A randomized controlled trial protocol of herbal formulas for modifying susceptible body constitution to enhance COVID-19 resistance in Hong Kong residents

Introduction

Background

New coronavirus infection (new coronavirus pneumonia) is a respiratory disease caused by the continuously mutated acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has the characteristics of strong infectivity and rapid transmission. Typical symptoms include fever (≥37.3 ℃), persistent dry cough, dyspnea (oxygen saturation ≤94% in room air) and general fatigue. The secondary symptoms may involve systemic inflammatory reaction, such as headache, sore throat and muscle soreness (visual analogue scale ≥4), fatigue (Chalder Fatigue Scale ≥6), and gastrointestinal disturbances such as nausea/vomiting (CTCAE grade ≥2) (1,2). Compared with other viral pneumonia, the symptoms of olfactory or gustatory hypoesthesia were more common in patients with new coronavirus pneumonia. The main systemic symptoms were significant fatigue. New coronavirus nucleic acid could be detected in respiratory secretions and feces, and new coronavirus specific immunoglobulin M (IgM) antibody and immunoglobulin G (IgG) antibody could be detected in serum. At present, most infected people with new coronavirus can recover completely, but the elderly or infected people with weak immunity are more likely to develop severe lung inflammation, multiple organ failure and other serious conditions, and even death in extreme cases. At present, the epidemic in Hong Kong has been effectively controlled by protecting the elderly and susceptible populations (3). However, due to the constant variation of coronavirus disease 2019 (COVID-19) strains and the decline of residents’ resistance, many people are still infected by COVID-19 (4,5). As of May 2025, there are 589 new cases of COVID-19 infection in Hong Kong (6). By the week ending May 10, 2025, the Centre for Health Protection of Hong Kong reported a COVID-19 sample positivity rate of 13.66% with the XDV and NB.1.8.1 strains becoming the dominant circulating variants. Hong Kong has achieved widespread vaccination coverage and high levels of hybrid immunity from natural infection and vaccination; however, hybrid immunity exhibits limited durability against newly evolved strains, with breakthrough infections and reinfections remaining common (4). Residents infected with COVID-19 have fever, sore throat, cough, fatigue (7), which has affected their quality of life. Although the large-scale epidemic in Hong Kong has ended in May 2023, local cases of Omicron infection still exist. Most of the cases come from vulnerable groups in Hong Kong, and the mortality rate increases with age (8). According to Hong Kong government statistics, the proportion of people over 65 years in Hong Kong will reach 30% in 2025 (9). Vaccination primarily induces humoral immunity targeting viral spike proteins, while TCM constitution modification regulates the body’s innate and adaptive immune function by improving Qi-Yang/Qi-Yin deficiency—addressing the root cause of host susceptibility to viral infection. This complementary preventive strategy is particularly critical for Hong Kong’s aging population and those with constitutional deficiencies. It is necessary for Hong Kong to formulate effective control measures to cope with the outbreak of the epidemic.

Rationale and knowledge gap

In Chinese Mainland, traditional Chinese medicine (TCM) has become an important alternative treatment for the prevention and treatment of COVID-19 (10,11). This is because coronaviruses belong to RNA viruses, which are more prone to mutations during replication than DNA viruses. It is this high variability that makes coronaviruses more susceptible to developing resistance to single chemical drugs (11). While TCM exerts anti-COVID-19 effects through a multi-target synergistic mechanism: enhancing the body’s innate and adaptive immune function to repel viral invasion, regulating host immune and metabolic function, and protecting vital organs from inflammatory damage (11,12). This multi-target mode of action avoids the induction of viral drug resistance. The idea of using TCM to treat pneumonia is to enhance the body’s own immune system and repel the invasion of viruses (12). It involves interventions for respiratory viral infections, regulation of host immune function, organ protection, and regulation of host metabolic function (13,14). This multi-target synergistic effect and immune regulation feature make it difficult to induce virus resistance mutations. For example, Qing Fei Hua Xian Decoration inhibits pulmonary fibrosis by modulating multiple targets of PI3K/Akt, IL-6, TNF, IL-1β, STAT3, MMP-9, and TGF-β1 to prevent inflammation and epithelial mesenchymal transition (15). The combination of TCM therapy and basic conventional therapy can effectively reduce the deterioration rate and mortality rate of patients with COVID-19 (16). In addition, personalized Chinese medicine treatment can also reduce the sequelae of patients with COVID-19 (17). Recent clinical studies have demonstrated that TCM herbal formulas such as Jinhua Qinggan and Lianhua Qingwen alleviate symptoms and increase the negative rate of nucleic acid testing for the virus in COVID-19 patients (18,19). However, these studies focus on general preventive and symptomatic interventions, with no stratification by TCM susceptible constitutions. A critical unmet clinical need is the lack of high-quality randomized controlled trial evidence on customized TCM herbal formula interventions targeting specific susceptible constitutions (Qi-Yang and Qi-Yin deficiency) for enhancing host resistance to COVID-19.

