key: cord-0749676-mgu419j4
authors: Brozat, Jonathan F.; Hanses, Frank; Haelberger, Martina; Stecher, Melanie; Dreher, Michael; Tometten, Lukas; Ruethrich, Maria M.; Vehreschild, Janne J.; Trautwein, Christian; Borgmann, Stefan; Vehreschild, Maria J. G. T.; Jakob, Carolin E. M.; Stallmach, Andreas; Wille, Kai; Hellwig, Kerstin; Isberner, Nora; Reuken, Philipp A.; Geisler, Fabian; Nattermann, Jacob; Bruns, Tony
title: COVID‐19 mortality in cirrhosis is determined by cirrhosis‐associated comorbidities and extrahepatic organ failure: Results from the multinational LEOSS registry
date: 2022-04-28
journal: United European Gastroenterol J
DOI: 10.1002/ueg2.12232
sha: 0ed20aaf1da73019c963eafba9e6eb967cacfd53
doc_id: 749676
cord_uid: mgu419j4

BACKGROUND AND OBJECTIVE: International registries have reported high mortality rates in patients with liver disease and COVID‐19. However, the extent to which comorbidities contribute to excess COVID‐19 mortality in cirrhosis is controversial. METHODS: We used the multinational Lean European Open Survey on SARS‐CoV‐2‐infected patients (LEOSS) to identify patients with cirrhosis documented between March 2020 and March 2021, when the wild‐type and alpha variant were predominant. We compared symptoms, disease progression and mortality after propensity score matching (PSM) for age, sex, obesity, smoking status, and concomitant diseases. Mortality was also compared with that of patients with spontaneous bacterial peritonitis (SBP) without SARS‐CoV‐2 infection, a common bacterial infection and well‐described precipitator of acute‐on‐chronic liver failure. RESULTS: Among 7096 patients with SARS‐CoV‐2 infection eligible for analysis, 70 (0.99%) had cirrhosis, and all were hospitalized. Risk factors for severe COVID‐19, such as diabetes, renal disease, and cardiovascular disease were more frequent in patients with cirrhosis. Case fatality rate in patients with cirrhosis was 31.4% with the highest odds of death in patients older than 65 years (43.6% mortality; odds ratio [OR] 4.02; p = 0.018), Child‐Pugh class C (57.1%; OR 4.00; p = 0.026), and failure of two or more organs (81.8%; OR 19.93; p = 0.001). After PSM for demographics and comorbidity, the COVID‐19 case fatality of patients with cirrhosis did not significantly differ from that of matched patients without cirrhosis (28.8% vs. 26.1%; p = 0.644) and was similar to the 28‐day mortality in a comparison group of patients with cirrhosis and SBP (33.3% vs. 31.5%; p = 1.000). CONCLUSIONS: In immunologically naïve patients with cirrhosis, mortality from wild‐type SARS‐CoV‐2 and the alpha variant is high and is largely determined by cirrhosis‐associated comorbidities and extrahepatic organ failure.

As of December 2019, the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the evolving COVID-19 pandemic pose an ongoing threat to both infected individuals and treating physicians. Overburdened health services and mutating viral strains have resulted in more than 476 million cases and more than 6 million deaths worldwide (covid19.who.int, as accessed on 26 March 2022).

