Introduction

Hepatitis A virus (HAV), a prevalent infectious agent globally, is classified as a positive-sense RNA virus within the Hepatovirus genus of the Picornaviridae family1,2. Interestingly, HAV was identified by Feinslone et al. (1973) through immunoelectron microscopy in the fecal samples of affected individuals during the acute phase of the disease3. HAV exhibits a spherical morphology with a diameter of approximately 27 nanometers. The viral capsid features a symmetrical icosahedral structure and is made up of 60 protein subunits, consisting of 4 distinct peptides: VP1, VP2, VP3, and VP44. Moreover, infections caused by HAV may be either symptomatic or asymptomatic in human hosts5.

The primary mode of HAV transmission is via the fecal-oral pathway, which includes direct personal and the consumption of water or food contaminated with the feces of infected individual6. Rarely, HAV infection can be spread through the transfusion of blood products from a donor who is infected with the virus7,8. Based on the incidence of HAV, areas can be categorized into very low, low, moderate, and high endemic regions9,10,11. It has been established that most cases are infected during early childhood in highly epidemiological areas12. In regions with low HAV incidence, initial exposure to the virus among adults frequently occurs through travel to or residence in areas with high HAV incidence, or through high-risk activities, including interaction with patients, male-to-male sexual contact, and the consumption of illicit substances9,13,14. Clinically, the primary manifestations of HAV infection include liver function abnormalities, enlarged liver, loss of appetite, and fatigue2. Sometimes, jaundice is the predominant presentation, especially during acute hepatitis15. However, it should be also be borne in mind that asymptomatic infections are frequent. HAV-related mortality includes deaths resulting from clinical conditions caused by hepatitis A, containing secondary infections, hepatorenal syndrome, hepatic encephalopathy, and liver failure5,16.

Due to the widespread administration of the HAV vaccine and improvements in sanitation, there has been a notable decrease in HAV infection rates in endemic areas, leading to effective control of the virus’s incidence17,18. Over the past two decades, the implementation of HAV vaccination and changes in lifestyle have led to a significant reduction in HAV infection rates in China18. Current evidence suggests that lifestyle changes significantly reduce the risk of HAV infection in areas experiencing rapid GDP growth18. Moreover, data from 2004 to 2009 showed that the majority of HAV infections in China were clustered in Sichuan, Henan, Guizhou, Yunnan, Gansu provinces, and Xinjiang representing 44–51% of the total national infections during the study period. Approximately 30% of these cases involved children under the age of 1519. One study indicate that public health emergencies related to HAV predominantly occur within primary and secondary educational institutions, with the majority of cases being identified among the student population20. Additionally, it is widely thought that age and regional variations significantly affect the incidence of HAV9.

The aim of this study is to provide hitherto undocumented information on the incidence and fatality rates of HAV in China from 2004 to 2018, with a comprehensive analysis of the regional and age-related attributes of affected individuals, providing the basis for novel reforms and strategies aiming at the control and prevention of this contagious disease in China.

Methods

Data collection

For this research, data concerning the HAV incidence and HAV-associated mortality were accessed from China Public Health Science Data Center (CPHSD) searching with the terms “HAV”, “Hepatitis A”, “Hepatitis A Virus” and “Hepatitis“21. Data on HAV infections, reported cases, and deaths associated with HAV were collected from 31 regions across mainland China (not including Macau, Hong Kong, and Taiwan) for the period from 2004 to 2018. The criteria for defining surveillance cases followed the ‘Diagnostic Criteria for Viral Hepatitis A (WS298-2008)’, a health industry standard set by the Ministry of Health of the People’s Republic of China. Based on the guidelines of the existing Chinese infectious disease reporting system, HAV surveillance cases were identified as those that are either clinically diagnosed or confirmed through laboratory tests. The cases included in this study consisted of both clinically diagnosed cases and laboratory-confirmed cases. Laboratory confirmation involved serological testing for anti-HAV IgM antibodies, which is considered the gold standard for diagnosing acute HAV infections. Clinically diagnosed cases were those that met specific clinical criteria outlined in the diagnostic guidelines without laboratory confirmation but were under strict medical supervision and follow-up to ensure accuracy. According to the CPHSD, the incidence was equal to the number of reported cases of HAV/population ×100,000, while the mortality of HAV patients was calculated by the number of deaths/population ×100,000. Age and regional stratification were performed to examine variations in HAV incidence.

In this study, we utilized publicly available data from the CPHSD. This database contains anonymized and de-identified information, which is collected and managed in compliance with national regulations and ethical standards. Because all statistics utilized in this research were fully anonymized and publicly available, the absence of ethical review was reasonable.

Statistical analysis

To investigate variations in HAV incidence and HAV-related mortality, subgroup analysis was performed according to age strata and geographic regions. To examine age-related differences in HAV incidence, we categorized the patients into 3 age groups: 0–20 years, > 20–50 years, and over 50 years. To capture the variability in HAV infection rates and mortality across different age cohorts more precisely, this study categorized individuals aged 0–80 into the following age groups: 0–10, > 10–20, > 20–30, > 30–40, > 40–50, > 50–60, > 60–70, > 70–80, and over 80 years. The results were expressed as mean ± SD (standard deviation) and mean ± SE (standard error), or as a percentage, depending on the context. Regarding continuous variables following a normal distribution, Student’s t-test and one-way ANCOVA were utilized to assess the differences. A p-value less than 0.05 was considered statistically significant. Statistical analyses were carried out utilizing SPSS version 18, while line graphs and histograms were created with GraphPad Prism 6. The geographic distribution of HAV incidence and mortality were mapped using Adobe Illustrator CS6.

Results

Incidence and related death with HAV in China

Both the incidence of HAV (per 100,000 population) and HAV-related mortality (per 100,000 population) showed a declining trend (Fig. 1). Specifically, the rates were 7.1997 and 0.0031 in 2004, 2.6430 and 0.0003 in 2010, and 1.1659 and 0.0002 in 2018, respectively (Table 1). Findings from the linear regression analysis also indicated a strong consistency (r2 > 0.715, p < 0.05) in Fig. 1C,D. In addition, from 2004 to 2018, there were 631,053 (42,070 ± 24,366) cases of HAV and 234 (15.6 ± 14.1) HAV-related deaths.

Fig. 1
figure 1

Trends in the incidence of HAV infections and HAV-associated mortality in China (2004–2018). (A) Incidence of HAV cases (1/100,000) in the Chinese population from 2004 to 2018. (B) HAV-associated mortality rate (1/100,000) in the Chinese population from 2004 to 2018. (C) Linear regression analysis of the correlation between incidence of HAV and year. (D) Linear regression analysis of the correlation between number of HAV-associated mortality and year.

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Table 1 Incidence of HAV and HAV-associated mortality in China from 2004 to 2018.
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Regional distribution differences in HAV incidence

The current research encompassed 31 regions across China. Our team created histograms and charted the geographical distribution to illustrate regional variations in the incidence of HAV and HAV-associated deaths (Fig. 2). Based on the incidence of HAV instances, the 3 provinces with the highest rates were Sichuan, Xinjiang and Yunnan. Sichuan has an average annual incidence exceeding 4,000 (Fig. 2A,B). The average annual incidence of HAV-associated deaths across the 31 regions varied from 0 to 1.93, with no significant differences observed among the regions. Guizhou recorded the highest rate of HAV-associated deaths at 1.93 (Fig. 2C,D). In Beijing, the occurrence rate of HAV saw a significant decline from 0.2093 in January 2004 to 0.0598 in January 2018 (p < 0.05). The most substantial decrease was found in regions with the highest occurrence rate of HAV, including Sichuan province (p < 0.05).

