Revue of the literature of MC cases associated with HEV infection

1. Mixed cryoglobulinemia related to
chronic HEV infection
Samir Haffar
Gastroenterologist

2. Growing interest in HEV infection
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0
50
100
150
200
250
300
350
127
103
140
175 185
229 230
263
293
319
Number of publications on “hepatitis E” indexed
in PubMed over the last decade

3. Worldwide prevalence of HEV
Endemic regions of hepatitis E
where >25% of acute viral hepatitis is due to HEV
Wedemeyer H et al. Gastroenterology2012;142:1388-1397.

4. Global Burden of HEV
Genotypes 1 and 2 in 2005
• Methods Annual disease burden of G1 & 2 for 9 of 21 regions
Represent 71% of world’s population
Defined for Global Burden of Diseases, Injuries, and
Risk Factors Study (the GBD 2010 Study)
• Results Incident 20.1 million 95% Cr.I.: 2.8-37.0
Symptomatic3.4 milliom 95% CrI: 0.5-6.5
Death 70.000 95% CrI: 12,400-132,732
Stillbirths 3.000 95% CrI: 1,892 – 4,424
CrI: Credible Interval
Rein DB et al. Hepatology 2012;55:988-997.

5. Genomic organization of HEV
Zakim & Boyer hepatology 2012 – 6th edition.
Short untranslated regions (UTR) at both ends
Three open reading frames (ORFs)
ORF1: encodes nonstructural polyprotein (nsp)
ORF2: encodes the viral capsid protein
ORF3: encodes small regulatory phosphoprotein

6. Genotypes of HEV
• HEV is classified into four major genotypes
• All four genotype represent a single serotype
which has facilitated efforts to develop hep E vaccines

7. HEV infections according to genotype
Characteristic Genotypes 1 and 2
Epidemic
Genotypes 3 and 4
Autochthonous
Distribution Developing countries Developing & developed countries
Pattern of spread Epidemic & sporadic Sporadic
Species Human Swine, human
Mode of spread Waterborne Foodborne
Icteric illness High Low
Age Adolescents & young older
Sex M = W Higher in men
Mortality High in pregnancy High in older
Extra-hepatic features Few Neurologic
Chronic infection None In immunosuppressed patients
Therapy None known Ribavirin, PEG-IFN
Prevention Vaccine Vaccine
Hoofnagle JH et al. N Engl J Med 2012;367:1237-44 .

8. Geographic distribution of different HEV genotypes
Kamar N et al. Hepatitis E (seminar). Lancet 2012;379:2477–88.

9. Hepatic manifestations of Hepatitis E
• Inapparent or asymptomatic infection
• Anicteric hepatitis: biochemical abnormalities–no jaundice
• Icteric hepatitis: similar to other forms of viral hepatitis
• Severe hepatitis: leading to fulminant hepatic failure
• Acute-on-chronic liver disease
• Chronic hepatitis
Most HEV infections have clinically silent course

10. • Incubation period 3 – 8 weeks
• Prodromal phase Short
• Symptoms or jaundice Days to several weeks
• Most cases are self-limited
• Case fatality rate 1 – 2%
25% in 3rd trimester pregnancy
Hoofnagle JH et al. N Engl J Med 2012;367:1237-44 .
Icteric acute hepatitis E
Similar to other forms of viral hepatitis

11. Chronic hepatitis E
It came as surprise when it was described
• First reported in 2008
• Immuno-compromised : Transplant recipients
HIV infection
Hematological diseases
• Genotype 3 only Not reported in other genotypes
• Liver histology Fibrosis & in some cases cirrhosis
Kamar N et al. N Engl J Med 2008;358:811-817.
Rare cases of chronic HEV infection in immunocompetent patients

12. Anti-HEV IgG
ALT
HEV RNA blood/stool
Diagnosis of chronic hepatitis E
Persistence of HEV RNA in blood and/or stool > 6 months
Wedemeyer H, Pischke S, Manns MP. Pathogenesis and treatment of hepatitis E virus infection.
Gastroenterology 2012;142:1388-1397.

13. HEV 239 vaccine – Hecolin®
Phase III – Double blind placebo-controlled RCT
• 112 604 healthy subjects, men & women, 16 – 65 years
• Compagny: Xiamen Innovax Biotech – China
• Randomization: HEV vaccine versus HBV vaccine
• Primary end-point: prevention of clinically overt HEV infection
• Genotype 1 & 4 prevalent – Predominant genotype 4
• 30 μg IM at 0, 1, 6 months
• Follow-up period: 13 month post-vaccination
• Efficacy after 3rd dose: 100%
• No side effects
Zhu FC et al. Lancet 2010;376:895-902.

