High Aspartate Aminotransferase to Alanine Aminotransferase Ratio on Admission as Risk Factor for Poor Prognosis in COVID-19 Patients

doi:10.21203/rs.3.rs-32531/v1

This study aimed to analyze aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio in COVID-19 patients. After exclusion, 567 inpatients were included in this study and separated into two groups according to their AST/ALT ratio on admission. Poor prognosis included death and transfer to other hospitals due to deterioration. Of 567 patients, 56 (9.9%) had AST/ALT ≥ 2. Of the 56 patients, older age (median age 65.5 years), fatigue (29 [51.8%] cases), comorbidities (33 [58.9%] cases) and outcomes were significantly different from patients with AST/ALT < 2. They also had worse chest computed tomography (CT) findings, laboratory results and severity scores. Levels of platelet count (OR = 0.989, 95% CI [0.983-0.996]) were independently associated with AST/ALT ≥ 2 on admission. Furthermore, a high AST/ALT ratio on admission was an independent risk factor for poor prognosis (OR = 22.02, 95% CI [1.84-263.2]), especially in patients with AST levels > 40 U/L. In subsequent monitoring, the AST/ALT ratio was decreased in both patients with AST/ALT < 2 or ≥ 2 on admission. COVID-19 patients who are older, or have fatigue, comorbidities are more likely to have AST/ALT ≥ 2 on admission, which might be the indication of worse status and outcomes.

General Biochemistry

Infectious Diseases

Virology

Critical Care & Emergency Medicine

Internal Medicine

COVID-19

Aspartate Aminotransferase

Alanine Aminotransferase

AST/ALT Ratio

Coronaviruses, consisting of four genera (Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus), are members of the Coronaviridae family. In contrast to the majority of human coronaviruses that only cause mild respiratory infections, highly pathogenic coronaviruses can induce severe human respiratory syndromes and threaten public health ¹. In 2002 and 2003, the worldwide outbreak of severe acute respiratory syndrome (SARS), which is caused by SARS coronavirus (SARS-CoV), infected over 8400 people in at least 30 countries and resulted in more than 800 reported deaths (approximately 10% mortality) ². Ten years later, Middle East respiratory syndrome coronavirus (MERS-CoV) spread in 27 countries and caused 779 deaths in 2182 MERS cases (approximately 35% mortality) ³. At present, the world is experiencing a pandemic of coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2 and has contributed to far more cases and deaths than SARS and MERS ⁴.

SARS-CoV-2 is a novel RNA virus and belongs to the Betacoronavirus genus. Its genome sequence shares approximately 79% identity with SARS-CoV and 50% identity with MERS-CoV ⁵. Notably, SARS-CoV-2 employs angiotensin-converting enzyme 2 (ACE2) as a host-cell entry receptor, which is similarly used by SARS-CoV ⁶. In December 2019, the first series of cases were confirmed in Wuhan, Hubei Province, China ⁷. Since then, COVID-19 has affected over 200 countries and infected over three million people, with over one hundred thousand deaths as of May 2020. According to the clinical investigation of COVID-19 patients, fever and respiratory symptoms predominate ^8-10. In addition, a recent study found that digestive symptoms, including abdominal pain, diarrhea, vomiting and nausea, are also present in 26% of COVID-19 patients ¹¹. Similarly, such digestive problems have been reported in large numbers of SARS and MERS cases ^12,13. In addition to clinical evidence, single-cell analysis data suggested that some cells in the digestive system also express ACE2, which might mediate SARS-CoV-2 infection in the liver ¹⁴ and gut ^15,16. Furthermore, a retrospective study involving 191 patients showed that sepsis was the most frequent complication ¹⁷, which could cause systemic damage, including liver injury ¹⁸. Therefore, the digestive system, especially the liver, might play a significant role in the course of COVID-19. Clinical studies have reported that approximately 20%-30% of COVID-19 patients have liver dysfunction, which is represented by elevated levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ^8,19. Although higher AST levels are likely to associate with death in COVID-19 patients ²⁰, there is still a lack of clinical studies on AST/ALT ratio to predict disease course in COVID-19 patients. In addition to individual values of ALT and AST, the AST/ALT ratio has been explored as an important indicator for assessing liver diseases. An elevated AST/ALT ratio might indicate alcoholic liver disease, cirrhosis ²¹, and poor prognosis in acute viral hepatitis ²². In this study, we described the clinical characteristics, laboratory results and outcomes of COVID-19 patients with AST/ALT < 2 and ≥ 2 on admission in Wuhan, Hubei Province. Furthermore, the changes in AST/ALT ratio during hospitalization were analyzed. In conclusion, higher AST/ALT ratio indicates worse clinical status and poor prognosis and should be considered by clinicians during the treatment of COVID-19 patients.

