key: cord-0887732-3h4wavqc
authors: Iavarone, Massimo; D’Ambrosio, Roberta; Soria, Alessandro; Triolo, Michela; Pugliese, Nicola; Del Poggio, Paolo; Perricone, Giovanni; Massironi, Sara; Spinetti, Angiola; Buscarini, Elisabetta; Viganò, Mauro; Carriero, Canio; Fagiuoli, Stefano; Aghemo, Alessio; Belli, Luca S.; Lucà, Martina; Pedaci, Marianna; Rimondi, Alessandro; Rumi, Maria Grazia; Invernizzi, Pietro; Bonfanti, Paolo; Lampertico, Pietro
title: High rates of 30-day mortality in patients with cirrhosis and COVID-19
date: 2020-06-09
journal: J Hepatol
DOI: 10.1016/j.jhep.2020.06.001
sha: 0786e2d733781762ac23bbe927881282f71ca8f2
doc_id: 887732
cord_uid: 3h4wavqc

BACKGROUND AND AIMS: Coronavirus disease (COVID-19) is a major worldwide threat for healthy individuals as well as for patients with comorbidities, but its impact on patients with cirrhosis is currently unknown. This study aimed at evaluating the impact of COVID-19 on the clinical outcome of these patients. METHODS: In this multicenter retrospective study, cirrhotic patients with confirmed Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection were enrolled between 1(st) and 31(th) March 2020. Clinical and biochemical data at COVID-19 and at the last outpatient visit were obtained through review of medical records. RESULTS: Fifty cirrhotic patients with confirmed SARS-CoV-2 infection were enrolled (age 67 years, 70% men, 38% virus-related, 52% previously compensated cirrhosis). At diagnosis, 64% of patients presented fever, 42% shortness of breath/polypnea, 22% encephalopathy, 96% needed hospitalization or prolonged an ongoing one. Respiratory-support was necessary in 71%, 52% received antivirals, 80% heparin. Serum albumin significantly decreased, while bilirubin, creatinine and prothrombin time significantly increased at COVID-19 diagnosis compared to last available data. The proportion of patients with MELD≥15 increased from 13% to 26% (p=0.037), acute-on-chronic liver failure and and de novo acute liver injury occurred in 14 (28%) and 10 patients, respectively. Seventeen patients died after a median of 10 (4-13) days from COVID-19 diagnosis, with a 30-day-mortality rate of 34%. Severity of lung and liver (according to CLIF-C, CLIF-OF and MELD scores) diseases independently predicted mortality. Mortality was significantly higher in hospitalized cirrhotics with COVID-19 than in those hospitalized for bacterial infections. CONCLUSION: COVID-19 is associated with liver function deterioration and elevated mortality in cirrhotic patients.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus first detected in Wuhan, China, that causes coronavirus disease 2019 (COVID- 19) . 1 Since initial virus detection, more than 1,350,000 cases of COVID-19 have been confirmed worldwide, with the first reported cases in the Lombardy region, Northern Italy, occurring on end of February, 2020. 2 The number of cases in our region continues to rise; as of April 2, 2020, there had been 46,071 confirmed SARS-CoV-2 infections and 7,600 deaths. 3 At least seven relatively large-scale case studies from China have reported the clinical features of patients with COVID-19. [4] [5] [6] [7] [8] [9] [10] These data indicate that 2-11% of patients with COVID-19 had preexisting liver diseases. Recently, Grasselli et al, reported that, among the first 1,591 patients admitted to intensive care units (ICU) in Lombardy due to SARS-CoV-2 infection, 3% had a history of chronic liver disease. 11 Patients with pre-existing cirrhosis might be more susceptible to SARS-CoV-2 infection because of their systemic immunocompromised status. Moreover, in these patients, the severity of COVID-19 and the rate of complications, potentially leading to increased 6 liver-related mortality, might be more pronounced than in general population. This hypothesis derives from studies on bacterial infections, a common cause of decompensation in patients with cirrhosis; conversely, data on the impact of viral infections have been less studied in this population. 12 It has been reported that viral influenza may increase the risk of decompensation in cirrhotic patients, and recently a high risk of hepatic function deterioration during the pandemic of 2009 H1N1 influenza virus, even in patients with stable liver disease, has been reported. 13 In the study by Premkumar et al, 82% of patients with cirrhosis and A/H1N1/09 died of pneumonia and acute respiratory distress syndrome despite timely antiviral treatment, with the severity of both respiratory distress and kidney impairment being independent predictors of mortality. 13 Since data on COVID-19 in patients with cirrhosis are lacking, we performed a multicenter retrospective study to describe the demographic, clinical and biochemical characteristics of cirrhotic patients with SARS-CoV-2 infection in the Lombardy region and their outcomes.

