Poor Outcomes in Patients with Cirrhosis and COVID-19

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Introduction
Since 30th January 2020, when India reported its rst case of coronavirus disease  caused by the novel severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2), the total number of cases have increased to 4,40,462 as on 22nd June 2020 [1]. Although the COVID-19 disease predominantly presents as a respiratory illness in the majority of the patients, extrapulmonary manifestations also have been described [2]. The tropism of the virus to angiotensin-converting enzyme-2 (ACE-2) receptors [3] and its presence on the hepatic endothelial cells and cholangiocytes [4] may predispose to direct hepatotoxic injury [5].
Liver enzyme derangements are common, seen in 14 to 53% of COVID-19 cases [2]. The clinical consequences are not well known in patients without liver disease since the majority of these derangements are mild in nature and hence clinically inconsequential [6]. However, their impact on patients with underlying liver diseases is beginning to emerge. Evolving data from a global registry suggests a poor outcome in patients with cirrhosis. Among these, 45% presented with new decompensation, and the mortality rate was 33%. In contrast, 303 patients with chronic liver disease (CLD) without cirrhosis fared better with a mortality rate of 8% [7].
Genetic variability across the world can potentially impact the severity of SARS-CoV2 infection which account for a myriad of possible presentations and outcomes. However, there is a paucity of data on the presentations and outcomes of COVID-19 infected patients with underlying liver diseases from different part of the world. We report our experience of patients with liver disease and COVID-19.

Patient population
In this observation study, all consecutive patients with known liver disease presenting between 22nd April 2020 and 22th June 2020 were included. Patients were diagnosed as COVID-19 (RT-PCR positive for SARS-CoV-2) as per the Indian Council of Medical Research (ICMR) criteria [8]. Data was collected from a prospectively maintained database of all patients from admission until endpoint of the study (discharge or death or deadline of 22nd June 2020).
We compared the results of COVID positive patients with age, sex, and severity matched cirrhosis patients (historical controls) from previously published data from our center [9,10].

Patient evaluation and treatment
All consecutive patients with liver disease presenting to the emergency with either fever or respiratory symptoms or chest X-ray showing in ltrates were tested for COVID-19 as per the hospital policy. Patients who had no symptoms or tested negative initially were offered to retest based on the development of new respiratory symptoms or fever at the discretion of the treating physician. Nasal and throat swabs were taken and transported in a viral transport media (Hank's balanced salt solution) and tested by reverse transcriptase-polymerase chain reaction (RT-PCR). Patients with con rmed COVID-19 pneumonia were offered broad-spectrum antibiotics, hydroxychloroquine (HCQ) with or without ivermectin according to the evolving consensus [11]. Complications of liver disease including organ failures were managed according to the standard guidelines [12].

De nitions
Abnormalities in the liver function tests (LFT) were based on our hospital cut-offs-bilirubin (>1 mg/dl), aspartate aminotransferase (AST >40 IU/L), alanine aminotransferase (ALT >40 IU/L), and alkaline phosphatase (ALP >280 IU/L). Cirrhosis was de ned by the presence of a nodular outline of liver on imaging and concomitant evidence of portal hypertension, such as a dilated portal vein, splenomegaly.
Patients with cirrhosis who had a current history of variceal bleed, ascites, hepatic encephalopathy or jaundice were labelled as having Acute Decompensation (AD). Acute-on-chronic liver failure (ACLF) was predictors of in-hospital mortality. A p-value of < 0.05 was considered signi cant. Data were analyzed using IBM SPSS statistical software (Version 20.0, Chicago, IL, USA).

Ethical clearance
In this retrospective analysis requirement of consent was waived off. The study was approved by the institutional ethics committee.

Presentations and Outcomes
Patients without cirrhosis Both non-cirrhotic patients, one with NAFLD and other with EHPVO, presented with respiratory symptoms. None of the two developed liver-related complications. The LFTs were normal at admission in both patients. The patient with EHPVO was pregnant at the time of admission and had gestational diabetes mellitus (GDM). Both these patients recovered uneventfully without the need for oxygen or mechanical ventilation.

Patients with compensated cirrhosis
One patient had NAFLD-related compensated cirrhosis with baseline Child-Pugh-Turcotte (CTP) score of 5, and a MELD score of 9. His associated comorbidities included diabetes mellitus (DM) and coronary artery disease (CAD). He presented with respiratory symptoms and developed ACLF (grade III) during his hospital stay with respiratory, cardiovascular and renal failures. The patient succumbed to multiorgan failure on day 4 of hospital admission. The clinical severity of COVID-19 was severe in this patient.
Comparison of characteristics between cirrhotic patients with COVID-19 and historical controls We compared COVID-19 patients with cirrhosis (n = 26) with age, sex and severity matched historical controls (n = 78), from a previously published data from our center (Table 1). There was no difference in characteristics between the COVID-positive cases and historical controls except platelet count and alkaline phosphatase, which were higher in historical controls.