14. In December 2011,
the China Food & Drug Administration
approved the hepatitis E vaccine Hecolin®
for use in subjects ≥ 16 year old
Haffar S, Bazerbachi F, Lake JR. Making the case for the development of a vaccination against
hepatitis E virus. Liver international 2014 (in press)

15. Hecolin®
Xiamen Innovax Biotech – China

16. • Acute pancreatitis
• Neurological syndromes Guillian-Barre syndrome
Meningoencephalitis
Pseudotumor cerebri
Cranial nerve palsies
Bilateral pyramidal syndrome
Peripheral neuropathy
• Hematological manifestations Thrombocytopenia, hemolysis
• Renal manifestations Membranous glomerulonephritis
± Mixed cryoglobulinemia (MC)
Extra-hepatic manifestations of HEV infection (rare)
Aggarwal R & Shahid J. Hepatology 2011;54:2218-2226.
Mostly as case reports or small case series
Based usually on detection of anti-HEV IgM rather than HEV RNA

17. Viral causes of mixed cryoglobulinemia
Relative frequency Responsible viruses Remarks
Most frequent cause Hepatitis C virus 30 - 90% of MC cases
Less frequent causes Human Immunodeficiency virus
Hepatitis B virus
Infrequent causes Hepatitis A virus
Cytomegalovirus
Parvovirus B-19
Epstein-Barr virus
Chikungunya virus
Hantavirus
case reports
Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias.
Lancet. 2012 Jan 28;379:348-60.

18. Classification of cryoglobulinemia
Types % Monoclonal Polyclonal Associated diseases
Type I 10-15 Monoclonal
IgM or IgG
– Lymphoproliferative
disorders
Type II
‘also called MC’
50-60 Monoclonal
IgM
Polyclonal
IgG
Infections (mainly HCV)
Autoimmune disorders
Lymphoproliferative
disorders
Type III
‘also called MC’
30-40 – Polyclonal
IgM & IgG
Often autoimmune disorders
Infections (mainly HCV)
Ferri C. Mixed cryoglobulinaemia. Orphanet J Rare Dis 2008; 3: 25.

19. Clinical manifestations of MC
• Asymptomatic
Many patients remain asymptomatic
• Cryoglobulinemic disease or cryoglobulinemic vasculitis
Circulating cryoglobulins and typical organ involvement
Mainly skin, kidney or peripheral nervous system
Mild in half, moderate to severe in 1/3, and life-threatening in 15%
• Life-threatening cryoglobulinemia
Glomerulonephritis & RF, gastrointestinal vasculitis, pulmonary
hemorrhage, CNS involvement, & myocardial involvement
No standardized classification of disease severity
Usually based on personal experience and expert opinions
Ferri C. Mixed cryoglobulinaemia. Orphanet J Rare Dis 2008;3:25.

20. Triad of MC
• Purpura
• Arthralgia
• Weakness
Reported in 80% of patients at disease onset

21. Purpura in mixed cryoglobulinemia
Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias.
Lancet 2012 Jan 28;379:348-60.

22. Published cases of MC related to HEV infection
• Marson 1 case with co-infection with HCV
1995 HEV RNA not documented – Probable case
• Kamar 8 cases
2012 HEV RNA documented – Genotype 3
Symptoms during active infection
• Pischke 1 case
2014 HEV RNA documented – Genotype not mentioned
Symptoms developed after HEV clearance
Marson P et al. Hematologica 1995;80:574-575.
Kamar N et al. Transplantation 2012; 93 (6):617-623.
Pischke S et al. The Lancet Infection Diseases 2014;14:678-9.

23. 9 documented cases of MC related to chronic HEV
Kamar N et al. Transplantation 2012; 93 (6):617-623.
Pischke S et al. The Lancet Infection Diseases 2014;14:678-9.
Authors
Country
N Age/sex Co-
morbidity
MC Chronic hepatitis E
type manifestations dg GT treatment outcome
Kamar
France
8 NM organ
transplants
II-III GN1 – NS2 RNA 3 IFN/riba recovery
Pischke
Germany
1 35/M liver
transplant
III arthralgia- rush
Myalgia - ↑ CK
thrombocytopenia
RNA NM steroid death
mucositis
(1) glomerulonephritis – (2) NS: nephrotic syndrome – NM : not mentioned

24. MC related to HEV infection
• 9 documented cases
• Chronic hepatitis in all patients
• All Immunosuppresed (SOT)
• All from Western Europe
• Genotype 3 confirmed in 8 cases
• All MC type II or III

25. Treatment of MC related to HEV infection
• Kamar 3 months after end of Peg IFN or ribavirin
HEV clearance achieved in all patients
Negativity of cryoglobulinemia in all patients
SVR not documented
• Pischke HEV clearance after dose reduction of IS
Symptoms appears after viral clearance
Improved with steroids & re-increase of IS
2 relapses after corticosteroids reduction
During 2nd relapse: severe fatal intestinal mucositis
Kamar N et al. Transplantation 2012; 93 (6):617-623.
Pischke S et al. The Lancet Infection Diseases 2014;14:678-9.

26. Conclusion
• 9 documented cases of HEV-related MC
HEV should be added to other viral infections causing MC
• All patients have chronic hep E, are immunosuppressed (SOT),
& originate from Western Europe where genotype 3 is prevalent
• Antiviral or immunosuppressive treatment, depending on the
presence or absence of viral replication, is effective in all cases
• Further studies needed to confirm theses preliminary data

27. Thank You