Signs and symptoms

Onset

The length of time between exposure to the virus and the development of symptoms (incubation period) is between 2 and 21 days,[1][15] and usually between 4 and 10 days.[16] However, recent estimates based on mathematical models predict that around 5% of cases may take greater than 21 days to develop.[17]

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Symptoms usually begin with a sudden influenza-like stage characterized by feeling tired, fever, weakness, decreased appetite, muscular pain, joint pain, headache, and sore throat.[1][16][18][19] The fever is usually higher than 38.3 °C (101 °F).[20] This is often followed by vomiting, diarrhea and abdominal pain.[19] Next, shortness of breath and chest pain may occur, along with swelling, headaches and confusion.[19] In about half of the cases, the skin may develop a maculopapular rash, a flat red area covered with small bumps, 5 to 7 days after symptoms begin.[16][20]

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Bleeding

In some cases, internal and external bleeding may occur.[1] This typically begins five to seven days after the first symptoms.[21] All infected people show some decreased blood clotting.[20] Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50 percent of cases.[22] This may cause vomiting blood, coughing up of blood, or blood in stool.[23] Bleeding into the skin may create petechiae, purpura, ecchymoses or hematomas (especially around needle injection sites).[24] Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually located within the gastrointestinal tract.[20][25]

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Recovery and death

Recovery may begin between 7 and 14 days after first symptoms.[19] Death, if it occurs, follows typically 6 to 16 days from first symptoms and is often due to low blood pressure from fluid loss.[2] In general, bleeding often indicates a worse outcome, and blood loss may result in death.[18] People are often in a coma near the end of life.[19]

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Those who survive often have ongoing muscular and joint pain, liver inflammation, decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight.[19][26] Problems with vision may develop.[27]

Additionally, survivors develop antibodies against Ebola that last at least 10 years, but it is unclear if they are immune to repeated infections.[28]

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Cause

EVD in humans is caused by four of five viruses of the genus Ebolavirus. The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV) and one simply called Ebola virus (EBOV, formerly Zaire Ebola virus).[29] EBOV, species Zaire ebolavirus, is the most dangerous of the known EVD-causing viruses, and is responsible for the largest number of outbreaks.[30] The fifth virus, Reston virus (RESTV), is not thought to cause disease in humans, but has caused disease in other primates.[31][32] All five viruses are closely related to marburgviruses.[29]

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Virology

Ebolaviruses contain single-stranded, non-infectious RNA genomes.[33] Ebolavirus genomes contain seven genes including 3'-UTR-NP-VP35-VP40-GP-VP30-VP24-L-5'-UTR.[24][34] The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses, ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched.[34][35] In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm.[36]

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Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins, DC-SIGN, or integrins, which is followed by fusion of the viral envelope with cellular membranes.[37] The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved.[37] This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid.[37] The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells.[38] The viral RNA polymerase, encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs, which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny.[39] Newly synthesized structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane. Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics.[40]

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Transmission

It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease.[41][42][43] Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen.[4][28] The WHO states that only people who are very sick are able to spread Ebola disease in saliva, and whole virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit.[44] Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions.[28] Ebola may be spread through large droplets; however, this is believed to occur only when a person is very sick.[45] This contamination can happen if a person is splashed with droplets.[45] Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection.[46][47] The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person.[28][48]

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The Ebola virus may be able to persist for more than 3 months in the semen after recovery, which could lead to infections via sexual intercourse.[4][49][50] Virus persistence in semen for over a year has been recorded in a national screening programme.[51] Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again.[5] The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood.[52] Otherwise, people who have recovered are not infectious.[46]

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The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low.[53] Usually when someone has symptoms of the disease, they are unable to travel without assistance.[54]

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Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk.[53] 69% of the cases of Ebola infections in Guinea during the 2014 outbreak are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals.[55][56]

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Health-care workers treating people with Ebola are at greatest risk of infection.[46] The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly.[46] This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly.[57]There has been transmission in hospitals in some African countries that reuse hypodermic needles.[58][59] Some health-care centers caring for people with the disease do not have running water.[60] In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures.[61]

