During 1 November 2016–23 May 2018, a total of 589 hepatitis A cases were reported; 502 (85%) were confirmed by RT-PCR to match 1 of the genotype IB strains (Table 2). Median patient age was 43 years (range, 5–87 years), 400 (68%) were male, and 404 (69%) were hospitalized. Among 20 (3%) patients who died of causes associated with hepatitis A, 19 (95%) had underlying factors (eg, cirrhosis, diabetes, or cardiomyopathy) that may have contributed to increased risk of severe outcomes, 14 (70%) reported homelessness, and 2 (10%) had relapsing HAV infection, defined as recurrent disease within 6 months of last recovery [21]. No patients reported having received the full, 2-dose vaccination series before becoming infected. Among the 589 confirmed and probable cases, outbreak risk factor data were available for 535 (91%), 200 (37%) of whom reported both homelessness and illicit drug use, 91 (17%) reported homelessness only, and 77 (14%) reported illicit drug use only.

Among the 291 patients who reported experiencing homelessness, 79 (27%) did not report any other ACIP indications for vaccination (Table 2). Of the 212 (73%) PEH with at least 1 known indication, 200 (94%) reported illicit drug use, 72 (34%) were coinfected with HBV or HCV, 6 (2.8%) were MSM, and 4 (1.9%) reported recent international travel to Mexico, which is a country with intermediate or high rates of HAV.

During a hepatitis A outbreak in San Diego County with approximately 600 reported cases, we identified homelessness as an independent risk factor for HAV transmission and severe hepatitis A disease. Homelessness is a recognized risk factor for a range of health conditions and diseases [22] and has been associated with outbreaks of hepatitis A in the past [23–25], but homelessness was not recognized by the ACIP as an independent risk factor for hepatitis A infection at the time of the outbreak [4, 5].

PEH, especially those who are unsheltered, may be at increased risk of HAV infection because of high population density and inadequate facilities for sanitation and hygiene and at increased risk of severe outcomes because of a high prevalence of associated comorbidities, malnutrition, and alcohol-related liver disease [26]. Studies have reported that homelessness may be an independent risk factor for HAV antibody positivity [27], and targeted vaccination of PEH is feasible [28] and helped control previous outbreaks among PEH [25]. Using the framework of a recent consensus report from the National Academy of Sciences [29], further research should assess whether hepatitis A is a “housing-sensitive condition” from a public health perspective because of risks for PEH acquiring and transmitting HAV.

San Diego City and County, with an estimated 9116 people who were homeless in 2017, ranks fourth highest among US city areas and second only to Los Angeles in the number of people who are homeless and unsheltered [30]. The relatively high burden of homelessness may have contributed to the size and severity of this outbreak. Therefore, COSD targeted interventions toward PEH beginning with the recommendation to vaccinate PEH in the first health alert sent by the county on 10 March 2017 [3]. To reach this population, approximately 2500 HAV vaccination events occurred through stationary points of dispensary, mobile vans, and vaccination foot teams consisting of a nurse and law enforcement officer [31]. Hepatitis A virus vaccinations were also administered by other community partners at homeless shelters, jails, emergency departments, and during influenza vaccination drives. Beyond vaccination, other interventions for this risk group included transitional housing in tent cities, 24-hour public bathrooms and handwashing stations, enhanced street sanitation, targeted health messaging, personal hygiene kits, and temporary convalescent housing after hospital discharge [31].

Case-fatality ratios from recent outbreaks, including San Diego County, are higher than historical outbreaks and may result in part from a shifting case demographic toward older patients [11]. The increasing risk of hospitalization and death among older patients in this outbreak is consistent with previous studies that reported that case fatality increased with age from 0.1% among children aged less than 15 years, 0.3% among people aged 15–39 years, and 2.1% among adults aged 40 years or older [5, 32].

The median age of 43 years among confirmed and probable cases is similar among patients reporting homelessness (median, 44 years) and not reporting homelessness (median, 42 years) and is consistent with contemporaneous outbreaks in other states [11]. While the occurrence of hepatitis A has decreased nationally in all age groups since 2000, incidence of the disease is lowest among persons aged 0–9 years and 10–19 years compared with older age groups as of 2016 [33].

Our study limitations include possible misclassification of sensitive topics including homelessness status and history of illicit drug use, although we expect such misclassification to be independent of case-control status because of the delayed receipt of confirmatory RT-PCR test results. Self-reported vaccination history was cross-referenced and supplemented using the San Diego Immunization Registry, although vaccinations received outside San Diego County are more likely to be missed. The prevalence of comorbidities may be underestimated by using coinfection status with HBV or HCV as an incomplete surrogate for chronic liver disease caused by risk factors such as chronic alcoholism.

In this investigation, we suspect that the measured association between homelessness and HAV infection is likely underestimated, because associations between homelessness and other causes of symptoms consistent with viral hepatitis infection may inflate the prevalence of homelessness among the test-negative control subjects. Additionally, PEH may be preferentially hospitalized for reasons beyond those measured [34, 35], but we expect that the outcome of case fatality is robust to this potential bias.

These findings strongly support the ACIP recommendation to add homelessness as an indication for hepatitis A vaccination [8], as well as the need to improve adult hepatitis A vaccination rates among groups who are at risk and to address the underlying causes of homelessness [26]. Approximately half of all patients in this outbreak, and three-quarters of PEH, had at least 1 previously known ACIP indication for vaccination (Table 2), yet none received the 2-dose HAV vaccination series before infection. Outbreak response vaccination with 1 dose of HAV vaccine was found to be feasible in San Diego County and elsewhere [31, 36, 37], and previous studies have shown that the single vaccine can confer protection for 4–11 years [38, 39].