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OBJECTIVES 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.

Background: 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. Keywords: Biomarkers, Gene expression, Respiratory tract infections, Coinfection, Diagnosis, Precision medicine

Objectives The Infectious Disease Society of America recommends that all patients with candidemia undergo a dilated retinal exam to exclude endogenous Candida endophthalmitis. Our objective was to determine if there are significant risk factors in candidemic patients for developing endogenous Candida endophthalmitis Methods We conducted a retrospective study of all candidemic patients at three academic medical centers between 2012 and 2017. We extracted risk factors for Candida endophthalmitis based on prior literature and compared them between patients with and without endophthalmitis. We then built a multivariate logistic regression model to assess which ones were significant. Results We found 771 patients with candidemia. 120 (15.6%) of these patients were diagnosed with Candida endophthalmitis. In our logistic regression analysis, central venous catheter presence (OR 8.35), intravenous drug use (OR 4.76), immunosuppression (OR 2.40), total parenteral nutrition recipient (OR 2.28), race (OR 1.65), age (OR 1.02), and gender (OR 0.57) were risk factors for developing Candida endophthalmitis. Additionally, Candida albicans was more likely to result in Candida endophthalmitis (OR 1.86). Conclusions This cohort represents the largest study of risk factors for candidemic patients who developed endogenous Candida endophthalmitis. Based on our findings, clinicians should develop targeted and cost-effective strategies for endophthalmitis screening.

OBJECTIVEDepression is the most prevalent affective disorder in the US, and patients with spinal deformity are at increased risk. Postoperative delirium has been associated with inferior surgical outcomes, including morbidity and mortality. The relationship between depression and postoperative delirium in patients undergoing spine surgery is relatively unknown. The aim of this study was to determine if depression is an independent risk factor for the development of postoperative delirium in patients undergoing decompression and fusion for deformity.METHODSThe medical records of 923 adult patients (age ≥ 18 years) undergoing elective spine surgery at a single major academic institution from 2005 through 2015 were reviewed. Of these patients, 255 (27.6%) patients had been diagnosed with depression by a board-certified psychiatrist and constituted the Depression group; the remaining 668 patients constituted the No-Depression group. Patient demographics, comorbidities, and intra- and postoperative complication rates were collected for each patient and compared between groups. The primary outcome investigated in this study was rate of postoperative delirium, according to DSM-V criteria, during initial hospital stay after surgery. The association between depression and postoperative delirium rate was assessed via multivariate logistic regression analysis.RESULTSPatient demographics and comorbidities other than depression were similar in the 2 groups. In the Depression group, 85.1% of the patients were taking an antidepressant prior to surgery. There were no significant between-group differences in intraoperative variables and rates of complications other than delirium. Postoperative complication rates were also similar between the cohorts, including rates of urinary tract infection, fever, deep and superficial surgical site infection, pulmonary embolism, deep vein thrombosis, urinary retention, and proportion of patients transferred to the intensive care unit. In total, 66 patients (7.15%) had an episode of postoperative delirium, with depressed patients experiencing approximately a 2-fold higher rate of delirium (10.59% vs 5.84%). In a multivariate logistic regression analysis, depression was an independent predictor of postoperative delirium after spine surgery in spinal deformity patients (p = 0.01).CONCLUSIONSThe results of this study suggest that depression is an independent risk factor for postoperative delirium after elective spine surgery. Further studies are necessary to understand the effects of affective disorders on postoperative delirium, in hopes to better identify patients at risk.

