Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center Study.

BACKGROUND & AIMS: Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19).
METHODS: We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD.
RESULTS: Of the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19.
CONCLUSIONS: The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084.

Background

The clinical outcomes of patients with chronic liver disease (CLD) and the novel coronavirus disease 2019 (COVID-19) are not well-defined. Also, it is not clear which patients with CLD are most vulnerable to adverse outcomes from COVID-19.

Findings

In this large study of 867 patients from 21 centers across the US with CLD with COVID-19 we determine that patients with alcohol-related liver disease (ALD), decompensated cirrhosis, and hepatocellular carcinoma have a high risk for all-cause mortality from COVID-19. Lack of adequate COVID-19 testing during the early phase of the pandemic could have led to decreased representation of patients with CLD and mild COVID-19 in our cohort.

Implications for patient care

Our findings will enable risk stratification and personalized management of patients with CLD who acquire COVID-19. Moreover, the association between ALD and poor outcomes with COVID-19 has broad public health implications because of recent concerns about increased alcohol consumption during the pandemic.

Chronic liver disease (CLD) is a major international public health concern, and its prevalence has been increasing over the past 2 decades. , Around 1.5 billion people have CLD worldwide, and it causes more than 2 million deaths per year. , With the rapid spread of the global pandemic of coronavirus disease 2019 (COVID-19), there has been significant concern that patients with CLD represent a vulnerable population at higher risk for complications.

Initial concerns were based on the observation that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is genetically related to SARS-CoV and Middle East respiratory syndrome coronavirus, both of which impair liver function. , These concerns appear to have been substantiated, with early studies reporting elevations in liver enzymes in up to 50% of patients with COVID-19, with higher prevalence in those with worse prognosis. , Preliminary studies from the United States (US) and Europe also suggest that patients with CLD who acquire COVID-19 have high rates of hospitalization and mortality.9, 10, 11 Although these reports raise the alarm, it is not known whether all patients with CLD are affected equally or whether there are specific subgroups at higher risk for COVID-19 related mortality and morbidity.

Identifying predictors of mortality will allow for risk stratification of patients with CLD affected by COVID-19 and help improve healthcare delivery. To comprehensively characterize the clinical outcomes of COVID-19 in patients with CLD, we undertook a multicenter, observational study of patients with CLD who were diagnosed with COVID-19 in 21 centers across the US.

Methods

Study Design

This is a multicenter observational cohort study. The consortium of investigators to study COVID-19 in chronic liver disease (COLD) study was formed on April 14, 2020, and accrual of data started immediately (registered Clinicaltrials.gov NCT04439084). A total of 21 centers from the US participated in the study (Supplementary Table 1). The institutional review board of each participating center reviewed and approved the study protocol. Inclusion criteria constituted age older than 18 years, laboratory-confirmed diagnosis of COVID-19, and presence of preexisting CLD (according to predefined International Classification of Diseases [ICD]-10 codes listed in Supplementary Table 2 and confirmed by manual chart review). Patients who had undergone liver transplantation were excluded. Patients with COVID-19 diagnosis based on clinical suspicion were excluded. All participating institutions independently identified patients meeting inclusion criteria by searching their electronic medical records and collected data as per the previously established data accrual plan. The study retrospectively identified cases diagnosed between March 1 and April 14, and subsequent cases diagnosed with COVID-19 between April 15 and May 30, 2020 were identified prospectively. All data were collected until death or date of last follow-up. Death was attributed to COVID-19 if it was clinically related to COVID-19 illness, and there were no other unrelated causes of death.

Supplementary Table 1

List of Participating Institutions and Investigators From Each Site

	Institution	Principal investigator
1	Ochsner Medical Center, LA	Nyann Latt
2	Massachusetts General Hospital, MA	Patricia P. Bloom
3	Mount Sinai School of Medicine, NY	Ponni Perumalswami
4	University of California San Francisco, Fresno, CA	Marina Roytman
5	Hennepin County Medical Center, MN	Elizabeth Aby, Jose Debes
6	Brigham and Women’s Hospital, MA	Kathleen Viveiros, Walter Chan
7	Duke University, NC	Kara Wegermann, Tzu-Hao Lee
8	Beth Israel Deaconess Medical Center, MA	Maria Andreea Catana
9	Stanford University, CA	Donghee Kim, Nia Adeniji, Paul Kwo, Renumathy Dhanasekaran
10	University of Pennsylvania, PA	Rotonya Carr
11	Rush University Medical Center, IL	Costica Aloman
12	University of Michigan, MI	Vincent Chen
13	Veterans Administration (VA) Medical Center, Washington, DC	Atoosa Rabiee
14	University of Minnesota, MN	Elizabeth Aby
15	Georgetown University, Washington DC	Brett Sadowski
16	University of Arizona/Banner Health, AZ	Veronica Nguyen
17	The University of Kansas Medical Center, KS	Winston Dunn
18	University Hospitals Cleveland Medical Center, OH	Kenneth Chavin
19	University of Southern California, CA	Kali Zhou
20	Mayo Clinic, AZ	Blanca Lizaola-Mayo
21	Weill Cornell Medicine, NY	Sonal Kumar

Supplementary Table 2

List of International Classification of Diseases-10 Codes for Chronic Liver Disease and COVID-19

COVID-19	SARS-CoV-2 Lab Code
U07.1 COVID-19	LAB9309
NASH/NAFLD	Unspecified chronic liver disease
K75.81 Nonalcoholic steatohepatitis (NASH)	K73 Chronic hepatitis
K76.0 NAFLD (nonalcoholic fatty liver disease)	K73.0 Chronic persistent hepatitis
Alcohol-related liver disease	K73.1 Chronic lobular hepatitis
K70 Alcoholic liver disease	K73.2 Chronic active hepatitis
K70.1 Alcoholic hepatitis	K73.8 Other chronic hepatitis, Recurrent hepatitis
K70.10 …… without ascites	K73.9 Chronic hepatitis, unspecified
K70.11 …… with ascites	K74 Fibrosis and cirrhosis of liver
K70.2 Alcoholic fibrosis and sclerosis of liver	K74.0 Hepatic fibrosis
K70.3 Alcoholic cirrhosis of liver	K74.1 Hepatic sclerosis
K70.30 …… without ascites	K74.2 Hepatic fibrosis with hepatic sclerosis
K70.31 …… with ascites	K74.4 Secondary biliary cirrhosis
K70.4 Alcoholic hepatic failure	K74.5 Biliary cirrhosis, unspecified
K70.40 …… without coma	K74.6 Other and unspecified cirrhosis of liver
K70.41 …… with coma	K74.60 Unspecified cirrhosis of liver
K70.9 Alcoholic liver disease, unspecified	K74.69 Other cirrhosis of liver
Chronic Hepatitis C/Hepatitis B	K71.7 Toxic liver disease with fibrosis and cirrhosis
B18.2 Chronic hepatitis C	K71.3 Toxic liver disease with chronic hepatitis
K74.6 Chronic hepatitis C with cirrhosis	K71.4 Toxic liver disease with chronic lobular hepatitis
K74.69, B19.2 cirrhosis to HCV	K71.5 Toxic liver disease with chronic active hepatitis
B18.1 Chronic hepatitis B	K71.50 …… without ascites
K74.6, B19.1 Chronic hepatitis B with cirrhosis	K71.51 …… with ascites
PBC/PSC/Autoimmune hepatitis	K76.6 Portal hypertension
K74.3 Primary biliary cirrhosis (PBC)	K76.7 Hepatorenal syndrome
K74.3 Cirrhosis due to primary sclerosing cholangitis (PSC)	K76.81 Hepatopulmonary syndrome
K83.01 Primary sclerosing cholangitis	Decompensated cirrhosis
K75.4 Autoimmune hepatitis	K72.9 Decompensated hepatic cirrhosis
	K74.69 Decompensated liver disease

