Skip to main content
Top
Published in: Critical Care 1/2019

Open Access 01-12-2019 | Septicemia | Research

The association between autoimmune disease and 30-day mortality among sepsis ICU patients: a cohort study

Authors: Mallory Sheth, Corey M. Benedum, Leo Anthony Celi, Roger G. Mark, Natasha Markuzon

Published in: Critical Care | Issue 1/2019

Login to get access

Abstract

Introduction

Sepsis results from a dysregulated host response to an infection that is associated with an imbalance between pro- and anti-inflammatory cytokines. This imbalance is hypothesized to be a driver of patient mortality. Certain autoimmune diseases modulate the expression of cytokines involved in the pathophysiology of sepsis. However, the outcomes of patients with autoimmune disease who develop sepsis have not been studied in detail. The objective of this study is to determine whether patients with autoimmune diseases have different sepsis outcomes than patients without these comorbidities.

Methods

Using the Multiparameter Intelligent Monitoring in Intensive Care III database (v. 1.4) which contains retrospective clinical data for over 50,000 adult ICU stays, we compared 30-day mortality risk for sepsis patients with and without autoimmune disease. We used logistic regression models to control for known confounders, including demographics, disease severity, and immunomodulation medications. We used mediation analysis to evaluate how the chronic use of immunomodulation medications affects the relationship between autoimmune disease and 30-day mortality.

Results

Our study found a statistically significant 27.00% reduction in the 30-day mortality risk associated with autoimmune disease presence. This association was found to be the strongest (OR 0.71, 95% CI 0.54–0.93, P = 0.014) among patients with septic shock. The autoimmune disease-30-day mortality association was not mediated through the chronic use of immunomodulation medications (indirect effect OR 1.07, 95% CI 1.01–1.13, P = 0.020).

