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. Author manuscript; available in PMC: 2024 Apr 15.
Published in final edited form as: Hepatology. 2021 Apr 19;74(1):28–40. doi: 10.1002/hep.31645

Factors Associated With Hepatitis A Mortality During Person-to-Person Outbreaks: A Matched Case–Control Study—United States, 2016-2019

Megan G Hofmeister 1, Jian Xing 1, Monique A Foster 1, Ryan J Augustine 1, Cole Burkholder 2, Jim Collins 2, Shannon McBee 3, Erica D Thomasson 3,4, Douglas Thoroughman 4,5, Mark K Weng 1, Philip R Spradling 1
PMCID: PMC11017379  NIHMSID: NIHMS1978977  PMID: 33217769

Abstract

BACKGROUND AND AIMS:

During 2016-2020, the United States experienced person-to-person hepatitis A outbreaks that are unprecedented in the vaccine era, during which case–fatality ratios reported by some jurisdictions exceeded those historically associated with hepatitis A.

APPROACH AND RESULTS:

To identify factors associated with hepatitis A–related mortality, we performed a matched case–control study (matched on age [±5 years] and county of residence in a 1:4 ratio) using data collected from health department and hospital medical records of outbreak-associated patients in Kentucky, Michigan, and West Virginia. Controls were hepatitis A outbreak–associated patients who did not die. There were 110 cases (mean age 53.6 years) and 414 matched controls (mean age 51.9 years); most cases (68.2%) and controls (63.8%) were male. Significantly (P < 0.05) higher odds of mortality were associated with preexisting nonviral liver disease (adjusted odds ratio [aOR], 5.2), history of hepatitis B (aOR, 2.4), diabetes (aOR, 2.2), and cardiovascular disease (aOR, 2.2), as well as initial Model for End-Stage Liver Disease (MELD) score ≥ 30 (aOR, 10.0), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio > 2 (aOR, 10.3), and platelet count < 150,000/μL (aOR, 3.7) among hepatitis A outbreak–associated patients in the independent multivariable conditional logistic regression analyses (each model adjusted for sex).

CONCLUSIONS:

Preexisting liver disease, diabetes, cardiovascular disease, and initial MELD score ≥ 30, AST/ALT ratio ≥ 1, and platelet count < 150,000/μL among hepatitis A patients were independently associated with higher odds of mortality. Providers should be vigilant for such features and have a low threshold to escalate care and consider consultation for liver transplantation. Our findings support the recommendation of the Advisory Committee on Immunization Practices to vaccinate persons with chronic liver disease, though future recommendations to include adults with diabetes and cardiovascular disease should be considered.


Hepatitis A virus (HAV) infection typically results in a mild, self-limited illness; however, serious complications do occur in rare instances and are more frequent among adults.(1,2) Historically, hepatitis A mortality in the United States was thought to be low overall (approximately 0.3%-0.6%) but higher in older age groups (approximately 1.8% among adults aged >50 years).(3) More recently, according to the National Notifiable Diseases Surveillance System, all-age mortality for hepatitis A in the United States ranged between 0.7% and 1.0% during 2013-2016 among those reported cases with complete information on death.(4) During that same time period, hepatitis A–related mortality in adults aged 45-64 years consistently exceeded the US overall hepatitis A–related mortality rate, with even higher rates recorded among adults aged >65 years.(5)

In prior studies, older age has been the characteristic most commonly associated with hepatitis A–related mortality.(610) In 2010, the highest mortality rates among decedents with hepatitis A in the United States were observed among persons aged ≥45 years old.(8) The mean age at death among decedents with HAV infection increased in the United States from 48.0 years in 1999 to 76.2 years in 2011.(9) Investigators have identified a variety of additional characteristics, including chronic liver disease, male sex, extended hospitalizations, homelessness, and elevated bilirubin levels associated with hepatitis A-related mortality in the literature.(6,7,913) Additional studies have developed prognostic models aimed at predicting the risk of transplant or death in patients with hepatitis A–related acute liver failure.(14,15) These studies have identified combinations of presenting features such as age, abnormal laboratory results (e.g., alanine aminotransferase [ALT], ammonia, bilirubin, creatinine, hemoglobin, international normalized ratio), intubation status, and administration of vasopressors as components of models that accurately predict outcomes in patients with acute liver failure caused by hepatitis A.(14,15)

Multiple US states are experiencing person-to-person hepatitis A outbreaks that are unprecedented in the vaccine era. The infections are spreading primarily through close contact among persons who use drugs, persons experiencing homelessness, and men who have sex with men (MSM).(16) Between July 1, 2016, and October 16, 2020, state health departments publicly reported >35,500 outbreak-associated patients, >21,700 hospitalizations, and >335 deaths.(17)

During these ongoing person-to-person hepatitis A outbreaks, several jurisdictions reported high numbers of hepatitis A–related deaths and case–fatality ratios higher than those historically associated with hepatitis A surveillance and outbreak data in the United States. Given the high number of deaths reported in recent outbreaks, we sought to identify risk factors for hepatitis A–related mortality in the setting of person-to-person transmission outbreaks. The aims of this study were to identify patient characteristics that could guide clinical decision-making and to identify findings that could inform new hepatitis A vaccination recommendations or support existing ones. We conducted a matched case–control study in three states, selecting Kentucky, Michigan, and West Virginia to maximize the study’s impact as these three states accounted for 56% of the person-to-person hepatitis A–related deaths that had been publicly reported nationwide at the end of the study period.

