Immune enhancement in patients with predicted severe acute necrotising pancreatitis: a multicentre double-blind randomised controlled trial

Intensive Care Medicine - Tập 48 - Trang 899-909 - 2022
Lu Ke1,2, Jing Zhou1,3, Wenjian Mao3, Tao Chen4, Yin Zhu5, Xinting Pan6, Hong Mei7, Vikesh Singh8, James Buxbaum9, Gordon Doig10, Chengjian He11, Weili Gu12, Weihua Lu13, Shumin Tu14, Haibin Ni15, Guoxiu Zhang16, Xiangyang Zhao17, Junli Sun18, Weiwei Chen19, Jingchun Song20, Min Shao21, Jianfeng Tu22, Liang Xia5, Wenhua He5, Qingyun Zhu6, Kang Li7, Hongyi Yao11, Jingyi Wu13, Long Fu14, Wendi Jiang1, He Zhang23, Jiajia Lin1, Baiqiang Li1, Zhihui Tong1, John Windsor24, Yuxiu Liu1,25, Weiqin Li1,3,2
1Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
2National Institute of Healthcare Data Science, Nanjing University, Nanjing, China
3Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China
4Department of Public Health, Policy and Systems, Institute of Population Health, Whelan Building, Quadrangle, The University of Liverpool, Liverpool, UK
5Pancreatic Disease Centre, Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
6Department of Emergency Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, China
7Department of Critical Care Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, China
8Pancreatitis Centre, Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, USA
9Division of Gastroenterology, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, USA
10Northern Clinical School, Royal North Shore Hospital, University of Sydney, Sydney, Australia
11Department of Critical Care Medicine, the Affiliated Nanhua Hospital, University of South China, Hengyang, China
12Department of Critical Care Medicine, Affiliated Hospital 2 of Nantong University, Nantong, China
13Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
14Department of Emergency Medicine, Shangqiu First People’s Hospital, Shangqiu, China
15Department of Emergency Medicine, Jiangsu Provincial Hospital of Integrated Chinese and Western Medicine, Nanjing, China
16Department of Emergency Medicine, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
17Department of Intensive Care Unit, Qilu Hospital of Shandong University, Qingdao, China
18Department of Intensive Care Unit, Luoyang Central Hospital, Zhengzhou University, Luoyang, China
19Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou, China
20Department of Critical Care Medicine, 94Th Hospital of PLA, Nanchang, China
21Department of Intensive Care Unit, The First Affiliated Hospital of Anhui Medical University, Hefei, China
22Department of Emergency Medicine, Zhejiang Provincial People’s Hospital, Hangzhou, China
23Department of Critical Care Medicine, Jinling Hospital, Medical School of Southeast University, Nanjing, China
24Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
25Department of Medical Statistics, Jinling Hospital, Medical School of Nanjing University, Nanjing, China

Tóm tắt

Infected pancreatic necrosis (IPN) is a highly morbid complication of acute necrotising pancreatitis (ANP). Since there is evidence of early-onset immunosuppression in acute pancreatitis, immune enhancement may be a therapeutic option. This trial aimed to evaluate whether early immune-enhancing Thymosin alpha 1 (Tα1) treatment reduces the incidence of IPN in patients with predicted severe ANP. We conducted a multicentre, double-blind, randomised, placebo-controlled trial involving ANP patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 8 and a computed tomography (CT) severity score ≥ 5 admitted within 7 days of the advent of symptoms. Enrolled patients were assigned to receive a subcutaneous injection of Tα1 1.6 mg every 12 h for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebos (normal saline). The primary outcome was the development of IPN during the index admission. A total of 508 patients were randomised, of whom 254 were assigned to receive Tα1 and 254 placebo. The vast majority of the participants required admission to the intensive care unit (ICU) (479/508, 94.3%). During the index admission, 40/254(15.7%) patients in the Tα1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95% CI − 7.4 to 5.1%]; p = 0.48). The results were similar across four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15%), bleeding (6.3% vs. 3.5%), and gastrointestinal fistula (2% vs. 2.4%). The immune-enhancing Tα1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.

