Abstract
Background
The effectiveness and safety of Huashibaidu granule (HSBD) in treating mild Corona Virus Disease 2019 (COVID-19) patients infected with SARS-CoV-2 remain to be identified. We aimed to evaluate the effectiveness of HSBD in mild COVID-19 patients.
Methods
A prospective, non-randomized, controlled study in mild COVID-19 patients was conducted in Shanghai, from April 8 to May 6, 2022. The enrolled patients were diagnosed as mild COVID-19. Finally, 360 patients received HSBD, and 368 patients received TCM placebo (administered orally 20 g twice daily for 7 days). The primary endpoints were the negative conversion rate of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the negative conversion time. Secondary endpoints included the hospitalized days and the improvement in the clinical condition.
Results
The negative conversion rate of SARS-CoV-2 at 7 days posttreatment in the HSBD group was higher than that in the control group (95.28% vs. 82.61%, P < 0.001). The median negative conversion time in the HSBD group was markedly decreased by 2 days compared with the control group (3 [3–6] vs. 5 [4–7], P < 0.001). In addition, the median hospitalized day was shortened in the HSBD group by 1 day compared with the control group (6 [4–7] vs. 7 [5–9], P < 0.001). The clinical improvement rate (275/360 [76.39%]) in the HSBD group within 7 days was significantly higher than that (203/368 [55.16%]) in the control group (P < 0.001). The improvement of symptom scores in the HSBD group was higher than that in the control group (2 [1–4] vs. 1 [1–2], P < 0.001). No severe adverse events occurred.
Conclusions
Our study suggested that HSBD effectively increased the negative conversion rate of SARS-CoV-2 and shortened the negative conversion time and hospitalized days in mild COVID-19 patients.
Clinical trial registration
Chinese Clinical Trial Registry, ChiCTR2200058668
Keywords: COVID-19, Traditional Chinese Medicine, Huashibaidu granules
1. Introduction
In November 2021, the Omicron variant of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged, with multiple deletions and mutations, which leaded to higher immune escape, higher viral binding affinity, and increased transmissibility.1,2 Eventually, Omicron spread rapidly throughout the world and gradually caused significant impacts in China.3 As of February 21, 2023, Corona Virus Disease 2019 (COVID-19), a global pandemic caused by SARS-CoV-2virus, has resulted in more than 757.26 million cases and 6.85 million deaths.4 COVID-19 imposed a heavy burden on medical and health service systems, economies, and societies worldwide.5,6 It is important to develop effective therapeutic drugs to treat COVID-19. Paxlovid is authorized by Food and Drug Administration (FDA) to treat mild-to-moderate COVID-19 in patients aged 12 years or older who are at high risk for progression to severe disease and weigh at least 40 kg.7 However, there were no effective drugs to treat mild COVID-19.
Traditional Chinese medicine (TCM) has a long history and rich experience in treating infectious diseases. TCM has been rapidly used to treat COVID-19 since the outbreak in December 2019, which effectively improved the cure rate, shortened the course of the disease, delayed disease progression, and reduced the mortality rate.8 TCM formula Huashibaidu granule (HSBD) is modified from eight classical formulas (Maxingshigan decoction, Huoxiang Zhengqi San, Xuanbai Chengqi Decoction, and Dayuanyin, et al.),9 which was recommended to treat COVID-19 in Diagnosis and Treatment protocol for COVID-19 (Trial 9th edition) released by National Health Commission (NHC) of the People's Republic of China.10 During the Omicron variant predominance in Shanghai, HSBD was used to treat patients with mild COVID-19. In this study, we tried to evaluate the effectiveness and safety of HSBD in treating patients with mild COVID-19.
2. Methods
2.1. Study design
This study was a prospective, non-randomized, single-blinded, controlled study. The protocol of this study was registered at Chinese Clinical Trial Registry (ChiCTR2200058668). Patients were recruited from the mobile cabin hospital of City Footprint Hall in Shanghai, China. The study was conducted from April 8, 2022, to May 6, 2022, and patients diagnosed with mild COVID-19 (n = 728) were enrolled. The patients were grouped according to the researcher's judgment. The judgment was made based on the patient factors, management factors and organizational factors in the mobile cabin hospital on the day of allocation, including the number of patients, bed availability, the dispensing of drugs, the arrangement of researchers, et al. All participants were treated for 7 days with HSBD or TCM placebo and were not aware of whether they were taking HSBD or placebo. To avoid assessment bias, the evaluation of clinical outcomes was performed by an investigator who was blind to the study group allocation.