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Data Collection

We collected de-identified data using 170 structured and text variables in 10 different categories. Complete details on the data collection tool are available in Supplementary Table 3. Diagnosis of cirrhosis was confirmed by documentation of fibrosis by magnetic resonance elastography, fibroscan, Fibrosis-4, or biopsy, which was available in 75% of patients (655/867). Diagnosis of cirrhosis was ascertained in other patients by detailed chart review for clinical, radiologic, or biochemical evidence of liver cirrhosis. Alcohol use was defined as no drinking, social drinking (2 drinks/day for men and up to 1 drink/day for women), or current daily drinking (drinking more than social drinking limits on a daily basis). Data on decompensation were collected from chart review for clinical events. The presence and severity of ascites, encephalopathy, variceal bleeding, and other major decompensating events at baseline and during COVID-19 were collected. If patients developed acute worsening of ascites, hepatic encephalopathy, or variceal bleeding during COVID-19, they were deemed to have decompensated during COVID-19.

Supplementary Table 3

Data Elements of the COLD Study Data Collection Forms

Variable	Category
Center-specific record ID	Identifier
Center name
Age (at diagnosis of COVID)
Gender	MaleFemaleOther
Race	WhiteAfrican AmericanAsianAmerican IndianOther
Ethnicity	Hispanic or LatinoNon-Hispanic
Date of data collection
Home Address Zip Code
Residence	Home: apartmentHome: single family homeSkilled nursing homeLong-term care facilityAssisted living facilityOtherDo not knowNone/Shelter
Number of people at home
Insurance	Medicare/MedicaidPrivate insuranceUninsuredDo not know
Date of COVID-19 diagnosis
Mode of diagnosis of COVID-19	Positive PCR testPositive serologic testNot clearOther
Risk factors for COVID-19	Travel to high risk regionSick contactsHospitalization within the past monthHealthcare workerEssential workerNursing home residentOther
Indication of testing	Travel to high risk regionContacts who tested positive for COVID-19SymptomsHealthcare worker surveillanceSurveillanceOther
Hospitalization for COVID-19	YesNo
Use of supplemental oxygen	YesNo
Use of vasopressors	YesNo
Number of pressors used
ICU admission	YesNo
Mechanical ventilation	YesNo
Noninvasive positive pressure ventilation	YesNo
Length of hospital stay (days)
Death related to COVID-19	YesNo
Symptoms	Cough, shortness of breath, sore throat, runny nose, fatigue, myalgias, chest pain, diarrhea, nausea/vomiting, anorexia, anosmia, confusion
Number of years since the patient has a known diagnosis of chronic liver disease
Etiology	Hepatitis C: currentHepatitis C: curedHepatitis BNonalcoholic fatty liver disease: hepatic steatosis aloneNonalcoholic steatohepatitisAlcoholic liver diseaseCryptogenic cirrhosisPrimary biliary cholangitisPrimary sclerosing cholangitisAutoimmune hepatitisHepatocellular carcinoma (HCC)Other
Cirrhosis	YesNo
Fibroscan	F0-1F2F3F4
Fibrosis-4	F0-1F2F3F4
NAFLD fibrosis score	F0-1F2F3F4
MR elastography	F0-1F2F3F4
US elastography	F0-1F2F3F4
Biopsy	F0-1F2F3F4
Other	F0-1F2F3F4
Comorbidities	DiabetesHypertensionHyperlipidemiaObesityTobacco smokingCoronary artery diseaseCongestive heart FailureHIV positiveCOPDAsthmaNon-liver malignancyOpioid use disorderObstructive sleep apneaChronic lung disease: non-asthma, non-COPDVapingMarijuana use
Tobacco smoking status	Never smokerFormer smoker (smoked at least 100 cigarettes in lifetime) Current smoker
Alcohol use	Do not drink currentlySocial drinkingDaily drinking
Has the patient received a liver transplantation?	YesNo
Date of transplant
Type of immunosuppression at the time of COVID-19 diagnosis	TacrolimusCyclosporinePrednisone (<20 mg/day)Prednisone (>21 mg/day)MycophenolateAzathioprine mTOR inhibitors (Sirolimus, Everlolimus)
Did the patient receive any of these within 6 months of COVID-19 diagnosis?	Intravenous methyprednisoloneAnti-thymocyte globulin (ATG)BasiliximabRituximab
Other immunosuppression
Was immunosuppression modified during COVID-19?	YesNo
How was immunosuppression modified?
Did the patient experience acute rejection during COVID-19?	YesNo
Laboratory data (before COVID-19, at diagnosis of COVID-19, peak during COVID-19, after COVID-19)	ALT, AST, Alkaline Phosphatase, GGT, Total Bilirubin, Albumin, Creatinine, Sodium, INR, Platelets, Ferritin, WBC, Lymphocytes, Neutrophils, Triglycerides, LDL, HbA1c, CK
Decompensation before COVID-19	NoneAscitesVariceal bleedHepatic encephalopathyOther
Did the patient decompensate during COVID-19?	YesNo
Ascites before COVID-19 (field annotation: 1–6 months before COVID-19)	NoneMild-ModerateSevere
Encephalopathy before COVID-19 (field annotation: 1–6 months before COVID-19)	NoneMild-ModerateSevere
Ascites during COVID-19	NoneMild-ModerateSevere
Encephalopathy during COVID-19	NoneMild-ModerateSevere
Ascites after COVID-19	NoneMild-ModerateSevere
Encephalopathy after COVID-19	NoneMild-ModerateSevere
Did the patient develop variceal bleeding during COVID-19?	YesNo
Were any of the following delayed or cancelled due to diagnosis of COVID-19?	Endoscopy for esophageal varices surveillanceImaging for HCC surveillanceParacentesis for symptomatic ascitesHepatitis C treatmentHepatitis B treatmentLiver transplant evaluationLiver transplantationOther
Were ambulatory clinic visits to hepatology delayed or canceled due to COVID-19?	YesNo
Were ambulatory clinic visits to primary care or other specialties delayed or cancelled due to COVID-19?	YesNo
Were medical procedures not related to liver disease delayed or cancelled?	YesNo
Was care impacted not directly by COVID-19 but because of health system overload?	YesNo
Did the patient have a telehealth visit during COVID-19?	YesNo
COVID-19 treatment	RemdesivirChloroquineHydroxychloroquineAzithromycinPrednisone or MethylprednisoloneLopinavir/ritonavirDonor plasmaOtherNone
Did the patient receive any of the following antibiotics during COVID-19?	Amoxicillin/ClavulanateCephalosporinsAminoglycosidesMacrolidesMinocyclineAnti-tuberculosis drugsFluoroquinolonesAzithromycinNone
Did the patient receive any of the following hepatotoxic medications for more than 3 days during COVID-19 infection?	Acetaminophen >2 g per dayNSAIDsAnticonvulsants: Phenytoin, Valproic acid, CarbamazepineAzolesAmiodaroneAnesthetics: Halothane, IsofluraneStatinsOther hepatotoxic medicationsNone
Was the patient chronically on any of the following medications before acquiring COVID-19 infection?	Proton pump inhibitorsACE inhibitorsAngiotensin receptor blockers
If the patient had HCC, had they received any of the following?	Transarterial therapyAblative therapyTyrosine kinase inhibitorsImmunotherapyNone
Date of last follow-up
Status	Alive, fully recoveredAlive, still impacted by COVID-19Death from COVID-19Death from other causes

ACE, angiotensin-converting enzyme; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; COLD, COVID-19 in chronic liver disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; GGT, gamma-glutamyl transferase; HbA1c, glycosylated hemoglobin; HIV, human immunodeficiency virus; ICU, intensive care unit; INR, international normalized ratio; LDL, low-density lipoprotein; MR, magnetic resonance; NAFLD, nonalcoholic fatty liver disease; NSAIDs, nonsteroidal anti-inflammatory drugs; PCR, polymerase chain reaction; US, ultrasound; WBC, white blood cell count.

