Early Immunoparalysis Was Associated with Poor Prognosis in Elderly Patients with Sepsis: Secondary Analysis of the ETASS Study

Fei Pei, Guan-Rong Zhang, Li-Xin Zhou, Ji-Yun Liu, Gang Ma, Qiu-Ye Kou, Zhi-Jie He, Min-Ying Chen, Yao Nie, Jian-Feng Wu, Xiang-Dong Guan, China Critical Care Immunotherapy Research Group, Fei Pei, Guan-Rong Zhang, Li-Xin Zhou, Ji-Yun Liu, Gang Ma, Qiu-Ye Kou, Zhi-Jie He, Min-Ying Chen, Yao Nie, Jian-Feng Wu, Xiang-Dong Guan, China Critical Care Immunotherapy Research Group

Abstract

Purpose: Although immune dysfunction has been investigated in adult septic patients, early immune status remains unclear. In this study, our primary aim was to assess early immune status in adult patients with sepsis stratified by age and its relevance to hospital mortality.

Patients and methods: A post hoc analysis of a multicenter, randomized controlled trial was conducted; 273 patients whose immune status was evaluated within 48 hours after onset of sepsis were enrolled. Early immune status was evaluated by the percentage of monocyte human leukocyte antigen-DR (mHLA-DR) in total monocytes within 48 hours after onset of sepsis and it was classified as immunoparalysis (mHLA-DR ≤30%) or non-immunoparalysis (>30%). Three logistic regression models were conducted to explore the associations between early immunoparalysis and hospital mortality. We also developed two sensitivity analyses to find out whether the definition of early immune status (24 hours vs 48 hours after onset of sepsis) and immunotherapy affect the primary outcome.

Results: Of the 181 elderly (≥60yrs) and 92 non-elderly (<60yrs) septic patients, 71 (39.2%) and 25 (27.2%) died in hospital, respectively. The percentage of early immunoparalysis in the elderly was twice of that in the non-elderly patients (32% vs 16%, p=0.006). For the elderly, hospital mortality was higher in the immunoparalysis ones than the non-immunoparalysis ones (53.4% vs 32.5%, p=0.009). But there was no significant difference in hospital mortality between immunoparalysis non-elderly patients and non-immunoparalysis non-elderly ones (33.5% vs 26.0%, p=0.541). By means of logistic regression models, we found that early immunoparalysis was independently associated with increased hospital mortality in elderly, but not in non-elderly patients. Sensitivity analysis further confirmed the definition of early immune status and immunotherapy did not affect the outcomes.

Conclusion: The elderly were more susceptible to early immunoparalysis after onset of sepsis. Early immunoparalysis was independently associated with poor prognosis in elderly, but not in non-elderly patients.

Keywords: early immune status; elderly; immunoparalysis; immunosuppression; mHLA-DR; sepsis.

Conflict of interest statement

All authors declare that they have no competing interests.

© 2020 Pei et al.

Figures

Figure 1
Figure 1
Flow chart. In this study, 181 elderly and 92 non-elderly septic patients whose mHLA-DR was obtained within 48 hours after onset of sepsis were enrolled.
Figure 2
Figure 2
The changes of mHLA-DR in survivors and non-survivors in different age. The mHLA-DR in elderly non-survivors was lower than that of survivors on day 0 and day 3. However, the mHLA-DR of non-elderly non-survivors was similar to that of survivors on day 0, but mHLA-DR decreased rapidly in non-elderly non-survivors on day 3.
Figure 3
Figure 3
Early immune status and change of immune status in patients with sepsis. (A) The percentage of early immunoparalysis in elderly patients was twice of that of non-elderly patients (32% vs 16%, p=0.008). (B) About half of elderly (82/159, 52%) and non-elderly (38/80, 47%) patients had immune status improvement on day 3 (**p value <0.01).
Figure 4
Figure 4
Immune status and hospital mortality. (A) The hospital mortality of immunoparalysis elderly patients were higher than that of non-immunoparalysis ones (31/58 vs 40/123), but there was no significant difference in hospital mortality in the non-elderly between immunoparalysis and non-immunoparalysis (5/15 vs 20/77). (B) Septic patients with immune status improvement on day 3 had lower hospital mortality than patients with non-improvement in both the elderly and the non-elderly groups (*p value <0.05; **p value <0.01).

