Clinical Focus


  • Pulmonary Disease
  • Pulmonary & Critical Care

Honors & Awards


  • Parker B. Francis Fellow 2014, Parker B. Francis Foundation (2014-2017)
  • K08 Awardee, NIH-NHLBI (8/2015)

Professional Education


  • Board Certification: American Board of Internal Medicine, Pulmonary Disease (2008)
  • Board Certification: American Board of Internal Medicine, Critical Care Medicine (2009)
  • Medical Education: Tufts University School of Medicine (2002) MA
  • Fellowship: Stanford University Pulmonary and Critical Care Fellowship (2009) CA
  • Residency: Stanford University Internal Medicine Residency (2005) CA
  • Internship: Stanford University Internal Medicine Residency (2003) CA
  • Residency, Stanford University, Internal Medicine (2005)
  • MPH, Boston University, Epidemiology (1996)

Current Research and Scholarly Interests


My lab is interested in translational research with a focus on pulmonary diseases in immune compromised persons. Using an airway transplant model, we have identified modifiable risk factors that may promote pathogen invasion in lung transplant recipients. We hope that these discoveries will lead to novel treatments for these prevalent infections. I am also the director of the Lung Graft Versus Host Disease clinic. In this clinic we are developing imaging methods for the earlier diagnosis of lung GVHD and conducting a phase II randomized controlled trial to study Pirfenidone for treatment of bronchiolitis obliterans syndrome after hematopoietic cell transplant.

Clinical Trials


  • A Study to Investigate Acute Respiratory Virus Infections in Participants at High Risk for Severe Illness Recruiting

    The purpose of the study is to describe the rate of occurrence of clinical diagnosis of acute respiratory infection (an infection that affects normal breathing) and different types of respiratory pathogens (harmful organisms) of new respiratory infections in a population at high risk for severe illness.

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  • The Longitudinal Impact of Respiratory Viruses on Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Cell Transplantation (The RV-BOS Study) Recruiting

    This observational trial studies whether respiratory viruses are the cause of lung disease (bronchiolitis obliterans syndrome [BOS] or graft-versus-host disease of the lung) and changes in lung function in patients who have received a donor stem cell transplant. Patients with chronic graft-versus-host disease (cGVHD) are at higher risk of developing BOS. Studies have also shown that patients who had a respiratory viral illness early after their transplant are at higher risk of developing lung problems later on. Patients who are at risk and who already have BOS might benefit from being monitored more closely. Spirometry is a way of assessing a patient's lung function and is often used to diagnose lung disease. Spirometry measured at home with a simple handheld device may reduce the burden of performing pulmonary function testing at a facility and potentially help patients get their lung disease diagnosed and treated sooner.

    View full details

  • The Safety and Tolerability of Pirfenidone for BOS After HCT Not Recruiting

    This is a phase 1, non-randomized, single-arm, open label, single center clinical trial to determine the tolerability and safety of pirfenidone in patients with BOS associated with lung GVHD after hematopoietic cell transplant.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joe L Hsu, MD, MPH, 650-725-9536.

    View full details

Stanford Advisees


All Publications


  • Coronavirus Disease-2019 Pneumonia: Clinical Manifestations. Clinics in chest medicine Sharifi, H., Hsu, J. 2023; 44 (2): 227-237

    Abstract

    Coronavirus disease-2019 (COVID-19) pneumonia has diverse clinical manifestations, which have shifted throughout the pandemic. Formal classifications include presymptomatic infection and mild, moderate, severe, and critical illness. Social risk factors are numerous, with Black, Hispanic, and Native American populations in the United States having suffered disproportionately. Biological risk factors such as age, sex, underlying comorbid burden, and certain laboratory metrics can assist the clinician in triage and management. Guidelines for classifying radiographic findings have been proposed and may assist in prognosis. In this article, we review the risk factors, clinical course, complications, and imaging findings of COVID-19 pneumonia.

    View details for DOI 10.1016/j.ccm.2022.11.006

    View details for PubMedID 37085216

    View details for PubMedCentralID PMC9682061

  • NCCN Guidelines Insights: Hematopoietic Cell Transplantation, Version 3.2022. Journal of the National Comprehensive Cancer Network : JNCCN Saad, A., Loren, A., Bolanos-Meade, J., Chen, G., Couriel, D., Di Stasi, A., El-Jawahri, A., Elmariah, H., Farag, S., Gundabolu, K., Gutman, J., Ho, V., Hoeg, R., Horwitz, M., Hsu, J., Kassim, A., Kharfan Dabaja, M., Magenau, J., Martin, T., Mielcarek, M., Moreira, J., Nakamura, R., Nieto, Y., Ninos, C., Oliai, C., Patel, S., Randolph, B., Schroeder, M., Tzachanis, D., Varshavsky-Yanovsky, A. N., Vusirikala, M., Algieri, F., Pluchino, L. A. 2023; 21 (2): 108-115

    Abstract

    The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease-a major complication of allogeneic HCT-to enable the patient and clinician to assess management options in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.

    View details for DOI 10.6004/jnccn.2023.0007

    View details for PubMedID 36791762

  • IMPACT OF C-REACTIVE PROTEIN ON ANTICOAGULATION MONITORING IN EXTRACORPOREAL MEMBRANE OXYGENATION Madhok, J., ODonnell, C., Jin, J., Owyang, C., Weimer, J., Pashun, R., Shudo, Y., McNulty, J., Chadwick, B., Ruoss, S., Rao, V., Zehnder, J., Hsu, J. LIPPINCOTT WILLIAMS & WILKINS. 2023: 54
  • A value-based approach to optimize red blood cell transfusion in patients receiving extracorporeal membrane oxygenation. Perfusion Shudo, Y., Cheng, N., He, H., Rosenberg, C., Hiesinger, W., Hadhazy, E., Shepard, J., Krishna, P., Resnik, J., Fong, R., Hill, C., Hsu, J. L., Maggio, P. M., Chang, S., Boyd, J. H., Woo, Y. J. 2022: 2676591221128138

    Abstract

    INTRODUCTION: The risk, cost, and adverse outcomes associated with packed red blood cell (RBC) transfusions in patients with cardiopulmonary failure requiring extracorporeal membrane oxygenation (ECMO) have raised concerns regarding the overutilization of RBC products. It is, therefore, necessary to establish optimal transfusion criteria and protocols for patients supported with ECMO. The goal of this study was to establish specific criteria for RBC transfusions in patients undergoing ECMO.METHODS: This was a retrospective cohort study conducted at Stanford University Hospital. Data on RBC utilization during the entire hospital stay were obtained, which included patients aged ≥18years who received ECMO support between 1 January 2017, and 30 June 2020 (n = 281). The primary outcome was in-hospital mortality.RESULTS: Hemoglobin (HGB) levels >10g/dL before transfusion did not improve in-hospital survival. Therefore, we revised the HGB threshold to ≤10g/dL to guide transfusion in patients undergoing ECMO. To validate this intervention, we prospectively compared the pre- and post-intervention cohorts for in-hospital mortality. Post-intervention analyses found 100% compliance for all eligible records and a decrease in the requirement for RBC transfusion by 1.2 units per patient without affecting the mortality.CONCLUSIONS: As an institution-driven value-based approach to guide transfusion in patients undergoing ECMO, we lowered the threshold HGB level. Validation of this revised intervention demonstrated excellent compliance and reduced the need for RBC transfusion while maintaining the clinical outcome. Our findings can help reform value-based healthcare in this cohort while maintaining the outcome.

    View details for DOI 10.1177/02676591221128138

    View details for PubMedID 36148806

  • Epidemiology of lower respiratory tract infections and community-acquired respiratory viruses in patients with bronchiolitis obliterans syndrome after hematopoietic cell transplant: a retrospective cohort study. Transplantation and cellular therapy Epstein, D. J., Liang, E. C., Sharifi, H., Lai, Y. K., Arai, S., Graber-Naidich, A., Sundaram, V., Nelson, J., Hsu, J. L. 2022

    Abstract

    Among 55 patients with bronchiolitis obliterans syndrome, 34 (61.8%) developed lower respiratory tract infections, which were associated with impaired lung function and a trend toward increased mortality. Rhinovirus/enterovirus and Pseudomonas aeruginosa infections predominated; 10 (18.2%) patients developed non-tuberculous mycobacterial infections.

