Peripheral T‑lymphocyte and natural killer cell population imbalance is associated with septic encephalopathy in patients with severe sepsis

Lu,Cheng‑Xiang; Qiu,Ting; Tong,Hua‑Sheng; Liu,Zhi‑Feng; Su,Lei; Cheng,Biao

doi:10.3892/etm.2016.3000

Peripheral T‑lymphocyte and natural killer cell population imbalance is associated with septic encephalopathy in patients with severe sepsis

Authors:
- Cheng‑Xiang Lu
- Ting Qiu
- Hua‑Sheng Tong
- Zhi‑Feng Liu
- Lei Su
- Biao Cheng
View Affiliations

Affiliations: Department of Intensive Care Unit, Affiliated General Hospital of Guangzhou Military Command of Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Neurology, Zhongshan Hospital Xiamen University, Xiamen, Fujian 361004, P.R. China, Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China, Department of Plastic Surgery, Affiliated General Hospital of Guangzhou Military Command of Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: January 15, 2016 https://doi.org/10.3892/etm.2016.3000
Pages: 1077-1084

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Septic encephalopathy (SE) is a diffuse cerebral dysfunction resulting from a systemic inflammatory response, and is associated with an increased risk of mortality. The pathogenesis of SE is complex and multifactorial, but unregulated immune imbalance may be an important factor. The current retrospective study examined the clinical data of 86 patients with severe sepsis who were admitted to the Intensive Care Unit at Zhongshan Hospital, Xiamen University (Xiamen, China) from January, 2014 to January, 2015. The patients were assigned to SE and non‑SE patient groups according to the presence or absence of SE. The proportion of T‑lymphocyte subsets and natural killer (NK) cells in the immune cell population, representing the function of the immune system, were analyzed for their association with SE and compared with other clinical predictors and biomarkers. The incidence of SE in the patients was 39.5%, and this group demonstrated higher mortality rates (38 vs. 10% in non‑SE patients; P=0.001). Univariate analysis revealed that the SE patients reported a lower percentage of cluster of differentiation 4+(CD4+) T‑lymphocytes (51.67±7.12 vs. 60.72±3.70% in non‑SE patients; P<0.01), a lower CD4+/cluster of differentiation 8+(CD8+) ratio (1.59±0.32 vs. 1.85±0.26% in non‑SE patients; P<0.01) and a higher percentage of NK cells (11.80±1.44 vs. 9.19±2.36% in non‑SE patients; P<0.01). Using a binary logistic regression model, the Acute Physiology and Chronic Health Evaluation II score and the percentage of CD4+ T‑lymphocytes were demonstrated to be independently associated with SE (respectively, P=0.012 and OR, 4.763; P=0.005 and OR, 0.810). An area under the curve analysis of a receiver operating characteristic curve of the two indicators revealed that these were equally powerful measures in prediction of SE (Z=1.247, P>0.05). The present results confirm that SE leads to higher mortality in patients with severe sepsis, and demonstrate that immune imbalance is important in the development of SE. The proportion of CD4+ T‑lymphocytes present were revealed in the current study to be a powerful predictor of SE in patients with severe sepsis.

