IV Immunoglobulin for Necrotising Fasciitis

A 40 year old woman presented with painful swelling of the right side of the neck. She had previously suffered a haematological malignancy and received a bone marrow transplant. A presumptive diagnosis of necrotising fasciitis was made and the neck, shoulder and chest underwent surgical debridement. Postoperatively, the patient remained ventilated in septic shock. Further debridement was required at 24 hours. Group A streptococcus was grown from the debrided tissue and IV immunoglobulins was commenced. The patient gradually weaned from support and was discharged from ICU several days later.

Does IV immunoglobulin have a role to play in the treatment of necrotising fasciitis?

David Garry

Necrotising soft tissue infections can be classified into 4 types according to the causative organism:
• Type I – polymicrobial, often a mix of gram –ve and gram +ve organisms
• Type II – monomicrobial gram +ve organisms, often Group A Streptococcus
• Type III – monomicrobial gram –ve organisms
• Type IV – fungal organisms

The cornerstones of the treatment of necrotising soft tissue infections are resuscitation, urgent surgical debridement and appropriate antimicrobial cover.

Group A Streptococcus (type II infections) produces several exotoxins that exhibit superantigenic activity leading to widespread activation of antigen presenting T cells with subsequent massive cytokine release (1). Experimental studies have shown that immunoglobulin neutralises superantigen toxins and opsonise bacteria that are not cleared by antibiotics or surgery alone (2,3,4). One retrospective case controlled study (5) and one randomised controlled trial (6) suggest that this effect could translate into clinical benefit.

The observational study recruited 21 consecutive patients between December 1994 and April 1995 with streptococcal toxic shock syndrome who were treated with IV immunoglobulin. These patients were then compared with 32 patients that had been treated for streptococcal toxic shock syndrome between 1992 and 1995 but who did not receive immunoglobulin (historical controls). The primary outcome measure was 30-day survival, secondary outcome measures included ability of patient plasma to inhibit T cell activation induced by the infecting strain. The treatment group had a higher 30-day survival (67% vs 34%, p=0.02). Patient plasma in the treatment group showed an enhanced ability to neutralise bacterial mitogenicity, and reduced T cell production of IL-6 and TNFα. Of note, a greater proportion of patients in the treatment group received clindamycin and were more likely to receive surgical intervention.

The prospective trial was designed as a multicentre, randomised, double blind placebo controlled trial but was terminated early due to poor patient recruitment, with only 21 patients included in the final analysis. Ten patients received immunoglobulin, 11 received placebo. The primary end point (28 day mortality) showed a 3.6-fold increase in mortality in the placebo group. This failed to reach statistical significance, likely as a result of the small sample size. The secondary end points included a significant decrease in the sepsis-related organ failure assessment score at days 2 (p=0.02) and 3 (p=0.04) along with a significant increase in plasma neutralizing activity against superantigens expressed by autologous isolates (p=0.03) in the immunoglobulin group.

These 2 trials are referenced in the 2008 DoH paper “Clinical Guidelines for Immunoglobulin Use” (7).It states that Immunoglobulin is recommended for use in “severe invasive group A streptococcal disease if other approaches have failed (grade C recommendation, level III evidence)”.

Lessons learnt

The cornerstones of treatment for necrotising fasciitis are resuscitation, early surgical debridement and adequate antimicrobial cover. Intravenous immunoglobulin is a grade C recommendation for use in severe group A streptococcal disease if other approached have failed.

References

1. Norrby-Teglund A, Thulin P, Gan B et al. Evidence for Superantigen Involvement in Severe Group A Streptococcal Tissue Infections. The Journal of Infectious Diseases 2001;184:853–60
2. Norrby-Teglund A, Kaul R, Low DE et al. Plasma from patients with severe invasive group A streptococcal infections treated with normal polyspecific IgG inhibits streptococcal superantigen-induced T cell proliferation and cytokine production. J Immunol 1996;156:3057–64.
3. Basma H, Norrby-Teglund A, McGeer A et al. Opsonic antibodies to the surface M protein of group A streptococci in pooled normal immunoglobulins (IVIG): potential impact on the clinical efficacy of IVIG therapy for severe invasive group A streptococcal infections. Infect Immun 1998;66:2279–83.
4. Sriskandan S, Ferguson M, Elliot V et al. Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation. J Antimicrob Chemother 2006;58:117–24.
5. Kaul R, McGeer A, Norrby-Teglund A et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome–a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis 1999;28:800–7.
6. Darenberg J, Ihendyane N, Sjölin J et al; StreptIg Study Group. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2003;37:333–40.
7. Department of Health. Clinical Guidelines for Immunoglobulin Use. May 2008. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/153239/dh_130393.pdf.pdf. Accessed on 01/05/13