In the last decade, costs of U.S. healthcare expenditures have been soaring, with billions of dollars spent on hospital readmissions. Identifying causes and risk factors can reduce soaring readmission rates and help lower healthcare costs. The aim of this is to determine if post-operative delirium in the elderly is an independent risk factor for 30-day hospital readmission after spine surgery. The medical records of 453 consecutive elderly (≥65years old) patients undergoing spine surgery at Duke University Medical Center from 2008 to 2010 were reviewed. We identified 17 (3.75%) patients who experienced post-operative delirium according to DSM-V criteria. Patient demographics, comorbidities, and post-operative complication rates were collected for each patient. Elderly patients experiencing post-operative delirium had an increased length of hospital stay (10.47days vs. 5.70days, p=0.009). Complication rates were similar between the cohorts with the post-operative delirium patients having increased UTI and superficial surgical site infections. In total, 12.14% of patients were re-admitted within 30-days of discharge, with post-operative delirium patients experiencing approximately a 4-fold increase in 30-day readmission rates (Delirium: 41.18% vs. No Delirium: 11.01%, p=0.002). In a multivariate logistic regression analysis, post-operative delirium is an independent predictor of 30-day readmission after spine surgery in the elderly (p=0.03). Elderly patients experiencing post-operative delirium after spine surgery is an independent risk factor for unplanned readmission within 30-days of discharge. Preventable measures and early awareness of post-operative delirium in the elderly may help reduce readmission rates.

Recent studies have reported that decompression with fusion leads to superior outcomes in correction of spinal deformity. The aim of this study was to determine if there is a difference in intraoperative and 30-day postoperative complication rates in patients undergoing spinal fusion with and without decompression.Medical records of 874 adult (≥18 years old) patients with spinal deformity undergoing elective spinal fusion at a major academic institution from 2005 to 2015 were reviewed; 374 (42.8%) patients underwent laminectomy in addition to spinal fusion. The primary outcome investigated was the rate of intraoperative and 30-day complications.Patient demographics and comorbidities were similar between groups. The laminectomy cohort had significantly higher estimated blood loss (P0.0001), incidence of allogeneic blood transfusions (P = 0.0001), and rate of intraoperative durotomies (laminectomy cohort 10.4% vs. no-laminectomy cohort 3.1%; P0.0001). The laminectomy cohort had a significantly higher proportion of patients in the intensive care unit (28.6% vs. 17.7%; P 0.001). There was no significant difference in 30-day readmission rate between cohorts (laminectomy cohort 13.0% vs. no-laminectomy cohort 9.8%; P = 0.13). Within 30 days after initial discharge, the laminectomy cohort had significantly higher rates of altered mental status (3.2% vs. 1.2%; P = 0.05), urinary tract infection (4.3% vs. 1.4%; P = 0.009), wound drainage (7.2% vs. 3.1%; P = 0.007), and instrumentation failure (1.1% vs. 0.0%; P = 0.03).Patients undergoing spinal fusion with laminectomy may have higher complication rates than patients undergoing spinal fusion alone.

The aim of this study is to determine if there are differences in 30-day postoperative complication and readmission rates between patients with spinal deformity undergoing complex spinal fusion with and without intraoperative monitoring (IOM).The medical records of 643 adult patients with spine deformity undergoing elective complex spinal fusion (≥4 levels) at a major academic institution from 2005 to 2015 were reviewed. We identified 122 cases (19%) that involved IOM including electromyography, somatosensory evoked potential, and/or transcranial motor evoked potential and 521 (81%) that did not (IOM, n = 122; no-IOM, n = 521). The primary outcome investigated was the rate of 30-day postoperative complications and readmission.Patient demographics and comorbidities were similar between both groups, including age, gender, body mass index, and smoking status. IOM cases had significantly increased operative time (IOM, 360.9 ± 153.8 minutes vs. no-IOM, 290.3 ± 127.1 minutes; P0.0001), with no differences in the incidences of spinal cord injury, nerve injury, and durotomy. Both cohorts had similar postoperative complications and length of hospital stay, with the no-IOM cohort having a greater incidence of intensive care unit transfer (no-IOM, 27.1% vs. IOM, 16.1%, P = 0.015). There was no significant difference in 30-day readmission between the cohorts (IOM, 8.2% vs. no-IOM, 12.3%; P = 0.27) or differences in sensorimotor deficits. Although the overall 30-day complication rate trended to be higher in the no-IOM cohort, these factors were not attributed to IOM use.Our study suggests that the use of IOM may not have a significant impact on overall surgical outcomes and 30-day readmission rates.