Statistical Analysis

A predefined statistical data analysis plan was followed. Continuous variables are expressed as medians and interquartile ranges (IQRs) or mean and standard deviation, as appropriate. Categorical variables are summarized as counts and percentages. The statistical significance of differences between groups was evaluated by using the independent t test or the Mann-Whitney U test for continuous variables and the χ2 test for categorical variables. No imputation was made for missing data. The primary outcome studied was overall survival. The secondary outcomes were COVID-19 related mortality and a composite endpoint for severe COVID-19 (death, hospitalization, oxygen requirement, intensive care unit [ICU] admission, requirement of vasopressors, or mechanical ventilation).

To determine the independent risk factors for the outcome, we performed univariate Cox proportional hazards analysis. Variables were selected for inclusion in the models on the basis of clinical plausibility, statistical significance in the univariate model, and availability in more than 90% of the patients. Multivariate analysis was performed by using Cox proportional hazards analysis for outcomes regarding all-cause mortality and deaths due to COVID-19. To investigate the independent determining factors for mortality among patients with and without cirrhosis, analyses were performed by using backward stepwise logistic regression (probability to enter = 0.05 and probability to remove = 0.1) because of insufficient outcome events. All analyses were performed by using STATA 15.1 (StataCorp, College Station, TX). Two-sided P values were used and considered statistically significant if P ≤ .05. All authors had access to the study data and reviewed and approved the final manuscript.

Results

Demographic and Clinical Features of the Study Cohort

We collected data from 21 institutions across 13 states representing all 5 regions of the United States (Supplementary Table 1). Data were collected from a total of 978 patients with CLD, of whom 867 patients met the inclusion criteria (Supplementary Figure 1). The largest proportion of the cases were from the Northeast (41.8%) and Southeast (28.4%) regions of the US. The overall all-cause mortality in the cohort was 14.0% (n = 121), and 61.7% (n = 535) patients experienced the composite endpoint of severe COVID-19. Table 1 shows the demographic and clinical characteristics of the patients in the overall cohort and also their proportional distribution based on clinical outcomes. The mean age at the time of COVID-19 diagnosis was 56.9 ± 14.5 years, and 271 patients (31.3%) were ≥65 years (Supplementary Figure 2). Patient ethnicity was relatively evenly distributed: non-Hispanic white (268, 30.9%), non-Hispanic black (267, 30.8%), or Hispanic (219, 25.3%) (Supplementary Figure 3). The overall median follow-up of patients was 38 days (interquartile range [IQR], 15–94). Most patients (776, 89.5%) had at least 1 comorbid medical condition in addition to CLD, whereas 261 (30.1%) had more than 3 nonhepatic comorbidities. The most common comorbidities were hypertension (492, 56.8%), diabetes mellitus (372, 42.9%), obesity (365, 42.1%), and hyperlipidemia (335, 38.6%) (Supplementary Figure 4).

Supplementary Figure 1

Patient study cohort. The flowchart shows how the study cohort was selected. CLD, chronic liver disease; COVID-19, coronavirus disease 2019.

Table 1

Clinical Characteristics of Patients With Chronic Liver Disease and Clinical Outcome of COVID-19

	Total (n = 867)	All-cause mortality status (n = 817)		P value	Severe COVID-19 (n = 857)		P value
		Alive (n = 696)	Died (n = 121)		No (n = 322)	Yes (n = 535)
Demographic factors
Age (y)	56.9 ± 14.5	55.7 ± 14.4	65.4 ± 12.7	<.001	52.1 ± 13.7	59.8 ± 14.3	<.001
<65	596 (68.7)	497 (71.4)	62 (51.2)	<.001	260 (80.8)	330 (61.7)	<.001
≥65	271 (31.3)	199 (28.6)	59 (48.8)		62 (19.3)	205 (38.3)
Gender (male, %)	473 (54.7)	377 (54.3)	68 (56.2)	.702	159 (49.5)	308 (57.6)	.022
Race/ethnicity				.431			.020
Non-Hispanic white	268 (30.9)	204 (29.3)	46 (38.0)		107 (33.2)	156 (29.2)
Non-Hispanic black	267 (30.8)	217 (31.2)	37 (30.6)		112 (34.8)	152 (28.4)
Hispanic	219 (25.3)	183 (26.3)	25 (20.7)		69 (21.4)	148 (27.7)
Non-Hispanic Asian	43 (5.0)	31 (4.5)	6 (5.0)		14 (4.3)	29 (5.7)
Other	38 (4.4)	32 (4.6)	5 (4.15)		8 (2.5)	30 (5.4)
Missing	32 (3.6)	29 (4.2)	2 (1.7)		12 (3.7)	20 (3.7)
Liver-related factors
Etiology				<.001			<.001
HCV	190 (21.9)	143 (20.6)	34 (28.1)		56 (17.4)	130 (24.3)
HBV	62 (7.2)	49 (7.0)	5 (4.1)		25 (7.8)	37 (6.9)
NAFLD	456 (52.6)	394 (56.6)	46 (38.0)		199 (61.8)	256 (47.9)
ALD	94 (10.8)	58 (8.3)	28 (23.1)		18 (5.6)	72 (13.5)
Other	65 (7.5)	52 (7.5)	8 (6.6)		24 (7.5)	40 (7.5)
Missing	0 (0)	0 (0)	0 (0)		0 (0)	0 (0)
Cirrhosis				<.001			<.001
No cirrhosis	620 (71.5)	529 (76.0)	62 (51.2)		254 (78.9)	363 (67.9)
Compensated cirrhosis	134 (15.4)	107 (15.4)	19 (15.7)		48 (14.9)	83 (15.5)
Decompensated cirrhosis	93 (10.7)	48 (6.9)	38 (31.4)		14 (4.3)	77 (14.4)
Missing	20 (2.3)	12 (1.7)	2 (1.7)		6 (1.9)	12 (2.2)
Hepatocellular carcinoma	22 (2.5)	10 (1.4)	9 (7.4)	<.001	3 (0.9)	18 (3.4)	.026
Comorbidities
Diabetes	372 (42.9)	294 (42.2)	66 (54.5)	.012	110 (34.2)	259 (48.4)	<.001
Hypertension	492 (56.8)	387 (55.6)	83 (68.6)	.008	165 (51.2)	321 (60.0)	.012
Obesity	365 (42.1)	305 (43.8)	47 (38.8)	.307	150 (46.6)	213 (39.8)	.052
Hyperlipidemia	335 (38.6)	273 (39.2)	53 (43.0)	.419	113 (35.1)	218 (40.8)	.100
Cardiovascular disease	150 (17.3)	111 (16.0)	33 (27.3)	.003	32 (9.9)	116 (21.7)	<.001
HIV	24 (2.8)	21 (3.0)	1 (0.8)	.169	8 (2.5)	16 (3.0)	.664
COPD	77 (8.9)	54 (7.8)	20 (16.5)	.002	15 (4.7)	62 (11.6)	.001
Asthma	91 (10.5)	78 (11.2)	10 (8.3)	.335	29 (9.0)	61 (11.4)	.268
Other cancer	68 (7.8)	48 (6.9)	15 (12.4)	.036	21 (6.5)	45 (8.4)	.315
Behavioral factors
Alcohol use				<.001			.001
Current daily drinking	107 (12.3)	75 (10.8)	25 (20.7)		34 (10.6)	70 (13.1)
Social drinking	532 (61.3)	424 (60.9)	81 (66.9)		183 (56.8)	345 (64.5)
Do not drink currently	172 (19.8)	153 (22.0)	10 (8.3)		85 (26.4)	85 (15.9)
Missing	56 (6.5)	44 (6.3)	5 (4.1)		20 (6.2)	35 (6.5)
Smoking
Current smoker	95 (10.9)	70 (10.1)	19 (15.7)	<.001	35 (10.9)	59 (11.0)	.032
Past smoker	259 (29.8)	195 (28.0)	50 (41.3)		82 (25.5)	175 (32.7)
Never smoker	482 (55.6)	414 (59.5)	46 (38.0)		199 (61.8)	278 (52.0)
Missing	31 (3.6)	24 (3.4)	6 (4.9)		6 (1.9)	23 (4.3)
Opioid use	31 (3.6)	23 (3.3)	2 (1.7)	.330	8 (2.5)	22 (4.1)	.209
Marijuana use	24 (2.8)	17 (2.4)	5 (4.1)	.548	10 (3.1)	13 (2.4)	.553
Treatment
Remdesivir	39 (4.5)	31 (4.5)	5 (4.1)	.874	0 (0.0)	39 (7.3)	<.001
Steroids	54 (6.2)	44 (6.3)	10 (8.3)	.427	4 (1.2)	50 (9.4)	<.001
Hydroxychloroquine	87 (10.0)	69 (9.9)	12 (9.9)	.999	4 (1.2)	83 (15.5)	<.001
Azithromycin	101 (11.7)	78 (11.2)	21 (17.4)	.056	25 (7.8)	76 (14.2)	.005
Hydroxychloroquine + azithromycin	135 (15.6)	95 (13.7)	38 (31.4)	<.001	4 (1.2)	131 (24.5)	<.001

