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Le Infezioni in Medicina, n. 2, 212-222, 2020 212 REVIEWS

Clinical aspects of disease: a review

Simran Batra1, Rohan Kumar Ochani1, Mufaddal Najmuddin Diwan1, Farah Yasmin1, Suha Safi Qureshi2, Sameer Bhimani3, Shehryar Shaikh4, Muhammad Ali Tariq4, Muhammad Ahmed Ashraf2, Hamza Ahmed Farooqi2, Sunil Kumar Dodani5 1Department of Internal , Dow University of Health Sciences, Karachi, Pakistan; 2Department of , Ziauddin Medical University, Karachi, Pakistan; 3Department of Internal Medicine, Jinnah Sindh Medical University, Karachi, Pakistan; 4Department of Internal Medicine, Dow International Medical College, DUHS, Karachi, Pakistan; 5Department of Infectious Diseases, Sindh Institute of and Transplantation, Karachi, Pakistan

SUMMARY Ebola Virus Disease (EVD), also known as Ebola disposing factors. This generally provides enough ev- Hemorrhagic Fever (EHF), initially emerged over 40 idence for clinicians to consider EHF and begin sup- years ago in the Democratic Republic of Congo. En- portive treatment until the virus is confirmed through demic to Africa, outbreaks have been recorded in six laboratory findings. Management of patients involves African countries since its detection in 1976. Fruit supportive care such as maintaining fluid along with are believed to be the natural hosts of Ebola electrolyte balance, blood pressure and oxygen sat- (EBoV), with and other serving uration. This also includes treating complications as accidental hosts. Transmission of EBoV has been arising from secondary infections. The main options reported in various ways, including to hu- include: prophylactic strategies, anti-viral for man transmission through close contact with blood EVD, immunotherapies, , and ZMapp. Final- and bodily fluids. The virus has an incubation period ly, the key to managing EBoV epidemics is to stop the ranging from two to twenty-one days, followed by a transmission of disease in the most severely affected multitude of clinical manifestations such as the sud- population, as prevention has become of utmost im- den onset of high fever, chills and myalgia depicting portance to alleviate the significant physical and eco- a flu-like syndrome. It is usually diagnosed based on nomic burden. several clinical symptoms such as the sudden onset of illness, high fevers for less than three weeks, and Keywords: Ebola virus; outbreaks; Ebola hemorrhagic at least two hemorrhagic symptoms despite no pre- fever; filovirus.

n INTRODUCTION in the Democratic Republic of Congo (DRC) [1]. The Ebola virus belongs to the Filo- bola Virus Disease (EVD), also known as the viridae, along with the genus virus. This EEbola Hemorrhagic Fever (EHF), initially highly virulent virus consists of a characteristic emerged in 1976 with a deadly infectious epidem- filamentous or branching convoluted shape and ic characterized by acute . is enveloped containing linear non-segmented, This outbreak constituted of 318 cases and a high negative-sense single-stranded RNA [2]. mortality rate of 88% (280 deaths) in ; There are five of this virus, with each sub- hence, it was named Ebola after the having different biologic characteristics and virulence [2, 3]. Fruit bats belonging to the Pter- opodidae family are thought to be responsible for Corresponding author the dissemination of this zoonotic virus, believed Simran Batra to be the natural hosts of Ebola viruses (EBoV), E-mail: [email protected] with humans and other mammals serving as ac- Clinical aspects of Ebola virus disease: a review 213

