Ebola Virus Disease (EVD) Information for Clinicians in U.S. Healthcare Settings
Who this is for: Hospital-based clinicians and other U.S. healthcare providers.
What this is for: To provide updated information about Ebola virus disease (EVD) to clinicians working in U.S. hospitals and health clinics.
How to use: Use this guidance for more information on clinical presentation and clinical course, pathogenesis, laboratory findings, and evaluation of patients under investigation (PUIs) for EVD.
The Centers for Disease Control and Prevention is working closely with the World Health Organization, state and local health departments, clinicians, and other partners to better understand and manage the public health risks posed by Ebola virus disease (EVD). From August 2014 through April 2015, a total of eleven EVD patients were cared for in hospitals in the United States. These included seven EVD patients who were evacuated from West Africa for further medical care, and two imported cases and two secondary cases of EVD who were diagnosed in the United States. The purpose of this document is to provide updated information about EVD to clinicians working in U.S. hospitals and health clinics.
- 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.
- Gastrointestinal symptoms may develop after about 5 days to develop symptoms such as severe watery diarrhea, nausea, vomiting, and abdominal pain.
- 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.
- 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%.
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.
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).
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
- Additional information on evaluating PUIs is available here
- 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: email@example.com
Travelers from areas 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.
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 icon[PDF – 1 page]. In general, laboratory testing should be kept to the minimum as required for patient care.
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.
How to Obtain More Information About Availability and Access to Investigational Vaccines and Therapeutics for EVD
- Clinicians at Ebola treatment units in DRC have access to the following investigational treatments for people with confirmed cases of Ebola
- mAb114 (co-discovered by NIAID and the DRC’s National Institute for Biomedical Research (INRB), and developed by NIAID)
- A monoclonal antibody molecule that binds to the important surface protein on Ebola virus (Zaire ebolavirus), thus flagging the Ebola virus for action by the immune system.
- Licensed to Ridgeback Biotherapeutics for advanced development.
- For use in infected adults and children who are at early stages of infection symptoms.
- ZMapp (developed by Mapp Biopharmaceutical, Inc.)
- First used during the 2014 West Africa Ebola outbreak
- Three monoclonal antibody combination/cocktail (bind to the important surface protein)
- For use in patients of any age with Zaire ebolavirus
- GS-5734, also known as remdesivir (developed by Gilead Sciences, Inc.)
- An antiviral screened for activity against hemorrhagic fever viruses by CDC
- Began animal testing in 2015 at the US Army Medical Research Institute for Infectious Diseases (USAMRIID).
- Now undergoing human trials
- A novel nucleotide analog prodrug
- For use in patients of any age with confirmed Ebola infection
- REGN-EB3 (developed by Regeneron)
- Now undergoing human trials
- Three monoclonal antibody combination/ cocktail (bind to the important surface protein)
- For use in all patients
- mAb114 (co-discovered by NIAID and the DRC’s National Institute for Biomedical Research (INRB), and developed by NIAID)
- The investigational treatments have data to support their use, including testing in the laboratory, animals, and humans. However, none of the drugs have yet been approved by regulatory authorities for the treatment of Ebola outside of investigational use.
- The investigational treatments are available to patients with confirmed Ebola in the DRC in two ways:
- Investigational treatments have been recommended by a WHO panel under the ethical framework known as Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI). People with Ebola may receive these treatments through an expanded access protocol. Under MEURI, patients provide informed consent to receive an investigational treatment.
- People with Ebola also may receive an investigational treatment through a randomized, controlled clinical trial (RCT) protocol known as PALM (an abbreviation of the Swahili phrase “PAmoja TuLinde Maisha,” which roughly translates to “Together Save Lives”):
- The clinical trialexternal icon is organized through an international research consortium coordinated by the WHO. It is led and funded by Institut National pour la Recherche Biomedicale (INRB) in DRC and NIAID and also involves several additional international partners: Médecins Sans Frontières (MSF), the Alliance for International Medical Action (ALIMA) and the International Medical Corps (IMC).
- Patients who give informed consent to enroll in the trial are assigned at random to receive one of the investigational treatments.