SARS-CoV-2 infection can present with a range of symptoms from mild febrile infection to acute respiratory distress syndrome and consecutive multiple organ failure. 1 Older age and pre-existing comorbidities such as obesity, diabetes, cardiovascular disease, respiratory disease, impaired renal function and conditions associated with immunosuppression or immune dysfunction were identified as the most important risk factors for severe disease progression, hospitalisation, and death due to COVID-19. [2] [3] [4] Consistent with the fact that many of these conditions frequently diagnosed in patients with liver disease, chronic liver disease and cirrhosis have been identified as risk factors for COVID-19-related deaths in large analyses of electronic health records 4 and meta-analyses of observational studies. [5] [6] [7] Patients with advanced chronic liver disease are at increased risk for infection-related complications and death 8, 9 due to multiple contributing pathways including deregulated systemic inflammation, dysfunctional innate and adaptive immune responses, and a predisposition to hepatic and extrahepatic organ failure. [10] [11] [12] In addition to bacterial infections, viral respiratory infections can also act as triggers of acute-on-chronic liver failure (ACLF), as shown for the influenza virus 13 and SARS-CoV-2 alike. 14, 15 According to available case series, the most common cause of death in SARS-CoV-2infected patients with chronic liver disease is lung failure followed by liver-related mortality. 15, 16 Given the paucity and heterogeneity of available data, it remains unclear to what extent the presence of liver cirrhosis itself promotes a severe course of COVID-19 in comparison to patients without liver disease but comparable extrahepatic comorbidities.

Early publications reported case fatality rates of 24%-35% in SARS-CoV-2-infected patients with cirrhosis but were often limited by the small number of patients included or the lack of a control group of patients without cirrhosis. 5, [16] [17] [18] A larger data set from an online open-report form confirmed a mortality rate of 32% for cirrhosis, which exceeded 54% for hospitalized patients with decompensated

Child-Pugh C cirrhosis and 90% for ventilated patients. 15 A recent analysis of electronic health record data from the US concluded considerably lower estimates: The overall 30-day cumulative mortality rate among patients with cirrhosis, about 50% of whom were 410 -UNITED EUROPEAN GASTROENTEROLOGY JOURNAL hospitalized, was 9%, with the highest mortality (up to 13%) among patients with decompensated cirrhosis, older age, renal disease, or heart failure. 19 This wide range of mortality rates has led to discussions about the extent to which cirrhosis per se is a risk factor for a complicated course of COVID-19 or whether these rates can be explained by associated comorbidities. 20, 21 These data also highlight the need to interpret mortality rates in the context of time periods, geographical location, ethnicity and severity of underlying disease, cirrhosisassociated extrahepatic comorbidities and complications.

The aim of this study was to determine the presentation, disease course and outcomes of SARS-CoV-2-infected patients with cirrhosis using a matched-control cohort design using the large Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS registry). A second aim of our study was to compare the mortality after SARS-CoV-2 infection to that of a common bacterial infection and welldescribed precipitator of ACLF in cirrhosis, specifically spontaneous bacterial peritonitis (SBP).

The Lean European Open Survey on SARS-CoV-2 (LEOSS) is an international registry established in March 2020 to address the lack of knowledge about the epidemiology and clinical course of SARS-CoV-2 infections. 22 To compare case fatality rates in cirrhosis to non-SARS-CoV-2 infections in patients with cirrhosis, a historical cohort of 169 patients with cirrhosis and SBP recruited for previous studies at the Jena University Hospital was analysed. 23, 24 Spontaneous bacterial peritonitis was diagnosed per current guidelines by neutrophil concentration >250/μl ascites fluid and the exclusion of secondary causes of peritonitis. The recorded clinical characteristics included age, aetiology cirrhosis, cirrhosis severity as assessed by Child-Pugh Score, Model-of-End-Stage-Liver-Disease (MELD) score, laboratory parameters, and 28-day mortality.

What is the established knowledge?

� SARS-CoV-2 infections pose a threat to healthy individuals, but especially to vulnerable patient populations with pre-existing comorbidities, such as chronic liver disease and cirrhosis.

� Viral infections can precipitate acute-on-chronic liver failure (ACLF), and SARS-CoV-2-related mortality in patients with decompensated cirrhosis is extraordinarily high.

� The heterogeneity of available data has sparked debate about whether cirrhosis per se or extrahepatic comorbidities contribute more to the excess mortality rates in cirrhosis.