Conclusions

We demonstrated that autoimmune diseases are associated with a lower 30-day mortality risk in sepsis. Our findings suggest that autoimmune diseases affect 30-day mortality through a mechanism unrelated to the chronic use of immunomodulation medications. Since this study was conducted within a single study center, research using data from other medical centers will provide further validation.
Appendix
Available only for authorised users
Literature
1.
go back to reference Angus DC, Van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840–51.CrossRef Angus DC, Van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840–51.CrossRef
3.
go back to reference Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets—an updated view. Mediat Inflamm. 2013;3(3):155–8. Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets—an updated view. Mediat Inflamm. 2013;3(3):155–8.
4.
go back to reference Angus DC. The search for effective therapy for sepsis: back to the drawing board? JAMA. 2011;306:2614–5.CrossRef Angus DC. The search for effective therapy for sepsis: back to the drawing board? JAMA. 2011;306:2614–5.CrossRef
5.
go back to reference Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–74.CrossRef Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–74.CrossRef
6.
go back to reference Chaudhry H, Zhou J, Zhong YIN, Ali MM, McGuire F, Nagarkatti PS, et al. Role of cytokines as a double-edged sword in sepsis. In Vivo. 2013;27:669–84.PubMedPubMedCentral Chaudhry H, Zhou J, Zhong YIN, Ali MM, McGuire F, Nagarkatti PS, et al. Role of cytokines as a double-edged sword in sepsis. In Vivo. 2013;27:669–84.PubMedPubMedCentral
7.
go back to reference Jaffer U, Wade RG, Gourlay T. Cytokines in the systemic inflammatory response syndrome: a review. HSR Proc Intensive Care Cardiovasc Anesth. 2010;2:161.PubMedPubMedCentral Jaffer U, Wade RG, Gourlay T. Cytokines in the systemic inflammatory response syndrome: a review. HSR Proc Intensive Care Cardiovasc Anesth. 2010;2:161.PubMedPubMedCentral
8.
go back to reference Rose NR, Mackay IR. The autoimmune diseases. 5th ed. San Diego: Academic Press; 2014. Rose NR, Mackay IR. The autoimmune diseases. 5th ed. San Diego: Academic Press; 2014.
9.
go back to reference Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345:340–50.CrossRef Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345:340–50.CrossRef
10.
go back to reference Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol. 2012;33:571–7.CrossRef Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol. 2012;33:571–7.CrossRef
11.
go back to reference Li X, Xiao B-G, Xi J-Y, Lu C-Z, Lu J-H. Decrease of CD4+ CD25highFoxp3+ regulatory T cells and elevation of CD19+ BAFF-R+ B cells and soluble ICAM-1 in myasthenia gravis. Clin Immunol. 2008;126:180–8.CrossRef Li X, Xiao B-G, Xi J-Y, Lu C-Z, Lu J-H. Decrease of CD4+ CD25highFoxp3+ regulatory T cells and elevation of CD19+ BAFF-R+ B cells and soluble ICAM-1 in myasthenia gravis. Clin Immunol. 2008;126:180–8.CrossRef
12.
go back to reference Santamaria P. Cytokines and chemokines in autoimmune disease: an overview. Adv Exp Med Biol. 2003;520:1–7.CrossRef Santamaria P. Cytokines and chemokines in autoimmune disease: an overview. Adv Exp Med Biol. 2003;520:1–7.CrossRef
13.
go back to reference Colbert JF, Schmidt EP, Faubel S, Ginde AA. Severe sepsis outcomes among hospitalizations with inflammatory bowel disease. Shock. 2017;47:128.CrossRef Colbert JF, Schmidt EP, Faubel S, Ginde AA. Severe sepsis outcomes among hospitalizations with inflammatory bowel disease. Shock. 2017;47:128.CrossRef
14.
go back to reference Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. 2016;126:23–31.CrossRef Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. 2016;126:23–31.CrossRef
15.
go back to reference Cuenca AG, Delano MJ, Kelly-Scumpia KM, Moreno C, Scumpia PO, LaFace DM, et al. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med. 2011;17:281–92.CrossRef Cuenca AG, Delano MJ, Kelly-Scumpia KM, Moreno C, Scumpia PO, LaFace DM, et al. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med. 2011;17:281–92.CrossRef
16.
go back to reference van der Poll T. Myeloid-derived suppressor cells in sepsis. Am J Respir Crit Care Med. 2017;196:256–8.CrossRef van der Poll T. Myeloid-derived suppressor cells in sepsis. Am J Respir Crit Care Med. 2017;196:256–8.CrossRef
17.
go back to reference Uhel F, Azzaoui I, Grégoire M, Pangault C, Dulong J, Tadié J-M, et al. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in septic patients. Am J Respir Crit Care Med. 2017;196(3):315–27.CrossRef Uhel F, Azzaoui I, Grégoire M, Pangault C, Dulong J, Tadié J-M, et al. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in septic patients. Am J Respir Crit Care Med. 2017;196(3):315–27.CrossRef
19.
go back to reference 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;348:1546–54.CrossRef 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;348:1546–54.CrossRef