cidental hosts [4]. Transmission of the EBoV has government-led Consolidation and Stabilization been reported in various ways, including human Plan for long term Ebola survivor care following to human transmission through close contact with the end of the outbreak declaration to strengthen blood and bodily fluids such as saliva, breast milk, the emergency response capacity and prepared- urine and semen from another infected human or ness, and overall resilience of the health systems animal, either by direct contact or indirectly from [8, 9]. Despite several warnings and discussions, contaminated objects like needles and syringes. regular outbreaks of EVD have been noticed in Moreover, it is not spread through aerosol drop- the past decade, making this disease crucial for lets or by water and food contamination [5]. and infectious diseases specialists to Since the original case of this life-threatening tackle. However, the question arises: when this disease in DRC, the majority of the outbreaks of will stop? Therefore, to answer this question, this EBoV disease have been reported in Africa. The narrative review was designed to highlight the 2014-2016 outbreaks emerged in the rural setting clinical aspects associated with EVD, along-with of southeastern Guinea which eventually spread its diagnostic and management approach. to the crowded urban areas and across borders thus becoming a global epidemic. These outbreaks n METHODS were declared as a Emergency of International Concern (PHEIC) by World Health For this review, a literature search was conduct- Organization (WHO) resulting in more than ed using PubMed and Google Scholar from in- 28,600 cases and 11,325 deaths. Furthermore, due ception to September 2019. The following search to widespread transmission, countries includ- string was used: “Ebola” OR “Ebola virus” OR ing Guinea, Senegal, Nigeria, and United States “Ebola outbreak” OR “Ebola virus pathogenesis” amongst others were also affected during the ep- OR “Ebola transmission” OR “Ebola diagnosis” idemic [6]. The EBoV has an incubation period OR “Ebola management.” Articles in languages ranging from two to twenty-one days, followed other than English were excluded. by a multitude of clinical manifestations such as the sudden onset of high fever, chills and myalgia Epidemiology and outbreaks depicting a flu-like syndrome [2, 7]. In June 1976, an individual from a rural area in Su- In 2018-2019, the tenth and largest EVD outbreak dan, worked in a factory in the township of Nzara occurred in the DRC since Zaire Ebola virus was presented with complaints of headache, chest pain first discovered there in 1976. This epidemic in- and fever. The patient developed epistaxis, bleed- volved 1600 patients with a case fatality rate of ing from the mouth and bloody diarrhea the next 67%. The outbreak was first reported as a clus- day. After infecting several of his colleagues and ter of cases of acute hemorrhagic fever in North family members, the patient died on July 6, four Kivu following which EVD was also detected in days after his admission to the hospital. Accord- Ituri province and important commercial hubs ing to the WHO, the characteristics of the disease close to mainly due to travel and health were found to be similar to those in patients in care transmission mechanisms. Additionally, Marburg, Germany, nine years ago. After lasting the non-specific clinical manifestations of EVD for five months from June-November 1976 and including vomiting, diarrhea, sweating, dehy- infecting 284 people, the epidemic was brought dration, and hypovolemic shock coupled with under control, with the mortality being 53% [10]. undifferentiated symptoms of headache and fa- Endemic to Africa, 36 outbreaks have been re- tigue further complicated the diagnosis due to corded in 6 African countries since its detection a simultaneous high burden of other febrile in- in 1976. While outbreaks and isolated cases have fectious diseases. A concurrent wave of also been reported in the United States, United cases was reported in Beni which enhanced the Kingdom, Canada, Spain, and Thailand, however, difficulty of diagnosis and increased the number they have been reported as intermittent imported of people exposed to Ebola in overcrowded health cases [11]. Table 1 and Figure 1 outline Ebola out- care facilities with inadequate infection preven- breaks from 1976 to 2018 in various parts of the tion and control measures. Eventually, the Min- world, constituting of mainly Africa [12]. istry of Health in support of WHO developed a The largest outbreak to date has been reported 214 S. Batra, R.K. Ochani, M.N. Diwan, et al.

between the years 2013 and 2016 in West Africa, area in the provinces of Equateur and the North notably in Guinea, Sierra Leone, and Liberia [13]. Kivu in the DRC in May and June 2018, respec- Liberia has accounted for roughly 11,000 cases, tively. According to the reports, most of these out- and over 4,800 deaths out of the unmatched glob- breaks have been recorded in remote rural areas, ally reported 28,616 cases and 11,310 casualties but the outbreak in Gulu, Uganda, in 2000 was in [11]. This outbreak included both rural and urban a semi-urban area. areas with a very high incidence and mortality. The Figure 2 outlines the most recent outbreak in Nonetheless, the actual burden might have been Democratic Republic of Congo and Uganda [14]. markedly greater, owing to under-reporting [13]. Nevertheless, small outbreaks might not have Most recent outbreaks were recorded in a remote been identified as such. According to various

