Profil citokina kod kritično obolelih bolesnika i/ili povređenih osoba sa sekundarnom sepsom – uticaj različitih patogena
Sažetak
Uvod/Cilj. Uloga kompleksnog imunskog odgovora u sepsi i dalje nije do kraja razjašnjena i ostaje predmet istraživanja. Danas se smatra da je sepsa dinamički sindrom koji karakterišu mnogi, često antagonistički fenomeni, u rasponu od hiperinflamacije do anergije i imunoparalize. Cilj rada bio je da se na osnovu nivoa pro- i anti-inflamacijskih medijatora kod kritično obolelih osoba sa sekundarnom sepsom utvrdi da li se citokinski profil razlikuje u odnosu na vrstu bakterijskog uzročnika, kao i da se proceni prognostička vrednost ovog nalaza u odnosu na ishod. Mera ishoda bila je hospitalni mortalitet. Metode. Uzorci seruma periferne krvi uzeti su od 125 kritično obolelih bolesnika primljenih u hiruršku jedinicu intenzivne nege sa potvrđenom teškom sekundarnom sepsom kao komplikacijom peritonitisa, pankreatitisa ili traume. Prosečna starost bolesnika bila je 57,7 ± 17,3 godina. Od ukupnog broja obolelih, 84 (67,2%) su bili muškarci, a 41 (32,8%) žene. Određeni su nivoi pro-inflamacijskih interleukina (IL)-1α, IL-1β, IL-6, IL-8, IL-12р70, IL-17А, faktora nekroze tumora (TNF)-α, interferona (IFN)-γ, IFN-γ-inducibilnog proteina-10 (IP-10), monocitnog hemoatraktantnog proteina (MCP)-1, inflamacijskog proteina makrofaga (MIP)-1α i MIP-1β i anti-inflamacijskih medijatora IL -4, IL-10, IL-13, IL-27, IL-31 i IL-33 u tri vremenska intervala – na dan prijema (prvi dan) a potom trećeg i petog dana. Standardnim mikrobiološkim ispitivanjima određena je vrsta bakterijskog uzročnika. Rezultati. Trećeg dana merenja ustanovljene su značajne razlike u nivoima citokina u odnosu na prirodu bakterijemije kod svih pro- i anti-inflamacijskih citokina, osim kod IL-8. Generalno, najniži nivoi utvrđeni su kod bolesnika sa polimikrobnom hemokulturom. Prvog i petog dana merenja nisu nađene značajne razlike u nivoima citokina u odnosu na prirodu bakterijemije. Jedini značajan prediktor fatalnog ishoda prvog dana merenja bio je IL-17А, Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) 0,665 (95% interval poverenja 0,519–0,791; р = 0.034) kod bolesnika sa sekundarnom sepsom kao komplikacijom peritonitisa. Zaključak. Prema vrsti bakterijskog prouzrokovača utvrđeno je da su najniži nivoi citokina bili kod bolesnika sa polimikrobnom hemokulturom. Niska koncentracija IL-17A prvog dana merenja je dobar prediktor smrtnog ishoda kod bolesnika sa sekundarnom sepsom koja je nastala kao komplikacija peritonitisa. Nasuprot tome, nivoi ostalih citokina korelisali su sa ishodom tek petog dana merenja i bili su viši kod preživelih, u odnosu na umrle bolesnike.
Reference
Monneret G, Venet F. Sepsis-induced immune alterations moni-toring by flow cytometry as a promising tool for individualized therapy. Cytom B Clin Cytom 2016; 93(4): 376–86.
Gentile LF, Cuenca AG, Efron PA, Ang D, Bihorac A, McKinley BA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg 2012; 72(6): 1491–501.
Surbatovic M, Veljovic M, Jevdjić J, Popovic N, Djordjevic D, Rada-kovic S. Immunoinflammatory response in critically ill patients: severe sepsis and/or trauma. Mediators Inflamm 2013; 2013: 362793.
Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011; 306(23): 2594–605.
Monneret G, Venet F, Pachot A, Lepape A. Monitoring immune dysfunctions in the septic patient: a new skin for the old cer-emony. Mol Med 2008; 14(1–2): 64–78.
Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001; 166(11): 6952–63.
