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

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). As of November 19, 2014, six EVD patients have been evacuated from West Africa for further medical care, and two imported cases and two secondary cases of EVD have been 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.

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. Due to these nonspecific symptoms, particularly early in the course, EVD often can be confused with other more common infectious diseases such as malaria, typhoid fever, meningococcemia, and other bacterial infections (e.g., pneumonia).

Patients can progress from the initial non-specific 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 from 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 multi-organ failure and septic shock (mean of 7.5 days from symptom-onset to death during the current outbreak in West Africa). In non-fatal cases, patients may have fever for several days and improve, typically around day 6. Patients that survive can have a prolonged convalescence. The case fatality proportion among patients in West Africa with a known outcome is about 71% (ranges from 46% in Nigeria to 69%-72% in Guinea, Liberia, and Sierra Leone). 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 (diarrhea, chest pain, cough, difficulty breathing, difficulty swallowing, conjunctivitis, sore throat, confusion, hiccups, and coma or unconsciousness).

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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 (e.g., 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 multi-organ 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 patients known or suspected to have EVD

Patients known or suspected to have EVD presenting to healthcare settings should be placed in appropriate precautions as soon as possible to prevent transmission of Ebola virus to others. See CDC’s infection control guidance

Patients from countries currently affected by the Ebola outbreak 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.

Additional information about fever in travelers returning from affected countries is available here.

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).

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

Non-urgent questions can be emailed to: malaria@cdc.gov

Travelers from Ebola-affected countries are advised to self-monitor their health for 21 days after departure and to seek healthcare 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 Persons with Potential Ebola Virus Exposure.

The current CDC definition for a person under investigation is available at Case Definition for Ebola Virus Disease (EVD).

Currently a person under investigation 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, and additional symptoms such as severe headache, fatigue, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage; AND 2) epidemiologic risk factors within the past 3 weeks before the onset of symptoms, such as contact with blood or other body fluids of a patient known to have or suspected to have EVD; residence in—or travel to—country with widespread transmission (Guinea, Liberia, Sierra Leone) or Mali; participation in funeral and burial rituals, or direct handling of bats, rodents, or primates from disease-endemic areas.

Facilities evaluating a person under investigation 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 patients with suspected infection with Ebola virus, see CDC’s Interim Guidance for Specimen Collection, Transport, testing, and Submission for Persons Under Investigation for Ebola Virus Disease in the United States, and the accompanying infographic. 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 FDA-approved vaccines or therapeutics available for prevention, post-exposure, or treatment for Ebola virus infection. Clinical management of EVD should focus on supportive care of complications, such as hypovolemia, electrolyte abnormalities, hematologic abnormalities, refractory shock, hypoxia, hemorrhage, septic shock, multi-organ failure, and DIC.

Recommended care includes volume repletion, maintenance of blood pressure (with vasopressors if needed), and maintenance of oxygenation, pain control, nutritional support, as well as treating 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.

Some information on the clinical features and clinical management for patients with Ebola virus disease 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 Ebola management is available from The University of Nebraska Medical Center and Emory University Hospital. Canadian guidance on clinical management of Ebola virus disease patients 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 Ebola

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 are currently being planned in West Africa. 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 no controlled clinical trials have been conducted to date. Therefore, there are no data on the safety, efficacy or effectiveness of any experimental drugs or convalescent plasma for treatment of patients with EVD. Since these investigational treatments are still at early stages of development and production, the availability of these products varies. 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 further information.

To request FDA’s authorization for single-patient emergency IND for an investigational biological product (e.g., 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 Coordination)
  • Visit FDA/CBER’s website for further information.

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References

Bah EI, Lamah MC, Fletcher T, Jacob ST, Brett-Major DM, Sall AA et al. Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea. N Engl J Med. 2014 Nov 5. [Epub ahead of print]

Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N et al. Emergence of Zaire Ebola virus disease in Guinea. N Engl J Med. 2014 Oct 9;371(15):1418-25.

Brett-Major DM, Jacob ST, Jacquerioz FA, Risi GF, Fischer WA 2nd, Kato Y et al. Beng Ready to Treat Ebola Virus Disease Patients. Am J Trop Med Hyg. 2014 Dec 15. Pii: 14-0746. [Epub ahead of print]

Chertow DS, Kleine C, Edwards JK, Scaini R, Giuliani R, Sprecher A. Ebola Virus Disease in West Africa - Clinical Manifestations and Management. N Engl J Med. 2014 Nov 27;371(22):2054-7.

Feldmann H , Geisbert TW. Ebola Haemorrhagic Fever. Lancet. 2011 Mar 5;377(9768):849-62.

Fowler RA, Fletcher T, Fischer WA 2nd, Lamontagne F, Jacob S, Brett-Major D et al. Caring for Critically Ill Patients with Ebola Virus Disease: Perspectives from West Africa. Am J Respir Crit Care Med. 2014 Oct 1;190(7):733-7.

Kortepeter MG, Bausch DG, Bray M. Basic Clinical and Laboratory Features of Filoviral Hemorrhagic Fever. J Infect Dis. 2011 Nov;204 Suppl 3:S810-6.

Kreuels B, Wichmann D, Emmerich P, Schmidt-Chanasit J, de Heer G, Kluge S et al. A Case of Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia. N Engl J Med. 2014 Dec 18;371(25):2394-2401.

Lyon GM, Mehta AK, Varkey JB, Brantly K, Plyler L, McElroy AK et al. Clinical Care of Two Patients with Ebola Virus Disease in the United States. N Engl J Med. 2014 Dec 18;371(25):2402-2409.

Parra JM, Salmerón OJ, Velasco M. The First Case of Ebola Virus Disease Acquired outside Africa. N Engl J Med. 2014 Nov 19. [Epub ahead of print]

Schieffelin JS, Shaffer JG, Goba A, Gbakie M, Gire SK, Colubri A et al. Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone. N Engl J Med. 2014 Oct 29. [Epub ahead of print]

WHO Ebola Response Team. Ebola Virus Disease in West Africa – The First 9 Months of the Epidemic and Forward Projections. N Engl J Med. 2014 Oct 16;371(16):1481-95.

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