Table 2.
Studies on COVID-19 with chronic liver disease patients.
| Patient Number | Patient's Condition | Risk Factors of Severe COVID-19/Higher Mortality | Outcome | Treatment | |
|---|---|---|---|---|---|
| Chronic hepatitis B(CHB) | |||||
| Bin Zhang et al. [6] | N=23 | HBV carriers: 15 CHB: 7 Hepatitis B Cirrhosis: 1 |
/ | 3 (13.0%) patients progressed to severe, and 2 (8.7%) progressed to critically ill. All patients were discharged after treatment. | 23 patients were treated with antiviral drugs and 13 were treated with liver-protecting drugs. |
| Rui Liu et al. [8] | N=220 | COVID-19 patients with HBV: 50 COVID-19 alone: 6 HBeAg-negative CHB: 57 Healthy controls: 57 |
/ | COVID-19 with HCVpatients posed a higher extent of dysregulation of host functions at the onset of COVID-19. | 7 patients under continuous anti-HBV treatment (Entecavir or Lamivudine) in the HBV coinfected COVID-19 group. |
| Yang Li et al. [9] | N=28 | COVID-19 co-infected HBV: 7 COVID-19 without chronic HBV infection: 21 |
/ | No patient was admitted to the ICU or had any severe complicationsincluding liver failure during hospitalization. | All patients were treated with antiviral drugs (lopinavir/ritonavir; interferon α-2b; arbidol; oseltamivir) and empirical antibiotic therapy. 2 patients received anti-HBV treatment with entecavir. 2 patients were given corticosteroids and 1 patient was given gamma globulin. |
| Sergio Rodríguez-Tajes et al. [11] | N=61 | Patients with HBsAg negative/anti-HBc positive: 61 | / | Nocases of HBsAg seroreversion. | 38 (62%) patients received entecavir and 23 (38%) did not. The most frequently used immunosuppressant drug was tocilizumab (72%); 25 patients (41%) received high doses of steroids alone (n=5) or in combination with other immune modulators (n=20). 22 patients (36%) received prednisone for 1 month or longer; 15 of them had undergone high-dose steroid therapy. |
| HCVinfcction | |||||
| Bianca Cerbu et al. [12] (meta analysis) |
N=1,057 | / | Active HCV is associated with severe COVID-19. | Non-active HCV infection patients: 88 (92.6%) had mild or moderate COVID-19, while 7 patients (7.4%) presented a severe form. Active HCV infection patients: 21 (67.7%) had mild or moderate COVID-19, while 10 (32.3%) presented with severe COVID-19 infection. |
The treatment scheme for all patients with COVID-19included a standard association of remdesivir, dexamethasone, azithromycin antibiotic prophylaxis, and anticoagulation using enoxaparin. |
| Non-alcoholic/metabolic dysfunction-associatedfatty liver disease(NAFLD/MAFLD) | |||||
| Rui Huang et al. [17] | N=280 | COVID-19 with NAFLD diagnosed by HSI: 86 Abnormal liver function:100 |
Age over 50 yearsand concurrent NAFLD were independent risk factors of ALT elevation in COVID-19 patients. | No patient developed liver failure and death. 28 (10.0%) patients were transferred to the ICU during hospitalization. |
Atomized inhalation of IFNα-2b, lopinavir/ritonavir, and arbidol account for 57.1%, 72.5%, and 49.3% . 73.6% of patients received empirical antibiotic treatment. 73 (26.1%) patients were given corticosteroidsand 35 (12.5%) patients were treated with gamma globulin. |
| Giovanni Targher et al. [24] | N=310 | COVID-19 with MAFLD: 94 | MAFLD patients with increased FIB-4 or NFS are associated with severe COVID-19 illness. | / | / |
| Yujie Zhou et al. [25] | N=110 | COVID-19 with MAFLD: 45 | MAFLD is associated withsevere COVID-19. | / | / |
| Autoimmune hepatitis (AIH) | |||||
| Tatyana Kushner et al. [29] | N=110 | AIH: 110 Cirrhosis: 32 Comorbid conditions: 53 Malignancy: 5 (active in COVID-19:2) |
Cirrhosis with AIHwas the strongest predictor for severe COVID-19. | Antivirals was associated with liver injury, while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury. The rates of severe COVID-19 and all-cause mortality were not different between AIH and non-AIH CLD. |
Most patients (92.7%) were on immunosuppressive therapy before the COVID-19 diagnosis, 65 (59.1%) patients were on prednisone therapy (alone or in combination with other immunosuppressants) with a median dose of 5 (range, 2.5-60) mg/day. |
| Thomas Marjot et al. [30] | N=932 | Non-alcoholic liver disease: 362, ALD: 233 Chronic HCV infection: 128 Chronic HBV infection: 121 AIH: 70 |
Age, Child-Pugh class B and C cirrhosis in the AIH cohort were associated with deathwithin the AIH cohort. | AIH and non-AIH CLD had no significant differences in the rates of all major outcomes. | 58 (83%) patients with AIH were taking immunosuppression: prednis (ol)one 41 (71%), thiopurines (azathioprine or 6-mercaptopurine) 32 (55%), mycophenolate mofetil (MMF) 9 (16%), tacrolimus 5 (9%), and budesonide 4 (7%). 30 (52%) patients with AIH were on combined immunosuppression with ≥2 agents. |
| VahinVuppalanchi et al. [31] | N=420 | AIH:420 Liver biopsy reported cirrhosis:78 |