    View details for DOI 10.1016/j.jtct.2022.07.016

    View details for PubMedID 35872303

  • Macrophage Lysosomal Alkalinization Drives Invasive Aspergillosis in a Mouse Cystic Fibrosis Model of Airway Transplantation. Journal of fungi (Basel, Switzerland) Matthaiou, E. I., Chiu, W., Conrad, C., Hsu, J. 2022; 8 (7)

    Abstract

    Cystic fibrosis (CF) lung transplant recipients (LTRs) exhibit a disproportionately high rate of life-threatening invasive aspergillosis (IA). Loss of the cystic fibrosis transmembrane conductance regulator (CFTR-/-) in macrophages (mphis) has been associated with lyosomal alkalinization. We hypothesize that this alkalinization would persist in the iron-laden post-transplant microenvironment increasing the risk of IA. To investigate our hypothesis, we developed a murine CF orthotopic tracheal transplant (OTT) model. Iron levels were detected by immunofluorescence staining and colorimetric assays. Aspergillus fumigatus (Af) invasion was evaluated by Grocott methenamine silver staining. Phagocytosis and killing of Af conidia were examined by flow cytometry and confocal microscopy. pH and lysosomal acidification were measured by LysoSensorTM and LysotrackerTM, respectively. Af was more invasive in the CF airway transplant recipient compared to the WT recipient (p < 0.05). CFTR-/- mphis were alkaline at baseline, a characteristic that was increased with iron-overload. These CFTR-/- mphis were unable to phagocytose and kill Af conidia (p < 0.001). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles acidified lysosomes, restoring the CFTR-/- mphis' ability to clear conidia. Our results suggest that CFTR-/- mphis' alkalinization interacts with the iron-loaded transplant microenvironment, decreasing the CF-mphis' ability to kill Af conidia, which may explain the increased risk of IA. Therapeutic pH modulation after transplantation could decrease the risk of IA.

    View details for DOI 10.3390/jof8070751

    View details for PubMedID 35887506

  • Graft-versus-host disease may cause pulmonary restriction, but not all restriction is graft-versus-host disease. Blood advances Sheshadri, A., Huang, H. J., Bashoura, L., Alousi, A. M., Alkhunaizi, M. A., Sharifi, H., Hsu, J. L. 2022

    View details for DOI 10.1182/bloodadvances.2022008201

    View details for PubMedID 35793452

  • The safety and tolerability of pirfenidone for bronchiolitis obliterans syndrome after hematopoietic cell transplant (STOP-BOS) trial. Bone marrow transplantation Matthaiou, E. I., Sharifi, H., O'Donnell, C., Chiu, W., Owyang, C., Chatterjee, P., Turk, I., Johnston, L., Brondstetter, T., Morris, K., Cheng, G., Hsu, J. L. 2022

    Abstract

    Bronchiolitis obliterans syndrome (BOS) is the most morbid form of chronic graft-versus-host disease (cGVHD) after hematopoietic cell transplantation (HCT). Progressive airway fibrosis leads to a 5-year survival of 40%. Treatment options for BOS are limited. A single arm, 52-week, Phase I study of pirfenidone was conducted. The primary outcome was tolerability defined as maintaining the recommended dose of pirfenidone (2403mg/day) without a dose reduction totaling more than 21 days, due to adverse events (AEs) or severe AEs (SAEs). Secondary outcomes included pulmonary function tests (PFTs) and patient reported outcomes (PROs). Among 22 participants treated for 1 year, 13 (59%) tolerated the recommended dose, with an average daily tolerated dose of 2325.6mg/day. Twenty-two SAEs were observed, with 90.9% related to infections, none were attributed to pirfenidone. There was an increase in the average percent predicted forced expiratory volume in 1s (FEV1%) of 7 percentage points annually and improvements in PROs related to symptoms of cGVHD. In this Phase I study, treatment with pirfenidone was safe. The stabilization in PFTs and improvements in PROs suggest the potential of pirfenidone for BOS treatment and support the value of a randomized controlled trial to evaluate the efficacy of pirfenidone in BOS after HCT. The study is registered in ClinicalTrials.gov (NCT03315741).

    View details for DOI 10.1038/s41409-022-01716-4

    View details for PubMedID 35641662

  • From Mass to Flow: Emerging Sepsis Diagnostics Based on Flow Cytometry Analysis of Neutrophils. American journal of respiratory and critical care medicine Verdonk, F., Hsu, J. L., Gaudilliere, B. 2021

    View details for DOI 10.1164/rccm.202110-2291ED

    View details for PubMedID 34788202

  • Harnessing the Potential of Multiomics Studies for Precision Medicine in Infectious Disease. Open forum infectious diseases Ward, R. A., Aghaeepour, N., Bhattacharyya, R. P., Clish, C. B., Gaudilliere, B., Hacohen, N., Mansour, M. K., Mudd, P. A., Pasupneti, S., Presti, R. M., Rhee, E. P., Sen, P., Spec, A., Tam, J. M., Villani, A., Woolley, A. E., Hsu, J. L., Vyas, J. M. 2021; 8 (11): ofab483

    Abstract

    The field of infectious diseases currently takes a reactive approach and treats infections as they present in patients. Although certain populations are known to be at greater risk of developing infection (eg, immunocompromised), we lack a systems approach to define the true risk of future infection for a patient. Guided by impressive gains in "omics" technologies, future strategies to infectious diseases should take a precision approach to infection through identification of patients at intermediate and high-risk of infection and deploy targeted preventative measures (ie, prophylaxis). The advances of high-throughput immune profiling by multiomics approaches (ie, transcriptomics, epigenomics, metabolomics, proteomics) hold the promise to identify patients at increased risk of infection and enable risk-stratifying approaches to be applied in the clinic. Integration of patient-specific data using machine learning improves the effectiveness of prediction, providing the necessary technologies needed to propel the field of infectious diseases medicine into the era of personalized medicine.

    View details for DOI 10.1093/ofid/ofab483

    View details for PubMedID 34805429

  • Head-to-head Comparison of Qualitative Radiologist Assessment With Automated Quantitative Computed Tomography Analysis for Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplantation. Journal of thoracic imaging Sharifi, H., Guenther, Z. D., Leung, A. N., Johnston, L., Lai, Y. K., Hsu, J. L., Guo, H. H. 2021

    Abstract

    PURPOSE: Computed tomography (CT) findings of bronchiolitis obliterans syndrome (BOS) can be nonspecific and variable. This study aims to measure the incremental value of automated quantitative lung CT analysis to clinical CT interpretation. A head-to-head comparison of quantitative CT lung density analysis by parametric response mapping (PRM) with qualitative radiologist performance in BOS diagnosis was performed.MATERIALS AND METHODS: Inspiratory and end-expiratory CTs of 65 patients referred to a post-bone marrow transplant lung graft-versus-host-disease clinic were reviewed by 3 thoracic radiologists for the presence of mosaic attenuation, centrilobular opacities, airways dilation, and bronchial wall thickening. Radiologists' majority consensus diagnosis of BOS was compared with automated PRM air trapping quantification and to the gold-standard diagnosis of BOS as per National Institutes of Health (NIH) consensus criteria.RESULTS: Using a previously established threshold of 28% air trapping on PRM, the diagnostic performance for BOS was as follows: sensitivity 56% and specificity 94% (area under the receiver operator curve [AUC]=0.75). Radiologist review of inspiratory CT images alone resulted in a sensitivity of 80% and a specificity of 69% (AUC=0.74). When radiologists assessed both inspiratory and end-expiratory CT images in combination, the sensitivity was 92% and the specificity was 59% (AUC=0.75). The highest performance was observed when the quantitative PRM report was reviewed alongside inspiratory and end-expiratory CT images, with a sensitivity of 92% and a specificity of 73% (AUC=0.83).CONCLUSIONS: In the CT diagnosis of BOS, qualitative expert radiologist interpretation was noninferior to quantitative PRM. The highest level of diagnostic performance was achieved by the combination of quantitative PRM measurements with qualitative image feature assessments.

