Emergency (****); * (*): *-* This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 3 Emergency (2015); 3 (1): 3-7 REVIEW ARTICLE Ebola Hemorrhagic Fever as a Public Health Emergency of International Concern; a Review Article Saeed Safari1, Alireza Baratloo1*, Alaleh Rouhipour2, Parisa Ghelichkhani3, Mahmood Yousefifard4 1. Department of Emergency Medicine, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Department of Pediatrics, Valeeasr Hospital, Ghazvin University of Medical Sciences, Abyek, Iran. 3. Department of Intensive Care Nursing, School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran. 4. Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. *Corresponding Author: Alireza Baratloo; Department of Emergency Medicine, Shohadaye Tajrish Hospital, Tehran, Iran. Postal code: 1989934148; Tel: +989122884364; Fax: +982122721155; Email: alirezabaratloo@yahoo.com Received: 18 Sep 2014; Accepted: 10 Nov 2014 Abstract Ebola hemorrhagic fever (EHF) was first reported in 1976 with two concurrent outbreaks of acute viral hemor- rhagic fever centered in Yambuku (near the Ebola river), Democratic Republic of Congo, and in Nzara, Sudan. The current outbreak of the Ebola virus was started by reporting the first case in March 2014 in the forest regions of southeastern Guinea. Due to infection rates raising over 13,000% within a 6-month period, Ebola is now considered as a global public health emergency and on August 8th, 2014 the World Health Organization (WHO) declared the epidemic to be a Public Health Emergency of International Concern. With more than 5000 involved cases and nearly 3000 deaths, this event has turned into the largest and most dangerous Ebola virus outbreak in the world. Based on the above-mentioned, the present article aimed to review the virologic characteristics, transmission, clinical manifestation, diagnosis, treatment, and prevention of Ebola virus disease. Key words: Hemorrhagic fever, Ebola; health; emergency responders; virology; infection control Cite this article as: Safari S, Baratloo A, Rouhipour A, Ghelichkhani P, Yousefifard M. Ebola hemorrhagic fever as a public health emergency of international concern; a review article. Emergency. 2015;3(1):3-7. Introduction: bola hemorrhagic fever (EHF) was first reported in 1976 with two concurrent outbreaks of acute viral hemorrhagic fever centered in Yambuku (near the Ebola River), Democratic Republic of Congo, and also in Nzara, Sudan. There have been almost 20 other outbreaks that involve nearly 2500 cases hap- pened before 2014. With the exception of a single case identified in the Republic of Ivory Coast in the 1990s, all of them were reported in sub-Saharan Africa involving the Sudan, Gabon, Uganda, and Democratic Republic of Congo (1). But the current outbreak (2014), which is the largest one ever documented, is the first recorded out- break of Ebola in West Africa (2). The previous largest outbreaks of Ebola virus was identified in Uganda in 2000–2001, which was caused by Sudan Ebola virus (SUDV) subtype. This outbreak resulted in nearly 400 cases, 216 of which were laboratory confirmed and had 53% overall case-fatality rate (3). The 25th known out- break of the Ebola Virus was started by reporting the first case in March 2014 in the forest regions of south- eastern Guinea. Its infection rates reached 13,000% within a 6-month period. In August 8, 2014 the World Health Organization (WHO) declared the epidemic to be a Public Health Emergency of International Concern (2, 4). Thereafter, Ebola virus has spread through the West Africa and appeared in Senegal, Sierra Leone, Liberia, Ni- geria, and now it has been reported in Spain and United States of America, too. With more than 5000 involved cases and nearly 3000 deaths, this event has turned into the largest and most dangerous Ebola virus outbreak all around the world (5). Based on the above-mentioned, the present article aimed to review the virologic charac- teristics, transmission, clinical manifestation, diagnosis, treatment, and prevention of Ebola virus disease. Virologic characteristics Ebola virus is a lipid-enveloped ribonucleic acid (RNA) virus, which belongs to the Flavivirus family and known since 1976. It consists of five different sub-types and Ebola virus Zaire sub-type (ZEBOV) was the first one to be recognized in the Democratic Republic of Congo. The current Ebola virus has 97% homology with ZEBOV (6, 7). Other subtypes include Bundibugyo (BDBV), SUDV, Côte d'Ivoire or Tai Forest (TAFV) and Reston Ebola vi- ruses (RESTV). Ebola hemorrhagic fever (EHF), caused by ZEBOV, has the highest fatality (57%–90%), followed E http://www.ncbi.nlm.nih.gov/mesh/68019142 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Emergency (2015); 3 (1): 3-7 4 by SUDV (41%–65%) and BDBV (40%) and these 3 sub- types are responsible for the large outbreaks that re- cently occurred in Africa. However to date, RESTV infec- tion has been observed in animals in Asia and as an asymptomatic disease in humans, while