Low-dose immunoglobulin G is not associated with mortality in patients with sepsis and septic shock

To decrease the high mortality associated with sepsis [1], various adjunctive therapies have been suggested. The administration of low-dose intravenous immunoglobulin G (IVIgG) (5 g/day for 3 days, total 15 g) is widely used as an adjunctive therapy for patients with sepsis in Japan [2]. This practice was approved for clinical use based on a randomized controlled trial (RCT) by Masaoka et al. in 2000 [3] showing beneficial effects in septic patients. In this study, the administration of IVIgG, even at a low dose, was associated with earlier improvement of clinical signs and symptoms of sepsis. Although this study had a relatively large sample size (n = 682), it was not sufficiently powered for important outcomes including mortality, with a follow-up of only 7 days. Since that time, no high-quality studies have examined the efficacy of low-dose IVIgG in patients with sepsis. To investigate the association between the administration of low-dose IVIgG (5 g/day for 3 days) and clinically important outcomes in patients with sepsis (with or without septic shock), we reviewed a large Japanese database.

This study is a post-hoc analysis of the database of the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study (University Hospital Medical Information Network Individual Clinical Trials Registry (UMIN-CTR000012543, http://www.umin.ac.jp/icdr/index-j.html). This study followed the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of each participating hospital (Additional file 1: Table S1). Because of the anonymous and retrospective nature of this study, the board of each hospital waived the need for informed consent.

The JSEPTIC DIC study was conducted using data from 42 intensive care units (ICUs) in 40 institutions throughout Japan [4]. We reviewed all patients admitted to ICUs between January 2011 and December 2013 for the treatment of sepsis (formerly defined as severe sepsis by the International Sepsis Definitions Conference criteria, 2003 [5]). Patients younger than 16 years old and patients who developed sepsis after their ICU admission were excluded.

The following data were collected: ICU characteristics (number of beds, ICU model, preference for disseminated intravascular coagulation (DIC) therapy), age, gender, weight, admission route to the ICU, Acute Physiology and Chronic Health Evaluation (APACHE) II score, pre-existing organ dysfunction (using chronic health evaluation score in APACHE II), pre-existing hemostatic disorders, Sequential Organ Failure Assessment (SOFA) score (days 1, 3, and 7), systemic inflammatory response syndrome (SIRS) score (days 1, 3, and 7), primary infection site, blood culture results, microorganisms responsible for sepsis, daily results from laboratory tests during the first week after ICU admission, serum lactate levels (days 1, 3, and 7), administration of adjunctive medications (including anti-DIC drugs, other anticoagulants, IVIgG, and low-dose steroids) during the first week after ICU admission, transfusion volume (red blood cell (RBC) concentration, fresh frozen plasma (FFP), platelet concentrate) and bleeding complications during the first week after ICU admission, therapeutic interventions including surgical interventions at the infection site, renal replacement therapy, renal replacement therapy for non-renal indications, polymyxin B direct hemoperfusion, plasma exchange, extracorporeal membrane oxygenation (ECMO), and intra-aortic balloon pump use during the first week after ICU admission, duration of mechanical ventilation, vasoactive drugs and renal replacement therapy use up to 28 days after ICU admission, and ICU mortality and in-hospital mortality.

Figure 1 shows Kaplan-Meier survival curves, and Cox regression analysis revealed no significant difference in the in-hospital survival after ICU admission between the propensity score-matched groups (hazard ratio (HR) 0.941, 95% CI 0.765–1.158, p = 0.566).

Interactions between high APACHE II score (29 and over, highest interquartile range in propensity score-matched groups) and IVIgG administration, and interactions between immunodeficiency and IVIgG use and mortality were also evaluated. There were no interactions between high APACHE II score and IVIgG use on ICU mortality (p value for interaction = 0.095), and in-hospital mortality (p value for interaction = 0.218). There was no interaction between immunodeficiency and IVIgG use on ICU mortality (p value for interaction = 0.247), or in-hospital mortality (p value for interaction = 0.378).

This is the first large cohort study to evaluate the association between low-dose IVIgG and clinically important outcomes in patients with sepsis and septic shock in Japan. Propensity-matched analysis shows that low-dose IVIgG administration (total 15 g: approximate total 0.3 g/kg) is not associated with a decrease in either ICU mortality or in-hospital mortality. Interactions between high APACHE II score and between immunodeficiency and IVIgG use were not detected with mortality.

Recently, Tagami et al. [6] reported similar results from a large nationwide database (n = 8264) showing that the use of low-dose IVIgG does not reduce mortality in patients with septic shock and pneumonia undergoing mechanical ventilation. They also reported a lack of effect of low-dose IVIgG in patients undergoing mechanical ventilation with septic shock who underwent laparotomy for lower gastrointestinal perforations [7]. These studies used the database of the Japanese Diagnosis Procedure Combination which includes administrative claims and discharge abstract data, but does not include severity scores such as the APACHE II or SOFA scores. The database used in the present study includes more clinically relevant indices which potentially reflect outcomes. The large database used by Tagami et al. and the more clinically relevant database used in this study both support the recommendation against the use of IVIgG in the Surviving Sepsis Campaign 2016 [8].

Several reasons can be postulated why the present study failed to show a benefit of low-dose IVIgG administration. First, IVIgG may not reduce mortality, although IVIgG has several theoretical advantages in the treatment of patients with sepsis. The mechanisms of these advantages are multifaceted, including pathogen recognition, clearance, and toxin scavenging. IVIgG preparations may have beneficial effects on the host response to infection [9, 10]. However, the current consensus does not favor the use of IVIgG [8].

There were two RCTs with a relatively large sample size (>500 patients) to evaluate the efficacy of IVIgG in the treatment of patients with sepsis. The SBITS study was conducted in Germany, and showed that the administration of 0.9 g/kg IVIgG (0.6 g/kg day 1; day 2, 0.3 g/kg; total 0.9 g/kg) did not decrease the 28-day mortality in patients with severe sepsis [11]. This study also reported a shortened duration of mechanical ventilation in the IVIgG group. The SBITS study was well designed with a large sample size (n = 653), but failed to show beneficial effects of IVIgG on mortality. Another large RCT (n = 682) was performed in Japan in 2000 by Masaoka et al. [3] and reported that the administration of low-dose IVIgG (5 g/day for 3 days) to patients with sepsis (most patients included were immunocompromised with hematologic diseases) resulted in earlier improvement of clinical parameters and recovery. The study had a large sample size, but many limitations. There was no placebo group, and intention-to-treat analysis was not used. The effects of IVIgG on survival were not examined in that study. A Cochrane database of systematic reviews showed that the administration of IVIgG is associated with a significant reduction in mortality in patients with sepsis compared with placebo or no intervention (relative risk 0.81, 95% CI 0.70–0.93), but sensitivity analysis of trials with a low risk of bias showed no reduction in mortality with IVIgG in adults (relative risk 0.97, 95% CI 0.81–1.15; five trials, n = 945) [12]. These clinical data did not suggest a beneficial effect of IVIgG on mortality in patients with sepsis.

Second, the dose of IVIgG given may be insufficient in patients with sepsis. Turgeon et al. [13] reported in a meta-analysis that regimens using 1 g or more per kilogram, duration of therapy longer than 2 days, and use of IVIgG in more severely ill patients is associated with increased survival [13]. The dose of IVIgG given in the present study is approximately 0.3 g/kg, which is the lowest among the 20 RCTs used in the meta-analysis.

This study has several acknowledged limitations. Data regarding the administration of IVIgG during the first week after ICU admission is limited to a binary condition (yes or no). The exact timing, dose, and duration of administration of IVIgG was not available in the database. The timing of administration in some patients might be better correlated with severity on day 2 or later. To adjust the severity within the first week, we added supplemental analyses and the results were not changed. We could not evaluate the effect of IVIgG administered after the first week. Some institutions may have administered larger or smaller doses of IVIgG than 5 g/day for 3 days. However, the average dose of IVIgG administered in this database may be close to 15 g, since no more than 5 g/day for 3 days is the dose approved (and reimbursed) by the Ministry of Health, Labor and Welfare in Japan. Second, the retrospective nature of this study may introduce residual confounding factors not accounted for by the propensity matching analysis. Although this database has a large number of clinically relevant factors potentially affecting the outcomes of patients with sepsis, residual confounding factors might bias the results. Third, the effects of other therapeutic interventions on mortality are unclear. In fact, more adjunctive therapeutic interventions were used in patients who received IVIgG (Table 2). In the propensity score analysis, we did not include those interventions because whether other interventions were administered before or after the administration of IVIgG is unknown. To compensate for this limitation, we added multivariable logistic regression analysis including adjunctive therapeutic interventions as independent variables, which resulted in negative results (Table 4). Although the possibility of reverse causality cannot be excluded, the effect of adjunctive interventions appears to be minimal. Fourth, interactions between high APACHE II score, immunodeficiency, and the effects of IVIgG on mortality cannot be totally excluded. In this context, we added an analysis of those interactions, with negative results.

In this large cohort of patients with sepsis (with or without septic shock), the administration of low-dose IVIgG (approximate total 0.3 g/kg) as adjunctive therapy was not independently associated with ICU or in-hospital mortality. Based on the results of this study and previous ones, the clinical indications for the use of low-dose IVIgG in patients with sepsis cannot be recommended at this time.