Impact of ursodeoxycholic acid therapy in autoimmune liver disease patients with COVID-19 and its clinical prognosis

Highlights

• •Scientific question: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which presents with multiple clinical features. The relation between SARS-CoV-2 infection and autoimmune liver disease (AILD) remains unclear.
• •Evidence before this study: Patients with stable chronic liver diseases such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), or PSC are more susceptible to SARS-CoV-2 infection. Researchers from the University of Cambridge published a novel finding in Nature demonstrating that ursodeoxycholic acid (UDCA) could inhibit ACE2 receptor expression, thus reducing SARS-CoV-2 infection.
• •New findings: UDCA is associated with low SARS-CoV-2 incidence in AILD patients, while immunosuppressant increases its incidence instead. Patients receiving UDCA treatment have a longer recovery time after being infected.
• •Significance of the study: Our study on AILD patients with SARS-CoV-2 infection suggests that the utilization of UDCA might reduce the occurrence of SARS-CoV-2 infection in AILD patients, thereby providing a foundation for preventive and therapeutic strategies involving concurrent use of UDCA treatment.

Abstract

To explore the impact of ursodeoxycholic acid (UDCA) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and clinical outcomes in patients with autoimmune liver disease (AILD). Patients diagnosed with AILD were enrolled and divided into a UDCA group and a non-UDCA group based on whether they received UDCA treatment. Relevant data were collected regarding AILD diagnosis, treatment, biochemical indicators, and imaging examination. The incidence of SARS-CoV-2 infection and the prognosis of AILD patients were observed. A total of 1,138 patients completed follow-up. The usage rate of hormone (P = 0.003) and immunosuppressant (P = 0.001) used for treating AILD in the non-UDCA group was markedly lower than in the UDCA group. The UDCA usage rate was markedly lower in SARS-CoV-2 infected patients than in uninfected patients (P = 0.003). The rate of SARS-CoV-2 infection in the non-UDCA group was significantly higher than in the UDCA group (P = 0.018). Logistic regression analysis showed that UDCA use (P = 0.003) was correlated to a lower incidence of SARS-CoV-2, while immunosuppressant use (P = 0.017) increased the incidence. Recovery time from SARS-CoV-2 infection was markedly longer for those receiving UDCA treatment than those in the non-UDCA group (P = 0.018). UDCA is associated with low SARS-CoV-2 incidence in AILD patients, while immunosuppressant increases its incidence instead. Patients receiving UDCA treatment have a longer recovery time after being infected.

1. Introduction

Autoimmune liver disease (AILD) is a kind of chronic liver disease caused by immune dysfunction in humans, mainly consisting of primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome [1], [2]. Treatment often requires immunosuppressive drugs, glucocorticoids, and ursodeoxycholic acid (UDCA) [1], [2]. The clinical curative effect of UDCA on PBC has been investigated in multiple clinical trials, and PBC patients receiving UDCA therapy have better survival rates [3], [4]. The American Association for the Study of Hepatology [5] and the European Guidelines for the Study of Hepatology [6] recommend UDCA as first-line therapy for all patients with PBC.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which presents with multiple clinical features. Although lung manifestations are the most common, liver lesions will occur in up to 50 % of infected individuals [7]. The etiopathogenesis of SARS-CoV-2 mediated liver damage may be attributed to the angiotensin-converting enzyme 2 (ACE2) receptors expression in hepatic cells and bile duct cells. Nevertheless, the expression of ACE2 receptors in hepatic cells is markedly lower than that in bile duct cells [8]. Therefore, the liver damage caused by COVID-19 may result in direct viral injury to bile duct epithelial cells, which play a crucial effect on liver regeneration and immune response [9]. Patients with stable chronic liver diseases such as AIH, PBC, or PSC are more susceptible to SARS-CoV-2 infection [7]. According to the latest update report of the international registry of SARS-CoV-2-infected patients with chronic liver disease (SECURE CARROSIS and COVID Hep) in 2020, approximately 7 % of cirrhosis cases were attributed to AIH [10], [11].

