{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:20:07Z","timestamp":1778736007494,"version":"3.51.4"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chinese herbal acupoint application (HAA) is recommended by certain guidelines for treating mild-to-moderate COVID-19; however, evidence supporting its effectiveness remains limited. This study aimed to evaluate the effectiveness and safety of HAA in adult patients with fever and mild-to-moderate COVID-19.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This multicenter, randomized, double-blind, placebo-controlled trial was conducted at six hospitals in China. Overall, 364 participants were randomly assigned in a 1:1 ratio to receive either the herbal or placebo acupoint application. All participants received applications at the Dazhui (GV14) and Feishu (BL13) acupoints three times daily for 2 h per application over 5 days and <jats:italic>Fuzheng Jiebiao Decoction<\/jats:italic> orally three times daily, three bags per dose. The primary outcome was complete fever relief time. Secondary outcomes included the onset time of fever reduction, changes in symptom scores, routine blood tests, and acetaminophen usage rates and dosages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Regarding the primary outcome, HAA significantly reduced complete fever relief time compared to placebo (31.75 vs. 52.00 h; <jats:italic>p<\/jats:italic> &amp;lt; 0.0001). Regarding secondary outcomes, the herbal group also demonstrated a shorter onset time of fever reduction than the placebo group (24.35 vs. 34.42 h; <jats:italic>p<\/jats:italic> &amp;lt; 0.0001). HAA significantly reduced total symptom scores, particularly fever, headache, and cough symptoms. Moreover, 52 patients (29.05%) in the herbal group used acetaminophen, with a median dosage of 0.3 g (0.3, 0.6), which was significantly lower than that in the placebo group, with 94 patients using 0.6 g (0.3, 0.9; <jats:italic>p<\/jats:italic> &amp;lt; 0.05). No significant differences were observed in routine blood test results between the groups (<jats:italic>p<\/jats:italic> &amp;gt; 0.05), and no serious adverse events (SAEs) were reported in either group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Chinese herbal acupoint application effectively and safely shortened the complete fever relief time and onset time of fever reduction; alleviated clinical symptoms, particularly fever, headache, and cough; and reduced the need for antipyretic analgesics in adult patients with fever and mild-to-moderate COVID-19.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p><jats:ext-link>https:\/\/www.chictr.org.cn\/showproj.html?proj=188270<\/jats:ext-link>, identifier: ChiCTR2200067178.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2025.1577976","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T08:56:29Z","timestamp":1750323389000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Effectiveness and safety of Chinese herbal acupoint application in adult patients with fever and mild-to-moderate COVID-19: a multicenter, randomized, double-blind, placebo-controlled trial"],"prefix":"10.3389","volume":"16","author":[{"given":"Yicheng","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaheng","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zongchen","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benliang","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiuyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peili","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenhao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhixi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baojin","family":"Hua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luqi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wensheng","family":"Qi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41392-022-00997-x","article-title":"SARS-CoV-2 omicron variant: recent progress and future perspectives","volume":"7","author":"Fan","year":"2022","journal-title":"Signal Transduct Target Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"968","DOI":"10.3390\/vaccines11050968","article-title":"Clinical characteristics of mild patients with breakthrough infection of omicron variant in China after relaxing the dynamic zero COVID-19 policy","volume":"11","author":"He","year":"2023","journal-title":"Vaccines."},{"key":"B3","doi-asserted-by":"publisher","first-page":"7","DOI":"10.7507\/1671-6205.202301036","article-title":"Symptom reported by hospital staff with mild COVID-19 during the Omicron epidemicin Chongqing","volume":"22","author":"Feng","year":"2023","journal-title":"Chin J Respir Crit Care Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1016\/j.scib.2024.04.040","article-title":"Effectiveness and safety of sanhan huashi granules versus nirmatrelvir-ritonavir in adult patients with COVID-19: a randomized, open-label, multicenter trial","volume":"69","author":"Zou","year":"2024","journal-title":"Science Bulletin."},{"key":"B5","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/j.joim.2023.08.003","article-title":"The role and advantage of traditional Chinese medicine in the prevention and treatment of COVID-19","volume":"21","author":"Huang","year":"2023","journal-title":"J Integr Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e35081","DOI":"10.1016\/j.heliyon.2024.e35081","article-title":"Effectiveness of seven oral traditional Chinese medicines against mild or moderate COVID-19: an updated systematic review and network meta-analysis","volume":"10","author":"Zhang","year":"2024","journal-title":"Heliyon."},{"key":"B7","doi-asserted-by":"publisher","first-page":"462","DOI":"10.13703\/j.0255-2930.20200302-k0009","article-title":"Guidance of acupuncture intervention on coronavirus disease 2019","volume":"40","author":"Shi","year":"2020","journal-title":"Chin Acupunct Moxibustion"},{"key":"B8","doi-asserted-by":"publisher","first-page":"681","DOI":"10.16368\/j.issn.1674-8999.2020.04.154","article-title":"Expert consensus on rehabilitation of Chinese medicine for COVID-19 (First Edition)","volume":"35","author":"Li","year":"2020","journal-title":"China J Chin Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"390","DOI":"10.13703\/j.0255-2930.20210330-k0005","article-title":"Acupoint application for exogenous fever: a multi-central retrospective cohort study","volume":"42","author":"Li","year":"2022","journal-title":"Chin Acupunct Moxibustion."},{"key":"B10","doi-asserted-by":"publisher","first-page":"241","DOI":"10.13703\/j.0255-2930.20210907-0002","article-title":"Gao R. Influence of acupoint application on clinical use of antibiotics: a real world study of 123 million primary clinic patients","volume":"42","author":"Li","year":"2022","journal-title":"Chin Acupunct Moxibustion."},{"key":"B11","year":"2022","journal-title":"Guidelines for the Diagnosis and Treatment of Coronavirus Disease2019 (trial version ninth)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"155025","DOI":"10.1016\/j.phymed.2023.155025","article-title":"Efficacy and safety of huashi baidu granule plus nirmatrelvir-ritonavir combination therapy in patients with high-risk factors infected with omicron (B11529): a multi-arm single-center, open-label, randomized controlled trial","volume":"120","author":"Yu","year":"2023","journal-title":"Phytomedicine."},{"key":"B13","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nri3843","article-title":"Fever and the thermal regulation of immunity: the immune system feels the heat","volume":"15","author":"Evans","year":"2015","journal-title":"Nat Rev Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1002\/path.5471","article-title":"Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19)","volume":"251","author":"Bourgonje","year":"2020","journal-title":"J Pathol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.jiph.2011.05.002","article-title":"Fever, fever patterns and diseases called \u2018fever' \u2013 a review","volume":"4","author":"Ogoina","year":"2011","journal-title":"J Infect Public Health."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1016\/S0140-6736(22)00462-7","article-title":"Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B11529) and delta (B16172) variants in England: a cohort study","volume":"399","author":"Nyberg","year":"2022","journal-title":"Lancet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"n3103","DOI":"10.1136\/bmj.n3103","article-title":"Covid-19: runny nose, headache, and fatigue are commonest symptoms of omicron, early data show","volume":"375","author":"Iacobucci","year":"2021","journal-title":"BMJ."},{"key":"B19","doi-asserted-by":"publisher","first-page":"8012","DOI":"10.26355\/eurrev_202112_27652","article-title":"Omicron SARS-CoV-2 new variant: global prevalence and biological and clinical characteristics","volume":"25","author":"Meo","year":"2021","journal-title":"Eur Rev Med Pharmacol Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1016\/S0140-6736(22)00327-0","article-title":"Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID study","volume":"399","author":"Menni","year":"2022","journal-title":"Lancet."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001065","article-title":"Elevated temperature inhibits SARS-CoV-2 replication in respiratory epithelium independently of IFN-mediated innate immune defenses","author":"Herder","year":"2021","journal-title":"PLoS Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"m1086","DOI":"10.1136\/bmj.m1086","article-title":"Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists","volume":"368","author":"Day","year":"2020","journal-title":"BMJ."},{"key":"B23","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1002\/art.41593","article-title":"Nonsteroidal antiinflammatory drugs and susceptibility to COVID-19","volume":"73","author":"Chandan","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1259.e5","DOI":"10.1016\/j.cmi.2020.06.003","article-title":"Ibuprofen use and clinical outcomes in COVID-19 patients","volume":"26","author":"Rinott","year":"2020","journal-title":"Clin Microbiol Infect."},{"key":"B25","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1164\/rccm.201802-0229LE","article-title":"Nonsteroidal antiinflammatory drug use and clinical outcomes of community-acquired pneumonia","volume":"198","author":"Basille","year":"2018","journal-title":"Am J Respir Crit Care Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1258\/jrsm.2010.090441","article-title":"The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis","volume":"103","author":"Eyers","year":"2010","journal-title":"J R Soc Med."},{"key":"B27","first-page":"2968","article-title":"Molecular mechanism of Mahuang Decoction in treating fever caused by coronavirus disease 2019: a network pharmacology-based analysis","volume":"42","author":"Tang","year":"2020","journal-title":"Guangxi Med J."