Ebola Virus Disease (EVD) Information for Clinicians in U.S. Healthcare Settings

Key Points

1. EVD can be confused with other more common infectious diseases such as malaria, typhoid fever, meningococcemia, and other bacterial infections. Follow CDC’s PPE guidance for confirmed Ebola patients.
2. Gastrointestinal symptoms may develop after about 5 days to develop symptoms such as severe watery diarrhea, nausea, vomiting, and abdominal pain.
3. Ebola virus enters the patient through mucous membranes, breaks in the skin, or parenterally. Healthcare personnel must prevent direct contact or splashes with blood and body fluids, contaminated equipment, and soiled environmental surfaces.
4. Travelers with possible exposure to Ebola virus may need public health monitoring and movement controls depending on the risk of exposure and clinical presentation. Clinicians should contact local or state health departments for more information.

Clinical Presentation and Clinical Course

Patients with EVD generally have abrupt onset of fever and symptoms typically 8 to12 days after exposure (incubation period for current outbreak has a mean of approximately 9 to 11 days). Initial signs and symptoms are nonspecific and may include elevated body temperature or subjective fever, chills, myalgias, and malaise. Because of these nonspecific symptoms, particularly early in the course of the disease, EVD often can be confused with other more common infectious diseases such as malaria, typhoid fever, meningococcemia, and other bacterial infections (for example, pneumonia).

Patients can progress from the initial nonspecific symptoms after about 5 days to develop gastrointestinal symptoms such as severe watery diarrhea, nausea, vomiting, and abdominal pain. Other symptoms such as chest pain, shortness of breath, headache, or confusion also may develop. Patients often have conjunctival injection. Hiccups have been reported. Seizures may occur, and cerebral edema has been reported. Bleeding is not universally present but can manifest later in the course as petechiae, ecchymosis/bruising, or oozing from venipuncture sites and mucosal hemorrhage. Frank hemorrhage is less common. In the current outbreak unexplained bleeding has been reported in only 18% of patients, most often blood in the stool (about 6%). Patients may develop a diffuse erythematous maculopapular rash by day 5 to 7 (usually involving the neck, trunk, and arms) that can desquamate. Pregnant women may experience spontaneous miscarriages. The most common signs and symptoms reported from West Africa during the current outbreak from symptom-onset to the time the case was detected include: fever (87%), fatigue (76%), vomiting (68%), diarrhea (66%), and loss of appetite (65%).

Patients with fatal disease usually develop more severe clinical signs early during infection and die typically between days 6 and 16 of complications including multiorgan failure and septic shock (mean of 7.5 days from symptom onset to death during the current outbreak in West Africa). In nonfatal cases, patients may have fever for several days and improve, typically around day 6. Patients who survive can have a prolonged convalescence. The case fatality proportion among patients with a known outcome in Guinea, Liberia, and Sierra Leone is 70%; this proportion is 61% among hospitalized patients. Risk factors significantly associated with a fatal outcome in the affected countries in West Africa include: age >45 years old; unexplained bleeding; and a number of other signs and symptoms such as diarrhea, chest pain, cough, difficulty breathing, difficulty swallowing, conjunctivitis, sore throat, confusion, hiccups, and coma or unconsciousness. Mortality reported for patients cared for in Ebola treatment units in West Africa ranged from 37-74%. Of 27 patients with Ebola virus disease who were managed in hospitals in the U.S. or Europe, 9 received non-invasive or invasive mechanical ventilation and 5 received continuous renal replacement therapy; the case fatality proportion for these 27 EVD patients was 18.5%.

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Pathogenesis

Ebola virus enters the patient through mucous membranes, breaks in the skin, or parenterally and infects many cell types, including monocytes, macrophages, dendritic cells, endothelial cells, fibroblasts, hepatocytes, adrenal cortical cells, and epithelial cells. The incubation period may be related to the infection route (6 days for injection versus 10 days for contact). Ebola virus migrates from the initial infection site to regional lymph nodes and subsequently to the liver, spleen, and adrenal gland. Although not infected by Ebola virus, lymphocytes undergo apoptosis resulting in decreased lymphocyte counts. Hepatocellular necrosis occurs and is associated with dysregulation of clotting factors and subsequent coagulopathy. Adrenocortical necrosis also can be found and is associated with hypotension and impaired steroid synthesis. Ebola virus appears to trigger a release of pro-inflammatory cytokines with subsequent vascular leak and impairment of clotting ultimately resulting in multiorgan failure and shock.

