The hepatitis A virus (HAV) is a ribonucleic acid virus in the Picornaviridae family, with humans as its only natural reservoir [1]. The main hepatitis A symptoms include fever, fatigue, loss of appetite, abdominal pain, and jaundice. Symptom severity increases with age and about 70% of infants aged < 6 years are asymptomatic. The hepatitis A vaccine is high effective if administered within 2 weeks of HAV exposure and can be prophylactic if administered after exposure [2].

The HAV is usually transmitted by the fecal–oral route through contaminated water, food, or close contact with an infected person. In nations with low endemicity, there have been reports of hepatitis A outbreaks that have occurred through various situations and foods. Hepatitis A outbreaks occur in medical facilities provide care for critically ill patients, elderly patients, and children [3,4] and in locations with poor hygienic conditions [5]. With regard to food items, there have been outbreak reports associated with unheated of insufficiently heated clams [6], frozen fruits [7], semi-dried fruits [8], and vegetables [9].

In Korea, between 2011 and 2018, the year 2011 had the largest number of reported hepatitis A cases with 5,521, while 2013 had the lowest number of reported cases with 867 [10]. In 2019, there were 17,598 reports of hepatitis A. Specially on June 25 and July 26, 2019, the Korea Disease Control and Prevention Agency (KDCA) reported that salted clams were the source of infection for some of small-scale hepatitis A clusters [11,12]. However, this was an insufficient explanation for the cause of rapid increases compared to the same period in the previous year, being more than 6 times.

In the spring of 2019, the number of patients with hepatitis A was rapidly increasing in the regions of Daejeon, Chungcheong Province, and the Seoul Metropolitan area. In Busan, until early July, there were approximately 5 weekly cases of hepatitis A, which was similar to the rate during other years. Then, during the second week of July 2019 (July 6 to 12), hepatitis A cases increased to 9 cases, and to 18 cases during the third week of July (July 13 to 19). Inspecting the spatial aggregation of cases reported during the second and third weeks of July, eight patients had been reported in district B, one of the 16 districts of Busan city. Following that weekend, there were 15 cases of hepatitis A on the single day of July 22. In-depth interviews were conducted with these 15 patients. It was found that 12 patients of 15 patients had visited restaurant A located in district B during June 2019. Therefore restaurant A was suspected to be associated with the outbreak. To ascertain the source of infection and prevent further transmission of the disease, the city of Busan and the Busan Center for Infectious Disease Control and Prevention established an epidemiological investigation team on July 23 and engaged in a comprehensive epidemiological investigation.

The investigation on this outbreak was conducted as a cohort study, using information obtained through an inquiry for the list of customers who paid by card over a 2-month period. The current study is significant as this was the first foodborne infectious disease epidemiological investigation in Korea using a list of customers who paid by card to establish the total cohort, which was then used to conduct the actual study.

The source of infection for the hepatitis A outbreak that occurred at a restaurant in Busan was determined to be salted clams. The distribution of incubation period had a median of 31 days, which was identical to the average incubation period of hepatitis A, and the results of a multivariate logistic regression analysis indicated that the ingestion of salted clams increased the risk of hepatitis A by 68.12 times (95% CI, 9.22 to 510.87). Moreover, the genotype analysis of specimens collected from 90 patients indicated that 89 of them had HAV genotype IA, which was identical to the genotype of the HAV detected in the salted clams found in an unopened container that was secured during the traceback investigation. The ingestion of semi-cooked or uncooked filter feeding bivalve shellfish is a common cause of outbreaks involving gastrointestinal infections transmitted via the fecal–oral route, such as the norovirus or hepatitis A [14,15]. Since the viruses excreted by patients with hepatitis A cannot be removed sufficiently through sewage treatment [16], they end up contaminating coastal waters: the habitat of filter-feeding bivalve shellfish. Due to the filter-feeding nature of the bivalve shellfish, these viruses are easily concentrated in the digestive organs of the shellfish [14]. The main source of infection of the 1988 mass outbreak of hepatitis A in Shanghai, China, which led to 290,000 reported cases of hepatitis A, was determined to be uncooked clams [6].

