Evaluation of Drug-Induced Liver Injury in Hospitalized Patients with SARS-CoV-2 Infection
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. Data Collection
2.3. Definitions
- Mild illness: signs and symptoms of COVID-19, but without pulmonary involvement
- Moderate illness: pulmonary involvement, but with blood oxygen saturation level (SpO2) greater than 93% on room air
- Severe illness: pulmonary involvement and at least one of: SpO2 < 94%, respiratory rate over 30 breaths/min, the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) below 300 mm Hg, infiltrates in over 50% of the lungs.
2.4. Statistical Analysis
3. Results
3.1. Characteristics of the Study Participants
3.2. COVID-19 Therapy Administered during Hospitalization
3.3. Characteristics of Liver Injury in the Study Participants
3.4. Evaluation of Hepatocellular Injury in Relation to Potentially Hepatotoxic Drugs Included in the Current SARS-CoV-2 Therapeutic Guidelines
3.5. Evaluation of Cholestatic Injury in Relation to Potentially Hepatotoxic Drugs Included in the Current SARS-CoV-2 Therapeutic Guidelines
4. Discussion
4.1. Tocilizumab (TCZ)
4.2. Anakinra (ANK)
4.3. Favipiravir (FVP)
4.4. Remdesivir (RDV)
4.5. Administration of at Least Three Potentially Hepatotoxic Drugs
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Variables | All Patients (N = 396) |
---|---|
Age (years), mean ± SD | 58.3 ± 14.8 |
Male, n (%) | 248 (62.6) |
BMI (kg/m2), mean ± SD | 28.4 ± 5.4 |
Comorbidity, n (%) Cardiovascular diseases Obesity Diabetes mellitus Chronic pulmonary diseases Pre-existing liver disease Chronic kidney diseases Active cancer Multiple comorbidities No comorbidities | 330 (83.3) 220 (55.6) 148 (37.4) 72 (18.2) 34 (8.6) 29 (7.3) 23 (5.8) 15 (3.8) 93 (23.5) 66 (16.7) |
Pre-existing liver disease, n (%) Chronic HBV infection Chronic HCV infection Unspecified liver tumor Polycystic liver disease Autoimmune liver disease Malignant bile duct obstruction HBV infection diagnosed on admission HCV infection diagnosed on admission | 29 (7.3) 9 (2.3) 6 (1.5) 3 (0.75) 1 (0.25) 1 (0.25) 1 (0.25) 2 (0.5) 6 (1.5) |
COVID-19 severity, n (%) Mild Moderate Severe | 14 (3.5) 106 (26.8) 276 (69.7) |
Outcome Discharge, n (%) Duration of hospitalization (days), mean ± SD IMV, n (%) Death, n (%) | 391 (99) 10.7 ± 5.4 5 (1.26) 4 (1) |
COVID-19 Therapy | All Patients (N = 396) |
---|---|
LMWH/NOAC, n (%) RDV, n (%) Duration (days), mean ± SD FPV, n (%) Duration (days), mean ± SD ANK, n (%) Duration (days), mean ± SD Cumulative dose (mg), mean ± SD TCZ, n (%) No. of administrations, mean ± SD Cumulative dose (mg), mean ± SD FVP/ANK, n (%) RDV/TCZ, n (%) RDV/ANK, n (%) FVP/TCZ, n (%) At least 3 potentially hepatotoxic drugs, n (%) | 390 (98.7) 210 (53) 4.76 ± 1.11 199 (50.3) 5.75 ± 2.61 102 (25.8) 5.25 ± 2.39 865.6 ± 408.2 81 (20.5) 1.98 ± 0.72 1066.33 ± 535.35 63 (15.9) 54 (13.6) 49 (12.4) 36 (9.1) 168 (42.4) |