Fig. 2
figure 2figure 2

Annual incidence of HAV cases and HAV- associated mortality by region in the Chinese population from 2004 to 2018. (A,B) Annual incidence of HAV cases based on regional distribution; (C,D) Annual incidence of HAV-related death based on regional distribution. Coordinate numbers on the X axis of the Histogram (A,C) represent different regions: 1-Beijing, 2-Tianjin, 3-Hebei, 4-Shanxi, 5-Inner Mongolia, 6-Liaoning, 7-Jilin, 8-Heilongjiang, 9-Shanghai, 10-Jiangsu, 11-Zhejiang, 12-Anhui, 13-Fujian, 14-Jiangxi, 15-Shandong, 16-Henan, 17-Hubei, 18-Hunan, 19-Guangdong, 20-Guangxi, 21-Hainan, 22-Chongqing, 23-Sichuan, 24-Guizhou, 25-Yunnan, 26-Tibet, 27-Shaanxi, 28-Gansu, 29-Qinghai, 30-Ningxia, 31-Xinjiang.

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Age-specific HAV incidence

To examine age-related differences in HAV incidence, we categorized the patients into 3 age groups: 0–20 years, > 20–50 years, and over 50 years. It was observed that the > 20–50 years age group had the highest incidence of HAV cases, which was significantly higher than the incidence in the over 50 years age group (p < 0.05). Additionally, the incidence of HAV-associated deaths was highest in the over 50 years age group, and this rate was significantly higher than that in the 0–20 years age group (p < 0.05) (Fig. 3).

Fig. 3
figure 3

Age-specific incidence of HAV and HAV- associated mortality in different age groups in the Chinese population from 2004 to 2018 (Statistical significance was determined using the Student’s t-test). (A) HAV incidence in different age groups in the Chinese population from 2004 to 2018; (B) HAV-related death in different age groups in the Chinese population from 2004 to 2018; (C) Incidence of HAV and HAV-related deaths.

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To delve deeper into capture the variability in HAV infection rates and mortality across different age cohorts, this study categorized individuals aged 0–80 into the following age groups: 0–10, > 10–20, > 20–30, > 30–40, > 40–50, > 50–60, > 60–70, > 70–80, and over 80 years. The results indicated that the occurrence rate of HAV declined as age increased. Among these groups, the HAV incidence in cases aged 0–10 was the highest and significantly higher compared to those in the > 50–60, > 60–70, > 70–80, and over 80 years age groups (p < 0.05). The highest rate of HAV-associated fatalities was observed in the 41–50 years age group, while the lowest rate was found in the 21–30 years age group. A significant variation in the occurrence of HAV-associated deaths was noted between the > 20–30 and > 40–50 age groups. Furthermore, while there was a significant increase in HAV incidence among individuals aged 71–80 years compared to those over 80 years (p < 0.05), the occurrence of HAV- associated fatalities did not differ significantly between these 2 age groups (p > 0.05). (Fig. 4).

Fig. 4
figure 4

Age-specific annual incidence of HAV and HAV- associated mortality in the Chinese population from 2004 to 2018 (Statistical significance was determined using the Student’s t-test). (A) HAV incidence in the Chinese population from 2004 to 2018; (B) HAV-related deaths in the Chinese population from 2004 to 2018.

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Discussion

In this study, our evaluation of publicly obtainable data from the CPHSD indicated a reduction in the yearly incidence of HAV infections and HAV-associated mortality rates in China between 2004 and 2018. Additionally, we observed considerable regional and age-specific differences in both incidence and mortality.