We included cirrhotic patients with laboratory-confirmed SARS-CoV-2 infection who were managed in nine hospitals in Lombardy, Northern Italy, between March 1 st and March 31 th , 2020. Therefore, all information registered by 3 April 2020 (data-lock) were entered into the database.

A confirmed case of SARS-CoV-2 was defined by a positive result on a reverse-transcriptasepolymerase-chain-reaction (RT-PCR) assay of a specimen collected on a nasopharyngeal swab, as previously described. 5 Demographic and clinical data, including clinical symptoms or signs at presentation, laboratory and radiologic results during COVID-19 management as well as administered antiviral therapies and anti-thrombotic prophylaxis, were collected. All laboratory tests and radiologic assessments were performed at treating physician discretion. Data of the last outpatient clinic visit before COVID-19 were also collected for comparison. When SARS-CoV-2 infection occurred during hospitalization, data of COVID-19 diagnosis were compared to those collected at hospital admission. Liver Disease (MELD, CLIF-OF, CLIF-C) scores were assessed. Liver injury was defined as alanine aminotransferase (ALT) level > 30 U/L for males and 19 U/L for females in those patients with normal ALT levels at last outpatient visit. 14 Hepatic flare was defined as ALT level ≥5 x upper limit of normality. Acute on chronic liver failure (ACLF) at diagnosis of COVID-19 was retrospectively defined and graded according to the EASL-CLIF definition. 15 Any coexisting conditions were obtained from medical records. Scrutiny for other causes of liver function deterioration included history of over the counter medication use, over-diuresis, alcohol intake and use of hepatotoxic medications.

To assess the impact of SARS-CoV-2 infection on survival of hospitalized cirrhotic patients, we compared the survival of this cohort with that of a control group which included cirrhotic patients hospitalized in the last year for liver decompensation due to bacterial infection in two Units 8 involved in this multicenter study. These control patients, identified from the discharge database, were consecutively selected among those diagnosed with cirrhosis and infection (i.e. pneumonia, urinary tract infection, spontaneous bacterial peritonitis, or spontaneous bacteraemia), all their data retrieved from hospital records.

To compare the mortality of COVID-19 patients with and without cirrhosis, we retrospectively extracted the mortality rates due to COVID-19 in patients without cirrhosis hospitalized at the Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico within the same period. Finally, SARS-CoV-2-related mortality data for general population were retrieved from the Regional report of the Italian Istituto Superiore di Sanità (ISS), and used as benchmark.

Descriptive statistics were used to summarize the data; results have been reported as median and interquartile range (IQR) or mean and standard deviation, as appropriate. Categorical variables have been compared using the χ 2 or the Fisher's exact tests; continuous variables have been compared using the Student-t-test, the Mann-Whitney U-test or the Kruskall-Wallis test, when appropriate. All tests were two-sided and used a significance level of 0.05. Survival curves were estimated by the Kaplan-Meier method, Cox regression analysis was used to identify factors associated with 30-day mortality. Data handling and analysis were performed using STATA software (release 7.0, Stata Corporation, College Station, TX). At SARS-CoV-2 diagnosis, 44 (88%) patients presented at least one symptom: 18 (36%) presented with cough, 21 (42%) with polypnea or shortness of breath, 32 (64%) with fever and 11 (22%) with acute hepatic encephalopathy ( Table 2 ). Six (12%) patients were asymptomatic at presentation: in these cases, nasopharyngeal swab was performed according to surveillance protocols (i.e. contact with positive subjects).

Finally, 48 (96%) patients were hospitalized, which included 10 patients already hospitalized for other reasons and 38 who required admission for SARS-CoV-2 infection itself.

Thirty-two (64%) patients needed non-invasive respiratory support during hospitalization, while two patients were admitted to ICU and received invasive mechanical ventilation (Table 2 ). In detail, an acute respiratory distress syndrome was present in 26 (52%) patients: mild (200 mmHg < PaO2/FiO2 ≤ 300 mmHg) in 12, moderate (100 mmHg < PaO2/FiO2 ≤ 200 mmHg) in 11 and severe (PaO2/FiO2 < 100 mmHg) in 3 patients. Moreover, 4 (8%) patients experienced hypotension and needed vasopressors.

