods to prevent pregnancy for 2 months

        • Consider avoiding close contact with high-risk people for up to 6 weeks

        • Avoid donating blood for at least 6 weeks

        • Avoid sharing needles, razors, toothbrushes, and eating/ drinking utensils and dishes for 2 weeks

    • Advisory Committee on Immunization Practices (of CDC) recommends preexposure vaccination for the following groups of adults aged 18 years or older in the United States who are at highest risk for potential occupational exposure to Ebola virus: ^[38][40][41]

      • Responders to an Ebola virus disease outbreak

      • Health care workers at federally designated Ebola virus disease treatment centers

      • Staff at biosafety level 4 facilities

      • Health care workers at special pathogens treatment centers

      • Laboratory workers and support staff at Laboratory Response Network facilities

    • Generally preferred if both vaccine regimens are available, as it is single dose and immunity is more quickly achieved ^[42]

    • For everyone (even vaccinated persons), it is important to continue infection prevention precautions against Ebola virus because the vaccine may not be 100% effective

  • AD26.ZEBOV (Zabdeno) plus MVA-BN-Filo (Mvabea)

    • European Medicines Agency has also granted marketing authorization for use of a 2-dose prophylactic vaccine regimen consisting of recombinant adenoviral AD26.ZEBOV (sold as Zabdeno) and modified vaccinia MVA-BN-Filo (sold as Mvabea) for persons aged 1 year or older ^[43]

      • These 2 vaccines have not yet been approved by FDA

      • Regimen

        • AD26.ZEBOV (Zabdeno)

          • Zabdeno, INN-Ebola vaccine (Ad26.ZEBOV-GP [recombinant]) suspension for injection; Children and Adolescents: 0.5 mL IM as a single dose, followed by a dose of MVA-BN-Filo (Mvabea) 8 weeks later.

          • Zabdeno, INN-Ebola vaccine (Ad26.ZEBOV-GP [recombinant]) suspension for injection; Adults: 0.5 mL IM as a single dose, followed by a dose of MVA-BN-Filo (Mvabea) 8 weeks later. ^[44]

        • MVA-BN-Filo (Mvabea)

          • Mvabea, INN-Ebola vaccine (MVA-BN-Filo [recombinant]) suspension for injection; Children and Adolescents: 0.5 mL IM as a single dose at least 8 weeks after the AD26.ZEBOV (Zabdebo) dose.

          • Mvabea, INN-Ebola vaccine (MVA-BN-Filo [recombinant]) suspension for injection; Adults: 0.5 mL IM as a single dose at least 8 weeks after the AD26.ZEBOV (Zabdebo) dose. ^[45]