Methods

We performed a matched case–control study using data collected from state health department and hospital medical records for hepatitis A outbreak–associated patients with onset between July 1, 2016, and June 10, 2019. Individuals eligible for study participation were residents of Kentucky, Michigan, or West Virginia and had been designated by the respective state health department as a person-to-person outbreak-associated hepatitis A patient. We obtained deidentified hepatitis A outbreak records from the Kentucky Department for Public Health, the Michigan Department of Health and Human Services, and the West Virginia Bureau for Public Health, current as of June 11, 2019; August 16, 2019; and June 13, 2019, respectively. We defined study cases as hepatitis A outbreak–associated patients who died and whose deaths were determined to be associated with hepatitis A by the respective state health department. Study controls were hepatitis A outbreak–associated patients who had not died and were matched to cases on age (±5 years) and county of residence in a 4:1 ratio. If insufficient controls were available in a case’s county of residence, we attempted to identify additional controls from randomly selected contiguous counties. If all potential controls in immediately contiguous counties were exhausted, we ended enrollment for that case even if fewer than four controls were identified. We reviewed all available hospital medical records and state health department outbreak records using a standardized data abstraction instrument. If discrepancies existed between the medical and health department records, investigators recorded the positive response.

We obtained demographic (age, sex, race, ethnicity, county and state of residence), risk factor (drug use [injection and noninjection], homelessness, unstable housing, transient living, MSM status, incarceration, international travel, epidemiological linkage), clinical (comorbid medical conditions, pregnancy status, signs or symptoms consistent with hepatitis A, laboratory results), and outcome (hospitalization, acute liver failure, liver transplant, death) data for study participants. Risk factors were assessed based on their presence or absence during a participant’s exposure period (i.e., the 15-50 days prior to symptom onset). Epidemiological linkage was defined as being a close contact of a known hepatitis A outbreak–associated patient.

We assessed the following comorbid medical conditions: history of hepatitis B (laboratory evidence of prior exposure or current infection or hepatitis B diagnosed in the medical record), history of hepatitis C (laboratory evidence of prior exposure or current infection or hepatitis C diagnosed in the medical record), other preexisting liver disease (e.g., alcohol-associated liver disease, nonalcoholic fatty liver disease, cirrhosis), diabetes, immunosuppression (e.g., HIV/AIDS; hemodialysis; recipient of solid organ, bone marrow, or stem cell transplant; recipient of high-dose steroids, chemotherapy, or immunomodulators at the time of hepatitis A diagnosis; primary immunodeficiency condition), and cardiovascular disease (e.g., coronary artery disease, hypertension, congestive heart failure, valvular heart disease, dyslipidemia, arrhythmia, peripheral artery disease, stroke). For laboratory results, we abstracted the result most temporally proximal to the collection time of the specimen that produced the HAV immunoglobulin M (IgM)–positive result. The Model for End-Stage Liver Disease (MELD) score was calculated in accordance with current Organ Procurement and Transplantation Network guidance and was based on laboratory results closest in time to admission for the hepatitis A hospitalization.(18)

We categorized participants as having been hospitalized if they had evidence of an inpatient hospital admission, evidence of an admission order from an emergency department physician if a patient had left against medical advice, or evidence of >24 hours of observation. Participants who were evaluated in an outpatient clinic, who were discharged to home from the emergency department with a duration of stay ≤24 hours, or whose hospitalization status was unknown were not considered hospitalized. If a participant was hospitalized more than once for hepatitis A, we combined the days from each hospitalization and reported the total. We categorized participants as having acute liver failure if the diagnosis was documented in the medical record or there was evidence of concurrent coagulopathy and hepatic encephalopathy in a patient with previously stable liver function.

Abstracted data were entered into a REDCap database.(19,20) A second author independently reviewed and verified the accuracy of each participant record in the database. We calculated descriptive statistics among participants with available data and conducted multivariable conditional logistic regression analyses to determine factors associated with hepatitis A–related mortality in the setting of person-to-person transmission outbreaks. We adjusted the multivariable models by sex, except for the MSM and pregnancy variables. We included all liver-related comorbidities as well as comorbidities that were identified as significantly associated with hepatitis A–related mortality in the initial multivariable analyses, in additional conditional logistic regression analyses examining the association of diabetes and mortality (after controlling for sex, history of hepatitis B, history of hepatitis C, other preexisting liver disease, and cardiovascular disease), and the association of cardiovascular disease and mortality (after controlling for sex, history of hepatitis B, history of hepatitis C, other preexisting liver disease, and diabetes). All ORs presented are matched ORs. We conducted all analyses using SAS software, version 9.4 (SAS Institute Inc., Cary, NC).