Variables | Total | On Admission | During Hospitalization |
---|---|---|---|
Liver injury (elevated hepatocytolysis and/or cholestasis enzymes), n (%) | 312 (78.78) | 225 (56.82) | 277 (69.95) |
Elevated aminotransferases (ALT and/or AST), n (%) Grade 1: (1–3) ×ULN Grade 2: [3–5) ×ULN Grade 3: [5–10) ×ULN Grade 4: ≥10 ×ULN | 295 (74.5) 212 (53.54) 54 (13.64) 23 (5.81) 6 (1.51) | 184 (46.47) 162 (40.91) 18 (4.55) 3 (0.76) 1 (0.25) | 262 (66.16) 191 (48.23) 42 (10.6) 23 (5.81) 6 (1.52) |
Elevated ALT, n (%) Grade 1: (1–3) ×ULN Grade 2: [3–5) ×ULN Grade 3: [5–10) ×ULN Grade 4: ≥10 ×ULN | 275 (69.44) 198 (50) 49 (12.38) 22 (5.55) 6 (1.51) | 142 (35.86) 126 (31.82) 14 (3.54) 1 (0.25) 1 (0.25) | 257 (64.89) 189 (47.73) 40 (10.1) 22 (5.55) 6 (1.51) |
Elevated AST, n (%) Grade 1: (1–3) ×ULN Grade 2: [3–5) ×ULN Grade 3: [5–10) ×ULN Grade 4: ≥10 ×ULN | 204/395 (51.64) 180/395 (45.57) 19/395 (4.81) 5/395 (1.26) 0 | 147/387 (37.98) 135/387 (34.88) 9/387 (2.33) 3/387 (0.77) 0 | 144/364 (39.56) 128/364 (35.17) 13/364 (3.57) 3/364 (0.82) 0 |
(AST/ULN) > (ALT/ULN), n (%) | 101 (25.5) | 83 (20.96) | 46 (11.62) |
Elevated cholestasis enzymes, n (%) Isolated GGT GGT and ALP Isolated ALP | 176/389 (45.24) 154/389 (39.59) 20/389 (5.14) 2/389 (0.51) | 138/378 (36.51) 117/378 (30.95) 19/378 (5.03) 2/378 (0.53) | 131/274 (47.81) 120/274 (43.8) 10/274 (3.65) 1/274 (0.36) |
Elevated hepatocytolysis and cholestasis enzymes, n (%) | 159/389 (40.87) | 97/378 (25.66) | 121/274 (44.16) |
Elevated bilirubin, n (%) DBIL IBIL | 83/373 (22.2) 6/373 (1.6) | 62/373 (16.62) 4/361 (1.11) | 35/216 (16.2) 4/215 (1.86) |
Elevated LDH, n (%) Grade 1: (1–3) ×ULN Grade 2: [3–5) ×ULN Grade 3: ≥5 ×ULN | 331 (83.59) 313 (79.04) 15 (3.79) 3 (0.76) | 295 (74.5) 281 (70.96) 11 (2.78) 3 (0.76) | 255/360 (70.83) 247/360 (68.61) 8/360 (2.22) 0 |
Peak ALT | Peak AST | Peak LDH | ||||
---|---|---|---|---|---|---|
Univariate Analysis | Multivariate Analysis | Univariate Analysis | Multivariate Analysis | Univariate Analysis | Multivariate Analysis | |
RDV | p = 0.446 | - | p = 0.066 | - | p = 0.595 | - |
FVP | p = 0.013 * | p = 0.426 | p = 0.965 | - | p = 0.667 | - |
ANK | p = 0.020 * | p = 0.053 | p = 0.344 | - | p = 0.829 | - |
TCZ | p = 0.001 * | p = 0.000 * R = 0.271 a | p = 0.012 * | p = 0.033 * R = 0.112 | p = 0.082 | - |
RDV/TCZ | p = 0.046 * | p = 0.137 | p = 0.041 * | p = 0.115 | p = 0.026 * | p = 0.404 |
RDV/ANK | p = 0.339 | - | p = 0.337 | - | p = 0.439 | - |
