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Published in: Annals of Intensive Care 1/2018

Open Access 01-12-2018 | Research

Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients

Authors: Giorgio Berlot, Michele Claudio Vassallo, Nicola Busetto, Margarita Nieto Yabar, Tatiana Istrati, Silvia Baronio, Giada Quarantotto, Mattia Bixio, Giulia Barbati, Roberto Dattola, Irene Longo, Antonino Chillemi, Alice Scamperle, Fulvio Iscra, Ariella Tomasini

Published in: Annals of Intensive Care | Issue 1/2018

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Abstract

Background

The administration of endovenous immunoglobulins in patients with septic shock could be beneficial and preparations enriched with IgA and IgM (ivIgGAM) seem to be more effective than those containing only IgG. In a previous study Berlot et al. demonstrated that early administration of ivIgGAM was associated with lower mortality rate. We studied a larger population of similar patients aiming either to confirm or not this finding considering also the subgroup of patients with septic shock by multidrug-resistant (MDR) pathogens.

Methods

Adult patients with septic shock in intensive care unit (ICU) treated with ivIgGAM from August 1999 to December 2016 were retrospectively examined. Collected data included the demographic characteristics of the patients, the diagnosis at admission, SOFA, SAPS II and Murray Lung Injury Score (LIS), characteristics of the primary infection, the adequacy of antimicrobial therapy, the delay of administration of ivIgGAM from the ICU admission and the outcome at the ICU discharge. Parametric and nonparametric tests and logistic regression were used for statistic analysis.

Results

During the study period 107 (30%) of the 355 patients died in ICU. Survivors received the ivIgGAM earlier than nonsurvivors (median delay 12 vs 14 h), had significantly lower SAPS II, SOFA and LIS at admission and a lower rate of MDR- and fungal-related septic shock. The appropriateness of the administration of antibiotics was similar in survivors and nonsurvivors (84 vs 79%, respectively, p: n.s). The delay in the administration of ivIgGAM from the admission was associated with in-ICU mortality (odds ratio per 1-h increase = 1.0055, 95% CI 1.003–1.009, p < 0.001), independently of SAPS II, LIS, cultures positive for MDR pathogens or fungi and onset of septic shock. Only 46 patients (14%) had septic shock due to MDR pathogens; 21 of them (46%) died in ICU. Survivors had significantly lower SAPS II, SOFA at admission and delay in administration of ivIgGAM than nonsurvivors (median delay 18 vs 66 h). Even in this subgroup the delay in the administration of ivIgGAM from the admission was associated with an increased risk of in-ICU mortality (odds ratio 1.007, 95% CI 1.0006–1.014, p = 0.048), independently of SAPS II.

