In turn, it is unknown whether the main goal of IVIG in sepsis has to be to refill low levels of endogenous Igs or alternatively whether IVIG could exert a beneficial effect independently of these levels

In turn, it is unknown whether the main goal of IVIG in sepsis has to be to refill low levels of endogenous Igs or alternatively whether IVIG could exert a beneficial effect independently of these levels. of sepsis is not considered. In conclusion, addressing these factors could help to individualise treatment with IVIG for sepsis, which could enhance the opportunities of this drug to show benefits in terms of survival in this severe condition. == Introduction == Mortality associated with severe sepsis and septic shock ranges from 20% to 30% [1]. Many different approaches tested for treating this disease failed to improve survival [1]. The presence of low levels of immunoglobulins (Igs) in serum is a frequent finding in severe sepsis and septic shock, ranging from 25% to 61% of the patients in the case of IgG and 19% to 33% for IgM [2-4]. Nonetheless, results from BM28 clinical trials evaluating exogenous Igs for treatment of this disease are controversial [5,6]. A meta-analysis published in 2013 concluded that there was a protective effect of polyclonal intravenous immunoglobulins (IVIGs) against mortality among adults with sepsis, which was not seen in trials with low risk of bias [5]. In contrast, Kreymann and colleagues [7] reported that the mortality-reducing effect of IVIG was also seen in trials with the highest methodological quality. In our view, clinical trials assessing IVIG for the treatment of sepsis do not appropriately address a number of important factors that could greatly affect the final result TH 237A (Figure1). == Figure 1. == Potential confounding factors not appropriately considered in the design or analysis of the clinical trials evaluating IVIG for the treatment of sepsis.Main factors are in bold. Other factors related to them are in standard type. IVIG, intravenous immunoglobulin; NK, natural killer. == Factors related to the patient == == The TH 237A influence of endogenous levels of immunoglobulins == The influence of endogenous levels of Igs on prognosis remains unclear. Whereas the SBITS (Score-Based Immunoglobulin Therapy of Sepsis) study [8] did not show any negative influence of a low IgG level on 28-day mortality [2], Taccone and colleagues [9] found that patients with community-acquired septic shock and hypo-IgG had higher mortality. Similarly, Prcha and colleagues [10] reported the presence of IgG hypogammaglobulinemia in patients with severe sepsis as an independent factor of mortality. In turn, we have recently demonstrated the existence of a statistical association between low endogenous levels of Igs and poor outcome in severe sepsis and septic shock [4]. Differences among studies could be explained in part by the different composition of the patient cohorts. In the SBITS study, percentile 25 for IgG distribution was 610 mg/dL, whereas TH 237A in our study it was 374 mg/dL, probably because of a higher frequency of patients with prior immunosuppressive conditions in our cohort (Werdan K, personal communication). Although it remains to be elucidated whether low levels of endogenous Igs are a marker of disease severity rather than a cause of mortality, our opinion is that it is a potential confounding factor that has to be taken into account in the IVIG trials. In TH 237A addition, the distinct Ig subclasses and isotypes (IgG1, IgM, and IgA) have a different influence on prognosis in sepsis [4]. Combined deficits of these isotypes are associated with higher risk of mortality [4]. Assessing levels of basal Ig isotypes could help us to understand the potential effect of IVIG preparations containing only IgG and of those enriched in IgM or IgA or both. It could be also important to evaluate the presence/absence of pre-existing specific antibodies against the microbe causing the septic insult [11]. == Accuracy of antibiotic prescription == Early administration of an appropriate antibiotic treatment, along with life support measures, is.