In late 2019, multiple cases of novel viral pneumonia were reported in Wuhan City, China. Since then, the SARS-CoV-2 virus has spread rapidly, leading to the global COVID-19 pandemic (1), which has considerably affected patient health and health-care systems (2). SARS-CoV-2 is primarily transmitted through direct or indirect respiratory tract exposure (3). After binding to the angiotensin-converting enzyme 2 (ACE2) receptor on the respiratory epithelium, SARS-CoV-2 begins replicating, migrates down to the airway, and enters alveolar epithelial cells in the lungs, thus resulting in asymptomatic infection progressing to severe respiratory failure (3). Most unvaccinated patients develop asymptomatic, mild, or moderate COVID-19 infection. However, in some patients, epithelial cells in the respiratory tract stimulate immune cells, resulting in a cytokine storm, which is considered the leading cause of the severe clinical manifestation and mortality in patients with COVID-19 (4). To preserve medical capacity and reduce adverse health effects on individuals, preventing the progression of asymptomatic, mild, or moderate COVID-19 infection into severe COVID-19 is essential.

In January 2022, five SARS-CoV-2 variants have been designated as variants of concern (VOC) by the World Health Organization: Alpha, Beta, Gamma, Delta, and Omicron (5). The variants have been spread worldwide, and the dominant VOC have changed over time (5). Various possible mutation pathways of SARS-CoV-2 have been proposed, including ligand-receptor interactions, genomic alterations, lysosomal activity, recombination, conditional mutations, complementation, genetic robustness, and benign relationship (6). Global pandemic outbreaks and genome sequence profiles revealed that SARS-CoV-2 has a high mutation potential and high infectivity, enabling the virus to evolve resistance to newly developed therapeutic strategies rapidly (6). As the pandemic progressed, the mutation of the SARS-CoV-2 genome led to different clinical and socio-economical impacts, which observed dynamic risks of transmissibility, vaccine breakthrough infection, hospitalization, and critical condition (5).

Many COVID-19 vaccines have been proven to prevent hospitalization and mortality in adults (7). To date (January 19, 2022), 60.1% of the world population has received at least one dose of a COVID-19 vaccine. However, only 9.6% of people in low-income countries have received at least one dose (8). The BNT162b2 vaccine in 12-to-15-year-old recipients has been reported favorable safety and highly effective against COVID-19 (9). However, due to the limited information from short-term trials and high post-inoculation severe adverse effects and deaths, there are still concerns that lag the vaccination rate on children/adolescents (10).

In 2020, compared with most industrialized countries, Taiwan was not considerably affected by the COVID-19 pandemic, which can be attributed to rapid national border control, nonpharmaceutical interventions, and cooperation between the government and people (11, 12). However, an outbreak of the Alpha variant of SARS-CoV-2 occurred in mid-May 2021, at which point a relatively low proportion of individuals had received the vaccine (0.55 doses administered per 100 people) (13). Except for standard management, potential complementary therapies for preventing severe COVID-19 should be investigated.

Emerging evidence indicates that the combination of traditional Chinese medicine (TCM) and standard management may play a vital role in treating patients with COVID-19 (14–17). The findings of in vitro pharmacological assays demonstrated the efficacy of Taiwan Chingguan Yihau (NRICM101) in inhibiting the spike protein/ACE2 interaction, 3CL protease activity, viral plaque formation, and cytokine production (e.g., production of interleukin [IL]-6 and tumor necrosis factor [TNF]-α) (14). Because of its antiviral and anti-inflammatory effects, NRICM101 may be used to inhibit SARS-CoV-2 invasion and proliferation (14); however, the changes that can be achieved in clinical parameters and outcomes remain unclear. During the pandemic, the Chinese government recommended 6 TCM formulas, referred to as “3-drugs-3-formulas,” for treating SARS-CoV-2 infection (18). Five of the formulas were based on the core Maxing Shigan decoction, which possesses anti-inflammatory and antiviral properties (18). Studies have reported that TCM as an adjuvant therapy combined with conventional treatment may be effective and safe for treating mild-to-moderate COVID-19 (15–17). However, because most of the results have been reported as odds ratios, including the improvement rate of symptoms or lung images, quantification of the clinical effects is difficult.

Jing Si Herbal Tea (JSHT), a novel TCM formula, was developed to treat COVID-19. The ingredients of JSHT have been reported to exert anti-SARS-CoV-2, anti-inflammatory, and antithrombotic effects, thus targeting the main pathophysiological pathways in COVID-19 (14, 19–23). We hypothesized that JSHT effectively shortens the viral shedding duration and alleviates respiratory and systemic inflammation. This study analyzed the clinical efficacy and safety of JSHT in patients with mild-to-moderate COVID-19.

This is the first study to investigate the efficacy and safety of JSHT combined with standard management in patients with mild-to-moderate COVID-19. The results demonstrated that JSHT combined with standard management more effectively reduced the SARS-CoV-2 viral load and systemic inflammation and alleviated lung infiltrates in adult patients with mild-to-moderate COVID-19, especially in male and older patients (those aged ≥60 years). In addition, the patients treated with JSHT combined with standard management had 51, 30, and 100% lower risks of intubation, MICU admission, and mortality compared with the patients treated with standard management only. This finding indicates the potential of complementary JSHT treatment in preventing critical status and mortality.

The hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in COVID-19 (31). Increased IL-6 level is associated with COVID-19 severity and poor prognosis (32). Zhang et al. reported that an IL-6 concentration of >37.65 pg/mL was predictive of in-hospital death (33). Our findings revealed low IL-6 levels in both the JSHT and control groups before and after the study, indicating that the included patients with COVID-19 had relatively low disease severity and low mortality risk. IL-8 is a proinflammatory cytokine that may recruit neutrophils to the infected areas and is associated with tissue damage (34). Li et al. demonstrated that IL-8 is a sensitive biomarker in patients with mild or severe COVID-19, whereas IL-6 is a biomarker of severe COVID-19 (34). Ma et al. reported that patients with COVID-19 with a high IL-8 level (≥10.65 pg/mL) had a significantly longer illness duration than did those with a low IL-8 level (<10.65 pg/mL) (35). We observed low serum IL-8 levels in both the JSHT and control groups after the study. IL-10 has potent anti-inflammatory and immunosuppressive effects (31). An increase in the IL-10 level can be interpreted as an attempt to suppress hyperinflammation (36). However, a marked early increase in the level of the proinflammatory cytokine IL-10 may be associated with COVID-19 severity (37). Han et al. reported that IL-6 and IL-10 are disease severity predictors of COVID-19 (38). Our results revealed low serum IL-10 levels in both the JSHT and control groups after the study. Although CRP levels were more significantly improved in the JSHT group compared with the control group, no significant differences in changes in IL-6, IL-8, or IL-10 levels were observed between the groups. The multiple active ingredients of JSHT may exert an anti-inflammatory effect through multiple signaling pathways and thus contribute to reducing systemic inflammation.

JSHT potentially targeted 3 main pathophysiological pathways: anti-infective, anti-inflammation, and anti-thrombosis. HC, GG and PF exert an anti-infective effect against SARS-CoV-2 (14, 19, 39–41). The main protease (M^pro) of SARS-CoV-2 is a crucial enzyme of coronaviruses and plays a pivotal role in mediating viral replication and transcription (42). HC blocks binding between ACE2 and the spike protein of SARS-CoV-2 (14). Regarding the active ingredients of HC, 6-hydroxyondansetron has higher binding affinity toward 2 SARS-CoV-2 receptor proteins, namely M^pro and papain-like protease (PL^pro). In addition, quercitrin has been identified as another promising inhibitor because it exhibits the highest binding affinity toward the ADP ribose phosphatase of SARS-CoV-2 (19, 39). GG exerts an anti-infective effect (19). The main active ingredients of GG, glycyrrhizin, targeted the ACE2 receptor with structural affinity and prevented SARS-CoV-2 entry in silicon and docking studies (40, 41). Moreover, PF exerts an anti-infective effect and significantly reduced the pulmonary viral load (in vivo anti-SARS-CoV-2 assay) in a female golden Syrian hamster model (19).

HC, AA, AI, and PG exerts anti-inflammatory effects against pulmonary inflammation. The phytoconstituents of HC, including afzelin, hyperoside and, quercitrin, could reduce inflammation (43). HC extracts and the bioactive molecules in HC possess both anti-inflammatory and anti-oxidative properties (43). AA and its active compound, dehydromatricarin A, markedly reduced pulmonary inflammation by suppressing inducible nitric oxide synthase (iNOS) expression and nuclear factor kappa B (NF-κB) phosphorylation, thus reducing the levels of TNF-α and IL-6 (20). AI inhibited the inflammatory mediator nitric oxide and TNF-α and IL-12 production in lipopolysaccharide/IFN-γ-activated macrophages (21). PG was discovered to exert apophlegmatic, antitussive, anti-inflammatory, and antioxidative effects (22).

Thrombotic events that occur in COVID-19 are strongly associated with increased disease severity and poor clinical outcomes (44). Distinctive microvascular abnormalities in COVID-19 include endothelial inflammation, intercellular junction disruption, and microthrombus formation (44). OJ exerted antithrombotic effects by inhibiting venous thrombosis mainly through protecting endothelial cells and reducing leukocyte–endothelial cell adhesion (23).

Based on the in vivo and in vitro experiments, NRICM101 inhibits SARS-CoV-2 invasion and proliferation through its antiviral and anti-inflammatory properties (14). In clinical practice, NRICM101 was used as an optional alternative therapy in treating COVID-19 in Taiwan and was observed to be effective. However, statistically analyzed real-world data have not been reported. According to previous meta-analysis studies, the combination of traditional Chinese herbal medicine with conventional therapy was effective and safe in the treatment of mild to moderate COVID-19, which improved lung CT parameters, CRP, and clinical symptoms (fever, cough, and fatigue) (15–17). The formulas showed similar therapeutical effects as JSHT (15–17). According to the preliminary data, the worldwide dominant Omicron variant shows increased transmissibility compared to Delta and may evade vaccine-induced immunity (45). As more patients may quarantine at home, JSHT, suitable for mild-to-moderate COVID-19, is also suggested for home care management.

JSHT combined with standard management more effectively reduced the SARS-CoV-2 viral load and systemic inflammation and alleviated lung infiltrates in patients with mild-to-moderate COVID-19, especially in male and older patients (those aged ≥60 years). JSHT combined with standard management may prevent critical status and mortality in patients with mild-to-moderate COVID-19. Concerning the efficacy and safety of JSHT, we suggest JSHT as a promising complementary therapy for patients with mild-to-moderate COVID-19.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Research Ethics Committee of Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation. The patients/participants provided their written informed consent to participate in this study.

CYS, Y-CC, and Y-KW: study conception and design. C-HL, K-WT, and Y-KW: data collection. P-CH, I-ST, and Y-KW: statistical analysis. P-CH, C-HL, K-WT, and Y-KW: interpretation of results. P-CH and Y-KW: drafting manuscript. CYS and Y-CC: supervision. Y-KW: project administration. All authors reviewed the results and approved the final version of the manuscript.

This study was supported by grants from the Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan (TCRD-TPE-111-RT-3 (1/3) and TCRD-TPE-110-44).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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