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Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks,[3] and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates, but not from primates to primates.[41][47] Spread of EBOV by water, or food other than bushmeat, has not been observed.[46][47] No spread by mosquitos or other insects has been reported.[46] Other possible methods of transmission are being studied.[48]

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The apparent lack of airborne transmission among humans is believed to be due to low levels of the virus in the lungs and other parts of the respiratory system of primates, insufficient to cause new infections.[62] A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream.[63] Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough.[64] By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs.[64] It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air.[63][64]

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Pathophysiology

Similar to other filoviruses, EBOV replicates very efficiently in many cells, producing large amounts of virus in monocytes, macrophages, dendritic cells and other cells including liver cells, fibroblasts, and adrenal gland cells.[78] Viral replication triggers the release of high levels of inflammatory chemical signals and leads to a septic state.[26]

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EBOV is thought to infect humans through contact with mucous membranes or through skin breaks.[41] Once infected, endothelial cells (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as macrophages, monocytes, and dendritic cells are the main targets of infection.[41] Following infection with the virus, the immune cells carry the virus to nearby lymph nodes where further reproduction of the virus takes place.[41] From there, the virus can enter the bloodstream and lymphatic system and spread throughout the body.[41] Macrophages are the first cells infected with the virus, and this infection results in programmed cell death.[36] Other types of white blood cells, such as lymphocytes, also undergo programmed cell death leading to an abnormally low concentration of lymphocytes in the blood.[41] This contributes to the weakened immune response seen in those infected with EBOV.[41]

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Endothelial cells may be infected within three days after exposure to the virus.[36] The breakdown of endothelial cells leading to blood vessel injury can be attributed to EBOV glycoproteins. This damage occurs due to the synthesis of Ebola virus glycoprotein (GP), which reduces the availability of specific integrins responsible for cell adhesion to the intercellular structure and causes liver damage, leading to improper clotting. The widespread bleeding that occurs in affected people causes swelling and shock due to loss of blood volume.[79] The dysfunction in bleeding and clotting commonly seen in EVD has been attributed to increased activation of the extrinsic pathway of the coagulation cascade due to excessive tissue factor production by macrophages and monocytes.[16]

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After infection, a secreted glycoprotein, small soluble glycoprotein (sGP or GP) is synthesized. EBOV replication overwhelms protein synthesis of infected cells and the host immune defenses. The GP forms a trimeric complex, which tethers the virus to the endothelial cells. The sGP forms a dimeric protein that interferes with the signaling of neutrophils, another type of white blood cell, which enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. The presence of viral particles and the cell damage resulting from viruses budding out of the cell causes the release of chemical signals (such as TNF-α, IL-6 and IL-8), which are molecular signals for fever and inflammation.[citation needed]

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Immune system evasion

Filoviral infection also interferes with proper functioning of the innate immune system.[37][39] EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha, interferon-beta, and interferon gamma.[38][80]

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The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5) or outside of the cytosol (such as Toll-like receptor 3 (TLR3), TLR7, TLR8 and TLR9), recognize infectious molecules associated with the virus.[38] On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signaling cascade that leads to the expression of type 1 interferons.[38] The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighboring cell.[38] Once interferon has bound to its receptors on the neighboring cell, the signaling proteins STAT1 and STAT2 are activated and move to the cell's nucleus.[38] This triggers the expression of interferon-stimulated genes, which code for proteins with antiviral properties.[38] EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signaling protein in the neighboring cell from entering the nucleus.[38] The VP35 protein directly inhibits the production of interferon-beta.[80] By inhibiting these immune responses, EBOV may quickly spread throughout the body.[36]

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Diagnosis

When EVD is suspected in a person, his or her travel and work history, along with an exposure to wildlife, are important factors to consider with respect to further diagnostic efforts.

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Laboratory testing

Possible non-specific laboratory indicators of EVD include a low platelet count; an initially decreased white blood cell count followed by an increased white blood cell count; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time, partial thromboplastin time, and bleeding time.[81] Filovirions, such as EBOV, may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy, but this method cannot distinguish the various filoviruses.[82]

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The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture, detecting the viral RNA by polymerase chain reaction (PCR)[16] and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover.[83] IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected 6 to 18 days after symptom onset.[16] During an outbreak, isolation of the virus via cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA.[84] In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission.[85] In 2015 a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected.[86]

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