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The original sins of clinical trials with intravenous immunoglobulins in sepsis

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Abstract

Intravenous immunoglobulins (IVIGs) have not yet demonstrated robust evidence in the benefit for treatment of sepsis. In spite of multiple clinical trials performed with IVIG in sepsis, it remains an experimental therapy for this severe condition. Nonetheless, these trials do not address a number of potential confounding factors, concerning both the patient and the IVIG preparations, which could greatly affect the final result. To name a few, endogenous levels of immunoglobulin isotypes and subclasses are not assessed prior to treatment. The presence/absence of patient antibodies against the microorganism(s) causing sepsis is not evaluated. The accuracy of antibiotic prescription is not included as an adjusting variable. The degree of patient immunosuppression (previous or induced by sepsis) is not documented. In turn, the concentration and antimicrobial specificities of the antibodies contained in the batches of IVIG are not assessed. Neither the pharmacokinetics of IVIG nor its potential immunomodulatory effects are evaluated. In addition, the concept of ‘window of opportunity’ for IVIG administration following diagnosis of sepsis is not considered. In conclusion, addressing these factors could help to individualise treatment with IVIG for sepsis, which could enhance the opportunities of this drug to show benefits in terms of survival in this severe condition.

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Abbreviations

Ig:

Immunoglobulin

IVIG:

Intravenous immunoglobulin

SBITS:

Score-Based Immunoglobulin Therapy of Sepsis

References

  1. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840–51.

    Article  CAS  Google Scholar 

  2. Päsler M, Dietz S, Werdan K. Hypogammaglobulinemia in Sepsis. In: Vincent PJ-L, editor. Annual Update in Intensive Care and Emergency Medicine 2012. Berlin Heidelberg: Springer; 2012. p. 98–108.

    Chapter  Google Scholar 

  3. Venet F, Gebeile R, Bancel J, Guignant C, Poitevin-Later F, Malcus C, et al. Assessment of plasmatic immunoglobulin G, A and M levels in septic shock patients. Int Immunopharmacol. 2011;11:2086–90.

    Article  CAS  Google Scholar 

  4. Bermejo-Martín JF, Rodriguez-Fernandez A, Herrán-Monge R, Andaluz-Ojeda D, Muriel-Bombín A, Merino P, et al. Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med. 2014;276:404–12.

    Article  Google Scholar 

  5. Alejandria MM, Lansang MAD, Dans LF, Mantaring JB. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013;9, CD001090.

    Google Scholar 

  6. Shankar-Hari M, Spencer J, Sewell WA, Rowan KM, Singer M. Bench-to-bedside review: immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective. Crit Care. 2012;16:206.

    Article  Google Scholar 

  7. Kreymann KG, de Heer G, Nierhaus A, Kluge S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med. 2007;35:2677–85.

    CAS  PubMed  Google Scholar 

  8. Werdan K, Pilz G, Bujdoso O, Fraunberger P, Neeser G, Schmieder RE, et al. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med. 2007;35:2693–701.

    Article  CAS  Google Scholar 

  9. Taccone FS, Stordeur P, De Backer D, Creteur J, Vincent J-L. Gamma-globulin levels in patients with community-acquired septic shock. Shock Augusta Ga. 2009;32:379–85.

    Article  CAS  Google Scholar 

  10. Průcha M, Zazula R, Herold I, Dostál M, Hyánek T, Bellingan G. Presence of hypogammaglobulinemia - a risk factor of mortality in patients with severe sepsis, septic shock, and SIRS. Prague Med Rep. 2013;114:246–57.

    Article  Google Scholar 

  11. Adhikari RP, Ajao AO, Aman MJ, Karauzum H, Sarwar J, Lydecker AD, et al. Lower antibody levels to Staphylococcus aureus exotoxins are associated with sepsis in hospitalized adults with invasive S. aureus infections. J Infect Dis. 2012;206:915–23.

    Article  CAS  Google Scholar 

  12. Liesenfeld O, Lehman L, Hunfeld K-P, Kost G. Molecular diagnosis of sepsis: new aspects and recent developments. Eur J Microbiol Immunol. 2014;4:1–25.

    Article  CAS  Google Scholar 

  13. Andaluz-Ojeda D, Iglesias V, Bobillo F, Almansa R, Rico L, Gandía F, et al. Early natural killer cell counts in blood predict mortality in severe sepsis. Crit Care. 2011;15:R243.

    Article  Google Scholar 

  14. Bermejo-Martín JF, Tamayo E, Ruiz G, Andaluz-Ojeda D, Herrán-Monge R, Muriel-Bombín A, et al. Circulating neutrophil counts and mortality in septic shock. Crit Care. 2014;18:407.

    Article  Google Scholar 

  15. Berlot G, Vassallo MC, Busetto N, Bianchi M, Zornada F, Rosato I, 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.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Group of Biomedical Research in Critical Care Medicine (BioCritic), Hospital Clínico Universitario de Valladolid, Avda. Ramón y Cajal, 3. 47005, Valladolid, Spain

    Raquel Almansa, Eduardo Tamayo, David Andaluz-Ojeda, Leonor Nogales, Jose Maria Eiros, Jose Ignacio Gomez-Herreras & Jesus F Bermejo-Martin

  2. Servicio de Medicina Intensiva, Hospital Universitario Rio Hortega, Calle Dulzaina, 2, 47012, Valladolid, Spain

    Jesús Blanco

  3. Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Calle Sinesio Delgado, 4, 28029, Madrid, Spain

    Jesús Blanco

Authors
  1. Raquel Almansa
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  2. Eduardo Tamayo
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  3. David Andaluz-Ojeda
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  4. Leonor Nogales
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  5. Jesús Blanco
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  6. Jose Maria Eiros
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  7. Jose Ignacio Gomez-Herreras
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  8. Jesus F Bermejo-Martin
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Corresponding author

Correspondence to Jesus F Bermejo-Martin.

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The authors declare that they have no competing interests.

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Almansa, R., Tamayo, E., Andaluz-Ojeda, D. et al. The original sins of clinical trials with intravenous immunoglobulins in sepsis. Crit Care 19, 90 (2015). https://doi.org/10.1186/s13054-015-0793-0

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  • DOI: https://doi.org/10.1186/s13054-015-0793-0

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