Clinical features

Overall, 567 hospitalized patients with confirmed COVID-19 were included in this study. The median age was 55 years (IQR, 37-67), and 247 (43.6%) patients were male. The median duration from symptom onset to hospital admission was 7 days (IQR, 4-10). The most common symptoms on admission were fever (455 [80.2%]), cough (370 [65.3%]), chest tightness (222 [39.2%]), fatigue (208 [36.7%]), and myalgia (143 [25.2%]). In contrast, the less common symptoms of the included patients were diarrhea (51[9%]), headache (36 [6.3%]), and chest pain (27 [4.8%]). Of the 567 patients, 250 (44.1%) had coexisting diseases. A total of 183 (32.3%) patients had hypertension, 85 (15%) patients had diabetes, and 53 (9.3%) patients had cardiovascular disease, which were the most common comorbidities. In contrast, chronic obstructive pulmonary disease (36 [6.3%]), cerebrovascular disease (32 [5.6%]), and chronic kidney disease (31 [5.5%]) were less common comorbidities (Table 1).

Of the 567 included patients, 56 patients (9.9%) had AST/ALT ≥ 2. Compared with the patients with AST/ALT < 2 on admission (n = 511, 90.1%), patients with AST/ALT ≥ 2 were older (median age, 65.5 years [IQR, 41.25-74.5] vs 54 years [IQR, 37-66]; P = 0.001), more likely to have fatigue (29 [51.8%] vs 179 [35%]; P = 0.014) and coexisting diseases (33 [58.9%] vs 217 [42.5%]; P = 0.018), especially cardiovascular diseases (14 [25%] vs 39 [7.6%]; P < 0.001), cerebrovascular diseases (9 [16.1%] vs 23 [4.5%]; P = 0.001) and chronic kidney diseases (7 [12.5%] vs 24 [4.7%]; P = 0.033), on admission (Table 1). Additionally, patients with AST/ALT ≥ 2 on admission were less likely to be recovery and discharge (34 [60.7%] vs 456 [89.2%]; P < 0.001) but more likely to be death (19 [33.9%] vs 46 [9%]; P < 0.001).

AST/ALT ≥ 2 on admission indicates more severe chest CT findings, worse laboratory results and higher severity of illness scores

On admission, all enrolled patients experienced a variety of measures and tests according to their clinical care needs. There were differences on chest CT, in laboratory findings and in severity of illness scores between patients with AST/ALT < 2 or ≥ 2 (Table 2).

Compared with the patients with AST/ALT < 2, patients with AST/ALT ≥ 2 were more likely to have lesion presence higher than 60% lung (19 [33.9%] vs 111 [21.7%]; P = 0.039) (Table 2). Among laboratory findings, the blood count showed that patients AST/ALT ≥ 2 had lower lymphocyte count (median number, 0.8 ×10⁹/L [IQR, 0.5-1.1] vs 1.1 ×10⁹/L [IQR, 0.7-1.4]; P = 0.001), hemoglobin (median number, 123 g/L [IQR, 109.3-133.8] vs 129 g/L [IQR, 121-140.3]; P = 0.006) and platelet count (median number, 149 ×10⁹/L [IQR, 100.5-205.3] vs 181 ×10⁹/L [IQR, 139-227.3]; P = 0.001) than those with AST/ALT < 2. However, patients with AST/ALT ≥ 2 had slightly lower total bilirubin levels (median number, 7.7 μmol/L [IQR, 5.4-11.4] vs 8.7 μmol/L [IQR, 6.5-11.9]; P = 0.047) than other COVID-19 patients. In the kidney function test, patients with AST/ALT ≥ 2 had significantly higher blood urea nitrogen (BUN) (median number, 4.8 mmol/L [IQR, 3.3-6.9] vs 4 mmol/L [IQR, 3.2-5.3]; P = 0.02) and creatinine (median number, 71.7 μmol/L [IQR, 58.7-88.7] vs 63.8 μmol/L [IQR, 51.5-77.4]; P = 0.023). In the myocardial enzyme spectrum test, patients with AST/ALT ≥ 2 had significantly higher CK-MB (median number, 10 U/L [IQR, 6.5-15.1] vs 8 U/L [IQR, 6-11.25]; P = 0.008), and LDH (median number, 221 U/L [IQR, 165-375] vs 186 U/L [IQR, 150-243.5]; P = 0.005). The abovementioned differences suggest that patients with AST/ALT ≥ 2 are more likely to encounter systemic injury, including the circulatory system, kidneys, and heart. Consistently, some parameters of systemic inflammation were also significantly increased in the patients with AST/ALT ≥ 2, including CRP (median number, 4.4 mg/dL [IQR, 0.7-7.4] vs 1.4 mg/dL [IQR, 0.4-4.1]; P = 0.001) and procalcitonin (median number, 0.08 ng/mL [IQR, 0.05-0.27] vs 0.05 ng/mL [IQR, 0.04-0.08]; P = 0.001). In addition, coagulation markers were also significantly elevated in the patients with AST/ALT ≥ 2, such as D-dimer (median number, 0.9 μg/mL [IQR, 0.4-1.9] vs 0.5 μg/mL [IQR, 0.2-1]; P = 0.001).