For the current study, hepatitis A ARs by age were 2.9% for ages less than 20 years, 6.8% for people in their 20s, 8.2% for people in their 30s, 6.9% for people in their 40s, and 2.1% for people aged > 50 years, with people in their 20s, 30s, and 40s showing relatively high ARs. This coincides with the 2019 study showing that the hepatitis A IgG antibody positive rates in Korea were 61.7% for people in their 10s, 32.8% for people in their 20s, 32.4% for people in their 30s, 63.2% for people in their 40s, and ≥ 95% for people in their 50s [17,18]. The results of the multivariate analysis indicated that there were no statistically significant differences between groups of ARs by age. The effect of age seems to have disappeared due to the correlation between the strongest risk factor—ingestion of salted clams—and age. Moreover, the AR of female appeared to be lower in the bivariate and multivariate analyses. Given that the antibody positive rate of Korean adults does not show statistically significant differences by sex [18-20], this could be the result of salted clam consumption that was not included in the survey results or specific qualities of the exposed group that are different from the general population. Other food items that indicated statistically significant differences in AR—such as sliced pork, seasoned soybean paste, and plain rice—are thought to be the result of cross-contamination or actual or residual confounding caused by inter-item correlation. Since salted shrimps are in a selectional relationship with salted clams, it was thought to have indicated a negative correlation, although it was not statistically significant.

The average incubation period of hepatitis A is long, at 28 days (minimum 15 days, maximum 50 days) [21], so it is easily confused for a case of sporadic that stretches over a few months when low-level contaminations are sustained or small clusters occur simultaneously in multiple regions: it is also difficult to find the relationship between hepatitis A and the food item that serves as the source of infection [22]. For the hepatitis A epidemic in 2019 in Korea, although it had started in March, the fact that it had been caused by a single type of food item was not known until the Ministry of Food and Drug Safety recommended on September 27 to stop consumption of salted clams [13]. As a result, people were constantly exposed to salted clams for months. After people were recommended to avoid uncooked clams and food sampling test standards for salted clams were expanded, the number of hepatitis A decreased rapidly. However, the reality is that, even in 2020 and 2021, there are continuous reports of small-scale outbreaks of hepatitis A caused by salted clams [23,24]. To prevent people from ingesting uncooked clams, there needs to be more publicity efforts regarding the dangers of uncooked clams; the food sampling test standards for salted clams should also be expanded. Moreover, to recognize outbreaks early in their occurrence from reported cases of hepatitis A, the local health authority must commit efforts to monitor the spatial and temporal clustering of cases and conduct detailed interviews with patients. Furthermore, for hepatitis A outbreaks that are caused by food items that have complex and international supply chains, there have been multiple cases where the outbreak was recognized through molecular genetics analysis [7,25,26]. Therefore, to detect hepatitis A outbreaks early, Korea needs a surveillance system based on laboratory molecular genetics. For the current study, the identical genotype of HAV was detected in the human samples and salted clams, but there were no phylogenetic analysis results based on molecular genetics. Laboratory surveillance data must be accumulated, which can then be utilized to prove the causal relationship between outbreaks and food items that serve as the source of infection.

The current study has the following limitations. First, IgG antibody tests could not be conducted on the participants. Strictly speaking, the AR must be calculated using only the susceptibles, which can be conducted by excluding IgG-positive participants from the denominator. In future epidemiological investigations of hepatitis A, the IgG test must be included to derive accurate ARs and lead to accurate analysis of results. Furthermore, since only 376 (76.6%) of 491 symptomatic patients were tested (Figure 1), the AR could have been calculated to be lower than the actual rate. Second, the response rate for the food item ingestion survey was low at 50.1%, and the amount consumed was not recorded. Since the amount ingested can have a significant effect, this needs to be evaluated and can be an important factor for evaluating the causality via the analysis of dose-response relationship. Third, since the study created the list using only the customers who paid by card, people who paid by cash have been excluded from the cohort. According to the Bank of Korea, the proportion of people who paid by cash at restaurants and cafes in 2019 was 16.4%, which tended to be higher for people in older age groups [27]. To minimize the exclusion of people who paid by cash, there needs to be a legal basis for securing the list of people who paid by cash and asked for a cash receipt.

Since the IgG antibody-positive rate is low for age groups between 20s and 40s, the susceptible population is large in Korea, which leads to the occurrence of hepatitis A outbreaks every few years [10]. Moreover, since the severity of hepatitis A increases with age [21], the severity is expected to increase along with the age of the current susceptible population. To detect outbreaks early in their occurrence, surveillance systems based on molecular genetics must be established, and the epidemiological investigation capabilities of regional govermnents must be strengthened. Furthermore, there needs to be a more comprehensive testing for food items that could potentially be contaminated with the HAV.