Ebola Virus Infection Treatment & Management
- Author: John W King, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD more...
General medical support is critical and should include replacement of coagulation factors and heparin if disseminated intravascular coagulation develops. Such care must be administered with strict attention to barrier isolation. All body fluids (blood, saliva, urine, and stool) contain infectious virions and should be handled with great care.
Currently, no specific therapy is available that has demonstrated efficacy in the treatment of Ebola hemorrhagic fever. Surgical intervention generally follows a mistaken diagnosis in which Ebola-associated abdominal signs are mistaken for a surgical abdominal emergency. Such a mistake may be fatal for the patient and for any surgical team members who become contaminated with the patient’s blood.
There are no commercially available Ebola vaccines. However, a recombinant human monoclonal antibody directed against the envelope GP of Ebola has been demonstrated to possess neutralizing activity. This Ebola neutralizing antibody may be useful in vaccine development or as a passive prophylactic agent. Work on a vaccine continues.
Supportive therapy with attention to intravascular volume, electrolytes, nutrition, and comfort care is of benefit to the patient. Intravascular volume repletion is one of the most important supportive measures.
Survivors can produce infectious virions for prolonged periods. Therefore, strict barrier isolation in a private room away from traffic patterns must be maintained throughout the illness. Patient’s urine, stool, sputum, and blood, along with any objects that have come in contact with the patient or the patient’s body fluids (such as laboratory equipment), should be disinfected with a 0.5% sodium hypochlorite solution. Patients who have died of Ebola virus disease should be buried promptly and with as little contact as possible.
Nucleoside analogue inhibitors of the cell-encoded enzyme S-adenosylhomocysteine hydrolase (SAH) have been shown to inhibit Zaire Ebolavirus replication in adult BALB/c mice infected with mouse-adapted Ebola virus. Inhibition of SAH indirectly inhibits transmethylation reactions required for viral replication. Treatment response was dose-dependent. When doses of 0.7 mg/kg or more every 8 hours were begun on day 0 or 1 of infection, mortality was completely prevented. Even when the drug was given on day 2, 90% survived.
Smith et al found that in rhesus macaques infected with a lethal dose of Ebola virus, treatment with interferon beta early after exposure led to a significant increase in survival time, though it did not reduce mortality significantly. These findings suggest that early postexposure interferon-beta therapy may be a promising adjunct in the treatment of Ebola virus infection.
Passive immunity has been attempted by using equine-derived hyperimmune globulins and human-derived convalescent immune globulin preparations. In Ebolavirus -infected cynomolgus macaques, use of human recombinant interferon alfa-2b in conjunction with hyperimmune equine immunoglobulin G (IgG) delayed but did not prevent death.
Equine IgG containing high-titer neutralizing antibodies to Ebola virus protected guinea pigs and baboons but was not effective in protecting infected rhesus monkeys.
During the 1995 outbreak in Kikwit, DRC, human convalescent plasma was used to treat 8 patients with proven Ebola disease, and only 1 patient died. Subsequent studies could not demonstrate survival benefit conferred by convalescent plasma products. The survival of these patients suggests that passive immunity may be of benefit in some patients.
Four laboratory workers in Russia who had possible Ebola exposure were treated with a combination of a goat-derived anti-Ebola immunoglobulin plus recombinant human interferon alfa-2. One of these patients had a high-risk exposure and developed clinical evidence of Ebola virus infection. All 4 patients recovered.
A recombinant human monoclonal antibody directed against the envelope glycoprotein (GP) of Ebola virus has been demonstrated to possess neutralizing activity. This Ebola virus−neutralizing antibody may be useful in vaccine development or as a passive prophylactic agent.
DNA vaccines expressing either envelope GP or nucleocapsid protein (NP) genes of Ebola virus have been demonstrated to induce protection in adult mice exposed to the virus. These vaccines were administered by coating gold beads with DNA expressing the genes for either GP or NP, and they were delivered by skin particle bombardment using a PowderJect-XR gene gun. Both vaccines induced measurable antibody responses detected by enzyme-linked immunosorbent assay (ELISA) and induced cytotoxic T-cell immunity.
Other experimental therapies that use available drugs, though not approved by the US Food and Drug Administration (FDA) for treatment of Ebola virus infection, may be considered. Agents that may reduce mortality without directly effecting viral replication include activated protein C and a recombinant nematode anticoagulant protein (NAP) that inhibits activated factor VII-tissue factor complex. NAP resulted in attenuation of the coagulopathy associated with decreased fibrinolysis and fibrin deposition with a resultant decrease in the severity of the systemic inflammatory response syndrome.