In addition to massive differences in laboratory findings, some life-threatening signs were also clearly distinct (Table 2). Blood gas analysis showed that compared with patients who had AST/ALT < 2, patients with AST/ALT ≥ 2 had lower partial pressure of arterial oxygen to fraction of inspired oxygen ratios (PaO₂/FiO₂) (median number, 254.5 mmHg [IQR, 172.5-420] vs 393 mmHg [IQR, 256-520]; P < 0.001), which indicates respiratory dysfunction ²³. Furthermore, patients with AST/ALT ≥ 2 also had higher severity of illness scores, including APACHE II (median score, 5 [IQR, 2-10] vs 3 [IQR, 1-5]; P < 0.001), SOFA (median score, 3 [IQR, 1-4] vs 1 [IQR, 0-2]; P < 0.001) and CURE-65 (median score, 1 [IQR, 0-2] vs 0 [IQR, 0-1]; P < 0.001) (Table 2).

Platelet count risk factor for AST/ALT ≥ 2

To assess the risk factors among other laboratory indicators for AST/ALT ≥ 2 in COVID-19 patients, we performed logistic regression analysis for significant differences of the abovementioned laboratory parameters, including lymphocyte count, hemoglobin, platelet count, total bilirubin, BUN, creatinine, LDH, CK-MB, CRP, procalcitonin, D-dimer and PaO₂/FiO₂ (Table 3). In collinearity diagnostics, all included laboratory parameters had no significant collinearity. In multivariate logistic regression, levels of platelet count (adjusted OR = 0.989; 95% CI [0.983–0.996]; P = 0.001) was relatively independent risk factors for AST/ALT ≥ 2 in COVID-19 patients (Table 3).

Elevated AST/ALT ratio on admission indicates poor prognosis as an independent risk factor

Of the 567 included patients, 490 (86.4%) recovered and were discharged after comprehensive clinical assessment of symptoms, chest CT and viral clearance. However, 77 (13.6%) patients had a poor prognosis, including death or transfer to other specialized hospitals due to patient deterioration after clinical evaluation. To analyze the risk factors of biochemical findings on poor prognosis of the included 567 COVID-19 patients, we performed logistic regression analysis (Table 4). In univariate analysis, in addition to AST/ALT (crude OR = 3.36; 95% CI [2.23–5.05]; P < 0.001), high levels of many other serum biochemical parameters were risk factors for poor prognosis as well, including AST levels (crude OR = 1.01; 95% CI [1–1.02]; P = 0.015), total bilirubin (crude OR = 1.06; 95% CI [1.02–1.1]; P = 0.004), BUN (crude OR = 1.13; 95% CI [1.08–1.18]; P < 0.001), creatinine (crude OR = 1.002; 95% CI [1.001–1.003]; P < 0.001), LDH (crude OR = 1.009; 95% CI [1.006–1.011]; P < 0.001), CK (crude OR = 1.001; 95% CI [1–1.002]; P = 0.012), CK-MB (crude OR = 1.005; 95% CI [1.02–1.09]; P = 0.002), white blood cell count (crude OR = 1.157; 95% CI [1.08–1.24]; P < 0.001), neutrophil count (crude OR = 1.22; 95% CI [1.13–1.31]; P < 0.001), lactate (crude OR = 2.38; 95% CI [1.83–3.1]; P < 0.001), D-dimer (crude OR = 1.02; 95% CI [1–1.04]; P = 0.024), fibrinogen (crude OR = 1.47; 95% CI [1.12–1.93]; P = 0.005), IL-6 (crude OR = 1.04; 95% CI [1.02–1.06]; P = 0.024), C-reactive protein (crude OR = 1.23; 95% CI [1.17–1.31]; P < 0.001) and procalcitonin (crude OR = 60.1; 95% CI [15.4–233.9]; P < 0.001). In contrast, in some parameters, high levels were protective factors, including lymphocyte count (crude OR = 0.2; 95% CI [0.11–0.38]; P < 0.001), hemoglobin (crude OR = 0.98; 95% CI [0.97–0.99]; P = 0.003) and platelet count (crude OR = 0.99; 95% CI [0.98–0.99]; P < 0.001) (Table 4).

To assess independent risk factors for poor prognosis, we performed logistic regression analysis on liver enzymes and other biochemical parameters. However, collinearity was significant among BUN, creatinine, white blood cell count and neutrophil count (VIF = 8, 8.5, 18.2 and 18.3, respectively). Therefore, we performed Spearman’s rank correlation analysis in order to select variables and reduce collinearity. BUN and neutrophil count had higher correlation coefficients than creatinine (0.31 vs 0.24) and white blood cell count (0.17 vs 0.1), respectively. Therefore, creatinine and white blood cell counts were excluded from the subsequent multivariate logistical regression. In multivariate analysis, high AST/ALT ratio (adjusted OR = 22.02; 95% CI [1.84–263.2]; P = 0.015), LDH (adjusted OR = 1.02; 95% CI [1–1.03]; P = 0.037), lactate (adjusted OR = 12.04; 95% CI [2.22–65.21]; P = 0.004), and IL-6 (adjusted OR = 1.05; 95% CI [1.02–1.09]; P = 0.005) on admission were relatively independent risk factors for poor prognosis of the COVID-19 patients (Table 4).

To assess the AST/ALT ratio on poor prognosis of patients with different liver enzyme levels ²⁰, we separated the COVID-19 patients into two groups according to their AST levels (≤ 40 or > 40 U/L) on admission (Table 5). Of the patients with normal liver enzyme levels and AST/ALT < 2 (n = 420), 42 (10%) patients had poor prognosis, while of the patients with AST/ALT ≥ 2 (n = 40), 11 (27.5%) patients had poor prognosis (crude OR = 3.4; 95% CI [1.6–7.4]; P = 0.002). Of the patients with AST levels > 40 U/L and AST/ALT < 2 (n = 91), 13 (14.3%) patients had poor prognosis, while of the patients with AST/ALT ≥ 2 (n = 16), 11 (68.75%) patients had poor prognosis (crude OR = 13.2; 95% CI [3.9–43.5]; P < 0.001) (Table 5). Therefore, AST/ALT ≥ 2 was a risk factor for poor prognosis in both groups of patients but had a more obvious impact on patients with abnormal AST levels on admission.

Monitoring AST/ALT ratio during hospitalization

Most patients also received liver enzyme tests on other hospital days (days 3, 7 and 14) in addition to on the day of admission according to their clinical care needs. In patients with AST/ALT < 2 on admission, their AST/ALT ratio significantly decreased during hospitalization (Fig. 1 A). Similarly, the AST/ALT ratio of patients with AST/ALT ≥ 2 on admission also decreased noticeably from day 1 to day 7. From day 7 to day 14, the AST/ALT ratio also tended to decrease, but there was no statistical significance (Fig. 1B)

Among a variety of recent publications about COVID-19, accumulated evidence suggests that SARS-CoV-2 infections might cause multiple and systemic injuries, including acute renal failure, myocardial dysfunction, and acute liver injury ^20,24,25. Additionally, there are recent studies analyzing COVID-19 patients in detail with respect to liver enzymes, such as ALT and AST ^20,26. The underlying mechanism of elevated liver enzymes in COVID-19 patients remains unclear. Direct liver infection is a potential reason. Several studies have suggested that ACE2 is possibly expressed in the liver ^14,27,28 and might serve as the entry point for SARS-CoV-2 virus to the liver. Additionally, elevated liver enzymes may also be associated with hypoxemia and systemic inflammation response ²⁰. However, the relationship between COVID-19 and AST/ALT ratio was still not revealed.

In this study, we described COVID-19 patients admitted with different AST/ALT ratio, we found that a high AST/ALT ratio was a risk factor for poor prognosis and monitored changes in AST/ALT ratio during hospitalization. Older COVID-19 patients had a higher case fatality rate ²⁹. Similarly, having comorbidities might also contribute to worse outcomes ³⁰. In this study, there was a higher proportion of older and comorbid patients with AST/ALT ≥ 2. Interestingly, cardiovascular, cerebrovascular and chronic kidney diseases were the most significant coexisting diseases among the 6 comorbidities of patients with AST/ALT ≥ 2 on admission. Additionally, patients with AST/ALT ≥ 2 on admission were also likely to have poor prognosis such as death and transfer. Therefore, liver tests on elderly COVID-19 patients with comorbidities are necessary on admission.

The relationship between AST/ALT ratio and other laboratory findings in COVID-19 patients is unclear. This study described massive differences in laboratory parameters between the two groups of patients. Patients with AST/ALT ≥ 2 had lower hemoglobin, lymphocyte and platelet counts, which might be related to the disease severity ^31,32. Furthermore, compared with patients with AST/ALT < 2, those patients were also susceptible to have worse kidney function (higher BUN and creatinine levels), worse myocardial function (higher LDH and CK-MB levels), more severe systemic inflammation (higher CRP and procalcitonin levels) and a higher clotting tendency (higher D-dimer levels). In general, AST/ALT ≥ 2 might indicate that the patients were suffering from more intensive systemic injuries. In addition, more severe chest CT results (showing a larger proportion of lesions in the lung), worse blood gas analysis (lower PaO₂/FiO₂) and higher severity of illness scores (higher APACHE II, SOFA and CURB-65) were also more frequent in patients with AST/ALT ≥ 2. Importantly, a higher D-dimer levels and SOFA score have been recommended as indictors for worse outcomes in early COVID-19 patients ¹⁷. Moreover, in multivariate analysis, patients with lower levels of platelet count were susceptible to have AST/ALT ≥ 2, which suggested that the AST/ALT ≥ 2 might be the result of vascular endothelial injuries and following hypoperfusion of liver in COVID-19 ³³.

