Ebola virus

Introduction Filoviridae Ebola, Marburg viruses Nonsegmented, negative-sense, single-stranded RNA viruses Viral hemorrhagic fever or Ebola virus disease(EVD) Marburg virus single species Fatality rate : 21% in the 1967 outbreak in Europe 80-90% in 2000 in Congo & in 2005 in Angola Ebola virus Five different species the Zaire, Sudan, Ivory Coast, Bundibugyo, and Reston Differ in their virulence for humans

Ebola virus Zaire virus First recognized appearance in 1976 Multiple large outbreaks with mortality rates of % Sudan virus approximate 50% case-fatality rate in four known epidemics Two in Sudan in the 1970s, one in Uganda in 2000, and another in Sudan in 2004 Ivory Coast virus Ethologist performed a necropsy on a chimpanzee found dead in the Tai Forest Bundibugyo virus Outbreak of hemorrhagic fever with 30% case-fatality rate in 2007 in Uganda Reston virus Animal reservoir in the Philippines, not be found in the africa Outbreak of lethal infection in nonhuman privates imported into the United States in 1989 Animal caretakers show seroconversion, but not become ill Outbreak in pig in 2008 in Philippines

Epidemiology First recognition Importation of infected monkeys from Uganda into Germany and Yugoslavia in the 1967 (Marburg virus) All large outbreaks of filoviral disease have occurred in sub-Saharan Africa Animal transmission Spreading among wild nonhuman primates Marked reduction in chimpanzee and gorilla populations Consumption of sick or dead animals as a source of food

Viral reservoir Non-human primate Suspected to be maintenance hosts for Marburg virus after infected monkeys introduced the agent into Europe As susceptible as humans to rapidly lethal filoviral disease Bats Large numbers at the sites of several filovirus outbreaks and are known to maintain other pathogenic RNA viruses Strong link between exposure to bats and subsequent filoviral disease Isolation of Marburg virus from fruit bats captured at a cave in Uganda in 2009

Transmission Route Ingestion, inhalation, passage through breaks in the skin in laboratory animals Nonhuman primate : droplet inoculation of virus into the mouth or eyes Person-to-person Direct contact of broken skin or mucous membranes with virus-containing body fluids Detected in blood, urine, feces, vomit, semen, breast milk, saliva, tears and sweat ?? The most infectious body fluids are blood, feces, and vomit Contact with previously contaminated surfaces and objects Transmission from person to person by the respiratory route is rare

Pathogenesis Systemic inflammatory response Coagulation defects Impairment of adaptive immunity

Clinical manifestation Incubation period Abrupt onset of symptoms 8 to 12 days after exposure (range 2 to 21 days) Type of exposure ( 6 days for percutaneous exposure and 10 days for contact exposure) There is no evidence that asymptomatic persons in incubation period are infectious to others

Clinical manifestation Symptoms and signs Nonspecific flu like symptoms : Fever(87%), Chill, fatigue(76%), malaise weakness, anorexia, and pain in the muscles Rash : diffuse erythematous, nonpruritic maculopapular rash by day five to seven of illness GI symptoms : watery diarrhea(66%), nausea, vomiting(68%), abdominal pain Hemorrhage : petechiae, ecchymosis/bruising, oozing from venipuncture sites, and/or mucosal hemorrhage not observed in the early phase, but manifest in the terminal phase (20%) Other : hiccups, chest pain, shortness of breath, headache, confusion, seizures, cerebral edema, conjunctival injection, dark red discoloration of the soft palate In non-fatal cases, patients improve approximately 6 days after the onset of symptoms Death typically occurs between days 6 and 16

Assessment Clinical findings that are consistent with Ebola virus disease and a possible exposure to Ebola virus within 21 days prior to the onset of symptoms Clinical finding Fever ( > 38°C), severe headache, weakness, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage Exposure Contact with blood, body fluids, or human remains of a patient suspected to have EVD Residence in or travel to an area with widespread Ebola virus transmission Direct handling of bats, rodents, or primates from endemic areas

Preventing transmission

Principle #1: Rigorous and repeated training Principle #2: No skin exposure when PPE is worn Principle #3: Trained monitor

Diagnosis Laboratory diagnosis RT-PCR : detect specific RNA sequences Virus is generally detectable between 3 and 10 days after the onset of symptoms ELISA : detect viral antigens Other lab finding Leukopenia : lymphopenia ( WBC < 1.000/uL ) Thrombocytopenia : around day 6 – 8 of illness ( PLT < /uL) AST/ALT elevation Coagulation abnormality : PT/aPTT prologation, DIC Renal abnormality : proteinuria

Treatment There is no approved specific therapy Supportive care Preventing intravascular volume depletion (5 to 10 liters per day) Avoiding the complications of shock Correcting profound electrolyte abnormalities (hyponatremia, hypokalemia, and hypocalcemia) Empiric antimicrobial treatment should be considered when severe gastrointestinal symptom Experimental therapies “Cocktail" of three monoclonal antibodies directed against the Ebola viral glycoprotein ( Zmapp ) Use of whole blood or serum from survivors of Ebola virus disease Brincidofovir : in vitro activity against the Ebola virus RNA interference agent (TKM-Ebola) : suppresses the production of viral proteins Phase I clinical trial

Treatment Viral persistence Virus can persist for some time in certain bodily fluids, such as semen and breast milk Virus was detected in semen of male for up to three months Virus was detected in the breast milk even after virus was no longer detectable in blood Two negative PCR test on whole blood, separated by at least 48hr for discharge

Postexposure prophylaxis There are no approved forms of postexposure prophylaxis Live virus vaccine Recombinant vesicular stomatitis virus encoding the Ebola or Marburg surface glycoproteins Small interfering RNAs Synthetic small molecule drug (BCX4430) Inhibits viral RNA polymerase function Monoclonal antibodies against Ebola virus Interferon-alpha

2014 Outbreak Ebola virus disease (Zaire species) in West Africa Guinea, Liberia, Nigeria, Senegal, Sierra Leone October 14, confirmed and probable cases 4555 deaths The true numbers of cases and deaths are certainly higher

2014 Outbreak Epidemic began (Guinea) EVD outbreak (WHO) “Public health emergency of international concern” Reported cases and deaths↑ in Liberia and Sierra leone

2014 Outbreak No new case reported in Senegal No new case reported in Nigeria The first travel associated case was reported in USA > Two healthcare workers subsequently develop EVD The first case in Spain, Europe

Result Case fatality rate : 70.8% Incubation period : 11.4 days Basic reproduction numbers (R0) : 1.71 – 2.02 Doubling time : 15.7 – 30.2 days DiseaseCase fatality rate SARS(2003)9.6% Influenza (1918)3-6% Ebola70%

Result

2014 Outbreak