Clinical course and risk factors for mortality of COVID-19 patients with pre-existing cirrhosis: a multicentre cohort study

Abstract

COVID-19 has rapidly become a global challenge.1 We read with interest the article by Bezzio et al 1 that reported the characteristics and outcomes of COVID-19 patients with pre-existing IBD. Patients with pre-existing cirrhosis, who have immune dysfunction and poorer outcomes from acute respiratory distress syndrome (ARDS) than patients without cirrhosis, are also considered a high-risk population for COVID-19.2 3In previous studies, the proportion of COVID-19 patients with pre-existing liver conditions ranged from 2% to 11%.2 However, the clinical course and risk factors for mortality in these patients has not yet been reported. This retrospective multicentre study (COVID-Cirrhosis-CHESS, ClinicalTrials.gov NCT04329559) included consecutive adult patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pre-existing cirrhosis from 16 designated hospitals in China between 31 December 2019 and 24 March 2020. Patient characteristics are summarised in table 1. Twenty-one COVID-19 patients with pre-existing cirrhosis (Child-Pugh class A, B and C in 16, 3 and 2 patients, respectively) were included in the analysis. The median age was 68 years; 11 (52.4%) were male. Most patients had compensated cirrhosis (81.0%) and chronic HBV infection was the most common aetiology (57.1%). Comorbidities other than cirrhosis were present in most patients (66.7%). In previous studies, older age, male sex and pre-existing comorbidities were associated with higher risk of mortality for COVID-19.4 5 Here, there were no significant differences between survivors (n=16) and non-survivors (n=5) in age, sex, comorbidities, aetiology of cirrhosis, stage of cirrhosis, Child-Pugh class, Model for End-stage Liver Disease (MELD) score, interval between onset and admission, or onset symptoms of COVID-19. Comorbidities have been associated with adverse outcomes in cirrhosis,6 but our analysis did not show clear prognostic associations—possibly due to the small size and narrow composition of the study population. Table 1 Clinical, laboratory and radiographic findings on admission Total(n=21) Non-survivor(n=5) Survivor(n=16) P value Clinical characteristics  Age, years 68 (52–75) 68 (50–75) 69 (52–75) 0.842  Sex 0.311   Male 11 (52.4%) 4 (80.0%) 7 (43.8%) –  Aetiology of cirrhosis 0.489   Chronic hepatitis B 9 (42.9%) 2 (40.0%) 7 (43.8%) –   Chronic hepatitis C 2 (9.5%) 0 (0.0%) 2 (12.5%) –   Alcoholic liver disease 2 (9.5%) 1 (20.0%) 1 (6.2%) –   Schistosomiasis 1 (4.8%) 1 (20.0%) 0 (0%)   Autoimmune hepatitis 1 (4.8%) 0 (0.0%) 1 (6.2%)   Other* 6 (28.6%) 1 (20.0%) 4 (25.0%) –  Stage of cirrhosis 0.228   Decompensated 4 (19.0%) 2 (40.0%) 2 (12.5%) –  Child-Pugh class 0.354   A 16 (76.2%) 3 (60.0%) 13 (81.3%) –   B 3 (14.3%) 0 (0.0%) 3 (18.8%) –   C 2 (9.5%) 2 (40.0%) 0 (0.0%) –  MELD score 8 (7–11) 11 (7–14) 8 (7–9) 0.398  Exposure history 20 (95.2%) 5 (100.0%) 15 (93.8%) 1.000  Interval between onset and admission, days  8 (3–14)  3 (3–20)  8 (4–15) 0.495  Onset symptoms   Fever 16 (76.2%) 5 (100.0%) 11 (68.8%) 0.278   