Risk of Severe Illness and Risk Factors of Outcomes of COVID-19 in Hospitalized Patients with Chronic Liver Disease in a Major U. S. Hospital Network

Methods We studied 2731 patients with known CLD who were hospitalized at the Johns Hopkins Health System with COVID-19 between March 1, 2020, and December 15, 2021. The primary outcome was all-cause mortality, and secondary outcomes were MV and vasopressors. Multivariable Cox regression models were performed to explore factors associated with the outcomes. Results Overall, 80.1% had severe COVID-19, all-cause mortality was 8.9%, 12.8% required MV, and 11.2% received vasopressor support. Older patients with underlying comorbidities were more likely to have severe COVID-19. There was association between elevated aminotransferases and total bilirubin with more severe COVID-19. Hepatic decompensation was independently associated with all-cause mortality (HR 2.94; 95% CI 1.23–7.06). Alcohol-related liver disease (ALD, HR 2.79, 95% CI, 1.00–8.02) was independently associated with increased risk for MV, and independent factors related to vasopressor support were chronic pulmonary disease and underlying malignancy. Conclusions COVID-19 infection in patients with CLD is associated with poor outcomes. SARS-CoV-2 infection in patients with hepatic decompensation was associated with an increased risk of in-hospital mortality hazard, and ALD among patients with COVID-19 was associated with an increased hazard for MV.


Introduction
Coronavirus disease 2019 (COVID-19) has been a devastating infectious disease, with a rapid surge in cases and deaths since frst documented in Wuhan, China, in December 2019 [1]. As of September 7, 2022, its causative agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for over 603 million confrmed cases and nearly 6.4 million deaths globally [2]. Te clinical severity of COVID-19 varies from asymptomatic to fatal [3]. Available data have shown that known risk factors associated with poor outcomes in patients with COVID-19 include older age and underlying comorbidities such as obesity, hypertension, diabetes, chronic liver disease (CLD), and heart disease [4,5]. A meta-analysis including 51,225 patients showed a pooled OR of 1.09 for obesity (95% CI: 0.84 to 1.41), 2.12 for diabetes (95% CI: 1.79 to 2.52), 2.61 for hypertension (95% CI: 2.19 to 3.17), 2.98 for cardiovascular disease (95% CI: 2.51 to 3.53) and 1.80 for CLD (95% CI: 1.35 to 2.39) . [6] However, it remains unclear to what extent CLD should be considered a risk factor due to a shortage of appropriate studies [7]. Additionally, the global burden of CLD is vast and has been steadily increasing over the years. Ominously, CLD causes approximately 2 million deaths per year worldwide [8].
Available data suggest that patients with CLD who acquire COVID-19 have high hospitalization rates, and the mortality risk is close to 30-40% [9][10][11]. Still, preliminary studies were limited, and it remains unknown whether all patients with CLD or particular subgroups are at an increased risk for COVID-19-related adverse outcomes. First, existing data are controversial on the outcome following COVID-19 infection in patients with CLD and making it difcult to determine a prognosis for these patients [9,12,13]. Moreover, earlier studies collected data during the early pandemic when variants were not prevalent. An extensive, granular, representative clinical study is required to improve our understanding of the risk factors and severity of COVID-19 among patients with CLD. Finally, there is an under-representation of data about whether patients with CLD have an increased risk of the most intensive care of vasopressor support or mechanical ventilation. To address the abovementioned knowledge gaps, we analyzed a cohort of hospitalized patients with CLD and COVID-19 from a large health system in the United States. Our analysis focused on the independent associations between abnormal liver chemistry, clinical severity, and the risk of in-hospital mortality. ). Patients were considered right-censored if they were discharged from the hospital alive or remained in the hospital at the end of the follow-up. We assessed the time-toevent in days from the date of hospital admission to the date of in-hospital death or hospital discharge alive or end of followup. Te event-free survival probability was calculated using the Kaplan-Meier method, where the log-rank test compared diferent groups for signifcance. Cox regression analysis was used to explore the factors associated with mortality, mechanical ventilation, or vasopressor support using hazard ratios (HR) and 95% confdence intervals (CI). Univariable analyses frst identifed potential risk factors associated with the risk of death, mechanical ventilation, or vasopressor support. Subsequently, age, gender, ethnicity, race, smoking status, body mass index, etiology of liver diseases, and all pre-existing comorbidities were adjusted in multivariable Cox proportional hazards models. We also used Cox models to estimate HRs for the grade of liver chemistry elevation associated with major outcomes. All tests were two-tailed and used a signifcance level of P values <0.05. Analyses were performed using Stata (version SE16; StataCorp, College Station, TX).