Additionally, the AST/ALT ratio was found to be an independent risk factor for poor prognosis such as death or transfer of COVID-19 patients, especially those patients with abnormal AST levels on admission. For the underlying mechanism, a higher level of AST in serum might indicate worse hepatocyte injuries because AST is mainly distributed in the mitochondria ³⁴. In addition, AST/ALT ≥ 2 was also a risk factor for poor prognosis in patients with normal liver enzyme levels. Therefore, some patients might also suffer from liver injuries even though their liver enzyme levels were within normal ranges. Besides that, the AST/ALT ratio, for unclear reasons, has some extrahepatic implications, including predicting poor outcomes of pancreatic cancer patients ³⁵ and heart injury in Kawasaki disease ³⁶. Therefore, the role of the AST/ALT ratio in COVID-19 remains to be further analyzed. We monitored the dynamic AST/ALT ratio during hospitalization. The AST/ALT ratio tended to decrease during hospitalization in patients with AST/ALT < 2 or ≥ 2 on admission. Therefore, liver condition in COVID-19 patients might be eased to a large extent after receiving medical treatment. Future studies on the mechanism of liver injury in COVID-19 are needed. Moreover, a deeper analysis of the AST/ALT ratio in COVID-19 patients is also required.

In summary, our results suggested that older COVID-19 patients with coexisting diseases were more likely to have AST/ALT ≥ 2 on admission. We also provided evidence that AST/ALT ≥ 2 was significantly associated with more severe chest CT findings, worse laboratory results, higher severity of illness scores, and poor prognosis as an independent risk factor of COVID-19 patients. Therefore, it is necessary to provide advanced medical care to COVID-19 patients with AST/ALT ≥ 2 on admission, especially in patients with abnormal AST levels.

Study Design and Patients

This retrospective study was approved by the Ethics Committee of The Central Hospital of Wuhan. All methods were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants for extracting data from their clinical records. All authors had access to the study data and reviewed and approved the final manuscript. The Central Hospital of Wuhan is a major tertiary hospital and is responsible for the treatment of COVID-19 patients. A total of 584 patients with confirmed COVID-19 in the Central Hospital of Wuhan from January 1 to February 15, 2020 were enrolled and diagnosed according to the interim guidance from the World Health Organization ³⁷. Only cases confirmed by laboratory testing were included in this study. Five patients with chronic liver diseases, including chronic hepatitis B infection and cirrhosis, were excluded from this study. Twelve patients were excluded due to incomplete liver enzyme data on admission. Ultimately, 567 patients were included and separated into two groups according to their AST/ALT ratio on admission (< 2 or ≥ 2).

Procedures

The symptoms, signs, coexisting conditions, laboratory results, computed tomography (CT) findings, and outcomes were obtained from the medical records of enrolled patients in the Central Hospital of Wuhan. All patient testing was carried out according to clinical needs. The duration from onset of illness to hospital admission was recorded. The chest CT findings, laboratory data, Sequential Organ Failure Assessment (SOFA) scores, CURB-65 scores and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were measured on admission unless stated otherwise. Laboratory assessments consisted of a complete blood count, blood chemical analysis, liver and renal function evaluation, coagulation testing, and levels of C-reactive protein (CRP), procalcitonin, lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-MB (CK-MB), lactate, and interleukin-6 (IL-6). Medical records were comprehensively reviewed and extracted by a standardized chart review form. The clinical outcomes were documented up to the final follow-up date of March 25, 2020.

Statistics

We described the categorical variables as numbers with percentages and continuous variables as medians with interquartile range (IQR) values. Categorical variables and count data were compared using the Chi-square tests, and Continuous correction chi-squared tests was performed if relevant data were limited. Normally distributed data of continuous variables were compared using independent group t-tests; when the data were not normally distributed, Mann-Whitney U tests were performed. Furthermore, univariate and multivariate logistic regression analysis was performed after collinearity diagnostics. A variance inflation factor (VIF) greater than 5 was considered significant collinearity. Spearman’s rank correlation analysis was performed to select variables for further multivariate analysis. Paired Wilcoxon's tests were performed to compare the AST/ALT ratio on different hospitalization days. All data were statistically analyzed using SPSS software, version 25.0. In this study, a two-tailed P value less than 0.05 was considered statistically significant.