NOTE. Data are expressed as mean ± standard deviation or number (proportion). Boldface indicates statistical significance.

ALD, alcohol-related liver disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection; HIV, human immunodeficiency virus; NAFLD, nonalcoholic fatty liver disease.

Supplementary Figure 2

Age at time of diagnosis of COVID-19 in patients with CLD stratified by overall mortality. Histogram shows distribution of age (years) in the entire patient cohort compared with deceased patients. CLD, chronic liver disease; COVID-19, coronavirus disease 2019.

Supplementary Figure 3

Patient demographics stratified by clinical outcomes. (A) Clinical outcomes of patients with CLD and COVID-19 stratified by race and ethnicity. (B) Clinical outcomes of patients with CLD and COVID-19 stratified by sex. CLD, chronic liver disease; COVID-19, coronavirus disease 2019; ICU, intensive care unit; ns, not significant.

Supplementary Figure 4

Comorbidities in patients with CLD and COVID-19. (A) Clinical severity of patients with CLD and COVID-19 CLD stratified by comorbidities that affect cardiovascular health. (B) Clinical severity of patients with CLD and COVID-19 stratified by comorbidities that affect pulmonary health. Graph shows the percentage of patients with a specific comorbidity who had these outcomes. Significance determined by comparing clinical outcomes in patients with (shown) vs those without (not shown) the specific comorbidity. CAD, coronary artery disease; CHF, congestive heart failure; CLD, chronic liver disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; DM, diabetes mellitus; HLD, hyperlipidemia; HTN, hypertension; ICU, intensive care unit; OSA, obstructive sleep apnea. ∗indicates a significantly higher proportion. ∗P < .05; ∗∗P < 0.01; ∗∗∗P < .001; ∗∗∗∗P < .0001; ∗∗∗∗∗P < .00001.

The most common cause of CLD was nonalcoholic fatty liver disease (456, 52.6%), followed by hepatitis C virus infection (190, 21.9%), alcohol-related liver disease (ALD) (94, 10.8%), and hepatitis B virus infection (62, 7.2%) (Supplementary Figures 5 and 6). The majority of patients had non-cirrhotic stage disease (620, 71.5%); 227 patients (26.2%) had a diagnosis of cirrhosis. Most patients with cirrhosis were well-compensated at the time of inclusion (134, 59.1%), with 93 patients (40.9%) having decompensated cirrhosis before diagnosis with COVID-19. Among patients with decompensated cirrhosis, 71 (76.3%) had ascites, 51 (54.8%) had hepatic encephalopathy, 24 (25.8%) had history of variceal bleeding, and 10 (10.8%) had other decompensating events. Among the patients with preexisting hepatocellular carcinoma (HCC) (22, 2.5%), 8 (36.4%) of them had received locoregional therapy, 2 (9.1%) had received immunotherapy, and none of them were on tyrosine kinase inhibitors.

Supplementary Figure 5

Etiology of CLD among patients with COVID-19. (A) Prevalence of different etiologies of CLD in patients with COVID-19. (B) Stage of CLD in patients with COVID-19. AIH, autoimmune hepatitis; ALD, alcohol-related liver disease; CC, cholangiocarcinoma; CLD, chronic liver disease; COVID-19, coronavirus disease 2019; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

Supplementary Figure 6

Etiology of CLD and severity of COVID-19. Comparing the proportion of patients with different etiologies of CLD requiring hospitalization, ICU admission, mechanical ventilation, vasopressors or mortality. ALD, alcohol-related liver disease; CLD, chronic liver disease; COVID-19, coronavirus disease 2019; HBV, hepatitis B virus; HCV, hepatitis C virus; ICU, intensive care unit; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001; ∗∗∗∗∗P < .00001.

Clinical Course of Coronavirus Disease 2019 in Patients With Chronic Liver Disease

The majority of patients were tested for COVID-19 because they presented with symptoms (772, 89%) (Supplementary Figure 7). The top 3 risk factors for acquiring COVID-19 were exposure to sick contacts (255, 29.4%), recent visit to a healthcare facility (95, 11.0%), or nursing home stay (73, 8.4%). The most common presenting symptom was cough (620, 77.4%), followed by fever (561, 69.3%), shortness of breath (494, 61.8%), fatigue (341, 49.9%), and diarrhea (190, 26.6%) (Table 2 , Supplementary Figure 8). Patients presenting with gastrointestinal symptoms of diarrhea (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.30–2.74) or nausea/vomiting (OR, 1.84; 95% CI, 1.27–2.68) were more likely to have severe COVID-19 than patients without gastrointestinal symptoms (Table 2). Also, patients presenting with respiratory symptoms such as shortness of breath, sore throat, runny nose, or confusion were at higher risk for both mortality and severe COVID-19.

Supplementary Figure 7

Indications for testing and risk factors for COVID-19 and in patients with CLD. (A) Indications of COVID-19 testing in patients with CLD. (B) Risk factors for acquiring COVID-19 in patients with CLD. CLD, chronic liver disease; COVID-19, coronavirus disease 2019.