Table 1 - Outbreaks of Ebola virus from 1976-2020 [12]. Cases Deaths # Year Country Species reported Reported 1 Sudan Sudan 284 151 (53%) 1976 2 Democratic (formerly Zaire) 318 280 (88%) 3 1979 Sudan 64 22 (65%) 4 1989 Philippines Reston ebolavirus 3 0 (0%) 5 1990 United States of America Reston ebolavirus 4 0 (0%) 6 1994 Zaire ebolavirus 51 31 (61%) 7 1995 Democratic Republic of the Congo (formerly Zaire) Zaire ebolavirus 315 254 (81%) 8 Zaire ebolavirus 2 1 (50%) 1996 9 Gabon Zaire ebolavirus 60 45 (95%) 10 2000 Uganda Sudan ebolavirus 425 224 (53%) 11 Democratic Republic of the Congo (formerly Zaire) Zaire ebolavirus 59 44 (75%) 2001 12 Gabon Zaire ebolavirus 65 53 (81%) 13 2003 Democratic Republic of the Congo (formerly Zaire) Zaire ebolavirus 143 128 (89%) 14 2004 Sudan Sudan ebolavirus 17 7 (41%) 15 2005 Democratic Republic of the Congo (formerly Zaire) Zaire ebolavirus 12 10 (83%) 16 Uganda 131 42 (32%) 2007 17 Democratic Republic of the Congo (formerly Zaire) Zaire ebolavirus 264 187 (71%) 18 Democratic Republic of the Congo (formerly Zaire) Zaire ebolavirus 32 15 (47%) 2008 19 Philippines Reston ebolavirus 6 0 (0%) 20 Uganda Sudan ebolavirus 6 3 (50%) 21 2012 Democratic Republic of the Congo (formerly Zaire) Bundibugyo ebolavirus 38 13 (34%) 22 Uganda Sudan ebolavirus 11 4 (36%) 23 Democratic Republic of the Congo (formerly Zaire) Zaire ebolavirus 69 49 (71%) 24 Guinea, Liberia, Sierra Leone (West African Epidemic) Zaire ebolavirus 28610 11,308 (39%) 25 2014 Mali Zaire ebolavirus 8 6 (75%) 26 Nigeria Zaire ebolavirus 20 8 (40%) 27 United States of America Zaire ebolavirus 4 1 (25%) 28 2017 Democratic Republic of the Congo (formerly Zaire) Zaire ebolavirus 8 4 (50%) 29 Democratic Republic of the Congo (formerly Zaire), Zaire ebolavirus 3310 2264 (68.4%) 2018-20 Uganda Clinical aspects of Ebola virus disease: a review 215

Figure 1 - Global distribution of EBoV from 1976-2018. studies, EVD is mainly endemic to African coun- ebolavirus (Taï Forest virus), and finally Reston tries, with some spread to its neighboring coun- ebolavirus ( (RESTV) (Figure 3). tries [13]. The EBoV virion is a single-stranded, non-seg- mented, negative-sense RNA that is approximate- Pathogenesis ly 19,000 long, consisting of 7 EBoV, formerly known as Zaire EBoV, belongs to and 9 [15]. Unlike most of the viral infec- the family. This species is associated tions, EBOV has high pathogenicity with debili- with the greatest number of outbreaks and the tating complications, and fatal outcome [16]. highest case-fatality rates among the other four This pathogenicity is primarily related to its struc- viruses sharing the EBoV genus. The other vi- ture, as EBoV is a lipid-enveloped virus that aids ruses include Sudan ebolavirus (SUDV), Bundi- the virus into entering the host cell. The viral en- bugyo ebolavirus (Bundibugyo virus), Taï Forest velope glycoprotein (GP) essentially binds to the receptor and binds the with the host membrane [17]. Initially, the virus turns off the immune system by affecting the macrophag- es and dendritic cells (-presenting cells), causing their replication. This leads to modula- tion of the genes, which then undergo apoptosis and release viral particles to extracellular tissues [18]. However, later it may affect other several types of cells such as Kupffer cells, hepatocytes, fibroblasts, adrenal gland cells leading to the spread of disease, and causing vascular damage and multi-organ failure [19]. The virus disrupts the immune system by sup- pressing the maturation of dendritic cells, which Figure 2 - EBoV from 2018-2020. leads to disruption in the production of inflam- 216 S. Batra, R.K. Ochani, M.N. Diwan, et al.

