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SPECIAL ARTICLE
Year : 2014  |  Volume : 32  |  Issue : 4  |  Page : 364-370
 

The threat of Ebola: An update


Department of Microbiology, All India Institute of Medical Sciences, Bhubaneswar 751 019, Orissa, India

Date of Submission02-Sep-2014
Date of Acceptance12-Sep-2014
Date of Web Publication4-Oct-2014

Correspondence Address:
Baijayantimala Mishra
Department of Microbiology, All India Institute of Medical Sciences, Bhubaneswar 751 019, Orissa
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0255-0857.142230

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How to cite this article:
Mishra B. The threat of Ebola: An update. Indian J Med Microbiol 2014;32:364-70

How to cite this URL:
Mishra B. The threat of Ebola: An update. Indian J Med Microbiol [serial online] 2014 [cited 2019 Sep 17];32:364-70. Available from: http://www.ijmm.org/text.asp?2014/32/4/364/142230



 ~ Introduction Top


The world experienced the largest and most widespread Ebola virus outbreak in West Africa, 2014. The current outbreak which began in Guinea in December, 2013, and came to notice in March, 2014, has already affected five African countries. Till now, the threat of the virus for the world outside Africa was mainly for its potential as a biological weapon. The present one is the largest, longest and most widespread outbreak shaking the world for the first time with the scare of Ebola virus disease (EVD), due to the possibility of natural disease transmission from the affected African countries which was never realized before so seriously. On 28 th August 2014 the World Health Organization (WHO) warned that the number of people affected by Ebola virus could rise to 20,000 within coming 9 months. Nearly 45% of the total number of reported cases have occurred only within a span of 3 weeks with cumulative number of 3944 cases and 2097 deaths (as of 5 th September 2014) despite significant gaps in reporting. [1] On 8 th August, 2014 WHO declared the West Africa Ebola virus outbreak as a "Public Health Emergency of International concern" (PHEIC).

The current outbreak

The epicenter of the present outbreak which began in December, 2013 was the remote South-east rainforest region of Guinea. The index case, a 2-year-old boy, resident of Meliandou Village of Guéckédou, died on 6 th of December 2013. Three of his family members along with two healthcare workers who had come in contact with the index case, had also died of Ebola virus infection. [2] The infection then spread to the neighbouring villages, and finally crossed the Guinea border and entered sequentially to Liberia, Sierra Leone, Nigeria and Senegal in March, May, July and August affecting near 4000 cases and more than 2000 deaths (by 5 th September 2014; [Figure 1]). [1],[3] [Figure 2] depicts the important timeline of the current outbreak.
Figure 1: Ebola outbreak West Africa 2014 as at 5th September 2014

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Figure 2: Timeline of West Africa Ebola virus disease outbreak 2014

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Ebola virus (formerly Zaire ebolavirus), was found to be the causative strain of the present outbreak, for the first time, in West Africa. The phylogenetic analysis has shown the present Guinean strain is an outlier within the EBOV, suggesting that the introduction of the virus into West Africa has not occurred recently. [2] Phylogenetic comparison to genomes from previous outbreaks has revealed that the divergence from Central African strain had occurred at around a decade back in 2004, and have been circulating amongst the bat population in Guinea, suggesting there by an independent zoonotic event for the current outbreak. [3] Genetic similarities among the samples of the 2014 West Africa outbreak suggests a single event of virus transmission from the natural reservoir, followed by sustained human to human transmission. [3]

The virus

The family Filoviridae consists of two genera, Ebola virus and Marburg virus. Filoviruses have a uniform diameter of 80 nm and variable length, which may be up to 1400 nm. The viral genome is a single stranded, negative sense, non-segmented RNA molecule, that encodes seven genes; nucleoprotein (NP), virion protein (VP) 35, VP40, glycoprotein (GP), VP30, VP24, RNA-dependent RNA polymerase (L). Amongst these, NP, VP35, VP30 and RNA-dependent RNA polymerase are associated with viral replication and transactivation. VP40 is the matrix protein and involves in budding and release of viral particle, whereas VP24 is the minor matrix protein and associated with nucleocapsid formation. Both the matrix proteins, VP40 and VP24 are known to block interferon signaling. The only surface protein possessed by the filovirus is the glycoprotein, present as trimeric spikes consisting of GP 1 and GP 2 . The non-structural soluble form of glycoprotein, sGP, a unique product of EBOV GP gene, gets secreted from infected cells. [4]

Ebola virus has five species, Zaire, Sudan, Tai Forest, Reston and Bundibugyo. The sequence difference within species is rarely more than 3%. Among the Ebola virus species, maximum divergence has been reported between Tai Forest virus and Reston virus [5] , whereas the maximum divergence is 3% between the strains of current West Africa outbreak (Gueéckeédou-C05) and 1994 Gabon strain. [2]