Table 2

Clinical Presentation of Patients With Chronic Liver Disease and COVID-19 and Clinical Outcomes

	Total (n = 867)	All-cause mortality status (n = 817)		P value	Severe COVID-19 (n = 857)		P value
		Alive	Died		No	Yes
General symptom
Fever (n = 810)	561 (69.3)	463 (69.9)	76 (69.1)	.858	189 (64.3)	371 (72.2)	.019
Cough (n = 801)	620 (77.4)	524 (79.3)	68 (66.7)	.004	236 (80.0)	383 (76.0)	.191
Shortness of breath (n = 799)	494 (61.8)	388 (59.2)	86 (78.9)	<.001	122 (42.8)	371 (72.6)	<.001
Sore throat (n = 699)	144 (20.6)	136 (23.0)	7 (8.8)	.004	71 (27.1)	73 (16.8)	.001
Runny nose (n = 667)	117 (17.5)	105 (18.9)	9 (10.8)	.073	56 (22.5)	61 (14.7)	.010
Fatigue (n = 684)	341 (49.9)	277 (49.8)	54 (55.7)	.288	109 (45.6)	231 (52.1)	.103
Myalgia (n = 692)	290 (41.9)	249 (43.4)	28 (31.8)	.039	106 (43.0)	182 (41.0)	.592
Chest pain (n = 719)	140 (19.5)	118 (19.7)	17 (19.3)	.933	45 (17.2)	95 (20.8)	.249
Confusion (n = 711)	99 (13.9)	51 (8.8)	44 (43.1)	<.001	7 (2.7)	92 (20.4)	<.001
Gastrointestinal symptom
Diarrhea (n = 715)	190 (26.6)	158 (26.7)	23 (25.0)	.733	48 (19.0)	141 (30.7)	.001
Nausea/vomiting (n = 738)	183 (24.8)	153 (25.0)	22 (23.7)	.773	47 (17.7)	134 (28.5)	.001
Anorexia (n = 614)	150 (24.4)	120 (23.8)	25 (30.9)	.169	30 (14.2)	119 (29.7)	<.001
Anosmia (n = 517)	71 (13.7)	62 (14.5)	6 (9.4)	.269	33 (19.1)	38 (11.1)	.013

NOTE. Data are expressed as the number (proportion among patients with reported symptoms).

COVID-19, coronavirus disease 2019.

Supplementary Figure 8

Presenting symptoms of COVID-19 among patients with CLD. (A) Tiled heatmap of symptoms of COVID-19 stratified by severity of COVID-19. Each vertical bar represents a single patient. (B) Frequency of different COVID-19 symptoms in patients with CLD. CLD, chronic liver disease; COVID-19, coronavirus disease 2019.

Among patients with CLD and COVID-19, 60.4% (n = 524) were hospitalized, 49.9% (n = 433) required supplemental oxygen, 23.0% (n = 199) were admitted to the ICU, 15.7% (n = 136) received vasopressors, and 17.8% (n = 154) required mechanical ventilation. The majority of the deaths were due to COVID-19 (86.7%, n = 105). Sixteen patients had non–COVID-19 related mortality, and the cause of death was available in 37.5% of these patients (n = 6). Two of them died of cardiac failure, 2 of acute liver failure due to acute alcoholic hepatitis, 1 of bleeding complications due to coagulopathy, and 1 of septic shock in the setting of acute cholecystitis. New or worsening hepatic decompensation during COVID-19 was noted in 67 patients (7.7%); 23 patients (34.3%) had severe hepatic encephalopathy, 11 (16.4%) had severe ascites, and 7 (10.4%) had variceal bleed during the clinical course of COVID-19. Median baseline liver tests before COVID-19 were aspartate aminotransferase, 28.0 IU/L (IQR 25); alanine aminotransferase 27.0 IU/L (IQR 27); alkaline phosphatase 88 IU/L (IQR 59); and bilirubin 0.5 mg/dL (IQR 0.5). As shown in previous studies, peak values of all liver tests were significantly elevated during COVID-19 (Supplementary Figure 9).

Supplementary Figure 9

Liver tests during COVID-19. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio.

The combination of azithromycin and hydroxychloroquine (135, 15.6%), azithromycin alone (101, 11.6%), and hydroxychloroquine alone (87, 10.0%) were the most commonly used medications for COVID-19. A higher proportion of patients who received medications directed against COVID-19 had more severe disease (Supplementary Figure 10).

Supplementary Figure 10

Treatment for COVID-19 among patients with CLD. (A) Frequency of COVID-19 treatments in patients with CLD. (B) Tiled heatmap of treatment of COVID-19 stratified by severity of disease. Each horizontal bar represents a single patient. CLD, chronic liver disease; COVID-19, coronavirus disease 2019; HCQ, hydroxychloroquine.

Predictors of All-Cause Mortality and Coronavirus Disease 2019–Related Mortality in Patients With Chronic Liver Disease

To identify the predictors of all-cause mortality and COVID-19 related mortality, we performed univariate and multivariate survival analysis (Table 3 ). The multivariate model for all-cause mortality was adjusted for age, sex, race/ethnicity, etiology of CLD, cirrhosis, hepatic decompensation, HCC, diabetes, hypertension, cardiovascular disease, chronic obstructive pulmonary disease (COPD), smoking status, and alcohol consumption, all of which were statistically significant in the univariate model and are plausibly clinically relevant.

Table 3

Univariate and Multivariate Analyses: Overall Survival in Patients With Chronic Liver Disease and COVID-19

	Univariate model for all-cause mortality		Multivariate model for all-cause mortality (events = 121)		Multivariate model for mortality due to COVID-19 (events = 105)
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Demographic factors
Age (per 10 year)	1.55 (1.35–1.77)	<.001	1.44 (1.21–1.71)	<.001	1.52 (1.27–1.82)	<.001
Male	1.16 (0.81–1.66)	.416	1.16 (0.77–1.75)	.472	1.23 (0.79–1.91)	.359
Race/ethnicity
Non-Hispanic white	1		1		1
Non-Hispanic black	0.75 (0.48–1.15)	.186	0.81 (0.50–1.32)	.400	0.84 (0.50–1.43)	.524
Hispanic	0.73 (0.45–1.20)	.216	0.94 (0.56–1.60)	.830	1.20 (0.69–2.09)	.522
Non-Hispanic Asian	1.03 (0.44–2.42)	.941	1.60 (0.54–4.70)	.395	1.93 (0.64–5.77)	.244
Other	0.77 (0.31–1.94)	.580	0.60 (0.18–1.96)	.393	0.80 (0.24–2.66)	.711
Liver-related factors
Etiology of liver disease
HCV	1		1		1
ALD	1.75 (1.06–2.89)	.028	2.42 (1.29–4.55)	.006	2.69 (1.44–5.02)	.002
NAFLD	0.48 (0.31–0.75)	.001	1.05 (0.59–1.87)	.872	1.08 (0.59–1.97)	.804
HBV	0.57 (0.22–1.47)	.247	0.80 (0.23–2.74)	.718	0.81 (0.23–2.83)	.746
Other	0.69 (0.32–1.49)	.344	1.66 (0.72–3.81)	.236	1.15 (0.42–3.13)	.782
Presence of cirrhosis
No	1		1		1
Compensated cirrhosis	1.45 (0.87–2.42)	.158	0.83 (0.46–1.49)	.532	0.90 (0.49–1.65)	.743
Decompensated cirrhosis	5.26 (3.51–7.89)	<.001	2.91 (1.70–5.00)	<.001	2.41 (1.34–4.32)	.003
Presence of HCC	4.91 (2.48–9.70)	<.001	3.31 (1.53–7.16)	.002	3.96 (1.74–8.98)	.001
Comorbidities
Diabetes	1.49 (1.04–2.13)	.028	1.59 (1.02–2.46)	.040	1.82 (1.15–2.89)	.011
Hypertension	1.55 (1.05–2.27)	.003	1.77 (1.11–2.81)	.016	1.69 (1.04–2.76)	.034
Cardiovascular disease	1.70 (1.14–2.53)	.010	1.10 (0.70–1.74)	.667	0.86 (0.53–1.42)	.564
COPD	2.01 (1.25–3.26)	.004	1.77 (1.03–3.05)	.040	2.29 (1.32–3.96)	.003
Behavioral factors
Smoking status
No	1		1		1
Past smoker	2.18 (1.46–3.25)	<.001	1.30 (0.82–2.05)	.263	1.39 (0.86–2.26)	.179
Current smoker	2.67 (1.56–4.56)	<.001	2.48 (1.30–4.73)	.006	2.99 (1.56–5.72)	.001
Alcohol consumption
Do not drink currently	1		1
Social drinking	0.35 (0.18–0.67)	.002	0.61 (0.31–1.22)	.160
Current daily drinking	1.63 (1.04–2.56)	.032	1.37 (0.77–2.46)	.287

