Single Immunoglobulin Dose Yields Plasma-Neutralizing Activity Against Streptococcal Superantigens

Optimal dosage has been an ongoing issue in intravenous immunoglobulin G (IVIG) treatments for severe bacterial infections. A new study has found that relatively small doses are enough to neutralize some strains of superantigenic activity.

The INSTINCT study was a randomized, placebo-controlled trial of patients with necrotizing soft tissue infections (NSTIs) investigating the effects of polyspecific IVIG. According to the study authors, the results showed no differences in the physical component Short Form 36 (SF-36), a questionnaire meant to reflect 8 domains of health, including physical functioning, physical role, pain, general health, vitality, social function, emotional role, and mental health.

However, they did note a favorable trend in the subgroup of participants with NSTIs of the head, neck, and extremities, which are associated with a higher rate of group A streptococcal (GAS) or staphylococcal infections. This finding aligns with recent meta-analyses of IVIG therapy in clindamycin-treated streptococcal toxic shock syndrome (STSS), in which adjunctive IVIG was associated with a survival benefit. In this setting, investigators found that IVIG neutralized GAS superantigens and minimized inflammation.

The INSTINCT trial used a fixed dose of 25 g per day for 3 days, which is lower than the dosages used in previous studies of IVIG therapy in STSS. A single dose of IVIG was also allowed prior to randomization in the trial, and 40% of patients in the placebo group had received prior IVIG therapy, compared with 16% of patients in the IVIG group.

In a new study, investigators continued this line of research by selecting a subgroup of patients with monomicrobial GAS from the INSTINCT trial and a subgroup of patients from the INFECT trial who had not been treated with IVIG prior to inclusion and who had 2 or more plasma samples available. From these 2 cohorts, they identified matched groups of non-IVIG or IVIG-treated patients, including clindamycin, septic shock, and renal replacement treatment.

In the follow-up to INSTINCT, investigators tested the IVIG preparation at different concentrations for its ability to neutralize superantigenic activity in different GAS NSTI strains. The researchers did observe a dose-dependent neutralization of the bacterial supernatants, although there was variation between different GAS strains. Still, the study authors said all of the supernatants were more than 90% neutralized.

Daily plasma samples collected from the 19 INSTINCT participants were tested using supernatants from 2 selected GAS isolates, and investigators compared plasma collected at days 0 and 3. The GAS supernatants generally saw high proliferation of peripheral blood mononuclear cells in plasma collected from non-IVIG-treated patients, whereas patients treated with IVIG saw a significant decline in proliferation. Notably, administration of 25 g of IVIG resulted in efficient plasma neutralization of the superantigen response to GAS strain 5013, and a less efficient response to strain 2006.

Based on these findings, the authors concluded that, in most cases, 25 g of IVIG was sufficient to achieve plasma neutralization of GAS superantigenic activity, although there were notable variations between strains. For some strains, they said repeated doses were necessary to achieve a significant reduction in superantigenic responses.

REFERENCE

Bergsten H, Madsen M, Bergey F, Hyldegaard O, et al. Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patient with Necrotizing Soft Tissue Infections. Clinical Infectious Diseases; October 2020. https://academic.oup.com/cid/article/71/7/1772/5698680. Accessed November 12, 2020.