Severe
Disease. In all, 2187 (80.1%) patients were classifed as severe cases during hospitalization. Patients in the severe group were older, obese, and likely to have more underlying comorbidities (Table 1). In addition, the severe disease was associated with signifcantly higher white blood cells, neutrophils, creatine, blood urea nitrogen (BUN), prothrombin time (PT), and international normalization ratio (INR). In contrast, absolute lymphocyte, albumin, and total protein levels were lower in patients with severe disease (Supplementary Table 2).

Analysis and Distribution of Abnormal Liver
Chemistries during Hospitalization. Abnormal liver chemistries were more common in patients with severe disease; most patients had mild elevations within 1-2 × ULN (Table 1). Te median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were 24 and 28 U/L, respectively, in nonsevere diseases compared to 30 and 38 U/L in severe cases (P < 0.001). Elevated aminotransferase levels at >2-5 × ULN and >5 × ULN were signifcantly more common among patients with severe diseases than nonsevere. Te median level of alkaline phosphatase (ALP) was higher in patients with severe disease, whereas no diference was noted in median total bilirubin (T. Bil) between these two severities.

Risk Factors Associated with Vasopressor Support and
Mechanical Ventilation. In all, 307 (14%) patients with severe COVID-19 required vasopressors, and 350 (12.8%) received invasive mechanical ventilation. Patients who required vasopressor support or mechanical ventilation were older and more likely to have pre-existing comorbidities (Supplementary Table 3). In general, ALT, AST, and T. Bil values were signifcantly higher in these patients. However, there was no diference in median ALP in either of these outcomes. Furthermore, patients who required vasopressor support or mechanical ventilation had varying degrees of abnormal liver chemistries. COPD and underlying malignancy were associated with vasopressor support (Table 2). In addition, compared to patients with normal AST, the risk for vasopressors increased 1.32-fold (95% CI 1.00-1.76) when AST >1-2 × ULN and 2.81-fold (95% CI 1.18-6.71) when AST >5 × ULN. Abnormal ALT and T-Bil levels were not independently associated with an increased risk of vasopressor support. Viral hepatitis (HR 0.56, 95% CI, 0.37-0.85) was associated with lower vasopressor support hazards in multivariable analysis.

