The Challenge of Hepatitis E Berne, November 15, 2017 · Hepatitis E Diagnosis Béguelin C, Fraga M...
Transcript of The Challenge of Hepatitis E Berne, November 15, 2017 · Hepatitis E Diagnosis Béguelin C, Fraga M...
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Division of Gastroenterology and Hepatology Centre Hospitalier Universitaire Vaudois
University of Lausanne
Darius Moradpour
[email protected] www.gastro-hepato.ch
Swiss Hepatitis Strategy Symposium Berne, November 15, 2017
l Most common cause of acute hepatitis and jaundice in the world
l HEV gt 1 and 2 infect 20 mio people and claim 70,000 lives every year1
l HEV gt 3 and 4 increasingly recognized as zoonotic infection in the developed world (seroprevalence rates up to 86%)2
l HEV gt 3 can persist in immunocompro-mised pts and cause neurologic complic.
1Rein DB et al. Hepatology 2012;55:988-997. 2Mansuy JM, Gallian P et al. Hepatology 2016;63:1145-1154.
Reviewed in Hoofnagle JH et al. NEJM 2012;367:1237-1244, Kamar N et al. Lancet 2012;379:2477-2488 and Dalton HR et al. Nat Rev Neurol 2016;12:77-85.
The Challenge of Hepatitis E
l Suspected in the late 1970ies1, discovered in 19832 and cloned in 19903
l Family Hepeviridae, genus Orthohepevirus4
l Non-enveloped virus, resistant capsid, 7.2-kb (+)-strand RNA genome
l One serotype, four major genotypes 1Khuroo MS. Am J Med 1980;68:818-824 | 2Balayan MS et al. Intervirology 1983;20:23-31 |
3Reyes GR et al. Science 1990;247:1335-1339 | 4Smith DB et al. JGV 2017, in press. Reviewed in Emerson SU and Purcell RH. In: Fields Virology, 6th ed, 2013,
pp. 2242-2258 and Debing Y et al. J Hepatol 2016;65:200-212.
Hepatitis E Virus Capsid
RNA
32-34 nm
The Expanding Hepeviridae Family
Debing Y et al. J Hepatol 2016;65:200-212.
Green A. Lancet 2017;390:443-444.
Hepatitis E in Europe ECDC Surveillance Report 2005-2015
https://ecdc.europa.eu/en/hepatitis-e.
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Kupferschmidt K. Science 2016;353:862-863 | See also Lancet 2017;390:334. Müller A et al. Int J Food Microbiol 2017;242:107-115 | Schnegg A et al. PLoS One.
2013;8:e62980 | Niederhauser C et al. Vox Sang 2016;111 (Suppl 1):305. Moradpour D and Frossard J-L. Rev Med Suisse 2017;13:1451-1452 and refs. therein.
l 300,000 new cases per year estimated in Germany ...
l ... and 100,000 in the UK
l 1500 to 10,000 or more new cases per year in CH
l Mean seroprevalence in Swiss domestic pigs 58.1%
l 1.3% of Swiss pig livers HEV RNA-positive
l Mean seroprevalence in Swiss blood donors ~20% (4.2-21.8% in VD, 33.6% in TI)
Switzerland
??
SheepBatCowChickenRabbitRat
PigWild boarDeerCamel
Blood orBlood products
Dire
ct tr
ansm
issio
n
Mussels
Sewage
Food consumption
Run-off fromfarms and land
Irrigation
Crops
Adapated from Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514.
Symptoms
0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks
Anti-HEV IgM
Anti-HEV IgG
ALT
HEV in stool
Viremia
Acute Hepatitis E
Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514.
Hepatitis E Diagnosis
Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514.
l Broad spectrum of liver disease severity: asymptomatic - mild hepatitis - liver failure1
l Extrahepatic manifestations2,3 l High fatality rate in pregnant women (gt 1)4
and patients with underlying liver disease l Autochthonous acute hepatitis E "hides"
in drug-induced5 and other liver injuries l Chronic hepatitis and cirrhosis in immuno-
compromised patients6,7
1Manka P et al. CGH 2015;13:1836-1842 | 2Dalton HR et al. NRN 2016;12:77-85 | 3Pischke S et al. J Hepatol 2017;66:1082 | 4Krain LJ et al. AJTMH 2014;90:365 |
5Davern TJ et al. Gastroenterology 2011;141:1665-1672 | 6Kamar N et al. NEJM 2008;358:811-817 | 7Kamar N et al. NEJM 2014;370:1111-1120.
Clinical Manifestations of Hepatitis E
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1 2 3 4 5 62011 2013 2012 2015 2014 2016
Positive samples Negative samples
Num
ber o
f sam
ples
test
ed
Year
PCR Analyses for HEV RNA Performed at the CHUV
Fraga M et al. Liver Int, in press (epub Aug 23, 2017).
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l 110 HEV RNA-positive cases of hepatitis E
102 autochthonous (gt 3 or 4)
8 travel-related (gt 1 or 4)
93 acute 9 chronic
Hepatitis E in Switzerland The CHUV Experience
Fraga M et al. Liver Int, in press (epub Aug 23, 2017).
l Median HEV RNA 7.5 x 104 IU/ml (5.3 to 4.7 x 107 IU/ml)
l HEV gt 3 in 75 and gt 4 in 3 patients (undeterm. in 15)
l Fourty-nine patients (53%) presented with jaundice; median peak ALT 1378 U/l (range, 80-5001 U/l)
l Symptomatic cases were predominantly middle-aged or elderly men (71/93 [76%] men | 49/71 [69%] ≥ 50 yrs)
l Particularly severe courses in patients with pre-existing chronic liver disease (two †)
l Six patients (7%) with neuralgic amyotrophy and several with severe myalgia
Acute Hepatitis E Acquired in Switzerland The CHUV Experience
Fraga M et al. Liver Int, in press (epub Aug 23, 2017).