Overall, 26 (52%) patients received specific anti-SARS-CoV-2 treatment: 9 (18%) received hydroxychloroquine alone, 3 (6%) received antiviral therapy with lopinavir-ritonavir, and 14 (28%) received both anti-viral treatment and hydroxychloroquine; none of the patients have been treated with tocilizumab or remdesivir. Only mild gastrointestinal adverse events were reported in patients treated with hydroxychloroquine, whilst one patient showed a mild increase in ALT values. In one case, treated with hydroxychloroquine plus lopinavir-ritonavir, a prolongation of electrocardiographic QT interval occurred, leading to treatment discontinuation, however without sequelae.

Thromboprophylaxis with heparin (mainly with low molecular weight heparin, LMWH) was started at COVID-19 diagnosis in 80% of patients, with two minor haemorrhagic events (epistaxis and haematuria were still hospitalized [median stay length at data-lock 15 (9-33) days].

When compared to the last outpatient visit [median time-lapse 1.7 (1.0-4.0) months], or to blood tests performed at admission, but before SARS-CoV-2 infection, most parameters had changed at the time of COVID-19 diagnosis. Bilirubin, INR, ALT and creatinine (p=0.007) significantly increased (p=0.026, p=0.042, and p=0.024, respectively), whilst albumin levels significantly decreased (p=0.0003), thus influencing both CPT and MELD scores ( Table 3 ). The distribution of CPT scores significantly changed (p=0.05, Table 3 The 30-day cumulative probability of overall mortality was 34% [95% Confidence Interval (CI) 23-49] ( Figure 1A) . The corresponding features for COVID-19-and liver-related mortality were 25% (95% CI 15-40) and 12% (95% CI 5-26), respectively ( Figure 1B) . Predictors of mortality are reported in Table 4 . In the multivariate analysis, only CLIF-OF (HR 1.426, 95%CI 1.122-1.668, p≤0.0001) and moderate/severe lung failure (HR 1.608, 95%CI 1.079-2.395, p=0.019) independently predicted mortality. When CLIF-C was introduced, MELD, CLIF-C and moderate/severe respiratory failure remained as independent predictors. MELD and CLIF independently predicted mortality also when analysed as dichotomous variables. Figure 2a and 2b show the cumulative probability of mortality according to MELD≥15 and CLIF-OF>9 at diagnosis.

MELD≥15 at development of SARS-CoV-2 infection occurred in 2/33 (6%), 5/10 (50%) and 6/7 (86%) of patients with MELD scores of 6, 7-11 and >11 at last record before SARS-CoV-2 infection, respectively (p<0.0001). Table 5 shows the comparison between the main cohort (i.e. 48 cirrhotics hospitalized with COVID-19) and 47 cirrhotics hospitalized for acute liver decompensation due to bacterial infection, which served as controls. In the control group, bacterial pneumonia was diagnosed in 18 (38%) patients, spontaneous bacteraemia in 14 (30%), cholangitis in 5 (11%), urinary tract infection in 4 (9%), spontaneous bacterial peritonitis in 4 (9%) patients, arthritis in one (2%) and gastroenteritis due to Clostridioides difficile in one (2%). Patients with COVID-19 were significantly older, with lower white blood cells counts despite concomitant infection, and lower MELD and CPT B/C scores. However, ACLF prevalence was similar ( 

This case series clearly demonstrates the poor outcome of cirrhotic patients (either with compensated or decompensated liver disease) who develop COVID-19. The main causes of death were respiratory complications but also the sudden worsening of liver function leading to end-stage liver disease. To the best of our knowledge, this is the first report on the clinical impact of SARS-CoV-2 infection in patients with cirrhosis.

We retrospectively collected data on 50 patients with known cirrhosis and COVID-19 managed in nine hospitals in Lombardy. Interestingly, a health-care related SARS-CoV-2 infection was registered in 40% of our patients. This fact could be the consequence of their general increased need of hospitalization and assistance due to cirrhosis complications, as well as their increased susceptibility to infections. According to the Italian ISS report, the nosocomial SARS-CoV-2 infection rate was 9.9% in Italy, which is lower than what we observed in our cohort. Moreover, the clinical presentation of SARS-CoV-2 infection in our cohort of cirrhotics slightly differed from what reported in the general population. Indeed, fever was less frequent, 16 whilst an expected increase in cirrhosis complications rate was observed, particularly hepatic encephalopathy. In our study, the 30-days mortality rate was higher in those patients with moderate/severe respiratory failure and in those who had a more deteriorated liver function, as indicated by the increased MELD and CLIF-OF scores at COVID-19 diagnosis. While the association between severity of lung failure and early mortality was expected, this study is the first to define the predictive role of CLIF and MELD scores in the setting of acute failure of chronic liver disease due to COVID-19.

