Endogenous IgG hypogammaglobulinaemia in critically ill adults with sepsis: systematic review and meta-analysis

Abstract

This systematic review identifies studies of limited quality reporting heterogeneous sepsis cohorts with varying lower limits of normal for IgG. Although our data suggest that a subnormal IgG measurement on the day of sepsis diagnosis does not identify a subgroup of patients with a higher risk of death, further studies are needed to confirm or refute this finding, and whether optimal cut-offs and time windows can be defined for IgG measurement. This would determine whether patients receiving intravenous immunoglobulin therapy for sepsis could be stratified using IgG levels.

The protective association of endogenous immunoglobulins against sepsis mortality is restricted to patients with moderate organ failure

“…Nonetheless, the impact of endogenous immunoglobulins levels on the risk of mortality in sepsis remains a controversial issue. A recent meta-analysis leaded by Shankar-Hari M found that the prevalence of IgG hypogammaglobulinemia on the day of sepsis diagnosis is as high as 70%, but this finding did not identify a subgroup of patients with a higher risk of death [2]. Recently, results from the SBITs (Score-based immunoglobulin G therapy of patients with sepsis) study showed that initial low IgG levels did not discriminate between survival and non-survival in patients with severe sepsis and septic shock [3].…”

“…There are a number of factors that in our opinion have not been appropriately addressed in the studies evaluating the predictive ability of immunoglobulins: (1) we have demonstrated in a recent article that disease severity strongly influences biomarker performance in sepsis [6]; (2) the influence of previous immunosuppression has not been evaluated [5]; (3) the impact of immunoglobulins on hospital mortality has not been sufficiently studied, with the majority of works being focused on the acute period of the disease [2]; (4) finally, the ability of endogenous immunoglobulin levels to predict mortality in patients fulfilling the SEPSIS-3 criteria [7, 8] has not been reported to the present moment.…”

Estimating attributable fraction of mortality from sepsis to inform clinical trials

“…For example, intravenous immunoglobulin (IVIg) trials test effects of immunomodulation and normalisation of low immunoglobulin levels in sepsis, with no consistent benefits [31]. However, enriching on low immunoglobulins alone may not overcome this [32], but enriching a sepsis population with combination of low immunoglobulin levels alongside raised free light chains implying impaired immunoglobulin production, might [33]. Prognostic enrichment, which uses the risk of the study outcome as predicted by baseline covariates, relies on the observation that treatment effects usually exert a fixed relative risk of benefit regardless of the individual patient's risk of the outcome.…”

Immunotherapy of Sepsis: Blind Alley or Call for Personalized Assessment?

“…There is no doubt that sepsis leads to a significant dysfunction of the immune system; however, the evaluation of immune dysfunction is not a common clinical practice. There are few clinical sites where immunoglobulin concentrations are measured despite the fact that significant hypogammaglobulinemia could be a risk factor for increased mortality in critically ill patients (Shankar-Hari et al 2015). Increased mortality was observed in immunoparalysis condition which can be recognized using relatively simple methods.…”