RationaleAsthma exacerbations often occur due to infectious triggers, but determining whether infection is present and whether it is bacterial or viral remains clinically challenging. A diagnostic strategy that clarifies these uncertainties could enable personalized asthma treatment and mitigate antibiotic overuse.ObjectivesTo explore the performance of validated peripheral blood gene expression signatures in discriminating bacterial, viral, and noninfectious triggers in subjects with asthma exacerbations.MethodsSubjects with suspected asthma exacerbations of various etiologies were retrospectively selected for peripheral blood gene expression analysis from a pool of subjects previously enrolled in emergency departments with acute respiratory illness. RT-PCR quantified 87 gene targets, selected from microarray-based studies, followed by logistic regression modeling to define bacterial, viral, or noninfectious class. The model-predicted class was compared to clinical adjudication and procalcitonin.ResultsOf 46 subjects enrolled, 7 were clinically adjudicated as bacterial, 18 as viral, and 21 as noninfectious. Model prediction was congruent with clinical adjudication in 15/18 viral and 13/21 noninfectious cases, but only 1/7 bacterial cases. None of the adjudicated bacterial cases had confirmatory microbiology; the precise etiology in this group was uncertain. Procalcitonin classified only one subject in the cohort as bacterial. 47.8% of subjects received antibiotics.ConclusionsOur model classified asthma exacerbations by the underlying bacterial, viral, and noninfectious host response. Compared to clinical adjudication, the majority of discordances occurred in the bacterial group, due to either imperfect adjudication or model misclassification. Bacterial infection was identified infrequently by all classification schemes, but nearly half of subjects were prescribed antibiotics. A gene expression-based approach may offer useful diagnostic information in this population and guide appropriate antibiotic use.

A century of advances in infectious disease diagnosis and treatment changed the face of medicine. However, challenges continue to develop including multi-drug resistance, globalization that increases pandemic risks, and high mortality from severe infections. These challenges can be mitigated through improved diagnostics, and over the past decade, there has been a particular focus on the host response. Since this article was originally published in 2015, there have been significant developments in the field of host response diagnostics, warranting this updated review. Areas Covered: This review begins by discussing developments in single biomarkers and pauci-analyte biomarker panels. It then delves into 'omics, an area where there has been truly exciting progress. Specifically, progress has been made in sepsis diagnosis and prognosis; differentiating viral, bacterial, and fungal pathogen classes; pre-symptomatic diagnosis; and understanding disease-specific diagnostic challenges in tuberculosis, Lyme disease, and Ebola. Expert Commentary: As 'omics have become faster, more precise, and less expensive, the door has been opened for academic, industry, and government efforts to develop host-based infectious disease classifiers. While there are still obstacles to overcome, the chasm separating these scientific advances from the patient's bedside is shrinking.

Background The Infectious Disease Society of America recommends that all patients with candidemia undergo a dilated retinal examination to exclude invasive ocular candidiasis. However, it remains unclear whether there are patients with candidemia who do not warrant routine surveillance because the risk of ocular infection is low. Methods We conducted a retrospective cohort study of all patients with candidemia diagnosed at three academic medical centers (Duke, University of North Carolina and University of Virginia) from 2012 to 2017. We collected risk factors for invasive ocular candidiasis based on previous literature and compared them between patients with and without invasive ocular candidiasis. We then built a multivariate logistic regression model to assess which risk factors were significant for developing invasive ocular candidiasis. Results Overall, 942 patients were diagnosed with candidemia over the study period. The mean age was 55.9 years, 56% were men, 25% were non-White. Among these patients, 120 (13%) were also diagnosed with invasive ocular candidiasis, 10% with chorioretinitis and 3% with vitreous involvement. In our logistic regression analysis, central venous catheter presence [OR 8.35 (3.53, 19.77)], intravenous drug use [OR 5.02 (2.63, 9.58)], immunosuppression [OR 2.40 (1.55, 3.70)], total parenteral nutrition [OR 2.28 (1.42, 3.66)], non-White race [OR 1.65 (1.07, 2.55)], older age [OR 1.02 (1.01, 1.03)],and female gender [OR 0.57 (0.37, 0.89)] were risk factors for developing invasive ocular candidiasis. In addition, we found that persons with candidemia due to C. albicans were more likely to have invasive ocular candidiasis [OR 1.86 (1.22, 2.85)]. Conclusion This cohort represents the largest study of patients with candidemia who developed invasive ocular candidiasis to date. Based on our findings, clinicians should develop targeted and cost-effective strategies for endophthalmitis screening. Disclosures All authors: No reported disclosures.