Figure 3 - of Ebola Virus.

matory cytokines that impairs their ability to acti- EBoV [24]. With an incubation period of 4 to 10 vate T-cells [2, 19, 20]. In vitro studies indicate that days, EBoV has a 4 and category VP35 is involved in blocking the host A pathogen with a significant trans- production and signaling by suppressing the ac- mission probability throughout the nation [11]. tivation of T-cells and expression of cytokines Liquid or dried material both can help the virus when activated by a RIGI-like receptor signaling. survive for many days [25]. While, VP24 directly inhibits a/b and Blood, feces, and vomit are considered as most Interferon g (IFN) signaling by inhibiting the di- infectious bodily fluids, according to WHO [26]. merization of phosphorylated STAT1, ultimately Such fluids are considered as highly transmitta- blocking the of anti-viral genes [15, ble by direct contact from dead or living infected 21]. Additionally, IFNs also upregulate expression persons. Non-animal objects contaminated with of major histocompatibility complex on host cell infected bodily fluids (fomites) may also transmit surfaces’ which generally plays an essential role the disease [25]. However, the relative infectivity in innate immune response [2]. of the various body fluids of patients with EVD Furthermore, the virus further suppresses the im- has not been established yet. Although well docu- munity by causing apoptosis of bystander lympho- mented, the risk associated with sexual transmis- cytes, most probably via FasL/FasR receptor bind- sion remains low [24]. ing (extrinsic pathway), and possibly via upregulat- So far, direct contact with a symptomatic or dead ing TNF-α production inducing viral damage to the EVD case is the major route of transmission [25]. surrounding tissue (intrinsic pathway) [2, 22, 23]. In Humans can also get infected with EBoV via addition to weakening the immune system, the re- contact with wild animals in situations such as lease of vast amounts of cytokines and chemokines, hunting and preparing meat from infected ani- results in increased activation of coagulation cas- mals [26]. cade causing damage to the vascular integrity and Along with no documentation of airborne trans- permeability. This damage in the vessels may lead mission, attempts to culture virus from the amni- to hypovolemic shock, and subsequently, dissemi- otic fluid have not been reported either. Further- nated intravascular coagulation plays a huge role in more, high levels of viral RNA in amniotic fluid the mortalities associated with EHF [19, 20, 23]. of pregnant women infected with EVD and on the placenta and fetus right after delivery. These fac- Vectors, transmission and reservoirs tors, along with elevated in utero fetal and neona- Members of the Pteropodidae family, Fruit bats, are tal fatality rates, are strong indicators of vertical considered as the most likely natural reservoir of transmission of EVD [24, 25]. Clinical aspects of Ebola virus disease: a review 217

