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Predictors of Outcomes of COVID-19 in Patients with Chronic Liver Disease: US Multi-center Study
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According to the Center for Disease Control (CDC), patients with CLD might be at increased risk for severe illness with COVID-19 16. 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 multi-center 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 like older age, hypertension, diabetes and COPD. Additionally, 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.
Clinical Gastroenterology and Hepatology September 17, 2020
ABSTRACT
Background
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.
The most common cause of CLD was nonalcoholic fatty liver disease (NAFLD) (456 [52.6%]), followed by hepatitis C virus (HCV) infection (190 [21.9%]), alcohol-related liver disease (ALD) (94 [10.8%]) and hepatitis B virus infection (HBV) (62 [7.2%]) (Figure S5, S6). The majority of patients had non-cirrhotic stage disease (620 [71.5%]); 227 (26.2%) patients had a diagnosis of cirrhosis. Most patients with cirrhosis were well compensated at the time of inclusion (134 [59.1%]), with 93 (40.9%) patients having decompensated cirrhosis prior to 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 pre-existing hepatocellular carcinoma (HCC) (22 [2.5%]), eight (36.4%) of them had received locoregional therapy, two (9.1%) had received immunotherapy and none of them were on tyrosine kinase inhibitors.
The liver-specific predictors of all-cause mortality were ALD (hazard ratio [HR] 2.42, 95% confidence interval [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). 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. Further, we did not find significant interactions between ALD and decompensated CLD or HCC for overall survival on multivariate analysis (test of interaction P > 0.2) (Table S4).
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), 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) (Table S5).
Predictors of Severe COVID-19 in Patients with CLD
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 (odds ratio [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).
DISCUSSION
According to the Center for Disease Control (CDC), patients with CLD might be at increased risk for severe illness with COVID-19 16. 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 multi-center 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 like older age, hypertension, diabetes and COPD. Additionally, 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.
Given that 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 using a de-identified research network database, and reported a hospitalization rate of 52% and mortality 12%, similar rates to our study 9. Preliminary data from an international registry of 152 patients with CLD however reported a higher overall mortality rate of 31% and a hospitalization rate of 95% for patients with cirrhosis 11. 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 17,18. 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 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 due to the underlying dysregulation of the immune system 20. ALD is associated with a sterile inflammatory state induced by damage-associated molecular patterns (DAMPs), which leads to the systemic production of pro-inflammatory cytokines by various immune cells 21,22. 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 23. Moreover, there has been significant concern about increased alcohol use during the COVID-19 pandemic, highlighting the importance of this association 24,25. In our study, up to a 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 alcohol liver disease (ALD) who are at higher risk for adverse outcomes with COVID-19.
Another subgroup that was found in our study 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 14,26. Patients with HCC may be uniquely susceptible to COVID-19 related complications due to 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 to 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 27,28
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 both 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 since not all patients with CLD have a documented ICD9/10 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. Lastly, 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 additionally 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.
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