The global incidence of coronavirus disease 2019 (COVID-19) continues to increase despite health care efforts. The disease is caused by coronavirus 2 with high transmission and mortality rates. Little is known about the management of COVID-19 in advanced liver disease. The aim of work was to propose a plan for management of this drastic disease in case of this specific population with review of medications that could be suitable for advanced liver disease. All the guidelines and medications available for treatment of COVID-19 were reviewed with selection of the less toxic medications that could be used in advanced liver disease. Drugs suitable to manage COVID-19 in patients with liver disease might include remdesivir intravenously, nitazoxanide + sofosbuvir, ivermectin, tocilizumab, convalescent plasma, and low molecular weight heparin in certain situations. Advanced liver disease is associated with portal hypertension and splenomegaly with reduction of blood elements and immune dysfunction and impaired T cell function. Thus, when confronted by cytokine storm as an immune response to COVID-19, there may be an increase in the mortality rate of these patients. Through this review, a plan to treat COVID-19 in this special group of patients with advanced cirrhosis is proposed.

Serious viral infections are still evolving and are a significant health hazard, leading to unexpected and frequently occurring waves of viral epidemics in the previous decades. These include severe acute respiratory syndrome (SARS) by coronavirus (CoV) in 2002, H1N1 influenza in 2009, and the Middle East respiratory syndrome (MERS) CoV in Saudi Arabia in 2012.

In China, on December 31, 2019, an unexplained outbreak of pneumonia was attributed to a novel virus belonging to genus beta-coronavirus corona virus 2 (SARS-CoV-2); coronavirus disease 2019 (COVID-19). CoVs are single-stranded ribonucleic acid (RNA) viruses, crown-shaped due to the spiky appearance of their envelope induced by the arrangement of surface glycoproteins[1]. There are four subtypes of CoVs: Alpha-coronavirus, beta-coronavirus, delta-coronavirus, and gamma-coronavirus[2].

Viral subtypes that affect humans are 229E (alpha coronavirus), NL63 (alpha coronavirus), OC43 (beta coronavirus), and HKU1 (beta coronavirus); they can cause self-limited upper respiratory infections, and it was suggested that nearly 2% of the population are healthy carriers of a CoVs[3]. Other human CoVs, mainly beta CoVs, can cause epidemics with varying clinical severity including broncho-pulmonary and extra-pulmonary manifestations, with mortality rates approaching 35%. The newly isolated CoV showed more than 80% of nucleotide mimicry with bat SARS like CoV-ZXC21[4,5].

Patients with advanced cirrhosis have higher morbidity and mortality after exposure to such an aggressive form of viral infection due to inefficient immune function. The reported occurrence of acute hepatic insult with COVID-19 should be clarified and linked to the severity of COVID-19. In addition, it should be determined whether hepatic injury is due to overwhelming immune response, to direct viral invasion, or to the hepatotoxic effects of the utilized drugs in treatment.

Liver function can be evaluated by measuring biomarkers of liver cell injury mainly transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], bile duct malfunction or bile stasis such as alkaline phosphatase, gamma-glutamyltransferase (GGT), and 5'-nucleotidase, hepatic secretion capacity by detecting serum bilirubin, and synthetic efficiency by measuring prothrombin time and serum albumin. Transaminases may be falsely elevated in COVID-19 due to complicating myositis, which is associated with increased creatinine kinase[6].

The cutoff values of ALT, AST, GGT, and serum total bilirubin that indicate abnormal liver function are > 40 U/L, > 40 U/L, > 49 U/L, and > 1 mg/dL respectively[7]. COVID-19 associated hepatic injury should be defined as a significant increase in hepatocellular and cholangiocytic markers mainly serum aminotransferases and bilirubin from the baseline level in healthy subjects or patients with a documented chronic liver disease during the active course of SARS-CoV-2.

