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Published in: Intensive Care Medicine 8/2015

01-08-2015 | Systematic Review

Endogenous IgG hypogammaglobulinaemia in critically ill adults with sepsis: systematic review and meta-analysis

Authors: Manu Shankar-Hari, Nicholas Culshaw, Benjamin Post, Eduardo Tamayo, David Andaluz-Ojeda, Jesús F. Bermejo-Martín, Sebastian Dietz, Karl Werdan, Richard Beale, Jo Spencer, Mervyn Singer

Published in: Intensive Care Medicine | Issue 8/2015

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Abstract

Purpose

Plasma immunoglobulin concentrations are acutely altered in critically ill patients with sepsis. However, the association between immunoglobulin levels on the day of sepsis diagnosis and subsequent mortality is inconsistent.

Methods

Systematic review of studies that report immunoglobulin measurements and mortality among adults with sepsis managed in a critical care setting. Fixed and random effect meta-analyses were conducted using low IgG levels as primary exposure and acute mortality as the primary outcome. Both variables were used as defined in individual studies.

Results

The prevalence of a low immunoglobulin G (IgG) concentration on the day of sepsis diagnosis was variable [58.3 % (IQR 38.4–65.5 %)]. Three cut-off points (6.1, 6.5 and 8.7 g/L) were used to define the lower limit of IgG concentrations in the included studies. A subnormal IgG level on the day of sepsis diagnosis was not associated with an increased risk of death in adult patients with severe sepsis and/or septic shock by both fixed and random effect meta-analysis (OR [95 % CI] 1.32 [0.93–1.87] and 1.48 [0.78–2.81], respectively).

