Ideas and O pin io n s Ebola Hemorrhagic Fever in 2014: The Tale of an Evolving Epidemic C arlos del Rio, M D ; A neesh K. M e h ta , M D ; G . M a rs h a ll Lyon III, M D ; and Je a n n ette G uarner, M D
Sometimes a woman would clutch his sleeve, crying shrilly: “Doctor, you’ll save him, w on’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
bola 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: Marhurgvirus 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 EBOY (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). Libe ria, 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 virtu ally 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);
E
This article was published online first at www.annals.org on 19 August 2014. 7 4 6 © 2014 American College of Physicians
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 leuko penia, thrombocytopenia, elevated levels of transaminases and prothrombin, and partial thromboplastin times with presence of fibrin split products indicating diffuse intravas cular 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 dis seminates 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 pro duction 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, ty phoid fever, bacterial meningitis, or Lassa fever. When the diagnosis is suspected, reverse transcriptase polymerase chain 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 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 flu ids with mucosal surfaces or skin or through parenteral injection. Thus, most cases occur in persons providing di rect care to patients, such as family members or health care professionals. Traditional medical practices and funerals contribute to transmission to household members. Ampli fied transmission occurs in health care facilities, with ap proximately one quarter of cases occurring among health care workers. The most important measure to control an outbreak is implementing strict barrier and droplet precau-
See also: R elated a r t ic le s ............................................................ 7 4 2 -7 5 4
Ebola Hemorrhagic Fever in 2014
Table.
Ideas a n d O p i n i o n s
C a s e s o f E b o la H e m o r r h a g ic F e v e r in A fric a , 1 9 7 6 to 2 0 1 4 *
Year
Country
Town
1976
Democratic Republic o f the Congo South Sudan
Yambuku
318
280
EBOV
Nzara
284
151
SUDV
Democratic Republic o f the Congo South Sudan Gabon
Tandala
1
1979 1994
Nzara M ekouka
1 22
EBOV SUDV
1994
Ivory Coast
1995 1996
Democratic Republic o f the Congo Gabon
1976 1977
Cases,
n
Species
31
EBOV
Tai Forest
1
0
TAFV
K ikw it M a yib o u t
315 37
250 21
EBOV
60
45
EBOV
2 425
1
EBOV EBOV
Gabon
Booue
1996
South Africa
2000 2001
Uganda Gabon
Johannesburg Gulu
2001
Republic o f the Congo Republic o f the Congo
N ot specified M bom o
Republic o f the Congo South Sudan
M bom o
2004 2007 2007
Democratic Republic o f the Congo Uganda
2008
Luebo
2011
Democratic Republic o f the Congo Uganda
2012 2012
Uganda Democratic Republic o f the Congo
Kibaale District Isiro Health Zone
2012
Uganda
2014
Guinea, Sierra Leone, Liberia, Nigeria
2003
Deaths,
34 52
1996
2002
n
Libreville
Yambio Luebo Bundibugyo Luwero District
Luwero District M u ltiple
224
EBOV
65
53
EBOV
57 143
43 128
EBOV EBOV
35
29
EBOV
17 264 149
7 187
EBOV EBOV BDBV
32
15
EBOV
1
1
SUDV
11 + 36+
4+ 13+
SUDV BDBV
6+ 1009+
3+ 574+
SUDV
37
EBOV
BDBV = Bundibugyo virus; EBOV = Ebola virus; SU D V = Sudan virus; TAFV = Tai Forest virus. * Adapted from www.cdc.gov/vhf/ebola/resources/distribution-map.html. t 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. Incinera tion 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, 8, 9). Use of plasma from patients who have recovered from infection and recombinant hu man protein C have also been tried but have been reported to be unsuccessful (1). No licensed vaccine is currently available, and the de velopment of a preventive vaccine was not a priority until recently. Ebola virus is now considered a category A bio logical 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 unprece dented 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 be cause Ebola, unlike Chikungunya, is not transmitted by a vector and, although it is highly infectious, is only acquired www.annals.org
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 re cent history (< 3 weeks) of travel to West Africa who pres ents with compatible signs and symptoms. Most important, as we confront an unprecedented Ebola epidemic in West African countries that had previ ously not been affected and in an age when air travel brings us together like never before, we must stay abreast of in formation that is, fortunately, readily accessible on reliable Web 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/fsl03/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 Healrh of Emory University and Emory University School of Medicine, Atlanta, Georgia.
Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOflnterestForms.do?msNum=Ml4-1880. D is c lo s u re s :
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, [email protected]. R e q u e s ts f o r S in g le R e p rin ts :
18 November 2014 Annals of Internal Medicine Volume 161 • Number 10 747
Ideas
a n d
O
p in io n s
Ebola Hemorrhagic Fever in 2014
C u rren t au th o r addresses an d author contributions are available at www .annals.org.
A nn Intern Med. 2 0 1 4 ;161:746-748. doi:10.7326/M 14-1880
R e fe re n c e s 1. Feldmann H , Geisbert T W . Ebola haemorrhagic fever. Lancet. 2011 ;377: 849-62. [PMID: 21084112] doi: 10.1016/SO140-6736(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. W ong G, Qiu X, Olinger GG, Kobinger GP. Post-exposure therapy of filovirus infections. Trends Microbiol. 2014;22:456-463. [PMID: 24794572] doi: 10.10l6/j.tim .20l4.04.002 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. C D C urges all US residents to avoid nonessential travel to Liberia, Guinea, and Sierra Leone because of an
unprecedented outbreak of Ebola. Adanta, 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. Q iu X, Audet J, W ong 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. W arren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, 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/nature13027 10. 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
D ownload Important References T o C itation M anagers
At www.annals.org, article citations may be directly downloaded to any of the following formats: RIS (Zotero) EndNote, Reference Manager, ProCite, BibTeX, RefWorks, or Medlars.
7 4 8 18 November 2014 Annals of Internal Medicine Volume 161 • Number 10
w w w .a n n a ls .o rg
Copyright © American College of Physicians 2014.
Sometimes a woman would clutch his sleeve, crying shrilly: “Doctor, you’ll save him, w on’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
bola 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: Marhurgvirus 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 EBOY (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). Libe ria, 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 virtu ally 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);
E
This article was published online first at www.annals.org on 19 August 2014. 7 4 6 © 2014 American College of Physicians
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 leuko penia, thrombocytopenia, elevated levels of transaminases and prothrombin, and partial thromboplastin times with presence of fibrin split products indicating diffuse intravas cular 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 dis seminates 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 pro duction 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, ty phoid fever, bacterial meningitis, or Lassa fever. When the diagnosis is suspected, reverse transcriptase polymerase chain 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 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 flu ids with mucosal surfaces or skin or through parenteral injection. Thus, most cases occur in persons providing di rect care to patients, such as family members or health care professionals. Traditional medical practices and funerals contribute to transmission to household members. Ampli fied transmission occurs in health care facilities, with ap proximately one quarter of cases occurring among health care workers. The most important measure to control an outbreak is implementing strict barrier and droplet precau-
See also: R elated a r t ic le s ............................................................ 7 4 2 -7 5 4
Ebola Hemorrhagic Fever in 2014
Table.