Clinical manifestations Moreover, the EHF presents with early non-spe- With an incubation period ranging from 2 to 21 cific symptoms and a high index of suspicion is days - high fever, fatigue, malaise, body aches, needed in diagnosis. However, identification of and chills represent EVD as a flu-like syndrome. the EBoV is not required for the initial diagnosis The disease also commonly manifests as gastro- of EHF. It is usually diagnosed based on multi- intestinal (abdominal pain and anorexia), respira- ple virologic consequences such as sudden onset tory (chest pain and dyspnea), vascular (postural of illness, high fevers (>101°F) for less than three hypotension and edema), and rarely neurologic weeks, at least two hemorrhagic symptoms (e.g., (headache, delirium, confusion and coma) disor- epistaxis, bloody stools, or hemoptysis) despite ders [2, 13]. Furthermore, low serum concentra- no predisposing factors for hemorrhagic manifes- tions of potassium, sodium and calcium have also tations generally provides ample evidence to the been commonly reported in EVD patients, prov- clinicians to consider EHF and begin supportive ing them to be important causes of death along treatment until confirmation of the virus is pro- with dehydration [27]. Although discretely visible vided by the laboratory findings [29]. on patients with dark skin, a maculopapular rash The specific diagnosis of EHF and EVD requires has also been reported as one of the findings [13]. laboratory evidence that should be performed in If pregnant, such women have a high probability a well-equipped laboratory with biosafety level of transmitting the disease to their infants either 4 bio-contaminant facilities keeping in view the by breast milk or by close contact. Such women high biohazardrisk associated with testing [30]. also have an increased risk of miscarriage, and as Serologic testing for the Ebola viral antibodies suggested by clinical findings, high children of in- includes enzyme-linked immunosorbent assay fected mothers have a high mortality rate [2]. (ELISA), radioimmunoassay (RIA), radioimmu- Death typically occurs between days 6 and 16, noprecipitation assay (RIPA), and Western blot even though the patients with the fatal disease analysis which is an immunoassay of viral pro- develop clinical manifestation during early in- teins separated by polyacrylamide gel electropho- fection. The causes of death include hypovolemic resis and transferred to a paper medium [31]. RIA shock and multiorgan failure [2]. Although in cer- is a sensitive radioimmunoassay that uses 125I-Ia- tain cases, sudden death can occur due to cardi- beled staphylococcal A and was utilized ac arrhythmias. Nevertheless, if patients survive by Douglas and Cleveland to distinguish between the stage of shock, there is a possibility of gradu- the two strains of the Ebola virus from the 1976 al recovery. Even though several studies tried to outbreaks of acute hemorrhagic fever in southern identify clinical manifestations for EVD, their di- Sudan (SUDV) and northern Zaire (EOBV) [32]. agnostic accuracy was too little to rely upon, ren- The RIPA and the Western blot analysis measure dering them inaccurate to be included in clinical antibody responses to individual viral proteins, triage systems [13]. thus showing molecular specificity to response and are used as secondary confirmatory serologic Diagnosis tools. The most sensitive serologic tool to detect The EVD presents with clinical manifestations de- antibodies to EBoV is the ELISA used for both pri- picting a flu-like syndrome, and many differential mates and humans. It is favorable in epidemiolog- diagnoses must be considered to eliminate the ical studies and on-going surveillance programs. possibility of diseases including malaria, typhoid Immunoglobulin (Ig) M antibodies to Ebola virus fever and meningococcal meningitis. Hence, it appear as early as six days after symptoms begin is imperative for clinicians to consider the travel and disappear in less than 90 days while IgG an- and exposure history when treating a suspected tibodies appear more slowly after symptom on- patient returning from an endemic area of EVD [2, set but persist for many months (>400 days) [31]. 7]. In accordance with a study conducted by Col- IgM and IgG antibodies do not develop in all lier et al., abnormal laboratory findings in an EVD fatal cases and can only be used in a fraction of involves leukopenia (as low as 1000 cells/L) with symptomatic patients, requiring seroconversion a left shift, thrombocytopenia (50,000-100,000 or a substantial increase in antibody titer for un- cells/L) prolonged bleeding time and prothrom- ambiguous diagnosis. However, it is the method bin time, hyperproteinemia and hematuria [28]. utilized by clinicians to diagnose asymptomatic 218 S. Batra, R.K. Ochani, M.N. Diwan, et al.

