COVID-19 in patients with pre-existing chronic liver disease – predictors of outcomes

Table 1 Studies showing clinical outcomes of chronic liver disease in coronavirus disease 2019 and associated risk factors

Ref.	Type	Clinical outcomes	Predictors of outcomes
Iavarone et al[53]	Multicentric retrospective study of 50 cirrhotics	ACLF and de novo acute liver injury: 28%; 30-d mortality: 34%	Predictors of mortality: CLIF-OF (HR: 1.426); Moderate/severe respiratory failure (HR: 1.608)
Marjot et al[22]	Retrospective data from United Kingdom hospital network including 745 patients with CLD (386 with and 359 without cirrhosis)	Acute hepatic decompensation: 46%; ACLF: 50%; Mortality in cirrhosis, ACLF, and non-cirrhotics: 32%, 65%, and 8%	Predictors of mortality: ALD (OR: 1.79); Child-Pugh class: Child-Pugh A +2.0%, Child-Pugh B +20.0%, Child-Pugh C +38.1%. Predictors of decompensation: Child-Pugh class
Ge et al[16]	Data from the National COVID Cohort Collaborative (N3C) dataset of 6.4 million cases	3.31 times adjusted hazard of death in cirrhotics at 30 d than non-cirrhotics	Predictors of 30-d mortality: Age (aHR: 1.05 per year); Hispanic ethnicity (aHR: 1.20); Chronic hepatitis C (aHR: 1.27); ALD (aHR: 1.40); Modified CCI (aHR: 1.07 per point)
Elhence et al[24]	Retrospective analysis of 221 cirrhosis patients	Compensated cirrhosis: 8.1%; Acute decompensation: 62.9%; ACLF: 29.0%; MODS: 55.6%; Type 1 respiratory failure: 20.0%; Sudden cardiac arrest: 6.7%; GI bleeding: 3.3%	Predictors of mortality: Higher TLC [HR: 1.054]; Elevated creatinine [HR: 1.184]; MELD score [HR: 1.038]; Alkaline phosphatase [HR: 1.003]; COVID-19 severity [HR: 2.573]; ACLF on presentation (HR: 2.573)
Xiao et al[52]	Medical records collected from 23 Chinese hospitals	Decompensated cirrhosis: 57.5%; Mortality: 28.9%	Factors associated with mortality: Child-Pugh class (OR: 5.71); CURB65 (OR: 5.88)
Grgurevic et al[48]	4014 patients	Four times higher risk of 30-d mortality in cirrhosis	Predictor of 30-d mortality: Cirrhosis (HR: 2.95)
Mendizabal et al[17]	Prospective cohort of 96 cirrhosis patients	Mortality in cirrhotic: 47% vs 16% in non-cirrhotics; Acute decompensation: 61.4%; ACLF: 55.2%	Factors associated with mortality: Age > 65 yr (OR: 7.2); Male gender (OR: 1.8); BMI > 30 (OR: 1.7); Cirrhosis (OR: 3.1)
Kim et al[18]	Multicentre observational cohort study in 21 institutes in United States with 867 CLD cases (227 with cirrhosis)	Mortality: 25%; Hepatic decompensation: 7.7%; Hepatic encephalopathy: 34.3%; Ascites: 16.4%; Variceal bleed: 10.4%	Predictors of all-cause mortality: ALD (HR: 2.42); Hepatic decompensation at baseline (HR: 2.91); HCC (HR: 3.31); Increasing age (HR:1.44 per 10 yr); Diabetes (HR: 1.59); Hypertension (HR:1.77); COPD (HR:1.77); Current smoking (HR: 2.48)
Sarin et al[37]	Retrospective data from 13 Asian countries with228 patients [185 CLD without cirrhosis and 43 with cirrhosis]	ACLF: 11.6%; Acute decompensation: 9%; Mortality rate: 43% among decompensated cirrhotics	Predictors of sever liver injury: In CLD without cirrhosis, diabetes [57.7% vs 39.7%, OR: 2.1 (1.1-3.7)]; In cirrhotics, obesity [64.3% vs 17.2%, OR: 8.1 (1.9-38.8). Predictor of mortality: CTP score of 9 or more at presentation [AUROC 0.94, HR:19.2]
Xiang et al[54]	Retrospective cohort study of 267 patients	Severe COVID-19: 15%; High-flow oxygen support: 14%; Mechanical ventilator support: 4%; Death: 1	Predictor of severity: FIB-4 > 3.25

ACLF: Acute-on-chronic liver failure; ALD: Alcohol related liver disease; AUROC: Area under the receiver operator curve; BMI: Body mass index; COVID: Coronavirus disease; CLD: Chronic liver disease; CCI: Charlson’s comorbidity index; CLIF OF: Chronic liver failure consortium organ failure; CLIF-C: Chronic liver failure consortium; COPD: Chronic obstructive pulmonary disease; CTP: Child-Turcotte-Pugh score; FIB-4: Fibrosis 4; HCC: Hepatocellular carcinoma; MELD Na: Model for end stage liver disease sodium score; MODS: Multiorgan dysfunction syndrome; NACSELD: North American Consortium for the Study of End-Stage Liver Disease.

Table 2 Clinical outcomes in patients with underlying alcoholic liver disease during coronavirus disease 2019

Ref.	Study	Outcomes
Deutsch-Link et al[23]	Retrospective analysis - pre (January 2017 to December 2017) and post-COVID era (February 2020)	Increase in the monthly percent change of crude ALD-related mortality: Males: 3.18 vs 0.96; Females: 3.8 vs 1.18
Yeo et al[26]	16813 patients with ALD before and 11625 during the pandemic	OR of death in ALD - 18.7 during the pandemic vs 0.995 in the pre-pandemic era

ALD: Alcohol related liver disease; COVID: Coronavirus disease; LT: Liver transplant; NASH: Non-alcoholic fatty liver disease; OR: Odds ratio; UNOS: United network for organ sharing.

Table 3 Studies evaluating outcomes and predictors of severity in non-alcoholic fatty liver disease with coronavirus disease 2019

Ref.	Type of study	Patients included	Outcomes	Predictors
Chang et al[27]	Retrospective study	3122 COVID-19 cases [FLI (fatty liver index) was calculated]	Severe disease: 223 (7.14%); Mechanical ventilation: 82 (2.63%); ICU admission: 126 (4.04%) High-flow oxygen therapy: 75 (2.40%); Death: 94 (3.01%)	FLI associated with severe complications from COVID-19 (aOR: 1.77)
Vrsaljko et al[28]	Prospective observational study	120 NAFLD patients (of 216 COVID-19 patients)	Patients with NAFLD had more high-flow nasal cannula or non-invasive ventilation (21.66%, vs 10.42%), longer duration of hospitalization (10 d vs 9 d), and more pulmonary thromboembolism risk (26.66% vs 13.54%)	Delayed time to recovery (HR: 0.64); Increased pulmonary thrombosis (OR: 2.15) among NAFLD patients
Velazquez et al[29]	Retrospective cohort study	359 NAFLD patients as per Dallas steatosis index (DSI) out of total 470 cases	Lower oxygen saturation levels; Higher D-dimer; Elevated LDH; Higher lymphocyte count among NAFLD	On multivariable analysis, NAFLD is a predictor of mortality (OR: 2.13)
Madan et al[36]	Retrospective observational case control study	289 NAFLD patients among 446 cases	Similar in-hospital mortality, ICU requirement, ventilatory support, and duration of ICU and hospital stay	Predictors of in-hospital mortality: High total leukocyte count (OR: 1.082); High FIB-4 (OR: 1.606)
Chen et al[34]	Retrospective single centre cohort study	172 patients with hepatic steatosis (HS) among 342 cases	19% of patients expired; > 50% required ICU admission	Increased intubation (aOR: 2.75); Vasopressor requirements (aOR: 1.22); ALT > 5 x ULN (aOR: 7.09)
Sarin et al[37]	Retrospective multinational cohort	113 NAFLD cases out of 228 cases (185 without cirrhosis and 43 with cirrhosis)	Higher risk of acute liver injury in obese cirrhotics vs normal weight patients (OR: 8.9)	Higher risk of liver injury: In non-cirrhotics, diabetes [57.7% vs 39.7%, OR: 2.1]; In cirrhotics, obesity, [64.3% vs 17.2%, OR: 8.1]
Li et al[31]	Observational study	Genome-wide meta-analysis (GWMA) of 3711 NAFLD cases and 426252 controls from United Kingdom Biobank data	No significant association of NAFLD and severe COVID-19 after adjusting for confounders	Predictors of severity: Body mass index (OR: 1.73); Waist circumference (OR: 1.76); Hip circumference (OR: 1.33)
Yao et al[30]	Retrospective study in China	86 COVID-19 patients with NAFLD	NAFLD patients with advanced fibrosis (NFS > -1.5) had more fever (81.6% vs 50%), shortness of breath (18.4% vs 0%), and severe disease (28.9% vs 2.1)	Predictors of severe disease: Diabetes (OR: 8.264); Advanced liver fibrosis [NFS > -1.5] (OR: 11.057)
Targher et al[35]	Retrospective study	94 NAFLD cases among 310 patients		Factors associated with severity: Increasing FIB-4 (aOR: 1.90); Increasing NFS (aOR: 2.57)

aOR: Adjusted odds ratio; ALT: Alanine transaminase; AST: Aspartate aminotransferase; COVID: Coronavirus disease; CLD: Chronic liver disease; FIB-4: Fibrosis 4; NFS: NAFLD fibrosis score; FLI: Fatty liver index; GWAS: Genome wide association studies; ICU: Intensive care unit; LDH: Lactate dehydrogenase; NAFLD: Non-alcoholic fatty liver disease; TLC: Total leukocyte count; ULN: Upper limit of normal.