TAFV has only been identified in 2 human cases, both of which were nonfatal (4, 8, 9). Transmission Some authors claimed that a 44-year-old man suffering from malaria was the first identified fatal case of EHF who was infected using a contaminated needle for ad- ministration of parenteral chloroquine in the Demo- cratic Republic of Congo (previously named Zaire) in 1976 (1). On the other hand, some researches indicated that the first person became infected through contact with an infected animal (4). Fruit bats that live in Guinea and its neighboring countries are considered as the nat- ural hosts of Ebola viruses, and other mammals serve as accidental hosts. This virus has been implicated as one of the major causes of decreasing African chimpanzee and gorilla populations in recent decades (1, 10, 11). Ebola is one of the zoonotic viruses that can lead to a highly fatal disease in human beings. Humans are also one of the ac- cidental hosts and can be infected through close contact with blood and bodily fluids of another infected case (in- cluding humans and animals), either by direct contact or indirectly from a contaminated environment. It seems that mosquitoes and other insects do not play a role in virus transmission and also it is not spread through the air (1, 4, 10). Ebola virus has high transmissibility and virulence and less than 10 viral particles are enough for becoming infected. The incubation period range is 2-21 days (average 5-6). Fortunately, the disease is not trans- missible until the patient becomes symptomatic, but it continues to be contagious, even postmortem (2, 12). Family and healthcare providers caring for Ebola pa- tients are at the highest risk for becoming infected be- cause of their possible contact with contaminated blood or body fluids. So the virus can easily spread if reasona- ble preventive precautions are not taken (4). Clinical Manifestation The patients with suggestive symptoms, including unex- plained hemorrhage and risk factors within the last 3 weeks such as contact with suspected or confirmed EHF cases, or travel to an endemic area should be evaluated for EHF (2). EHF is a fatal disease (mortality rate 50%- 70%) that can occur 2-21 days after exposure to the vi- rus. The initial clinical presentation is non-specific. Early clinical symptoms of EHF include abrupt onset of fever, fatigue, myalgia and headache followed by progressive gastrointestinal symptoms such as anorexia, nausea, and abdominal discomfort accompanied by vomiting and di- arrhea within 1-2 days. This process can lead to intravas- cular volume depletion and also profound electrolyte disorders, hypoperfusion, shock, and multi-organ failure (acute respiratory, liver, and renal failure) within a few days. The “hemorrhage” in the phrase “Ebola hemor- rhagic fever” is a late manifestation, which usually oc- curs as gastrointestinal bleeding, conjunctival hemor- rhage, epistaxis, and hemorrhagic rash. Some others be- lieve that these symptoms occur only in a minority of pa- tients, that is why they use “Ebola virus disease” instead (1, 2, 5, 9, 10, 12-16). Complete blood count usually shows leucopenia and thrombocytopenia, but hemoglo- bin levels almost never decrease significantly. Intravas- cular volume depletion and hypoperfusion are mani- fested by metabolic lactic acidosis and renal insuffi- ciency. Massive diarrhea associates with profound hypokalemia and hematogenous spread of virus to the liver and spleen and leads to hepatocellular injury marked by elevated liver enzymes (2, 5, 12-14). Analysis of coagulation profile shows increased prothrombin and partial thromboplastin times (PT and PTT) accompanied by detection of fibrin degradation products in the occur- rence of disseminated intravascular coagulation (DIC) (6). Diagnosis Apart from Ebola virus, there are other types of viruses that can cause hemorrhagic fever, including Crimean- Congo hemorrhagic fever virus, Marburg virus, Lassa vi- rus, and emerging ones such as Lujo virus. These viruses have particular public health importance because of their spreading ability to healthcare workers, difficulties in their rapid recognition, lack of effective specific ther- apeutics, and high fatality rate (10). Definite diagnosis of a clinically suspected case of Ebola virus infection re- quires laboratory confirmation. In EHF, viremia devel- ops after the fever and takes up to 3 days to confirm the diagnosis by proper laboratory evaluation. It is neces- sary to collect serum, plasma, or whole blood samples of at least 4 milliliters, and take them to the appropriate health department, refrigerated or on ice, for further testing. Early diagnosis is confirmed via detecting viral antigens by using polymerase chain reaction (PCR) or enzyme-linked immunosorbent assay (ELISA) on the blood sample. Later in the disease course, antibodies against the virus such as Immunoglobulin M (IgM) and Immunoglobulin G (IgG) can also be detected. If the test results were positive, local and state health departments should be notified immediately. However, because of the extreme biohazard risk, using antigen- or antibody- based assays or PCR testing should be performed in level 4 biosafety laboratories, which is more possible in devel- oped countries where such laboratories are available (1, 2, 17). Centers of Disease Control and Prevention (CDC) have performed standardized enzyme-linked immuno- sorbent assay (ELISA) for detection of Ebola virus spe- cific antibodies. This test has high sensitivity and can be used for detecting antibodies in human beings even 10 years after exposure to the virus (6). