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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?