The efficacy of thymosin alpha 1 for severe sepsis (ETASS): A multicenter, single-blind, randomized and controlled trial

Critical Care

Volumn 17, Issue 1, 2013, Pages

  Wu, Jianfeng ^a   Zhou, Lixin ^b   Liu, Jiyun ^c   Ma, Gang ^d   Kou, Qiuye ^e   He, Zhijie ^f   Chen, Juan ^a   Ou Yang, Bin ^a   Chen, Minying ^a   Li, Yinan ^b   Wu, Xiaoqin ^c   Gu, Baochun ^d   Chen, Lei ^e   Zou, Zijun ^f   Qiang, Xinhua ^b   Chen, Yuanyuan ^c   Lin, Aihua ^g   Zhang, Guanrong ^g   Guan, Xiangdong ^a  

^a THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIVERSITY   (China)

^b Department of Critical Care Medicine   (China)

^c GUANGZHOU FIRST PEOPLE'S HOSPITAL   (China)

^d SUN YAT SEN UNIVERSITY CANCER CENTER   (China)

^e THE SIXTH AFFILIATED HOSPITAL OF SUN YAT SEN UNIVERSITY   (China)

^f SUN YAT SEN MEMORIAL HOSPITAL OF SUN YAT SEN UNIVERSITY   (China)

^g SUN YAT SEN UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

HLA DR ANTIGEN; THYMOSIN ALPHA1;

ADULT; AGED; ARTICLE; CHINA; CLINICAL EVALUATION; CONTROLLED STUDY; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; FEMALE; HOSPITAL ADMISSION; HUMAN; INTENSIVE CARE UNIT; INTENTION TO TREAT ANALYSIS; MAJOR CLINICAL STUDY; MALE; MONOCYTE; MORTALITY; MULTICENTER STUDY; OUTCOME ASSESSMENT; PRIORITY JOURNAL; PROSPECTIVE STUDY; RANDOMIZATION; RANDOMIZED CONTROLLED TRIAL; SEPSIS; SEQUENTIAL ORGAN FAILURE ASSESSMENT SCORE; SINGLE BLIND PROCEDURE; STATISTICAL SIGNIFICANCE; TERTIARY HEALTH CARE; UNIVERSITY HOSPITAL;

EID: 84872263573     PISSN: 13648535     EISSN: 1466609X     Source Type: Journal    
DOI: 10.1186/cc11932     Document Type: Article

References (48)

