Efficacy of Thymosin Alpha 1 in the Treatment of COVID-19: A Multicenter Cohort Study

Jiao Liu, Yanfei Shen, Zhenliang Wen, Qianghong Xu, Zhixiong Wu, Huibin Feng, Zhongyi Li, Xuan Dong, Sisi Huang, Jun Guo, Lidi Zhang, Yizhu Chen, Wenzhe Li, Wei Zhu, Hangxiang Du, Yongan Liu, Tao Wang, Limin Chen, Jean-Louis Teboul, Djillali Annane, Dechang Chen, Jiao Liu, Yanfei Shen, Zhenliang Wen, Qianghong Xu, Zhixiong Wu, Huibin Feng, Zhongyi Li, Xuan Dong, Sisi Huang, Jun Guo, Lidi Zhang, Yizhu Chen, Wenzhe Li, Wei Zhu, Hangxiang Du, Yongan Liu, Tao Wang, Limin Chen, Jean-Louis Teboul, Djillali Annane, Dechang Chen

Abstract

Background: Thymosin alpha 1 (Tα1) is widely used to treat patients with COVID-19 in China; however, its efficacy remains unclear. This study aimed to explore the efficacy of Tα1 as a COVID-19 therapy.

Methods: We performed a multicenter cohort study in five tertiary hospitals in the Hubei province of China between December 2019 and March 2020. The patient non-recovery rate was used as the primary outcome.

Results: All crude outcomes, including non-recovery rate (65/306 vs. 290/1,976, p = 0.003), in-hospital mortality rate (62/306 vs. 271/1,976, p = 0.003), intubation rate (31/306 vs. 106/1,976, p = 0.001), acute respiratory distress syndrome (ARDS) incidence (104/306 vs. 499/1,976, p = 0.001), acute kidney injury (AKI) incidence (26/306 vs. 66/1,976, p < 0.001), and length of intensive care unit (ICU) stay (14.9 ± 12.7 vs. 8.7 ± 8.2 days, p < 0.001), were significantly higher in the Tα1 treatment group. After adjusting for confounding factors, Tα1 use was found to be significantly associated with a higher non-recovery rate than non-Tα1 use (OR 1.5, 95% CI 1.1-2.1, p = 0.028). An increased risk of non-recovery rate associated with Tα1 use was observed in the patient subgroups with maximum sequential organ failure assessment (SOFA) scores ≥2 (OR 2.0, 95%CI 1.4-2.9, p = 0.024), a record of ICU admission (OR 5.4, 95%CI 2.1-14.0, p < 0.001), and lower PaO2/FiO2 values (OR 1.9, 95%CI 1.1-3.4, p = 0.046). Furthermore, later initiation of Tα1 use was associated with a higher non-recovery rate.

Conclusion: Tα1 use in COVID-19 patients was associated with an increased non-recovery rate, especially in those with greater disease severity.

Keywords: COVID-19; disease severity; efficacy; non-recovery; thymosin alpha 1.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Liu, Shen, Wen, Xu, Wu, Feng, Li, Dong, Huang, Guo, Zhang, Chen, Li, Zhu, Du, Liu, Wang, Chen, Teboul, Annane and Chen.

Figures

Figure 1
Figure 1
Flow chart of the present study.
Figure 2
Figure 2
Interactions between thymosin-α1 use and different disease severity indexes. Subgroup analysis according to maximum SOFA score, ICU admission, PaO2/FiO2, mechanical ventilation, and development of ARDS. The crude outcomes are presented in (A), and the adjusted outcomes are presented in (B).

References

    1. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical Predictors of Mortality Due to COVID-19 Based on an Analysis of Data of 150 Patients From Wuhan, China. Intensive Care Med (2020) 46(5):846–8. 10.1007/s00134-020-05991-x
    1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. . Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan, China. Lancet (2020) 395(10223):497–506. 10.1016/S0140-6736(20)30183-5
    1. Moore JB, June CH. Cytokine Release Syndrome in Severe COVID-19. Science (2020) 368(6490):473–4. 10.1126/science.abb8925
    1. Yu K, He J, Wu Y, Xie B, Liu X, Wei B, et al. . Dysregulated Adaptive Immune Response Contributes to Severe COVID-19. Cell Res (2020) 30(9):814–6. 10.1038/s41422-020-0391-9
    1. Subir R, Jagat JM, Kalyan KG. Pros and Cons for Use of Statins in People With Coronavirus Disease-19 (COVID-19). Diabetes Metab Syndr (2020) 14(5):1225–9. 10.1016/j.dsx.2020.07.011
    1. Group RC, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. . Dexamethasone in Hospitalized Patients With Covid-19. N Engl J Med (2021) 384(8):693–704. 10.1056/NEJMoa2021436
    1. Liu J, Zhang S, Dong X, Li Z, Xu Q, Feng H, et al. . Corticosteroid Treatment in Severe COVID-19 Patients With Acute Respiratory Distress Syndrome. J Clin Invest (2020) 130(12):6417–28. 10.1172/JCI140617
    1. Liu Y, Pang Y, Hu Z, Wu M, Wang C, Feng Z, et al. . Thymosin Alpha 1 (Talpha1) Reduces the Mortality of Severe COVID-19 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells. Clin Infect Dis (2020) 71(16):2150–7. 10.1093/cid/ciaa630
    1. Sun Q, Xie J, Zheng R, Li X, Chen H, Tong Z, et al. . The Effect of Thymosin Alpha1 on Mortality of Critical COVID-19 Patients: A Multicenter Retrospective Study. Int Immunopharmacol (2021) 90:107143. 10.1016/j.intimp.2020.107143
    1. Wang Y, Yan X, Huang C, Sun Y, Yao C, Lin Y, et al. . Risk Factors of Mortality and Contribution of Treatment in Patients Infected With COVID-19: A Retrospective Propensity Score Matched Study. Curr Med Res Opin (2021) 37(1):13–9. 10.1080/03007995.2020.1853508
    1. Wu M, Ji JJ, Zhong L, Shao ZY, Xie QF, Liu ZY, et al. . Thymosin Alpha1 Therapy in Critically Ill Patients With COVID-19: A Multicenter Retrospective Cohort Study. Int Immunopharmacol (2020) 88:106873. 10.1016/j.intimp.2020.106873
    1. Romani L, Bistoni F, Montagnoli C, Gaziano R, Bozza S, Bonifazi P, et al. . Thymosin Alpha1: An Endogenous Regulator of Inflammation, Immunity, and Tolerance. Ann NY Acad Sci (2007) 1112:326–38. 10.1196/annals.1415.002
    1. Pei F, Guan X, Wu J. Thymosin Alpha 1 Treatment for Patients With Sepsis. Expert Opin Biol Ther (2018) 18(sup1):71–6. 10.1080/14712598.2018.1484104
    1. Naylor PH, Mutchnick MG. Immunotherapy for Hepatitis B in the Direct Acting Antiviral Era: Reevaluating the Thymosin Alpha1 Efficacy Trials in the Light of a Combination Therapy Approach. J Viral Hepat (2018) 25(1):4–9. 10.1111/jvh.12807
    1. Romani L, Oikonomou V, Moretti S, Iannitti RG, D’Adamo MC, Villella VR, et al. . Thymosin Alpha1 Represents a Potential Potent Single-Molecule-Based Therapy for Cystic Fibrosis. Nat Med (2017) 23(5):590–600. 10.1038/nm.4305
    1. Wu J, Zhou L, Liu J, Ma G, Kou Q, He Z, et al. . The Efficacy of Thymosin Alpha 1 for Severe Sepsis (ETASS): A Multicenter, Single-Blind, Randomized and Controlled Trial. Crit Care (2013) 17(1):R8. 10.1186/cc11932
