The level of plasma C-reactive protein is closely related ...

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The level of plasma C-reactive protein is closely related to the liver injury in patients with COVID-19

Lu Li1,2#, Shuang Li3#, Manman Xu1,2, Sujun Zheng1,2, Zhongping Duan1,2, Yu Chen1,2*, Junfeng Li4*

1 Difficult & Complicated Liver Diseases and Artificial Liver Center, Beijing You'an Hospital, Capital Medical University, Beijing, China, 100069; &2 Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China, 100069; &3 Hemodialysis Room, Urinary Center, Beijing You'an Hospital, Capital Medical University, Beijing, China,100069; &4 Institute of Infectious Diseases, Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000,P.R. China

*Corresponding author: Yu Chen Difficult & complicated liver diseases and artificial liver center, Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China. E-mail: chybeyond@ Junfeng Li Institute of Infectious Diseases, Department of Infectious Diseases, The First Hospital of Lanzhou University, 1 Donggangxi Road, 730000, Lanzhou, China

Email junfenglee@ #Co-first authors

Lu Li and Shuang Li contributed equally to this work.

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

medRxiv preprint doi: ; this version posted March 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Abstract Aim: Coronavirus disease 2019 (COVID-19) has rapidly become the most severe public health issue all over the world. Despite acute respiratory failure, liver dysfunction has also been observed in clinical settings This study aimed to investigate the factors involved with hepatic injury in COVID-19 patients. Methods: A total of 26 hospitalized patients who were diagnosed with COVID-19 treated at Beijing You'an Hospital were retrospectively analyzed. According to the diagnostic criteria, they were divided into mild group (n=3), ordinary group (n=6), serious group (n=11) and critical group (n=6). Blood count, blood chemistry, coagulation test, liver and renal function, C-reactive protein, procalcitonin, lactic acid, cardiac markers and arterial partial pressure was compared between these groups. Independent risk factors of ALT increase was selected. Results: There were 8 patients with ALT elevation in the patients with COVID-19, accounting for 30.8% (8/26). There was no difference in sex ratio between normal and elevated ALT population, and there was an increasing trend in age. The CRP index was significantly higher in the population with elevated ALT, and the increase of CRP was independently related to ALT level, and the OR value was 1.023 (P = 0.024). Conclusions:

medRxiv preprint doi: ; this version posted March 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

COVID-19 related hepatic injury may be a result of cytokine storm syndrome, a positive correlative relationship between the increase of CRP and liver injury. Early detection and timely treatment of hepatic injury is necessary. Key word: Coronavirus disease 2019 (COVID-19), liver injury, Cytokine storm syndrome

Funding: National Key R&D Program of China No.2017YFA0103000 ; National

Science and Technology Key Project on "Major Infectious Diseases such as

HIV/AIDS, Viral Hepatitis Preventon and Treatment" NO. 2017ZX10203201-005 ;Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support NO.ZYLX201806

medRxiv preprint doi: ; this version posted March 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Introduction

Novel coronavirus pneumonia NCP is a newly emerging infectious disease caused

by a novel coronavirus mutant with outstanding symptoms of acute atypical pneumonia and pulmonary damage. Since December 2019, this new disease has rapidly become the most severe public health issue in China, threatening the overall health and socioeconomic well-being of our society1-4. Studies have shown that COVID-19, which belongs to the beta-coronavirus family, has distinct genetic differences from SARSr-CoV and MERSr-Cov5. In February 2020, the WHO announced the virus a novel coronavirus mutant and officially named it as coronavirus disease 2019 (COVID-19). Up until February 26th 2020, there have been 78,211 COVID-19 cases resulting in 2,720 deaths. Despite atypical pneumonia being the primary symptom, liver dysfunction has also been observed in clinical settings, indicating a possibility for COVID-19 to cause hepatic injury. However, the reason and mechanism behind the hepatic injury is still unclear. For the time being, there has been a lack of research regarding this issue and it remains controversial. Therefore, a more thorough investigation of the relationship between COVID-19 and hepatic injury is critical in terms of solving practical clinical problems as well as improving clinical treatment and cure rate. We selected the representative COVID-19 patients and focused on the characteristics of their hepatic injury and the possible influences from COVID-19, aiming to provide new clues and data for clinical diagnosis and treatment.

medRxiv preprint doi: ; this version posted March 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Methods

