Adobe Systems Department of infectious diseases, Masaryk univerzity, Univerzity hospital Brno 1 Yellow fever Ebola Tomáš Gergel Svatava Snopková Adobe Systems 2 Yellow fever •mosquito-borne viral hemorrhagic fever with a high case-fatality rate •acute, systemic infection with organ dysfunction and hemorrhage •vector: Aedes sp. in Africa, Haemagogus sp. in South America •etiological agent: omember of the family Flaviviridae, enveloped, positive-sense, single-stranded RNA virus that replicates in the cytoplasm of infected cells osingle serotype, antigenically conserved = vaccine protects against all strains of the virus o1927 - first isolation from human. First proven mosquito-borne viral infection ocause infection of human and primates (both serve as reservoir) •life-long immunity develops after the infection ̶ Adobe Systems 3 Epidemiology •WHO ofrom 1980 –↑ numbers of cases worldwide o200 000 reported cases/year (10 – 250x more in reality) o˃ 60 000 deaths/year o90 % of all cases in Africa (↑ inhabitants in city agglomeration + ↑ % infected mosquitoes + ↓ vaccinaton prevalence rate) •tropical regions of South America and sub-Saharan Africa where the disease is endemic •endemic YF has never been reported in Asia (only imported infections) ̶ Adobe Systems https://www.cdc.gov/yellowfever/maps/south_america.html 4 Adobe Systems https://www.cdc.gov/yellowfever/maps/africa.html 5 A global strategy to Eliminate Yellow fever Epidemics (EYE) 2017-2026. WHO 2018. ISBN 978-92-4-151366-1. Bryant JE. Out of Africa. www.ncbi.nlm.nih.gov/pmc/articles/PMC1868956 Spread of yellow fever •17c. - transatlantic slave trade = most important way of spreading from Africa to western hemisphere o1648 Yukatan – 1. epidemics at western hemisphere •17c. – 19c. – multiple epidemics at North America and Europe (ports) o1793 – Philadelphia – approx. 10 % of inhabitants died; 1880 – epid. related with Panama canal construction 6 Adobe Systems A global strategy to Eliminate Yellow fever Epidemics (EYE) 2017-2026. WHO 2018. ISBN 978-92-4-151366-1. 7 Pandemic potential of YF •outbreak in Luanda, Angola → spreading to Kinshasa (DRC) and China (first cases in Asia) - 11 chinese workers returned from Angola •real danger of rapid spreading in Asia (air transport, non-immunised travelers, presence of vector – Aedes aegyptii) •there was no further spread in China - air temperatures were lower than necessary for vector activity 2016 Adobe Systems 8 YF transmission cycles http://www.goodtrips.org/?page_id=808 1.Sylvatic cycle (ape-mosquito-human, "jungle yellow fever") – Africa, SA 2.Intermediate cycle („savanah cycle“)– Africa 3.Urban cycle (human-mosquito-human, "urban yellow fever„) – Africa, SA Adobe Systems 9 Transmission 1.infected female mosquito bite - virus replication at the site of inoculation (dendritic cells in epidermis) → 2.regional lymph nodes → 3.other organs via the lymph and then the bloodstream (viremia) → 4.other tissues (large amount replication of virus in the liver, lymph nodes, and spleen) •Incubation period: 3-6 days Adobe Systems Define footer – presentation title / department 10 Clinical manifastation 1.Subclinical infection 2.Abortive, nonspecific febrile illness without jaundice 3.Life-threatening disease with fever, jaundice, renal failure, and hemorrhage 4. Adobe Systems 11 Stages of classical illness 1.Period of infection („red period“) • 3-4 days lasting viremia •malaise, headache, photophobia, pain in the lower extremities, myalgia, anorexia, nausea, vomiting, restlessness, irritability, and dizziness - nonspecific, impossible to distinguish yellow fever from other acute infections •PE: patient appears acutely ill, flushed skin, conjunctivitis, epigastric tenderness, +- hepatomegaly, tongue - red at the tip and sides with a white coating in the center, Faget's sign (↓puls rate relative to ↑temperature (39-41ºC) •Lab.: leukopenia (1500 to 2500 per ul) relative neutropenia; elevated serum transaminase Adobe Systems 12 2.Period of remission •lasting up to 72 hours •abatement of fever and symptoms •patients with abortive infections recover at this stage Adobe Systems 13 3.Period of intoxication (sever yellow fever, „yellow period“) •approxx. 