Ursodeoxycholic acid for coronavirus disease 2019 prevention.

Dear Editor, The novel coronavirus disease 2019 (COVID-19) has had a tremendous impact worldwide [1]. Although the management of COVID-19 has improved, the chemoprevention of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection remains a challenge. In 2022, the potential of ursodeoxycholic acid (UDCA) against COVID-19 was first reported [2]. Furthermore, the association of UDCA with a decrease in SARS-CoV-2 infection and reduction in symptomatic COVID-19 was retrospectively demonstrated [3]. These reports suggested the utility of UDCA in preventing COVID-19. However, the Omicron variant—predominant since early 2022—causes milder disease, including asymptomatic infection, compared to previously predominant variants [4]. If the infected patients had no or mild symptoms, they might not have tested for COVID-19; therefore, they might be unaware of their infection. A more objective evaluation of infection proportions in a cross-sectional cohort is needed to accurately evaluate the preventive ability. Here, we cross-sectionally examined the impact of UDCA on SARS-CoV-2 infection in early 2023. The infection was defined based on medical interviews and SARS-CoV-2 immunoglobulin G against the nucleocapsid protein (IgG-N), which could detect the previous SARS-CoV-2 infection regardless of vaccination [5]. The cutoff value for IgG-N was set at 5 AU/mL [6], which identifies infections for approximately 1 year (unpublished data), covering the Omicron variant–dominant period in Japan. Subclinical infection was defined as IgG-N positivity without interview-based infection. Outpatients attending the Department of Gastroenterology at The University of Tokyo Hospital between January 1, 2023, and February 10, 2023, were included (Fig. S1). The UDCA treatment group was compared with patients without a history of UDCA prescription (non-UDCA group) and patients with viral hepatitis without a history of UDCA prescription (non-UDCA viral hepatitis group). Age, sex, and the number of vaccinations were matched using propensity score-matching (PSM) analysis (nearest-neighbor matching at a ratio of 1:1 was performed using a caliper of 0.1). The study protocol was approved by the Research Ethics Committee of the Faculty of Medicine at the University of Tokyo (approval number:2019300NI-4-(3)). Informed consent was obtained through an opt-out form. In the entire cohort, the SARS-CoV-2 infection proportion was not significantly different between the UDCA and non-UDCA groups (Fig. 1A and Table S1). The UDCA group tended to be older and had a higher proportion of women, while the vaccination status was similar. After PSM, there was no difference in the SARS-CoV-2 infection proportion between the two groups; however, the subclinical infection proportion tended to be higher in the UDCA group than non-UDCA group (Fig. 1B and Table S1). Between the UDCA and non-UDCA viral hepatitis groups, the SARS-CoV-2 infection proportion was not significantly different in the entire cohort (Fig. 1A and Table S2). Background factors were similar, except the proportion of women was higher in the UDCA group. After PSM, there was no difference in the SARS-CoV-2 infection proportion between the two groups; however, the subclinical infection proportion tended to be higher in the UDCA group than in the non-UDCA viral hepatitis group (Fig. 1C and Table S2). In this cross-sectional study, the SARS-CoV-2 infection proportion in patients with UDCA was not significantly different compared with patients without UDCA. We further compared the proportion with non-UDCA-treated patients with viral hepatitis. However, the infection proportions were similar between the groups. These results suggest that UDCA may be insufficient to prevent COVID-19. Interestingly, in the PSM analysis, the proportion of subclinical infection was higher in the UDCA treatment group than in the other two groups. These results suggest UDCA treatment reduces the severity of COVID-19, thereby reducing the likelihood of patient awareness of the infection. Notably, in non-vaccinated persons—in which the effects of UDCA might be more directly reflected—the UDCA group had a lower proportion of interview-based infection (Table S3). These results are consistent with a previous study identifying a correlation between UDCA treatment and favorable clinical outcomes of COVID-19. This study has several limitations. First, because the study was a single-center experience, a multicenter study with larger participants would be needed. Second, regarding the interview-based data, it was not mandatory to confirm test results or certificates of the SARS-CoV-2 infection considering clinical situations during the COVID-19 pandemic. Finally, the severity of COVID-19 was not accurately obtained through a medical interview. Considering these limitations and that the subjects were limited to patients attending a university hospital, careful consideration is required when applying to other populations. In conclusion, UDCA might be insufficient for preventing SARS-CoV-2 infection but might be effective in reducing COVID-19 severity. Further studies on the chemoprevention of COVID-19 using UDCA or its derivatives are warranted. All authors contributed to the study design and interpretation of data. Kazuya Okushin and Takeya Tsutsumi contributed to the study conception. Kazuya Okushin, the UTH-UDCA Study Group, and Mitsuhiro Fujishiro contributed to the data acquisition. Makoto Kurano and the UTH-UDCA Study Group contributed to the laboratory tests. Kazuya Okushin, Makoto Kurano, and Takeya Tsutsumi drafted the manuscript, and all authors revised it critically for important intellectual content. All authors approved the final manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The authors sincerely acknowledge the cooperation from The UTH-UDCA Study Group that includes Ryosuke Tateishi, Yousuke Nakai, Yosuke Tsuji, Yoku Hayakawa, Tatsuya Minami, Hideaki Ijichi, Nobumi Suzuki, Masaya Sato, Ryota Takahashi, Yoshiki Sakaguchi, Takuma Nakatsuka, Naminatsu Takahara, Tomoharu Yamada, Tsuyoshi Hamada, Akira Kado, Rin Yokoyama, Yuki Nakano, Naru Nakatsuka, Keisuke Murayama, Sohei Harada, Nobuhiko Satoh, Daisuke Ohki, Mayo Tsuboi, Ryu Yoneda, Kazuhiko Ohe, and Yosui Sato. This work was partly supported by the Nakatani Foundation. The funder played no role in the study design, data collection or analysis, decision to publish, or manuscript preparation. The authors declare no conflicts of interest for this article. Nakatani Foundation Supplementary Table 1 Characteristics and SARS-CoV-2 infection proportion of UDCA group and no-UDCA group Supplementary Table 2 Characteristics and SARS-CoV-2 infection proportion of UDCA group and no-UDCA viral hepatitis group Supplementary Table 3 SARS-CoV-2 infection proportion of UDCA group, no-UDCA group, and no-UDCA viral hepatitis group among non-vaccinated persons Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.