Billie Bixby

Interests

Research

Thoracic oncology, early identification of lung cancer, advanced bronchoscopy, management of malignant and benign pleural disease.

Teaching

Pleural disease, thoracic oncology, complex airway disease, pulmonary procedures, bronchoscopy, critical care.

Courses

No activities entered.

Scholarly Contributions

Journals/Publications

• Khemasuwan, D., Wilshire, C., Reddy, C., Gilbert, C., Gorden, J., Balwan, A., Sanchez, T. M., Bixby, B., Sorensen, J. S., & Shojaee, S. (2025). Machine Learning Model Predictors of Intrapleural Tissue Plasminogen Activator and DNase Failure in Pleural Infection: A Multicenter Study. Annals of the American Thoracic Society, 22(2), 187-192.
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  Intrapleural enzyme therapy (IET) with tissue plasminogen activator (tPA) and DNase has been shown to reduce the need for surgical intervention for complicated parapneumonic effusion/empyema (CPPE/empyema). Failure of IET may lead to delayed care and increased length of stay. The goal of this study was to identify risk factors for failure of IET. We performed a multicenter, retrospective study of patients who received IET for the treatment of CPPE/empyema. Clinical and radiological variables at the time of diagnosis were included. We compared four different machine learning classifiers (L1-penalized logistic regression, support vector machine [SVM], extreme gradient boosting [XGBoost], and light gradient-boosting machine [LightGBM]) by multiple bootstrap-validated metrics, including F-β, to demonstrate model performances. A total of 466 participants who received IET for pleural infection were included from five institutions across the United States. Resolution of CPPE/empyema with IET was achieved in 78% ( = 365). SVM performed superiorly, with median F-β of 56%, followed by L1-penalized logistic regression, LightGBM, and XGBoost. Clinical and radiological variables were graded based on their ranked variable importance. The top two significant predictors of IET failure using SVM were the presence of an abscess/necrotizing pneumonia (17%) and pleural thickening (13%). Similarly, LightGBM identified abscess/necrotizing pneumonia (35%) and pleural thickening (26%) and XGBoost indicated pleural thickening (36%) and abscess/necrotizing pneumonia (17%) as the most significant predictors of treatment failure. Predictors identified by the L1-penalized logistic regression model were pleural thickening (18%) and pleural fluid lactate dehydrogenase (LDH) (9%). The presence of abscess/necrotizing pneumonia and pleural thickening consistently ranked among the strongest predictors of IET failure in all machine learning models. The difference in rankings between models may be a consequence of the different algorithms used by each model. These results indicate that the presence of abscess/necrotizing pneumonia and pleural thickening may predict IET failure. These results should be confirmed in larger studies.
• Aggarwal, N. R., Nordwall, J., Braun, D. L., Chung, L., Coslet, J., Der, T., Eriobu, N., Ginde, A. A., Hayanga, A. J., Highbarger, H., Holodniy, M., Horcajada, J. P., Jain, M. K., Kim, K., Laverdure, S., Lundgren, J., Natarajan, V., Nguyen, H. H., Pett, S. L., , Phillips, A., et al. (2024). Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 78(6), 1490-1503.
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  Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials.
• Ahmadian, D., Gleadhill, C. M., Wehbi, N., Bixby, B. A., & Yip, H. T. (2024). Predictors of response to endoscopic management of subglottic/tracheal stenosis in patients without tracheostomy. American journal of otolaryngology, 45(1), 104055.
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  Subglottic and tracheal stenosis (SGTS) in adults is an acquired or idiopathic condition that can lead to dyspnea, and even life-threatening airway obstruction. Endoscopic techniques have advanced and largely eclipsed open surgery, with open surgery now reserved for refractory cases (Hseu et al., 2013; Feinstein et al., 2017). Currently, there is no accepted guideline for the endoscopic treatment of SGTS. Thus, the aim of the present study is to examine the impact of various clinical and pathological characteristics on outcomes to endoscopic treatment in a cohort of SGTS patients.
• Ahmadian, D., Wehbi, N., Tseng, P., Bixby, B., & Yip, H. T. (2024). Assessing the interrater and intrarater reliability of subglottic stenosis grading systems. American journal of otolaryngology, 45(4), 104323.
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  Subglottic stenosis (SGS) is a condition leading to narrowing of the upper airway which can lead to dyspnea and life-threatening airway obstruction. Although other proposed grading systems exist, the Cotton Myer (CM) and percent stenosis systems are the most widespread in clinical practice. Despite this, the CM system has not yet been validated for visual assessment of SGS.
• Bixby, B., Vrba, L., Lenka, J., Oshiro, M. M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2024). Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid. Scientific reports, 14(1), 2939.
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  Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p 
• Jensen, T. O., Grandits, G. A., Jain, M. K., Murray, T. A., Grund, B., Shaw-Saliba, K., Matthay, M. A., Abassi, M., Ardelt, M., Baker, J. V., Chen, P., Dewar, R. L., Goodman, A. L., Hatlen, T. J., Highbarger, H. C., Holodniy, M., Lallemand, P., Laverdure, S., Leshnower, B. G., , Looney, D., et al. (2024). Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19. The Journal of infectious diseases, 229(3), 671-679.
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  Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.
• Jensen, T. O., Murray, T. A., Grandits, G. A., Jain, M. K., Grund, B., Shaw-Saliba, K., Matthay, M. A., Abassi, M., Ardelt, M., Baker, J. V., Chen, P., Dewar, R. L., Goodman, A. L., Hatlen, T. J., Highbarger, H. C., Holodniy, M., Lallemand, P., Laverdure, S., Leshnower, B. G., , Looney, D., et al. (2024). Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study. The Lancet. Microbe, 5(6), e559-e569.