Recently, researchers from the University of Cambridge published a novel finding in Nature demonstrating that UDCA could inhibit ACE2 receptor expression, thus reducing SARS-CoV-2 infection [12]. However, the relation between SARS-CoV-2 infection and AILD remains unclear. No existing literature reports whether UDCA usage in patients with AILD can reduce the SARS-CoV-2 infection rate and improve the clinical outcomes after viral infection. This study aims to investigate whether UDCA treatment can effectively lower the SARS-CoV-2 infection rate or mitigate disease progression in AILD patients in real-world clinical settings.

2. Materials and methods

2.1. Research participants

This study was an investigative telephone follow-up study. Patients enrolled in this study visited Beijing Ditan Hospital between January 2022 and January 2023. Inclusion criteria included: 1. Meeting the definition of AILD. 2. Being over 18 years old. 3. Those who have not received UDCA therapy for at least 12 weeks or who did not receive UDCA therapy. Exclusive criteria consisted of: (1) Patients with decompensated liver cirrhosis; (2) Co-infection with other viruses such as hepatitis A virus, HIV, CMV, hepatitis B virus, hepatitis D virus, and hepatitis C virus; (3) Presence of severe mental and physical diseases consisting of uncontrolled primary kidney, heart, lung, vascular, nervous, digestive, and metabolic severe diseases, and immune deficiency, etc.; (4) With malignant tumors or a history of thereof.

2.2. Definition

The definition of SARS-CoV-2 infection was based on positive detection of SARS-CoV-2 nucleic acid or antigen, with or without confirmation through clinical and imaging examinations.

2.3. Data collection

After enrollment, patient demography data, AILD therapy information, including UDCA medication and usage of corticosteroids and immunosuppressants, SARS-CoV-2 vaccination status, and the incidence of SARS-CoV-2 infection were collected. Meanwhile, we gathered biochemical markers, pulmonary imaging results, SARS-CoV-2 nucleic acid and antigen test results, clinical symptoms, and examination data for other organs. The SARS-CoV-2 infected patients were monitored for body temperature, clinical symptoms/signs, cardiac examination, pulmonary imaging, biochemical indicators, and blood routine tests. The severity of SARS-CoV-2 infection and negative time to conversion from positive to negative on SARS-CoV-2 nucleic acid and antigen test, hospitalization duration, and clinical outcome were recorded.

2.4. Statistical analysis methods

Data was analyzed using IBM SPSS statistics 26.0 (SPSS Inc., Chicago, USA) and Microsoft Excel 15.19.1. The categorical variable was described as a percentage, and the Chi-squared test assessed the difference between groups. For continuous variables following a normal distribution, mean ± standard deviation (mean ± SD) was described, and an independent sample t-test was used to compare differences between groups. Non-normally distributed variables were described with the median (Quartile 25, 75), and the difference between the two groups was compared using the Mann-Whitney U test. The univariable and multivariable logistic regression analyses were conducted to identify independent influencing factors associated with COVID-19 infection, while the odds ratio (OR) and 95 % confidence interval (CI) were calculated. All tests were conducted using a bilateral test, and P < 0.05 was statistically significant.

3. Results

3.1. Clinical characteristics of patients with autoimmune liver disease

Patients with AILD treated in Beijing Ditan Hospital from January 2022 to January 2023 were screened and followed up. A total of 1,184 patients were collected, of which 46 (3.89 %) were lost to follow-up, leaving a final enrollment of 1,138 patients (Fig. 1), including 254 males and 884 females with an average age of 57.94 ± 12.15 years old. Based on whether they had taken UDCA treatment for at least 12 weeks, patients were divided into the UDCA group 62.04 % (706) and the non-UDCA group 37.96 % (432). The proportion of female patients in the UDCA and non-UDCA groups was dramatically higher than that of male patients (P < 0.001). The age in the UDCA group was significantly higher than that in the non-UDCA group (P = 0.022) (Table 1). The overall vaccination rate of SARS-CoV-2 was 66.96 %, and the vaccination rate of SARS-CoV-2 in the UDCA group was significantly higher than that in the non-UDCA group (62.89 % vs 73.61 %, P = 0.000) (Table 1). The utilization rate of hormone and immunosuppressant therapy among all AILD patients was 10.90 % and 4.48 %, respectively; however, the utilization rates of hormone (13.03 % vs. 7.41 %, P = 0.003) and immunosuppressant (6.09 % vs. 1.85 %, P = 0.001) were dramatically higher than those in the non-UDCA group (Table 1).