As this study was determined not to be human subjects research by the Centers for Disease Control and Prevention and the Michigan Department of Health and Human Resources Institutional Review Board (IRB), it was exempt from IRB review.

Results

CHARACTERISTICS AND OUTCOMES

We identified 110 cases (59 from Kentucky, 30 from Michigan, and 21 from West Virginia) and 414 matched controls (223 from Kentucky, 109 from Michigan, and 82 from West Virginia) for our study sample. Cases had a mean age of 53.6 years, while controls had a mean age of 51.9 years. Most cases and controls were male (68.2% and 63.8%, respectively). Among those with available information, 52.2% versus 55.1% reported drug use; 11.2% versus 10.8% reported homelessness, unstable housing, or transient living; 7.5% versus 16.7% reported current or recent incarceration at the time of hepatitis A diagnosis; and 51.9% versus 50.4% had an epidemiological link to a known hepatitis A outbreak-associated patient (cases vs. controls, respectively) (Table 1).

TABLE 1.

Multivariable Associations With Mortality During Person-to-Person Hepatitis A Outbreaks—Kentucky, Michigan, and West Virginia, 2016-2019

Characteristic Cases, n (%) (n = 110)* Controls, n (%) (n = 414)* aOR (95% CI) P
Demographic
Age, year
 Mean (SE) 53.6 (1.4) 51.9 (0.7)
 Median (range) 55.0 (24.0-87.0) 53.0 (21.0-90.0)
Age categories
 20-29 6 (5.5) 21 (5.1)
 30-39 11 (10.0) 51 (12.3)
 40-49 28 (25.5) 104 (25.1)
 50-69 47 (42.7) 189 (45.7)
 ≥70 18 (16.4) 49 (11.8)
Sex
 Male 75 (68.2) 264 (63.8) 1.2 (0.6-2.1) 0.660
 Female 35 (31.8) 150 (36.2) REF
Race/ethnicity (n = 318)
 Caucasian/NH 85 (96.6) 195 (84.8) REF
 African American/NH 3 (3.4) 33 (14.3) 0.2 (0.0-0.8) 0.022
 Other 0 (0.0) 2 (0.9) N/A N/A
Risk factor §
Drug use (n = 431)
 Yes 47 (52.2) 188 (55.1) 1.0 (0.6-1.8) 0.990
 No 43 (47.8) 153 (44.9) REF
Injection drug use (n = 389)
 Yes 31 (39.2) 122 (39.4) 1.1 (0.5-2.4) 0.770
 No 48 (60.8) 188 (60.6) REF
Noninjection drug use (n = 333)
 Yes 23 (33.8) 109 (41.1) 0.7 (0.3-1.4) 0.290
 No 45 (66.2) 156 (58.9) REF
Homelessness, unstable housing, or transient living (n = 451)
 Yes 11 (11.2) 38 (10.8) 1.1 (0.5-2.3) 0.830
 No 87 (88.8) 315 (89.2) REF
MSM (n = 134)
 Yes 3 (15.8) 14 (12.2) 1.3 (0.3-5.2) 0.750
 No 16 (84.2) 101 (87.8) REF
Incarcerated (n = 244)
 Yes 3 (7.5) 34 (16.7) 1.7 (0.3-11.3) 0.570
 No 37 (92.5) 170 (83.3) REF
International travel (n = 352)
 Yes 0 (0.0) 0 (0.0) N/A N/A
 No 69 (100.0) 283 (100.0) REF
Epidemiologically linked (n = 158)
 Yes 14 (51.9) 66 (50.4) 2.0 (0.5-8.9) 0.350
 No 13 (48.1) 65 (49.6) REF
Clinical
History of hepatitis B (n = 434)
 Yes 22 (21.8) 36 (10.8) 2.4 (1.3-4.4) 0.006
 No 79 (78.2) 297 (89.2) REF
History of hepatitis C (n = 469)
 Yes 49 (46.2) 142 (39.1) 1.6 (1.0-2.6) 0.077
 No 57 (53.8) 221 (60.9) REF
Other preexisting liver disease (n = 186)
 Yes 60 (81.1) 55 (49.1) 5.2 (2.0-13.9) <0.001
 No 14 (18.9) 57 (50.9) REF
Diabetes (n = 358)
 Yes 41 (42.7) 60 (22.9) 2.2 (1.2-3.8) 0.007
 No 55 (57.3) 202 (77.1) REF
Pregnancy (n = 119)#
 Yes 0 (0.0) 3 (3.3) N/A N/A
 No 27 (100.0) 89 (96.7) REF
Immunosuppression (n = 289)
 Yes 7 (8.1) 12 (5.9) 1.1 (0.4-3.1) 0.880
 No 79 (91.9) 191 (94.1) REF
Cardiovascular disease (n = 332)
 Yes 66 (69.5) 125 (52.7) 2.2 (1.2-3.9) 0.010
 No 29 (30.5) 112 (47.3) REF
Signs or symptoms
Fever (n = 490)
 Yes 50 (48.5) 141 (36.4) 1.6 (1.0-2.4) 0.045
 No 53 (51.5) 246 (63.6) REF
Headache (n = 400)
 Yes 16 (19.5) 48 (15.1) 1.7 (0.8-3.4) 0.168