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Laboratory Findings

Laboratory findings at admission may include leukopenia frequently with lymphopenia followed later by elevated neutrophils and a left shift. Platelet counts often are decreased in the 50,000 to 100,000 range. Amylase may be elevated, reflecting pancreatic involvement (inflammation/infection). Hepatic transaminases are elevated with aspartate aminotransferase (AST) exceeding alanine aminotransferase (ALT); these values may peak at more than 1,000 IU/L. Proteinuria may be present. Prothrombin (PT) and partial thromboplastin times (PTT) are prolonged and fibrin degradation products are elevated, consistent with disseminated intravascular coagulation (DIC).

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Initial Evaluation of Persons Under Investigation (PUIs) or Patients with Confirmed EVD

Patients under investigation (PUIs) or patients with confirmed EVD presenting to healthcare settings should be handled with appropriate precautions as soon as possible to prevent transmission of Ebola virus to others. See CDC’s infection control guidance

• Algorithm for Evaluation of the Returned Traveler [PDF – 1 page]
• Additional information on evaluating PUIs is available here
• Guidance for Emergency Services, Hospitals, and Outpatient Settings
• Interim Guidance for Environmental Infection Control in Hospitals for Ebola Virus

Patients from countries with Ebola outbreaks who present with fever could have other potentially fatal infectious diseases that should be considered in the differential diagnosis, including but not limited to malaria, typhoid fever, and bacterial infections such as pneumonia. Evaluation of febrile illness in a recent traveler should include a thorough travel and exposure history.

See additional information about fever in travelers returning from affected countries.

For information about malaria please see CDC’s malaria website.

Health care providers needing assistance with diagnosis or management of suspected cases of malaria should call the CDC Malaria Hotline at:
770-488-7788 or 855-856-4713 toll-free (M-F, 9 a.m.-5 p.m., EST).

For emergency consultation after hours, call: 770-488-7100 and request to speak with a CDC Malaria Branch clinician.

Nonurgent questions can be emailed to: malaria@cdc.gov

Travelers from countries with Ebola outbreaks are advised to self-monitor their health for 21 days after departure and to seek health care if fever and symptoms develop. Travelers with possible exposure to Ebola virus, for example in a healthcare setting, may need additional public health monitoring and movement controls depending on the risk of exposure and clinical presentation. Clinicians should contact the local or state health department to determine whether these measures are needed. For additional information, see CDC’s Interim U.S. Guidance for Monitoring and Movement of People with Potential Ebola Virus Exposure.

The current CDC definition of a PUI is available at Case Definition for Ebola Virus Disease (EVD).

Currently a PUI for EVD is defined as illness in a person who has both consistent symptoms and risk factors as follows: 1) Clinical criteria, which include elevated body temperature or subjective fever or additional symptoms such as severe headache, fatigue, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage; AND 2) epidemiologic risk factors within the past 21 days before the onset of symptoms, such as contact with blood or other body fluids of a PUI or patient with confirmed EVD; residence in—or travel to—a country with widespread transmission or cases in urban settings with uncertain control measures; participation in funeral and burial rituals, or direct handling of bats, rodents, or primates from disease-endemic areas.

Facilities evaluating a PUI should contact their local or state health department for testing. Health departments should contact the CDC Emergency Operations Center at 770-488-7100 for testing and consultation.

All laboratory testing should be performed using appropriate laboratory safety guidance. For information regarding guidance of specimen collection, transport, testing, and submission for PUIs, see CDC’s Guidance for Collection, Transport, Testing, and Submission of Specimens for Ebola Virus Testing, and the accompanying infographic [PDF – 1 page]. In general, laboratory testing should be kept to the minimum as required for patient care.