Fig. 1.

The flow chart of patients' enrollment and follow-up. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; UDCA, ursodeoxycholic acid.

Table 1.

Clinical characteristics of 1,138 patients with autoimmune liver disease.

Item	All patients (n = 1,138)	UDCA group (n = 706)	Non-UDCA group (n = 432)	Test of significance
Female*	884 (77.68)	587 (83.14)	297 (68.75)	χ2 = 32.028; P = 0.000
Age, years**	57.94 ± 12.15	58.59 ± 11.34	56.89 ± 13.33	t = 2.289; P = 0.022
SARS-CoV-2 vaccination	762 (66.96)	444 (62.89)	318 (73.61)	χ2 = 13.925; P = 0.000
Usage rate of hormones, %	10.90	13.03	7.41	χ2 = 8.730; P = 0.003
Usage rate of immunosuppressant, %	4.48	6.09	1.85	χ2 = 11.249; P = 0.001

Abbreviations: UDCA, ursodeoxycholic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^*Numbers without parentheses are the number of people. Numbers in the parentheses are percentages (%).

^**Ages are indicated as “mean ± standard deviation”.

3.2. Occurrence of SARS-CoV-2 infection in AILD patients

The overall infection rate was 80.93 %. There was no significant difference in the sex distribution between uninfected and infected patients (P = 0.178), but the average age of uninfected patients was markedly older than that of infected patients (P < 0.001). The SARS-CoV-2 vaccination rate was similar between uninfected and infected patients (P = 0.070), and the utilization rate of UDCA in infected patients was dramatically lower than in uninfected patients (P = 0.003) (Table 2).

Table 2.

Clinical characteristics and factor analysis of all patients with SARS-CoV-2 infection.

Item	Group of patients			Univariate logistic regression		Multivariable logistic regression
	Infected patients(n=921)	Uninfected patients(n=217)	Test of significance	OR (95% CI)	P value	OR (95% CI)	P value
Female*	708 (76.87)	176 (81.11)	χ2 = 1.815; P = 0.178	0.774 (0.533–1.124)	0.179	_	_
Age, years**	57.10 ± 11.98	61.51 ± 12.26	t = 4.585; P = 0.000	0.972 (0.959–0.986)	0.000	0.970 (0.957–0.983)	0.000
SARS-CoV-2 vaccination*	628 (68.19)	134 (61.75)	χ2 = 3.283; P = 0.070	1.348 (0.991–1.832)	0.057	_	_
Usage rate of UDCA, %	59.93	70.97	χ2 = 9.077; P = 0.003	0.622 (0.447–0.866)	0.005	0.605 (0.437–0.838)	0.003
Usage rate of hormones, %	11.62	7.83	χ2 = 2.590; P = 0.108	1.546 (0.906–2.639)	0.110	_	_
Usage rate of immunosuppressant, %	5.21	1.38	χ2 = 6.016; P = 0.014	3.822 (1.127–12.960)	0.031	4.228 (1.295–13.810)	0.017

“_” indicates that the variable was not included in multivariable logistic regression analysis.

Abbreviations: UDCA, ursodeoxycholic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; OR, odds ratio; CI, confidence interval.

^*Numbers without parentheses are the number of people. Numbers in the parentheses are percentages (%).

^**Age is indicated as “mean ± standard deviation”.

Furthermore, the rate of SARS-CoV-2 infection in the UDCA group was significantly lower than that in the non-UDCA group (73.65 % vs. 85.42 %, χ² = 9.007, P = 0.003) (Fig. 2). Among patients using hormones and immunosuppressants for treating AILD, there was no significant difference in hormone use rate between uninfected and infected patients (P = 0.108), but the use rate of immunosuppressant in uninfected patients was markedly lower compared to infected patients (P = 0.014) (Table 2). Logistic regression analysis revealed that age (P = 0.000) and UDCA usage (P = 0.003) were associated with a reduced incidence of SARS-CoV-2 infection, while immunosuppressant usage was associated with an increased incidence of SARS-CoV-2 infection (P = 0.017) (Table 2).

