Ebola Virus and its Background

Abstract

This paper explores the background, pathophysiology, assessment and interventions pertinent to the effective management and treatment of the Ebola virus. This virus was first seen in 1976, but the recent epidemic in 2014-2016 that affected numerous individuals throughout the globe has brought Ebola to the forefront. When the 2014-2016 epidemic arose, many were not well informed or equipped on how to adequately address the issue and in turn many individuals perished as a result. It is important as healthcare practitioners to make ourselves knowledgeable and aware of potential diseases processes that can affect our communities in order to adequately combat them if they were to occur. Becoming well versed in terms of pathophysiology specific to Ebola we can better understand the disease process in order to correlate symptoms individuals may present, and more importantly be better informed on how to perform a thorough assessment and plan to prevent a future epidemic. Moreover, in-depth assessment of molecular and cellular processes innate to the virus will prompt researchers to come up with medical therapies to improve management and potentially eradicate the disease.

Introduction

Ebola virus disease, formerly known as Ebola hemorrhagic fever, is a rare yet dangerous disease that affects humans as well as nonhuman primates, that occurs mainly in regions within sub-sharan Africa. It is one of at least thirty known viruses that can cause viral hemorrhagic fever syndrome (Medscape, 2018). The Ebola virus is a member of the Filoviridae family and the disease is transmitted via direct contact with body fluids (blood, urine, emesis, stool, semen, breast milk, saliva, sweat, tears etc.) and or tissue of an infected animal, usually bats or nonhuman primates (chimpanzees, gorillas, monkeys, etc.), or individuals that have the disease or have died as a result of the disease (CDC, 2018). Bats have been confirmed as natural reservoir for the Ebola virus,  and therefore it is possible to implement interventions to control and eliminate viral reservoirs of transmission to human populations (Murray, 2015). In prior epidemics, the reuse of nonsterile injections was responsible for many healthcare associated transmissions (BMJ, 2018). The Ebola virus first appeared in 1976 in South Sudan and the Democratic Republic of Congo concurrently, and since this outbreak there have been several incidences of the disease within this region of Africa. The most recent outbreak was reported in August of this year in the Democratic Republic of Congo, and medical staff are working diligently to contain the disease and cease widespread transmission.

One of the largest and most devastating outbreaks of the Ebola virus occurred between 2014-2016, originating in Guinea, West Africa and spreading to other West African countries such as Liberia and Sierra Leone, and abroad to Italy, Spain, the United Kingdom, as well as the United states. The widespread outbreak of the disease was mainly attributed to, crowded urban areas, increased mobilization across borders, and conflict between key infection control practices and prevailing cultural and traditional practices (CDC, 2018). In the United States there were approximately eleven individuals that were treated for the virus during the 2014-2016 epidemic, with two individuals eventually succumbing to the effects of the disease process. I choose to write about this topic because my family is originally from Guinea, West Africa. Fortunately, none of my direct family members were affected, but some family friends had family members who were affected by the disease. On a recent trip to Guinea in September of 2017 I was able to visit some of the healthcare facilities throughout the country, and saw how inadequately equipped these facilities were. This had made me increasingly concerned about the potential of another outbreak, and the inability to adequately combat the disease as a country. Through a better understanding of the etiology, pathophysiology, clinical presentation, and interventions I hope to be better equipped to bestow the knowledge that I have attained to my family members, which they can share with their community.

Pathophysiology

The Ebola virus genome is 19kb long and is covered with a lipid envelope, with seven open full-length transmembrane form, with seven open reading frames encoding structural proteins, including the virion envelope glycoprotein (GP), nucleoprotein (NP) and matrix proteins, and contains a single stranded RNA strand. The glycoprotein for the virus is synthesized in a secreted full-length transmembrane form expressed in two molecular forms (GP1 and GP2), and each gene product has distinct biochemical and biological properties. The amounts of GP1 and GP2 expression are correlated with both the production and release of the virus. Glycoproteins allow the Ebola virus cells to introduce its contents into both macrophages and monocytes that in turn cause the release of cytokines into endothelial cells, which damage vascular integrity (Sullivan et.al, 2003). The Ebola virus enters the host via mucous membranes, breaks in the skin or parenterally and affects cell types such as monocytes, macrophages, endothelial cells, fibroblasts, hepatocytes, endothelial cells, epithelial cells, etc. Several molecules such as C-type leptins, tyrosine kinase receptors,  integrin receptor, and Niemann Pick C1 proteins have been proposed as potential cell receptors or mediators for the virus (Murray, 2015) After the virus is introduced into the body it is then able to invade almost all human cells via various mechanisms, and are able to be transmitted throughout the body via uptake mechanisms such as lipid raft, receptor mediated endocytosis and micropinocytosis. The glycoproteins hold the viral particles to the cell surface. The fusion of the viral and cellular membrane via the viral spike protein, GP2,  leads to the release of the viral nuceloplasid into the cytoplasm of the infected cell where transcription and replication of the viral genome take place. Moreover, soluble glycoproteins are able to promote immune evasion by serving as an antibody decoy via the presentation of alternative antibody epitopes (Falasca et.al, 2015).The virus first affects the immune system, specifically immune cells (macrophages) and antigen presenting cell (dendritic cells), and then is eventually able to affect other organs such as the liver, adrenal glands, gastrointestinal tract, etc. (Marcinkiewicz et.al, 2014).