Table 4 Studies showing outcomes and predictors of severity in hepatitis B virus-infected patients with coronavirus disease 2019

Ref.	Study	Patients	Results	Predictors
Yang et al[38]	Single centre retrospective study	Patients with HBV infection out of 2899 COVID patients. Resolved hepatitis B (n = 503); HBeAg (-) CHB/infection (n = 44); HBeAg (+) CHB/infection (n = 55); HBV reactivation (n = 6)	HBeAg (+) CHB/infection and HBV reactivation were associated with more abnormal liver function, severe disease, longer ICU stay, and death	Increased ICU admission (HR: 1.86) and mortality (HR: 3.19) in HBeAg (+) CHB/infection
Choe et al[40]	Nationwide population-based cohort study	676 chronic HBV infection cases (19160 COVID-19 cases)	Mortality in HBV infected vs non-infected patients with COVID-19: 8.2% vs 13.5%	No difference in mortality, ICU admission, or organ failure
Wang et al[8]	Multicentre retrospective cohort study	109 CHB and 327 non-CHB patients with COVID-19	CHB vs non-CHB patients: Severe disease (27.5% vs 12.84%) and more dyspnoea (55.05% vs 43.12%) and mechanical ventilation requirement (22.49% vs 7.95%) in CHB	Increased mortality in CHB patients (OR: 3.748). Predictors of mortality: AST; ALT; ALP; Bilirubin; LDH; Elevated D-dimer. Protective effect: ALB (HR: 0.13); ALB/GLO (HR: 0.123)
Yip et al[44]	Retrospective cohort study	Current (353) and past HBV infection (359) out of total 5639 COVID cases	Mortality in current HBV vs past HBV vs non-HBV infection: 2.3% vs 5.8% vs 2.2%	Acute liver injury associated with mortality (aHR: 2.45), more than current (aHR: 1.29) or past (aHR: 0.90) HBV infection
Kang et al[42]	Nationwide cohort study	7723 COVID-19 cases and 46231 controls	Lower SARS-CoV-2 positivity rate in CHB, after adjusting for comorbidities (aOR: 0.65)	Reduced SARS-CoV-2 positivity (aOR: 0.49) on antivirals
Liu et al[39]	Retrospective cohort study	347 COVID-19 patients (21 vs 326 with or without chronic HBV infection)	Severe COVID-19 in 30% vs 31.4% in the HBV vs non-HBV group	Similar SARS-CoV-2 clearance and severe COVID-19

ALB: Albumin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; COVID: Coronavirus disease; CHB: Chronic hepatitis B; GLO: Globulin; HBV: Hepatitis B virus; LDH: Lactate dehydrogenase.

Table 5 Studies evaluating outcomes and predictors in autoimmune hepatitis with coronavirus disease 2019

Ref.	Study	Patients	Results	Predictors of outcomes
Efe et al[47]	Multicentre retrospective study from 34 centres in Europe and the Americas	110 AIH patients	Acute liver injury: 37.1%	Predictor of severe COVID-19: cirrhosis (OR: 17.46); Immunosuppression not associated with severe COVID-19 (OR: 0.26)
Di Giorgio et al[46]	Phone based survey in tertiary centre	adult AIH patients: AIH (n = 97, 96%); PSC/AIH overlap (n = 2, 2%); PBC/AIH (n = 2, 2%); 4 patients had confirmed COVID	Severe COVID: 1; Death: 1	No difference in risk factors of mortality
Marjot et al[49]	Retrospective data from three international registries	70 AIH cases among 932 patients with CLD with COVID-19	No differences between AIH and non-AIH related CLD in Hospitalization (76% vs 85%); ICU admission (29% vs 23%); Death (23% vs 20%)	Factors predicting mortality in AIH: Age (OR: 2.16/10 yr); Child-Pugh class [B (OR: 42.48) and C (OR: 69.30)] cirrhosis
Efe et al[50]	Retrospective data from 15 countries	254 AIH patients	Hospitalization: 94 (37%); Death: 18 (7.1%)	Factors associated with COVID-19 severity: Systemic glucocorticoids (aOR: 4.73); Thiopurines (aOR: 4.78); Mycophenolate mofetil (aOR: 3.56); Tacrolimus (aOR: 4.09)

AIH: Autoimmune hepatitis; COVID: Coronavirus disease; CLD: Chronic liver disease; ICU: Intensive care unit; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis.

Table 6 Risk factors associated with adverse outcomes in coronavirus disease 2019 affected patients with chronic liver disease

Demographics	Etiology	Clinical parameters	Underlying disease severity	Biochemical parameters
Age > 60 yr; Hispanic and black ethnicity; Diabetes mellitus; Hypertension; Obesity	Alcohol; HBeAg positivity among CHB; AIH on immunosuppressants	Respiratory failure: CURB-65 score; Decompensation at baseline; ACLF at presentation	CTP score; MELD score; FIB-4 index	Elevated creatinine; Leucocytosis; AST levels; ALT levels; CRP

ACLF: Acute-on-chronic liver failure; AIH: Autoimmune hepatitis; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; CTP: Child-Turcotte-Pugh score; CURB-65: Confusion, Uremia, Respiratory rate, BP, age > 65 years, FIB-4: Fibrosis 4 score; MELD: Model for end stage liver disease.