Background: The optimal surgical strategy for patients with spinal metastases remains unknown. The aim of this study was to determine if performing an anterior column reconstruction to a posterolateral approach adds to perioperative complications. Methods: A retrospective review of all adult patients with spinal metastases who had a posterolateral approach for resection between January 2000 and December 2008. Perioperative complications and functional outcomes were determined. Results: A total of 23 patients met the study criteria. Eleven patients underwent a costotransversectomy (CT) approach with anterior column reconstruction while 12 patients had a transpedicular (TP) approach without anterior column reconstruction. The mean age was 55.9 and 59.3 years in the CT and TP groups, respectively. There was no intraoperative death in either group. One death attributed to sepsis occurred in the TP group. A total of 5 (45.5%) complications occurred in the CT group and 7 (58.3%) in the TP group (P=0.68). An improvement in American Spinal Injury Association (ASIA) impairment scale grades was observed in 3 (27.3%) patients in the CT group and 1 (8.3%) in TP group. ASIA grades remained the same in 8 (72.7%) patients in CT and 10 (83.3%) patients in TP groups. No patient worsened in the CT group whereas 1 (8.3%) patient in TP group worsened. The median survival was 12.2 months in the CT group and 19.0 months in the TP group (P=0.37). Conclusions: The addition of anterior column reconstruction does not appear to be associated with more operative or perioperative complications when compared to decompression alone. Anterior column reconstruction should not be aborted in fear of increasing perioperative complications.

Background Smoking status has been shown to affect postoperative outcomes after surgery. The aim of this study was to determine whether patients' smoking status impacts 30-day complication and readmission rates after elective complex spinal fusion (≥3 levels). Methods The medical records of 839 adult spinal deformity patients undergoing elective complex spinal fusion (≥3 levels) at a major academic institution from 2005 to 2015 were reviewed. We identified 124 (14.8%) smokers and 715 (85.2%) nonsmokers. Patient demographics, comorbidities, intraoperative and postoperative complications, and 30-day readmission rates were collected for each patient. The primary outcome investigated in this study was the rate of 30-day postoperative complication and readmission rates. Results Patient demographics and comorbidities were similar between both groups, including age, sex, and body mass index. Median [interquartile] number of fusion levels and operative time were similar between the cohorts (smoker: 5 [4–7] vs. nonsmoker: 5 [4–8], P = 0.58) and (smoker: 309.6 ± 157.9 minutes vs. nonsmoker: 287.5 ± 131.7 minutes, P = 0.16), respectively. Both cohorts had similar postoperative complication rates and lengths of hospital stay. There was no significant difference in 30-day readmission between the cohorts (smoker: 12.9% vs. nonsmoker: 10.8%, P = 0.48). There were no observed differences in 30-day complication rates, including pain ( P = 0.46), UTI ( P = 0.54), hardware failure ( P = 0.36), wound dehiscence ( P = 0.29), and wound drainage ( P = 0.86). Smokers had greater rates of 30-day cellulitis (smoker: 1.6% vs. nonsmoker: 0.3%, P = 0.05) and DVT (smoker: 0.8% vs. nonsmoker: 0.0%, P = 0.02). Conclusions Our study suggests that smoking does not significantly affect 30-day readmission rates after complex spinal surgery requiring ≥3 levels of fusion. Further studies are necessary to corroborate our findings.

