Three and one cases of anti-HEV IgM positivity were detected among employees of a food manufacturing facility during annual health examinations for employees on April 13 and April 20, , respectively. All of these first-detected four cases were asymptomatic. The infectious disease control center in the provincial government subsequently initiated an epidemiological investigation of the presumed HEV outbreak on April 26. The subjects of the investigation were 646 employees working at the facility, including at a production plant, research company, and contractor-in-charge of cleaning or washing from February 1 to April 26, , considering the incubation period of HEV infection. Epidemiological investigators requested serum anti-HEV IgM testing for all employees. Fifteen testing rounds were subsequently performed from April 21 to May 20, identifying a total of 24 cases of anti-HEV IgM positivity. On-site investigations were conducted by epidemiological investigators from Gyeonggi Province, the health center, and sanitation departments of the city. Epidemiological data, such as demographic and clinical characteristics of the employees, meal intake history, and environmental factors, were obtained from company records and interviews with workers. This study was approved by the IRB of Seoul National University Bundang Hospital (IRB number: X--781-902), and the need for informed consent was waived due to the retrospective research design.
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Currently, the only approved anti-HEV IgM testing kit in South Korea is the enzyme-linked immunosorbent assay produced by AB Diagnostic System GmbH (Berlin, Germany), abia HEV IgM. Among the 24 cases of anti-HEV IgM positivity, 17 obtained on May 6 and May 9 were tested for HEV RNA using the PowerCheck HEV virus qRT-PCR kit (Kogene Biotech, Seoul, Korea), which included primers and probes with HEV genome sequences in the ORF2/3 region. Environmental samples were obtained from the facility and tested for HEV RNA by qRT-PCR using TaqMan analysis with primers and probes targeting the ORF 2/3 region. These samples included groundwater, common items, water purifiers, raw and complete food products, cooking utensils, and preserved food materials, especially meat and shellfish, in the cafeteria for employees (May 4 to 9). The factory operated a closed production system, meaning no direct contact with the raw materials of products for employees.
Only the employees used one cafeteria in the factory. The intake of the group meal was traced using the meal card tagging system data from February 1 to April 26, the presumed incubation period of the HEV. The meal intake group was defined as those who ate meals at least once in the cafeteria that served four meals per day (breakfast, lunch, dinner, or late-night meals; n=508), while those who never used the cafeteria were defined as the non-intake group (n=138). Comparison of anti-HEV IgM positivity between the meal intake and non-intake groups was shown as the relative risk (RR), and statistically significant data were included as variables for further univariate and multivariate analyses to identify factors associated with anti-HEV IgM positivity.
Using COVID-19 information and the vaccination management system operated by the Korea Disease Control and Prevention Agency, we analyzed the COVID-19 infection and vaccination statuses of 576 employees among a total of 646 subjects. The COVID-19 infection rates within 90 days prior to anti-HEV testing between the anti-HEV IgM-positive and -negative groups were subsequently compared. Additionally, COVID-19 vaccination rates and vaccine types were compared between the anti-HEV IgM-positive and -negative groups. Univariate and multivariate analyses were performed to determine whether these variables were independent factors affecting the HEV antibody positivity.
The epidemiological characteristics of the groups are descriptively presented as frequencies for nominal variables and median and interquartile range or mean and standard deviation for continuous variables. The Fisher exact test for nominal variables and the Mann-Whitney U test for continuous variables were used for comparison between the two groups. Comparisons between anti-HEV IgM positivity in a specific day meal intake group and non-intake group were analyzed using RR. Univariate and multivariate analyses were performed using logistic regression to identify independent variables related to anti-HEV IgM positivity, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. Statistical analysis was performed using R (version x64 4.0.5; R Foundation for Statistical Computing, Vienna, Austria) and SPSS version 21 (IBM Corp., Armonk, NY, USA), and p<0.05 was considered statistically significant.
Among 646 employees, the HEV-IgM positivity rate was 3.7% (n=24). In-depth interviews with the 24 employees showed that eight people had a history of eating undercooked meat or salted fish/shellfish (beef tartare in four, salted and fermented squid in four, salted pollack roe in one, and salted small octopus in one person). However, none of the patients showed symptoms of hepatitis. None visited the health management office in the facility or clinic because of hepatitis-related symptoms during the study period, which was confirmed by checking the Drug Utilization Review system. Eight patients had a history of hypertension or diabetes, and one person had been diagnosed with liver cirrhosis. Among the 10 patients who were tested for alanine aminotransferase, three showed mildly elevated alanine aminotransferase levels (45, 59, and 98 IU/L) (Table 1). Also, none of the anti-HEV IgM positivity cases showed hepatitis A virus infection in their test result, likewise four employees who tested positive for hepatitis A virus showed no HEV infection. There were no differences in terms of age, sex, affiliated workplace, and occupation between the anti-HEV positive and negative groups, as shown in Table 1. The median age was 42.5 years, 76.5% were men, and anti-HEV IgM positivity was not concentrated in a specific workplace.