In a rhesus macaque model of Ebola hemorrhagic fever, which carries a mortality approaching 100%, Geisbert et al administered recombinant nematode anticoagulant protein, a potent inhibitor of TF-initiated coagulation. One third of the monkeys given the nematode anticoagulant protein survived a lethal dose of Ebola virus, whereas 16 of the 17 (94%) control animals died. This approach targeted the hemorrhagic disease component of the infection rather than the virus itself.
In April 2016, the FDA granted orphan designation to aphidicolin for the treatment of Ebola virus infection. Aphidicolin is an inhibitor of B-family DNA polymerases, which inhibit the cell cycle at the G1/S border. If the cell is exposed to aphidicolin during S-phase, DNA replication is interrupted.
In a benchtop experiment analyzing the influence of cell cycle arrest on Ebola virus infection, cells in G1/S phase were exposed to aphidicolin, a potent cell cycle inhibitor. A dose-dependent decrease in Ebola-infected cells was noted. Cells exposed to aphidicolin were allowed to resume cell cycle and then exposed to Ebola virus, which showed a time-dependent increase in infected cells.
Small interfering RNA
One approach to blocking Ebola virus replication involves the use of antisense nucleotides that are complementary to sequences in the RNA polymerase complex. Shortly after a lethal challenge of Zaire Ebola virus was given, the administration of small interfering RNAs (siRNAs) packaged in stable nucleic acid-lipid particles targeting the RNA polymerase L protein protected guinea pigs and macaques .
More recently, third-generation synthetic antisense oligonucleotides called phosphorodiamidate morpholino oligomers (PMOs) have been shown to sterically hinder mRNA processing. Positively charged Ebola virus–specific PMOs that target VP24 and VP35 mRNA sequences (AVI-6002, a combination of AVI-7537 and AVI-7539) protect rhesus monkeys after lethal viral challenge.[27, 28] In addition, a recently completed phase I study of AVI-6002 in human volunteers showed that the drug was safe and well-tolerated.
Preliminary studies in cynomolgus macaques given a cocktail of 3 different murine monoclonal antibodies (mAbs; ZMab) directed against Ebola virus envelope glycoprotein epitopes demonstrated postexposure prophylactic activity 1-2 days after an Ebola virus challenge. That result was matched by a mixture of 3 chimerized anti–Ebola virus mAbs (MB-003) having human constant regions produced in genetically modified tobacco plants. When given as postexposure prophylaxis 2 days after viral challenge, MB-003 was active both in mice and rhesus macaques.[31, 32]
The focus of mAb research is now shifting toward treatment of established infection. In that regard, 43% of rhesus macaques treated with MB-003 after onset of Ebola virus infection survived versus none of the untreated controls. Established infection was defined as fever and positive Ebola virus reverse-transcription polymerase chain reaction (RT-PCR) result. Similarly, ZMab yielded a 50% survival rate in cynomolgus macaques when given starting on day 4 after viral challenge.
Recently, an optimized combination of humanized mAbs produced in genetically modified tobacco plants and having specificity for 3 different Ebola virus glycoprotein epitopes rescued 100% of rhesus macaques even when given at advanced stages of disease 5 days after viral challenge (ZMapp; Mapp Biopharmaceutical, Inc., San Diego, CA, USA; and Defyrus, Inc., Toronto, Canada).[35, 36] In addition, two patients with Ebola virus disease in the United States who recently received ZMapp through emergency investigational new drug approval (US FDA) experienced declines in viral load and survived. Subsequently, another 3 of 4 individuals treated with ZMapp survived. These results suggest that ZMapp may prove useful for the treatment of established infection in humans.
Diet and Activity
Nutrition is complicated by the patient’s nausea, vomiting, and diarrhea.
Recovery often requires months, and delays may be expected before full resumption of normal activities. Weight gain and return of strength are slow. Ebola virus continues to be present for many weeks after resolution of the clinical illness. Semen from men recovering from Ebola infection has been shown to contain infectious virus, and Ebola has been transmitted by sexual intercourse involving recovering men and their sex partners. Any individuals who were exposed to infected patients should be watched closely for signs of early Ebola virus disease.
