Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis

Jian-Feng Wu, Jie Ma, Juan Chen, Bin Ou-Yang, Min-Ying Chen, Li-Fen Li, Yong-Jun Liu, Ai-Hua Lin, Xiang-Dong Guan, Jian-Feng Wu, Jie Ma, Juan Chen, Bin Ou-Yang, Min-Ying Chen, Li-Fen Li, Yong-Jun Liu, Ai-Hua Lin, Xiang-Dong Guan

Abstract

Introduction: Many studies have shown that monocyte human leukocyte antigen-DR (mHLA-DR) expression may be a good predictor for mortality in severe septic patients. On the contrary, other studies found mHLA-DR was not a useful prognostic marker in severe sepsis. Few studies have taken changes of mHLA-DR during treatment into consideration. The objective of this study was to estimate the prognostic value of changes of mHLA-DR to predict mortality in severe sepsis.

Methods: In this prospective observational study, mHLA-DR was measured by flow cytometry in peripheral blood from 79 adult patients with severe sepsis. mHLA-DR levels were determined on day 0, 3, 7 after admission to the surgical intensive care unit (SICU) with a diagnosis of severe sepsis. ΔmHLA-DR₃ and ΔmHLA-DR₇ were defined as the changes in mHLA-DR value on day 3 and day 7 compared to that on day 0. Data were compared between 28-day survivors and non-survivors. Receiver operating characteristic (ROC) curves were plotted to measure the performance and discriminating threshold of ΔmHLA-DR₃, ΔmHLA-DR₇, ΔmHLA-DR₇-₃, mHLA-DR₀, mHLA-DR₃ and mHLA-DR₇ in predicting mortality of severe sepsis.

Results: ROC curve analysis showed that ΔmHLA-DR₃ and ΔmHLA-DR7 were reliable indicators of mortality in severe sepsis. A ΔmHLA-DR₃ value of 4.8% allowed discrimination between survivors and non-survivors with a sensitivity of 89.0% and a specificity of 93.7%; similarly, ΔmHLA-DR₇ value of 9% allowed discrimination between survivors and non-survivors with a sensitivity of 85.7% and a specificity of 90.0%. Patients with ΔmHLA-DR₃ ≤ 4.8% had higher mortality than those with ΔmHLA-DR₃ > 4.8% (71.4% vs. 2.0%, OR 125.00, 95% CI 13.93 to 1121.67); patients with ΔmHLA-DR7 ≤ 9% had higher mortality than those with ΔmHLA-DR₇ > 9% (52.9% vs. 2.0%, OR 54.00, 95% CI 5.99 to 486.08). The mean change of mHLA-DR significantly increased in the survivor group with the passage of time; from day 0 to day 3 and day 7, changes were 6.45 and 16.90 (P < 0.05), respectively.

Conclusions: The change of mHLA-DR over time may be a reliable predictor for mortality in patients with severe sepsis.

Figures

Figure 1
Figure 1
Trial profile. ICU, intensive care unit.
Figure 2
Figure 2
Receiver operating characteristic (ROC) of ΔmHLA-DR3, ΔmHLA-DR7, and ΔmHLA-DR7-3. ROC analysis depicted the discriminating value of (a) ΔmHLA-DR3, (b) ΔmHLA-DR7, and (c) ΔmHLA-DR7-3 for 28-day mortality in severe sepsis. ΔmHLA-DR3 and ΔmHLA-DR7 were defined as the value change in mHLA-DR on days 3 and 7 compared with that on day 0, and ΔmHLA-DR7-3 was defined as the value change in mHLA-DR on day 7 compared with that on day 3. mHLA-DR, monocyte human leukocyte antigen-DR.
Figure 3
Figure 3
Survival curves of ΔmHLA-DR. Comparison of 28-day mortality by means of Kaplan-Meier survival curves for (a) patients with ΔmHLA-DR3 of greater than 4.8% (continuous line) and ΔmHLA-DR3 of not more than 4.8% (dashed line), (b) patients with ΔmHLA-DR7 of greater than 9% (continuous line) and ΔmHLA-DR7 of not more than 9% (dashed line), and (c) patients with ΔmHLA-DR7-3 of greater than 3.5% (continuous line) and ΔmHLA-DR7-3 of not more than 3.5% (dashed line). ΔmHLA-DR3 and ΔmHLA-DR7 were defined as the value change in mHLA-DR on days 3 and 7 compared with that on day 0, and ΔmHLA-DR7-3 was defined as the value change in mHLA-DR on day 7 compared with that on day 3. mHLA-DR, monocyte human leukocyte antigen-DR.