NOTE. Multivariate model for all-cause mortality was adjusted for age, gender, race/ethnicity, etiology of chronic liver disease, cirrhosis, HCC, diabetes, hypertension, cardiovascular disease, COPD, smoking status, and alcohol consumption. Multivariate model for death due to COVID-19 was adjusted for age, gender, race/ethnicity, etiology of chronic liver disease, cirrhosis, HCC, diabetes, hypertension, obesity, cardiovascular disease, COPD, and smoking status. Boldface indicates statistical significance.

ALD, alcohol-related liver disease; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; HBV, hepatitis B virus infection; HCC, hepatocellular carcinoma; HCV, hepatitis C virus infection; HR, hazard ratio; NAFLD, nonalcoholic fatty liver disease.

The liver-specific predictors of all-cause mortality were ALD (hazard ratio [HR], 2.42; 95% CI, 1.29–4.55), presence of hepatic decompensation at baseline (HR, 2.91; 95% CI, 1.70–5.00), and HCC (HR, 3.31; 95% CI, 1.53–7.16) (Figure 1 ). Other independent predictors of all-cause mortality were increasing age (HR, 1.44; 95% CI, 1.21–1.71 per 10 years), presence of diabetes (HR, 1.59; 95% CI, 1.02–2.46), hypertension (HR, 1.77; 95% CI, 1.11–2.81), COPD (HR, 1.77; 95% CI, 1.03–3.05), and history of current smoking (HR, 2.48; 95% CI, 1.30–4.73). For the secondary outcome of deaths due to COVID-19 (Table 3), the results were largely identical. Furthermore, we did not find significant interactions between ALD and decompensated CLD or HCC for overall survival on multivariate analysis (test of interaction P > .2) (Supplementary Table 4).

Figure 1

Liver-specific factors predicting overall survival in patients with chronic liver disease and COVID-19. (A) Overall survival from time of diagnosis of COVID-19 in patients with alcohol-related liver disease (ALD) compared with other liver disease etiologies. (B) Overall survival in patients with liver disease stratified into those with no cirrhosis vs compensated cirrhosis vs decompensated cirrhosis. Significant and hazard ratios are derived from comparison of decompensated cirrhosis vs no cirrhosis. (C) Overall survival from time of diagnosis of COVID-19 in patients with underlying hepatocellular carcinoma (HCC). COVID-19, coronavirus disease 2019.

Supplementary Table 4

Interaction of Alcoholic Liver Disease and Decompensated Cirrhosis/HCC With the Risk for All-Cause Mortality/Mortality due to COVID-19

	Univariate model	Multivariable model
	P for interaction	P for interaction
All-cause mortality
Alcoholic liver disease∗decompensated cirrhosis	.033	.278
Alcoholic liver disease∗HCC	.976	.771
Mortality due to COVID-19
Alcoholic liver disease∗decompensated cirrhosis	.044	.225
Alcoholic liver disease∗HCC	.640	.531

NOTE. Multivariate model for all-cause mortality was adjusted for age, gender, race/ethnicity, etiology of chronic liver disease, decompensated cirrhosis, HCC, diabetes, hypertension, cardiovascular disease, COPD, smoking status, alcohol consumption, and the interaction term (alcoholic liver disease∗decompensated cirrhosis or alcoholic liver disease∗HCC). Multivariate model for mortality due to COVID-19 was adjusted for age, gender, race/ethnicity, etiology of chronic liver disease, decompensated cirrhosis, HCC, diabetes, hypertension, cardiovascular disease, COPD, smoking status, and the interaction term (alcoholic liver disease∗decompensated cirrhosis or alcoholic liver disease∗HCC).

COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; HCC, hepatocellular carcinoma.

Next we performed a subgroup survival analysis in patients with cirrhosis and COVID-19 (Table 4 ). The liver-specific factors associated with higher all-cause mortality in patients with cirrhosis were prior hepatic decompensation (HR, 3.89; 95% CI, 2.18–6.95) and HCC (HR, 3.66; 95% CI, 1.67–8.01). In the subgroup of patients with non-cirrhotic CLD, ALD was associated with higher all-cause mortality (HR, 4.72; 95% CI, 2.05–10.85) and higher COVID-19 related mortality (HR, 7.39; 95% CI, 2.96–18.46) (Supplementary Table 5).

Table 4

Univariate and Multivariate Analyses of Risk for Survival in Patients With Cirrhosis and COVID-19 (n = 212)

	Univariate model for all-cause mortality		Multivariate model for all-cause mortality (events = 57)		Multivariate model for mortality due to COVID-19 (events = 45)
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Demographic factors
Age (per 10 year)	1.20 (0.97–1.50)	.095
Male	0.77 (0.46–1.30)	.329
Race/ethnicity
Non-Hispanic white	1
Non-Hispanic black	0.84 (0.46–1.58)	.609
Hispanic	0.66 (0.33–1.34)	.249
Non-Hispanic Asian	—	—
Other	1.43 (0.49–4.15)	.592
Liver-related factors
Etiology of liver disease
HCV	1
ALD	1.64 (0.85–3.14)	.138
NAFLD	1.08 (0.53–2.22)	.829
HBV	—	—
Other	1.22 (0.48–3.12)	.679
Decompensated cirrhosis	3.67 (2.11–6.37)	<.001	3.89 (2.18–6.95)	<.001	3.12 (1.68–5.79)	<.001
Presence of HCC	3.26 (1.52–6.97)	.002	3.66 (1.67–8.01)	.001	3.61 (1.58–8.25)	.002
Comorbidities
Diabetes	0.96 (0.57–1.62)	.888
Hypertension	0.88 (0.53–1.49)	.652
Cardiovascular disease	1.15 (0.64–2.04)	.646
COPD	1.60 (0.76–3.38)	.217			3.12 (1.68–5.79)	<.001
Behavioral factors
Smoking status
No	1
Past smoker	1.42 (0.79–2.58)	.244
Current smoker	2.16 (1.03–4.53)	.042
Alcohol consumption
Do not drink currently	1
Social drinking	0.26 (0.04–1.91)	.187
Current daily drinking	2.44 (1.38–4.30)	.002	2.34 (1.27–4.30)	.006

NOTE. To identify candidate risk factors of mortality, we performed a stepwise backward logistic regression analysis (probability to enter = 0.05 and probability to remove = 0.1) using all variables in the univariate model. Boldface indicates statistical significance.

ALD, alcohol-related liver disease; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; HBV, hepatitis B virus infection; HCC, hepatocellular carcinoma; HCV, hepatitis C virus infection; HR, hazard ratio; NAFLD, nonalcoholic fatty liver disease.

