Download Sanchez-HepatitisEUpdate - Texas Department of State Health

Locally Acquired Hepatitis E Infections
Roger Sanchez B.S.
Epidemiologist
San Antonio Metropolitan Health District
First Recognized Outbreak of Hepatitis E
New Delhi, India, 1955-56
 29,300 cases acute jaundice (population 1.6 million)
 Estimated 67,000 non-jaundiced cases
 Infection linked to drinking water from municipal
water system contaminated by sewage
 Case-fatality rate among pregnant women: 10.5%
 At the time, considered as a waterborne hepatitis A
outbreak that “overpowered” immune system
Indian j. med. Res. 1957; 45 (supp. 1): 1-29
2
Background: 1995 - 1999
• Significant HEV seroprevalence is seen in developed countries
• Anti-HEV IgG detected in Nepali pigs
• A third HEV genotype is detected in the United States
• HEV genotype 3 is isolated from (feral) pigs in the US
• HEV serologic tests are compared and found to vary markedly
3
Geographic Distribution of HEV
Outbreaks or Confirmed Infection in >25%
of Sporadic Non-ABC Hepatitis
4
Hepatitis E - Clinical Features
Incubation period:
Clinical illness:
Mean: 40 days
Range:15-60 days
Asymptomatic
symptomatic
Symptomatic illness:
Increases with age
Severity of illness:
Increases with age
Ratio of Symptomatic to
Asymptomatic Infection
Not well documented
Reported 1:2 to 1:13
Cannot be clinically distinguished
from other forms of viral hepatitis (A, B, C)
5
Epidemiology Comparison with HAV
• Similarities to hepatitis A
– Fecal-orally transmitted
– Incubation period: 2-12 weeks
• Differences with hepatitis A
– Relatively poorly transmitted person-to-person
• Low rates of within-household transmission
• Many adults remain susceptible
– Outbreaks: water-borne transmission rather
than person-to-person
– Zoonotic transmission
Epizootiology
• Antibodies (anti-HEV) in many species,
including:
– Swine
– Cattle, sheep, goats, camels
– Rodents
– Dogs, cats
– Chickens
7
Is endemic HEV (genotype 3) in
developed countries a foodborne
illness?
Year
Country
[cases]
2001-2
2001-4
2001
2003
Japan [10]
Japan [32]
Moldova
Denmark
2001-6
2006-7
Association
(undercooked) pig liver consumption
(raw/rare) pig liver/intestine
51.1% in swine workers (vrs 24.7%)
anti-HEV 50.4% in farmers;
but 20.6% in blood donors
Hungary
recovered from liver of boar/pig
Germany [45] offal/wild boar consumption
8
Swine HEV in Pigs
Anti HEV
% (range)
USA
Nepal
China
Taiwan
India
Korea
Japan
63 (0-100)
33
31 (24-43)
37
64 (43-95)
41 (15-60)
44 (7-90)
HEV RNA
% (range)
n=273
n=55
n=72
n=275
n=234
n=140
n=2500
35
6
10
3
8
2
7
n=36
n=47
(1-20)
n=263
n=810
(5-11)
n=341
n=128
(0-15)
n=1360
Pig livers (packed) in U.S. grocery stores: 11%
( Feagins AR et al. J Gen Virol 2007;88:912-7 )
n=127
9
Prevalence of anti-HEV
Variable
Country of birth
US (reference)
Mexico
Other
Region of residence
South (reference)
Northeast
Midwest
West
N
% Positive (95% CI)
15 051
2 357
1 233
20.1 (18.1, 22.0)
30.9 (28.9, 32.9)*
26.2 (22.9, 29.5)*
8 168
2 372
3 655
4 500
14.7 (12.3, 17.0)
20.8 (16.5, 25.1)*
26.6 (22.4, 30.8)*
25.0 (20.9, 29.1)*
* p < 0.05 compared to reference group
18,695 serum samples from The National Health and Nutrition Examination Survey (NHANES), 1988-1994
11
• Four HEV genotypes have been identified
to date. While genotypes 1, 2, and 4 have
been causing epidemics in developing
countries, genotype 3 is causing sporadic
disease in the US, Europe and Japan.
• Since HEV genotype 3 has shown high
similarity to the HEV isolated from swine,
raising the existence of potential zoonotic
reservoirs for HEV.
Anti-HEV Positive
Prevalence of Anti-HEV – U.S. Workers
with Exposure to Swine
8 U.S. States
North Carolina, U.S.-Born Workers
(Meng XJ. J Clin Micro 2002; Antigen: SAR-55)
(Withers MR. Am J Trop Med Hyg 2002)
40%
8%
30%
6%
20%
4%
10%
2%
Swine Veterinarians
Blood Donors
0%
0%
20
30
40
50
60
70
Swine
Workers
Non-Swine
Workers
Age (Years)
Among veterinarians, no association between
anti-HEV and measures of swine exposure
14
Sequence Analysis of HEV Sequence
HEV-3
JRA
US-Swine
Kyrgyz
Swine HEV
US1
Genotype 3
Genotype 2
Genotype 4
M1
Ct1
Genotype 1
P2
I3
I2
Np1 B2
•
B1
P1
I1
C1
C4
C2 C3
HEV sequence from case # 2 belong to genotype 3 with 98% similarity to US-2 Swine
HEV Investigation
• A total of three patients with acute
hepatitis were diagnosed with HEV
infection in San Antonio were reported to
the Texas DSHS by reference laboratories
and admitting hospital.