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Prophylaxis and Treatment

There are no Food and Drug Administration (FDA)-approved vaccines or therapeutics available for prevention, postexposure, or treatment for EVD. Clinical management of EVD should focus on supportive care of complications, such as hypovolemia, electrolyte abnormalities, hematologic abnormalities, refractory shock, hypoxia, hemorrhage, septic shock, multiorgan failure, and DIC.

Recommended care includes volume repletion, maintenance of blood pressure (with vasopressors if needed), and maintenance of oxygenation, pain control, nutritional support, and treatment of  secondary bacterial infections and pre-existing comorbidities. Among patients medically evacuated from West Africa with EVD, large volumes of intravenous fluids often have been required to correct dehydration due to diarrhea and vomiting. Some patients may develop profound third-spacing of fluids due to vascular leak. Some organizations have suggested the addition of broad-spectrum antimicrobials, particularly in patients with evidence of septic shock. Infection prevention and control measures are a critical part of clinical management; all bodily fluids and clinical specimens should be considered potentially infectious.

Information on the clinical features and clinical management for patients with EVD in the U.S. at the University of Nebraska Medical Center and Emory University Hospital is available from a COCA call on October 20, 2014.

In addition, information on EVD management is available from The University of Nebraska Medical Center and Emory University Hospital. Canadian guidance on clinical management of patients with EVD is available from the Canadian Critical Care Society.

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How to Obtain More Information About Availability and Access to Investigational Vaccines and Therapeutics for EVD

Several investigational vaccines for prevention of Ebola virus infection are in development and are currently being evaluated in Phase I trials. In addition, Phase II trials of candidate Ebola vaccines are  being implemented  in West Africa. Information on clinical trials of candidate Ebola vaccines is available at: https://clinicaltrials.gov/  One investigational vaccine has also been used for post-exposure prophylaxis (through an Emergency Investigational New Drug [IND] application authorized by the FDA) following a high-risk exposure to Ebola virus. When a vaccine or drug is not approved, the FDA can authorize access to potentially promising products through other mechanisms, such as an emergency, individual-patient or open-label expanded access Investigational IND application. In order for an experimental treatment to be administered in the United States, certain criteria must be met and such a request must be submitted to and authorized by the FDA. For more information on expanded access (also called compassionate use), please see http://www.fda.gov/forpatients/other/expandedaccess/default.htm.

Several investigational drugs and convalescent plasma from recovered Ebola virus disease patients have been used to treat patients with EVD during the current outbreak, but data from controlled clinical trials of any investigational therapeutics are unavailable. Therefore, there are no data on the safety, efficacy or effectiveness of any experimental drugs or convalescent plasma for treatment of patients with EVD to inform clinical management. Since these investigational treatments are still at early stages of development and production, the availability of these products varies. A randomized controlled trial of investigational therapeutics for treatment of Ebola virus disease patients has been approved. Clinicians may contact the CDC Ebola Clinical Team by calling 770-488-7100 (CDC’s Emergency Operations Center) for additional information on use of experimental therapeutics for treatment of EVD and vaccines for post-exposure prophylaxis following a high-risk occupational exposure to Ebola virus. For information about availability and access to investigational therapeutics and vaccines, please contact the manufacturers or the Food and Drug Administration.

To request FDA’s authorization for single-patient emergency IND for an investigational antiviral drug, contact the Division of Antiviral Products (DAVP)/FDA

• During regular business hours M-F from 8:00 a.m.–4:30 p.m. EST call 301-796-1500 or email DAVPEINDREQUEST@fda.hhs.gov
• After regular business hours call 301-796-8240 (FDA Emergency Coordinator) or 301-796-9900 (CDER Emergency Coordinator)
• Visit FDA/CDER’s website for more information.

To request FDA’s authorization for single-patient emergency IND for an investigational biological product (convalescent plasma, vaccine), contact CBER/FDA

• During regular business hours M-F from 8:00 a.m.–4:30 p.m. EST call 240-402-7800
• After regular business hours call 301-796-8240 or 866-600-4374 (FDA Emergency Coordinator)
• Visit FDA/CBER’s website for further information.

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