簡易檢索 / 詳目顯示

研究生: 李曜洲
Lee, Yao-Chou
論文名稱: 創傷弧菌所致壞死性筋膜炎之病患死亡預後因子的分析及其機轉探討:從臨床到基礎的研究
The studies of prognostic factor of mortality in patients with necrotizing fasciitis caused by Vibrio vulnificus and its mechanisms of pathogenesis: from clinical to basic
指導教授: 謝式洲
Shieh, Shyh-Jou
何漣漪
Hor, Lien-I
學位類別: 碩士
Master
系所名稱: 醫學院 - 臨床醫學研究所碩士在職專班
Institute of Clinical Medicine(on the job class)
論文出版年: 2014
畢業學年度: 102
語文別: 英文
論文頁數: 86
中文關鍵詞: 壞死性筋膜炎創傷弧菌
外文關鍵詞: Necrotizing fasciitis, Vibrio vulnificus
相關次數: 點閱:66下載:1
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 背景:在台灣,海島地理及肝炎盛行成就了創傷弧菌的高致病率,成功的治療取決於早期診斷、合適的抗生素使用、積極外科治療、及生命徵象的支持治療,然而,對於開刀治療的時機點及免疫調節藥物的使用仍是兩個主要的挑戰及爭論,在此篇研究中,我們試著去釐清開刀治療的角色及調查腫瘤壞死因子阿爾法阻斷藥物的治療效果。

    方法:在臨床實驗中,我們回顧在成功大學附設醫院中從1996年1月至2011年12月經細菌培養證實為創傷弧菌感染的個案,而那些經由開刀證實為壞死性筋膜炎的患者將被進一步分析來探討其預後因子。在動物實驗中,我們先證實了一個可模擬人類創傷弧菌軟組織感染的小鼠模式,接著我們利用這個動物模式來探討開刀治療的角色,以及恩博凍晶注射劑(Etanercept)這個抑制腫瘤壞死因子阿爾法藥物的治療效果。

    結果:在臨床實驗中,我們找出病程超過3天是一個預後不良的獨立因子(OR: 10.75; 95% CI: 1.02-113.39, p = 0.048)。在動物實驗中,我們證實早期開刀治療相較於延遲開刀治療有較好的存活率,若於感染前施以恩博凍晶注射劑(Etanercept)來抑制腫瘤壞死因子阿爾法,更發現可以改善創傷弧菌感染後未開刀控制組及延遲開刀治療組的存活率。

    結論:於受傷後或症狀發生3天內得到早期診斷及積極治療,是創傷弧菌所導致壞死性筋膜炎的治療目標,對於病程超過3天的壞死性筋膜炎患者,使用抑制腫瘤壞死因子阿爾法的藥物當作輔助治療可能值得我們進一步研究。

    Background: In Taiwan, the aquatic environment and endemic hepatitis contribute to the high susceptibility of V. vulnificus infection. Successful treatments depend on early diagnosis, adequate antibiotics, aggressive surgical interventions, and hemodynamic supports. However, two main challenges and debates exist regarding the timing of operation and the use of immunomodulatory agents. In this study, we tried to clarify the role of surgical intervention and to investigate the therapeutic effects of TNF-α inhibitor.

    Methods: In clinical study, cases of culture-confirmed V. vulnificus infection between January 1996 to December 2011 in NCKUH were reviewed. Patients with surgically confirmed necrotizing fasciitis were further analyzed to identify the prognostic factors. In animal study, we verified a mouse model to mimic V. vulnificus soft tissue infection and then investigated the role of surgical intervention and the therapeutic effects of etanercept.

    Results: In clinical study, we identified the prolonged disease course longer than 3 days was an independent factor indicating a poor prognosis (OR: 10.75; 95% CI: 1.02-113.39, p = 0.048). In animal study, we demonstrated early operation had a better survival outcome compared with delayed group. Pretreatment with etanercept can not only improve the survival of the infected control group but also the delayed operation group.

    Conclusions: Early diagnosis and prompt treatment within 3 days post-injury or symptom onset should be the goal for treating patients with necrotizing fasciitis caused by V. vulnificus. Adjunctive treatment to rescue patients with a prolonged disease course of necrotizing fasciitis (≧3 days) by using TNF-α inhibitor may warrant further investigation.