        There are numerous pathogenic mechanisms involved in the clinical manifestations of the Ebola virus, including a direct cytopathogenic effect of the virus that leads to the destruction and impairment of crucial body functions. Studies have shown that monocytes, macrophages and dendritic cells are early replication sites for the Ebola virus, and more specifically lead to the dissemination of the virus by migrating out of the lymph node and spleen to other tissues. The virus is able to impair as well as evade type-1 interferon production related to the actions of the two proteins the virus encodes (VP24, VP35), as well as leading to wide spread cytokine and chemokine production by monocytes and macrophages. The shed glycoproteins are able to activate non-infected dendritic cells and macrophages thus inducing the secretion of chemokines, eotaxins, as well as both proinflammatory and anti-inflammatory cytokines and lead to cytokine storm associated with the virus. This storm allows for the recruiting of additional macrophages and dendritic cells to the infected area making other cells susceptible to viral exploitation (Falasca et.al, 2015). 

Nitric oxide production has been associated with the progression of the Ebola virus disease process and thus leads to apoptosis of lymphocytes, tissue damage and loss of vascular integrity that contributes to shock correlated with the disease process. As the viral replication within the host becomes more widespread there is a triggering of the coagulation cascade, which is associate with death and hemorrhage related to elevated thrombomodulin and ferritin levels. Soluble mediations such as MCSF, IP-10, and sICAM have demonstrated the potential to recruit leukocytes to areas of inflammation and lead to leukocyte adhesion and eventually cause deregulated hemostasis via consumption of coagulation factors, fibrin deposits, microtrombin production which would manifest as a hemorrhage. The liver is also targeted by the virus and leads to impaired synthesis of protein and enzymes that are crucial to coagulation and thus lead to hepatocellular necrosis. The effect on the vascular system leads to disseminated intravascular coagulation, hemorrhage, circulatory failure, shock and death

Plasma free amino acids are essential in immune cell proliferation during inflammatory states, and Ebola virus has also been observed to cause an acute reduction in plasma free amino acids therefore leading to decreased immune cell activity and thus increased activity of the virus. T lymphocytes and NK cells are also impaired during the viral process via apoptosis and inhibits the production of specific anti-virus antibodies, but likelihood of survival is predicated on how drastic of a decrease there is in the amount left circulating in the bloodstream. With the blocking of T cell function there is no helper functions on CD-8 mediated cytotoxicity and production of antibodies by B cells, therefore the adaptive immune system cannot respond appropriately.

Symptoms of Ebola virus may manifest anywhere from two to twenty-one days after contact with the virus, with an average of 8-10 days. Individuals often present to medical providers within a week of symptoms that often mimic tropical illness such as dengue, malaria, typhoid, etc. (Martinez et. al, 2015). The symptoms are often progressive and occur in three phases. Most situations present with fevers, headaches, muscle pain, fatigue and chills and are thus nonspecific. Women and children are particularly vulnerable populations  that often present with unspecified symptomology. As time progressive there is an increased occurrence of gastrointestinal symptoms including diarrhea, nausea, vomiting and discomfort which can lead to fluid depletion. The profuse diarrhea and bleeding can result in massive fluid loss and lead to dehydration and potentially hypovolemic shock. In the second stage the individual may either recover or fall into the third stage developing neurological symptoms, rash, multiorgan failure and potential death (Khalafallah et. al, 2017). Bleeding is a late clinical manifestation of the virus that occurs in less than 20% of patients affected with the Ebola virus (Martinez et.al, 2015). Some uncommon symptoms that may be seen in people with Ebola virus are chest pain, shortness of breath, sore throat and hiccups. Patients typically die between six to sixteen days after the onset of symptoms.