    1. Soy M, Keser G, Atagunduz P, Tabak F, Atagunduz I, Kayhan S. Cytokine Storm in COVID-19: Pathogenesis and Overview of Anti-Inflammatory Agents Used in Treatment. Clin Rheumatol (2020) 39(7):2085–94. 10.1007/s10067-020-05190-5
    1. Soldati G, Giannasi G, Smargiassi A, Inchingolo R, Demi L. Contrast-Enhanced Ultrasound in Patients With COVID-19: Pneumonia, Acute Respiratory Distress Syndrome, or Something Else? J Ultrasound Med (2020) 39(12):2483–9. 10.1002/jum.15338
    1. National Health Commission of the People’s Republic of China . Diagnosis and Treatment of COVID-19 Guidelines (Trial Version 7). Available at: .
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, et al. . The SOFA (Sepsis-Related Organ Failure Assessment) Score to Describe Organ Dysfunction/Failure. On Behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med (1996) 22(7):707–10. 10.1007/BF01709751
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A Severity of Disease Classification System. Crit Care Med (1985) 13(10):818–29. 10.1097/00003246-198510000-00009
    1. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. . Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA (2012) 307(23):2526–33. 10.1001/jama.2012.5669
    1. Khwaja A. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Nephron Clin Pract (2012) 120(4):c179–84. 10.1159/000339789
    1. Huang I, Pranata R. Lymphopenia in Severe Coronavirus Disease-2019 (COVID-19): Systematic Review and Meta-Analysis. J Intensive Care (2020) 8:36. 10.1186/s40560-020-00453-4
    1. Yu Y, Xu D, Fu S, Zhang J, Yang X, Xu L, et al. . Patients With COVID-19 in 19 ICUs in Wuhan, China: A Cross-Sectional Study. Crit Care (2020) 24(1):219. 10.1186/s13054-020-02939-x
    1. Zhang L, Liu Y. Potential Interventions for Novel Coronavirus in China: A Systematic Review. J Med Virol (2020) 92(5):479–90. 10.1002/jmv.25707
    1. Shao C, Tian G, Huang Y, Liang W, Zheng H, Wei J, et al. . Thymosin Alpha-1-Transformed Bifidobacterium Promotes T Cell Proliferation and Maturation in Mice by Oral Administration. Int Immunopharmacol (2013) 15(3):646–53. 10.1016/j.intimp.2012.12.031
    1. Serafino A, Pierimarchi P, Pica F, Andreola F, Gaziano R, Moroni N, et al. . Thymosin Alpha1 as a Stimulatory Agent of Innate Cell-Mediated Immune Response. Ann NY Acad Sci (2012) 1270:13–20. 10.1111/j.1749-6632.2012.06707.x
    1. Matteucci C, Minutolo A, Balestrieri E, Petrone V, Fanelli M, Malagnino V, et al. . Thymosin Alpha 1 Mitigates Cytokine Storm in Blood Cells From Coronavirus Disease 2019 Patients. Open Forum Infect Dis (2021) 8(1):ofaa588. 10.1093/ofid/ofaa588
    1. Giacomini E, Severa M, Cruciani M, Etna MP, Rizzo F, Pardini M, et al. . Dual Effect of Thymosin Alpha 1 on Human Monocyte-Derived Dendritic Cell In Vitro Stimulated With Viral and Bacterial Toll-Like Receptor Agonists. Expert Opin Biol Ther (2015) 15 Suppl 1:S59–70. 10.1517/14712598.2015.1019460
    1. Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. . COVID-19 Infection: The Perspectives on Immune Responses. Cell Death Differ (2020) 27(5):1451–4. 10.1038/s41418-020-0530-3
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. . Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA (2020) 323(11):1061–9. 10.1001/jama.2020.1585
    1. King R, Tuthill C. Immune Modulation With Thymosin Alpha 1 Treatment. Vitam Horm (2016) 102:151–78. 10.1016/bs.vh.2016.04.003

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi