Effectiveness of Five-Element Regulatory Therapy for Long COVID Symptoms

While the global COVID-19 pandemic has been declared over, its various sequelae continue to afflict the physical and mental health of a large number of patients in China (1 –6). A systematic review covered 194 studies and 735,006 participants found that the five most common symptoms of post-COVID infection were fatigue (28.4%), pain/discomfort (29.7%), sleep disturbances (23.5%), breathing difficulties (22.6%), and activity limitations (22.3%) (7). A recent large-scale study on COVID-19 sequelae provided a systematic definition of "long COVID" for the first time (8). The research found that approximately 10% of individuals develop long COVID after infection with the Omicron variant, with up to 12 different symptoms including fatigue, cough, palpitations, hair loss, loss of sense of smell and taste, brain fog, chest pain, and changes in libido.

Current scientific understanding of long COVID suggests a complex, multi-system condition, with symptoms persisting for months or even years after the initial infection. The mechanisms remain incompletely understood but involve multiple interconnected pathways, including viral persistence (9), chronic inflammation (10), endothelial damage (11), mitochondrial (12), and autonomic nervous system dysregulation (13). Additionally, SARS-CoV-2's broad tissue tropism via ACE2 receptors contributes to multi-organ damage, with cardiovascular, pulmonary, and metabolic sequelae being particularly prevalent (14). Emerging evidence also highlights the overlap with post-infectious syndromes, characterized by post-exertional malaise and unrefreshing sleep, with COVID-19 increasing the risk of post-infectious syndromes (15).

Current treatments for long COVID being investigated in clinical trials include non-pharmacological interventions such as physical exercise, rehabilitation therapy, and behavioral therapy, as well as pharmacological therapies like herbs, Paxlovid, and fluvoxamine (16). Psychological interventions like "awe therapy" also demonstrate benefits in reducing depression and stress (17). However, targeted and clinically proven therapies remain limited, with most current approaches focusing primarily on symptom management rather than treating the root pathological mechanisms.

Traditional Chinese Medicine (TCM) formulations including Shenhuang granule (18), JingYinGuBiao Formula (19), and Bufei Huoxue capsules (20) have demonstrated therapeutic potential in COVID-19 management within the Chinese clinical context. In the treatment of post-COVID sequelae, these TCM formulations have also exhibited significant therapeutic potential (21). Five-Element Regulation Therapy (FERT) is a set of therapeutic methods summarized by our team based on the theory of TCM constitution and clinical practice (22, 23). It classifies patients into five syndrome types (wood, fire, earth, metal, water) according to different main symptoms, and adopts different treatment approaches for groups with different syndrome types. Our research team has employed FERT for post-COVID syndrome management and observed certain therapeutic effects in case studies. However, these preliminary findings remain at the anecdotal evidence level and cannot provide evidence-based support for FERT's clinical application in post-COVID treatment. To investigate the clinical effects of FERT in managing post-COVID symptoms, we conducted a retrospective cohort study analyzing its application at the COVID Recovery Clinic within the Department of Traditional Chinese Medicine at Peking University Third Hospital.

Five-Element Regulation Therapy originates from TCM constitution theory and is a therapeutic method developed through our team's clinical practice. During the COVID-19 outbreak in Beijing in 2022, the Department of TCM at Peking University Third Hospital established a dedicated COVID clinic. In its later stages, this clinic treated a large number of patients suffering from post-COVID sequelae. Based on the symptom profiles observed in this patient population, our team applied FERT as a treatment. However, the comparative effectiveness of FERT versus conventional TCM treatment remained unclear. This study employed a retrospective cohort design to analyze the differences in efficacy between FERT and conventional TCM therapy. The findings suggest that FERT may be more effective than conventional TCM treatment for alleviating post-COVID symptoms.

