Ebola, the killer virus
© Ghazanfar et al.; licensee BioMed Central. 2015
Received: 27 January 2015
Accepted: 29 March 2015
Published: 8 April 2015
Ebola virus disease (EVD) has mostly affected economically deprived countries as limited resources adversely affect a country’s infrastructure and administration. Probing into the factors that led to the widespread outbreak, setting forth plans to counter EVD cases in developing countries, and devising definitive measures to limit the spread of the disease are essential steps that must be immediately taken. In this review we summarize the pathogenesis of EVD and the factors that led to its spread. We also highlight interventions employed by certain countries that have successfully limited the epidemic, and add a few preventive measures after studying the current data. According to the available data, barriers to prevent and control the disease in affected countries include irresolute and disorganized health systems, substandard sanitary conditions, poor personal hygiene practices, and false beliefs and stigma related to EVD. The public health sector along with the respective chief authorities in developing countries must devise strategies, keeping the available resources in mind, to deal with the outbreak before it occurs. As a first step, communities should be educated on EVD’s symptoms, history, mode of transmission, and methods of protection, including the importance of personal hygiene practices, via seminars, newspapers, and other social media. A popular opinion leader (POL) giving this information would further help to remove the misconception about the nature of the disease and indirectly improve the quality of life of affected patients and their families.
KeywordsEbola hemorrhagic fever Epidemiology Ebola virus/physiology Hemorrhagic fever Ebola/transmission Ebola/prevention and control
Please see Additional file 1 for translation of the abstract into the six official working languages of the United Nations.
We conducted a narrative clinical review on the epidemiology, transmission, clinical manifestation, diagnosis, and prevention of Ebola virus. We searched for online articles using MEDLINE® and Google Scholar. The keywords/phrases used were: “Ebola virus disease”, “Epidemiology of Ebola virus disease”, “Mortality and morbidity associated with Ebola virus disease”, “Pathogenesis of Ebola virus disease”, “Clinical manifestation of Ebola virus disease”, and “Prevention of Ebola virus disease”. Articles dated from 1976 to 2015 were included in the study. Articles were reviewed from November 2014 to March 2015. Search results yielded a total of 174 articles out of which 52 articles were included in this study.
What is Ebola virus?
Ebola virus belongs to the family Filoviridae, which compromises three genera: Cuevavirus, Marburgvirus, and Ebolavirus . This family belongs to the order Mononegavirales . Five species of Ebola virus have been identified: Zaire, Sudan, Bundibugyo, Reston, and Taï Forest. Bundibugyo ebolavirus, Zaire ebolavirus, and Sudan ebolavirus have been associated with large outbreaks in Africa. The current West African outbreak was caused by Zaire ebolavirus, which is also the most virulent among the five species. Since 1976 it has caused multiple outbreaks in Central Africa, with a mortality rate of 55%–88% [11-14]. The Ebola virus genome contains a single strand of non-segmented, negative-sense viral genomic RNA .
How is Ebola virus transmitted?
Pteropodidae families of fruit bats are thought to be the natural reservoirs of Ebola virus . Humans can be infected by Ebola virus by direct contact with blood and body fluids of infected animals such as apes, gorillas, fruit bats, and monkeys [6,17,18]. There is no evidence that pet cat and dogs, mosquitoes, or other insects can transmit Ebola virus . Human-to-human transmission occurs via direct contact with the blood, organs, secretion, and other bodily fluids (such as urine, feces, semen, breast milk, mucus, vomit) of an infected person, and via surface and materials contaminated with these fluids [6,19-21]. Infected syringes and needles are other ways by which the virus can be transmitted from an infected human to uninfected humans . The Ebola virus does not spread through air or water . Breaches in infection control precautions have resulted in frequent infections of health workers treating this outbreak. Direct contact with the body of a deceased person during burial ceremonies is another way by which Ebola virus can be transmitted .