For those individuals that are able to overcome and survive the disease process, there are still complication and sequelae secondary to the virus. Most sequelae are based on the severity and length of the disease process and are a potential result of,  sustained immune activation, delayed hypersensitivity reaction autoimmune disease. Some studies have shown activated CD4 and CD8 counts months after the disease, as well as elevated IgG antibody titers. Symptoms of fatigue, arthralgias, muscle pain, abdominal pain, blurred vision, sleep disturbances, retro-orbital pain, hearing loss, difficulty swallowing and anorexia are common in. Often times the sequelae occur in the first few weeks  and potentially last for years, however intensity of the symptoms decreases over time survivors (Vetter et.al, 2016). Arthralgias are most often reported and are seen more in the knees, back, hips, elbows etc. Similarly, ocular issues have become a major issue in survivors and there is often a potential for permanent visual impairments and blindness. Neurological sequelae are potential related to the shock, hypoperfusion, and encephalitis experienced by individuals during the disease process. The virus is often quickly cleared from most body fluids, but may be delayed in the semen, chambers of the eye, central nervous system, placenta, etc. Recrudescence rarely occurs after the convalescence period, but if it does occur it is usually correlated to the delayed clearing from body fluids that tend to retain remnants of the virus for longer periods.

Assessment & Intervention

        The early diagnosis of Ebola virus can be difficult due to the have that the presentation often mimics that of malaria, dengue fever and various bacterial infections. Physical examinations of individuals that are suspected to have the disease should be performed with personal protective equipment. The WHO and CDC have established criteria for diagnosis of the virus that include sudden onset of fever and at least three of the following symptoms: vomiting, loss of appetite, lethargy, stomach pain, headache, diarrhea, aching muscles/joints, dysphagia, dyspnea or hiccupping. Laboratory diagnosis can often be nonspecific due to similarity with other conditions, this can only be achieved by ensuring an assessment of host specific immune response to the Ebola virus and detection of viral components in the bloodstream after symptoms have begun to manifest. Viral particles are able to be detected in the blood via transcription polymerase chain reaction after three to ten days of symptoms. Some Ebola specific diagnostic tests are the RT-PCR, which should be repeated within 48 hours if negative, and ELISA testing, which is usually positive on days 3-6 of symptoms and has high specificity. CBC are a nonspecific diagnostic test and may show thrombocytopenia, marked lymphopenia, neutrophil leukocytosis, decreased platelet count, low hemoglobin, and prolonged prothrombin time/ activated partial thromboplastin time. Arterial blood gases and serum electrolytes are also nonspecific and can help detect hypoperfusion, sepsis, decreased potassium associated with emesis and diarrhea and decreased calcium levels that are related to widespread infectious process. Liver function and renal function can show elevated ALT and AST, increased serum creatinine or urea (acute kidney injury), hematuria and proteinuria.

        Prevention is extremely imperative in the management of the viral process and prompt notification of the appropriate authorities (WHO, CDC) is necessary in order to decrease the potential for transmission because there is currently no specific therapy available for treatment of the Ebola virus. Individuals should be taught to avoid contact with infected animals and consumption of bush meat, regular handwashing should be encouraged, safe sex practices should be recommended, and safe burial of deceased victims of the disease should be performed promptly. If an assessment if highly indicative of an individual with Ebola the person must be quarantined in a private area that is closed and interactions should be limited and appropriate use of personal protective equipment should be implemented. The treatment of Ebola virus is supportive and symptomatic and initiation of continuous monitoring of vital signs, electrolytes, urine output and mental status should be maintained. Fluid hydration and electrolyte balance are imperative in successful management of Ebola patients.  Rehydration can be accomplished orally or intravenously with normal saline and lactated ringers. Symptoms of fever and headaches can be treated with Paracetamol, vomiting can be treated with Metoclopramide, Chlorpromazine and Ondansetron. Sepsis can be treated with broad spectrum antibiotics such as third generation cephalosporins, and seizures can be treated with Diazepam. NSAIDs are not recommended due to the potential of bleeding and nephrotoxicity. Renal replacement therapy should be initiated in patients with renal insufficiency, and major bleeding can be addressed with blood transfusions.

        Some promising therapies include convalescent serum therapies where the serum of an individual who has survived Ebola is infused to those who are acutely ill. Another therapy is a combination of monoclonal antibodies, ZMapp, that have shown to reverse the infectious process in nonhuman primates after onset of symptoms. Other therapies that are being explored are T-20 Enfuvirtide, which inhibits membrane fusion by the virus, small-interfering RNA's, cytokine inhibitors, nucleoside analogs, antisense oligonucleotides, etc. Small interfering RNA's target the virus by causing cleavage in the messenger RNAs, thus preventing production of the viral proteins made by the virus. Faviporarvir is a nucleotide analog and viral RNA polymerase inhibitor that lead to antiviral effects against RNA viruses. Brincidofivir is an oral nucleotide analog that prevents replication of the virus via inhibition of DNA polymerase. There are a multitude of new therapies as well as vaccines that are being explored as potential treatments for the Ebola virus.

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