Prevention in healthcare personnel
Recent (2014) guidance from the CDC recommends that healthcare personnel who care for patients infected with Ebola virus (ie, physicians, nurses, other clinicians) wear personal protective equipment (PPE) that does not expose any skin. This includes a surgical hood that covers the head and neck and a single-use full face shield (rather than goggles), in addition to either a N95 respirator or powered air-purifying respirator instead of a mask.
The CDC now recommends that clinicians train rigorously at donning and doffing PPE in a stepwise manner and demonstrate competency. A trained monitor should oversee each time a clinician puts on and takes off this gear.
During patient care, the PPE should not be adjusted, and the worker’s gloved hands should be disinfected frequently using an alcohol-based hand rub (ABHR), especially after body fluids are handled.
Work continues on a vaccine for Ebola virus infection in primates. Sullivan et al reported on the combination of naked DNA vaccine capable of encoding Ebola proteins followed by a booster vaccination with a recombinant adenoviral vector expressing Ebola GP(Z).
In this study, cynomolgus macaques were injected with 3 doses of the DNA vaccine, 1 dose every 4 weeks. Twelve weeks later, the macaques were vaccinated with the recombinant adenoviral vector. After another 12 weeks, unvaccinated macaques and vaccinated macaques were injected with a lethal dose of Ebola virus. All of the unvaccinated macaques died, whereas none of the vaccinated macaques died.
This work indicates that primates can be vaccinated against Ebola virus and can develop both a cell-mediated response (thought to be a result of the DNA vaccine) and a humoral antibody response (thought to be a result of the recombinant adenoviral vaccine).
Other efforts to design vaccines that work in primates used strategies that were successful in mice and guinea pigs. Geisbert et al studied a series of vaccines containing RNA replicon particles from an attenuated strain of Venezuelan equine encephalitis virus that expressed Ebola virus GP and NP, a recombinant vaccinia virus that expressed Ebola virus GP, liposomes containing lipid A and inactivated Ebola virus, and a concentrated, inactivated whole-virion Ebola preparation.
Although these vaccines protected rodents against an Ebola virus challenge, they did not protect cynomolgus macaques or rhesus macaques against exposure to the virus.
Ebola is transmissible from person to person via direct contact with an infected patient’s blood or other body fluids. Airborne transmission of Reston ebolavirus is known to have occurred among primates; thus, although most cases in humans occur after direct contact with a patient or their blood or body fluids, transmission of Ebola virus via the airborne route cannot be dismissed.
Infection control inside and outside of medical facilities relies on barrier protection using double gloves, fluid-impermeable gowns, face shields with eye protection, and coverings for legs and shoes.
Whenever the diagnosis of Ebola or any other viral hemorrhagic fever is considered, the Centers for Disease Control and Prevention (CDC), along with local and state health officials, should be contacted. A consultation with an infectious diseases physician should be promptly obtained, and strict barrier isolation should be instituted.
No attempt should be made to culture the virus, except when culture can be performed in a maximum-containment biosafety level 4 laboratory with laboratory personnel wearing positive-pressure suits equipped with high-efficiency particulate air filters and an umbilical-fed air supply.
Hensley LE, Stevens EL, Yan SB, et al. Recombinant human activated protein C for the postexposure treatment of Ebola hemorrhagic fever. J Infect Dis. 2007 Nov 15. 196 Suppl 2:S390-9. [Medline].
Geisbert TW, Hensley LE, Jahrling PB, et al. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet. 2003 Dec 13. 362(9400):1953-8. [Medline].
Centers for Disease Control and Prevention (CDC). Travel Health Notices. Centers for Disease Control and Prevention (CDC). Available at http://wwwnc.cdc.gov/travel/notices. Accessed: October 17, 2014.
Sanchez A, Trappier SG, Mahy BW, Peters CJ, Nichol ST. The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proc Natl Acad Sci U S A. 1996 Apr 16. 93(8):3602-7. [Medline].
Leroy EM, Baize S, Volchkov VE, et al. Human asymptomatic Ebola infection and strong inflammatory response. Lancet. 2000 Jun 24. 355(9222):2210-5. [Medline].
Roddy P, Howard N, Van Kerkhove MD, et al. Clinical manifestations and case management of Ebola haemorrhagic fever caused by a newly identified virus strain, Bundibugyo, Uganda, 2007-2008. PLoS One. 2012. 7(12):e52986. [Medline]. [Full Text].
Amblard J, Obiang P, Edzang S, Prehaud C, Bouloy M, Guenno BL. Identification of the Ebola virus in Gabon in 1994. Lancet. 1997 Jan 18. 349(9046):181-2. [Medline].