20.
go back to reference Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:775–87.CrossRef Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:775–87.CrossRef
21.
go back to reference Bale C, Kakrani AL, Dabadghao VS, Sharma ZD. Sequential organ failure assessment score as prognostic marker in critically ill patients in a tertiary care intensive care unit. Int J Med Public Health. 2013;3:165974. Bale C, Kakrani AL, Dabadghao VS, Sharma ZD. Sequential organ failure assessment score as prognostic marker in critically ill patients in a tertiary care intensive care unit. Int J Med Public Health. 2013;3:165974.
22.
go back to reference Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care. 1998;36:8–27.CrossRef Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care. 1998;36:8–27.CrossRef
23.
go back to reference Bishop CM. Pattern recognition and machine learning. New York: Springer; 2006. Bishop CM. Pattern recognition and machine learning. New York: Springer; 2006.
24.
go back to reference Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol. 1993;138:923–36.CrossRef Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol. 1993;138:923–36.CrossRef
25.
go back to reference Mickey RM, Greenland S. The impact of confounder selection criteria on effect estimation. Am J Epidemiol. 1989;129:125–37.CrossRef Mickey RM, Greenland S. The impact of confounder selection criteria on effect estimation. Am J Epidemiol. 1989;129:125–37.CrossRef
26.
go back to reference Valeri L, VanderWeele TJ. Mediation analysis allowing for exposure–mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18:137.CrossRef Valeri L, VanderWeele TJ. Mediation analysis allowing for exposure–mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18:137.CrossRef
27.
go back to reference Richter A, Listing J, Schneider M, Klopsch T, Kapelle A, Kaufmann J, et al. Impact of treatment with biologic DMARDs on the risk of sepsis or mortality after serious infection in patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75:1667–73.CrossRef Richter A, Listing J, Schneider M, Klopsch T, Kapelle A, Kaufmann J, et al. Impact of treatment with biologic DMARDs on the risk of sepsis or mortality after serious infection in patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75:1667–73.CrossRef
28.
go back to reference Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–8.CrossRef Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–8.CrossRef
29.
go back to reference MacKinnon DP. Introduction to statistical mediation analysis. New York: Routledge; 2008. MacKinnon DP. Introduction to statistical mediation analysis. New York: Routledge; 2008.
30.
go back to reference R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2013. 2014 R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2013. 2014
31.
go back to reference SAS Institute Inc. SAS 9.4 [Computer software]. SAS Institute Inc Cary, NC; 2013. SAS Institute Inc. SAS 9.4 [Computer software]. SAS Institute Inc Cary, NC; 2013.
32.
go back to reference Ono S, Ueno C, Aosasa S, Tsujimoto H, Seki S, Mochizuki H. Severe sepsis induces deficient interferon-gamma and interleukin-12 production, but interleukin-12 therapy improves survival in peritonitis. Am J Surg. 2001;182:491–7.CrossRef Ono S, Ueno C, Aosasa S, Tsujimoto H, Seki S, Mochizuki H. Severe sepsis induces deficient interferon-gamma and interleukin-12 production, but interleukin-12 therapy improves survival in peritonitis. Am J Surg. 2001;182:491–7.CrossRef
33.
go back to reference Reddy RC, Chen GH, Tekchandani PK, Standiford TJ. Sepsis-induced immunosuppression: from bad to worse. Immunol Res. 2001;24:273.CrossRef Reddy RC, Chen GH, Tekchandani PK, Standiford TJ. Sepsis-induced immunosuppression: from bad to worse. Immunol Res. 2001;24:273.CrossRef
34.
go back to reference Munoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88:1747–54.CrossRef Munoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88:1747–54.CrossRef
35.
go back to reference Appel SH, Wellhausen SR, Montgomery R, DeWeese RC, Polk HC Jr. Experimental and clinical significance of endotoxin-dependent HLA-DR expression on monocytes. J Surg Res. 1989;47:39–44.CrossRef Appel SH, Wellhausen SR, Montgomery R, DeWeese RC, Polk HC Jr. Experimental and clinical significance of endotoxin-dependent HLA-DR expression on monocytes. J Surg Res. 1989;47:39–44.CrossRef
36.
go back to reference Reddy RC, Chen GH, Newstead MW, Moore T, Zeng X, Tateda K, et al. Alveolar macrophage deactivation in murine septic peritonitis: role of interleukin 10. Infect Immun. 2001;69:1394–401.CrossRef Reddy RC, Chen GH, Newstead MW, Moore T, Zeng X, Tateda K, et al. Alveolar macrophage deactivation in murine septic peritonitis: role of interleukin 10. Infect Immun. 2001;69:1394–401.CrossRef
37.
go back to reference Te Velde AA, Huijbens RJ, Heije K, de Vries JE, Figdor CG. Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood. 1990;76:1392. Te Velde AA, Huijbens RJ, Heije K, de Vries JE, Figdor CG. Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood. 1990;76:1392.
38.
go back to reference Jenkins JK, Arend WP. Interleukin 1 receptor antagonist production in human monocytes is induced by IL-1α, IL-3, IL-4 and GM-CSF. Cytokine. 1993;5:407–15.CrossRef Jenkins JK, Arend WP. Interleukin 1 receptor antagonist production in human monocytes is induced by IL-1α, IL-3, IL-4 and GM-CSF. Cytokine. 1993;5:407–15.CrossRef
39.
go back to reference Monneret G, Finck M-E, Venet F, Debard A-L, Bohé J, Bienvenu J, et al. The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol Lett. 2004;95:193–8.CrossRef Monneret G, Finck M-E, Venet F, Debard A-L, Bohé J, Bienvenu J, et al. The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol Lett. 2004;95:193–8.CrossRef
40.
go back to reference Netea MG, van der Meer JW, van Deuren M, Kullberg BJ. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol. 2003;24:254–8.CrossRef Netea MG, van der Meer JW, van Deuren M, Kullberg BJ. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol. 2003;24:254–8.CrossRef
41.
go back to reference Takeyama N, Tanaka T, Yabuki T, Nakatani K, Nakatani T. Effect of interferon gamma on sepsis-related death in patients with immunoparalysis. Crit Care. 2004;8:P207.CrossRef Takeyama N, Tanaka T, Yabuki T, Nakatani K, Nakatani T. Effect of interferon gamma on sepsis-related death in patients with immunoparalysis. Crit Care. 2004;8:P207.CrossRef
42.
go back to reference Hershman MJ, Appel SH, Wellhausen SR, Sonnenfeld G, Polk HC Jr. Interferon-gamma treatment increases HLA-DR expression on monocytes in severely injured patients. Clin Exp Immunol. 1989;77:67.PubMedPubMedCentral Hershman MJ, Appel SH, Wellhausen SR, Sonnenfeld G, Polk HC Jr. Interferon-gamma treatment increases HLA-DR expression on monocytes in severely injured patients. Clin Exp Immunol. 1989;77:67.PubMedPubMedCentral
43.
go back to reference Stanilova SA, Karakolev ZT, Dimov GS, Dobreva ZG, Miteva LD, Slavov ES, et al. High interleukin 12 and low interleukin 10 production after in vitro stimulation detected in sepsis survivors. Intensive Care Med. 2005;31:401–7.CrossRef Stanilova SA, Karakolev ZT, Dimov GS, Dobreva ZG, Miteva LD, Slavov ES, et al. High interleukin 12 and low interleukin 10 production after in vitro stimulation detected in sepsis survivors. Intensive Care Med. 2005;31:401–7.CrossRef
44.
go back to reference DiPiro JT, Howdieshell TR, Goddard JK, Callaway DB, Hamilton RG, Mansberger AR. Association of interleukin-4 plasma levels with traumatic injury and clinical course. Arch Surg. 1995;130:1159–63.CrossRef DiPiro JT, Howdieshell TR, Goddard JK, Callaway DB, Hamilton RG, Mansberger AR. Association of interleukin-4 plasma levels with traumatic injury and clinical course. Arch Surg. 1995;130:1159–63.CrossRef
45.
go back to reference Ashare A, Powers LS, Butler NS, Doerschug KC, Monick MM, Hunninghake GW. Anti-inflammatory response is associated with mortality and severity of infection in sepsis. Am J Physiol-Lung Cell Mol Physiol. 2005;288:L633–40.CrossRef Ashare A, Powers LS, Butler NS, Doerschug KC, Monick MM, Hunninghake GW. Anti-inflammatory response is associated with mortality and severity of infection in sepsis. Am J Physiol-Lung Cell Mol Physiol. 2005;288:L633–40.CrossRef
46.
go back to reference Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev. 2003;2:119–25.CrossRef Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev. 2003;2:119–25.CrossRef
47.
go back to reference Cooper GS, Bynum ML, Somers EC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun. 2009;33:197–207.CrossRef Cooper GS, Bynum ML, Somers EC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun. 2009;33:197–207.CrossRef
48.
go back to reference Hayter SM, Cook MC. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun Rev. 2012;11:754–65.CrossRef Hayter SM, Cook MC. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun Rev. 2012;11:754–65.CrossRef
49.
go back to reference Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky’s postulates revisited). Immunol Today. 1993;14:426–30.CrossRef Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky’s postulates revisited). Immunol Today. 1993;14:426–30.CrossRef
50.
go back to reference Grolleau-Julius A, Ray D, Yung RL. The role of epigenetics in aging and autoimmunity. Clin Rev Allergy Immunol. 2010;39:42–50.CrossRef Grolleau-Julius A, Ray D, Yung RL. The role of epigenetics in aging and autoimmunity. Clin Rev Allergy Immunol. 2010;39:42–50.CrossRef
Metadata
Title
The association between autoimmune disease and 30-day mortality among sepsis ICU patients: a cohort study
Authors
Mallory Sheth
Corey M. Benedum
Leo Anthony Celi
Roger G. Mark
Natasha Markuzon
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2019
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-019-2357-1

Other articles of this Issue 1/2019

Critical Care 1/2019 Go to the issue