Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Infectious Disease Reports
Published in: Current Infectious Disease Reports 5/2012

01-10-2012 | Sepsis (J Russell, Section Editor)

Immunoglobulins in Adult Sepsis and Septic Shock

Authors: Susanne Toussaint, Herwig Gerlach

Published in: Current Infectious Disease Reports | Issue 5/2012

Login to get access

Abstract

For more than 30 years, intravenously administered immunoglobulins (ivIG) have been used to treat primary and secondary syndromes of immune deficiency. Increasing insight into pathomechanisms of severe sepsis and septic shock have led to the implementation of ivIG therapy in the strategies for adjunctive therapy in sepsis in both adults and children. Direct antitoxic effects, as well as indirect immunomodulatory mechanisms of ivIG have been described in the literature and were the basis for the rationale to use these substances in life-threatening infections and hyperinflammatory states. Several clinical trials have been performed, most of them as minor, investigator-initiated protocols. This review summarizes the results of clinical investigations and systematic meta-analyses that have implications for the development of therapeutic strategies, and international guidelines for the management of severe sepsis and septic shock in adult patients.
Literature
1.
2.
• Engel C, Brunkhorst FM, Bone H-G, et al. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 2007;33:606–18. Excellent study with a randomized design to exclude biases such as hospital size, seasonal variations etc.
3.
Karlsson S, Varpula M, Roukonen E, et al. Incidence, treatment and outcome of severe sepsis in ICU-treated adults in Finland: the Finnsepsis study. Intensive Care Med. 2007;33:435–43.PubMedCrossRef
4.
EMEA Committee For Proprietary Medicinal Products: note for guidance on plasma-derived medicinal products. CPMP/BPWG/269/95. Ser. 2, London, 1998.
5.
Europäisches Arzneibuch, Monograph No. 918: “Human Immunoglobulins for intravenous application”. Edited by Govi Publisher, Eschborn, Germany, 3rd Edition, 1997.
6.
Gaines A, Varricchio F, Kapit R. Renal insufficiency and failure associated with globulin intravenous administration in immune thrombocytopenic purpura patients. Blood. 2000;95:2523–9.PubMed
7.
Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens. J Clin Invest. 1993;91:602–7.PubMedCrossRef
8.
9.
Norrby-Teglund A, Basma H, Andersson J, et al. Varying titers of neutralizing antibodies to streptococcal superantigens in different preparations of normal polyspecific immunoglobulin G: implications for therapeutic efficacy. Clin Infect Dis. 1998;26:631–9.PubMedCrossRef
10.
Darenberg J, Söderquist B, Normark BH, Norrby-Teglund A. Differences in Potency of intravenous polyspecific immunoglobulin G against streptococcal and staphylococcal superantigens: implications for therapy of toxic shock syndrome. Clin Infect Dis. 2004;38:836–42.PubMedCrossRef
11.
• Schrage B, Duan G, Yang LP, Fraser JD, Proft T. Different preparations of intravenous immunoglobulin vary in their efficacy to neutralize streptococcal superantigens: implications for treatment of streptococcal toxic shock syndrome. Clin Infect Dis. 2006;43:743–6. Systematic analysis of the quality of different ivIG preparations demonstrating the potential impact on the design and outcome of clinical trials..PubMedCrossRef
12.
Stevens DL. Rationale for the use of intravenous gamma globulin in the treatment of streptococcal toxic shock syndrome. Clin Infect Dis. 1998;26:639–41.PubMedCrossRef
13.
Gitlin D, Janeway CA. Agammaglobulinemia: congenital, acquired and transient forms. Prog Hematol. 1956;1:318–29.PubMed
14.
Gitlin D, Gross PA, Janeway CA. The gamma globulins and their clinical significance. II. Hypogammaglobulinemia. N Engl J Med. 1959;260:72–6.PubMedCrossRef
15.
Imbach P, Barandun S, Baumgartner C, et al. High-dose intravenous gammaglobulin therapy of refractory, in particular idiopathic thrombocytopenia in childhood. Helv Paediatr Acta. 1981;36:81–6.PubMed
16.
•• Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345:747–55. First class review for readers that are interested in the broad field pathophysiology, pharmacodynamics, of clinical use of ivIG, especially in patients with inflammatory and autoimmune diseases..PubMedCrossRef
17.