Discussion
In this analysis from a tertiary care center in India we describe the clinical presentations and outcomes of COVID-19 infection in patients with underlying liver disease. Over 8 weeks, we noted 28 patients with underlying liver disease presenting with COVID-19 infection. A higher number of patients reported in the latter part of the study were in accordance with the increasing incidence of COVID-19 infections in India [15]. Overall, COVID-19 severity was mild in 15 (57.7%), moderate in 2 (7.7%) and severe in 9 (34.6%), We observed that COVID-19 patients with cirrhosis presented with complications of cirrhosis in 12 (46.2%), respiratory symptoms in 3 (11.5%) and combined complications of cirrhosis and respiratory symptoms in 11 (42.3%). The high rate of respiratory symptoms is expected as SARS-CoV-2 is transmitted via the respiratory route. Our data suggest that cirrhosis patients presenting with respiratory symptoms and recent onset of decompensation/deterioration of underlying liver disease should be evaluated for SARS-CoV-2 infection. Patients with cirrhosis and ACLF are at increased risk of severe COVID-19 infection because of impaired immune status. We observed patients with compensated cirrhosis deteriorate after COVID-19 infection. Furthermore, none of ACLF patients with concomitant COVID-19 survived in our study, as compared to 47% survival rate in ACLF patients of historical control. The presence of pneumonia in more than 50% of patients in the COVID-19 group could have led to a higher proportion of patients developing AD and ACLF. On multivariate analysis, we found requirement of invasive ventilation to be an independent predictor of outcome in COVID positive patients. The higher mortality rates in COVID-19 patients could possibly could be because of extrahepatic organ failures especially respiratory failure. The severity of lung injury and CLIF-C have been associated with poor outcomes in COVID-19 patients with cirrhosis [16]. Pulmonary vascular changes including capillary microthrombi, are common in patients with COVID-19 [17]. The exact mechanisms related to poor outcomes needs exploration.
The outcome parameters in our study are similar to those reported by a multicenter registry (dated 19th Of the 303 patients with CLD without cirrhosis, the requirement of invasive ventilation was 18%, and mortality was 8%. Among the 379 patients with cirrhosis (alcohol 32%, non-alcoholic steatohepatitis 20%, viral 18% and alcohol and HCV combined 5%) decompensation occurred in 45%, the requirement of invasive ventilation was 19% and death occurred in 33%. Among the 151-liver transplant (LT) patients, the requirement of invasive ventilation was 19%, and death occurred in 19% of patients. These results suggest that patients with cirrhosis are at a higher risk of mortality post-COVID-19 infection.
Infections are common in patients with ACLF and are associated with poor outcomes [9]. Whether SARS-CoV-2 infection outcomes are similar to other acute precipitants, including bacterial infection in patients developing ACLF, is unclear. A recent study reported poor outcomes in COVID-19 positive patients as compared to those with bacterial infection [16]. The de nite management of ACLF is LT. The current society guidelines differ in their opinion regarding LT in the current scenario. The American Association for the Study of Liver disease (AASLD) recommends not to postpone transplants as it is an essential medical service while the EASL and Asian Paci c Association for the Study of the Liver (APASL) recommend restricting transplants to those with poor short term prognosis [18]. The medical treatment options that have been tried for management of COVID-19 patients include drugs like hydroxychloroquine, remdesivir, other antivirals, and plasma therapy. None of these therapies have been shown to de nitely improve the outcome. Moreover, most of these have hepatic side effects. Therefore, there is an urgent need for effective therapies to improve outcomes. We followed the standard recommendation for the management of all complications. For patients who presented with UGIB, we delayed endoscopy and managed patients with vasoconstrictors like terlipressin and patients were started on carvedilol for secondary prophylaxis [19]. All the patients could be managed medically without an increased risk of rebleeding.
We found that the proportion of patients with COVID-19 with alcohol etiology was less as compared to our previous experience [20]. In the pre-COVID era, the highest fraction of CLD patients admitted was due to alcohol etiology [9]. Lockdown was implemented by the Indian government, and alcohol was not available; this could be a reason, and another possible reason could be the fact the borders of the states were sealed, which would reduce the number of patients reaching the hospital.
The derangement of liver function tests at presentations has been reported in up to 50% of patients without liver disease [21]. The exact signi cance of the rise in transaminases and its relation to outcomes is unclear. The rise in liver enzymes could be multifactorial due to drugs side effects, associated ischemic hepatitis, and possibly related to SARS-CoV-2 infection per se or the associated cytokine storm [2].
Limitations of the study include its descriptive nature. Due to a small number of patients, we cannot rule out chances of type II statistical errors. The comparison group was taken from historical control admitted during different time frame. The drug therapies varied as per the evolving guidelines and treating team's consensus. Our center is a tertiary care center; the proportion of patients with advanced liver disease was higher as compared to chronic hepatitis and compensated cirrhosis. Our results need to be validated in larger sample size before generalization.
In conclusion, COVID-19 infection in patients presenting as ACLF is associated with a poor outcome.
Overall, in cirrhotic patients, COVID-19 appears to confer higher mortality as compared to those without it. Mechanical ventilation is associated with a poor outcome. In the absence of de nite therapies available for COVID-19, it is imperative to prevent infection in patients with cirrhosis.  Abbreviations: AD, acute decompensation; ACLF, acute-on-chronic liver failure; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; Alk P, alkaline phosphatase; AST, aspartate aminotransferase; CTP, Child-Turcotte-Pugh; HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized ratio; MELD, model for end-stage liver disease.