Background
Over 65 million people have long COVID. Evidence for using Chinese herbal medicine (CHM) to treat long COVID is growing. A systematic review of evidence for guiding clinical decision is warranted.
Objective
To examine the effects and safety of CHM in alleviating the severity of dyspnea, fatigue, exercise intolerance, depression, anxiety and insomnia in long COVID adults based on registered randomized clinical trials (RCT).
Search strategy
World Health Organization International Clinical Trials Registry Platform and Chinese Clinical Trial Registry were searched for registered trial protocols from database inception to February 10, 2023. English (PubMed, Embase, AMED and CINAHL) and Chinese databases (CNKI, Wanfang Data and CQVIP) were then searched to identify relevant publications from December 2019 through April 6, 2023.
Inclusion criteria
Registered RCTs that compared the effects of Chinese herbal medicines or Chinese herbal formulas against a control treatment (i.e., the placebo or usual care) in adults with persistent symptoms of long COVID. The primary outcome of dyspnea, and secondary outcomes of fatigue, exercise intolerance, depression, anxiety and insomnia were measured using validated tools at the end of the treatment.
Data extraction and analysis
Data were extracted, and eligible RCTs were evaluated using version 2 of the Cochrane risk-of-bias tool for randomized trials and Grading of Recommendations, Assessment, Development and Evaluations independently by two researchers. Effect sizes were estimated by random-effects modelling and mean difference (MD). Heterogeneity between trials was quantified by I2.
Results
Among the 38 registered clinical trials we identified, seven RCTs (1,519 patients) were included in the systematic review. One RCT had a low overall risk of bias. Compared to the control, CHM reduces dyspnea on the Borg Dyspnea Scale score (MD = –0.2, 95% confidence interval [CI] = –0.65 to 0.25) with moderate certainty, and reduces fatigue on the Borg Scale (MD = –0.48, 95% CI = –0.74 to –0.22) with low certainty. CHM clinically reduces depression on Hamilton Depression Rating Scale score (MD = –6.00, 95% CI = –7.56 to –4.44) and anxiety on Hamilton Anxiety Rating Scale score (MD = –6.10, 95% CI = –7.67 to –4.53), and reduces insomnia on the Insomnia Severity Index (MD = –4.86, 95% CI = –12.50 to 2.79) with moderate certainty. Meta-analysis of two RCTs (517 patients) showed that CHM clinically improves exercise intolerance by increasing 6-minute walking distance (MD = –15.92, 95% CI = –10.20 to 42.05) with substantial heterogeneity (I2 = 68%) and low certainty.
Conclusion
CHM is associated with a post-treatment clinical reduction in depression and anxiety in long COVID adults, compared to the control, but it does not have a strong treatment effect on dyspnea and insomnia. Effects of CHM on exercise intolerance and fatigue are uncertain, and the safety of using CHM remains questionable.

Key words: Long COVID, Dyspnea, Chinese herbal medicine, Effectiveness, Safety