References

    1. Martin CM, Priestap F, Fisher H, Fowler RA, Heyland DK, Keenan SP, Longo CJ, Morrison T, Bentley D, Antman N. A prospective, observational registry of patients with severe sepsis: the Canadian Sepsis Treatment and Response Registry. Crit Care Med. 2009;37:81–88. doi: 10.1097/CCM.0b013e31819285f0.
    1. Heron M, Hoyert DL, Murphy SL, Xu J, Kochanek KD, Tejada-Vera B. Deaths: final data for 2006. Natl Vital Stat Rep. 2009;57:1–134.
    1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310. doi: 10.1097/00003246-200107000-00002.
    1. Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, Fang Q, Xu Q, Wang D, Jin Y, Yuan S, Wang J, Du Z, Sun Y, Fang X. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med. 2007;35:2538–2546. doi: 10.1097/01.CCM.0000284492.30800.00.
    1. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–150. doi: 10.1056/NEJMra021333.
    1. Monneret G, Venet F, Pachot A, Lepape A. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med. 2008;14:64–78.
    1. Monneret G, Venet F, Kullberg BJ, Netea MG. ICU-acquired immunosuppression and the risk for secondary fungal infections. Med Mycol. 2011;49(Suppl 1):S17–23.
    1. Gogos C, Kotsaki A, Pelekanou A, Giannikopoulos G, Vaki I, Maravitsa P, Adamis S, Alexiou Z, Andrianopoulos G, Antonopoulou A, Athanassia S, Baziaka F, Charalambous A, Christodoulou S, Dimopoulou I, Floros I, Giannitsioti E, Gkanas P, Ioakeimidou A, Kanellakopoulou K, Karabela N, Karagianni V, Katsarolis I, Kontopithari G, Kopterides P, Koutelidakis I, Koutoukas P, Kranidioti H, Lignos M, Louis K. et al.Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection. Crit Care. 2010;14:R96. doi: 10.1186/cc9031.
    1. Genel F, Atlihan F, Ozsu E, Ozbek E. Monocyte HLA-DR expression as predictor of poor outcome in neonates with late onset neonatal sepsis. J Infect. 2010;60:224–228. doi: 10.1016/j.jinf.2009.12.004.
    1. Ditschkowski M, Kreuzfelder E, Rebmann V, Ferencik S, Majetschak M, Schmid EN, Obertacke U, Hirche H, Schade UF, Grosse-Wilde H. HLA-DR expression and soluble HLA-DR levels in septic patients after trauma. Ann Surg. 1999;229:246–254. doi: 10.1097/00000658-199902000-00013.
    1. Höflich C, Meisel C, Volk HD. The role and measurement of HLA-DR in septic patients. Adv Sepsis. 2005;4:134–139.
    1. Volk HD, Thieme M, Heym S, Docke WD, Ruppe U, Tausch W, Manger D, Zuckermann S, Golosubow A, Nieter B. Alterations in function and phenotype of monocytes from patients with septic disease--predictive value and new therapeutic strategies. Behring Inst Mitt. 1991. pp. 208–215.
    1. Lukaszewicz AC GM, Resche-Rigon M, Pirracchio R, Faivre V, Boval B, Payen D. Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med. 2009;37:2746–2752. doi: 10.1097/CCM.0b013e3181ab858a.
    1. Landelle C, Lepape A, Voirin N, Tognet E, Venet F, Bohe J, Vanhems P, Monneret G. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010;36:1859–1866. doi: 10.1007/s00134-010-1962-x.
    1. Lekkou A, Karakantza M, Mouzaki A, Kalfarentzos F, Gogos CA. Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections. Clin Diagn Lab Immunol. 2004;11:161–167.
    1. Asadullah K, Woiciechowsky C, Docke WD, Egerer K, Kox WJ, Vogel S, Sterry W, Volk HD. Very low monocytic HLA-DR expression indicates high risk of infection--immunomonitoring for patients after neurosurgery and patients during high dose steroid therapy. Eur J Emerg Med. 1995;2:184–190. doi: 10.1097/00063110-199512000-00003.
    1. Perry SE, Mostafa SM, Wenstone R, Shenkin A, McLaughlin PJ. Is low monocyte HLA-DR expression helpful to predict outcome in severe sepsis? Intensive Care Med. 2003;29:1245–1252. doi: 10.1007/s00134-003-1686-2.
