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==Pathophysiology== | ==Pathophysiology== | ||
===Transmission=== | ===Transmission=== | ||
Among humans, the virus is transmitted by direct contact with infected [[body fluid]]s, 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. | * Among humans, the virus is transmitted by direct contact with infected [[body fluid]]s, 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. | ||
* Human-to-human airborne transmission has not been reported in any reported epidemics. | |||
* 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. | |||
* 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 [[autoclave]]s are unavailable or too expensive. In modern hospitals with disposable needles and knowledge of basic hygiene and [[Universal precautions|barrier nursing]] techniques, Ebola has never spread on such a large scale. | |||
* In the early stages, particularly when the patient is asymptomatic, Ebola is not generally contagious. Contact with someone in early stages very rarely transmits the disease. As the illness progresses, bodily fluids from diarrhea, vomiting, and bleeding represent an extreme [[biohazard]]. | |||
* Other than samples that are grossly contaminated with body fluids, Ebola virus is rarely detected on environmental surfaces and thus transmission by fomites is not very common. However, given that the infectious dose of the virus is low, and that current evaluation techniques such as cell culture and RT-PCR have not been well validated for environmental detection (unknown sensitivity and specificity), the true risk of transmission by contaminated surfaces is unknown.<ref name="pmid17940942">{{cite journal| author=Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A et al.| title=Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. | journal=J Infect Dis | year= 2007 | volume= 196 Suppl 2 | issue= | pages= S142-7 | pmid=17940942 | doi=10.1086/520545 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17940942 }} </ref> | |||
The | ====Transmission in Recovering Patients and Continued Shedding==== | ||
* Ebola virus has been isolated in the semen of recovering patients 40 days after the onset of illness. This stresses the risk of sexual transmission during the recovery phase. The ''Zaire Ebola virus'' in particular has a higher risk of continued shedding in the semen. It has been detected in samples for up to 90 days after the onset of illness. | |||
* Continued shedding may be detected in many bodily fluids with varying durations. The only bodily fluid that does not contain Ebola virus, even during the symptomatic phase of the infection, is urine. This is probably related to the inability of the kidney to filter the Ebola virus particles. | |||
* It is generally recommended to abstain from sex or to use condoms for up to 3 months after the onset of illness. It is also recommended to avoid breastfeeding and contact with the mucous membranes of the eye for the same amount of time.<ref name="pmid17940942">{{cite journal| author=Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A et al.| title=Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. | journal=J Infect Dis | year= 2007 | volume= 196 Suppl 2 | issue= | pages= S142-7 | pmid=17940942 | doi=10.1086/520545 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17940942 }} </ref> | |||
===Tropism=== | ===Tropism=== | ||
* Ebola [[virus]] infects mainly the cells of the mononuclear phagocyte system, but also [[fibroblasts]], [[hepatocytes]], spongiocytes, adrenal cortical cells and [[endothelial cells]].<ref name="pmid8678836">{{cite journal| author=Ryabchikova E, Kolesnikova L, Smolina M, Tkachev V, Pereboeva L, Baranova S et al.| title=Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. | journal=Arch Virol | year= 1996 | volume= 141 | issue= 5 | pages= 909-21 | pmid=8678836 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8678836 }} </ref> | * Ebola [[virus]] infects mainly the cells of the mononuclear phagocyte system, but also [[fibroblasts]], [[hepatocytes]], spongiocytes, adrenal cortical cells and [[endothelial cells]].<ref name="pmid8678836">{{cite journal| author=Ryabchikova E, Kolesnikova L, Smolina M, Tkachev V, Pereboeva L, Baranova S et al.| title=Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. | journal=Arch Virol | year= 1996 | volume= 141 | issue= 5 | pages= 909-21 | pmid=8678836 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8678836 }} </ref> | ||
Revision as of 17:05, 2 October 2014
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Ebola Microchapters |
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Ebola pathophysiology On the Web |
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American Roentgen Ray Society Images of Ebola pathophysiology |
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.[1][2][3][4]
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.
- Human-to-human airborne transmission has not been reported in any reported epidemics.
- 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.
- 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, particularly when the patient is asymptomatic, Ebola is not generally contagious. Contact with someone in early stages very rarely transmits the disease. As the illness progresses, bodily fluids from diarrhea, vomiting, and bleeding represent an extreme biohazard.
- Other than samples that are grossly contaminated with body fluids, Ebola virus is rarely detected on environmental surfaces and thus transmission by fomites is not very common. However, given that the infectious dose of the virus is low, and that current evaluation techniques such as cell culture and RT-PCR have not been well validated for environmental detection (unknown sensitivity and specificity), the true risk of transmission by contaminated surfaces is unknown.[5]
Transmission in Recovering Patients and Continued Shedding
- Ebola virus has been isolated in the semen of recovering patients 40 days after the onset of illness. This stresses the risk of sexual transmission during the recovery phase. The Zaire Ebola virus in particular has a higher risk of continued shedding in the semen. It has been detected in samples for up to 90 days after the onset of illness.
