A Dysregulated Balance of Proinflammatory and Anti-Inflammatory Host Cytokine Response Early During Therapy Predicts Persistence and Mortality in Staphylococcus aureus Bacteremia

Abstract

Objectives: The contribution of individual immune response to Staphylococcus aureus bacteremia on outcome has not been well studied. The objective was to relate the host cytokine response to outcome of Staphylococcus aureus bacteremia.

Design: Prospective observational study.

Setting: Three U.S. university-affiliated medical centers.

Patients: Adult patients infected with Staphylococcus aureus bacteremia hospitalized between July 2012 and August 2014.

Interventions: Blood specimens were obtained at Staphylococcus aureus bacteremia onset and 72 hours after therapy initiation. Levels of tissue necrosis factor, interleukin-6, interleukin-8, interleukin-17A, and interleukin-10 were measured by enzyme-linked immunosorbent assay at each time point and compared between those with persistent bacteremia (≥ 4 d) and resolving bacteremia. Primary outcome was persistent bacteremia after 4 days of effective therapy. Secondary outcomes were 30-day mortality and 30-day recurrence.

Measurements and main results: A total of 196 patients were included (mean age, 59 yr); of them, 33% had methicillin-resistant Staphylococcus aureus bacteremia. Forty-seven percent of the methicillin-resistant Staphylococcus aureus strains were staphylococcal cassette chromosome mec IV. Persistent bacteremia occurred in 24% of patients (47/196); they were more likely to die than resolving bacteremia group (28% vs 5%; p < 0.001). Compared with resolving bacteremia group, persistent bacteremia patients had higher initial median levels of tissue necrosis factor (44.73 vs 21.68 pg/mL; p < 0.001), interleukin-8 (124.76 vs 47.48 pg/mL; p = 0.028), and interleukin-10 (104.31 vs 29.72 pg/mL; p < 0.001). Despite 72 hours of treatment, levels remained higher for the persistent bacteremia group than for the resolving bacteremia group (tissue necrosis factor: 26.95 vs 18.38 pg/mL, p = 0.02; interleukin-8: 70.75 vs 27.86 pg/mL, p = 0.002; interleukin-6: 67.50 vs 21.81 pg/mL, p = 0.005; and interleukin-10: 30.98 vs 12.60 pg/mL, p < 0.001). Interleukin-17A levels were similar between groups at both time points. After controlling for confounding variables by multivariate analysis, interleukin-10/tissue necrosis factor ratio at 72 hours most significantly predicted persistence (odds ratio, 2.98; 95% CI, 1.39-6.39; p = 0.005) and mortality (odds ratio, 9.87; 95% CI, 2.64-36.91; p < 0.001) at values more than 1.00 and more than 2.56, respectively.

Conclusions: Sustained elevation of interleukin-10/tissue necrosis factor ratio at 72 hours suggests a dysregulated immune response and may be used to guide management to improve outcomes.

Figure 1:. Cytokine Profile at Initial Presentation of Bacteremia and 72 Hours After Receiving Effective Treatment Grouped by Day 4 Outcome

Abbreviations: IL, interleukin; TNF, tumor necrosis factor; Median reported, error bars represent IQR, Wilcoxon rank sum test. Dark grey bars represent resolving SAB group (TNF initial n=138; TNF 72 hour n=146; IL-6 initial n=94; IL-6 72 hour n=100; IL-8 initial n=94; IL-8 72 hour n=104; IL-17A initial n=121; IL-17A 72 hour n=118; IL-10 initial n=131; IL-10 72 hour n=132). White bars represent persistent SAB group (TNF initial n=46; TNF 72 hour n=43; IL-6 initial n=25; IL-6 72 hour n=26; IL-8 initial n=26; IL-8 72 hour n=27; IL-17A initial n= 44; IL-17A 72 hour n= 41; IL-10 initial n= 45; IL-10 72 hour n= 42).

Figure 2:

ROC analysis of IL-10/TNF Ratio at 72 hours of Therapy in Relation to Day 4 Outcomes