TCM believes that Qi is the fundamental substance and energy that constitutes the human body and sustains life activities. It has the function of protecting the muscle surface and preventing the invasion of pathogens. In addition, there are two attributes in the human body, yin and yang. Only when yin and yang are in a balanced state can the body maintain a healthy state. If one of yin and yang is weak and causes imbalance, it will lead to diseases (20,21). Modern research has confirmed that pneumonia patients often have Qi Yin deficiency and Qi Yang deficiency (22-25). For such situations, applying methods of replenishing qi and regulating yin and yang can achieve good therapeutic effects (26,27).

The group with insufficient Qi and Yin (Qi and Yin deficiency) is characterized by fatigue, dryness, feverish sensation, dry mouth, and easy sweating during sleep. From a modern medical perspective, these symptoms may reflect a state of chronic energy depletion and fluid imbalance, potentially associated with impaired mucosal barrier function, dysregulation of autonomic nervous system, and a low-grade inflammatory status, all of which could compromise innate immune defenses against viral invasion like SARS-CoV-2. People with insufficient Qi and Yang (Yang deficiency) are characterized by fatigue, fear of cold, cold limbs, and diarrhea. This constitution suggests reduced basal metabolic rate and thermogenesis, which in modern terms might correlate with poor peripheral circulation, low basal body temperature, and potentially suboptimal immune cell function, particularly in mounting effective inflammatory responses and thermoregulation during infection. The disruption of Yin-Yang balance, a core concept in TCM signifying health, can be analogized to the loss of homeostasis in modern medicine, involving dysregulation of the immune system, neuroendocrine-immune axis, and metabolic functions.

This study focuses on Hong Kong residents due to the unique healthcare and epidemiological challenges in the Hong Kong SAR: (I) a fragmented TCM information system with inconsistent clinical practice standards, leading to non-uniform TCM intervention for COVID-19 prevention in clinical settings; (II) an integrated but non-standardized Western/TCM healthcare landscape, with limited evidence-based localized TCM guidelines for COVID-19 prevention and no clear recommendations for constitution-targeted TCM interventions; (III) Hong Kong’s aging population [30% of residents aged ≥65 years by 2025 (9)] and a high prevalence of Qi-Yang/Qi-Yin deficiency constitutions, making constitutional modification a highly relevant and targeted preventive strategy for COVID-19. This trial aims to generate high-quality localized clinical evidence to establish authoritative TCM guidelines for COVID-19 prevention in Hong Kong, filling the gap between TCM clinical practice and evidence-based medicine in the region and providing a feasible constitution-targeted preventive approach for local healthcare institutions.

Objective

The present study aims to provide a preventive approach based on TCM constitution identification and evidence-based prescriptions to enhance the overall resilience and potentially modulate immune function against COVID-19 for Hong Kong residents. This method is based on the specific physical vulnerability found in TCM and combined with the perspective of modern medicine. The purpose is to strengthen the physiological barrier, optimize the immune response, promote the internal balance and reduce the infection rate of COVID-19. We present this article in accordance with the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2423/rc).