Ebola virus infections, which are characterized by Management and treatment extremely low viremia and development of IgG Management of patients suffering from EVD in- and IgM about three weeks after infection [33]. volves supportive care such as maintaining fluid Real-time reverse transcription-polymerase chain along with electrolyte balance, blood pressure (RT-PCR) reaction for clinical blood and oral swab and oxygen saturation. This also includes treating specimens, as well as immunohistochemistry on a complications arising from secondary infections. skin biopsy, are most used to diagnose post-mortem However, multiple medical, immunotherapy and EVD in people who died before hospitalization nucleic acid therapy approaches have been re- [34, 35]. RT-PCR was used for the rapid diagno- ported and are under further investigation. sis of EHF during the largest outbreak in Uganda (2000-2001). After the initial diagnosis of SUDV, Prophylactic strategies for EVD viral antigen detection by ELISA and RT-PCR was In the absence of pre-exposure prophylaxis to used to diagnose SUDV infection in suspected prevent the disease through non-pharmacologic patients and proved very useful for detecting the means by creating a barrier to transmission, an- virus in patient serum, plasma, and whole blood. ti-viral agents could be used for post-exposure The RT-PCR assay could also detect the Ebola vi- prophylaxis or treatment to reduce the disease rus 24-48 hours prior to detection by antigen cap- severity, virus transmission, and duration of clin- ture in a sample collected during the early phase ical manifestations. These therapeutic agents are of infection [36]. RT-PCR was originally devel- available in different formulations and can be oped and implemented during the EHF outbreaks administered via the oral, intramuscular, or in- in Gabon in 1996. Due to the high mortality and travenous routes. Measurement of end-organ and transmissibility rates, immediate diagnoses using immune system function, in addition to the fre- relatively sophisticated techniques were essential quency and duration of prophylaxis, must all be for surveillance and control. Since the peripheral considered for an effective post-exposure prophy- blood mononuclear cell (PBMC) is known to be lactic agent [39, 40]. targets for filovirus; this technique was utilized to detect the Ebola virus in these cells. RT-PCR Anti-viral therapy for EVD results were also compared with ELISA antigen Due to the requirement of biosafety level 4 facil- capture, and Ebola specific IgM and IgG antibody ities in a laboratory, researches have employed detection [37]. reverse genetics to identify new targets within RT-PCR proved to be more sensitive in identi- viral of the EBoV for drug and fying acute infection and early convalescence development. Reverse genetics allows the devel- as compared to antigen and IgM detection with opment of recombinant filoviruses, such as EBoV, a sensitivity of 100% and 91%, respectively. The containing key sequences but are non-rep- specificity compared with antigen detection and licating and hence non-infective. This technique IgM assay combined was 97%. Antigen capture has been used by Martinez and colleagues to un- was able to detect only 83% of those viruses iden- derstand gene function in EBoV research to study tified by PCR, while only 67% of the viruses were virus entry, replication and assembly [41]. Ribavi- identified by IgM [36]. A novel technique of im- rin and have been tried as a means to munohistochemistry (IHC) testing using forma- treat EVD. Ribavirin interferes with the capping lin-fixed postmortem skin specimens (skin biop- of the viral mRNA, while lamivudine is a nucle- sy) was used as a diagnostic procedure for the oside analogue that interferes in gene replication. EHF outbreak in the DRC (1995). In the IHC test- However, ribavirin resulted in reduced mortality ing, EBoV were seen primarily within in human cases of and monkeys with endothelial cells, mononuclear phagocytic cells, virus but has not been effective and hepatic sinusoids, indicating these cells to be in animal models of filoviral and flaviviral in- the primary target of Filovirus. IHC also showed fections [42]. Furthermore, no apparent survival an association of cellular damage with the viral benefit was observed with lamivudine treatment infection and abundant viral antigens in the skin [43]. Another anti-viral agent known as T-705 (fa- of EHF patients showed transmission by contact vipiravir) has undergone animal trials to evaluate to be responsible for epidemics [38]. its efficacy against EBoV. Although it was initially Clinical aspects of Ebola virus disease: a review 219