Conclusions

This systematic review identifies studies of limited quality reporting heterogeneous sepsis cohorts with varying lower limits of normal for IgG. Although our data suggest that a subnormal IgG measurement on the day of sepsis diagnosis does not identify a subgroup of patients with a higher risk of death, further studies are needed to confirm or refute this finding, and whether optimal cut-offs and time windows can be defined for IgG measurement. This would determine whether patients receiving intravenous immunoglobulin therapy for sepsis could be stratified using IgG levels.
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Literature
1.
go back to reference Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, Sccm/Esicm/Accp/Ats/Sis (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 31:1250–1256PubMedCrossRef Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, Sccm/Esicm/Accp/Ats/Sis (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 31:1250–1256PubMedCrossRef
2.
3.
go back to reference Hutchins NA, Unsinger J, Hotchkiss RS, Ayala A (2014) The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 20:224–233PubMedCentralPubMedCrossRef Hutchins NA, Unsinger J, Hotchkiss RS, Ayala A (2014) The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 20:224–233PubMedCentralPubMedCrossRef
6.
go back to reference Soares MO, Welton NJ, Harrison DA, Peura P, Shankar-Hari M, Harvey SE, Madan JJ, Ades AE, Palmer SJ, Rowan KM (2012) An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis. Health Technol Assess 16:1–186CrossRef Soares MO, Welton NJ, Harrison DA, Peura P, Shankar-Hari M, Harvey SE, Madan JJ, Ades AE, Palmer SJ, Rowan KM (2012) An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis. Health Technol Assess 16:1–186CrossRef
7.
go back to reference Shankar-Hari M, Spencer J, Sewell WA, Rowan KM, Singer M (2012) Bench-to-bedside review: immunoglobulin therapy for sepsis—biological plausibility from a critical care perspective. Crit Care 16:206PubMedCentralPubMedCrossRef Shankar-Hari M, Spencer J, Sewell WA, Rowan KM, Singer M (2012) Bench-to-bedside review: immunoglobulin therapy for sepsis—biological plausibility from a critical care perspective. Crit Care 16:206PubMedCentralPubMedCrossRef
8.
go back to reference Biomarkers Definitions Working G (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95CrossRef Biomarkers Definitions Working G (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95CrossRef
9.
go back to reference Buyse M, Sargent DJ, Grothey A, Matheson A, de Gramont A (2010) Biomarkers and surrogate end points—the challenge of statistical validation. Nat Rev Clin Oncol 7:309–317PubMedCrossRef Buyse M, Sargent DJ, Grothey A, Matheson A, de Gramont A (2010) Biomarkers and surrogate end points—the challenge of statistical validation. Nat Rev Clin Oncol 7:309–317PubMedCrossRef
10.
go back to reference (2014) Abstracts for ESICM-Barcelona 2014. Intensive Care Med 40(Suppl 1):1–308 (2014) Abstracts for ESICM-Barcelona 2014. Intensive Care Med 40(Suppl 1):1–308
11.
go back to reference Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269PubMedCrossRef Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269PubMedCrossRef
12.
go back to reference Bone RC, Sibbald WJ, Sprung CL (1992) The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 101:1481–1483PubMedCrossRef Bone RC, Sibbald WJ, Sprung CL (1992) The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 101:1481–1483PubMedCrossRef
13.
go back to reference Andaluz-Ojeda D, Iglesias V, Bobillo F, Almansa R, Rico L, Gandia F, Loma AM, Nieto C, Diego R, Ramos E, Nocito M, Resino S, Eiros JM, Tamayo E, de Lejarazu RO, Bermejo-Martin JF (2011) Early natural killer cell counts in blood predict mortality in severe sepsis. Crit Care 15:R243PubMedCentralPubMedCrossRef Andaluz-Ojeda D, Iglesias V, Bobillo F, Almansa R, Rico L, Gandia F, Loma AM, Nieto C, Diego R, Ramos E, Nocito M, Resino S, Eiros JM, Tamayo E, de Lejarazu RO, Bermejo-Martin JF (2011) Early natural killer cell counts in blood predict mortality in severe sepsis. Crit Care 15:R243PubMedCentralPubMedCrossRef
14.
go back to reference Bermejo-Martin JF, Rodriguez-Fernandez A, Herran-Monge R, Andaluz-Ojeda D, Muriel-Bombin A, Merino P, Garcia-Garcia MM, Citores R, Gandia F, Almansa R, Blanco J, Group G (2014) Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med 276:404–412PubMedCrossRef Bermejo-Martin JF, Rodriguez-Fernandez A, Herran-Monge R, Andaluz-Ojeda D, Muriel-Bombin A, Merino P, Garcia-Garcia MM, Citores R, Gandia F, Almansa R, Blanco J, Group G (2014) Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med 276:404–412PubMedCrossRef
15.
go back to reference Huang SW, Chen J, Ouyang B, Yang CH, Chen MY, Guan XD (2009) Immunotherapy improves immune homeostasis and increases survival rate of septic patients. Chin J Traumatol 12:344–349PubMed Huang SW, Chen J, Ouyang B, Yang CH, Chen MY, Guan XD (2009) Immunotherapy improves immune homeostasis and increases survival rate of septic patients. Chin J Traumatol 12:344–349PubMed
16.
go back to reference Ekdahl K, Rollof J, Oxelius VA, Engellau J, Braconier JH (1994) Analysis of immunoglobulin isotype levels in acute pneumococcal bacteremia and in convalescence. Eur J Clin Microbiol Infect Dis 13:374–378PubMedCrossRef Ekdahl K, Rollof J, Oxelius VA, Engellau J, Braconier JH (1994) Analysis of immunoglobulin isotype levels in acute pneumococcal bacteremia and in convalescence. Eur J Clin Microbiol Infect Dis 13:374–378PubMedCrossRef
17.
go back to reference Heredia-Rodriguez M, Gutierrez-Junco S, Gomez-Sanchez E, Alvarez-Fuente E, Ruiz-Granado P, Almansa R (2013) Endogenous immunoglobulin subclasses and isotypes in septic shock patients in the postoperative period. Eur J Anaesthesiol 30:185CrossRef Heredia-Rodriguez M, Gutierrez-Junco S, Gomez-Sanchez E, Alvarez-Fuente E, Ruiz-Granado P, Almansa R (2013) Endogenous immunoglobulin subclasses and isotypes in septic shock patients in the postoperative period. Eur J Anaesthesiol 30:185CrossRef
18.
go back to reference Venet F, Gebeile R, Bancel J, Guignant C, Poitevin-Later F, Malcus C, Lepape A, Monneret G (2011) Assessment of plasmatic immunoglobulin G, A and M levels in septic shock patients. Int Immunopharmacol 11:2086–2090PubMedCrossRef Venet F, Gebeile R, Bancel J, Guignant C, Poitevin-Later F, Malcus C, Lepape A, Monneret G (2011) Assessment of plasmatic immunoglobulin G, A and M levels in septic shock patients. Int Immunopharmacol 11:2086–2090PubMedCrossRef
19.
go back to reference Tamayo E, Fernandez A, Almansa R, Carrasco E, Goncalves L, Heredia M, Andaluz-Ojeda D, March G, Rico L, Gomez-Herreras JI, de Lejarazu RO, Bermejo-Martin JF (2012) Beneficial role of endogenous immunoglobulin subclasses and isotypes in septic shock. J Crit Care 27:616–622PubMedCrossRef Tamayo E, Fernandez A, Almansa R, Carrasco E, Goncalves L, Heredia M, Andaluz-Ojeda D, March G, Rico L, Gomez-Herreras JI, de Lejarazu RO, Bermejo-Martin JF (2012) Beneficial role of endogenous immunoglobulin subclasses and isotypes in septic shock. J Crit Care 27:616–622PubMedCrossRef
20.
go back to reference Taccone FS, Stordeur P, De Backer D, Creteur J, Vincent JL (2009) Gamma-globulin levels in patients with community-acquired septic shock. Shock 32:379–385PubMedCrossRef Taccone FS, Stordeur P, De Backer D, Creteur J, Vincent JL (2009) Gamma-globulin levels in patients with community-acquired septic shock. Shock 32:379–385PubMedCrossRef
21.
go back to reference Almansa R, Wain J, Tamayo E, Andaluz-Ojeda D, Martin-Loeches I, Ramirez P, Bermejo-Martin JF (2013) Immunological monitoring to prevent and treat sepsis. Crit Care 17:109PubMedCentralPubMedCrossRef Almansa R, Wain J, Tamayo E, Andaluz-Ojeda D, Martin-Loeches I, Ramirez P, Bermejo-Martin JF (2013) Immunological monitoring to prevent and treat sepsis. Crit Care 17:109PubMedCentralPubMedCrossRef
22.
go back to reference Werdan K, Pilz G, Bujdoso O, Fraunberger P, Neeser G, Schmieder RE, Viell B, Marget W, Seewald M, Walger P, Stuttmann R, Speichermann N, Peckelsen C, Kurowski V, Osterhues HH, Verner L, Neumann R, Muller-Werdan U, Score-Based Immunoglobulin Therapy of Sepsis Study G (2007) Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med 35:2693–2701PubMedCrossRef Werdan K, Pilz G, Bujdoso O, Fraunberger P, Neeser G, Schmieder RE, Viell B, Marget W, Seewald M, Walger P, Stuttmann R, Speichermann N, Peckelsen C, Kurowski V, Osterhues HH, Verner L, Neumann R, Muller-Werdan U, Score-Based Immunoglobulin Therapy of Sepsis Study G (2007) Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med 35:2693–2701PubMedCrossRef
23.
go back to reference Dietz S, Lautenschlaeger C, Mueller-Werdan U, Werdan K (2010) Low levels of immunoglobulin G in patients with sepsis or septic shock: a signum mali ominis? Crit Care 14:P26PubMedCentralCrossRef Dietz S, Lautenschlaeger C, Mueller-Werdan U, Werdan K (2010) Low levels of immunoglobulin G in patients with sepsis or septic shock: a signum mali ominis? Crit Care 14:P26PubMedCentralCrossRef
24.
go back to reference Shankar-Hari M, Singer M, Cornelius V, Sanderson B, Gordon A, Terblanche M, Rowan K, Beale R, Spencer J (2013) Low immunoglobulin G levels at admission reduced the odds for 28 day mortality compared to normal levels: prospective cohort study in severe sepsis. Intensive Care Med 39(2):151 (abstract 0177) Shankar-Hari M, Singer M, Cornelius V, Sanderson B, Gordon A, Terblanche M, Rowan K, Beale R, Spencer J (2013) Low immunoglobulin G levels at admission reduced the odds for 28 day mortality compared to normal levels: prospective cohort study in severe sepsis. Intensive Care Med 39(2):151 (abstract 0177)
25.
go back to reference Myrianthefs PM, Boutzouka E, Baltopoulos GJ (2010) Gamma-globulin levels in patients with community-acquired septic shock. Shock 33:556–557; author reply 557PubMedCrossRef Myrianthefs PM, Boutzouka E, Baltopoulos GJ (2010) Gamma-globulin levels in patients with community-acquired septic shock. Shock 33:556–557; author reply 557PubMedCrossRef
26.
27.
go back to reference Michaelsen TE, Sandlie I, Bratlie DB, Sandin RH, Ihle O (2009) Structural difference in the complement activation site of human IgG1 and IgG3. Scand J Immunol 70:553–564PubMedCrossRef Michaelsen TE, Sandlie I, Bratlie DB, Sandin RH, Ihle O (2009) Structural difference in the complement activation site of human IgG1 and IgG3. Scand J Immunol 70:553–564PubMedCrossRef
28.
go back to reference Nordenfelt P, Waldemarson S, Linder A, Morgelin M, Karlsson C, Malmstrom J, Bjorck L (2012) Antibody orientation at bacterial surfaces is related to invasive infection. J Exp Med 209:2367–2381PubMedCentralPubMedCrossRef Nordenfelt P, Waldemarson S, Linder A, Morgelin M, Karlsson C, Malmstrom J, Bjorck L (2012) Antibody orientation at bacterial surfaces is related to invasive infection. J Exp Med 209:2367–2381PubMedCentralPubMedCrossRef
29.
go back to reference Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS (2014) Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 42:383–391PubMedCrossRef Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS (2014) Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 42:383–391PubMedCrossRef
30.
go back to reference Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA (2005) Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol 174:3765–3772PubMedCrossRef Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA (2005) Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol 174:3765–3772PubMedCrossRef
31.
go back to reference Inoue S, Suzuki-Utsunomiya K, Okada Y, Taira T, Iida Y, Miura N, Tsuji T, Yamagiwa T, Morita S, Chiba T, Sato T, Inokuchi S (2013) Reduction of immunocompetent T cells followed by prolonged lymphopenia in severe sepsis in the elderly. Crit Care Med 41:810–819PubMedCrossRef Inoue S, Suzuki-Utsunomiya K, Okada Y, Taira T, Iida Y, Miura N, Tsuji T, Yamagiwa T, Morita S, Chiba T, Sato T, Inokuchi S (2013) Reduction of immunocompetent T cells followed by prolonged lymphopenia in severe sepsis in the elderly. Crit Care Med 41:810–819PubMedCrossRef
32.
go back to reference Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD 2nd, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS (2011) Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306:2594–2605PubMedCentralPubMedCrossRef Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD 2nd, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS (2011) Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306:2594–2605PubMedCentralPubMedCrossRef
33.
go back to reference Boomer JS, Shuherk-Shaffer J, Hotchkiss RS, Green JM (2012) A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis. Crit Care 16:R112PubMedCentralPubMedCrossRef Boomer JS, Shuherk-Shaffer J, Hotchkiss RS, Green JM (2012) A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis. Crit Care 16:R112PubMedCentralPubMedCrossRef
34.
35.
go back to reference Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC (2014) The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C? Crit Care Med 42:1714–1721PubMedCentralPubMedCrossRef Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC (2014) The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C? Crit Care Med 42:1714–1721PubMedCentralPubMedCrossRef
Metadata
Title
Endogenous IgG hypogammaglobulinaemia in critically ill adults with sepsis: systematic review and meta-analysis
Authors
Manu Shankar-Hari
Nicholas Culshaw
Benjamin Post
Eduardo Tamayo
David Andaluz-Ojeda
Jesús F. Bermejo-Martín
Sebastian Dietz
Karl Werdan
Richard Beale
Jo Spencer
Mervyn Singer
Publication date
01-08-2015
Publisher
Springer Berlin Heidelberg
Published in
Intensive Care Medicine / Issue 8/2015
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-015-3845-7

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