Supplementary Table 5

Univariate and Multivariate Survival Analyses in Patients With Non-Cirrhotic Chronic Liver Disease and COVID-19

	Univariate model for all-cause mortality		Multivariate model for all-cause mortality (events = 62)		Multivariate model for mortality due to COVID-19 (events = 59)
	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
Demographic factors
Age (per 10 year)	1.76 (1.46–2.12)	<.001	1.72 (1.40–2.12)	<.001	1.66 (1.34–2.04)	<.001
Male	1.63 (0.97–2.73)	.064
Race/ethnicity
Non-Hispanic white	1
Non-Hispanic black	0.73 (0.40–1.34)	.310
Hispanic	0.80 (0.41–1.59)	.532
Non-Hispanic Asian	1.52 (0.58–4.01)	.395
Other	0.29 (0.04–2.16)	.227
Liver-related factors
Etiology of liver disease
HCV	1
ALD	1.48 (0.62–3.55)	.376	4.72 (2.05–10.85)	<.001	7.39 (2.96–18.46)	<.001
NAFLD	0.43 (0.24–0.76)	.004
HBV	0.67 (0.23–1.99)	.472
Other	0.30 (0.07–1.31)	.110
Comorbidities
Diabetes	2.15 (1.30–3.61)	.003	1.87 (1.08–3.23)	.025
Hypertension	3.15 (1.64–6.05)	.001	2.04 (1.00–4.15)	.049	2.36 (1.14–4.91)	.021
Cardiovascular disease	2.02 (1.16–3.53)	.014
COPD	2.20 (1.15–4.22)	.018			2.01 (1.00–4.04)	.050
Behavioral factors
Smoking status
No	1
Past smoker	2.30 (1.33–3.97)	.003
Current smoker	2.43 (1.10–5.38)	.028	3.46 (1.52–7.84)	.003	2.97 (1.24–7.13)	.014
Alcohol consumption
Do not drink currently	1
Social drinking	0.43 (0.21–0.88)	.021
Current daily drinking	0.74 (0.32–1.74)	.489

NOTE. Boldface indicates statistical significance.

ALD, alcohol-related liver disease; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; HBV, hepatitis B virus infection; HCC, hepatocellular carcinoma; HCV, hepatitis C virus infection; HR, hazard ratio; NAFLD, nonalcoholic fatty liver disease.

Serial liver-related lab results were available in a majority of the hospitalized patients but not in the majority of those managed as outpatient. We performed a subgroup analysis in hospitalized patients in whom serial lab values were available for analysis. Peak values of aspartate aminotransferase, bilirubin, alkaline phosphatase, and Model for End-Stage Liver Disease score were observed to predict mortality (Supplementary Table 6).

Supplementary Table 6

Laboratory Characteristics Among Hospitalized Patients With Chronic Liver Disease and COVID-19 (n = 524)

	All-cause mortality status		P value
	Alive	Died
ALT
Before COVID-19 (n = 374)	27 (18–40)	21 (15–33)	.075
At COVID-19 diagnosis (n = 467)	35 (22–63)	31.5 (24–57)	.220
Peak (n = 428)	50 (28–104)	40.5 (23–88)	.307
Delta-ALT (n = 410)	0 (0–27.5)	3 (0–22.5)	.278
AST
Before COVID-19 (n = 375)	27 (20–40)	32 (21–65)	.178
At COVID-19 diagnosis (n = 463)	50 (30–81.5)	63.5 (38–63.5)	.021
Peak (n = 428)	65 (39–120)	92.5 (51.5–225)	.001
Delta-AST (n = 406)	5 (0–35)	22 (0–123)	.075
ALP
Before COVID-19 (n = 373)	89 (69–128)	109 (75–152)	.032
At COVID-19 diagnosis (n = 467)	83 (63–119)	91.5 (63–91.5)	.374
Peak (n = 427)	99 (70–158.5)	131 (79–235)	.001
Delta-ALP (n = 413)	8.5 (0–48)	5.0 (0–87)	.330
Bilirubin
Before COVID-19 (n = 372)	0.5 (0.4–0.8)	0.7 (0.5–1.7)	.004
At COVID-19 diagnosis (n = 467)	0.6 (0.4–0.9)	0.8 (0.5–2.2)	<.001
Peak (n = 428)	0.7 (0.4–1.2)	1.5 (0.7–4.0)	<.001
Delta-bilirubin (n = 409)	0.1 (0–0.5)	0.2 (0–1.6)	.037
MELD score
Before COVID-19 (n = 276)	10.0 (7–14)	11.0 (8–21)	<.001
At COVID-19 diagnosis (n = 375)	10.5 (7–18)	16.5 (11–24)	<.001
Peak (n = 291)	14.0 (8–21)	21.5 (13–32)	<.001
Delta-MELD (n = 254)	1.0 (0–4)	5.0 (0–12.5)	<.001

NOTE. Data are expressed as median (interquartile range). Mann-Whitney U test was performed for comparison between groups.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019.

Predictors of Severe Coronavirus Disease 2019 in Patients With Chronic Liver Disease

Overall, 535 patients with CLD met criteria for the composite endpoint of severe COVID-19. As shown in Table 5 , multivariate analysis showed that a history of hepatic decompensation (OR, 2.50; 95% CI, 1.20–5.21) predicted severe COVID-19. Other independent predictors were increasing age (OR, 1.43; 95% CI, 1.25–1.65), Hispanic ethnicity (OR, 2.33; 95% CI, 1.47–3.70), diabetes (OR, 1.51; 95% CI, 1.04–2.19), cardiovascular disease (OR, 1.85; 95% CI, 1.09–3.13), and COPD (OR, 2.26; 95% CI, 1.15–4.45).

Table 5

Univariate and Multivariate Analyses: Risk of Severe COVID-19 (Composite Endpoint) Among Patients With Chronic Liver Disease and COVID-19

	Univariate model for severe COVID-19		Multivariate model for severe COVID-19
	OR (95% CI)	P value	OR (95% CI)	P value
Demographic factors
Age (per 10 year)	1.46 (1.32–1.62)	<.001	1.43 (1.25–1.65)	<.001
Male	1.38 (1.05–1.83)	.022	1.28 (0.90–1.81)	.172
Race/ethnicity
Non-Hispanic white	1		1
Non-Hispanic black	0.93 (0.66–1.32)	.685	0.83 (0.54–1.28)	.406
Hispanic	1.47 (1.01–2.14)	.045	2.33 (1.47–3.70)	<.001
Non-Hispanic Asian	1.42 (0.72–2.81)	314	1.90 (0.85–4.27)	.124
Other	2.57 (1.14–5.83)	.024	3.40 (1.31–8.81)	.012
Liver-related factors
Etiology of liver disease
HCV	1		1
ALD	1.72 (0.94–3.15)	.077	2.08 (0.97–4.45)	.059
NAFLD	0.55 (0.39–0.80)	.001	0.68 (0.41–1.13)	.137
HBV	0.64 (0.35–1.15)	.139	0.99 (0.46–2.13)	.973
Other	0.72 (0.40–1.30)	.275	1.27 (0.60–2.70)	.536
Presence of cirrhosis
No	1		1
Compensated cirrhosis	1.21 (0.82–1.79)	.338	0.70 (0.43–1.14)	.152
Decompensated cirrhosis	3.85 (2.13–6.95)	<.001	2.50 (1.20–5.21)	.015
Presence of HCC	3.70 (1.08–12.67)	.037	2.99 (0.62–14.36)	.171
Comorbidities
Diabetes	1.81 (1.36–2.41)	<.001	1.51 (1.04–2.19)	.029
Hypertension	1.43 (1.08–1.89)	.012	1.16 (0.80–1.68)	.434
Obesity	0.76 (0.57–1.00)	.052	1.21 (0.84–1.76)	.302
Cardiovascular disease	2.51 (1.65–3.81)	<.001	1.85 (1.09–3.13)	.022
COPD	2.68 (1.49–4.80)	.001	2.26 (1.15–4.45)	.019
Behavioral factors
Smoking status
No	1		1
Past smoker	1.53 (1.11–2.10)	.009	0.96 (0.65–1.43)	.855
Current smoker	1.21 (0.76–1.90)	.419	1.00 (0.54–1.83)	.990
Alcohol consumption
Do not drink currently	1		1
Social drinking	0.53 (0.37–0.75)	<.001	0.84 (0.55–1.26)	.390
Current daily drinking	1.09 (0.70–1.71)	.699	0.98 (0.53–1.83)	.953

