Emerging Encephalitis ESCMID Online Lecture Library © by Author
Emerging encephalitis
Nipah, Enterovirus 71, West Nile, and others … © by author O. Epaulard Department of Infectious Diseases ESCMID OnlineGrenoble Lecture University HospitalLibrary Unit of Virus - host cell interactions UMI 3265 UJF-EMBL-CNRS Declaration of interest
• No contradictory interest
© by author ESCMID Online Lecture Library Menu
• General considerations
• Flaviviruses West Nile virus
• Henipaviruses © by author • Enterovirus 71
• ESCMIDHEV Online Lecture Library DNA viruses
RNA viruses
© by author ESCMID Online Lecture Library Hepeviridae Rubivirus Alphavirus Caliciviridae Flavivirus (HEV) (Rubella) (Chikungunya, O Nyong- (Norwalk) (YF, Dengue, JE, Nyong, Am. Eq. Enc.) WNV, TBE)
Togaviridae Hepacivirus Enterovirus (HCV) (Coxsackie, echovirus, …) Flaviviridae Hepatovirus (HAV) picornaviridae Rabies Rhinovirus Rhabdoviridae Parechovirus RNA viruses Coronaviridae
Morbillivirus Filoviridae (measles) (Marburg, Ebola) Paramyxoviridae© by author
Orthomyxoviridae RubulavirusESCMIDPneumovirus OnlineBunyaviridae Lecture Library (mumps) (RSV) Henipavirus Retroviridae (Nipah, Hendra) Hantaviruses influenza Hepeviridae Rubivirus Alphavirus Flavivirus Caliciviridae (HEV) (Rubella) (Chikungunya, O Nyong- (Y (Norwalk) F, Dengue, JE, Nyong, Am. Eq. Enc.) TBE, WNV)
Enterovirus Togaviridae Hepacivirus (Coxsackie, echovirus, …) (HCV) Hepatovirus Flaviviridae (HAV) picornaviridae Rhinovirus Rabies Rhabdoviridae Parechovirus
RNA viruses Coronaviridae
Morbillivirus Filoviridae (measles) (Marburg, Ebola) Paramyxoviridae© by author
Orthomyxoviridae RubulavirusESCMIDPneumovirus OnlineBunyaviridae Lecture Library (mumps) (RSV) Henipavirus Retroviridae (Nipah, Hendra) Hantaviruses influenza Emerging diseases are mostly …
• Viral
• RNA
• Zoonotic © by author
• ESCMIDNo cross-immunity Online Lecture Library Why do infectious diseases emerge ?
• Because they always have • Huge animal reservoir • Climate evolution • Air travel © by author • Urbanization • ESCMIDVirus mutation Online Lecture Library – Poor fidelity of polymerases of RNA viruses Did you mention bats ?
• SARS-co • MERS-co • Nipah RNA viruses … • Hendra • Ebola © by author • Marburg • ESCMIDRabies Online Lecture Library Did you mention bats ?
• SARS-co • MERS-co • Nipah • Hendra Drexler 2013 • Ebola © by author • Marburg • ESCMIDRabies Online Lecture Library © by author ESCMID Online Lecture Library
Drexler 2013 Coronavirus in feces
Astrovirus in feces
© by author
AdenovirusESCMID in feces Online Lecture Library
Drexler 2013 Did you mention bats ?