The pattern of hepatic impairment in COVID-19 is hepatocellular when serum transaminases exceed more than three times the upper normal limit, cholangiocytic if alkaline phosphatase or GGT doubles the normal values, and mixed type if patients have both laboratory abnormalities[7]. Generally, liver function abnormalities are infrequent in mild cases of COVID, but it was noticed in severe cases and in cases with pre-existing liver disease.

There is a wide variation in reports of the incidence of abnormal levels of serum transaminases; ALT elevations ranged between 4%-33% in Chinese patients, and 39% in a large group from United States[8-10]. AST abnormalities were seen in 4%-53% of Chinese patients and up to 58% in a cohort of patients in the United States[8,11,12], and generally, AST and ALT elevations were mild, not exceeding five times the upper normal limit.

Abnormally elevated alkaline phosphatase was reported in up to 5% of patients[8,13], GGT was elevated in 13%-54% of patients with an average 23%[13,14], and total serum bilirubin elevations may be elevated in up to 18% of patients at admission[14,15]. The clinical significance of elevated liver function test biomarkers in COVID-19 still need to be clarified, as they may reflect the clinical severity of COVID-19[16,17]. However, some studies did not find any relation between these tests and mortality, intensive care unit admission, or duration of admission[18,19].

Advanced liver disease is associated with the upregulation of angiotensin-converting enzyme 2 (ACE2) as a physiological mechanism to counteract splanchnic vasodilatation, hepatic fibrosis, and portal hypertension mediated by angiotensin II. ACE2 catalyzes the conversion of angiotensin II to Ang-(1-7), which opposes angiotensin II through the Mas receptor[20]. At the same ACE2 also serves as a receptor for CoV, which is more numerous more in cholangiocytes than hepatocytes, which explains the bilopathic effect of COVID-19. This occurs with the help of trans-membrane serine protease 2, and as the oral and gastrointestinal mucosa express both ACE2 and transmembrane serine protease 2, they are commonly and early affected in COVID-19[21,22].

From the histopathological point of view, biopsies from deceased patients (n = 48) revealed no specific viral inclusion bodies. The main finding was endothelitis and fibrin microthrombi in liver sinusoids, massive dilation of portal venules with intraluminal thrombosis, and portal fibrosis; 15 samples out of 22 examined for SARS-CoV-2 RNA by RNA scope were positive, indicating that the liver effect was due to systemic inflammatory effect[23].

Mild COVID-19 is manifested by fever, malaise, cough, headache, myalgia, and diarrhea. Moderate COVID-19 is any symptom of mild disease and lung ultrasound features with hypoxemia on pulse oximetry. Severe COVID-19 is life threatening complications, mainly respiratory failure and the need for mechanical ventilation, denoted by presence of tachypnea > 30/min, oxygen saturation ≤ 93%, partial pressure of oxygen/fraction of inspired oxygen ≤ 300 mmHg, or evidence of other organ failure that needs intensive care unit admission[11].

Advanced liver disease is associated with portal hypertension and splenomegaly with reduction of blood elements and immune dysfunction and impaired T cell function. Thus, when the cytokine storm is confronted as an immune response to COVID-19, it may increase the mortality rate of these patients as well as the risk of hepatotoxicity that may occur by the utilized medications.

Treatment should be tailored according to the current hepatic status, whether non-cirrhotic liver or cirrhotic liver or liver transplantation, according to model for end-stage liver disease (MELD) score or Child Turcotte Pugh (CTP) score.

Based on our experience, guidelines for managing COVID-19, and the current knowledge of medications suitable for patients with advanced liver disease; we propose an approach to treat COVID-19 in patients with liver disease (Figure 1).

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Figure 1 A diagram for managing coronavirus disease 2019 in patients with liver disease. COVID: Coronavirus disease 2019; HBV: Hepatitis B virus; PCR: Polymerase chain reaction.

Any patient with suspected liver disease and COVID 19 infection should be evaluated regarding the severity of COVID-19 (mild-moderate-severe), presence of liver cirrhosis by Fibrosis 4, abdominal ultrasonography criteria, and fibroscan reading > 12.5 kPa, and severity of cirrhosis by CTP score and MELD score to evaluate the prognosis.