The Center for Disease Control and Prevention (CDC-US) and the WHO have recommended that infected individuals should be quarantined for 21 days. The incubation period of Ebola virus is 2–21 days after infection. Latest studies have shown that Ebola virus transmission occurs when there is a high viral load of bodily fluids . The person remains infectious as long as the virus is present in their blood and bodily fluids. Patients who have completely recovered from the Ebola virus cannot spread it. Ebola virus has been detected in semen of recovered patients, but it’s not known yet if it can spread through sex. The WHO advises to abstain from sex or use condoms for a period of three months after the patient is cured . There is no evidence yet on when women recovering from the Ebola virus can resume breastfeeding in .
What are the clinical symptoms of EVD?
The initial symptoms of EVD include fever, headache, fatigue, sore throat, and muscle pain, which are followed by anorexia, nausea, diarrhea, vomiting, rash, abdominal pain, cough, shortness of breath, postural hypotension, edema, headache, confusion, and coma . In some cases, a maculopapular rash develops after 5–7 days of symptoms . In severe cases, the patient also develops hemorrhagic complications (such as mucosal hemorrhages, nose bleeding, vomiting/coughing up blood, blood in stool, petechiae, ecchymoses, uncontrollable bleeding from venipuncture sites), severe metabolic disturbances, convulsion, shock, and multiple organ failure. These complications are the most common causes of death in patients . Symptoms can appear anywhere between 2–21 days . Gastrointestinal symptoms are the most common in the current outbreak .
How is EVD diagnosed?
Ebola virus usually reaches detectable levels in blood after three days of symptoms . A negative test before this does not rule out EVD. IgM enzyme-linked immunosorbent assay (ELISA), antigen-capture ELISA, polymerase chain reaction (PCR), and virus isolation are the diagnostic tests available to diagnose a patient who presents at a health facility within a few days of showing symptoms . IgM and IgG antibodies are used for diagnosis later in the disease course or after recovery. Laboratory findings in EVD include Leukopenia, thrombocytopenia, and elevated liver enzyme. Early and well-regulated inflammatory response with elevated IL-6 concentration and IL-1beta presence in a symptomatic patient is indicative of a good outcome, while a defective innate immune reaction with excessive macrophage/monocyte activation with release of interleukin-10, absent antibody response and elevated concentration of interleukin-1RA, and neopterin after a few days of onset of disease is associated with a fatal outcome . According to one study, lymphoid depletion and lymphopenia associated with Zaire ebolavirus is most likely due to lymphocyte apoptosis via Fas/FasL interaction . The excessive macrophage/monocyte activation leads to a “cytokine storm” triggering disseminated intravascular coagulation, hypotension, and vascular dysfunction, resulting in multiple organ failure, vascular collapse, and shock . According to a recent study, elevated thrombomodulin and ferritin levels have been associated with death and hemorrhage in Ebola virus infected patients .
How to prevent the spread of EVD?
According to an estimate, 2–8 patients are exported from the three major Ebola-inflicted countries in Africa monthly, with 64% of the destinations being economically deprived countries . This poses (still unidentified) problems for communities, which might get affected by Muslims travelling from these countries for Hajj, the annual Muslim pilgrimage to Mecca. Screening at all the export portals of the three afflicted countries would be the most effective way of containing the outbreak. However, implementing such screening protocols is beyond the abilities of any individual country without international assistance. One thing that can be implemented, however, is the banning of all transportation from the affected countries, not only via air travel but also via ships. A study in China calculated the number of imported cases of EVD using the basic reproductive number (R0) and found that early interventions led to a substantial decrease in the prevalence and duration of the epidemic . Hence, urgent measures need to be taken so that all predominantly Muslim countries are prepared to combat this epidemic.
According to the available data, barriers to prevent and control the disease in affected countries include irresolute and disorganized health systems, substandard sanitary conditions, poor personal hygiene practices, and false beliefs and stigma related to EVD . There are further hindrances due to the unavailability of electricity, water, adequate communication services between health officials, and poor facilities for transportation of patients and specimens . The public health sector along with the respective chief authorities in developing countries must devise strategies, keeping the available resources in mind, to deal with the outbreak before it occurs.