Patient selection For this retrospective, single-center study, we recruited 26 patients with COVID-19 from Jan 28 to Feb 22, 2020, at the You'an Hospital of Capital Medical University, Beijing, China. Diagnosis of COVID-19 and clinical classification according to the new coronavirus pneumonia diagnosis and treatment plan (trial version 6) developed by the National Health Committee of the People's Republic of China (). The clinical classifications are as follows: (1) mild, only mild symptoms, no sign of pneumonia in imaging. (2) ordinary, with fever, respiratory tract symptoms, and imaging shows pneumonia. (3) moderate, meet any of

the following: a) respiratory distress, respiratory rate 30 beats / min; b) in the resting state, means oxygen saturation 93%; c) arterial blood oxygen partial pressure/ oxygen concentration 300mmHg (1mmHg = 0.133kPa). Pulmonary imaging

showed that the lesions progressed more than 50% within 24-48 hours, and the patients were managed according to moderate case. (4) severe, one of the following conditions: a) respiratory failure occurs and requires mechanical ventilation; b) Shock occurs; c) ICU admission is required for combined organ failure. The research ethics was approved by the ethics committee of Beijing You'an Hospital of Capital Medical University(2020-022). Baseline data collection

medRxiv preprint doi: ; this version posted March 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Collect the laboratory data of 26 patients at admission. Laboratory assessments consisted of complete blood count, blood chemistry, coagulation test, liver and renal function, C-reactive protein, procalcitonin, lactic acid, cardiac markers, arterial partial pressure of oxygen and CT scan. Statistical analysis Age and days were represented by median (range), categorical variables by number (%), and laboratory data by mean (interquartile range). Compared the differences between the two groups with t-test, chi-square test or Mann-Whitney U test. logistic regression was used to select independent risk factors that affect ALT increase. Analyses were performed using SPSS 22.0 statistical package (SPSS, Inc., Chicago, IL, USA). P-value < 0.05 was considered statistically significant.

Results

Clinical characteristics of patients with COVID-19 The characteristics of patients with COVID-19 in the present study were shown in Table 1. The average age of the patients with COVID-19 was 65.81 years old, the sex ratio was similar. The average ALT value was 37.31U/L, and the AST level slightly increased. The average value of total bilirubin and direct bilirubin were in the normal range. The average level of creatinine was normal. C-reactive protein increased significantly, the average value of lymphocyte was close to the normal low value. The average value of creatine kinase was normal. In terms of clinical classification, the

medRxiv preprint doi: ; this version posted March 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

proportion of severe patients was 42.3%, followed by common and critical patients. At the same time, the patient had no history of liver disease.

Characteristics of liver injury in patients with COVID-19 The results were shown in Table 2. There were 8 patients with ALT elevation in the whole population, accounting for 30.8% (8/26). There was no difference in sex ratio between normal and elevated ALT population, and there was an increasing trend in age. The bilirubin level was normal between the two groups. However, the CRP index was significantly higher in the population with elevated ALT. At the same time, neutrophils also increased. There was no significant difference in clinical classification between the two groups, however, the results showed that the proportion of severe patients in the ALT increased group was higher, reaching 62.5%.

The factor related to ALT elevation in Multivariate analysis The CRP and neutrophils with significant differences in the univariate analysis were analyzed in logistic regression. It was found that the increase of CRP was independently related to ALT level, and the OR value was 1.023 (P = 0.024).

Discussion Our study reported on the factors involved with hepatic injury in COVID-19 patients. It was noticed for the first time that the injury was closely related to CRP, indicative of an inflammatory response. This discovery gave new evidence for the mechanism of COVID-19 patient's hepatic injury.

medRxiv preprint doi: ; this version posted March 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

As the number of patients diagnosed with COVID-19 infection continues to rise, it is apparent that, similar to SARS (Severe Acute Respiratory Syndrome), COVID-19 mainly causes pulmonary symptoms, but may simultaneously lead to the injury of non-pulmonary organs including the liver, kidneys and cardiac muscle6-9. A recent study published in The Lancet revealed that 43 out of 99 COVID-19 cases from the Wuhan Jinyintan Hospital had shown transaminase elevation (ALT or AST elevation), with one patient suffering severe hepatic injury (ALT 7590 U/L, AST 1445 U/L)6.

However no further research or explanation had been provided. The latest research

from the Liver Cancer Institute at Zhongshan Hospital of Fudan University has shown that bile duct cell has high specific expression of coronavirus receptor ACE-2 and low expression of hepatocytes, indicating the capability of COVID-19 to bind to ACE-2 positive bile duct cells directly, leading to the dysfunction of the bile duct, while biliary epithelial cell plays a key role in liver regeneration and immunoreaction7. Additionally, most scholars believe that cytokine storm syndrome (CCS) and drug-induced liver injury may be the main mechanism behind hepatic injury. The Lancet also recently published a case report authored by Dr. Fusheng Wang's team from the Fifth Medical Center of PLA General Hospital ( 302 Hospital ). On January 27 2020, Dr. Wang's team performed a pathological autopsy on a deceased COVID-19 patient. According to their report, the patient's liver biopsy specimen revealed medium microvascular lipoid degeneration and active inflammation in the

hepatic lobule portal area8. Due to the usage of interferon -2b, lopinavir/ritonavir on

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