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Meta-analysis: Intravenous Immunoglobulin in Critically Ill Adult Patients with Sepsis

Alexis F. Turgeon, MD, MSc; Brian Hutton, MSc; Dean A. Fergusson, MHA, PhD; Lauralyn McIntyre, MD, MSc; Alan A. Tinmouth, MD, MSc; D. William Cameron, MD; and Paul C. Hébert, MD, MSc
[+] Article and Author Information

From the Center for Transfusion and Critical Care Research, Ottawa Health Research Institute, the University of Ottawa, and the Canadian Blood Service, Ottawa, Ontario, Cananda.


Note: Presented in part at the fellows' competition of the 10th Toronto Critical Care Medicine Symposium, Toronto, Ontario, Canada, 26-28 October 2005.

Acknowledgments: The authors thank the following study authors for providing additional data or for clarifying the methods of their trial: Drs. Burns, Tugrul, and Masaoka. They also thank Dr. Sandra Froeschl for her translation of German-language studies; Dr. Behrooz M. Yagchi, Jean Burelle, and Üstün B. Reinart for their translation of the Turkish-language study; Dr. Yoko Schreiber and Satoshi Kaj for their translation of the Japanese-language study, as well as Steve Doucette for producing the figures and Leslie Webb, Louise Roy, and Nancy Cleary for their administrative support.

Grant Support: By the Ontario Ministry of Health and Long-Term Care. Dr Turgeon is a recipient of a research fellowship grant from the Fonds de la Recherche en Santé du Québec. Dr. Fergusson holds a Canadian Institutes of Health Research New Investigator Award and an Ontario Ministry of Health and Long-Term Care Career Scientist Award. Dr Tinmouth holds a Canadian Blood Services/Canadian Institutes of Health Research New Investigator Award. Dr. Hébert holds a Chair in Transfusion and Critical Care Research, Ottawa Health Research Institute and the University of Ottawa.

Potential Financial Conflicts of Interest: Honoraria: A.A. Tinmouth (Bayer).

Requests for Single Reprints: Alexis F. Turgeon, MD, MSc, Center for Transfusion and Critical Care Research, Ottawa Health Research Institute, Clinical Epidemiology Unit, 501 Smyth Road, Box 208, Ottawa, Ontario, Canada K1H-8L6; e-mail, alexisturgeon@yahoo.ca.

Current Author Addresses: Drs. Turgeon, Fergusson, McIntyre, Tinmouth, Cameron, and Hébert and Mr. Hutton: Clinical Epidemiology Unit, Ottawa Health Research Institute, 501 Smyth Road, Box 201, Ottawa K1H-8L6, Ontario, Canada.

Author Contributions: Conception and design: A.F. Turgeon, B. Hutton, D.A. Fergusson.

Analysis and interpretation of the data: A.F. Turgeon, B. Hutton, D.A. Fergusson, L. McIntyre, P.C. Hébert.

Drafting of the article: A.F. Turgeon, B. Hutton, D.A. Fergusson.

Critical revision of the article for important intellectual content: A.F. Turgeon, B. Hutton, D.A. Fergusson, L. McIntyre, A.A. Tinmouth, D.W. Cameron, P.C. Hébert.

Final approval of the article: A.F. Turgeon, B. Hutton, D.A. Fergusson, L. McIntyre, A.A. Tinmouth, D.W. Cameron, P.C. Hébert.

Statistical expertise: B. Hutton, D.A. Fergusson.

Obtaining of funding: D.A. Fergusson.

Collection and assembly of data: A.F. Turgeon, B. Hutton.


Ann Intern Med. 2007;146(3):193-203. doi:10.7326/0003-4819-146-3-200702060-00009
Text Size: A A A

Background: Intravenous immunoglobulin therapy has been proposed as an adjuvant treatment for sepsis. Yet, its benefit remains unclear, and its use is not currently recommended.

Purpose: To evaluate the effect of polyclonal intravenous immunoglobulin therapy on death in critically ill adult patients with sepsis.