Serum HEV RNA was negative in 17 employees with anti-HEV IgM positivity. The blood sampling interval between anti-HEV and HEV RNA testing ranged from to 3&#;15 days. Moreover, HEV-RNA was not detected in any of the environmental samples, including six samples collected from water purifiers, washing water, and common objects in the factory; seven samples from groundwater wells used for washing equipment; and four from raw materials and products.
During the study period, four out of 340 meals (1.2%) showed a significantly higher proportion of anti-HEV positivity in the meal intake group than in the non-intake group (Table 2). The detailed menu of the four meals is as follows: stir-fried pork kimchi (lunch on February 2: RR, 3.95; 95% CI, 1.38 to 11.34), braised pork ribs, chicken fillet (dinner on February 14: RR, 3.21; 95% CI, 1.31 to 7.85), pork cutlet (dinner on February 17: RR, 3.55; 95% CI, 1.24 to 10.21), and fried chicken (dinner on February 18: RR, 3.78; 95% CI, 1.32 to 10.86), although all dishes were completely cooked by boiling or deep frying. HEV-anti-IgM test results were negative for all nine food handlers.
Table 2. Summary of Significantly Higher RRs of Anti-HEV Positivity in the Eaters of Institutional Group Meals Compared to the Non-eaters
DateTypeExposed (eaters)Unexposed (non-eaters)RR (95% CI)p-valueSubtotalAnti-HEV IgM+Prevalence rateSubtotalAnti-HEV IgM+Prevalence rateFebruary 2Lunch..53.95 (1.38&#;11.34)0.02February 14Dinner..93.21 (1.31&#;7.85)0.02February 17Dinner..53.55 (1.24&#;10.21)0.04February 18Dinner..53.78 (1.32&#;10.86)0.03RR, relative risk; HEV, hepatitis E virus; IgM, immunoglobulin M; CI, confidence interval.
Among the 24 HEV antibody-positive and 522 HEV IgM-negative employees, COVID-19 infection and vaccination before anti-HEV testing were investigated using the national COVID-19 management system. We identified no significant difference in the cumulative COVID-19 infection rate (45.8% vs 40.9%) or 90-day COVID-19 infection rate before anti-HEV testing (29.2% vs 35.5%) between the anti-HEV IgM-positive and -negative groups (Table 3). More than 97% of the employees were vaccinated at least once against COVID-19. However, the anti-HEV IgM positive group showed a significantly higher rate of COVID-19 vaccination more than two times (83.3% vs 48.7%, p=0.021), as well as a higher rate of recent vaccination within 90 days before anti-HEV testing (45.8% vs 19.7%, p=0.008). Interestingly, a significant difference was found in the most recent COVID-19 vaccine used; namely, the Moderna vaccine was more commonly used in the anti-HEV IgM positive group (75.0%) than in the negative group (14.5%) (p<0.001) (Table 3).
Table 3. Comparison of the Rates of COVID-19 Infection and Vaccination before HEV Antibody Testing Date between the Anti-HEV Positive and Negative Groups
COVID-19 infection or vaccination before HEV testing dateAnti HEV-IgM positive (n=24)Anti HEV-IgM negative (n=552)p-valueCOVID-19 infection Ever infected11 (45.8)226 (40.9)0.675 Recent infection (<90 day)7 (29.2)196 (35.5)0.664COVID-19 vaccination Ever vaccinated24 (100)535 (96.9)1.000 No. of vaccination0.021 (1.8) 24 (16.7)256 (46.4) 320 (83.3)266 (48.2) 403 (0.5) Recent vaccination (<90 day)11 (45.8)109 (19.7)0.008 Last vaccine manufacturer<0.001 Moderna18 (75.0)80 (14.5) Pfizer6 (25.0)411 (74.5) Janssen07 (1.3) AstraZeneca (AZ)03 (0.5) Novavax01 (0) Missing033 (6.0)Detailed vaccination profile<0.001 1st Pfizer05 (0.9) Janssen04 (0.7) Missing01 (0.2) 1st-2nd Moderna-Moderna3 (12.5)161 (29.2) Pfizer-Pfizer1 (4.2)11 (2.0) Janssen-Pfizer010 (1.8) Janssen-Moderna039 (7.1) Others016 (2.9) 1st-2nd-3rd Moderna-Moderna-Moderna13 (54.2)16 (2.9) Pfizer-Pfizer-Pfizer5 (20.8)192 (34.8) AZ-AZ-Moderna1 (4.2)16 (2.9) AZ-AZ-Pfizer1 (4.2)9 (1.6) AZ-Pfizer-Pfizer08 (1.4) Pfizer-Pfizer-Moderna02 (0.4) Missing022 (4.0) 1st-2nd-3rd-4th AZ-AZ-Moderna-Novavax01 (0.2) AZ-AZ-Moderna-Pfizer01 (0.2) AZ-AZ-AZ-Pfizer01 (0.2)COVID-19, coronavirus disease ; HEV, hepatitis E virus; IgM, immunoglobulin M.