Methods

Design and setting

This is a randomized, prospective, quadruple-blind (participant, care provider, investigator, outcomes assessor) clinical trial. The trial has been ongoing since April 30, 2021. We expect data collection to be completed by November 30, 2022. This trial has been registered on the ClinicalTrials.gov website (ID: NCT04668222). Our trial was conducted in accordance with ICH-GCP (International Council for Harmonisation of Good Clinical Practice) to ensure the scientificity, ethics and protection of the rights and interests of the subjects in the clinical trial. The diagram in Figure 1 illustrates the various stages of the research.

Figure 1 Consort diagram: flow of the participants through the study. COVID-19, coronavirus disease 2019.

Sample size determination

The calculation of the required sample size for all outcome measures was performed for a two-tailed test using the online calculator Granmo version 7.12, which is created by the Mar Institute of Medical Research Foundation. Please note that there might be temporary issues accessing the link due to network problems, and you may need to check the link’s validity or try again later. The required statistical parameters were determined using data from two studies, including one by Chen et al. (28), which focused on COVID-19 treatment, the study by An et al. (29) revealed the mechanism of action of various Chinese medicines and formulas for COVID-19 and provided relevant clinical data.

The sample size calculation was conducted for the primary outcome (Fatigue Assessment Scale score) based on a stratified parallel two-arm design. We assumed a mean change [standard deviation (SD)] of −8.5 (±6.0) in the active group and −5.0 (±6.0) in the placebo group, yielding an effect size of 0.58. For a two-sided α=0.05 and 80% power (independent t-test), 92 participants per constitution stratum (46 per active/placebo group) are required. Factoring in a 15% dropout rate, we aim to recruit 108 participants per stratum (54 per group), resulting in a total target sample size of 216.

Participants

Participants in this study will be recruited at the University of Hong Kong-Shenzhen Hospital primarily through its Post-COVID-19 Rehabilitation Clinic, supplemented by referrals from other departments (Respiratory Medicine, General Practice). Participants characterized by a “Qi and Yin deficiency” or “Qi and Yang deficiency” body constitution, as identified through the “TCM-based self-assessment for body constitution classification and determination”, will be eligible for inclusion in this research. Potential participants will undergo an evaluation to ascertain whether they fulfill the additional inclusion and exclusion criteria prior to being granted the chance to engage in the study.

Randomization

Eligible participants will first be classified into one of two TCM constitution strata: Qi-Yang deficiency (QYang-D) or Qi-Yin deficiency (QYin-D). Within each constitution stratum, a sequence of consecutive numbers will be prepared and randomly allocated to the two corresponding study groups [i.e., QYang vs. placebo control of invigorating Qi and Yang (PQYang) within the QYang-D stratum; QYin vs. placebo control of invigorating Qi and Yin (PQYin) within the QYin-D stratum] using an impartial computer program (www.random.org). The investigator responsible for recruitment and baseline assessments will sequentially assign these numbers to participants without any prior knowledge of group allocations. The allocation list linking numbers to specific groups will be accessible only to the investigator who administers the interventions. Due to the manual nature of the intervention, this investigator cannot be blinded, as they must refer to the allocation list to provide the correct treatment. However, the blinding remains effective for the recruiting investigator and the participants, thus safeguarding against selection bias during recruitment and outcome assessment.

Blinding

Overview of blinding methodology

Participants were blinded to their specific treatment prescriptions and solely followed researchers’ instructions for medication administration and symptom documentation. Clinical staff responsible for medication dispensing and care guidance remained blinded to participants’ group allocation. Research coordinators handling drug distribution and data collection were similarly blinded to individual participants’ group assignments. Outcome assessors evaluating treatment efficacy were restricted to accessing anonymized case report forms (CRFs) or participant assessment records without access to group allocation data or direct participant contact.

Randomization and Implementation of blinding

Randomization was performed with the use of an unbiased computerized program (www.random.org). After the participant provided informed consent, a unique randomization number was assigned to each participant, which was linked to the group assignment. However, neither the participants nor the research team members were aware of the specific grouping.