2.2. Patient population
The subjects were individuals who fulfilled the inclusion and exclusion criteria set out in the protocol. All participants provided written informed consent before taking part in this study. According to the guideline for Diagnosis and treatment of COVID-19 (Trial Version 9) issued by the NHC of the People's Republic of China,10 the COVID-19 patients were diagnosed using a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for novel coronavirus via nasopharyngeal swab.
2.3. Inclusion criteria
Inclusion criteria in this study were the following: (1) signed informed consent; (2) aged at least 18 years; (3) COVID-19 diagnosis based on polymerase chain reaction (PCR) testing; (4) patients meeting the definition of mild COVID-19 case (patients with mild symptoms but no manifestation of pneumonia on imaging) at admission and the presenting symptoms mainly include low fever, mild fatigue, taste disorder and smell disorder according to the ninth edition guideline;10 (5) no participation in other clinical trials during the study period.
2.4. Exclusion criteria
Exclusion criteria were as follows: (1) unwillingness to receive TCM treatment; (2) patients with allergic reactions or patients allergic to some herbs in HSBD; (3) patients with severe primary diseases of heart, liver, kidney and hematopoietic system;(4) females who are pregnant, lactating planning to become pregnant. Patients who voluntarily withdrew from the trial or transferred out for other reasons without treatment were regarded as having dropped out of the trial.
2.5. Intervention
Both the participants in the HSBD and the control groups received conventional treatment according to the guideline (Trial version 9).10 During the 7-day treatment period, patients in the HSBD group received HSBD granules, and patients in the control group received TCM placebo. HSBD granules was consisted of Mahuang (Ephedra; Ephedra sinica Stapf) 6 g, Kuxingren (Bitter Almond; Prunus armeniaca L. [Rosaceae]) 9 g, Shigao (Gypsum) 15 g, Gancao (Glycyrrhiza uralensis; Glycyrrhiza glabra L. [Fabaceae]) 3 g, Huoxiang (Agastache rugosus; Pogostemon cablin (Blanco) Benth. [Lamiaceae]) 10 g, Houpu (Officinal magnolia bark; Magnolia officinalis Rehder & E.H.Wilson [Magnoliaceae]) 10 g, Cangzhu (Atractylodes lancea; Atractylodes lancea (Thunb.) DC. [Asteraceae]) 15 g, Caoguo (Glycyrrhiza uralensis Fisch; Lanxangia tsao-ko (Crevost & Lemarié) M.F.Newman & Skornick. [Zingiberaceae]) 10 g, Fabanxia (Pinellia ternata; Pinellia ternata (Thunb.) Makino [Araceae]) 9 g, Fuling (Poria; Poria cocos(Schw.)Wolf) 15 g, Dahuang (Rhubarb Tangute Rhubarb, Rheum palmatum L. [Polygonaceae]) 5 g, Huangqi (Milkvetch Root; Astragalus mongholicus Bunge [Fabaceae]) 10 g, Tinglizi (Pepperweed Seed; Descurainia sophia (L.) Webb ex Prantl [Brassicaceae])10 g, Chishao (Red Paeoniae Trichocarpae; Paeonia lactiflora Pall. [Paeoniaceae]) 10 g. TCM placebo consists of gancao 1 g and huoxiang 1 g, which is similar to HSBD in shape, smell, color, taste and packaging.11 HSBD granules and TCM placebo were made by Guangdong Yifang Pharmaceutical Co., Ltd (Gu, China) with Good Manufacturing Practice (GMP) qualification (Chinese medicine C20210002). HSBD granules and TCM placebo were tested for safety and quality. Treatment was started within 6 h since the patient was enrolled. The HSBD or TCM placebo was dissolved in warm water and administered orally 20 g twice daily for 7 days.
