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Virale hemorragische koorts in de importpathologie

Fons Van GompelInstituut voor Tropische

Ziekten Antwerpen

14 december 2004

Ebola virus, Electron microscopy, copyright ITMwith special thanks to Guido Van der Groen

Principalsof InternalMedicineHarrison2004

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• Ebola virus, Filoviridae family• 4 distinct subtypes: Zaïre, Sudan,Côte d’Ivoire and

Reston. • Death in 50-90% of all clinically ill cases • Incubation period: two to 21 days• Reservoir unknown• Transmission via

– ill or dead monkeys / apes– Nosocomial / contact with contaminated body fluids – BUT only during symptomatic phase– Aerosol ? Not Zaïre/Sudan/Cd’Yvoir

http://www.who.int/wer/2004/en/wer7949.pdf

http://www.who.int/mediacentre/factsheets/fs103/en/print.html

YAMBUKU 1976

The historical publication of S.R. Pattyn of 1977, summarizing the first Ebola Colloquium at ITM. http://www.itg.be/ebola

1995

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http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

Symptoms

• Acute fever

• GBP - severe malaise

• Conjunctival redness (no pus)

• Dysphagia

• Abdominal pain

• DIC with bleeding: – thrombocytopenia– endothelum damaged– liver damage

Patient with Ebola haemorrhagic feverwith bleeding at injection sites. Photo Dr Van den Enden, Copyright ITM

Patient infected with Ebola virus two days before death. He got infected by caring for his sick smaller brother and carrying him on hisback when they left Kikwit town. Picture taken in a small village near Kikwit, Congo 1995. Copyright ITM

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"Physicians during the Ebola epidemic in Kikwit, Congo, 1995. Dr De Roo is being disinfected after leaving the ""hot zone"".

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

Ebola epidemic in Kikwit, Congo 1995. Protective clothing. With special thanks to Dr Ann De Roo. Copyright ITM

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

Ebola epidemic in Kikwit, Congo 1995. A journalist trying to get a picture of a new patient. The patient died 48h later. Copyright ITM

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6

2001

WWW.PROMEDMAIL.ORG

2003

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Ebola, 2003, Kelle, Congo. Physician and assistant in front of patient (man in sport clothes) and his wife(unprotected). To convey the message of infectiousness is rather difficult under field circumstances. Photo Dr Erwin Van den Enden, Copyright ITM

Ebola, 2003, Kelle, Congo. Patient presenting with bleeding gums, a sign of haemorrhagic diathesis. Photo Dr Erwin Van den Enden, Copyright ITM

http://www.who.int/csr/disease/ebola/en/ebolacongofr.pdf

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http://www.who.int/wer/2004/en/wer7949.pdf

2004

http://www.who.int/csr/don/en/EbolaLeafletEnglish.pdf

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Symptoms• Aspecific : characterized by the sudden onset of

fever, intense weakness, muscle pain, headacheand sore throat.

• This is often followed by vomiting, diarrhoea, rash, impaired kidney and liver function, and in some cases, both internal and external bleeding.

• Laboratory findings show low counts of white blood cells and platelets as well as elevated liverenzymes.

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/vhfmanualfr/all.pdfhttp://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

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Diagnosis• Specialized laboratory tests on blood specimens detect

specific antigens and/or genes of the virus. • Antibodies to the virus can be detected, and the virus

can be isolated in cell culture. • Tests on samples present an extreme biohazard risk and

are only conducted under maximum biologicalcontainment conditions.

• New developments in diagnostic techniques include non-invasive methods of diagnosis (testing saliva and urine samples) and testing inactivated samples to providerapid laboratory diagnosis to support case management during outbreak control activities.

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

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treatment

Severe cases require intensive supportive care, as patients are frequently dehydrated and in need of intravenous fluids or oralrehydration with solutions containing electrolytes

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

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Nieuws ?

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24 people who had been in close contact with infected family membersbut had never become ill.

In 11 people, the researchers found antibodies to the Ebola virus, indicating they had been infected.

Seven of the 11 people also had genetic material from the Ebola virus in their blood …

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Symptomless Ebola is likely due to a particularly strong immune response :

The researchers suggest that viral replication in these cases was controlled byeffective inflammatory responses triggered 4–6 days after infection. These responses were characterised by detectable concentrations of severalcytokines, such as interleukin (IL)-1, IL-6, andtumour-necrosis factor (TNF).

Therapy and vaccine• No specific treatment or vaccine is yet available

for Ebola haemorrhagic fever. • Several vaccine candidates are being tested but

it could be several years before any are available.

• Experimental studies involving the use of hyper-immune sera on animals have demonstrated noprotection against the disease.

• A new drug therapy has shown early promise in laboratory studies and is currently beingevaluated further. However, this too will takeseveral years.

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Findings• Both treatment regimens prolonged survival time

– 33% survival rate in the treatment group. Survivors are still alive and healthy after 9 months.

– All but one of the 17 controls died.

– The mean survival for the six rNAPc2-treated macaques that died was 11·7 days compared with 8·3 days for untreated controls (p=0·0184).

• rNAPc2 attenuated – the coagulation response– the proinflammatory response

Accelerated vaccination for Ebola virus haemorrhagic fever in non-humanprimates.

Sullivan NJ, Geisbert TW, Geisbert JB, Xu L, Yang ZY, Roederer M, KoupRA, Jahrling PB, Nabel GJ.

Nature 424, 681 - 684 (07 August 2003)

• … Here, we report the development of accelerated vaccinationagainst Ebola virus in non-human primates. …. The antibody response to immunization with an adenoviral (ADV) vector encoding the Ebola glycoprotein (GP) was induced more rapidlythan with DNA priming and ADV boosting, but it was of lowermagnitude.

• Even when animals were immunized once with ADV-GP/NP and challenged 28 days later, they remained resistant to challenge witheither low or high doses of virus.

• ….This accelerated vaccine provides an intervention that may help to limit the epidemic spread of Ebola, and is applicable to otherviruses.

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RESERVOIR

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• We tested for EBO virus in the organs of 242 small mammals capturedduring ecological studies in the Central African Republic.

• EBO virus glycoprotein or polymerase gene sequences were detected byreverse transcription PCR in RNA extracts of the organs of 7 animals and byPCR in DNA extract of one animal.

• Neither live virus nor virus antigen was detected in any organ sample. • Direct sequencing of amplicons identified the virus as being of the

Zaire/Gabon subtype. • Virus-like nucleocapsids were observed by electron microscopy in the

cytoplasm of the spleen cells of one animal. • The animals belonged to two genera of rodents (Muridae; Mus setulosus,

Praomys sp1 and P. sp2) and one species of shrew (Soricidae; Sylvisorexollula).

• These preliminary results provide evidence that common terrestrial smallmammals living in peripheral forest areas have been in contact with the EBO virus and demonstrate the persistence of EBO virus RNA and DNA in the organs of the animals.

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Deel 2

Overige VHF van de “bende van 4”(nosocomiale infecties door EBO, MAR,Lassa

& CCHF)

&

andere VHF

http://www.who.int/emc-documents/surveillance/docs/whocdscsredc2004.pdf

Negative stain image of an isolate of Marburg virus, showing filamentousparticles as well as the characteristic"Shepherd's Crook". Magnificationapproximately 100,000 times.Image courtesy of Russell Regnery, Ph.D., DVRD, NCID, CDC.

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/marburg.htm#marburgem

Patient with acute fever, bleeding tendency and red conjunctivae. This clinical presentation resembles severe leptospirosis, but in this case, the patient had Marburg Haemorrhagic Fever. Patient died next day. Durba, DRC, 1999. Copyright R. Colebunders - ITM

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Hard tick: female Hyalomma aegyptium. Copyright ITM

http://www.cdc.gov/ncidod/dvrd/spb/images/slideset/lassaslideset.pps#273,1,Lassa Fever

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/Fact_Sheets/Lassa_Fever_Fact_Sheet.pdf

http://www.hpa.org.uk/infections/topics_az/VHF/Lassa_FactSheet.pdf

Lassa

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• between 100 000 and 300 000 people getLassa fever in West Africa each year

• approximately 15 to 20 % of patientshospitalized for Lassa fever die from the illness; there are about 5000 deaths a year

• however, approximately 80 percent of human infections with Lassa virus are mild or asymptomatic,

• and 1 percent of infections overall result in death

Lassa

in some areas of eastern Sierra Leone, the disease accounts for

• 30 % of medical deaths in-hospital• 30 % of deafness• 70 % of spontaneous abortion• 8 to 52 % of the population are seropositive

Lassa

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

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Arenavirussen : Nieuwe wereld

"Yellow fever with haematemesis(""vomito negro""). Photo prof Eyckmans, copyright ITM"

GELE KOORTS

Gele Koorts

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Dengue

://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/Fact_Sheets/Rift_Valley_Fever_Fact_Sheet.pdf

Rift Valley, Kenya.

Map Rift Valley Fever, seroprevalence in sheep

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http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

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Deel 3

Importpathologie

Médecine Tropicale

1999; 59(4):411

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In 2000

a British aid worker in Sierra Leone

a case imported from Sierra Leone to the Netherlands

2 cases imported to Germany from Ghana and Coteand one instance of asymptomatic seroconversion was reported in a Europeanphysician

LASSA: Kliniek

• Incubatietijd 7-18 dagen• Keelpijn, koorts, malaise• Rode ogen, gezwollen

gelaat• Dyspnoe, hoest, pleuraal

vocht• Buikpijn, diarree• Levernecrose,

bloedingen, shock• Residuele doofheid bij

1/3

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Activities during stay in the Gambia Travelled with a local guide through the country, always accompanied by her son, staying at anhotel in Bakau "African village" Villages that were visited : Serrekunda (visit of the market place) Tangi : village of fisherman

Bintan Bolong, Brikama, Barra

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Clinic• Day 7 of stay in The Gambia: onset with acute high fever,

frontal headache, back and muscle pain, asthenia• Day 2 of illness: return to Belgium; sore throat• Day 3: diarrhoea, nausea• Day 4: admission to hospital; discrete jaundice, anuria;

transaminases ↑ ↑, bilirubin ↑• Day 5: persisting anuria; haemodialysis• Day 6: YF diagnosed by PCR (BNI Hamburg);

gastrointestinal haemorrhage, bleeding at injection sites,hypovolaemic shock; prothrombin ↓↓

• Day 7: status epilepticus, coma; received murineneutralising antibodies (from RKI Berlin), transfusion

• Day 8: exitus letalis• Autopsy: massive gastrointestinal bleeding

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Bloed en serum zestig minuten inactiveren bij 56%uF0B0C en daarna Triton%uF0E2 X-100 toevoegen (eind concentratie 0.1%).

LCI NL

http://www.enivd.DE/VHFDISEASES/fs_vhfdiseases.htm

The list of VFHs comprise more than a 100 pathogens endemic in different parts of the world. No laboratory alone is capable to cover the whole spectrum. Therefore …..ENIVD

ENIVD

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http://www.infectieziekten.info/index.php3protocollen infectieziekten LCI-Nl

Deel 4

Koorts met bloedingen in de importpathologie

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Lancet Volume 352, Number 9141 21 November 1998

Correspondence

Fièvre hémorragique à virus Ebola dans lesud du Soudan – bulletin n°7

22 juin 2004

• Le 20 juin, les autorités sanitaires du comté de Yambio et l’équipequi les assiste ont réévalué le nombre des cas en tenant compte du tableau clinique, de l’épidémiologie et des résultats de laboratoire.

• En conséquence, on considère désormais que 18 cas de fièvrehémorragique à virus Ebola et 6 décès ont été notifiés.

• Les derniers résultats donnés par le Centre collaborateur de l’OMSaux Centers for Disease Control and Prevention (CDC) des Etats-Unis, ont permis d’établir que 12 des 30 cas signalés dernièrementétaient des cas de rougeole. Il y a eu des cas de rougeole dans cecomté et ils ont été signalés pour la première fois au réseau OMS d’alerte rapide et d’action (EWARN) dans le sud du Soudan dans la deuxième semaine de mars 2004. L’augmentation de leur nombre a été décelée grâce au système de surveillance active mis en place pour la fièvre hémorragique à virus Ebola. De nouvelles analyses de laboratoire sont en cours.La surveillance active et le suivi des contacts se poursuivent.

http://www.who.int/csr/don/2004_06_22/fr/http://www.who.int/csr/don/2004_06_22/en/

http://www.who.int/csr/resources/publications/IGWG_IHR_WP12_03-en.pdf

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Zie pdf in bijlage : KoortsBloed Tab

Zie pdf in bijlage : KoortsBloed Tab

Zie pdf in bijlage : KoortsBloed Tab

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Zie pdf in bijlage : KoortsBloed Tab

Deel 5

www

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http://www.who.int/csr/disease/ebola/en/

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/vhfmanualfr/all.pdfhttp://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual/entire.pdf

http://www.who.int/emc-documents/haem_fevers/whoemcdis977c.html

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http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/Fact_Sheets/Ebola_Fact_Booklet.pdf

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/Fact_Sheets/Marburg_Hemmorhagic_Fever_Fact_Sheet.pdf

http://jama.ama-assn.org/cgi/reprint/287/18/2391.pdf

www.promedmail.orgsearch archives

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