Epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg virus disease.pdf

19/10/2014 Epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg virus disease… 1/17 Official reprint from UpToDate ©2014 UpToDate Author Mike Bray, MD, MPH Section Editor Martin S Hirsch, MD Deputy Editor Jennifer Mitty, MD, MPH Epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg viru
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  19/10/2014Epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg virus disease…1/17 Official reprint from UpToDate ©2014 UpToDate Author  Mike Bray, MD, MPH Section Editor  Martin S Hirsch, MD Deputy Editor  Jennifer Mitty, MD, MPH Epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg virus disease  All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Sep 2014. | This topic last updated: Oct 17, 2014. INTRODUCTION  — The filoviruses, Ebola and Marburg, are among the most virulent pathogens of humans,causing severe disease that resembles fulminant septic shock [1   ]. The case fatality rate in the epidemic of Ebola virus disease in West Africa has been estimated to be approximately 70 percent [2]; rates in earlier outbreaks in Africa (including Marburg virus disease in 2005) reached 80 to 90 percent [3]. No approved therapyis available for the treatment of these diseases, but progress has been made in new experimental approachesto postexposure prophylaxis and/or treatment that are effective in laboratory primates [4-11].The epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg virus disease will bepresented here, including new knowledge emerging from the 2014 epidemic of Ebola virus disease in West Africa. The diagnosis and treatment of these infections and a general approach to diseases acquired in sub-Saharan Africa are discussed elsewhere. (See Diagnosis and treatment of Ebola and Marburg virus disease and Diseases potentially acquired by travel to sub-Saharan Africa .) CLASSIFICATIONGeneral concepts  — Ebola and Marburg viruses are nonsegmented, negative-sense, single-stranded RNAviruses that resemble rhabdoviruses and paramyxoviruses in their genome organization and replicationmechanisms (see Clinical manifestations and diagnosis of rabies  and Clinical presentation and diagnosis of  measles ). Together, they make up the family Filoviridae, taken from the Latin filum, meaning thread-like,based upon their filamentous structure.Ebola and Marburg virus are also classified as hemorrhagic fever viruses based on their clinicalmanifestations, which include coagulation defects, a capillary leak syndrome, and shock [12,13   ]. Other types of viral hemorrhagic fever include Rift Valley fever, Crimean-Congo hemorrhagic fever, Lassa fever, yellow fever,and dengue hemorrhagic fever. Marburg virus  — All isolates of Marburg virus are currently considered to be members of a single species.However, there is evidence that they vary in their pathogenicity for humans, since the overall fatality rate in the1967 outbreak in Europe was 21 percent, whereas mortality among identified cases in 2000 in the DemocraticRepublic of Congo and in 2005 in Angola was in the range of 80 to 90 percent [14,15]. Alternatively, the striking difference in outcome may reflect the paucity of medical resources where the latter outbreaks took place. Ebola virus  — The genus Ebola virus is divided into five different species (the Zaire, Sudan, Ivory Coast,Bundibugyo, and Reston agents), which differ in their virulence for humans [4]. ®® Since its first recognized appearance in 1976, the Zaire species has caused multiple large outbreaks withmortality rates of 55 to 88 percent [2,16-21].●The Sudan virus has been associated with an approximate 50 percent case-fatality rate in four knownepidemics: two in Sudan in the 1970s, one in Uganda in 2000, and another in Sudan in 2004 [22-26].●The Ivory Coast virus has only been identified as the causative agent in one person, who survived [27   ].●  19/10/2014Epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg virus disease…2/17 The fifth Ebola species, the Reston virus, differs markedly from the others, because it is apparently maintainedin an animal reservoir in the Philippines and has not been found in Africa [29,30   ] (see 'Viral reservoirs' below).Ebola Reston virus was first recognized when it caused an outbreak of lethal infection in macaques importedinto the United States in 1989. This episode brought the filoviruses to worldwide attention through thepublication of Richard Preston's book, The Hot Zone [31]. Three more outbreaks occurred among nonhumanprimates in quarantine facilities in the United States and Europe before the Philippine animal supplier ceasedoperations. None of the personnel who were exposed to sick animals without protective equipment became ill,but several animal caretakers showed evidence of seroconversion.Nothing further was heard of the Reston virus until 2008, when the investigation of an outbreak of disease inpigs in the Philippines unexpectedly revealed that some of the sick animals were infected both by an arterivirus,porcine reproductive and respiratory disease virus, and by Ebola Reston virus [32]. Serologic studies haveshown that a small percentage of Philippine farm workers exposed to swine have IgG antibodies against theagent, in the absence of any history of severe illness, providing additional evidence that Ebola Reston virus isable to cause asymptomatic infection in humans. The relationship between the virus circulating in swine andthat previously recovered from Philippine macaques is not known. EPIDEMIOLOGY  — The filoviruses were first recognized in 1967, when the inadvertent importation of infectedmonkeys from Uganda into Germany and Yugoslavia resulted in explosive outbreaks of severe illness amongvaccine plant workers who came into direct contact with the animals by killing them, removing their kidneys, or preparing primary cell cultures for polio vaccine production [33]. Since that time, with the exception of a fewaccidental laboratory infections, all large outbreaks of filoviral disease have occurred in sub-Saharan Africa. Thefrequency of recognized outbreaks has been increasing since 1990.Ebola virus has also been spreading among wild nonhuman primates, apparently as a result of their contactwith the unidentified reservoir host [34-37]. This has contributed to a marked reduction in chimpanzee andgorilla populations and has also triggered human epidemics, presumably due to consumption of sick or deadanimals as a source of food [34,38]. (See 'Transmission' below and 'Viral reservoirs' below.) 