    View details for DOI 10.1097/RTI.0000000000000595

    View details for PubMedID 33999570

  • The Use of Factor Eight Inhibitor Bypass Activity (FEIBA) for the Treatment of Perioperative Hemorrhage in Left Ventricular Assist Device Implantation. Journal of cardiothoracic and vascular anesthesia O'Donnell, C., Rodriguez, A. J., Madhok, J., Sharifi, H., Wang, H., O'Brien, C. G., Boyd, J., Hiesinger, W., Hsu, J., Hill, C. C. 2021

    Abstract

    OBJECTIVE: To test the hypothesis that factor eight inhibitor bypassing activity (FEIBA) can be used to control bleeding following left ventricular assist device (LVAD) implantation without increasing the 14-day composite thrombotic outcome of pump thrombus, ischemic cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis.DESIGN: Retrospective cohort study.SETTING: Academic hospital.PARTICIPANTS: Three hundred nineteen consecutive patients who underwent LVAD implantation (December 1, 2009 to December 30, 2018).INTERVENTION: FEIBA administered to control perioperative hemorrhage.MEASUREMENTS AND MAIN RESULTS: The 82 patients (25.7%) in the FEIBA cohort had more risk factors for perioperative hemorrhage, such as lower preoperative platelet count (169 ± 66 v 194 ± 68 * 103/mL, p = 0.004), prior cardiac surgery (36.6% v 21.9%, p = 0.008), and longer cardiopulmonary bypass (CPB) time (100.3 v 75.2 minutes, p = 0.001) than the 237 controls. After 16.6 units (95% CI: 14.3-18.9) of blood products were given, 992 units (95% CI: 821-1163) of FEIBA were required to control bleeding in the FEIBA cohort. Compared to the controls, there were no differences in the 14-day composite thrombotic outcome (11.0% v 7.6%, p = 0.343) or mortality rate (3.7% v 1.3%, p = 0.179). Multivariate logistical regression identified preoperative international normalized ratio (odds ratio [OR]: 1.30, 95% CI: 1.04-1.62) and CPB time (OR: 1.11, 95% CI: 1.02-1.20) as risk factors for 14-day thrombotic events, but FEIBA usage was not associated with an increased risk.CONCLUSIONS: In this retrospective cohort study, the use of FEIBA (1,000 units, 13 units/kg) to control perioperative hemorrhage following LVAD implantation was not associated with increases in mortality or composite thrombotic outcome.

    View details for DOI 10.1053/j.jvca.2021.04.030

    View details for PubMedID 34034934

  • Thoracic epidural analgesia in a lung transplant patient with an activated partial thromboplastin time falsely elevated by C-reactive protein. Canadian journal of anaesthesia = Journal canadien d'anesthesie Simon, E. R., Hsu, J., Nwokeabia, D., Leong, M., Keeyapaj, W. 2021

    View details for DOI 10.1007/s12630-021-01946-y

    View details for PubMedID 33598886

  • THE SAFETY AND EFFICACY OF PERIOPERATIVE FEIBA AFTER LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION ODonnell, C., Rodriguez, A., Madhok, J., Wang, H., Shad, R., Sharifi, H., Boyd, J., William, H., Hsu, J., Hill, C. LIPPINCOTT WILLIAMS & WILKINS. 2021: 168
  • Hematopoietic Cell Transplantation Version 2.2020 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Saad, A., de Lima, M., Anand, S., Bhatt, V., Bookout, R., Chen, G., Couriel, D., Di Stasi, A., El-Jawahri, A., Giralt, S., Gutman, J., Ho, V., Horwitz, M., Hsu, J., Juckett, M., Dabaja, M., Loren, A. W., Meade, J., Mielcarek, M., Moreira, J., Nakamura, R., Nieto, Y., Roddy, J., Satyanarayana, G., Schroeder, M., Tan, C., Tzachanis, D., Burns, J. L., Pluchino, L. A. 2020; 18 (5): 599–634
  • Physiology of the Assisted Circulation in Cardiogenic Shock: A State-of-the-Art Perspective. The Canadian journal of cardiology Guihaire, J., Haddad, F., Hoppenfeld, M., Amsallem, M., Christle, J. W., Owyang, C., Shaikh, K., Hsu, J. L. 2020; 36 (2): 170–83

    Abstract

    Mechanical circulatory support (MCS) has made rapid progress over the last 3 decades. This was driven by the need to develop acute and chronic circulatory support as well as by the limited organ availability for heart transplantation. The growth of MCS was also driven by the use of extracorporeal membrane oxygenation (ECMO) after the worldwide H1N1 influenza outbreak of 2009. The majority of mechanical pumps (ECMO and left ventricular assist devices) are currently based on continuous flow pump design. It is interesting to note that in the current era, we have reverted from the mammalian pulsatile heart back to the continuous flow pumps seen in our simple multicellular ancestors. This review will highlight key physiological concepts of the assisted circulation from its effects on cardiac dynamic to principles of cardiopulmonary fitness. We will also examine the physiological principles of the ECMO-assisted circulation, anticoagulation, and the haemocompatibility challenges that arise when the blood is exposed to a foreign mechanical circuit. Finally, we conclude with a perspective on smart design for future development of devices used for MCS.

    View details for DOI 10.1016/j.cjca.2019.11.002

    View details for PubMedID 32036862

  • Machine learning algorithms to differentiate among pulmonary complications after hematopoietic cell transplant. Chest Sharifi, H. n., Lai, Y. K., Guo, H. n., Hoppenfeld, M. n., Guenther, Z. D., Johnston, L. n., Brondstetter, T. n., Chhatwani, L. n., Nicolls, M. R., Hsu, J. L. 2020

    Abstract

    Pulmonary complications, including infections, are highly prevalent in patients after hematopoietic cell transplant with chronic graft-versus-host disease. These comorbid diseases can make the diagnosis of early lung graft-versus-host disease (bronchiolitis obliterans syndrome) challenging. A quantitative method to differentiate among these pulmonary diseases can address diagnostic challenges and facilitate earlier and more targeted therapy.We conducted a single center study of 66 patients with computed tomography chest scans analyzed with a quantitative imaging tool known as parametric response mapping. Parametric response mapping results were correlated with pulmonary function tests and clinical characteristics. Five parametric response mapping metrics were applied to K-means clustering and support vector machine models to distinguish among post-transplant lung complications solely from quantitative output.Compared to parametric response mapping, spirometry showed a moderate correlation with radiographic air trapping, and total lung capacity and residual volume showed a strong correlation with radiographic lung volumes. K-means clustering analysis distinguished 4 unique clusters. Clusters 2 and 3 represented obstructive physiology (encompassing 81% of patients with bronchiolitis obliterans syndrome) in increasing severity (percent air trapping 15.6% and 43.0%, respectively). Cluster 1 was dominated by normal lung, and cluster 4 was characterized by patients with parenchymal opacities. A support vector machine algorithm differentiated bronchiolitis obliterans syndrome with specificity of 88%, sensitivity of 83%, accuracy of 86% and an area under the receiver operating characteristic curve of 0.85.Our machine learning models offer a quantitative approach for the identification of bronchiolitis obliterans syndrome versus other lung diseases, including late pulmonary complications after hematopoietic cell transplant.

    View details for DOI 10.1016/j.chest.2020.02.076

    View details for PubMedID 32343962

  • Differences in prevalence of ICU protocols between neurologic and non-neurologic patient populations JOURNAL OF CRITICAL CARE Billington, M. E., Seethala, R. R., Hou, P. C., Takhar, S. S., Askari, R., Aisiku, I. P., O'Keeffe, T., Collins, C., Rokowski, L., Liebler, J., Ahoui, A., Nersiseyan, A., Shah, U., Shigemitsu, H., Thaiyananthan, N., Hsu, J., Ho, L., Barr, J., Kaufman, D., Siner, J. M., Siegel, M. D., Martin, G. S., Coopersmith, C., Fisher, M., Gutteridge, D., Brown, M., SangLee, Smith, A., Leeper, K., Cribbs, S., Esper, A., Dosunmu, O., Ka, W., Hassan, Z., Ridder, J., Atkinson, M., Draftz, A., Durgin, J., Rikhman, Y., Sheckel, J., Walthers, M., Luger, G., Downer, C., Sadikot, R. T., Javaid, K., Rodgers, D., Sharma, V., Sevransky, J., Checkley, W., Geocadin, R., Murphy, D., Needham, D., Sapirstein, A., Schwartz, S., Whitman, G., Winters, B., Workneh, A., Zakaria, S., Keith, F., Johnson, S., Herr, D., Shanholtz, G., Sampaio, A., Titus, J., Eberlein, M., Rotello, L., Anderson, J., Shahul, S., Howell, M., Hunziker, S., Nielsen, V., Stevens, J., Talmor, D., Patil, N., Chin, L., Myers, M., Ryan, S., Bander, J., Park, P., Blum, J., Arora, V., Brierley, K., DeVito, J., Harris, J., Jewell, E., Rohner, D., To, K., Pickering, B. W., Giru, J., Kashyap, R., Trivedi, N., Dwyer, T., Brownback, K., Chang, S., Cohen, Z., Italian, F., Kahn, Z., Patrawalla, A., Gonzales, D., Campbell, P., Chong, D., Yip, N., Pastores, S. M., Pietropaoli, A., Falluter, K., Bouck, T., Mattingly, A., Morris, P. E., Flores, L. S., Butt, A., Mazer, M., Jernigan, K., Wright, P., Grote, S., McLean, J., Overton, A., Guzman, J. A., El Fadl, M., Frederick, T., Gustavo-Cumbo-Nacheli, Komara, J., O'Brien, J. M., Ali, N., Exline, M., Hoag, J., Albu, D., McLaughlin, P., Abramian, E., Zeibeq, J., Prasad, M., Zuick, S., Fremont, R. D., Emuwa, C. O., Nwazue, V. C., Owolabi, O. S., Cotton, B., Hart, G., Jenkins, J., Rice, T. W., Girard, T. D., Hays, M., Mogan, S., Brown, S., Grissom, C., Miller, R., Austin, A., Gallo, H., Kumar, N., Putman, M., Ondrush, J., USIITG-CIOS Investigators 2019; 52: 63–67