2.6. Outcomes
The primary endpoints were the negative conversion rate of SARS-CoV-2 at 7 days posttreatment and negative conversion time. The negative conversion time of SARS-CoV-2 RNA was defined as the time from enrollment to the first day of at least 2 consecutive negative RT-PCR results separated by 24 h apart. SARS-CoV-2 was considered negative if the Ct values of the open reading frames 1ab (ORF1ab) gene and the N gene were equal or over 35. The discharge criteria was at least 2 consecutive negative RT-PCR results separated by 24 h apart.
Secondary endpoints included the hospitalized days and the improvement in the clinical condition (the clinical improvement rate and improvement in clinical symptoms). The clinical improvement rate is the percentage of patients discharged from the cabin mobile hospital after treatment. The symptoms of COVID-19 (cough, hypodynamia, headache, stuffy nose, runny nose, pharyngalgia, myalgia, chest distress, vomiting, abdominal distension, stomachache and diarrhea) were recorded and the improvement of symptoms was assessed by symptom scores. The absence of the above symptoms is scored with 0 point and the presence of one symptom is scored with 1 point and the final symptom scores were calculated by summing the fourteen individual symptom scores (range from 0 to 14). Symptoms were recorded and assessed before and after the treatment. The symptom improvement scores were calculated by subtracting the symptom score at post-treatment from the symptom score at pre-treatment. Symptom improvement was defined as reporting at least one of the symptoms or signs disappeared (symptom improvement scores ≥ 1).
The safety evaluation included the incidence of adverse events, adverse reactions, and severe adverse events (SAEs). The symptoms, severity, and causality of adverse events were documented.
2.7. Statistical analysis
The Per Protocol (PP) analysis set was the primary population for the preliminary effectiveness analysis, and the per-protocol data set was defined as all patients who completed the study drug treatment.
Statistical analysis was performed using IBM SPSS Statistics for Windows (version 25.0) and R software (version 4.1.3). Forest plots were generated using the “forestplot” R package. Continuous variables are presented as means ± standard error (SE) and analyzed by two independent sample t-test, because the large sample size ensured the robustness of the t-test. Categorical variables were represented as frequency and proportions (n (%)) and tested by the Chi-squared test or Mann-Whitney U test. The Kaplan-Meier method was used to estimate the cumulative rate of negative conversion and clinical improvement rate, and the log-rank test to compare the Kaplan-Meier estimate curves between groups. Multivariate Cox risk regression analysis was applied to identify the influential factors of SARS-CoV-2 negative conversion and clinical improvement (patients discharge). Additional subgroup analyses were performed using Multivariate Cox proportional hazards regression. All tests were two-tailed and P < 0.05 was considered statistically significant.
3. Results
3.1. Patient characteristics
A total of 760 patients participated in the preliminary screening in the mobile cabin hospital of City Footprint Hall in Shanghai, from April 8, 2022 to May 6, 2022. Of these, 6 were excluded because they did not meet inclusion criteria. Then 754 patients were non-randomly assigned to either the HSBD group (n = 377) or the control group (n = 377). Subsequently, 26 patients were excluded due to withdrawing their informed consent, including 17 cases of the HSBD group and 9 cases of the control group. Thus, a total of 728 patients completed this study and were included in the final analysis (360 in the HSBD group and 368 in the control group) (Fig. 1). Of the patients included in the study, the mean age was 48.47±15.36 years and 364 (50%) were men. Patients in the HSBD group were older (51.06±16.05 years vs. 45.93±14.24 years), and with more symptoms (72 (20.00%) vs. 35 (9.51%) in fever and 56 (15.56%) vs. 28 (7.61%) in myalgia), as well as have a higher rate of comorbidities (116 (32.22%) vs. 26 (7.07%), including hypertension, diabetes, heart disease, chronic respiratory disease, liver disease and other comorbidities) compared with the control group (P < 0.05). (Table 1).
Fig. 1.
Study flowchart. 760 patients were enrolled, and 6 patients were excluded because they did not meet the inclusion criteria. 754 patients were assigned into the HSBD group (n = 377) and the control group (n = 377). Subsequently, 26 patients were excluded, including 17 cases of the HSBD group and 9 cases of the control group. Finally, 728 patients, including 360 in the HSBD group and 368 in the control group, completed this study and were included in the final analysis. *, Patients were excluded due to withdrawal of informed consent.