developed by Fujifilm, Japan for treating influen- turing new vaccines. Regulatory and ethical re- za virus infection by inhibiting a viral enzyme, views of protocols were immediately the animal studies have now confirmed that fa- done in Europe, North America, and Africa [49]. vipiravir is effective in treating animals infected Anti-Ebola Virus vaccine efforts have been in pro- with the aerosolized E718 strain of EBoV [44, 45]. gress for the past 2 decades, culminating in over 12 different vaccine candidates that have been Immunotherapies placed into several clinical trials [50]. However, Passive immune therapy or convalescent im- it was not until December 19th, 2019 when finally mune plasma for treatment of EVD was original- the U.S. Food and Drug Administration approved ly used in a 1995 outbreak in Kikwit, Zaire. Mu- the rVSV-ZEBOV. The rVSV-ZE- papa and his colleagues utilized this therapy to BOV vaccine is a single dose injection, and is a treat eight patients with EVD, out of which seven live, attenuated vaccine that has been genetically survived [46]. This technique uses plasma from engineered to contain a protein from the Zaire eb- recovered EVD patients to neutralize antibodies. olavirus. WHO issued recent guidelines for the potential The approval of rVSV-ZEBOV is supported by use of blood products from EVD survivors. This a study conducted in Guinea during the 2014- guideline addressed various issues ranging from 2016 outbreak in individuals 18 years of age and identification of suitable blood or plasma donors older. This study was an open-label, cluster-ran- among EVD survivors, donor consent and selec- domized phase III trial using an innovative ring tion, donor blood collection, as well as storage of vaccination protocol [51, 52]. The phase III clinical whole blood and plasma along with transporta- trial study reported promising results providing tion [47]. significant protection against EBOV-mediated disease and no new cases reported in either ran- Zmapp domized or non-randomized clusters of contacts This experimental drug was used for some pa- around confirmed EBOV virus disease patients. tients during the 2014 West Africa Ebola out- break, and several people survived. It compris- Disease control es of a combination of three humanized murine The key to managing EBoV epidemics is to stop antibodies generated by EBoV infected mice and the transmission and interrupt the spread of dis- produced in tobacco plants. This combination of ease in the most affected population. This is pos- antibodies binds to and inactivates the virus. In sible through early case identification/interven- animal studies, 43% of infected mice survived tion, rapid isolation, clinical management, public with Zmapp treatment. However, no randomized awareness and support, and transversal coordina- controlled clinical trials exist to investigate wheth- tion. Insufficient resources and lack of awareness er Zmapp is effective for patients suffering from played a major role in the 2014 Ebola outbreak. It EVD [43, 44 ,48]. was an alarming situation highlighting the weak- ened and understaffed health care system. Hence, Vaccination and prevention in August 2014, a partnership between WHO, Despite the discovery of the EBoV in 1976, it was Ministries of Health, Centers for Disease Control not until 2014 the world saw the virus’s destruc- and Prevention (CDC) and others was established tive potential. The epidemic outbreak of Ebola in to uplift the infection prevention and control West Africa leading to unprecedented numbers of practices in health care facilities [13, 53]. cases and deaths, heralded the scientific commu- Rapid identification requires aggressive surveil- nities throughout the world to work on the de- lance systems for the anticipation of outbreaks velopment of the Ebola vaccine, ideal for use in in areas at risk. Advanced technology and relia- an outbreak setting. WHO and a number of other ble laboratory testing techniques are vital for the public health experts, trial centers, funders, glob- immediate detection of the EBoV and other hem- al stakeholders and agencies collaborated for this orrhagic fever viruses. The advantages of nov- cause. Various clinical trials were rapidly initiated el diagnostic technologies and rapid laboratory in Africa and Australia, while the United States, response are highlighted in managing the EBoV Europe, and Asia started designing and manufac- outbreak in the DRC in 2018 [54]. 220 S. Batra, R.K. Ochani, M.N. Diwan, et al.