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As shown in Table 4, univariate analysis revealed that the specific day group meal intake (lunch on February 2, dinner on February 14, and dinner on February 17), vaccination rate within 90 days of anti-HEV testing (OR, 3.44; 95% CI, 1.50 to 7.89; p=0.004), receiving over 3 doses of COVID-19 vaccination (OR, 5.26; 95% CI, 1.78 to 15.59; p=0.003), and Moderna vaccine use as the last vaccine (OR, 17.06; 95% CI, 6.57 to 44.30; p<0.001) were significantly related to HEV IgM positivity (Table 4). In four multivariable models, three or more COVID-19 vaccinations and the use of the Moderna vaccine as the last vaccine were consistently associated with anti-HEV IgM positivity, while specific day group meal intake was a significant factor in the model. Among the 24 individuals tested as anti-HEV positive, 17 were not exposed to any of the four related group meals (no exposure group), and seven had at least one of these meals (exposure group). Compared to the exposure group, the non-exposure group showed a significantly higher rate of COVID-19 vaccination over three times and a higher rate of the last vaccination within 90 days of anti-HEV testing (Table 5).
Table 4. Results of Logistic Regression Analysis for Factors Associated with Anti HEV-IgM Positivity
Univariate modelMultivariate model 1Multivariate model 2Multivariate model 3Multivariate model 4OR (95% CI)p-valueOR (95% CI)p-valueOR (95% CI)p-valueOR (95% CI)p-valueOR (95% CI)p-valueAge0.99 (0.95&#;1.03)0.611Female sex1.36 (0.55&#;3.34)0.507Production worker0.95 (0.40&#;2.25)0.901Group meal (lunch on February 2)2.92 (1.05&#;8.15)0..93 (0.88&#;9.74)0.079Group meal (dinner on February 14)3.21 (1.23&#;8.41)0..04 (0.99&#;9.32)0.052Group meal (dinner on February 17)3.55 (1.35&#;9.32)0..26 (1.03&#;10.31)0.044Group meal (dinner on February 18)2.74 (0.99&#;7.64)0..34 (0.71&#;7.63)0.161COVID-19 infection within 90 day of HEV antibody testing0.90 (0.36&#;2.20)0.808COVID-19 vaccination within 90 day of HEV antibody testing3.44 (1.50&#;7.89)0..07 (0.74&#;5.81)0..78 (0.64&#;4.91)0..71 (0.61&#;4.75)0..78 (0.65&#;4.91)0.264More than 3 time of COVID-19HEV, hepatitis E virus; IgM, immunoglobulin M; OR, odds ratio; CI, confidence interval.
Table 5. Comparison of the Rates of COVID-19 Infection and Vaccination before HEV Antibody Testing According to Exposure to the High-Risk Group Meal* in the Anti-HEV Positive Group
Anti-HEV positive persons (n=24)p-valueNo exposure (n=17)Exposure (n=7)COVID-19 infection Ever infected7 (41.2)4 (57.1)0.476 Recent infection (<90 day)5 (29.4)2 (28.6)0.967COVID-19 vaccination Ever vaccinated17 (100)7 (100)1.000 No. of vaccination0.027 21 (5.9)3 (42.9) 316 (94.1)4 (57.1) Recent vaccination (<90 day)10 (58.8)1 (14.3)0.047 Last vaccine manufacturer0.195 Moderna14 (82.4)4 (57.1) Pfizer3 (17.6)3 (42.9)Detailed vaccination profile0.011 1st-2nd Moderna-Moderna1 (5.9)2 (28.6) Pfizer-Pfizer01 (14.3) 1st-2nd-3rd Moderna-Moderna-Moderna13 (76.5)0 Pfizer-Pfizer-Pfizer3 (17.6)2 (28.6) AZ-AZ-Moderna01 (14.3) AZ-AZ-Pfizer01 (14.3)COVID-19, coronavirus disease ; HEV, hepatitis E virus; AZ, AstraZeneca.
*Definition of high-risk group meal: patient who had exposure to lunch on the February 2, dinner on the February 14, dinner on the February 17, or dinner on the February 18.