Bayry J, Thirion M, Misra N, et al. Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases. Neurol Sci. 2003;24:S217–21.PubMedCrossRef
18.
•• Durandy A, Kaveri SV, Kuijpers TW, et al. Intravenous immunoglobulins – understanding properties and mechanisms. Clin Exp Immunol. 2009;158 Suppl 1:2–13. Our favorite review on the complex pathways by which ivIG preparations exert immunomodulatory effects..PubMedCrossRef
19.
Ramakrishna C, Newo ANS, Shen YW, Cantin E. Passively administered pooled human immunoglobulins exert IL-10 dependent anti-inflammatory effects that protect against fatal HSV encephalitis. PLoS Pathogen. 2011;7:e1002071.CrossRef
20.
Basta M. Ambivalent effect of immunoglobulins on the complement system: activation versus inhibition. Mol Immunol. 2008;45:4073–9.PubMedCrossRef
21.
• Hartung HP, Mouthon L, Ahmed R, et al. Clinical applications of intravenous immunoglobulins (IVIg) – beyond immunodeficiencies and neurology. Clin Exp Immunol. 2009;158 Suppl 1:23–33. Excellent review especially for readers from the area of neurology and congenital syndromes where ivIG preparations are part of standard therapy..PubMedCrossRef
22.
Jolles S, Sewell WAC, Misbah SA. Clinical uses of intravenous immunoglobulin. Clin Exp Immunol. 2005;142:1–11.PubMedCrossRef
23.
Moiseeva KG, Nikiforova TV, Kharitonova AI, Koz’minykh LF, Pavlovskaia EN. Intravenous administration of immunoglobulins in young children with staphylococcal infections. Probl Gematol Pereliv Krovi. 1977;2:35–8.PubMed
24.
Lindquist L, Lundbergh P, Maasing R. Pepsin-treated human gamma globulin in bacterial infections. A randomized study in patients with septicaemia and pneumonia. Vox Sang. 1981;40:329–37.PubMedCrossRef
25.
Glinz W, Grob PJ, Nydegger UE, et al. Polyvalent immunoglobulins for prophylaxis of bacterial infections in patients following multiple trauma. A randomized, placebo-controlled study. Intensive Care Med. 1985;11:288–94.PubMedCrossRef
26.
Cometta A, Baumgartner JD, Glauser MP. Polyclonal intravenous immune globulin for prevention and treatment of infections in critically ill patients. Clin Exp Immunol. 1994;97:69–72.PubMed
27.
Fang KC. Monoclonal antibodies to endotoxin in the management of sepsis. West J Med. 1993;158:393–9.PubMed
28.
•• Ziegler EJ, Fisher Jr CJ, Sprung CL, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin – a randomized, double-blind, placebo-controlled trial. N Engl J Med. 1991;324:429–36. Definitely a “milestone” paper, although the results were disappointing. Readers will learn a lot!.PubMedCrossRef
29.
Albertson TE, Panacek EA, MacArthur RD, et al. Multicenter evaluation of a human monoclonal antibody to Enterobacteriaceae common antigen in patients with Gram-negative sepsis. Crit Care Med. 2003;31:419–27.PubMedCrossRef
30.
Christman JW. Potential treatment of sepsis syndrome with cytokine-specific agents. Chest. 1992;102:613–7.PubMedCrossRef
31.
St John RC, Dorinsky PM. Immunologic therapy for ARDS, septic shock, and multiple-organ failure. Chest. 1993;103:932–43.PubMedCrossRef
32.
Reinhart K, Menges T, Gardlund B, et al. Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study. Crit Care Med. 2001;29:765–9.PubMedCrossRef
33.
Opal SM, Fisher Jr CJ, Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med. 1997;25:1115–24.PubMedCrossRef
34.
Shah SS, Hall M, Srivastava R, Subramony A, Levin JE. Intravenous immunoglobulin in children with streptococcal toxic shock syndrome. Clin Infect Dis. 2009;49:1369–76.PubMedCrossRef
35.
Kaul R, McGeer A, Norrby-Teglund A, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome – a comparative observational study. Clin Infect Dis. 1999;28:800–7.PubMedCrossRef
36.
• Darenberg J, Ihendyane N, Sjölin J, et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2003;37:333–40. The most important study on ivIG in streptococcal toxic shock syndrome, still being the base for recommendations for the use of ivIG in these patients..PubMedCrossRef
37.
Valiquette L, Low DE, McGeer AJ. Assessing the impact of intravenous immunoglobulin in the management of streptococcal toxic shock syndrome: a noble but difficult question. Clin Infect Dis. 2009;49:1377–9.PubMedCrossRef
38.
Vincent JL, Sun Q, Dubois MJ. Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin Infect Dis. 2002;34:1084–93.PubMedCrossRef
39.
40.
Laupland KB. Polyclonal intravenous immunoglobulin for the treatment of infection in critically ill patients. Can J Infect Dis. 2002;13:100–6.
41.
42.
Pildal J, Gotzsche PC. Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review. Clin Infect Dis. 2004;39:38–46.PubMedCrossRef
43.
Norrby-Teglund A, Haque KN, Hammarstrom L. Intravenous polyclonal IgM-enriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis. J Intern Med. 2006;260:509–16.PubMedCrossRef
44.
Turgeon AF, Hutton B, Fergusson DA, et al. Metaanalysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med. 2007;146:193–203.PubMed
45.
• 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. Although all of the meta-analyses from Ref. 41 to Ref. 48 are important, this one was performed in a sound matter..PubMedCrossRef
46.
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.PubMedCrossRef
47.
• Alejandria MM, Lansang MA, Dans LF, Mantaring JB. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock (review). Cochrane Library. 2010; doi:10.​1002/​14651858.​CD001090. Together with Ref. 41, this review is the confirming analysis for the limited evidence on the use of ivIG in adult patients with sepsis.
48.
•• Soares MO, Welton NJ, Harrison DA, et al. An evaluation of the feasibility, cost and value of information of a multicenter 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. 2012;16:1–186. Definitely a “must” for everybody who wants sufficient information on this topic. Many sub-analyses, many graphs, something like a “handbook” for EBM in severe sepsis..PubMed
49.
•• Werdan K, Pilz G, Bujdoso O, et al. Score-based immunoglobulin G therapy of patients with sepsis: The SBITS study. Crit Care Med. 2007;35:2693–701. The most important RCT on ivIG in adult patients with severe sepsis..PubMedCrossRef
50.
• Brocklehurst P, Farrell B, King A, for the INIS Collaborative Group, et al. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med. 2011;365:1201–11. Extremely important, large RCT, although limited to very low weight newborns..PubMedCrossRef
51.
Burns ER, Lee V, Rubinstein A. Treatment of septic thrombocytopenia with immune globulin. J Clin Immunol. 1991;11:363–8.PubMedCrossRef
52.
• Hentrich M, Fehnle K, Ostermann H, et al. IgM-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial. Crit Care Med. 2006;34:1319–25. The only available, good quality trial on the use of IgM-enriched ivIG in adult septic patients..PubMedCrossRef
53.
Rodriguez A, Rello J, Neira J, et al. Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. Shock. 2005;23:298–304.PubMedCrossRef
54.
Ioannidis JP. Effect of the statistical significance of results on the time to completion and publication of randomized efficacy trials. JAMA. 1998;279:281–6.PubMedCrossRef
55.
Dickersin K. How important is publication bias? A synthesis of available data. AIDS Educ Prev. 1997;9(Suppl):15–21.PubMed
56.
Trzeciak S, Zanotti-Cavazzoni S, Parrillo JE, Dellinger RP. Inclusion criteria for clinical trials in sepsis: did the American College of Chest Physicians/Society of Critical Care Medicine consensus conference definitions of sepsis have an impact? Chest. 2005;127:242–5.PubMedCrossRef
57.
Schedel I, Dreikhausen U, Nentwig B, et al. Treatment of Gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. Crit Care Med. 1991;19:1104–13.PubMedCrossRef
Metadata
Title
Immunoglobulins in Adult Sepsis and Septic Shock
Authors
Susanne Toussaint
Herwig Gerlach
Publication date
01-10-2012
Publisher
Current Science Inc.
Published in
Current Infectious Disease Reports / Issue 5/2012
Print ISSN: 1523-3847
Electronic ISSN: 1534-3146
DOI
https://doi.org/10.1007/s11908-012-0287-z

Other articles of this Issue 5/2012

Current Infectious Disease Reports 5/2012 Go to the issue

Skin, Soft Tissue, Bone and Joint Infections (N Safdar, Section Editor)

Chronic Osteomyelitis

Skin, Soft Tissue, Bone and Joint Infections (N Safdar, Section Editor)

From Ulcer to Infection: An Update on Clinical Practice and Adjunctive Treatments of Diabetic Foot Ulcers

Skin, Soft Tissue, Bone, and Joint Infections (N Safdar, Section Editor)

Prosthetic Joint Infections

Skin, Soft Tissue, Bone, and Joint Infections (N Safdar, Section Editor)

Subcutaneous Fungal Infections

Sepsis (J Russell, Section Editor)

HMG-CoA Reductase Inhibitors for Prevention and Treatment of Severe Sepsis

Sepsis (J Russell, Section Editor)

Pediatric Sepsis: Preparing for the Future Against a Global Scourge
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits