Abstract
Background
SARS-CoV-2 caused a pandemic and global threat for human health. Presence of liver injury was commonly reported in patients with coronavirus disease 2019 (COVID-19). However, reports on severe liver dysfunction (SLD) in critically ill with COVID-19 are lacking. We evaluated the occurrence, clinical characteristics and outcome of SLD in critically ill patients with COVID-19.
Methods
Clinical course and laboratory was analyzed from all patients with confirmed COVID-19 admitted to ICU of the university hospital. SLD was defined as: bilirubin ≥ 2 mg/dl or elevation of aminotransferase levels (> 20-fold ULN).
Results
72 critically ill patients were identified, 22 (31%) patients developed SLD. Presenting characteristics including age, gender, comorbidities as well as clinical presentation regarding COVID-19 overlapped substantially in both groups. Patients with SLD had more severe respiratory failure (paO2/FiO2: 82 (58–114) vs. 117 (83–155); p < 0.05). Thus, required more frequently mechanical ventilation (95% vs. 64%; p < 0.01), rescue therapies (ECMO) (27% vs. 12%; p = 0.106), vasopressor (95% vs. 72%; p < 0.05) and renal replacement therapy (86% vs. 30%; p < 0.001). Severity of illness was significantly higher (SAPS II: 48 (39–52) vs. 40 (32–45); p < 0.01). Patients with SLD and without presented viremic during ICU stay in 68% and 34%, respectively (p = 0.002). Occurrence of SLD was independently associated with presence of viremia [OR 6.359; 95% CI 1.336–30.253; p < 0.05] and severity of illness (SAPS II) [OR 1.078; 95% CI 1.004–1.157; p < 0.05]. Mortality was high in patients with SLD compared to other patients (68% vs. 16%, p < 0.001). After adjustment for confounders, SLD was independently associated with mortality [HR3.347; 95% CI 1.401–7.999; p < 0.01].
Conclusion
One-third of critically ill patients with COVID-19 suffer from SLD, which is associated with high mortality. Occurrence of viremia and severity of illness seem to contribute to occurrence of SLD and underline the multifactorial cause.
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Background
The coronavirus disease 2019 (COVID-19) caused by novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for a global threat for human health. Since its initial detection in Wuhan (China) in December 2019 COVID-19 spread and accounts for the ongoing pandemic with more than 30 million infections and 900.000 deaths [1, 2]. The disease is mainly characterized by mild flu-like symptoms or can be complicated by respiratory deterioration, potentially leading to acute respiratory distress syndrome (ARDS) and/or other organ failure [3,4,5]. A severe course of COVID-19 with need of intensive care unit (ICU) admission can be observed in up to 20% of hospitalized patients [6, 7]. Patients admitted to ICU suffer from high mortality [7, 8]. Several large studies reported clinical features and revealed that older age and underlying comorbidities increase the risk of unfavorable outcome [5, 6, 9,10,47]. Further, SAPS II [OR 1.078; 95% CI 1.004–1.157] was independently associated with occurrence of SLD which confirms previous studies [47].
In general, liver injury and failure is a frequently observed in critically ill patients [23]. Traditionally, HLI and CLD were regarded as late features in critical illness [24]. However, recent findings showed that they are found early in life-threatening illness on the ICU [23,24,25]. In our cohort, SLD developed within one week after admission, with a median of 6 (4–11.3) days. The occurrence of HLI or CLD is associated with increased morbidity and mortality [21,22,23]. In the medical ICU about 20% develop CLD and 10% suffer from HLI [21, 22, 25]. In our cohort, we observed a higher rate of SLD, mainly as a consequence of the severity of COVID-19 with pronounced respiratory failure accompanied by sepsis and cardiac failure. Of interest, about 23% of patients with SLD had reduced ejection fraction measured by echocardiography. Further, Septic shock preceded SLD in 56% of patients. Presumably, the cause of SLD was septic shock combined with ARDS in more than 70% of our patients. However, data on patients with severe respiratory failure and/or ARDS are lacking. Mortality rates in patients with SLD were significantly higher in patients suffering from SLD. However, even after splitting injury patterns in HLI or CLD alone and a mixed injury pattern observed mortality rates were generally comparable between groups. Of interest, at time of death 12 of 15 patients met criteria of SLD. Highest mortality rate was observed in patients presenting with HLI injury pattern. Recent data showed that HLI accompanied by CLD increases complications and mortality [22]. After adjusting for covariables SLD was the most indicative factor [HR 3.347 95% CI 1.401–7.999] for mortality in our cohort of critically ill patients with COVID-19. A recent study showed that viral load can serve as predictor for mortality in patients with COVID-19 [48]. Interestingly, presence of viremia [OR 6.359 95% CI 1.336–30.253] was the most important factor associated with occurrence of SLD in our cohort, but was not associated with mortality. However, we observed significantly higher viral load as well as presence of viremia (defined as detection of viral RNA > 1000 copies/ml) in patients with SLD. This finding is novel and direct causation of liver injury by viral effects could be one explanation. Viremia was not associated with mortality in our cohort; this could be explained by the rather small number of patients included. Nevertheless, occurrence of viremia in critically ill patients (especially in patients with SLD) could serve as an early risk marker and should prompt close surveillance of liver function. Different clinical patterns and complications, like hypo-/hyperglycemia, hyperammonemia, respiratory failure or acute kidney injury in patients with SLD are associated with increased mortality [21,22,23,24, 46, 47]. Due to occurrence of SLD within a dynamic process in patients with multi-organ failure patients are generally not eligible for liver transplantation. However, even though no specific treatment of SLD is available, prevention of complications is of central importance. All in all, our data clearly demonstrate that occurrence of SLD is a multifactorial event. Severity of illness as well as complications during ICU, and direct viral effects play an important role in development of SLD.
