Dataset Information

A Prognostic Model of Persistent Bacteremia and Mortality in Complicated Staphylococcus aureus Bloodstream Infection.

ABSTRACT:

Background

Staphylococcus aureus is a leading cause of bacteremia, yet there remains a significant knowledge gap in the identification of relevant biomarkers that predict clinical outcomes. Heterogeneity in the host response to invasive S. aureus infection suggests that specific biomarker signatures could be utilized to differentiate patients prone to severe disease, thereby facilitating earlier implementation of more aggressive therapies.

Methods

To further elucidate the inflammatory correlates of poor clinical outcomes in patients with S. aureus bacteremia, we evaluated the association between a panel of blood proteins at initial presentation of bacteremia and disease severity outcomes using 2 cohorts of patients with S. aureus bacteremia (n = 32 and n = 124).

Results

We identified 13 candidate proteins that were correlated with mortality and persistent bacteremia. Prognostic modeling identified interleukin (IL)-8 and CCL2 as the strongest individual predictors of mortality, with the combination of these biomarkers classifying fatal outcome with 89% sensitivity and 77% specificity (P < .0001). Baseline IL-17A levels were elevated in patients with persistent bacteremia (P < .0001), endovascular (P = .026) and metastatic tissue infections (P = .012).

Conclusions

These results demonstrate the potential utility of selected biomarkers to distinguish patients with the highest risk for treatment failure and bacteremia-related complications, providing a valuable tool for clinicians in the management of S. aureus bacteremia. Additionally, these biomarkers could identify patients with the greatest potential to benefit from novel therapies in clinical trials.

SUBMITTER: Guimaraes AO

PROVIDER: S-EPMC6481998 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

A Prognostic Model of Persistent Bacteremia and Mortality in Complicated Staphylococcus aureus Bloodstream Infection.

Guimaraes Alessander O AO Cao Yi Y Hong Kyu K Mayba Oleg O Peck Melicent C MC Gutierrez Johnny J Ruffin Felicia F Carrasco-Triguero Montserrat M Dinoso Jason B JB Clemenzi-Allen Angelo A Koss Catherine A CA Maskarinec Stacey A SA Chambers Henry F HF Fowler Vance G VG Baruch Amos A Rosenberger Carrie M CM

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20190401 9

<h4>Background</h4>Staphylococcus aureus is a leading cause of bacteremia, yet there remains a significant knowledge gap in the identification of relevant biomarkers that predict clinical outcomes. Heterogeneity in the host response to invasive S. aureus infection suggests that specific biomarker signatures could be utilized to differentiate patients prone to severe disease, thereby facilitating earlier implementation of more aggressive therapies.<h4>Methods</h4>To further elucidate the inflamma ...[more]

PMID: 30165412

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Project description:Abstract Background SAB is a serious, common infection. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery set of patients, and then evaluated the nominally significant genes in a replication set of patients using custom-capture sequencing. Methods The discovery set comprised 84 complicated SAB cases (endocarditis or bone/joint infection) frequency-matched by age (in deciles), sex, and bacterial clonal complex (CC5/30, CC8) to 84 uncomplicated SAB controls. All were white inpatients at Duke University. WES utilized Agilent SureSelect 72Mb capture kits, followed by sequencing on an Illumina HiSeq2000, alignment and base calling with a standard pipeline. The SKAT-O and EPACTS packages were used for gene-based association tests and logistic regression models with Firth bias correction, respectively. Both controlled for age, sex, and clonal complex as covariates. The replication set of 122 complicated SAB cases and 118 uncomplicated SAB controls was frequency matched by age, sex, and clonal complex. All were white Europeans collected by the Statens Serum Institute. An Agilent SureSelect 2Mb capture array captured genic sequence for 342 genes nominally associated with complicated SAB in discovery (SKAT-O P < 0.035). Sequencing and data analysis proceeded as for WES. A Bonferroni-corrected gene-based test P-value of 1.5×10–4 determined significance in the replication set. Results One gene, GLS2, was significantly associated with complicated SAB in the replication set (P = 1.2 x 10–4). The strongest single-variant association in all 342 genes was rs2657878 in GLS2 (p = 5×10−4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4x10-3) in which the minor allele (associated here with complicated SAB) has previously been shown to reduce circulating glutamine levels. Conclusion Comprehensive examination of the coding sequence for association with complicated SAB in a two-stage discovery/replication design identified a novel candidate gene. GLS2 is an interesting candidate for complicated SAB due to its role in regulating glutamine production, a key factor in activation of T-cell production. Disclosures V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, Basilea, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Research grant; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: author on several chapters, Royalties

