Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Polyclonal intravenous immunoglobulin reduced mortality in bacterial sepsis

ACP J Club. 1999 Nov-Dec;131:70. doi:10.7326/ACPJC-1999-131-3-070


Source Citation

Alejandria MM, Lansang MA, Dans LF, Mantaring JB. Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Review, latest version 22 Feb 1999. In: The Cochrane Library. Oxford: Update Software.


Abstract

Question

In patients with bacterial sepsis or septic shock, does intravenous immunoglobulin (IVIG) reduce length of hospital stay, mortality, or bacteriologic failure rates?

Data sources

Studies were identified by searching the registry of the Cochrane Infectious Diseases Group, Cochrane Library, MEDLINE, and EMBASE/Excerpta Medica with the terms immunoglobulins; septicemia; sepsis; and shock, septic. Authors and organizations were contacted, and bibliographies were reviewed.

Study selection

Randomized controlled trials (RCTs) were selected if the patients had bacterial sepsis or septic shock; if monoclonal or polyclonal IVIGs were compared with placebo or no intervention; and if all-cause mortality, mortality from septic shock, bacteriologic failure rates, or length of hospital stay was reported.

Data extraction

Data were extracted on study quality, year, and location; baseline characteristics; inclusion and exclusion criteria; preparation and dose of IVIG; and outcomes.

Main results

20 studies (4800 patients) met the inclusion criteria. 3 studies each evaluated infants with sepsis and adults with sepsis after surgery, 1 study evaluated obstetric and gynecology patients with septic shock, and 13 studies evaluated adults with sepsis or septic shock. Heterogeneity was shown, and data were not pooled for all studies of mortality. Subgroup analysis showed reduced mortality with polyclonal IVIG compared with placebo or no treatment for all patients (Table) and adults only. IgM-enriched polyclonal IVIG showed a greater reduction in mortality than standard polyclonal IVIG; both were more effective than placebo or no treatment (Table). Monoclonal IVIG did not reduce all-cause mortality. Hospital length of stay was unchanged (5 studies) (weighted mean difference 1.8 d, 95% CI -1.3 to 4.9). 1 study showed a higher bacterial eradication rate with IVIG (40% vs 8%, P < 0.01).

Conclusion

Polyclonal but not monoclonal intravenous immunoglobulin reduces all-cause mortality in sepsis or septic shock.

Sources of funding: Department for International Development, UK, and European Commission (Directorate General XII), Belgium.

For correspondence: Dr. M.A. Lansang, Clinical Epidemiology Unit, University of the Philippines Manila, College of Medicine, 547 P. Gil Street, Ermita, Manila, Philippines 1000. FAX 63-2-526-4265.


Table. All-cause mortality for intravenous immunoglobulin (IVIG) vs placebo or no treatment in sepsis or septic shock (follow-up 14 to 56 d)*

Preparations Weighted event rates RRR (95% CI) NNT (CI)
IVIG Placebo or no treatment
Polyclonal IVIG 26% 45% 42% (26 to 55) 6 (4 to 10)
Enriched polyclonal IVIG 13% 36% 62% (33 to 72) 5 (3 to 9)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

Both monoclonal (monoclonal antibodies [MAbs]) and polyclonal IVIGs, which are designed to inhibit microbial toxins or potentially harmful host inflammatory mediators, have been studied in patients with sepsis. Alejandria and colleagues concluded that polyclonal but not monoclonal IVIGs are effective in sepsis; however, this conclusion may not be correct.

First, 2 RCTs in the monoclonal IVIG group (which provided 20% of the 4800 patients in this meta-analysis) assessed interleukin-1-receptor antagonist, a recombinant protein that is different from IVIG (1, 2). Second, 2 large RCTs of 392 patients showing that polyclonal IVIG did not reduce mortality in surgical patients with severe infection were omitted (3, 4). Third, preliminary results from a large RCT of 653 patients showing that polyclonal IVIG did not reduce mortality in sepsis (5) were not considered. Finally, a recent meta-analysis of 20 studies assessing the effects of 6 mediator-specific anti-inflammatory agents in 8808 patients with sepsis showed reduced mortality (6). 8 of these studies assessed anti-tumor necrosis factor (TNF) MAbs in > 4000 patients. Although benefits were small and do not support clinical use, they do support the development and testing of mediator-specific agents, such as anti-TNF MAbs, in sepsis.

Polyclonal or monoclonal IVIGs may be useful in sepsis and septic shock, but neither has shown convincing benefit in RCTs. However, the heterogeneity of severely infected patients and their host-defense responses suggests that IVIGs may be effective only in specific, but not yet defined, patient subgroups.

Xizhong Cui, MD
Peter Q. Eichacker, MDNational Institutes of HealthBethesda, Maryland, USA


References

1. Fisher CJ Jr, Slotman GJ, Opal SM, et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group. Crit Care Med. 1994;22:12-21.

2. Fisher CJ Jr, Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271:1836-43.

3. Just HM, Metzger M, Vogel W, Pelka RB. [Effect of adjuvant immunoglobulin therapy on infections in patients in an surgical intensive care unit. Results of a randomized controlled study]. Klin Wochenschr. 1986;64:245-56.

4. Jesdinsky HJ, Tempel G, Castrup HJ, Seifert J. Cooperative Group of Additional Immunoglobulin Therapy in Severe Bacterial Infections: results of a multicenter randomized controlled trial in cases of diffuse fibrinopurulent peritonitis. Klin Wochenschr. 1987;65:1132-8.

5. Werdan K, Pilz G. Supplemental immune globulins in sepsis: a critical appraisal. Clin Exp Immunol. 1996;104 Suppl 1:83-90.

6. Freeman BD, Eichacker PQ, Natanson C. The role of inflammation in sepsis and septic shock: a meta-analysis of both clinical and preclinical trials of anti-inflammatory therapies. In: Gallin JI, Snyderman R, eds. Inflammation: Basic Principles and Clinical Correlates, 3d ed. Philadelphia: Lippincott Williams & Wilkins; 1999:965-76.