Severity of COVID should be evaluated as mild if manifested by acute onset of fever, malaise, cough, headache, myalgia, and diarrhea; moderate COVID-19 if any symptom of mild disease and lung ultrasound features with hypoxemia on pulse oximetry, and severe COVID-19 if life threatening complications, mainly respiratory failure and the need for mechanical ventilation.

COVID should be suspected if there is unsatisfactory response to antibiotics or there is a history of travel to places with confirmed cases, contact with a COVID-19 RNA positive patient, or even if there is unexplained deterioration of the patient’s general condition, including unexplained disturbed conscious level. Lung ultrasound may show thickened irregular pleural lines sub-pleural pulmonary consolidations, and high resolution computed tomography (CT) chest may show ground-glass opacities, with a rounded morphology and peripheral lung affection[80,81].

Non-cirrhotic patients, after judging by platelet count > 150/cm, ultrasonography, and fibroscan value < 12.5 kPa or patient with compensated cirrhosis Child Pugh class A and MELD score < 9 should be treated as normal subjects.

Patients with cirrhosis Child Pugh class B, fibroscan < 20 kPa, ultrasound documented absence of ascites, and MELD score < 10-29 should be given COVID therapy with very close monitoring of liver function.

Cirrhotic patients with Child Pugh class C, fibroscan > 20 kPa, ultrasound documented presence of ascites, MELD score > 30 with added additional morbidity such as hepatocellular carcinoma or hepatic encephalopathy should be given supportive therapy and medications with very minimal hepatic effect.

Favipiravir is changed into the hydroxylated form by aldehyde oxidase and xanthine oxidase, and in patients with Child Pugh C, there is a marked accumulation of theses metabolites. Thus, it should be reduced or avoided[82].

Lopinavir is degraded mainly by CYP3A, and ritonavir is an inhibitor of CYP3A. Therefore, hepatic impairment led to a 30% accumulation of lopinavir, leading to elevated liver enzymes and bilirubin with worsening of liver function[83].

Aerosolized IFN-α is by nature contraindicated in patients with autoimmune hepatitis or decompensated liver disease[84].

Remdesivir has a short plasma half-life with a faster systemic elimination, and it has low hepatocytotoxicity in vitro. It should be given with caution in hepatic impairment if benefit outweighs the potential risk. It should not be initiated in patients with ALT ≥ 5 times the upper limit of normal at baseline[85].

Patients with chronic liver disease due to active HCV with positive viremia and acute COVID can get benefit from treatment with sofosbuvir, daclatasvir, and ribavirin.

Patients with liver transplantation should have certain precautions. Special consideration should be taken into account when there was travel to a residence in a high-risk area, contact with a suspected case of COVID-19 ≤ 21 d, or contact with a confirmed case of COVID-19 ≤ 28 d before acute onset of fever > 38 °C, malaise or flu-like symptoms, new cough, shortness of breath, unexplained abdominal pain, nausea or diarrhea, or loss of sense of taste or smell.

Liver grafts recovered from COVID-19-positive deceased donors 21–28 d after symptom resolution and two negative swabs 24 h apart are considered safe for transplantation. High-risk donors with clinical symptoms within 28 d before organ procurement should not be considered, even if they test negative.

For living donors, 14-21 d self or hospital-based quarantining has been recommended. COVID-19-positive or high-risk living donors should postpone donation until at least 21-28 d after symptom resolution and until two negative polymerase chain reaction (PCR) tests have been observed. The recipient should undergo a real-time PCR test within 24 h of transplantation. Recipients with clinical suspicion or active SARS-CoV-2 infection should have transplantation deferred until 28 d after symptom resolution and after two negative tests at least 24 h apart[86].

A large Italian liver transplantation survey (n = 640) showed COVID-19 in only 1.25%, with the majority having mild disease[87]. However, the report showed bad outcome in long-term LT recipients, with higher risk of severe disease, denoting that immunosuppression did not increase the risk of severe COVID-19 and that metabolic complications that occurred on the long term run were responsible for the increased risk of severe COVID-19 in this population. In addition, immunosuppression may cause longer shedding time of the virus[87].

There is a postulated protective role of immunosuppression against systemic inflammation in COVID-19 and lung injury. In mild COVID, immunosuppression modifications are discouraged. On the other hand, reduction or discontinuation of antiproliferative agents and lymphocyte-depleting agents is indicated in severe lymphopenia and progressing pneumonia with secondary bacterial or fungal infection (e.g., by the American Association for the Study of Liver Diseases; see Related links). The interaction between COVID-19 treatments interaction with immunosuppressive drugs needs further studies[88].

Patients with liver cirrhosis and in need of upper endoscopy or endoscopic retrograde cholangiopancreatography should be left for emergency cases, mainly gastrointestinal bleeding or sepsis due to bacterial cholangitis, as the risk of infection is high due to droplet infection[89]. Endoscopy should be done with great caution and after complete protection of the medical staff, better in negative pressure chambers, and the medical staff should receive ivermectin for 3 d after the procedure.

The patients should be managed according to CTP score, MELD score, and fibroscan value and whether the liver is decompensated or not. Regarding anticoagulation, patients with ARDS or severe lung affection with significantly increased D-dimer should receive anticoagulation after securing variceal bleeding by band ligation and according to CTP score. Non-cirrhotic and cirrhotic CTP class A can be given enoxaparin then rivaroxaban 10 mg; however, decompensated cirrhosis with ascites may be given low dose enoxaparin and warfarin guided by prothrombin time and international normalized ratio values.

Fortunately, most pediatric patients develop mild COVID; however, rare cases may develop severe symptoms with multisystem affection[90]. Obesity is considered a risk factor for severe COVID in pediatric patients[91]. Red flag signs of disease progression are worsening tachypnea, disturbed conscious level, increasing serum lactate, bilateral lung infiltration, pleural effusion or rapid spread of the lesions, and associated morbidity as congenital heart disease, anemia, and severe malnutrition.

Multisystem inflammatory syndrome is characterized by rise of temperature more than 3 d and skin rash, mucocutaneous inflammatory affection, shock, coronary vasculitis, coagulopathy, diarrhea and abdominal pain, elevated CRP, or procalcitonin[92].

The treatment approach is tailored according to severity. In asymptomatic and mild cases, only antipyretics if needed (paracetamol 10-15 mg/kg), and non-steroidal anti-inflammatory drugs should be avoided. In severe or critical cases remdesivir (dose in children < 40 kg, in the first day, 5 mg/kg IV infused in 30 min) followed by 2.5 mg/kg IV day for 9 d, together with ivermectin, dexamethasone or methyl-prednisolone, oxygen therapy, adequate hydration, and caloric intake. Regarding anticoagulation, pediatric population have a much lower risk of thrombosis than adults, and prophylaxis is not supported except in neonates and adolescents, as the risk is higher especially in multisystem inflammatory syndrome or ARDS[93]. Empirical antibiotics are indicated with increased procalcitonin, CRP, and neutrophilic leucocytosis. 

Patients should be isolated at home or hospitalized according to the severity of the clinical condition with great attention to the red flag signs as severe dyspnea, tachycardia > 100 beat/min, impending respiratory failure, systolic blood pressure < 90 mmHg, immunocompromised, and age ≥ 60 years.

Medications should be empirically given according to the clinical situation, drug availability, and till investigations are revealed, which should include chest X-ray, CT of the chest, arterial blood gases, CRP, complete blood count for lymphopenia, PCR for COVID-19, influenza RNA in respiratory secretions, rapid antigen tests for influenza viruses A and B, adenovirus, respiratory syncytial virus, para influenza virus, and varicella-zoster virus according to clinical circumstances.