Table 1.
Baseline Characteristics of the Patients.
| Characteristic | Total (n = 728) | HSBD (n = 360) | Control (n = 368) | P-value |
|---|---|---|---|---|
| Age (years), | 48.47±15.36 | 51.06±16.05 | 45.93±14.24 | < 0.001⁎⁎⁎ |
| Male | 364 (50.00) | 184 (51.11) | 180 (48.91) | 0.553 |
| BMI (kg/m2)*, n (%)† | 0.116 | |||
| < 25 | 428 (69.48) | 178 (66.17) | 250 (72.05) | |
| ≥ 25 | 188 (30.52) | 91 (33.83) | 97 (27.95) | |
| ORF 1ab gene | 25.53±5.36 | 25.32±5.69 | 25.74±5.01 | 0.296 |
| N gene | 24.79±5.78 | 24.92±6.19 | 24.66±5.35 | 0.541 |
| Interval time‡, day | 2.90±2.22 | 2.98±2.70 | 2.83±1.65 | 0.416 |
| Symptoms, n (%) | 595 (81.73) | 284 (78.89) | 311 (84.51) | 0.050 |
| Fever | 107 (14.70) | 72 (20.00) | 35 (9.51) | <0.001⁎⁎⁎ |
| Cough | 423 (58.10) | 206 (57.22) | 217 (58.97) | 0.633 |
| Hypodynamia | 140 (19.23) | 71 (19.72) | 69 (18.75) | 0.739 |
| Headache | 111 (15.25) | 57 (15.83) | 54 (14.67) | 0.663 |
| Stuffy nose | 179 (24.59) | 95 (26.39) | 84 (22.83) | 0.264 |
| Runny nose | 161 (22.12) | 86 (23.89) | 75 (20.38) | 0.254 |
| Pharyngalgia | 229 (31.46) | 113 (31.39) | 116 (31.52) | 0.969 |
| Myalgia | 84 (11.54) | 56 (15.56) | 28 (7.61) | <0.001⁎⁎⁎ |
| Chest distress | 57 (7.83) | 30 (8.33) | 27 (7.34) | 0.617 |
| Vomiting | 18 (2.47) | 9 (2.50) | 9 (2.45) | 0.962 |
| Abdominal distension | 16 (2.20) | 11 (3.06) | 5 (1.36) | 0.118 |
| Characteristic | Total (n = 728) | HSBD (n = 360) | Control (n = 368) | P-value |
| Stomachache | 15 (2.06) | 8 (2.22) | 7 (1.90) | 0.761 |
| Diarrhea | 41 (5.63) | 23 (6.39) | 18 (4.89) | 0.381 |
| Comorbidities, n(%) | 142 (19.51) | 116 (32.22) | 26 (7.07) | < 0.001⁎⁎⁎ |
| Hypertension | 82 (11.26) | 68 (18.89) | 14 (3.80) | < 0.001⁎⁎⁎ |
| Diabetes | 37 (5.08) | 28 (7.78) | 9 (2.45) | 0.001⁎⁎ |
| Heart disease | 30 (4.12) | 26 (7.22) | 4 (1.09) | < 0.001⁎⁎⁎ |
| Chronic respiratory disease | 10 (1.37) | 10 (7.22) | 0 (0.00) | 0.001⁎⁎ |
| Liver disease | 21 (2.88) | 17 (4.72) | 4 (1.09) | 0.003⁎⁎ |
| Others§ | 19 (2.61) | 16 (4.44) | 3 (0.82) | 0.002⁎⁎ |
Note: * BMI was divided into two groups according to the standards of the World Health Organization (WHO), that overweight is defined as body mass index (BMI) of ≥ 25 kg/m2. † 112 patients have missing BMI data ‡ Interval time was defined as the duration from diagnosis with COVID-19 to admission (day), and 65 patients have missing interval time data.§ Others include Chronic renal insufficiency, Chronic liver disease, malignancies and Rheumatic immune disease. **, P < 0.05; ***, P < 0.001.
HSBD, Huashibaidu granule. BMI, Body mass index.