During the early battle against COVID-19 in Wuhan in 2020, TCM experts identified the disease as a "cold-dampness syndrome," providing direction for its TCM treatment (24 –27). In our clinical observations of Beijing patients, we identified distinct manifestations at different stages of post-COVID sequelae. Initially, most patients self-medicated, with some developing cough. Subsequently, patients primarily sought medical attention for cough and dyspnea. Later, their chief complaints shifted toward panic attacks, chest tightness, and palpitations. In later stages, psychological symptoms such as insomnia, irritability, anxiety, and depression were frequently observed. Some patients progressed to develop chronic fatigue, dry mouth, low-grade fever, or even reproductive dysfunction. These manifestations align with the TCM Five Elements Theory, and the data confirmed the progression sequence (Metal → Earth → Fire → Wood → Water), supporting our hypothesis. Patients were categorized into one of the Five Phase groups, and tailored body recuperative formulas were designed accordingly.

Five-Element Regulation Therapy employs five distinct prescriptions corresponding to the five symptom patterns. In this study, we observed the effects of four prescriptions, but data for the Metal Formula is lacking. This is because the Metal Formula, derived from a modified Qingfei Paidu Decoction (28, 29), primarily targets early-stage infection symptoms, including fever, cough, headache, and fatigue. However, as most patients self-administered antipyretic drugs during the initial COVID-19 phase, subsequent fever symptoms were generally mild. Consequently, the application of this specific formula in the outpatient setting was limited, resulting in an insufficient number of patients categorized under the Metal phase for observation.

The potential reasons for FERT's superiority over conventional TCM treatment lie in its innovative integration of the dynamic pattern differentiation framework from TCM Five Elements theory with the unique pathological progression of post-COVID sequelae. The therapy precisely categorizes symptom progression into five sequential syndrome patterns according to the generative cycle of the Five Phases: Early-stage pulmonary symptoms (Metal Disease, mean 38 days), Persistent respiratory impairment (Earth Disease, mean 38 days), Cardiovascular disturbances (Fire Disease, mean 56 days), Emotional dysregulation (Wood Disease, mean 73 days), Systemic exhaustion in advanced stages (Water Disease, mean 114 days). FERT employs tailored prescriptions targeting the core pathogenesis of each stage, with individualized modifications based on specific symptoms. This temporally stratified intervention strategy effectively aligns with the characteristic sequential multi-system damage observed in post-COVID sequelae. In contrast, conventional TCM's static pattern differentiation fails to capture this dynamic progression. Consequently, FERT demonstrates significant advantages, evidenced by a 75% clinical cure rate for the Water Disease and a 95.8% response rate for the Fire Disease – markedly higher than the control group. These benefits are particularly pronounced in middle-to-late-stage patients.

We acknowledge several limitations in this study. First, as an observational retrospective cohort study, it is inherently prone to selection bias and confounding factors, which may compromise the validity of results. Retrospective data reliance on existing records may lack standardized documentation for some variables, increasing information bias and distorting FERT-outcome associations. Non-randomized design also leaves baseline group differences unbalanced, causing residual confounding. Second, the small sample size, especially when stratified by TCM syndrome types, reduces statistical power to detect subgroup differences and raises type II error risk. Third, lacking long-term follow-up beyond 2 weeks hinders conclusions on FERT's durability and long-term efficacy. Fourth, the single-tertiary-hospital outpatient population in Beijing limits generalizability to other regions, settings, or ethnic groups. Fifth, the primary endpoints of observation were all based on subjective symptom reports, lacking objective indicators. Finally, the absence of placebo control prevents isolating FERT's specific effects, as other factors may contribute.

This retrospective cohort study investigated the potential role of FERT in managing post-COVID-19 sequelae. The results demonstrated that FERT may be superior to conventional TCM therapy in improving post-COVID symptoms including chronic cough, fatigue, insomnia, and pain. However, given the study's retrospective design and limitations such as the lack of a blank control group, these findings should be interpreted with caution. Future high-quality studies are warranted to further analyze the therapeutic effects of FERT.