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* Temporal and geographical clusters
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gt 4
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Acute Hepatitis E Acquired in Switzerland The CHUV Experience
Fraga M et al. Liver Int, in press (epub Aug 23, 2017).
Hepatitis E Neurologic Complications
l Develop in ~5% of autochthon. cases l Neuralgic amyotrophy (brachial neuritis,
Parsonage-Turner syndrome)1,2
l Guillain-Barré syndrome, meningo-encephalitis and likely others
l Hepatitis usually mild l Include hepatitis E early in diagnostic
algorithm! 1van Eijk JJ et al. Neurology 2014;82:498-503.
2van Eijk JJ, Dalton HR, Ripellino P et al. Neurology 2017;89:909-917. Reviewed in Dalton HR et al. Nat Rev Neurol 2016;12:77-85.
Courtesy of Paolo Ripellino and Claudio Gobbi
• 57 HEV + compared to 61 HEV cases • Bilat. involvement 80.0 vs. 8.6% (p < 0.001) • Damage outside brachial plexus
58.5 vs. 10.5% (p < 0.01)
Hepatitis E Neurologic Complications
l Develop in ~5% of autochthon. cases l Neuralgic amyotrophy (brachial neuritis,
Parsonage-Turner syndrome)1,2
l Guillain-Barré syndrome, meningo-encephalitis and likely others
l Hepatitis usually mild l Include hepatitis E early in diagnostic
algorithm! 1van Eijk JJ et al. Neurology 2014;82:498-503.
2van Eijk JJ, Dalton HR, Ripellino P et al. Neurology 2017;89:909-917. Reviewed in Dalton HR et al. Nat Rev Neurol 2016;12:77-85. Kamar N et al. N Engl J Med 2008;358:811-817.
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Chronic Hepatitis E l Immunosuppressed patients (transplant
recipients, hematologic cancer, HIV, ...) l HEV genotype 3 (as well as 4 and 7) l May rapidly progress to liver cirrhosis l Serology often negative ! HEV RNA l Reduction of immunosuppr. ! RBV l RBV resistance emerges as a challenge
! need for new therapeutic options Kamar N et al. NEJM 2008;358:811-817 and 2014;370:1111-1120; Debing Y et al. J Hepatol.
2016;65:499; Todt D, Gisa A et al. Gut 2016;65:1733 | Reviewed in Kamar N et al. Lancet. 2012;379:2477; Behrendt P et al. J Hepatol 2014;61:1418-1429; Gouttenoire J et al.
Gut 2016;65:1583 and Todt D et al. Viruses 2016;8:283.
1Hogema BM et al. Transfusion 2016;56:722-8 | 2Sauleda S et al. Transfusion. 2015;55:972-9 | 3Baylis SA et al. Vox Sang 2012;102:182-3 | 4Hauser L et al. Blood 2014;123:796-7 |
5Mallet V et al. Ann Intern Med 2016;164:851-2 | 6Gallian P et al. EID 2014;20:1914-7 | 7Hewitt PE et al. Lancet 2014;384:1766-73.
Domanovic D et al. Euro Surveill 2017;22:30514.
HEV in the Blood Supply l Prevalence of HEV RNA-positive blood
donations ~1:2000 (1:7261 - 1:3,3332) l 10% of plasma fractionation pools + 3 l Current inactiv. procedures inefficient4,5
l Most viremic donors neg. for anti-HEV6,7
l Level and duration of viremia variable l UK: 79 of 225'000 (1:2848) donations +
! 18/43 recipients (42%) infected7
l Hepatitis E represents a major global health challenge
l Two patterns of hepatitis E l Broad and evolving spectrum of clinical
manifestations l Varying sensitivity and specificity of
serologic assays l Chronic hepatitis in immunosuppressed
patients (gt 3)
Conclusions l Improved understanding of the molecular
virology and pathogenesis l Optimization and standardization of
diagnostic assays l Deeper insight into the epidemiology of
autochthonous hepatitis E l Further delineation of clinical phenotype l Implementation of preventive measures l Implications for blood supply
Challenges
The CHUV Hepatitis E Aficionados l Basic research
Viet Loan Dao Thi and Jérôme Gouttenoire l Seroprevalence studies
Katharine E.A. Darling and Matthias Cavassini l Serologic diagnostics
Vincent Aubert and Giuseppe Pantaleo l Molecular diagnostics
Roland Sahli, Amalio Telenti and Gilbert Greub l Clinical epidemiology and management
Montserrat Fraga and Christopher Doerig l Neurology
David Benninger and Thierry Kuntzer
Alessio Aghemo Hepatitis C
Cristina Marcu and Andreas Cerny Tough hepatitis cases
Charles M. Rice Hepatitis B
Heiner Wedemeyer Hepatitis E
10th Challenges in Viral Hepatitis CHUV, January 18, 2018
www.gastro-hepato.ch