Invasive Streptococcal A Infections and Intravenous Immunoglobulin

A middle aged woman presented with a one day history of swollen, painful red thigh after a prodromal sore throat. She had a exquisitely tender left thigh and knee with cellulitis. She was apyrexial, with normal heart rate and blood pressure, but had a respiratory rate of 24. She had a neutrophilia (28), elevated CRP, hyperlactataemia (4.1) an acute kidney injury (creat 170) and a mild coagulopathy. She was given analgesia, broad spectrum antibiotics (including clindamycin) and underwent a CT thigh which showed muscle swelling in the anterior compartment with fluid tracking up to the hip. Knee aspirate showed large number of gram positive cocci, later confirmed as Streptococcus A. Two hours into her admission the inflammation was involving the groin. She underwent exploration and debridement in theatre, and was noradrenaline dependent postoperatively. She was commenced on intravenous immunoglobulin on the same day. She required further debridement of the leg and lower abdomen on day 3. She gradually weaned off support, and underwent several more operations for closure of wounds and reconstructive surgery.

What is the role of IVIG in Invasive Streptococcal Infections

Craig Walker (twitter)

Worldwide, there has been a dramatic increase in the incidence of invasive group A streptococcal (GAS) infections, including necrotising fasciitis and streptococcal toxic-shock syndrome (STSS) (1).

These streptococci express capsule-, M- and fibronectinbinding-proteins that are used to evade phagocytosis and adhere to host cells and tissue. They also secrete superantigens, streptolysins, peptidases and proteases that are important for bacterial growth and dissemination and induce the host inflammatory responses (the most important induction agent being the superantigens) (1).

It was observed that low levels of antibodies against the M-protein and superantigens correlated with invasive GAS disease, which suggested that immunoglobulins may be beneficial therapies. Intravenous immunoglobulin (IVIg) contains antibodies pooled from several thousand donors and therefore exerts high polyspecificity to cover the different serotypes of GAS.

There have been numerous studies into the use of intravenous immunoglobulin (IVIg) as an adjunctive therapy in sepsis. However, most of these have had small patient numbers and/or methodological limitations and, as such, there remains concern about effectiveness. Currently, IVIg is considered to be an accepted adjuvant therapy by the U.S. Food and Drug Administration for Group A STSS (2).

A Cochrane review in 2001 reviewed monoclonal and polyclonal IVIg in adults and neonates. In the 11 trials using polyclonal IVIg, a significant reduction in all-cause mortality was demonstrated in the treatment group (RR 0.64; 95% CI 0.51-0.80). In post hoc sub analysis, there was a greater reduction in mortality in patients given IgM-enriched IVIg compared with standard polyclonal IVIg (0.48 vs. 0.68) (3).

It was noted that most of the studies were small and many had significant methodological weaknesses. This Grade C evidence caused the authors to conclude that, “large, multicenter studies are needed to confirm the effectiveness of polyclonal IVIgs in reducing mortality in patients with sepsis”.

Such a study was long-awaited and published in 2007; its enrollment period was 1991 to 1995. The multicenter Score-Based Immunoglobulin G Therapy of patients with Sepsis (SBITS) compared 321 patients randomized to receive intravenous immunoglobulin G (IVIgG) with 303 placebo controls receiving human serum albumin and it did not show a statistically significant reduction in 28-day mortality (39.3% vs. 37.3%) (4).

There is evidence that preparations enriched with IgA and IgM (IgGAM) preparations may be more effective than IVIgG; it has superior antibody content, more intense compliment activation and a fall in APACHE II score of 5 points has been observed in patients with endotoxaemic septic shock (5). In their meta-analysis, Kreymann and colleagues included 8 studies (n=560) regarding IgGAM use in sepsis and noted a strong trend in favor of IgGAM (RR _ 0.66, 95% CI 0.51– 0.84, p < .0009) compared with preparations containing only IgG (RR _ 0.85, 95% CI 0.73– 0.99, p < .04) (6).

There have been a few meta-analyses since the initial Cochrane review around IVIG and sepsis (6)(7)(8)(9). Unfortunately, despite largely basing their analyses on the same trials, they have drawn different conclusions from the evidence. This appears mainly due to different decision-making criteria as to what constitutes a high-quality Randomised Controlled Trial (RCT). In the accompanying editorial to the SBITS study and Kreymann’s meta-analysis, it was noted that, “the beneficial ivIg effect is relatively stable and persists even in high-quality trials (IVIgG, all trials: OR, 0.85; IVIgG, high-quality trials: OR, 0.86; IgGAM, all trials: OR, 0.66; IgGAM, high-quality trials: OR, 0.40)” (10).

Kreymann and colleagues concluded that IgGAM could reduce mortality in adults by 34% and in neonates by 50%. They helpfully graded the evidence available; elaborating that the IVIG trials are of Grade II evidence (i.e. small randomized trials with uncertain results) except for the SBITS study that was of Grade I evidence (large randomized trial with clear-cut results) and therefore the case for adjunctive therapy with polyvalent immunoglobulins for sepsis or septic shock deserves a grade C recommendation.

Lessons Learned

As with many therapies, it seems that larger RCTs are needed to be certain that intravenous immunoglobulins lead to significant survival benefits as adjunctive therapy in severe sepsis and septic shock. However, until they are available, it appears that the polyvalent IgGAM preparation shows the most promise and should be considered in such patients on the basis of Grade C recommendations.

References