• All three patients were diagnosed with
hepatitis E infection between September
and November 2009 and were admitted to
the same hospital.
HEV Investigation
• Case #1 21-year-old Hispanic female was
admitted 9-3- 09 to local hospital. The patient
died on10-2-09 two months before the
investigation.
• Case #2 44-year-old Hispanic woman admitted
on 9-03-09 same hospital because of jaundice.
• Case #3 53-year-old white male admitted to
same on 11-02-09 because of lethargy and
altered mental status, weight loss, decreased
appetite and increased abdominal distention.
Case #1
• Due to the fulminant liver failure, she was placed
on the liver transplant list by mid-September
2009. However, on October 2, 2009, during the
transplant operation, she went into cardiac
arrest resulting from a cardiac embolus and
died.
• Liver biopsy showed “severe hepatitis”
• Her tests were only partially confirmed by CDC
– IgG negative,, RNA negative, IgM positive
Case #1
Date of blood
collection
9/5/2009
IgM anti -HEV
scr*
IgG anti-HEV
scr*
HEV RNA
2.2
1.6
Not detected in
stool specimen
Liver biopsy was compatible with viral
hepatitis or other form of immunologic
reaction.
Pregnancy test (home) was positive in July
but test was negative at hospital.
Hepatitis E in Pregnant Women
• Hepatitis E more severe among pregnant women
– higher attack rate
– more severe illness (fulminant hepatitis)
– higher mortality
• Spontaneous abortions and stillbirths relatively frequent
• Vertical transmission is common with 3rd trimester
20
Case # 2
• 44-year-old Hispanic woman admitted on
September 3, 2009 because of jaundice. At the
end of August 2009, she noticed jaundice and
dark urine.
• She denied nausea, vomiting, abdominal pain,
diarrhea or fever.
• Physical exam revealed icteric sclera and
laboratory tests showed elevated liver enzymes
Case # 2
Date of blood
collection
IgM anti HEV scr*
IgG anti-HEV scr*
9/5/2009
2.6
3.7
9/16/2009
3.1
3.7
HEV RNA
Positive. Genotype 3
isolated from stool
(98% homology to the
US-2 swine isolate).
Case # 2
• Liver biopsy on September 10, 2009
showed evidence of severe hepatitis with
some necrosis.
• Pt was a nurse’s aid, and her tasks
included changing diapers and washing
residents.
• Household and family contacts were all
negative.
Case #3
• Case-patient 3 is a 53-year-old white man
admitted to same hospital on November 12,
2009 because of lethargy and altered mental
status. His wife reported an increase in leg
swelling, weight loss, decreased appetite and
increased abdominal distention
• IgM was postive IgG negative for HEV- done by
reference lab, not CDC
• CDC’s results were all negative
• Case was dismissed- cancer
Why such a high prevalence of anti-HEV
in the United States,
Where acute HEV is rare?
• Currently considered hypothesis:
– Widespread but low level exposure to HEV or HEVlike viruses
– Low-dose exposures lead to sub-clinical infection
– Genotype III HEV not as virulent
– Cross reaction of serologic tests
25
What could be possible exposures?
• Exposure to pets
• Anti-HEV is found in many animals but HEV RNA is rarely detected
• Pets may be dead-end hosts
• Travel
• Significant association of anti-HEV with foreign birth
• Food-borne
• Consistent with other studies organ meat consumption associated with
anti-HEV
• Other routes of exposure
• Association with anti-HCV and anti-HBc – IVDU transmission?
• Cocaine & crack use not associated with anti-HEV
26
Remaining Questions
• Where do sporadic acute cases of HEV
come from?
• Why are they acute?
• What is the true prevalence of HEV
infection in the US, and what is the
source of infection?
• What can we do to get more
information on the epidemiology of
HEV in the US?
Performance of Available Anti-HEV
Tests
• Acute disease, endemic areas– probably high
sensitivity and positive predictive value
• Acute disease, non-endemic regions • Seroprevalence studies – needed
• Problem – high discordance among tests,
between reference labs and CDC tests.
28
Facts/Conclusions
•
•
•
•
HEV infections are definitely occurring in the US
Domestic and feral pigs are infected
It is a zoonotic disease
People have been infected by eating raw pig livers or undercooked
livers
– Are there other ways of contracting HEV from feral pigs?
• Commercial pig livers have been found to be infected
• How many infections occur as a results of zoonotic transmission?
• More HEV awareness by physicians patients with hepatitis
symptoms that are A,B,& C negative.
• Test feral pig hunters?
• Deer hunters?