Swanepoel R, Leman PA, Burt FJ, et al. Experimental inoculation of plants and animals with Ebola virus. Emerg Infect Dis. 1996 Oct-Dec. 2(4):321-5. [Medline].
Johnson E, Jaax N, White J, Jahrling P. Lethal experimental infections of rhesus monkeys by aerosolized Ebola virus. Int J Exp Pathol. 1995 Aug. 76(4):227-36. [Medline].
Allela L, Boury O, Pouillot R, et al. Ebola virus antibody prevalence in dogs and human risk. Emerg Infect Dis. 2005 Mar. 11(3):385-90. [Medline].
Centers for Disease Control and Prevention. Review of Human-to-Human Transmission of Ebola Virus. Available at http://www.cdc.gov/vhf/ebola/transmission/human-transmission.html. Accessed: October 17, 2014.
Centers for Disease Control and Prevention (CDC). 2014 Ebola Outbreak in West Africa. Centers for Disease Control and Prevention (CDC). Available at http://www.cdc.gov/vhf/ebola/outbreaks/guinea/. Accessed: September 4, 2014.
Baize S, Pannetier D, Oestereich L, et al. Emergence of Zaire Ebola Virus Disease in Guinea - Preliminary Report. N Engl J Med. 2014 Apr 16. [Medline].
Wilson J. Peace Corps evacuates west Africa volunteers due to Ebola threat. CNN. Available at http://www.cnn.com/2014/07/30/health/ebola-american-aid-workers/index.html?hpt=hp_t1. Accessed: July 30, 2014.
Alsop Z. Ebola outbreak in Uganda "atypical", say experts. Lancet. 2007 Dec 22. 370(9605):2085. [Medline].
Barrette RW, Metwally SA, Rowland JM, et al. Discovery of swine as a host for the Reston ebolavirus. Science. 2009 Jul 10. 325(5937):204-6. [Medline].
[Guideline] CDC. Evaluating Patients for Ebola: CDC Recommendations for Clinicians. Medscape Medical News. Oct 3 2014. [Full Text].
Abutaleb Y. U.S. FDA Issues Emergency Authorization for Two New Ebola Tests. Medscape. Oct 28 2014. [Full Text].
Geisbert TW, Jahrling PB. Differentiation of filoviruses by electron microscopy. Virus Res. 1995 Dec. 39(2-3):129-50. [Medline].
Huggins J, Zhang ZX, Bray M. Antiviral drug therapy of filovirus infections: S-adenosylhomocysteine hydrolase inhibitors inhibit Ebola virus in vitro and in a lethal mouse model. J Infect Dis. 1999 Feb. 179 Suppl 1:S240-7. [Medline].
Smith LM, Hensley LE, Geisbert TW, et al. Interferon-ß Therapy Prolongs Survival in Rhesus Macaque Models of Ebola and Marburg Hemorrhagic Fever. J Infect Dis. 2013 Jan 15. [Medline].
Baranovskiy AG, Babayeva ND, Suwa Y, Gu J, Pavlov YI, Tahirov TH. Structural basis for inhibition of DNA replication by aphidicolin. Nucleic Acids Res. 2014 Dec 16. 42 (22):14013-21. [Medline]. [Full Text].
Kota KP, Benko JG, Mudhasani R, Retterer C, Tran JP, Bavari S, et al. High content image based analysis identifies cell cycle inhibitors as regulators of Ebola virus infection. Viruses. 2012 Sep 25. 4 (10):1865-77. [Medline]. [Full Text].
Geisbert TW, Hensley LE, Kagan E, et al. Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference. J Infect Dis. 2006 Jun 15. 193(12):1650-7. [Medline].
Geisbert TW, Lee AC, Robbins M, et al. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet. 2010 May 29. 375(9729):1896-905. [Medline].
Warren TK, Warfield KL, Wells J, et al. Advanced antisense therapies for postexposure protection against lethal filovirus infections. Nat Med. 2010 Sep. 16(9):991-4. [Medline].
Iversen PL, Warren TK, Wells JB, et al. Discovery and early development of AVI-7537 and AVI-7288 for the treatment of Ebola virus and Marburg virus infections. Viruses. 2012 Nov 6. 4(11):2806-30. [Medline]. [Full Text].
Heald AE, Iversen PL, Saoud JB, et al. Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against ebola virus and marburg virus: results of two single-ascending-dose studies. Antimicrob Agents Chemother. 2014 Nov. 58(11):6639-47. [Medline]. [Full Text].