Fig. 2.

The rate of SARS-CoV-2 infection in UDCA group and Non-UDCA group. Abbreviations: UDCA, ursodeoxycholic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

3.3. Clinical outcomes of COVID-19 infection in patients with or without UDCA therapy

The proportion of female COVID-19 infection patients in the UDCA and non-UDCA groups was higher than that of male patients (P < 0.001). COVID-19 patients’ age in the non-UDCA group was markedly lower than in the UDCA group (P = 0.006). The recovery time for SARS-CoV-2 infection in patients with UDCA therapy was markedly more prolonged than in patients without UDCA therapy (P = 0.018) (Table 3). However, there was no significant difference between the two groups regarding remission time of SARS-CoV-2 infection symptoms (P = 0.787), hospitalization rate (P = 0.699), and hospitalization time (P = 0.475) (Table 3). Most infected patients experienced mild symptoms in both groups, but there was no significant difference in disease severity after infection (χ² = 5.213; P = 0.074) (Fig. 3).

Table 3.

Clinical characteristics of SARS-CoV-2 infection patients with and without UDCA therapy.

Item	UDCA group (n = 552)	Non-UDCA group (n = 369)	Test of significance
Female*	457 (82.79)	251 (68.02)	χ2 = 27.131; P = 0.000
Age, years**	57.98 ± 11.22	55.79 ± 12.95	t = 2.731; P = 0.006
Infection recovery time, days**	9.57 ± 6.58	8.56 ± 5.68	t = 2.372; P = 0.018
Remission time of infection symptoms, days**	7.11 ± 5.59	7.01 ± 5.59	t = 0.270; P = 0.787
Hospitalization rate, %	3.44	2.98	χ2 = 0.149; P = 0.699
Hospitalization time, days (95% CI)	13.00 (6.00 − 15.00)	7.00 (3.00 − 20.00)	Z = −0.715; P = 0.475
Mortality, %	0.00	0.00

Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; UDCA, ursodeoxycholic acid; CI, confidence interval.

^*Numbers without parentheses are the number of people; Numbers in the parentheses are percentages (%).

^**These factors are indicated as “mean ± standard deviation”.

Fig. 3.

Comparison of the severity of SARS-CoV-2 infection between UDCA group and non-UDCA group. Abbreviations: UDCA, ursodeoxycholic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

No notable difference existed between the SARS-CoV-2 vaccine coverage rate of infected and uninfected patients receiving UDCA therapy (χ² = 2.787; P = 0.095) (Fig. 4). Regardless of whether treated with UDCA, no deaths occurred among COVID-19 patients, and clinical outcomes demonstrated an improving trend.

Fig. 4.

The SARS-CoV-2 vaccination rate of infected and non-infected patients in UDCA group. Abbreviations: UDCA, ursodeoxycholic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

4. Discussion

The dissemination of SARS-CoV-2 worldwide has resulted in the widespread occurrence of SARS-CoV-2 infection, which has profoundly impacted global public health [13]. AILD is a particular type of chronic liver disease caused by human immune dysfunction. Effective treatment strategies primarily focus on drugs that ameliorate cholestasis, such as UDCA. Previous studies on AILD patients infected with SARS‐CoV‐2 have been limited to a minority of patients in European regions like Belgium and Italy [14], [15], [16]. To the best of our knowledge, the actual effect of SARS-CoV-2 infection on AILD patients has not been sufficiently elucidated [17]. Notably, one research demonstrated that UDCA could suppress ACE2 receptor expression and consequently inhibit viral infection [12]. However, there are few reports regarding the effect of UDCA usage on SARS-CoV-2 infection among AILD patients. It is unclear whether UDCA has the potential to reduce SARS-CoV-2 infection rate or disease severity during clinical management.

