There were 369 and 801 decedents in the United States with hepatitis A listed as a cause of death during the non-outbreak and outbreak periods respectively (Table 1). Hepatitis A-listed deaths were more common among men than women during both the non-outbreak (57.7% vs. 42.3%) and outbreak periods (68.2% vs. 31.8%). The ≥70-year-old age category accounted for the highest percentage of hepatitis A-listed deaths by age group during the non-outbreak period (38.2%) and outbreak period (31.3%). Similarly, hepatitis A-listed deaths were most common among non-Hispanic White persons during both the non-outbreak period (69.0%) and the outbreak period (84.6%). The proportion of hepatitis A-listed deaths that occurred in inpatient hospital settings increased from 45.8% during the non-outbreak period to 60.4% during the outbreak period. Coinfection with HBV, HCV or HIV was less frequently reported among hepatitis A-listed deaths during the outbreak period (28.3%) than during the non-outbreak period (38.8%).

The age-adjusted hepatitis A mortality rate increased 150%, from 0.02 (95% CI, 0.02–0.02) deaths per 100,000 population during the non-outbreak period to 0.05 (95% CI, 0.05–0.06) deaths per 100,000 population during the outbreak period (p < 0.001) (Table 2). Compared with the non-outbreak period, the age-adjusted mortality rate increased among men by 300% (p < 0.001) and among women by 50% (p < 0.001) in the outbreak period. Similarly, the age-adjusted hepatitis A mortality rate increased significantly (p < 0.001) over time for all age categories ≥18 years old, with the largest change in rate occurring among 40–49-year olds (250%) and the smallest change in rate occurring among ≥70-year olds (89%). The age-adjusted mortality rate increased 150% for non-Hispanic White persons (p < 0.001) from the non-outbreak period to the outbreak period, remained steady for non-Hispanic Black (p = 0.646) and Hispanic (p = 0.373) persons, and declined 33% for Asian and Pacific Islander persons (p = 0.259).

Among decedents with hepatitis A listed, the proportion of decedents with hepatitis A recorded as the underlying cause (rather than the contributing cause) increased from 33.1% during the non-outbreak period to 48.2% during the outbreak-period (Table 1). When hepatitis A was listed as a contributing cause of death, rather than as the underlying cause of death, mental and behavioural disorders were more frequently listed as an underlying cause of death in the outbreak period (4.6%) than during the non-outbreak period (1.6%; p = 0.044). There were no other significant differences in underlying cause of death between the two periods. However, the mental and behavioural disorder estimates are considered unreliable based on NCHS standards because the death count was <20 in both the non-outbreak and outbreak periods.

The median (interquartile range [IQR]) age at death for hepatitis A-listed decedents was significantly younger during the outbreak period (62 years [IQR 53–73]) than during the non-outbreak period (64 years [IQR 56–77], p < 0.001) (Table 3). The median age at hepatitis A-listed death was 61 years for males in both periods, but decreased significantly for females from 72 years (IQR 58–83) during the non-outbreak period to 66 years (IQR 53–77) during the outbreak period (p < 0.001). Non-Hispanic White persons had a significantly younger median age at death during the outbreak period (61 years [IQR 53–72]) than during the non-outbreak period (66 years [IQR 57–80], p < 0.001).

The median (IQR) age at death among decedents with hepatitis A listed as the underlying cause of death declined significantly from the non-outbreak period (70 years [IQR 59–82]) to the outbreak period (61 years [IQR 52–73], p < 0.001) (Table 3). When hepatitis A was listed as a contributing cause of death, rather than as the underlying cause, the median age at death significantly (p < 0.05) decreased by at least 5 years from the non-outbreak period to the outbreak period among the following underlying causes of death: hepatitis C; HBV, HCV or HIV coinfection; and mental and behavioural disorders. The predominant mental and behavioural disorder underlying the cause of death codes that were observed shifted from those related to dementia during the non-outbreak period to those related to drug and alcohol use during the outbreak period.

The median age at hepatitis A-listed death in the United States during the outbreak period was 62 (IQR 53–73) years, which was significantly younger than the median age at death among decedents without hepatitis A listed as a COD (76 years [IQR 64–86], p < 0.001) (Table 4). Hepatitis A-listed decedents had younger median age at death compared with decedents without hepatitis A listed as a cause of death for all underlying cause of death categories examined except for the injury, trauma and poisoning category. The difference was statistically significant (p < 0.05) for the following underlying cause of death categories: hepatitis B; hepatitis C; HBV, HCV or HIV coinfection; liver cancer; mental and behavioural disorders; diseases of the circulatory, respiratory, digestive (non-liver) systems; diseases of the liver, non-alcohol-related; and ‘other’ underlying cause of death.

During the outbreak period, the highest number (225) and age-adjusted rate (0.06 [95% CI, 0.05–0.07] deaths per 100,000 population) of hepatitis A-listed deaths occurred in 2019, while the lowest number (91) and rate (0.02 [95% CI, 0.02–0.03] deaths per 100,000 population) occurred in 2017 (Table 5). The age-adjusted mortality rate during the outbreak period also peaked in 2019 for several subpopulations, including males, decedents aged ≥40 years, and non-Hispanic White decedents. During each year of the outbreak period, the age-adjusted mortality rate among men was over two times the rate among women. In general, during each outbreak year, the proportion and rate of hepatitis A-listed deaths increased with increasingly older age group categories. Decedents aged ≥70 years accounted for the highest proportion and mortality rate of hepatitis A-listed deaths by age group for each of the outbreak years except 2019, when decedents aged 60–69 years accounted for the highest proportion and an equal mortality rate. Decedents aged <40 years accounted for <10% of hepatitis A-listed deaths in each of the outbreak years. Non-Hispanic White decedents accounted for >75% of hepatitis A-listed deaths annually during 2017–2021.