 No 66 (80.5) 270 (84.9) REF
Malaise (n = 468)
 Yes 61 (64.2) 208 (55.8) 1.6 (0.9-2.8) 0.082
 No 34 (35.8) 165 (44.2) REF
Anorexia (n = 464)
 Yes 42 (44.7) 145 (39.2) 1.3 (0.8-2.3) 0.310
 No 52 (55.3) 225 (60.8) REF
Nausea (n = 503)
 Yes 79 (79.0) 317 (78.7) 1.0 (0.6-1.8) 0.890
 No 21 (21.0) 86 (21.3) REF
Vomiting (n = 482)
 Yes 53 (53.0) 176 (46.1) 1.5 (0.9-2.4) 0.093
 No 47 (47.0) 206 (53.9) REF
Diarrhea (n = 440)
 Yes 32 (34.8) 112 (32.2) 1.3 (0.8-2.2) 0.380
 No 60 (65.2) 236 (67.8) REF
Abdominal pain (n = 505)
 Yes 73 (70.9) 285 (70.9) 1.1 (0.7-1.9) 0.650
 No 30 (29.1) 117 (29.1) REF
Dark urine (n = 444)
 Yes 42 (49.4) 196 (54.6) 0.9 (0.5-1.5) 0.640
 No 43 (50.6) 163 (45.4) REF
Acholic stool (n = 163)
 Yes 13 (41.9) 67 (50.8) 1.1 (0.4-3.1) 0.860
 No 18 (58.1) 65 (49.2) REF
Jaundice/icterus (n = 494)
 Yes 92 (85.2) 296 (76.7) 1.8 (1.0-3.2) 0.059
 No 16 (14.8) 90 (23.3) REF
Date of symptom onset (range) 9/1/2016–5/23/2019 8/17/2016–6/1/2019 N/A N/A
Laboratory results
ALT (IU/L) (n = 512)
 ≤ 200 18 (16.7) 45 (11.1) REF
 201-1,500 39 (36.1) 161 (39.9) 0.7 (0.4-1.3) 0.198
 1,501-3,000 23 (21.3) 122 (30.2) 0.5 (0.2-1.0) 0.037
 > 3,000 28 (25.9) 76 (18.8) 0.9 (0.4-1.8) 0.710
AST (IU/L) (n = 510)
 ≤ 200 14 (13.0) 70 (17.4) REF
 201-1,500 38 (35.2) 175 (43.5) 1.1 (0.6-2.2) 0.780
 1,501-3,000 28 (25.9) 108 (26.9) 1.3 (0.6-2.6) 0.490
 > 3,000 28 (25.9) 49 (12.2) 2.6 (1.2-5.6) 0.013
AST/ALT ratio (n = 510)
 < 1 42 (38.9) 297 (73.9) REF
 1-2 46 (42.6) 90 (22.4) 3.6 (2.2-6.1) <0.001
 > 2 20 (18.5) 15 (3.7) 10.3 (4.7-22.3) <0.001
Total bilirubin (mg/dL) (n = 382)
 < 3 21 (20.4) 53 (19.0) REF
 3-6 15 (14.6) 85 (30.5) 0.4 (0.2-0.9) 0.023
 6-9 12 (11.7) 67 (24.0) 0.4 (0.2-1.1) 0.066
 > 9 55 (53.4) 74 (26.5) 2.1 (1.1-4.2) 0.026
Platelet count (K/μL) (n = 357)
 < 150 51 (50.5) 58 (22.7) 3.7 (2.1-6.5) <0.001
 ≥ 150 50 (49.5) 198 (77.3) REF
MELD score (n = 324)
 ≤ 19 11 (11.1) 118 (52.4) 0.1 (0.0-0.4) <0.001
 20-29 38 (38.4) 93 (41.3) REF
 ≥ 30 50 (50.5) 14 (6.2) 10.0 (3.7-26.7) <0.001
HBsAg (n = 437)
 Positive/reactive 16 (15.8) 19 (5.7) 3.2 (1.5-7.1) 0.004
 Negative/nonreactive 85 (84.2) 317 (94.3) REF
IgM anti-HBc (n = 428)
 Positive/reactive 8 (7.9) 21 (6.4) 1.4 (0.6-3.4) 0.470
 Negative/nonreactive 90 (89.1) 304 (93.0) REF
 Indeterminate/borderline 3 (3.0) 2 (0.6) 4.3 (0.7-26.1) 0.119
Anti-HCV (n = 446)
 Positive/reactive 47 (45.6) 129 (37.6) 1.7 (1.0-2.8) 0.045
 Negative/nonreactive 56 (54.4) 214 (62.4) REF
HCV RNA viral load (n = 96)
 Undetectable 18 (46.2) 28 (49.1) REF
 Detected but not quantifiable 5 (12.8) 9 (15.8) 0.3 (0.0-11.9) 0.520
 Detected and quantifiable 16 (41.0) 20 (35.1) 0.2 (0.0-2.9) 0.230
Outcome
Hospitalized (n = 513)
 Yes 103 (95.4) 248 (61.2) 17.1 (6.1-47.7) <0.001
 No 5 (4.6) 157 (38.8) REF
Length of hospitalization, days (n = 346)**
 1-3 15 (14.9) 85 (34.7) REF
 4-7 28 (27.7) 110 (44.9) 1.2 (0.6-2.6) 0.630
 8-14 28 (27.7) 37 (15.1) 4.7 (2.1-11.0) <0.001
 ≥ 15 30 (29.7) 13 (5.3) 16.4 (5.7-47.3) <0.001
Intensive care unit (n = 332)**
 Yes 81 (83.5) 26 (11.1) 45.3 (14.1-144.9) <0.001
 No 16 (16.5) 209 (88.9) REF
Number of hepatitis A–related hospitalizations**
 1 62 (60.2) 229 (92.3) REF
 2 32 (31.1) 18 (7.3) 6.9 (3.2-14.8) <0.001
 3 6 (5.8) 1 (0.4) 11.8 (1.3-105.3) 0.027
 > 3 3 (2.9) 0 (0.0) N/A N/A
Acute liver failure (n = 354)
 Yes 74 (80.4) 14 (5.3) 218.9 (27.8-1721.2) <0.001
 No 18 (19.6) 248 (94.7) REF
Liver transplant (n = 355)
 Yes 1 (1.1) 0 (0.0) N/A N/A
 No 90 (98.9) 264 (100.0) REF