The study medications were identical in appearance, packaging, and administration methods, and were labeled with the same numbering system, making it impossible to distinguish between them based on appearance. Participants were aware that they were participating in a study but were not informed of their specific group assignments. They were instructed to take the medication as directed by the researchers and to record any changes in symptoms through the EpiData 3.1. Care providers, who were responsible for medication distribution and care instructions, were also unaware of the participants’ specific group assignments. They operated solely based on the medication allocation records within the EpiData 3.1. The investigator, who was responsible for medication allocation and data collection, was similarly unaware of the specific group assignments of each participant and could only proceed according to the established study protocol. Outcome assessors had access only to anonymized data or participant assessment reports through the EpiData 3.1 and had no knowledge of the participants’ group assignments or direct contact with the participants.

Data management and quality control

Participants completed symptom record forms via EpiData 3.1 and data were uploaded to the database in real time. During the dosing period, healthcare workers recorded drug distribution and basic information of participants in EpiData 3.1. Data were managed and monitored with EpiData 3.1 to ensure completeness and accuracy of the data. Data validation rules were established in EpiData 3.1 system, such as limiting the range of symptom scores to ensure the rationality of the data. For critical data, such as changes in symptoms, adverse drug reactions, mandatory fields and logical validation rules were set to prevent missing data and errors. Backup and clean the database regularly to ensure the security and integrity of the data. In the EpiData 3.1 system, all participant data were anonymized and identified only by random numbers. Research team members had access to the respective data modules according to their respective responsibilities and permissions to ensure data confidentiality and the double-blind design of the study. At the start of the study, we will collect information on demographic characteristics, health status, comorbidities, and lifestyle factors as baseline covariates. The primary analytical purposes of these data include: (I) constructing statistical adjustment models to control for potential confounding factors when evaluating primary outcomes (such as constitution improvement); (II) conducting exploratory subgroup analyses to identify factors that may influence intervention efficacy (effect modification), such as age or underlying diseases; (III) providing a design basis for future precision prevention studies targeting specific high-risk populations (such as individuals aged ≥65 years). For data collection, our strategy will integrate standardized questionnaires with routine data sources such as electronic health records from the Hong Kong Hospital Authority to improve the accuracy and comprehensiveness of information.

Maintenance and breaking of blinding

During the study period, all members of the research team were required to strictly adhere to the blinding design and not to disclose group assignment information. At the baseline visit, after providing informed consent, participants will undergo a comprehensive baseline assessment which includes demographic data collection, completion of the three primary scales (TCM Constitution Self-assessment, TCM Symptom Questionnaire, Fatigue Assessment Scale), and blood draw for biomarker analysis. Regular training was conducted for the research team to ensure their understanding of the importance of blinding and strict compliance with operational procedures. Blinding was only broken at the end of the study or in the event of a serious adverse event. After the study concluded, an independent statistician was responsible for breaking the blind by matching random numbers with group assignment information for data analysis. All data analyses were conducted based on anonymized data prior to unblinding to ensure the objectivity of the results.

Withdrawal criteria and management

Inclusion criteria

• Applicants must be 18 years of age or older, with no gender-specific limitations.
• Utilizing the “Self-Assessment for Classifying and Evaluating Body Constitution Based on Traditional Chinese Medicine (TCM) Principles”, participants with Qi deficiency, either Yin or Yang-related, will qualify for inclusion.
• A history of allergies to TCM must be absent among potential participants.
• Candidates must possess the ability to comprehend and respond to a Chinese-language questionnaire.
• Willingness to engage in the study and follow its procedures is a prerequisite for inclusion.

Exclusion criteria

• Participants whose physical constitution does not belong to the syndrome type defined by the research criteria.
• Individuals who are confirmed cases of COVID-19.
• Applicants exhibiting symptoms such as fever (body temperature exceeding 37 ℃), cough, or other respiratory manifestations.
• Candidates who have traveled to an epidemic area and have not completed the mandatory 14-day quarantine period upon returning to Hong Kong.
• Women who are pregnant, planning pregnancy, or lactating.
• Individuals with severe hepatic impairment or severe renal impairment. Patients who meet all inclusion criteria and no exclusion criteria are invited to join the study, accompanied by a comprehensive verbal and written explanation. Participants will be informed that they are to be randomly allocated to different study groups, with each group receiving a distinct yet suitable treatment modality. The goal is to ascertain which treatment yields the most favorable outcomes. To uphold the principle of blinding, patients will remain unaware of their specific group assignment. Upon agreeing to take part, patients will then sign a form indicating their informed consent. Then, the recruiting investigator will carry out the baseline evaluation.

Intervention

The intervention will be delivered by the same care provider, using standardized operating procedures (SOPs) to ensure that care providers are only serving according to pre-established guidance, without knowledge of the specific nature or grouping of medications. Four groups will be treated with medication for 4 weeks.

QYang-group procedure

Yu-Ping-Feng and Xiang-Sha-Liu-Jun formulae, which are both registered Chinese medicinal mixtures (registration numbers: HKC-08255 and HKC-08252, respectively), will be given to members. Manufactured by PuraPharm International (H.K.) Ltd. (Hong Kong, China), these formulas will be taken orally at a dosage of 5 grams, twice daily. Yu-Ping-Feng and Xiang-Sha-Liu-Jun decoctions are specifically designed for the study’s purposes.

PQYang-group procedure

The placebo will consist of a 5% blend of Yu-Ping-Feng and Xiang-Sha-Liu-Jun formulas, both registered Chinese medicinal preparations. For the “Qi and Yang deficiency” group, the placebo will specifically be formulated as a 5% combination of YPF and XSLJ formulas.

QYin-group procedure

The Yu-Ping-Feng and Liu-Wei-Di-Huang formulas, which are both officially registered Chinese medicinal concoctions (registration numbers: HKC-08255 and HKC-08273, respectively), will be given to attendees. Manufactured by PuraPharm International (H.K.) Ltd., these formulas will be consumed at a dosage of 5 grams, twice daily.

PQYin-group procedure

The placebo will be a blend 5% mixture of Yu-Ping-Feng and Liu-Wei-Di-Huang formulas, both registered Chinese medicinal formulations. Specifically for the “Qi and Yin deficiency” group, the placebo will consist of a 5% combination of Yu-Ping-Feng and Liu-Wei-Di-Huang formulas.

Outcome measurements

Primary outcomes

The experimenters will evaluate the effect of TCM prevention strategies on improving the physical condition of patients susceptible to Xinguan pneumonia. The efficacy of TCM preventative interventions in ameliorating COVID-19 susceptible body types (“Qi Yang deficiency” or “Qi Yin deficiency”) will be examined using three metrics: the “TCM Theory-Based Self-Assessment for Body Constitution Classification (30)”, a TCM Symptom Questionnaire (31), and a Fatigue Assessment Scale (32). The Traditional Chinese Medicine (TCM) Constitution Classification Self-Assessment Scale categorizes individuals into nine constitution types: balanced constitution (BC), Qi-deficient constitution (QDC), Yang-deficient constitution (YADC), Yin-deficient constitution (YIDC), phlegm-dampness constitution (PDC), damp-heat constitution (DHC), blood stasis constitution (SBC), Qi depression constitution (SQC), and inherited special constitution (ISC) (33). Each type is evaluated using a 5-point Likert scale (1= “never” to 5= “always”), reflecting physiological, psychological characteristics, and adaptability. Since 2009, this scale has been incorporated into China’s National Basic Public Health Service Standards and is widely used for health management and disease prevention (34-37). To ensure accuracy, trained researchers administered the scale via face-to-face interviews rather than self-reports, avoiding misinterpretation of TCM terminology. Second, the “TCM Symptom Questionnaire” scale is used to measure changes in TCM-specific symptoms before and after treatment, such as changes in “irritability” and “insomnia”. The “TCM Symptom Questionnaire” scale comprises 20 items, each with 4 response options. Scores for each symptom range from 1 (lowest) to 4 (highest), with the total score of the scale being 80. Higher scores on specific items represent stronger correlations with corresponding TCM symptoms. Additionally, there is ample justification for selecting the Fatigue Assessment Scale as a primary endpoint. The Fatigue Assessment Scale is a 13-item scale designed to measure fatigue status, with items scored using a 0–4 response scale anchored by “not at all” to “very much”. To derive a fatigue score, all items are summed to produce a single score ranging from 0 to 52, where higher scores indicate a stronger association with fatigue. Fatigue is one of the most common symptoms of acute sequelae following SARS-CoV-2 infection (PASC). For example, from 2020 to 2021, 63% of patients with long COVID in Tunisia had fatigue symptoms (38). From the perspective of TCM theory, fatigue is a core manifestation of the “Qi deficiency” syndrome; thus, alleviating fatigue through interventions directly reflects the therapeutic effect of “strengthening vital Qi”. Evidence further demonstrates that improvements in fatigue correlate with enhanced immune function, enabling this metric to reasonably translate to the study’s primary objective of “enhancing resistance to COVID-19”. The scale employed in this study exhibits high responsiveness to change, allowing it to sensitively detect improvements resulting from short-term interventions.

Depending on the identified body type, participants will undergo treatment tailored to their specific condition with a combination of “Yu-Ping-Feng” along with either “Xiang-Sha-Liu-Jun” for Qi and Yang deficiency or “Liu-Wei-Di-Huang” for Qi and Yin deficiency. In addition, based on the distribution characteristics of the COVID-19 incubation period (median incubation period of 5–8 days, with 90% of cases developing symptoms within 14 days and 99% within 21 days), this study employed a 1-month follow-up period to comprehensively capture infection events. This design ensures adequate assessment of susceptibility differences among various populations. Furthermore, from a feasibility perspective, an excessively long observation period would increase the risk of loss to follow-up, which is counterproductive to obtaining reliable conclusions. To mitigate the limitations of single-timepoint assessment, we will supplement infection data through monthly telephone follow-ups to ensure information completeness.

Alternative endpoints

Determine the biomarker variations caused by COVID-19 infection, following the guidelines set forth in the 7th Edition of “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia” (39).

Referring to the guidelines presented in the 7th Edition of the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia” jointly released by the National Health Commission and the State Administration of Traditional Chinese Medicine, we will carefully monitor and analyze the changes in specific biomarkers that are known to vary in response to COVID-19 infection. These encompass inflammatory markers [e.g., C-reactive protein (CRP), interleukin-6 (IL-6)] and immunological indicators such as CD4⁺ and CD8⁺ T-cell counts. By tracking these biomarker variations, we aim to gain insights into the disease’s progression and response to treatment, ultimately contributing to improved diagnosis, prognosis, and management of COVID-19 cases in Hong Kong.

The biochemical parameters under investigation encompass a comprehensive array, including:

• Hematological indices: complete blood picture and erythrocyte sedimentation rate (ESR) hepatic facility assessment: aspartate aminotransferase and alanine aminotransferase;
• Cardiac role evaluation: lactate dehydrogenase and troponin I;
• Renal activity monitoring: creatinine and blood urea nitrogen;
• Inflammatory and immunological markers: CRP, IL-6, CD4⁺ lymphocytes, and CD8⁺ lymphocytes.

Data management

To ensure data integrity and facilitate analysis, each set of scale responses and corresponding blood samples will be assigned a unique serial number that directly correlates with the questionnaires collected. For data entry, we will utilize EpiData 3.1, a specialized software that incorporates validation checks to prevent the entry of invalid or erroneous data. Upon completion of data entry, it is imperative to conduct data validation and cleaning. Any missing information, logical inconsistencies, errors, or uncertain data will be presented to the researchers in the form of a query list by the principal investigator, who is responsible for addressing these queries. Following verification, the database will be revised accordingly. Issues identified during the data validation and cleaning process should be promptly communicated to the supervisor, and researchers are required to provide responses. All queries and answers must be recorded on answer sheets, including requests for data supplementation and re-examination. Detailed documentation and proper storage of all query forms, erroneous data content, and modification outcomes are mandatory. The data from this study may be published in medical journals; however, we will ensure the confidentiality of the subjects’ information in accordance with legal requirements, and personal information of the subjects will not be disclosed unless required by pertinent legislation. Upon completion of the study, the raw data will be securely archived for a period of 5 years, ensuring its availability for potential follow-up analyses or future reference. After this retention period, the data will be destroyed unless an extension request is submitted to and approved by the Institutional Review Board (IRB), adhering to ethical guidelines and data protection protocols. Prior to any statistical analysis, all personal identifiers will be meticulously removed from the dataset to safeguard participant privacy and confidentiality.