3.2. Primary clinical outcomes
Patients with HSBD had a significantly higher negative conversion rate of SARS-Cov-2 at 7 days posttreatment than the patients in the control group (343/360 [95.28%] vs. 304 /368 [82.61%], P < 0.001). The similar results were obtained when compared at different time points (Table S1). In the log-rank analysis, patients who were assigned to the HSBD group had approximately 2.095 fold [95%CI: 1.747–2.512, P < 0.001] higher than that in the control group to achieve a negative conversion. In addition, negative conversion time was significantly reduced in the HSBD group compared with those in the control group (3.00 days [3.00–6.00] vs. 5.00 days [4.00–7.00], P < 0.001). (Fig. 2A, 2B).
Fig. 2.
HSBD treatment improved the viral infectious indicators of SARS-CoV-2 in patients with mild COVID-19. (A) Negative conversion rates of SARS-CoV-2; (B) Negative conversion time; (C) Cumulative clinical improvement rates; (D) Hospitalized days. The cumulative negative conversion rates and clinical improvement rates were drawn using the Kaplan-Meier method with log-rank tests. The negative conversion time of SARS-CoV-2 RNA was defined as the time from enrollment to the first day of at least 2 consecutive negative RT-PCR results separated by 24 h apart. The cumulative clinical improvement rate is the percentage of patients discharged from the cabin mobile hospital, and hospitalized days in all patients were analyzed. ⁎⁎⁎, P < 0.001.
3.3. Secondary clinical outcomes
For all patients, the cumulative improvement rate (the percentage of patients discharged) in the HSBD group within 7 days was significantly higher than that in the control group (275/360 [76.39%] vs. 203/368 [55.16%], P < 0.001). In addition, HSBD treatment notably shortened the median hospitalized days compared with placebo treatment (6.00 days vs. 7.00 days; Hazard ratio (HR) = 2.11, 95% CI: 1.72–2.58; log-rank P value < 0.001). (Fig. 2C, 2D).
Then the improvement of symptoms was analyzed. There were no significant differences in the disappearance rates of total symptoms between the two groups (79.58% vs. 73.31%, P = 0.073) (Table 2). However, the median improvement of symptom scores in the HSBD group was higher than that in the control group (2.0 [1.0–4.0] vs. 1.0 [1.0–2.0], P < 0.001). (Fig. S1.)
Table 2.
Disappearance rate of symptoms in patients with mild COVID-19.
| Symptoms | HSBD (n = 360), n / total (%) | Control (n = 368), n / total (%) | P-value |
|---|---|---|---|
| Fever | 70/72 (97.22) | 33/35 (94.29) | 0.596 |
| Cough | 162/206 (78.64) | 154/217 (70.97) | 0.070 |
| Tired | 66/71 (92.96) | 59/69 (85.51) | 0.154 |
| Headache | 54/57 (94.74) | 52/54 (96.30) | 1.000 |
| Snuffle | 91/95 (95.79) | 79/84 (94.05) | 0.736 |
| Running nose | 78/86 (90.70) | 71/75 (94.67) | 0.338 |
| Sore throat | 105/113 (92.92) | 105/116 (90.52) | 0.510 |
| Myalgia | 55/56 (98.21) | 26/28 (92.86) | 0.257 |
| Chest tightness | 28/30 (93.33) | 26/27 (96.30) | 1.000 |
| Vomiting | 8/9 (88.89) | 9/9 (100.00) | 1.000 |
| Abdominal distension | 10/11 (90.91) | 5/5 (100.00) | 1.000 |
| Stomachache | 8/8 (100.00) | 7/7 (100.00) | - |
| Diarrhea | 21/23 (91.30) | 15/18 (83.33) | 0.638 |
| Total | 226/284 (79.58) | 228/311 (73.31) | 0.073 |
Note: Disappearance rates of symptoms in all patients with mild COVID-19 post-treatment within 7 days were analyzed.
HSBD, Huashibaidu granule.