Statistically significant associations are highlighted in bold.

*

Percentages are calculated based on participants with available information and may not sum to 100.0% due to rounding.

Adjusted by sex, except for MSM and pregnancy. All ORs presented are matched ORs after matching for age (±5 years) and county of residence.

Other: Hispanic ethnicity.

§

Risk factors were assessed based on their presence or absence during a participant’s exposure period (i.e., the 15-50 days prior to symptom onset).

Restricted to those with available information on reported drug use (n = 431).

Restricted to male study participants (n = 339).

#

Restricted to female study participants (n = 185).

**

Restricted to hospitalized study participants (n = 351).

Abbreviations: ALT, alanine aminotransferase; anti-HCV, hepatitis C antibody; AST, aspartate aminotransferase; CI, confidence interval; HBsAg, hepatitis B surface antigen; IgM anti-HBc, immunoglobulin M hepatitis B core antibody; MELD, Model for End-Stage Liver Disease; MSM, men who have sex with men; NH, non-Hispanic; OR, odds ratio; REF, reference category; SE, standard error.

Compared to controls, higher proportions of cases had medical comorbidities including history of hepatitis B, history of hepatitis C, other preexisting liver disease, diabetes, immunosuppression, and cardiovascular disease. Jaundice/icterus (85.2% vs. 76.7%), nausea (79.0% vs. 78.7%), and abdominal pain (70.9% vs. 70.9%) were the most frequently reported signs and symptoms (cases versus controls, respectively) (Table 1). Among those with available data on hospitalization status, 95.4% of cases were hospitalized for a mean of 13.1 days, while 61.2% of controls were hospitalized for a mean of 5.8 days. Among hospitalized patients, 39.8% of cases and 7.7% of controls had multiple hepatitis A–related hospitalizations (Table 1). Demographic, risk factor, clinical, and outcome characteristics of the study sample stratified by state are described in the accompanying Supporting Information.

FACTORS ASSOCIATED WITH MORTALITY

Clinical factors were identified as significantly associated (P < 0.05) with higher odds of mortality among hepatitis A outbreak–associated patients through multivariable conditional logistic regression (adjusted for sex). Preexisting conditions and symptoms of hepatitis A that were associated with higher odds of mortality included other preexisting liver disease (adjusted odds ratio [aOR], 5.2, 95% CI 2.0-13.9), history of hepatitis B (aOR, 2.4; 95% CI, 1.3-4.4), diabetes (aOR, 2.2; 95% CI, 1.2-3.8), cardiovascular disease (aOR, 2.2; 95% CI, 1.2-3.9), and fever (aOR, 1.6; 95% CI, 1.0-2.4). Initial laboratory indicators were also associated with higher odds of mortality: MELD score ≥ 30 (aOR, 10.0; 95% CI, 3.7-26.7, compared to MELD score 20-29), aspartate aminotransferase (AST)/ALT ratio ≥1 (aOR, 3.6; 95% CI, 2.2-6.1 for AST/ALT ratio 1-2 and aOR, 10.3; 95% CI, 4.7-22.3 for AST/ALT ratio >2, compared to AST/ALT ratio <1), platelet count <150,000/μL (aOR, 3.7; 95% CI, 2.1-6.5), HBsAg-positive (aOR, 3.2; 95% CI, 1.5-7.1), AST >3,000 IU/L (aOR, 2.6; 95% CI, 1.2-5.6, compared to AST ≤200 IU/L), total bilirubin >9 mg/dL (aOR, 2.1; 95% CI, 1.1-4.2, compared to <3 mg/dL), and anti-HCV-positive (aOR, 1.7; 95% CI, 1.0-2.8). Additionally, clinical outcomes were associated with higher odds of mortality: acute liver failure (aOR, 218.9; 95% CI, 27.8-1,721.2), intensive care unit admission (aOR, 45.3; 95% CI, 14.1-144.9), hospitalization (aOR, 17.1; 95% CI, 6.1-47.7), hospital length of stay >7 days (aOR, 4.7; 95% CI, 2.1-11.0 for 8-14 days and aOR, 16.4; 95% CI, 5.7-47.3 for ≥15 days, compared to 1-3 days), and two or three hepatitis A–related hospitalizations (aOR, 6.9; 95% CI, 3.2-14.8 and aOR, 11.8; 95% CI, 1.3-105.3, respectively, compared to one hepatitis A–related hospitalization). MELD score ≤19 (aOR, 0.1; 95% CI, 0.0-0.4, compared to MELD score 20-29) and African American/non-Hispanic race/ethnicity (aOR, 0.2; 95% CI, 0.0-0.8, compared to Caucasian/non-Hispanic) were significantly associated with lower odds of mortality (Table 1).