Otto GP, Sossdorf M, Claus RA, Rödel J, Menge K, Reinhart K, et al. The late phase of sepsis is characterized by an increased mi-crobiological burden and death rate. Crit Care 2011; 15(4): R183.
Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B, Brownstein BH, et al. Reactivation of multiple viruses in patients with sepsis. PLoS One 2014; 9(2): e98819.
Tsirigotis P, Chondropoulos S, Gkirkas K, Meletiadis J, Dimopoulou I. Balanced control of both hyper and hypo-inflammatory phases as a new treatment paradigm in sepsis. J Thorac Dis 2016; 8(5): E312–6.
Prucha M, Zazula R, Russwurm S. Immunotherapy of Sepsis: Blind Alley or Call for Personalized Assessment? Arch Immu-nol Ther Exp (Warsz) 2017; 65(1): 37–49.
Pène F, Pickkers P, Hotchkiss RS. Is this critically ill patient im-munocompromised? Intensive Care Med 2016; 42(6): 1051–4. Erratum in: Intensive Care Med 2016; 42(6): 1106.
Shankar-Hari M. How could we enhance translation of sepsis immunology to inform immunomodulation trials in sepsis? Crit Care 2017; 21(1): 125.
Surbatovic M, Grujic K, Cikota B, Jevtic M, Filipovic N, Romic P, et al. Polymorphisms of genes encoding tumor necrosis factor-alpha, interleukin-10, cluster of differentiation-14 and inter-leukin-1ra in critically ill patients. J Crit Care 2010; 25(3): 542.e1–8.
Martin S, Pérez A, Aldecoa C. Sepsis and immunosenescence in the elderly patient: a review. Front Med (Lausanne) 2017; 4: 20.
Andreis DT, Singer M. Catecholamines for inflammatory shock: a Jekyll-and-Hyde conundrum. Intensive Care Med 2016; 42(9): 1387–97.
Asehnoune K, Villadangos J, Hotchkiss RS. Understanding host-pathogen interaction. Intensive Care Med 2016; 42(13): 2084–6.
Antonakos N, Tsaganos T, Oberle V, Tsangaris I, Lada M, Pistiki A, et al. Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome. Crit Care 2017; 21(1): 48.
Surbatovic M, Popovic N, Vojvodic D, Milosevic I, Acimovic G, Stojicic M, et al. Cytokine profile in severe Gram-positive and Gram-negative abdominal sepsis. Sci Rep 2015; 5: 11355.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, An-nane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8): 801–10.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Fer-rer R, et al. Surviving Sepsis Campaign: International Guide-lines for Management of Sepsis and Septic Shock: 2016. In-tensive Care Med 2017; 43(3): 304–77.
Delano MJ, Ward PA. The immune system’s role in sepsis pro-gression, resolution, and long-term outcome. Immunol Rev 2016; 274(1): 330–53.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guide-lines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medi-cine. Chest 1992; 101(6): 1644–55.
Rhee C, Klompas M. New Sepsis and Septic Shock Definitions: Clinical Implications and Controversies. Infect Dis Clin North Am 2017; 31(3): 397–413.
Tamayo E, Fernández A, Almansa R, Carrasco E, Heredia M, La-jo C, et al. Pro- and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock. Eur Cytokine Netw 2011; 22(2): 82–7.
Novotny AR, Reim D, Assfalg V, Altmayr F, Friess HM, Em-manuel K, et al. Mixed antagonist response and sepsis severity-dependent dysbalance of pro- and anti-inflammatory responses at the onset of postoperative sepsis. Immunobiology 2012; 217(6): 616–21.
Pickkers P, Kox M. Towards precision medicine for sepsis pa-tients. Crit Care 2017; 21(1): 11.
Pène F, Vincent JL, Martin-Loeches I. On the verge of using an immune toolbox in the intensive care unit? Intensive Care Med 2017; 43(8): 1154–6.
Mera S, Tatulescu D, Cismaru C, Bondor C, Slavcovici A, Zanc V, et al. Multiplex cytokine profiling in patients with sepsis. APMIS 2011; 119(2): 155–63.
Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care 2007; 11(2): R49.
Jekarl DW, Kim JY, Lee S, Kim M, Kim Y, Han K, et al. Diag-nosis and evaluation of severity of sepsis via the use of bi-omarkers and profiles of 13 cytokines: a multiplex analysis. Clin Chem Lab Med 2015; 53(4): 575–81.
