Table 6.
Studies of Intravenous Immunoglobulin in Necrotizing Soft Tissue Infections and Sepsis
| Author | Study design | Population | Sample size | Control | Intervention | Adjustment | Death or survival IVIG vs. none |
|---|---|---|---|---|---|---|---|
| STREPTOCOCCAL TOXIC SHOCK SYNDROME | |||||||
| Randomized Controlled Trials | |||||||
| Darenberg et al (2003) | Multicenter, double blind, RCT, placebo controlled | STSS | 21 | Placebo 1% albumin, n = 21 | IVIG endobulin 1g/kg day 1 and 0.5 g/kg for days 2–3, N = 10 | RCT | 28-day survival: 9/10 (90%) vs. 7/11(65%), p = 0.3; similar results when restricted to culture proven GAS |
| Observational Studies | |||||||
| Kaul et al (1999) | Prospective, controlled | STSS | 53 | n = 22 | IVIG initially 0.4 g/kg/d for 5 days, then changed to 2 g/kg once and repeated in 28 h if still unstable, N = 21 | Yes, multivariate | 30-day survival: 14/21 (67%) vs. 11/32 (34%), p = 0.02; OR 7.7 (1.5–14.3); aOR 8.1 (6–45); propensity aOR 10 (1.4–70) |
| Mehta et al (2006) | Population-based surveillance | GAS | 62 | n = 27 | Polyclonal IVIG, N = 35 | No | No difference in use of IVIG between survivors and non-survivors: 57% vs. 56%, p = 1.0 |
| Linner et al (2014) | Swedish nationwide surveillance | STSS | 67 | n = 44 | IVIG 0.5 g/kg for 1–6 d, n = 23 | Yes, multi-variable | 28-day survival: 87% vs. 50%, p < 0.01; aOR for survival 5.6 (1.2–26.9), p = 0.03; for patients with NF: 6.0 (0.4–85.2), p = NS, but n = 19 |
| SEPSIS | |||||||
| Meta-analyses/Systematic Reviews | |||||||
| Alejandria et al (2013) | Systematic review/meta-analysis | Sepsis/severe sepsis/ septic shock | 43 trials | Various | All | In-hospital mortality: 0.81 (0.70–0.93); IgM enriched: 0.66 (0.51–0.85); sensitivity analysis of low bias studies: IVIG+IgM studies 0.97 (0.81–1.15) | |
| Laupland et al (2007) | Systematic review/meta-analysis | Severe sepsis/septic shock | 14 trials | Various | All | In-hospital mortality: 0.66 (0.53–0.83); low bias studies: 0.96 (0.71–1.3) | |
| Kreymann et al (2007) | Systematic review/meta-analysis | Severe sepsis/septic shock | 27 trials, n = 15 on adults | Various | All | In-hospital mortality: 0.79 (0.69–0.90) | |
| Tugeon et al (2007) | Systematic review/meta-analysis | Sepsis/severe sepsis/septic shock | 20 trials | Various | All | In-hospital mortality: 0.74 (0.62–0.89); low bias studies: 0.56 (0.31–1.01) | |
| Neilson et al (2005) | Systematic review/meta-analysis | Severe sepsis/septic shock | 9 trials | Various | Pentaglobulin | OR 0.57 (0.31–0.74) | |
| Pildal et al (2004) | Systematic review/meta-analysis | Sepsis | 20 trials, neonates and adults | Various | Polyclonal IVIG | 0.77 (0.68–0.88); low bias studies: 1.02 (0.84–1.24) | |
| Randomized Controlled Trials | |||||||
| Hamano et al (2013) | Single center RCT | Severe sepsis/septic shock | 79 | IVIG 5 g/d for 3 d, n = 42 | IVIG 15 g/d for 1 d within 24 h, n = 37 | N/A | 28-day survival: NS |
| Werdan et al (2007) | Multicenter, double blind, RCT, placebo controlled | Severe sepsis | 653 | Placebo 5% albumin 12 mg/kg day 0 and 6 mg/kg day 1, n = 332 | IVIG 0.6g/kg day 0 and then 0.3 g/kg day 1, n = 321 | N/A | 28-day survival: 60.7% vs. 62.7%, p = 0.67 |
| Rodriguez et al (2005) | Single center RCT, double blind, placebo controlled | Severe sepsis or septic shock undergoing surgery for abdominal sepsis | 56 | Placebo was 5% albumin, n = 27 | N = 29, IVIG Pentaglobin 7 mL/kg/d for 5 d, n = 29 | N/A | In-hospital survival: 20/28(72.5%) vs. 15/28(52.9%), p = 0.06; OR 2.43 (0.80–7.39), p = 0.06 |
| Tugrul et al (2002) | Single center RCT | Severe sepsis, majority abdominal sepsis | 42 | No placebo, n = 21 | IVIG IgM and IgA-enriched Pentaglobin, 5 mL/kg per day for 3 d, n = 21 | N/A | 28-day survival: 16/21(76.2%) vs. 14/21(66.7%), p = 0.70 |
| Tagami et al (2015) | Japanese inpatient database | Severe sepsis | 8,264 | Propensity matched controls, n = 1045 | IVIG within 48 h 5 g/day for 3 days, n = 1,045 | Yes, multivariable | 28-day mortality: 383/1,045(36.7%) vs. 376/1,045(36.0%); 1.03 (0.86–1.23) |
| Ishida et al (2015) | Retrospective, single center | Severe sepsis | 41 | n = 22 | IVIG 5 g/d for 3 d, n = 19 | None | 28-day survival: 94.7% vs. 81.8%, p = NS |
| Tagami et al (2015) | Japanese inpatient database | Septic shock after emergency laparotomy | 4,919 | Propensity matched controls, n = 1,081 | IVIG within 48 h 5 g/d for 3 d, n = 1081 | Yes, multivariable | 28-day mortality: 221/1,081(20.4%) vs. 209/1,081(19.3%), 1.1 (0.87–1.30), p = NS |
| Cavazzuti et al (2014) | Retrospective, single center | Septic shock | 168 | Controls, n = 76; propensity matched, n = 59 | IgM within 24 h of shock, 20 mg/kg/h for 3 d, n = 92 (n = 59 propensity matched) | Yes, multivariable | 30-day mortality: aOR 0.17 (0.06–0.49), propensity aOR 0.35 (0.14–0.85); 15/59 (25.4%) vs. 27/59 (45.8%), p = 0.021 |
| Yavuz et al (2012) | Retrospective, single center | Severe sepsis | 188 | Controls, n = 62 | N = 56 IgM enriched IVIG, Pentaglobulin 5 g/kg/d for 3 d | No | 28-day mortality: 14/56 (25%) vs. 43/62 (69.4%), p < 0.0001 |
| Berlot et al (2012) | Retrospective, single center | Severe sepsis/septic shock | 129 | Controls, none | N = 129 IgM enriched IVIG, 250 mg/kg day 1, and for 3 d, N = 129 | ICU survivors received IVIG earlier: 23 vs. 63 h, p < 0.05, aOR for ICU death with each 1 h delay: 1.07 (1.01–1.10), p < 0.001 | |
| Buda et al (2005) | Retrospective, single center | Sepsis/severe sepsis/septic shock, post- cardiac surgery | 66 | Controls, N = 44 | IgM enriched IVIG, 5 mL/kg/d for 3 d, N = 22 | No | Death: 5/22 (22.7%) vs. 16/44 (36.3%), p = NS; severe sepsis: 1/15(6.6%) vs. 12/32(37.5%), p = 0.04; aOR 0.11 (0.01–1.01) |
IVIG = intravenous immunoglobulin; RCT = randomized controlled trial; STSS = streptococcal toxic shock syndrome; GAS = group A Streptococcus; OR = odds ratio; aOR = adjusted odds ratio; IgM = immunoglobulin M; IgA = immunoglobulin A.