Conclusions

Earlier administration of ivIgGAM was associated with decreased risk of in-ICU mortality both in patients with septic shock caused by any pathogens and in patients with MDR-related septic shock.
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Literature
1.
go back to reference Boomer JS, Green JM, Hotchkiss RS. The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? Virulence. 2014;5:45–56.CrossRef Boomer JS, Green JM, Hotchkiss RS. The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? Virulence. 2014;5:45–56.CrossRef
2.
go back to reference van Vught LA, Klein Klouwenberg PM, Spitoni C, et al. Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA. 2016;315:1469–79.CrossRef van Vught LA, Klein Klouwenberg PM, Spitoni C, et al. Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA. 2016;315:1469–79.CrossRef
3.
go back to reference Venet F, Gebeile R, Bancel J, et al. Assessment of plasmatic immunoglobulin G, A and M levels in septic shock patients. Int Immunopharmacol. 2011;11:2086–90.CrossRef Venet F, Gebeile R, Bancel J, et al. Assessment of plasmatic immunoglobulin G, A and M levels in septic shock patients. Int Immunopharmacol. 2011;11:2086–90.CrossRef
4.
go back to reference Taccone FS, Stordeur P, De Backer D, et al. Gamma-globulin levels in patients with community-acquired septic shock. Shock. 2009;32:379–85.CrossRef Taccone FS, Stordeur P, De Backer D, et al. Gamma-globulin levels in patients with community-acquired septic shock. Shock. 2009;32:379–85.CrossRef
5.
go back to reference Myrianthefs PM, Boutzouka E, Baltopoulos GJ. Gamma-globulin levels in patients with community-acquired septic shock. Shock. 2010;33:556–7.CrossRef Myrianthefs PM, Boutzouka E, Baltopoulos GJ. Gamma-globulin levels in patients with community-acquired septic shock. Shock. 2010;33:556–7.CrossRef
6.
go back to reference Späth PJ. Structure and Function of Immunoglobulins. Sepsis. 1999;3:197–218.CrossRef Späth PJ. Structure and Function of Immunoglobulins. Sepsis. 1999;3:197–218.CrossRef
7.
go back to reference Pildal J, Gøtzsche PC. Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review. Clin Infect Dis. 2004;39:38–46.CrossRef Pildal J, Gøtzsche PC. Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review. Clin Infect Dis. 2004;39:38–46.CrossRef
8.
go back to reference Laupland KB, Kirkpatrick AW, Delaney A. Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med. 2007;35:2686–92.PubMed Laupland KB, Kirkpatrick AW, Delaney A. Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med. 2007;35:2686–92.PubMed
9.
go back to reference Turgeon AF, Hutton B, Fergusson DA, et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med. 2007;146:193–203.CrossRef Turgeon AF, Hutton B, Fergusson DA, et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med. 2007;146:193–203.CrossRef
10.
go back to reference Kreymann KG, de Heer G, Nierhaus A, et al. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med. 2007;35:2677–8.PubMed Kreymann KG, de Heer G, Nierhaus A, et al. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med. 2007;35:2677–8.PubMed
11.
go back to reference Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45:486–552.CrossRef Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45:486–552.CrossRef
12.
go back to reference Welte T, Dellinger RP, Ebelt H, et al. Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study). Intens Care Med. 2018;44:438–48.CrossRef Welte T, Dellinger RP, Ebelt H, et al. Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study). Intens Care Med. 2018;44:438–48.CrossRef
13.
go back to reference Almansa R, Tamayo E, Andaluz-Ojeda D, et al. The original sins of clinical trials with intravenous immunoglobulins in sepsis. Crit Care. 2015;19:90.CrossRef Almansa R, Tamayo E, Andaluz-Ojeda D, et al. The original sins of clinical trials with intravenous immunoglobulins in sepsis. Crit Care. 2015;19:90.CrossRef
14.
go back to reference Esen F, Tugrul S. IgM-enriched Immunoglobulins in Sepsis. In: Vincent JL, editor. Intensive Care Medicine, vol. 2009., Annual UpdateNY: New York; 2009. p. 102–10.CrossRef Esen F, Tugrul S. IgM-enriched Immunoglobulins in Sepsis. In: Vincent JL, editor. Intensive Care Medicine, vol. 2009., Annual UpdateNY: New York; 2009. p. 102–10.CrossRef
15.
go back to reference Trautmann M, Held TK, Susa M, et al. Bacterial lipopolysaccharide (LPS)-specific antibodies in commercial human immunoglobulin preparations: superior antibody content of an IgM-enriched product. Clin Exp Immunol. 1998;111:81–90.CrossRef Trautmann M, Held TK, Susa M, et al. Bacterial lipopolysaccharide (LPS)-specific antibodies in commercial human immunoglobulin preparations: superior antibody content of an IgM-enriched product. Clin Exp Immunol. 1998;111:81–90.CrossRef
