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Ebola Hemorrhagic Fever in 2014: The Tale of an Evolving EpidemicEbola Hemorrhagic Fever in 2014 FREE

Carlos del Rio, MD; Aneesh K. Mehta, MD; G. Marshall Lyon III, MD; and Jeannette Guarner, MD
[+] Article and Author Information

This article was published online first at www.annals.org on 19 August 2014.


From Rollins School of Public Health of Emory University and Emory University School of Medicine, Atlanta, Georgia.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1880.

Requests for Single Reprints: Carlos del Rio, MD, Hubert Department of Global Health, Rollins School of Public Health of Emory University, 1518 Clifton Road NE, Claudia Nance Rollins Building 7011, Atlanta, GA 30322; e-mail, cdelrio@emory.edu.

Current Author Addresses:Dr. del Rio: Hubert Department of Global Health, Rollins School of Public Health of Emory University, 1518 Clifton Road NE, Claudia Nance Rollins Building 7011, Atlanta, GA 30322.

Drs. Mehta and Lyon: Division of Infectious Diseases, Emory University School of Medicine, 101 Woodruff Circle, WMRB 2101, Atlanta, GA 30322.

Dr. Guarner: Emory University Hospital, Clinical Laboratory, 1364 Clifton Road NE, Atlanta, GA 30322.

Author Contributions:Conception and design: C. del Rio.

Analysis and interpretation of the data: C. del Rio.

Drafting of the article: C. del Rio, A.K. Mehta.

Critical revision of the article for important intellectual content: C. del Rio, A.K. Mehta, G.M. Lyon, J. Guarner.

Final approval of the article: C. del Rio, A.K. Mehta, G.M. Lyon, J. Guarner.

Administrative, technical, or logistic support: C. del Rio, G.M. Lyon.

Collection and assembly of data: C. del Rio, J. Guarner.


Ann Intern Med. 2014;161(10):746-748. doi:10.7326/M14-1880
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Sometimes a woman would clutch his sleeve, crying shrilly: “Doctor, you'll save him, won't you?” But he wasn't there for saving life; he was there to order a sick man's evacuation. How futile was the hatred he saw on faces then! “You haven't a heart!” a woman told him on one occasion. She was wrong; he had one. It saw him through his twenty-hour day, when he hourly watched men dying who were meant to live.

—Albert Camus, The Plague

Ebola virus disease is a zoonosis caused by a virus of the family Filoviridae, whose members comprise 2 genera of enveloped, negative, single-stranded RNA viruses: Marburgvirus and Ebolavirus. The latter includes 5 viruses: Ebola (EBOV) (formerly known as Zaire), Sudan (SUDV), Tai Forest (TAFV), Bundibugyo (BDBV), and Reston (RESTV), all of which are pathogenic to humans except RESTV, which is only pathogenic to nonhuman primates (1). Fruit bats of the Pteropodidae family are believed to be the natural reservoir (2).

Ebola was first recognized in 1976 when 2 epidemics occurred almost simultaneously in Zaire and Sudan. Since then, more than 20 outbreaks have occurred, mostly in Equatorial Africa and most due to EBOV (Table). The disease has had an aggregated case-fatality rate of 78% (3).

Table Jump PlaceholderTable. Cases of Ebola Hemorrhagic Fever in Africa, 1976 to 2014 

The current outbreak, which began in December 2013 and is the largest ever, was first detected in March 2014 when cases were recognized in southern Guinea (4). Liberia, Sierra Leone, and Nigeria are now also involved in the epidemic. The challenge is unprecedented because these countries have some of the worst physician–patient ratios in West Africa (more than 86 000 patients per physician in Liberia and 45 000 patients per physician in Sierra Leone). Through 1 August 2014, a total of 1603 suspected and confirmed cases (1009 of which are laboratory-confirmed) and 887 deaths have been reported, for a mortality rate of approximately 55%. Because contemporary international travel affords the ability to board an airplane and be virtually anywhere in the world in less than 24 hours, there is substantial concern that the disease could spread beyond West Africa to such places as Europe and North America. For this reason, on 31 July 2014, the Centers for Disease Control and Prevention issued a level 3 travel advisory urging all U.S. residents to avoid nonessential travel to the affected region (5).