� This large multi-national registry analysis of SARS-CoV-2-infected patients in Europe allows risk factors and comorbidities to be balanced in a propensity scoreadjusted case-control design.

� Before matching, the case fatality rate was higher in patients with cirrhosis and SARS-CoV-2 infection than in patients without cirrhosis, whereas the matched patients had a similar case fatality rate, demonstrating a role of cirrhosis-associated extrahepatic comorbidities and complications.

� In contrast to decompensation alone, failure of two or more organs was strongly associated with a high mortality rate, underscoring the importance of ACLF in SARS-CoV-2 infection. -411

Due to all data being collected anonymously, patients can be included in the LEOSS database without further informed consent. Data were recorded anonymously without any patient-identifying information, afterwards categorized and aggregated. In order to ensure anonymity in all steps of the analysis process, an individual LEOSS Scientific Use File was created, which is based on the LEOSS Public Use File principles described in Jakob et al. 25 

The primary aim of the analysis was to compare the overall mortality after SARS-CoV-2 infection in patients with cirrhosis with that in matched controls without cirrhosis, and only cases for which SARS- 

Propensity score matching (PSM) was implemented to account for differences in demographical and clinical characteristics of SARS-CoV-2-infected patients with and without cirrhosis. The following variables were used to create a propensity score: age category, gender, obesity, smoking status, DM, CKD, coronary heart disease and a modified Charlson Comorbidity Index (CCI). These eight variables were chosen a priori on the basis of proven or likely association with outcome in COVID-19 but less likely to be otherwise strongly associated with cirrhosis. A Fuzz of 0.0001 was used and cases were matched to 4 controls. In a post-hoc sensitivity analysis, an alternative 1:4 PSM controlling for age category, gender, and the modified CCI was also performed.

The modified CCI was calculated as the sum based on the documented comorbidities present at baseline: dementia, cerebrovascular disease, myocardial infarction, chronic heart failure, peripheral vascular disease, chronic obstructive lung disease, connective tissue disease, peptic ulcer disease, diabetes without endorgan damage, CKD (all scores of one point each), hemiplegia, diabetes with end-organ damage, leukemia, lymphoma, solid tumour without metastasis (all scores of two points each) and solid tumour with metastasis (6 points). To avoid overfitting of the propensity score, age category and liver disease were not considered for the modified CCI. The category HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrom) was not evaluated due to potentially identifying information due to a low number of patients.

To compare case fatality rates between SARS-CoV-2 infection and SBP, PSM for patients with cirrhosis and SARS-CoV-2 infection and patients with cirrhosis and SBP was performed 1:1, controlling for age, gender, and Child-Pugh class C (Fuzz 0.0001). As these cohorts con- 95.4%, p = 0.522). Patients with cirrhosis and COVID-19 were statistically more often active smokers, but with similar rates of diagnosed COPD (Table 1) .

To account for differences in demographics and comorbidities, we calculated propensity scores for age category, gender, obesity, smoking status, diabetes, CKD, coronary heart disease and modified CCI (without age category, liver disease and HIV). Sixty-six SARS-Cov2-infected patients with cirrhosis were successfully matched to 264 SARS-Cov2-infected patients without cirrhosis resulting in largely balanced baseline characteristics (Table 1) .

Only adjusting for age category, gender and the modified CCI in an alternative PSM model, resulted in a less well-balanced patient matching with relevant differences (p < 0.10) in the frequency of CKD, diabetes, asthma, malignant disease, and smoking status (Supplementary Table 1 ). 

Patients with SARS-CoV-2 infection and cirrhosis presented more frequently with at least two-fold elevated aspartate aminotransferase (AST; 27.1 vs. 6.7%, p < 0.001) and total serum bilirubin concentrations (21.7 vs. 0.8%, p < 0.001) at baseline and during the course of infection (AST: 36.4 vs. 20.1%, p = 0.005; bilirubin: 24.2 vs. 6.4%, p < 0.001) than patients without cirrhosis. Notably, alanine transaminase (ALT) elevations were not observed more frequently in SARS-CoV2-infected patients with cirrhosis (Table 3) .