View Figures

View References

1	Sprung CL, Peduzzi PN, Shatney CH, Schein RM, Wilson MF, Sheagren JN and Hinshaw LB: Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med. 18:801–806. 1990. View Article : Google Scholar : PubMed/NCBI
2	Eidelman LA, Putterman D, Putterman C and Sprung CL: The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities. JAMA. 275:470–473. 1996. View Article : Google Scholar : PubMed/NCBI
3	Straver JS, Keunen RW, Stam CJ, Tavy DL, de Ruiter GR, Smith SJ, Thijs LG, Schellens RG and Gielen G: Nonlinear analysis of EEG in septic encephalopathy. Neurol Res. 20:100–106. 1998.PubMed/NCBI
4	Schraag S: Studying septic encephalopathy: What animal models can predict. Intensive Care Med. 29:667–668. 2003.PubMed/NCBI
5	Eggers V, Fügener K, Hein OV, Rommelspacher H, Heyes MP, Kox WJ and Spies CD: Antibiotic-mediated release of tumour necrosis factor alpha and norharman in patients with hospital-acquired pneumonia and septic encephalopathy. Intensive Care Med. 30:1544–1551. 2004. View Article : Google Scholar : PubMed/NCBI
6	Angel MJ and Young GB: Metabolic encephalopathies. Neurol Clin. 29:837–882. 2011. View Article : Google Scholar : PubMed/NCBI
7	Koo DJ, Jackman D, Chaudry IH and Wang P: Adrenal insufficiency during the late stage of polymicrobial sepsis. Crit Care Med. 29:618–622. 2001. View Article : Google Scholar : PubMed/NCBI
8	Tsao N, Hsu HP, Wu CM, Liu CC and Lei HY: Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis. J Med Microbiol. 50:812–821. 2001. View Article : Google Scholar : PubMed/NCBI
9	Basler T, Meier-Hellmann A, Bredle D and Reinhart K: Amino acid imbalance early in septic encephalopathy. Intensive Care Med. 28:293–298. 2002. View Article : Google Scholar : PubMed/NCBI
10	Deng YY, Fang M, Zhu GF, Zhou Y and Zeng HK: Role of microglia in the pathogenesis of sepsis-associated encephalopathy. CNS Neurol Disord Drug Targets. 12:720–725. 2013. View Article : Google Scholar : PubMed/NCBI
11	Munford RS and Pugin J: Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med. 163:316–321. 2001. View Article : Google Scholar : PubMed/NCBI
12	Oberholzer A, Oberholzer C and Moldawer LL: Sepsis syndromes: Understanding the role of innate and acquired immunity. Shock. 16:83–96. 2001. View Article : Google Scholar : PubMed/NCBI
13	Abraham E and Singer M: Mechanisms of sepsis-induced organ dysfunction. Crit Care Med. 35:2408–2416. 2007. View Article : Google Scholar : PubMed/NCBI
14	Rittirsch D, Flierl MA and Ward PA: Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 8:776–787. 2008. View Article : Google Scholar : PubMed/NCBI
15	Luyt CE, Combes A, Deback C, Aubriot-Lorton MH, Nieszkowska A, Trouillet JL, Capron F, Agut H, Gibert C and Chastre J: Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med. 175:935–942. 2007. View Article : Google Scholar : PubMed/NCBI
16	Kollef KE, Schramm GE, Wills AR, Reichley RM, Micek ST and Kollef MH: Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria. Chest. 134:281–287. 2008. View Article : Google Scholar : PubMed/NCBI
17	Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran NS, Huang ML, Hayes Santo TK, Corey L and Boeckh M: Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 300:413–422. 2008. View Article : Google Scholar : PubMed/NCBI
18	Schwartz M and Baruch K: The resolution of neuroinflammation in neurodegeneration: Leukocyte recruitment via the choroid plexus. EMBO J. 33:7–22. 2014. View Article : Google Scholar : PubMed/NCBI
19	Tian L, Ma L, Kaarela T and Li Z: Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases. J Neuroinflammation. 9:1552012. View Article : Google Scholar : PubMed/NCBI
20	Neumann H: Control of glial immune function by neurons. Glia. 36:191–199. 2001. View Article : Google Scholar : PubMed/NCBI
21	Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL and Ramsay G: International Sepsis Definitions Conference: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 29:530–538. 2003. View Article : Google Scholar : PubMed/NCBI
22	Cotena S and Piazza O: Sepsis-associated encephalopathy. Transl Med UniSa. 2:20–27. 2012.PubMed/NCBI