Data Sources: MEDLINE (1966 to May 2006) and the Cochrane Central Register of Controlled Trials (May 2006 edition).

Study Selection: All randomized, controlled trials of critically ill adult patients with sepsis, severe sepsis, or septic shock who received polyclonal intravenous immunoglobulin therapy or placebo or no intervention were selected. No restrictions were made for study language or type of publication.

Data extraction: Data were independently extracted by 2 investigators using a standardized form.

Data Synthesis: The literature search identified 4096 articles, of which 33 were deemed to be potentially eligible. Twenty trials (n = 2621) met eligibility criteria and were included in the analysis. Polyclonal intravenous immunoglobulin therapy was associated with an overall survival benefit (risk ratio, 0.74 [95% CI, 0.62 to 0.89]) compared with placebo or no intervention. In sensitivity analyses, documented survival improved when the analysis was limited to published, peer-reviewed trials (risk ratio, 0.72 [CI, 0.58 to 0.89]) (17 trials [n = 1865]) and blinded trials (risk ratio, 0.61 [CI, 0.40 to 0.93) (7 trials [n = 896]). Severe sepsis or septic shock (risk ratio, 0.64 [CI, 0.52 to 0.79]) (11 trials [n = 689]), receiving a total dose regimen of 1 gram or more per kilogram of body weight (risk ratio, 0.61 [CI, 0.40 to 0.94]) (7 trials [n = 560]), and receiving therapy for longer than 2 days (risk ratio, 0.66 [CI, 0.53 to 0.82]) (17 trials [n = 1847]) were strongly associated with this survival benefit.

Limitations: Most trials were published before new developments modifying the care and outcome of critically ill patients with sepsis including early goal-directed therapy and activated protein C treatment, were introduced.

Conclusions: A survival benefit was observed for patients with sepsis who received polyclonal intravenous immunoglobulin therapy compared with those who received placebo or no intervention. A large, randomized, controlled trial of polyclonal intravenous immunoglobulin therapy should be performed on the basis of the methodological limitations of the current literature, the potential benefit from this therapy in more severely ill patients, and the potential effect of dosage and duration of this therapy.

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

IVIG = intravenous immunoglobulin.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Difference in the number of deaths between patients who received intravenous immunoglobulin (IVIG) and those who received placebo or no intervention.
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Grahic Jump Location
Figure 3.
Death according to treatment regimen, severity of disease, or methodological quality.
Grahic Jump Location

Tables

References

Letters

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Risks of IVIG in sepsis affect trial design
Posted on May 9, 2007
Sujoy Khan
Path Links Immunology
Conflict of Interest: None Declared

The meta-analysis by Alexis Turgeon on the use of intravenous immunoglobulin (IVIG) in adults with sepsis suggests that larger trials should be performed incorporating modern sepsis management techniques. However, there was no mention of the side effects of using IVIG in sepsis in their meta-analysis.

All immunologists recognise that immunoglobulin replacement therapy must be withheld in patients with infections, as severe reactions commonly develop [1]. An audit of adverse reactions in antibody deficient patients showed that an intercurrent infection was the major cause of reactions to replacement IVIG therapy [2]. This multi-centre prospective study of 459 patients reported that the reaction rate would have been halved if infusions were not administered to patients who had an inter-current infection. 28 of 111 adverse reactions were attributed to underlying infections. Prophylaxis with antibiotics and delaying IVIG infusion in patients with inter-current infection is now the standard of care.

In view of this, it is important that future trials using IVIG in sepsis not only consider reporting adverse events but also consider effective antibiotics before considering treatment with IVIG. This may well prove to be crucial, as the study by Rodriguez et al on IVIG in sepsis from abdominal infections had concluded that the initial choice of antibiotics had a dramatic impact on outcome [3].

A novel mechanism of action of IVIG can profoundly affect the outcome in sepsis. Naturally occurring anti-Siglec-9 autoantibodies in IVIG can cause accelerated apoptosis of neutrophils and may then lead to neutropenia [4]. This effect is enhanced by high levels of IFN-g and ROS, present in sepsis.