© by author ESCMID Online Lecture Library
Smith 2013 © by author ESCMID Online Lecture Library
Smith 2013 Flaviviruses
© by author ESCMID Online Lecture Library Flaviviruses: highly successful
Hepacivirus
Pestivirus
Flaviviridae © by author Flavivirus ESCMID Online Lecture Library Flaviviruses: highly successful
© by author ESCMID Online Lecture Library Dengue
• From 9 to 100 countries concerned • 2,5 billions of people exposed • 50 to 100 millions cases a year, increasing • More explosive outbreaks • More northern© every by year author ESCMID– Including Europe Online Lecture Library © by author ESCMID Online Lecture Library Aedes albopictus in Europe (2012)
© by author ESCMID Online Lecture Library Dengue Madeira 2012
© by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library TBE
© by author ESCMID Online Lecture Library
ECDC datas © by author ESCMID Online Lecture Library
ECDC datas © by author ESCMID Online Lecture Library 2009
© by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library
Duffy 2009 Zika fever in French Polynesia
© by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library
INVS datas August 1999, New York, New York
• 2 then 8 then finally 59 cases of encephalitis in New York area
© by author ESCMID Online Lecture Library August 1999, New York, New York
© by author ESCMID Online Lecture Library August 1999, New York, New York
• 2 then 8 then finally 59 cases of encephalitis in New York area • First hypothesis : St Louis encephalitis – Because of outdoor activities of all patients – Serologic tests consistent • Concurrent outbreak© by in author crows – Including substantial crow death ESCMID Online Lecture Library – With encephalitis at necropsy August 1999, New York, New York
• Final diagnosis of West Nile virus infection – In local crows – In a chilean flamingoe from a local zoo
• Leading to the identification of the same virus in human cases© by author ESCMID Online Lecture Library
Nash 2001 © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library
Roehrig 2013 © by author ESCMID Online Lecture Library
May 2010 © by author ESCMID Online Lecture Library In USA : 16000 to 28000 patients 40% (?) neuro-invasive Roehrig 2013 1500 deaths © by author ESCMID Online Lecture Library
Roehrig 2013 © by author ESCMID Online Lecture Library
Petersen 2013 © by author ESCMID Online Lecture Library
Petersen 2013 Meanwhile in Europe…
193 cases in 2013
© by author ESCMID Online Lecture Library 2010
163 cases 109 neuroinvasive infections © by author ESCMID Online Lecture Library 2011 West Nile virus
• First isolated in Uganda, West Nile district, 1937
• Reservoir an amplificating host: birds – Mammals (including human) : dead-end • Viremia too weak© and by to authorshort
• Vector:ESCMID mainly OnlineCulex mosquitoes Lecture Library © by author ESCMID Online Lecture Library
Kramer 2008 © by author ESCMID Online Lecture Library
Petersen 2013 © by author ESCMID Online Lecture Library
Petersen 2013 West Nile virus fever
• 25% of infected patient develop symptoms
• In >50% of symptomatic patients : – Headache – Weakness – Rash (morbilliform/maculopapular) – Mild fever – Myalgia © by author • Less commonly : – Joint pain ESCMID– Eye pain Online Lecture Library – Vomiting/diarrhea – lymphadenopathy West Nile neuroinvasive diseases
• 1/200 infected patients (1/10 symptomatic) – 1/50 in patients >65 yo – 1/800 in patients 16-24 yo – More frequent if cancer, diabetes, hypertension, alcohol abuse, renal disease
• Abrupt onset © by author • Different forms ESCMID– Meningitis Online Lecture Library – Encephalitis – Acute flaccid paralysis © by author ESCMID Online Lecture Library
Roehrig 2013 © by author ESCMID Online Lecture Library
Petropoulou 2005 - Ali 2005 WNV infection diagnosis
• Plasma serology
• CSF serology
• CSF PCR © by author ESCMID Online Lecture Library West Nile virus infection treatment
• Treatment: only supportive – Ribavirin – Interferon α-2b – Polyclonal γ-globulins No effect – Neutralizing specific antibodies Antisens strategies – © by author • Preventive vaccines: ESCMID– Phases I and Online II (derived Lecture from equine Library vaccines) – No phase III © by author • Fatal encephalitis in a 10-y old boy of Powassan, ESCMIDOntario Online Lecture Library • Inoculation to newborn mice: encephalitis in 5d Powassan virus
• Flavivirus related to TBE complex