Initial therapy is supportive by fluids and oxygen, broad spectrum IV antibiotic such as levofloxacin 750 once daily or cefotriaxone 2 g daily or piperacillin/ tazobactam 4.5 gm if bacterial superinfections were suspected + oral acyclovir 400/6 h + ivermectin 200 µg/kg and immune support by zinc gluconate 25-75 mg daily + vitamin C 1000 mg/12 h.

Liver function can be supported by adding silymarin 420 mg and ursodeoxycholic acid 500 mg daily, especially if viral infection is associated with rising transaminases and serum total bilirubin. Supportive treatment of ascites should be initiated if associated with signs of impending hepatorenal syndrome denoted by rising serum creatinine > 1.5 mg, serum cystatin c, prolonged international normalized ratio, and hypoalbuminemia. In suspected critically ill patients with hepatorenal syndrome, supportive therapy can be given as nor-epinephrine IV as a continuous infusion (0.5 to 3 mg/h) aiming to raise the mean arterial pressure by 10 mmHg; albumin is given for the first 2 d as an IV bolus (1 g/kg per day, 100 g maximum then 25-50 mg daily) or terlipressin given as an IV bolus (1 to 2 mg every 4-6 h) and albumin, as mentioned above, in addition to COVID medications as ivermectin, daclatasvir, and CPT.

Clinical improvement with negative PCR for COVID-19 RNA should be confirmed twice with a time interval of 48 h. However, if COVID-19 positivity was confirmed, patients should be hospitalized and with cautious selection of medications that will not worsen liver function, as mentioned above.

Monitoring with serum ferritin and CRP is important as higher values are associated with exacerbated COVID-19 or secondary bacterial infection, cytokine storm with multi-organ failure, and poor prognosis[94].

Patients should be transferred to intensive care unit if oxyhemoglobin saturation < 93%, respiratory rate > 30/min, heart rate > 120/min, or signs of organ failure were documented. CALL score was postulated to predict deterioration in COVID-19 pneumonia, which included associated co-morbidity. Older age > 60 years, lower lymphocyte count < 1000, and higher lactate dehydrogenase > 500 at presentation were independent high-risk factors for COVID-19 progression[95].

For patients with severe respiratory distress or significant pleural effusion on CT scan, a high-flow nasal oxygen or non-invasive mechanical ventilation would be provided to maintain positive end-expiratory pressure to guard against alveolar collapse and avoidance of volume overload by fluids. Clinical worsening despite these efforts necessitates invasive mechanical ventilation using lower tidal volume, lower inspiratory pressures, and higher positive end-expiratory pressure.

Indications of extracorporeal membrane oxygenation in COVID-19 are hypoxemic respiratory failure with partial pressure of oxygen/fraction of inspired oxygen < 100 mmHg despite optimization of mechanical ventilation, hypercapnic respiratory failure with an arterial pH < 7.20, cardiogenic shock refractory to treatment, and refractory septic shock with cardiac arrest.

The use of corticosteroid in patients with advanced liver disease should be avoided, but in case of a serious respiratory viral infection as COVID-19, methylprednisolone in a low dose of 40 mg/8 h may be considered, especially with increasing lung infiltrates and worsening clinical status even under invasive mechanical ventilation. However, its use still controversial and should be left to real-life clinical circumstances[96].

The use of IL-6 inhibitors as TOCI in advanced liver diseases should be judged according to clinical circumstances with great precaution. The use of anticoagulation in advanced liver disease should be based on the evaluation of risk factors as D-Dimer and sepsis induced coagulopathy score ≥ 4 with the use of low molecular weight heparin as enoxaparin or oral rivaroxaban 10 mg daily in non-cirrhotic or Child A cirrhosis. In decompensated cirrhosis, when there is a need of anticoagulation, endoscopy should be done to treat esophageal band ligation before commencing warfarin.

In summary, COVID-19 put the health care systems of many countries under great pressure, and it has been particularly challenging because of the lack of prediction parameters and effective pharmacotherapies for treating COVID-19 in advanced liver disease. We provided herein a stepwise approach to treat COVID-19 in advanced liver disease, hoping for its application in a multicenter research trial.