Locally Acquired Hepatitis E Infections

Roger Sanchez B.S.Epidemiologist

San Antonio Metropolitan Health District

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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 systemIndian j. med. Res. 1957; 45 (supp. 1): 1-29

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• 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

Background: 1995 - 1999

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Geographic Distribution of HEV

Outbreaks or Confirmed Infection in >25% of Sporadic Non-ABC Hepatitis

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Hepatitis E - Clinical Features

Incubation period:

Clinical illness:

Symptomatic illness:

Severity of illness:

Ratio of Symptomatic toAsymptomatic Infection

Mean: 40 daysRange:15-60 days Asymptomatic symptomatic

Increases with age

Increases with age

Not well documentedReported 1:2 to 1:13

Cannot be clinically distinguished from other forms of viral hepatitis (A, B, C)

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

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Epizootiology

• Antibodies (anti-HEV) in many species, including:– Swine– Cattle, sheep, goats, camels– Rodents– Dogs, cats– Chickens

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Is endemic HEV (genotype 3) in developed countries a foodborne

illness?Year Country Association

[cases]

2001-2 Japan [10] (undercooked) pig liver consumption2001-4 Japan [32] (raw/rare) pig liver/intestine2001 Moldova 51.1% in swine workers (vrs 24.7%) 2003 Denmark anti-HEV 50.4% in farmers;

but 20.6% in blood donors 2001-6 Hungary recovered from liver of boar/pig2006-7 Germany [45] offal/wild boar consumption

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Swine HEV in PigsSwine HEV in Pigs

Anti HEV HEV RNA

% (range) % (range)

USA 63 (0-100) n=273 35 n=36

Nepal 33 n=55 6 n=47

China 31 (24-43) n=72 10 (1-20) n=263

Taiwan 37 n=275 3 n=810

India 64 (43-95) n=234 8 (5-11) n=341

Korea 41 (15-60) n=140 2 n=128

Japan 44 (7-90) n=2500 7 (0-15) n=1360

Pig livers (packed) in U.S. grocery stores: 11%Pig livers (packed) in U.S. grocery stores: 11% n=127 ( Feagins AR et al. J Gen Virol 2007;88:912-7 )

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Prevalence of anti-HEVVariable N % Positive (95% CI)Country of birth US (reference) 15 051 20.1 (18.1, 22.0) Mexico 2 357 30.9 (28.9, 32.9)* Other 1 233 26.2 (22.9, 29.5)*Region of residence South (reference) 8 168 14.7 (12.3, 17.0) Northeast 2 372 20.8 (16.5, 25.1)* Midwest 3 655 26.6 (22.4, 30.8)* West 4 500 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

• 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.

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Prevalence of Anti-HEV – U.S. Workerswith Exposure to Swine

0%

10%

20%

30%

40%

20 30 40 50 60 70

Age (Years)

An

ti-H

EV

Po

sit

ive

Swine Veterinarians

Blood Donors

8 U.S. States(Meng XJ. J Clin Micro 2002; Antigen: SAR-55)

0%

2%

4%

6%

8%

SwineWorkers

Non-SwineWorkers

North Carolina, U.S.-Born Workers

(Withers MR. Am J Trop Med Hyg 2002)

Among veterinarians, no association between anti-HEV and measures of swine exposure

Sequence Analysis of HEV Sequence

• HEV sequence from case # 2 belong to genotype 3 with 98% similarity to US-2 Swine

HEV-3

Ct1M1

P2

I3I2Np1B2

B1

I1C1

C4C2 C3

P1

US1

US-Swine JRA

Genotype 1

Genotype 2

Kyrgyz Swine HEV

Genotype 3

Genotype 4

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 #1Date of blood collection

IgM anti -HEV scr*

IgG anti-HEV scr*

HEV RNA

9/5/2009

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.

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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

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* HEV RNA

9/5/2009 2.6 3.7

9/16/2009 3.1 3.7

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

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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 HEV-

like viruses– Low-dose exposures lead to sub-clinical infection– Genotype III HEV not as virulent – Cross reaction of serologic tests

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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

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?

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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.

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?