ACE2, Angiotensin-Converting Enzyme 2; ALT, Alanine Aminotransferase; APCHE II, Acute Physiology and Chronic Health Evaluation II; AST, Aspartate Aminotransferase; BUN, Blood Urea Nitrogen; CK, Creatine Kinase; COVID-19, Coronavirus Disease 2019; CRP, C-reactive Protein; IL6, Interleukin-6; IQR, Interquartile Range; LDH, Lactate Dehydrogenase; CT, Computed Tomography; MERS-CoV, Middle East Respiratory Syndrome Coronavirus; SARS-CoV-2, Severe Acute Respiratory Syndrome-Coronavirus 2; SOFA, Sequential Organ Failure Assessment; VIF, Variance Inflation Factor.

Acknowledgements: Not applicable

Funding statement: This study was supported by the National Natural Science Foundation of China (81773215 to Dr. Weibin Wang; 81972321 to Dr. Lei You).

Conflict of interest disclosure: The authors declare that they have no competing interests.

Ethics approval: This study was approved by the Ethics Committee of The Central Hospital of Wuhan.

Authors’ contributions: W. W., L. Y. and Y. W. directed and guided this study. C. Q., Y. W., X. L. and B. Z. collected data and drafted this manuscript. Y. F., T. L., H. C., X. Y. and X. Z. made critical revisions to this manuscript. All authors read and approved the final manuscript.

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32 Bi, X. et al. Prediction of severe illness due to COVID-19 based on an analysis of initial Fibrinogen to Albumin Ratio and Platelet count. Platelets, 1-6, doi:10.1080/09537104.2020.1760230 (2020).

33 Guzik, T. J. et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res, doi:10.1093/cvr/cvaa106 (2020).

34 Jung, K., Pergande, M., Rej, R., Schreiber, G. & Schimmelpfennig, W. Mitochondrial enzymes in human serum: comparative determinations of glutamate dehydrogenase and mitochondrial aspartate aminotransferase in healthy persons and patients with chronic liver diseases. Clin Chem 31, 239-243 (1985).

35 Riedl, J. M. et al. The AST/ALT (De Ritis) ratio predicts clinical outcome in patients with pancreatic cancer treated with first-line nab-paclitaxel and gemcitabine: post hoc analysis of an Austrian multicenter, noninterventional study. Ther Adv Med Oncol 12, 1758835919900872, doi:10.1177/1758835919900872 (2020).

36 Wang, J. et al. Association between Alanine Aminotransferase/Aspartate Aminotransferase Ratio (AST/ALT Ratio) and Coronary Artery Injury in Children with Kawasaki Disease. Cardiol Res Pract 2020, 8743548, doi:10.1155/2020/8743548 (2020).

37 Global Surveillance for human infection with coronavirus disease (COVID-19), <WHO/2019-nCoV/SurveillanceGuidance/2020.6> (2020).

Table 1. Clinical characteristics of the included COVID-19 patients. Values are numbers (percentages) unless stated otherwise.

Characteristics	All patients (n=567)	AST/ALT < 2 (n=511)	AST/ALT ≥2 (n=56)	P Value
Age, median (IQR), years	55(37-67)	54(37-66)	65.5(41.25-74.5)	0.001*
Sex				0.306
Male	247(43.6)	219(42.9)	28(50)
Female	320(56.4)	292(57.1)	28(50)
Time
illness onset to hospital admission, median (IQR), days	7(4-10)	7(4-10)	7(5-9.8)	0.802
Signs and symptoms
Fever	455(80.2)	408(79.8)	47(83.9)	0.466
Myalgia	143(25.2)	127(24.9)	16(28.6)	0.543
Fatigue	208(36.7)	179(35)	29(51.8)	0.014*
Headache	36(6.3)	33(6.5)	3(5.4)	0.97
Cough	370(65.3)	330(64.6)	40(71.4)	0.307
Chest tightness	222(39.2)	196(38.4)	26(46.4)	0.24
Chest pain	27(4.8)	26(5.1)	1(1.8)	0.441
Diarrhea	51(9)	48(9.4)	3(5.4)	0.316
Comorbidities
Any	250(44.1)	217(42.5)	33(58.9)	0.018*
COPD	36(6.3)	29(5.7)	7(12.5)	0.089
Hypertension	183(32.3)	162(31.7)	21(37.5)	0.378
Diabetes	85(15)	77(15.1)	8(14.3)	0.876
Cardiovascular disease	53(9.3)	39(7.6)	14(25)	<0.001*
Cerebrovascular disease	32(5.6)	23(4.5)	9(16.1)	0.001*
Chronic kidney disease	31(5.5)	24(4.7)	7(12.5)	0.033*
Outcomes
Recovery and Discharge	490(86.4)	456(89.2)	34(60.7)	<0.001*
Death	65(11.5)	46(9)	19(33.9)	<0.001*
Transfer to specialized hospitals	12(2.1)	9(1.8)	3(5.4)	0.198

*: A two-tailed P value less than 0.05 was considered statistically significant.