1. Heron M, Hoyert DL, Murphy SL, Xu J, Kochanek KD, Tejada-Vera B. Deaths: final data for 2006. Natl Vital Stat Rep 2009, 57:1-134.
2. Martin CM, Priestap F, Fisher H, Fowler RA, Heyland DK, Keenan SP, Longo CJ, Morrison T, Bentley D, Antman N, STAR Registry Investigators A prospective, observational registry of patients with severe sepsis: the Canadian Sepsis Treatment and Response Registry. Crit Care Med 2009, 37:81-88. 10.1097/CCM.0b013e31819285f0, 19050636, STAR Registry Investigators.
3. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29:1303-1310. 10.1097/00003246-200107000-00002, 11445675.
4. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M, Regan S, Angus DC. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med 2010, 36:222-231. 10.1007/s00134-009-1738-3, 2826633, 20069275.
5. Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J. Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med 2004, 30:589-596. 10.1007/s00134-004-2157-0, 14963646.
6. Brun-Buisson C, Meshaka P, Pinton P, Vallet B, EPISEPSIS Study Group EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med 2004, 30:580-588. EPISEPSIS Study Group.
7. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ, Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001, 344:699-709. 10.1056/NEJM200103083441001, 11236773, Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group.
8. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003, 348:138-150. 10.1056/NEJMra021333, 12519925.
9. Hotchkiss RS, Opal S. Immunotherapy for sepsis - a new approach against an ancient foe. N Engl J Med 2010, 363:87-89. 10.1056/NEJMcibr1004371, 20592301.
10. Goldstein AL, Guha A, Zatz MM, Hardy MA, White A. Purification and biological activity of thymosin, a hormone of the thymus gland. Proc Natl Acad Sci USA 1972, 69:1800-1803. 10.1073/pnas.69.7.1800, 426805, 4505657.
11. Romani L, Bistoni F, Montagnoli C, Gaziano R, Bozza S, Bonifazi P, Zelante T, Moretti S, Rasi G, Garaci E, Puccetti P. Thymosin alpha1: an endogenous regulator of inflammation, immunity, and tolerance. Ann N Y Acad Sci 2007, 1112:326-338. 10.1196/annals.1415.002, 17495242.
12. Goldstein AL. From lab to bedside: emerging clinical applications of thymosin alpha 1. Expert Opin Biol Ther 2009, 9:593-608. 10.1517/14712590902911412, 19392576.
13. Tuthill C, Rios I, McBeath R. Thymosin alpha 1: past clinical experience and future promise. Ann N Y Acad Sci 2010, 1194:130-135. 10.1111/j.1749-6632.2010.05482.x, 20536460.
14. Chen H, He MY, Li YM. Treatment of patients with severe sepsis using ulinastatin and thymosin alpha1: a prospective, randomized, controlled pilot study. Chin Med J (Engl) 2009, 122:883-888.
15. Li Y, Chen H, Li X, Zhou W, He M, Chiriva-Internati M, Wachtel MS, Frezza EE. A new immunomodulatory therapy for severe sepsis: Ulinastatin Plus Thymosin {alpha} 1. J Intensive Care Med 2009, 24:47-53.
16. Lin HY. [Clinical trial with a new immunomodulatory strategy: treatment of severe sepsis with Ulinastatin and Maipuxin]. Zhonghua Yi Xue Za Zhi 2007, 87:451-457.
17. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL, , et al. International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008, 34:17-60. 10.1007/s00134-007-0934-2, 2249616, 18058085, International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases.
18. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005, 171:388-416.
19. Degoricija V, Sharma M, Legac A, Gradiser M, Sefer S, Vucicevic Z. Survival analysis of 314 episodes of sepsis in medical intensive care unit in university hospital: impact of intensive care unit performance and antimicrobial therapy. Croat Med J 2006, 47:385-397. 2080418, 16758516.
20. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003, 31:2742-2751. 10.1097/01.CCM.0000098031.24329.10, 14668610.
21. Wu JF, Ma J, Chen J, Ou-Yang B, Chen MY, Li LF, Liu YJ, Lin AH, Guan XD. Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Crit Care 2011, 15:R220. 10.1186/cc10457, 3334765, 21933399.
22. Huang SW, Guan XD, Chen J, OuYang B. [Clinical study and long-term evaluation of immunomodulation therapy on trauma, severe sepsis and multiple organ dysfunction syndrome patients]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006, 18:653-656.
23. Remick DG. Pathophysiology of sepsis. Am J Pathol 2007, 170:1435-1444. 10.2353/ajpath.2007.060872, 1854939, 17456750.
24. Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Pennington JE, Wherry JC, TNF-alpha MAb Sepsis Study Group Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. JAMA 1995, 273:934-941. 10.1001/jama.1995.03520360048038, 7884952, TNF-alpha MAb Sepsis Study Group.
25. Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C, Monoclonal Anti-TNF: a Randomized Controlled Sepsis Study Investigators Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med 2004, 32:2173-2182. Monoclonal Anti-TNF: a Randomized Controlled Sepsis Study Investigators.
26. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997, 3:678-681. 10.1038/nm0697-678, 9176497.
