Abstract
BackgroundDecreased monocytic (m)HLA-DR expression is the most studied biomarker of sepsis-induced immunosuppression. To date, little is known about the relationship between sepsis characteristics, such as the site of infection, causative pathogen, or severity of disease, and mHLA-DR expression kinetics.MethodsWe evaluated mHLA-DR expression kinetics in 241 septic shock patients with different primary sites of infection and pathogens. Furthermore, we used unsupervised clustering analysis to identify mHLA-DR trajectories and evaluated their association with outcome parameters.ResultsNo differences in mHLA-DR expression kinetics were found between groups of patients with different sites of infection (abdominal vs. respiratory, p = 0.13; abdominal vs. urinary tract, p = 0.53) and between pathogen categories (Gram-positive vs. Gram-negative, p = 0.54; Gram-positive vs. negative cultures, p = 0.84). The mHLA-DR expression kinetics differed between survivors and non-survivors (p < 0.001), with an increase over time in survivors only. Furthermore, we identified three mHLA-DR trajectories (‘early improvers’, ‘delayed or non-improvers’ and ‘decliners’). The probability for adverse outcome (secondary infection or death) was higher in the delayed or non-improvers and decliners vs. the early improvers (delayed or non-improvers log-rank p = 0.03, adjusted hazard ratio 2.0 [95% CI 1.0–4.0], p = 0.057 and decliners log-rank p = 0.01, adjusted hazard ratio 2.8 [95% CI 1.1–7.1], p = 0.03).ConclusionSites of primary infection or causative pathogens are not associated with mHLA-DR expression kinetics in septic shock patients. However, patients showing delayed or no improvement in or a declining mHLA-DR expression have a higher risk for adverse outcome compared with patients exhibiting a swift increase in mHLA-DR expression. Our study signifies that changes in mHLA-DR expression over time, and not absolute values or static measurements, are of clinical importance in septic shock patients.
Highlights
Decreased monocytic (m)HLA-DR expression is the most studied biomarker of sepsis-induced immunosuppression
Patient characteristics We included 241 septic shock patients of which the characteristics are listed in Table 1. mHLA-DR was determined in 203 patients on days 1–2, 206 patients on days 3–4 (4838 AB/cell [2972–7715]), and 133 patients on days 6–8 (6507 AB/cell [4104–9353]), yielding a significantly increased expression over time (p = 0.02)
MHLA-DR expression within the group of patients with an abdominal infection increased over time, whereas it remained unchanged within the respiratory focus group (Fig. 1a and Supplementary Fig. 2A)
Summary
Decreased monocytic (m)HLA-DR expression is the most studied biomarker of sepsis-induced immunosuppression. Little is known about the relationship between sepsis characteristics, such as the site of infection, causative pathogen, or severity of disease, and mHLA-DR expression kinetics. Immunological heterogeneity is a well-known phenomenon in sepsis patients, as they may present with both hyperinflammatory and immunosuppressive phenotypes. Decreased monocytic (m)HLA-DR expression is the most studied biomarker of sepsis-induced immune suppression [3,4,5]. We set out to evaluate whether the kinetics of mHLA-DR expression, measured using a standardized assay, vary between patients with different primary sites of infection and different pathogens in a large cohort of septic shock patients. Using unsupervised clustering analysis, we aimed to identify specific mHLADR trajectories and relate these to outcome parameters such as the occurrence of secondary infections and mortality
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