    Abstract

    To compare the differences in the presence of protocols aimed at addressing complications for neurologically injured patients vs. non-neurologic injured patients in a large sample of ICUs across the United States.Prospective observational multi-center cohort study. This was a subgroup analysis of the multi-centered prospective observational cohort study of medical, surgical, and mixed intensive care units from across the country. USCIITG-CIOS study group.Sixty-nine ICUs participated in the study of which 25 (36%) were medical, 24 were surgical (35%) and 20 (29%) were of mixed type, and 64 (93%) were in teaching hospitals. There were 6179 patients across all sites with 1266 (20.4%) with central nervous system diagnoses. Protocol utilization in central nervous system vs. non- central nervous system patients was as follows: Sedation interruption 973/1266 (76.9%) vs. 3840/4913 (78.2%) (p = .32); acute lung injury ventilation 847/1266 (66.9%) vs. 4069/4913 (82.8%) (p < .0001); ventilator associated pneumonia 1193/1266 (94.2%) vs. 4760/4913 (96.9%) (p < .0001); ventilator weaning 1193/1266 (94.2%) vs. 4490/4913 (91.4%) (p = .0009); and early mobility 378/1266 (29.9%) vs. 1736/4913 (35.3%) (p = .0002).In this cohort, we found differences in the prevalence of respiratory illness prevention protocols between critically ill patients with neurologic illness and the general critically ill population.

    View details for DOI 10.1016/j.jcrc.2019.03.002

    View details for Web of Science ID 000471240500010

    View details for PubMedID 30981927

  • Iron: an essential nutrient for Aspergillus fumigatus and a fulcrum for pathogenesis. Current opinion in infectious diseases Matthaiou, E. I., Sass, G., Stevens, D. A., Hsu, J. L. 2018; 31 (6): 506–11

    Abstract

    PURPOSE OF REVIEW: Aspergillus fumigatus is a ubiquitous saprophytic fungus that can cause life-threatening invasive aspergillosis in immunocompromised patients. Apart from the immune status of the host only a few characterized virulence factors have been identified. In this review, we describe the role of iron in the manifestation of A. fumigatus virulence.RECENT FINDINGS: We gathered recent clinical evidence suggesting that tissue iron overload increases the risk of invasive aspergillosis occurrence. Furthermore, we summarize the mechanisms that A. fumigatus employs to achieve iron homeostasis and their importance in A. fumigatus proliferation in vitro. We describe two recent in-vivo models that clearly demonstrate the importance of iron in A. fumigatus growth and invasion.SUMMARY: Based on these recent findings, therapy aimed at managing A. fumigatus iron homeostasis locally could make conditions more favorable to the host.

    View details for PubMedID 30379731

  • Microhemorrhage-associated tissue iron enhances the risk forAspergillus fumigatusinvasion in a mouse model of airway transplantation. Science translational medicine Hsu, J. L., Manouvakhova, O. V., Clemons, K. V., Inayathullah, M. n., Tu, A. B., Sobel, R. A., Tian, A. n., Nazik, H. n., Pothineni, V. R., Pasupneti, S. n., Jiang, X. n., Dhillon, G. S., Bedi, H. n., Rajadas, J. n., Haas, H. n., Aurelian, L. n., Stevens, D. A., Nicolls, M. R. 2018; 10 (429)

    Abstract

    Invasive pulmonary disease due to the moldAspergillus fumigatuscan be life-threatening in lung transplant recipients, but the risk factors remain poorly understood. To study this process, we used a tracheal allograft mouse model that recapitulates large airway changes observed in patients undergoing lung transplantation. We report that microhemorrhage-related iron content may be a major determinant ofA. fumigatusinvasion and, consequently, its virulence. Invasive growth was increased during progressive alloimmune-mediated graft rejection associated with high concentrations of ferric iron in the graft. The role of iron inA. fumigatusinvasive growth was further confirmed by showing that this invasive phenotype was increased in tracheal transplants from donor mice lacking the hemochromatosis gene (Hfe -/- ). The invasive phenotype was also increased in mouse syngrafts treated with topical iron solution and in allograft recipients receiving deferoxamine, a chelator that increases iron bioavailability to the mold. The invasive growth of the iron-intolerantA. fumigatusdouble-knockout mutant (ΔsreA/ΔcccA) was lower than that of the wild-type mold. Alloimmune-mediated microvascular damage and iron overload did not appear to impair the host's immune response. In human lung transplant recipients, positive staining for iron in lung transplant tissue was more commonly seen in endobronchial biopsy sections from transplanted airways than in biopsies from the patients' own airways. Collectively, these data identify iron as a major determinant ofA. fumigatusinvasive growth and a potential target to treat or preventA. fumigatusinfections in lung transplant patients.

    View details for PubMedID 29467298

  • Pulmonary Infections in Immunocompromised Hosts: Clinical. Journal of thoracic imaging Vazquez Guillamet, C. n., Hsu, J. L., Dhillon, G. n., Vazquez Guillamet, R. n. 2018

    Abstract

    Pulmonary infections in immunocompromised patients remain a significant contributor to mortality, morbidity, and health care-associated costs in such a vulnerable patient population. Their epidemiology is changing, set forth by new trends in immunosuppressive regimens and also prophylaxis. The host characteristics, presenting clinical symptomatology, along with radiographic patterns, have also evolved. The microbiology diagnostics are now enriched with nonculture methods for better identification of the causative pathogens. Chest imaging remains the cornerstone of the initial workup. Our article will examine the new trends in epidemiology, clinical findings, and diagnostics for immunocompromised patients with pulmonary infections (transplant recipients, neutropenic hosts, HIV-infected patients, and patients with autoimmune conditions). We will also review the differential diagnosis that most of the times includes malignancies and drug or radiation-related toxicities.

    View details for PubMedID 30048345

  • Aspergillus-related pulmonary diseases in lung transplantation MEDICAL MYCOLOGY Pasupneti, S., Manouvakhova, O., Nicolls, M. R., Hsu, J. L. 2017; 55 (1): 96-102

    Abstract

    While lung transplantation is an attractive treatment option for many end stage lung diseases, the relatively high 5-year mortality continues to be a significant limiting factor. Among the foremost reasons for this is the eventual development of obstructive chronic lung allograft dysfunction. Infections, which the lung allograft is especially prone to, are a major risk factor. Specifically, the Aspergillus species cause a higher burden of disease among lung transplant recipients, due to unique risk factors, such as relative hypoxemia. However, these risk factors also provide unique opportunities for treatment and preventative strategies, as outlined in this review.

    View details for DOI 10.1093/mmy/myw121

    View details for Web of Science ID 000393896500013

  • Enhanced Electrochemical Sensing with Carbon Nanotubes Modified with Bismuth and Magnetic Nanoparticles in a Lab-on-a-Chip CHEMNANOMAT Jothimuthu, P., Hsu, J. L., Chen, R., Inayathullah, M., Pothineni, V. R., Jan, A., Gurtner, G. C., Rajadas, J., Nicolls, M. R. 2016; 2 (9): 904-910

    Abstract

    Iron plays an especially important role in human physiological functions and pathological impairments. The superior properties of carbon nanotubes (CNTs) and their modification with bismuth and magnetic nanoparticles as developed in this work have led to an extraordinary and novel material to facilitate ultrasensitive detection in the nanomolar range. Here, we present the development of an electrochemical sensor for detection of ferrous (Fe(2+)) and ferric (Fe(3+)) iron by means of CNTs modified with bismuth and magnetic nanoparticles for higher sensitivity of detection. The sensor fabrication includes microfabrication methodologies, soft lithography, and electrodeposition. Cyclic voltammetry and differential pulse voltammetry are used for the electroanalytical studies and detection of the ions in samples. The sensor has a dynamic range of detection from 0.01 nm to 10 mm. The performance of the sensor with modified CNTs was explored for sensitivity and specificity. CNTs, modified with bismuth and magnetic nanoparticles by means of electrodeposition, enhanced the detection limit significantly down to 0.01 nm.