FPV/ANK | p = 0.011 * | p = 0.261 | p = 0.157 | - | p = 0.569 | - |
FVP/TCZ | p = 0.000 * | p = 0.003 * R = 0.285 b | p = 0.006 * | p = 0.013 * R = 0.131 | p = 0.218 | - |
3MED | p = 0.000 * | p = 0.000 * R = 0.312 b | p = 0.000 * | p = 0.002 * R = 0.166 | p = 0.648 | - |
Peak ALT ≥ 3×ULN | Peak ALT ≥ 5×ULN | Peak AST ≥ 3×ULN | ||||
---|---|---|---|---|---|---|
Univariate Analysis | Multivariate Analysis | Univariate Analysis | Multivariate Analysis | Univariate Analysis | Multivariate Analysis | |
RDV | p = 0.275 | - | p = 0.919 | - | p = 0.946 | - |
FVP | p = 0.295 | - | p = 0.245 | - | p = 0.776 | - |
ANK | p = 0.017 * OR = 1.95 95%CI = 1.11–3.40 | p = 0.011 * Exp(B) = 2.10 95%CI = 1.19–3.72 N = 0.076 a | p = 0.118 | - | p = 0.233 | - |
TCZ | p = 0.003 * OR = 2.37 95%CI = 1.32–4.25 | p = 0.058 | p = 0.000 * OR = 3.79 95%CI = 1.72–8.37 | p = 0.001 * Exp(B) = 3.75 95%CI = 1.67–8.41 N = 0.125 a | p = 0.063 | - |
RDV/TCZ | p = 0.031 * OR = 2.06 95%CI = 1.05–4.04 | p = 0.159 | p = 0.004 * OR = 3.35 95%CI = 1.42–7.88 | p = 0.007 * Exp(B) = 3.36 95%CI = 1.40–8.07 N = 0.105 a | p = 0.150 | - |
RDV/ANK | p = 0.187 | - | p = 0.045 * OR = 2.49 95%CI = 0.99–6.23 | - | p = 0.105 | - |
FPV/ANK | p = 0.183 | - | p = 0.855 | - | p = 0.263 | - |
FVP/TCZ | p = 0.039 * OR = 2.21 95%CI = 1.02–4.76 | p = 0.118 | p = 0.004 * OR = 3.70 95%CI = 1.44–9.46 | p = 0.010 * Exp(B) = 3.51 95%CI = 1.34–9.21 N = 0.100 a | p = 0.019 * OR = 3.86 95%CI = 1.16–12.89 | p = 0.028 * Exp(B) = 3.86 95%CI = 1.16–12.89 N = 0.037 |
3MED | p = 0.001 * OR = 2.44 95%CI = 1.42–4.19 | p = 0.001 * Exp(B) = 2.45 95%CI = 1.41–4.25 N = 0.094 a | p = 0.001 * OR = 4.26 95%CI = 1.76–10.3 | p = 0.001 * Exp(B) = 4.36 95%CI = 1.78–10.69 N = 0.140 a | p = 0.054 | - |
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Mihai, N.; Tiliscan, C.; Visan, C.A.; Stratan, L.; Ganea, O.; Arama, S.S.; Lazar, M.; Arama, V. Evaluation of Drug-Induced Liver Injury in Hospitalized Patients with SARS-CoV-2 Infection. Microorganisms 2022, 10, 2045. https://doi.org/10.3390/microorganisms10102045
Mihai N, Tiliscan C, Visan CA, Stratan L, Ganea O, Arama SS, Lazar M, Arama V. Evaluation of Drug-Induced Liver Injury in Hospitalized Patients with SARS-CoV-2 Infection. Microorganisms. 2022; 10(10):2045. https://doi.org/10.3390/microorganisms10102045
Chicago/Turabian StyleMihai, Nicoleta, Catalin Tiliscan, Constanta Angelica Visan, Laurentiu Stratan, Oana Ganea, Stefan Sorin Arama, Mihai Lazar, and Victoria Arama. 2022. "Evaluation of Drug-Induced Liver Injury in Hospitalized Patients with SARS-CoV-2 Infection" Microorganisms 10, no. 10: 2045. https://doi.org/10.3390/microorganisms10102045