To investigate whether AST elevations in cirrhosis were a correlate of acute severe alcoholic hepatitis, 28 we applied the published clinical criteria for alcoholic hepatitis. 29 The incidence of patients with alcohol-related liver disease, a total serum bilirubin greater than 2-fold above the upper normal limit, and an aspartate aminotransferase between 1 and 10-fold was 3%.

All patients with cirrhosis identified from the LEOSS database were hospitalized as compared to 93% of patients without cirrhosis ( 

Among the investigated baseline characteristics and demographics, only older age >65 years (OR 4.02, 95% CI 1.28-12.66, p = 0.018) and Child-Pugh class C (OR 4, 95% CI 1.18-13.54, p = 0.026) were significantly associated with mortality in this data set ( Table 4 ). The case fatality rate in patients with cirrhosis and SARS-CoV-2 infection aged 65 years and older was nearly three times that in patients younger than 65 years (43.6% vs. 16.1%, Figure 1a ). Like-wise, the mortality rate in patients with a Child-Pugh score C was more than twice that in patients with a Child-Pugh class A or B (57.1% vs. 25.0%, Figure 1b) (Table 4) .

cirrhosis, such as proton pump inhibitors, beta blockers, antibiotics, and diuretics, were not significantly associated with mortality in patients with cirrhosis and SARS-CoV-2 infection (Table 4 ).

Of the 70 patients with cirrhosis and SARS-CoV-2 infection, 57

initially presented in the uncomplicated phase (UC), meaning they were either asymptomatic or had mild symptoms. Eight patients initially presented with symptoms of complicated disease Figure S1) . The reasons for withholding ICU treatment were not given in the LEOSS registry. Interestingly, there were six deaths reported amongst patients who did not meet the pre-specified LEOSS criteria for complicated or critical disease phase during observation ( Figure 2 ). Reported causes of death in these patients were COVID-19 (n = 1), multiple organ failure (n = 3), comorbid conditions (n = 1), or unknown (n = 1). In contrast to liver failure, the occurrence of extrahepatic organ failure was a significant predictor of mortality in patients with cirrhosis and COVID-19 ( 

An external cohort was introduced to compare SARS-CoV-2associated mortality to that by bacterial infections. For this purpose, data on 169 hospitalized patients with SBP from two previously published studies 23, 24 were analysed. Before matching, patients with SBP were younger and had more advanced liver disease than patients with SARS-CoV-2 infection (Table 6) . COVID-19 case fatality rate was comparable to 28-day mortality after SBP (31.4 vs. 27.2%, p = 0.531).

As age and Child-Pugh stage C were significant predictors of death in SARS-CoV-2 infected patients according to our analysis, we performed a 1:1 PSM controlling for age category, sex and Child-Pugh class C. Using these criteria, 54 patients with SARS-CoV-2 infection were successfully matched with 54 patients with SBP. After matching, markers of systemic inflammation were higher in patients with SBP than in patients with SARS-CoV-2 infection, and elevated bilirubin levels continued to be observed more frequently (Table 6 ). However, the COVID-19 case-fatality rate remained similar In line with international registries 7,15 and observational cohort studies, 16, 18 the COVID-19 case fatality rate was 31% in hospitalised patients with cirrhosis with an independent contribution of both older age and more advanced liver disease. 15, 19 The high case fatality in cirrhosis could be explained to a significant part by the present extrahepatic comorbidities that exist in SARS-CoV-2 infected patients with cirrhosis. In accordance with a population-based analysis by the US National COVID Cohort Collaborative (N3C), 19 One difference between our study and previous literature 15, 17 is that SARS-CoV-2 associated mortality in patients with cirrhosis was largely related to extrahepatic comorbidities in our study, although other research groups have also employed matching techniques. Bajaj et al. 17 reported higher mortality rates in inpatients with cirrhosis and COVID-19 as compared to inpatients with COVID-19 without cirrhosis matching for age and gender but not comorbidities. Marjot et al. 15 In the LEOSS registry CKD was prevalent in 35% of inpatients with cirrhosis and COVID-19. Considering that renal function is one of the main determinants of outcome in cirrhosis and renal failure is the most prognostically relevant single organ failure in cirrhosis, 26 matching for renal function could explain these differences. In contrast to these studies, we demonstrated that the number and severity of 18 predefined comorbidities were well balanced between cases and controls after PSM according to the modified CCI.