This epidemiological investigation of 24 cases of anti-HEV IgM positivity initially presumed to be an HEV outbreak showed that anti-HEV IgM positivity may be a false-positive result related to COVID-vaccination over three times and use of the Moderna vaccine, while a portion of true HEV infection may not be excluded because a certain-day group meal intake was significantly associated with anti-HEV IgM positivity in multivariate analysis. This peculiar experience should raise awareness regarding the COVID-19 pandemic and widespread COVID-19 vaccination.
In Korea, cases of acute hepatitis caused by HEV have rarely been reported since ; however, cases may still occur sporadically and can be accompanied by typical hepatitis symptoms. As a class 2 notifiable infectious disease the reported number of hepatitis E cases over the 2 years from July to June was 938. However, the HEV antibody prevalence (IgG anti-HEV) of individuals using blood samples from the National Health and Nutrition Survey in and during to showed an increase with age: less than 10% in individuals in their 30s, 10% to 20% in 40s, 20% to 30% in 50s, 40% in 60s or older, and 5.9% in the domestic population aged 10 to 55 years.10,11 The large gap between the number of cases and HEV seroprevalence suggests that the majority of HEV infections are asymptomatic, which is consistent with the results of this study.
In the present study, intake of the four groups of meats was higher in the anti-HEV IgM-positive group than in the negative group, and intake of dinner on February 18 was an independent factor associated with anti-HEV IgM positivity in multivariate analysis. This result was compatible with Hills criteria, including the intensity of association, temporal precedence, and biological plausibility. This indicates that group meal intake may be associated with HEV infection or anti-HEV IgM positivity, although we did not detect HEV RNA in the related foods. In addition, among the anti-HEV positive individuals, a subgroup that consumed the risk group meal showed a lower rate of COVID-19 vaccination than the non-intake group.
The examination of these 24 cases of anti-HEV IgM positivity was interesting as this was the second event of an HEV outbreak in South Korea. However, all cases were asymptomatic and all HEV RNA tests were negative. In addition, the anti-HEV IgM positivity rates among the tested employees in the same factory were 0% in to , 0.8% in , 1.7% in , and 3.7% in . Therefore, we believe that these peculiar findings may reflect a false-positive reaction of anti-HEV IgM related to widespread COVID-19 infection or COVID-19 vaccination. However, we found no significant difference in the cumulative COVID-19 infection rate or the rate within the 90 days prior to anti-HEV testing between the anti-HEV IgM-positive and -negative groups.
In our analysis, multiple vaccinations against COVID-19 (over three times) and the use of the Moderna vaccine were consistently associated with anti-HEV IgM positivity in our four multivariate analysis models. This suggests a false-positive reaction to anti-HEV IgM after the COVID-19 vaccination. COVID-19 infection causes liver injuries such as cholangiopathy and chronic cholestasis,12,13 and COVID-19 vaccination may induce autoimmune hepatitis. However, COVID-vaccination-induced false-positive HEV serology reaction was not yet reported. Because anti-HEV false positivity was observed in hepatitis A, Epstein-Barr infection, and autoimmune hepatitis, the assumed mechanism of false positivity in our study was a systemic inflammatory response generated by COVID-19 vaccination with predominantly RNA vaccines. Both the Pfizer and Moderna vaccines are lipid-formulated RNA vaccines. The vaccine adjuvant activity of the lipid formulation itself or modified or unmodified single-stranded RNA induces a strong innate immune response.14 Recent studies have shown that Moderna has a higher antibody titer, lasts longer, and prevents breakthrough infection better than the Pfizer vaccine,15 which may be related to differences in RNA amount, lipid nanoparticle composition, and vaccination interval.16 In fact, a recent study reported that false reactivity in common infectious disease serologies such as Epstein-Barr virus, measles, and rubella after mRNA vaccination and it was more likely to occur in those receiving the Moderna vaccine in a longitudinal cohort.17 These findings are consistent with our results showing a strong association between anti-HEV positivity and the use of Moderna vaccine. To the best of our knowledge, this is the first study to report an association between COVID-19 vaccination and anti-HEV positivity.
This study has several limitations including its retrospective cohort nature and the non-optimal timing of HEV RNA testing for blood and environmental samples. Furthermore, detailed laboratory results including complete blood count with differential were not available due to the epidemiological investigation setting. Finally, there is no standard diagnostic method for hepatitis E that is commonly used worldwide until now,18 and only one available test was performed in this study. Finally, there is a lack of basic studies and literature reports on the mechanisms for the false-positive results of anti-HEV IgM after COVID-19 vaccination.
In conclusion, the results of this study indicate that anti-HEV IgM positivity may be a false-positive result related to COVID-vaccination over three times and the use of the Moderna vaccine, while a portion of true HEV infection may not be excluded. Further studies on the mechanisms underlying these results are warranted.
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