Ebola pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Michael Maddaleni, B.S.; Guillermo Rodriguez Nava, M.D. [2]

Overview

The Ebola virus infects the mononuclear phagocyte system, but also other cells such as hepatocytes, spongiocytes, fibroblasts and endothelial cells, inducing tissue necrosis and disrupting the hematological and coagulation systems. The Ebola virus is transmitted by direct contact with infected patients or animals. The natural reservoir has not been identified.

Pathophysiology

Transmission

Among humans, the virus is transmitted by direct contact with infected body fluids, or to a lesser extent, skin or mucous membrane contact. The incubation period can be anywhere from 2 to 21 days, but is generally between 5 and 10 days.

Although airborne transmission between monkeys has been demonstrated by an accidental outbreak in a laboratory located in Virginia, USA, there is very limited evidence for human-to-human airborne transmission in any reported epidemics. Nurse Mayinga might represent the only possible case. The means by which she contracted the virus remains uncertain.

The infection of human cases with Ebola virus has been documented through the handling of infected chimpanzees, gorillas, and forest antelopes--both dead and alive--as was documented in Côte d'Ivoire, the Republic of Congo and Gabon. The transmission of the Ebola Reston strain through the handling of cynomolgus monkeys has also been reported.

So far, all epidemics of Ebola have occurred in sub-optimal hospital conditions, where practices of basic hygiene and sanitation are often either luxuries or unknown to caretakers and where disposable needles and autoclaves are unavailable or too expensive. In modern hospitals with disposable needles and knowledge of basic hygiene and barrier nursing techniques, Ebola has never spread on such a large scale.

In the early stages, Ebola may not be highly contagious. Contact with someone in early stages may not even transmit the disease. As the illness progresses, bodily fluids from diarrhea, vomiting, and bleeding represent an extreme biohazard. Due to lack of proper equipment and hygienic practices, large scale epidemics occur mostly in poor, isolated areas without modern hospitals or well-educated medical staff. Many areas where the infectious reservoir exists have just these characteristics. In such environments, all that can be done is to immediately cease all needle-sharing or use without adequate sterilization procedures, to isolate patients, and to observe strict barrier nursing procedures with the use of a medical rated disposable face mask, gloves, goggles, and a gown at all times. This should be strictly enforced for all medical personnel and visitors.

Ebola is unlikely to develop(sometimes) into a pandemic, or world-wide infection, due to its difficulty in spreading by airborne transmission and the period of time that the virus can use a living and contagious victim to spread compared to other infectious diseases. In isolated settings such as a quarantined hospital or a remote village, most victims are infected shortly after the first case of infection is present. In addition, the quick onset of symptoms from the time the disease becomes contagious in an individual makes it easy to identify sick individuals and limits an individual's ability to spread the disease by traveling. Because bodies of the deceased are still infectious, many doctors implemented measures to properly dispose of dead bodies in spite of some traditional local burial rituals.

Tropism

• Ebola virus infects mainly the cells of the mononuclear phagocyte system, but also fibroblasts, hepatocytes, spongiocytes, adrenal cortical cells and endothelial cells.
• The infection of the mononuclear phagocyte system cells plays a key role in the pathogenesis and spread of the disease as they carry the virus from of the initial infection site, through the lymphatic system and blood, to the regional lymph nodes,spleen and liver.
• The next table summarizes the pathogenesis of the disease according to the virus tropism.

Pathogenesis

Organ/Tissue	Effect
Endothelial cells	Glycoprotein (GP) on the virion envelope allows introduction of its content into the endothelial cells, which induces a cytopathic effect and damage to the endothelial barrier function that, together with effects of TNF-α released by infected mononuclear cells, leads to the loss of vascular integrity and increased leakage.
Liver	Causes hepatocellular necrosis which could impair the synthesis of proteins of the coagulation system
Adrenal cortex	Affects the synthesis of enzymes responsible for the synthesis of steroids, leading to hypotension, and fluid and electrolytes disturbances.
Lymphatic system	Necrosis of the spleen, lymph nodes and thymus; Apoptosis of lymphocytes leading to lymphopenia.

Immune response

• The virus activates the macrophages synthesis of interleukins (IL), which leads the Th1/Th2 balance towards a more pronounced Th1-cell mediated response.
• Some inflammatory mediators produced during the ebola virus infection include: interferon (IFN)-alpha, IFN-beta, IL-2, IL-6, IL-8, IL-10, interferon-inducible protein 10; monocyte chemoattractant protein 1; regulated upon activation normal T cell expressed and secreted (RANTES); TNF-alpha; and reactive oxygen and nitrogen species.
• Some viral proteins, such as VP35 and VP24, block the type I interferon response, which plays a key role of the pathogenesis of the disease.
• The reactive oxygen and nitrogen species contribute to the cell and tissue damage, and therefore vascular and organ damage.
• The nitric oxide is known to be an important vasodilator, therefore it plays and important role in the development of hypotension and shock.

Coagulation system

• Ebola infection is associated with hemorrhage in 50% of patients.
• Alterations of the coagulation system are induced by the ebola virus, and are thought to be mediated by the production of tissue factor:

Alterations of the coagulation system
Consumption of clotting factors
Increased concentrations of fibrin degradation products
Disseminated intravascular coagulation

The internal bleeding is caused by a chemical reaction between the virus and the platelets, which creates a chemical that will cut cell sized holes into the capillary walls. After 5-7 days, the person will die of "a million cuts." Occasionally, internal and external hemorrhage from orifices, such as the nose and mouth may also occur, as well as from incompletely healed injuries such as needle-puncture sites.

Viral Reservoirs

Despite numerous studies, the wildlife reservoir of Ebolavirus has not been identified. Between 1976 and 1998, from 30,000 mammals, birds, reptiles, amphibians, and arthropods sampled from outbreak regions, no Ebolavirus was detected apart from some genetic material found in six rodents (Mus setulosusand Praomys species) and a shrew (Sylvisorex ollula) collected from the Central African Republic in 1998. Ebolavirus was detected in the carcasses of gorillas, chimpanzees and duikers during outbreaks in 2001 and 2003 (the carcasses were the source of the initial human infections) but the high mortality from infection in these species precludes them from acting as reservoirs. Plants, arthropods, and birds have also been considered as reservoirs, however bats are considered the most likely candidate. Bats were known to reside in the cotton factory in which the index cases for the 1976 and 1979 outbreaks were employed and have also been implicated in Marburg infections in 1975 and 1980. Of 24 plant species and 19 vertebrate species experimentally inoculated with Ebolavirus, only bats became infected. The absence of clinical signs in these bats is characteristic of a reservoir species. In 2002-03, a survey of 1,030 animals from Gabon and the Republic of the Congo including 679 bats found Ebolavirus RNA in 13fruit bats (Hyspignathus monstrosus, Epomops franquetti and Myonycteris torquata). Bats are also known to be the reservoirs for a number of related viruses including Nipah virus, Hendra virus andlyssaviruses.

Microscopic Pathology

The images below display key features of the Ebola virus.

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  This transmission electron micrograph (TEM) demonstrates the ultrastructural morphology displayed by an Ebola virus. Source: CDC microbiologist Frederick A. Murphy.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  This transmission electron micrograph (TEM) demonstrates the ultrastructural morphologic changes in this tissue sample isolate.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Scanning electron micrograph (SEM) revealing ultrastructural morphologic features of the Ebola virus from the Ivory Coast of Africa.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Negatively-stained transmission electron micrograph (TEM) demonstrating the ultrastructural curvilinear morphologic features displayed by the Ebola virus from the Ivory Coast of Africa.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.