Состояние иммунной системы при абдоминальном сепсисе
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Koshelev R.V., Vatazin A.V., Zulkarnayev A.B., Faenko A.P. The state of the immune system in abdominal sepsis. Therapeutic Archive. 2019; 91 (2): 8–86. DOI: 10.26442/00403660.2019.02.000064
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Цель исследования. Оценить прогностическую ценность показателей цитокинового профиля, активности фагоцитоза, концентрации и активности эндотоксина в крови при грамотрицательном сепсисе.
Материалы и методы. В одноцентровое когортное исследование включено 78 пациентов с абдоминальным сепсисом, из них умерло 45. Всем пациентам производилась оценка концентрации циркулирующих цитокинов (фактор некроза опухоли-α – ФНО-α, интерферон-γ – ИНФ-γ, интерлейкин-6 – ИЛ-6, ИЛ-8, ИЛ-10), клеточных молекул (CD3, CD45RO, CD95 и HLA-DR), бактерицидная и фагоцитарная активность нейтрофилов и уровень эндотоксина (липополисахарида) в периферической крови.
Результаты и обсуждение. В целом у выживших больных концентрации всех цитокинов были несколько ниже. При этом значимые различия были отмечены для ФНО-α (p=0,001), ИЛ-6 (p=0,001), ИЛ-8 (p=0,007). Экспрессия молекул HLA-DR была несколько выше (p=0,055), а CD95 – ниже (p=0,146) у выживших, чем у умерших. Тем не менее различия не достигли необходимого уровня статистической значимости. При этом показатели фагоцитарной (p<0,001) и бактерицидной (p=0,002 для стимулированного зимозаном восстановления нитросинего тетразолия – HCTинд и p=0,001 для спонтанного восстановления нитросинего тетразолия – HCTспонт) активности нейтрофилов значительно различались. У выживших пациентов мы отметили бо’льшие значения HCTинд и индекса переваривания, чем у умерших. Уровень HCTспонт у выживших был ниже. У умерших впоследствии больных уровень эндотоксиновой нагрузки был выше, чем у выживших больных: уровень концентрации липополисахаридов (p=0,002), активности эндотоксина (p=0,032) и активности нейтрофилов (p=0,028).
Заключение. Оценка уровня цитокинов является информативной, но в связи с высоким разбросом показателей у разных пациентов должна проводиться в динамике. Наиболее информативными прогностическими показателями при сепсисе являются концентрация и активность липополисахаридов (эндотоксина), фагоцитарная и бактерицидная активность нейтрофиллов. Оценка EAA (endotoxin activity assay) должна проводиться совместно с оценкой «response» нейтрофилов.
Ключевые слова: сепсис, цитотоксины, эндотоксины, активность нейтрофилов.
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Sepsis is a serious condition characterized by a complex dysfunction of internal organs and systems. In the basis of the pathogenesis of sepsis, the leading role is played by the dysregulation of the immune response to the infectious agent, in particular endotoxin of gramnegative bacteria, which is an obligate lipopolysaccharide of the bacterial wall.
Aim. To evaluate the prognostic value of cytokine profile, phagocytosis activity indices, endotoxin concentration and activity in blood in gram-negative sepsis.
Materials and methods. 78 patients with abdominal sepsis were included in a one-center prospective cohort study, of them 45 died. All the patients were evaluated for the concentration of circulating cytokines (TNF-α, IFN-γ, IL-6, IL-8, IL-10), cellular molecules (CD3, CD45RO, CD95 and HLA-DR), bactericidal and phagocytic activity of neutrophils and endotoxin (lipopolysaccharide) level in peripheral blood.
Results and discussion. The concentrations of all cytokines were slightly lower in the survivors. Significant differences were noted for TNF-α (p=0.001), IL-6 (p=0.001), and IL-8 (p=0.007). The expression of HLA-DR molecules was slightly higher (p=0.055), and CD95 was lower (p=0.146) in survivors than in the dead. However, the differences have not reached the required level of statistical significance. The phagocytic (p<0.001) and bactericidal activity (р=0.002 for stimulated activity and p=0.001 for spontaneous activity) of neutrophils is significantly different. In survived patients, we noted large values of stimulated bactericidal activity and phagocytic index than the dead. Level of spontaneous activity in survivors was lower. In subsequently deceased patients, the level of endotoxin load was higher than in the surviving patients: level of lipopolysaccharide concentration (p=0.002), endotoxin activity (p=0.032) and neutrophils activity (p=0.028).
Conclusion. Evaluation of cytokine levels is informative, but due to the high spread of indicators in different patients, should be carried out in the dynamics. The most informative prognostic parameters in sepsis are the concentration and activity of lipopolysaccharides (endotoxin), phagocytic and bactericidal activity of neutrophils. The EAA (endotoxin activity assay) assessment should be conducted in conjunction with the neutrophil "response" assessment.
Keywords: sepsis, cytotoxins, endotoxins, neutrophil activity.
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1. Singer M, Deutschman C, Seymour C, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10. doi: 10.1001/jama.2016.0287
2. Alexandraki I, Palacio C. Gram-negative versus Gram-positive bacteremia: what is more alarmin(g)? Crit Care. 2010;14(3):161. doi: 10.1186/cc9013
3. Ani C, Farshidpanah S, Bellinghausen Stewart A, Nguyen H. Variations in organism-specific severe sepsis mortality in the United States: 1999-2008. Crit Care Med. 2015;43(1):65-77. doi: 10.1097/CCM.0000000000000555
4. Bell J, Turnidge J, Coombs G, et al. Australian Group on Antimicrobial Resistance Australian Enterobacteriaceae Sepsis Outcome Programme annual report, 2014. Commun Dis Intell Q Rep. 2016;40(2):229-35.
