Date Published: February 21, 2018
Publisher: Public Library of Science
Author(s): Sara Cajander, Gunlög Rasmussen, Elisabet Tina, Anders Magnuson, Bo Söderquist, Jan Källman, Kristoffer Strålin, Marco Magalhaes.
In the pathogenesis of sepsis, activation of both pro- and anti-inflammatory responses are key components, but knowledge is lacking on the association between bacterial etiology and development of dysregulated responses with sustained immunosuppression. The aim of this study was to evaluate how the immunosupression marker HLA-DR on monocytes (mHLA-DR) is associated with bacterial etiology and markers of inflammation during the clinical trajectory of bloodstream infection (BSI).
Ninety-one adults, predominantly non-ICU patients, with BSI caused by Streptococcus pneumoniae (n = 27), Staphylococcus aureus (n = 22), Escherichia coli/Klebsiella pneumoniae (n = 23), and other species (n = 19) were prospectively included, and sampled on admission (day 0) and on days 1–2, 3, 7±1, 14±2, and 28±4.
The dynamics of mHLA-DR, measured by flow cytometry, differed significantly between etiology groups (p<0.001). Patients with S. pneumoniae and S. aureus BSI demonstrated low initial mHLA-DR, with the S. aureus group showing delayed recovery over time. Eleven patients (55% S. aureus) had negative outcome (secondary bacteremia or death) and they demonstrated sustained C-reactive protein elevation, neutrophilia, lymphocytopenia, and loss of mHLA-DR. Dynamics of mHLA-DR varied according to the bacterial etiology of infection, with delayed recovery in patients with S. aureus BSI. Patients with negative outcome showed sustained CRP elevation, neutrophilia, lymphocytopenia, and low levels of mHLA-DR, supporting the theory of a dysregulated host response with persistent inflammation and immunosuppression in late stages of deleterious sepsis.
During the past decade, it has been recognized that the role of the immune system in sepsis is perhaps more complex than previously imagined . The previous dogma of sepsis pathobiology based on excessive inflammation is insufficient [2, 3]. This is illustrated by repeated failures of interventional trials aiming to alter the trajectory of the disease by blocking pro-inflammatory pathways . In contrast to previous dogma, more recent research has shown that pro- and antiinflammation appear simultaneously in sepsis  and that a dysregulated response with sustained inflammation and immunosuppression is linked to development of critical illness with deleterious secondary infections [5, 6]. In an autopsy study, Torgesen et al. found that more than 70% of patients who died from sepsis had unresolved infectious foci despite antibiotic treatment . Two other post-mortem studies of patients who died following sepsis demonstrated findings consistent with profound immunosuppression, including extensive lymphocyte apoptosis  and diminished expression of human leukocyte antigen-DR (HLA-DR) in lung and spleen tissue . According to this and to advances in basic research of sepsis pathobiology, the definition of sepsis was updated in 2016 . The underlying pathogenesis is today described as a dysregulated host response to infection . However, the mechanisms leading to dysregulated immune responses with sustained immunosuppression are still not clearly understood. In particular, differences related to the etiology of infection have not been addressed in this context previously. This is important to consider, as different etiological bacterial pathogens have different virulence properties and are thus prone to cause different types of infection, including chronic infections for some pathogens .
In this study of patients with community-onset BSI, the dynamics of mHLA-DR differed depending on the bacterial etiology and were inversely associated with dynamics of CRP and neutrophil counts. Patients with negative outcome showed sustained CRP elevation, neutrophilia, and lymphocytopenia, and low levels of mHLA-DR. During the early phase of infection, both S. pneumoniae and S. aureus BSI were associated with low mHLA-DR levels, in contrast to E. coli/K. pneumoniae BSI. These etiology-related expressions of mHLA-DR remained after multivariate adjustments for baseline factors and the presence/absence of sepsis.