Discussion
Our study has highlighted several important fndings amongst a large cohort of CLD patients hospitalized with COVID-19 infection at a large academic center in the United States. First, we observed all-cause mortality of 8.9%; 12.8%  required mechanical ventilation; and 11.2% received vasopressor support. Second, patients with decompensated cirrhosis were independently associated with an increased risk of COVID-19-related mortality. Additionally, baseline factors such as older age, high levels of T-Bil, and increased infammatory markers such as CRP and D-Dimer were associated with death. Tird, during hospitalization, a liverspecifc factor associated with the need for mechanical ventilation from COVID-19 was ALD. In addition, we noticed that high serum neutrophil and BUN levels were independently associated with respiratory support through intubation. Fourth, we observed independent factors related to vasopressor support: chronic pulmonary disease and underlying malignancy. Fifth, there were strong associations between elevated AST or T. Bil with more severe COVID-19 infections.
In our study, hepatic decompensation was independently associated with a higher risk of COVID-19-related inhospital mortality. Ge et al. have reported data from the N3C Consortium in the USA with more than 220,000 CLD patients highlighted the adverse impact of advanced liver disease, with cirrhosis being associated with a 2.38 times mortality hazard in an adjusted model of mortality 30-days following SARS-CoV-2 infection [14]. In addition, when compared with SARS-CoV-2 patients with cirrhosis/negative and patients with decompensated cirrhosis, SARS-CoV-2 positivity (cirrhosis/positive) was associated with a 2.20 times adjusted hazard of death within 30 days [12]. Similarly, Mallet et al. have reported the outcomes of hospitalized COVID-19 from the French National Hospital Discharge database with a cohort of >259,000 inpatients with COVID-19, including 15,476 with pre-existing CLD, and demonstrated that patients with decompensated cirrhosis were at 2.21 adjusted odds of increased adjusted risk for mortality, highlighting the importance of delineating cirrhosis severity when prognosticating outcomes [15]. In contrast to these fndings, one nationwide Swedish CLD cohort did not demonstrate any associations between cirrhosis and COVID-19-related mortality [16]. However, this study only included patients with biopsy-proven CLD diagnoses prior to 2017. Terefore, more advanced liver disease may be under-represented because these patients were not subjected to biopsy or died before the onset of the pandemic. Patients with hepatic decompensation had a 2.9-fold increased mortality risk in our cohort. Direct infection of hepatocytes and cholangiocytes has been proposed [17,18]. However, single-cell RNA sequencing has indicated the sparse hepatocyte expression of receptors necessary for viral uptake. Hence, hepatocyte injury caused by SARS-CoV-2 may be more related to cytokine overproduction. Te resulting systemic infammatory response syndrome is linked to the lung-liver axis, leading to organ dysfunction [19,20]. Infammatory cytokine storms during COVID-19 infections are not uncommon and can result in sudden patient clinical   deterioration and multiorgan failure [21]. Hence, decompensated liver disease appears to be a signifcant risk factor for mortality in patients with COVID-19. In addition, the cirrhotic liver has shown a more than a 30-fold increase in ACE2 receptor expression compared to healthy livers [22]. Tis fnding highlights that cirrhotic patients may be uniquely susceptible to SARS-CoV-2-mediated hepatic dysfunction [20]. Furthermore, a study by Wanner et al. has shown that specifc SARS-CoV-2 hepatotropic, further associating the ability of the virus to trigger decompensation in patients with pre-existing CLD [3,23]. Patients with decompensated cirrhosis should be monitored closely to manage their disease-defning events and take extra precautions to minimize the risk of SARS-CoV-2 exposure. Currently, the reason for the worse prognosis of COVID-19 patients with ALD remains unclear. Patients with ALD were notably more likely to require mechanical ventilation in our COVID-19 study cohort. A study by Wang et al. highlighted that the risk of severe COVID-19 was signifcantly associated with alcoholic liver damage (OR, 7.05; 95% CI, 6.30 to 7.88) and alcoholic liver cirrhosis (OR, 7.00; 95% CI, 6.15 to 7.97) [24]. ALD is associated with immune system dysregulation, leading to an increased risk of infection-related morbidity and mortality [25]. Moreover, ALD can suppress chemokine production and impair the expression of proteins that allow neutrophils to adhere to other cells at the site of infection [26]. Finally, ALD primes the alveolar epithelium for injury by promoting oxidative stress, increasing epithelial permeability and protein leak, and impairing fuid clearance through tight junction proteins within the epithelial barrier alterations [27]. Tese phenomena explain ALD patients' pathophysiological propensity to develop