Statistical analysis

The entire dataset will undergo statistical scrutiny using either R or SPSS software. For quantitative comparisons between two groups, the Student’s t-test will be adopted as the preferred method. When dealing with more than two groups for comparative analysis, the Repeated Measures analysis of variance (ANOVA) test will be employed to account for the repeated measures design. Categorical variables will be evaluated with the Chi-squared test to determine statistical significance. In addition, this research employs logistic and linear regression models to conduct multi-factor analysis. Outcomes exhibiting a P value below 0.05 will be considered statistically significant. The study leader will evaluate the preliminary findings to decide on the continuation of the trial and will ensure prompt reporting to the ethics committee for oversight and approval. Of particular importance, to enhance the methodological rigor of the study protocol, we have pre-specified a detailed statistical plan for handling missing data and addressing participant attrition. Primarily, two main analysis sets will be explicitly defined: the Full Analysis Set (FAS), which adheres to the Intention-to-Treat (ITT) principle and includes all randomized participants, and the Per-Protocol Set (PPS), which excludes participants with major protocol deviations. For managing missing data arising in the primary outcome analysis, priority will be given to employing the Multiple Imputation method. Furthermore, a sensitivity analysis is planned, wherein the results obtained after imputation will be compared with those from a complete-case analysis to rigorously test the robustness of the conclusions. Regarding potential participant attrition, a maximum acceptable threshold of 15% has been pre-defined. Should the actual attrition rate exceed this threshold, statistical methods such as pattern mixture models will be utilized to assess the potential bias introduced by the attrition. Moreover, the reasons for all participant withdrawals will be meticulously documented and compared across the different trial groups. All these analytical strategies have been explicitly pre-specified to ensure transparency throughout the analysis process and to bolster the credibility of the final results. Safety outcomes will be analyzed using descriptive statistics (incidence rate, severity grade) and the Chi-squared test/Fisher’s exact test for comparing adverse event rates between groups, while continuous safety indicators will be analyzed using the independent samples t-test.

Adverse events

In this research endeavor, an adverse event encompasses any untoward manifestation, be it a symptomatic issue or an abnormal outcome from laboratory evaluations, irrespective of its correlation to the therapeutic intervention. Examples of such occurrences encompass abdominal discomfort and distension, nausea, diarrhea, gastrointestinal disorders, and headaches. In the event that any of these adverse events surface during the course of treatment, participants will promptly discontinue the consumption of either TCM or the placebo, ensuring their well-being is prioritized. Furthermore, participants will receive prompt and vital TCM-based clinical management as necessary. All adverse reactions, along with their incidence rates, duration, severity, treatment measures, outcomes, and the relationship between the medication and dosage, will be meticulously and comprehensively documented.

Trial monitoring

The IRB of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB) is tasked with reviewing the scientific and ethical aspects of the research protocol and making recommendations on whether to continue or terminate the study. The IRB ensures the rationality of the research design and safeguards the rights and interests of the research subjects. Two members of the board are independent of the sponsors and researchers, with no conflicts of interest. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent will be obtained from all participants prior to any research activities. The study was reviewed and approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB) and the reference number is UW 20-480.

Discussion

The susceptibility of individuals with Qi deficiency to diseases can be explained from the perspectives of low immune function and energy metabolism disorders. In terms of immunity, patients with Qi deficiency may exhibit reduced lymphocyte function (such as T cells and B cells), decreased secretion of cytokines (such as IL-6 and IFN-γ), leading to a decrease in immune response ability (40,41). Meanwhile, individuals with Qi deficiency may experience mitochondrial dysfunction, leading to reduced ATP production, insufficient cellular energy supply, and affecting the function of immune cells (42-45). In addition, energy metabolism disorders lead to a decrease in cell repair and regeneration capabilities, making it difficult for the body to cope with external stress.