    View details for DOI 10.1002/cnma.201600174

    View details for Web of Science ID 000383766800009

    View details for PubMedCentralID PMC5110256

  • Enhanced Electrochemical Sensing with Carbon Nanotubes Modified with Bismuth and Magnetic Nanoparticles in a Lab-on-a-Chip. ChemNanoMat : chemistry of nanomaterials for energy, biology and more Jothimuthu, P., Hsu, J. L., Chen, R., Inayathullah, M., Pothineni, V. R., Jan, A., Gurtner, G. C., Rajadas, J., Nicolls, M. R. 2016; 2 (9): 904-910

    Abstract

    Iron plays an especially important role in human physiological functions and pathological impairments. The superior properties of carbon nanotubes (CNTs) and their modification with bismuth and magnetic nanoparticles as developed in this work have led to an extraordinary and novel material to facilitate ultrasensitive detection in the nanomolar range. Here, we present the development of an electrochemical sensor for detection of ferrous (Fe(2+)) and ferric (Fe(3+)) iron by means of CNTs modified with bismuth and magnetic nanoparticles for higher sensitivity of detection. The sensor fabrication includes microfabrication methodologies, soft lithography, and electrodeposition. Cyclic voltammetry and differential pulse voltammetry are used for the electroanalytical studies and detection of the ions in samples. The sensor has a dynamic range of detection from 0.01 nm to 10 mm. The performance of the sensor with modified CNTs was explored for sensitivity and specificity. CNTs, modified with bismuth and magnetic nanoparticles by means of electrodeposition, enhanced the detection limit significantly down to 0.01 nm.

    View details for DOI 10.1002/cnma.201600174

    View details for PubMedID 27857882

    View details for PubMedCentralID PMC5110256

  • Microvascular injury after lung transplantation CURRENT OPINION IN ORGAN TRANSPLANTATION Nicolls, M. R., Hsu, J. L., Jiang, X. 2016; 21 (3): 279-284

    Abstract

    Airway microvessel injury following transplantation has been implicated in the development of chronic rejection. This review focuses on the most recent developments in the field describing preclinical and clinical findings that further implicate the loss of microvascular integrity as an important pathological event in the evolution of irreversible fibrotic remodeling.When lungs are transplanted, the airways appear vulnerable from the perspective of perfusion. Two vascular systems are lost, the bronchial artery and the lymphatic circulations, and the remaining vasculature in the airways expresses donor antigens susceptible to alloimmune-mediated injury via innate and adaptive immune mechanisms. Preclinical studies indicate the importance of hypoxia-inducible factor-1α in mediating microvascular repair and that hypoxia-inducible factor-1α can be upregulated to bolster endogenous repair.Airway microvascular injury is a feature of lung transplantation that limits short-term and long-term organ health. Although some problems are attributable to a missing bronchial artery circulation, another significant issue involves alloimmune-mediated injury to transplant airway microvessels. For a variety of reasons, bronchial artery revascularization surgery at the time of transplantation has not been widely adopted, and the current best hope for this era may be new medical approaches that offer protection against immune-mediated vascular injury or that promote microvascular repair.

    View details for DOI 10.1097/MOT.0000000000000307

    View details for Web of Science ID 000376015500007

    View details for PubMedID 26967995

  • Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Nazik, H., Penner, J. C., Ferreira, J. A., Haagensen, J. A., Cohen, K., Spormann, A. M., Martinez, M., Chen, V., Hsu, J. L., Clemons, K. V., Stevens, D. A. 2015; 59 (10): 6514-6520

    Abstract

    Iron acquisition is crucial for the growth of Aspergillus fumigatus. A. fumigatus biofilm formation occurs in vitro and in vivo and is associated with physiological changes. In this study, we assessed the effects of Fe chelators on biofilm formation and development. Deferiprone (DFP), deferasirox (DFS), and deferoxamine (DFM) were tested for MIC against a reference isolate via a broth macrodilution method. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to DFP, DFM, DFP plus FeCl3, or FeCl3 alone. A preformed biofilm was exposed to DFP with or without FeCl3. The DFP and DFS MIC50 against planktonic A. fumigatus was 1,250 μM, and XTT gave the same result. DFM showed no planktonic inhibition at concentrations of ≤2,500 μM. By XTT testing, DFM concentrations of <1,250 μM had no effect, whereas DFP at 2,500 μM increased biofilms forming in A. fumigatus or preformed biofilms (P < 0.01). DFP at 156 to 2,500 μM inhibited biofilm formation (P < 0.01 to 0.001) in a dose-responsive manner. Biofilm formation with 625 μM DFP plus any concentration of FeCl3 was lower than that in the controls (P < 0.05 to 0.001). FeCl3 at ≥625 μM reversed the DFP inhibitory effect (P < 0.05 to 0.01), but the reversal was incomplete compared to the controls (P < 0.05 to 0.01). For preformed biofilms, DFP in the range of ≥625 to 1,250 μM was inhibitory compared to the controls (P < 0.01 to 0.001). FeCl3 at ≥625 μM overcame inhibition by 625 μM DFP (P < 0.001). FeCl3 alone at ≥156 μM stimulated biofilm formation (P < 0.05 to 0.001). Preformed A. fumigatus biofilm increased with 2,500 μM FeCl3 only (P < 0.05). In a strain survey, various susceptibilities of biofilms of A. fumigatus clinical isolates to DFP were noted. In conclusion, iron stimulates biofilm formation and preformed biofilms. Chelators can inhibit or enhance biofilms. Chelation may be a potential therapy for A. fumigatus, but we show here that chelators must be chosen carefully. Individual isolate susceptibility assessments may be needed.

    View details for DOI 10.1128/AAC.01684-15

    View details for Web of Science ID 000367591800078

    View details for PubMedCentralID PMC4576070

  • Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm. Antimicrobial agents and chemotherapy Nazik, H., Penner, J. C., Ferreira, J. A., Haagensen, J. A., Cohen, K., Spormann, A. M., Martinez, M., Chen, V., Hsu, J. L., Clemons, K. V., Stevens, D. A. 2015; 59 (10): 6514-20

    Abstract

    Iron acquisition is crucial for the growth of Aspergillus fumigatus. A. fumigatus biofilm formation occurs in vitro and in vivo and is associated with physiological changes. In this study, we assessed the effects of Fe chelators on biofilm formation and development. Deferiprone (DFP), deferasirox (DFS), and deferoxamine (DFM) were tested for MIC against a reference isolate via a broth macrodilution method. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to DFP, DFM, DFP plus FeCl3, or FeCl3 alone. A preformed biofilm was exposed to DFP with or without FeCl3. The DFP and DFS MIC50 against planktonic A. fumigatus was 1,250 μM, and XTT gave the same result. DFM showed no planktonic inhibition at concentrations of ≤2,500 μM. By XTT testing, DFM concentrations of <1,250 μM had no effect, whereas DFP at 2,500 μM increased biofilms forming in A. fumigatus or preformed biofilms (P < 0.01). DFP at 156 to 2,500 μM inhibited biofilm formation (P < 0.01 to 0.001) in a dose-responsive manner. Biofilm formation with 625 μM DFP plus any concentration of FeCl3 was lower than that in the controls (P < 0.05 to 0.001). FeCl3 at ≥625 μM reversed the DFP inhibitory effect (P < 0.05 to 0.01), but the reversal was incomplete compared to the controls (P < 0.05 to 0.01). For preformed biofilms, DFP in the range of ≥625 to 1,250 μM was inhibitory compared to the controls (P < 0.01 to 0.001). FeCl3 at ≥625 μM overcame inhibition by 625 μM DFP (P < 0.001). FeCl3 alone at ≥156 μM stimulated biofilm formation (P < 0.05 to 0.001). Preformed A. fumigatus biofilm increased with 2,500 μM FeCl3 only (P < 0.05). In a strain survey, various susceptibilities of biofilms of A. fumigatus clinical isolates to DFP were noted. In conclusion, iron stimulates biofilm formation and preformed biofilms. Chelators can inhibit or enhance biofilms. Chelation may be a potential therapy for A. fumigatus, but we show here that chelators must be chosen carefully. Individual isolate susceptibility assessments may be needed.