    1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644–1655. doi: 10.1378/chest.101.6.1644.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–829. doi: 10.1097/00003246-198510000-00009.
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–710. doi: 10.1007/BF01709751.
    1. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837–845. doi: 10.2307/2531595.
    1. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546–1554. doi: 10.1056/NEJMoa022139.
    1. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990;113:227–242.
    1. Flohe S, Scholz M. HLA-DR monitoring in the intensive care unit--more than a tool for the scientist in the laboratory? Crit Care Med. 2009;37:2849–2850. doi: 10.1097/CCM.0b013e3181ad7ac9.
    1. Cheron A, Floccard B, Allaouchiche B, Guignant C, Poitevin F, Malcus C, Crozon J, Faure A, Guillaume C, Marcotte G, Vulliez A, Monneuse O, Monneret G. Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after major trauma. Crit Care. 2010;14:R208. doi: 10.1186/cc9331.
    1. Frazier WJ, Hall MW. Immunoparalysis and adverse outcomes from critical illness. Pediatr Clin North Am. 2008;55:647–668. doi: 10.1016/j.pcl.2008.02.009.
    1. Monneret G, Lepape A, Voirin N, Bohe J, Venet F, Debard AL, Thizy H, Bienvenu J, Gueyffier F, Vanhems P. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. 2006;32:1175–1183. doi: 10.1007/s00134-006-0204-8.
    1. Schefold JC. Measurement of monocytic HLA-DR (mHLA-DR) expression in patients with severe sepsis and septic shock: assessment of immune organ failure. Intensive Care Med. 2010;36:1810–1812. doi: 10.1007/s00134-010-1965-7.
    1. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180:640–648. doi: 10.1164/rccm.200903-0363OC.
    1. Nierhaus A, Montag B, Timmler N, Frings DP, Gutensohn K, Jung R, Schneider CG, Pothmann W, Brassel AK, Schulte Am Esch J. Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med. 2003;29:646–651.
    1. Schneider C, von Aulock S, Zedler S, Schinkel C, Hartung T, Faist E. Perioperative recombinant human granulocyte colony-stimulating factor (Filgrastim) treatment prevents immunoinflammatory dysfunction associated with major surgery. Ann Surg. 2004;239:75–81. doi: 10.1097/01.sla.0000103062.21049.82.
    1. Lin HY. [Clinical trial with a new immunomodulatory strategy: treatment of severe sepsis with Ulinastatin and Maipuxin] Zhonghua Yi Xue Za Zhi. 2007;87:451–457.
    1. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997;3:678–681. doi: 10.1038/nm0697-678.
    1. Schefold JC, von Haehling S, Corsepius M, Pohle C, Kruschke P, Zuckermann H, Volk HD, Reinke P. A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a. Shock. 2007;28:418–425. doi: 10.1097/shk.0b013e31804f5921.
    1. Hirasawa H, Oda S, Matsuda K. Continuous hemodiafiltration with cytokine-adsorbing hemofilter in the treatment of severe sepsis and septic shock. Contrib Nephrol. 2007;156:365–370.
    1. Volk HD, Reinke P, Krausch D, Zuckermann H, Asadullah K, Muller JM, Docke WD, Kox WJ. Monocyte deactivation--rationale for a new therapeutic strategy in sepsis. Intensive Care Med. 1996;22(Suppl 4):S474–481.
    1. Monneret G, Elmenkouri N, Bohe J, Debard AL, Gutowski MC, Bienvenu J, Lepape A. Analytical requirements for measuring monocytic human lymphocyte antigen DR by flow cytometry: application to the monitoring of patients with septic shock. Clin Chem. 2002;48:1589–1592.
    1. Docke WD, Hoflich C, Davis KA, Rottgers K, Meisel C, Kiefer P, Weber SU, Hedwig-Geissing M, Kreuzfelder E, Tschentscher P, Nebe T, Engel A, Monneret G, Spittler A, Schmolke K, Reinke P, Volk HD, Kunz D. Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem. 2005;51:2341–2347. doi: 10.1373/clinchem.2005.052639.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir