Randomized, waitlist-controlled trial of Cordyceps sinensis mycelium culture extract (Cs4) for long COVID patients in Hong Kong

Abstract

We assessed Cordyceps sinensis mycelium culture extract (Cs4) for alleviating long COVID symptoms. In this randomized trial 110 participants were assigned to receive Cs4 (55 participants) or were waitlisted (55 participants) for 12 weeks. The primary outcome was the change in long COVID symptom severity at 12 weeks, as measured by the modified COVID-19 Yorkshire Rehabilitation Scale. The secondary outcomes included changes in the Brief Fatigue Inventory Form, Insomnia Severity Index, Hospital Anxiety and Depression Scale, St. George’s Respiratory Questionnaire, and the Short Form 12 health survey at 12 weeks. Participants receiving Cs4 showed improvement in long COVID symptoms compared to the waitlist control group (MD, −10.1; 95% CI, −14.1 to −6.1; P < 0.001) at 12 weeks. Cs4 recipients also experienced improvement in fatigue (MD, −8.1; 95% CI, −14.2 to −2.0; P = 0.011), insomnia (MD, −2.9; 95% CI, −4.6 to −1.2; P = 0.001), and respiratory symptoms (MD, −6.3; 95% CI, −11.4 to −1.2; P = 0.018). Cs4 also improved the quality of life (physical component MD, 7.0; 95% CI, 4.2–9.8; P < 0.001; mental component MD, 6.8; 95% CI, 2.9–10.7; P < 0.001). No severe adverse events were reported. Cs4 may be a beneficial treatment for patients with long COVID symptoms.

Keywords

Long COVID / Cordyceps sinensis (Berk) Sacc / Cs4 / randomized trial / modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm)

References

[1] WHO. Post COVID-19 condition (Long COVID) . 2022 [https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition] Cited January 22, 2025.

[2] Michelen M, Manoharan L, Elkheir N, Cheng V, Dagens A, Hastie C, et al.: Characterising Long COVID: A Living Systematic Review. BMJ Global Health 2021, 6: e005427.

[3] Aiyegbusi OL, Hughes SE, Turner G, Rivera SC, McMullan C, Chandan JS, et al.: Symptoms, Complications and Management of Long COVID: A Review. Journal of the Royal Society of Medicine 2021, 114: 428-442.

[4] Stein SR, Ramelli SC, Grazioli A, Chung JY, Singh M, Yinda CK, et al.: SARS-CoV-2 Infection and Persistence in the Human Body and Brain at Autopsy. Nature 2022, 612: 758-763.

[5] Choutka J, Jansari V, Hornig M, Iwasaki A: Unexplained Post-Acute Infection Syndromes. Nature Medicine 2022, 28: 911-923.

[6] Moss P: The T Cell Immune Response against SARS-CoV-2. Nature Immunology 2022, 23: 186-193.

[7] Chi Y, Ge Y, Wu B, Zhang W, Wu T, Wen T, et al.: Serum Cytokine and Chemokine Profile in Relation to the Severity of Coronavirus Disease 2019 in China. The Journal of Infectious Diseases 2020, 222: 746-754.

[8] Peluso MJ, Lu S, Tang AF, Durstenfeld MS, Ho HE, Goldberg SA, et al.: Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. The Journal of Infectious Diseases 2021, 224: 1839-1848.

[9] Schultheiß C, Willscher E, Paschold L, Gottschick C, Klee B, Henkes SS, et al.: The IL-1β, IL-6, and TNF Cytokine Triad is Associated with Post-Acute Sequelae of COVID-19. Cell Reports Medicine 2022, 3: 100663.

[10] Bateman L, Bested AC, Bonilla HF, Chheda BV, Chu L, Curtin JM, et al.: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management. Mayo Clinic Proceedings 2021, 96: 2861-2878.

[11] Bolton MJ, Chapman BP, Van Marwijk H: Low-Dose Naltrexone as a Treatment for Chronic Fatigue Syndrome. BMJ Case Reports 2020, 13: e232502.

[12] Davis HE, McCorkell L, Vogel JM, Topol EJ . Long COVID: Major Findings, Mechanisms and Recommendations. Nature Reviews Microbiology 2023, 21: 133-146.

[13] Zhang L, Xu Z, Mak JWY, Chow KM, Lui G, Li TCM, et al.: Gut Microbiota-Derived Synbiotic Formula (SIM01) as a Novel Adjuvant Therapy for COVID-19: An Open-Label Pilot Study. Journal of Gastroenterology and Hepatology 2022, 37: 823-831.

[14] Badran BW, Huffman SM, Dancy M, Austelle CW, Bikson M, Kautz SA, et al.: A Pilot Randomized Controlled Trial of Supervised, At-Home, Self-Administered Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) to Manage Long COVID Symptoms. Bioelectronic Medicine 2022, 8: 13.

[15] Chen J, Chan WM, Leung HY, Leong PK, Yan CTM, Ko KM . Anti-Inflammatory Effects of a Cordyceps Sinensis Mycelium Culture Extract (Cs-4) on Rodent Models of Allergic Rhinitis and Asthma. Molecules 2020, 25: 4051.

[16] Hoi YL, Tai MY, Kam MK: Antioxidant and Immunopotentiating Effects of Cordyceps Mycelium Extract, Chicken Essence, and Their Combination in Experimental Model. Chinese Medicine 2021, 12.

[17] Kishimoto N, Satoshi S, Kyo M, Tokio F: In Vitro Antifungal and Antiviral Activities of. GAMMA.-and. DELTA.-Lactone Analogs Utilized as Food Flavoring. Biocontrol Science 2005, 10: 31-36.

[18] Klok FA, Boon GJAM, Barco S, Endres M, Geelhoed JJM, Knauss S, et al.: The Post-COVID-19 Functional Status Scale: A Tool to Measure Functional Status Over Time After COVID-19. European Respiratory Journal 2020, 56: 2001494.

[19] NICE. Covid-19 Rapid Guideline: Managing the Long-Term Effects of Covid-19 . 2020, 19.

[20] NHS England . National Guidance for Post-COVID Syndrome Assessment Clinics . 2021.

[21] Sivan M, Preston N, Parkin A, Makower S, Gee J, Ross D, et al.: The Modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) Patient-Reported Outcome Measure for Long Covid or Post-COVID-19 Syndrome. Journal of Medical Virology 2022, 94: 4253-4264.

[22] Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al.: The Rapid Assessment of Fatigue Severity in Cancer Patients: Use of the Brief Fatigue Inventory. Cancer 1999, 85: 1186-1196.

[23] Bastien CH, Vallières A, Morin CM: Validation of the Insomnia Severity Index as an Outcome Measure for Insomnia Research. Sleep Medicine 2001, 2: 297-307.

[24] Zigmond AS, Snaith RP . The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica 1983, 67: 361-370.

[25] Jones PW, Quirk FH, Baveystock CM . The St George’s Respiratory Questionnaire. Respiratory Medicine 1991, 85(Suppl B): 25-31; discussion 33-37.

[26] Ware J, Jr, Kosinski M, Keller SD: A 12-Item Short-Form Health Survey: Construction of Scales and Preliminary Tests of Reliability and Validity. Medical Care 1996, 34: 220-233.

[27] Sakpal TV: Sample Size Estimation in Clinical Trial. Perspectives in Clinical Research 2010, 1: 67-69.

[28] Lau RI, Su Q, Lau ISF, Ching JYL, Wong MCS, Lau LHS, et al.: A Synbiotic Preparation (SIM01) for Post-Acute COVID-19 Syndrome in Hong Kong (RECOVERY): A Randomised, Double-Blind, Placebo-Controlled Trial. The Lancet Infectious Diseases 2024, 24: 256-265.

[29] Xiao Y, Huang X, Zhu J: Randomized Double-Blind Placebo-Controlled Clinical Trial and Assessment of Fermentation Product of Cordyceps Sinensis (Cs-4) in Enhancing Aerobic Capacity and Respiratory Function of the Healthy Elderly Volunteers. Chinese Journal of Integrative Medicine 2004, 10: 187-192.