As a first step, communities should be educated on EVD’s symptoms, history, mode of transmission, and methods of protection, including the importance of personal hygiene practices, via seminars, newspapers, and other social media. A popular opinion leader (POL) giving this information would further help to remove the misconception about the nature of the disease and indirectly improve the quality of life of affected patients and their families [37,38]. In addition, health systems should formulate proper plans for emergency care, ensuring adequate quarantine facilities, proper surveillance, case management, and contact tracing. Training should be given to healthcare providers in areas such as prompt diagnosis and isolation of a suspected patient, the importance of wearing personal protective equipment, and safe burial techniques . There should be adequate distribution of gloves, gowns, masks, soaps, and disinfectants to healthcare facilities, and safety precautions should be devised especially for laboratory personnel including pre-transfusion testing . The CDC guidelines for monitoring patients (including symptomatic and asymptomatic), and precautions for healthcare professionals (including wearing personal protective equipment, practicing personal hygiene, use of disposable medical instruments, minimizing pricking and aerosol producing procedures, monitoring exposed staff, and adequate environment control) should be practiced . Special ambulances should be reserved to enable the safe transport of EVD patients.
At state level, funds for proper sanitation, especially in rural areas, should be reserved. Measures should be taken to ensure the availability of water and electricity in all areas. Internet and telephone services should be made available round the clock in all hospitals and healthcare facilities for effective communication, and for reporting and enrolling EVD cases. Home protective kits can further enhance control measures, thus their distribution at household-level should be considered .
Incident management systems (IMSs), such as the one adopted by the CDC for the control of the current epidemic, have proven efficacious in preventing the spread and adequately controlling the disease [42,43]. A report about the employment of an IMS divulged that Nigeria has successfully limited the outbreak and no further cases have been reported since August 31, 2014 . The employment of such a system has resulted in a decrease of EVD patients in Liberia . Thus, an IMS may be adopted and modified keeping in view the available resources and infrastructure of the respective country. The system involves authorizing representative health personnel to fulfill specific tasks including international correspondence, setting forth important measures to respond to the event (including surveillance), supporting affected families, devising plans to curtail chaos among the public, and monitoring healthcare providers . The CDC also recommends limiting the movement of patients (restriction of public transport especially aircrafts, ships, trains, and buses), which states should implement if EVD strikes their nation . Rapid identification and treatment of EVD-infected patients can significantly reduce the possibility of secondary transmission .
Many drugs are being probed as preventive medications for EVD, such as amiodarone, chloroquine, and clomiphene . An effective vaccine is also being devised; recombinant vesicular stomatitis virus vaccine has been the most promising, yet its efficacy has so far not been tested in humans [47-50]. Another study found that virus-like particles (VLPs) can provide post-exposure protection by amplifying Type 1 interferon signaling in macrophages and dendritic cells, which are thought to be the initial Ebola virus infection sites . One study showed that even if there was a vaccine, when the nature of the disease is considered, vaccination wouldn’t be efficacious and cost-effective in controlling the current outbreak, and would divert the attention of health authorities from proven effective control measures . However, vaccination can reduce case fatality and prevent further outbreaks. Another problem is that Ebola virus mostly affects low-income countries, which might not have enough resources to develop a vaccine. However, as EVD is considered a weapon of bioterrorism, this may drive the developed world to work out a definitive and safe vaccine soon enough. Until then, countries should concentrate on early detection, isolation, prompt treatment, contact tracing, and proper burials.
The public health sector along with the respective chief authorities in developing countries must devise strategies, keeping the available resources in mind, to deal with the outbreak before it occurs.
Authors are grateful to Dr Saima Perwaiz Iqbal and Dr Ashraf Hussain for their continuous support and help throughout the research.
- Report of a WHO/International Study Team. Ebola haemorrhagic fever in Sudan, 1976. Bull World Health Org. 1978;56:247–70.PubMed CentralGoogle Scholar
- Report of an International Commission. Ebola haemorrhagic fever in Zaire, 1976. Bull World Health Org. 1978;56:271–93.PubMed CentralGoogle Scholar
- Johnson KM, Lange JV, Webb PA, Murphy FA. Isolation and partial characterisation of a new virus causing acute haemorrhagic fever in Zaire. Lancet. 1977;1:569–71.View ArticlePubMedGoogle Scholar
- 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;371(15):1418–25.View ArticlePubMedGoogle Scholar
- Camacho A, Kucharski AJ, Funk S, Breman J, Piot P, Edmunds WJ. Potential for large outbreaks of Ebola virus disease. Epidemics. 2014;9:70–8.View ArticlePubMed CentralPubMedGoogle Scholar
- Ebola Virus Disease. World Health Organization; Fact sheet N°103. [Accessed on 14 December 2014] Available at http://www.who.int/mediacentre/factsheets/fs103/en/.