Table 2. Chest CT findings, laboratory results and severity of illness scores of COVID-19 patients on admission. Values are medians (interquartile ranges) unless stated otherwise.

	All patients (n=567)	AST/ALT < 2 (n=511)	AST/ALT ≥ 2 (n=56)	P Value
Chest CT, numbers (percentages)
lesions occupy <30% lung	309/554(55.8)	282(55.2)	26(46.4)	0.212
lesions occupy 30%-60% lung	115/554(20.8)	108(21.1)	7(12.5)	0.127
lesions occupy >60% lung	130/554(23.5)	111(21.7)	19(33.9)	0.039*
Laboratory findings
White blood cell count, ×109/L	4.9(3.7-6.5)	4.9(3.8-6.4)	4.8(3.5-6.8)	0.964
Neutrophil count, ×109/L	3.2(2.2-4.7)	3.2(2.2-4.7)	3.6(2.2-5.1)	0.294
Lymphocyte count, ×109/L	1(0.7-1.4)	1.1(0.7-1.4)	0.8(0.5-1.1)	0.001*
Hemoglobin, g/L	128(119.8-140)	129(121-140.3)	123(109.3-133.8)	0.006*
Platelet count, ×109/L	178(134-225)	181(139-227.3)	149(100.5-205.3)	0.001*
Total bilirubin, μmol/L	8.5(6.4-11.9)	8.7(6.5-11.9)	7.7(5.4-11.4)	0.047*
Blood urea nitrogen, mmol/L	4.1(3.2-5.4)	4(3.2-5.3)	4.8(3.3-6.9)	0.02*
Creatinine, μmol/L	64.4(51.8-78.1)	63.8(51.5-77.4)	71.7(58.7-88.7)	0.023*
Lactate dehydrogenase, U/L ¶	188(150.3-251.8)	186(150-243.5)	221(165-375)	0.005*
Creatinine kinase, U/L ¶	77(48-139)	76(48-131)	103(45-248)	0.091
Creatine kinase–MB, U/L §	8(6-12)	8(6-11.25)	10(6.5-15.1)	0.008*
C-reactive protein, mg/dL	1.6(0.4-4.4)	1.4(0.4-4.1)	4.4(0.7-7.4)	0.001*
Procalcitonin, ng/mL †	0.05(0.04-0.09)	0.05(0.04-0.08)	0.08(0.05-0.27)	0.001*
IL-6 pg/mL ‡	4.7(2.3-17.9)	4.1(2.2-13.5)	12.4(2.8-38.5)	0.08*
D-dimer, μg/mL	0.5(0.3-1.1)	0.5(0.2-1)	0.9(0.4-1.9)	0.001*
Fibronectin g/L	3(2.5-3.5)	2.9(2.5-3.5)	3.1(2.6-3.6)	0.221
Lactate, mmol/L	1.2(0.8-1.9)	1.05(0.7-1.4)	1.25(0.8-2)	0.262
PaO₂/FiO₂, mm Hg	363(243-520)	393(256-520)	254.5(172.5-420)	<0.001*
Severity of illness scores
APACHE II	3(1-5)	3(1-5)	5(2-10)	<0.001*
SOFA	1(0-3)	1(0-2)	3(1-4)	<0.001*
CURB65	0(0-1)	0(0-1)	1(0-2)	<0.001*

*: A two-tailed P value less than 0.05 was considered statistically significant.

Missing data for over 5% of patients are indicated:

¶: Data on LDH and creatine kinase were missing for 47 patients (8.3%), including 42 patients with AST/ALT < 2 (8.2%) and 5 patients with AST/ALT ≥ 2 (8.9%).

§: Data on creatine kinase-MB were missing for 42 patients (7.4%), including 39 patients with AST/ALT < 2 (7.6%) and 3 patients with AST/ALT ≥ 2 (5.4%).

†: Data on procalcitonin were missing for 45 patients (7.9%), including 40 patients with AST/ALT < 2 (7.8%) and 5 patients with AST/ALT ≥ 2(8.9%).

‡: Data on creatine IL-6 were missing for 413 patients (72.8%), including 378 patients with AST/ALT < 2 (74%) and 35 patients with AST/ALT ≥ 2 (62.5%).

Table 3. Multivariate analysis of AST/ALT ≥ 2.

