scholarly journals 1218. Comparing the Diagnostic Accuracy of Clinician Judgement to a Novel Host Response Diagnostic for Acute Respiratory Illness

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S630-S630
Author(s):  
Ian S Jaffe ◽  
Anja K Jaehne ◽  
Eugenia Quackenbush ◽  
Micah T McClain ◽  
Geoffrey S Ginsburg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diagnostic Accuracy ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Treatment Plan ◽  
Respiratory Illness ◽  
Host Gene ◽  
Host Gene Expression ◽  
Net Benefit ◽  
Material Support

Abstract Background Discriminating bacterial and viral infections remains clinically challenging. The resulting antibacterial misuse contributes to antimicrobial resistance. Host gene expression-based tests are a promising strategy to discriminate of bacterial and viral infections, but their potential clinical utility has not yet been evaluated. Methods A host gene expression biosignature was measured using either qRT-PCR or microarray in 683 ED subjects with suspected infection. Based on chart reviews, we recorded clinical diagnosis as defined both by the provider assessment and by the provider treatment plan. The biosignature, diagnosis, treatment plan, and procalcitonin were compared to clinical adjudication as the reference standard. With this as a baseline, we then calculated average weighted accuracy (AWA) and change in overall net benefit (∆NB), weighting bacterial false negatives four times more seriously than false positives. Results Gene expression correctly classified the three possible disease etiologies (bacterial, viral, or non-infectious) 76.1% of the time, outperforming provider diagnosis, provider treatment, and procalcitonin (Table 1). Overall accuracy was higher in subjects with bacterial infections (n=278, 83.8% accurate) compared to those with viral (n=234, 76.5%) and non-infectious (n=171, 63.2%) etiologies. Due to a strong sensitivity bias to treat bacterial infections at the expense of diagnostic accuracy and specificity, the provider diagnosis was overall more accurate than the corresponding treatment plan (71.4% accuracy vs. 68.1%), resulting in inappropriate antibiotic use in 41.0% of cases where antibiotics were prescribed. The gene expression test had significantly higher AWA for the diagnosis of bacterial infection than both procalcitonin and provider treatment (82.4% vs. 70.3% and 74.4%, respectively; p < 0.0001). Consequently, the host gene expression test had greater net benefit than provider treatment (∆NBbact = 9.9%), provider diagnosis (∆NBbact = 4.4%), and procalcitonin (∆NBbact = 27.1%). Table 1: Summary of provider, procalcitonin, and host gene expression test performance in a cohort of 683 subjects. Conclusion Host gene expression-based tests to distinguish bacterial and viral infection can facilitate more appropriate treatment, leading to improved patient outcomes and mitigating the antibiotic resistance crisis. Disclosures Geoffrey S. Ginsburg, MD PhD, Predigen, Inc (Shareholder, Other Financial or Material Support) Ephraim L. Tsalik, MD, MHS, PhD, Predigen (Shareholder, Other Financial or Material Support, Founder)

scholarly journals Comparing the Diagnostic Accuracy of Clinician Judgement to a Novel Host Response Diagnostic for Acute Respiratory Illness

2021 ◽  
Author(s):  
Ian S Jaffe ◽  
Anja K Jaehne ◽  
Eugenia Quackenbush ◽  
Emily R Ko ◽  
Emanuel P Rivers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bacterial Infection ◽  
Respiratory Illness ◽  
Host Gene ◽  
Diagnostic Strategy ◽  
Host Gene Expression ◽  
Net Benefit ◽  
Suspected Infection ◽  
Diagnostic Strategies ◽  
Recommended Treatment

Abstract Background 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 four diagnostic strategies were compared to 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 one diagnostic strategy to 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 non-infectious 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<0.0001 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.

scholarly journals 2018. Host Gene Expression Classifiers Distinguish Bacterial and Viral Infections in Sri Lankan Patients with Acute Febrile Respiratory Illness

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S588-S588
Author(s):  
L Gayani Tillekeratne ◽  
Sunil Suchindran ◽  
Emily Ko ◽  
Elizabeth Petzold ◽  
Champica K Bodinayake ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Infections ◽  
Respiratory Illness ◽  
Host Gene ◽  
Sri Lankan ◽  
Host Gene Expression ◽  
Febrile Respiratory Illness

scholarly journals 1226. Performance of a Host Response Test for Bacterial/Viral Discrimination in Immunocompromised Patients

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S633-S634
Author(s):  
Rachael E Mahle ◽  
Sunil Suchindran ◽  
Ricardo Henao ◽  
Julie M Steinbrink ◽  
Thomas W Burke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bacterial Infection ◽  
Viral Infection ◽  
Host Response ◽  
Host Gene ◽  
Response Strategy ◽  
Solid Organ ◽  
Host Gene Expression ◽  
Material Support ◽  
Response Test

Abstract Background Difficulty distinguishing bacterial and viral infections contributes to excess antibiotic use. A host response strategy overcomes many limitations of pathogen-based tests, but depends on a functional immune system. This approach may therefore be limited in immunocompromised (IC) hosts. Here, we evaluated a host response test in IC subjects, which has not been extensively studied in this manner. Methods An 81-gene signature was measured using qRT-PCR in previously enrolled IC subjects (chemotherapy, solid organ transplant, immunomodulatory agents, AIDS) with confirmed bacterial infection, viral infection, or non-infectious illness (NI). A regularized logistic regression model estimated the likelihood of bacterial, viral, and noninfectious classes. Clinical adjudication was the reference standard. Results A host gene expression model trained in a cohort of 136 immunocompetent subjects (43 bacterial, 41 viral, and 52 NI) had an overall accuracy of 84.6% for the diagnosis of bacterial vs. non-bacterial infection and 80.8% for viral vs. non-viral infection. The model was validated in an independent cohort of 134 IC subjects (64 bacterial, 28 viral, 42 NI). The overall accuracy was 73.9% for bacterial infection (p=0.03 vs. training cohort) and 75.4% for viral infection (p=0.27). Test utility could be improved by reporting probability ranges. For example, results divided into probability quartiles would allow the highest quartile to be used to rule in infection and the lowest to rule out infection. For IC subjects in the lowest quartile, the test had 90.1% and 96.4% sensitivity for bacterial and viral infection, respectively. For the highest quartile, the test had 91.4% and 84.0% specificity for bacterial and viral infection, respectively. The type or number of immunocompromising conditions did not impact performance. Illness Etiology Probabilities Conclusion A host gene expression test discriminated bacterial, viral, and non-infectious etiologies at a lower overall accuracy in IC patients compared to immunocompetent patients, though this difference was only significant for bacterial vs non-bacterial disease. With modified interpretive criteria, a host response strategy may offer clinically useful and complementary diagnostic information for IC patients. Disclosures Thomas W. Burke, PhD, Predigen, Inc (Consultant) Geoffrey S. Ginsburg, MD PhD, Predigen, Inc (Shareholder, Other Financial or Material Support) Christopher W. Woods, MD, MPH, FIDSA, Predigen, Inc (Shareholder, Other Financial or Material Support) Ephraim L. Tsalik, MD, MHS, PhD, FIDSA, Predigen, Inc (Scientific Research Study Investigator, Shareholder, Other Financial or Material Support)

scholarly journals Host Gene Expression of Macrophages in Response to Feline Coronavirus Infection

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1431 ◽  
Author(s):  
Yvonne Drechsler ◽  
Elton J. R. Vasconcelos ◽  
Lisa M. Griggs ◽  
Pedro P. P. V. Diniz ◽  
Ellen Collisson
Keyword(s):  
Gene Expression ◽  
Viral Infections ◽  
Ex Vivo ◽  
Host Gene ◽  
Host Responses ◽  
Host Gene Expression ◽  
Feline Infectious Peritonitis ◽  
Host Immune Responses ◽  
Individual Host ◽  
Feline Coronavirus

Feline coronavirus is a highly contagious virus potentially resulting in feline infectious peritonitis (FIP), while the pathogenesis of FIP remains not well understood, particularly in the events leading to the disease. A predominant theory is that the pathogenic FIPV arises from a mutation, so that it could replicate not only in enterocytes of the intestines but also in monocytes, subsequently systemically transporting the virus. The immune status and genetics of affected cats certainly play an important role in the pathogenesis. Considering the importance of genetics and host immune responses in viral infections, the goal of this study was to elucidate host gene expression in macrophages using RNA sequencing. Macrophages from healthy male cats infected with FIPV 79-1146 ex vivo displayed a differential host gene expression. Despite the virus uptake, aligned viral reads did not increase from 2 to 17 h. The overlap of host gene expression among macrophages from different cats was limited, even though viral transcripts were detected in the cells. Interestingly, some of the downregulated genes in all macrophages were involved in immune signaling, while some upregulated genes common for all cats were found to be inhibiting immune activation. Our results highlight individual host responses playing an important role, consistent with the fact that few cats develop feline infectious peritonitis despite a common presence of enteric FCoV.

scholarly journals Host gene expression classifiers diagnose acute respiratory illness etiology

2016 ◽  
Vol 8 (322) ◽  
pp. 322ra11-322ra11 ◽  
Author(s):  
Ephraim L. Tsalik ◽  
Ricardo Henao ◽  
Marshall Nichols ◽  
Thomas Burke ◽  
Emily R. Ko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Respiratory Illness ◽  
Host Gene ◽  
Acute Respiratory Illness ◽  
Host Gene Expression

scholarly journals Suppression of Proinflammatory Signal Transduction and Gene Expression by the DualNucleic Acid Binding Domains of the Vaccinia Virus E3L Proteins

2006 ◽  
Vol 80 (20) ◽  
pp. 10083-10095 ◽  
Author(s):  
Jeffrey O. Langland ◽  
John C. Kash ◽  
Victoria Carter ◽  
Matthew J. Thomas ◽  
Michael G. Katze ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Vaccinia Virus ◽  
Cellular Response ◽  
Viral Infections ◽  
Host Gene ◽  
Host Gene Expression ◽  
Danger Signals ◽  
Binding Domains ◽  
Z Dna

ABSTRACT Cells have evolved elaborate mechanisms to counteract the onslaught of viral infections. To activate these defenses, the viral threat must be recognized. Danger signals, or pathogen-associated molecular patterns, that are induced by pathogens include double-stranded RNA (dsRNA), viral single-stranded RNA, glycolipids, and CpG DNA. Understanding the signal transduction pathways activated and host gene expression induced by these danger signals is vital to understanding virus-host interactions. The vaccinia virus E3L protein is involved in blocking the host antiviral response and increasing pathogenesis, functions that map to separate C-terminal dsRNA- and N-terminal Z-DNA-binding domains. Viruses containing mutations in these domains allow modeling of the role of dsRNA and Z-form nucleic acid in the host response to virus infection. Deletions in the Z-DNA- or dsRNA-binding domains led to activation of signal transduction cascades and up-regulation of host gene expression, with many genes involved in the inflammatory response. These data suggest that poxviruses actively inhibit cellular recognition of viral danger signals and the subsequent cellular response to the viral threat.

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