The highest incidence rate was observed among kids and teens, which may be related to frequent school clusters of hepatitis A cases. The higher incidence of hepatitis A in children and adolescents is consistent with relevant studies in China22,23,24,25. Liang Jinjun et al. conducted a retrospective analysis of 24 outbreaks that occurred in Hunan Province from 2005 to 2008. It was found that all the outbreaks occurred in schools, and the population was mainly primary and secondary school students22. Li Haixia et al. analyzed the epidemic situation of viral hepatitis A in Henan Province from 2013 to 2014 and indicated that the incidence of hepatitis A was mainly concentrated in students, scattered children and farmers, and hepatitis A in students and kindergartens was easy to cause hepatitis A outbreaks23. Dong Yan et al. analyzed the epidemic of viral hepatitis A in Xinjiang in 2004 ~ 2009, and found that infants and young children were higher than adults, and scattered children were significantly higher than other groups24. There was no statistically significant variation in incidence between the > 50 years and 0–20 years groups, but the > 50 years group had a significantly higher number of deaths (p < 0.05). This result is consistent with the clinical features of hepatitis A, where it is generally accepted that host age, immune status, and underlying liver disease are the main determinants of hepatitis A severity. Hepatitis A is mostly asymptomatic in children and worsens with age26. The highest incidence rates were observed in Xinjiang and Sichuan provinces. However, the yearly hepatitis A incidence showed a decline, as illustrated in Fig. 1; Table 1. Given China’s extensive territory, there are significant disparities in economic development among its regions. As shown in Fig. 2, regions with high HAV incidence were primarily clustered in the western part of China, even though the population there is notably smaller compared to the southeast. Suboptimal economic and hygiene conditions may explain the high HAV incidence in western China, including regions such as Yunnan, Sichuan, and Xinjiang. The HAV tends to circulate more easily in low-income areas, where sanitation and water quality are poor, improvements in socio-economic and sanitary conditions have contributed to the reduction of HAV transmission14,27,28,29.

The persistence of HAV, particularly in developing nations, continues to pose a significant challenge for global public health authorities14,16. In this study, the decline in annual HAV incidence and related mortality rates underscores the effectiveness of China’s preventive and control strategies. It is widely recognized that HAV incidence is strongly linked to economic circumstances and hygiene practices14,30. Over the past decade, as China’s economy has developed, there have been notable improvements in healthcare and medical infrastructure. Public knowledge about preventive measures for disease has also risen, and the HAV vaccine has seen widespread use. These factors have collectively contributed to the reduction in both fatality and infection rates of hepatitis A in China31,32.

HAV is the leading cause of acute hepatic disorders globally, with an estimated 159 million new infections, resulting in 2.3 million disability-adjusted life years and 39,000 fatalities33,34. The majority of cases and deaths were concentrated in the WHO regions of Southeast Asia, Africa, and the Eastern Mediterranean2. In total, 66% of new acute hepatitis A cases and 97% of hepatitis A-related deaths were reported in low-income and lower-middle-income countries2. HAV is prevalent globally, particularly in developing countries, and its incidence is closely linked to sanitation standards, potable water security, and economic factors16,27,29. In endemic regions, the seriousness of HAV infection is strongly related with age, predominantly impacting young children, and although often asymptomatic, it can still cause illness and, in some cases, even lead to death35. Current evidence indicates that symptomatic disease is more common in older children and adults who are infected36. In more advanced regions, the incidence is low due to good sanitary hygiene, health care facilities and high economic status. However, community immunity remains low, and epidemics are frequently reported37.

Adults frequently develop symptomatic hepatitis due to HAV, whereas in children, it often leads to asymptomatic subclinical infections, with the typical incubation period for the virus being approximately 28 days38. Clinical symptoms usually manifest rapidly following the incubation period, including abdominal pain, reduced weight, headaches, fever, yellowing of the skin, ark urine, diarrhea, vomiting, nausea, and a reduced interest in smoking or drinking alcohol2,15. As one gets older, the probability of exhibiting symptoms increases. Most children under 10 years old who contract HAV are typically symptom-free, whereas over 70% of adolescents and adults develop jaundice, and they might also suffer from hepatosplenomegaly38,39. An acute illness caused by HAV infection, usually lasting no longer than 2 months, exhibits clinical manifestations that are similar to many other gastrointestinal and fever-related conditions. This leads to difficulties in differentiating it from other forms of viral-induced acute hepatitis40,41. An increasing body of evidence suggests that waterborne HAV infections predominantly occur from consuming water that has been tainted by nearby septic systems or through exposure to waters polluted with waste42,43. Foodborne transmission of HAV typically happens when the virus is passed from the feces of infected individuals to food in the course of preparation, or when food crops are polluted by the feces of carriers during procurement and processing44,45. Fecal-oral transmission can also result from close and frequent human interaction between an infected individual and someone who is susceptible, for instance, in settings like schools and daycare centers, men who have sex with men (MSM) can be at risk of contracting HAV through the sharing of personal items46,47. Thus, the transmission of HAV via the fecal-oral route can be significantly decreased by placing more emphasis on dietary hygiene, like ensuring food and water are heated to at least 85 degrees Celsius for a minute, and by avoiding raw foods and untreated water44,48.Moreover, safeguarding vulnerable groups and youth via induced immunity (passive or active) is the essential approach. Passive immunity involves administering immunoglobulins for prophylaxis either before or, in some cases, after exposure, with the duration of protection varying based on the dose given48. Vaccines play a crucial role in providing active immunization against HAV. The introduction and broad adoption of the HAV vaccine in the 1990s marked a significant advancement in disease prevention. Initial efforts focused on vaccinating children in high-incidence areas and other specific high-risk populations49,50. In 2006, the Centers for Disease Control and Prevention (CDC) recommended HAV vaccination for all children aged 12 to 23 months51. In China, the hepatitis A vaccine was introduced as an essential vaccine for children and became part of the Expanded Program on Immunization (EPI) for Children in May 2008.

With a population of 1.4 billion and as a developing nation, China faces significant challenges in controlling the transmission of HAV. A notable example is the 1988 hepatitis A outbreak in Shanghai, which affected almost 300,000 individuals and was linked to the consumption of raw clams52. With purchasing power increased, along with improvements in hygiene and the widespread implementation of HAV vaccinations nationwide, the reported incidence of hepatitis A dropped from more than 50 per 100,000 in 1990 to 1.55 per 100,000 in 201753. Our research revealed that the HAV incidence varies by region and age, with the highest rates observed in Sichuan and Xinjiang. Moreover, we found that children and adolescents were more susceptible to HAV infection. The highest mortality rate was observed in individuals aged 40–50, markedly higher than in those aged 20–30.

Some limitations observed in the present research should be recognized. The analyzed data may not reflect the characteristics of the total HAV-infected people within China, and the unavailability of HAV epidemiological statistics from Macau, Taiwan, and Hong Kong could introduce bias into this research. Moreover, the publicly available data were insufficient, which precluded the analysis of additional risk factors such as gender, socioeconomic status, urban/rural residence, ethnicity, occupation, blood donation history, living environment, and preventive measures and clinical outcomes related to HAV. In future research, it will be crucial to include these variables to achieve a more thorough understanding of HAV epidemiology. Our research examines the variations in HAV by region and age within mainland China and found that HAV displays distinct regional and age-related differences. Hepatitis A virus transmission in areas such as Sichuan warrants more attention. Greater attention should be given to the transmission of HAV among children and teenagers, and the public ought to implement additional preventive measures to decrease the risk and occurrence of hepatitis A.

Conclusion

In conclusion, this study examined the epidemiological features of HAV in China over the period from 2004 to 2018. Despite the decrease in both HAV incidence and mortality rates, significant variations in the incidence were observed across different regions and age groups. The maximum incidence of HAV was observed in Sichuan, with youths and teens being particularly susceptible to transmission. Hepatitis A virus transmission in areas such as Sichuan warrants more attention. More emphasis should be placed on preventing transmission among children and adolescents.