The resistance of people with Yin deficiency will decrease, which is related to chronic inflammation and oxidative stress. The levels of pro-inflammatory cytokines (such as IL-6 and TNF-α) may increase in individuals with Yin deficiency, leading to chronic low-grade inflammation (46). In addition, the activity of antioxidant enzymes (such as SOD and GSH Px) in individuals with Yin deficiency is reduced, leading to the accumulation of free radicals and damage to cells and tissues (47). Chronic inflammation and oxidative stress can damage immune cells and cause a decline in the body’s immune function.

The ability of defense against pathogens in patients with Yang deficiency is weakened, and hypothyroidism of thyroid and adrenal cortex is a typical example. The decrease of thyroid hormone level leads to the decline of basic metabolic rate and the weakening of immune function (48,49). At the same time, its cortisol secretion is insufficient, which causes the decline of stress response ability and affects immune regulation (50).

In TCM, COVID-19 is classified as an “epidemic disease” caused by external pathogenic factors. The virus enters the body through the nose and mouth, primarily targeting the lungs and respiratory system. According to TCM principles of the five phases (wood, fire, earth, metal, water) and their interactions—mutual generation, restriction, and counter-restriction—the pathogen may spread to or exacerbate dysfunction in other organs, such as the heart, spleen, stomach, liver, and kidneys. This progression is fundamentally linked to the weakness of the body’s vital energy, which corresponds to immunity in modern medicine. As stated in the Huangdi Neijing, “When vital energy is sufficient, pathogenic factors cannot invade; where pathogens gather, the vital energy must be deficient”. This underscores the centrality of vital energy in disease resistance. Consequently, TCM emphasizes protecting and enhancing this energy through herbal therapies that replenish Qi and nourish blood. By strengthening the body’s innate defenses to block viral invasion, mitigate systemic damage, and restore balance, aligning with both classical TCM theory and contemporary understandings of immune modulation.

In TCM, COVID-19 interventions are categorized into Qi-Yang deficiency and Qi-Yin deficiency based on constitutional differences. Qi-Yang deficiency requires warming and tonifying therapies. Yupingfeng San boosts immunity, while Xiangsha Liujunzi Tang strengthens the spleen and Yang. Qi-Yin deficiency focuses on nourishing Yin. Yupingfeng San is paired with Liuwei Dihuang Wan to consolidate defenses and replenish fluids. This approach aligns with TCM’s “syndrome differentiation”) and modern evidence on immune modulation and antiviral effects.

In short, TCM has rich knowledge and practical experience in the prevention of pulmonary infectious diseases, which can develop new ideas for the clinical prevention and control of new coronal pneumonia. Therefore, it is important to further develop TCM to prevent COVID-19.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2423/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2423/prf

Funding: This research received partial support from the University of Hong Kong Research Council (Nos. 104004092 and 104004460); Wong’s donation (No. 200006276); the Gaia Family Trust of New Zealand (No. 200007008); Hong Kong RGC (Nos. 740608, 766211, 17152116, and 17121419); Health and Medical Research Fund (Nos. 15162961, 16172751, 18192141, and 21222101); HKU Enhanced New Staff Start-up Fund (No. 204610519); HKU Pre-emptive Retention Fund (No. 202007002); and the Hubei Provincial International Science & Technology Cooperation Program (No. 2022EHB046).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2423/coif). All authors report that this research received partial support from the University of Hong Kong Research Council (Nos. 104004092 and 104004460); Wong’s donation (No. 200006276); the Gaia Family Trust of New Zealand (No. 200007008); Hong Kong RGC (Nos. 740608, 766211, 17152116, and 17121419); Health and Medical Research Fund (Nos. 15162961, 16172751, 18192141, and 21222101); HKU Enhanced New Staff Start-up Fund (No. 204610519); HKU Pre-emptive Retention Fund (No. 202007002); and the Hubei Provincial International Science & Technology Cooperation Program (No. 2022EHB046). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are 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 study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent will be obtained from all participants prior to any research activities. The study was reviewed and approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB) and the reference number is UW 20-480.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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