This online-first version will be replaced with a final version when it is included in the issue.

The final version may differ in small ways.

Ideas and Opinions

Annals of Internal Medicine

Ebola Hemorrhagic Fever in 2014: The Tale of an Evolving Epidemic

Carlos del Rio, MD; Aneesh K. Mehta, MD; G. Marshall Lyon III, MD; and Jeannette Guarner, MD

Sometimes a woman would clutch his sleeve, crying

shrilly: Doctor, youll save him, wont you? But he
wasnt there for saving life; he was there to order a sick
mans evacuation. How futile was the hatred he saw on
faces then! You havent 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

bola hemorrhagic fever (Ebola) 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).
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 physicianpatient 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 aminotransferase 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 lymph nodes, the liver, and the 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
leads 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 precauSee also:
Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

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

2014 American College of Physicians 1

Downloaded From: http://annals.org/ on 09/19/2014

This online-first version will be replaced with a final version when it is included in the issue. The final version may differ in small ways.

Ideas and Opinions

Ebola Hemorrhagic Fever in 2014

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

Year

Country

Town

Cases, n

Deaths, n

Species

1976
1976
1977
1979
1994
1994
1995
1996
1996
1996
2000
2001
2001
2002
2003
2004
2007
2007
2008
2011
2012
2012
2012
2014

Democratic Republic of the Congo

South Sudan
Democratic Republic of the Congo
South Sudan
Gabon
Ivory Coast
Democratic Republic of the Congo
Gabon
Gabon
South Africa
Uganda
Gabon
Republic of the Congo
Republic of the Congo
Republic of the Congo
South Sudan
Democratic Republic of the Congo
Uganda
Democratic Republic of the Congo
Uganda
Uganda
Democratic Republic of the Congo
Uganda
Guinea, Sierra Leone, Liberia, Nigeria

Yambuku
Nzara
Tandala
Nzara
Mekouka
Tai Forest
Kikwit
Mayibout
Booue
Johannesburg
Gulu
Libreville
Not specified
Mbomo
Mbomo
Yambio
Luebo
Bundibugyo
Luebo
Luwero District
Kibaale District
Isiro Health Zone
Luwero District
Multiple

318
284
1
34
52
1
315
37
60
2
425
65
57
143
35
17
264
149
32
1
11
36
6
1009

280
151
1
22
31
0
250
21
45
1
224
53
43
128
29
7
187
37
15
1
4
13
3
574

EBOV
SUDV
EBOV
SUDV
EBOV
TAFV
EBOV
EBOV
EBOV
EBOV
EBOV
EBOV
EBOV
EBOV
EBOV
EBOV
EBOV
BDBV
EBOV
SUDV
SUDV
BDBV
SUDV
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.

tions. 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 when symptoms have already appeared. 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, 8, 9). 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
2

Annals of Internal Medicine

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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).
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?msNumM14-1880.
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.
www.annals.org

This online-first version will be replaced with a final version when it is included in the issue. The final version may differ in small ways.
Ebola Hemorrhagic Fever in 2014
Current author addresses and author contributions are available at www
.annals.org.
Ann Intern Med. doi:10.7326/M14-1880

References
1. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377:
849-62. [PMID: 21084112] doi:10.1016/S0140-6736(10)60667-8
2. 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 filovirus infections. Trends Microbiol. 2014;22:456-463. [PMID: 24794572] doi:
10.1016/j.tim.2014.04.002
4. Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N,
et al. Emergence of Zaire Ebola virus disease in Guinea - preliminary report. N
Engl J Med. 2014. [PMID: 24738640]
5. Centers for Disease Control and Prevention. CDC urges all US residents to
avoid nonessential travel to Liberia, Guinea, and Sierra Leone because of an

www.annals.org

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Ideas and Opinions

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.
6. 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. [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. Successful
treatment of Ebola virus-infected cynomolgus macaques with monoclonal
antibodies. Sci Transl Med. 2012;4:138ra81. [PMID: 22700957] doi:10.1126
/scitranslmed.3003876
9. Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren
SA, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature. 2014;508:402-5. [PMID: 24590073] doi:
10.1038/nature13027
10. Marzi A, Feldmann H. Ebola virus vaccines: an overview of current approaches. Expert Rev Vaccines. 2014;13:521-31. [PMID: 24575870] doi:
10.1586/14760584.2014.885841

Annals of Internal Medicine

This online-first version will be replaced with a final version when it is included in the issue. The final version may differ in small ways.

Ideas and Opinions

Annals of Internal Medicine

Ebola Hemorrhagic Fever in 2014: The Tale of an Evolving Epidemic

Carlos del Rio, MD; Aneesh K. Mehta, MD; G. Marshall Lyon III, MD; and Jeannette Guarner, MD

Sometimes a woman would clutch his sleeve, crying

shrilly: Doctor, youll save him, wont you? But he
wasnt there for saving life; he was there to order a sick
mans evacuation. How futile was the hatred he saw on
faces then! You havent 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

bola hemorrhagic fever (Ebola) 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).
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 physicianpatient 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 aminotransferase 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 lymph nodes, the liver, and the 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
leads 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 precauSee also:
Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

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

2014 American College of Physicians 1

Downloaded From: http://annals.org/ on 09/19/2014