Laboratory Parameters	Multivariable OR (95% CI)	P Value
Lymphocyte count	0.95(0.532-1.694)	0.861
Hemoglobin	0.992(0.975-1.01)	0.4
Platelet count	0.989(0.983-0.996)	0.001*
Total bilirubin	0.941(0.869-1.02)	0.14
Blood urea nitrogen	0.999(0.881-1.133)	0.987
Creatinine	0.999(0.995-1.003)	0.552
Lactate dehydrogenase	1.002(0.999-1.005)	0.133
Creatine kinase–MB	1.012(0.991-1.033)	0.28
C-reactive protein	0.995(0.894-1.109)	0.933
Procalcitonin	1.795(0.447-7.207)	0.409
D-dimer	1.048(0.983-1.116)	0.149
PaO2/FiO2	0.999(0.996-1.002)	0.44

*: A two-tailed P value less than 0.05 was considered statistically significant.

Table 4. Univariate and multivariate analysis on poor prognosis.

Biochemical parameters	Univariate analysis		Selection process of variables			Multivariate analysis
Biochemical parameters	OR	P Value	VIF	Correlation coefficient	P Value	OR	P Value
Liver
AST	1.01(1-1.02)	0.015*	6.4	--	--	0.97(0.92-1.03)	0.311
ALT	0.99(0.98-1)	0.182	5.5	--	--
AST/ALT	3.36(2.23-5.05)	<0.001*	3.2	--	--	22.02(1.84-263.2)	0.015*
Total bilirubin	1.06(1.02-1.1)	0.004*	1.2	--	--	0.98(0.89-1.09)	0.726
Kidney
Blood urea nitrogen	1,13(1.08-1.18)	<0.001*	8.2	0.31	<0.001*	1.35(0.97-1.89)	0.075
Creatinine	1.002(1.001-1.003)	<0.001*	8.6	0.24	<0.001*	--	--
Heart
Lactate dehydrogenase	1.009(1.006-1.011)	<0.001*	3.4	--	--	1.02(1-1.03)	0.037*
Creatinine kinase	1.001(1-1.002)	0.012*	1.7	--	--	1(1-1.01)	0.061
Creatine kinase–MB	1.005(1.02-1.09)	0.002*	1.6	--	--	0.83(0.63-1.09)	0.181
Blood
White blood cell count	1.157(1.08-1.24)	<0.001*	18.8	0.1	0.015*
Neutrophil count	1.22(1.13-1.31)	<0.001*	18.4	0.17	<0.001*	0.56(0.27-1.16)	0.116
Lymphocyte count	0.2(0.11-0.38)	<0.001*	2.8	--	--	0.17(0.02-1.77)	0.137
Hemoglobin	0.98(0.97-0.99)	0.003*	1.3	--	--	0.94(0.88-1.01)	0.07
Platelet count	0.99(0.98-0.99)	<0.001*	1.7	--	--	1.01(0.99-1.03)	0.359
Microcirculation dysfunction
Lactate	2.38(1.83-3.1)	<0.001*	1.6	--	--	12.04(2.22-65.21)	0.004*
D-dimer	1.02(1-1.04)	0.024*	1.4	--	--	0.99(0.96-1.03)	0.671
Fibrinogen	1.47(1.12-1.93)	0.005*	1.8	--	--	1.48(0.48-4.53)	0.493
Systematic inflammation
IL-6	1.04(1.02-1.06)	<0.001*	1.6	--	--	1.05(1.02-1.09)	0.005*
C-reactive protein	1.23(1.17-1.31)	<0.001*	2.7	--	--	0.82(0.6-1.11)	0.187
Procalcitonin	60.1(15.45-233.9)	<0.001*	2.4	--	--	1.17(0.04-31.42)	0.927

Poor prognosis includes death and transfer to specialized hospitals for extremely critical COVID-19 patients.

#: Variance inflation factor (VIF) > 5 was considered collinearity.

*: A two-tailed P value less than 0.05 was considered statistically significant.

Table 5. Univariate analysis of the AST/ALT ratio on poor prognosis in the two groups of patients. Values are numbers (percentages) unless stated otherwise.

Patients with normal AST levels (n=460)

Patients with AST > 40 U/L (n=107)

Outcomes

AST/ALT < 2

(n=420)

AST/ALT ≥ 2

(n=40)

P

Value

OR

(95% CI)

AST/ALT < 2

(n=91)

AST/ALT ≥2

(n=16)

P

Value

OR

(95% CI)

Poor

prognosis

42(10)

11(27.5)

0.002

*

3.4

(1.6-7.4)

13(14.3)

11(68.75)

<0.001

*

13.2

(3.9-43.5)

Recovery

and Discharge

378(90)

29(72.5)

78(85.7)

5(31.25)

Poor prognosis includes death and transfer to specialized hospitals for extremely critical COVID-19 patients.

*: A two-tailed P value less than 0.05 was considered statistically significant.

High Aspartate Aminotransferase to Alanine Aminotransferase Ratio on Admission as Risk Factor for Poor Prognosis in COVID-19 Patients

Status:

Journal Publication

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Abstract

Figures

Introduction

results

Discussion

methods

Abbreviations

Declarations

references

tables

Status:

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