The clinical efficacy of intravenous IgM-enriched immunoglobulin (pentaglobin) in sepsis or septic shock: a meta-analysis with trial sequential analysis

Sepsis and the related syndrome of multiple organ failure remain worldwide problems, with high mortality and morbidity rates [1]. The standard surviving sepsis campaign (SSC) approach, including early eradication of septic foci, administration of anti-infective agents, and maintenance of hemodynamic stability through fluid administration and vasopressors, remains the cornerstone of treatment for sepsis and, in particular, septic shock [2]. However, sepsis is a complex syndrome in that different types of microorganisms (e.g., bacteria, fungi) that vary in virulence (e.g., endotoxin production) and resistance to antibiotics may infect one or more body sites in patients with varying comorbidities. These patients, in turn, may vary widely in their responses to infection (e.g., hyper-inflammation, immune paralysis) and treatments.

The recent Third International Consensus (Sepsis-3) defined sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection [3]. The host response to an infection consists of an exert inflammatory storm and concurrent immunosuppression, characterized by overwhelming promotive tissue damage, down-regulation of activating cell-surface molecules, T cell exhaustion and increased apoptosis of immune cells [4]. These immunodisturbances cause a profound dysfunction in innate/adaptive immune responses [5] and seem to play a vital role in patient outcomes, particularly in older patients and those with preexisting immune dysfunction. Since only anti-inflammation therapies failed to save sepsis lives, an increased use of strategies designed to balance the immune system seems more reasonable.

Polyclonal intravenous immunoglobulins (IVIG), which have pleiotropic effects on inflammatory and immune mechanisms, have been proposed as adjuvant therapy to modulate both pro- and anti-inflammatory processes [6]. In 2016, SSC guidelines suggested against IVIG use in sepsis, which was based on weak evidence of efficacy from previous studies [7]. However, results from recent trials and systematic meta-analyses indicate that intravenous IgM-enriched immunoglobulins (IVIgGM) may be effective in septic patients [8–10]. The present study therefore conducted a meta-analysis with trial sequential analysis (TSA) to evaluate the clinical effectiveness of IVIgGM in septic patients, with a view to helping guide clinicians in making treatment decisions.

This meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews of Interventions and presented based on Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (PRISMA) [11]. The review protocol was registered at the PROSPERO registry of systematic reviews in February 2018 (Registry Number: CRD42018084120).

The present meta-analysis, which included 15 RCTs, involving 712 patients, and four cohort studies, involving 818 patients, assessed the use of IVIgGM preparations in adults with sepsis. IVIgGM administration significantly reduced mortality rates, with an RR of 0.60 (95% CI 0.52–0.69). Subgroup analysis showed that these results were generally consistent, regardless of duration of treatment, daily dose, total dose, variety of disease severity scores, follow-up duration, study design and year of publication. However, use of IVIgGM shortens mechanical ventilation days but not ICU LOS.

This systematic review and meta-analysis have a number of methodological strengths. The research question was focused to include a specific clinically relevant population and a specific intervention. First, the protocol of this study was registered on PROSPERO. A registered protocol may increase the transparency and quality of meta-analyses. Second, the present study took account of disease severity grades for subgroup analysis and included length of mechanical ventilation and ICU LOS as an outcome. Third, TSA was used to assess the risk of random errors (spurious findings), with results supporting the contention that a 20% relative increase or decrease in all-cause mortality can be confidently excluded. Finally, we provided the evidence body level using the GRADE approach, which classifies the conclusions of studies as having high, moderate, low, or very low quality of evidence.

Several recent systematic reviews and/or meta-analyses have evaluated the effects of IVIG on outcomes in patients with sepsis [10, 32–37], but these analyses have yielded conflicting results. Several previous meta-analyses found that treatment with IVIgGM more consistently reduced mortality than treatment with standard polyclonal IgG [10]. Because of the limited number of articles, meta-analyses focused on a single type of IVIG (IVIgGM) had been not conducted. A recent review [37] summarizing current data on the established clinical uses of IVIgGM in patients with sepsis did not statistically pool available data to analyze whether IVIgGM treatment was associated with patient mortality.

The results of this systematic review and meta-analysis indicate that, although IVIgGM did not shorten ICU LOS, it significantly reduced patient mortality rates and shorten ventilation days. In addition, our TSA of the primary outcome provided conclusive evidence that further trials were not required. Because many of these studies included mixed patient cohorts and patients at high risk, GRADE deemed the certainty of the body of evidence as low for both benefits and IVIgGM. Based on these findings, our center will be cautious in treating sepsis patients with IVIgGM as adjuvant therapy.