- World Health Organization. Ebola situation report, 4 February 2015. Geneva, Switzerland: World Health Organization; 2015. [Accessed on 8 March 2015] Available at http://apps.who.int/iris/bitstream/10665/151311/1/roadmapsitrep_4Feb15_eng.pdf?ua=1&ua=1.Google Scholar
- World Health Organization. Ebola situation report, 4 March 2015. Geneva, Switzerland: World Health Organization; 2015. [Accessed on 9 March 2015] Available at http://apps.who.int/ebola/en/current-situation/ebola-situation-report.Google Scholar
- World Health Organization. Ebola response roadmap situation report, 10 December 2014. Geneva, Switzerland: World Health Organization; 2014. [Accessed on 14 December 2014] Available at http://www.who.int/csr/disease/ebola/situation-reports/en/.Google Scholar
- Forrester JD, Pillai SK, Beer KD, Neatherlin J, Massaquoi M, Nyenswah TG, et al. Assessment of ebola virus disease, health care infrastructure, and preparedness - four counties, Southeastern Liberia, august 2014. MMWR Morb Mortal Wkly Rep. 2014;63(40):891–3.PubMedGoogle Scholar
- WHO Ebola Response Team. Ebola virus disease in West Africa--the first 9 months of the epidemic and forward projections. N Engl J Med. 2014;371:1481.View ArticleGoogle Scholar
- Georges-Courbot MC, Lu CY, Lansoud-Soukate J, Leroy E, Baize S. Isolation and partial molecular characterisation of a strain of Ebola virus during a recent epidemic of viral haemorrhagic fever in Gabon. Lancet. 1997;349(9046):181.View ArticlePubMedGoogle Scholar
- Khan AS, Tshioko FK, Heymann DL, Le Guenno B, Nabeth P, Kerstiëns B, et al. J Infect Dis. 1999;179 Suppl 1:S76-86.Google Scholar
- Grard G, Biek R, Tamfum JJ, Fair J, Wolfe N, Formenty P, et al. Emergence of divergent Zaire ebola virus strains in Democratic Republic of the Congo in 2007 and 2008. J Infect Dis. 2011;204 Suppl 3:S776–84.View ArticlePubMedGoogle Scholar
- Sanchez A, Kiley MP, Klenk HD, Feldmann H. Sequence analysis of the Marburg virus nucleoprotein gene: comparison to Ebola virus and other non-segmented negative-strand RNA viruses. J Gen Virol. 1992;73(Pt 2):347–57.View ArticlePubMedGoogle Scholar
- Leroy EM, Kumulungui B, Pourrut X, Rouquet P, Hassanin A, Yaba P, et al. Fruit bats as reservoirs of Ebola virus. Nature. 2005;438(7068):575–6.View ArticlePubMedGoogle Scholar
- Transmission. Centers for Disease Control and Prevention; [Accessed on 14 December, 2014]. Ebola Virus Disease. Available at http://www.cdc.gov/vhf/ebola/transmission/.
- Leroy EM, Rouquet P, Formenty P, Souquière S, Kilbourne A, Froment JM, et al. Multiple Ebola virus transmission events and rapid decline of central African wildlife. Science. 2004;303(5656):387–90.View ArticlePubMedGoogle Scholar
- Wamala JF, Lukwago L, Malimbo M, Nguku P, Yoti Z, Musenero M, et al. Ebola hemorrhagic fever associated with novel virus strain, Uganda, 2007–2008. Emerg Infect Dis. 2010;16(7):1087–92.View ArticlePubMed CentralPubMedGoogle Scholar
- Chowell G, Nishiura H. Transmission dynamics and control of Ebola virus disease (EVD): a review. BMC Med. 2014;12(1):196.View ArticlePubMed CentralPubMedGoogle Scholar
- Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis. 2007;196 Suppl 2:S142–7.View ArticlePubMedGoogle Scholar
- Legrand J, Grais RF, Boelle PY, Valleron AJ, Flahault A. Understanding the dynamics of Ebola epidemics. Epidemiol Infect. 2007;135(4):610–21. Epub 2006 Sep 26.View ArticlePubMed CentralPubMedGoogle Scholar
- Drazen JM, Kanapathipillai R, Campion EW, Rubin EJ, Hammer SM, Morrissey S, et al. Ebola and quarantine. N Engl J Med. 2014;371(21):2029–30.View ArticlePubMedGoogle Scholar
- Recommendations for Breastfeeding/Infant Feeding in the Context of Ebola. Centers for Disease Control and Prevention. Ebola Virus Disease [Accessed on 14 December 2014]. Available at http://www.cdc.gov/vhf/ebola/hcp/recommendations-breastfeeding-infant-feeding-ebola.html.
- Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849–62.View ArticlePubMed CentralPubMedGoogle Scholar
- Hoenen T, Groseth A, Falzarano D, Feldmann H. Ebola virus: unravelling pathogenesis to combat a deadly disease. Trends Mol Med. 2006;12(5):206–15. Epub 2006 Apr 17.View ArticlePubMedGoogle Scholar
- Ebola Virus Disease Signs and Symptoms. Centers for Disease Control and Prevention. [Accessed on 14 December 2014]. Available at http://www.cdc.gov/vhf/ebola/symptoms/.
- Goeijenbier M, van Kampen JJ, Reusken CB, Koopmans MP, van Gorp EC. Ebola virus disease: a review on epidemiology, symptoms, treatment and pathogenesis. Neth J Med. 2014;72(9):442–8.PubMedGoogle Scholar
- Diagnosis. Centers for Disease Control and Prevention; [Accessed on 16 December, 2014]. Available at http://www.cdc.gov/vhf/ebola/diagnosis/index.html.
- Baize S, Leroy EM, Georges AJ, Georges-Courbot MC, Capron M, Bedjabaga I, et al. Inflammatory responses in Ebola virus-infected patients. Clin Exp Immunol. 2002;128(1):163–8.View ArticlePubMed CentralPubMedGoogle Scholar
- Wauquier N, Becquart P, Padilla C, Baize S, Leroy EM. Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. PLoS Negl Trop Dis. 2010;5:4(10).Google Scholar
- McElroy AK, Erickson BR, Flietstra TD, Rollin PE, Nichol ST, Towner JS, et al. Ebola hemorrhagic fever: novel biomarker correlates of clinical outcome. J Infect Dis. 2014;210(4):558–66.View ArticlePubMedGoogle Scholar
- Bogoch II, Creatore MI, Cetron MS, Brownstein JS, Pesik N, Miniota J, et al. Assessment of the potential for international dissemination of Ebola virus via commercial air travel during the 2014 west African outbreak. Lancet. 2015;385(9962):29–35.View ArticlePubMed CentralPubMedGoogle Scholar
- Chen T, Ka-Kit Leung R, Liu R, Chen F, Zhang X, Zhao J, et al. Risk of imported Ebola virus disease in China. Travel Med Infect Dis. 2014;12(6PA):650–8.View ArticlePubMedGoogle Scholar
- Osungbade KO, Oni AA. Outbreaks-of Ebola virus disease in the West African sub-region. Afr J Med Med Sci. 2014;43(2):87–97.Google Scholar
- Koenig KL, Majestic C, Burns MJ. Ebola virus disease: essential public health principles for clinicians. West J Emerg Med. 2014;15(7):728–31.View ArticlePubMed CentralPubMedGoogle Scholar
- Davtyan M, Brown B, Folayan MO. Addressing Ebola-related stigma: lessons learned from HIV/AIDS. Glob Health Action. 2014;7:26058.PubMedGoogle Scholar
- Li L, Guan J, Liang LJ, Lin C, Wu Z. Popular opinion leader intervention for HIV stigma reduction in health care settings. AIDS Educ Prev. 2013;25(4):327–35.View ArticlePubMed CentralPubMedGoogle Scholar
- Katz LM, Tobian AA. Ebola virus disease, transmission risk to laboratory personnel, and pretransfusion testing. Transfusion. 2014;54(12):3247–51.View ArticlePubMedGoogle Scholar
- Infection Prevention and Control Recommendations for Hospitalized Patients with Known or Suspected Ebola Virus Disease in U.S. Hospitals. Ebola Virus Diesease. Centers for Disease Control and Prevention; [Accessed on 17 December, 2014]. Available at http://www.cdc.gov/vhf/ebola/hcp/infection-prevention-and-control-recommendations.html.