In this cross-sectional analysis of hepatitis A-listed deaths in the United States during non-outbreak and outbreak periods, we found that decedents with hepatitis A-listed on the death certificate were most commonly men, aged ≥60 years, and non-Hispanic White during both the non-outbreak (2011–2015) and outbreak (2017–2021) periods. Overall, the hepatitis A-listed age-adjusted mortality rate increased 150% and the number of deaths more than doubled from the non-outbreak period to the outbreak period. The median age at death for hepatitis A-listed decedents was significantly younger during the outbreak period (62 years) compared with both the median age at death for hepatitis A-listed decedents during the non-outbreak period (64 years) and for decedents without hepatitis A listed as a cause of death during the outbreak period (76 years).

Our analysis reinforces results from prior studies that older age is associated with hepatitis A mortality [4, 17–20]. During both the non-outbreak and outbreak periods, the ≥70-year-old age category accounted for the highest percentage of hepatitis A-listed deaths and the highest mortality rates overall. Because of changes in the epidemiology of hepatitis A in the United States after the introduction of hepatitis A vaccines in 1996 and universal childhood vaccination in 2006, susceptibility to HAV infection in older adult age groups (that are at increased risk for serious consequences of HAV infection, including death) has increased over time [9]. The association of older age with hepatitis A mortality is observed in the US MCOD data—for the entire analysis period, the hepatitis A mortality rate increased by increasing age category among all adults. During the outbreak period of 2017–2021, approximately 58% of hepatitis A-listed decedents were aged ≥60 years despite a report indicating that <10% of all hepatitis A patients linked to the recent outbreaks associated with person-to-person transmission during 2016–2020 were aged ≥60 years [6].

With the exception of age, the characteristics of hepatitis A-listed decedents during the outbreak period generally reflected the characteristics of outbreak-associated hepatitis A cases involved in the recent hepatitis A outbreaks associated with person-to-person transmission. Sixty-two per cent of outbreak-associated cases were male, compared to 68% of hepatitis A-listed decedents; 81% of outbreak-associated cases were White (ethnicity not available) while 85% of hepatitis A-listed decedents were non-Hispanic White; and 31% of outbreak-associated cases were coinfected with HBV or HCV, compared with 28% of hepatitis A-listed decedents with HBV, HCV or HIV coinfection listed as a cause of death [6]. Similarly, the highest number (225) and age-adjusted rate (0.06 [95% CI, 0.05–0.07] deaths per 100,000 population) of hepatitis A-listed deaths occurred in 2019, the same year when cases peaked during the outbreaks [3].

Our findings are subject to limitations. First, the analysis utilised MCOD data which are predicated on clinician judgement regarding the comparative role and importance that conditions played in contributing to death. Studies have demonstrated that death certificates are subject to high rates of error [21–23]. Medical record validation studies have shown that vital statistics mortality data underestimate the true mortality burden of infections generally, and viral infections causing hepatitis B and hepatitis C specifically [24–26]. A recent death certificate analysis found that hepatitis A was documented as an underlying or contributing cause of death on only 60% of death certificates from decedents whose deaths were considered hepatitis A outbreak-related by state health departments [13]. Second, racial and ethnic misclassification is common on death certificates [27], which could have led to an underestimate of hepatitis A-listed deaths among certain racial/ethnic minority groups. Third, the number of deaths used to calculate percentages and rates was small, which reduced the stability and reliability of some of these estimates when stratified by the characteristic groups examined in our analysis. Fourth, the ‘other’ underlying cause of death category included ICD-10 codes for COVID-19, which might at least partially account for the increase observed in ‘other’ listed as the underlying cause of death when hepatitis A was listed as a contributing cause of death from the non-outbreak period (prior to the COVID-19 pandemic) to the outbreak period. Finally, the US Census Bureau, in collaboration with NCHS, started transitioning from using bridged race categories to single/multiple race categories for both the MCOD data and population estimates in 2018 and was fully transitioned in 2021 for mortality rate calculations [28, 29]. Because our analysis included this transition period and bridged race and single/multiple race categories are not directly comparable, we were unable to present race/ethnicity data in a consistent manner throughout the analysis and had to adjust how race/ethnicity data were presented in the tables.

Over the course of widespread community outbreaks that occurred during 2017–2021, hepatitis A-listed decedents died at a median age that was 14 years younger than that of the general US population without hepatitis A listed as a cause of death. Hepatitis A is a vaccine-preventable disease. Safe and highly effective vaccines have been recommended in the United States since 1996 for adults at increased risk for HAV infection or severe disease from HAV infection (e.g., people who use drugs, men who have sex with men, international travellers and people with chronic liver disease), and since 2006 for all children aged 12–23 months [30]. During the recent outbreaks, the Advisory Committee on Immunization Practices (ACIP) expanded the indications for adult hepatitis A vaccination to include people experiencing homelessness and people living with HIV [30, 31]. According to a recent National Health and Nutrition Examination Survey analysis, during 2015–March 2020, more than 60% of US-born adult participants aged ≥30 years were susceptible to HAV infection [9]. Given the increased susceptibility to HAV infection among adults and the higher likelihood of severe outcomes from HAV infection among older adults, efforts are needed to optimise vaccination of medically underserved populations that are currently recommended to receive hepatitis A vaccination to prevent additional premature hepatitis A deaths.