The efficacy and safety of high-dose intravenous polyspecific immunoglobulin G (IVIG) as adjunctive therapy in streptococcal toxic shock syndrome (STSS) were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. The trial was prematurely terminated because of slow patient recruitment, and results were obtained from 21 enrolled patients (10 IVIG recipients and 11 placebo recipients). The primary end point was mortality at 28 days, and a 3.6-fold higher mortality rate was found in the placebo group. A significant decrease in the sepsis-related organ failure assessment score at days 2 (P=.02) and 3 (P=.04) was noted in the IVIG group. Furthermore, a significant increase in plasma neutralizing activity against superantigens expressed by autologous isolates was noted in the IVIG group after treatment (P=.03). Although statistical significance was not reached in the primary end point, the trial provides further support for IVIG as an efficacious adjunctive therapy in STSS.

The relatedness of group A streptococcal (GAS) strains isolated from 35 Canadian patients with invasive disease of different severity was investigated by a variety of molecular methods. All patients were infected with M1T1 strains and, based on clinical criteria, were classified as severe (n ‫؍‬ 21) and nonsevere (n ‫؍‬ 14) invasive GAS infection cases. All the M1 strains studied had the emm1.0 allele and the same streptococcal pyrogenic exotoxin (Spe) genotype, speA ؉ speB ؉ speC speF ؉ speG ؉ speH smeZ ؉ ssa. All isolates had the same speA allotype, speA2. The randomly amplified polymorphic DNA banding pattern with two different primers was identical for all strains, and pulsed field gel electrophoresis analysis showed that 33 and 30 isolates had identical banding patterns after DNA digestion with SfiI or SmaI, respectively; the nonidentical isolates differed from the main pattern by only one band. A relatively high degree of polymorphism in specific regions of the sic gene was observed among isolates; however, this polymorphism was not associated with disease severity. Likewise, although the phenotypic expression of SpeA, SpeB, and SpeF proteins varied among the M1T1 isolates, there was no correlation between the amount of Spe expressed and disease severity. Importantly, mitogenic and cytokine responses induced by partially purified bacterial culture supernatants containing a mixture of expressed superantigens were very similar for isolates from severe and nonsevere cases (P > 0.1). Together, the data indicate that highly related invasive M1T1 isolates, some indistinguishable, can cause disease of varying severity in different individuals. These findings underscore the contribution of host factors to the outcome of invasive GAS infections.Group A streptococci (GAS) are responsible for a variety of human diseases ranging from simple pharyngitis to highly severe infections, such as necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS) (16). Since the late 1980s, a marked increase in the incidence and severity of invasive infections has been reported in the United States, Canada, Japan, and many regions of Europe (11,13,16,17,20,22,37). Whether this dramatic rise in the incidence of invasive GAS infections resulted from changes in virulence properties of the bacteria and/or alterations of host protective immunity against specific strains or specific virulence factors remains an area of intense investigation.Among the many virulence factors produced by GAS, the M protein and the streptococcal pyrogenic exotoxins (Spes) are considered important virulence factors in the pathogenesis of invasive GAS infections. The Spes belong to the superantigen (SAg) family and thus can induce massive secretion of inflammatory cytokines, such as gamma interferon (IFN-␥), interleukin-1 (IL-1), and tumor necrosis factor ␣. Overproduction of these cytokines can lead to tissue damage, organ failure, and shock (reviewed by Kotb [15]).GAS are classified by their surface M protein type (4, 10). To date, more than 100 d...

Immunotherapy targeted against microbial toxins and host mediators has been studied in many preclinical investigations and clinical trials of sepsis during the past 20 y. Intravenous immunoglobulin, including both monoclonal and polyclonal antibodies, represents one such immunotherapeutic strategy. Mononclonal antibodies directed against endotoxin or tumour necrosis factor-alpha have been tested extensively in clinical trials, but have so far failed to reveal a significant effect on mortality rates. Several studies have assessed the efficacy of polyclonal intravenous immunoglobulin (IVIG) in sepsis, with varying results. Although there are no conclusive data available to date to support the use of IVIG therapy in all sepsis cases, there are strong indications that certain defined septic subgroups, such as streptococcal toxic shock syndrome caused by group A streptococcus, will benefit from its use. This review briefly summarizes the clinical trials on IVIG therapy in sepsis, and describes in more detail the mechanistic actions of IVIG and the clinical data that support the use of IVIG as adjunctive therapy in severe invasive group A streptococcal infections.

In this study we compared the ability of different immunoglobulin (Ig) preparations containing IgG, IgM, and/or IgA to neutralize the activity of streptococcal pyrogenic exotoxin A (SpeA) or culture supernatant from a clinical group A streptococcal isolate. All Ig preparations markedly inhibited the mitogenic and cytokine-inducing activity of SpeA and culture supernatant at concentrations of 0.05-0.5 mg/mL, and at 0.5 mg/mL, most caused 95-100% inhibition of both stimuli. A significantly higher (P< or =.05) inhibition of SpeA was achieved by Pentaglobin (IgG, IgM, and IgA) and IgAbulin (IgA and IgG), as compared with pure IgG preparations. IgM- and IgA-enriched preparations had significantly higher inhibitory activity against SpeA than against culture supernatant, whereas the reverse was true for the IgG preparations (P< or =.05). The data show that IgM and IgA are potent inhibitors of specific streptococcal superantigens. These findings may have implications for the optimization of immunotherapy in invasive streptococcal infections.