Project description:ObjectiveTo identify risk factors and outcomes associated with thrombocytopenia at sepsis onset in Staphylococcus aureus bacteremia.Patients and methodsThis single-center, retrospective, cohort study consists of all adult patients with a first episode of clinical S aureus bacteremia between April 1, 1988, and September 30, 1994, and between January 1, 1999, and December 31, 2007. Thrombocytopenia was defined as a platelet count less than 150 × 10(9)/L. The primary outcome was 30-day all-cause mortality. Risk factors for 30-day all-cause mortality were identified using univariate and multivariable analyses. Multivariable analysis was conducted using forward step logistic regression analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for risk of death.ResultsA total of 1052 patients had clinical S aureus bacteremia. Thrombocytopenia at sepsis onset was present in 235 patients (22.3%). Thrombocytopenia was associated with community-acquired bacteremia, infections caused by methicillin-sensitive S aureus, high-magnitude bacteremia (defined as >4 positive blood cultures [≥ 3 separate positive blood culture sets]), and endocarditis. Patients with thrombocytopenia presented more commonly with severe sepsis reflected by septic shock and acute renal failure. Thirty-day mortality was significantly higher among patients with thrombocytopenia (132/235 [56.2%]) vs those without thrombocytopenia (281/817 [34.4%]; P<.001). Higher mortality was associated with the degree of thrombocytopenia. In multivariable analysis, thrombocytopenia at baseline remained an independent risk factor for 30-day mortality (OR, 2.82; 95% CI, 1.87-4.24). The adjusted association between thrombocytopenia and death remained similar among the 917 patients with monomicrobial bacteremia (OR, 2.88; 95% CI, 1.83-4.53) and the 945 patients who did not die within the first 48 hours (OR, 2.88; 95% CI, 1.87-4.45.).ConclusionWe observed a strong association between thrombocytopenia at sepsis onset and all-cause mortality in S aureus bacteremia, possibly related to mechanisms other than sepsis alone.

Project description:The role of host genetic variation in the development of complicated Staphylococcus aureus bacteremia (SAB) is poorly understood. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 complicated and 84 uncomplicated, frequency matched by age, sex, and bacterial clonal complex [CC]), and then evaluated the most significantly associated genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched for age, sex, and CC) using targeted sequence capture. In the discovery sample, gene-based analysis using the SKAT-O program identified 334 genes associated with complicated SAB at p<3.5 x 10-3. These, along with eight biologically relevant candidate genes were examined in the replication sample. Gene-based analysis of the 342 genes in the replication sample using SKAT-O identified one gene, GLS2, significantly associated with complicated SAB (p = 1.2 x 10-4) after Bonferroni correction. In Firth-bias corrected logistic regression analysis of individual variants, the strongest association across all 10,931 variants in the replication sample was with rs2657878 in GLS2 (p = 5 x 10-4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4 x 10-3) in which the minor allele (associated here with complicated SAB) has been previously associated with lower plasma concentration of glutamine. In a microarray-based gene-expression analysis, individuals with SAB exhibited significantly lower expression levels of GLS2 than healthy controls. Similarly, Gls2 expression is lower in response to S. aureus exposure in mouse RAW 264.7 macrophage cells. Compared to wild-type cells, RAW 264.7 cells with Gls2 silenced by CRISPR-Cas9 genome editing have decreased IL1-β transcription and increased nitric oxide production after S. aureus exposure. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in leukocyte activation.

Dataset Information

A Prognostic Model of Persistent Bacteremia and Mortality in Complicated Staphylococcus aureus Bloodstream Infection.

Background

Methods

Results

Conclusions

Publications

A Prognostic Model of Persistent Bacteremia and Mortality in Complicated Staphylococcus aureus Bloodstream Infection.

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