Browsing by Author "Jaehne, Anja K"
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Item Open Access An integrated transcriptome and expressed variant analysis of sepsis survival and death.(Genome Med, 2014) Tsalik, Ephraim L; Langley, Raymond J; Dinwiddie, Darrell L; Miller, Neil A; Yoo, Byunggil; van Velkinburgh, Jennifer C; Smith, Laurie D; Thiffault, Isabella; Jaehne, Anja K; Valente, Ashlee M; Henao, Ricardo; Yuan, Xin; Glickman, Seth W; Rice, Brandon J; McClain, Micah T; Carin, Lawrence; Corey, G Ralph; Ginsburg, Geoffrey S; Cairns, Charles B; Otero, Ronny M; Fowler, Vance G; Rivers, Emanuel P; Woods, Christopher W; Kingsmore, Stephen FBACKGROUND: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. METHODS: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes. RESULTS: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. CONCLUSIONS: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.Item Open Access Comparing the Diagnostic Accuracy of Clinician Judgment to a Novel Host Response Diagnostic for Acute Respiratory Illness.(Open forum infectious diseases, 2021-12) Jaffe, Ian S; Jaehne, Anja K; Quackenbush, Eugenia; Ko, Emily R; Rivers, Emanuel P; McClain, Micah T; Ginsburg, Geoffrey S; Woods, Christopher W; Tsalik, Ephraim LBackground
Difficulty discriminating bacterial from viral infections drives antibacterial misuse. Host gene expression tests discriminate bacterial and viral etiologies, but their clinical utility has not been evaluated.Methods
Host gene expression and procalcitonin levels were measured in 582 emergency department participants with suspected infection. We also recorded clinician diagnosis and clinician-recommended treatment. These 4 diagnostic strategies were compared with clinical adjudication as the reference. To estimate the clinical impact of host gene expression, we calculated the change in overall Net Benefit (∆NB; the difference in Net Benefit comparing 1 diagnostic strategy with a reference) across a range of prevalence estimates while factoring in the clinical significance of false-positive and -negative errors.Results
Gene expression correctly classified bacterial, viral, or noninfectious illness in 74.1% of subjects, similar to the other strategies. Clinical diagnosis and clinician-recommended treatment revealed a bias toward overdiagnosis of bacterial infection resulting in high sensitivity (92.6% and 94.5%, respectively) but poor specificity (67.2% and 58.8%, respectively), resulting in a 33.3% rate of inappropriate antibacterial use. Gene expression offered a more balanced sensitivity (79.0%) and specificity (80.7%), which corresponded to a statistically significant improvement in average weighted accuracy (79.9% vs 71.5% for procalcitonin and 76.3% for clinician-recommended treatment; P<.0001 for both). Consequently, host gene expression had greater Net Benefit in diagnosing bacterial infection than clinician-recommended treatment (∆NB=6.4%) and procalcitonin (∆NB=17.4%).Conclusions
Host gene expression-based tests to distinguish bacterial and viral infection can facilitate appropriate treatment, improving patient outcomes and mitigating the antibacterial resistance crisis.Item Open Access Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test.(Critical care medicine, 2021-10) Tsalik, Ephraim L; Henao, Ricardo; Montgomery, Jesse L; Nawrocki, Jeff W; Aydin, Mert; Lydon, Emily C; Ko, Emily R; Petzold, Elizabeth; Nicholson, Bradly P; Cairns, Charles B; Glickman, Seth W; Quackenbush, Eugenia; Kingsmore, Stephen F; Jaehne, Anja K; Rivers, Emanuel P; Langley, Raymond J; Fowler, Vance G; McClain, Micah T; Crisp, Robert J; Ginsburg, Geoffrey S; Burke, Thomas W; Hemmert, Andrew C; Woods, Christopher W; Antibacterial Resistance Leadership GroupObjectives
Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test.Design
Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results.Setting
Four U.S. emergency departments.Patients
Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis.Interventions
Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes.Measurements and main results
Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance.Conclusions