The corresponding 30-day mortality rate in non-cirrhotic patients hospitalized following COVID-19 diagnosis was significantly lower, with higher median age of deceased patients. Unfortunately, no data are available on the role of factors (i.e. co-morbidities, lung failure severity, etc) potentially influencing mortality rates in this control group, as the ICD-9 system has been used for data collection. In the same period, 7,600 (16%) of 46,071 patients with SARS-CoV-2 infection died in Lombardy, with a median age of 79 years (73-87). These data significantly differ from what reported in our cirrhotic cohort, characterized by a higher mortality rate and lower age at death.

in otherwise stable cirrhotic patients: 25 CPT A patients with low MELD score experienced a rapid deterioration in their liver function, so that CPT score increased to B/C after COVID-19 diagnosis in more than a third of them. This was even worst for those patients with a decompensated disease before SARS-CoV-2 infection, since we reported that high MELD scores at last visit independently predicted the risk of MELD≥15 at COVID-19 diagnosis. The short interval between the last outpatient visit (or hospital admission) before SARS-CoV-2 diagnosis, supports the role of this acute infection in worsening liver function, which is common in cirrhotic patients of any aetiology.

The comparative analysis with cirrhotic patients hospitalized for decompensation due to bacterial infections, confirmed that mortality rate due to infections is high, independently of the etiological agent. However, the 30-day mortality for COVID-19 cirrhotics was higher than that reported among cirrhotics hospitalized following bacterial infections, although MELD score was lower in the former group. Multivariate analysis confirmed that COVID-19, together with high CLIF-OF, was independently associated with 30-day mortality. This is probably due to several factors, which include the unavailability of effective treatments against SARS-CoV-2 as well as the impact of lung failure on early mortality even in patients who died because of ESLD. In fact, also in cirrhotic patients who died for ESLD, respiratory function had been severely compromised by SARS-CoV-2, since all of them needed respiratory support.

Several papers reported the impact of SARS-CoV-2 infection on transaminases levels in the general population, although they were not specifically focused on the clinical significance of these alterations in terms of both morbidity and mortality, especially in cirrhotic patients. 18 In the setting of chronic liver diseases, persistent and/or severe alteration of transaminases may negatively impact cirrhosis course, also in those patients who had remained stable and free from liver-complications for long time. Recently, Dong et al reported a 50% ALT increase in 202 consecutive patients with confirmed COVID-19, which included 38% with non-alcoholic fatty liver disease (NAFLD).

Interestingly, the authors reported that NAFLD patients had higher likelihood of abnormal liver function tests from admission to discharge [70% (53/76) vs 11.1% (14/126) p<0.0001]. 18 Our study is the first reporting the impact of SARS-CoV-2 infection on ALT levels in patients with cirrhosis, showing that acute liver injury was observed in nearly a half of patients with previously normal transaminases values. Moreover, a hepatitis flare was not uncommon at SARS-CoV-2 diagnosis.

However, more data are needed to clarify the impact of ALT increase in the natural history of cirrhotic patients with SARS-CoV-2, and to better explain the pathogenic mechanism of coronavirus in causing liver damage at the level of liver cells. A potential direct cytopathic effect has been suggested, since the abundant ACE2 receptors in the liver might favour SARS-CoV-2 entry into the hepatocytes. 19 Otherwise, the liver might be indirectly involved in the severe inflammatory response following SARS-CoV-2 infection, as it contains a large number of macrophages (Kupffer cells) and is a potent cytokine producer. 20 Specific treatment against SARS-CoV-2 was not standardized in our cohort, but rather based upon regional guidelines issued by scientific societies and expert opinions. Single physician's decision on every patient was the balance between rapidly available repurposed drugs and acceptable tolerability and safety. Most of the patients received hydroxychloroquine, while only one third received lopinavir/ritonavir. With all the caveats of a small sample size, only one major adverse event was reported (QT prolongation leading to drug discontinuation). Generally, lopinavir/ritonavir has been used cautiously in patients with more advanced cirrhosis, due to its known hepatic metabolism and its possible detrimental effect on residual hepatic function. At the time of data collection, a phase II trial with tocilizumab was available only in few referral centers, thus excluding the chance to enrol patients with cirrhosis. In the period before data-lock, access to remdesivir was reserved to mechanically ventilated patients on the basis of a treating physicianinitiated request in a compassionate use program. The two intubated patients of our cohort did not receive remdesivir. The reason for not applying for compassionate use in these two cases are unknown but could be due to the difficult access in programs of experimental drugs in the dramatic hospital emergency we faced in March 2020 in Lombardy.