23	Dal-Pizzol F, Tomasi CD and Ritter C: Septic encephalopathy: Does inflammation drive the brain crazy? Rev Bras Psiquiatr. 36:251–258. 2014. View Article : Google Scholar : PubMed/NCBI
24	Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al: Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 41:580–637. 2013. View Article : Google Scholar : PubMed/NCBI
25	Karmen A, Worblewski F and Landue JS: Transaminases activity in human blood. J Clin Invest. 34:126–131. 1955. View Article : Google Scholar : PubMed/NCBI
26	Milbrandt EB and Angus DC: Bench-to-bedside review: Critical illness-associated cognitive dysfunction - mechanisms, markers, and emerging therapeutics. Crit Care. 10:2382006. View Article : Google Scholar : PubMed/NCBI
27	Ebersoldt M, Sharshar T and Annane D: Sepsis-associated delirium. Intensive Care Med. 33:941–950. 2007. View Article : Google Scholar : PubMed/NCBI
28	Zhang LN, Wang XT, Ai YH, Guo QL, Huang L, Liu ZY and Yao B: Epidemiological features and risk factors of sepsis-associated encephalopathy in intensive care unit patients: 2008–2011. Chin Med J (Engl). 125:828–831. 2012.PubMed/NCBI
29	Zauner C, Gendo A, Kramer L, Kranz A, Grimm G and Madl C: Metabolic encephalopathy in critically ill patients suffering from septic or nonseptic multiple organ failure. Crit Care Med. 28:1310–1315. 2000. View Article : Google Scholar : PubMed/NCBI
30	Taylor SL, Morgan DL, Denson KD, Lane MM and Pennington LR: A comparison of the Ranson, Glasgow, and APACHE II scoring systems to a multiple organ system score in predicting patient outcome in pancreatitis. Am J Surg. 189:219–222. 2005. View Article : Google Scholar : PubMed/NCBI
31	Bone RC, Sprung CL and Sibbald WJ: Definitions for sepsis and organ failure. Crit Care Med. 20:724–726. 1992. View Article : Google Scholar : PubMed/NCBI
32	Babior BM: NADPH oxidase: An update. Blood. 93:1464–1476. 1999.PubMed/NCBI
33	Wang CX and Shuaib A: Involvement of inflammatory cytokines in central system injury. Prog Neurobiol. 67:161–172. 2002. View Article : Google Scholar : PubMed/NCBI
34	Choi SH, Lee DY, Kim SU and Jin BK: Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo: Role of microglial NADPH oxidase. J Neurosci. 25:4082–4090. 2005. View Article : Google Scholar : PubMed/NCBI
35	Sprung CL, Cerra FB, Freund HR, Schein RM, Konstantinides FN, Marcial EH and Pena M: Amino acid alterations and encephalopathy in the sepsis syndrome. Crit Care Med. 19:753–757. 1991. View Article : Google Scholar : PubMed/NCBI
36	Kadoi Y and Saito S: An alteration in the gamma-aminobutyric acid receptor system in experimentally induced septic shock in rats. Crit Care Med. 24:298–305. 1996. View Article : Google Scholar : PubMed/NCBI
37	Nguyen DN, Spapen H, Su F, Schiettecatte J, Shi L, Hachimi-Idrissi S and Huyghens L: Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med. 34:1967–1974. 2006. View Article : Google Scholar : PubMed/NCBI
38	Piazza O, Cotena S, De Robertis E, Caranci F and Tufano R: Sepsis associated encephalopathy studied by MRI and cerebral spinal fluid S100B measurement. Neurochem Res. 34:1289–1292. 2009. View Article : Google Scholar : PubMed/NCBI
39	Piazza O, Russo E, Cotena S, Esposito G and Tufano R: Elevated S100B levels do not correlate with the severity of encephalopathy during sepsis. Br J Anaesth. 99:518–521. 2007. View Article : Google Scholar : PubMed/NCBI
40	van den Boogaard M, Ramakers BP, van Alfen N, van der Werf SP, Fick WF, Hoedemaekers CW, Verbeek MM, Schoonhoven L, van der Hoeven JG and Pickkers P: Endotoxemia-induced inflammation and the effect on the human brain. Crit Care. 14:R812010. View Article : Google Scholar : PubMed/NCBI
41	Omari KM and Dorovini-Zis K: CD40 expressed by human brain endothelial cells regulates CD4⁺ T cell adhesion to endothelium. J Neuroimmunol. 134:166–178. 2003. View Article : Google Scholar : PubMed/NCBI
42	Sankowski R, Mader S and Valdés-Ferrer SI: Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci. 9:282015. View Article : Google Scholar : PubMed/NCBI