The incubation period of Ebola is generally 1 to 2 weeks but can range from 2 to 21 days. Initial clinical symptoms are nonspecific, with sudden onset of fever, chills, myalgia, and malaise. This is followed by flu-like symptoms (nasal discharge, cough, and shortness of breath);gastrointestinal symptoms (diarrhea, nausea, vomiting, and abdominal pain); and, finally, hemorrhagic symptoms in the most severe cases. Poor prognosis is associated with the development of shock, encephalopathy, and extensive hemorrhage. Laboratory findings include leukopenia, thrombocytopenia, elevated levels of transaminases and prothrombin, and partial thromboplastin times with presence of fibrin split products indicating diffuse intravascular coagulation (1).

The pathogenesis of the disease is not well-understood. Studies in nonhuman primates have shown that EBOV replicates in monocytes, macrophages, and dendritic cells (6); however, in situ hybridization and electron microscopy have also shown the presence of virus in endothelial cells, fibroblasts, hepatocytes, and adrenal cells. The virus disseminates to the lymph nodes, liver, and spleen. There is little inflammatory response and significant lymphocyte apoptosis, which leads to lymphopenia and seems to be a marker of prognosis. Inhibition of the type I interferon response seems to be important in the pathogenesis of Ebola. Dysregulation of the coagulation cascade and production of proinflammatory cytokines by macrophages lead to shock and multiorgan failure in the terminal phase (1).

Diagnosis of Ebola can be difficult initially because the symptoms can be confused with those of diseases that are more common in Equatorial Africa, such as malaria, typhoid fever, bacterial meningitis, or Lassa fever. When the diagnosis is suspected, reverse transcriptase polymerase chain reaction and antigen detection by enzyme-linked immunosorbent assay are the most useful tests. Unfortunately, these tests are only available in referral centers or national reference laboratories and have not been readily available in remote areas of Africa where most outbreaks have occurred (1).

Infection occurs through contact of infected body fluids with mucosal surfaces or skin or through parenteral injection. Thus, most cases occur in persons providing direct care to patients, such as family members or health care professionals. Traditional medical practices and funerals contribute to transmission to household members. Amplified transmission occurs in health care facilities, with approximately one quarter of cases occurring among health care workers. The most important measure to control an outbreak is implementing strict barrier and droplet precautions. Personal protective equipment and sterile injection equipment are also important. When a patient dies, the body should be handled with extreme caution. Incineration is recommended but is not a usual practice in Africa and is rarely available in the field.

Treatment of patients is primarily symptomatic and supportive and has not changed appreciably since the 1950s (7). No antiviral drug has been proved to be useful in nonhuman primates after the emergence of symptoms. Recent studies have shown promise for a combination of monoclonal antibodies and for a small interfering RNA compound (BCX4430) as postexposure prophylaxis in nonhuman primates (3, 89). Use of plasma from patients who have recovered from infection and recombinant human protein C have also been tried but have been reported to be unsuccessful (1).

No licensed vaccine is currently available, and the development of a preventive vaccine was not a priority until recently. Ebola virus is now considered a category A biological threat, and several vaccine approaches are being evaluated in nonhuman primate models, including DNA, subunit, and several viral vectors (10).

The recent airlifting of 2 patients to Emory University Hospital in Atlanta, Georgia, has brought an unprecedented level of media attention to this illness as well as concern for spread in the U.S. population, similar to the reaction to recent reports of Chikungunya diagnoses in U.S. citizens. However, such concerns are unfounded because Ebola, unlike Chikungunya, is not transmitted by a vector and, although it is highly infectious, is only acquired by direct contact with infected secretions. Even if cases are imported, the likelihood of further transmission beyond the index patient is near zero because hospital infection control practices are an effective barrier. However, clinics, hospitals, and emergency departments worldwide should be prepared to immediately isolate any patient with a recent history (<3 weeks) of travel to West Africa who presents with compatible signs and symptoms.

Most important, as we confront an unprecedented Ebola epidemic in West African countries that had previously not been affected and in an age when air travel brings us together like never before, we must stay abreast of information that is, fortunately, readily accessible on reliable Web sites from the Centers for Disease Control and Prevention (www.cdc.gov/vhf/ebola and http://emergency.cdc.gov/han/han00364.asp) and the World Health Organization (www.who.int/mediacentre/factsheets/fs103/en and www.afro.who.int/en/clusters-a-programmes/dpc/epidemic-a-pandemic-alert-and-response/outbreak-news.html).