16.
go back to reference Garbett ND, Munro CS, Cole PJ. Opsonic activity of a new intravenous immunoglobulin preparation: pentaglobin compared with Sandoglobulin. Clin Exp Immunol. 1989;76:8–12.PubMedPubMedCentral Garbett ND, Munro CS, Cole PJ. Opsonic activity of a new intravenous immunoglobulin preparation: pentaglobin compared with Sandoglobulin. Clin Exp Immunol. 1989;76:8–12.PubMedPubMedCentral
17.
go back to reference Walpen AJ, Laumonier T, Aebi C, et al. Immunoglobulin M-enriched intravenous immunoglobulin inhibits classical pathway complement activation, but not bactericidal activity of human serum. Xenotransplantation. 2004;11:141–8.CrossRef Walpen AJ, Laumonier T, Aebi C, et al. Immunoglobulin M-enriched intravenous immunoglobulin inhibits classical pathway complement activation, but not bactericidal activity of human serum. Xenotransplantation. 2004;11:141–8.CrossRef
18.
go back to reference Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol. 2010;10:778–86.CrossRef Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol. 2010;10:778–86.CrossRef
19.
go back to reference Shankar-Hari M, Spencer J, Sewell WA, et al. Bench-to-bedside review: immunoglobulin therapy for sepsis–biological plausibility from a critical care perspective. Crit Care. 2012;16:206.CrossRef Shankar-Hari M, Spencer J, Sewell WA, et al. Bench-to-bedside review: immunoglobulin therapy for sepsis–biological plausibility from a critical care perspective. Crit Care. 2012;16:206.CrossRef
20.
go back to reference Rossmann FS, Kropec A, Laverde D, et al. In vitro and in vivo activity of hyperimmune globulin preparations against multiresistant nosocomial pathogens. Infection. 2015;43:169–75.CrossRef Rossmann FS, Kropec A, Laverde D, et al. In vitro and in vivo activity of hyperimmune globulin preparations against multiresistant nosocomial pathogens. Infection. 2015;43:169–75.CrossRef
21.
go back to reference Stehr SN, Knels L, Weissflog C, et al. Effects of IgM-enriched solution on polymorphonuclear neutrophil function, bacterial clearance, and lung histology in endotoxemia. Shock. 2008;29:167–72.PubMed Stehr SN, Knels L, Weissflog C, et al. Effects of IgM-enriched solution on polymorphonuclear neutrophil function, bacterial clearance, and lung histology in endotoxemia. Shock. 2008;29:167–72.PubMed
22.
go back to reference Rieben R, Roos A, Muizert Y, et al. Immunoglobulin M-enriched human intravenous immunoglobulin prevents complement activation in vitro and in vivo in a rat model of acute inflammation. Blood. 1999;93:942–51.PubMed Rieben R, Roos A, Muizert Y, et al. Immunoglobulin M-enriched human intravenous immunoglobulin prevents complement activation in vitro and in vivo in a rat model of acute inflammation. Blood. 1999;93:942–51.PubMed
23.
go back to reference Berlot G, Vassallo MC, Busetto N, et al. Relationship between the timing of administration of IgM and IgA enriched immunoglobulins in patients with severe sepsis and septic shock and the outcome: a retrospective analysis. J Crit Care. 2012;27:167–71.CrossRef Berlot G, Vassallo MC, Busetto N, et al. Relationship between the timing of administration of IgM and IgA enriched immunoglobulins in patients with severe sepsis and septic shock and the outcome: a retrospective analysis. J Crit Care. 2012;27:167–71.CrossRef
24.
go back to reference Singer M, Deutschmann CS, Seymour CW, et al. The 3rd international consensus definitions for sepsis and septic shock. JAMA. 2016;315:801–10.CrossRef Singer M, Deutschmann CS, Seymour CW, et al. The 3rd international consensus definitions for sepsis and septic shock. JAMA. 2016;315:801–10.CrossRef
25.
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
26.
go back to reference Mira JC, Gentile LF, Mathias BJ, et al. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit Care Med. 2017;45:253–62.CrossRef Mira JC, Gentile LF, Mathias BJ, et al. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit Care Med. 2017;45:253–62.CrossRef
27.
go back to reference Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72:1491–501.CrossRef Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72:1491–501.CrossRef
28.
go back to reference Cohen J, Vincent JL, Adhikari NK, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581–614.CrossRef Cohen J, Vincent JL, Adhikari NK, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581–614.CrossRef
29.