Cough 15 (71.4%) 4 (80.0%) 11 (68.8%) 1.000   Shortness of breath 12 (57.1%) 3 (60.0%) 9 (56.3%) 1.000   Sputum 7 (33.3%) 2 (40.0%) 5 (31.3%) 1.000   Sore throat 3 (14.3%) 0 (0.0%) 3 (18.8%) 0.549   Diarrhoea 2 (9.5%) 1 (20.0%) 1 (6.3%) 0.429  Comorbidities   Any 13 (61.9%) 5 (100.0%) 8 (50.0%) 0.111   Hypertension 7 (33.3%) 2 (40.0%) 5 (31.3%) 1.000   Diabetes 4 (19.0%) 2 (40.0%) 2 (12.5%) 0.228   Coronary heart disease 4 (19.0%) 2 (40.0%) 2 (12.5%) 0.228   Chronic kidney disease 2 (9.5%) 0 (0.0%) 2 (12.5%) 1.000   Malignancy 3 (14.3%) 1 (20.0%) 2 (12.5%) 1.000 Laboratory characteristics  White cell, ×109/L 4.34 (2.81–5.52) 4.60 (1.86–9.05) 4.28 (3.10–5.15) 0.905  Neutrophils, ×109/L 2.64 (1.68–4.30) 4.01 (1.54–7.45) 2.48 (1.64–4.22) 0.548  Lymphocytes, ×109/L 0.78 (0.51–1.24) 0.36 (0.20–1.10) 0.86 (0.70–1.29) 0.040*  Platelets, ×109/L 120 (70–182) 77 (44–93) 126 (83–201) 0.032*  ALT, U/L 30 (19–41) 30 (22–52) 28 (17–38) 0.603  AST, U/L 38 (27–55) 42 (32–105) 31 (26–51) 0.275  GGT, U/L 23 (20–59) 61 (22–151) 22 (17–27) 0.098  Total bilirubin, μmol/L 14.5 (10.60–22.50) 22.2 (16.60–34.60) 12.6 (8.90–20.00) 0.075  Direct bilirubin, μmol/L 4.8 (2.50–10.90) 12.0 (9.40–14.60) 3.90 (2.23–6.90) 0.006*  Albumin, g/L 34.2 (26.90–38.60) 29.0 (22.30–36.00) 37.5 (27.60–38.70) 0.354  LDH, U/L 306 (238–429) 409 (178–573) 289 (234–344) 0.179  BUN, mmol/L 5.50 (3.97–7.65) 5.50 (3.98–10.40) 5.30 (3.85–7.10) 0.660  SCr, μmol/L 66.0 (48.70–90.40) 66.2 (59.30–94.50) 60.1 (47.20–87.90) 0.398  Glucose, mmol/L 6.20 (5.10–7.91) 7.90 (5.65–14.15) 6.06 (4.95–7.60) 0.208  Creatine kinase, U/L 87 (52–135) 63 (46–416) 91 (50–131) 0.968  APTT, s 29.1 (22.70–32.90) 32.9 (30.00–46.50) 28.1 (22.10–32.60) 0.075  Prothrombin time, s 12.8 (11.80–14.60) 14.0 (11.70–17.50) 12.6 (11.60–14.40) 0.445  INR 1.08 (1.00–1.30) 1.31 (1.00–1.59) 1.08 (0.99–1.17) 0.275  C-reactive protein, mg/L 18.30 (1.88–73.71) 50.00 (13.91–116.40) 7.20 (1.50–56.13) 0.153  Procalcitonin, ng/mL 0.05 (0.00–0.35) 0.10 (0.05–1.19) 0.04 (0.00–0.09) 0.130 CT evidence of pneumonia  Typical signs of SARS-CoV-2 infection 18 (85.7%) 4 (80.0%) 14 (87.5%) 1.000 Data are expressed as median (IQR) or n (%). P values were calculated by Mann-Whitney U test or Fisher’s exact test, as appropriate. *Other: one for with HBV and HCV co-infection, one for hepatitis B infection with history of alcohol abuse, one for hepatitis B infection with schistosomiasis and three for unknown causes of cirrhosis. ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; ESR, erythrocyte sedimentation rate; GGT, γ-glutamyl transpeptidase; INR, international normalised ratio; LDH, lactate dehydrogenase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SCr, serum creatinine. Fever and cough were the most common symptoms on admission, similar to previous studies of COVID-19 among general populations.7 8 Elevations in aspartate transaminase, alanine aminotransferase and gamma-glutamyl transferase levels were present in 8 (38.1%), 5 (23.8%) and 5 (23.8%) patients, respectively. Leucopenia, lymphopenia and thrombocytopenia occurred in 8 (38.3%), 15 (71.4%) and 8 (38.1%) patients, respectively. Although abnormal haematological