- The trial aims to compare survival rates among patients who receive either mAb114, remdesivir or REGN-EB3 with a control group of patients who receive ZMapp. ZMapp showed benefit in Ebola patients treated in W Africa, but the studies were started late in the outbreak so the number of people enrolled were not sufficient to license the drug.
- Site clinicians monitor patients’ symptoms and take blood samples for laboratory tests. Patients remain in the Ebola treatment unit until they fully recover from the disease, and are asked to return to the clinic approximately two months after receiving treatment for a check-up and to provide additional blood samples for laboratory tests.
- A randomized, controlled clinical trial is important for obtaining reliable data about the safety and efficacy of investigational Ebola treatments.
- MEURI is offered at a site until such time that the RCT can begin at that site. MEURI experts support the RCT and have explicitly stated that an RCT provides the best means to evaluate investigational therapies and to identify the therapies that can benefit patients with Ebola.
- Patients receiving the experimental Ebola therapeutics REGN-EB3 and mAb114 had a greater chance of survival compared to patients receiving ZMapp or remdesivir, according to preliminary results in 499 patients in a clinical trial taking place at Ebola treatment centers in the DRC.
- Based on this preliminary data, an independent data and safety monitoring board (DSMB) recommended the study be stopped and all future patients be randomized to receive REGN-EB3 or mAb114 in an extension phase of the study.
- Outcomes in patients receiving REGN-EB3 met a predetermined boundary for halting the study. However, the preliminary analysis indicated REGN-EB3 and mAb114 were very similar. Therefore, the DSMB recommended that both drugs continue to be offered to patients.
- The data are preliminary and based on an incomplete data set from 499 patients. The full data set for all 681 enrolled patients, will be available in mid-September, at which point the complete results will be analyzed and submitted for publication in the peer-reviewed medical literature as soon as possible.
- The overall survival for those receiving either mAb114 or REGN-EB3 was approximately 70% and for those presenting with a low viral load it was approximately 90%.
- There is currently no vaccine licensed by the U.S. Food and Drug Administration (FDA) to protect people from Ebola virus.
- Several investigational vaccines for prevention of Ebola virus infection are in development and are being evaluated in clinical trials.
- The DRC Ethics Review Committee and National Regulatory Authority have approved the use of the Merck rVSV-ZEBOV vaccine in the DRC for this outbreak under “compassionate use.” This vaccine has been shown to be safe and protective against the Zaire ebolavirus species of Ebola.
- For more information on the WHO vaccination program in the DRC, see: https://www.who.int/ebola/drc-2018/faq-vaccine/en/.
- WHO’s Strategic Advisory Group of Experts (SAGE) issued recommendations to address vaccination challenges in the ongoing Ebola outbreak in DRC in May. Recommendations included expansion of the eligible population to include pregnant women beyond the first trimester, lactating women, infants 6-11 months of age, addition of a ‘third ring’ (contacts of contacts of contacts), and adjusting the dosage of the rVSV-ZEBOV vaccine and using a second investigational vaccine produced by Janssen under a research protocol.
- The Janssen vaccine is a 2-dose regimen with a prime dose followed by a second “boost” dose of different composition 56 days later.
- The Janssen vaccine would protect against the Zaire strain of the Ebola virus disease.
- Following the SAGE recommendation, the DRC ethical review board approved a protocol amendment to implement vaccination of new populations (pregnant women beyond the first trimester, lactating women, and infants down to 6 months of age) and to implement vaccination at half the previous DRC dosage, which provides a similar potency to the vaccine used in the West African outbreak. These changes have been implemented in the field since early June 2019.
- It is not possible to get Ebola from the vaccine being studied because the vaccine does not contain the whole Ebola virus. Only the whole Ebola virus can cause an infection. The vaccine contains only a small piece of the Ebola virus (a gene) that helps the body build defenses against Ebola.
- Even after receiving the vaccine, you need to keep protecting yourself against Ebola (for example, washing hands, avoiding contact with blood and body fluids,) because the vaccine may not be 100% effective for everyone.
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 websiteexternal icon 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 websiteexternal icon for further information.
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