Diabetes (aOR, 5.3; 95% CI, 1.2-23.0) remained significantly associated (P < 0.05) with higher odds of mortality among hepatitis A outbreak–associated patients through multivariable conditional logistic regression even after adjusting for history of hepatitis B, history of hepatitis C, other preexisting liver disease, cardiovascular disease, and sex. Cardiovascular disease (aOR, 3.1; 95% CI, 0.9-11.2) was also associated with higher odds of hepatitis A–related mortality after adjusting for history of hepatitis B, history of hepatitis C, other preexisting liver disease, diabetes, and sex; however, the association was not statistically significant (Table 2).

TABLE 2.

Multivariable Conditional Logistic Regression Analyses of Non-Liver-Related Comorbidities Associated With Mortality During Person-to-Person Hepatitis A Outbreaks—Kentucky, Michigan, and West Virginia, 2016-2019

Characteristic aOR (95% CI)* P
Diabetes
 Yes 5.3 (1.2-23.0) 0.027
 No REF
Cardiovascular disease
 Yes 3.1 (0.9-11.2) 0.078
 No REF

Statistically significant associations are highlighted in bold.

*

All ORs presented are matched ORs after matching for age (±5 years) and county of residence.

Adjusted by sex, history of hepatitis B, history of hepatitis C, other preexisting liver disease, and cardiovascular disease.

Adjusted by sex, history of hepatitis B, history of hepatitis C, other preexisting liver disease, and diabetes.

Abbreviation: REF, reference category.

Discussion

We performed a matched case–rontrol study of hepatitis A outbreak–associated patients from three states that experienced extensive person-to-person outbreaks and found significantly higher odds of mortality associated with certain comorbidities and initial laboratory indicators. We identified patient characteristics that could guide clinical decision-making, findings that support existing Advisory Committee on Immunization Practices (ACIP) hepatitis A vaccination recommendations, and findings that could inform new vaccination recommendations.

Abnormal laboratory results for tests commonly performed in the setting of hepatitis A were associated with mortality. We found that a serum AST/ALT ratio ≥1 was associated with higher odds of hepatitis A–related mortality, with the odds increasing with increasing AST/ALT ratio. In the setting of acute viral hepatitis infections, ALT is usually higher than AST, resulting in AST/ALT ratios <1.(21) However, AST/ALT ratios >1 can occasionally occur in the setting of hepatitis A infection and typically represent cases of acute liver failure with poor prognosis.(22) AST/ALT ratios >1 have also been associated with chronic viral hepatitis that has progressed to fibrosis and cirrhosis, while ratios >2 have been associated with alcohol-associated hepatitis.(2224) In our study, compared to a total bilirubin <3 mg/dL, total bilirubin >9 mg/dL was associated with higher odds of mortality. Similarly, in a single-center study of patients with hepatitis A hospitalized in France during 1987-2000, a high bilirubin level was significantly related to the risk of death or transplantation.(13) Platelet counts <150,000/μL were also significantly associated with higher odds of hepatitis A–related mortality. Lower-than-normal platelet counts have been associated with cirrhosis and progression to hepatic decompensation among patients with chronic hepatitis C.(25) Additionally, bleeding complications and decreasing platelet counts after admission for acute liver failure of any etiology have been associated with systemic inflammation and poor prognosis.(26,27) Further research is needed to determine whether the observed hepatitis A–related mortality associations with AST/ALT ratio ≥1 and thrombocytopenia are indicative of preexisting liver disease or an acute manifestation of hepatitis A infection. We also found that MELD scores ≥30 were associated with higher odds of mortality, while MELD scores ≤19 were associated with 90% lower odds of mortality, compared with scores 20-29. This is consistent with research that prospectively validated the MELD score among patients awaiting liver transplantation with a variety of liver diseases.(28) MELD scores ≥30 have been associated with ≥50% estimated 3-month mortality.(28) Additionally, we analyzed the MELD score as a continuous variable and found that the odds of hepatitis A–related mortality significantly increased with increasing MELD score (aOR, 1.2; 95% CI, 1.2-1.3). While hepatitis A–related mortality was not specifically assessed, an analysis of San Diego, California, hepatitis A outbreak–associated cases hospitalized at a single medical center demonstrated that a higher MELD-sodium score independently predicted acute liver failure.(29)