In line with our study, cirrhosis was not independently associated with the development of severe complications, including mortality, in patients with COVID-19 in a nationwide cohort study from Korea. 21 Respiratory failure develops in only 2%-5% of patients with acute decompensation of cirrhosis and it is associated with more severe ACLF grades and the highest mortality as observed in the CANONIC and the PREDICT study. 26, 30, 31 Although respiratory virus infections have been reported in association with acute decompensation of cirrhosis, organ failure, and death, 13 pneumonia-associated mortality in patients with cirrhosis is comparable and not significantly higher than SBP based on large international studies and health insurance data. 33, 34 In our cohort, suspected or proven bacterial superinfection was associated with increased mortality in SARS-CoV-2-infected patients with liver cirrhosis.

Our study also provides information on the presentation and disease course of SARS-CoV-2 infection in patients with cirrhosis. admissions had cirrhosis. 35 In two large U.S. studies, the incidence of cirrhosis among patients with SARS-CoV-2 was 0.3%-1.8% 36, 37 and in a study from a Portuguese referral centre, the frequency was 0.8%. 38 This registry-based matched cohort study has strengths and limitations. Strengths of the study are the propensity score-matched design, the identical timeframe of hospitalization for multinational cirrhotic and non-cirrhotic patients, the comparatively large cohort of patients with cirrhosis, and the analysis of disease phase transitions.

As with any registry study, there is a potential lack of data verification, patients may not have completed follow-up, missing data must be dealt with, and duplicate registration is possible in principle. For example, a small number of patients with cirrhosis were recorded as having died of multiple organ failure following SARS-CoV-2 infection, but were only registered in the LEOSS definition of uncomplicated disease.

Our study has several limitations. One specific limitation of the LEOSS database is the categorization of continuous parameters, which results in the loss of information and may underestimate the true predictive performance of certain variables. Because LEOSS is an anonymized registry, data were not stored under a pseudonym and most data were queried in categories, making reverse database searches in the hospital information system nearly impossible. As a result, we are unable report post hoc on composite scores that are computed through continuous variables, such as the MELD score or the CLIF-C ACLF score. Furthermore, the results may not be transferable to all areas of Europe, as the majority of patients in the LEOSS database were documented in Germany. Although university hospitals in larger cities had the highest documentation rates in the LEOSS database, specialised liver departments may be underrepresented as questionnaire items such as "MELD score at diagnosis" and "worst MELD score" were often not reported. Another limitation is the predominance of patients with Caucasian/White ethnicity, which reflects on the European populace, but might limit generalizability for other ethnicities. Although our study provides the opportunity to compare data from patients with and without cirrhosis within one very detailed registry, the relatively small number of patients with cirrhosis (1%) allows only an approximate estimate of mortality within the 95% CI of 20%-43%. In addition, the number of patients with decompensated cirrhosis in this cohort during the first phases of the pandemic is low. began in Germany in late December 2020. This is why our results may not be transferable to newer variants or disease course in immunized and vaccinated individuals.

As the prevalence of liver disease and cirrhosis has plateaued at 850 per 100,000 population in Europe, 39 patients with chronic liver disease remain a group at increased risk of severe disease and death.