    View details for DOI 10.1128/AAC.01684-15

    View details for PubMedID 26239975

    View details for PubMedCentralID PMC4576070

  • Targeted complement inhibition and microvasculature in transplants: a therapeutic perspective. Clinical and experimental immunology Khan, M. A., Hsu, J. L., Assiri, A. M., Broering, D. C. 2015

    Abstract

    Active complement mediators play a key role in graft-versus-host diseases, but little attention has been given to the angiogenic balance and complement modulation during allograft acceptance. The complement cascade releases the powerful proinflammatory mediators C3a and C5a anaphylatoxins, C3b, C5b opsonins and terminal membrane attack complex into tissues, which are deleterious if unchecked. Blocking complement mediators has been considered to be a promising approach in the modern drug discovery plan, and a significant number of therapeutic alternatives have been developed to dampen complement activation and protect host cells. Numerous immune cells, especially macrophages, develop both anaphylatoxin and opsonin receptors on their cell surface and their binding affects the macrophage phenotype and their angiogenic properties. This review discusses the mechanism that complement contributes to angiogenic injury, and the development of future therapeutic targets by antagonizing activated complement mediators to preserve microvasculature in rejecting the transplanted organ.

    View details for DOI 10.1111/cei.12713

    View details for PubMedID 26404106

  • Erratum for Nazik et al., effects of iron chelators on the formation and development of Aspergillus fumigatus biofilm. Antimicrobial agents and chemotherapy Nazik, H. n., Penner, J. C., Ferreira, J. A., Haagensen, J. A., Cohen, K. n., Spormann, A. M., Martinez, M. n., Chen, V. n., Hsu, J. L., Clemons, K. V., Stevens, D. A. 2015; 59 (11): 7160

    View details for PubMedID 26464401

  • Efficacy of Transthoracic Echocardiography for Diagnosing Heart Failure in Septic Shock AMERICAN JOURNAL OF THE MEDICAL SCIENCES Beraud, A., Guillamet, C. V., Hammes, J. L., Meng, L., Nicolls, M. R., Hsu, J. L. 2014; 347 (4): 295-298

    Abstract

    Cardiac dysfunction occurs in up to 80% of patients with septic shock. Transthoracic echocardiography (TTE) is an ideal tool for the detailed characterization of cardiac function. Its feasibility is perceived to be poor in critically ill patients, but this has never been studied. To address this question, the authors evaluated the efficacy of TTE to diagnose heart failure in septic shock.This was a retrospective study. Patients admitted to the intensive care unit with septic shock and who had a TTE within 72 hours of intensive care unit admission were identified by a computer algorithm and validated by chart review. Echocardiography images were reviewed by a single cardiologist blinded to clinical outcomes. Clinical information was collected from patients' medical record.Seventy-six patients met the studies' inclusion criteria. The feasibility of TTE to calculate left ventricular ejection fraction was 90% and to assess diastolic function was 74%. Significant mitral regurgitation or aortic stenosis was the most frequent impediments for the assessment of diastolic function. Seventy-four percent of all patients showed some type of cardiac dysfunction (left or right ventricular systolic dysfunction and/or left ventricular diastolic dysfunction). In regression analyses, TTE feasibility was not impacted by factors previously associated with poor image acquisition: high body mass index, mechanical ventilation, tachycardia, advanced age or high severity of illness.This study demonstrated that TTE is a useful tool to assess myocardial function in critically ill patients and suggested its potential to assist in the management of patients with septic shock.

    View details for DOI 10.1097/MAJ.0b013e318297d616

    View details for Web of Science ID 000335788700008

    View details for PubMedID 24051955

  • Application of a non-amplification-based technology to detect invasive fungal pathogens DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE Hsu, J. L., Binkley, J., Clemons, K. V., Stevens, D. A., Nicolls, M. R., Holodniy, M. 2014; 78 (2): 137-140

    Abstract

    Current diagnostic techniques for fungal diseases could be improved with respect to sensitivity, specificity, and timeliness. To address this clinical need, we adapted a non-amplification-based nucleic acid detection technology to identify fungal pathogens. We demonstrate a high-specificity, detection sensitivity, reproducibility, and multiplex capacity for detecting fungal strains.

    View details for DOI 10.1016/j.diagmicrobio.2013.11.013

    View details for Web of Science ID 000330149700007

    View details for PubMedID 24359934

  • Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles. Biomaterials Jiang, X., Malkovskiy, A. V., Tian, W., Sung, Y. K., Sun, W., Hsu, J. L., Manickam, S., Wagh, D., Joubert, L., Semenza, G. L., Rajadas, J., Nicolls, M. R. 2014; 35 (2): 803-813

    Abstract

    Airway tissue ischemia and hypoxia in human lung transplantation is a consequence of the sacrifice of the bronchial circulation during the surgical procedure and is a major risk factor for the development of airway anastomotic complications. Augmented expression of hypoxia-inducible factor (HIF)-1α promotes microvascular repair and alleviates allograft ischemia and hypoxia. Deferoxamine mesylate (DFO) is an FDA-approved iron chelator which has been shown to upregulate cellular HIF-1α. Here, we developed a nanoparticle formulation of DFO that can be topically applied to airway transplants at the time of surgery. In a mouse orthotopic tracheal transplant (OTT) model, the DFO nanoparticle was highly effective in enhancing airway microvascular perfusion following transplantation through the production of the angiogenic factors, placental growth factor (PLGF) and stromal cell-derived factor (SDF)-1. The endothelial cells in DFO treated airways displayed higher levels of p-eNOS and Ki67, less apoptosis, and decreased production of perivascular reactive oxygen species (ROS) compared to vehicle-treated airways. In summary, a DFO formulation topically-applied at the time of surgery successfully augmented airway anastomotic microvascular regeneration and the repair of alloimmune-injured microvasculature. This approach may be an effective topical transplant-conditioning therapy for preventing airway complications following clinical lung transplantation.

    View details for DOI 10.1016/j.biomaterials.2013.09.092

    View details for PubMedID 24161166

  • Aspergillus fumigatus Invasion Increases with Progressive Airway Ischemia PLOS ONE Hsu, J. L., Khan, M. A., Sobel, R. A., Jiang, X., Clemons, K. V., Nguyen, T. T., Stevens, D. A., Martinez, M., Nicolls, M. R. 2013; 8 (10)

    Abstract

    Despite the prevalence of Aspergillus-related disease in immune suppressed lung transplant patients, little is known of the host-pathogen interaction. Because of the mould's angiotropic nature and because of its capacity to thrive in hypoxic conditions, we hypothesized that the degree of Aspergillus invasion would increase with progressive rejection-mediated ischemia of the allograft. To study this relationship, we utilized a novel orthotopic tracheal transplant model of Aspergillus infection, in which it was possible to assess the effects of tissue hypoxia and ischemia on airway infectivity. Laser Doppler flowmetry and FITC-lectin were used to determine blood perfusion, and a fiber optic microsensor was used to measure airway tissue oxygen tension. Fungal burden and depth of invasion were graded using histopathology. We demonstrated a high efficacy (80%) for producing a localized fungal tracheal infection with the majority of infection occurring at the donor-recipient anastomosis; Aspergillus was more invasive in allogeneic compared to syngeneic groups. During the study period, the overall kinetics of both non-infected and infected allografts was similar, demonstrating a progressive loss of perfusion and oxygenation, which reached a nadir by days 10-12 post-transplantation. The extent of Aspergillus invasion directly correlated with the degree of graft hypoxia and ischemia. Compared to the midtrachea, the donor-recipient anastomotic site exhibited lower perfusion and more invasive disease; a finding consistent with clinical experience. For the first time, we identify ischemia as a putative risk factor for Aspergillus invasion. Therapeutic approaches focused on preserving vascular health may play an important role in limiting Aspergillus infections.