- Lewnard JA, Ndeffo Mbah ML, Alfaro-Murillo JA, Altice FL, Bawo L, Nyenswah TG, et al. Dynamics and control of Ebola virus transmission in Montserrado, Liberia: a mathematical modelling analysis. Lancet Infect Dis. 2014;14(12):1189–95.View ArticlePubMedGoogle Scholar
- Pillai SK, Nyenswah T, Rouse E, Arwady MA, Forrester JD, Hunter JC, et al. Centers for Disease Control and Prevention (CDC). Developing an incident management system to support Ebola response – Liberia, July-August 2014. MMWR Morb Mortal Wkly Rep. 2014;63(41):930–3.PubMedGoogle Scholar
- Shuaib F, Gunnala R, Musa EO, Mahoney FJ, Oguntimehin O, Nguku PM, et al. Ebola virus disease outbreak - Nigeria, July-September 2014. MMWR Morb Mortal Wkly Rep. 2014;63(39):867–72.PubMedGoogle Scholar
- Nyenswah TG, Westercamp M, Kamali AA, Qin J, Zielinski-Gutierrez E, Amegashie F, et al. Evidence for declining numbers of ebola cases - montserrado county, liberia, june-october 2014. MMWR Morb Mortal Wkly Rep. 2014;63(46):1072–6.PubMedGoogle Scholar
- Interim U.S. Guidance for Monitoring and Movement of Persons with Potential Ebola Virus Exposure. Ebola Virus Diesease. Centers for Disease Control and Prevention; [Accessed on 17 December, 2014]. Available at http://www.cdc.gov/vhf/ebola/exposure/monitoring-and-movement-of-persons-with-exposure.html.
- Koonin LM, Jamieson DJ, Jernigan JA, Van Beneden CA, Kosmos C, Harvey MC, et al. Systems for rapidly detecting and treating persons with ebola virus disease - United States. MMWR Morb Mortal Wkly Rep. 2015;64(8):222–5.PubMedGoogle Scholar
- Marzi A, Ebihara H, Callison J, Groseth A, Williams KJ, Geisbert TW, et al. Vesicular stomatitis virus-based Ebola vaccines with improved cross-protective efficacy. J Infect Dis. 2011;204 Suppl 3:S1066–74.View ArticlePubMed CentralPubMedGoogle Scholar
- Mire CE, Geisbert JB, Marzi A, Agans KN, Feldmann H, Geisbert TW. Vesicular stomatitis virus-based vaccines protect nonhuman primates against Bundibugyo ebolavirus. PLoS Negl Trop Dis. 2013;7(12):e2600.View ArticlePubMed CentralPubMedGoogle Scholar
- Geisbert TW, Bausch DG, Feldmann H. Prospects for immunization against Marburg and Ebola viruses. Rev Med Virol. 2010;20(6):344–57.View ArticlePubMed CentralPubMedGoogle Scholar
- Lai L, Davey R, Beck A, Xu Y, Suffredini AF, Palmore T, et al. Emergency postexposure vaccination with vesicular stomatitis virus-vectored ebola vaccine after needlestick. JAMA. 2015;313(12):1249–55.View ArticlePubMedGoogle Scholar
- Ayithan N, Bradfute SB, Anthony SM, Stuthman KS, Bavari S, Bray M, et al. Virus-like particles activate type I interferon pathways to facilitate post-exposure protection against Ebola virus infection. PLoS One. 2015;10(2):e0118345.View ArticlePubMed CentralPubMedGoogle Scholar
- MacNeil A, Rollin PE. Ebola and Marburg hemorrhagic fevers: neglected tropical diseases? PLoS Negl Trop Dis. 2012;6(6):e1546.View ArticlePubMed CentralPubMedGoogle Scholar
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