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Ebola Hemorrhagic Fever in 2014: The Tale of an Evolving EpidemicCarlos del Rio, MD; Aneesh K. Mehta, MD; G. Marshall Lyon III, MD; and Jeannette Guarner, MD

Sometimes a woman would clutch his sleeve, cryingshrilly: Doctor, youll save him, wont you? But hewasnt there for saving life; he was there to order a sickmans evacuation. How futile was the hatred he saw onfaces then! You havent a heart! a woman told him onone occasion. She was wrong; he had one. It saw himthrough his twenty-hour day, when he hourly watchedmen dying who were meant to live.

Albert Camus, The Plague

Ebola hemorrhagic fever (Ebola) is a zoonosis caused bya virus of the family Filoviridae, whose members com-prise 2 genera of enveloped, negative, single-stranded RNAviruses: Marburgvirus and Ebolavirus. The latter includes 5viruses: Ebola (EBOV) (formerly known as Zaire), Sudan(SUDV), Tai Forest (TAFV), Bundibugyo (BDBV) andReston (RESTV), all of which are pathogenic to humansexcept RESTV, which is only pathogenic to nonhumanprimates (1). Fruit bats of the Pteropodidae family are be-lieved to be the natural reservoir (2).

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

The current outbreak, which began in December 2013and is the largest ever, was first detected in March 2014when cases were recognized in southern Guinea (4). Libe-ria, Sierra Leone, and Nigeria are now also involved in theepidemic. The challenge is unprecedented because thesecountries have some of the worst physicianpatient ratiosin West Africa (more than 86 000 patients per physician inLiberia and 45 000 patients per physician in Sierra Leone).Through 1 August 2014, a total of 1603 suspected andconfirmed cases (1009 of which are laboratory-confirmed)and 887 deaths have been reported for a mortality rate ofapproximately 55%. Because contemporary internationaltravel affords the ability to board an airplane and be virtu-ally anywhere in the world in less than 24 hours, there issubstantial concern that the disease could spread beyondWest Africa to such places as Europe and North America.For this reason, on 31 July 2014, the Centers for DiseaseControl and Prevention issued a level 3 travel advisoryurging all U.S. residents to avoid nonessential travel to theaffected region (5).

The incubation period of Ebola is generally 1 to 2weeks but can range from 2 to 21 days. Initial clinicalsymptoms are nonspecific, with sudden onset of fever,chills, myalgia, and malaise. This is followed by flu-likesymptoms (nasal discharge, cough, and shortness of breath);

gastrointestinal symptoms (diarrhea, nausea, vomiting, andabdominal pain); and, finally, hemorrhagic symptoms inthe most severe cases. Poor prognosis is associated with thedevelopment of shock, encephalopathy, and extensivehemorrhage. Laboratory findings include leukopenia,thrombocytopenia, elevated levels of aminotransferase andprothrombin, and partial thromboplastin times with pres-ence of fibrin split products indicating diffuse intravascularcoagulation (1).

The pathogenesis of the disease is not well-understood.Studies in nonhuman primates have shown that EBOVreplicates in monocytes, macrophages, and dendritic cells(6); however, in situ hybridization and electron microscopyhave also shown the presence of virus in endothelial cells,fibroblasts, hepatocytes, and adrenal cells. The virus dis-seminates to lymph nodes, the liver, and the spleen. Thereis little inflammatory response and significant lymphocyteapoptosis, which leads to lymphopenia and seems to be amarker of prognosis. Inhibition of the type I interferonresponse seems to be important in the pathogenesis ofEbola. Dysregulation of the coagulation cascade and pro-duction of proinflammatory cytokines by macrophagesleads to shock and multiorgan failure in the terminal phase(1).

Diagnosis of Ebola can be difficult initially because thesymptoms can be confused with those of diseases that aremore common in Equatorial Africa, such as malaria, ty-phoid fever, bacterial meningitis, or Lassa fever. When thediagnosis is suspected, reverse transcriptase polymerasechain reaction and antigen detection by enzyme-linked im-munosorbent assay are the most useful tests. Unfortu-nately, these tests are only available in referral centers ornational reference laboratories and have not been readilyavailable in remote areas of Africa where most outbreakshave occurred (1).