Ideas a n d O p i n i o n s
C a s e s o f E b o la H e m o r r h a g ic F e v e r in A fric a , 1 9 7 6 to 2 0 1 4 *
Year
Country
Town
1976
Democratic Republic o f the Congo South Sudan
Yambuku
318
280
EBOV
Nzara
284
151
SUDV
Democratic Republic o f the Congo South Sudan Gabon
Tandala
1
1979 1994
Nzara M ekouka
1 22
EBOV SUDV
1994
Ivory Coast
1995 1996
Democratic Republic o f the Congo Gabon
1976 1977
Cases,
n
Species
31
EBOV
Tai Forest
1
0
TAFV
K ikw it M a yib o u t
315 37
250 21
EBOV
60
45
EBOV
2 425
1
EBOV EBOV
Gabon
Booue
1996
South Africa
2000 2001
Uganda Gabon
Johannesburg Gulu
2001
Republic o f the Congo Republic o f the Congo
N ot specified M bom o
Republic o f the Congo South Sudan
M bom o
2004 2007 2007
Democratic Republic o f the Congo Uganda
2008
Luebo
2011
Democratic Republic o f the Congo Uganda
2012 2012
Uganda Democratic Republic o f the Congo
Kibaale District Isiro Health Zone
2012
Uganda
2014
Guinea, Sierra Leone, Liberia, Nigeria
2003
Deaths,
34 52
1996
2002
n
Libreville
Yambio Luebo Bundibugyo Luwero District
Luwero District M u ltiple
224
EBOV
65
53
EBOV
57 143
43 128
EBOV EBOV
35
29
EBOV
17 264 149
7 187
EBOV EBOV BDBV
32
15
EBOV
1
1
SUDV
11 + 36+
4+ 13+
SUDV BDBV
6+ 1009+
3+ 574+
SUDV
37
EBOV
BDBV = Bundibugyo virus; EBOV = Ebola virus; SU D V = Sudan virus; TAFV = Tai Forest virus. * Adapted from www.cdc.gov/vhf/ebola/resources/distribution-map.html. t 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. Incinera tion 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, 8, 9). Use of plasma from patients who have recovered from infection and recombinant hu man protein C have also been tried but have been reported to be unsuccessful (1). No licensed vaccine is currently available, and the de velopment of a preventive vaccine was not a priority until recently. Ebola virus is now considered a category A bio logical 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 unprece dented 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 be cause Ebola, unlike Chikungunya, is not transmitted by a vector and, although it is highly infectious, is only acquired www.annals.org
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 re cent history (< 3 weeks) of travel to West Africa who pres ents with compatible signs and symptoms. Most important, as we confront an unprecedented Ebola epidemic in West African countries that had previ ously not been affected and in an age when air travel brings us together like never before, we must stay abreast of in formation that is, fortunately, readily accessible on reliable Web 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/fsl03/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 Healrh of Emory University and Emory University School of Medicine, Atlanta, Georgia.
Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOflnterestForms.do?msNum=Ml4-1880. D is c lo s u re s :
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, [email protected]. R e q u e s ts f o r S in g le R e p rin ts :
18 November 2014 Annals of Internal Medicine Volume 161 • Number 10 747
Ideas
a n d
O
p in io n s
Ebola Hemorrhagic Fever in 2014
C u rren t au th o r addresses an d author contributions are available at www .annals.org.
A nn Intern Med. 2 0 1 4 ;161:746-748. doi:10.7326/M 14-1880
R e fe re n c e s 1. Feldmann H , Geisbert T W . Ebola haemorrhagic fever. Lancet. 2011 ;377: 849-62. [PMID: 21084112] doi: 10.1016/SO140-6736(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. W ong G, Qiu X, Olinger GG, Kobinger GP. Post-exposure therapy of filovirus infections. Trends Microbiol. 2014;22:456-463. [PMID: 24794572] doi: 10.10l6/j.tim .20l4.04.002 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. C D C urges all US residents to avoid nonessential travel to Liberia, Guinea, and Sierra Leone because of an
unprecedented outbreak of Ebola. Adanta, 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. Q iu X, Audet J, W ong 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. W arren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, 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/nature13027 10. 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
D ownload Important References T o C itation M anagers
At www.annals.org, article citations may be directly downloaded to any of the following formats: RIS (Zotero) EndNote, Reference Manager, ProCite, BibTeX, RefWorks, or Medlars.
7 4 8 18 November 2014 Annals of Internal Medicine Volume 161 • Number 10
w w w .a n n a ls .o rg
Copyright © American College of Physicians 2014.