15 % of infected enter this stage (˃50% travelers from nonendemic countries) o20 – 50% mortality (non-treated), 5% (treated) osurvivors – without consequences + life-long immunity •return of fever, nausea, vomiting, epigastric pain, jaundice, oliguria and hemorrhagic diathesis (coffee-grounds hematemesis, melena, hematuria, metrorrhagia, petechiae, ecchymoses, epistaxis, oozing of blood from the gums, and bleeding from needle puncture sites) •↓viremia, ↑antibodies Adobe Systems 14 3)Period of intoxication •Organ dysfuncion: oLiver - apoptosis of hepatocytes in the midzone of the liver lobule, no disruption of the architecture of the liver, healing is complete without postnecrotic fibrosis (in nonfatal cases) oKidney - direct viral injury and nonspecific changes due to hypotension and the hepatorenal syndrome oThe hemorrhagic diathesis - decreased synthesis of vitamin K-dependent coagulation factors by the liver, disseminated intravascular coagulation, and platelet dysfunction oEncefalopathy - result of microvascular dysfunction oMyocardial injury - rare, arrythmias, myocardial insufficiency → MOF - high levels of proinflammatory cytokines (IL-1, IL-6, TNF-α - as in bacterial sepsis, SIRS) o ̶ Adobe Systems 15 https://truthtalk13.files.wordpress.com/2014/09/yellowfever_thumb.jpg?w=490&h=319 Lab: •↓ Leuko, relat. lymfocytosis, ↓ PLT •AST (↑↑) > ALT (due to concomitant viral injury to the myocardium and skeletal muscle) ALP normal ↑ bilirubin typically between 85-170 umol/L •decreased synthesis of coagulation factors (f. II, V, VII, IX, X) •↑myoglobin +↑CK (myositis) Adobe Systems 16 Yellow fever - diagnostic 1.sérology: ELISA - IgM antibodies, ↑ lvl in acute faze, ↓ in covalescens ̶ can be cross-reactions with other flaviviruses, particularly in Africa where multiple flaviviruses circulate ̶ the neutralization test is more specific but requires a specialized laboratory 2.PCR: viral genom detection from blood or tissue samples 3.Liver sample histology – only post mortem. During illness high risk of fatal bleeding (see Liver in organ dysfuncion, slide 14) ̶ •positive results must be confirmed by WHO or CDC certified laboratory Adobe Systems 17 Yellow fever - treatment •no specific antiviral therapy available •supportive care = modern intensive care (generally not available in remote areas) omaintenance of nutrition oprevention of hypoglycemia onasogastric suction to prevent gastric distention and aspiration ohypotension - fluid replacement and vasoactive drugs (norepinephrine, terlipressine) ooxygen omanagement of metabolic acidosis otreatment of bleeding - fresh-frozen plasma orenal failure - dialysis if indicated otreatment of secondary infections ̶ Adobe Systems 18 Yellow fever - prevention 1.Mosquito bite prevention (repelents (DEET), clothing, mosquito net etc.) 2.Vaccination: othe primary tool for prevention of YF ovaccine protects against all strains of the virus olive-attenuated vaccine (f.e. Stamaril®) osingle dose provides lifelong protection for most people, booster is not recommended oVaccine is recommended for people aged 9 months or older and who are traveling to or living in areas at risk for yellow fever virus in Africa and SA oCAVE !!! age ˂ 9 months, ˃ 60 years, pregnancy, immunocompromised patients – high risk of sever adver effects (as at all live vaccines) oYellow fever vaccine may be required for entry into certain countries Adobe Systems 19 Ebola RNA, non-segmented, family Filoviridae (from latin „filum“ = thread like) 6 types: •Zaire ebola virus – most common, the deadliest, mortality 55-88%, central and west Africa •Sudan ebola virus – mortality as in Zaire, Sudan (1970, 2004), Uganda (2000) •Tai Forest ebola virus (former Cote d´Ivoire ebola virus) – west Afrika •Bundibugyo ebola virus – mortality 22-30%, Uganda (2007), DRC (2012) •Reston ebola virus – in Phillipines (not in Africa), infects only nonhuman primates •Bombali ebola virus – newly izolated from bats, infectiosity for humans not known Adobe Systems 20 Ebola Ebolavirus – the most virulent patogen known • natural reservoirs are not yet identified (probably some species of bats) • stable for a long time at room temperature, in blood or water for • sensitive to high temperatures, UV light, γ radiation Adobe Systems 21 since 1976 •several outbreaks, in remote, isolated areas of small villages, low population density, near rain forrests •Fewer than 100 cases, contained within a period of weeks to a few months 2013-2016 •the biggest epidemy in history - Guineia, Liberia, Siera Leone, Nigeria, Senegal, and Mali (Zaire ebola virus) •Almost 29k confirmed cases, 11,000 deaths (40% mortality). 881 infected healthcare workers - 60 %percent died Boštíková V. očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP v Dekokratické republice Kongo. Vakcinologie 2019;3:106-109. WHO-ebola virus disease-external situation report. Adobe Systems 22 August 2018 – June 2020 10. epidemy of ebola in DRC, 2. biggest in history •EBOV-Zaire •3470 confirmed cases with 2287 deaths, a fatality rate of 66 % •162 zdravotnických pracovníků Boštíková V. očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP v Dekokratické republice Kongo. Vakcinologie 2019;3:106-109. WHO-ebola virus disease-external situation report. Adobe Systems 23 Patogenesis •most data obtained from laboratory experiments (mice, guinea pigs, nonhuman primates) •virus → musous membranes (mouth, eyes), broken skin → necrosis of macrophages and dendritic cells → release of large amount of new virions → virus-induced suppression of type I interferon responses → rapid spred to lymph nodes and bloodstream → infected almost all body cells •lymfocytes and neurons are only cell types not infected •failure of adaptive immunity (impaired dendritic cell function and lymphocyte apoptosis) → ability of filoviruses to cause a severe, frequently fatal illness Adobe Systems 24 Transmission images (10).jpg Rezervoir and the mode of transmission •greatest mystery •data suggest bats and other wild animals Transmission Direct contact •body fluids of infected human and animal •high risk – blood, feces and vomitus •also detected in urine, semen, saliva, aqueous humor, vaginal fluid, and breast milk Indirect contact surfaces and objects – beding, clothes, needles … Others •accidental infection of workers in any Biosafety-Level-4 (BSL-4) facility where filoviruses are being studied •bioterrorism •airbourne transmisson wasn´t proven . Chlíbek R. et al. Horečka ebola a marburská horečka – epidemie virových hemoragických horeček. KMIL 2006;12(6):217-223. Adobe Systems 25 Transmission – „Bushmeat“ •available source of livelihood •source of infection - insufficiently heat-treated meat of an infected animal (raw, dried), organs, body fluids (bat soup, grilled bat, primate meat…) • •DRC – yearly hunted ˃6 mil tons of wildlife meat oapprox 90 tons of meat is illegaly imoprted to USA every yeatr o↑spreading infection risk Adobe Systems 26 Clinical manifestation ̶Incubation: 6-12 days (range 2-21 days) – prolonged incubation = difficulty to find contacts, ↑ risk of spreading the infection Symptoms: •abrupt onset of fever and chills, fatigue, headache, loss of appetite •Rash – diffuse erythematous, nonpruritic maculopapular rash by day 5 to 7 of illness, usually involves the face, neck, trunk, and arms, and can desquamate •Gastrointestinal –common, first few days of illness, watery diarrhea (up to 10 liters per day) nausea, vomiting, and abdominal pain → severe fluid loss → dehydration → hypotension → hypovolemic shock → death •Hemorrhage –blood in the stool, petechiae, ecchymoses, oozing from venipuncture sites, and/or mucosal bleeding oclinically significant hemorrhage in the terminal phase of illness and in pregnancy Adobe Systems 27 Clinical manifestation •Neurologic – meningoencephalitis, days 8 to 10 of illness. •Cardiac – relative bradycardia, pericarditis, myocarditis •Respiratory – tachypnea, shortness of breath, hypoxia, hypoventilation due to respiratory muscle fatigue orespiratory failure also as consequence of fluid resuscitation •Ocular – conjuncitivitis, uveitis (also in convalescnece) •death usually during 2. week of illness • •Lab.: leukopenia with lymphopenia, trombocytopenia, elevated ALT, AST, coagulation abnormalities (prolonged PT, aPTT, ↑fibrin degradation products), proteinuria, azotemia, electrolyte abnormalities (↓Na, ↓K, ↑K, ↓Mg, ↓Ca) Adobe Systems 28 Clinical manifestation Remember.... •major hemorrhage is less common than previously described (usualy at the end of the fatal course) •volume losses from vomiting and diarrhea made a greater contribution to severe illness Convalescence - can persist for more than two years •weakness, fatigue, muscle and joint pain, insomnia, headache, urinary frequency, memory loss, and failure to regain weight that was lost during illness Adobe Systems 29 Diagnosis Determine the risk of exposure https://www.researchgate.net/profile/Suresh_Rewar/publication/275965188/figure/tbl2/AS:669689235644 425@1536677764331/Diagnostic-Tests.png Adobe Systems 30 Diagnosis Symptomatic patients with identifiable risk •infection control precautions should be used, health care workers - personal protective equipment recommended for the care of patients with Ebola virus disease (or highest available) •patients should be isolated in a single room with a private bathroom, closed door •inform the hospital infection control program, hospital leadership, local and state health departments •phlebotomy and laboratory testing limited to tests that are essential for diagnosing or ruling out Ebola virus • •Ebola virus belongs to category bio-safety level 4 (BLS-4) („VNN - vysoce nebezpečné nákazy“ in czech) •only 2 hospitals in Czech republic are capable to take care of BLS-4 – Bulovka univerzity hospital Prague, Těchonin military hospital Adobe Systems 31 Adobe Systems 32 Diagnosis Asymptomatic individuals with identifiable risk •monitoring for symptoms and signs of Ebola virus disease •should be monitored for 21 days after the last known exposure •immediately report the development of fever or other clinical manifestations suggestive of Ebola virus disease •self-monitoring and reporting versus direct observation by a designated health official •need for travel restrictions, restricted movement within the community, and/or quarantine Adobe Systems 33 Diagnosis - testing •„OraQuick Ebola rapid Antigen Test“ orapid diagnostic test–10/2019 FDA approval orapid patient isolation and treatment – epidemiologically significant •serology - ELISA – antigen and antibodies •PCR - blood, tissues •virus isolation - VERO cells •electron microscopy •skin biopsy → PCR ̶ Adobe Systems 34 Diagnosis - testing Adobe Systems 35 Treatment Specific antivarals are not available •4 experimental drugs in trials o3x monoclonal antibody o1x nucleotide analgue - remdesivir Supportive care •fluid and electrolytes replacement, transfusions •complex intensive care – oxygen, artificial ventilation, hemodialysis Adobe Systems 36 Adobe Systems 37 Adobe Systems 38 Adobe Systems 39 Adobe Systems 40 Prevention •protective personal equipement (see above) •strict isolation •desinfeciton of surfaces, body fluids • •reproduction rate (RR) = 2-4 • Vaccinaton Ring vaccination strategy - contacts and their contacts = approx. 120-150 people in 1 ring Adobe Systems 41 Prevention 2018 rVSV-ZEBOV-GP 2019 approved by FDA, EMA as ERVEBO® •live attenuated vesicular stomatitis virus (VSV) carries ebola Zaire surface glykoprotein •2 doses •antibodies at least for 1 year •even in pregnancy (100% mortality of ebola in pregnant women) •efficiency 95,8-98,5 % Adobe Systems COVID-19 pandemic, 1.wave 42 Thank you for your attention !