Infection occurs through contact of infected body flu-ids with mucosal surfaces or skin or through parenteralinjection. Thus, most cases occur in persons providing di-rect care to patients, such as family members or health careprofessionals. Traditional medical practices and funeralscontribute to transmission to household members. Ampli-fied transmission occurs in health care facilities, with ap-proximately one quarter of cases occurring among healthcare workers. The most important measure to control anoutbreak is implementing strict barrier and droplet precau-

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

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tions. Personal protective equipment and sterile injectionequipment are also important. When a patient dies, thebody should be handled with extreme caution. Incinera-tion is recommended but is not a usual practice in Africaand is rarely available in the field.

Treatment of patients is primarily symptomatic andsupportive and has not changed appreciably since the1950s (7). No antiviral drug has been proved to be usefulin nonhuman primates when symptoms have already ap-peared. Recent studies have shown promise for a combina-tion of monoclonal antibodies and for a small interferingRNA compound (BCX4430) as postexposure prophylaxisin nonhuman primates (3, 8, 9). Use of plasma from pa-tients who have recovered from infection and recombinanthuman protein C have also been tried but have been re-ported to be unsuccessful (1).

No licensed vaccine is currently available, and the de-velopment of a preventive vaccine was not a priority untilrecently. Ebola virus is now considered a category A bio-logical threat, and several vaccine approaches are beingevaluated in nonhuman primate models, including DNA,subunit, and several viral vectors (10).

The recent airlifting of 2 patients to Emory UniversityHospital in Atlanta, Georgia, has brought an unprece-dented level of media attention to this illness as well asconcern for spread in the U.S. population, similar to thereaction to recent reports of Chikungunya diagnoses inU.S. citizens. However, such concerns are unfounded be-cause Ebola, unlike Chikungunya, is not transmitted by avector and, although it is highly infectious, is only acquired

by direct contact with infected secretions. Even if cases areimported, the likelihood of further transmission beyondthe index patient is near zero because hospital infectioncontrol practices are an effective barrier. However, clinics,hospitals, and emergency departments worldwide shouldbe prepared to immediately isolate any patient with a re-cent history (3 weeks) of travel to West Africa who pres-ents with compatible signs and symptoms.

Most important, as we confront an unprecedentedEbola epidemic in West African countries that had previ-ously not been affected and in an age when air travel bringsus together like never before, we must stay abreast of in-formation that is, fortunately, readily accessible on reliableWeb sites from the Centers for Disease Control and Pre-vention (www.cdc.gov/vhf/ebola and http://emergency.cdc.gov/han/han00364.asp) and the World Health Organiza-tion (www.who.int/mediacentre/factsheets/fs103/en andwww.afro.who.int/en/clusters-a-programmes/dpc/epidemic-a-pandemic-alert-and-response/outbreak-news.html).

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

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNumM14-1880.

Requests for Single Reprints: Carlos del Rio, MD, Hubert Departmentof Global Health, Rollins School of Public Health of Emory University,1518 Clifton Road NE, Claudia Nance Rollins Building 7011, Atlanta,GA 30322; e-mail, [email protected].

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

Year Country Town Cases, n Deaths, n Species

1976 Democratic Republic of the Congo Yambuku 318 280 EBOV1976 South Sudan Nzara 284 151 SUDV1977 Democratic Republic of the Congo Tandala 1 1 EBOV1979 South Sudan Nzara 34 22 SUDV1994 Gabon Mekouka 52 31 EBOV1994 Ivory Coast Tai Forest 1 0 TAFV1995 Democratic Republic of the Congo Kikwit 315 250 EBOV1996 Gabon Mayibout 37 21 EBOV1996 Gabon Booue 60 45 EBOV1996 South Africa Johannesburg 2 1 EBOV2000 Uganda Gulu 425 224 EBOV2001 Gabon Libreville 65 53 EBOV2001 Republic of the Congo Not specified 57 43 EBOV2002 Republic of the Congo Mbomo 143 128 EBOV2003 Republic of the Congo Mbomo 35 29 EBOV2004 South Sudan Yambio 17 7 EBOV2007 Democratic Republic of the Congo Luebo 264 187 EBOV2007 Uganda Bundibugyo 149 37 BDBV2008 Democratic Republic of the Congo Luebo 32 15 EBOV2011 Uganda Luwero District 1 1 SUDV2012 Uganda Kibaale District 11 4 SUDV2012 Democratic Republic of the Congo Isiro Health Zone 36 13 BDBV2012 Uganda Luwero District 6 3 SUDV2014 Guinea, Sierra Leone, Liberia, Nigeria Multiple 1009 574 EBOV