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  Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes.
• Scott, A. M., Bixby, B., & Sam, A. (2024). A Rare Presentation of Disseminated Coccidioidomycosis Requiring Procedural Intervention. Journal of bronchology & interventional pulmonology, 31(1), 82-83.
• Bixby, B., Vrba, L., Lenka, J., Oshiro, M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2023). Cell-Free DNA Methylation Analysis as a Marker of Malignancy in Pleural Fluid. Research square.
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  Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology malignant pleural effusion diagnosis is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion.
• Highland, J., Torrecillas, V., Redding, T., Bixby, B., Iravani, A., Haller, T., Firpo, M., Nouraei, R., & Smith, M. (2023). Optimization of Subglottic View During Flexible Laryngoscopy With Patient Positioning. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery, 169(6), 1556-1563.
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  Determine the ideal head position to optimize visualization of the subglottis using flexible laryngoscopy.
• Jergović, M., Watanabe, M., Bhat, R., Coplen, C. P., Sonar, S. A., Wong, R., Castaneda, Y., Davidson, L., Kala, M., Wilson, R. C., Twigg, H. L., Knox, K., Erickson, H. E., Weinkauf, C. C., Bime, C., Bixby, B. A., Parthasarathy, S., Mosier, J. M., LaFleur, B. J., , Bhattacharya, D., et al. (2023). T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults. GeroScience, 45(3), 1713-1728.
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  In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18-39 years old. To understand age-specific immune pathobiology of COVID-19, we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.
• Kala, M., Weinkauf, C. C., Bixby, B. A., Nikolich-Žugich, J., Bhattacharya, D., LaFleur, B. J., Mosier, J. M., Parthasarathy, S., Bime, C., Erickson, H. E., Knox, K., Twigg, H. L., Wilson, R. C., Davidson, L., Castaneda, Y., Wong, R., Sonar, S. A., Coplen, C. P., Bhat, R., , Watanabe, M., et al. (2023). T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults. GeroScience. doi:10.1007/s11357-022-00724-y
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  In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18–39 years old. To understand age-specific immune pathobiology of COVID-19, we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.
• , A. L., Lundgren, J. D., Grund, B., Barkauskas, C. E., Holland, T. L., Gottlieb, R. L., Sandkovsky, U., Brown, S. M., Knowlton, K. U., Self, W. H., Files, D. C., Jain, M. K., Benfield, T., Bowdish, M. E., Leshnower, B. G., Baker, J. V., Jensen, J. U., Gardner, E. M., Ginde, A. A., , Harris, E. S., et al. (2021). A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. The New England journal of medicine, 384(10), 905-914.
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  LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.
• Harris, D. T., Badowski, M., Jernigan, B., Sprissler, R., Edwards, T., Cohen, R., Paul, S., Merchant, N., Weinkauf, C. C., Bime, C., Erickson, H. E., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., Campion, J., , Chopra, M., et al. (2021). SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus. Biomedicines, 9(5).
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  SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
• Bixby, B. (2020). Core needle biopsy with endobronchial ultrasonography: single center experience with 100 cases. Journal of the American Society of Cytopathology.
• Bixby, B., Maddock, S. D., Reddy, C., Iravani, A., & Ansari, S. (2020). Acquired esophago-respiratory fistulae in adults. Shangai Chest. doi:10.21037/shc.2019.11.06
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  Esophago-respiratory fistulae (ERF) are an uncommon group of abnormal connections between the esophagus and various locations in the respiratory tract. While rare, they confer significant morbidity and mortality, especially given that the majority of ERF in adults are acquired due to malignancy. As a result, management strategies are often complicated and should be undertaken with consultation between oncology, thoracic surgery, gastroenterology, and interventional pulmonary colleagues. In this review article we discuss the epidemiology, clinical presentations, etiologies, and diagnosis of ERF. We also discuss management strategies, complications related to management, and the differences in management between benign and malignant etiologies with a focus on bronchoscopic interventions.
• Bixby, B., Ansari, S., Stringham, J. C., Lee, J., Iravani, A., & Reddy, C. R. (2019). A LIFE-THREATENING PRESENTATION OF A BENIGN ENTITY. Chest. doi:10.1016/j.chest.2019.08.147
• Bixby, B. (2018). Renal replacement therapy in patients with acute respiratory distress syndrome: a single-center retrospective study. International Journal of Nephrology and Renovascular Disease.
• Bixby, B., & Knepler, J. L. (2018). Medical Image of the week: postpneumonectomy syndrome.. Southwest Journal of Pulmonary & Critical Care. 2018;16(6): p. 332-3., 16(6), 332-3.. doi:https://doi.org/10.13175/swjpcc071-18

Proceedings Publications

• Bixby, B., & Upson, S. (2022). The Endobronchial Enigma. In American Thoracic Society.
• Bixby, B., & Upson, S. (2022). The Silent Solitary Fibrous Tumor. In American Thoracic Society.
• Bixby, B., Bixby, B., Sam, A., Sam, A., Scott, A., & Scott, A. (2022). A Rare Presentation of Disseminated Coccidioidomycosis Requiring Mechanical Intervention. In American Thoracic Society.
• Bixby, B., Khemasuwan, D., Shojaee, S., Balwan, A., Sanchez, T., Sorensen, J., & Reddy, C. (2021). Machine Learning Model to Predict Failure of Intrapleural tPA/DNase in Patients with Complicated Parapneumonic Effusions/Empyema: A Multicenter Study. In American Thoracic Society.