acute respiratory distress syndrome. ALD is associated with suppressing complement activation and systemic production of proinfammatory cytokines by various immune cells [28]. A direct efect of alcohol and alcohol-related efects on alveolar epithelial dysfunction and decreased concentration of pulmonary antioxidants in addition to immune function in individuals with chronic alcohol abuse [29]. In addition, patients with alcohol use disorder often have other comorbidities, such as smoking, metabolic syndrome, and chronic kidney disease, which have been independently associated with severe outcomes in SARS-CoV-2 patients [30,31]. Patients with ALD had a 2.7-times higher hazard of mechanical ventilation in our cohort. Based on our fndings, we could hypothesize that ALD patients with advanced stages are characterized by a severe condition, which negatively impacts their prognosis. In addition, a superimposed cytokine storm triggered by SARS-CoV-2 could exacerbate the heightened infammatory state in patients with ALD, thus leading to worse outcomes.
Studies have shown that patients with abnormal liver chemistries have a signifcantly higher risk of developing severe pneumonia [20,21,32]. Our study fndings suggest that elevated liver chemistries should be regarded as a red fag indicating a more severe disease course and major inhospital outcomes in COVID-19 patients. Abnormal liver function occurs in the setting of direct hepatocyte injury caused by the SARS-CoV-2 and may be closely related to systemic infammatory response syndrome. Our data imply a potential association between liver injury and the infammatory responses induced by SARS-CoV-2 infection [21]. Given the profound multisystemic involvement in severe COVID-19, liver injury is likely to be multifactorial [22,23]. Candidate mechanisms of liver injury include hypoxic hepatitis, drug-induced liver injury, intrahepatic immune activation, and microvascular thrombosis.
Our study has some limitations. First, it is retrospective and limited to a single healthcare system. Te analysis represented only hospitalized patients, who were more likely to have severe COVID-19. Te relationships detected in our study could be afected by collider bias due to the specifc qualities of those hospitalized vs. those with the outcomes of interest [3]. In addition, there may have been referral bias due to the tertiary hospital setting of the study. However, our cohort represented an ethnically diverse population with varying stages of liver disease. We could also have enrollment bias because not all patients with CLD have documented ICD codes in their electronic health records. Despite our best attempts, we may not have identifed all hospitalized patients with CLD and COVID-19. Although we attempted to collect data on the most relevant covariables, there remained a possibility of unmeasured confounding not captured by our registry, which was designed to allow rapid data entry during the pandemic's peak. Importantly, we had a smaller ALD and compensated cirrhosis sample due to undercoding and a lack of specifc ICD-9-CM and ICD-10-CM codes. Te causes of death in COVID-19 patients may involve multiple organ injuries, and it was challenging to diferentiate Abbreviations: HT, hypertension; CHF, congestive heart failure; CKD, chronic kidney disease; CC, compensated cirrhosis; DC, decompensated cirrhosis; NAFLD, nonalcoholic fatty liver disease; ALD, alcohol-related liver disease; ALT, alanine aminotransferases; ALP, alkaline phosphatase; GGT: c-glutamyl transpeptidase; AST, aspartate aminotransferase; T-Bil, total bilirubin; INR, international normalized ratio; BUN, blood urea nitrogen; PT, prothrombin time; CRP, C-reactive protein; LDH, lactate dehydrogenase; HR, hazard ratio; CI, confdence interval, IO, insufcient observation. * Age, gender, ethnicity, race, body mass index, smoking use, etiology of liver diseases, and all the pre-existing comorbidities were adjusted as confounders in the multivariable Cox proportional hazards model. CLD as the primary or direct cause of death. Our data were not able to include COVID-19 vaccines nor SARS-CoV-2 variants to assess the impact in accuracy in patients with CLD. We did not have data regarding treatment for autoimmune liver disease or viral hepatitis. Finally, we could not obtain long-term outcomes due to a comparatively short observation period. Further studies with long-term periods are needed to understand the long-term impact of COVID-19 on the liver and elucidate the pathogenic mechanisms.

Conclusion
Our study highlighted the myriad risk factors for poor clinical outcomes among patients with CLD and COVID-19 infection. Hepatic decompensation was associated with allcause mortality, whereas ALD was independently associated with mechanical ventilation. In addition, liver enzymatic abnormalities may indicate more severe COVID-19 and help support clinical decisions regarding monitoring or risk stratifcation. Overall, our fndings emphasized the need for patients with CLD to follow recommended preventive measures against SARS-CoV-2 exposure.