This European registry study analysing real-world data confirms a high risk of death in hospitalised patients with cirrhosis and SARS-CoV-2 infection comparable to that of specific bacterial infections such as SBP. Patients over 65 years of age and patients with cirrhosis were at the highest risk. Propensity score matching suggests that a large proportion of this excess mortality is due to cirrhosis-associated extrahepatic comorbidities. The development of respiratory failure and two-organ failure were associated with a mortality rate of 80%.

University Hospital Jena (Maria Madeleine Ruethrich)

The LEOSS study infrastructure group: Jörg Janne Vehreschild

Bernd Franke (University Hospital of Cologne) und Fabian Praβer (Charité, Universitätsmedizin Berlin). The LEOSS registry was supported by the

German Centre for Infection Research (DZIF) and the Willy Robert Pitzer Foundation. TB is supported by the German Research Foundation (SFB1382 Project

Open access funding enabled and organized by Projekt DEAL

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the lombardy region

Obesity and COVID-19 in New York city: a retrospective cohort study

Population risk factors for severe disease and mortality in COVID-19: a global systematic review and meta-analysis

Factors associated with COVID-19-related death using OpenSAFELY

Prevalence of chronic liver disease in patients with COVID-19 and their clinical outcomes: a systematic review and meta-analysis

Metabolic associated fatty liver disease is associated with an increased risk of severe COVID-19: a systematic review with meta-analysis

COVID-19 in liver transplant candidates: pretransplant and post-transplant outcomes -an ELITA/ELTR multicentre cohort study

Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology

Risk factors and outcome of bacterial infections in cirrhosis

Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance

Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure

COVID-19 and liver disease: mechanistic and clinical perspectives

Influenza virus infection as precipitating event of acute-on-chronic liver failure

SARS-CoV-2 as an extrahepatic precipitator of acute-on-chronic liver failure

Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study

High rates of 30-day mortality in patients with cirrhosis and COVID-19

Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort

Predictors of outcomes of COVID-19 in patients with chronic liver disease: US multi-center study

Outcomes of SARS-CoV-2 infection in patients with chronic liver BROZAT ET AL

disease and cirrhosis: a national COVID cohort collaborative study

Chronic liver disease not a significant comorbid condition for COVID-19

Impact of liver cirrhosis on the clinical outcomes of patients with COVID-19: a nationwide cohort study of Korea

First results of the "lean European open Survey on SARS-CoV-2-infected patients (LEOSS)

Peritoneal level of CD206 associates with mortality and an inflammatory macrophage phenotype in patients with decompensated cirrhosis and spontaneous bacterial peritonitis

Genetic variants of TRAF6 modulate peritoneal immunity and the risk of spontaneous bacterial peritonitis in cirrhosis: a combined prospective-retrospective study

Design and evaluation of a data anonymization pipeline to promote Open Science on COVID-19. Sci Data

Acute-on-Chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology

Acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis

Acute-on-chronic liver failure (ACLF) precipitated by severe alcoholic hepatitis: another collateral damage of the COVID-19 pandemic?

Grand rounds: alcoholic hepatitis

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis

Clinical features and evolution of bacterial infection-related acute-on-chronic liver failure

Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide

High mortality of pneumonia in cirrhotic patients with ascites

Trends and the course of liver cirrhosis and its complications in Germany: nationwide population-based study

Clinical characteristics and outcomes of coronavirus disease 2019 among patients with preexisting liver disease in the United States: a multicenter research network study. Gastroenterology

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area

Cirrhosis management in a major referral center during COVID-19

Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies

COVID-19 mortality in cirrhosis is determined by cirrhosis-associated comorbidities and extrahepatic organ failure: results from the multinational LEOSS registry

The authors have no conflicts of interest to declare.

Data availability is described here: https://leoss.net/wp-content/uploads/2020/04/Appendix-C_Data-Use-and-Access-Policy-V2.1.pdf.