Although, the number comorbidities in our cohort were high, no patient suffered from pre-existing liver disease. Pre-existing liver diseases were reported in up to 11% of patients with COVID-19 [1, 5, 8, 10] and were associated with fast deterioration of liver function and elevated mortality [20]. Thirty-two per-cent of patients presented with a BMI > 30 kg/m2. Although, we did not observe differences in occurrence of SLD in our cohort patients with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis are probably at risk for SLD. However, whether COVID-19 aggravates occurrence of SLD or not must be addressed in larger analyses of critically ill patients with COVID-19 and pre-existing liver disease.
This study has strengths and limitations. First, the sample size of our study is rather small. However, this is the first and most comprehensive study describing the occurrence of SLD in critically ill patients with COVID-19. Second, for SLD we used a combination of well-established definitions of HLI and CLD. Both entities can be caused by different underlying mechanism, therefore our definition has to be interpreted with caution when comparing or data to other studies. Third, for detection of pre-existing liver disease, we carefully reviewed patient charts and due to routine clinical care patients were screened for presence of liver disease. However, due to the retrospective character of the study, we cannot entirely exclude the presence of pre-exiting liver disease. Fourth, we show results of a center experienced in management of ARDS and liver failure, and results and conclusions may not be generally transferable to other settings with less experience. Fifth, direct viral effects of SARS-CoV-2 could not be further validated in this clinical study and should be addressed in future studies. Sixth, residual confounding from unmeasured covariables is a matter of concern and cannot be entirely excluded. Future larger studies should be conducted to confirm these results.
Conclusion
In conclusion, our study could demonstrate that occurrence of SLD is a frequent observation in critically ill patients with COVID-19 and is associated with high mortality rates. Severity of illness as well as viremia seems to contribute to the occurrence of SLD and underline the multifactorial cause. Our findings highlight the significant contribution and impact on outcome of SLD in critically ill patients with COVID-19.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article.
Abbreviations
- ARDS:
-
Acute respiratory distress syndrome
- CCI:
-
Charlson Comorbidity Index
- CLD:
-
Cholestatic liver dysfunction
- COVID-19:
-
Coronavirus disease 2019
- ECMO:
-
Extracorporeal membrane oxygenation
- HFNC:
-
High-flow nasal cannula
- HLI:
-
Hypoxic liver injury
- ICU:
-
Intensive care unit
- IQR:
-
Interquartile range
- MAP:
-
Mean arterial pressure
- MV:
-
Mechanical ventilation
- NIV:
-
Non-invasive ventilation
- RRT:
-
Renal replacement therapy
- SARS-CoV-2:
-
Severe acute respiratory syndrome coronavirus-2
- SAPS II:
-
Simplified Acute Physiologic Assessment Score
- SOFA:
-
Sequential Organ Failure Assessment
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Acknowledgements
We sincerely thank the study nurses of the Department of Intensive Care Medicine involved in data acquisition and management—Grit Ringeis, Melanie Kerinn, Lisa Krebs, and Andrea Conrad
Funding
Open Access funding enabled and organized by Projekt DEAL. This study was supported exclusively by institutional funds of the Department of Intensive Care Medicine.
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KR, VF and SK conceived and designed the study. KR and DJ, DW, AD, OB, MK, GdH, CB, DF, BS and ML were involved in data acquisition and laboratory analysis. KR, DJ, DW, AD, AN and VF analyzed and interpreted the data. KR and VF drafted the manuscript. DW, ML, AN, VF and SK critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
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The Ethics Committee of the Hamburg Chamber of Physicians was informed about the study (No.: WF-142/20). The study was approved by the local clinical institutional review board and complied with the Declaration of Helsinki.
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Competing Interests
KR, DJ, AD, OB, GDH BS, CB and VF do not report any conflicts of interest. SK received research support by Ambu, E.T.View Ltd, Fisher & Paykel, Pfizer and Xenios, lecture honoraria from ArjoHuntleigh, Astellas, Astra, Basilea, Bard, Baxter, Biotest, CSL Behring, CytoSorbents, Fresenius, Gilead, MSD, Orion, Pfizer, Philips, Sedana, Sorin, Xenios and Zoll, and consultant honorarium from AMOMED, Astellas, Baxter, Bayer, Fresenius, Gilead, MSD, Pfizer and Xenios. AN received research funds, lecture honoraria and travel reimbursement within the last 5 years from CytoSorbents Europe, Biotest AG and ThermoFisher Scientific. DF reports lecture honoraria within the last 5 years from Xenios AG. DW received lecture and consultant honorarium from Gilead, MSD, Pfizer, Shionogi and reports no other potential conflict of interest relevant to this article.
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Supplementary Information
Additional file 1: Table S1.
Biomarkers stratified according no liver dysfunction and severe liver dysfunction. Table S2. Viral characteristics in patients with and without severe liver dysfunction. Table S3a. Cox regression model for factors associated with ICU mortality.
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Roedl, K., Jarczak, D., Drolz, A. et al. Severe liver dysfunction complicating course of COVID-19 in the critically ill: multifactorial cause or direct viral effect?. Ann. Intensive Care 11, 44 (2021). https://doi.org/10.1186/s13613-021-00835-3
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DOI: https://doi.org/10.1186/s13613-021-00835-3