NOTE. Multivariate model for all-cause mortality was adjusted for age, gender, race/ethnicity, etiology of chronic liver disease, cirrhosis, HCC, diabetes, hypertension, obesity, cardiovascular disease, COPD, smoking status, and alcohol consumption. Boldface indicates statistical significance.

ALD, alcohol-related liver disease; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; HBV, hepatitis B virus infection; HCC, hepatocellular carcinoma; HCV, hepatitis C virus infection; NAFLD, nonalcoholic fatty liver disease; OR, odds ratio.

Discussion

According to the Centers for Disease Control, patients with CLD might be at increased risk for severe illness with COVID-19. CLD represents a clinical spectrum ranging from mild asymptomatic disease to severe decompensated cirrhosis. It is not clear which subgroups of patients with CLD are more vulnerable to adverse outcomes with COVID-19. In this multicenter study, we investigated predictors of mortality and COVID-19 disease severity in patients with CLD and SARS-CoV-2 infection. Among the 867 patients with CLD from 21 centers across the US, we observed an all-cause mortality of 14.0%; 60.4% were hospitalized, and 23% were admitted to the ICU. New or worsening hepatic decompensation during COVID-19 was noted in 7.7% of patients. We identified the liver-specific factors ALD, hepatic decompensation, and HCC as predictors of adverse outcomes from COVID-19, apart from established factors such as older age, hypertension, diabetes, and COPD. In addition, we found that patients of Hispanic ethnicity had a higher risk for severe COVID-19. Thus, our large multicenter study identifies specific subgroups of patients with CLD who have higher mortality with COVID-19.

Because COVID-19 is a novel pandemic, our knowledge of its impact on patients with CLD is still evolving. Singh et al recently identified 250 patients with COVID-19 who had an underlying CLD by using a de-identified research network database and reported a hospitalization rate of 52% and mortality of 12%, similar rates to our study. However, preliminary data from an international registry of 152 patients with CLD reported a higher overall mortality rate of 31% and a hospitalization rate of 95% for patients with cirrhosis. The higher mortality rates in this clinician-reported registry study may have been due to selection bias. Around 90% of the patients with CLD and COVID-19 in our cohort had mild liver disease with either non-cirrhotic stage disease or compensated cirrhosis at baseline, and they had relatively favorable outcomes. Patients with decompensated cirrhosis were disproportionately adversely affected by COVID-19, with an all-cause mortality rate of 31.4% in this subgroup. These findings are in line with the higher morbidity and mortality in patients with decompensated cirrhosis and influenza pneumonia. , We posit the less favorable outcomes noted in patients with decompensated cirrhosis may be due to cirrhosis-associated immune dysfunction and fragile physiological buffers, likely increasing susceptibility to severe COVID-19. Our findings highlight the challenges in taking extra precautions to minimize the risk of exposure to SARS-CoV-2 in the vulnerable patients with decompensated cirrhosis, while continuing to optimally manage their decompensating events.

In our study, ALD was independently associated with a higher risk of poor survival and COVID-19 related mortality. This is a novel association and one that has significant implications for patients with CLD. Patients with ALD are known to be at higher risk for infections because of the underlying dysregulation of the immune system. ALD is associated with a sterile inflammatory state induced by damage-associated molecular patterns, which leads to the systemic production of proinflammatory cytokines by various immune cells. , We hypothesize that the superimposed cytokine storm triggered by SARS-CoV-2 could exacerbate the heightened inflammatory state in patients with ALD, thus leading to worse outcomes. Moreover, there has been significant concern about increased alcohol use during the COVID-19 pandemic, highlighting the importance of this association. , In our study, up to one third of patients with CLD and an alarming 50% of patients with ALD reported daily alcohol consumption, which was disconcertingly associated with poor outcomes in patients with cirrhosis and COVID-19. These findings emphasize the need to implement an aggressive remote care plan for patients with ALD to manage their alcohol use disorder, while simultaneously minimizing the risk of exposure to COVID-19. Future studies will be needed to analyze specific subgroups within the spectrum of ALD who are at higher risk for adverse outcomes with COVID-19.

Another subgroup in our study that was found to be at significantly high risk for mortality was that of patients with HCC. The all-cause mortality rate in this subgroup was 52.4% (n = 11), almost 7-fold higher than in patients without HCC; however, the number of patients is small. Patients with cancer, in general, have worse clinical outcomes after COVID-19. , Patients with HCC may be uniquely susceptible to COVID-19 related complications because of a constellation of active malignancy, presence of cirrhosis, as well as the presence of an active underlying liver disease that led to that cirrhosis, all resulting in compromised immune function, which may be further complicated by HCC-directed treatment.

Our cohort includes a racially and ethnically diverse population that is 31% non-Hispanic white, 31% non-Hispanic black, and 25% Hispanic. We found that patients of Hispanic ethnicity had a higher risk of developing severe COVID-19 compared with non-Hispanic whites, even after adjusting for age, comorbidities, and hepatic decompensation. These findings are in line with recent reports showing higher age-adjusted rates of hospitalization in Hispanic patients. ,

The strengths of our study include large sample size, broad geographical distribution of sites across the US, as well as the granularity of the collected data. We have included patients treated as outpatients or inpatients and also patients with non-cirrhotic or cirrhotic stage CLD, thus making our findings generalizable. Limitations of our study include the retrospective-prospective timeline, which was used mainly because of the rapidly evolving nature of the pandemic. Another limitation of our study is the restriction of SARS-CoV-2 testing during the earlier phase of the pandemic, likely leading to decreased representation of mild COVID-19. Also, we could have enrollment bias because not all patients with CLD have a documented ICD-9/10 code in their electronic health records. Also, despite our best efforts, it is possible that not all patients with CLD and COVID19 were identified from the participating centers. Last, the majority of the contributing centers are tertiary medical health systems, potentially introducing referral bias. However, our cohort represents an ethnically diverse population with varying stages of liver disease. Larger and longer-term studies will be needed to confirm these findings.

To date, this is the largest study on COVID-19 among patients with CLD in the United States. Our cohort of 867 patients with CLD had substantial rates of all-cause mortality (14.0%), hospitalization (60.4%), and ICU admission (23%). We identify decompensated cirrhosis, ALD, and HCC to be determinants of mortality in patients with CLD and also show that Hispanic ethnicity is independently associated with severe COVID-19. These findings can be used to prospectively design protective measures for these vulnerable populations, such as continuing the emphasis on telemedicine, prioritizing them for future vaccinations, as well as actively including these patients in prospective COVID-19 surveillance studies and drug trials.