BDBV Bundibugyo virus; EBOV Ebola virus; SUDV Sudan virus; TAFV Tai Forest virus.* Adapted from www.cdc.gov/vhf/ebola/resources/distribution-map.html. Laboratory-confirmed cases only.


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http://www.cdc.gov/vhf/ebolahttp://emergency.cdc.gov/han/han00364.asphttp://emergency.cdc.gov/han/han00364.asphttp://www.who.int/mediacentre/factsheets/fs103/enhttp://www.afro.who.int/en/clusters-a-programmes/dpc/epidemic-a-pandemic-alert-and-response/outbreak-news.htmlhttp://www.afro.who.int/en/clusters-a-programmes/dpc/epidemic-a-pandemic-alert-and-response/outbreak-news.htmlhttp://www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1880http://www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1880mailto:[email protected]

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Ann Intern Med. doi:10.7326/M14-1880

References1. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377:849-62. [PMID: 21084112] doi:10.1016/S0140-6736(10)60667-82. 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. [PMID:16319873]3. Wong G, Qiu X, Olinger GG, Kobinger GP. Post-exposure therapy of filo-virus infections. Trends Microbiol. 2014;22:456-463. [PMID: 24794572] doi:10.1016/j.tim.2014.04.0024. Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N,et al. Emergence of Zaire Ebola virus disease in Guinea - preliminary report. NEngl J Med. 2014. [PMID: 24738640]5. Centers for Disease Control and Prevention. CDC urges all US residents toavoid nonessential travel to Liberia, Guinea, and Sierra Leone because of an

unprecedented outbreak of Ebola. Atlanta, GA: Centers for Disease Control andPrevention; 2014. Accessed at http://wwwnc.cdc.gov/travel/notices/warning/ebola-liberia on 6 August 2014.6. Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB,et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidencethat dendritic cells are early and sustained targets of infection. Am J Pathol.2003;163:2347-70. [PMID: 14633608]7. Smadel JE. Epidemic hemorrhagic fever. Am J Public Health Nations Health.1953;43:1327-30. [PMID: 13092304]8. Qiu X, Audet J, Wong G, Pillet S, Bello A, Cabral T, et al. Successfultreatment of Ebola virus-infected cynomolgus macaques with monoclonalantibodies. Sci Transl Med. 2012;4:138ra81. [PMID: 22700957] doi:10.1126/scitranslmed.30038769. Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van TongerenSA, et al. Protection against filovirus diseases by a novel broad-spectrum nucleo-side analogue BCX4430. Nature. 2014;508:402-5. [PMID: 24590073] doi:10.1038/nature1302710. Marzi A, Feldmann H. Ebola virus vaccines: an overview of current ap-proaches. Expert Rev Vaccines. 2014;13:521-31. [PMID: 24575870] doi:10.1586/14760584.2014.885841


Ideas and OpinionsEbola Hemorrhagic Fever in 2014

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http://www.annals.orghttp://www.annals.orghttp://wwwnc.cdc.gov/travel/notices/warning/ebola-liberiahttp://wwwnc.cdc.gov/travel/notices/warning/ebola-liberia

Current Author Addresses: Dr. del Rio: Hubert Department of GlobalHealth, Rollins School of Public Health of Emory University, 1518Clifton Road NE, Claudia Nance Rollins Building 7011, Atlanta, GA30322.Drs. Mehta and Lyon: Division of Infectious Diseases, Emory UniversitySchool of Medicine, 101 Woodruff Circle, WMRB 2101, Atlanta, GA30322.Dr. Guarner: Emory University Hospital, Clinical Laboratory, 1364Clifton 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. delRio, 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.


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