3.4. Multivariate Cox hazards regression analysis
Multivariate Cox proportional hazards regression analysis was used to estimate the relative factors involved in the negative conversion of SARS-Cov2. Our results showed that the treatment of HSBD, Ct values of the ORF gene, and interval time contributed to the negative conversion of SARS-Cov2 (HR=1.88, 95% Confidence interval (CI):1.59–2.21, P < 0.001; HR=1.95, 95%CI:1.65–2.30, P < 0.001; HR=1.31, 95% CI:1.11–1.54, P = 0.001). The differences in gender, age, presence or absence of symptoms (fever, myalgia), and comorbidities (hypertension, diabetes, heart disease, chronic respiratory disease, liver disease and other comorbidities) in baseline data didn't affect the negative conversion (P > 0.05) (Fig. 3A.). We did the similar analysis for the clinical improvement (patients discharge). And the results showed that the treatment of HSBD, Ct values of the ORF gene, interval time, and gender contributed to the clinical improvement (HR=1.81, 95% CI:1.53–2.13, P < 0.001; HR=1.67, 95%CI:1.42–1.97, P < 0.001; HR=1.33, 95% CI:1.13–1.57, P = 0.001; HR=1.21, 95% CI:1.03–1.41, P = 0.020) (Fig. 3B.).
Fig. 3.
Many factors affect the negative conversion of SARS-Cov2 and the clinical improvement, while these confounding factors do not affect the therapeutical effect of HSBD. (A) Negative conversion; (B) Clinical improvement; (C) Subgroup analysis of negative conversion rates of SARS-CoV-2. Cox proportional hazards regression analysis was used to estimate the relative factors involved in the negative conversion of SARS-Cov2 and the clinical improvement (patients discharge). The factors in the Cox proportional hazards regression analyses include HSBD, Ct values of the ORF gene, interval time, gender, presence or absence of symptoms (fever, myalgia) and comorbidities (hypertension, diabetes, heart disease, chronic respiratory disease, liver disease and other comorbidities). All patients in both groups were assigned into subgroups according to the relevant factors that may correlate with the negative conversion of SARS-CoV-2 and the clinical improvement. Multivariate Cox regression analysis of influence factors for negative conversion rates of SARS-CoV-2 in subgroups was done.*, Because Ct values of the ORF gene were highly correlated with Ct values of the N gene, two variables can not be enrolled into this model simultaneously. We used the Ct values of the ORF gene as a confounder to be analyzed in other subgroups. †,65 patients have missing interval time data.
3.5. Clinical outcomes in subgroups
Further analysis in subgroups showed that there were no effects on the beneficial effectiveness of HSBD treatment contributing to the negative conversion of SARS-CoV-2, including age (≤ 60 yr vs. > 60 yr), gender, Ct values (ORF or N gene, grouped by median), interval time (grouped by median), symptom presentation and comorbidity (Fig. 3C.).
3.6. Safety
No death or serious adverse events were reported in either group, with the exception of one patient who showed diarrhea in the HSBD group.
4. Discussion
TCM has a long history of using herbal medicine to treat infectious diseases, including influenza, the infection of Severe Acute Respiratory Syndrome (SARS) virus and COVID-19.12, 13, 14 In 2003, TCM and traditional medical physicians significantly contributed to combating SARS in China. During the fight against the outbreak of COVID-19 in China, TCM showed some significant benefits in alleviating symptoms and preventing disease deterioration.15 According to a retrospective study on 1305 COVID-19 cases in Wuhan, the patients who took Chinese medicine treatment had a smaller death risk than those who did not.16 As one of the first two TCM for treating COVID-19 approved by the National Medical Products Administration of China, HSBD has been demonstrated excellent effectiveness and safety profile in previous COVID-19 cases.17,18 In this study, HSBD was used to treat patients with mild COVID-19. Our results showed that HSBD effectively improved the negative conversion rate and shortened the negative conversion time in mild COVID-19 patients. This suggested that HSBD could promote virus clearance in patients infected with the SARS-CoV-2. Our findings indicated that HSBD could significantly promote the recovery of mild COVID-19 patients, including the shortened hospitalized days and the improvement of the clinical conditions (the higher percentage of patients discharged and the better symptom scores). It's more important that the beneficial effectiveness of HSBD for the primary endpoint was not affected by some of the factors including age, gender, Ct values interval time, symptoms and comorbidities. These results affirmed the therapeutic advantages of TCM, and are crucial for strengthening health systems dealing with major public health challenges.
