PATHOGENESIS — Ebola virus enters the body through mucous membranes, breaks in the skin, or parenterally. The pathogen infects many cell types, including monocytes, macrophages, dendritic cells, endothelial cells, fibroblasts, hepatocytes, adrenal cortical cells, and epithelial cells . Because of the difficulty of performing clinical studies under outbreak conditions, almost all data on the pathogenesis of Ebola and Marburg virus diseases have been obtained from laboratory experiments employing mice, guinea pigs, and a variety of nonhuman primates.

Cell entry and tissue damage — Whatever the point of entry into the body, macrophages and dendritic cells are probably the first cells to be infected. Filoviruses replicate readily within these ubiquitous "sentinel" cells, causing their necrosis and releasing large numbers of new viral particles into extracellular fluid. Spread to regional lymph nodes results in further rounds of replication, followed by dissemination of virus to dendritic cells and fixed and mobile macrophages in the liver, spleen, thymus, and other lymphoid tissues.

Rapid systemic spread is aided by virus-induced suppression of type I interferon responses As the disease progresses, hepatocytes, adrenal cortical cells, fibroblasts, and many other cell types also become infected, resulting in extensive tissue necrosis.

Systemic inflammatory response — In addition to causing extensive tissue damage, filoviruses also induce a systemic inflammatory syndrome by inducing the release of cytokines, chemokines, and other proinflammatory mediators from infected macrophages and other cells

Macrophages infected with Ebola Zaire virus produce tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, macrophage chemotactic protein (MCP)-1, and nitric oxide (NO)]. These and other substances have also been identified in blood samples from Ebola-infected macaques and from acutely ill patients in Africa. Breakdown products of necrotic cells also stimulate the release of the same mediators]. It is thus the host response to infection, rather than any toxic effect of the virus, that is responsible for the fever, malaise, vasodilatation, increased vascular permeability, hypotension, and shock of filoviral disease].

Coagulation defects — The coagulation defects seen in Ebola and Marburg virus disease are also induced indirectly. Virus-infected macrophages synthesize cell-surface tissue factor (TF), triggering the extrinsic coagulation pathway. Proinflammatory cytokines also induce macrophages to produce TF]. The simultaneous occurrence of these two stimuli helps to explain the early appearance, rapid development, and ultimate severity of the coagulopathy in filovirus infection.

Blood samples from Ebola-infected monkeys contain D-dimers within 24 hours after virus challenge, and D-dimers are also present in the plasma of humans with Ebola hemorrhagic fever. In macaques, activated protein C is decreased on day two, but the platelet count does not begin to fall until days three or four, suggesting that activated platelets are adhering to endothelial cells. As the disease progresses, hepatic injury may also cause a decline in plasma levels of certain coagulation factors.

Impairment of adaptive immunity — Failure of adaptive immunity, through impaired dendritic cell function and lymphocyte apoptosis, helps to explain how these viruses are able to cause severe, frequently fatal illness.

Filoviruses act both directly and indirectly to disable antigen-specific immune responses. Dendritic cells, which have primary responsibility for the initiation of adaptive immune responses, are a major site of filoviral replication. In vitro studies have shown that infected cells fail to undergo maturation and are unable to present antigens to naive lymphocytes, potentially explaining why patients dying from Ebola hemorrhagic fever do not develop antibodies to the virus]. Adaptive immunity is also impaired by the massive loss of lymphocytes that accompanies lethal Ebola virus infection. Lymphocytes remain uninfected, but undergo "bystander" apoptosis, presumably induced by inflammatory mediators and/or the loss of support signals from dendritic cells. A similar phenomenon is observed in septic shock]. However, one study has shown that, at least in mice, virus-specific lymphocyte proliferation still occurs, in spite of the surrounding massive apoptosis, but it arrives too late to prevent a fatal outcome. Discovering ways to accelerate and strengthen such responses may prove to be a fruitful area of research.

CLINICAL MANIFESTATIONS — The diseases caused by Ebola and Marburg viruses in humans are similar in their clinical manifestations, differing only in severity and case-fatality rate. Over the roughly 40 years since the filoviruses were first discovered, a number of publications have described the clinical and laboratory features of Ebola and Marburg virus disease, which have been summarily reviewed. Of note, despite the traditional name of Ebola or Marburg hemorrhagic fever, bleeding is not a common finding, and is typically seen only in the terminal phase of illness. In the West Africa epidemic, the term Ebola virus disease has been used rather than the name Ebola hemorrhagic fever. The clinical manifestations are outlined below.

Incubation period — Patients with Ebola virus disease typically have an abrupt onset of symptoms 8 to 12 days after exposure (range 2 to 21 days). The incubation period for the individual patient depends, in part, upon the type of exposure (eg, approximately 6 days for percutaneous exposure versus 10 days for contact exposure). There is no evidence that asymptomatic persons still in the incubation period are infectious to others. However, all symptomatic individuals should be assumed to have high levels of virus in the blood and other body fluids and appropriate safety precautions should be taken]. Symptoms and signs — Patients with Ebola virus disease initially present with non-specific influenza-like symptoms and can progress to multiorgan failure and septic shock. The most common signs and symptoms reported from West Africa during the 2014 outbreak include: fever (87 percent), fatigue (76 percent), vomiting (68 percent), diarrhea (66 percent), and loss of appetite (65 percent)

Important clinical findings of patients with Ebola and Marburg virus disease are as follows:

●Nonspecific flu-like symptoms — Ebola and Marburg hemorrhagic fever typically begin with the abrupt onset of fever, chills, and general malaise. Other signs and symptoms include weakness, anorexia, severe headache, and pain in the muscles of the trunk and lower back High fever may be accompanied by relative bradycardia, as seen in typhoid fever. A nonproductive cough and pharyngitis, with the sensation of a lump or "ball" in the throat, are also frequently present.

●Rash — Some patients develop a diffuse erythematous, nonpruritic maculopapular rash by day five to seven of illness. The rash usually involves the face, neck, trunk, and arms, and can desquamate

●Gastrointestinal — Gastrointestinal signs and symptoms usually develop several days after the initial presentation. These include watery diarrhea, nausea, vomiting, and abdominal pain.

●Hemorrhage — Bleeding is often not observed in the early phase of illness, but may manifest later in the course of disease as petechiae, ecchymosis/bruising, oozing from venipuncture sites, and/or mucosal hemorrhage. Frank hemorrhage is seen most commonly in the terminal phase of illness. During the outbreak in West Africa, approximately 20 percent of patients have unexplained bleeding, which is most commonly manifested as blood in the stool (about 6 percent)].

●Other findings — Patients with Ebola virus disease can present with additional findings such as hiccups, chest pain, shortness of breath, headache, confusion, seizures, and/or cerebral edema. Conjunctival injection and dark red discoloration of the soft palate are common physical findings Pregnant women may experience spontaneous miscarriages.

In non-fatal cases, patients typically improve approximately 6 days after the onset of symptoms. The formation of antigen-antibody complexes during recovery may cause acute arthralgias and other symptoms  Fatal disease has been characterized by more severe clinical signs early during infection and progression to multiorgan failure and septic shock. Death typically occurs between days 6 and 16.