    Content list 考試合格證明 中文摘要 i English Abstract ii 誌謝 iii Content list iv-v List of table vi List of figure vii-viii Abbreviations ix-x Background Necrotizing fasciitis 1-5 Vibrio vulnificus 6-8 Clinical study Introduction 9-10 Materials and methods 11-12 Results 13-16 Discussion 17-21 Summary 22 Animal study Introduction 23-25 Materials and methods 26-29 Results 30-35 Discussion 36-43 Summary 44 References 45-53 Tables 54-63 Figures 64-79 Grants 80 List of thesis related publications 81 Curriculum vitae 82 Honor roll 83 Publications 84-86

    Andreasen TJ, Green SD, Childers BJ. Massive infectious soft-tissue injury: diagnosis and management of necrotizing fasciitis and purpura fulminans. Plast Reconstr Surg. 107(4): 1025-1035. (2001)
    Arslan A, Pierre-Jerome C, Borthne A. Necrotizing fasciitis: unreliable MRI findings in the preoperative diagnosis. Eur J Radiol. 36(3): 139-143. (2000)
    Baethge BA, West BC. Vibrio vulnificus: did Hippocrates describe a fatal case? Rev Infect Dis. 10(3): 614-615. (1988)
    Bilton BD, Zibari GB, McMillan RW, Aultman DF, Dunn G, McDonald JC. Aggressive surgical management of necrotizing fasciitis serves to decrease mortality: a retrospective study. Am Surg. 64(5): 397-400; discussion 400-391. (1998)
    Blake PA, Merson MH, Weaver RE, Hollis DG, Heublein PC. Disease caused by a marine Vibrio. Clinical characteristics and epidemiology. N Engl J Med. 300(1): 1-5. (1979)
    Bowdre JH, Poole MD, Oliver JD. Edema and hemoconcentration in mice experimentally infected with Vibrio vulnificus. Infect Immun. 32(3): 1193-1199. (1981)
    Brewer G, Meleney F. Progressive gangrenous infection of the skin and subcutaneous tissues, following operation for acute appendicitis. Ann Surg. 84(3): 438-450. (1926)
    Chao WN, Tsai SJ, Tsai CF, Su CH, Chan KS, Lee YT, Ueng KC, Lin DB, Chen CC, Chen SC. The Laboratory Risk Indicator for Necrotizing Fasciitis score for discernment of necrotizing fasciitis originated from Vibrio vulnificus infections. J Trauma Acute Care Surg. 73(6): 1576-1582. (2012)
    Chao WN, Tsai CF, Chang HR, Chan KS, SU CH, Lee YT, Ueng KC, Chen CC, Chen SC, Lee MC. Impact of timing of surgery on outcome of Vibrio vulnificus-related necrotizing fasciitis. Am J Surg. 206(1):32-9. (2013)
    Chen SC, Lee YT, Tsai SJ, Chan KS, Chao WN, Wang PH, Lin DB, Chen CC, Lee MC. Antibiotic therapy for necrotizing fasciitis caused by Vibrio vulnificus: retrospective analysis of an 8 year period. J Antimicrob Chemother. 67(2): 488-493. (2012)
    Chiang SR, Tang HJ, Chang PC, Cheng KC, Ko WC, Chen CH, Chuang YC. Synergistic antimicrobial effect of cefotaxime and minocycline on proinflammatory cytokine levels in a murine model of Vibrio vulnificus infection. J Microbiol Immunol Infect. 40(2): 123-133. (2007)
    Chorinchath BB, Kong LY, Mao L, McCallum RE. Age-associated differences in TNF-alpha and nitric oxide production in endotoxic mice. J Immunol. 156(4): 1525-1530. (1996)
    Chuang YC, Yuan CY, Liu CY, Lan CK, Huang AH. Vibrio vulnificus infection in Taiwan: report of 28 cases and review of clinical manifestations and treatment. Clin Infect Dis. 15(2): 271-276. (1992)
    Chuang YC, Liu JW, Ko WC, Lin KY, Wu JJ, Huang KY. In vitro synergism between cefotaxime and minocycline against Vibrio vulnificus. Antimicrob Agents Chemother. 41(10): 2214-2217. (1997)
    Chuang YC, Ko WC, Wang ST, Liu JW, Kuo CF, Wu JJ, Huang KY. Minocycline and cefotaxime in the treatment of experimental murine Vibrio vulnificus infection. Antimicrob Agents Chemother. 42(6): 1319-1322. (1998)