Manufacturers are at present unable to provide a constant supply for the ever increasing demand for IVIG and this has resulted in escalating costs of the product [5]. This particularly affects countries that rely on foreign sources of plasma, such as the United Kingdom. Off-label use must therefore be avoided, especially when alternatives are available. We therefore recommend extreme caution in designing future trials of IVIG in patients with sepsis, paying close attention to adverse reactions. Trial designers must remember that the IVIG supply is limited and reduction in availability for licensed use will have tremendous impact on quality-of- life of patients with primary immunodeficiency disorders who have an absolute requirement for this drug.

References:

1. Orange JS, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the primary immunodeficiency committee of the American Academy of Allergy, Asthma and Immunology. Journal of Allergy & Clinical Immunology 2006; 117: S525-553

2. Brennan VM, Salome-Bentley NJ, Chapel HM; Immunology Nurses Study. Prospective audit of adverse reactions occurring in 459 primary antibody- deficient patients receiving intravenous immunoglobulin. Clin Exp Immunol. 2003; 133(2): 247-51.

3. Rodriguez A, Rello J, Neira J, Maskin B, Ceraso D, Vasta L, Palizas F. Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. Shock. 2005; 23(4): 298-304.

4. von Gunten S, Schaub A, Vogel M, Stadler BM, Miescher S, Simon HU. Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations. Blood. 2006; 108(13): 4255-9.

5. McGinnity E. Eye on IVIG: A series of unfortunate supply chain events. Healthcare Purchasing News. 2007; 31(3): 70-71.

Conflict of Interest:

None declared

Re: Risks of IVIG in sepsis affect trial design
Posted on May 18, 2007
Alexis Turgeon
Clinical Epidemiology Unit, Ottawa Health Research Institute, Ottawa, Ontario, Canada
Conflict of Interest: None Declared

We would like to thank Drs Khan and Sewell for their interest and relevant comments regarding our study. As pointed out in their letter, adverse reactions following the administration of intravenous immunoglobulin (IVIG) use have been observed in patients with severe infections. However, these severe adverse effects were described in patients with hypogammaglobulinemia receiving their usual replacement treatment of IVIG during an intercurrent infection, which differs from the broad population of patients with sepsis of our study (1). Moreover, in the same obervational study of more than 13,500 IVIG infusions, the incidence of adverse events was 0.8% and none of these reactions were reported as severe (2). In our meta-analysis, adverse reactions were reported in only 6 studies. Interestingly, most of these adverse effects were considered mild to moderate and when severe (dyspnea, shock), they were thought to be secondary to the primary disease rather than to the treatment regimen (1). Neutropenia was also not reported as a consequence of IVIG use. However, ensuring the safety of participants with independent data safety, monitoring committees and diligent reporting of adverse events within clinical trials is very important in general, as well as for future prospective trials evaluating use of IVIG.

Costs and potential supply problems associated with the use of IVIG in a broad population of patients with severe sepsis and septic shock are crucial if considering recommending the use of IVIG. Albeit, important costs and supply should not supercede overall benefits such as improvements in survival and quality of life; a clear survival benefit in any population should be given priority over other indications with lower evidence of a clinical benefit (3,4). On the other hand, the estimated cost of IVIG (1 g/kg) is currently about half the cost of activated protein-C used in the same population. We agree that a good management of IVIG supply should be prioritized by basing the use of IVIG on current evidence of clinical benefit. For these reasons and considering the potential benefit of the therapy, we believe that is important that IVIG should be further evaluated in adult patients with severe sepsis and septic shock receiving current standard of care therapy.

1. Turgeon AF, Hutton B, Fergusson DA, McIntyre L, Tinmouth AA, Cameron DW et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med. 2007 Feb 6;146(3):193-203.

2. Brennan VM, Salome-Bentley NJ, Chapel HM; Immunology Nurses Study. Prospective audit of adverse reactions occurring in 459 primary antibody- deficient patients receiving intravenous immunoglobulin. Clin Exp Immunol. 2003; 133(2): 247-51.

3. Chen C, Danekas LH, Ratko TA, Vlasses PH, Matuszewski KA. A multicenter drug use surveillance of intravenous immunoglobulin utilization in US academic health centers. Ann Pharmacother 2000; 34: 295-9.

4. Pendergrast JM, Sher GD, Callum JL. Changes in intravenous immunoglobulin prescribing patterns during a period of severe product shortages, 1995-2000. Vox Sang. 2005 Oct;89(3):150-60.

Conflict of Interest:

None declared

Duplicate publication in meta-analysis
Posted on May 24, 2007
Kevin B. Laupland
University of Calgary
Conflict of Interest: None Declared

While the IVIG for sepsis meta-analysis by Turgeon et al was conducted carefully, we would like to inform the authors of an error arising from unrecognized duplicate publication (1). The authors included the final results of a trial including 206 patients reported by Hentrich et al (2) as well as the interim results of the first 52 patients reported by Behre and colleagues (3). As compared to albumin control, the mortality reduction associated with IVIG in the first 52 patients was much greater [10/22 (45%) albumin vs. 9/30 (30%) IVIG] as compared to patients enrolled after interim analysis [19/81 (24%) albumin vs. 18/73 (25%) IVIG].

This raises two important points. First, by including the initial 52 patients twice, their reported overall summary relative risk for effect is somewhat overestimating the true summarized treatment effect (4). Second, this error highlights the need for authors and journals to explicitly state when patients have been included in previously published reports. While it is evident based on overlapping enrollment periods and centers that these 52 patients were included twice in these reports (and confirmed by correspondence with the authors), an explicit statement to this effect in the second publication would have avoided this error.

1. Turgeon AF, Hutton B, Fergusson DA, et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med. 2007;146(3):193-203.

2. Hentrich M, Fehnle K, Ostermann H, et al. IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial. Crit Care Med. 2006;34(5):1319-25.

3. Behre G, Ostermann H, Schedel I, et al. Endotoxin concentrations and therapy with polyclonal IgM-enriched immunoglobulins in neutropenic cancer patients with sepsis syndrome: pilot study and interim analysis of a randomized trial. Anti-infective Drugs Chemother. 1995;13(2):129-134.

4. Tramer MR, Reynolds DJ, Moore RA, McQuay HJ. Impact of covert duplicate publication on meta-analysis: a case study. Bmj. 1997;315(7109):635-40.

Conflict of Interest:

None declared

Re: Duplicate publication in meta-analysis
Posted on May 30, 2007
Alexis F. Turgeon
Clinical Epidemiology Unit, Ottawa Health Research Institute, Ottawa, Ontario
Conflict of Interest: None Declared

Despite important efforts made to minimize the incidence of duplicate publications in systematic reviews and meta-analyses, such situations still occur. In our meta-analysis (1), we contacted authors of the primary studies when we were unclear on any item of data abstraction or study eligibility. We did not receive a reply from the corresponding author of the study by Hentrich et al. (2) concerning potential duplicate publication (3). Because the prior publication was not cited in the manuscript, we considered the results independent. The removal of the patients in the Hentrich study did not change the direction or magnitude of the benefit. The revised relative risk estimate remains 0.74 as does the 95% confidence intervals (0.62"“0.89). We agree with Dr Laupland that authors have a responsibility to be explicit about prior publications of study results.

1. Turgeon AF, Hutton B, Fergusson DA, et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med. 2007;146(3):193-203.

2. Hentrich M, Fehnle K, Ostermann H, et al. IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial. Crit Care Med. 2006;34(5): 1319-25.

3. Behre G, Ostermann H, Schedel I, et al. Endotoxin concentrations and therapy with polyclonal IgM-enriched immunoglobulins in neutropenic cancer patients with sepsis syndrome: pilot study and interim analysis of a randomized trial. Anti-infective Drugs Chemother. 1995;13(2):129-134.

Conflict of Interest:

None declared

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