• Russia, Canada, USA – Imported from Russia ? In 1950s © by author • Zoonosis transmitted by ticks ESCMID– Dermacentor Online & Ixodes Lecture Library 2012 © by author ESCMID Online Lecture Library Powassan cases in the USA, 2001-2012
© by author ESCMID Online Lecture Library
CDC datas Usutu virus
© by author ESCMID Online Lecture Library
Pauli 2014 Usutu virus
• Birds cases
© by author ESCMID Online Lecture Library
Beck 2013 Usutu virus
© by author ESCMID Online Lecture Library Other flavivirus encephalitis
© by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author • RecentlyESCMID considered Online to be theLecture same virus Library that Israel Turkey meningoencephalomyelitis virus © by author ESCMID Online Lecture Library Nipah (and Hendra) viruses
© by author ESCMID Online Lecture Library • 265 cases / Fatality rate 40%
• First supposed to be Japanese EV - but: – More adults than children – High attack rate – Several cases in the© householdby author
• FirstESCMID viral isolate Online at Kampung Lecture Sungai Nipah Library (march 1999)
• The outbreak was stopped after slaughtering 1.1 M pigs • 3 pig farmers • Clinics: – Fever, headache, altered consciousness – Dysautonomia / brainstem dysfunction – Hypotension and© death by author • Necropsy: ESCMID– Vasculitis-induced Online thrombosis Lecture Library – Viral inclusions in neurons – Cross-reactivity to Hendra Virus Nipah encephalitis virus
• Natural host: pteropus bat • Tested positive in… – Cambodia – Thailand – Indonesia India – © by author – Madagascar ESCMID– Ghana Online Lecture Library Nipah encephalitis virus
• Natural host: pteropus bat • Paramyxoviridae
© by author ESCMID Online Lecture Library Nipah encephalitis virus
• Natural host: pteropus bat • Paramyxoviridae • First documented cases: – Pigs in 1996 (retrospectively) • Transmission from bats • Due to modification/intensification of pig farming – Human in 1998© by author ESCMID– Cats, dogs, Onlinegoats… : dead-end Lecture Library Kulkarni 2013 Outbreaks in India & Bangladesh: 292 patients, 221 deaths
© by author ESCMID Online Lecture Library Nipah virus transmission
• Detectable in urine, feces, saliva
• Malaysia, Singapore : – pig to human • At risk : pig farmers, pig slaughters
• India, Bangladesh : – Bats to human © by author • Climbing to palm tree ESCMID• Drinking freshOnline date palm Lecture sap Library – Human to human • Including to HCW in hospital (Siliguri outbreak) © by author ESCMID Online Lecture Library Siliguri outbreak, India
© by author ESCMID Online Lecture Library Siliguri outbreak, India
© by author ESCMID Online Lecture Library
Chadah 2006 Nipah encephalitis in human
• Incubation <2 weeks in >90% – 4 days to ? 2 months
• Possible subclinical infection (10-50%) Chan 2002 © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library Nipah: CSF fluid examination
© by author • Nipah virus is detectable in CSF by PCR ESCMID Online Lecture Library © by author ESCMID Online Lecture Library 2001
• 140 patients – 54 before study,© or by refused author ribavirin • Death 54% ESCMID– 86 receiving Online ribavirin Lecture Library • 2g day 1, 3.6g days 2-4, 2.4g days 5-6, 1.2g days 7-10 • Death 32% 2014
© by author
• ESCMIDm102.4 Online Lecture Library • Phase I study to be initiated in Australia 1995
• First described in Australia, 1994 – Outbreak in 21 horses, 14 deaths – 2 cases in humans, all working with horses; one death (pneumonia) • Mainly respiratory© signsby author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library Hendra virus
• Outbreaks in horses – 48 described, all in Australia
• Rare cases in human : seven described – All with close contact with ill horses – 4 deaths (1994,© 2008, by 2009)author – 1 with pneumonia, 3 with encephalitis ESCMID Online Lecture Library © by author
NakkaESCMID 2012 Online Lecture Library Enterovirus 71
© by author ESCMID Online Lecture Library Enteroviruses: previous classification
• Coxsackievirus A (23 serotypes)
• Coxsackievirus B (6 serotypes)
• Polioviruses (3 serotypes)
• Echovirus (68 serotypes)© by author
• ESCMIDOthers Human Online EnteroViruses Lecture isolated Library after 1970 – HEV68 Enterovirus: new classification
© by author ESCMID Online Lecture Library Solomon 2010 © by author ESCMID Online Lecture Library
© Richard Hunt HMFD: skin and mucosa
© by author ESCMID Online Lecture Library
Ooi 2010 Enterovirus 71
• Isolated in 1969 (1963?)
• HFMD outbreaks (mainly Pacific-Asia area)
• Aseptic meningitis, brainstem encephalitis, acute flaccid paralysis© by author ESCMID Online Lecture Library • Frequently associated with pulmonary oedema and shock © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library
Ooi 2010 ESCMIDSarawak, Online LectureMalaysia Library
© by author neoiu 71 Enterovirus HFMD HFMD cases Solomon 2010 Solomon © by author ESCMID Online Lecture Library
Huang 2014 © by author ESCMID Online Lecture Library All cases
© by author ESCMID Online Lecture Library
Ho 1999 Severe cases
© by author ESCMID Online Lecture Library
Ho 1999 © by author ESCMID Online Lecture Library
Ho 1999 © by author ESCMID Online Lecture Library Enterovirus 71 –associated lung failure
© by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author
725 children ESCMID OnlineOoi 2009 Lecture Library © by author ESCMID Online Lecture Library 2001 © by author ESCMID Online Lecture Library
McMinn 2001 – 9 month-old © by author ESCMID Online Lecture Library
McMinn 2001 – 19 month-old © by author ESCMID Online Lecture Library
Chen 1999 CSF parameters
© by author ESCMID Online Lecture Library
Perez-Velez 2007 © by author ESCMID Online Lecture Library
Perez-Velez 2007 Enterovirus 71 : antiviral therapy • Anti-polymerase – Ribavirine • Active on other RNA viruses but not EV • Capside binders – Pleconaril • Inhibits the entry and decoating of enteroviruses … Not active on EV71 – Vapendavir (initially© developped by author for rhinovirus) – pirodavir • ESCMIDProtease inhibitor Online Lecture Library – SG85 – Rupintrivir Enterovirus 71 : other treatments
• Milrinone – Inotropic agent – For neurogenic pulmonary edema
© by author ESCMID Online Lecture Library
Chi 2013 Venancio 2013
© by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library HEV
© by author ESCMID Online Lecture Library Hepatitis E virus
• Discovered 1983 in Afghanistan – Nude RNA virus of its own genus
• Probably the most common cause of acute hepatitis in the world – But chronic form may develop in immunocompromised© by hosts author • 4 serotypes ESCMID– 1 & 2 : water-borne Online infection Lecture in developing Library countries – 3 & 4 : zoonotic (pig) reservoir HEV
© by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library Hepatitis E virus infection with CNS involvment
• Immunocompromised and immunocompetent patients
• Acute (I.competent) or chronic (I.compromised) infection © by author
• LiverESCMID enzymes Online elevated Lecture during acute Library infection – Although mild : ALT 300-1000 IU/L HEV Plasma CSF infection Nervous Medical status Phase system and lesions HEV HEV RNA Protein Leukocytes HEV RNA ALT, IU/L 3 genotype IgG/IgM g/L /mm
Acute Not immunocompr. PRN +/+ + 623 Neg 1.27 145 3e Acute Not immunocompr. neuritis +/+ + 1160 ND - 3e Acute Not immunocompr. PRN +/+ + 384 Neg 2 14 3f Kidney–pancr. Tx Chronic PRN +/+ + 173 Pos 0.71 1 recipient 3f Chronic encephali Kidney Tx Recipient -/+ + 110 Pos 0.8 8 3f tis Chronic Kidney Tx Recipient PRN +/+ + 105 Pos 0.76 7 3f © by author Chronic HIV positive Ataxia +/+ + 150 Pos 0.47 1 3f Acute encephali Not immunocompr.ESCMID Online-/+ Lecture + 479 Library Pos 0.56 12 3f tis
Not immunocompr. Acute radiculitis +/- NA 1612 NA 0.68 <5
Adapted from Kamar 2011 and Deroux 2014 © by author ESCMID Online Lecture Library