SARS-CoV-2 infection presented multiple clinical features. The innate immune was the first line of defense against SARS-CoV-2 infection [18]. Research progress in small molecule drugs, monoclonal antibodies, and rapid virus detection was vital for treating COVID-19 [19]. UDCA is recommended as the first-line therapy for AILD. In our study, patients treated with UDCA had a notably higher average age than those without UDCA therapy, consistent with previous studies that elderly patients often have less symptomatic at presentation but show great response to treatment once symptoms appear [20], [21], [22]. Some studies suggested that combining azathioprine and corticosteroids may reduce the cumulative steroid-induced side effects. This combined therapy has resulted in high response rates in PBC patients with features of AIH, and these patients may benefit from such combined therapy [23], [24], [25]. Our results indicated that the inoculation rate of the SARS-CoV-2 vaccine, hormone use rate, and immunosuppressant use rate of patients receiving UDCA treatment were markedly higher than those of patients not receiving it, which may be attributed to more pronounced cholestasis or significant liver lesions in patients receiving UDCA treatment, while patients not receiving it might experience good efficacy through liver protective drugs without using hormones or other immunosuppressive agents.

This study analyzed the clinical features and factor analysis of all AILD patients with SARS-CoV-2 infection. The results indicated that uninfected patients’ age was markedly higher than infected patients, suggesting a potential correlation to older adults going out less during the epidemic period. The utilization rate of UDCA in uninfected patients was significantly higher than that in SARS-CoV-2 infected patients, while the rate of SARS-CoV-2 infection in patients with UDCA therapy was markedly lower than that in patients without UDCA therapy. Logistic regression analysis also demonstrated that UDCA usage was correlated to a decreased risk of SARS-CoV-2 infection among AILD patients, suggesting that incorporating UDCA into the clinical treatment practice of patients with AILD may help reduce the infection rate of SARS-CoV-2 by potentially inhibiting ACE2 receptor expression [12].

Additionally, it was observed that uninfected patients had a markedly lower usage rate of immunosuppressants compared to infected patients. The usage of immunosuppressants appeared to be associated with an increased risk for SARS-CoV-2 infection, possibly due to their impact on immune function suppression in patients caused by Immunosuppressive drugs [26]. However, some studies suggested that AILD patients infected with SARS-CoV-2 receiving immunosuppressant therapy may experience a similar disease course as non-immunosuppressive people [15], [27].

For patients with SARS-CoV-2 infection, our data showed that the infection recovery time in patients receiving UDCA therapy was significantly longer than that without UDCA therapy, which attributed to the severe illness and compromised physical condition of patients undergoing UDCA therapy, leading to an extended recovery time after SARS-CoV-2 infection, nevertheless, regardless of whether UDCA was taken. The severity of SARS-CoV-2 infection clinical outcomes were improved.

In summary, our study on AILD patients with SARS-CoV-2 infection suggests that the utilization of UDCA might reduce the occurrence of SARS-CoV-2 infection in AILD patients, thereby providing a foundation for preventive and therapeutic strategies involving concurrent use of UDCA treatment.

Ethics statement

The Ethics Committee of Beijing Ditan Hospital (NO. DTEC-KY2023-012-01) reviewed the research. The clinicaltrials.gov ID of this research was NCT05812612.

Acknowledgements

We are grateful to all the staff and patients involved in this research. This study was funded by the National Key Research and Development Program (2022YFC2603500, 2022YFC2603505), Beijing Municipal Health Commission high-level public health technical personnel construction project, discipline leader -03-26, Beijing Hospitals Authority Clinical medicine Development of special funding support (XMLX 202127), the capital health research and development of special public health project (2022-1-2172); The Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXZ0302).

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Author contributions

Minghui Li, Weihua Cao: Writing– original draft, Data curation, Writing– review & editing. Tingting Jiang, Wen Deng, Shiyu Wang, Xiaoyan Ding, Ge Shen: Data curation, Visualization, Investigation. Yuanjiao Gao, Hongxiao Hao, Xiaoxue Chen, Leiping Hu, Mengjiao Xu: Data curation, Supervision. Shuling Wu, Lu Zhang, Yao Lu, Min Chang, Ruyu Liu: Data curation, Software, Validation. Yuyong Jiang, Wei Yi, Rui Song: Conceptualization, Methodology, Software. Yao Xie: Conceptualization, Methodology, Software, Writing– review & editing.