2014 outbreak in West Africa  — By far, the largest outbreak of Ebola virus disease ever recorded is currentlyoccurring in West Africa with the Zaire species of the virus [19,20,39-44]. Although most previous Ebolaoutbreaks occurred in Central Africa, this outbreak started in the West African nation of Guinea in late 2013 andwas confirmed by the World Health Organization in March 2014 [20,21]. The initial case was a two-year-oldchild in Guinea, who developed fever, vomiting, and black stools, without other evidence of hemorrhage [20   ].The outbreak subsequently spread to Liberia, Sierra Leone, Nigeria, and Senegal [45,46]. Sequence analysis of viruses isolated from patients in Sierra Leone indicates that the epidemic has resulted from sustained person-to-person transmission, without additional introductions from animal reservoirs [47]. The case-fatality rate hasbeen estimated to be approximately 70 percent [2].The magnitude of the outbreak, especially in Liberia and Sierra Leone, has probably been underestimated; thisis due in part to individuals with Ebola virus disease being cared for outside the hospital setting [48]. As of October 14, 2014, the cumulative number of probable, suspected, and laboratory-confirmed cases attributed toEbola virus is 9216, including 4555 deaths [49]. These include 423 healthcare workers, of whom approximately55 percent have died. However, Nigeria and Senegal have not reported any new cases since September 5,2014, and August 29, 2014, respectively [49-52].Cases of Ebola virus disease related to this outbreak have also been reported outside of West Africa [49].The exposure occurred when an ethologist performed a necropsy on a chimpanzee found dead in the TaiForest, where marked reductions in the great ape population had been observed.The Bundibugyo virus emerged in Uganda in 2007, causing an outbreak of hemorrhagic fever with a lower case-fatality rate (approximately 30 percent) than has typically been caused by the Zaire and Sudanviruses. Sequencing has shown that the agent is most closely related to the Ivory Coast agent [28].●  19/10/2014Epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg virus disease…3/17 These cases have occurred in healthcare workers caring for patients with Ebola virus disease, as well as areturning traveler. As an example, on September 30, 2014, the first travel-associated case of Ebola wasreported in the United States [53]. An individual who traveled from Liberia to Dallas, Texas first developedclinical findings consistent with Ebola virus disease approximately five days after arriving in the United States.The patient was asymptomatic prior to and during the flight. Two healthcare workers involved in his caresubsequently developed Ebola virus disease [54]. (See Diagnosis and treatment of Ebola and Marburg virus disease , section on 'Diagnostic considerations' and Diagnosis and treatment of Ebola and Marburg virusdisease , section on 'Public health response'.) 2014 outbreak in the Democratic Republic of Congo  — In August of 2014, an outbreak of Ebola virusdisease was reported in the Democratic Republic of Congo [55]. The index case was a pregnant woman whoprepared bushmeat from an animal that had been killed by her husband. As of October 9, 2014, a total of 68cases of Ebola virus disease (confirmed, probable, and suspect), including 49 deaths, have been connected tothis outbreak [46   ]. Sequence analysis has shown that the Zaire strain of Ebola virus causing this outbreak ismost closely related to one that caused the 1995 outbreak in Kikwit; there is no connection with the currentepidemic in West Africa [56]. VIRAL RESERVOIRS  — Perhaps the greatest mysteries regarding the filoviruses are the identity of their natural reservoir and the mode of transmission from the reservoir to wild apes and humans [4,36].Nonhuman primates were initially suspected to be maintenance hosts for Marburg virus after infected monkeysintroduced the agent into Europe. However, subsequent studies have shown that these animals are at least assusceptible as humans to rapidly lethal filoviral disease, precluding any role as a host for persistent viralinfection [57].Instead, it appears likely that Ebola and Marburg viruses are maintained in species of small animals that serveas a source of infection for both humans and wild primates. Bats have long headed the list of suspects, becausethey have been present in large numbers at the sites of several filovirus outbreaks and are known to maintainother pathogenic RNA viruses, such as rabies.Epidemiologic data have suggested a strong link between exposure to bats and subsequent filoviral disease.Finally, after numerous attempts, scientists at the United States Centers for Disease Control and Preventionand their African colleagues reported in 2009 the isolation of Marburg virus from fruit bats captured at a cave inUganda [58]. The recovered viruses showed considerable genetic diversity, suggesting that they had long beenpresent in the