Isolation of the suspected case and monitoring of their honor and traditions. Therefore, improving the contacts is the next major step to interrupt the these procedures by making them more flexible chains of transmission. Establishment of Ebola in accordance with the community traditions and treatment centers (ETCs) where quality care and ensuring all the essential safety precautions can well-equipped staff are provided for the patients, significantly increase the compliance of safe bur- is crucial in to achieve this. These treatment ial activities. Also, female members should be a centers should be located close to the affected part of the burial team to bury female bodies [57]. communities and should be designed in a way Implementation of all the interventions men- that families can get involved in the care of their tioned above will not be possible without interna- close ones and visit their affected family mem- tional aid and funds, a high level of coordination bers. Efficient transportation facilities should also and acceptance from the community. Nonethe- be available to move the patient quickly [55-57]. less, if all the mentioned approaches are success- Setting up these ETCs in time, especially in re- fully implemented, there is a pronounced likeli- mote areas where the virus usually emerges, re- hood of controlling the spread of the disease. quires the importation of equipment, supplies, and experts in medical professionals along with n CONCLUSION logistical support for proper planning of the in- frastructure. For this to happen, we need global Frequent outbreaks of EBoV have caused numer- organizations that provide rapid comprehensive ous mortalities and morbidities. Since the virus epidemic support and the resources that are re- may lead to a , its prevention has be- quired for clinical management [58]. Medical pro- come of utmost importance as it is highly capable fessionals and the healthcare workers involved in of causing significant physical and economic bur- patient transport and cleanup of infectious mate- den. Hence, there is a dire need to conduct clini- rial should be vaccinated. Moreover, they should cal trials on EBoV to establish possible treatment use personal care equipment to safeguard them- regimens to prevent any further outbreaks. selves and avoid contact with blood and body flu- ids of Ebola patients [59]. Funding Public awareness, in order to gain the public sup- None port, is essential to limit the spread of the disease. Various strategies like contact tracing, burial prac- Conflict of interest tices, /restriction of the movements None to declare have the potential to curtail an outbreak. Howev- er, resistance from the community is a significant n REFERENCES hindrance to the implementation of these strate- gies, primarily because of the people’s perception [1] Report of an International Commission. Ebola haemorrhagic fever in Zaire, 1976. Bull World Health Or- regarding their social and cultural values being gan. 1978; 56 (2), 271-93. violated. Contact tracing includes identification, [2] H. Feldmann, T.W. Geisbert. Ebola haemorrhagic fe- listing, and monitoring of the contacts of patients ver. Lancet. 2012; 377 (9768), 849-62. with the EBoV. A survey in Liberia during 2014- [3] J.H. Kuhn, S. Becker, H. Ebihara, et al. Proposal for 2015 highlighted the success of this strategy as a revised taxonomy of the family Filoviridae: classifi- it helped in detecting 3-6% of new cases [60]. Al- cation, names of taxa and viruses, and virus abbrevia- though scarcity of resources like ambulances and tions. Arch Virol. 2010; 155 (12), 2083-2103. skilled human force might restrict the practice [4] Leroy EM, Kumulungui B, Pourrut X, et al. Fruit of contact tracing, effective community involve- bats as reservoirs of Ebola virus. . 2005; 438 ment and reciprocity will allow contact tracing (7068), 575-6. [5] Groseth, H. Feldmann, J.E. Strong. The ecology of even when the resources are limited. Addition- Ebola virus. Trends Microbiol. 2007; 15 (9), 408-16. ally, enforcement of safe burial practices is a ma- [6] Centers for Disease Control and Prevention. 2014-2016 jor contribution to control of the EBoV outbreak. Ebola Outbreak in West Africa. Retrieved from https:// However, practices such as the use of plastic bags www.cdc.gov/vhf/ebola/history/2014-2016-outbreak/ without burial clothes and prayers face a massive index.html. Last accessed March 16, 2020. backlash from the community as they are against [7] Sanchez TW, Feldmann GH. Filoviridae. Marburg Clinical aspects of Ebola virus disease: a review 221

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