References

    1. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–810. doi:10.1001/jama.2016.0287
    1. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167–1174. doi:10.1097/CCM.0b013e31827c09f8
    1. Suarez De La Rica A, Gilsanz F, Maseda E. Epidemiologic trends of sepsis in western countries. Ann Transl Med. 2016;4(17):325. doi:10.21037/atm.2016.08.59
    1. Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306(23):2594–2605. doi:10.1001/jama.2011.1829
    1. Mira JC, Gentile LF, Mathias BJ, et al. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit Care Med. 2017;45(2):253–262. doi:10.1097/CCM.0000000000002074
    1. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862–874. doi:10.1038/nri3552
    1. Gouel-Cheron A, Allaouchiche B, Floccard B, Rimmele T, Monneret G. Early daily mHLA-DR monitoring predicts forthcoming sepsis in severe trauma patients. Intensive Care Med. 2015;41(12):2229–2230. doi:10.1007/s00134-015-4045-1
    1. Wu JF, Ma J, Chen J, et al. Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Crit Care. 2011;15(5):R220. doi:10.1186/cc10457
    1. Landelle C, Lepape A, Voirin N, et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010;36(11):1859–1866. doi:10.1007/s00134-010-1962-x
    1. Monneret G, Lepape A, Voirin N, et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. 2006;32(8):1175–1183. doi:10.1007/s00134-006-0204-8
    1. Lin HY, Guo XS, Yao YM, et al. Clinical trial to verify the value of the CD14(+) monocyte human leukocyte antigen DR as a marker in evaluating immunosuppression in patients with severe sepsis. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2003;15(3):135–138.
    1. Meisel C, Schefold JC, Pschowski R, et al. 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(7):640–648. doi:10.1164/rccm.200903-0363OC
    1. Caruso C, Buffa S, Candore G, et al. Mechanisms of immunosenescence. Immun Ageing. 2009;6(1):10. doi:10.1186/1742-4933-6-10
    1. Martin S, Perez A, Aldecoa C. Sepsis and immunosenescence in the elderly patient: a review. Front Med (Lausanne). 2017;4:20. doi:10.3389/fmed.2017.00129
    1. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007;35(5):1244–1250. doi:10.1097/01.CCM.0000261890.41311.E9
    1. Baykara N, Akalin H, Arslantas MK, et al. Epidemiology of sepsis in intensive care units in Turkey: a multicenter, point-prevalence study. Crit Care. 2018;22(1):93. doi:10.1186/s13054-018-2013-1
    1. Lee SH, Hsu TC, Lee MG, et al. Nationwide trend of sepsis: a comparison among octogenarians, elderly, and young adults. Crit Care Med. 2018;46(6):926–934. doi:10.1097/CCM.0000000000003085
    1. Inoue S, Suzuki-Utsunomiya K, Okada Y, et al. Reduction of immunocompetent T cells followed by prolonged lymphopenia in severe sepsis in the elderly. Crit Care Med. 2013;41(3):810–819. doi:10.1097/CCM.0b013e318274645f
    1. Suzuki K, Inoue S, Kametani Y, et al. Reduced immunocompetent B cells and increased secondary infection in elderly patients with severe sepsis. Shock. 2016;46(3):270–278. doi:10.1097/SHK.0000000000000619
    1. Muszynski JA, Nofziger R, Moore-Clingenpeel M, et al. Early immune function and duration of organ dysfunction in critically iii children with sepsis. Am J Respir Crit Care Med. 2018;198(3):361–369. doi:10.1164/rccm.201710-2006OC
    1. Wu J, Zhou L, Liu J, et al. The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Crit Care. 2013;17(1):R8. doi:10.1186/cc11932
    1. World Health Organization. China country assessment report on ageing and health. 2015. Available from: . Accessed October13, 2019..
    1. Pfortmueller CA, Meisel C, Fux M, Schefold JC. Assessment of immune organ dysfunction in critical illness: utility of innate immune response markers. Intensive Care Med Exp. 2017;5(1):49. doi:10.1186/s40635-017-0163-0
    1. Volk HD, Reinke P, Krausch D, et al. Monocyte deactivation–rationale for a new therapeutic strategy in sepsis. Intensive Care Med. 1996;22(Suppl 4):S474–S481. doi:10.1007/BF01743727
    1. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286(14):1754–1758. doi:10.1001/jama.286.14.1754
    1. Remy S, Kolev-Descamps K, Gossez M, et al. Occurrence of marked sepsis-induced immunosuppression in pediatric septic shock: a pilot study. Ann Intensive Care. 2018;8(1):36. doi:10.1186/s13613-018-0382-x
    1. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13(3):260–268. doi:10.1016/S1473-3099(13)70001-X
    1. Biston P, Aldecoa C, Devriendt J, et al. Outcome of elderly patients with circulatory failure. Intensive Care Med. 2014;40(1):50–56. doi:10.1007/s00134-013-3121-7
    1. Flaatten H, de Lange DW, Artigas A, et al. The status of intensive care medicine research and a future agenda for very old patients in the ICU. Intensive Care Med. 2017;43(9):1319–1328. doi:10.1007/s00134-017-4718-z
    1. Lukaszewicz AC, Grienay M, Resche-Rigon M, et al. Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med. 2009;37(10):2746–2752. doi:10.1097/CCM.0b013e3181ab858a
    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(8):1245–1252. doi:10.1007/s00134-003-1686-2

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner