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

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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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Abbreviations

APACHE II score:

Acute physiology and chronic health evaluation II score

ARDS:

Acute respiratory distress syndrome

Ig:

Immunoglobulin

IVIg:

Intravenous immunoglobulin

NOS:

Newcastle–Ottawa score checklist

RCT:

Randomised controlled trial

References

  1. 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 31:1250–1256

    Article  PubMed  Google Scholar 

  2. Angus DC, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med 369:840–851

    Article  CAS  PubMed  Google Scholar 

  3. Hutchins NA, Unsinger J, Hotchkiss RS, Ayala A (2014) The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 20:224–233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Marshall JC (2014) Why have clinical trials in sepsis failed? Trends Mol Med 20:195–203

    Article  PubMed  Google Scholar 

  5. Shankar-Hari M, Deutschman CS, Singer M (2015) Do we need a new definition of sepsis? Intensive Care Med. doi:10.1007/s00134-015-3680-x

  6. 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 16:1–186

    Article  CAS  Google Scholar 

  7. 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 16:206

    Article  PubMed Central  PubMed  Google Scholar 

  8. Biomarkers Definitions Working G (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95

    Article  Google Scholar 

  9. 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 7:309–317

    Article  PubMed  Google Scholar 

  10. (2014) Abstracts for ESICM-Barcelona 2014. Intensive Care Med 40(Suppl 1):1–308

  11. 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 151:264–269

    Article  PubMed  Google Scholar 

  12. Bone RC, Sibbald WJ, Sprung CL (1992) The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 101:1481–1483

    Article  CAS  PubMed  Google Scholar 

  13. 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:R243

    Article  PubMed Central  PubMed  Google Scholar 

  14. 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 276:404–412

    Article  CAS  PubMed  Google Scholar 

  15. 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 12:344–349

    CAS  PubMed  Google Scholar 

  16. 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 13:374–378

    Article  CAS  PubMed  Google Scholar 

  17. 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 30:185

    Article  Google Scholar 

  18. 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 11:2086–2090

    Article  CAS  PubMed  Google Scholar 

  19. 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 27:616–622

    Article  CAS  PubMed  Google Scholar 

  20. Taccone FS, Stordeur P, De Backer D, Creteur J, Vincent JL (2009) Gamma-globulin levels in patients with community-acquired septic shock. Shock 32:379–385

    Article  CAS  PubMed  Google Scholar 

  21. 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 17:109

    Article  PubMed Central  PubMed  Google Scholar 

  22. 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 35:2693–2701

    Article  CAS  PubMed  Google Scholar 

  23. 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:P26

    Article  PubMed Central  Google Scholar 

  24. 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)

    Google Scholar 

  25. Myrianthefs PM, Boutzouka E, Baltopoulos GJ (2010) Gamma-globulin levels in patients with community-acquired septic shock. Shock 33:556–557; author reply 557

    Article  PubMed  Google Scholar 

  26. Lee WL, Slutsky AS (2010) Sepsis and endothelial permeability. N Engl J Med 363:689–691

    Article  CAS  PubMed  Google Scholar 

  27. 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 70:553–564

    Article  CAS  PubMed  Google Scholar 

  28. 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 209:2367–2381

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS (2014) Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 42:383–391

    Article  PubMed  Google Scholar 

  30. 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 174:3765–3772

    Article  CAS  PubMed  Google Scholar 

  31. 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 41:810–819

    Article  PubMed  Google Scholar 

  32. 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 306:2594–2605

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. 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:R112

    Article  PubMed Central  PubMed  Google Scholar 

  34. de Pablo R, Monserrat J, Prieto A, Alvarez-Mon M (2014) Role of circulating lymphocytes in patients with sepsis. BioMed Res Int 2014:671087

    Article  PubMed Central  PubMed  Google Scholar 

  35. 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 42:1714–1721

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

MSH, RB, JS and MS acknowledge the support of the UK National Institute for Health Research (NIHR) Biomedical Research Centre schemes. MS is a recipient of a UK NIHR Senior Investigator Fellowship.

Conflicts of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Critical Care Medicine, Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, 1st Floor, East Wing, London, SE17EH, UK

    Manu Shankar-Hari, Nicholas Culshaw, Benjamin Post & Richard Beale

  2. Division of Asthma, Department of Intensive Care Medicine, Allergy and Lung Biology, King’s College London, London, SE1 7EH, UK

    Manu Shankar-Hari & Richard Beale

  3. Peter Gorer Department of Immunbiology, King’s College London, London, UK

    Manu Shankar-Hari & Jo Spencer

  4. Hospital Clínico Universitario de Valladolid, Valladolid, Spain

    Eduardo Tamayo, David Andaluz-Ojeda & Jesús F. Bermejo-Martín

  5. St. Marienkrankenhaus Siegen, Kampenstraße 52, 57072, Siegen, Germany

    Sebastian Dietz & Karl Werdan

  6. University College London, Cruciform Building, Gower St, London, WC1E 6BT, UK

    Mervyn Singer

Authors
  1. Manu Shankar-Hari
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  2. Nicholas Culshaw
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  3. Benjamin Post
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  9. Richard Beale
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  11. Mervyn Singer
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Corresponding author

Correspondence to Manu Shankar-Hari.

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Shankar-Hari, M., Culshaw, N., Post, B. et al. Endogenous IgG hypogammaglobulinaemia in critically ill adults with sepsis: systematic review and meta-analysis. Intensive Care Med 41, 1393–1401 (2015). https://doi.org/10.1007/s00134-015-3845-7

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  • DOI: https://doi.org/10.1007/s00134-015-3845-7

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