Tài liệu tham khảo

Xiao AY, Tan ML, Wu LM, Asrani VM, Windsor JA, Yadav D, Petrov MS (2016) Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol 1:45–55 Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS, Acute Pancreatitis Classification Working G (2013) Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus. Gut 62:102–111 Trikudanathan G, Wolbrink DRJ, van Santvoort HC, Mallery S, Freeman M, Besselink MG (2019) Current concepts in severe acute and necrotizing pancreatitis: an evidence-based approach. Gastroenterology 156(1994–2007):e1993 Schepers NJ, Bakker OJ, Besselink MG, Ahmed Ali U, Bollen TL, Gooszen HG, van Santvoort HC, Bruno MJ, Dutch Pancreatitis Study G (2019) Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis. Gut 68:1044–1051 Mowbray NG, Ben-Ismaeil B, Hammoda M, Shingler G, Al-Sarireh B (2018) The microbiology of infected pancreatic necrosis. Hepatobiliary Pancreat Dis Int 17:456–460 Mittal A, Phillips AR, Middleditch M, Ruggiero K, Loveday B, Delahunt B, Cooper GJ, Windsor JA (2009) The proteome of mesenteric lymph during acute pancreatitis and implications for treatment. JOP 10:130–142 Wittau M, Mayer B, Scheele J, Henne-Bruns D, Dellinger EP, Isenmann R (2011) Systematic review and meta-analysis of antibiotic prophylaxis in severe acute pancreatitis. Scand J Gastroenterol 46:261–270 Besselink MG, van Santvoort HC, Buskens E, Boermeester MA, van Goor H, Timmerman HM, Nieuwenhuijs VB, Bollen TL, van Ramshorst B, Witteman BJ, Rosman C, Ploeg RJ, Brink MA, Schaapherder AF, Dejong CH, Wahab PJ, van Laarhoven CJ, van der Harst E, van Eijck CH, Cuesta MA, Akkermans LM, Gooszen HG (2008) Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 371:651–659 Lim CL, Lee W, Liew YX, Tang SS, Chlebicki MP, Kwa AL (2015) Role of antibiotic prophylaxis in necrotizing pancreatitis: a meta-analysis. J Gastrointest Surg 19:480–491 de Vries AC, Besselink MG, Buskens E, Ridwan BU, Schipper M, van Erpecum KJ, Gooszen HG (2007) Randomized controlled trials of antibiotic prophylaxis in severe acute pancreatitis: relationship between methodological quality and outcome. Pancreatology 7:531–538 Ueda T, Takeyama Y, Yasuda T, Shinzeki M, Sawa H, Nakajima T, Ajiki T, Fujino Y, Suzuki Y, Kuroda Y (2006) Immunosuppression in patients with severe acute pancreatitis. J Gastroenterol 41:779–784 Yu WK, Li WQ, Li N, Li JS (2004) Mononuclear histocompatibility leukocyte antigen-DR expression in the early phase of acute pancreatitis. Pancreatology 4:233–243 Pan T, Zhou T, Li L, Liu Z, Chen Y, Mao E, Li M, Qu H, Liu J (2017) Monocyte programmed death ligand-1 expression is an early marker for predicting infectious complications in acute pancreatitis. Crit Care 21:186 Li J, Yang WJ, Huang LM, Tang CW (2014) Immunomodulatory therapies for acute pancreatitis. World J Gastroenterol 20:16935–16947 Hotchkiss RS, Monneret G, Payen D (2013) Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 13:862–874 Garaci E (2007) Thymosin alpha1: a historical overview. Ann N Y Acad Sci 1112:14–20 Wang X, Li W, Niu C, Pan L, Li N, Li J (2011) 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 34:198–202 (2021) Abstracts of Papers Submitted to the 52nd Meeting of the American Pancreatic