indices and portal hypertension are common in cirrhosis, patients with COVID-19 who died had lower total lymphocyte and platelet counts, and also higher direct bilirubin levels than patients who survived (p=0.040, 0.032 and 0.006, respectively). These findings are consistent with previous studies in the general COVID-19 population.9 10 Treatment and complications occurring during hospitalisation are summarised in table 2. The frequency of ARDS and GI bleeding were higher in non-survivors than survivors (100.0% vs 6.3%, p<0.001, and 60.0% vs 6.3%, p=0.028, respectively). Of the five non-survivors, all patients developed ARDS and two patients progressed to multiple organ dysfunction syndrome. One patient who died developed clear evidence of acute-on-chronic liver failure. Table 2 Treatment, complications and outcomes Total(n=21) Non-survivor(n=5) Survivor(n=16) P value Treatment  ICU admission 5 (23.8%) 4 (80.0%) 1 (6.3%) 0.004*  Antiviral treatment 17 (81.0%) 4 (80.0%) 13 (81.3%) 1.000  Antibiotic treatment 15 (71.4%) 5 (100.0%) 10 (62.5%) 0.262  Glucocorticoids 8 (38.1%) 5 (100.0%) 3 (18.8%) 0.003*  Intravenous immunoglobulin 5 (23.8%) 3 (60.0%) 2 (12.5%) 0.063  Non-invasive ventilation 4 (19.0%) 3 (60.0%) 1 (6.3%) 0.028*  Invasive mechanical ventilation 3 (14.3%) 3 (60.0%) 0 (0.0%) 0.008*  CRRT 2 (9.5%) 2 (40.0%) 0 (0.0%) 0.048*  ECMO 2 (9.5%) 2 (40.0%) 0 (0.0%) 0.048* Complications during hospitalisation  Secondary infection 6 (28.6%) 3 (60.0%) 3 (18.8%) 0.115  Ascites 5 (23.8%) 2 (40.0%) 3 (18.8%) 0.553  Upper GI bleeding 4 (19.0%) 3 (60.0%) 1 (6.3%) 0.028*  Acute-on-chronic liver failure 1 (4.8%) 1 (20.0%) 0 (0.0%) 0.238  Acute kidney injury 1 (4.8%) 1 (20.0%) 0 (0.0%) 0.238  Septic shock 3 (14.3%) 2 (40.0%) 1 (6.3%) 0.128  ARDS 6 (28.6%) 5 (100.0%) 1 (6.3%) <0.001* Length of stay, days 16 (11–32) 16 (7–39) 16 (11–31) 0.842 One patient died in the emergency department without intensive care. Data are expressed as median (IQR) or n (%). P values were calculated by Mann-Whitney U test or Fisher’s exact test, as appropriate. *A two-sided p-value of less than 0.05 was considered statistically significant. ARDS, acute respiratory distress syndrome; CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit. In contrast to Western populations, the main cirrhosis aetiology in this China-based study was chronic HBV, so it is unclear if our findings are generalisable to other geographic regions. To further define the clinical course of COVID-19 patients with pre-existing cirrhosis and confirm risk factors for mortality, larger prospective studies comprising patients with different cirrhosis aetiologies are expected. In conclusion, we provide the first report of the demographic characteristics, comorbidities, laboratory and radiographic findings, and clinical outcomes in SARS-CoV-2-infected patients with pre-existing cirrhosis. The cause of death in most patients was respiratory failure rather than progression of liver disease (ie, development of acute-on-chronic liver failure). Lower lymphocyte and platelet counts, and higher direct bilirubin level might represent poor prognostic indicators in this patient population.