Epidemiology

In 1976, outbreak of haemorrhagic fever was reported in two adjacent localities in Africa, southern Sudan and northern Zaire (presently named as Democratic Republic of Congo (DRC)). The outbreak started with an index case with malaria like symptoms and spread due to use of unsterilized needles in the hospital, affected 318 cases with a case fatality rate of 88%. An unknown pathogen was isolated from patients' blood sample, which was named as Ebola virus after the name of the Ebola river in North Western DRC. [6] The two outbreaks were initially thought to be caused by two different viruses, which later found to be two species of Ebola virus, Sudan Ebola virus (SEBOV) and Zaire Ebola virus (ZEBOV). [7] The third species, Tai forest Ebola virus (previously called Ivory Coast or Coˆ te d'Ivoire) was isolated from an individual who worked in Tai forest and had conducted a necropsy on a chimpanzee that had stayed with a troop where several members had died due to Ebola haemorrhagic fever. [8] The latest human pathogenic Ebola virus is the Bundibugyo virus, found in equatorial region of Africa. [9] Another species of Ebola virus, Reston Ebola virus, is considered non-pathogenic for humans. This species was first discovered in Reston, Virginia, USA, in November, 1989 where high mortality was noticed in a shipment of Cyanomolgus monkeys that was imported from Philippines. Serological testing amongst animal handlers showed the evidence of recent infection in four, but none of them developed any manifestation of haemorrhagic fever like illness. [10] Several outbreaks due to various species of Ebola virus have been recorded in different parts of Africa.

Ecology

Ebola virus disease is a classical zoonotic disease. Evidences suggest fruit bats as the reservoir for both Ebola and Marburg virus. The viral RNA and antibodies of Zaire Ebola virus have been detected in three species of fruit bats; Hypsignathus monstrosus (the hammer-headed fruit bat), Epomops franqueti (Franquet'sepauletted fruit bat) and Monycteris torquata (the little-collared bat) and therefore have been implicated as the potential spill over source for Ebola virus. [11] Detection of similar EBOV sequences from fruit bats and the infected patients in the outbreak locality also reconfirms bats as the reservoir of filoviruses. [12],[13] Spill over from bats is believed to cause outbreaks. The infection in bats is or associated with sub-clinical infection. Mammalian species including non-human primates that are susceptible to infection are regarded as the dead end hosts. Possibilities of seasonal effect on introduction of Ebola virus infection have also been hypothesised. [14],[15] Besides this, stress due to alteration of diet, scarcity of diet as well as physiological conditions like pregnancy, all have been observed to increase viral replication and thereby increase the risk of virus transmission. [16]

Clinical features

The severity of different species has been found to be of variable grade. ZEBOV is the most severe and a case fatality rate approaching 90%, followed by Sudan EBOV (SEBOV) which has been associated with 53-66% mortality. [17],[18] The case fatality in Bundibugyo virus is estimated to be near 40%, whereas Tai Forest virus has been described only in a single case, who had recovered from the disease. [8],[19],[20]

The disease usually starts with an abrupt onset, after an incubation period of 2-21 days (average 4-10 days). [21] The initial manifestations are fever, chills and myalgia. Subsequently haemorrhagic manifestation sets in, which manifests with petechiae, ecchymoses, and finally subcutaneous/mucosal/internal bleeding occurs involving multiple organs. Appearance of maculopapular rash associated with erythema at around 5-7 days of illness is often considered as an important differential feature, which later isfollowed by desquamation. In the end stage, metabolic disturbances, diffuse coagulopathy and circulatory collapse supervene. [22],[23] The outcome of the disease in terms of death or recovery usually is observed during 6-11 days of illness. [24] Absence of haemorrhagic manifestations at the time of diagnosis was noted in majority of the patients during the present outbreak. This has highlighted the importance of the term "Ebola virus disease" instead of "Ebola haemorrhagic fever", which would help in early recognition of cases. [2]

Pathogenesis

The outbreak of EVD begins with the introduction of virus into human population from infected bats or non-human primates. Thereafter, the transmission from human to human occurs through close contact with patients or cadaver of Ebola-infected patients. The first part generates the outbreak, occurs due to spill over of zoonotic infection where the virus is acquired by close contact with bats or non-human primates through hunting, butchering, eating or handling organs or cells of these animals or through exposure to bat inhabited caves. [25],[26] The second part, i.e, the human to human transmission, is responsible for spreading the outbreak. This occursmainly through direct contact with patient's blood or various body fluids like urine, semen, genital secretion, sweat, bloody stool and vomitus and indirect contact with environment contaminated with infected body fluids. [27] The virus has been found in semen for up to 7 weeks after recovery from the illness, suggesting the possibility of sexual mode of transmission. [21]