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 5 Safari et al Emergency (2014); 2 (3): ***-*** Treatment There is no specific antiviral agent or vaccine against Ebola viruses. Therefore, supportive care is the most im- portant aspect of its management. Aggressive preven- tion of intravascular volume depletion is critical to avoid life-threatening complications by using proper fluid therapy, oxygen therapy, correcting profound electro- lyte abnormalities, and preventing the complications of shock such as acid–base derangements. Treatment of other infections, if they occur, and close monitoring of vi- tal signs and regular biochemical and blood gas checks should be done. These proceedings are considered as the foundation of critical care medicine and should be ap- plied to both resource-rich and resource-constrained settings. With improving supportive cares, EHF out- comes may also improve. Symptom control with taking narcotics and benzodiazepines were often reported as the end-of-life therapy in some patients (2, 5, 14). A va- riety of chemotherapeutic agents have been tested for different stages of development. Recombinant human activated protein C and recombinant nematode antico- agulant protein C2 are also among them. One drug iden- tified as ZMAPP, has been used on several patients, how- ever it remains unclear if it is effective or not. Therefore, no Food and Drug Administration (FDA) approved agent exists against Ebola (4, 6, 18-23). Figure 1 shows the lat- est CDC algorithm regarding emergency department evaluation and management for possible Ebola infected patients. Prevention The current outbreak of EHF highlighted the importance of prevention strategies. Health care workers have rep- resented a considerable proportion of all infected cases. So educating and training the medical staff on universal precautions, risk assessment, and use of personal pro- tective equipment is crucial. Patients initially identified as having a possible viral hemorrhagic fever should be isolated until the results of their specific diagnosis are obtained from reference laboratories. It is important not to delay diagnosis and treatment of more common dis- eases, such as malaria or typhoid, during this period. Fol- low-up of contact cases is essential for infection contain- ment in case the patient tests are positive. Specially equipped ambulances and trained staff should be pre- pared to do the transferring when needed (1, 10, 24). Early diagnosis and rapid laboratory confirmation along with isolation of patients and following their contacts, as well as access to protective equipment and environmen- tal decontamination are the mainstay of prevention. Acknowledgments: We would like to thank Centers of Disease Control and Prevention (CDC) for investment of its algorithm regard- ing emergency department evaluation and management for possible Ebola infected patients based on inquiry number: [ref:_00DU0YCBU._500U0FPuoD:ref]. Conflict of interest: None Funding support: None Authors’ contributions: All authors met four criteria for authorship contribution based on recommendations of the International Commit- tee of Medical Journal Editors. References: 1. Laupland KB, Valiquette L. 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Downloaded from: www.jemerg.com Emergency (2015); 3 (1): 3-7 6 VIIa/tissue factor: a study in rhesus monkeys. The Lancet. 2003;362(9400):1953-8. 20. Choi JH, Croyle MA. Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment. Biodrugs. 2013;27(6):565-83. 21. Warren TK, Wells J, Panchal RG, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature. 2014;508(7496):402-5. 22. Elshabrawy HA, Fan J, Haddad CS, et al. Identification of a Broad-Spectrum Antiviral Small Molecule against Severe Acute Respiratory Syndrome Coronavirus and Ebola, Hendra, and Nipah Viruses by Using a Novel High-Throughput Screening Assay. J Virol. 2014;88(8):4353-65. 23. Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res. 2014;105:17-21. 24. Woodrow CJ, Eziefula AC, Agranoff D, et al. Early risk assessment for viral haemorrhagic fever: experience at the Hospital for Tropical Diseases, London, UK. J Infect. 2007;54(1):6-11. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 7 Safari et al Emergency (2014); 2 (3): ***-*** Figure 1: Shows the latest CDC algorithm regarding emergency department evaluation and management for possible Ebola infected patients.