27. Serrate SA, Schulof RS, Leondaridis L, Goldstein AL, Sztein MB. Modulation of human natural killer cell cytotoxic activity, lymphokine production, and interleukin 2 receptor expression by thymic hormones. J Immunol 1987, 139:2338-2343.
28. Sztein MB, Serrate SA. Characterization of the immunoregulatory properties of thymosin alpha 1 on interleukin-2 production and interleukin-2 receptor expression in normal human lymphocytes. Int J Immunopharmacol 1989, 11:789-800. 10.1016/0192-0561(89)90133-1, 2599716.
29. Pierluigi B, D'Angelo C, Fallarino F, Moretti S, Zelante T, Bozza S, De Luca A, Bistoni F, Garaci E, Romani L. Thymosin alpha1: the regulator of regulators?. Ann N Y Acad Sci 2010, 1194:1-5. 10.1111/j.1749-6632.2010.05465.x, 20536444.
30. Romani L, Bistoni F, Gaziano R, Bozza S, Montagnoli C, Perruccio K, Pitzurra L, Bellocchio S, Velardi A, Rasi G, Di Francesco P, Garaci E. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood 2004, 103:4232-4239. 10.1182/blood-2003-11-4036, 14982877.
31. Bozza S, Gaziano R, Bonifazi P, Zelante T, Pitzurra L, Montagnoli C, Moretti S, Castronari R, Sinibaldi P, Rasi G, Garaci E, Bistoni F, Romani L. Thymosin alpha1 activates the TLR9/MyD88/IRF7-dependent murine cytomegalovirus sensing for induction of anti-viral responses in vivo. Int Immunol 2007, 19:1261-1270. 10.1093/intimm/dxm097, 17804687.
32. Yang X, Qian F, He HY, Liu KJ, Lan YZ, Ni B, Tian Y, Fu XL, Zhang J, Shen ZG, Li J, Yin Y, Li JT, Wu YZ. Effect of thymosin alpha-1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro. Braz J Med Biol Res 2012, 45:25-32. 10.1590/S0100-879X2011007500159, 22245858.
33. Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, Fang Q, Xu Q, Wang D, Jin Y, Yuan S, Wang J, Du Z, Sun Y, Fang X. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med 2007, 35:2538-2546. 10.1097/01.CCM.0000284492.30800.00, 17828034.
34. Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering. Lancet 2002, 359:614-618. 10.1016/S0140-6736(02)07750-4, 11867132.
35. Monneret G, Venet F, Pachot A, Lepape A. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med 2008, 14:64-78. 2078557, 18026569.
36. Schefold JC. Measurement of monocytic HLA-DR (mHLA-DR) expression in patients with severe sepsis and septic shock: assessment of immune organ failure. Intensive Care Med 2010, 36:1810-1812. 10.1007/s00134-010-1965-7, 20652681.
37. Lukaszewicz AC GM, Resche-Rigon M, Pirracchio R, Faivre V, Boval B, Payen D. Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med 2009, 37:2746-2752. 10.1097/CCM.0b013e3181ab858a, 19707128.
38. Monneret G, Lepape A, Voirin N, Bohe J, Venet F, Debard AL, Thizy H, Bienvenu J, Gueyffier F, Vanhems P. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 2006, 32:1175-1183. 10.1007/s00134-006-0204-8, 16741700.
39. Menges T, Engel J, Welters I, Wagner RM, Little S, Ruwoldt R, Wollbrueck M, Hempelmann G. Changes in blood lymphocyte populations after multiple trauma: association with posttraumatic complications. Crit Care Med 1999, 27:733-740. 10.1097/00003246-199904000-00026, 10321662.
40. Zhang Y, Chen H, Li YM, Zheng SS, Chen YG, Li LJ, Zhou L, Xie HY, Praseedom RK. Thymosin alpha1- and ulinastatin-based immunomodulatory strategy for sepsis arising from intra-abdominal infection due to carbapenem-resistant bacteria. J Infect Dis 2008, 198:723-730. 10.1086/590500, 18613793.
41. Wang X, Li W, Niu C, Pan L, Li N, Li J. Thymosin alpha 1 is associated with improved cellular immunity and reduced infection rate in severe acute pancreatitis patients in a double-blind randomized control study. Inflammation 2011, 34:198-202. 10.1007/s10753-010-9224-1, 20549321.
42. Saenz JJ, Izura JJ, Manrique A, Sala F, Gaminde I. Early prognosis in severe sepsis via analyzing the monocyte immunophenotype. Intensive Care Med 2001, 27:970-977. 10.1007/s001340100962, 11497155.
43. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 2009, 180:640-648. 10.1164/rccm.200903-0363OC, 19590022.
44. Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulme R, Lepage E, Le Gall R. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 2002, 28:108-121. 10.1007/s00134-001-1143-z, 11907653.
45. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gardlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD, PROWESS-SHOCK Study Group Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012, 366:2055-2064. 10.1056/NEJMoa1202290, 22616830, PROWESS-SHOCK Study Group.
46. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K, German Competence Network Sepsis (SepNet) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008, 358:125-139. 10.1056/NEJMoa070716, 18184958, German Competence Network Sepsis (SepNet).
47. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Hodis HN, Kitabchi AE, Mack WJ, Mudaliar S, Ratner RE, Williams K, Stentz FB, Musi N, Reaven PD, ACT NOW Study Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 2011, 364:1104-1115. 10.1056/NEJMoa1010949, 21428766, ACT NOW Study.
48. Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, Cuttler L, Nathan DM, Tollefsen S, Wilfley D, Kaufman F. TODAY Study Group A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012, 366:2247-2256. 3478667, 22540912, TODAY Study Group.