The choice of the control intervention had a potential impact on the overall treatment effect. In contrast to one meta-analysis [36] and in accordance with another [34], a subgroup analysis based on type of control arm found that IVIgGM did not significantly reduce mortality rates when compared with HAS, but did significantly reduce mortality rates when compared with no treatment. Moreover, the effect of IVIgGM tended to be smaller and less consistent when compared with HAS than when compared with no treatment, suggesting that HAS may have had a biological effect. HAS has oncotic, carrier, antioxidant and anti-inflammatory properties and has been associated with a significant reduction in mortality rates in patients with septic shock [38]. Alternatively, the use of HAS may be an indicator of more appropriate blinding, thus being associated with an overall higher study quality and lower risk of bias.

A meta-analysis [34] has shown that different dosing regimens and durations of treatment appeared to affect the mortality rates. Our meta-regression analysis revealed that lower daily and total doses of IVIgGM tended to be associated with greater and more consistent reductions in mortality rate, although these differences were not statistically significant. As previously described [35], it is difficult to identify a clinical rationale for these associations. Thus, these results should be interpreted with caution, especially because of the high variability in study characteristics and patients differing in the severity of sepsis.

Timing of IVIg administration is controversial. A recent study investigated the protective association between endogenous IVIg level and sepsis mortality [39]. They found there is a risky level of immunoglobulins attribute to mortality in moderate (SOFA < 8) but not severe sepsis(SOFA ≥ 8), which drove researchers concerning much about IVIg substitution is worthy in different populations. Our subgroup analysis reveals that IVIgGM is beneficial for sepsis regardless of the disease severity (higher SOFA score, shock, or not). Although we deem believe more evidence should be added in, the present results conveyed a certain of confidence for clinicians to treat sepsis patients.

For secondary outcomes, as the heterogeneity of available data, this meta-analysis did not find a significant reduction of ICU LOS after IVIgGM administration. ICU stay is a heterogeneous variable per se. Numerous social factors complicated with medical resources control influent the length of ICU stay [40]. More reliable parameters like ventilation duration or free of ventilation days (VFDs) should be considered in clinical trials. With the available data extracted from literatures, ventilations days are significantly reduced in IVIgGM group patients, however, IVIgGM use did not increase VFDs (Additional file 6: Figure S3). Further research should evaluate this respiratory benefit.

This systematic review had several limitations. First, study characteristics varied widely, including in duration and dose of IVIgGM and control interventions. However, our meta-analysis verified that IVIgGM treatment of adult patients with sepsis has a consistent rationale and was associated with a reduction in the relative risk of mortality, with low heterogeneity (I² = 0). Second, the number of observational studies was relatively small, and there were few latest RCTs, indicating a need for large, multi-centered RCTs to support the present results. This study included data from the last 30 years. There have been many improvements in intensive care over the last half-century, including wider ranges of patients, as determined by both age and comorbidities, now treated within a critical care environment, suggesting a possibility of bias. Although the inclusion criteria for studies may not have changed, the populations in these studies have altered. Many patients not considered appropriate for critical care in the 1980s and 1990s now constitute the majority of patients in many critical care units in developed countries. Our exploration of subgroup hypotheses, including the era in which the studies were conducted, and the failure to identify any effect modification. Furthermore, the latest CIGMA study (Welte et al. 2018) [14] is strongly consistent with the final results, which markedly diminishes this concern. Fourth, all included studies enrolled patients based on previous diagnostic criteria for sepsis, as patients diagnosed by Sepsis-3 is more severe than Sepsis-2. Although the subgroup analysis is consistent with overall effect (sepsis vs severe sepsis or septic shock), we suspect that using the new Sepsis-3 criteria could change the efficacy of IVIgGM. Fifth, the reduction in mortality rate associated with IVIgGM was greater in studies performed among populations with higher baseline risk. Many patient-related factors may influence the clinical effect of IVIgGM therapy, such as an underlying state of immunosuppression, basal levels of endogenous Ig, time from sepsis diagnosis and IVIgGM administration or concurrent treatments [41–43]. Finally, it was not possible to analyze IVIgGM-related adverse effects, as these were reported by few of the included studies included. The use of IVIgGM, especially sucrose-stabilized IVIG preparations, has been associated with the onset of acute renal failure due to osmotic nephrosis in the proximal tubules [44, 45]. A specific review is required to clarify this point.

The administration of IVIgGM to adult septic patients may have a rationale and may be associated with reduced mortality rates. Because current evidence is insufficient and too low quality to support the widespread use of IVIgGM as adjunctive therapy for sepsis, large-scale high-quality RCTs, using recently published Sepsis 3 definitions, are warranted to assess the benefits and potential uses of IVIgGM in the treatment of sepsis syndrome.