43	Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, Osborne DF, Freeman BD, Cobb JP, Buchman TG and Karl IE: Sepsis-induced apoptosis causes progressive profound depletion of B and CD4⁺ T lymphocytes in humans. J Immunol. 166:6952–6963. 2001. View Article : Google Scholar : PubMed/NCBI
44	Roth G, Moser B, Krenn C, Brunner M, Haisjackl M, Almer G, Gerlitz S, Wolner E, Boltz-Nitulescu G and Ankersmit HJ: Susceptibility to programmed cell death in T-lymphocytes from septic patients: A mechanism for lymphopenia and Th2 predominance. Biochem Biophys Res Commun. 308:840–846. 2003. View Article : Google Scholar : PubMed/NCBI
45	Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD II, Kreisel D, Krupnick AS, et al: Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 306:2594–2605. 2011. View Article : Google Scholar : PubMed/NCBI
46	Sunkara B, Bheemreddy S, Lorber B, Lephart PR, Hayakawa K, Sobel JD, Kaye KS and Marchaim D: Group B Streptococcus infections in non-pregnant adults: The role of immunosuppression. Int J Infect Dis. 16:e182–e186. 2012. View Article : Google Scholar : PubMed/NCBI
47	Ferguson NR, Galley HF and Webster NR: T helper cell subset ratios in patients with severe sepsis. Intensive Care Med. 25:106–109. 1999. View Article : Google Scholar : PubMed/NCBI
48	Cheadle WG, Pemberton RM, Robinson D, Livingston DH, Rodriguez JL and Polk HC Jr: Lymphocyte subset responses to trauma and sepsis. J Trauma. 35:844–849. 1993. View Article : Google Scholar : PubMed/NCBI
49	Wakefield CH, Carey PD, Foulds S, Monson JR and Guillou PJ: Changes in major histocompatibility complex class II expression in monocytes and T cells of patients developing infection after surgery. Br J Surg. 80:205–209. 1993. View Article : Google Scholar : PubMed/NCBI
50	Chalifour A, Jeannin P, Gauchat JF, Blaecke A, Malissard M, N'Guyen T, Thieblemont N and Delneste Y: Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production. Blood. 104:1778–1783. 2004. View Article : Google Scholar : PubMed/NCBI
51	Andaluz-Ojeda D, Iglesias V, Bobillo F, Almansa R, Rico L, Gandía F, Loma AM, Nieto C, Diego R, Ramos E, et al: Early natural killer cell counts in blood predict mortality in severe sepsis. Crit Care. 15:R2432011. View Article : Google Scholar : PubMed/NCBI
52	Anduluz-Ojeda D, Iglesias V, Bobillo F, Almansa R, Rico L, Gandía F, Loma AM, Nieto C, Diego R, Ramos E, et al: Early natural killer cell counts in blood predict mortality in severe sepsis. Crit Care. 15:R2432011. View Article : Google Scholar : PubMed/NCBI
53	Markwart R, Condotta SA, Requardt RP, Borken F, Schubert K, Weigel C, Bauer M, Griffith TS, Förster M, Brunkhorst FM, et al: Immunosuppression after sepsis: Systemic inflammation and sepsis induce a loss of naïve T-cells but no enduring cell-autonomous defects in T-cell function. PLoS One. 9:e1150942014. View Article : Google Scholar : PubMed/NCBI
54	de Pablo R, Monserrat J, Reyes E, Diaz-Martin D, Zapata Rodriguez M, Carballo F, de la Hera A, Prieto A and Alvarez-Mon M: Mortality in patients with septic shock correlates with anti-inflammatory but not proinflammatory immunomodulatory molecules. J Intensive Care Med. 26:125–132. 2011. View Article : Google Scholar : PubMed/NCBI
55	Menges T, Engel J, Welters I, Wagner RM, Little S, Ruwoldt R, Wollbrueck M and Hempelmann G: Changes in blood lymphocyte populations after multiple trauma: Association with posttraumatic complications. Crit Care Med. 27:733–740. 1999. View Article : Google Scholar : PubMed/NCBI
56	Sarlis NJ, Chanock SJ and Nieman LK: Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. J Clin Endocrinol Metab. 85:42–7. 2000. View Article : Google Scholar : PubMed/NCBI
57	Toft P, Hokland M, Hansen TG and Tønnesen E: Changes in lymphocyte subpopulations and adhesion/activation molecules following endotoxemia and major surgery. APMIS. 103:261–266. 1995. View Article : Google Scholar : PubMed/NCBI
58	Lemaire LC, van Deventer SJ, van Lanschot JJ, Meenan J and Gouma DJ: Phenotypical characterization of cells in the thoracic duct of patients with and without systemic inflammatory response syndrome and multiple organ failure. Scand J Immunol. 47:69–75. 1998. View Article : Google Scholar : PubMed/NCBI