5. Ergönül Ö, Aydin M, Azap A, et al. Healthcare-associated Gram-negative bloodstream infections: antibiotic resistance and predictors of mortality. J Hosp Infect. 2016;94(4):381-5. doi: 10.1016/j.jhin.2016.08.012
6. Ivlichev АV, Chuvashova MS, Lyapina EP, Lisko OB, Tsareva TD. Features of the course of sepsis according to the resuscitation department of the state health facility with SGKB № 2 them. V.I. Razumovsky of Saratov. Saratovskij Nauchno-Meditsinskij Zhurnal. 2016;12(2):222 (In Russ.)
7. Savina VA, Kolosovskaya EN, Lebedev VF. Relevant Issues of Sepsis Epidemiology. Meditsinskij Al'manakh. 2014;34(4):20-2 (In Russ.)
8. Opal SM. Endotoxins and other sepsis triggers. Contrib Nephrol. 2010;167:14-24. doi: 10.1159/000315915
9. Christodoulou S, Kyriazopoulou E, Chrysanthakopoulou M, et al. Lipid peroxidation in Gram-negative bacteremia modulates the risk for septic shock and infections by resistant Klebsiella pneumoniae. Eur J Clin Microbiol Infect Dis. 2017;36(11):2171-7. doi: 10.1007/s10096-017-3041-5
10. Boisramé-Helms J, Kremer H, Schini-Kerth V, Meziani F. Endothelial dysfunction in sepsis. Curr Vasc Pharmacol. 2013;11(2):150-60.
11. Brown KA, Brown GA, Lewis SM, Beale R, Treacher DF. Targeting cytokines as a treatment for patients with sepsis: A lost cause or a strategy still worthy of pursuit? Int Immunopharmacol. 2016;36:291-9. doi: 10.1016/j.intimp.2016.04.041
12. Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017;39(5):517-28. doi: 10.1007/s00281-017-0639-8
13. Balk R. Roger C. Bone, MD and the evolving paradigms of sepsis. Contrib Microbiol. 2011;17:1-11. doi: 10.1159/000323970
14. Opal SM. The evolution of the understanding of sepsis, infection, and the host response: a brief history. Crit Care Nurs Clin North Am. 2011;23(1):1-27. doi: 10.1016/j.ccell.2010.12.001
15. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77. doi: 10.1007/s00134-017-4683-6
16. Matsumoto N, Takahashi G, Kojika M, et al. Interleukin-8 induces an elevation in the endotoxin activity assay (EAA) level: does the EAA truly measure the endotoxin level? J Infect Chemother. 2013;19(5):825-32. doi: 10.1007/s10156-013-0567-z
17. Sridharan P, Chamberlain RS. The efficacy of procalcitonin as a biomarker in the management of sepsis: slaying dragons or tilting at windmills? Surg Infect (Larchmt). 2013;14(6):489-511. doi: 10.1089/sur.2012.028
18. Kellum JA, Kong L, Fink MP, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007;167(15):1655-63.
19. Bronkhorst MW, Patka P, Van Lieshout EM. Effects of Sequence Variations in Innate Immune Response Genes on Infectious Outcome in Trauma Patients: A Comprehensive Review. Shock. 2015;44(5):390-6. doi: 10.1097/SHK.0000000000000450
20. Mera S, Tatulescu D, Cismaru C, et al. Multiplex cytokine profiling in patients with sepsis. APMIS. 2011;119(2):155-63. doi: 10.1111/j.1600-0463.2010.02705.x
21. Chaudhry H, Zhou J, Zhong Y, et al. Role of cytokines as a double-edged sword in sepsis. In Vivo. 2013;27(6):669-84.
22. Luzina IG, Lockatell V, Todd NW, et al. Splice isoforms of human interleukin-4 are functionally active in mice in vivo. Immunology. 2011;132(3):385-93. doi: 10.1111/j.1365-2567.2010.03393.x
23. Dolgushin II, Toropova LR, Savochkina AYu, et al. Dynamics of changes functional parameters of neutrophils in septic patients with a faroble outcome. Rossijskij Immunologicheskij Zhurnal. 2017;11(2):295-6 (In Russ.)
24. Power C, Wang JH, Sookhai S. Proinflammatory effects of bacterial lipoprotein on human neutrophil activation status, function and cytotoxic potential in vitro. Shock. 2001;15(6):461-6.
25. Yaroustovsky M, Rogalskaya E, Plyushch M, Klimovich L, Samsonova N, Abramyan M. The Level of Oxidative Neutrophil Response When Determining Endotoxin Activity Assay: A New Biomarker for Defining the Indications and Effectiveness of Intensive Care in Patients with Sepsis. Int J Inflam. 2017;2017:3495293. doi: 10.1155/2017/3495293
ГБУЗ МО «Московский областной научно-клинический институт им. М.Ф. Владимирского», Москва, Россия
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R.V. Koshelev, A.V. Vatazin, A.B. Zulkarnayev, A.P. Faenko
M.F. Vladimirskiy Moscow Regional Research and Clinical Institute (MONIKI), Moscow, Russia