    View details for DOI 10.1371/journal.pone.0077136

    View details for Web of Science ID 000325887300058

    View details for PubMedID 24155924

    View details for PubMedCentralID PMC3796538

  • Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus JOURNAL OF MOLECULAR MEDICINE-JMM Jiang, X., Hsu, J. L., Tian, W., Yuan, K., Olcholski, M., Perez, V. D., Semenza, G. L., Nicolls, M. R. 2013; 91 (9): 1081-1093

    Abstract

    Microvascular ischemia and infections are associated with the development of chronic rejection following lung transplantation. The von Hippel-Lindau protein (VHL) controls protein levels of hypoxia-inducible factors (HIFs), regulates vascular repair, and improves tissue perfusion. Here, we studied the role of VHL in microvascular repair by orthotopically transplanting tracheas into mice with VHL haplodeficiency in Tie2 lineage cells. We showed that VHL haplodeficiency prolonged airway microvascular perfusion and promoted tissue blood flow through the production of the angiogenic factors, SDF-1 and angiopoietin 1. VHL-haplodeficient pulmonary endothelial cells exhibited increased angiogenic activity, resistance to serum deprivation-induced cell death, and enhanced microvascular repair. By contrast, in recipient mice with HIF-1α deficiency in Tie2 lineage cells, microvascular repair was significantly diminished and suggested that recipient-derived HIF-1α normally participates in the repair of alloimmune-mediated microvascular damage. To evaluate the translational impact of our findings, we compared VHL-haplodeficient mice with wild-type controls using a model of Aspergillus airway infection. In 83 % of the VHL-haplodeficient recipients, Aspergillus fumigatus was noninvasive in contrast to 75 % of wild-type mice in which the mold was deeply invasive. Our study demonstrated that stabilization of HIF-1α in angiogenic cells, through Tie2 cell VHL haplodeficiency, promoted airway microvascular regeneration and vascular normalization and thereby minimized tissue ischemia and hypoxia. By also mitigating the virulence of A. fumigatus, a common pathogen and itself a risk factor for the development of lung transplant rejection, the selective enhancement of HIF-1α expression has the prospect of offering several novel therapeutic effects to transplant recipients.Microvascular loss and prolonged ischemia occurs with acute rejection. Von Hippel-Lindau (VHL) protein controls hypoxia inducible factors (HIFs). In tracheal allografts, VHL haplodeficient Tie2 cells promote neovascularization. Reduced transplant ischemia limits Aspergillus invasion.

    View details for DOI 10.1007/s00109-013-1063-8

    View details for Web of Science ID 000324068100007

  • Vasopressin Compared with Norepinephrine Augments the Decline of Plasma Cytokine Levels in Septic Shock AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Russell, J. A., Fjell, C., Hsu, J. L., Lee, T., Boyd, J., Thair, S., Singer, J., Patterson, A. J., Walley, K. R. 2013; 188 (3): 356-364

    Abstract

    Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus norepinephrine) could change plasma cytokine levels in early septic shock.Our hypotheses were that changes in plasma cytokine levels over 24 hours differ between survivors and nonsurvivors, and that there are different effects of vasopressin and norepinephrine on plasma cytokine levels in septic shock.We studied 394 patients in a randomized, controlled trial of vasopressin versus norepinephrine in septic shock. We used hierarchical clustering and principal components analysis of the baseline cytokine concentrations to subgroup cytokines; we then compared survivors to nonsurvivors (28 d) and compared vasopressin- versus norepinephrine-induced changes in cytokine levels over 24 hours.A total of 39 plasma cytokines were measured at baseline and at 24 hours. Hierarchical clustering and principal components analysis grouped cytokines similarly. Survivors (versus nonsurvivors) had greater decreases of overall cytokine levels (P < 0.001). Vasopressin decreased overall 24-hour cytokine concentration compared with norepinephrine (P = 0.037). In less severe septic shock, the difference in plasma cytokine reduction over 24 hours between survivors and nonsurvivors was less pronounced than that seen in more severe septic shock. Furthermore, vasopressin decreased interferon-inducible protein 10 and granulocyte colony-stimulating factor more than did norepinephrine in less severe septic shock, whereas vasopressin decreased granulocyte-macrophage colony-stimulating factor in patients who had more severe shock.Survivors of septic shock had greater decreases of cytokines, chemokines and growth factors in early septic shock. Vasopressin decreased 24-hour plasma cytokine levels more than did norepinephrine. The vasopressin-associated decrease of cytokines differed according to severity of shock. Clinical trial registered with www.controlled-trials.com (ISRCTN94845869).

    View details for DOI 10.1164/rccm.201302-0355OC

    View details for Web of Science ID 000322617800017

    View details for PubMedID 23796235

  • Propofol infusion syndrome resuscitation with extracorporeal life support: a case report and review of the literature. Annals of intensive care Mayette, M., Gonda, J., Hsu, J. L., Mihm, F. G. 2013; 3 (1): 32-?

    Abstract

    We report a case of propofol infusion syndrome (PRIS) in a young female treated for status epilepticus. In this case, PRIS rapidly evolved to full cardiovascular collapse despite aggressive supportive care in the intensive care unit, as well as prompt discontinuation of the offending agent. She progressed to refractory cardiac arrest requiring emergent initiation of venoarterial extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation (CPR). She regained a perfusing rhythm after prolonged (>8 hours) asystole, was weaned off ECMO and eventually all life support, and was discharged to home. We also present a review of the available literature on the use of ECMO for PRIS.

    View details for DOI 10.1186/2110-5820-3-32

    View details for PubMedID 24059786

    View details for PubMedCentralID PMC3850887

  • Potential for overuse of corticosteroids and vasopressin in septic shock. Critical care (London, England) Hsu, J. L., Liu, V., Patterson, A. J., Martin, G. S., Nicolls, M. R., Russell, J. A. 2012; 16 (5): 447

    View details for DOI 10.1186/cc11460

    View details for PubMedID 23102413

  • The diagnostic yield of CT-guided percutaneous lung biopsy in solid organ transplant recipients CLINICAL TRANSPLANTATION Hsu, J. L., Kuschner, W. G., Paik, J., Bower, N., Guillamet, M. C., Kothary, N. 2012; 26 (4): 615-621

    Abstract

    Despite the widespread use of computed tomography(CT)-guided percutaneous lung biopsy (PLB) in immunocompetent patients, the diagnostic yield and safety in solid organ transplant (SOT)recipients is unknown. The purpose of this investigation was to determine the test performance of CT-PLB in SOT recipients.We performed a 10-yr single-center, retrospective analysis among heart, lung, kidney, and liver transplant recipients. We included all adult patients who underwent a PLB of a parenchymal lung nodule following their transplantation.Within the study period, 1754 SOTs were performed, of which 45 biopsies met study criteria. Overall, the incidence of PLB in SOT was 3%.PLB established a diagnosis in 24 of 45 cases. The yield of PLB was better for combined biopsy technique (fine-needle aspiration biopsy [FNAB]) and core biopsy than for FNAB alone (odds ratio [OR]: 4.2, 95% confidence interval [CI]: 1.2, 15.6), and for lesions that were malignant (OR: 10.0, 95%CI: 1.8, 75.4) or caused by an invasive fungal infection (OR: 5.0, 95% CI:1.1, 27.9). Complications occurred in 13% (6/45) of patients.CT-guided PLB is a safe modality that provides a moderate yield for diagnosing pulmonary nodules of malignant or fungal etiology in SOT recipients.

    View details for DOI 10.1111/j.1399-0012.2011.01582.x

    View details for Web of Science ID 000307344400032

    View details for PubMedID 23050274

    View details for PubMedCentralID PMC3473075

  • Diagnosing invasive fungal disease in critically ill patients CRITICAL REVIEWS IN MICROBIOLOGY Hsu, J. L., Ruoss, S. J., Bower, N. D., Lin, M., Holodniy, M., Stevens, D. A. 2011; 37 (4): 277-312

    Abstract

    Fungal infections are increasing, with a changing landscape of pathogens and emergence of new groups at risk for invasive disease. We review current diagnostic techniques, focusing on studies in critically ill patients. Microbiological cultures, the current "gold standard", demonstrate poor sensitivity, thus diagnosis of invasive disease in the critically ill is difficult. This diagnostic dilemma results in under- or over-treatment of patients, potentially contributing to poor outcomes and antifungal resistance. While other current diagnostic tests perform moderately well, many lack timeliness, efficacy, and are negatively affected by treatments common to critically ill patients. New nucleic acid-based research is promising.

    View details for DOI 10.3109/1040841X.2011.581223

    View details for Web of Science ID 000295616800001

    View details for PubMedID 21749278

  • One-year outcomes of community-acquired and healthcare-associated pneumonia in the Veterans Affairs Healthcare System INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES Hsu, J. L., Siroka, A. M., Smith, M. W., Holodniy, M., Meduri, G. U. 2011; 15 (6): E382-E387

    Abstract

    While studies have demonstrated higher medium-term mortality for community-acquired pneumonia (CAP), mortality and costs have not been characterized for healthcare-associated pneumonia (HCAP) over a 1-year period.We conducted a retrospective cohort study to evaluate mortality rates and health system costs for patients with CAP or HCAP during initial hospitalization and for 1 year after hospital discharge. We selected 50 758 patients admitted to the Veterans Affairs (VA) healthcare system between October 2003 and May 2007. Main outcome measures included hospital, post-discharge, and cumulative mortality rates and cost during initial hospitalization and at 12 months following discharge.Hospital and 1-year HCAP mortality were nearly twice that of CAP. HCAP was an independent predictor for hospital mortality (odds ratio (OR) 1.62, 95% confidence interval (CI) 1.49-1.76) and 1-year mortality (OR 1.99, 95% CI 1.87-2.11) when controlling for demographics, comorbidities, pneumonia severity, and factors associated with multidrug-resistant infection, including immune suppression, previous antibiotic treatment, and aspiration pneumonia. HCAP patients consistently had higher mortality in each stratum of the Charlson-Deyo-Quan comorbidity index. HCAP patients incurred significantly greater cost during the initial hospital stay and in the following 12 months. Demographics and comorbid conditions, particularly aspiration pneumonia, accounted for 19-33% of this difference.HCAP represents a distinct category of pneumonia with particularly poor survival up to 1 year after hospital discharge. While comorbidities, pneumonia severity, and risk factors for multidrug-resistant infection may interact to produce even higher mortality compared to CAP, they alone do not explain the observed differences.

    View details for DOI 10.1016/j.ijid.2011.02.002

    View details for Web of Science ID 000290588800003

    View details for PubMedID 21393043

    View details for PubMedCentralID PMC3095751

  • Understanding and Identifying Bias and Confounding in the Medical Literature SOUTHERN MEDICAL JOURNAL Hsu, J. L., Banerjee, D., Kuschner, W. G. 2008; 101 (12): 1240-1245

    Abstract

    Bias and confounding are types of error that may be encountered in the collection, analysis, or interpretation of research data. Bias and confounding may result in erroneous research conclusions with adverse consequences for patients and health care providers. In this article, we provide clinician-friendly descriptions and examples of bias (including surveillance, information, selection, lead, length, and publication) and confounding. The purpose of the article is to help clinicians to recognize two important sources of error in research and in turn to help clinicians to assess the validity and generalizability of a research report.

    View details for Web of Science ID 000261778000015

    View details for PubMedID 19005435

  • Epstein-Barr virus and breast cancer: State of the evidence for viral carcinogenesis CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Glaser, S. L., Hsu, J. L., Gulley, M. L. 2004; 13 (5): 688-697

    Abstract

    As the etiology and progression of breast cancer remain incompletely understood, novel routes of disease pathogenesis are important to consider. Viral pathogens have not been much explored, but recent interest has focused on Epstein-Barr virus (EBV). Studies of an association of this ubiquitous herpesvirus with breast cancer have had notably inconsistent results, marked by varying EBV presence (from 0% to 50% of tumors) and the absence of certain viral characteristics found in other EBV-related malignancies. The research has been plagued by the technical challenges of localizing EBV to tumor cells and by a tendency to overlook epidemiological cofactors, shown in all other EBV-related cancers to impact the EBV association. Breast cancer studies to date have used several viral detection methods of varying or uncertain sensitivity and specificity; most have involved small and/or poorly characterized case series and paid insufficient attention to epidemiological cofactors relevant to breast cancer and to EBV-related malignancies. Given these limitations and the established complexity of the connection of EBV with other cancers, a definitive judgment regarding the presence of this virus in breast cancer cannot yet be rendered. Recent advances in laboratory methodologies should help overcome the challenges of EBV detection in breast cancers. Further research is warranted, given the potential for an EBV association to inform not only breast cancer etiology but also early detection, treatment, and prevention.

    View details for Web of Science ID 000221573300001

    View details for PubMedID 15159298

  • Hodgkin's disease in Asians: incidence patterns and risk factors in population-based data LEUKEMIA RESEARCH Glaser, S. L., Hsu, J. L. 2002; 26 (3): 261-269

    Abstract

    Hodgkin's disease (HD) has been reported to be rare in Asians. Data sparseness has hindered studies exploring the relative contributions of environment and heredity to HD etiology, and individual risk factors have never been studied in an Asian population. With the most recent, uniformly collected population-based data from the US and Asia, we compared HD incidence rates in Chinese, Japanese, Filipinos, and Asian Indians in the US and in Asia. HD incidence rates were quite low in all Asian subgroups, but approximately double in US Asians as in native Asians. In both, rates were lower for Japanese and Chinese than for Filipinos and Asian Indians. A modest young-adult rate peak occurred for most US Asian groups, but not for any population in Asia. In data from a population-based case-control study of HD in San Francisco area women, young-adult Asian cases, like young-adult cases of other racial/ethnic groups, had childhood social environments indicative of less early contact with children. Given environmental and lifestyle differences between the US and Asia, the consistently low rates of HD in Asians suggest genetic resistance to disease development, possibly associated with HLA type. International and inter-ethnic differences, and risk factor patterns in case-control data, implicate environmental influences in the etiology of HD.

    View details for Web of Science ID 000174697000007

    View details for PubMedID 11792415

  • Epstein-Barr virus-associated malignancies: epidemiologic patterns and etiologic implications CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY Hsu, J. L., Glaser, S. L. 2000; 34 (1): 27-53

    Abstract

    Epstein-Barr virus (EBV), a ubiquitous B-lymphotrophic herpesvirus, has been found in the tumor cells of a heterogeneous group of malignancies (Burkitt's lymphoma, lymphomas associated with immunosuppression, other non-Hodgkin's lymphomas, Hodgkin's disease, nasopharyngeal carcinoma, gastric adenocarcinoma, lymphoepithelioma-like carcinomas, and immunodeficiency-related leiomyosarcoma). As the epidemiologic characteristics of these cancers have not been considered together, this review seeks to relate their incidence patterns and risk factors to EBV biology and virus-host interaction in an attempt to help elucidate factors involved in EBV-related carcinogenesis. We include a brief review of EBV virology and primary infection to provide a biologic context for considering the epidemiology, summarize the most salient epidemiologic features of each malignancy, synthesize epidemiologic data by risk factor to uncover commonalities and informative contrasts across the diseases, and propose hypotheses regarding etiologic mechanisms, based on the possible effect of the risk factors at various stages in the viral life cycle.

    View details for Web of Science ID 000087010800002

    View details for PubMedID 10781747

  • Absence of Epstein-Barr virus EBER-1 transcripts in an epidemiologically diverse group of breast cancers INTERNATIONAL JOURNAL OF CANCER Glaser, S. L., Ambinder, R. F., DiGiuseppe, J. A., Horn-Ross, P. L., Hsu, J. L. 1998; 75 (4): 555-558

    Abstract

    Epstein-Barr virus (EBV), a ubiquitous herpesvirus associated with certain lymphomas and carcinomas, has been identified within the malignant cells of a small proportion of breast tumors. As breast cancer is a very common malignancy in women, a pathogenetic role of EBV for even a subgroup of patients could have important implications for etiology and prevention. Therefore, we attempted to confirm the EBV-breast cancer association by exploring it in a representative case series stratified by characteristics that modify breast cancer risk. We studied a sample of 97 female and 28 male patients identified from a US population-based cancer registry. Patients were selected randomly within age, sex, ethnicity and tumor estrogen-receptor status groups. With their archived tumor tissues, we examined EBV presence using in situ hybridization for the EBER-1 transcript. In the 107 technically adequate specimens, we did not detect this viral transcript in any tumors, including one from a woman who also had an EBER-positive nasopharyngeal carcinoma. Our uniformly negative findings are extremely unlikely to have occurred by chance and cannot be attributed to selective sampling, as our study group included persons at diverse risk for breast cancer. We conclude that the EBV EBER-1 transcript is not commonly expressed in breast cancer, based on a broadly representative case series, though we cannot exclude an association of EBV within a particular population subgroup.

    View details for Web of Science ID 000071797400010

    View details for PubMedID 9466655

  • Racial/ethnic differences in breast cancer survival among San Francisco Bay Area women JOURNAL OF THE NATIONAL CANCER INSTITUTE Hsu, J. L., Glaser, S. L., West, D. W. 1997; 89 (17): 1311-1312

    View details for Web of Science ID A1997XU08000014

    View details for PubMedID 9293922