},{"key":"B28","doi-asserted-by":"publisher","first-page":"22","DOI":"10.13935\/j.cnki.sjzx.220105","article-title":"Effects of Mahuang and Guizhi on Dazhui points on IL-6,IL-1\u03b2 and TNF-A in lung tissues of fever rats","volume":"17","author":"Li","year":"2022","journal-title":"World J Int Tradit Western Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"110679","DOI":"10.1016\/j.biopha.2020.110679","article-title":"Botany, traditional uses, phytochemistry, analytical methods, processing, pharmacology and pharmacokinetics of bupleuri radix: a systematic review","volume":"131","author":"Jiang","year":"2020","journal-title":"Biomed Pharmacother."},{"key":"B30","doi-asserted-by":"publisher","first-page":"116375","DOI":"10.1016\/j.jep.2023.116375","volume":"310","author":"Kang","year":"2023","journal-title":"J Ethnopharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"114138","DOI":"10.1016\/j.colsurfb.2024.114138","article-title":"Contribution of chemical permeation enhancers to the process of transdermal drug delivery: adsorption, microscopic interactions, and mechanism","volume":"243","author":"Jiang","year":"2024","journal-title":"Colloids Surf B Biointerfaces."},{"key":"B32","doi-asserted-by":"publisher","first-page":"155848","DOI":"10.1016\/j.phymed.2024.155848","article-title":"Advances and perspectives on pharmacological activities and mechanisms of the monoterpene borneol","volume":"132","author":"Hu","year":"2024","journal-title":"Phytomedicine."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.3109\/03639045.2015.1107095","article-title":"Effect of borneol on the transdermal permeation of drugs with differing lipophilicity and molecular organization of stratum corneum lipids","volume":"42","author":"Yi","year":"2016","journal-title":"Drug Dev Ind Pharm."},{"key":"B34","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.phymed.2018.05.010","article-title":"Comparison of the anti-inflammatory effects of Sinapis alba and Brassica juncea in mouse models of inflammation","volume":"50","author":"Xian","year":"2018","journal-title":"Phytomedicine."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1113583","DOI":"10.3389\/fphar.2023.1113583","article-title":"Sinapis semen: a review on phytochemistry, pharmacology, toxicity, analytical methods and pharmacokinetics","volume":"14","author":"Dang","year":"2023","journal-title":"Front Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"104195","DOI":"10.1016\/j.fitote.2019.104195","article-title":"Mechanisms of white mustard seed (Sinapis alba L) volatile oils as transdermal penetration enhancers","volume":"138","author":"Ruan","year":"2019","journal-title":"Fitoterapia."},{"key":"B37","doi-asserted-by":"publisher","first-page":"155","DOI":"10.19378\/j.issn.1003-9783.2018.02.006","article-title":"Effect of volatile oil from Sinapis semen on percutaneous permeability of the \u201cTreatment of Winter Disease in Summer\u201d prescription","volume":"29","author":"Ruan","year":"2018","journal-title":"Tradit Chin Drug Res Clin Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e34610","DOI":"10.1097\/MD.0000000000034610","article-title":"Acupressure in the treatment of patients with mild infection of COVID-19 omicron variant: a prospectively observational study","volume":"102","author":"Yang","year":"2023","journal-title":"Medicine."},{"key":"B39","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1007\/s11655-016-2497-y","article-title":"Association between skin reactions and efficacy of summer acupoint application treatment on chronic pulmonary disease: a prospective study","volume":"22","author":"Wu","year":"2016","journal-title":"Chin J Integr Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"119441","DOI":"10.1016\/j.jep.2025.119441","article-title":"Investigation of the efficacy and potential pharmacological mechanism of yupingfeng in treating chronic obstructive pulmonary disease: a meta-analysis and in silico study","volume":"343","author":"Xu","year":"2025","journal-title":"J Ethnopharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1002\/ptr.5628","article-title":"Adjuvant treatment with yupingfeng formula for recurrent respiratory tract infections in children: a meta-analysis of randomized controlled trials","volume":"30","author":"Song","year":"2016","journal-title":"Phytother Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"956736","DOI":"10.3389\/fphar.2022.956736","article-title":"Efficacy and safety of Chinese herbal medicine for pneumonia convalescence in children: a systematic review and meta-analysis","volume":"13","author":"Guo","year":"2022","journal-title":"Front Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.chmed.2022.02.001","article-title":"Identifying absorbable bioactive constituents of yupingfeng powder acting on COVID-19 through integration of UPLC-Q\/TOF-MS and network pharmacology analysis","volume":"14","author":"Wang","year":"2022","journal-title":"Chin Herb Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.21037\/lcm.2020.01.01","article-title":"Placebo and food cravings control: results from two randomized controlled trials","volume":"3","author":"Rodr\u00edguez-Mart\u00edn","year":"2020","journal-title":"Longhua Chin Med"},{"key":"B45","volume-title":"Pharmacopoeia of the People's Republic of China: 2020 Edition","year":"2020"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1577976\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T08:56:35Z","timestamp":1750323395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1577976\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":45,"alternative-id":["10.3389\/fneur.2025.1577976"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2025.1577976","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]},"article-number":"1577976"}}