- Continued shedding may be detected in many bodily fluids with varying durations. The only bodily fluid that does not contain Ebola virus, even during the symptomatic phase of the infection, is urine. This is probably related to the inability of the kidney to filter the Ebola virus particles.
- It is generally recommended to abstain from sex or to use condoms for up to 3 months after the onset of illness. It is also recommended to avoid breastfeeding and contact with the mucous membranes of the eye for the same amount of time.[5]
Tropism
- Ebola virus infects mainly the cells of the mononuclear phagocyte system, but also fibroblasts, hepatocytes, spongiocytes, adrenal cortical cells and endothelial cells.[1]
- 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.[6]
- The next table summarizes the pathogenesis of the disease according to the virus tropism.
| 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[6] |
| Adrenal cortex | Affects the synthesis of enzymes responsible for the synthesis of steroids, leading to hypotension, and fluid and electrolytes disturbances.[6] |
| Lymphatic system | Necrosis of the spleen, lymph nodes and thymus; Apoptosis of lymphocytes leading to lymphopenia.[6][7] |
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.[8]
- 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.[9][10][11]
- 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.[12]
- The reactive oxygen and nitrogen species contribute to the cell and tissue damage, and therefore vascular and organ damage.[13]
- 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:[14]
| 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.
References
- ↑ 1.0 1.1 Ryabchikova E, Kolesnikova L, Smolina M, Tkachev V, Pereboeva L, Baranova S; et al. (1996). "Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis". Arch Virol. 141 (5): 909–21. PMID 8678836.
- ↑ Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J (1998). "A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever". J Infect Dis. 178 (3): 651–61. PMID 9728532.
- ↑ Connolly BM, Steele KE, Davis KJ, Geisbert TW, Kell WM, Jaax NK; et al. (1999). "Pathogenesis of experimental Ebola virus infection in guinea pigs". J Infect Dis. 179 Suppl 1: S203–17. doi:10.1086/514305. PMID 9988186.
- ↑ Bray M, Hatfill S, Hensley L, Huggins JW (2001). "Haematological, biochemical and coagulation changes in mice, guinea-pigs and monkeys infected with a mouse-adapted variant of Ebola Zaire virus". J Comp Pathol. 125 (4): 243–53. doi:10.1053/jcpa.2001.0503. PMID 11798241.
- ↑ 5.0 5.1 Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A; et al. (2007). "Assessment of the risk of Ebola virus transmission from bodily fluids and fomites". J Infect Dis. 196 Suppl 2: S142–7. doi:10.1086/520545. PMID 17940942.
- ↑ 6.0 6.1 6.2 6.3 Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB; et al. (2003). "Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection". Am J Pathol. 163 (6): 2347–70. doi:10.1016/S0002-9440(10)63591-2. PMC 1892369. PMID 14633608.
- ↑ Zaki SR, Goldsmith CS (1999). "Pathologic features of filovirus infections in humans". Curr Top Microbiol Immunol. 235: 97–116. PMID 9893381.
- ↑ Qiu X, Audet J, Wong G, Fernando L, Bello A, Pillet S; et al. (2013). "Sustained protection against Ebola virus infection following treatment of infected nonhuman primates with ZMAb". Sci Rep. 3: 3365. doi:10.1038/srep03365. PMC 3842534. PMID 24284388.
- ↑ Villinger F, Rollin PE, Brar SS, Chikkala NF, Winter J, Sundstrom JB; et al. (1999). "Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection". J Infect Dis. 179 Suppl 1: S188–91. doi:10.1086/514283. PMID 9988183.
- ↑ Hensley LE, Young HA, Jahrling PB, Geisbert TW (2002). "Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily". Immunol Lett. 80 (3): 169–79. PMID 11803049.
- ↑ Baize S, Leroy EM, Georges AJ, Georges-Courbot MC, Capron M, Bedjabaga I; et al. (2002). "Inflammatory responses in Ebola virus-infected patients". Clin Exp Immunol. 128 (1): 163–8. PMC 1906357. PMID 11982604.
- ↑ Basler CF, Mikulasova A, Martinez-Sobrido L, Paragas J, Mühlberger E, Bray M; et al. (2003). "The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3". J Virol. 77 (14): 7945–56. PMC 161945. PMID 12829834.
- ↑ Sanchez A, Lukwiya M, Bausch D, Mahanty S, Sanchez AJ, Wagoner KD; et al. (2004). "Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels". J Virol. 78 (19): 10370–7. doi:10.1128/JVI.78.19.10370-10377.2004. PMC 516433. PMID 15367603.
- ↑ Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE (2003). "Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event". J Infect Dis. 188 (11): 1618–29. doi:10.1086/379724. PMID 14639531.