Qiu X, Audet J, Wong G, et al. Successful treatment of ebola virus-infected cynomolgus macaques with monoclonal antibodies. Sci Transl Med. 2012 Jun 13. 4(138):138ra81. [Medline].
Wilson JA, Hevey M, Bakken R, et al. Epitopes involved in antibody-mediated protection from Ebola virus. Science. 2000 Mar 3. 287(5458):1664-6. [Medline].
Olinger GG Jr, Pettitt J, Kim D, et al. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc Natl Acad Sci U S A. 2012 Oct 30. 109(44):18030-5. [Medline]. [Full Text].
Pettitt J, Zeitlin L, Kim do H, et al. Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail. Sci Transl Med. 2013 Aug 21. 5(199):199ra113. [Medline].
Qiu X, Wong G, Fernando L, et al. mAbs and Ad-vectored IFN-a therapy rescue Ebola-infected nonhuman primates when administered after the detection of viremia and symptoms. Sci Transl Med. 2013 Oct 16. 5(207):207ra143. [Medline].
Geisbert TW. Medical research: Ebola therapy protects severely ill monkeys. Nature. 2014 Oct 2. 514(7520):41-3. [Medline].
Lyon GM, Mehta AK, Varkey JB, et al. Clinical care of two patients with Ebola virus disease in the United States. N Engl J Med. 2014 Dec 18. 371(25):2402-9. [Medline].
Zhang Y, Li D, Jin X, Huang Z. Fighting Ebola with ZMapp: spotlight on plant-made antibody. Sci China Life Sci. 2014 Oct. 57(10):987-8. [Medline].
[Guideline] Centers for Disease Control and Prevention. Guidance on Personal Protective Equipment To Be Used by Healthcare Workers During Management of Patients with Ebola Virus Disease in U.S. Hospitals, Including Procedures for Putting On (Donning) and Removing (Doffing). Available at http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html. Accessed: October 21, 2014.
Sullivan NJ, Sanchez A, Rollin PE, Yang ZY, Nabel GJ. Development of a preventive vaccine for Ebola virus infection in primates. Nature. 2000 Nov 30. 408(6812):605-9. [Medline].
Geisbert TW, Pushko P, Anderson K, Smith J, Davis KJ, Jahrling PB. Evaluation in nonhuman primates of vaccines against Ebola virus. Emerg Infect Dis. 2002 May. 8(5):503-7. [Medline].
- Table 1. History of Sudan Ebola Virus Outbreaks
- Table 2. History of Zaire Ebola Virus Outbreaks
- Table 3. History of Tai Forest (Ivory Coast, Côte-d’Ivoire) Ebola Virus Outbreaks (No Deaths Reported)
- Table 4. History of Reston Ebola Virus Outbreaks (No Deaths Reported)
- Table 5. History of Bundibugyo Ebola Virus Outbreak
|Year||Location||Reported Cases, No.||Deaths, No. (%)|
|Data from Centers for Disease Control and Prevention and World Health Organization.
* Occurred after laboratory accident.
|Year||Location||Reported Cases, No.||Deaths, No. (%)|
|Jan 1996 to Apr 1996||Gabon||37||21 (57)|
|Jul 1996 to Jan 1997||Gabon||60||45 (74)|
|1996||South Africa (acquired in Gabon)||1||1 (100)|
|Oct 2001 to Mar 2002||Gabon||65||53 (82)|
|Oct 2001 to Mar 2002||DRC||59||44 (75)|
|Dec 2002 to Apr 2003||DRC||143||128 (89)|
|Nov 2003 to Dec 2004||DRC||35||29 (83)|
|Dec 2008 to Feb 2009||DRC||32||15 (47)|
|July 2012||Uganda||24||17 (71)|
|Nov 2012||DRC||77||36 (46)|
|Dec 2012||Uganda||7||4 (57)|
|2014 (as of October 17, 2014)||Guinea, Liberia, Sierra Leone, Nigeria, United States, Senegal, Spain (as of October 17, 2014)||8997 (as of October 17, 2014)||4493 (50) (as of October 17, 2014)|
|Data from Centers for Disease Control and Prevention and World Health Organization.|
|Year||Location||Proven * Cases Reported, No.|
|1989||Virginia, Texas, Pennsylvania||0|
|1990||Virginia and Texas||4|
|Data from Centers for Disease Control and Prevention and World Health Organization.
* Humans with serologic evidence of infection but without clinical disease.
† Associated with pig farming.[15, 16]