Background Bacterial and viral infections are difficult to clinically distinguish, leading to antibiotic overuse and resistance. Host response signatures are an alternative to traditional pathogen-detection methods to differentiate these etiologies. Several gene expression signatures have been described although performance in ambiguous clinical phenotypes is unknown. Here, we validate a host response signature and explore its performance in microbiology-negative and co-infection cases. Methods RT-PCR taqman low-density array (TLDA) was used to measure 87 gene targets in a training cohort of 151 samples from patients with microbiologically confirmed and clinically adjudicated phenotypes (48 bacterial; 54 viral; 49 non-infectious illness [NI]). This data were used to construct three distinct classifiers: bacterial vs. nonbacterial; viral vs. nonviral; and non-infectious vs. infectious. This model was then applied to 75 subjects with co-infection and 40 suspected bacterial cases without microbiological confirmation. Results Leave-one-out cross validation on the training cohort demonstrated AUC values of 0.85, 0.89, and 0.88 for bacterial, viral, and NI, respectively. In 40 subjects with microbiology-negative bacterial infections, a bacterial or co-infection signature was present in 72%. Of 75 subjects with co-infection, 53 included a bacterial infection following recent viral infection and 22 were bacterial infections in patients with chronic viral infection (e.g., HCV, HIV). Bacterial infection and co-infection were successfully identified in these varied scenarios. Conclusion This gene expression signature distinguished bacterial, viral, and noninfectious causes of illness. The host response was able to confirm the majority of suspected bacterial infection without confirmatory microbiology but also highlighted a viral response in many. Furthermore, the use of distinct viral and bacterial signatures was capable of identifying co-infection. Such a host gene expression strategy, when translated to a clinically useful platform, can offer new insights into the etiology of both simple and complex cases that are not currently available. Disclosures G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth

Background Asthma exacerbations often occur due to infectious triggers. However, determining whether an infection is present and whether it is bacterial or viral remains clinically challenging leading to antibiotic overuse. A diagnostic strategy that clarifies these uncertainties can enable personalized asthma treatment and mitigate antibiotic resistance. Host gene expression is a promising alternative to pathogen-detection methods. Methods Forty-six patients presenting to the emergency department with asthma exacerbations were enrolled. Cases were clinically adjudicated as having bacterial, viral, or non-infectious etiologies. RT-PCR taqman low density array (TLDA) was used to quantify 87 gene targets, followed by logistic regression modeling to define class. Etiologies were correlated with clinical information including symptoms and antibiotic prescriptions. Results Most clinical parameters were similar between groups including duration of symptoms, presence of sick contacts, and severity of nasal symptoms, cough, headache, throat discomfort, and malaise. Only fever/chills (P = 0.006) and a composite of all symptoms (P = 0.02) were significantly different. In contrast to clinically adjudicated phenotypes, host response signatures identified very few bacterial triggers. Notably, none of the adjudicated bacterial cases had positive confirmatory microbiology. Instead, 29 and 57% were identified as having a viral infection or no infection, respectively. Despite the absence of bacterial infections identified using host gene expression, antibiotics were prescribed in 47.8% of all cases. Conclusion Host response signatures indicated that asthma exacerbation is infrequently caused by bacterial infections, even when clinical adjudications suggest this to be the case. Instead, most are either of viral or non-infectious etiologies. Despite most cases being classified as nonbacterial, empiric antibiotics were prescribed nearly half the time. A host gene expression approach can offer clinically useful diagnostic information to guide more appropriate antibiotic use among patients with asthma exacerbation. Disclosures G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth < $100). C. W. Woods, Host Response: Founder, Licensing agreement or royalty; Qvella: Collaborator, Research support; BioFire: Collaborator, none. E. L. Tsalik, Host Response, Inc.: Founder, Equity.