bat population. Some sequences closely matched those of viruses that had infected miners in2007.The potential role of exposure to bats in acquisition of infection is discussed below. (See 'Transmission' below.) TRANSMISSION  — Experiments in laboratory animals indicate that filoviruses can initiate infection via manyroutes, including ingestion, inhalation, or passage through breaks in the skin [13]. Nonhuman primates can beinfected with Ebola or Marburg virus through droplet inoculation of virus into the mouth or eyes, suggesting thatcases of human infection result from the inadvertent transfer of virus to these sites from the patient's owncontaminated hands [59,60]. Person-to-person  — Person-to-person transmission occurs through direct contact of broken skin or unprotected mucous membranes with virus-containing body fluids from a person who has developed signs andsymptoms of illness [61]. The most infectious body fluids are blood, feces, and vomit. Ebola virus has also beendetected in urine, semen, and breast milk. Saliva and tears may also harbor the virus. Thus, contact with any of these fluids can pose potential risk. At present, it is unclear whether infectious virus exists in sweat [62]. Asdescribed below, such person-to-person transmission leads to outbreaks [40].One type of direct contact that leads to transmission is the ritual washing of Ebola victims at funerals [41]. An epidemiologic study found that family members were only at risk of infection if they had physical●  19/10/2014Epidemiology, pathogenesis, and clinical manifestations of Ebola and Marburg virus disease…4/17 Ebola virus may also be transmitted though contact with previously contaminated surfaces and objects. Limiteddata suggest that viable virus may exist for up to several days on fomites [64,65]. Although there are no high-quality data to confirm transmission through this type of exposure [66], the potential risk can be reduced byproper environmental cleaning [62]. (See Diagnosis and treatment of Ebola and Marburg virus disease , section on 'Environmental infection control'.)Ebola virus disease is rarely, if ever, spread from person to person by the respiratory route [67]. Althoughaerosolized filoviruses are highly infectious for laboratory animals, in humans, airborne transmission has onlybeen reported among healthcare workers who were exposed to aerosols generated during medical procedures.(See 'Nosocomial transmission' below.)Prior to the epidemic in West Africa, outbreaks of Ebola and Marburg virus disease were typically controlledwithin a period of weeks to a few months. This outcome was generally attributed to the relatively inefficientperson-to-person transmission of the virus in areas of the African rainforest where population density was lowand residents rarely traveled far from home. However, the epidemic in West Africa has shown that Ebola virusdisease can spread rapidly and widely as a result of the extensive movement of infected individuals (includingundetected travel across national borders) and the avoidance and/or lack of adequate medical isolation centers[49,68]. Contact with infected animals  — Human infection with Ebola virus can occur through contact with wildanimals (eg, hunting, butchering, and preparing meat from infected animals) [61,69   ]. In Mayibou, Gabon in1996, for example, a dead chimpanzee found in the forest was butchered and eaten by 19 people, all of whombecame severely ill over a short interval [38]. Since that time, several similar episodes have resulted fromhuman contact with infected gorillas or chimpanzees through hunting [70]. To help prevent infection, foodproducts should be properly cooked since the Ebola virus is inactivated through cooking [71]. In addition, basichygiene measures (eg, hand washing, changing clothes and boots after touching the animals) should befollowed. Exposure to bats  — Exposure to bat secretions or excretions may be a potential route for acquisition of Marburg virus. Two outbreaks of Marburg disease in the Democratic Republic of Congo (DRC) and Ugandahave involved men exposed to bats while working in abandoned gold mines [72,73]. Further support for the bathypothesis was provided by a case of a Dutch tourist who developed fatal Marburg disease after visiting a bat-infested cave in Uganda, during which time she was bumped by a bat [74]. Six months after the report of thedeath of this tourist, another woman from Colorado, who had visited the same cave in Uganda, requestedserologic testing for Marburg virus [75]. Convalescent sera, which had been archived after the patient had anunexplained febrile illness with hepatitis, coagulopathy, and encephalopathy, demonstrated evidence of prior infection with Marburg virus. Nosocomial transmission  — Transmission to healthcare workers may occur when appropriate personalprotective equipment is not available or is not properly used. As an example, during the outbreak in West Africa,a large number of healthcare workers developed Ebola virus disease, due in part, to shortages of personalprotective equipment and/or exposure to patients with unrecognized Ebola virus disease [19,49,76]. (See '2014 outbreak in West Africa' above.)Medical procedures have played a major role in some of the largest Ebola and Marburg epidemics by amplifyingthe spread of with sick individuals or their body fluids, or helped to prepare a corpse for burial [63].Healthcare workers are at risk of infection if they care for a patient with Ebola or Marburg virus diseasewithout appropriate protective measures. (See '2014 outbreak in West Africa' above and 'Nosocomial transmission' below.)● A tragic example of an iatrogenic point-source outbreak occurred in 1976, when an individual infected with●
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