Association, November 3–6, 2021, Miami Beach, Florida. Pancreas 50: 1044–1115 Zhou J, Mao W, Ke L, Chen T, He W, Pan X, Chen M, He C, Gu W, Wu J, Song J, Ni H, Tu J, Sun J, Zhang G, Chen W, Xue B, Zhao X, Shao M, Liu Y, Tong Z, Li W, Chinese Acute Pancreatitis Clinical Trials G (2020) Thymosin alpha 1 in the prevention of infected pancreatic necrosis following acute necrotising pancreatitis (TRACE trial): protocol of a multicentre, randomised, double-blind, placebo-controlled, parallel-group trial. BMJ Open 10:e037231 Balthazar EJ (2002) Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology 223:603–613 Working Group IAPAPAAPG (2013) IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 13:e1-15 Sun JK, Li WQ, Ni HB, Ke L, Tong ZH, Li N, Li JS (2013) A modified gastrointestinal failure score for patients with severe acute pancreatitis. Surg Today 43:506–513 Ke L, Ni HB, Tong ZH, Li WQ, Li N, Li JS (2012) D-dimer as a marker of severity in patients with severe acute pancreatitis. J Hepatobiliary Pancreat Sci 19:259–265 Bradley EL 3rd (1993) A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 128:586–590 Wang X, Zeng X, Yang B, Zhao S, Chen W, Guo X (2015) Efficacy of thymosin alpha1 and interferon alpha for the treatment of severe acute pancreatitis in a rat model. Mol Med Rep 12:6775–6781 Xue J, Sharma V, Habtezion A (2014) Immune cells and immune-based therapy in pancreatitis. Immunol Res 58:378–386 Gorelick FS, Lerch MM (2017) Do animal models of acute pancreatitis reproduce human disease? Cell Mol Gastroenterol Hepatol 4:251–262 Garg PK, Madan K, Pande GK, Khanna S, Sathyanarayan G, Bohidar NP, Tandon RK (2005) Association of extent and infection of pancreatic necrosis with organ failure and death in acute necrotizing pancreatitis. Clin Gastroenterol Hepatol 3:159–166 Wu J, Zhou L, Liu J, Ma G, Kou Q, He Z, Chen J, Ou-Yang B, Chen M, Li Y, Wu X, Gu B, Chen L, Zou Z, Qiang X, Chen Y, Lin A, Zhang G, Guan X (2013) The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Crit Care 17:R8 Ancell CD, Phipps J, Young L (2001) Thymosin alpha-1. Am J Health Syst Pharm 58:879–885 Rodriguez JR, Razo AO, Targarona J, Thayer SP, Rattner DW, Warshaw AL, Fernandez-del Castillo C (2008) Debridement and closed packing for sterile or infected necrotizing pancreatitis: insights into indications and outcomes in 167 patients. Ann Surg 247:294–299 Minkov GA, Yovtchev YP, Halacheva KS (2017) Increased circulating CD4+CD25+CD127low/neg regulatory T-cells as a prognostic biomarker in acute pancreatitis. Pancreas 46:1003–1010 Novotny AR, Reim D, Assfalg V, Altmayr F, Friess HM, Emmanuel K, Holzmann B (2012) Mixed antagonist response and sepsis severity-dependent dysbalance of pro- and anti-inflammatory responses at the onset of postoperative sepsis. Immunobiology 217:616–621 Simovic MO, Bonham MJ, Abu-Zidan FM, Windsor JA (1999) Anti-inflammatory cytokine response and clinical outcome in acute pancreatitis. Crit Care Med 27:2662–2665 Hotchkiss RS, Colston E, Yende S, Crouser ED, Martin GS, Albertson T, Bartz RR, Brakenridge SC, Delano MJ, Park PK, Donnino MW, Tidswell M, Mayr FB, Angus DC, Coopersmith CM, Moldawer LL, Catlett IM, Girgis IG, Ye J, Grasela DM (2019) Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med 45:1360–1371 Munir F, Jamshed MB, Shahid N, Hussain HM, Muhammad SA, Mamun AA, Zhang Q (2020) Advances in immunomodulatory therapy for severe acute pancreatitis. Immunol Lett 217:72–76 Johnson CD, Kingsnorth AN, Imrie CW, McMahon MJ, Neoptolemos JP, McKay C, Toh SK, Skaife P, Leeder PC, Wilson P, Larvin M, Curtis LD (2001) Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 48:62–69 Abu-Zidan FM, Windsor JA (2002) Lexipafant and acute pancreatitis: a critical appraisal of the clinical trials. Eur J Surg 168:215–219 Wang R, Yang F, Wu H, Wang Y, Huang Z, Hu B, Zhang M, Tang C (2013) High-dose versus low-dose octreotide in the treatment of acute pancreatitis: a randomized controlled trial. Peptides 40:57–64 Liu Y, Pan Y, Hu Z, Wu M, Wang C, Feng Z, Mao C, Tan Y, Liu Y, Chen L, Li M, Wang G, Yuan Z, Diao B, Wu Y, Chen Y (2020) Thymosin alpha 1 reduces the mortality of severe coronavirus disease 2019 by restoration of lymphocytopenia and reversion of exhausted T cells. Clin Infect Dis 71:2150–2157 Wu M, Ji JJ, Zhong L, Shao ZY, Xie QF, Liu ZY, Wang CL, Su L, Feng YW, Liu ZF, Yao YM (2020) Thymosin alpha1 therapy in critically ill patients with COVID-19: a multicenter retrospective cohort study. Int Immunopharmacol 88:106873 Gardner TB, Vege SS, Chari ST, Pearson RK, Clain JE, Topazian MD, Levy MJ, Petersen BT (2008) The effect of age on hospital outcomes in severe acute pancreatitis. Pancreatology 8:265–270 Weyand CM, Goronzy JJ (2016) Aging of the immune system. Mechanisms and therapeutic targets. Ann Am Thorac Soc 13(Suppl 5):S422–S428 Evans RP, Mourad MM, Pall G, Fisher SG, Bramhall SR (2017) Pancreatitis: Preventing catastrophic haemorrhage. World J Gastroenterol 23:5460–5468 Conway Morris A, Datta D, Shankar-Hari M, Stephen J, Weir CJ, Rennie J, Antonelli J, Bateman A, Warner N, Judge K, Keenan J, Wang A, Burpee T, Brown KA, Lewis SM, Mare T, Roy AI, Hulme G, Dimmick I, Rossi AG, Simpson AJ, Walsh TS (2018) Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study. Intensive Care Med 44:627–635 Gomatos IP, Xiaodong X, Ghaneh P, Halloran C, Raraty M, Lane B, Sutton R, Neoptolemos JP (2014) Prognostic markers in acute pancreatitis. Expert Rev Mol Diagn 14:333–346 Matta B, Gougol A, Gao X, Reddy N, Talukdar R, Kochhar R, Goenka MK, Gulla A, Gonzalez JA, Singh VK, Ferreira M, Stevens T, Barbu ST, Nawaz H, Gutierrez SC, Zarnescu NO, Capurso G, Easler J, Triantafyllou K, Pelaez-Luna M, Thakkar S, Ocampo C, de Madaria E, Cote GA, Wu BU, Paragomi P, Pothoulakis I, Tang G, Papachristou GI (2020) Worldwide Variations in demographics, management, and outcomes of acute pancreatitis. Clin Gastroenterol Hepatol 18:1567-1575 e1562 Tian X, Huang Y, Wang H (2017) Deviation of Chinese Adults' Diet from the Chinese Food Pagoda 2016 and Its Association with Adiposity. Nutrients 9 Li XY, Pu N, Chen WW, Shi XL, Zhang GF, Ke L, Ye B, Tong ZH, Wang YH, Liu G, Chen JM, Yang Q, Li WQ, Li JS (2020) Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis. Lipids Health Dis 19:63
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Intensive Care Medicine

Tập 48

899-909

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