Transmission through re-use of contaminated needles in hospitals had led to the first outbreak of Zaire and Sudan EBOV in 1976. [6] Exposure to infected monkey cells, blood and needle stick injury has also been reported. [28],[29],[30] Though evidences of aerosol transmission have been reported between monkeys in natural condition, proven in laboratory experiments and considered as an efficient route if given deliberately, the transmission pattern during outbreaks in humans does not suggest respiratory route of transmission. No evidence suggests the role of insects in disease transmission. [31],[32]

[Figure 3] depicts the various modes of Ebola virus transmission.
Figure 3: Modes of transmission of Ebola virus infection

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The virus gains entry into the body through mucosa, skin abrasion or directly through blood. Monocyte, macrophage and dendritic cells, hepatocyte, adrenal cortical cells and endothelial cells are the target cells. The initial replication occurs in monocytes, macrophage and dendritic cells and via these cells dissemination of virus occurs to lymph nodes, spleen, liver and other organs. [33],[34] The infected macrophage and dendritic cells get activated and release various proinflammatory cytokines like TNF-α, IL6, IL1-β, IL-8, macrophage inflammatory protein (MIP)-α, MIP-β, monocyte chemotactic protein (MCP)-1, and growth-regulated protein (GRO)-α. [35] High level of TNF-α mediates the increase endothelial permeability leading to vascular leakage. [36]

Various viral glycoproteins; GP1, 2 and VP40 have also been associated with increased endothelial permeability by triggering the expression of intracellular and vascular adhesion molecules (ICAM1 and VCAM-1) and E-selectin by activation of endothelial cells. [35]

Besides the endothelial damage, apoptosis of lymphocytes, necrosis of liver and adrenal gland have also been shown to have important role in disease pathogenesis. Lymphoid depletion has largely been attributed to apoptosis. Significant lymphoid depletion and lymphopenia have been reported in severe fatal cases. The possible pathway of lymphocyte apoptosis might involve TRAIL (TNF-related apoptosis inducing ligand) or Fas-receptor pathway, or Ebola virus-induced impairment of dendritic cell function. [33],[37],[38] Cells that are infected by Ebola virus, show the features of necrosis and do not undergo apoptosis. [33] The necrosis of liver cells is thought to be responsible for decreasing clotting factor and dysfunction of coagulation system. Infection and necrosis of adrenal cortex lead to decreased synthesis of steroids, leading to hypovolumia and shock, which are important end stage feature in severe Ebola haemorrhagic fever. [24] Increased level of proinflammatory cytokines and high viral load have been associated with fatal outcome, whereas, survival has been associated with antibody response to viral nucleoprotein (NP) and VP40, cell-mediated immune response against viral glycoprotein (GP), clearance of virus and activation of cytotoxic T lymphocytes. Decreased D- dimers, IL6, IL10, TNF-α along with low viral load have been reported among survivors in experimental animal experiment. [35] The association of soluble CD40 ligand (sCD40L) level with non-fatal outcome has been shown in a recent study in patients, indicating the repair of damaged endothelium by activated platelets. [39]

Diagnosis

Acute febrile illness is the usual presentation in the initial part of disease. In endemic countries, classical epidemiological history like travel to jungle, eating or hunting of bats or animals, exposure to cave, close contact with sick patients or dead bodies'helps in clinching the suspicion for Ebola virus infection. However, in absence of relevant epidemiological history, the clinical suspicion is difficult particularly during the initial part of illness without haemorrhagic manifestation, as the symptoms mimic other tropical infectious diseases like malaria, typhoid fever, leptospirosis, relapsing fever, anthrax, chikungunya, yellow fever, etc., which are also prevalent in these countries. Patient with haemorrhagic features may also be confused with Lassa fever. In non-endemic countries, patient with history of travel to endemic countries or outbreak affected localities, if develops acute febrile illness, should be suspected for Ebola virus infection.

Laboratory diagnosis is performed only in designated national and international laboratories. Blood, serum and tissues are the samples that are subjected for testing. While collecting the samples, the health care worker must follow (i) the use of appropriate barrier precautions, (ii) maintenance of sterility, (iii) proper disposal of materials after collection and (iv) avoidance of needle stick injury. The clinical materials are subjected for the test after rendering the samples non-infectious. Blood/serum samples for antibody detection are either gamma eradiated with Cobalt 60 or heat inactivated, whereas for nucleic acid detection, RNA isolation from clinical material can be done by treating with guanidiumisothiocyanate (GITC), a chaotropic agent that degrades the viral protein and makes the sample non-infectious. [24]

Detection of viral RNA, antigen and virus specific IgM and IgG are the major modalities of diagnosis. The diagnostic tests employed at various stage of illness are described in [Table 1]. Positive serology test helps in confirmation but negative result does not rule out the possibility of infection, as patient with severe fatal infection may not mount any antibody response. Among the other serological tests, Western blot and indirect immunofluorescence tests can be used for confirmation and screening, respectively. Sophisticated diagnostic tests like multiplex PCR and micro-array-based tests have also been developed based on the common clinical syndrome; however, the primitive facility in endemic countries makes them far from implementation. [31]
Table 1: Laboratory tests for Ebola virus diagnosis


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Treatment and prevention

Management of patient is largely based on supportive and symptomatic treatment which constitutes, broad spectrum antibiotics, IV fluid administration and management of organ failure. The other important aspect is prevention of disease transmission by strict isolation of patients and practicing barrier nursing procedures. As the virus can also be transmitted from the dead bodies of the infected patients, disposal of dead bodies should be carried by cremation or burial in hermetically sealed casket, using personal protective equipment and surface decontamination, following the safety procedure as described by CDC guideline. [40]

So far, no specific anti-Ebola drug has the approval for human use. The non-availability was much felt during the current outbreak and raised the controversies regarding slow process of anti-Ebola drug trial. The uncontrolled nature of the currently ongoing Ebola outbreak in West Africa, however, compelled the WHO to approve the use of experimental treatments in infected patents. [41] Several compounds have been tried in the recent past in non-human primates and appears promising for human use in future.

Monoclonal antibody based therapy gained the attention of the entire world during current outbreak, when the antibody preparation (ZMapp) was given to the two American health workers, who acquired Ebola virus infection while working during the current West Africa Ebola outbreak. The preparation named as "Secret serum" by the media. ZMapp TM consists of three "humanised" monoclonal antibodies (MB-003) manufactured in tobacco plant, Nicotiana. [42] It is an optimized combination of MB-003 components (Mapp) and ZMAb (Defyrus/PHAC) and is a collaborative product of Mapp Biopharmaceutical, Inc, LeafBio (San Diego, CA), Defyrus Inc. (Toronto, Canada) and Public Health Agency of Canada (PHAC). [43] The survival rate of 100%, 67% and 43% have been reported with MB-003 in non-human primates when given at 1hour, 24-48 hours and 120 hours, respectively, post-infection after onset of viremia and fever. Both the Americans who had received the monoclonal antibodies have recovered from the disease. However, whether the recovery can be attributed to the use of drug is a matter of debate, as both of them had received the antibody late in the course of disease where the overall chances of survival increases, and can also be due to high quality medical care. Nevertheless, the anti-Ebola drug therapy for the first time has generated hope to combat the mortality in patients.

Small interfering RNA molecules (siRNA) have been made targeting Ebola virus VP24, VP35 and polymerase (L) genes. Recently the combination of these three siRNAs encapsulated in stable nucleic acid lipid particles (SNALPs) has been reported to provide 100% protection against Ebola virus when given 30 minutes post-infection. [44] Tekmira's siRNA preparation targeting L gene of EBOV (TKM-Ebola) has recently got the approval by US Food and Drug Administration for use in infected patients. [45] PMOPlus (Positively charged phosphorodiamidatemorpholino oligomers), [46] BCX 4430 anadenosine analogue, [47] T-705, (favipiravir) a pyrazinecarboxamide derivative, are the other promising candidates, acts by inhibiting viral replication.

Ebola in indian perspective

The Ministry of Health and Family Welfare, Government of India, has issued several guidelines for effective management of the situation in case the virus gets entry into the country. However, beyond guidelines, keeping the required logistics in place, adequate training of healthcare workers for proper use and disposal of personal protective equipment are also essential. In the recent past India has shown its capability in prompt and effective containment of a similarly fatal viral haemorrhagic fever, Crimean Congo Haemorrhagic fever. The challenge of Ebola if it enters the country would be much more than CCHF, as the introduction can occur at multiple sites simultaneously, demanding a countrywide preparedness.

The knowledge on Ebola virus has progressed significantly, but still large gaps remain. The elusive virus ecology still has the upper hand and no advances have been made to predict any impending outbreak. The West African countries, the poorest of the world, when affected by the deadliest of the dreadful virus, ZEBOV, the explosive uncontrollable situation probably would have been anticipated much earlier. The limitations of diagnostic facilities, medical care, logistic constraints along with the cultural differences and hostile environment have compounded the problem of disease containment. The International communities have joined hands to contain this ever expanding Ebola outbreak and stopping the helpless West Africans to die.

 
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[PUBMED]    


    Figures

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    Tables

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