We found that persons with diabetes or cardiovascular disease had 2.2 times higher odds of hepatitis A–related mortality. Neither of these comorbidities is currently recognized by the ACIP as an independent risk factor for adverse consequences of HAV infection.(30) However, a previous analysis of the 2013 US foodborne hepatitis A outbreak associated with frozen pomegranate arils found that the presence of comorbidities, such as diabetes and cardiovascular disease, was associated with hospitalization.(31) When we further examined the associations of diabetes and cardiovascular disease with hepatitis A–related mortality after controlling for other comorbidities, we found that the strength of the mortality associations between diabetes (aOR, 5.3; 95% CI, 1.2-23.0) and cardiovascular disease (aOR, 3.1; 95% CI, 0.9-11.2) increased. However, the association between cardiovascular disease and hepatitis A–related mortality was no longer statistically significant. We expect that the results for both diabetes and cardiovascular disease are conservative estimates of the actual associations with hepatitis A–related mortality. We compared fatal hepatitis A cases to nonfatal hepatitis A controls. Had we used an approach that included patients without hepatitis A as controls, the associations with hepatitis A–related mortality might have been even stronger. This further supports future consideration of diabetes and cardiovascular disease by the ACIP as indications for adult hepatitis A vaccination.

As might be expected, acute liver failure and several hospitalization-related indicators of disease severity were significantly associated with higher odds of hepatitis A–related mortality in this study. Acute liver failure had the strongest association with hepatitis A–related mortality of any variable examined in this study (aOR, 218.9; 95% CI, 27.8-1,721.2). Historically, acute liver failure due to HAV infection has been rare in the United States, occurring in <1% of cases.(2) However, acute liver failure occurred in 4.3% of a random sample of person-to-person hepatitis A outbreak–associated patients in Kentucky, Michigan, and West Virginia during 2016-2019.(32) Participants who were hospitalized had higher odds of dying than those who were not hospitalized. Among hospitalized participants, longer hospitalizations, multiple hospitalizations, and intensive care unit admission were associated with mortality. Although these factors were associated with hepatitis A–related mortality in our study, these associations are not useful to providers from a prognostic standpoint at patient presentation; hospitalization and escalation of care should not be avoided if clinically indicated.

Consistent with previous studies, chronic liver disease was associated with higher odds of hepatitis A–related mortality.(7,10,11) In this study, participants with a history of hepatitis B, participants who were HBsAg-positive, participants who were anti-HCV-positive, and participants with other preexisting liver disease (e.g., alcohol-associated liver disease, nonalcoholic fatty liver disease, cirrhosis) had higher odds of hepatitis A–related mortality. Although the proportion of cases with a history of hepatitis C was higher than that for controls (aOR, 1.6; 95% CI, 1.0-2.6), the finding was not statistically significant. The significant association between alcohol-associated liver disease, nonalcoholic fatty liver disease, or cirrhosis and mortality is notable given the potential for those preexisting liver diseases to be underascertained. Detection of nonalcoholic fatty liver disease and cirrhosis was dependent on whether providers ordered ultrasound or computed tomographic imaging studies, whether medical records departments included imaging results while fulfilling records requests, and whether abstractors noticed imaging results consistent with these conditions.

We suspect that alcohol played a more significant role in hepatitis A–related mortality than we were able to discern through our study. Alcohol use was rarely documented in the medical records reviewed for this study; even in the rare instances when it was documented, insufficient details on quantity and frequency of alcohol consumption were present to accurately determine the presence of alcohol use disorder. The National Survey on Drug Use and Health is conducted annually by the US Substance Abuse and Mental Health Services Administration and provides national data on tobacco, alcohol, and drug use.(33) In 2018, during the most recent year for which data are available, approximately 32% of people (aged 12 and older) with illicit drug use disorder in the past year also had alcohol use disorder in the past year.(33) Given the high prevalence of drug use in our study, it is possible that a substantial proportion of participants could have had compromised liver function as a result of alcohol use disorder.

None of the risk factors for HAV infection (e.g., drug use, homelessness, unstable housing, transient living, MSM, incarceration, international travel, epidemiological linkage) that we examined were significantly associated with hepatitis A–related mortality. However, people experiencing homelessness had 3.9 times higher odds of hepatitis A–related mortality than those not experiencing homelessness in the 2016-2018 person-to-person hepatitis A outbreak in San Diego County, California.(12) This discrepancy may be attributable to the fact that the San Diego study used controls who were negative for HAV infection, while our study used nonfatal HAV-infected controls, 61% of whom were sufficiently ill to warrant hospitalization.