go back to reference Vincent JL. Individual gene expression and personalised medicine in sepsis. Lancet Respir Med. 2016;4:242–3.CrossRef Vincent JL. Individual gene expression and personalised medicine in sepsis. Lancet Respir Med. 2016;4:242–3.CrossRef
30.
go back to reference Giamarellos-Bourboulis EJ, Apostolidou E, Lada M, et al. Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome. Crit Care. 2013;17:R247.CrossRef Giamarellos-Bourboulis EJ, Apostolidou E, Lada M, et al. Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome. Crit Care. 2013;17:R247.CrossRef
31.
go back to reference Bermejo-Martin JF, Giamarellos-Bourboulis EJ. Endogenous immunoglobulins and sepsis: new perspectives for guiding replacement therapies. Int J Antimicrob Agents. 2015;46:S25–8.CrossRef Bermejo-Martin JF, Giamarellos-Bourboulis EJ. Endogenous immunoglobulins and sepsis: new perspectives for guiding replacement therapies. Int J Antimicrob Agents. 2015;46:S25–8.CrossRef
32.
go back to reference Bermejo-Martín JF, Rodriguez-Fernandez A, Herrán-Monge R, et al. Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med. 2014;276:404–12.CrossRef Bermejo-Martín JF, Rodriguez-Fernandez A, Herrán-Monge R, et al. Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med. 2014;276:404–12.CrossRef
33.
go back to reference Reinhart K, Brunkhorst FM, Bone HG, et al. Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)). Ger Med Sci. 2010;8:Doc14. Reinhart K, Brunkhorst FM, Bone HG, et al. Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)). Ger Med Sci. 2010;8:Doc14.
34.
go back to reference Cavazzuti I, Serafini G, Busani S, et al. Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock. Intensive Care Med. 2014;40:1888–96.CrossRef Cavazzuti I, Serafini G, Busani S, et al. Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock. Intensive Care Med. 2014;40:1888–96.CrossRef
35.
go back to reference Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589–96.CrossRef Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589–96.CrossRef
36.
go back to reference Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42:1749–55.CrossRef Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42:1749–55.CrossRef
37.
go back to reference Seymour CW, Kahn JM, Martin-Gill C, et al. Delays From First Medical Contact to Antibiotic Administration for Sepsis. Crit Care Med. 2017;45:759–65.CrossRef Seymour CW, Kahn JM, Martin-Gill C, et al. Delays From First Medical Contact to Antibiotic Administration for Sepsis. Crit Care Med. 2017;45:759–65.CrossRef
38.
go back to reference Martin-Loeches I, Muriel-Bombìn A, Ferrer R, et al. The protective association of endogenous immunoglobulins against sepsis mortality is restricted to patients with moderate organ failure. Ann Intensive Care. 2017;7(1):44.CrossRef Martin-Loeches I, Muriel-Bombìn A, Ferrer R, et al. The protective association of endogenous immunoglobulins against sepsis mortality is restricted to patients with moderate organ failure. Ann Intensive Care. 2017;7(1):44.CrossRef
39.
go back to reference Busani S, Serafini G, Mantovani E, et al. Mortality in patients with septic shock by multidrug resistant bacteria: risk factors and impact of sepsis treatments. J Intensive Care Med. 2017. Busani S, Serafini G, Mantovani E, et al. Mortality in patients with septic shock by multidrug resistant bacteria: risk factors and impact of sepsis treatments. J Intensive Care Med. 2017.
40.
go back to reference Giamarellos-Bourboulis EJ, Tziolos N, Routsi C, et al. Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins. Clin Microbiol Infect. 2016;22:499–506.CrossRef Giamarellos-Bourboulis EJ, Tziolos N, Routsi C, et al. Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins. Clin Microbiol Infect. 2016;22:499–506.CrossRef
41.
go back to reference Perner A, Myburgh J. Ten ‘short-lived’ beliefs in intensive care medicine. Intensive Care Med. 2015;41:1703–6.CrossRef Perner A, Myburgh J. Ten ‘short-lived’ beliefs in intensive care medicine. Intensive Care Med. 2015;41:1703–6.CrossRef
Metadata
Title
Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients
Authors
Giorgio Berlot
Michele Claudio Vassallo
Nicola Busetto
Margarita Nieto Yabar
Tatiana Istrati
Silvia Baronio
Giada Quarantotto
Mattia Bixio
Giulia Barbati
Roberto Dattola
Irene Longo
Antonino Chillemi
Alice Scamperle
Fulvio Iscra
Ariella Tomasini
Publication date
01-12-2018
Publisher
Springer International Publishing
Published in
Annals of Intensive Care / Issue 1/2018
Electronic ISSN: 2110-5820
DOI
https://doi.org/10.1186/s13613-018-0466-7

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