Can Concurrent Abnormalities in Free Light Chains and Immunoglobulin Concentrations Identify a Target Population for Immunoglobulin Trials in Sepsis?*

Abstract

To our knowledge, abnormalities and associations of free light chain in critically ill adults with sepsis have not been previously reported. The additional prognostic value of free light chain λ and the significance of allelic inclusion in B cells in sepsis require further investigation.

Immunoglobulins and sepsis

“…Low immunoglobulin concentrations [2] as well as abnormally high FLC levels [3] are seen in most adult sepsis patients. Although, low IgG is the commonest quantitative immunoglobulin abnormality in sepsis, a number of reasons explain why low IgG alone does not increase the risk of death in sepsis patients [2].…”

“…Although, low IgG is the commonest quantitative immunoglobulin abnormality in sepsis, a number of reasons explain why low IgG alone does not increase the risk of death in sepsis patients [2]. First, the nadir of immunoglobulin drop is often seen on day 3 following sepsis diagnosis [2,3]. Second, low levels of multiple endogenous immunoglobulins (IgG1, IgM and IgA) may be required to increase the risk of death [2][3][4].…”

“…First, the nadir of immunoglobulin drop is often seen on day 3 following sepsis diagnosis [2,3]. Second, low levels of multiple endogenous immunoglobulins (IgG1, IgM and IgA) may be required to increase the risk of death [2][3][4]. Third, the association between low immunoglobulins and mortality is observed in sepsis patients with less severe organ dysfunction [5].…”

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.…”

Intravenous immunoglobulin in sepsis: can we find the right dose?

“…Recent discoveries from the group of Shankar-hari et al help us to understand the biological processes of immunoglobulin deficiency and also point towards better diagnostic tools for stratification of critically ill patients with sepsis 9 . They demonstrated, that increased light chain levels with low immunoglobulin levels suggest impaired immunoglobulin assembly 10 .…”