    Daniels NA. Vibrio vulnificus oysters: pearls and perils. Clin Infect Dis. 52(6): 788-792. (2011)
    Descamps V, Aitken J, Lee MG. Hippocrates on necrotising fasciitis. Lancet 344(8921): 556. (1994)
    Dhakal BK, Lee W, Kim YR, Choy HE, Ahnn J, Rhee JH. Caenorhabditis elegans as a simple model host for Vibrio vulnificus infection. Biochem Biophys Res Commun. 346(3): 751-757. (2006)
    Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue infections. Risk factors for mortality and strategies for management. Ann Surg. 224(5): 672-683. (1996)
    Espat NJ, Auffenberg T, Abouhamze A, Baumhofer J, Moldawer LL, Howard RJ. A role for tumor necrosis factor-alpha in the increased mortality associated with Vibrio vulnificus infection in the presence of hepatic dysfunction. Ann Surg. 223(4): 428-433. (1996)
    Farmer JJ, 3rd. Vibrio ("Beneckea") vulnificus, the bacterium associated with sepsis, septicaemia, and the sea. Lancet 2(8148): 903. (1979)
    Fei Y, Wang W, Kwiecinski J, Josefsson E, Pullerits R, Jonsson IM, Maqnusson M, Jin T. The combination of a tumor necrosis factor inhibitor and antibiotic alleviates staphylococcal arthritis and sepsis in mice. J Infect Dis. 204(3): 348-357. (2011)
    File TM, Jr., Tan JS, DiPersio JR. Group A streptococcal necrotizing fasciitis. Diagnosing and treating the "flesh-eating bacteria syndrome". Cleve Clin J Med. 65(5): 241-249. (1998)
    Fries W, Muja C, Crisafulli C, Costantino G, Longo G, Cuzzocrea S, Mazzon E. Infliximab and etanercept are equally effective in reducing enterocyte APOPTOSIS in experimental colitis. Int J Med Sci. 5(4): 169-180. (2008)
    Goo SY, Han YS, Kim WH, Lee KH, Park SJ. Vibrio vulnificus IlpA-induced cytokine production is mediated by Toll-like receptor 2. J Biol Chem. 282(38): 27647-27658. (2007)
    Halow KD, Harner RC, Fontenelle LJ. Primary skin infections secondary to Vibrio vulnificus: the role of operative intervention. J Am Coll Surg. 183(4): 329-334. (1996)
    Hippocrates. Epidemics: (translated by WHS Jones). Heinemann, for Harvard University Press, London. (1957)
    Hollis DG, Weaver RE, Baker CN, Thornsberry C. Halophilic Vibrio species isolated from blood cultures. J Clin Microbiol. 3(4): 425-431. (1976)
    Hor LI, Gao CT, Wan L. Isolation and Characterization of Vibrio vulnificus Inhabiting the Marine Environment of the Southwestern Area of Taiwan. J Biomed Sci. 2(4): 384-389. (1995)
    Hor LI, Chang TT, Wang ST. Survival of Vibrio vulnificus in whole blood from patients with chronic liver diseases: association with phagocytosis by neutrophils and serum ferritin levels. J Infect Dis. 179(1): 275-278. (1999)
    Horseman MA, Surani S. A comprehensive review of Vibrio vulnificus: an important cause of severe sepsis and skin and soft-tissue infection. Int J Infect Dis. 15(3): e157-166. (2011)
    Hsueh PR, Lin CY, Tang HJ, Lee HC, Liu JW, Liu YC, Chuang YC. Vibrio vulnificus in Taiwan. Emerg Infect Dis. 10(8): 1363-1368. (2004)
    Jones J. Investigation upon the nature, course, and treatment of hospital gangrene as it prevailed in the Confederate armies 1861-1865. Riverside press, New York. (1871)
    Jones MK, Oliver JD. Vibrio vulnificus: disease and pathogenesis. Infect Immun. 77(5): 1723-1733. (2009)
    Klontz KC, Lieb S, Schreiber M, Janowski HT, Baldy LM, Gunn RA. Syndromes of Vibrio vulnificus infections. Clinical and epidemiologic features in Florida cases, 1981-1987. Ann InternMed. 109(4): 318-323. (1988)
    Kuo Chou TN, Chao WN, Yang C, Wong RH, Ueng KC, Chen SC. Predictors of mortality in skin and soft-tissue infections caused by Vibrio vulnificus. World J Surg. 34(7): 1669-1675. (2010)
    Kuo YL, Shieh SJ, Chiu HY, Lee JW. Necrotizing fasciitis caused by Vibrio vulnificus: epidemiology, clinical findings, treatment and prevention. Eur J Clin Microbiol Infect Dis. 26(11): 785-792. (2007)
    Lancerotto L, Tocco I, Salmaso R, Vindigni V, Bassetto F. Necrotizing fasciitis: classification, diagnosis, and management. J Trauma Acute Care Surg. 72(3): 560-566. (2012)
    Lee JY, Kim DM, Yun NR, Neupane GP, Jung SI, Park KH, Jang HC, Lee CS, Lee SH. Tumor necrosis factor-alpha and mortality in patients infected with Vibrio vulnificus. Am J Trop Med Hyg. 84(3): 426-428. (2011)
    Lee NY, Lee HY, Lee KH, Han SH, Park SJ. Vibrio vulnificus IlpA induces MAPK-mediated cytokine production via TLR1/2 activation in THP-1 cells, a human monocytic cell line. Mol Immunol. 49(1-2): 143-154. (2011)
    Lee YJ, Chuang YC. Ibuprofen augments pro-inflammatory cytokine release in a mouse model of Vibrio vulnificus infection. Microbiol Immunol. 54(9): 542-550. (2010)
    Leon LR, White AA, Kluger MJ. Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol. 275(1 Pt 2): R269-277. (1998)
    Linkous DA, Oliver JD. Pathogenesis of Vibrio vulnificus. FEMS Microbiol Lett. 174(2): 207-214. (1999)
    Lo HR, Lin JH, Chen YH, Chen CL, Shao CP, Lai YC, Hor LI. RTX toxin enhances the survival of Vibrio vulnificus during infection by protecting the organism from phagocytosis. J Infect Dis. 203(12): 1866-1874. (2011)
    McHenry CR, Piotrowski JJ, Petrinic D, Malangoni MA. Determinants of mortality for necrotizing soft-tissue infections. Ann Surg. 221(5): 558-563; discussion 563-555. (1995)
    Meleney F. Hemolytic streptococcal gangrene. Arch Surg. 9: 317-364. (1924)
    Morgan MS. Diagnosis and management of necrotising fasciitis: a multiparametric approach. J Hosp Infect. 75(4): 249-257. (2010)
    Newton A, Kendall M, Vugia DJ, Henao OL, Mahon BE. Increasing rates of vibriosis in the United States, 1996-2010: review of surveillance data from 2 systems. Clin Infect Dis. 54 Suppl 5: S391-395. (2012)
    Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock 16(2): 83-96. (2001)
    Poole MD, Oliver JD. Experimental pathogenicity and mortality in ligated ileal loop studies of the newly reported halophilic lactose-positive Vibrio sp. Infect Immun. 20(1): 126-129. (1978)
    Powell JL, Wright AC, Wasserman SS, Hone DM, Morris JG Jr. Release of tumor necrosis factor alpha in response to Vibrio vulnificus capsular polysaccharide in in vivo and in vitro models. Infect Immun. 65(9): 3713-3718. (1997)
    Quirk WF Jr, Sternbach G. Joseph Jones: infection with flesh eating bacteria. J Emerg Med. 14(6): 747-753. (1996)
    Reichelt JL, Baumann P, Baumann L. Study of genetic relationships among marine species of the genera Beneckea and Photobacterium by means of in vitro DNA/DNA hybridization. Arch Microbiol. 110(1): 101-120. (1976)
    Roland FP. Leg gangrene and endotoxin shock due to Vibrio parahaemolyticus--an infection acquired in New England coastal waters. N Engl J Med. 282(23): 1306. (1970)
    Shapiro RL, Altekruse S, Hutwagner L, Bishop R, Hammond R, Wilson S, Ray B, Thompson S, Tauxe RV, Griffin PM. The role of Gulf Coast oysters harvested in warmer months in Vibrio vulnificus infections in the United States, 1988-1996. Vibrio Working Group. J Infect Dis. 178(3): 752-759. (1998)
    Shimizu T, Tokuda Y. Necrotizing fasciitis. Intern Med. 49(12): 1051-1057. (2010)
    Shin SH, Shin DH, Ryu PY, Chung SS, Rhee JH. Proinflammatory cytokine profile in Vibrio vulnificus septicemic patients' sera. FEMS Immunol Med Microbiol. 33(2): 133-138. (2002)
    Stamenkovic I, Lew PD. Early recognition of potentially fatal necrotizing fasciitis. The use of frozen-section biopsy. N Engl J Med. 310(26): 1689-1693. (1984)
    Stamm LV. Role of TLR4 in the host response to Vibrio vulnificus, an emerging pathogen. FEMS Immunol Med Microbiol. 58(3): 336-343. (2010)
    Stamm LV, Drapp RL. TLR2 and TLR4 mediate the TNFalpha response to Vibrio vulnificus biotype 1. Pathog Dis. 71(3):357-361. (2014)
    Strom MS, Paranjpye RN. Epidemiology and pathogenesis of Vibrio vulnificus. Microbes Infect. 2(2): 177-188. (2000)
    Su YC, Chen HW, Hong YC, Chen CT, Hsiao CT, Chen IC. Laboratory risk indicator for necrotizing fasciitis score and the outcomes. ANZ J Surg. 78(11): 968-972. (2008)
    Sudarsky LA, Laschinger JC, Coppa GF, Spencer FC. Improved results from a standardized approach in treating patients with necrotizing fasciitis. Ann Surg. 206(5): 661-665. (1987)
    Surguladze D, Deevi D, Claros N, Corcoran E, Wang S, Plym MJ, Wu Y, Doody J, Mauro DJ, Witte L, Busam KJ, Pytowski B, Rodeck U, Tonra JR. Tumor necrosis factor-alpha and interleukin-1 antagonists alleviate inflammatory skin changes associated with epidermal growth factor receptor antibody therapy in mice. Cancer Res. 69(14): 5643-5647. (2009)
    Swartz MN. Clinical practice. Cellulitis. N Engl J Med. 350(9): 904-912. (2004)
    Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 17(1): 1-14. (2005)
    The Centers for Disease Control and Prevention (2014) Necrotizing Fasciitis: A Rare Disease, Especially for the Healthy. Available at:http://www.cdc.gov/Features/NecrotizingFasciitis/
    The Centers for Disease Control and Prevention (2014) Vibrio vulnificus. How is V. vulnificus infection treated? Available at: http://www.cdc.gov/vibrio/vibriov.html
    Tsai YH, Hsu RW, Huang KC, Huang TJ. Laboratory indicators for early detection and surgical treatment of Vibrio necrotizing fasciitis. Clin Orthop Relat Res. 468(8): 2230-2237. (2010)
    Tsai YH, Huang TJ, Hsu RW, Weng YJ, Hsu WH, Huang KC, Peng KT. Necrotizing soft-tissue infections and primary sepsis caused by Vibrio vulnificus and Vibrio cholerae non-O1. J Trauma. 66(3): 899-905. (2009)
    Tsao CH, Chen CC, Tsai SJ, Li CR, Chao WN, Chan KS, Lin DB, Sheu KL, Chen SC, Lee MC, Bell WR. Seasonality, clinical types and prognostic factors of Vibrio vulnificus infection. J Infect Dev Ctries. 7(7): 533-540. (2013)
    Van Dyk TK, Rosson RA. Photorhabdus luminescens luxCDABE promoter probe vectors. Methods Mol Biol. 102: 85-95. (1998)
    Weis KE, Hammond RM, Hutchinson R, Blackmore CG. Vibrio illness in Florida, 1998-2007. Epidemiol Infect. 139(4): 591-598. (2011)
    Wilson B. Necrotizing fasciitis. Am Surg. 18(4): 416-431. (1952)
    Wong CH, Khin LW, Heng KS, Tan KC, Low CO. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med. 32(7): 1535-1541. (2004)
    Wong CH, Chang HC, Pasupathy S, Khin LW, Tan JL, Low CO. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg Am. 85-A(8): 1454-1460. (2003)
    Wysoki MG, Santora TA, Shah RM, Friedman AC. Necrotizing fasciitis: CT characteristics. Radiology. 203(3): 859-863. (1997)
    Yuan CY, Yuan CC, Wei DC, Lee AM. [Septicemia and gangrenous change of the legs caused by marine vibrio, V. vulnificus--report of a case]. Taiwan Yi Xue Hui Za Zhi. 86(4): 448-451. (1987)

    無法下載圖示 校內:2019-09-04公開
    校外:不公開
    電子論文尚未授權公開,紙本請查館藏目錄
    QR CODE