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Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia.

ABSTRACT: BACKGROUND:Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes. METHODS:Patients from a prospective SAB cohort at two tertiary-care medical centers were enrolled. Blood was sampled at several timepoints (?5 d, 6-9 d, 10-13 d, 14-19 d, and???20 d) after SAB onset. TLR2 mRNA levels were determined via real-time PCR and serum tumor necrosis factor [TNF]-?, interleukin [IL]-6, and IL-10 levels were analyzed with multiplex-high-sensitivity electrochemiluminescent ELISA. RESULTS:TLR2 levels varied among 59 SAB patients. On days 2-5, TLR2 levels were significantly higher in SAB survivors than in healthy controls (p?=?0.040) and slightly but not significantly higher than non-survivors (p?=?0.120), and SAB patients dying within 7 d had lower TLR2 levels than survivors (P?=?0.077) although statistically insignificant. IL-6 and IL-10 levels were significantly higher in non-survivors than in survivors on days 2-5 post-bacteremia (P?=?0.010 and P?=?0.021, respectively), and those dying within 7 d of SAB (n?=?3) displayed significantly higher IL-10/TNF-? ratios than the survivors did (P?=?0.007). CONCLUSION:TLR2 downregulation and IL-6 and IL-10 concentrations suggestive of immune dysregulation during early bacteremia may be associated with mortality from SAB. TLR2 expression levels and associated cytokine reactions during early-phase SAB may be potential prognostic factors in SAB, although larger studies are warranted.

SUBMITTER: Kim NH

PROVIDER: S-EPMC7706030 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia.

Kim Nak-Hyun NH Sung Ji Yeon JY Choi Yoon Jung YJ Choi Su-Jin SJ Ahn Soyeon S Ji Eunjeong E Kim Moonsuk M Kim Chung Jong CJ Song Kyoung-Ho KH Choe Pyoeng Gyun PG Park Wan Beom WB Kim Eu Suk ES Park Kyoung Un KU Kim Nam-Joong NJ Oh Myoung-Don MD Kim Hong Bin HB

BMC infectious diseases 20201130 1

<h4>Background</h4>Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes.<h4>Methods</h4>Patients from a prospective SAB cohort at two tertiary-care medical ...[more]

PMID: 33256638

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Project description:BackgroundWe demonstrated that an early dysregulated cytokine response [high interleukin-10 to tissue necrosis factor (IL-10/TNF) ratio] predicted poor outcomes in patients with Staphylococcus aureus bacteremia (SAB). However, high interpatient variability in cytokine levels were observed. We grouped cytokine measurements in quartiles and assessed their additive value to clinical variables for predicting bacterial persistence and 30-day mortality in patients with SAB.MethodsA multicenter observational study was conducted in hospitalized patients with SAB. Medical charts were reviewed for relevant information. Blood samples were obtained for cytokine measurements by ELISA: interferon-gamma (IFNγ), interleukin (IL-1β, IL-6, IL-8, IL-10, IL-17) and tissue necrosis factor (TNF). Cytokine measurements were grouped into quartiles. Significant predictors for bacterial persistence and 30-day mortality were determined by multivariable logistic regression analysis. Area under the ROC curve (AUC) analysis was performed and predictive performance was compared between models with and without cytokine quartiles.ResultsAmong 606 patients with SAB, a subset of patients (n = 239) had Day 1 cytokine measurements and clinical data collected; of those, 53 (22%) had persistent bacteremia. Accounting for septic shock, the addition of either IL-10 (AUC 0.708) or TNF (AUC 0.714) quartiles measured on Day 1 improved model performance for predicting bacterial persistence. All patients had Day 4 cytokine measurements; 52 patients (8.5%) died within 30-days of SAB onset. Inclusion of either IL-10 (AUC 0.873) or TNF (AUC 0.879) quartiles, but not both, measured on Day 4 to the significant clinical predictors (coronary artery disease, Pitt bacteremia score ≥ 4, and septic shock) improved model performance for mortality.ConclusionsIL-10 or TNF levels falling within the range in the upper quartiles, when combined with clinical variables, improved model performance for predicting outcomes, and may potentially be used to support aggressive management and biomarker-guided studies to evaluate the benefit of adjunctive immunotherapy for SAB in the future.

Project description:Several management strategies may improve outcomes in patients with Staphylococcus aureus bacteremia.To review evidence of management strategies for S. aureus bacteremia to determine whether transesophageal echocardiography is necessary in all adult cases and what is the optimal antibiotic therapy for methicillin-resistant S. aureus (MRSA) bacteremia.A PubMed search from inception through May 2014 was performed to identify studies addressing the role of transesophageal echocardiography in S. aureus bacteremia. A second search of PubMed, EMBASE, and the Cochrane Library from January 1990 through May 2014 was performed to find studies addressing antibiotic treatment for MRSA bacteremia. Studies reporting outcomes from antibiotic therapy for MRSA bacteremia were included. All searches, which were limited to English and focused on adults, were augmented by review of bibliographic references from included studies. The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development and Evaluation system with consensus of independent evaluations by at least 2 of the authors.In 9 studies with a total of 4050 patients, use of transesophageal echocardiography was associated with higher rates of a diagnosis of endocarditis (14%-28%) compared with transthoracic echocardiography (2%-15%). In 4 studies, clinical or transthoracic echocardiography findings did not predict subsequent transesophageal echocardiography findings of endocarditis. Five studies identified clinical or transthoracic echocardiography characteristics associated with low risk of endocarditis (negative predictive values from 93% to 100%). Characteristics associated with a low risk of endocarditis include absence of a permanent intracardiac device, sterile follow-up blood cultures within 4 days after the initial set, no hemodialysis dependence, nosocomial acquisition of S. aureus bacteremia, absence of secondary foci of infection, and no clinical signs of infective endocarditis. Of 81 studies of antibiotic therapy for MRSA bacteremia, only 1 high-quality trial was identified. In that study of 246 patients with S. aureus bacteremia, daptomycin was not inferior to vancomycin or an antistaphylococcal penicillin, each in combination with low-dose, short-course gentamicin (clinical success rate, 44.2% [53/120] vs 41.7% [48/115]; absolute difference, 2.4% [95% CI, -10.2% to 15.1%]).All adult patients with S. aureus bacteremia should undergo echocardiography. Characteristics of low-risk patients with S. aureus bacteremia for whom transesophageal echocardiography can be safely avoided have been identified. Vancomycin and daptomycin are the first-line antibiotic choices for MRSA bacteremia. Well-designed studies to address the management of S. aureus bacteremia are needed.

Dataset Information

Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia.

Publications

Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia.

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