Immune suppressants for the AIH treatment do not increase the risk of severe COVID-19. | / | / |
| Alessio Gerussi et al. [32] | N=10 | AIH patients:10 Cirrhosis: 4 Decompensated cirrhosis (Child-Pugh B): 6 |
/ | 9 patients are still alive and asymptomatic, and 1 (patient 6) died. Patient 9 has experienced a relapse of AIH and is now being treated with prednisone 50 mg/day. |
All subjects received a combination of an antiretroviral drug with an antimalarial medication; 2 cases were treated with azithromycin. 2 patients (patients 2 and 4) were under high-dose steroids at the time of COVID-19. |
| Chronic liver disease with cirrhosis | |||||
| Shiv Kumar Sarin et al. [36] | N=288 | CLD without cirrhosis: 185 Cirrhosis:43 MAFLD: 113 Viral: 26 |
Pugh score of 9 or more at presentation predicted high mortality. Rising bilirubin and AST/ALT ratio predicted mortality among cirrhosis patients. |
The COVID-19 produces acute liver injury in 43% of CLD patients without cirrhosis. 20% of compensated cirrhosis patients develop either ACLF or acute decompensation. Liver-related complications were seen in nearly half of the decompensated cirrhotics. |
Hydroxychloroquine with azithromycin and antiviral drugs at admission in mild and moderate cases. The moderate and severe cases received antibiotics, convalescent plasma, steroids in form of intravenous methylprednisolone or IVIG, on a case-to-case basis. |
| Xiaolong Qi et al. [37] | N=21 | Compensated cirrhosis: 81% Comorbidities other than cirrhosis: 66.7% |
Lower lymphocyte and platelet counts, and higher direct bilirubin level might represent poor prognostic indicators. | The cause of death in most patients was respiratory failure rather than progression of liver disease (ie, development of acute-on-chronic liver failure). | / |
| Furong Liu et al. [38] | N=17 | COVID-19 with cirrhosis:17 (6 CSPH and 11 non-CSPH) |
Cirrhosis, especially CSPH, may play an important role in the progression of COVID-19. | 66.7% (4/6) of CSPH patients were severe cases, compared with 18.2% (2/11) of non-CSPH patients. 3 patients (17.6%) were admitted to the ICU, and two of them died. 1 CSPH patient developed esophageal gastric variceal bleeding (EGVB). |
Antiviral (88.2%), antimicrobial (76.5%), hepatoprotective (64.7%) and oxygen (35.3%) therapy were the most commonly used, and CSPH patients had a higher proportion of hepatoprotective therapy (6/6 vs 5/11, P = 0.025) and oxygen therapy (4/6 vs 2/11, P = 0.046) than non-CSPH patients. |
| Jasmohan S Bajaj et al. [40] | N=272 | Cirrhosis+COVID-19: 37 COVID-19:108 Cirrhosis:127 |
Charlson Comorbidity Index (CCI) was the only independent mortality predictor in the entire matched cohort. | Patients with cirrhosis+COVID-19 had higher mortality compared with patients with COVID-19 (30% vs 13%, P=0.03) but not between patients with cirrhosis+COVID-19 and patients with cirrhosis (30% vs 20%, P=0.16). CCI was significantly higher in cirrhosis regardless of COVID-19 status compared with patients with COVID-19 only. |
Antibiotic in COVID-19 patients with and without cirrhosis are mostly beta-lactam antibiotics, macrolides, and vancomycin. patients with cirrhosis+COVID-19 and COVID-19 alone were similar on non-steroidal anti-inflammatory drugs, acetaminophen, chloroquine/hydroxychloroquine, and open-label remdesivir. |
| Shalimar et al. [41] | N=116 | COVID-19 with known chronic liver disease: 28 Cirrhotic without COVID-19: 78 |
Cirrhosis, mechanical ventilationare associated with poor outcomes. ACLF is associated with worst survival rates. | All COVID-19 patients with ACLF (9/9) died compared with 53.3% (16/30) in ACLF of historical controls. The mortality rate was higher in COVID-19 patients with compensated cirrhosis and AD as compared with historical controls 2/17 (11.8%) vs. 2/48 (4.2%). The requirement of mechanical ventilation independently predicted mortality (hazard ratio 13.68). | They followed the standard recommendation for the management of all complications. For patients who presented with UGIB, they delayed endoscopy and managed patients with vasoconstrictors like terlipressin, and patients were started on carvedilol for secondary prophylaxis. |
| Massimo Iavarone et al. [42] | N=50 | Cirrhosis with COVID-19:50 (38% virus-related and 52% previously compensated cirrhosis) |
The severity of lung and liver (according to CLIF-C, CLIF-OF, and MELD scores) diseases in cirrhosispatients independently predicted mortality. | 34% patients died from diagnosis of SARS-CoV-2 infection. COVID-19 with respiratory failure was considered the cause of death in 71% patients, while end stage-liver disease (ESLD) accounted for death in 29%. In the multivariate analysis, only CLIF-OF and moderate/ severe lung failure independently predicted mortality. |