The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.Item Open Access Evaluating the discriminating capacity of cell death (apoptotic) biomarkers in sepsis.(Journal of intensive care, 2018-01) Duplessis, Christopher; Gregory, Michael; Frey, Kenneth; Bell, Matthew; Truong, Luu; Schully, Kevin; Lawler, James; Langley, Raymond J; Kingsmore, Stephen F; Woods, Christopher W; Rivers, Emanuel P; Jaehne, Anja K; Quackenbush, Eugenia B; Fowler, Vance G; Tsalik, Ephraim L; Clark, DanielleBackground
Sepsis biomarker panels that provide diagnostic and prognostic discrimination in sepsis patients would be transformative to patient care. We assessed the mortality prediction and diagnostic discriminatory accuracy of two biomarkers reflective of cell death (apoptosis), circulating cell-free DNA (cfDNA), and nucleosomes.Methods
The cfDNA and nucleosome levels were assayed in plasma samples acquired in patients admitted from four emergency departments with suspected sepsis. Subjects with non-infectious systemic inflammatory response syndrome (SIRS) served as controls. Samples were acquired at enrollment (T0) and 24 h later (T24). We assessed diagnostic (differentiating SIRS from sepsis) and prognostic (28-day mortality) predictive power. Models incorporating procalcitonin (diagnostic prediction) and APACHE II scores (mortality prediction) were generated.Results
Two hundred three subjects were included (107 provided procalcitonin measurements). Four subjects exhibited uncomplicated sepsis, 127 severe sepsis, 35 septic shock, and 24 had non-infectious SIRS. There were 190-survivors and 13 non-survivors. Mortality prediction models using cfDNA, nucleosomes, or APACHEII yielded AUC values of 0.61, 0.75, and 0.81, respectively. A model combining nucleosomes with the APACHE II score improved the AUC to 0.84. Diagnostic models distinguishing sepsis from SIRS using procalcitonin, cfDNA(T0), or nucleosomes(T0) yielded AUC values of 0.64, 0.65, and 0.63, respectively. The three parameter model yielded an AUC of 0.74.Conclusions
To our knowledge, this is the first head-to-head comparison of cfDNA and nucleosomes in diagnosing sepsis and predicting sepsis-related mortality. Both cfDNA and nucleosome concentrations demonstrated a modest ability to distinguish sepsis survivors and non-survivors and provided additive diagnostic predictive accuracy in differentiating sepsis from non-infectious SIRS when integrated into a diagnostic prediction model including PCT and APACHE II. A sepsis biomarker strategy incorporating measures of the apoptotic pathway may serve as an important component of a sepsis diagnostic and mortality prediction tool.Item Open Access Host gene expression classifiers diagnose acute respiratory illness etiology.(Sci Transl Med, 2016-01-20) Tsalik, Ephraim L; Henao, Ricardo; Nichols, Marshall; Burke, Thomas; Ko, Emily R; McClain, Micah T; Hudson, Lori L; Mazur, Anna; Freeman, Debra H; Veldman, Tim; Langley, Raymond J; Quackenbush, Eugenia B; Glickman, Seth W; Cairns, Charles B; Jaehne, Anja K; Rivers, Emanuel P; Otero, Ronny M; Zaas, Aimee K; Kingsmore, Stephen F; Lucas, Joseph; Fowler, Vance G; Carin, Lawrence; Ginsburg, Geoffrey S; Woods, Christopher WAcute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.Item Open Access Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection.(JAMA network open, 2022-04) Ko, Emily R; Henao, Ricardo; Frankey, Katherine; Petzold, Elizabeth A; Isner, Pamela D; Jaehne, Anja K; Allen, Nakia; Gardner-Gray, Jayna; Hurst, Gina; Pflaum-Carlson, Jacqueline; Jayaprakash, Namita; Rivers, Emanuel P; Wang, Henry; Ugalde, Irma; Amanullah, Siraj; Mercurio, Laura; Chun, Thomas H; May, Larissa; Hickey, Robert W; Lazarus, Jacob E; Gunaratne, Shauna H; Pallin, Daniel J; Jambaulikar, Guruprasad; Huckins, David S; Ampofo, Krow; Jhaveri, Ravi; Jiang, Yunyun; Komarow, Lauren; Evans, Scott R; Ginsburg, Geoffrey S; Tillekeratne, L Gayani; McClain, Micah T; Burke, Thomas W; Woods, Christopher W; Tsalik, Ephraim L; Antibacterial Resistance Leadership GroupImportance
Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship.Objective