African American/non-Hispanic race/ethnicity, compared to Caucasian/non-Hispanic race/ethnicity, was associated with 80% lower odds of hepatitis A–related mortality in this study. In contrast, US Multiple Cause of Death data show that age-adjusted hepatitis A mortality rates have historically been higher among non-Hispanic black persons than non-Hispanic white persons (0.49 versus 0.35 per 1,000,000 population, respectively, during 1990-1995; 0.36 versus 0.24, per 1,000,000 population, respectively, during 2000-2004).(7) More recently, however, there has been increased parity in hepatitis A mortality rates in the Multiple Cause of Death database; in 2010, the age-adjusted mortality rate among non-Hispanic black persons was 0.04 per 100,000 population, while the rate among non-Hispanic white persons was 0.03 per 100,000 population.(8) In our matched case-control study, there were only three African American/non-Hispanic cases; all three were residents of Michigan. Thus, our findings in this regard may have limited relevance.

Although the matched case–control design used in our study precludes exploration of the effect of age on hepatitis A–related mortality, we explored the age distribution of study cases versus all those hepatitis A patients who did not die (i.e., potential controls). Consistent with the body of literature that guided our a priori decision to match study cases and controls on age, the mean and median ages for study cases were older than the mean and median ages for all potential controls in each participating state.(610) In Kentucky, study cases were on average 49.7 years old (median 47.0 years old), while all potential controls were on average 37.5 years old (median 36.0 years old). In Michigan, study cases were on average 61.2 years old (median 58.5 years old), while all potential controls were on average 42.1 years old (median 39.0 years old). And in West Virginia, study cases were on average 53.7 years old (median 56.0 years old), while all potential controls were on average 38.8 years old (median 37.0 years old).

Our study has other limitations. First, the states involved in this study did not use an identical hepatitis A–related death case definition, which might have resulted in differential classification of deaths as being hepatitis A–related or not. Upon medical record review—after the point in time at which case and control eligibility had been determined—coauthors identified six controls who died and whose deaths were hepatitis A–related. We proceeded with the analysis using an intention-to-treat approach, maintaining the originally assigned case and control status based on the information that had been available to the state health departments at the time the study assignments were made. We did, however, conduct a sensitivity analysis excluding the 6 controls who died; the only difference in the multivariable conditional logistic regression models was that anti-HCV positivity was no longer statistically significantly associated with hepatitis A–related mortality (data not shown). Second, behavioral risk data were primarily self-reported and subject to recall and social desirability bias. Third, a substantial proportion of data was missing for many of the variables in the study. The populations most impacted by the ongoing person-to-person outbreaks are often difficult to reach, creating challenges for public health to conduct case investigation interviews and resulting in relatively high rates of loss to follow-up. While rates of loss to follow-up have varied widely between states affected by the person-to-person outbreaks, the rates were similar among the state participants in this study.(34,35) Finally, the generalizability of the study might be limited as only three states were involved. However, in June 2019, at the end of the study period, Kentucky, Michigan, and West Virginia accounted for 40% of the person-to-person hepatitis A outbreak–associated patients that had been publicly reported nationwide.

Given the relatively high number of hepatitis A–related deaths reported by Kentucky, Michigan, and West Virginia during their respective person-to-person hepatitis A outbreaks, we sought to characterize factors associated with hepatitis A–related mortality. We found that nonviral preexisting liver disease, history of hepatitis B, diabetes, cardiovascular disease, MELD score ≥ 30, AST/ALT ratio ≥ 1, and platelet count < 150,000/μL were independently significantly associated with higher odds of mortality. Patients with hepatitis A who have these comorbidities and laboratory abnormalities should prompt providers to have a low threshold to escalate care and consider consultation with transplant specialists. Our findings support the current ACIP recommendation to vaccinate all persons with chronic liver disease and highlight missed opportunities for prevention given that at least 75% of cases who died had some form of preexisting liver disease. In 2017, self-reported adult hepatitis A vaccination coverage among persons with chronic liver conditions with two or more doses was only 20.8%.(36) It is incumbent on health care providers of persons with chronic liver disease to improve hepatitis A vaccination coverage rates in accordance with the ACIP recommendations. The findings from our study suggest that adults with diabetes and cardiovascular disease could be considered for inclusion in future ACIP hepatitis A vaccination recommendations.

Supplementary Material

Supplemental Figure
Supplemental Table

Acknowledgment:

The authors extend their gratitude to Yuna Zhong for assistance with additional analysis (Division of Viral Hepatitis, Centers for Disease Control and Prevention); the Kentucky Department for Public Health (KDPH), Division of Epidemiology and Health Planning, Reportable Disease Section; Diana Carrier (KDPH); the Michigan Department of Health and Human Services, Surveillance and Infectious Disease Epidemiology Section; Terrie Lee (Infection Prevention & Employee Health, Charleston Area Medical Center); the West Virginia Bureau for Public Health Hepatitis A Outbreak Response Team; and local health department and hospital medical record department staff in Kentucky, Michigan, and West Virginia.

Disclaimer:

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Abbreviations:

ACIP

Advisory Committee on Immunization Practices

ALT

alanine aminotransferase

aOR

adjusted odds ratio

AST

aspartate aminotransferase

HAV

hepatitis A virus

MELD

Model for End-Stage Liver Disease

MSM

men who have sex with men

Footnotes

Potential conflict of interest: Nothing to report.

Supporting Information

Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.31645/suppinfo.

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Supplementary Materials

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