Interestingly, most patients (80%) in our cohort received thromboprophylaxis, mainly with LMWH, without any evidence of major haemorrhagic complications. The high prevalence of thromboprophylaxis in our cohort might be explained by the established awareness of the increased thrombotic risk in this population, as well as by the ascertained skill in anti-thrombotic management in most centers dealing with cirrhotic patients.

We are aware that our study suffers from some limitations, mainly due to the retrospective design of the study. They include the limited number of patients, the short follow-up following the diagnosis of SARS-CoV-2 infection and the low number of patients admitted in ICUs. However, we believe that this last point might be not only a consequence of the retrospective collection of data but also of the effective limited access to ICUs of patients with severe comorbidities, such as cirrhotics. In fact, during the study period, we faced with a dramatic scarcity of bed in ICUs trying to cope with the awesome outbreak of SARS-CoV-2 infection and COVID-19 in Italy. Another limitation is the imbalance of baseline characteristics (age and MELD) between patients with viral and bacterial infection, although multivariate analysis confirmed SARS-CoV-2 infection as an independent predictor of 30-day mortality. On the other hand, strengths of our study are the involvement of most tertiary referral Centers for both infectious and liver diseases in Lombardy, thus limiting the risk of underestimating the number of hospitalized cirrhotics within our Region.as well as the availability of "historical" information for almost all patients, The inclusion of control groups of well characterized hospitalized patients with cirrhosis and acute decompensation following bacterial infection and without cirrhosis but with COVID-19, further strengthens the present study.

In conclusion, as the current pandemic of SARS-CoV-2 is spreading, physicians and hepatologists should be aware of the potential detrimental effects of this infection on the short-term outcome of such a fragile patient population as cirrhotics. CLIF-OF score 7 (4-9) 7 (4-9) 0.92 22% (95%CI 20-38) 1 

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COVID-19 and liver disease

Other variables included in the univariate analysis did not result significantly associated to 30-day mortality: age, sex, aetiology of liver disease, diabetes mellitus, smoking history, HCC history, bilirubin level, albumin level, ferritin level, LDH level

*variation >5 points between last MELD before COVID-19 diagnosis and diagnosis of COVID-19

§ Model 1: MELD, delta-MELD, CLIF-OF and moderate/severe respiratory failure; # Model 2: MELD, delta-MELD, CLIF-C and moderate/severe respiratory failure

COVID-19: Coronavirus disease; HR: hazard ratio; CI: Confidence Interval; COPD: Chronic obstructive pulmonary disease; CPT: Child-Pugh-Turcotte; MELD: Model End-Stage Liver disease; COVID-19: Coronavirus disease; ACLF: Acute on Chronic Liver Failure; CLIF: European Foundation for the study of chronic liver failure; OF: Organ failure

Categorical variables have been compared using the χ 2 test, continuous variables have been compared using the Student-t-test

*All HCV patients achieved an SVR and all HBV patients were on effective nucleotide analogue (NA)-therapy

**11 autoimmune hepatitis and 8 NASH in the SARS-CoV-2 negative cohort

COVID-19: Coronavirus disease; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus-2

HCV: hepatitis C virus; HBV: hepatitis B virus; HCC: Hepatocellular carcinoma; HCC; LT: Liver Transplant; COPD: Chronic obstructive pulmonary disease; CRP: C-Reactive Protein; INR: Interval Normalized Ratio; PLT: Platelets; WBC: White-Blood Cells; ALT: Alanine aminotransferase; CPT: Child-Pugh-Turcotte; MELD: Model End-Stage Liver disease; ACLF: Acute on Chronic Liver Failure; CLIF: European Foundation for the study of chronic liver failure; SVR: Sustained Virological Response