References

Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011; 377:849-62.
PubMed
CrossRef
 
Leroy EM, Kumulungui B, Pourrut X, Rouquet P, Hassanin A, Yaba P, et al. Fruit bats as reservoirs of Ebola virus. Nature. 2005; 438:575-6.
PubMed
CrossRef
 
Wong G, Qiu X, Olinger GG, Kobinger GP. Post-exposure therapy of filovirus infections. Trends Microbiol. 2014; 22:456-463.
PubMed
CrossRef
 
Baize S, Oestereich L, Rieger T, Koivogui L, Feldmann H, Magassouba N, et al. Emergence of Zaire Ebola virus disease in Guinea—preliminary report. N Engl J Med. 2014; 377:849-62.
PubMed
 
Centers for Disease Control and Prevention.  CDC urges all US residents to avoid nonessential travel to Liberia, Guinea, and Sierra Leone because of an unprecedented outbreak of Ebola. Atlanta, GA: Centers for Disease Control and Prevention; 2014. Accessed at http://wwwnc.cdc.gov/travel/notices/warning/ebola-liberia on 6 August 2014.
 
Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB, et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am J Pathol. 2003; 163:2347-70.
PubMed
CrossRef
 
Smadel JE. Epidemic hemorrhagic fever. Am J Public Health Nations Health. 1953; 43:1327-30.
PubMed
CrossRef
 
Qiu X, Audet J, Wong G, Pillet S, Bello A, Cabral T, et al. Successful treatment of Ebola virus-infected cynomolgus macaques with monoclonal antibodies. Sci Transl Med. 2012; 4:138ra81.
PubMed
CrossRef
 
Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, VanTongeren SA, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature. 2014; 508:402-5.
PubMed
CrossRef
 
Marzi A, Feldmann H. Ebola virus vaccines: an overview of current approaches. Expert Rev Vaccines. 2014; 13:521-31.
PubMed
CrossRef
 

Figures

Tables

Table Jump PlaceholderTable. Cases of Ebola Hemorrhagic Fever in Africa, 1976 to 2014 

Videos

Author Insight Video - Carlos del Rio, MD

References

Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011; 377:849-62.
PubMed
CrossRef
 
Leroy EM, Kumulungui B, Pourrut X, Rouquet P, Hassanin A, Yaba P, et al. Fruit bats as reservoirs of Ebola virus. Nature. 2005; 438:575-6.
PubMed
CrossRef
 
Wong G, Qiu X, Olinger GG, Kobinger GP. Post-exposure therapy of filovirus infections. Trends Microbiol. 2014; 22:456-463.
PubMed
CrossRef
 
Baize S, Oestereich L, Rieger T, Koivogui L, Feldmann H, Magassouba N, et al. Emergence of Zaire Ebola virus disease in Guinea—preliminary report. N Engl J Med. 2014; 377:849-62.
PubMed
 
Centers for Disease Control and Prevention.  CDC urges all US residents to avoid nonessential travel to Liberia, Guinea, and Sierra Leone because of an unprecedented outbreak of Ebola. Atlanta, GA: Centers for Disease Control and Prevention; 2014. Accessed at http://wwwnc.cdc.gov/travel/notices/warning/ebola-liberia on 6 August 2014.
 
Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB, et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am J Pathol. 2003; 163:2347-70.
PubMed
CrossRef
 
Smadel JE. Epidemic hemorrhagic fever. Am J Public Health Nations Health. 1953; 43:1327-30.
PubMed
CrossRef
 
Qiu X, Audet J, Wong G, Pillet S, Bello A, Cabral T, et al. Successful treatment of Ebola virus-infected cynomolgus macaques with monoclonal antibodies. Sci Transl Med. 2012; 4:138ra81.
PubMed
CrossRef
 
Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, VanTongeren SA, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature. 2014; 508:402-5.
PubMed
CrossRef
 
Marzi A, Feldmann H. Ebola virus vaccines: an overview of current approaches. Expert Rev Vaccines. 2014; 13:521-31.
PubMed
CrossRef
 

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