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 antiviral treatment and hydroxychloroquine; none of the patients have been treated with tocilizumab or remdesivir. |
| Chronic liver disease | |||||
| Donghee Kim et al. [44] | N=867 | NAFLD:456 HCV infection:190 ALD: 94 HBV infection: 62 Cirrhosis: 227 |
ALD, decompensated cirrhosis, and HCC predict higher overall mortality among patients with CLD and COVID-19. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. |
The overall all-cause mortality was 14.0%, and 61.7%had severe COVID-19. | One (or more) of Remdesivir, Chloroquine, Hydroxychloroquine, Azithromycin, Prednisone or Methylprednisolone, Lopinavir/ritonavir, Donor Plasma, Others or None. |
| Liver transplant | |||||
| Chiara Becchetti et al. [53] | N=57 | Liver transplant recipients:57 (with) cardiovascular disease: 21 (with)arterial hypertension: 32 (with) diabetes mellitus: 21 |
A history of cancer was more frequent in patients with poorer outcomes. | Among hospitalized recipients, 4 (10%, 95% CI 3% to 23%) were admitted to the ICU and required invasive mechanical ventilation, while 11 (19%, 95% CI 10% to 32%) developed ARDS. Death was registered in seven cases (12%, median time from transplant to death was 6 years, IQR 3–13), all of whom were hospitalized with ARDS. | Overall, the reduction was observed in 22 (39%) patients, and complete discontinuation was reported in 4 cases (7%). Concerning specific therapy for COVID-19,including steroids, hydroxychloroquine,lopinavir/ritonavir, darunavir/cobicistat, and remdesivir, tocilizumab. 35 (63%) and 16 (29%) subjects received at least one antibiotic drug. 15 (27%) were treated with azithromycin. |
| Jacqueline Fraser et al. [54] (meta analysis) |
N=223 | / | Dyspnea on presentation, diabetes mellitus, and age 60 years or older were significantly associated with increased mortality. | 77.7% required hospitalization, 24% had mild disease, 40% had moderate disease, and 36% had severe disease. Immunosuppression was modified in 32.8% of recipients. The case fatality rate was 19.3%. | 17.0% (38/223) of cases augmented the baseline immune suppression regimen, reduction or cessation of antimetabolite in 76.3% (29/38) and calcineurin inhibitor in 52% (20/38). A total of 93 of 141 (66%) patients were prescribed hydroxychloroquine. 6 patients received immune-modulatory therapy, with 9 patients prescribed IL-6 inhibitors and 4 patients receiving systemic interferon. |
| Ashraf Imam et al. [56] | N=120 | Liver transplant:120 | liver transplant recipientshad higher rates of severe disease, complications, and mortality. | ICU admission occurred in 28.6% of patients. 72.7% of patients had recovered and were discharged with a median illness duration of 17 days, 13.6% of patients were alive and hospitalized at the time of publication with a median illness duration of 16 days, and 13.6% of patients had died with a median illness duration of 24 days. | Liver transplant patients infected with COVID-19 were maintained on Tac (79%), mycophenolate (MMF) (48.4%), and Prednisone (29.6%) and were managed by reducing MMF in 14.3% of patients and reducing Tac in 14.3% of patients. |
| Jordi Colmenero et al. [57] | N=111 | Liver transplant:111 | Baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19, particularly at doses higher than 1,000 mg/day. | 86.5% patients were admitted to the hospital and 19.8% patients required respiratory support. 10.8% patients were admitted to the ICU. The mortality rate was 18%, which was lower than in the matched general population. 31.5%patients met the criteria of severe COVID-19. | Patients would be treated with oral hydroxychloroquine and/or azithromycin for 5–7 days. In patients with moderate-severe COVID-19, antiviral therapy with lopinavir/ritonavir or remdesivir was allowed as compassionate use. Patients with acute distress respiratory syndrome could receive boluses of steroids and/or tocilizumab. |
Note: ARDS: acute respiratory distress syndrome, ACLF: acute on chronic liver failure, AD: acute decompensation, AIH: autoimmune hepatitis, ALD: alcohol associated liver disease, CCI :charlson comorbidity index, CHB:chronic hepatitis B, CI:confidence interval, CLD: chronic liver disease, CLIF:consortium organ failure score, COVID-19: coronavirus disease 2019, CSPH: clinically significant portal hypertension, EGVB: esophageal variceal bleeding, FIB-4:fibrosis-4 index, HBV/HCV:hepatitis B/C virus, HCC: hepatocellular carcinoma, HIS:hepatic steatosis index, ICU:intensive care unit, IVIG:intravenous immunoglobulin, LT: Lliver transplantation, MAFLD: metabolic dysfunction-associated fatty liver disease, NAFLD: non-alcoholic fatty liver disease, MELD: model for end-stage liver disease, NFS:nonalcoholic fatty liver fibrosis score, OR:odd ratio, UGBI:upper gastrointestinal bleeding.