To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI.Design, setting, and participants
This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc.Interventions
The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection.Main outcomes and measures
Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement.Results
Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection.Conclusions and relevance
In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.Item Open Access Renal systems biology of patients with systemic inflammatory response syndrome.(Kidney Int, 2015-10) Tsalik, Ephraim L; Willig, Laurel K; Rice, Brandon J; van Velkinburgh, Jennifer C; Mohney, Robert P; McDunn, Jonathan E; Dinwiddie, Darrell L; Miller, Neil A; Mayer, Eric S; Glickman, Seth W; Jaehne, Anja K; Glew, Robert H; Sopori, Mohan L; Otero, Ronny M; Harrod, Kevin S; Cairns, Charles B; Fowler, Vance G; Rivers, Emanuel P; Woods, Christopher W; Kingsmore, Stephen F; Langley, Raymond JA systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this, we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular-weight proteins and acute-phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and N-acetylaspartate were inversely correlated with the majority of significantly downregulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes were not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness.Item Open Access Validation of a host response test to distinguish bacterial and viral respiratory infection.(EBioMedicine, 2019-10-17) Lydon, Emily C; Henao, Ricardo; Burke, Thomas W; Aydin, Mert; Nicholson, Bradly P; Glickman, Seth W; Fowler, Vance G; Quackenbush, Eugenia B; Cairns, Charles B; Kingsmore, Stephen F; Jaehne, Anja K; Rivers, Emanuel P; Langley, Raymond J; Petzold, Elizabeth; Ko, Emily R; McClain, Micah T; Ginsburg, Geoffrey S; Woods, Christopher W; Tsalik, Ephraim LBACKGROUND:Distinguishing bacterial and viral respiratory infections is challenging. Novel diagnostics based on differential host gene expression patterns are promising but have not been translated to a clinical platform nor extensively tested. Here, we validate a microarray-derived host response signature and explore performance in microbiology-negative and coinfection cases. METHODS:Subjects with acute respiratory illness were enrolled in participating emergency departments. Reference standard was an adjudicated diagnosis of bacterial infection, viral infection, both, or neither. An 87-transcript signature for distinguishing bacterial, viral, and noninfectious illness was measured from peripheral blood using RT-PCR. Performance characteristics were evaluated in subjects with confirmed bacterial, viral, or noninfectious illness. Subjects with bacterial-viral coinfection and microbiologically-negative suspected bacterial infection were also evaluated. Performance was compared to procalcitonin. FINDINGS:151 subjects with microbiologically confirmed, single-etiology illness were tested, yielding AUROCs 0•85-0•89 for bacterial, viral, and noninfectious illness. Accuracy was similar to procalcitonin (88% vs 83%, p = 0•23) for bacterial vs. non-bacterial infection. Whereas procalcitonin cannot distinguish viral from non-infectious illness, the RT-PCR test had 81% accuracy in making this determination. Bacterial-viral coinfection was subdivided. Among 19 subjects with bacterial superinfection, the RT-PCR test identified 95% as bacterial, compared to 68% with procalcitonin (p = 0•13). Among 12 subjects with bacterial infection superimposed on chronic viral infection, the RT-PCR test identified 83% as bacterial, identical to procalcitonin. 39 subjects had suspected bacterial infection; the RT-PCR test identified bacterial infection more frequently than procalcitonin (82% vs 64%, p = 0•02). INTERPRETATION:The RT-PCR test offered similar diagnostic performance to procalcitonin in some subgroups but offered better discrimination in others such as viral vs. non-infectious illness and bacterial/viral coinfection. Gene expression-based tests could impact decision-making for acute respiratory illness as well as a growing number of other infectious and non-infectious diseases.