However, the specific mechanism of action of HSBD treatment for COVID-19 is still unclear. Inflammation and immune factors are closely related to disease presentations and severity in COVID-19 patients.19,20 Previous studies have shown that HSBD could effectively treat mild, moderate and severe COVID-19 patients by inhibiting inflammation and regulating immunity.17,18,21 Although immune response and the roles of inflammatory cytokines in mild COVID-19 are not conclusive, the cumulative studies have suggested that the dysregulation immune response in patients with COVID-19 could lead to the development of viral hyper-inflammation.22,23 Researches have confirmed that the innate and adaptive immune responses can contribute to virus clearance, inhibition of virus replication, and tissue repair in patients with COVID-19.24 Therefore, the roles of HSBD in regulating immunity maybe more critical in the treatment of mild COVID-19 patients infected with SARS-CoV-2. As the main chemical components of the extract of HSBD,25 flavone and saponin compounds have immunoregulatory effects in viral disease.26,27 Moreover, the compositions of the HSBD, like Shenghuangqi (Milkvetch Root; Astragali Radix), Gancao (Licorice; Glycyrrhizae Radix et Rhizoma), Fuling (Poria; Indian Buead Tuckahoe) et al. are all capable of regulating immune system (innate immunity and acquired immunity) in H1N1 influenza, H9N2 influenza, and other viral infections.28, 29, 30, 31 In further, more in-depth studies will be required to explore the key mechanism and the relevant substances of HSBD treating COVID-19.
There were several limitations in our study. Firstly, the non-randomized design does have its deficits, and patients in the HSBD group seem to be more likely to respond. Although, our risk regression and subgroup analyses showed that unbalanced factors at baseline did not affect the study outcomes. Secondly, our study was carried out in mobile cabin hospitals, and the data obtained from patients was limited. Despite efforts to collect all available data for a comprehensive and objective analysis, some unmeasured important confounding variables may affect our results, such as vaccination, lifestyle habits of patients and some serological indicators. In the future, more studies should be conducted to collect and adjust for these factors to conduct a more comprehensive assessment of the drug efficacy. Thirdly, we did a short-course study in patients with mild COVID-19, and the long-term evaluation was necessary for observing the recurrence or reinfection and so on in patients.
In conclusion, HSBD treatment markedly raised the negative conversion rate of SARS-CoV-2, shortened the negative conversion time and hospitalized days, as well as alleviated symptoms in patients with mild COVID-19.
CRediT authorship contribution statement
Bowu Chen: Formal analysis, Data curation, Writing – original draft. Yan Xue: Formal analysis, Data curation, Writing – original draft. Hua Jing: Methodology, Investigation. Xiaodong Wang: Methodology, Investigation. Peimin Zhu: Conceptualization, Methodology, Investigation. Weiwei Hao: Conceptualization, Methodology, Data curation, Writing – review & editing. Man Li: Methodology, Data curation, Writing – review & editing. Yueqiu Gao: Conceptualization, Methodology, Data curation, Writing – review & editing, Funding acquisition.
Acknowledgments
Conflict of interest
The authors have no competing interests to declare.
Funding
This work was supported by the three-year action plan for the development of traditional Chinese medicine in Shanghai, NO. ZY (2021–2023)−0103 and the emergency research projects of traditional Chinese medicine for preventing and treating Novel coronavirus-infected pneumonia, NO. 2022ZYLCYJ05–1.
Ethical statement
The study was designed in compliance with the Declaration of Helsinki and approved by the Ethics Committee of Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine (No.2022–1097–34–01). Informed consent was obtained from all participants.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Acknowledgments
We gratefully acknowledge the study participants who generously gave their time and biological specimens.
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.imr.2023.100950.
Supplementary Table 1. The cumulative negative conversion rates of SARS-CoV-2 during treatment.
Supplementary Fig. 1. The improvement of symptom score.
Contributor Information
Weiwei Hao, Email: hwwwork@163.com.
Man Li, Email: liman121000@shutcm.edu.cn.
Yueqiu Gao, Email: gaoyueqiu@shutcm.edu.cn.
Appendix. Supplementary materials
References
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.