Mehra S, Tiwari AK, Aggarwal G, Mehta SP, Chauhan R, Rajvanshi C, et al. Diagnostic value of different interleukins and procalcitonin in critically ill patients admitted with sus-pected sepsis. Indian J Pathol Microbiol 2022; 65(1): 111–6.
Gao H, Evans TW, Finney SJ. Bench-to-bedside review: sepsis, severe sepsis and septic shock - does the nature of the infect-ing organism matter? Crit Care 2008; 12(3): 213.
Tang Y, Liao C, Xu X, Song H, Shi S, Yang S. Th1/Th2 cyto-kine profiles in G+/G- bacteremia in pediatric hematolo-gy/oncology patients. Pediatr Blood Cancer 2012; 58(1): 50–4.
Cohen J. A role for the micro-organism in the outcome from infection? A principle challenged. Crit Care Med 2011; 39(8): 2001–2.
Mosevoll KA, Skrede S, Markussen DL, Fanebust HR, Flaatten HK, Aßmus J, et al. Inflammatory Mediator Profiles Differ in Sepsis Patients With and Without Bacteremia. Front Immunol 2018; 9: 691.
Feezor RJ, Oberholzer C, Baker HV, Novick D, Rubinstein M, Moldawer LL, et al. Molecular characterization of the acute in-flammatory response to infections with gram-negative versus gram-positive bacteria. Infect Immun 2003; 71(10): 5803–13.
Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006; 34(2): 344–53.
Zahar JR, Timsit JF, Garrouste-Orgeas M, Français A, Vesin A, Descorps-Declere A, et al. Outcomes in severe sepsis and pa-tients with septic shock: pathogen species and infection sites are not associated with mortality. Crit Care Med 2011; 39(8): 1886–95. Erratum in: Crit Care Med 2011; 39(10): 2392.
Bhavsar I, Miller CS, Al-Sabbagh M. Macrophage Inflammatory Protein-1 Alpha (MIP-1 alpha)/CCL3: As a Biomarker. In: Preedy V, Patel V, editors. General Methods in Biomarker Re-search and their Applications. Biomarkers in Disease: Meth-ods, Discoveries and Applications. 2015th ed. Dordrecht: Springer; 2015. p. 223–49.
De Pablo R, Monserrat J, Prieto A, Alvarez-Mon M. Role of cir-culating soluble chemokines in septic shock. Med Intensiva 2013; 37(8): 510–8. (English, Spanish)
Zambon M, Ceola M, Almeida-de-Castro R, Gullo A, Vincent JL. Implementation of the Surviving Sepsis Campaign guidelines for severe sepsis and septic shock: we could go faster. J Crit Care 2008; 23(4): 455–60.
Afuwape OO, Ayandipo OO, Kuti M, Adigun TA, Idowu OK. Tu-mor Necrosis Factor-Alpha and Interleukin-1 Alpha as Predic-tors of Survival in Peritonitis: A Pilot Study. Niger J Surg 2018; 24(2): 107–10.
Flierl MA, Rittirsch D, Gao H, Hoesel LM, Nadeau BA, Day DE, et al. Adverse functions of IL-17A in experimental sep-sis. FASEB J 2008; 22(7): 2198–205.
Freitas A, Alves-Filho JC, Victoni T, Secher T, Lemos HP, Sônego F, et al. IL-17 receptor signaling is required to control polymi-crobial sepsis. J Immunol 2009; 182(12): 7846–54.
Morrow KN, Coopersmith CM, Ford ML. IL-17, IL-27, and IL-33: A Novel Axis Linked to Immunological Dysfunction Dur-ing Sepsis. Front Immunol 2019; 10: 1982.
Ahmed Ali M, Mikhael ES, Abdelkader A, Mansour L, El Es-sawy R, El Sayed R, et al. Interleukin-17 as a predictor of sep-sis in polytrauma patients: a prospective cohort study. Eur J Trauma Emerg Surg 2018; 44(4): 621–6.
Tassinari M, Zannoli S, Farabegoli P, Pedna MF, Pierro A, Mastro-ianni A, et al. Rapid diagnosis of bloodstream infections in the critically ill: Evaluation of the broad-range PCR/ESI-MS technology. PLoS One 2018; 13(5): e0197436.